Performance of coagulation tests in patients on therapeutic doses of rivaroxaban. A cross-sectional pharmacodynamic study based on peak and trough plasma levels.

PubMed

Francart, Suzanne J; Hawes, Emily M; Deal, Allison M; Adcock, Dorothy M; Gosselin, Robert; Jeanneret, Cheryl; Friedman, Kenneth D; Moll, Stephan

2014-06-01

Knowledge of anticoagulation status during rivaroxaban therapy is desirable in certain clinical situations. It was the study objective to determine coagulation tests most useful for assessing rivaroxaban's anticoagulant effect. Peak and trough blood samples from 29 patients taking rivaroxaban 20 mg daily were collected. Mass spectrometry and various coagulation assays were performed. "On-therapy range" was defined as the rivaroxaban concentrations determined by LC-MS/MS. A "misprediction percentage" was calculated based on how often results of each coagulation assay were in the normal reference range, while the rivaroxaban concentration was in the "on-therapy" range. The on-therapy range was 8.9-660 ng/ml. The misprediction percentages for prothrombin time (PT) and activated partial thromboplastin time (aPTT), using multiple reagents and coagulometers, ranged from 10%-52% and 31%-59%, respectively. PT, aPTT and activated clotting time (ACT) were insensitive to trough rivaroxaban: 59%, 62%, and 80% of samples had a normal result, respectively. Over 95% of PT and ACT values were elevated at peak. Four different rivaroxaban calibrated anti-Xa assays had R² values >0.98, demonstrating strong correlations with rivaroxaban drug levels. In conclusion, PT, aPTT and ACT are often normal in patients on therapeutic doses of rivaroxaban. However, PT and ACT may have clinical utility at higher drug plasma levels. Rivaroxaban calibrated anti-factor Xa assays can accurately identify low and high on-therapy rivaroxaban drug levels and, therefore, have superior utility in all clinical situations where assessment of anticoagulation status may be beneficial.

Primary and key secondary results from the ROCKET AF trial, and their implications on clinical practice.

PubMed

Shah, Rohan; Patel, Manesh R

2017-03-01

The safety and efficacy of the oral anticoagulant rivaroxaban were studied in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF trial). A number of subanalyses of the ROCKET AF trial have subsequently analyzed the use of rivaroxaban in special patient populations. The outcomes of the ROCKET AF trial were reviewed. The use of rivaroxaban in higher risk populations, as determined by the presence of co-morbidities included in the CHADS2 criteria, was analyzed. Requirements for dose adjustment in patients with renal impairment and in East Asian patients were described. Finally, clinical management challenges, including interruptions in therapy, drug discontinuation, management of bleeding events, drug interactions, and management of patients requiring cardioversion/ablation were reviewed. Rivaroxaban is efficacious in high-risk populations, including elderly patients, patients with diabetes, heart failure, history of stroke, prior myocardial infarction, or peripheral arterial disease (PAD). Patients with PAD have a higher risk of bleeding with rivaroxaban compared with warfarin. East Asian populations do not require a dose adjustment for rivaroxaban, while a reduced dose of 15 mg daily is required for patients with moderate renal impairment. Rivaroxaban remains effective with temporary interruptions in therapy and in patients requiring cardioversion/ablation. Rates of major bleeding and subsequent outcomes were similar in patients on warfarin and rivaroxaban, although rates of gastrointestinal bleeding were higher with rivaroxaban. Concurrent use of antiarrhythmic therapy was not associated with adverse outcomes. Rivaroxaban represents an efficacious alternative to warfarin in high-risk patients with AF. Dose adjustment is required for patients with moderate renal impairment. Rivaroxaban can be used safely in a number of challenging clinical management scenarios although the concurrent use of amiodarone requires more study.

Activated protein C resistance in patients following venous thromboembolism receiving rivaroxaban versus vitamin K antagonists: assessment using Russell viper venom time-based assay.

PubMed

Goralczyk, Tadeusz; Wojtowicz, Katarzyna B; Undas, Anetta

2017-06-01

: Activated protein C resistance (APC-R) is assessed as part of thrombophilia screening, preferably in patients not taking oral anticoagulants. Rivaroxaban is known to alter some APC-R assays. To our knowledge, there have been no reports on the effect of rivaroxaban on the Russell viper venom time (RVVT)-based APC-R assay in real-life patients. In 168 consecutive outpatients suspected of having venous thromboembolism because of thrombophilia, APC-R was determined using the RVVT-based ProC Ac R assay (Siemens, Marburg, Germany). Patients receiving rivaroxaban or vitamin K antagonists were eligible. We measured rivaroxaban concentrations using the anti-Xa Biophen DiXal assay (Hyphen Biomed, Neuville-Sur-Oise, France) and factor V Leiden using the real-time PCR. APC-R was detected in 23 (28%) patients on rivaroxaban (n = 81) administrated 2-48 h since the blood draw, 15 (28%) patients on vitamin K antagonists (n = 54), and in four (12%) patients off anticoagulation (n = 33). Compared with nonanticoagulated patients, APC-R ratios were similar in patients on rivaroxaban, without any correlation with rivaroxaban concentrations (from 0 to 303 μg/l). None of the patients on rivaroxaban were found to have false-negative or false-positive APC-R ratios. Rivaroxaban concentrations up to 300 μg/l do not affect results of the ProC Ac R RVVT-based assay, which could be recommended in patients referred to a clinic for thrombophilia screening in whom the time since the last dose of rivaroxaban is uncertain.

Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation – the J-ROCKET AF study –.

PubMed

Hori, Masatsugu; Matsumoto, Masayasu; Tanahashi, Norio; Momomura, Shin-ichi; Uchiyama, Shinichiro; Goto, Shinya; Izumi, Tohru; Koretsune, Yukihiro; Kajikawa, Mariko; Kato, Masaharu; Ueda, Hitoshi; Iwamoto, Kazuya; Tajiri, Masahiro

2012-01-01

The global ROCKET AF study evaluated once-daily rivaroxaban vs. warfarin for stroke and systemic embolism prevention in patients with atrial fibrillation (AF). A separate trial, J-ROCKET AF, compared the safety of a Japan-specific rivaroxaban dose with warfarin administered according to Japanese guidelines in Japanese patients with AF. J-ROCKET AF was a prospective, randomized, double-blind, phase III trial. Patients (n=1,280) with non-valvular AF at increased risk for stroke were randomized to receive 15 mg once-daily rivaroxaban or warfarin dose-adjusted according to Japanese guidelines. The primary objective was to determine non-inferiority of rivaroxaban against warfarin for the principal safety outcome of major and non-major clinically relevant bleeding, in the on-treatment safety population. The primary efficacy endpoint was the composite of stroke and systemic embolism. Non-inferiority of rivaroxaban to warfarin was confirmed; the rate of the principal safety outcome was 18.04% per year in rivaroxaban-treated patients and 16.42% per year in warfarin-treated patients (hazard ratio [HR] 1.11; 95% confidence interval 0.87-1.42; P<0.001 [non-inferiority]). Intracranial hemorrhage rates were 0.8% with rivaroxaban and 1.6% with warfarin. There was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban vs. warfarin (HR, 0.49; P=0.050). J-ROCKET AF demonstrated the safety of a Japan-specific rivaroxaban dose and supports bridging the global ROCKET AF results into Japanese clinical practice.

Rivaroxaban as an oral anticoagulant for stroke prevention in atrial fibrillation

PubMed Central

Turpie, Alexander GG

2014-01-01

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the developed world and is associated with a fivefold increase in the risk of stroke, accounting for up to 15% of strokes in the general population. The European Society of Cardiology now recommends direct oral anticoagulants, such as rivaroxaban, apixaban, and dabigatran, in preference to vitamin K antagonist therapy for the prevention of stroke in patients with A F. This review focuses on the direct Factor Xa inhibitor rivaroxaban, summarizing the properties that make rivaroxaban appropriate for anticoagulant therapy in this indication (including its predictable pharmacokinetic and pharmacodynamic profile and once-daily dosing regimen) and describing data from the Phase III ROCKET AF trial, which showed once-daily rivaroxaban to be noninferior to warfarin for the prevention of stroke in patients with nonvalvular AF. In this trial, similar rates of major and nonmajor clinically relevant bleeding were observed; however, when compared with warfarin, rivaroxaban was associated with clinically significant reductions in intracranial and fatal bleeding. On the basis of these results, rivaroxaban was approved in both the United States and the European Union for the prevention of stroke and systemic embolism in patients with nonvalvular AF. Subanalyses of ROCKET AF data showed rivaroxaban to have consistent efficacy and safety across a wide range of patients, and studies to confirm these results in real-world settings are underway. This review also describes practical considerations for treatment with rivaroxaban in clinical practice (including dose reductions in specific high-risk patients, eg, those with renal impairment), recommendations for the transition from vitamin K antagonists to rivaroxaban, the management of bleeding events, and the measurement of rivaroxaban exposure. PMID:24711702

Primary and key secondary results from the ROCKET AF trial, and their implications on clinical practice

PubMed Central

Shah, Rohan; Patel, Manesh R.

2016-01-01

Background: The safety and efficacy of the oral anticoagulant rivaroxaban were studied in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF trial). A number of subanalyses of the ROCKET AF trial have subsequently analyzed the use of rivaroxaban in special patient populations. Methods: The outcomes of the ROCKET AF trial were reviewed. The use of rivaroxaban in higher risk populations, as determined by the presence of co-morbidities included in the CHADS2 criteria, was analyzed. Requirements for dose adjustment in patients with renal impairment and in East Asian patients were described. Finally, clinical management challenges, including interruptions in therapy, drug discontinuation, management of bleeding events, drug interactions, and management of patients requiring cardioversion/ablation were reviewed. Results: Rivaroxaban is efficacious in high-risk populations, including elderly patients, patients with diabetes, heart failure, history of stroke, prior myocardial infarction, or peripheral arterial disease (PAD). Patients with PAD have a higher risk of bleeding with rivaroxaban compared with warfarin. East Asian populations do not require a dose adjustment for rivaroxaban, while a reduced dose of 15 mg daily is required for patients with moderate renal impairment. Rivaroxaban remains effective with temporary interruptions in therapy and in patients requiring cardioversion/ablation. Rates of major bleeding and subsequent outcomes were similar in patients on warfarin and rivaroxaban, although rates of gastrointestinal bleeding were higher with rivaroxaban. Concurrent use of antiarrhythmic therapy was not associated with adverse outcomes. Conclusions: Rivaroxaban represents an efficacious alternative to warfarin in high-risk patients with AF. Dose adjustment is required for patients with moderate renal impairment. Rivaroxaban can be used safely in a number of challenging clinical management scenarios although the concurrent use of amiodarone requires more study. PMID:27555569

A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban

PubMed Central

Frost, Charles; Song, Yan; Barrett, Yu Chen; Wang, Jessie; Pursley, Janice; Boyd, Rebecca A; LaCreta, Frank

2014-01-01

Background Currently, there are no direct comparisons of apixaban and rivaroxaban, two new oral direct factor Xa inhibitors approved for management of thromboembolic disorders. Objective Compare the pharmacokinetics and anti-factor Xa activity (AXA) of apixaban and rivaroxaban. Methods In this randomized, open-label, two-period, two-treatment crossover study, healthy subjects (N=14) received apixaban 2.5 mg twice daily (BID) and rivaroxaban 10 mg once daily (QD) for 4 days with a ≥4.5-day washout. Plasma samples were obtained for pharmacokinetic and AXA assessments; parameters were calculated using noncompartmental methods. Results Median time-to-maximum concentration was 2 hours for both compounds, and the mean half-life was 8.7 and 7.9 hours for apixaban and rivaroxaban, respectively. Daily exposure, the area under the curve (AUC(0–24)), appeared similar for rivaroxaban (1,094 ng · h/mL) and apixaban (935 ng · h/mL), whereas mean peak-to-trough plasma concentration ratio was 3.6-fold greater for rivaroxaban (16.9) than apixaban (4.7). Coefficient of variation for exposure parameters (AUC0–24, Cmax, Cmin) was 20%–24% for apixaban versus 29%–46% for rivaroxaban. Peak AXA, AXA AUC(0–24), and AXA fluctuation were ~2.5-, 1.3-, and 3.5-fold higher for rivaroxaban than apixaban, respectively. Trough concentrations and AXA were lower for rivaroxaban (10 ng/mL and 0.17 IU/mL vs 17 ng/mL and 0.24 IU/mL for apixaban, respectively). Rivaroxaban exhibited a steeper concentration–AXA response (slope: 0.0172 IU/ng vs 0.0134 IU/ng for apixaban, P<0.0001). Conclusion Apixaban 2.5 mg BID demonstrated less intersubject variability in exposure, lower AXA AUC, and higher trough and smaller peak-to-trough fluctuations in plasma concentration and AXA, suggesting more constant anticoagulation compared with rivaroxaban 10 mg QD. However, the clinical impact of these differences on the relative efficacy and safety of apixaban and rivaroxaban remains to be determined. PMID:25419161

Rivaroxaban attenuates thrombosis by targeting the NF-κB signaling pathway in a rat model of deep venous thrombus

PubMed Central

Ma, Junhao; Li, Xinxi; Wang, Yang; Yang, Zhenwei; Luo, Jun

2017-01-01

Anticoagulant therapy is commonly used for the prevention and treatment of patients with deep venous thrombus. Evidence has shown that rivaroxaban is a potential oral anticoagulant drug for the acute treatment of venous thromboembolism. However, the rivaroxaban-mediated molecular mechanism involved in the progression of deep venous thrombosis has not been investigated. In the present study, we investigated the efficacy of rivaroxaban and the underlying signaling pathways in the prevention and treatment of rats with deep venous thrombosis. A rat model with deep vein thrombus formation was established and received treatment with rivaroxaban or PBS as control. The thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) were analyzed both in vitro and in vivo. The progression of thrombosis and stroke was evaluated after treatment with rivaroxaban or PBS. Nuclear factor-κB (NF-κB) signaling pathway in venous endothelial cells and in the rat model of deep venous thrombus was assessed. The therapeutic effects of rivaroxaban were evaluated as determined by changes in deep venous thrombosis in the rat model. Our results showed that rivaroxaban markedly inhibited TAFI and PAI-1 expression levels, neutrophils, tissue factor, neutrophil extracellular traps (NETs), myeloperoxidase and macrophages in venous endothelial cells and in the rat model of deep venous thrombus. Expression levels of ADP, PAIs, von Willebrand factor (vWF) and thromboxane were downregulated in vein endothelial cells and in serum from the experimental rats. Importantly, the incidences of inferior vena cava filter thrombus were protected by rivaroxaban during heparin-induced thrombolysis deep venous thrombosis in the rat model. We observed that activity of the NF-κB signaling pathway was inhibited by rivaroxaban in vein endothelial cells both in vitro and in vivo. Notably, immunohistology indicated that rivaroxaban attenuated deep venous thrombosis and the accumulation of inflammatory factors in the lesions in venous thrombus. Matrix metalloproteinase (MMP) expression and activity were downregulated in rivaroxaban-treated rats with deep venous thrombus. Rivaroxaban inhibited the elasticity of the extracellular matrix and collagen-elastin fibers. On the whole, these results indicate that rivaroxaban attenuates deep venous thrombus through MMP-9-mediated NF-κB signaling pathway. PMID:29039441

Rivaroxaban attenuates thrombosis by targeting the NF-κB signaling pathway in a rat model of deep venous thrombus.

PubMed

Ma, Junhao; Li, Xinxi; Wang, Yang; Yang, Zhenwei; Luo, Jun

2017-12-01

Anticoagulant therapy is commonly used for the prevention and treatment of patients with deep venous thrombus. Evidence has shown that rivaroxaban is a potential oral anticoagulant drug for the acute treatment of venous thromboembolism. However, the rivaroxaban-mediated molecular mechanism involved in the progression of deep venous thrombosis has not been investigated. In the present study, we investigated the efficacy of rivaroxaban and the underlying signaling pathways in the prevention and treatment of rats with deep venous thrombosis. A rat model with deep vein thrombus formation was established and received treatment with rivaroxaban or PBS as control. The thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) were analyzed both in vitro and in vivo. The progression of thrombosis and stroke was evaluated after treatment with rivaroxaban or PBS. Nuclear factor-κB (NF-κB) signaling pathway in venous endothelial cells and in the rat model of deep venous thrombus was assessed. The therapeutic effects of rivaroxaban were evaluated as determined by changes in deep venous thrombosis in the rat model. Our results showed that rivaroxaban markedly inhibited TAFI and PAI-1 expression levels, neutrophils, tissue factor, neutrophil extracellular traps (NETs), myeloperoxidase and macrophages in venous endothelial cells and in the rat model of deep venous thrombus. Expression levels of ADP, PAIs, von Willebrand factor (vWF) and thromboxane were downregulated in vein endothelial cells and in serum from the experimental rats. Importantly, the incidences of inferior vena cava filter thrombus were protected by rivaroxaban during heparin-induced thrombolysis deep venous thrombosis in the rat model. We observed that activity of the NF-κB signaling pathway was inhibited by rivaroxaban in vein endothelial cells both in vitro and in vivo. Notably, immunohistology indicated that rivaroxaban attenuated deep venous thrombosis and the accumulation of inflammatory factors in the lesions in venous thrombus. Matrix metalloproteinase (MMP) expression and activity were downregulated in rivaroxaban-treated rats with deep venous thrombus. Rivaroxaban inhibited the elasticity of the extracellular matrix and collagen-elastin fibers. On the whole, these results indicate that rivaroxaban attenuates deep venous thrombus through MMP-9-mediated NF-κB signaling pathway.

Rivaroxaban for Preventing Atherothrombotic Events in People with Acute Coronary Syndrome and Elevated Cardiac Biomarkers: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

PubMed

Pandor, Abdullah; Pollard, Daniel; Chico, Tim; Henderson, Robert; Stevenson, Matt

2016-05-01

As part of its Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures rivaroxaban (Xarelto, Bayer) to submit evidence of the clinical and cost effectiveness of rivaroxaban for the prevention of adverse outcomes in patients after the acute management of acute coronary syndrome (ACS). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology, based upon the company's submission to NICE. The evidence was derived mainly from a randomised, double-blind, phase III, placebo-controlled trial of rivaroxaban (either 2.5 or 5 mg twice daily) in patients with recent ACS [unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI)]. In addition, all patients received antiplatelet therapy [aspirin alone or aspirin and a thienopyridine either as clopidogrel (approximately 99 %) or ticlopidine (approximately 1 %) according to national or local guidelines]. The higher dose of rivaroxaban (5 mg twice daily) did not form part of the marketing authorisation. A post hoc subgroup analysis of the licensed patients who had ACS with elevated cardiac biomarkers (that is, patients with STEMI and NSTEMI) without prior stroke or transient ischaemic stroke showed that compared with standard care, the addition of rivaroxaban (2.5 mg twice daily) to existing antiplatelet therapy reduced the composite endpoint of cardiovascular mortality, myocardial infarction or stroke, but increased the risk of major bleeding and intracranial haemorrhage. However, there were a number of limitations in the evidence base that warrant caution in its interpretation. In particular, the evidence may be confounded because of the post hoc subgroup analysis, modified intention-to-treat analyses, high dropout rates and missing vital status data. Results from the company's economic evaluation showed that the deterministic incremental cost-effectiveness ratio (ICER) for rivaroxaban in combination with aspirin plus clopidogrel or with aspirin alone compared with aspirin plus clopidogrel or aspirin alone was £6203 per quality-adjusted life-year (QALY) gained. In contrast, the ERG's preferred base case estimate was £5622 per QALY gained. The ICER did not rise above £10,000 per QALY gained in any of the sensitivity analyses undertaken by the ERG, although the inflexibility of the company's economic model precluded the ERG from formally undertaking all desired exploratory analyses. As such, only a crude exploration of the impact of additional bleeding events could be undertaken. The NICE Appraisal Committee concluded that the ICERs presented were all within the range that could be considered cost effective and that the results of the ERG's exploratory sensitivity and scenario analyses suggested that the ICER was unlikely to increase to the extent that it would become unacceptable. The Appraisal Committee therefore concluded that rivaroxaban in combination with aspirin plus clopidogrel, or with aspirin alone, was a cost-effective use of National Health Service (NHS) resources for preventing atherothrombotic events in people with ACS and elevated cardiac biomarkers.

Efficacy and safety of rivaroxaban versus low-molecular-weight heparin therapy in patients with lower limb fractures.

PubMed

Long, Anhua; Zhang, Lihai; Zhang, Yingze; Jiang, Baoguo; Mao, Zhi; Li, Hongda; Zhang, Shanbao; Xie, Zongyan; Tang, Peifu

2014-10-01

Thromboprophylaxis with rivaroxaban has proved effective and safe in patients undergoing hip and knee replacement surgery. As it is unclear whether it is also effective and safe in fracture patients, the aim of the present study was to evaluate the efficacy and safety of rivaroxaban in patients with lower limb fractures. We performed a retrospective cohort study of 2,050 consecutive patients treated for lower limb fractures at our trauma center, comparing rates of venous thromboembolism (VTE), bleeding and surgical complications, and the length of hospital stay for 608 patients who received rivaroxaban and 717 who received a low-molecular-weight heparin (LMWH). Rates of symptomatic VTE were 4.9 and 8.6% in the rivaroxaban and LMWH groups, respectively (p = 0.008), and distal VTE rates were 1.8 and 5.7%, respectively (p = 0.036). The incidence of major bleeding events in the rivaroxaban group was also lower than in the LMWH group (0.2 vs 0.6%), but the difference between the groups was not statistically significant. The mean length of hospital stay was significantly shorter in the rivaroxaban group (12.2 vs 13.1 days, respectively; p = 0.016). This retrospective cohort study is the first report documenting the efficacy and safety of rivaroxaban in patients with lower extremity fractures. In comparison with LMWH, rivaroxaban reduced the incidence of VTE by 45% without increasing the risk of bleeding. However, prospective, randomized controlled trials comparing rivaroxaban and LMWH are needed to confirm our findings.

Use of apixaban after development of suspected rivaroxaban-induced hepatic steatosis; a case report.

PubMed

Anastasia, Emily J; Rosenstein, Robert S; Bergsman, Jeffrey A; Parra, David

2015-09-01

Postmarketing reports have emerged associating rivaroxaban with drug-induced liver injury (DILI); however, management strategies of patients with suspected rivaroxaban-induced liver injury requiring continued anticoagulation have not been published. The present report describes a 67-year-old male with atrial fibrillation receiving rivaroxaban who developed a 16-fold elevation in alanine transaminase, a nearly two-fold elevation in total bilirubin, and ultrasound confirmed hepatic steatosis. The patient was switched from rivaroxaban to apixaban with subsequent rapid resolution of laboratory abnormalities. Rapid improvement in liver function tests despite use of an alternative factor Xa inhibitor suggests that rivaroxaban's mechanism of hepatotoxicity may be unrelated to its pharmacologic action. When using rivaroxaban, clinicians should be aware of the small but potentially serious risk of DILI. Because most anticoagulants have been associated with DILI, selection of an alternative anticoagulant may be challenging; however, the use of apixaban in this case suggests it may be a reasonable alternative.

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF.

PubMed

Pokorney, Sean D; Piccini, Jonathan P; Stevens, Susanna R; Patel, Manesh R; Pieper, Karen S; Halperin, Jonathan L; Breithardt, Günter; Singer, Daniel E; Hankey, Graeme J; Hacke, Werner; Becker, Richard C; Berkowitz, Scott D; Nessel, Christopher C; Mahaffey, Kenneth W; Fox, Keith A A; Califf, Robert M

2016-03-08

Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS2 score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P<0.0001) were associated with higher all-cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C-index 0.677). In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival. URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Comparative effectiveness of rivaroxaban versus warfarin or dabigatran for the treatment of patients with non-valvular atrial fibrillation.

PubMed

Norby, Faye L; Bengtson, Lindsay G S; Lutsey, Pamela L; Chen, Lin Y; MacLehose, Richard F; Chamberlain, Alanna M; Rapson, Ian; Alonso, Alvaro

2017-09-06

Rivaroxaban is an oral anticoagulant approved in the US for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). We determined the effectiveness and associated risks of rivaroxaban versus other oral anticoagulants in a large real-world population. We selected NVAF patients initiating oral anticoagulant use in 2010-2014 enrolled in MarketScan databases. Rivaroxaban users were matched with warfarin and dabigatran users by age, sex, enrolment date, anticoagulant initiation date, and high-dimensional propensity score. Study endpoints, including ischemic stroke, intracranial bleeding (ICB), myocardial infarction (MI), and gastrointestinal (GI) bleeding, were identified from inpatient diagnostic codes. Multivariable Cox models were used to assess associations between type of anticoagulant and outcomes. The analysis included 44,340 rivaroxaban users matched to 89,400 warfarin and 16,957 dabigatran users (38% female, mean age 70) with 12 months of mean follow-up. Anticoagulant-naïve rivaroxaban initiators, but not those switching from warfarin, had lower risk of ischemic stroke [hazard ratio (HR) (95% confidence interval (CI)): 0.75 (0.62, 0.91)] and ICB [HR (95%CI): 0.55, (0.39, 0.78)] than warfarin users. In contrast, anticoagulant-experienced rivaroxaban initiators had higher risk of GI bleeding than warfarin users [HR (95%CI): 1.55 (1.32, 1.83)]. Endpoint rates were similar when comparing anticoagulant-naïve rivaroxaban and dabigatran initiators, with the exception of higher GI bleeding risk in rivaroxaban users [HR (95%CI) 1.28 (1.06, 1.54)]. There were no significant differences in the risk of MI among the comparison groups. In this large real-world sample of NVAF patients, effectiveness and risks of rivaroxaban versus warfarin differed by prior anticoagulant status, while effectiveness of rivaroxaban versus dabigatran differed in GI bleeding risk.

Rivaroxaban Versus Dabigatran or Warfarin in Real-World Studies of Stroke Prevention in Atrial Fibrillation: Systematic Review and Meta-Analysis.

PubMed

Bai, Ying; Deng, Hai; Shantsila, Alena; Lip, Gregory Y H

2017-04-01

This study was designed to evaluate the effectiveness and safety of rivaroxaban in real-world practice compared with effectiveness and safety of dabigatran or warfarin for stroke prevention in atrial fibrillation through meta-analyzing observational studies. Seventeen studies were included after searching in PubMed for studies reporting the comparative effectiveness and safety of rivaroxaban versus dabigatran (n=3), rivaroxaban versus Warfarin (n=11), or both (n=3) for stroke prevention in atrial fibrillation. Overall, the risks of stroke/systematic thromboembolism with rivaroxaban were similar when compared with those with dabigatran (stroke/thromboembolism: hazard ratio, 1.02; 95% confidence interval, 0.91-1.13; I 2 =70.2%, N=5), but were significantly reduced when compared with those with warfarin (hazard ratio, 0.75; 95% confidence interval, 0.64-0.85; I 2 =45.1%, N=9). Major bleeding risk was significantly higher with rivaroxaban than with dabigatran (hazard ratio, 1.38; 95% confidence interval, 1.27-1.49; I 2 =26.1%, N=5), but similar to that with warfarin (hazard ratio, 0.99; 95% confidence interval, 0.91-1.07; I 2 =0.0%, N=6). Rivaroxaban was associated with increased all-cause mortality and gastrointestinal bleeding, but similar risk of acute myocardial infarction and intracranial hemorrhage when compared with dabigatran. When compared with warfarin, rivaroxaban was associated with similar risk of any bleeding, mortality, and acute myocardial infarction, but a higher risk of gastrointestinal bleeding and lower risk of intracranial hemorrhage. In this systematic review and meta-analysis, rivaroxaban was as effective as dabigatran, but was more effective than warfarin for the prevention of stroke/thromboembolism in atrial fibrillation patients. Major bleeding risk was significantly higher with rivaroxaban than with dabigatran, as was all-cause mortality and gastrointestinal bleeding. Rivaroxaban was comparable to warfarin for major bleeding, with an increased risk in gastrointestinal bleeding and decreased risk of intracranial hemorrhage. © 2017 American Heart Association, Inc.

Costs of hospital visits among patients with deep vein thrombosis treated with rivaroxaban and LMWH/warfarin.

PubMed

Merli, Geno J; Hollander, Judd E; Lefebvre, Patrick; Laliberté, François; Raut, Monika K; Germain, Guillaume; Bookhart, Brahim; Pollack, Charles V

2016-01-01

For many years, the standard of care for patients diagnosed with deep vein thrombosis (DVT) has been low-molecular-weight heparin (LMWH) bridging to an oral Vitamin-K antagonist (VKA). The availability of new non-VKA oral anticoagulants (NOAC) agents as monotherapy may reduce the likelihood of hospitalization for DVT patients. To compare hospital visit costs of DVT patients treated with rivaroxaban and LMWH/warfarin. A retrospective claim analysis was conducted using the MarketScan Hospital Drug Database for care provided between January 2011 and December 2013. Adult patients using rivaroxaban or LMWH/warfarin with a primary diagnosis of DVT during the first day of a hospital visit were identified (i.e., index hospital visit). Based on propensity-score methods, historical LMWH/warfarin patients (i.e., patients who received LMWH/warfarin before the approval of rivaroxaban) were matched 4:1 to rivaroxaban patients. The hospital-visit cost difference between these groups was evaluated for the index hospital visit, as well as for total hospital-visit costs (i.e., including index and subsequent hospital visit costs). All rivaroxaban users (n = 134) in the database were well-matched with four LMWH/warfarin users (n = 536). The mean hospital-visit costs were $5257 for the rivaroxaban cohort and $6764 in the matched-cohort of patients using LMWH/warfarin. The $1508 cost difference was statistically significant between cohorts (95% CI = [-$2296; -$580]; p-value = 0.002). Total hospital-visit costs were lower for rivaroxaban compared to LMWH/warfarin users within 1, 2, 3, and 6 months after index visit (significantly lower within 1 and 3 months, p-values <0.05) LIMITATIONS: Limitations were inherent to administrative-claims data, completeness of baseline characteristics, adjustments restricted to observational factors, and lastly the sample size of the rivaroxaban cohort. The availability of rivaroxaban significantly reduced the costs of hospital visits in patients with DVT treated with rivaroxaban compared to LMWH/warfarin.

Effects of Rivaroxaban on Platelet Activation and Platelet–Coagulation Pathway Interaction

PubMed Central

Heitmeier, Stefan; Laux, Volker

2015-01-01

Introduction: Activation of coagulation and platelets is closely linked, and arterial thrombosis involves coagulation activation as well as platelet activation and aggregation. In these studies, we investigated the possible synergistic effects of rivaroxaban in combination with antiplatelet agents on thrombin generation and platelet aggregation in vitro and on arterial thrombosis and hemostasis in rat models. Materials and Methods: Thrombin generation was measured by the Calibrated Automated Thrombogram method (0.5 pmol/L tissue factor) using human platelet-rich plasma (PRP) spiked with rivaroxaban (15, 30, or 60 ng/mL), ticagrelor (1.0 µg/mL), and acetylsalicylic acid (ASA; 100 µg/mL). Tissue factor-induced platelet aggregation was measured in PRP spiked with rivaroxaban (15 or 30 ng/mL), ticagrelor (1 or 3 µg/mL), or a combination of these. An arteriovenous (AV) shunt model in rats was used to determine the effects of rivaroxaban (0.01, 0.03, or 0.1 mg/kg), clopidogrel (1 mg/kg), ASA (3 mg/kg), and combinations on arterial thrombosis. Results: Rivaroxaban inhibited thrombin generation in a concentration-dependent manner and the effect was enhanced with ticagrelor and ticagrelor plus ASA. Rivaroxaban and ticagrelor also concentration-dependently inhibited tissue factor-induced platelet aggregation, and their combination increased the inhibition synergistically. In the AV shunt model, rivaroxaban dose-dependently reduced thrombus formation. Combining subefficacious or weakly efficacious doses of rivaroxaban with ASA or ASA plus clopidogrel increased the antithrombotic effect. Conclusion: These data indicate that the combination of rivaroxaban with single or dual antiplatelet agents works synergistically to reduce platelet activation, which may in turn lead to the delayed/reduced formation of coagulation complexes and vice versa, thereby enhancing antithrombotic potency. PMID:25848131

Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects

PubMed Central

Mueck, Wolfgang; Kubitza, Dagmar; Becka, Michael

2013-01-01

Aims The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 (CYP2J2), CYP-independent mechanisms, and P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) (ABCG2). Methods The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P-gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers. Results Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co-administered with midazolam was slightly decreased by 11% (95% confidence interval [CI] −28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P-gp inhibitor; 34% increase [95% CI 23%, 46%]), clarithromycin (strong CYP3A4/moderate P-gp inhibitor; 54% increase [95% CI 44%, 64%]) and fluconazole (moderate CYP3A4, possible Bcrp [ABCG2] inhibitor; 42% increase [95% CI 29%, 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P-gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase [95% CI 136%, 182%] for a 400 mg once daily dose) and ritonavir (153% increase [95% CI 134%, 174%]). Conclusions Results suggest that rivaroxaban may be co-administered with CYP3A4 and/or P-gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P-gp and Bcrp (ABCG2) inhibitors (mainly comprising azole-antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi-pathway inhibitors of rivaroxaban clearance and elimination. PMID:23305158

Medication persistence and discontinuation of rivaroxaban versus warfarin among patients with non-valvular atrial fibrillation.

PubMed

Nelson, Winnie W; Song, Xue; Coleman, Craig I; Thomson, Erin; Smith, David M; Damaraju, C V; Schein, Jeffrey R

2014-12-01

To compare real-world persistence and discontinuation among non-valvular atrial fibrillation (NVAF) patients on rivaroxaban and warfarin in the US. A large nationally representative US claims database was used to conduct a retrospective cohort analysis of patients with NVAF treated with rivaroxaban or warfarin from 1 July 2010 through 31 March 2013. Index date was the date of the first prescription of rivaroxaban or warfarin. All patients were followed until the earliest of inpatient death, end of continuous enrollment, or end of study period. Rivaroxaban patients were matched 1:1 by propensity scores. Medication persistence was defined as absence of refill gap of ≥ 60 days. Discontinuation was defined as no additional refill for at least 90 days and until the end of follow-up. Cox proportional hazards models were estimated to examine the adjusted hazard ratios (aHRs) of rivaroxaban vs. warfarin on non-persistence and discontinuation. A total of 32,886 NVAF patients on rivaroxaban or warfarin met the study inclusion criteria. Each of the 7259 rivaroxaban patients identified were matched 1:1 to warfarin patients. Patients on rivaroxaban had a significantly better rate of persistence (aHR: 0.63, 95% CI 0.59-0.68) and lower rate of discontinuation (aHR: 0.54, 95% CI 0.49-0.58) compared to warfarin recipients. Claims data may have contained inaccuracies and miscoding. Confounding may remain even after propensity score matching and additional adjustments in model. Refill data may not fully reflect actual medication use. Longer follow-up may produce more precise estimates of persistence and discontinuation. This matched cohort analysis indicated that rivaroxaban was associated with significantly higher medication persistence and lower discontinuation rates compared to warfarin.

Measurement of rivaroxaban and apixaban in serum samples of patients

PubMed Central

Harenberg, Job; Krämer, Sandra; Du, Shanshan; Zolfaghari, Shabnam; Schulze, Astrid; Krämer, Roland; Weiss, Christel; Wehling, Martin; Lip, Gregory Y H

2014-01-01

Background The determination of rivaroxaban and apixaban from serum samples of patients may be beneficial in specific clinical situations when additional blood sampling for plasma and thus the determination of factor Xa activity is not feasible or results are not plausible. Materials and methods The primary aim of this study was to compare the concentrations of rivaroxaban and apixaban in serum with those measured in plasma. Secondary aims were the performance of three different chromogenic methods and concentrations in patients on treatment with rivaroxaban 10 mg od (n = 124) or 20 mg od (n = 94) or apixaban 5 mg bid (n = 52) measured at different time. Results Concentrations of rivaroxaban and apixaban in serum were about 20–25% higher compared with plasma samples with a high correlation (r = 0·79775–0·94662) using all assays (all P < 0·0001). The intraclass correlation coefficients were about 0·90 for rivaroxaban and 0·55 for apixaban. Mean rivaroxaban concentrations were higher at 2 and 3 h compared with 1 and 12 h after administration measured from plasma and serum samples (all P-values < 0·05) and were not different between 1 vs. 12 h (plasma and serum). Conclusions The results indicate that rivaroxaban and apixaban concentrations can be determined specifically from serum samples. PMID:24931429

Shorter Hospital Stays and Lower Costs for Rivaroxaban Compared With Warfarin for Venous Thrombosis Admissions.

PubMed

Margolis, Jay M; Deitelzweig, Steven; Kline, Jeffrey; Tran, Oth; Smith, David M; Bookhart, Brahim; Crivera, Concetta; Schein, Jeff

2016-10-06

Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, results in a substantial healthcare system burden. This retrospective observational study compared hospital length of stay (LOS) and hospitalization costs for patients with venous thromboembolism treated with rivaroxaban versus those treated with warfarin. Hospitalizations for adult patients with a primary diagnosis of deep vein thrombosis or pulmonary embolism who were initiated on rivaroxaban or warfarin were selected from MarketScan's Hospital Drug Database between November 1, 2012, and December 31, 2013. Patients treated with warfarin were matched 1:1 to patients treated with rivaroxaban using exact and propensity score matching. Hospital LOS, time from first dose to discharge, and hospitalization costs were reported descriptively and with generalized linear models (GLMs). The final study cohorts each included 1223 patients (751 with pulmonary embolism and 472 with deep vein thrombosis). Cohorts were well matched for demographic and clinical characteristics. Mean (±SD) LOS was 3.7±3.1 days for patients taking rivaroxaban and 5.2±3.7 days for patients taking warfarin, confirmed by GLM-adjusted results (rivaroxaban 3.7 days, warfarin 5.3 days, P<0.001). Patients with provoked venous thromboembolism admissions showed longer LOSs (rivaroxaban 5.1±4.5 days, warfarin 6.5±5.6 days, P<0.001) than those with unprovoked venous thromboembolism (rivaroxaban 3.3±2.4 days, warfarin 4.8±2.8 days, P<0.001). Days from first dose to discharge were 2.4±1.7 for patients treated with rivaroxaban and 3.9±3.7 for patients treated with warfarin when initiated with parenteral anticoagulants (P<0.001), and 2.7±1.7 and 3.7±2.1, respectively, when initiated without parenteral anticoagulants (P<0.001). Patients initiated on rivaroxaban incurred significantly lower mean total hospitalization costs ($8688±$9927 versus $9823±$9319, P=0.004), confirmed by modeling (rivaroxaban $8387 [95% confidence interval, $8035-$8739]; warfarin $10 275 [95% confidence interval, $9842-$10 708]). Rivaroxaban was associated with significantly shorter hospital LOS and lower hospitalization costs compared with warfarin. © 2016 The Authors, Janssen Scientific Affairs, LLC, and Truven Health Analytics. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Dissociation between the pharmacokinetics and pharmacodynamics of once-daily rivaroxaban and twice-daily apixaban: a randomized crossover study.

PubMed

Kreutz, R; Persson, P B; Kubitza, D; Thelen, K; Heitmeier, S; Schwers, S; Becka, M; Hemmrich, M

2017-10-01

Essentials In this crossover study the anticoagulant effects of rivaroxaban and apixaban were compared. Healthy volunteers received rivaroxaban 20 mg once daily or apixaban 5 mg twice daily. Rivaroxaban was associated with more prolonged inhibition of thrombin generation than apixaban. Rivaroxaban induced a clear prolongation of prothrombin time and activated partial thromboplastin time. Background The anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. Objectives To compare directly the steady-state pharmacokinetics and anticoagulant effects of rivaroxaban and apixaban at doses approved for stroke prevention in patients with non-valvular atrial fibrillation. Methods Twenty-four healthy Caucasian male volunteers were included in this open-label, two-period crossover, phase 1 study (EudraCT number: 2015-002612-32). Volunteers were randomized to receive rivaroxaban 20 mg once daily or apixaban 5 mg twice daily for 7 days, followed by a washout period of at least 7 days before they received the other treatment. Plasma concentrations and anticoagulant effects were measured at steady state and after drug discontinuation. Results Overall exposure was similar for both drugs: the geometric mean area under the plasma concentration-time curve for the 0-24-h interval was 1830 μg h L -1 for rivaroxaban and 1860 μg h L -1 for apixaban. Rivaroxaban was associated with greater inhibition of endogenous thrombin potential (geometric mean area under the curve relative to baseline during the 0-24-h interval: 15.5 h versus 17.5 h) and a more pronounced maximal prolongation relative to baseline of prothrombin time (PT) (1.66-fold versus 1.14-fold) and activated partial thromboplastin time (APTT) (1.43-fold versus 1.16-fold) at steady state than apixaban. Conclusions Despite similar exposure to both drugs, rivaroxaban 20 mg once daily was associated with greater and more sustained inhibition of thrombin generation than apixaban 5 mg twice daily. Sensitive PT and APTT assays can be used to estimate the anticoagulant effects of rivaroxaban. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Rivaroxaban does not influence hemorrhagic transformation in a diabetes ischemic stroke and endovascular thrombectomy model.

PubMed

Liu, Feng-Di; Zhao, Rong; Feng, Xiao-Yan; Shi, Yan-Hui; Wu, Yi-Lan; Shen, Xiao-Lei; Li, Ge-Fei; Liu, Yi-Sheng; Zhao, Ying; He, Xin-Wei; Yin, Jia-Wen; Zhuang, Mei-Ting; Zhao, Bing-Qiao; Liu, Jian-Ren

2018-05-09

Managing endovascular thrombectomy (ET) in diabetic ischemic stroke (IS) with novel anticoagulants is challenging due to putative risk of intracerebral hemorrhage. The study evaluates increased hemorrhagic transformation (HT) risk in Rivaroxaban-treated diabetic rats post ET. Diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of 60 mg/kg streptozotocin. After 4-weeks, rats were pretreated orally with 30 mg/kg Rivaroxaban/saline; prothrombin time was monitored. IS and ET was induced after 1 h, by thread-induced transient middle cerebral artery occlusion (tMCAO) that mimicked mechanical ET for proximal MCA occlusion at 60 min. After 24 h reperfusion, infarct volumes, HT, blood-brain barrier (BBB) permeability, tight junction at peri-ischemic lesion and matrix metalloproteinase-9 (MMP-9) activity was measured. Diabetic rats seemed to exhibit increased infarct volume and HT at 24 h after ET than normal rats. Infarct volumes and functional outcomes did not differ between Rivaroxaban and diabetic control groups. A significant increase in HT volumes and BBB permeability under Rivaroxaban treatment was not detected. Compared to diabetic control group, neither the occludin expression was remarkably lower in the Rivaroxaban group nor the MMP-9 activity was higher. Together, Rivaroxaban does not increase HT after ET in diabetic rats with proximal MCA occlusion, since Rivaroxaban has fewer effects on post-ischemic BBB permeability.

Direct Comparison of Dabigatran, Rivaroxaban, and Apixaban for Effectiveness and Safety in Nonvalvular Atrial Fibrillation.

PubMed

Noseworthy, Peter A; Yao, Xiaoxi; Abraham, Neena S; Sangaralingham, Lindsey R; McBane, Robert D; Shah, Nilay D

2016-12-01

The introduction of non-vitamin K antagonist oral anticoagulants (NOACs) has been a major advance for stroke prevention in atrial fibrillation (AF). Patients and clinicians now have a choice between different NOACs, but there is no direct comparative effectiveness evidence to guide decision-making. We aimed to compare the effectiveness and safety of dabigatran, rivaroxaban, and apixaban in clinical practice. Using a large US administrative claims database, we created three one-to-one propensity-score-matched cohorts of patients with nonvalvular AF who were users of dabigatran, rivaroxaban, or apixaban between October 1, 2010 and February 28, 2015 (rivaroxaban vs dabigatran, n = 31,574; apixaban vs dabigatran, n = 13,084; and apixaban vs rivaroxaban, n = 13,130). The primary outcomes were stroke and systemic embolism (effectiveness) and major bleeding (safety) that occurred during treatment. Cox proportional hazards models were used to compare outcomes in propensity-score-matched cohorts. We found no differences between the three NOACs in the risk of stroke or systemic embolism (hazard ratio [HR], 1.00; 95% CI, 0.75-1.32 for rivaroxaban vs dabigatran; HR, 0.82; 95% CI, 0.51-1.31 for apixaban vs dabigatran; and HR, 1.05; 95% CI, 0.64-1.72 for apixaban vs rivaroxaban). Apixaban was associated with a lower risk of major bleeding (HR, 0.50; 95% CI, 0.36-0.70; P < .001 vs dabigatran and HR, 0.39; 95% CI, 0.28-0.54; P < .001 vs rivaroxaban). Rivaroxaban was associated with an increased risk of major bleeding (HR, 1.30; 95% CI, 1.10-1.53; P < .01) and intracranial bleeding (HR, 1.79; 95% CI, 1.12-2.86; P < .05) compared with dabigatran. Dabigatran, rivaroxaban, and apixaban appear to have similar effectiveness, although apixaban may be associated with a lower bleeding risk and rivaroxaban may be associated with an elevated bleeding risk. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.

PubMed

Patel, Manesh R; Mahaffey, Kenneth W; Garg, Jyotsna; Pan, Guohua; Singer, Daniel E; Hacke, Werner; Breithardt, Günter; Halperin, Jonathan L; Hankey, Graeme J; Piccini, Jonathan P; Becker, Richard C; Nessel, Christopher C; Paolini, John F; Berkowitz, Scott D; Fox, Keith A A; Califf, Robert M

2011-09-08

The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).

Oral rivaroxaban for symptomatic venous thromboembolism.

PubMed

Bauersachs, Rupert; Berkowitz, Scott D; Brenner, Benjamin; Buller, Harry R; Decousus, Hervé; Gallus, Alex S; Lensing, Anthonie W; Misselwitz, Frank; Prins, Martin H; Raskob, Gary E; Segers, Annelise; Verhamme, Peter; Wells, Phil; Agnelli, Giancarlo; Bounameaux, Henri; Cohen, Alexander; Davidson, Bruce L; Piovella, Franco; Schellong, Sebastian

2010-12-23

Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

Healthcare costs associated with rivaroxaban or warfarin use for the treatment of venous thromboembolism.

PubMed

Coleman, Craig I; Baugh, Christopher; Crivera, Concetta; Milentijevic, Dejan; Wang, Sheng-Wei; Lu, Lang; Nelson, Winnie W

2017-02-01

Rivaroxaban has been shown to have similar efficacy but less major bleeding than warfarin in randomized trials of patients experiencing venous thromboembolism (VTE). This report sought to assess healthcare costs up to 12-months following an index VTE in patients prescribed either rivaroxaban or warfarin. This study analyzed claims from the MarketScan Commercial Claims and Encounters Database from November 2011-July 2015. It selected adults newly-diagnosed with VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) if they had an outpatient prescription claim for rivaroxaban or warfarin within 7-days of the index event. Warfarin users were 2:1 propensity-score matched to rivaroxaban users and followed until the end of insurance coverage, end of data availability or 12-months of follow-up. Total per patient healthcare costs, including inpatient, outpatient, and overall pharmacy costs, were compared using a multivariable generalized linear model. In total, 10,929 rivaroxaban patients were matched to 21,858 warfarin patients. Mean follow-up for rivaroxaban and warfarin patients was 317- and 321-days for those experiencing an index DVT, and 313- and 318-days for those with PE. Mean overall treatment costs per patient were lower for rivaroxaban vs warfarin users (-$1,116, p = .0016). This cost difference was driven by lower inpatient (-$622) and outpatient (-$1,156) treatment costs, and the higher pharmacy costs ($661) were, therefore, fully offset. Results were similar when analysis was restricted to DVT patients. No significant difference in total costs was observed in patients experiencing an index PE. Claims databases are subject to inaccuracies and missing data. Prescription claims may not fully reflect actual medication utilization. Despite propensity-score matching and regression, residual confounding cannot be excluded. Rivaroxaban was associated with significantly lower total per patient VTE treatment costs, despite higher pharmacy costs. These savings are the result of decreased inpatient and outpatient healthcare utilization costs associated with rivaroxaban.

Postoperative Bleeding After Administration of a Single Dose of Rivaroxaban to a Patient Receiving Antiretroviral Therapy.

PubMed

Corallo, Carmela E; Grannell, Louise; Tran, Huyen

2015-12-01

A 62-year-old man was admitted to hospital for elective revision of a left total hip arthroplasty. His history was significant for human immunodeficiency virus (HIV) infection for which he was taking the following antiretroviral agents (ARVs): etravirine, ritonavir, darunavir, raltegravir and tenofovir/emtricitabine. Rivaroxaban 10 mg daily was commenced on the second postoperative day for venous thromboembolism (VTE) prophylaxis. Approximately 24 h later, the patient developed hypotension and anaemia, accompanied by thigh swelling due to bleeding at the surgical site. Fluid resuscitation was commenced with red cell transfusion. The prothrombin time (PT) was prolonged at 24.3 (10.6-15.3) s, and a rivaroxaban level taken 24 h after administration was 75 ng/mL. Rivaroxaban was ceased, the PT normalised within 24 h of stopping the drug, and the patient made an uneventful recovery. None of the other coadministered drugs are known to interact with rivaroxaban, or are likely to, based on their metabolic pathways. Rivaroxaban, a substrate for cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), is contraindicated in patients concomitantly treated with strong inhibitors of both these systems, e.g. protease inhibitors (PIs) such as ritonavir (based on in vitro data and a pharmacokinetic study in healthy volunteers). No published data are available on the PI darunavir, a moderate inhibitor; however, concomitant use with rivaroxaban should also be avoided. A prolonged PT and a rivaroxaban trough level greater than eight times that predicted from pharmacokinetic modelling suggests that bleeding was due to increased exposure to rivaroxaban, probably due to an interaction with ritonavir and darunavir. This is supported by a Drug Interaction Probability Scale (DIPS) score of 8. An interaction between a single dose of rivaroxaban and ARVs may be clinically significant; therefore, the patient's medication history should be extensively evaluated to identify any potential interactions.

Is rivaroxaban associated with lower inpatient costs compared to warfarin among patients with non-valvular atrial fibrillation?

PubMed

Laliberté, François; Pilon, Dominic; Raut, Monika K; Nelson, Winnie W; Olson, William H; Germain, Guillaume; Schein, Jeff R; Lefebvre, Patrick

2014-08-01

Warfarin has been the mainstay treatment used by patients with a moderate-to-high risk of stroke due to non-valvular atrial fibrillation (NVAF). Unlike rivaroxaban, laboratory monitoring to allow the attainment of the prothrombin time international normalized ratio goal is required with warfarin, thereby potentially increasing a patient's hospitalization costs. To compare hospitalization costs between hospitalized NVAF patients using rivaroxaban versus warfarin in a real-world setting. A retrospective claims analysis was conducted using the Premier Perspective Comparative Hospital Database from November 2010 to September 2012. The study included adult patients hospitalized for NVAF after November 2011. Patients using rivaroxaban during hospitalization were matched with up to four warfarin users by propensity score analyses. Hospitalization costs were compared between the matched cohorts using generalized estimating equations. A sub-analysis was performed for patients who were first administered their treatment on day three or later of their hospital stay. Sensitivity analyses were conducted on matched cohorts with a primary diagnosis of AF. The matched cohorts' (2809 rivaroxaban and 11,085 warfarin users) characteristics were well balanced. The mean age of cohorts was 71 years and 49% of patients were female. The average hospitalization cost of rivaroxaban users was $11,993 compared to $13,255 for warfarin users. The cost difference was significantly lower by $1284 (P < 0.001). Patients who were administered rivaroxaban treatment on day three or after incurred significantly lower hospitalization costs (cost difference: $4350; P < 0.001) compared to warfarin users. Rivaroxaban users with a primary diagnosis of AF also had significantly lower costs compared to warfarin users. These included possible inaccuracies or omissions in diagnoses, completeness of baseline characteristics, and a study population that included patients newly initiated on and patients who continued anticoagulant therapy. Hospitalization costs for rivaroxaban were significantly lower than those for warfarin in NVAF patients treated with rivaroxaban.

Budget impact analysis of rivaroxaban vs. warfarin anticoagulation strategy for direct current cardioversion in non-valvular atrial fibrillation patients: the MonaldiVert Economic Study.

PubMed

Russo, Vincenzo; Rago, Anna; Papa, Andrea A; Bianchi, Valter; Tavoletta, Vincenzo; DE Vivo, Stefano; Cavallaro, Ciro; Nigro, Gerardo; D'Onofrio, Antonio

2018-02-01

Rivaroxaban is the first novel oral anticoagulant to receive regulatory approval for non-valvular atrial fibrillation (NVAF) patients who require cardioversion. The MonaldiVert real life experience showed positive benefit-risk profile of short term rivaroxaban administration for transesophageal echocardiogram guided cardioversion in patients who had not achieved adequate pre-procedural vitamin K antagonist (VKA) anticoagulation. Aim of our study was to perform a budget impact analysis of MonaldiVert anticoagulation strategy for direct current cardioversion in NVAF patients and to compare the following costs borne by the Regional Healthcare System (RHS) with those for a hypothetical cohort of identical patients underwent from the beginning to early rivaroxaban treatment before direct current cardioversion. The mean costs per each NVAF patient treated with VKA strategy and rivaroxaban rescue strategy were € 134.53 and € 189.83, respectively. Considering a hypothetical scenario in which all study population would be treated from the beginning with rivaroxaban (rivaroxaban early strategy), the mean cost per patient would have been € 81.11. The total cost borne by the RHS, including the cost of the cardioversion procedure, for the two therapeutic strategies carried out at Monaldi Hospital (VKA strategy and Rivaroxaban rescue strategy) was € 88,458.53. The total cost would be borne by the RHS for rivaroxaban early strategy, if applied to all study population, would have been € 69,989.15 with a saving of € 18,469.38 compared to the actually applied strategy. Rivaroxaban rescue strategy for transesophageal echocardiography guided direct current cardioversion in NVAF patients, who had not achieved adequate pre-procedural VKA anticoagulation, is an effective and safe strategy, which allows to not delay the procedure, reducing times and wastage of cardioversion slots, without substantial costs increase.

Plasma fibrin clot properties in the G20210A prothrombin mutation carriers following venous thromboembolism: the effect of rivaroxaban.

PubMed

Janion-Sadowska, Agnieszka; Natorska, Joanna; Siudut, Jakub; Ząbczyk, Michal; Stanisz, Andrzej; Undas, Anetta

2017-08-30

We sought to investigate whether the G20210A prothrombin mutation modifies plasma fibrin clot properties in patients after venous thromboembolism (VTE) and how rivaroxaban treatment affects these alterations. We studied 34 prothrombin mutation heterozygous carriers and sex- and age-matched 34 non-carriers, all at least three months since the first VTE episode, before and during treatment with rivaroxaban. Clot permeability (K s ) and clot lysis time (CLT) with or without elimination of thrombin activatable fibrinolysis inhibitor (TAFI) were assessed at baseline, 2-6 hours (h) after and 20-25 h after intake of rivaroxaban (20 mg/day). At baseline, the prothrombin mutation group formed denser clots (K s -12 %, p=0.0006) and had impaired fibrinolysis (CLT +14 %, p=0.004, and CLT-TAFI +13 %, p=0.03) compared with the no mutation group and were similar to those observed in 15 healthy unrelated prothrombin mutation carriers. The G20210A prothrombin mutation was the independent predictor for K s and CLT before rivaroxaban intake. At 2-6 h after rivaroxaban intake, clot properties improved in both G20210A carriers and non-carriers (K s +38 %, and +37 %, CLT -25 % and -25 %, CLT-TAFI -20 % and -24 %, respectively, all p<0.001), but those parameters were worse in the prothrombin mutation group (K s -12.8 %, CLT +17 %, CLT-TAFI +13 %, all p<0.001). Rivaroxaban concentration correlated with fibrin clot properties. After 20-25 h since rivaroxaban intake most clot properties returned to baseline. Rivaroxaban-related differences in clot structure were confirmed by scanning electron microscopy images. In conclusion, rivaroxaban treatment, though improves fibrin clot properties, cannot abolish more prothrombotic fibrin clot phenotype observed in prothrombin mutation carriers following VTE.

[Use of rivaroxaban in real-life treatment of venous thromboembolism: results of the TEV Survey, an Italian epidemiological study].

PubMed

Pesavento, Raffaele; Iori, Ido

2017-03-01

Rivaroxaban is a direct and selective inhibitor of factor Xa. The randomized clinical trials EINSTEIN evaluated the efficacy and safety of rivaroxaban for the treatment of venous thromboembolism (VTE) proving that the drug was non-inferior to standard treatment. The aim of this survey was to describe how rivaroxaban was used in a group of "real-life" patients with VTE. Between June and October 2014, physicians collected aggregate data, through an online questionnaire, on consecutive patients affected by VTE and treated with rivaroxaban in the previous 6 months. Descriptive statistics were performed on the collected data. A total of 345 questionnaires were filled out. The mean age of patients was 62 years, with a low prevalence of concomitant diseases and/or pharmacological treatments. Deep vein thrombosis was diagnosed in 90% of patients and pulmonary embolism in 47%; only 48% was hospitalized. Rivaroxaban was prescribed at the recommended doses and/or regimen in no more than 60% of cases. In 96% of patients, the initial therapeutic plan did not require changes. Adherence to the therapeutic plan and overall patient satisfaction with therapy were high. Rivaroxaban was found easy to use and was highly appreciated by patients.

Rivaroxaban in patients with atrial fibrillation: from ROCKET AF to everyday practice.

PubMed

Barón-Esquivias, Gonzalo; Marín, Francisco; Sanmartín Fernandez, Marcelo

2017-05-01

Registries and non-interventional studies offer relevant and complementary information to clinical trials, since they have a high external validity. Areas covered: The information regarding the efficacy and safety of rivaroxaban compared with warfarin, or rivaroxaban alone in clinical practice was reviewed in this manuscript. For this purpose, a search on MEDLINE and EMBASE databases was performed. The MEDLINE and EMBASE search included both medical subject headings (MeSH) and keywords including: atrial fibrillation (AF) OR warfarin OR clinical practice OR ROCKET AF AND rivaroxaban. Case reports were not considered. Expert commentary: In ROCKET AF, rivaroxaban was at least as effective as warfarin for the prevention of stroke in patients with nonvalvular AF at high risk of stroke, but, importantly, with a lesser risk of intracranial, critical and fatal bleedings. A number of observational comparative and non-comparative studies, with more than 60,000 patients included treated with rivaroxaban, have analyzed the efficacy and safety of rivaroxaban in real-life patients with AF in different clinical settings. These studies have shown that in clinical practice, rates of stroke and major bleeding were consistently lower than those reported in ROCKET AF, likely due to the lower thromboembolic and bleeding risk observed in these patients.

Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2.

PubMed

Morihara, Ryuta; Yamashita, Toru; Kono, Syoichiro; Shang, Jingwei; Nakano, Yumiko; Sato, Kota; Hishikawa, Nozomi; Ohta, Yasuyuki; Heitmeier, Stefan; Perzborn, Elisabeth; Abe, Koji

2017-09-01

This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin (0.2 mg/kg/day), low-dose rivaroxaban (60 mg/kg/day), high-dose rivaroxaban (120 mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90 min, followed by reperfusion with tPA (10 mg/kg/10 ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Medication persistence and discontinuation of rivaroxaban and dabigatran etexilate among patients with non-valvular atrial fibrillation.

PubMed

Nelson, Winnie W; Song, Xue; Thomson, Erin; Smith, David M; Coleman, Craig I; Damaraju, C V; Schein, Jeffrey R

2015-01-01

To compare real-world persistence and discontinuation among non-valvular atrial fibrillation (NVAF) patients on rivaroxaban and dabigatran in the US. A large nationally representative US claims database was used to conduct a retrospective cohort analysis of patients with NVAF on rivaroxaban or dabigatran between October 2010 and March 2013. The index date was the date of the first prescription of rivaroxaban or dabigatran. All patients had ≥6 months of data prior to the index date and were followed until the earliest of inpatient death, end of continuous enrollment, or end of the study period. Rivaroxaban patients were matched 1:1 with dabigatran patients using the propensity score matching technique. Cox proportional hazards models were employed to estimate the adjusted hazard ratios (aHRs) of non-persistence and discontinuation. Persistence was defined as absence of a refill gap of ≥60 days. Discontinuation was defined as no additional refill for at least 90 days and until the end of follow-up. A total of 30,337 NVAF patients on rivaroxaban or dabigatran met the study criteria. All 7259 rivaroxaban patients were matched 1:1 to dabigatran patients. Compared with dabigatran users, rivaroxaban patients were 11% less likely to become non-persistent with therapy (aHR: 0.89, 95% CI 0.84-0.95) and 29% less likely to discontinue therapy (aHR: 0.71, 95% CI 0.66-0.77). Claims data are subject to miscoding and inaccuracies. Refill data may not fully reflect actual medication taken. Confounding may remain even after propensity score matching and additional adjustments in model. Longer follow-up may produce more precise estimates of persistence and discontinuation. This matched cohort analysis indicated that, compared to dabigatran, rivaroxaban was associated with better persistence and lower rates of discontinuation.

Economic evaluation of rivaroxaban in stroke prevention for patients with atrial fibrillation in Greece

PubMed Central

2014-01-01

Background To undertake an economic evaluation of rivaroxaban relative to the standard of care for stroke prevention in patients with non-valvular atrial fibrillation (AF) in Greece. Methods An existing Markov model designed to reflect the natural progression of AF patients through different health states, in the course of three month cycles, was adapted to the Greek setting. The analysis was undertaken from a payer perspective. Baseline event rates and efficacy data were obtained from the ROCKET-AF trial for rivaroxaban and vitamin-K-antagonists (VKAs). Utility values for events were based on literature. A treatment-related disutility of 0.05 was applied to the VKA arm. Costs assigned to each health state reflect the year 2013. An incremental cost effectiveness ratio (ICER) was calculated where the outcome was quality-adjusted-life year (QALY) and life-years gained. Probabilistic analysis was undertaken to deal with uncertainty. The horizon of analysis was over patient life time and both cost and outcomes were discounted at 3.5%. Results Based on safety-on-treatment data, rivaroxaban was associated with a 0.22 increment in QALYs compared to VKA. The average total lifetime cost of rivaroxaban-treated patients was €239 lower compared to VKA. Rivaroxaban was associated with additional drug acquisition cost (€4,033) and reduced monitoring cost (-€3,929). Therefore, rivaroxaban was a dominant alternative over VKA. Probabilistic analysis revealed that there is a 100% probability of rivaroxaban being cost-effective versus VKA at a willingness to pay threshold of €30,000/QALY gained. Conclusion Rivaroxaban may represent for payers a dominant option for the prevention of thromboembolic events in moderate to high risk AF patients in Greece. PMID:24512351

Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial.

PubMed

Wong, Ka Sing Lawrence; Hu, Dai Yi; Oomman, Abraham; Tan, Ru-San; Patel, Manesh R; Singer, Daniel E; Breithardt, Günter; Mahaffey, Kenneth W; Becker, Richard C; Califf, Robert; Fox, Keith A A; Berkowitz, Scott D; Hacke, Werner; Hankey, Graeme J

2014-06-01

In Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban was noninferior to dose-adjusted warfarin in preventing stroke or systemic embolism among patients with nonvalvular atrial fibrillation at moderate to high stroke risk. Because of differences in patient demographics, epidemiology, and stroke risk management in East Asia, outcomes and relative effects of rivaroxaban versus warfarin were assessed to determine consistency among East Asians versus other ROCKET AF participants. Baseline demographics and interaction of treatment effects of rivaroxaban and warfarin among patients within East Asia and outside were assessed. A total of 932 (6.5%) ROCKET AF participants resided in East Asia. At baseline, East Asians had lower weight, creatinine clearance, and prior vitamin K antagonist use; higher prevalence of prior stroke; and less congestive heart failure and prior myocardial infarction than other participants. Despite higher absolute event rates for efficacy and safety outcomes in East Asians, the relative efficacy of rivaroxaban (20 mg once daily; 15 mg once daily for creatinine clearance of 30-49 mL/min) versus warfarin with respect to the primary efficacy end point (stroke/systemic embolism) was consistent among East Asians and non-East Asians (interaction P=0.666). Relative event rates for the major or nonmajor clinically relevant bleeding in patients treated with rivaroxaban and warfarin were consistent among East Asians and non-East Asians (interaction P=0.867). Observed relative efficacy and safety of rivaroxaban versus warfarin were similar among patients within and outside East Asia. Rivaroxaban, 20 mg once daily, is an alternative to warfarin for stroke prevention in East Asians with nonvalvular atrial fibrillation. © 2014 American Heart Association, Inc.

Rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation for the secondary prevention of stroke: a subgroup analysis of J-ROCKET AF.

PubMed

Tanahashi, Norio; Hori, Masatsugu; Matsumoto, Masayasu; Momomura, Shin-ichi; Uchiyama, Shinichiro; Goto, Shinya; Izumi, Tohru; Koretsune, Yukihiro; Kajikawa, Mariko; Kato, Masaharu; Ueda, Hitoshi; Iwamoto, Kazuya; Tajiri, Masahiro

2013-11-01

The overall analysis of the rivaroxaban versus warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial revealed that rivaroxaban was not inferior to warfarin with respect to the primary safety outcome. In addition, there was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban compared with warfarin. In this subanalysis of the J-ROCKET AF trial, we investigated the consistency of safety and efficacy profile of rivaroxaban versus warfarin among the subgroups of patients with previous stroke, transient ischemic attack, or non-central nervous system systemic embolism (secondary prevention group) and those without (primary prevention group). Patients in the secondary prevention group were 63.6% of the overall population of J-ROCKET AF. In the secondary prevention group, the rate of the principal safety outcome (% per year) was 17.02 in rivaroxaban-treated patients and 18.26 in warfarin-treated patients (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.70-1.29), while the rate of the primary efficacy endpoint was 1.66 in rivaroxaban-treated patients and 3.25 in warfarin-treated patients (HR 0.51; 95% CI 0.23-1.14). There were no significant interactions in the principal safety and the primary efficacy endpoints of rivaroxaban compared to warfarin between the primary and secondary prevention groups (P=.090 and .776 for both interactions, respectively). The safety and efficacy profile of rivaroxaban compared with warfarin was consistent among patients in the primary prevention group and those in the secondary prevention group. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Rivaroxaban-induced chest wall spontaneous expanding hematoma.

PubMed

Salemis, Nikolaos S

2017-03-22

Rivaroxaban is an oral direct Factor Xa inhibitor approved in the European Union and the United Sates for the single-drug treatment of several thromboembolic diseases in adults. Ιt has been evaluated in large phase III clinical trials and has been found to have similar efficacy and safety with standard therapy. Herein, is described a very rare case of a rivaroxaban-induced spontaneous expanding chest wall hematoma, that required surgical intervention, in a breast cancer patient. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 7) between the patient's development of hematoma and treatment with rivaroxaban. Physicians should be cautious when prescribing rivaroxaban in groups of patients associated with increased bleeding risk such as patients with impaired renal or hepatic function, hypertension, coronary heart disease, heart failure, patients with certain types of cancers and patients receiving concomitant medications which may alter the pharmacokinetic or pharmacodymamic parameters of rivaroxaban. Anticoagulant treatment should be tailored to each individual patient weighing the bleeding risk against the risk of recurrent thrombosis.

UPLC-MRM Mass Spectrometry Method for Measurement of the Coagulation Inhibitors Dabigatran and Rivaroxaban in Human Plasma and Its Comparison with Functional Assays.

PubMed

Kuhn, Joachim; Gripp, Tatjana; Flieder, Tobias; Dittrich, Marcus; Hendig, Doris; Busse, Jessica; Knabbe, Cornelius; Birschmann, Ingvild

2015-01-01

The fast, precise, and accurate measurement of the new generation of oral anticoagulants such as dabigatran and rivaroxaban in patients' plasma my provide important information in different clinical circumstances such as in the case of suspicion of overdose, when patients switch from existing oral anticoagulant, in patients with hepatic or renal impairment, by concomitant use of interaction drugs, or to assess anticoagulant concentration in patients' blood before major surgery. Here, we describe a quick and precise method to measure the coagulation inhibitors dabigatran and rivaroxaban using ultra-performance liquid chromatography electrospray ionization-tandem mass spectrometry in multiple reactions monitoring (MRM) mode (UPLC-MRM MS). Internal standards (ISs) were added to the sample and after protein precipitation; the sample was separated on a reverse phase column. After ionization of the analytes the ions were detected using electrospray ionization-tandem mass spectrometry. Run time was 2.5 minutes per injection. Ion suppression was characterized by means of post-column infusion. The calibration curves of dabigatran and rivaroxaban were linear over the working range between 0.8 and 800 μg/L (r >0.99). Limits of detection (LOD) in the plasma matrix were 0.21 μg/L for dabigatran and 0.34 μg/L for rivaroxaban, and lower limits of quantification (LLOQ) in the plasma matrix were 0.46 μg/L for dabigatran and 0.54 μg/L for rivaroxaban. The intraassay coefficients of variation (CVs) for dabigatran and rivaroxaban were < 4% and 6%; respectively, the interassay CVs were < 6% for dabigatran and < 9% for rivaroxaban. Inaccuracy was < 5% for both substances. The mean recovery was 104.5% (range 83.8-113.0%) for dabigatran and 87.0% (range 73.6-105.4%) for rivaroxaban. No significant ion suppressions were detected at the elution times of dabigatran or rivaroxaban. Both coagulation inhibitors were stable in citrate plasma at -20°C, 4°C and even at RT for at least one week. A method comparison between our UPLC-MRM MS method, the commercially available automated Direct Thrombin Inhibitor assay (DTI assay) for dabigatran measurement from CoaChrom Diagnostica, as well as the automated anti-Xa assay for rivaroxaban measurement from Chromogenix both performed by ACL-TOP showed a high degree of correlation. However, UPLC-MRM MS measurement of dabigatran and rivaroxaban has a much better selectivity than classical functional assays measuring activities of various coagulation factors which are susceptible to interference by other coagulant drugs. Overall, we developed and validated a sensitive and specific UPLC-MRM MS assay for the quick and specific measurement of dabigatran and rivaroxaban in human plasma.

UPLC-MRM Mass Spectrometry Method for Measurement of the Coagulation Inhibitors Dabigatran and Rivaroxaban in Human Plasma and Its Comparison with Functional Assays

PubMed Central

Kuhn, Joachim; Gripp, Tatjana; Flieder, Tobias; Dittrich, Marcus; Hendig, Doris; Busse, Jessica; Knabbe, Cornelius; Birschmann, Ingvild

2015-01-01

Introduction The fast, precise, and accurate measurement of the new generation of oral anticoagulants such as dabigatran and rivaroxaban in patients’ plasma my provide important information in different clinical circumstances such as in the case of suspicion of overdose, when patients switch from existing oral anticoagulant, in patients with hepatic or renal impairment, by concomitant use of interaction drugs, or to assess anticoagulant concentration in patients’ blood before major surgery. Methods Here, we describe a quick and precise method to measure the coagulation inhibitors dabigatran and rivaroxaban using ultra-performance liquid chromatography electrospray ionization-tandem mass spectrometry in multiple reactions monitoring (MRM) mode (UPLC-MRM MS). Internal standards (ISs) were added to the sample and after protein precipitation; the sample was separated on a reverse phase column. After ionization of the analytes the ions were detected using electrospray ionization-tandem mass spectrometry. Run time was 2.5 minutes per injection. Ion suppression was characterized by means of post-column infusion. Results The calibration curves of dabigatran and rivaroxaban were linear over the working range between 0.8 and 800 μg/L (r >0.99). Limits of detection (LOD) in the plasma matrix were 0.21 μg/L for dabigatran and 0.34 μg/L for rivaroxaban, and lower limits of quantification (LLOQ) in the plasma matrix were 0.46 μg/L for dabigatran and 0.54 μg/L for rivaroxaban. The intraassay coefficients of variation (CVs) for dabigatran and rivaroxaban were < 4% and 6%; respectively, the interassay CVs were < 6% for dabigatran and < 9% for rivaroxaban. Inaccuracy was < 5% for both substances. The mean recovery was 104.5% (range 83.8–113.0%) for dabigatran and 87.0% (range 73.6–105.4%) for rivaroxaban. No significant ion suppressions were detected at the elution times of dabigatran or rivaroxaban. Both coagulation inhibitors were stable in citrate plasma at -20°C, 4°C and even at RT for at least one week. A method comparison between our UPLC-MRM MS method, the commercially available automated Direct Thrombin Inhibitor assay (DTI assay) for dabigatran measurement from CoaChrom Diagnostica, as well as the automated anti-Xa assay for rivaroxaban measurement from Chromogenix both performed by ACL-TOP showed a high degree of correlation. However, UPLC-MRM MS measurement of dabigatran and rivaroxaban has a much better selectivity than classical functional assays measuring activities of various coagulation factors which are susceptible to interference by other coagulant drugs. Conclusions Overall, we developed and validated a sensitive and specific UPLC-MRM MS assay for the quick and specific measurement of dabigatran and rivaroxaban in human plasma. PMID:26699714

A Cross‐Study Analysis Evaluating the Effects of Food on the Pharmacokinetics of Rivaroxaban in Clinical Studies

PubMed Central

Peters, Gary; Haskell, Lloyd; Patel, Purve; Nandy, Partha; Moore, Kenneth Todd

2017-01-01

Abstract US prescribing guidelines recommend that 15‐ and 20‐mg doses of rivaroxaban be administered with food for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and for reduction in the risk of recurrence of DVT and PE. In addition, the US prescribing guidelines recommend these doses be administered with an evening meal to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). The purpose of this model‐based cross‐study comparison was to examine the impact of food, with regard to both meal timing and content, on the pharmacokinetics (PK) of rivaroxaban, using data collected during its clinical development. Results of this analysis showed that a PK model built from pooled data in the AF population (for whom rivaroxaban was administered with an evening meal) and in the DVT population (for whom rivaroxaban was administered with a morning meal) can describe both data sets well. Furthermore, the PK model built from data in the AF population alone can adequately predict the PK profile of the DVT population and vice versa. This cross‐study analysis also confirmed the findings from previous clinical pharmacology studies, which showed that meal content does not have a clinically relevant impact on the PK of rivaroxaban at 20 mg. Therefore, although the administration of rivaroxaban with food is necessary for maintaining high bioavailability, neither meal timing nor meal content appears to affect the PK of rivaroxaban. PMID:28679020

Design of the rivaroxaban for heparin-induced thrombocytopenia study.

PubMed

Linkins, Lori-Ann; Warkentin, Theodore E; Pai, Menaka; Shivakumar, Sudeep; Manji, Rizwan A; Wells, Philip S; Crowther, Mark A

2014-11-01

Rivaroxaban is an ideal potential candidate for treatment of heparin-induced thrombocytopenia (HIT) because it is administered orally by fixed dosing, requires no laboratory monitoring and is effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT study is a prospective, multicentre, single-arm, cohort study evaluating the incidence of new symptomatic venous and arterial thromboembolism in patients with suspected or confirmed HIT who are treated with rivaroxaban. Methodological challenges faced in the design of this study include heterogeneity of the patient population, differences in the baseline risk of thrombosis and bleeding dependent on whether HIT is confirmed or just suspected, and heterogeneity in laboratory confirmation of HIT. The rationale for how these challenges were addressed and the final design of the Rivaroxaban for HIT study is reviewed.

Rivaroxaban Levels in Patients' Plasmas are Comparable by Using Two Different Anti Xa Assay/Coagulometer Systems Calibrated with Two Different Calibrators.

PubMed

Martinuzzo, Marta E; Duboscq, Cristina; Lopez, Marina S; Barrera, Luis H; Vinuales, Estela S; Ceresetto, Jose; Forastiero, Ricardo R; Oyhamburu, Jose

2018-06-01

Rivaroxaban oral anticoagulant does not need laboratory monitoring, but in some situations plasma level measurement is useful. The objective of this paper was to verify analytical performance and compare two rivaroxaban calibrated anti Xa assays/coagulometer systems with specific or other branch calibrators. In 59 samples drawn at trough or peak from patients taking rivaroxaban, plasma levels were measured by HemosIL Liquid anti Xa in ACLTOP 300/500, and STA liquid Anti Xa in TCoag Destiny Plus. HemosIL and STA rivaroxaban calibrators and controls were used. CLSI guideline procedures EP15A3 for precision and trueness, EP6 for linearity, and EP9 for methods comparison were used. Coefficient of variation within run and total precision (CVR and CVWL respectively) of plasmatic rivaroxaban were < 4.2 and < 4.85% and BIAS < 7.4 and < 6.5%, for HemosIL-ACL TOP and STA-Destiny systems, respectively. Linearity verification 8 - 525 ng/mL a Deming regression for methods comparison presented R 0.963, 0.968 and 0.982, with a mean CV 13.3% when using different systems and calibrations. The analytical performance of plasma rivaroxaban was acceptable in both systems, and results from reagent/coagulometer systems are comparable even when calibrating with different branch material.

Evaluation of rivaroxaban use in patients with gynecologic malignancies at an academic medical center: A pilot study.

PubMed

Signorelli, Jessie R; Gandhi, Arpita S

2017-01-01

Background Patients with gynecologic malignancies are at an increased risk for venous thromboembolism. National guidelines recommend treatment of an acute venous thromboembolism with low molecular weight heparin for 5-10 days followed by long-term secondary prophylaxis with low molecular weight heparin for at least six months. Non-vitamin K oral anticoagulants are not currently recommended to be used in cancer patients for the management of venous thromboembolism because robust data on their efficacy and safety have yet to become available in cancer patients. The objectives of this study were to determine the proportion of gynecologic oncology patients with venous thromboembolism using rivaroxaban compared to warfarin or low molecular weight heparin as well as compare the safety and efficacy of these anticoagulants. Methods This study was a retrospective pilot analysis of adult patients with gynecologic malignancies who received either rivaroxaban, warfarin or low molecular weight heparin for treatment of venous thromboembolism at Augusta University Medical Center from 1 July 2013 to 30 June 2015. Statistical comparisons between the enoxaparin and rivaroxaban group were made using T-tests and Chi-square or Fisher's exact tests, where appropriate. Results Out of the 49 patients, 37% (18) patients were on rivaroxaban, 53% (26) on enoxaparin, and 10% (5) on warfarin. Only one patient (4%) in the enoxaparin group experienced a recurrent deep vein thrombosis while there were no cases of recurrent venous thromboembolism in the rivaroxaban and warfarin group. The incidence of major bleeding was 17% ( n = 2), 20% ( n = 1), and 8% ( n = 2) in patients receiving rivaroxaban, enoxaparin, and warfarin, respectively. The rate of switching to a different anticoagulant than originally prescribed was 42% ( n = 14) in the enoxaparin arm, and 5.5% ( n = 1) in the rivaroxaban arm. Conclusion A high proportion of our gynecologic oncology patients received rivaroxaban for the management of venous thromboembolism. The sample size of this pilot analysis was too small to draw any conclusions regarding efficacy and safety of rivaroxaban compared with enoxaparin and warfarin. High rate of rivaroxaban use in gynecologic oncology patients at our institution highlights the need for larger, well-designed randomized controlled trials to confirm the safety and efficacy of its use in this population.

Effectiveness of rivaroxaban for thromboprophylaxis of prosthetic heart valves in a porcine heterotopic valve model.

PubMed

Greiten, Lawrence E; McKellar, Stephen H; Rysavy, Joseph; Schaff, Hartzell V

2014-05-01

Warfarin is used to reduce the risk of stroke and thromboembolic complications in patients with mechanical heart valves. Yet, despite frequent blood testing, its poor pharmacokinetic and pharmacodynamic profiles often result in variable therapeutic levels. Rivaroxaban is a direct competitive factor Xa inhibitor that is taken orally. It inhibits the active site of factor Xa without the need for the cofactor antithrombin, and thus, its mechanism of action is differentiated from that of the fractionated heparins and indirect factor Xa inhibitors. No in vivo data exist regarding the effectiveness of rivaroxaban in preventing thromboembolic complications of mechanical heart valves. We tested the hypothesis that rivaroxaban is as effective as enoxaparin for thromboprophylaxis of mechanical valves that use a previously described heterotopic aortic valve porcine model. A modified bileaflet mechanical valved conduit that bypassed the native, ligated descending thoracic aorta was implanted into 30 swine. Postoperatively, the animals were randomly assigned to groups receiving no anticoagulation (n = 10), enoxaparin at 2 mg/kg subcutaneously twice daily (n = 10) or rivaroxaban at 2 mg/kg orally twice daily (n = 10). The amount of valve thrombus was measured on post-implantation day 30 as the primary end point. Quantitative evaluation of radiolabelled platelet deposition on the valve prostheses was done and embolic and haemorrhagic events were measured as secondary end points. Animals with no anticoagulation had a thrombus mean of 759.9 mg compared with 716.8 mg with enoxaparin treatment and 209.6 mg with rivaroxaban treatment (P = 0.05 for enoxaparin vs rivaroxaban). Similarly, the mean number of platelets deposited on the valve prosthesis was lower in the rivaroxaban group (6.13 × 10(9)) than in the enoxaparin group (3.03 × 10(10)) (P = 0.03). In this study, rivaroxaban was more effective than enoxaparin for short-term thromboprophylaxis of mechanical valve prosthetics in the heterotopic aortic position. It reduced valve thrombus and platelet deposition on day 30 following implantation without increased adverse events. Future studies would provide additional support for clinical trials evaluating rivaroxaban as an alternative to warfarin for appropriately selected patients with prosthetic aortic valves.

Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).

PubMed

Halperin, Jonathan L; Hankey, Graeme J; Wojdyla, Daniel M; Piccini, Jonathan P; Lokhnygina, Yuliya; Patel, Manesh R; Breithardt, Günter; Singer, Daniel E; Becker, Richard C; Hacke, Werner; Paolini, John F; Nessel, Christopher C; Mahaffey, Kenneth W; Califf, Robert M; Fox, Keith A A

2014-07-08

Nonvalvular atrial fibrillation is common in elderly patients, who face an elevated risk of stroke but difficulty sustaining warfarin treatment. The oral factor Xa inhibitor rivaroxaban was noninferior to warfarin in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). This prespecified secondary analysis compares outcomes in older and younger patients. There were 6229 patients (44%) aged ≥75 years with atrial fibrillation and ≥2 stroke risk factors randomized to warfarin (target international normalized ratio=2.0-3.0) or rivaroxaban (20 mg daily; 15 mg if creatinine clearance <50 mL/min), double blind. The primary end point was stroke and systemic embolism by intention to treat. Over 10 866 patient-years, older participants had more primary events (2.57% versus 2.05%/100 patient-years; P=0.0068) and major bleeding (4.63% versus 2.74%/100 patient-years; P<0.0001). Stroke/systemic embolism rates were consistent among older (2.29% rivaroxaban versus 2.85% warfarin per 100 patient-years; hazard ratio=0.80; 95% confidence interval, 0.63-1.02) and younger patients (2.00% versus 2.10%/100 patient-years; hazard ratio=0.95; 95% confidence interval, 0.76-1.19; interaction P=0.313), as were major bleeding rates (≥75 years: 4.86% rivaroxaban versus 4.40% warfarin per 100 patient-years; hazard ratio=1.11; 95% confidence interval, 0.92-1.34; <75 years: 2.69% versus 2.79%/100 patient-years; hazard ratio=0.96; 95% confidence interval, 0.78-1.19; interaction P=0.336). Hemorrhagic stroke rates were similar in both age groups; there was no interaction between age and rivaroxaban response. Elderly patients had higher stroke and major bleeding rates than younger patients, but the efficacy and safety of rivaroxaban relative to warfarin did not differ with age, supporting rivaroxaban as an alternative for the elderly. © 2014 American Heart Association, Inc.

Spotlight on advances in VTE management: CALLISTO and EINSTEIN CHOICE.

PubMed

Bach, Miriam; Bauersachs, Rupert

2016-09-28

Venous thromboembolism (VTE) is associated with numerous complications and high mortality rates. Patients with cancer are at high risk of developing cancer-associated thrombosis (CAT), and VTE recurrence is common. Evidence supporting use of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) in patients with cancer is lacking - direct comparisons between NOACs and low-molecular-weight heparin (LMWH) are needed, along with patient-reported outcomes. Cancer Associated thrombosis - expLoring soLutions for patients through Treatment and Prevention with RivarOxaban (CALLISTO) is an international research programme exploring the potential of the direct, oral factor Xa inhibitor rivaroxaban for the prevention and treatment of CAT, supplementing existing data from EINSTEIN DVT and EINSTEIN PE. Here, we focus on four CALLISTO studies: A Study to Evaluate the Efficacy and Safety of Rivaroxaban Venous Thromboembolism Prophylaxis in Ambulatory Cancer Participants receiving Chemotherapy (CASSINI), Anticoagulation Therapy in SELECTeD Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT-D), Rivaroxaban in the Treatment of Venous Thromboembolism in Cancer Patients - a Randomized Phase III Study (CONKO-011) and a database analysis. Optimal anticoagulation duration for VTE treatment has always been unclear. Following favourable results for rivaroxaban 20 mg once-daily (Q. D.) for secondary VTE prevention (EINSTEIN EXT), EINSTEIN CHOICE is assessing rivaroxaban safety and (20 mg Q. D. or 10 mg Q. D.) vs acetylsalicylic acid (ASA), and will investigate whether an alternative rivaroxaban dose (10 mg Q. D.) could offer long-term VTE protection. It is anticipated that results from these studies will provide important answers and expand upon current evidence for rivaroxaban in VTE management.

Effect of rivaroxaban on blood coagulation using the viscoelastic coagulation test ROTEM™.

PubMed

Casutt, M; Konrad, C; Schuepfer, G

2012-11-01

This study investigated the influence of the oral direct inhibitor of factor Xa rivaroxaban on blood coagulation measured by rotation thrombelastometry ROTEM™. Blood was obtained from 11 healthy male volunteers before and 2.5 h after oral administration of 10 mg rivaroxaban. In addition to standard coagulation tests clot formation was measured by ROTEM™ analyzing extrinsic (Extem) and intrinsic thrombelastometry (Intem). Significant differences to the baseline values were found in the Extem clotting time (Extem-CT, 58 ± 9 s and 87 ± 17 s, p < 0.01), Intem-CT (194 ± 26 s and 239 ± 43 s; p = 0.02), prothrombin time (PT, 86 ± 9% and 67 ± 7%; p < 0.01) and activated partial thromboplastin time (aPTT, 28 ± 1 s and 35 ± 2 s; p < 0.01). There was a low correlation between Extem-CT and PT as well as between Intem-CT and aPTT before and after rivaroxaban intake. The receiver operating characteristic curve (ROC) analysis determined aPTT to be the most appropriate parameter for the prediction of rivaroxaban-induced anticoagulation, Intem-CT and Extem-CT proved to be moderate tests and PT had no significance in the prediction of rivaroxaban-induced anticoagulation. Of utmost clinical importance was the fact that rivaroxaban treated patients could still show normal ROTEM™ values. Thus, ROTEM™ cannot be a suitable test method to exclude inhibition of blood coagulation by rivaroxaban.

Abnormal uterine bleeding in VTE patients treated with rivaroxaban compared to vitamin K antagonists.

PubMed

De Crem, Nico; Peerlinck, Kathelijne; Vanassche, Thomas; Vanheule, Kristine; Debaveye, Barbara; Middeldorp, Saskia; Verhamme, Peter; Peetermans, Marijke

2015-10-01

Rivaroxaban is a convenient oral anticoagulant for patients with venous thromboembolism (VTE). The impact of rivaroxaban and vitamin K antagonists (VKAs) on abnormal uterine bleeding (AUB) in real life has not been previously explored. We performed a single-center retrospective study on AUB in female VTE patients of reproductive age who were treated with either rivaroxaban or VKAs. Questionnaire results were available for 52 patients in each treatment group. Approximately two thirds of all women reported AUB after initiation of anticoagulant therapy. Patients using rivaroxaban were more likely to experience prolonged (>8days) menstrual bleeding (27 % vs. 8.3%, P=0.017). Rivaroxaban treatment increased the duration of menstrual bleeding from median 5 (IQR 3.5-6.0) days before start of treatment to 6 (IQR 4.1-8.9) days (P<0.001). VKA treatment did not lead to significant prolongation of the menstrual period. Patients on rivaroxaban more frequently reported an unscheduled contact with a physician for AUB than women using VKAs (41% vs. 25%, P=0.096). They also reported increased need for menorrhagia-related medical or surgical intervention (25% vs. 7.7%, P=0.032) and had more adaptations of anticoagulant therapy (15% vs. 1.9%, P=0.031). AUB is frequent after initiation of anticoagulant therapy for acute symptomatic VTE. Compared to VKAs, rivaroxaban was associated with prolonged menstrual bleeding and more medical interventions and adaptation of anticoagulant treatment for AUB. These data can guide proactive discussion with patients starting anticoagulant therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Predictive factors for bleeding during treatment with rivaroxaban and warfarin in Japanese patients with atrial fibrillation - Subgroup analysis of J-ROCKET AF.

PubMed

Hori, Masatsugu; Matsumoto, Masayasu; Tanahashi, Norio; Momomura, Shin-Ichi; Uchiyama, Shinichiro; Goto, Shinya; Izumi, Tohru; Koretsune, Yukihiro; Kajikawa, Mariko; Kato, Masaharu; Cavaliere, Mary; Iekushi, Kazuma; Yamanaka, Satoshi

2016-12-01

Results from the J-ROCKET AF study revealed that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcomes in patients with non-valvular atrial fibrillation. This subgroup analysis evaluated whether non-major clinically relevant bleeding (NMCRB) could be a predictive factor for major bleeding (MB). Other predictive factors for MB were also obtained in both rivaroxaban and warfarin treatment groups. The temporal incidence of MB was compared between the rivaroxaban and warfarin treatment groups. Assessment was made whether MB events were often preceded by NMCRB. Univariate and multivariate analyses were carried out to identify any independent predictive factors for MB in both treatment groups. The incidences of MB and NMCRB were 18.04% (138/639 patients) in the rivaroxaban arm, and 16.42% in the warfarin arm (124/639 patients). NMCRB preceded MB in only four patients in each treatment group (rivaroxaban: 4/117 and warfarin: 4/98). Multivariate analysis identified predictive factors for bleeding events: anemia with warfarin treatment and concomitant use of antiplatelet agents with rivaroxaban treatment. Results from this subgroup analysis, particularly the fact that there was no repeated or sequential pattern between NMCRB and MB occurrences in both treatment groups, suggests that NMCRB might not be a predictive factor for MB. On the contrary, anemia and concomitant use of antiplatelet therapy were likely predictive factors for bleeding with warfarin and rivaroxaban treatment, respectively. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Role of rivaroxaban in the management of atrial fibrillation: insights from clinical practice.

PubMed

Vimalesvaran, Kavitha; Dockrill, Seth J; Gorog, Diana A

2018-01-01

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and it leads to significant morbidity and mortality, predominantly from ischemic stroke. Vitamin K antagonists, mainly warfarin, have been used for decades to prevent ischemic stroke in AF, but their use is limited due to interactions with food and other drugs, as well as the requirement for regular monitoring of the international normalized ratio. Rivaroxaban, a direct factor Xa inhibitor and the most commonly used non-vitamin K oral anticoagulant, avoids many of these challenges and is being prescribed with increasing frequency for stroke prevention in non-valvular AF. Randomized controlled trial (RCT) data from the ROCKET-AF(Rivaroxaban once daily oral direct Factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation) trial have shown rivaroxaban to be non-inferior to warfarin in preventing ischemic stroke and systemic embolism and to have comparable overall bleeding rates. Applicability of the RCT data to real-world practice can sometimes be limited by complex clinical scenarios or multiple comorbidities not adequately represented in the trials. Available real-world evidence in non-valvular AF patients with comorbidities - including renal impairment, acute coronary syndrome, diabetes mellitus, malignancy, or old age - supports the use of rivaroxaban as safe and effective in preventing ischemic stroke in these subgroups, though with some important considerations required to reduce bleeding risk. Patient perspectives on rivaroxaban use are also considered. Real-world evidence indicates superior rates of drug adherence with rivaroxaban when compared with vitamin K antagonists and with alternative non-vitamin K oral anticoagulants - perhaps, in part, due to its once-daily dosing regimen. Furthermore, self-reported quality of life scores are highest among patients compliant with rivaroxaban therapy. The generally high levels of patient satisfaction with rivaroxaban therapy contribute to overall favorable clinical outcomes.

Measurement of rivaroxaban concentrations demonstrates lack of clinical utility of a PT, dPT and APTT test in estimating levels.

PubMed

Thom, I; Cameron, G; Robertson, D; Watson, H G

2018-05-02

Rivaroxaban concentrations were measured in 127 inpatient samples using an HPLC-MS/MS assay. We compared this measurement with a calibrated anti-Xa assay and performed PT, aPTT and dilute PT tests to assess the value of clot-based assays in clinical decision-making. The correlation between the anti-Xa assay and the HPLC-MS/MS at therapeutic concentrations was strong (R 2  = 0.98). The PT, RecombiPlasTin 2G, and aPTT, Actin FS, showed a linear dose-response but poor correlation (R 2  = 0.32 and 0.44, respectively) and at dilutions of 1 in 150 to 1 in 750 the dilute PT assay also showed poor correlation with rivaroxaban concentrations measured by specific assays. A normal PT or aPTT alone did not identify a likely safe rivaroxaban concentration to allow surgery or invasive procedures, but the combination of normal PT and aPTT identified a group of patients with rivaroxaban levels less than 90 ng/mL. Combined normal PT and aPTT had specificity and sensitivity of 0.97 (95% CI 0.92-0.99) and 0.37 (95% CI 0.1-0.74) for a rivaroxaban concentration < 32 ng/mL. The PT and aPTT show poor correlation with rivaroxaban levels measured by calibrated anti-Xa and HPLC-MS/MS assays. A normal combined PT and APTT identified low rivaroxaban levels with high specificity but lacked sensitivity. The dPT assay at several dilutions could not be used to quantify rivaroxaban in clinical samples. The utility of these PT, aPTT and dilute PT assays in a clinical setting is very limited, and results generated must be interpreted with caution. © 2018 John Wiley & Sons Ltd.

Rivaroxaban modulates electrical and mechanical characteristics of left atrium

PubMed Central

2013-01-01

Background Rivaroxaban reduces stroke in patients with atrial fibrillation (AF). Left atrium (LA) plays a critical role in the pathophysiology of AF. However, the electromechanical effects of rivaroxaban on LA are not clear. Results Conventional microelectrodes and a whole-cell patch-clamp were used to record the action potentials (APs) and ionic currents in rabbit LA preparations and isolated single LA cardiomyocytes before and after the administration of rivaroxaban. Rivaroxaban (10, 30, 100, and 300 nM) concentration-dependently reduced LA (n = 7) AP durations at 90% repolarization (APD90) from 76 ± 2 to 79 ± 3, 67 ± 4 (P < 0.05, vs. control), 59 ± 5, (P < 0.01, vs. control), and 56 ± 4 ms (P < 0.005, vs. control), respectively. Rivaroxaban (10, 30, 100, and 300 nM) concentration-dependently increased the LA (n = 7) diastolic tension by 351 ± 69 (P < 0.05, vs. control), 563 ± 136 (P < 0.05, vs. control), 582 ± 119 (P < 0.05, vs. control), and 603 ± 108 mg (P < 0.005, vs. control), respectively, but did not change LA contractility. In the presence of L-NAME (100 μM) and indomethacin (10 μM), additional rivaroxaban (300 nM) treatment did not significantly further increase the LA (n = 7) diastolic tension, but shortened the APD90 from 73 ± 2 to 60 ± 6 ms (P < 0.05, vs. control). Rivaroxaban (100 nM) increased the L-type calcium current and ultra-rapid delayed rectifier potassium current, but did not change the transient outward potassium current in isolated LA cardiomyocytes. Conclusions Rivaroxaban modulates LA electrical and mechanical characteristics with direct ionic current effects. PMID:23497194

Evaluation of clinical outcomes among nonvalvular atrial fibrillation patients treated with rivaroxaban or warfarin, stratified by renal function
.

PubMed

Weir, Matthew R; Haskell, Lloyd; Berger, Jeffrey S; Ashton, Veronica; Laliberté, François; Crivera, Concetta; Brown, Kip; Lefebvre, Patrick; Schein, Jeffrey

2018-05-01

Renal dysfunction increases the risk of thromboembolic and bleeding events in patients with nonvalvular atrial fibrillation (NVAF). Adult NVAF patients with ≥ 6 months prior to first warfarin or rivaroxaban dispensing were selected from the IMS Health Real-World Data Adjudicated Claims database (05/2011 - 06/2015) with electronic medical records. Ischemic stroke events, thromboembolic events (venous thromboembolism, myocardial infarction, or ischemic stroke), and major bleeding events were compared between patients by renal function identified by 1) relevant ICD-9-CM diagnosis codes and 2) estimated creatinine clearance (eCrCl). Baseline confounders were adjusted using inverse probability of treatment weights. The diagnosis-based analysis included 39,872 rivaroxaban and 48,637 warfarin users (3,572 and 8,230 with renal dysfunction, respectively). The eCrCl-based analysis included 874 rivaroxaban and 1,069 warfarin users (66 and 208 with eCrCl < 60 mL/min, respectively). In the diagnosis-based analysis, rivaroxaban users with renal dysfunction had a significantly lower stroke rate (HR = 0.55, p = 0.0004) compared to warfarin users; rivaroxaban users with and without renal dysfunction had significantly lower thromboembolic event rates (HR = 0.62, p < 0.0001; and HR = 0.64, p < 0.0001, respectively), and similar major bleeding rates to warfarin users. In the eCrCl-based analysis, rivaroxaban users with eCrCl ≥ 60 mL/min had a significantly lower thromboembolic event rate, but other outcomes were not statistically significant. Rivaroxaban-treated NVAF patients with diagnosed renal dysfunction had a significantly lower stroke rate compared to warfarin-treated patients. Regardless of renal dysfunction diagnoses, rivaroxaban users had lower thromboembolic event rates compared to warfarin users, and a similar rate of major bleeding. eCrCl-based analysis was limited by a small sample size.
.

Effects of thromboprophylactic doses of apixaban and rivaroxaban on coagulation and thrombin generation in association with total hip replacement.

PubMed

Helin, Tuukka A; Virtanen, Lauri; Manninen, Mikko; Leskinen, Jarkko; Leppilahti, Juhana; Joutsi-Korhonen, Lotta; Lassila, Riitta

2017-05-01

Factor Xa inhibitors (FXaI) apixaban and rivaroxaban are used for thromboprophylaxis after major elective orthopaedic surgery. Because few patient sample studies exist, we postoperatively assessed patients undergoing unilateral total hip arthroplasty, including 22 treated with apixaban (2.5 mg BID) and 20 treated with rivaroxaban (10 mg OD). We collected blood samples before and 3 h after drug intake at 4 time points, preoperatively, as well as on day 1, week 1 (day 2-8) and day 28 post-operation. APTT and PT were immediately analysed. Calibrated anti-FXa activity, Russel's Viper Venom Time (RVVT) and thrombin generation (TG; Calibrated Automated Thrombogram ® ) captured the effects of FXaI on coagulation and TG. APTT and PT remained within the reference interval throughout, and did not correlate with FXaI levels (PT R 2  = 0.44, APTT R 2  = 0.07). Mean apixaban concentration at the peak varied by eightfold (19-153 ng/mL), but rivaroxaban only by 1.5-fold (111-183 ng/mL). Rivaroxaban, but not apixaban prolonged RVVT at peak levels. Both FXaIs had a prolonged lag time of TG (p < 0.001). Rivaroxaban decreased ETP peak at all time points and reached a minimum at day 28 (540 nM/min at rivaroxaban 184 ng/mL, p < 0.001), while rivaroxaban trough levels were low and ETP values normal. However, with apixaban, after an initial decrease, ETP did not differ between peak and trough levels until decreasing on day 28 at peak (990 nM/min at apixaban 112 ng/mL, p = 0.005). In conclusion, due to different dosing and pharmacology rivaroxaban and apixaban distinctly inhibited TG under postoperative conditions.

A cost-analysis model for anticoagulant treatment in the hospital setting.

PubMed

Mody, Samir H; Huynh, Lynn; Zhuo, Daisy Y; Tran, Kevin N; Lefebvre, Patrick; Bookhart, Brahim

2014-07-01

Rivaroxaban is the first oral factor Xa inhibitor approved in the US to reduce the risk of stroke and blood clots among people with non-valvular atrial fibrillation, treat deep vein thrombosis (DVT), treat pulmonary embolism (PE), reduce the risk of recurrence of DVT and PE, and prevent DVT and PE after knee or hip replacement surgery. The objective of this study was to evaluate the costs from a hospital perspective of treating patients with rivaroxaban vs other anticoagulant agents across these five populations. An economic model was developed using treatment regimens from the ROCKET-AF, EINSTEIN-DVT and PE, and RECORD1-3 randomized clinical trials. The distribution of hospital admissions used in the model across the different populations was derived from the 2010 Healthcare Cost and Utilization Project database. The model compared total costs of anticoagulant treatment, monitoring, inpatient stay, and administration for patients receiving rivaroxaban vs other anticoagulant agents. The length of inpatient stay (LOS) was determined from the literature. Across all populations, rivaroxaban was associated with an overall mean cost savings of $1520 per patient. The largest cost savings associated with rivaroxaban was observed in patients with DVT or PE ($6205 and $2742 per patient, respectively). The main driver of the cost savings resulted from the reduction in LOS associated with rivaroxaban, contributing to ∼90% of the total savings. Furthermore, the overall mean anticoagulant treatment cost was lower for rivaroxaban vs the reference groups. The distribution of patients across indications used in the model may not be generalizable to all hospitals, where practice patterns may vary, and average LOS cost may not reflect the actual reimbursements that hospitals received. From a hospital perspective, the use of rivaroxaban may be associated with cost savings when compared to other anticoagulant treatments due to lower drug cost and shorter LOS associated with rivaroxaban.

Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation.

PubMed

Andersson, Niklas W; Svanström, Henrik; Lund, Marie; Pasternak, Björn; Melbye, Mads

2018-06-19

The comparative effectiveness and safety of individual direct oral anticoagulants (DOACs) in clinical practice is largely unknown. The study objectives were to compare effectiveness and safety of DOACs in patients with non-valvular atrial fibrillation (NVAF). Based on nationwide registers we established a population-based historical cohort study of 12,638 new users of standard dose DOACs (apixaban 5 mg twice daily, dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily) with NVAF in Denmark, July 2013 to March 2016. Patients were matched on propensity scores in a 1:1 ratio comparing apixaban vs. dabigatran (for a total of 6470 patients), apixaban vs. rivaroxaban (7352 patients), and rivaroxaban vs. dabigatran (5440 patients). Hazard ratios (HRs) for stroke or systemic embolism (effectiveness outcome) and major bleeding (safety outcome) were estimated. In propensity-matched comparisons of the risk of stroke or systemic embolism, the HRs were 1.27 (95% confidence interval [CI], 0.82-1.96) for apixaban vs. dabigatran, 1.25 (95% CI, 0.87-1.79) for apixaban vs. rivaroxaban, and 1.17 (95% CI, 0.69-1.96) for rivaroxaban vs. dabigatran. For the risk of major bleeding, the HRs were 0.94 (95% CI, 0.62-1.41) for apixaban vs. dabigatran, 0.88 (95% CI, 0.64-1.22) for apixaban vs. rivaroxaban, and 1.35 (95% CI, 0.91-2.00) for rivaroxaban vs. dabigatran. Among patients with NVAF in routine clinical practice, there were no statistically significant differences in risk of stroke or systemic embolism or major bleeding in propensity-matched comparisons between apixaban, dabigatran, and rivaroxaban used in standard doses. While analyses indicate that more than moderate differences can be excluded, smaller differences cannot be ruled out. Copyright © 2017 Elsevier B.V. All rights reserved.

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism.

PubMed

Weitz, Jeffrey I; Lensing, Anthonie W A; Prins, Martin H; Bauersachs, Rupert; Beyer-Westendorf, Jan; Bounameaux, Henri; Brighton, Timothy A; Cohen, Alexander T; Davidson, Bruce L; Decousus, Hervé; Freitas, Maria C S; Holberg, Gerlind; Kakkar, Ajay K; Haskell, Lloyd; van Bellen, Bonno; Pap, Akos F; Berkowitz, Scott D; Verhamme, Peter; Wells, Philip S; Prandoni, Paolo

2017-03-30

Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin. In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups. Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439 .).

Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial.

PubMed

Piccini, Jonathan P; Garg, Jyotsna; Patel, Manesh R; Lokhnygina, Yuliya; Goodman, Shaun G; Becker, Richard C; Berkowitz, Scott D; Breithardt, Günter; Hacke, Werner; Halperin, Jonathan L; Hankey, Graeme J; Nessel, Christopher C; Mahaffey, Kenneth W; Singer, Daniel E; Califf, Robert M; Fox, Keith A A

2014-07-21

There are no data regarding management and outcomes of major bleeding events in patients treated with oral factor Xa inhibitors. Using data from ROCKET AF, we analysed the management and outcomes of major bleeding overall and according to the randomized treatment. During a median follow-up of 1.9 years, 779 (5.5%) patients experienced major bleeding at a rate of 3.52 events/100 patient-years with a similar event rate in each arm (n = 395 rivaroxaban vs. n = 384 warfarin). The median number of transfused packed red blood cells (PRBC) per episode was similar in both arms [2 (25th, 75th: 2, 4) units]. Overall, few transfusions of whole blood (n = 14), platelets (n = 10), or cryoprecipitate (n = 2) were used. Transfusion of fresh frozen plasma (FFP) was significantly less in the rivaroxaban arm (n = 45 vs. n = 81 units) after adjustment for covariates [odds ratio (OR) 0.43 (95% CI 0.29-0.66); P < 0.0001]. Prothrombin complex concentrates (PCC) were administered less in the rivaroxaban arm (n = 4 vs. n = 9). Outcomes after major bleeding, including stroke or non-central nervous system embolism (4.7% rivaroxaban vs. 5.4% warfarin; HR 0.89; 95% CI 0.42-1.88) and all-cause death (20.4% rivaroxaban vs. 26.1% warfarin; HR 0.69, 95% CI 0.46-1.04) were similar in patients treated with rivaroxaban and warfarin (interaction P = 0.51 and 0.11). Among high-risk patients with atrial fibrillation who experienced major bleeding in ROCKET AF, the use of FFP and PCC was less among those allocated rivaroxaban compared with warfarin. However, use of PRBCs and outcomes after bleeding were similar among patients randomized to rivaroxaban or to warfarin. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

Severe jaundice due to intrahepatic cholestasis after initiating anticoagulation with rivaroxaban.

PubMed

Aslan, Abdullah N; Sari, Cenk; Baştuğ, Serdal; Sari, Sevil Ö; Akçay, Murat; Durmaz, Tahir; Bozkurt, Engin

2016-03-01

Rivaroxaban, a highly selective direct factor Xa inhibitor, is a new oral anticoagulant approved by the US Food and Drug Administration in November 2011 for stroke prophylaxis in patients with nonvalvular atrial fibrillation. Because of its efficacy and once-a-day dosing, it is commonly preferred in patients with nonvalvular atrial fibrillation and intolerance to warfarin in clinical practice. However, it can result in some adverse effects such as bleeding, rashes and liver injury. Here, we described a very rare adverse reaction of rivaroxaban, jaundice due to intrahepatic cholestasis, appeared in a 71-year-old male patient after taking rivaroxaban.

The anticoagulant effect of heparin during radiofrequency ablation (RFA) in patients taking apixaban or rivaroxaban.

PubMed

Brendel, L C; Dobler, F; Hessling, G; Michel, J; Braun, S L; Steinsiek, A L; Groha, P; Eckl, R; Deisenhofer, I; Hyseni, A; Roest, M; Ott, I; Steppich, B

2017-09-01

Measuring the anticoagulant effect of heparin during radiofrequency ablation (RFA) in patients taking apixaban and rivaroxaban is challenging, since the activated coagulation time (ACT) does not seem to reflect the true anticoagulant activity of these drugs. We therefore evaluated coagulation properties of apixaban and rivaroxaban during RFA by different coagulation assays to better monitor periprocedural hemostasis. The study included 90 patients (61 ± 12 years) with atrial fibrillation who underwent RFA procedures. Patients received 20 mg rivaroxaban (n = 73) once or 5 mg apixaban (n = 17) twice daily 4 weeks prior to the procedure. During RFA, unfractionated heparin i.v. was given to maintain an ACT of 250-300 s. Blood samples were taken before and 10, 60, and 360 min after heparin administration. Heparin displayed a lower anti-Xa activity in rivaroxaban-treated patients compared to apixaban-treated patients. In contrast, D-dimer and prothrombin fragment F1+2 plasma levels indicated a higher activation of the coagulation cascade in apixaban/heparin than in rivaroxaban/heparin patients. This discordant coagulative state measured in vitro had no clinical impact in terms of bleeding or thromboembolic complications. We found different biochemical responses to rivaroxaban/heparin and apixaban/heparin during RFA. Precaution is necessary when monitoring periprocedural hemostasis in DOAC patients to avoid mismanagement.

Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF.

PubMed

Girgis, I G; Patel, M R; Peters, G R; Moore, K T; Mahaffey, K W; Nessel, C C; Halperin, J L; Califf, R M; Fox, K A A; Becker, R C

2014-08-01

Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n = 161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF. © 2014, The American College of Clinical Pharmacology.

Effectiveness and safety of rivaroxaban versus warfarin for treatment and prevention of recurrence of venous thromboembolism.

PubMed

Coleman, Craig I; Bunz, Thomas J; Turpie, Alexander G G

2017-10-05

The efficacy and safety or rivaroxaban versus enoxaparin/vitamin K antagonist for treatment and prevention recurrence of venous thromboembolism (VTE) was demonstrated in the randomised EINSTEIN trials. We assessed the effectiveness and safety of rivaroxaban versus warfarin in VTE patients managed in routine practice. Using US MarketScan claims from 1/2012-6/2015, we included adults with a primary diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE) during a hospitalisation/emergency department visit, newly-initiated on rivaroxaban or warfarin within 30-days after the VTE and with ≥180-days of continuous medical/prescription benefits prior to the VTE (baseline). Patients with a claim for anticoagulation at baseline were excluded. Recurrent VTE, major bleeding, intracranial haemorrhage (ICH) and gastrointestinal bleeding (GIB) were assessed. Differences in baseline characteristics between cohorts were adjusted for using inverse probability of treatment weights based on propensity-scores. Patients had a maximum of 12-months period of follow-up post-VTE or until endpoint occurrence, switch/discontinuation of index anticoagulation, insurance disenrollment or end-of-follow-up. Cox regression was performed and reported as hazard ratios (HRs) with 95 % confidence intervals (CIs). In total, 13,609 rivaroxaban and 32,244 warfarin users experiencing VTE were included. Rivaroxaban was associated with an 19 % (95 %CI=10-27 %) reduction in recurrent VTE and a 21 % (95 %CI=4-35 %) reduction in major bleeding hazard versus warfarin. Rivaroxaban was also associated with significantly decreased hazards of ICH (HR=0.40) and GIB (HR=0.72). Rivaroxaban appears to reduce patients' hazard of both recurrent VTE and major bleeding in routine practice. These results appear consistent with EINSTEIN and post-marketing registry studies.

Comparative coronary risks of apixaban, rivaroxaban and dabigatran: a meta-analysis and adjusted indirect comparison

PubMed Central

Loke, Yoon K; Pradhan, Shiva; Yeong, Jessica Ka-yan; Kwok, Chun Shing

2014-01-01

Aims There are concerns regarding increased risk of acute coronary syndrome with dabigatran. We aimed to assess whether alternative treatment options such as rivaroxaban or apixaban carry a similar risk as compared with dabigatran. Methods We searched MEDLINE and EMBASE for randomized controlled trials of apixaban, dabigatran or rivaroxaban against control (placebo, heparin or vitamin K antagonist). We pooled odds ratios (OR) for adverse coronary events (acute coronary syndrome or myocardial infarction) using fixed effect meta-analysis and assessed heterogeneity with I2. We conducted adjusted indirect comparisons to compare risk of adverse coronary events with apixaban or rivaroxaban vs. dabigatran. Results Twenty-seven randomized controlled trials met the inclusion criteria. Dabigatran was associated with a significantly increased risk of adverse coronary events in pooled analysis of nine trials (OR 1.45, 95% CI 1.14, 1.86). There was no signal for coronary risk with apixaban from nine trials (pooled OR 0.89, 95% CI 0.78, 1.03) or rivaroxaban from nine trials (pooled OR 0.81, 95% CI 0.72, 0.93). Overall, adjusted indirect comparison suggested that both apixaban (OR 0.61, 95% CI 0.44, 0.85) and rivaroxaban (OR 0.54; 95% CI 0.39, 0.76) were associated with lower coronary risk than dabigatran. Restricting the indirect comparison to a vitamin K antagonist as a common control, yielded similar findings, OR 0.57 (95% CI 0.39, 0.85) for apixaban vs. dabigatran and 0.53 (95% CI 0.37, 0.77) for rivaroxaban vs. dabigatran. Conclusions There are significant differences in the comparative safety of apixaban, rivaroxaban and dabigatran with regards to acute coronary adverse events. PMID:24617578

Rivaroxaban for Thromboprophylaxis among Patients Recently Hospitalized for Acute Infectious Diseases: A Subgroup Analysis of the MAGELLAN Study.

PubMed

Cohoon, Kevin P; De Sanctis, Yoriko; Haskell, Lloyd; McBane, Robert D; Spiro, Theodore E

2018-05-12

Despite the well-established association between infection and venous thromboembolism (VTE), there are few data specifically assessing the efficacy and safety of the VTE prophylaxis strategies for patients hospitalized for acute infectious diseases. Estimate incidence of VTE and bleeding outcomes comparing prolonged prophylaxis with rivaroxaban 10 mg daily for 35 days with enoxaparin 40 mg daily for 10 days. A subgroup analysis of patients hospitalized for acute infectious diseases in the MAGELLAN trial was performed. The primary efficacy outcome was the composite of asymptomatic proximal or symptomatic VTE at days 10 and 35. The principal safety outcome was the composite of major or clinically relevant non-major bleeding. 3173 patients with acute infectious diseases leading to hospitalization were randomized to either rivaroxaban (n=1585) or enoxaparin/placebo (n=1588) and received at least one dose of study medication. At day 10, primary composite efficacy outcomes did not differ between prophylaxis strategies (rivaroxaban 2.7% and enoxaparin 3.7%). At day 35, VTE events were lower for rivaroxaban (4.2%) compared to enoxaparin (6.6%) (Relative risk [RR] 0.64; 95%CI, 0.45, 0.92). Patients with pulmonary infections randomized to rivaroxaban had lower incidence of VTE both at 10 days (RR 0.50, 95%CI 0.28, 0.90) and 35 days (RR 0.54, 95%CI 0.33, 0.87). Primary safety outcome events were higher for those receiving rivaroxaban (RR 2.42, 95%CI 1.60, 3.66). Prolonged rivaroxaban prophylaxis reduced VTE in patients hospitalized for acute infectious diseases particularly involving the lungs. Efficacy benefits were, in part, offset by bleeding outcomes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Clinical impact and course of major bleeding with rivaroxaban and vitamin K antagonists.

PubMed

Eerenberg, E S; Middeldorp, S; Levi, M; Lensing, A W; Büller, H R

2015-09-01

Rivaroxaban is a new oral anticoagulant (NOAC) that can be prescribed in a fixed dose, making regular monitoring and dose adjustments unnecessary. It has been proven to be safe and effective in comparison with enoxaparin/vitamin K antagonists (LMWH/VKA) for the (extended) treatment of venous thromboembolism in the EINSTEIN studies. Nevertheless, there is a need for information regarding the clinical impact of (major) bleeding events with NOACs such as rivaroxaban. A post-hoc analysis was performed to compare the severity of clinical presentation and subsequent clinical course of major bleeding with rivaroxaban vs. LMWH/VKA. Two investigators performed a blinded classification of major bleeding using a priori defined criteria. During the EINSTEIN studies, data concerning the clinical course and measures applied were prospectively collected for each major bleed. Treatment with LMWH/VKA caused more major bleeding events (1.7%) than rivaroxaban (1.0%; hazard ratio, 0.54; 95% confidence interval [CI], 0.37-0.79). Major bleeding events during rivaroxaban therapy had a milder presentation (23% were adjudicated to the worst categories vs. 38% for LMWH/VKA; hazard ratio or HR, 0.35; 95% CI, 0.17-0.74; P = 0.0062). The clinical course was severe in 25% of all major bleeding events associated with rivaroxaban, compared with 33% of LMWH/VKA-associated bleeds (HR, 0.46; 95% CI, 0.22-0.96; P = 0.040). Rivaroxaban-associated major bleeding events occurred less frequently, had a milder presentation and appeared to take a less severe clinical course compared with major bleeding with LMWH/VKA. © 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Bleeding risk with dabigatran, rivaroxaban, warfarin, and antiplatelet agent in Asians with non-valvular atrial fibrillation

PubMed Central

Tu, Hui-Tzu; Kuo, Chi-Tai; Chang, Shang-Hung; Wu, Lung-Sheng; Lee, Hsin-Fu; See, Lai-Chu

2017-01-01

It is not understood if dabigatran or rivaroxaban are superior to antiplatelet agents (AA) for safety outcomes in Asians with non-valvular atrial fibrillation (NVAF). In this study we evaluated the bleeding risk of dabigatran, rivaroxaban, warfarin and AA in Asians with NVAF. This national retrospective cohort study analyzed 6,600, 3,167, 5,338 and 8,238 consecutive NVAF patients taking dabigatran, rivaroxaban, warfarin or AAs (including aspirin, clopidogrel or ticlopidine), respectively, from June 1, 2012 to December 31, 2013. Propensity-score weighting was used to balance covariates across study groups. Patients were followed until the first occurrence of any bleeding outcome or the end of the study. The CHA2DS2-VASc scores were 4.1±1.6, 4.1±1.6, 3.3±1.8 and 2.4±1.6 for the dabigatran, rivaroxaban, warfarin, and AA groups, respectively. There were 5,822 (88.2%) and 164 (5.2%) patients taking low dose dabigatran and rivaroxaban, respectively. Hazard ratios (95% confidence intervals) for dabigatran, rivaroxaban, or warfarin versus AA were: intracranial hemorrhage, 0.36 (0.23-0.57;PP=0.0037) and 1.34 (0.89-2.02;P=0.1664); gastrointestinal bleeding, 0.44 (0.32-0.59;PP=0.0189); and all hospitalized major bleeding, 0.41 (0.32-0.53;PP=0.0644) and 0.90 (0.70-1.16;P=0.4130) after adjustment. The risk reduction of all major bleeding for dabigatran versus AA persisted on subgroup analysis. In conclusion, we observed that dabiagtran was associated with a lower risk of all major bleeding in Asians with NVAF, whereas rivaroxaban had a similar risk of all major bleeding compared with antiplatelet agents after adjustment of comorbidities. PMID:29228736

XANTUS: rationale and design of a noninterventional study of rivaroxaban for the prevention of stroke in patients with atrial fibrillation

PubMed Central

Camm, A John; Amarenco, Pierre; Haas, Sylvia; Hess, Susanne; Kirchhof, Paulus; van Eickels, Martin; Turpie, Alexander GG

2014-01-01

Atrial fibrillation (AF) is associated with a fivefold increase in the risk of stroke. The Phase III ROCKET AF (Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial showed that rivaroxaban, an oral, direct Factor Xa inhibitor, was noninferior to warfarin for the reduction of stroke or systemic embolism in patients with AF. Compared with warfarin, rivaroxaban significantly reduced rates of intracranial and fatal hemorrhages, although not rates of bleeding overall. XANTUS (Xarelto® for Prevention of Stroke in Patients with Atrial Fibrillation) is a prospective, international, observational, postauthorization, noninterventional study designed to collect safety and efficacy data on the use of rivaroxaban for stroke prevention in AF in routine clinical practice. The key goal is to determine whether the safety profile of rivaroxaban established in ROCKET AF is also observed in routine clinical practice. XANTUS is designed as a single-arm cohort study to minimize selection bias, and will enroll approximately 6,000 patients (mostly from Europe) with nonvalvular AF prescribed rivaroxaban, irrespective of their level of stroke risk. Overall duration of follow-up will be 1 year; the first patient was enrolled in June 2012. Similar studies (XANTUS-EL [Xarelto® for Prevention of Stroke in Patients with Nonvalvular Atrial Fibrillation, Eastern Europe, Middle East, Africa and Latin America] and XANAP [Xarelto® for Prevention of Stroke in Patients with Atrial Fibrillation in Asia-Pacific]) are ongoing in Latin America and Asia-Pacific. Data from these studies will supplement those from ROCKET AF and provide practical information concerning the use of rivaroxaban for stroke prevention in AF. PMID:25083135

Net clinical benefit of rivaroxaban versus warfarin in Japanese patients with nonvalvular atrial fibrillation: a subgroup analysis of J-ROCKET AF.

PubMed

Uchiyama, Shinichiro; Hori, Masatsugu; Matsumoto, Masayasu; Tanahashi, Norio; Momomura, Shin-Ichi; Goto, Shinya; Izumi, Tohru; Koretsune, Yukihiro; Kajikawa, Mariko; Kato, Masaharu; Ueda, Hitoshi; Iekushi, Kazuma; Yamanaka, Satoshi; Tajiri, Masahiro

2014-01-01

The risk factors that have been identified for bleeding events with rivaroxaban are predominantly the same as those predicting thromboembolic ones in patients with atrial fibrillation (AF). Our aim was to determine the net clinical benefit (NCB) from the results of the J-ROCKET AF trial, in which rivaroxaban was compared with warfarin in Japanese patients with AF. Two strategies were adopted to quantify the NCB. First, the NCB was calculated as the number of ischemic strokes avoided with anticoagulation minus the number of excess intracranial hemorrhage (ICH) with a weight of 1.5. Second, the composite end point of major bleeding events and secondary efficacy end points (stroke, noncentral nervous system systemic embolism, myocardial infarction and death) to ascertain the NCB were established. Subgroup analysis by CHADS2 score or creatinine clearance was also performed. The adjusted NCB, which was given a weight of 1.5 for ICH, was nominally significant in favor of rivaroxaban therapy (difference in incidence rate -2.13; 95% confidence interval [CI]: -.26 to -3.99). Furthermore, the event rate of the composite end point tended to be lower in patients treated with rivaroxaban than in those treated with warfarin (rivaroxaban: 4.97% per year, warfarin: 6.11% per year; difference in incidence rate: -1.14; 95% CI: -3.40 to 1.12). The event rate of the composite end point tended to be consistently low in patients treated with rivaroxaban in the subanalysis by CHADS2 score and renal function. Analysis of the NCB supports that rivaroxaban therapy provides clinical benefit for Japanese patients with AF. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

The emergence of factor Xa inhibitors for the treatment of cardiovascular diseases: a patent review.

PubMed

Pinto, Donald J P; Qiao, Jennifer X; Knabb, Robert M

2012-06-01

Factor Xa (FXa) is a critical enzyme in the coagulation cascade responsible for thrombin generation, the final enzyme that leads to fibrin clot formation. Significant success has recently been reported with compounds such as rivaroxaban, apixaban and edoxaban in the treatment and prevention of venous thromboembolism (VTE) and more recently in the prevention of stroke in atrial fibrillation (AF). The success these agents have demonstrated is now being reflected by a narrowing of new FXa patents over the past few years. The new patents appear to be structural modifications of previously published, small molecule inhibitors and bind in a similar manner to the FXa enzyme. SciFinder®, PubMed and Google websites were used as the main source of literature retrieval. Patent searches were conducted in the patent databases: HCAPlus, WPIX and the full text databases (USPAT2, USPATFULL, EPFULL, PCTFULL) using the following keywords: ((FXa) OR (F OR factor) (W) (Xa)) (S) (inhibit? or block? or modulat? or antagonist? or regulat?). The search was restricted to patent documents with the entry date on or after 1 January 2009. Literature and information related to clinical development was retrieved from Thomson Reuter's Pharma. A large body of Phase II and Phase III data is now available for FXa inhibitors such as rivaroxaban, apixaban, edoxaban and betrixaban. The clinical data demonstrate favorable benefit-risk profiles compared with the standards of care for short- and long-term anticoagulation (i.e., low molecular weight heparins (LMWHs) and wafarin). The potential exists that these agents will eventually be the agents of choice for the treatment of a host of cardiovascular disease states, offering improved efficacy, safety, and ease of use compared with existing anticoagulants.

Determination of rivaroxaban in patient's plasma samples by anti-Xa chromogenic test associated to High Performance Liquid Chromatography tandem Mass Spectrometry (HPLC-MS/MS).

PubMed

Derogis, Priscilla Bento Matos; Sanches, Livia Rentas; de Aranda, Valdir Fernandes; Colombini, Marjorie Paris; Mangueira, Cristóvão Luis Pitangueira; Katz, Marcelo; Faulhaber, Adriana Caschera Leme; Mendes, Claudio Ernesto Albers; Ferreira, Carlos Eduardo Dos Santos; França, Carolina Nunes; Guerra, João Carlos de Campos

2017-01-01

Rivaroxaban is an oral direct factor Xa inhibitor, therapeutically indicated in the treatment of thromboembolic diseases. As other new oral anticoagulants, routine monitoring of rivaroxaban is not necessary, but important in some clinical circumstances. In our study a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was validated to measure rivaroxaban plasmatic concentration. Our method used a simple sample preparation, protein precipitation, and a fast chromatographic run. It was developed a precise and accurate method, with a linear range from 2 to 500 ng/mL, and a lower limit of quantification of 4 pg on column. The new method was compared to a reference method (anti-factor Xa activity) and both presented a good correlation (r = 0.98, p < 0.001). In addition, we validated hemolytic, icteric or lipemic plasma samples for rivaroxaban measurement by HPLC-MS/MS without interferences. The chromogenic and HPLC-MS/MS methods were highly correlated and should be used as clinical tools for drug monitoring. The method was applied successfully in a group of 49 real-life patients, which allowed an accurate determination of rivaroxaban in peak and trough levels.

Prospective surveillance pilot of rivaroxaban safety within the US Food and Drug Administration Sentinel System.

PubMed

Chrischilles, Elizabeth A; Gagne, Joshua J; Fireman, Bruce; Nelson, Jennifer; Toh, Sengwee; Shoaibi, Azadeh; Reichman, Marsha E; Wang, Shirley; Nguyen, Michael; Zhang, Rongmei; Izem, Rima; Goulding, Margie R; Southworth, Mary Ross; Graham, David J; Fuller, Candace; Katcoff, Hannah; Woodworth, Tiffany; Rogers, Catherine; Saliga, Ryan; Lin, Nancy D; McMahill-Walraven, Cheryl N; Nair, Vinit P; Haynes, Kevin; Carnahan, Ryan M

2018-03-01

The US Food and Drug Administration's Sentinel system developed tools for sequential surveillance. In patients with non-valvular atrial fibrillation, we sequentially compared outcomes for new users of rivaroxaban versus warfarin, employing propensity score matching and Cox regression. A total of 36 173 rivaroxaban and 79 520 warfarin initiators were variable-ratio matched within 2 monitoring periods. Statistically significant signals were observed for ischemic stroke (IS) (first period) and intracranial hemorrhage (ICH) (second period) favoring rivaroxaban, and gastrointestinal bleeding (GIB) (second period) favoring warfarin. In follow-up analyses using primary position diagnoses from inpatient encounters for increased definition specificity, the hazard ratios (HR) for rivaroxaban vs warfarin new users were 0.61 (0.47, 0.79) for IS, 1.47 (1.29, 1.67) for GIB, and 0.71 (0.50, 1.01) for ICH. For GIB, the HR varied by age: <66 HR = 0.88 (0.60, 1.30) and 66+ HR = 1.49 (1.30, 1.71). This study demonstrates the capability of Sentinel to conduct prospective safety monitoring and raises no new concerns about rivaroxaban safety. Copyright © 2018 John Wiley & Sons, Ltd.

Safety and effectiveness of rivaroxaban and warfarin in moderate-to-advanced CKD: real world data.

PubMed

Di Lullo, Luca; Tripepi, Giovanni; Ronco, Claudio; De Pascalis, Antonio; Barbera, Vincenzo; Granata, Antonio; Russo, Domenico; Di Iorio, Biagio Raffaele; Paoletti, Ernesto; Ravera, Maura; Fusaro, Maria; Bellasi, Antonio

2018-06-07

In recent years, novel anticoagulant drugs have been introduced in the clinical armamentarium and have progressively gained momentum. Although their use is increasing among CKD patients, some skepticism about their risk-benefit ratio still persists. We sought to investigate the safety and effectiveness of rivaroxaban in a cohort of moderate-to-advanced CKD patients. This observational, retrospective, longitudinal study involved 347 consecutive CKD stage 3b-4 (according to NKF-KDOQI guidelines) patients enrolled from 8 cardiac outpatient clinics between March 2015 and October 2017. All patients received anticoagulation (100 warfarin vs. 247 rivaroxaban) as part of their non-valvular atrial fibrillation management at the attending physician's discretion. Clinical effectiveness (defined as the occurrence of ischemic stroke, venous thromboembolism, or transient ischemic attack) and safety (intracranial hemorrhage, gastrointestinal or other bleeding) were assessed separately. Over a mean follow-up period of 16 ± 0.3 months, 25 stroke episodes (15 hemorrhagic, and 10 ischemic) occurred in 24 warfarin treated patients vs. none in the rivaroxaban arm. There were 5 vs. 0 episodes of deep venous thrombosis and 8 vs. 2 major episodes of bleeding in the warfarin and rivaroxaban groups, respectively. In contrast, the proportion of minor episodes of bleeding was similar between groups. Rivaroxaban seems a safe and effective therapeutic option in CKD stage 3b-4 patients. However, future randomized controlled trials are needed to definitively establish the role of rivaroxaban in CKD patients.

Comparison of clinical characteristics of real-life atrial fibrillation patients treated with vitamin K antagonists, dabigatran, and rivaroxaban: results from the CRAFT study.

PubMed

Balsam, Paweł; Ozierański, Krzysztof; Tymińska, Agata; Żukowska, Katarzyna; Zaleska, Martyna; Szepietowska, Katarzyna; Maciejewski, Kacper; Peller, Michał; Grabowski, Marcin; Lodziński, Piotr; Praska-Ogińska, Anna; Zaboyska, Inna; Kołtowski, Łukasz; Kowalczuk, Anna; Bednarski, Janusz; Filipiak, Krzysztof J; Opolski, Grzegorz

2018-01-01

The first-line drugs for the treatment of non-valvular atrial fibrillation (AF) are non-vitamin K antagonist oral anticoagulants (NOACs), which are preferred over vitamin K antagonists (VKAs). There is some evidence that there are dis-crepancies between everyday clinical practice and the guidelines. The study aimed to compare the characteristics of patients on VKAs, dabigatran, and rivaroxaban in everyday practice (i.e. baseline characteristics, drug doses, risk factors for bleeding and thromboembolic events). Additionally, we assessed the frequency of prescription of different oral anticoagulants (OACs) in recent years. This study consisted of data from the multicentre CRAFT (MultiCentre expeRience in AFib patients Treated with OAC) study (NCT02987062). This was a retrospective analysis of hospital records of AF patients (hospitalised in the years 2011-2016) treated with VKAs (acenocoumarol, warfarin) and NOACs (dabigatran, rivaroxaban). A total of 3528 patients with non-valvular AF were enrolled in the CRAFT study. The total cohort consisted of 1973 patients on VKA, 504 patients on dabigatran, and 1051 patients on rivaroxaban. Patients on rivaroxaban were older (70.5 ± 13.1 years) and more often female (47.9%), compared with those on VKAs (67.0 ± 12.8 years, p < 0.001; 35.5%, p < 0.001) and on dabigatran (66.0 ± 13.9 years, p < 0.001; 38.9%, p = 0.001). Among NOACs, patients with persistent and permanent AF were more likely to receive rivaroxaban (54.7% and 73.4%, re-spectively) than dabigatran (45.3%, p < 0.001 and 26.6%, p = 0.002, respectively). Patients on rivaroxaban had higher risk of thromboembolic events (CHA2DS2VASc 3.9 ± 2.0, CHADS2 2.2 ± 1.4) than those on VKAs (3.3 ± 2.0, 1.9 ± 1.3) and on dabigatran (3.1 ± 2.0, 1.8 ± 1.3). Patients on rivaroxaban had also a higher rate of prior major bleeding (11.2%) than those on VKAs (6.7%, p < 0.001) and on dabigatran (7.3%, p = 0.02). Patients on lower doses of dabigatran and rivaroxaban had a significantly higher risk of thromboembolic and bleeding events. Use of VKAs in the year 2011 was reported in over 96% of patients on OACs, but this proportion decreased to 34.6% in 2016. In the last analysed year (2016) AF patients were treated mainly with NOACs - dabigatran (24.2%) and rivaroxaban (41.3%). The prescription of VKAs declined significantly after the introduction of NOACs. Patients treated with different OACs demonstrated a distinct baseline clinical profile. The highest risk of thromboembolic events and incidence of major bleedings was observed in patients on rivaroxaban, in comparison to patients on VKAs and dabigatran. Among NOACs, patients treated with lower doses of dabigatran and rivaroxaban were older and had a significantly higher risk of thromboembolic and bleeding events.

Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source.

PubMed

Hart, Robert G; Sharma, Mukul; Mundl, Hardi; Kasner, Scott E; Bangdiwala, Shrikant I; Berkowitz, Scott D; Swaminathan, Balakumar; Lavados, Pablo; Wang, Yongjun; Wang, Yilong; Davalos, Antonio; Shamalov, Nikolay; Mikulik, Robert; Cunha, Luis; Lindgren, Arne; Arauz, Antonio; Lang, Wilfried; Czlonkowska, Anna; Eckstein, Jens; Gagliardi, Rubens J; Amarenco, Pierre; Ameriso, Sebastian F; Tatlisumak, Turgut; Veltkamp, Roland; Hankey, Graeme J; Toni, Danilo; Bereczki, Daniel; Uchiyama, Shinichiro; Ntaios, George; Yoon, Byung-Woo; Brouns, Raf; Endres, Matthias; Muir, Keith W; Bornstein, Natan; Ozturk, Serefnur; O'Donnell, Martin J; De Vries Basson, Matthys M; Pare, Guillaume; Pater, Calin; Kirsch, Bodo; Sheridan, Patrick; Peters, Gary; Weitz, Jeffrey I; Peacock, W Frank; Shoamanesh, Ashkan; Benavente, Oscar R; Joyner, Campbell; Themeles, Ellison; Connolly, Stuart J

2018-06-07

Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001). Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial.

PubMed

Breithardt, Günter; Baumgartner, Helmut; Berkowitz, Scott D; Hellkamp, Anne S; Piccini, Jonathan P; Stevens, Susanna R; Lokhnygina, Yuliya; Patel, Manesh R; Halperin, Jonathan L; Singer, Daniel E; Hankey, Graeme J; Hacke, Werner; Becker, Richard C; Nessel, Christopher C; Mahaffey, Kenneth W; Fox, Keith A A; Califf, Robert M

2014-12-14

We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial. ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55-1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75-1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05-1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94-1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban. Many patients with 'non-valvular atrial fibrillation' have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial

PubMed Central

Breithardt, Günter; Baumgartner, Helmut; Berkowitz, Scott D.; Hellkamp, Anne S.; Piccini, Jonathan P.; Stevens, Susanna R.; Lokhnygina, Yuliya; Patel, Manesh R.; Halperin, Jonathan L.; Singer, Daniel E.; Hankey, Graeme J.; Hacke, Werner; Becker, Richard C.; Nessel, Christopher C.; Mahaffey, Kenneth W.; Fox, Keith A. A.; Califf, Robert M.

2014-01-01

Aims We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial. Methods and results ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55–1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75–1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05–1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94–1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban. Conclusions Many patients with ‘non-valvular atrial fibrillation’ have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants. PMID:25148838

Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF.

PubMed

Hankey, Graeme J; Patel, Manesh R; Stevens, Susanna R; Becker, Richard C; Breithardt, Günter; Carolei, Antonio; Diener, Hans-Christoph; Donnan, Geoffrey A; Halperin, Jonathan L; Mahaffey, Kenneth W; Mas, Jean-Louis; Massaro, Ayrton; Norrving, Bo; Nessel, Christopher C; Paolini, John F; Roine, Risto O; Singer, Daniel E; Wong, Lawrence; Califf, Robert M; Fox, Keith A A; Hacke, Werner

2012-04-01

In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA). In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2·0-3·0). Patients and investigators were masked to treatment allocation. Between Dec 18, 2006, and June 17, 2009, 14 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767. 7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2·79% rivaroxaban vs 2·96% warfarin; hazard ratio [HR] 0·94, 95% CI 0·77-1·16) and those without (1·44%vs 1·88%; 0·77, 0·58-1·01; interaction p=0·23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13·31% rivaroxaban vs 13·87% warfarin; HR 0·96, 95% CI 0·87-1·07) and those without (16·69%vs 15·19%; 1·10, 0·99-1·21; interaction p=0·08). There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF. Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare. Copyright © 2012 Elsevier Ltd. All rights reserved.

Determination of rivaroxaban in patient’s plasma samples by anti-Xa chromogenic test associated to High Performance Liquid Chromatography tandem Mass Spectrometry (HPLC-MS/MS)

PubMed Central

Derogis, Priscilla Bento Matos; Sanches, Livia Rentas; de Aranda, Valdir Fernandes; Colombini, Marjorie Paris; Mangueira, Cristóvão Luis Pitangueira; Katz, Marcelo; Faulhaber, Adriana Caschera Leme; Mendes, Claudio Ernesto Albers; Ferreira, Carlos Eduardo dos Santos; França, Carolina Nunes; Guerra, João Carlos de Campos

2017-01-01

Rivaroxaban is an oral direct factor Xa inhibitor, therapeutically indicated in the treatment of thromboembolic diseases. As other new oral anticoagulants, routine monitoring of rivaroxaban is not necessary, but important in some clinical circumstances. In our study a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was validated to measure rivaroxaban plasmatic concentration. Our method used a simple sample preparation, protein precipitation, and a fast chromatographic run. It was developed a precise and accurate method, with a linear range from 2 to 500 ng/mL, and a lower limit of quantification of 4 pg on column. The new method was compared to a reference method (anti-factor Xa activity) and both presented a good correlation (r = 0.98, p < 0.001). In addition, we validated hemolytic, icteric or lipemic plasma samples for rivaroxaban measurement by HPLC-MS/MS without interferences. The chromogenic and HPLC-MS/MS methods were highly correlated and should be used as clinical tools for drug monitoring. The method was applied successfully in a group of 49 real-life patients, which allowed an accurate determination of rivaroxaban in peak and trough levels. PMID:28170419

Effect of rivaroxaban on preventing deep vein thrombosis in aged diabetics with femoral neck fractures after hip replacement

PubMed Central

Jiang, Xin; Sun, Yan-Shan

2017-01-01

The present study estimates the effect of rivaroxaban on preventing deep vein thrombosis (DVT) in aged diabetics with femoral neck fractures after hip replacement. Our study consisted of 236 aged diabetics with femoral neck fractures, which were divided into the rivaroxaban and control groups. Reaction time (R time), clot formation time (K time), α angle (α), maximum amplitude (MA), clot elasticity (G) and coagulation index (CI), prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured. DVT was diagnosed by color duplex Doppler ultrasound (CDDU). The risk factors of DVT were analysed by logistic regression analysis. Compared with the control group, in the rivaroxaban group, R time and K time were extended and α, MA and G decreased 1 day before operation. One day after operation, the rivaroxaban group had less PT and APPT and lower incidence of DVT than the control group. In the two groups, preoperative and postoperative PT and APPT significantly differed. Body mass index (BMI) ≥25, abnormal coagulation indicators, use of cemented femoral hip prosthesis, high haemoglobin content and non-ankle pump exercise after operation were the risk factors for DVT. Rivaroxaban could prevent DVT in aged diabetics with femoral neck fractures after hip replacement. PMID:28442600

Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban-an oral, direct Factor Xa inhibitor.

PubMed

Burghaus, Rolf; Coboeken, Katrin; Gaub, Thomas; Niederalt, Christoph; Sensse, Anke; Siegmund, Hans-Ulrich; Weiss, Wolfgang; Mueck, Wolfgang; Tanigawa, Takahiko; Lippert, Jörg

2014-01-01

The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2-3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban.

Effect of the FXa inhibitors Rivaroxaban and Apixaban on platelet activation in patients with atrial fibrillation.

PubMed

Steppich, B; Dobler, F; Brendel, L C; Hessling, G; Braun, S L; Steinsiek, A L; Deisenhofer, I; Hyseni, A; Roest, M; Ott, I

2017-05-01

Rivaroxaban and Apixaban, increasingly used for stroke prevention in non-valvular atrial fibrillation (AF), might impact platelet reactivity directly or indirectly. By inhibition of Factor Xa (FXa) they preclude not only generation of relevant thrombin amounts but also block signalling of FXa via protease activated receptors. However, weather FXa-inhibition affects platelet haemostasis remains incompletely known. One hundred and twenty-eight patients with AF on chronic anticoagulation with either Rivaroxaban or Apixaban for at least 4 weeks were included in the study. In a time course group (25 on Rivaroxaban, 13 on Apixaban) venous blood samples were taken before NOAC medication intake in the morning as well as 2 and 6 h afterwards. In 90 patients (Rivaroxaban n = 73, Apixaban n = 17) blood samples were drawn during left atrial RFA procedures before as well as 10 and 60 min after the first heparin application (RFA group). Platelet reactivity analyzed by whole blood aggregometry (Multiplate Analyzer, Roche) in response to ADP, Collagen, TRAP and ASPI (arachidonic acid) was not altered by Rivaroxaban or Apixaban neither in the time course nor in the RFA group. Moreover, soluble P-selectin, Thrombospondin, von Willebrand Factor and beta thromboglobulin plasma levels, measured by ELISA, showed no statistically significant changes in both clinical settings for either FXa-inhibitor. The present study fails to demonstrate any significant changes on platelet reactivity in patients with AF under chronic Rivaroxaban or Apixaban medication, neither for trough or peak levels nor in case of a haemostatic activation in vivo as depicted by RFA procedures.

Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry

PubMed Central

Förster, Kati; Pannach, Sven; Ebertz, Franziska; Gelbricht, Vera; Thieme, Christoph; Michalski, Franziska; Köhler, Christina; Werth, Sebastian; Sahin, Kurtulus; Tittl, Luise; Hänsel, Ulrike; Weiss, Norbert

2014-01-01

Worldwide, rivaroxaban is increasingly used for stroke prevention in atrial fibrillation and treatment of venous thromboembolism, but little is known about rivaroxaban-related bleeding complications in daily care. Using data from a prospective, noninterventional oral anticoagulation registry of daily care patients (Dresden NOAC registry), we analyzed rates, management, and outcome of rivaroxaban-related bleeding. Between October 1, 2011, and December 31, 2013, 1776 rivaroxaban patients were enrolled. So far, 762 patients (42.9%) reported 1082 bleeding events during/within 3 days after last intake of rivaroxaban (58.9% minor, 35.0% of nonmajor clinically relevant, and 6.1% major bleeding according to International Society on Thrombosis and Haemostasis definition). In case of major bleeding, surgical or interventional treatment was needed in 37.8% and prothrombin complex concentrate in 9.1%. In the time-to-first-event analysis, 100-patient-year rates of major bleeding were 3.1 (95% confidence interval 2.2-4.3) for stroke prevention in atrial fibrillation and 4.1 (95% confidence interval 2.5-6.4) for venous thromboembolism patients, respectively. In the as-treated analysis, case fatality rates of bleeding leading to hospitalizations were 5.1% and 6.3% at days 30 and 90 after bleeding, respectively. Our data indicate that, in real life, rates of rivaroxaban-related major bleeding may be lower and that the outcome may at least not be worse than that of major vitamin K antagonist bleeding, and probably better. This trial was registered at www.clinicaltrials.gov as identifier #NCT01588119. PMID:24859362

Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects

PubMed Central

Kubitza, Dagmar; Becka, Michael; Mück, Wolfgang; Krätzschmar, Jöern

2014-01-01

Aims This study investigated relevant pharmacodynamic and pharmacokinetic parameters during the transition from warfarin to rivaroxaban in healthy male subjects. Methods Ninety-six healthy men were randomized into the following three groups: warfarin [international normalized ratio (INR) 2.0–3.0] transitioned to rivaroxaban 20 mg once daily (od; group A); warfarin (INR 2.0–3.0) followed by placebo od (group B); and rivaroxaban alone 20 mg od (group C) for 4 days. Anti-factor Xa activity, inhibition of factor Xa activity, prothrombin time (PT), activated partial thromboplastin time, HepTest, prothrombinase-induced clotting time, factor VIIa activity, factor IIa activity, endogenous thrombin potential and pharmacokinetics were measured. Results An additive effect was observed on the PT and PT/INR during the initial transition period. The mean maximal prolongation of PT was 4.39-fold [coefficient of variation (CV) 18.03%; range 3.39–6.50] of the baseline value in group A, compared with 1.88-fold (CV 10.35%; range 1.53–2.21) in group B and 1.57-fold (CV 9.98%; range 1.37–2.09) in group C. Rivaroxaban had minimal influence on the PT/INR at trough levels. Inhibition of factor Xa activity, activated partial thromboplastin time and endogenous thrombin potential were also enhanced, but to a lesser extent. In contrast, the effects of rivaroxaban on anti-factor Xa activity, HepTest and prothrombinase-induced clotting time were not affected by pretreatment with warfarin. Conclusions Changes in pharmacodynamics during the transition from warfarin to rivaroxaban vary depending on the test used. A supra-additive effect on PT/INR is expected during the initial period of transition, but pretreatment with warfarin does not influence the effect of rivaroxaban on anti-factor Xa activity. PMID:24528331

Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation.

PubMed

Yao, Xiaoxi; Abraham, Neena S; Sangaralingham, Lindsey R; Bellolio, M Fernanda; McBane, Robert D; Shah, Nilay D; Noseworthy, Peter A

2016-06-13

The introduction of non-vitamin K antagonist oral anticoagulants has been a major advance for stroke prevention in atrial fibrillation; however, outcomes achieved in clinical trials may not translate to routine practice. We aimed to evaluate the effectiveness and safety of dabigatran, rivaroxaban, and apixaban by comparing each agent with warfarin. Using a large US insurance database, we identified privately insured and Medicare Advantage patients with nonvalvular atrial fibrillation who were users of apixaban, dabigatran, rivaroxaban, or warfarin between October 1, 2010, and June 30, 2015. We created 3 matched cohorts using 1:1 propensity score matching: apixaban versus warfarin (n=15 390), dabigatran versus warfarin (n=28 614), and rivaroxaban versus warfarin (n=32 350). Using Cox proportional hazards regression, we found that for stroke or systemic embolism, apixaban was associated with lower risk (hazard ratio [HR] 0.67, 95% CI 0.46-0.98, P=0.04), but dabigatran and rivaroxaban were associated with a similar risk (dabigatran: HR 0.98, 95% CI 0.76-1.26, P=0.98; rivaroxaban: HR 0.93, 95% CI 0.72-1.19, P=0.56). For major bleeding, apixaban and dabigatran were associated with lower risk (apixaban: HR 0.45, 95% CI 0.34-0.59, P<0.001; dabigatran: HR 0.79, 95% CI 0.67-0.94, P<0.01), and rivaroxaban was associated with a similar risk (HR 1.04, 95% CI 0.90-1.20], P=0.60). All non-vitamin K antagonist oral anticoagulants were associated with a lower risk of intracranial bleeding. In patients with nonvalvular atrial fibrillation, apixaban was associated with lower risks of both stroke and major bleeding, dabigatran was associated with similar risk of stroke but lower risk of major bleeding, and rivaroxaban was associated with similar risks of both stroke and major bleeding in comparison to warfarin. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Comparison of Adherence to Rivaroxaban Versus Apixaban Among Patients With Atrial Fibrillation.

PubMed

McHorney, Colleen A; Peterson, Eric D; Laliberté, François; Germain, Guillaume; Nelson, Winnie W; Crivera, Concetta; Schein, Jeffrey; Lefebvre, Patrick

2016-11-01

Non-vitamin K antagonist oral anticoagulant medications are increasingly used for stroke prophylaxis in patients with nonvalvular atrial fibrillation (NVAF). This study aimed to compare adherence with rivaroxaban and apixaban among patients with NVAF in routine clinical practice. Using pharmacy and medical claims from Truven Health Analytics MarketScan databases, we identified NVAF patients aged ≥18 years treated with rivaroxaban or apixaban. Baseline demographic and clinical features were balanced using 1:1 propensity score matching. Adherence to therapy was measured at 90 and 180 days post-index date and was defined by the proportion of days covered (PDC) ≥0.80 and PDC ≥0.90. "Gaps in care," defined as those with 10 or more day gaps in supply, were also evaluated. Between June 2012 and April 2014, 11,477 rivaroxaban and 2992 apixaban users were identified. Baseline characteristics for rivaroxaban and apixaban users were well matched. Relative to apixaban users, rivaroxaban users were more likely to have a PDC ≥0.80 at both 90 days (85.3% vs 79.9%; P < 0.001) and 180 days (75.8% vs 72.2%; P = 0.001). Similar results were observed with PDC ≥0.90. The proportion of patients with at least one 5+ and 10+ day gap in prescriptions was significantly lower in the rivaroxaban versus apixaban cohorts: 54.2% versus 62.4% (P < 0.001) and 40.0% versus 49.2% (P < 0.001), respectively. Adherence to non-vitamin K antagonist oral anticoagulants among NVAF patients is less than ideal, and gaps in treatment are common. Those on once-a-day rivaroxaban had significantly higher adherence and fewer gaps in treatment compared with twice-a-day apixaban. Future studies are needed to explore whether these treatment differences affect comparative patient outcomes. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Rivaroxaban: An Affordable and Effective Alternative in Cancer-Related Thrombosis?

PubMed Central

Hoff, Paulo Marcelo Gehm; Braghiroli, Maria Ignez; Paterlini, Ana Carolina Carvalho Rocha; Souza, Karla Teixeira; Faria, Luiza Dib Batista Bugiato; Ferreira, Fernando Sergio Blumm; Machado, Karime Kalil; Fernandes, Gustavo dos Santos

2017-01-01

Background Venous thromboembolic events (VTEs) are common and potentially fatal complications in cancer patients, and they are responsible for the second most common cause of death. Low molecular weight heparin (LMWH) is the gold-standard treatment, but the costs involved limit its use, especially in developing countries. Recently, the oral anticoagulant rivaroxaban, which directly inhibits factor Xa, was approved for VTE treatment. Methods We conducted a retrospective analysis from January 2009 to February 2014 with patients who had cancer and VTE who were receiving rivaroxaban. We compared the efficacy, safety, and cost of rivaroxaban and low molecular weight heparin (LMWH) alone or followed by vitamin K antagonists. Results Forty-one patients were identified, with a median age of 62.5 years. The most frequent tumor histology was adenocarcinoma (78%), which was most often found in the colon (26.8%). Most participants had advanced disease and an implanted central venous catheter. Patients’ VTE risk-assessment scores were low (12.5%), intermediate (50%), and high (35.5%). Pulmonary thromboembolism was reported in 41.4% of patients, but inferior limb thrombosis was reported only in 14.6%; 43.9% of patients received enoxaparin before starting rivaroxaban. Rivaroxaban was used for a median time of 5.5 months. Nonmajor bleeding was reported in 12.2% of patients, and rethrombosis was reported in 12.2%. In our study, rivaroxaban was as safe and effective as enoxaparin/vitamin K antagonists (P = .54 and P = .25, respectively) or LMWH (P = .46 and P = .29, respectively). Conclusion Although our study was a retrospective analysis, our results suggest that in this cohort of oncologic patients, rivaroxaban was safe and effective. Its oral route and lower cost make it an attractive alternative to LMWH, improving management of patients with cancer in low-income countries. Additional studies are necessary to confirm our data. PMID:28717737

A RCT study of Rivaroxaban, low-molecular-weight heparin, and sequential medication regimens for the prevention of venous thrombosis after internal fixation of hip fracture.

PubMed

Tang, Yilun; Wang, Kunzheng; Shi, Zhibin; Yang, Pei; Dang, Xiaoqian

2017-08-01

The guidelines for the prevention of venous thromboembolism in orthopedic surgeries have reached a consensus on the postoperative conventional anticoagulation. However, the choice of anticoagulant drugs is yet controversial. The use of the drug rivaroxaban is expensive. Since the compliance of patients with low-molecular-weight heparin is considerably low, a cost-effective, efficacious and convenient anticoagulant program is essential. The present study investigated the efficacy, safety, patient compliance, and cost-effectiveness of low-molecular-weight heparin with sequential Rivaroxaban anticoagulant therapy in patients with a hip fracture, following internal fixation. A total of 287 patients with hip fractures were randomized into three groups: Rivaroxaban alone, Enoxaparin alone, and Enoxaparin followed by Rivaroxaban. The primary endpoint was the incidence of postoperative VTE, whereas the secondary endpoints were the compliance and treatment costs. Adverse reactions included bleeding and wound complications. The incidences of VTE were 5.21%, 14.74%, and 10.42% in the Rivaroxaban, low-molecular-weight heparin, and sequential therapy groups, respectively. The VTE-related mortality rates were 0%, 1.05%, and 1.04%. The average hospital stay was 12±8,15±7, and 11±5d, whereas the compliance rates of the three groups were 82.3%, 71.6%, and 88.5%, respectively. The incidences of adverse incisions were 14.6%, 4.2%, and 6.3% for the three groups examined. The effects and the incidence of postoperative bleeding in the treatment of low-molecular-weight heparin followed by Rivaroxaban did not differ significantly from that of Rivaroxaban alone. However, the postoperative drainage, the cost of treatment and the incidence of VTE reduced significantly, whereas the incidences of adverse incisions and the patient compliance were increased. ChiCTR-INR-17010495. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin: Insights From ROCKET AF.

PubMed

Fordyce, Christopher B; Hellkamp, Anne S; Lokhnygina, Yuliya; Lindner, Samuel M; Piccini, Jonathan P; Becker, Richard C; Berkowitz, Scott D; Breithardt, Günter; Fox, Keith A A; Mahaffey, Kenneth W; Nessel, Christopher C; Singer, Daniel E; Patel, Manesh R

2016-07-05

Despite rapid clinical adoption of novel anticoagulants, it is unknown whether outcomes differ among patients with worsening renal function (WRF) taking these new drugs compared with warfarin. We aimed to determine whether the primary efficacy (stroke or systemic embolism) and safety (major bleeding and nonmajor clinically relevant bleeding) end points from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial) differed among participants with WRF taking rivaroxaban and those taking warfarin. After excluding patients without at least 1 follow-up creatinine measurement (n=1624), we included all remaining patients (n=12 612) randomly assigned to either rivaroxaban or dose-adjusted warfarin. On-treatment WRF (a decrease of >20% from screening creatinine clearance measurement at any time point during the study) was evaluated as a time-dependent covariate in Cox proportional hazards models. Baseline characteristics were generally similar between patients with stable renal function (n=9292) and WRF (n=3320). Rates of stroke or systemic embolism, myocardial infarction, and bleeding were also similar, but WRF patients experienced a higher incidence of vascular death versus stable renal function (2.21 versus 1.41 events per 100 patient-years; P=0.026). WRF patients who were randomized to receive rivaroxaban had a reduction in stroke or systemic embolism compared with those taking warfarin (1.54 versus 3.25 events per 100 patient-years) that was not seen in patients with stable renal function who were randomized to receive rivaroxaban (P=0.050 for interaction). There was no difference in major or nonmajor clinically relevant bleeding among WRF patients randomized to warfarin versus rivaroxaban. Among patients with on-treatment WRF, rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin, without an increase in the composite bleeding end point. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767. © 2016 American Heart Association, Inc.

Safety and efficacy of rivaroxaban compared with warfarin in patients undergoing peripheral arterial procedures.

PubMed

Talukdar, Anjan; Wang, S Keisin; Czosnowski, Lauren; Mokraoui, Nassim; Gupta, Alok; Fajardo, Andres; Dalsing, Michael; Motaganahalli, Raghu

2017-10-01

Rivaroxaban is a United States Food and Drug Administration-approved oral anticoagulant for venous thromboembolic disease; however, there is no information regarding the safety and its efficacy to support its use in patients after open or endovascular arterial interventions. We report the safety and efficacy of rivaroxaban vs warfarin in patients undergoing peripheral arterial interventions. This single-institution retrospective study analyzed all sequential patients from December 2012 to August 2014 (21 months) who were prescribed rivaroxaban or warfarin after a peripheral arterial procedure. Our study population was then compared using American College of Chest Physicians guidelines with patients then stratified as low, medium, or high risk for bleeding complications. Statistical analyses were performed using the Student t-test and χ 2 test to compare demographics, readmissions because of bleeding, and the need for secondary interventions. Logistic regression models were used for analysis of variables associated with bleeding complications and secondary interventions. The Fisher exact test was used for power analysis. There were 44 patients in the rivaroxaban group and 50 patients in the warfarin group. Differences between demographics and risk factors for bleeding between groups or reintervention rate were not statistically significant (P = .297). However, subgroup evaluation of the safety profile suggests that patients who were aged ≤65 years and on warfarin had an overall higher incidence of major bleeding (P = .020). Patients who were aged >65 years, undergoing open operation, had a significant risk for reintervention (P = .047) when they received rivaroxaban. Real-world experience using rivaroxaban and warfarin in patients after peripheral arterial procedures suggests a comparable safety and efficacy profile. Subgroup analysis of those requiring an open operation demonstrated a decreased bleeding risk when rivaroxaban was used (in those aged <65 years) but an increased risk for secondary interventions. Further studies with a larger cohort are required to validate our results. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.

PubMed

Büller, Harry R; Prins, Martin H; Lensin, Anthonie W A; Decousus, Hervé; Jacobson, Barry F; Minar, Erich; Chlumsky, Jaromir; Verhamme, Peter; Wells, Phil; Agnelli, Giancarlo; Cohen, Alexander; Berkowitz, Scott D; Bounameaux, Henri; Davidson, Bruce L; Misselwitz, Frank; Gallus, Alex S; Raskob, Gary E; Schellong, Sebastian; Segers, Annelise

2012-04-05

A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism. In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups. A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.).

Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty.

PubMed

Anderson, David R; Dunbar, Michael; Murnaghan, John; Kahn, Susan R; Gross, Peter; Forsythe, Michael; Pelet, Stephane; Fisher, William; Belzile, Etienne; Dolan, Sean; Crowther, Mark; Bohm, Eric; MacDonald, Steven J; Gofton, Wade; Kim, Paul; Zukor, David; Pleasance, Susan; Andreou, Pantelis; Doucette, Steve; Theriault, Chris; Abianui, Abongnwen; Carrier, Marc; Kovacs, Michael J; Rodger, Marc A; Coyle, Doug; Wells, Philip S; Vendittoli, Pascal-Andre

2018-02-22

Clinical trials and meta-analyses have suggested that aspirin may be effective for the prevention of venous thromboembolism (proximal deep-vein thrombosis or pulmonary embolism) after total hip or total knee arthroplasty, but comparisons with direct oral anticoagulants are lacking for prophylaxis beyond hospital discharge. We performed a multicenter, double-blind, randomized, controlled trial involving patients who were undergoing total hip or knee arthroplasty. All the patients received once-daily oral rivaroxaban (10 mg) until postoperative day 5 and then were randomly assigned to continue rivaroxaban or switch to aspirin (81 mg daily) for an additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty. Patients were followed for 90 days for symptomatic venous thromboembolism (the primary effectiveness outcome) and bleeding complications, including major or clinically relevant nonmajor bleeding (the primary safety outcome). A total of 3424 patients (1804 undergoing total hip arthroplasty and 1620 undergoing total knee arthroplasty) were enrolled in the trial. Venous thromboembolism occurred in 11 of 1707 patients (0.64%) in the aspirin group and in 12 of 1717 patients (0.70%) in the rivaroxaban group (difference, 0.06 percentage points; 95% confidence interval [CI], -0.55 to 0.66; P<0.001 for noninferiority and P=0.84 for superiority). Major bleeding complications occurred in 8 patients (0.47%) in the aspirin group and in 5 (0.29%) in the rivaroxaban group (difference, 0.18 percentage points; 95% CI, -0.65 to 0.29; P=0.42). Clinically important bleeding occurred in 22 patients (1.29%) in the aspirin group and in 17 (0.99%) in the rivaroxaban group (difference, 0.30 percentage points; 95% CI, -1.07 to 0.47; P=0.43). Among patients who received 5 days of rivaroxaban prophylaxis after total hip or total knee arthroplasty, extended prophylaxis with aspirin was not significantly different from rivaroxaban in the prevention of symptomatic venous thromboembolism. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT01720108 .).

Nontraumatic spinal subdural hematoma complicating direct factor Xa inhibitor treatment (rivaroxaban): a challenging management.

PubMed

Dargazanli, Cyril; Lonjon, Nicolas; Gras-Combe, Guillaume

2016-05-01

We report on a 72-year-old male patient who developed a nontraumatic spinal subdural hematoma (SSDH) during rivaroxaban therapy, a relatively new orally administered direct factor Xa inhibitor. The patient sustained a sudden onset of interscapular pain, followed by gait impairment and paraplegia. Magnetic resonance imaging (MRI) of the spine demonstrated SSDH from T6 to T8. Laboratory tests revealed a high rivaroxaban level, associated with a major hemorrhagic risk. Surgery was, therefore, performed the following morning, after normalization of coagulation parameters. Determining the time of safe surgery remains challenging when hemorrhagic complications happen with direct factor Xa inhibitor, especially when neurological prognosis is engaged. Spinal subdural hematoma has not previously been reported following rivaroxaban therapy.

Discontinuation risk comparison among 'real-world' newly anticoagulated atrial fibrillation patients: Apixaban, warfarin, dabigatran, or rivaroxaban.

PubMed

Lip, Gregory Y H; Pan, Xianying; Kamble, Shital; Kawabata, Hugh; Mardekian, Jack; Masseria, Cristina; Phatak, Hemant

2018-01-01

Discontinuation of oral anticoagulants may expose non-valvular atrial fibrillation (NVAF) patients to an increased risk of stroke. This study describes the real-world discontinuation rates and compared the risk of drug discontinuation among NVAF patients initiating apixaban, warfarin, dabigatran, or rivaroxaban. This retrospective cohort study evaluated newly-anticoagulated NVAF patients in the MarketScan® data population from 01/01/2012 through 12/31/2014. Discontinuation was defined as a lack of subsequent prescription of the index drug within 30 days after the last supply day of the last prescription. A Cox model was used to estimate the hazard ratio (HR) of discontinuation, adjusted for age, sex, and comorbidities. Among 45,361 eligible NVAF patients, 15,461 (34.1%) initiated warfarin; 7,438 (16.4%) apixaban; 4,661 (10.3%) dabigatran; and 17,801 (39.2%) initiated rivaroxaban treatment. Compared to warfarin, patients who initiated dabigatran (adjusted HR [aHR]: 0.84, 95% confidence interval [CI]: 0.80-0.87, P<0.001), rivaroxaban (aHR: 0.70, 95% CI: 0.68-0.73, P<0.001), or apixaban (aHR: 0.57, 95% CI: 0.55-0.60, P<0.001) were 16%, 30%, and 43% less likely to discontinue treatment, respectively. When compared to apixaban, patients who initiated dabigatran (aHR: 1.46, 95% CI: 1.38-1.54, P<0.001) or rivaroxaban (aHR: 1.23, 95% CI: 1.17-1.28, P<0.001) were more likely to discontinue treatment. Among newly-anticoagulated NVAF patients in the real-world setting, initiation on rivaroxaban, dabigatran, or apixaban was associated with a significantly lower risk of discontinuation compared to warfarin. When compared to apixaban, patients who initiated treatment with warfarin, dabigatran, or rivaroxaban were more likely to discontinue treatment.

Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies.

PubMed

Prins, Martin H; Lensing, Anthonie Wa; Bauersachs, Rupert; van Bellen, Bonno; Bounameaux, Henri; Brighton, Timothy A; Cohen, Alexander T; Davidson, Bruce L; Decousus, Hervé; Raskob, Gary E; Berkowitz, Scott D; Wells, Philip S

2013-09-20

Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects. A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15 mg twice-daily for 21 days, followed by 20 mg once-daily) with standard-therapy (enoxaparin 1.0 mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12 months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75. A total of 8282 patients were enrolled; 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 (2.1%) rivaroxaban-treated patients compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66-1.19; pnoninferiority < 0.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37-0.79; p = 0.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots, and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban were similar compared with standard-therapy. The single-drug approach with rivaroxaban resulted in similar efficacy to standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups. ClinicalTrials.gov, NCT00439777; EINSTEIN-DVT: ClinicalTrials.gov, NCT00440193.

Comparison of the Effectiveness and Safety of Apixaban, Dabigatran, Rivaroxaban, and Warfarin in Newly Diagnosed Atrial Fibrillation.

PubMed

Hernandez, Inmaculada; Zhang, Yuting; Saba, Samir

2017-11-15

No studies have performed direct pairwise comparisons of the effectiveness and safety of warfarin and the new oral anticoagulants (NOACs) apixaban, dabigatran, and rivaroxaban. Using 2013 to 2014 claims from a 5% random sample of Medicare beneficiaries, we identified patients newly diagnosed with atrial fibrillation who initiated apixaban, dabigatran, rivaroxaban, warfarin, or no oral anticoagulation therapy in 2013 to 2014. Outcomes included the composite of ischemic stroke, systemic embolism (SE) and death, any bleeding event, gastrointestinal bleeding, intracranial bleeding, and treatment persistence. We constructed Cox proportional hazard models to compare outcomes between each pair of treatment groups. The composite risk of ischemic stroke, SE, and death was lower for NOACs than for warfarin: hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76 to 0.98 for apixaban; 0.73, 95% CI 0.63 to 0.86 for dabigatran; and 0.82, 95% CI 0.75 to 0.89 for rivaroxaban, all compared with warfarin. There were no differences in effectiveness across NOACs. The risk of any bleeding was lower with apixaban than with warfarin, but higher with rivaroxaban than with warfarin. Apixaban (HR 0.69, 95% CI 0.60 to 0.79) and dabigatran (HR 0.79, 95% CI 0.69 to 0.92) were associated with lower bleeding risk than rivaroxaban. Treatment persistence was highest for apixaban (82%), and lowest for dabigatran and warfarin (64%) (p value <0.001). Compared with warfarin, NOACs are more effective in preventing stroke but their risk of bleeding varies, with rivaroxaban having higher risk than warfarin. Altogether, apixaban had the most favorable effectiveness, safety, and persistence profile. Copyright © 2017 Elsevier Inc. All rights reserved.

Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review.

PubMed

Warkentin, Theodore E; Pai, Menaka; Linkins, Lori-Ann

2017-08-31

Direct oral anticoagulants (DOACs) are attractive options for treatment of heparin-induced thrombocytopenia (HIT). We report our continuing experience in Hamilton, ON, Canada, since January 1, 2015 (when we completed our prospective study of rivaroxaban for HIT), using rivaroxaban for serologically confirmed HIT (4Ts score ≥4 points; positive platelet factor 4 [PF4]/heparin immunoassay, positive serotonin-release assay). We also performed a literature review of HIT treatment using DOACs (rivaroxaban, apixaban, dabigatran, edoxaban). We focused on patients who received DOAC therapy for acute HIT as either primary therapy (group A) or secondary therapy (group B; initial treatment using a non-DOAC/non-heparin anticoagulant with transition to a DOAC during HIT-associated thrombocytopenia). Our primary end point was occurrence of objectively documented thrombosis during DOAC therapy for acute HIT. We found that recovery without new, progressive, or recurrent thrombosis occurred in all 10 Hamilton patients with acute HIT treated with rivaroxaban. Data from the literature review plus these new data identified a thrombosis rate of 1 of 46 patients (2.2%; 95% CI, 0.4%-11.3%) in patients treated with rivaroxaban during acute HIT (group A, n = 25; group B, n = 21); major hemorrhage was seen in 0 of 46 patients. Similar outcomes in smaller numbers of patients were observed with apixaban (n = 12) and dabigatran (n = 11). DOACs offer simplified management of selected patients, as illustrated by a case of persisting (autoimmune) HIT (>2-month platelet recovery with inversely parallel waning of serum-induced heparin-independent serotonin release) with successful outpatient rivaroxaban management of HIT-associated thrombosis. Evidence supporting efficacy and safety of DOACs for acute HIT is increasing, with the most experience reported for rivaroxaban. © 2017 by The American Society of Hematology.

[Rivaroxaban versus standard of care in venous thromboembolism prevention following hip or knee arthroplasty in daily clinical practice (Spanish data from the international study XAMOS)].

PubMed

Granero, J; Díaz de Rada, P; Lozano, L M; Martínez, J; Herrera, A

2016-01-01

To analyse the effectiveness and safety of rivaroxaban vs. standard treatment (ST) in the prevention of venous thromboembolism after hip or knee replacement in daily clinical practice in Spain. A sub-analysis of the Spanish data in the XAMOS international observational study that included patients>18 years who received 10mg o.d. rivaroxaban or ST. up to 3 months after surgery. incidence of symptomatic/asymptomatic thromboembolic events, bleeding, mortality, and other adverse events; use of health resources and satisfaction after hospital discharge. Of the total 801 patients included, 410 received rivaroxaban and 391 ST (64.7% heparin, 24.0% fondaparinux, 11% dabigatran). The incidence of symptomatic thromboembolic events and major bleeding was similar in both groups (0.2% vs. 0.8% wit ST and 0.7% vs. 1.3% with ST [EMA criteria]/0.0% vs. 0.3% with ST [RECORD criteria]). The adverse events incidence associated with the drug was significantly higher rivaroxaban (overall: 4.4% vs. 0.8% with ST, P=.001; serious: 1.5% vs. 0.0% with ST, P=.03). The rivaroxaban used less health resources after discharge, and the majority considered the tolerability as «very good« and the treatment as «very comfortable». Rivaroxaban is at least as effective as ST in the prevention of venous thromboembolism prevention in daily clinical practice, with a similar incidence of haemorrhages. It provides greater satisfaction/comfort, and less health resources after discharge. These results should be interpreted taking into account the limitations inherent in observational studies. Copyright © 2014 SECOT. Published by Elsevier Espana. All rights reserved.

Rivaroxaban in the Prevention of Stroke and Systemic Embolism in Patients with Non-Valvular Atrial Fibrillation: Clinical Implications of the ROCKET AF Trial and Its Subanalyses.

PubMed

Spencer, Ryan J; Amerena, John V

2015-12-01

Atrial fibrillation (AF) is an increasingly common cause of stroke and systemic embolism. While warfarin has been the mainstay of stroke prevention in patients with AF, newer novel oral anticoagulant medications are now available. Rivaroxaban, a direct factor Xa inhibitor with a rapid onset and offset after oral administration, offers potential advantages over warfarin, predominantly due to its predictable pharmacokinetics across wide patient populations. It requires no coagulation monitoring, and only two different doses are needed (20 mg daily for patients with normal renal function and 15 mg daily in those with reduced renal function). A large randomized trial (ROCKET AF) has shown non-inferiority to warfarin for preventing stroke or systemic embolism in the per-protocol population and superiority to warfarin in the on-treatment safety population. Several subanalyses confirm that the treatment effect of rivaroxaban is consistent across different patient subgroups, including those with reduced renal function. The tolerability of rivaroxaban appears similar to that of warfarin, with comparable overall bleeding rates in clinical trials. In ROCKET AF, significantly lower rates of fatal and intracranial bleeding were seen with rivaroxaban, while lower rates of gastrointestinal bleeding were seen with warfarin. Important contraindications to rivaroxaban include valvular AF, the presence of a prosthetic valve (mechanical or bioprosthetic) or valve repair, the need for concurrent dual antiplatelet therapy, and creatinine clearance <30 ml/min. Once-daily dosing and the lack of coagulation monitoring may increase utilization and adherence compared with warfarin, potentially decreasing the large burden of care associated with stroke secondary to AF. Overall, rivaroxaban offers a useful alternative to warfarin for stroke prevention in patients with AF.

Rivaroxaban versus warfarin in Japanese patients with non-valvular atrial fibrillation in relation to hypertension: a subgroup analysis of the J-ROCKET AF trial.

PubMed

Matsumoto, Masayasu; Hori, Masatsugu; Tanahashi, Norio; Momomura, Shin-Ichi; Uchiyama, Shinichiro; Goto, Shinya; Izumi, Tohru; Koretsune, Yukihiro; Kajikawa, Mariko; Kato, Masaharu; Ueda, Hitoshi; Iekushi, Kazuma; Yamanaka, Satoshi; Tajiri, Masahiro

2014-05-01

The majority of the patients enrolled in the rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial had hypertension. In this subgroup analysis, we investigated differences in the safety and efficacy of rivaroxaban and warfarin in subjects with and without hypertension. The baseline blood pressure (BP) measurements of patients with hypertension in the rivaroxaban and warfarin groups were 130/77 mm Hg and 131/77 mm Hg, respectively, whereas those of patients without hypertension were 123/74 mm Hg and 124/73 mm Hg, respectively. The incidence rates of the principal safety outcomes in the rivaroxaban and warfarin groups were 18.39% per year and 16.81% per year, respectively, among patients with baseline hypertension (hazard ratio (HR): 1.10; 95% confidence interval (CI): 0.84-1.45) and 16.71% per year and 15.00% per year, respectively, among patients without hypertension at baseline (HR: 1.14; 95% CI: 0.66-1.97), indicating no significant interaction (P=0.933). The incidence rates of the primary efficacy endpoints in the rivaroxaban group and the warfarin group were 0.54% per year and 2.24% per year, respectively, in patients without baseline hypertension (HR: 0.25; 95% CI: 0.03-2.25), and 1.45% per year and 2.71% per year, respectively, in patients with baseline hypertension (HR: 0.54; 95% CI: 0.25-1.16), indicating no significant interaction (P=0.509). In conclusion, the safety and efficacy profile of rivaroxaban was similar to that of warfarin, independent of baseline hypertensive status.

Comparative risks of bleeding, ischemic stroke and mortality with direct oral anticoagulants versus phenprocoumon in patients with atrial fibrillation.

PubMed

Ujeyl, Mariam; Köster, Ingrid; Wille, Hans; Stammschulte, Thomas; Hein, Rebecca; Harder, Sebastian; Gundert-Remy, Ursula; Bleek, Julian; Ihle, Peter; Schröder, Helmut; Schillinger, Gerhard; Zawinell, Anette; Schubert, Ingrid

2018-06-16

The pivotal trials for stroke prevention in non-valvular atrial fibrillation (NVAF) compared rivaroxaban, dabigatran, and apixaban with warfarin, as did most claims-based studies. Comparisons with phenprocoumon, the most frequently used vitamin K antagonist (VKA) in Germany, are scarce. Risk of bleeding, ischemic stroke, and all-cause mortality in patients with NVAF were analyzed using data for 2010 to 2014 from a large German claims database. New users of oral anticoagulants from January 2012 to December 2013 were included and observed over 1 year. Baseline characteristics were adjusted using propensity score matching and logistic regression. Several sensitivity analyses were carried out. Fifty-nine thousand four hundred forty-nine rivaroxaban, 23,654 dabigatran, 4894 apixaban, and 87,997 matched phenprocoumon users were included. Adjusted hazard ratios (95% confidence intervals) compared with phenprocoumon were as follows: hospitalized bleedings: rivaroxaban 1.04 (0.97; 1.11), dabigatran 0.87 (0.77; 0.98), and apixaban 0.65 (0.50; 0.86); ischemic stroke: rivaroxaban 1.05 (0.94; 1.17), dabigatran 1.14 (0.96; 1.35), and apixaban 1.84 (1.20; 2.84); all-cause mortality: rivaroxaban 1.17 (1.11; 1.22), dabigatran 1.04 (0.95; 1.13), and apixaban 1.14 (0.97; 1.34). With rivaroxaban, no significant differences were observed compared to phenprocoumon with regard to hospitalized bleedings or ischemic strokes. Dabigatran was associated with fewer bleedings and a similar risk of ischemic strokes compared to phenprocoumon. Apixaban was also associated with fewer bleedings but was unexpectedly associated with more ischemic strokes, possibly reflecting selective prescribing. The association of rivaroxaban with higher all-cause mortality unrelated to bleedings or strokes has been described previously but remains to be explained.

Thromboembolic and Major Bleeding Events With Rivaroxaban Versus Warfarin Use in a Real-World Setting.

PubMed

Russo-Alvarez, Giavanna; Martinez, Kathryn A; Valente, Megan; Bena, James; Hu, Bo; Luxenburg, Jennifer; Chaitoff, Alexander; Ituarte, Catherine; Brateanu, Andrei; Rothberg, Michael B

2018-01-01

Although randomized trials demonstrate the noninferiority of rivaroxaban compared with warfarin in the context of nonvalvular atrial fibrillation (AF), little is known about how these drugs compare in practice. To assess the relative effectiveness and safety of rivaroxaban versus warfarin in a large health system and to evaluate this association by time in therapeutic range (TTR). We conducted a retrospective cohort study with propensity matching in the Cleveland Clinic Health System. The study included patients initiated on warfarin or rivaroxaban for thromboembolic prevention in nonvalvular AF between January 2012 and July 2016. The main outcomes were thromboembolic events and major bleeds. Analyses were stratified by warfarin patients' TTR. The cohort consisted of 472 propensity-matched pairs. The mean age was 73.6 years (SD = 11.7), and the mean CHADS 2 score was 1.8. The median TTR for warfarin patients was 64%. In the propensity-matched analysis, there was no significant difference in thromboembolic or major bleeding events between groups. Among warfarin patients with a TTR <64% and their matched rivaroxaban pairs, there was also no significant difference in thromboembolic or major bleeding events. Under real-world conditions, warfarin and rivaroxaban were associated with similar safety and effectiveness, even among those with suboptimal therapeutic control. Individualized decision making, taking into account the nontherapeutic tradeoffs associated with these medications (eg, monitoring, half-life, cost) is warranted.

Rivaroxaban crushed tablet suspension characteristics and relative bioavailability in healthy adults when administered orally or via nasogastric tube.

PubMed

Moore, Kenneth T; Krook, Mark A; Vaidyanathan, Seema; Sarich, Troy C; Damaraju, C V; Fields, Larry E

2014-07-01

Because some patients have difficulty swallowing a whole tablet, we investigated the relative bioavailability of a crushed 20 mg rivaroxaban tablet and of 2 alternative crushed tablet dosing strategies. Stability and nasogastric (NG) tube adsorption characteristics of a crushed rivaroxaban tablet were assessed. Then, in 55 healthy adults, relative bioavailability of rivaroxaban administered orally as a whole tablet (Reference [Whole-Oral]), crushed tablet in applesauce suspension (Crushed-Oral), or crushed tablet in water suspension via NG tube (Crushed-NG) were determined. There were no significant changes in mean percent of non-degraded rivaroxaban recovered over 4 hours from crushed tablet suspensions (>98.4% recovery across all suspensions and time points) or after NG tube exposure (recovery: 99.1% for silicone and 98.9% for polyvinyl chloride NG tubes). Relative bioavailability was similar between Crushed-Oral and Reference dosing (Cmax and AUC∞ were within the 80-125% bioequivalence limits). Relative bioavailability was also similar between the Crushed-NG and Reference dosing (AUC∞ was within bioequivalence limits; Cmax [90% CI range: 78.5-85.8%] was only slightly below the 80% lower bioequivalence limit). A crushed rivaroxaban tablet was stable and when administered orally or via NG tube, displayed similar relative bioavailability compared to a whole tablet administered orally. © 2014, The American College of Clinical Pharmacology.

Intracranial subdural hematomas with elevated rivaroxaban concentration and subsequently detected spinal subdural hematoma: A case report.

PubMed

Yamaguchi, Yoshitaka; Koga, Masatoshi; Matsuki, Takayuki; Hino, Tenyu; Yokota, Chiaki; Toyoda, Kazunori

2016-07-01

A 79-year-old lean man with a height of 157cm and weight of 42kg (body mass index, 17.2kg/m(2)) receiving rivaroxaban developed an intracranial subdural hematoma and was treated conservatively. Because he had a reduced creatinine clearance of 44mL/min, his dosage of rivaroxaban was reduced from 15 to 10mg daily according to official Japanese prescribing information. However, he developed bilateral intracranial subdural hematomas 2weeks later. Plasma rivaroxaban concentration on anti-factor Xa chromogenic assay was elevated at 301ng/mL, suggesting excessive accumulation. He underwent burr hole drainage and resumed anticoagulation with warfarin. Subsequently, he developed a lumbosacral hematoma. He was treated conservatively and discharged without neurological sequelae. The main cause of the increased concentration of rivaroxaban was believed to be his older age and low body weight. The etiology of the spinal hematoma was suspected to be the migration of intracranial hematoma to the spinal subdural space. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lack of significant bleeding despite large acute rivaroxaban overdose confirmed with whole blood concentrations.

PubMed

Repplinger, Daniel J; Hoffman, Robert S; Nelson, Lewis S; Hines, Elizabeth Q; Howland, MaryAnn; Su, Mark K

2016-09-01

Since intentional overdose with rivaroxaban is expected to lead to significant coagulopathy and bleeding, prophylactic reversal has been suggested. We report a single massive ingestion confirmed by a blood concentration that was managed with expectant therapy alone. A 71-year-old man with atrial fibrillation, aortic valve replacement, and congestive heart failure presented to the emergency department after an intentional ingestion of 97 (1940 mg total) rivaroxaban tablets in a suicide attempt. Initial laboratories revealed: PT, 60.2 s; INR 7.2; aPTT, 55.7 s; BUN 28 mg/dL; and creatinine 1.2 mg/dL. A whole-blood rivaroxaban concentration obtained on hospital-day three was 160 ng/mL. The patient was admitted for continued observation and the coagulation markers trended downward with no major bleeding events. No reversal agents or blood products were given during his hospitalization. In the setting of a single, acute rivaroxaban overdose, with normal renal function, and no active bleeding, conservative therapy alone may be sufficient.

Effects of rivaroxaban versus warfarin on hospitalization days and other health care resource utilization in patients with nonvalvular atrial fibrillation: an observational study from a cohort of matched users.

PubMed

Laliberté, François; Cloutier, Michel; Crivera, Concetta; Nelson, Winnie W; Olson, William H; Schein, Jeffrey; Vanderpoel, Julie; Germain, Guillaume; Lefebvre, Patrick

2015-03-01

Compared with warfarin, the new target-specific oral anticoagulant agents may have advantages, such as shorter hospital length of stay, in patients with nonvalvular atrial fibrillation (NVAF). The objective of the present study was to assess, among patients with NVAF, the effects of rivaroxaban versus warfarin on the number of hospitalization days and other health care resource utilization in a cohort of rivaroxaban users and matched warfarin users. Data from health care claims dated from May 2011 to December 2012 from the Humana database were analyzed. Adult patients newly initiated on treatment with rivaroxaban or warfarin, with ≥2 diagnoses of AF (ICD-9-CM code 427.31), and without valvular AF were identified. Based on propensity score methods, warfarin recipients were matched 1:1 to rivaroxaban recipients. The end of the observation period was defined as the end of data availability, the end of insurance coverage, death, the date of a switch to another anticoagulant agent, or day 14 of treatment nonpersistence. The total number of hospitalization days and other health care resource utilization parameters (numbers of hospitalizations, emergency department [ED] visits, and outpatient visits) were evaluated using the method by Lin et al. Matches for all rivaroxaban recipients were found, and the characteristics of the matched groups (n = 2253 per group) were well balanced. The mean age of both cohorts was 74 years; 46% were female. The estimated mean total numbers of hospitalization days were significantly less in rivaroxaban users compared with those in warfarin users (all-cause, 2.71 vs 3.87 days [P = 0.032]; AF-related, 2.11 vs 3.02 days [P = 0.014]). The numbers of outpatient visits were also significantly less (all-cause, 25.26 vs 35.79 visits [P < 0.001]; AF-related, 5.48 vs 9.06 visits [P < 0.001]). Rivaroxaban users had a lesser estimated mean number of all-cause hospitalizations compared with warfarin users (0.55 vs 0.73; P = 0.084), and a significantly lesser estimated mean number of AF-related hospitalizations (0.40 vs 0.57; P = 0.022). The difference in the estimated mean numbers of all-cause ED visits was not statistically significant between the rivaroxaban and warfarin users. In this study conducted in clinical practice, the estimated mean numbers of hospitalization days, outpatient visits, and AF-related hospitalizations associated with rivaroxaban were significantly less than were those associated with warfarin in these patients with NVAF. The corresponding estimated difference in all-cause ED visits was not statistically significant. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Patient-Reported Treatment Satisfaction with Rivaroxaban for Stroke Prevention in Atrial Fibrillation. A French Observational Study, the SAFARI Study.

PubMed

Hanon, Olivier; Chaussade, Edouard; Gueranger, Pierre; Gruson, Elise; Bonan, Sabrina; Gay, Alain

2016-01-01

For antithrombotic treatments, Patient Reported Outcomes (PRO) and patient satisfaction with treatment are essential data for physicians because of the strong relationship between patient satisfaction and adherence to treatment. The impact of rivaroxaban on patient satisfaction and quality of life was not sufficiently documented in phase III studies. There is a need for further data in this field especially in real life conditions. The SAFARI study is composed of patients with non-valvular atrial fibrillation (AF), previously treated with vitamin K antagonist (VKA) and switched to rivaroxaban. Patient satisfaction with anticoagulant therapy was measured by the Anti-Clot Treatment Scale (ACTS), a validated 15-item patient-reported scale including a 12-item ACTS Burdens scale and a 3-item ACTS Benefits scale. Satisfaction of medication was compared between baseline and 1, 3 and 6 months. Study population was composed of 405 patients. Mean age was 74.8 (standard deviation = 9.0) years and 63.0% were male. Mean CHA2DS2-VASc score was 3.4 (1.5) and mean HAS-BLED score was 2.9 (1.0). After 3 months of treatment with rivaroxaban, patient satisfaction improved compared with VKA: mean ACTS burdens scores significantly increased by 8.3 (8.9) points (p<0.0001) and ACTS benefits scale by 0.4 (2.9) (p<0.001). Compared with baseline, the improvement in ACTS burdens and benefits became apparent at 1 month (46.5 vs. 53.6 p<0.001 and 10.4 vs. 10.7, p<0.05 respectively) and persisted at 6 months (46.5 vs. 54.76 p<0.001 and 10.4 vs. 10.8 p = 0.02 respectively). Rivaroxaban persistence was 88.7% at 6 months. SAFARI data support a good risk-benefit balance for rivaroxaban, with a good safety profile and encourage PRO design studies. The switch from VKA to rivaroxaban improved patient satisfaction at 1, 3 and 6 months after rivaroxaban initiation among patients with AF, particularly in reducing patient-reported anticoagulation burden.

Rivaroxaban

MedlinePlus

... rivaroxaban, you are at risk of having a blood clot form in or around your spine that could cause you to become paralyzed. Tell your doctor if you have an epidural catheter that is left in your body or have ...

A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study.

PubMed

Buller, Harry R; Lensing, Anthonie W A; Prins, Martin H; Agnelli, Giancarlo; Cohen, Alexander; Gallus, Alexander S; Misselwitz, Frank; Raskob, Gary; Schellong, Sebastian; Segers, Annelise

2008-09-15

We performed a randomized dose-ranging study, double-blind for rivaroxaban doses and open-label for the comparator (low-molecular-weight heparin followed by vitamin K antagonists) to assess the optimal dose of rivaroxaban for the treatment of deep vein thrombosis. A total of 543 patients with acute deep-venous thrombosis received rivaroxaban 20, 30, or 40 mg once daily or comparator. Treatment lasted for 84 days. The primary efficacy outcome was the 3-month incidence of the composite of symptomatic venous thromboembolic complications and asymptomatic deterioration in thrombotic burden as assessed by comparison of ultrasound and perfusion lung scanning at day 84 with baseline. The main safety outcome was the composite of major bleeding and clinically relevant nonmajor bleeding. A total of 449 (83%) of the 543 patients could be included in the per-protocol population. The primary efficacy outcome occurred in 6.1%, 5.4%, and 6.6% of the rivaroxaban 20-, 30-, and 40-mg treatment groups, respectively, and in 9.9% of those receiving standard therapy. The main safety outcome occurred in 5.9%, 6.0%, and 2.2% of the rivaroxaban 20-, 30-, and 40-mg treatment groups, respectively, and in 8.8% of those receiving standard therapy. These results with simple fixed-dose oral regimens justify phase 3 evaluations (www.ClinicalTrials.gov no.NCT00395772).

Early Rivaroxaban Use After Cardioembolic Stroke May Not Result in Hemorrhagic Transformation: A Prospective Magnetic Resonance Imaging Study.

PubMed

Gioia, Laura C; Kate, Mahesh; Sivakumar, Leka; Hussain, Dulara; Kalashyan, Hayrapet; Buck, Brian; Bussiere, Miguel; Jeerakathil, Thomas; Shuaib, Ashfaq; Emery, Derek; Butcher, Ken

2016-07-01

Early anticoagulation after cardioembolic stroke remains controversial because of the potential for hemorrhagic transformation (HT). We tested the safety and feasibility of initiating rivaroxaban ≤14 days after cardioembolic stroke/transient ischemic attack. A prospective, open-label study of patients with atrial fibrillation treated with rivaroxaban ≤14 days of transient ischemic attack or ischemic stroke (National Institute of Health Stroke Scale <9). All patients underwent magnetic resonance imaging <24 hours of rivaroxaban initiation and day 7. The primary end point was symptomatic HT at day 7. Sixty patients (mean±SD age 71±19 years, 82% stroke/18% transient ischemic attack) were enrolled. Median (interquartile range) time from onset to rivaroxaban was 3 (5) days. At treatment initiation, median National Institute of Health Stroke Scale was 2 (4), and median diffusion-weighted imaging volume was 7.9 (13.7) mL. At baseline, HT was present in 25 (42%) patients (hemorrhagic infarct [HI]1=19, HI2=6). On follow-up magnetic resonance imaging, no patients developed symptomatic HT. New asymptomatic HI1 developed in 3 patients, and asymptomatic progression from HI1 to HI2 occurred in 5 patients; otherwise, HT remained unchanged at day 7. These data support the safety of rivaroxaban initiation ≤14 days of mild-moderate cardioembolic stroke/transient ischemic attack. Magnetic resonance imaging evidence of petechial HT, which is common, does not appear to increase the risk of symptomatic HT. © 2016 American Heart Association, Inc.

Synthesis of high generation thermo-sensitive dendrimers for extraction of rivaroxaban from human fluid and pharmaceutic samples.

PubMed

Parham, Negin; Panahi, Homayon Ahmad; Feizbakhsh, Alireza; Moniri, Elham

2018-04-13

In this present study, poly (N-isopropylacrylamide) as a thermo-sensitive agent was grafted onto magnetic nanoparticles, then ethylenediamine and methylmethacrylate were used to synthesize the first generation of poly amidoamine (PAMAM) dendrimers successively and the process continued alternatively until the ten generations of dendrimers. The synthesized nanocomposite was investigated using Fourier transform infrared spectrometry, thermalgravimetry analysis, X-ray diffractometry, elemental analysis and vibrating-sample magnetometer. The particle size and morphology were characterized using dynamic light scattering, field emission scanning electron microscopy and transmission electron microscopy. Batch experiments were conducted to investigate the parameters affecting adsorption and desorption of rivaroxaban by synthesized nanocomposite. The maximum sorption of rivaroxaban by the synthesized nanocomposite was obtained at pH of 8. The resulting grafted magnetic nanoparticle dendrimers were applied for extraction of rivaroxaban from biologic human liquids and medicinal samples. The specifications of rivaroxaban sorbed by a magnetic nanoparticle dendrimer showed good accessibility and high capacity of the active sites within the dendrimers. Urine and drug matrix extraction recoveries of more than 92.5 and 99.8 were obtained, respectively. Copyright © 2018 Elsevier B.V. All rights reserved.

Model-based dose selection for phase III rivaroxaban study in Japanese patients with non-valvular atrial fibrillation.

PubMed

Tanigawa, Takahiko; Kaneko, Masato; Hashizume, Kensei; Kajikawa, Mariko; Ueda, Hitoshi; Tajiri, Masahiro; Paolini, John F; Mueck, Wolfgang

2013-01-01

The global ROCKET AF phase III trial evaluated rivaroxaban 20 mg once daily (o.d.) for stroke prevention in atrial fibrillation (AF). Based on rivaroxaban pharmacokinetics in Japanese subjects and lower anticoagulation preferences in Japan, particularly in elderly patients, the optimal dose regimen for Japanese AF patients was considered. The aim of this analysis was dose selection for Japanese patients from a pharmacokinetic aspect by comparison of simulated exposure in Japanese patients with those in Caucasian patients. As a result of population pharmacokinetics-pharmacodynamics analyses, a one-compartment pharmacokinetic model with first-order absorption and direct link pharmacokinetic-pharmacodynamic models optimally described the plasma concentration and pharmacodynamic models (Factor Xa activity, prothrombin time, activated partial thromboplastin time, and HepTest), which were also consistent with previous works. Steady-state simulations indicated 15 mg rivaroxaban o.d. doses in Japanese patients with AF would yield exposures comparable to the 20 mg o.d. dose in Caucasian patients with AF. In conclusion, in the context of the lower anticoagulation targets in Japanese practice, the population pharmacokinetic and pharmacodynamic modeling supports 15 mg o.d. as the principal rivaroxaban dose in J-ROCKET AF.

Standard and reduced doses of dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation: a nationwide cohort study.

PubMed

Staerk, L; Gerds, T A; Lip, G Y H; Ozenne, B; Bonde, A N; Lamberts, M; Fosbøl, E L; Torp-Pedersen, C; Gislason, G H; Olesen, J B

2018-01-01

Comparative data of non-vitamin K antagonist oral anticoagulants (NOAC) are lacking in patients with atrial fibrillation (AF). We compared effectiveness and safety of standard and reduced dose NOAC in AF patients. Using Danish nationwide registries, we included all oral anticoagulant-naïve AF patients who initiated NOAC treatment (2012-2016). Outcome-specific and mortality-specific multiple Cox regressions were combined to compute average treatment effects as 1-year standardized differences in stroke and bleeding risks (g-formula). Amongst 31 522 AF patients, the distribution of NOAC/dose was as follows: dabigatran standard dose (22.4%), dabigatran-reduced dose (14.0%), rivaroxaban standard dose (21.8%), rivaroxaban reduced dose (6.7%), apixaban standard dose (22.9%), and apixaban reduced dose (12.2%). The 1-year standardized absolute risks of stroke/thromboembolism were 1.73-1.98% and 2.51-2.78% with standard and reduced NOAC dose, respectively, without statistically significant differences between NOACs for given dose level. Comparing standard doses, the 1-year standardized absolute risk (95% CI) for major bleeding was for rivaroxaban 2.78% (2.42-3.17%); corresponding absolute risk differences (95% CI) were for dabigatran -0.93% (-1.45% to -0.38%) and apixaban, -0.54% (-0.99% to -0.05%). The results for major bleeding were similar for reduced NOAC dose. The 1-year standardized absolute risk (95% CI) for intracranial bleeding was for standard dose dabigatran 0.19% (0.22-0.50%); corresponding absolute risk differences (95% CI) were for rivaroxaban 0.23% (0.06-0.41%) and apixaban, 0.18% (0.01-0.34%). Standard and reduced dose NOACs, respectively, showed no significant risk difference for associated stroke/thromboembolism. Rivaroxaban was associated with higher bleeding risk compared with dabigatran and apixaban and dabigatran was associated with lower intracranial bleeding risk compared with rivaroxaban and apixaban. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Effectiveness and safety of rivaroxaban versus warfarin in patients with unprovoked venous thromboembolism: A propensity-score weighted administrative claims cohort study.

PubMed

Coleman, Craig I; Peacock, W Frank; Bunz, Thomas J; Beyer-Westendorf, Jan

2018-05-30

In phase III trials, rivaroxaban demonstrated non-inferiority over enoxaparin/warfarin to prevent recurrent venous thromboembolism (VTE), with a reduction of major bleeding. However, compared to provoked VTE, the risk-benefit ratio of rivaroxaban may be different for patients with unprovoked VTE. In a retrospective claims data analysis using US MarketScan claims from 1/2012 to 12/2016, we included adults with a primary diagnosis of VTE newly-initiated on rivaroxaban or warfarin within 30-days of the incident VTE and with ≥12-months of continuous insurance benefits prior to the VTE (baseline). Patients with provoked VTE, a claim for anticoagulation during baseline or who redeemed prescriptions for ≥1 oral anticoagulant were excluded. Our primary outcomes were recurrent VTE and major bleeding at 6-months using an intention-to-treat (ITT) analysis. Three-month ITT and 12-month on-treatment (30-day permissible gap) analyses were also performed. Inverse probability-of-treatment weights based on propensity-scores and Cox regression were used to compare outcomes. We identified 10,489 rivaroxaban users and 26,364 warfarin users with incident unprovoked VTE. At 6-months, rivaroxaban was associated with a hazard ratio (HR) of 0.60 (95% confidence interval [CI] = 0.54-0.67) for recurrent VTE (number-needed-to-treat: 59; 95%CI 49-76) and a HR = 0.80 (95% CI = 0.66-0.98) for major bleeding versus warfarin. Our findings remained consistent in the 3- and 12-month analyses. Consistent with the results from the EINSTEIN phase-III trials, findings of our routine practice study suggest that, in patients with unprovoked VTE, rivaroxaban has the potential to reduce both the risk of major bleeding and recurrent VTE compared to warfarin. Copyright © 2018 Elsevier Ltd. All rights reserved.

Safety and Efficacy of Rivaroxaban in Patients With Cardiac Implantable Electronic Devices: Observations From the ROCKET AF Trial.

PubMed

Leef, George C; Hellkamp, Anne S; Patel, Manesh R; Becker, Richard C; Berkowitz, Scott D; Breithardt, Günter; Halperin, Jonathan L; Hankey, Graeme J; Hacke, Werner; Nessel, Christopher C; Singer, Daniel E; Fox, Keith A A; Mahaffey, Kenneth W; Piccini, Jonathan P

2017-06-14

Although implantation of cardiac implantable electronic devices (CIEDs) in patients receiving warfarin is well studied, limited data are available on the use of oral factor Xa inhibitors in this setting. Using data from Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) (n=14 264), we compared baseline characteristics and clinical outcomes in patients with atrial fibrillation randomized to rivaroxaban versus warfarin who did and did not undergo CIED implantation or revision. In this post-hoc, postrandomization, on-treatment analysis, only the first intervention per patient was analyzed. During a median follow-up of 2.2 years, 453 patients (242 rivaroxaban group; 211 warfarin group) underwent de novo CIED implantation (64.2%) or revision procedures (35.8%). Patients who received CIEDs were older, more likely to be male, and more likely to have past myocardial infarction, but had similar stroke risk compared to patients who did not receive CIEDs. Most patients who received a device had study drug interrupted for the procedure and did not receive bridging anticoagulation. During the 30-day postprocedural period, 11 patients (4.55%) in the rivaroxaban group experienced bleeding complications compared with 15 (7.13%) in the warfarin group. Thromboembolic complications occurred in 3 patients (1.26%) in the rivaroxaban group and 1 (0.48%) in the warfarin group. Event rates were too low for formal hypothesis testing. Bleeding and thromboembolic events were low in both rivaroxaban- and warfarin-treated patients. Periprocedural use of oral factor Xa inhibitors in CIED implantation requires further study in prospective, randomized trials. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767. © 2017 The Authors, Bayer US LLC, and Janssen Research and Development. Published on behalf of the American Heart Association, Inc., by Wiley.

Efficacy and safety of rivaroxaban versus warfarin in patients from mainland China with nonvalvular atrial fibrillation: A subgroup analysis from the ROCKET AF trial.

PubMed

Sun, Yihong; Hu, Dayi; Stevens, Susanna; Lokhnygina, Yuliya; Becker, Richard C; Berkowitz, Scott D; Breithardt, Günter; Hacke, Werner; Halperin, Jonathan L; Hankey, Graeme J; Mahaffey, Kenneth W; Nessel, Christopher C; Piccini, Jonathan P; Singer, Daniel E; Fox, Keith A A; Patel, Manesh R

2017-08-01

The ROCKET AF study evaluated once-daily rivaroxaban versus dose-adjusted warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). In this analysis, we compared rivaroxaban with warfarin in patients with AF from China, East Asia, and the rest of the world (ROW). We assessed baseline demographics and interaction of treatment effects of rivaroxaban versus warfarin among patients from mainland China, other East Asian countries, and ROW. Of the 14,236 patients enrolled in the per-protocol population, 495 were from mainland China, 433 from other East-Asian regions, and 13,308 from the rest of the world (ROW). At baseline, patients from China had significantly higher rates of previous stroke/transient ischemic attack (TIA) compared with patients from other East Asian regions and ROW (79.6%, 44.6%, 51.6% respectively; p<0.0001) and lower rates of VKA use (33.7%, 66.7%, 63.4%, respectively; p<0.0001). The rates of stroke or systemic embolism among those on warfarin while on treatment was 5.23% in patients from China, 1.82% in those from other East Asian regions, and 2.07% from ROW; on rivaroxaban, the rates were 2.29% in patients from China, 1.86% in those from other east Asian regions, and 1.67% from ROW. There were no significant treatment-by-region interactions for any efficacy or safety outcome (all p>0.12). Numerically higher rates of intracranial bleeding were seen in patients from China receiving warfarin versus rivaroxaban. In patients from China, rates of intracranial hemorrhage were numerically lower among those receiving rivaroxaban and consistent with the overall trial. URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rivaroxaban as an effective alternative to warfarin in a patient with atrial fibrillation, thrombophilia, and left atrial appendage thrombus: a case report.

PubMed

Scarano, Michele; Casale, Matteo; Mantini, Cesare; Imbalzano, Egidio; Consorti, Cristiana; Clemente, Daniela; Dattilo, Giuseppe

2017-04-09

Atrial fibrillation is the most common cardiac arrhythmia. It is responsible for up to 20% of all ischemic strokes. Rate control and anticoagulation are crucial for atrial fibrillation management and stroke prevention. We present the case of an 84-year-old Italian woman with a left atrial appendage thrombus that developed despite her use of anticoagulant therapy with warfarin for a previous pulmonary embolism. She had atrial fibrillation and heterozygosity for both factor V Leiden and methylenetetrahydrofolate reductase C677T mutation, thus creating resistance to activated protein C. Anticoagulant therapy was switched to heparin for 1 week and then to rivaroxaban. After 3 months of rivaroxaban use, the thrombus disappeared. This case raises the issue of the ineffectiveness of warfarin therapy in complex cases involving particular thrombophilic conditions and the possibility of using rivaroxaban as a safe and effective alternative.

International Normalized Ratio Is Significantly Elevated With Rivaroxaban and Apixaban Drug Therapies: A Retrospective Study.

PubMed

Ofek, Fanny; Bar Chaim, Samuel; Kronenfeld, Nirit; Ziv-Baran, Tomer; Berkovitch, Matitiahu

2017-05-01

Direct factor Xa inhibitors such as rivaroxaban or apixaban may prolong prothrombin time (PT) and elevate international normalized ratio (INR). However, these tests are not reliable for assessing the anticoagulation effects of these agents. PT assay sensitivity is relatively weak at therapeutic drug concentrations and is subjected to significant variations depending on the reagent used. Conversion of PT to INR may even increase the variability. We conducted a retrospective cross-sectional study aiming to assess the prevalence and extent of INR elevation in hospitalized patients receiving rivaroxaban or apixaban as part of their home medications and to find out whether other existing factors could elevate INR apart from the drug entity itself. The data collected from 218 hospitalized patients׳ charts included PT and INR taken on admission, patients׳ characteristics, laboratory results, other medications regularly used, and coexisting clinical conditions. No statistically significant association between INR elevation and the parameters examined was found in our study. INR was significantly elevated in both drug groups (P < 0.001), with 84.2% of rivaroxaban patients and 78.3% of apixaban patients presenting with INR levels above the higher limit of the normal range. Furthermore, INR was significantly higher in the rivaroxaban group than in the apixaban group (P < 0.001). Both of the reviewed drugs significantly elevated INR. Moreover, rivaroxaban elevates INR significantly more than apixaban, and there are apparently no other factors affecting INR but the drugs themselves. Larger prospective studies are needed to confirm and clarify the clinical significance of these results. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Cost-effectiveness analysis of rivaroxaban for treatment and secondary prevention of venous thromboembolism in the Netherlands.

PubMed

Heisen, Marieke; Treur, Maarten J; Heemstra, Harald E; Giesen, Eric B W; Postma, Maarten J

2017-08-01

Until recently, standard treatment of venous thromboembolism (VTE) concerned a combination of short-term low-molecular-weight heparin (LMWH) and long-term vitamin-K antagonist (VKA). Risk of bleeding and the requirement for regular anticoagulation monitoring are, however, limiting their use. Rivaroxaban is a novel oral anticoagulant associated with a significantly lower risk of major bleeds (hazard ratio = 0.54, 95% confidence interval = 0.37-0.79) compared to LMWH/VKA therapy, and does not require regular anticoagulation monitoring. To evaluate the health economic consequences of treating acute VTE patients with rivaroxaban compared to treatment with LMWH/VKA, viewed from the Dutch societal perspective. A life-time Markov model was populated with the findings of the EINSTEIN phase III clinical trial to analyze cost-effectiveness of rivaroxaban therapy in treatment and prevention of VTE from a Dutch societal perspective. Primary model outcomes were total and incremental quality-adjusted life years (QALYs), as well as life expectancy and costs. Over a patient's lifetime, rivaroxaban was shown to be dominant, with health gains of 0.047 QALYs and cost savings of €304 compared to LMWH/VKA therapy. Dominance was robustly present in all sensitivity analyses. Major drivers of the differences between the two treatment arms were related to anticoagulation monitoring (medical costs, travel costs, and loss of productivity) and the occurrence of major bleeds. Rivaroxaban treatment of patients with venous thromboembolism results in health gains and cost savings compared to LMWH/VKA therapy. This conclusion holds for the Dutch setting, both for the societal perspective, as well as the healthcare perspective.

Use of prestudy heparin did not influence the efficacy and safety of rivaroxaban in patients treated for symptomatic venous thromboem-bolism in the EINSTEIN DVT and EINSTEIN PE studies.

PubMed

Prandoni, Paolo; Prins, Martin H; Cohen, Alexander T; Müller, Katharina; Pap, Ákos F; Tewes, Miriam C; Lensing, Anthonie W A

2015-02-01

In the EINSTEIN DVT and EINSTEIN PE studies, the majority of patients received heparins to bridge the period during venous thromboembolism (VTE) diagnosis confirmation and the start of the study. In contrast to vitamin K antagonists (VKAs), rivaroxaban may not require initial heparin treatment. To evaluate the effect of prestudy heparin on the efficacy and safety of rivaroxaban relative to enoxaparin/VKA, the 3-month incidence of recurrent VTE, and the 14-day incidence of major and nonmajor clinically relevant bleeding were compared in patients who did and did not receive prestudy heparin. Of the 8,281 patients randomized, 6,937 (83.8%) received prestudy heparin (mean ± SD duration = rivaroxaban: 1.04 [± 0.74] days; enoxaparin 1.03 [± 0.42] days), and 1,344 (16.2%) did not. In patients who did not receive prestudy heparin, the incidences of recurrent VTE were similar in rivaroxaban (15 of 649, 2.3%) and enoxaparin/VKA (13 of 695, 1.9%) patients (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI] = 0.52 to 2.37). The incidences of recurrent VTE were also similar in rivaroxaban (54 of 3,501, 1.5%) and enoxaparin/VKA (69 of 3,436, 2.0%) patients who did receive prestudy heparin (adjusted HR = 0.74; 95% CI = 0.52 to 1.06; pinteraction  = 0.32). The incidences of major or nonmajor clinically relevant bleeding with rivaroxaban were not significantly different from those with enoxaparin/VKA, either with (105 of 3,485, 3.0% vs. 104 of 3,428, 3.0%; adjusted HR = 0.98; 95% CI = 0.75 to 1.29) or without (24 of 645, 3.7% vs. 30 of 688, 4.4%; adjusted HR = 0.81; 95% CI = 0.46 to 1.40; pinteraction  = 0.68) prestudy heparin. Although the majority of patients in the EINSTEIN studies received prestudy heparin, there were no notable differences in treatment effect of rivaroxaban versus enoxaparin/VKA in those who did and did not receive it. © 2015 by the Society for Academic Emergency Medicine.

Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies.

PubMed

Wang, Yuqi; Wang, Chen; Chen, Zhong; Zhang, Jiwei; Liu, Zhihong; Jin, Bi; Ying, Kejing; Liu, Changwei; Shao, Yuxia; Jing, Zhicheng; Meng, Isabelle Ling; Prins, Martin H; Pap, Akos F; Müller, Katharina; Lensing, Anthonie Wa

2013-12-16

The worldwide EINSTEIN DVT and EINSTEIN PE studies randomized 8282 patients with acute symptomatic deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) and, for the first time in trials in this setting, included patients in China. This analysis evaluates the results of these studies in this subgroup of patients. A total of 439 Chinese patients who had acute symptomatic DVT (n=211), or PE with or without DVT (n=228), were randomized to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy of enoxaparin overlapping with and followed by an adjusted-dose vitamin K antagonist, for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or non-major clinically relevant bleeding. The primary efficacy outcome occurred in seven (3.2%) of the 220 patients in the rivaroxaban group and in seven (3.2%) of the 219 patients in the standard-therapy group (hazard ratio, 1.04; 95% confidence interval 0.36-3.0; p=0.94). The principal safety outcome occurred in 13 (5.9%) patients in the rivaroxaban group and in 20 (9.2%) patients in the standard-therapy group (hazard ratio, 0.63; 95% confidence interval 0.31-1.26; p=0.19). Major bleeding was observed in no patients in the rivaroxaban group and in five (2.3%) patients in the standard-therapy group. In fragile patients (defined as age >75 years, creatinine clearance <50 mL/min, and/or body weight ≤50 kg), the principal safety outcome occurred in four (8.9%) of the 45 patients who received rivaroxaban compared with seven (15.2%) of the 46 patients who received standard therapy. In Chinese patients with acute symptomatic DVT and/or PE, rivaroxaban was as efficacious as enoxaparin followed by vitamin K antagonist therapy, with a similar safety profile. The relative efficacy and safety of rivaroxaban compared with enoxaparin/vitamin K antagonist were consistent with that found in the rest of the world. EINSTEIN PE, ClinicalTrials.gov NCT00439777; EINSTEIN DVT, ClinicalTrials.gov NCT00440193.

Cost-effectiveness of edoxaban versus rivaroxaban for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) in the US

PubMed Central

Miller, Jeffrey D; Ye, Xin; Lenhart, Gregory M; Farr, Amanda M; Tran, Oth V; Kwong, W Jackie; Magnuson, Elizabeth A; Weintraub, William S

2016-01-01

Background Understanding the value of new anticoagulation therapies compared with existing therapies is of paramount importance in today’s cost-conscious and efficiency-driven health care environment. Edoxaban and rivaroxaban for stroke prevention in nonvalvular atrial fibrillation (NVAF) patients with CHADS2 scores ≥2 have been evaluated in pivotal trials versus warfarin. The relative value of edoxaban versus rivaroxaban would be of interest to health care stakeholders and patients who prefer a once-daily treatment option for long-term stroke prevention in NVAF. Objective To evaluate the relative cost-effectiveness of two once-daily regimens of novel oral anticoagulation therapy – edoxaban (60 mg/30 mg dose-reduced) versus rivaroxaban (20 mg/15 mg dose-reduced) – for stroke prevention in NVAF patients from a US health-plan perspective. Materials and methods A Markov model simulated lifetime risk and treatment of stroke, systemic embolism, major bleeding, clinically relevant nonmajor bleeding, myocardial infarction, and death in NVAF patients treated with edoxaban or rivaroxaban. Efficacy and safety data were derived from a network meta-analysis that utilized data from patients enrolled in ENGAGE AF-TIMI 48 and ROCKET-AF. Health care cost and utility data were obtained from published sources. Incremental cost-effectiveness ratios of $150,000 per quality-adjusted life year (QALY) gained were used as thresholds for “highly cost-effective”, “cost-effective”, and “not cost-effective” treatment options, respectively, as per American Heart Association/American College of Cardiology guidelines. Results Edoxaban was dominant relative to rivaroxaban, such that it was associated with lower total health care costs and better effectiveness in terms of QALYs in the base-case analysis. Results were supported by probabilistic sensitivity analyses that showed edoxaban as either dominant or a highly cost-effective alternative (incremental cost-effectiveness ratio <$50,000) to rivaroxaban in 88.4% of 10,000 simulations. Conclusion Results of this study showed that the once-daily edoxaban (60 mg/30 mg dose-reduced) regimen is a cost-saving or highly cost-effective treatment relative to rivaroxaban (20 mg/15 mg dose-reduced) for stroke prevention in NVAF patients with CHADS2 ≥2. PMID:27284259

Dabigatran and rivaroxaban do not affect AA- and ADP-induced platelet aggregation in patients receiving concomitant platelet inhibitors.

PubMed

Olivier, Christoph B; Weik, Patrick; Meyer, Melanie; Weber, Susanne; Diehl, Philipp; Bode, Christoph; Moser, Martin; Zhou, Qian

2016-08-01

Dabigatran and rivaroxaban are novel, vitamin K-independent oral anticoagulants (NOACs) and act via antagonism of the coagulation factor (F) IIa (dabigatran) or FXa (rivaroxaban), respectively. Compared to vitamin-K-antagonists, NOACs have shown non-inferiority of risk and benefit in patients with non valvular atrial fibrillation (AF). In clinical practice there is increasing use of NOACs combined with platelet inhibitors in patients with AF and coronary artery disease. However, whether NOACs affect the function of platelet inhibitors remains incompletely known. This observational study aimed to assess the platelet function in patients receiving dabigatran or rivaroxaban and concomitant platelet inhibitors. A single centre observational study was performed analysing the platelet aggregation of patients treated with dabigatran or rivaroxaban with or without concomitant platelet inhibitors. Measurements before the initiation of NOAC therapy served as the respective control group. Platelet aggregation was measured by multiple electrode aggregometry and was induced with adenosine diphosphate (ADP, 6.5 µM) and arachidonic acid (AA, 0.5 mM), respectively. In order to evaluate whether NOACs interact with platelet inhibition by ASA or the P2Y12-antagonist clopidogrel, 87 patients were grouped according to their concomitant antiplatelet medication. Comparing the ADP- and AA-induced platelet aggregation in patients without concomitant platelet inhibitors (n = 45) no significant differences under therapy with dabigatran (d) or rivaroxaban (r) compared to the control group (c) were observed. In patients taking clopidogrel as a concomitant platelet inhibitor (n = 21), neither dabigatran nor rivaroxaban affected the ADP-induced platelet aggregation (c 20 ± 11, d 21 ± 14, r 18 ± 8 AU*min, p = 0.200). Patients receiving dabigatran or rivaroxaban in combination with ASA (n = 42; 21 ASA only, 21 ASA + clopidogrel) showed no significant differences of the AA-induced aggregation compared to the control group (c 10 ± 8, d 9 ± 7, r 10 ± 8 AU*min, p = 0.810). The antiplatelet effects of ASA and clopidogrel monitored by AA- or ADP-induced platelet aggregation were not affected by NOAC therapy.

Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban—an oral, direct Factor Xa inhibitor

PubMed Central

Burghaus, Rolf; Coboeken, Katrin; Gaub, Thomas; Niederalt, Christoph; Sensse, Anke; Siegmund, Hans-Ulrich; Weiss, Wolfgang; Mueck, Wolfgang; Tanigawa, Takahiko; Lippert, Jörg

2014-01-01

The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2–3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban. PMID:25426077

Cost-Effectiveness Analysis of Apixaban, Dabigatran, Rivaroxaban, and Warfarin for Stroke Prevention in Atrial Fibrillation in Taiwan.

PubMed

Liu, Chieh-Yu; Chen, Hui-Chun

2017-03-01

The aim of this study was to evaluate the cost effectiveness of novel oral anticoagulants (NOACs) for stroke prevention among atrial fibrillation (AF) patients by incorporating Taiwanese demographic information derived from a population-based database, the National Health Insurance Research Database (NHIRD), into cost-effectiveness analysis. From 1 January to 31 December 2012, 98,213 AF patients were selected from the NHIRD database. A Markov model was constructed that combined published secondary data with the Taiwan NHIRD to compare the cost and incremental cost effectiveness of apixaban 5 mg twice daily, dabigatran 110 or 150 mg twice daily, rivaroxaban 20 mg once daily, and warfarin. The lifetime costs of warfarin, dabigatran 110 mg, dabigatran 150 mg, rivaroxaban 20 mg, and apixaban 5 mg were US$10,660, US$13,693, US$13,426, US$13,455, US$15,965, respectively. Apixaban resulted in an incremental cost effectiveness of US$39,351, US$27,039, US$41,298, and US$48,896 per quality-adjusted life-year (QALY) compared with warfarin, dabigatran 110 mg, dabigatran 150 mg, and rivaroxaban 20 mg, respectively. In Monte-Carlo analyses, apixaban 5 mg, rivaroxaban 20 mg, warfarin, and dabigatran 110 mg were cost effective in 83, 10.4, 7, and 0.8%, respectively, of the simulations using a willingness-to-pay (WTP) threshold of US$50,000 per QALY. Apixaban was more cost effective than warfarin, dabigatran, and rivaroxaban for stroke prevention in patients with AF. Among the anticoagulant therapies, the WTP threshold of apixaban was about US$50,000 per QALY gained. These cost-effectiveness estimations provide useful information to aid clinical decision making in stroke prevention for AF patients.

Rivaroxaban and apixaban in orthopaedics: is there a difference in their plasma concentrations and anticoagulant effects?

PubMed Central

Freyburger, Geneviève; Macouillard, Gérard; Khennoufa, Karim; Labrouche, Sylvie; Molimard, Mathieu; Sztark, François

2015-01-01

The aim of this study was to improve knowledge of what happens in the coagulation of orthopaedic patients under rivaroxaban and apixaban, in order to finalize and cross-validate effective measurement methods and to provide arguments for helping to reference one or the other drug in our central pharmacy. One hundred and two patients undergoing total hip or knee replacement were included. Half of them received rivaroxaban and the other half received apixaban. Blood samples (n = 244 with each drug) were taken at Cmax preoperatively and twice a week, apart from the day of the patient's discharge, when Ctrough concentration was targeted. Routine coagulation parameters, and functional and liquid chromatography tandem mass spectrometry assays for measurement of circulating concentrations were studied. The LC-MS/MS assay and the functional assays carried out in patients under routine conditions were highly correlated, apart from low concentrations (<30 ng/ml), which were affected by the variable individual potential to inhibit the exogenous bovine Xa used in the functional assays. After 1 week of treatment, the drugs differed: Cmax and Ctrough were closer when apixaban was taken twice daily (83 ± 39 and 58 ± 17 ng/ml) than with rivaroxaban taken once a day (113 ± 67 and 13 ± 20 ng/ml). Rivaroxaban had a greater influence on routine coagulation tests and reduced the maximum thrombin concentration more efficiently, as assessed by the thrombin generation test. Although rivaroxaban and apixaban present apparently similar constant rates, they exhibit significant differences in their concentrations and anticoagulant effects when studied ex vivo in orthopedic patients. PMID:26258673

Comparison of effectiveness and safety of treatment with apixaban vs. other oral anticoagulants among elderly nonvalvular atrial fibrillation patients.

PubMed

Deitelzweig, Steven; Luo, Xuemei; Gupta, Kiran; Trocio, Jeffrey; Mardekian, Jack; Curtice, Tammy; Lingohr-Smith, Melissa; Menges, Brandy; Lin, Jay

2017-10-01

To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) of elderly (≥65 years of age) nonvalvular atrial fibrillation (NVAF) patients initiating apixaban vs. rivaroxaban, dabigatran, or warfarin. NVAF patients with Medicare Advantage coverage in the US initiating oral anticoagulants (OACs, index event) were identified from the Humana database (1 January 2013-30 September 2015) and grouped into cohorts depending on OAC initiated. Propensity score matching (PSM), 1:1, was conducted among patients treated with apixaban vs. each other OAC, separately. Rates of S/SE and MB were evaluated in the follow-up. Cox regressions were used to compare the risk of S/SE and MB between apixaban and each of the other OACs during the follow-up. The matched pairs of apixaban vs. rivaroxaban (n = 13,620), apixaban vs. dabigatran (n = 4654), and apixaban vs. warfarin (n = 14,214) were well balanced for key patient characteristics. Adjusted risks for S/SE (hazard ratio [HR] vs. rivaroxaban: 0.72, p = .003; vs. warfarin: 0.65, p < .001) and MB (HR vs. rivaroxaban: 0.49, p < .001; vs. warfarin: 0.53, p < .001) were significantly lower during the follow-up for patients treated with apixaban vs. rivaroxaban and warfarin. Adjusted risks for S/SE (HR: 0.78, p = .27) and MB (HR: 0.82, p = .23) of NVAF patients treated with apixaban vs. dabigatran trended to be lower, but did not reach statistical significance. In the real-world setting after controlling for differences in patient characteristics, apixaban is associated with significantly lower risk of S/SE and MB than rivaroxaban and warfarin, and a trend towards better outcomes vs. dabigatran among elderly NVAF patients in the US.

Efficacy and safety of rivaroxaban compared with warfarin in patients with carotid artery disease and nonvalvular atrial fibrillation: Insights from the ROCKET AF trial.

PubMed

Kochar, Ajar; Hellkamp, Anne S; Lokhnygina, Yuliya; Jones, W Schuyler; Becker, Richard C; Berkowitz, Scott D; Breithardt, Günter; Fox, Keith A A; Halperin, Jonathan L; Hankey, Graeme J; Mahaffey, Kenneth W; Nessel, Christopher C; Singer, Daniel E; Piccini, Jonathan P; Patel, Manesh R

2018-01-01

Atrial fibrillation (AF) increases risk of stroke 5-fold. Carotid artery disease (CD) also augments the risk of stroke, yet there are limited data about the interplay of these 2 diseases and clinical outcomes in patients with comorbid AF and CD. Among patients with both AF and CD, use of rivaroxaban when compared with warfarin is associated with a lower risk of stroke. This post hoc analysis from ROCKET AF aimed to determine absolute rates of stroke/systemic embolism (SE) and bleeding, and the efficacy and safety of rivaroxaban compared with warfarin in patients with AF and CD (defined as history of carotid occlusive disease or carotid revascularization [endarterectomy and/or stenting]). A total of 593 (4.2%) patients had CD at enrollment. Patients with and without CD had similar rates of stroke or SE (adjusted hazard ratio [HR]: 0.99, 95% confidence interval [CI]: 0.66-1.48, P = 0.96), and there was no difference in major or nonmajor clinically relevant bleeding (adjusted HR: 1.04, 95% CI: 0.88-1.24, P = 0.62). The efficacy of rivaroxaban compared with warfarin for the prevention of stroke/SE was not statistically significant in patients with vs those without CD (interaction P = 0.25). The safety of rivaroxaban vs warfarin for major or nonmajor clinically relevant bleeding was similar in patients with and without CD (interaction P = 0.64). Patients with CD in ROCKET AF had similar risk of stroke/SE compared with patients without CD. Additionally, there was no interaction between CD and the treatment effect of rivaroxaban or warfarin for stroke prevention or safety endpoints. © 2018 Wiley Periodicals, Inc.

Net clinical benefit of rivaroxaban compared with warfarin in atrial fibrillation: Results from ROCKET AF.

PubMed

Barnett, Adam S; Cyr, Derek D; Goodman, Shaun G; Levitan, Bennett S; Yuan, Zhong; Hankey, Graeme J; Singer, Daniel E; Becker, Richard C; Breithardt, Günter; Berkowitz, Scott D; Halperin, Jonathan L; Hacke, Werner; Mahaffey, Kenneth W; Nessel, Christopher C; Fox, Keith A A; Patel, Manesh R; Piccini, Jonathan P

2018-04-15

The aim of this study was to determine the net clinical benefit (NCB) of rivaroxaban compared with warfarin in patients with atrial fibrillation. This was a retrospective analysis of 14,236 patients included in ROCKET AF who received at least one dose of study drug. We analyzed NCB using four different methods: (1) composite of death, stroke, systemic embolism, myocardial infarction, and major bleeding; (2) method 1 with fatal or critical organ bleeding substituted for major bleeding; (3) difference between the rate of ischemic stroke or systemic embolism minus 1.5 times the difference between the rate of intracranial hemorrhage; and (4) weighted sum of differences between rates of death, ischemic stroke or systemic embolism, intracranial hemorrhage, and major bleeding. Rivaroxaban was associated with a lower risk of the composite outcome of death, myocardial infarction, stroke, or systemic embolism (rate difference per 10,000 patient-years [RD]=-86.8 [95% CI -143.6 to -30.0]) and fatal or critical organ bleeding (-41.3 [-68 to -14.7]). However, rivaroxaban was associated with a higher risk of major bleeding other than fatal or critical organ bleeding (55.9 [14.7 to 97.2]). Method 1 showed no difference between treatments (-35.5 [-108.4 to 37.3]). Methods 2-4 favored treatment with rivaroxaban (2: -96.8 [-157.0 to -36.8]; 3: -65.2 [-112.3 to -17.8]; 4: -54.8 [-96.0 to -10.2]). Rivaroxaban was associated with favorable NCB compared with warfarin. The NCB was attributable to lower rates of ischemic events and fatal or critical organ bleeding. Copyright © 2017 Elsevier B.V. All rights reserved.

Integrated Population Pharmacokinetic Analysis of Rivaroxaban Across Multiple Patient Populations

PubMed Central

Zhang, Liping; Frede, Matthias; Kubitza, Dagmar; Mueck, Wolfgang; Schmidt, Stephan; Solms, Alexander; Yan, Xiaoyu; Garmann, Dirk

2018-01-01

The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population‐specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI). Rivaroxaban PK were adequately described by a one‐compartment disposition model with a first‐order absorption rate constant. Significant effects of CrCL, use of comedications, and study population on CL/F, age, weight, and gender on V/F, and dose on F were identified. CrCL had a modest influence on exposure, whereas age and BMI had a minor influence. The model was suitable to predict rivaroxaban exposure in patient subgroups of special interest. PMID:29660785

Length of stay and economic consequences with rivaroxaban vs enoxaparin/vitamin K antagonist in patients with DVT and PE: findings from the North American EINSTEIN clinical trial program.

PubMed

Bookhart, Brahim K; Haskell, Lloyd; Bamber, Luke; Wang, Maria; Schein, Jeff; Mody, Samir H

2014-10-01

Venous thromboembolism (VTE) (deep vein thrombosis [DVT] and pulmonary embolism [(PE]) represents a substantial economic burden to the healthcare system. Using data from the randomized EINSTEIN DVT and PE trials, this North American sub-group analysis investigated the potential of rivaroxaban to reduce the length of initial hospitalization in patients with acute symptomatic DVT or PE. A post-hoc analysis of hospitalization and length-of-stay (LOS) data was conducted in the North American sub-set of patients from the randomized, open-label EINSTEIN trial program. Patients received either rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily; n = 405) or dose-adjusted subcutaneous enoxaparin overlapping with (guideline-recommended 'bridging' therapy) and followed by a vitamin K antagonist (VKA) (international normalized ratio = 2.0-3.0; n = 401). The open-label study design allowed for the comparison of LOS between treatment arms under conditions reflecting normal clinical practice. LOS was evaluated using investigator records of dates of admission and discharge. Analyses were carried out in the intention-to-treat population using parametric tests. Costs were applied to the LOS based on weighted mean cost per day for DVT and PE diagnoses obtained from the Healthcare Cost and Utilization Project dataset. Of 382 patients hospitalized, 321 (84%), had acute symptomatic PE; few DVT patients required hospitalization. Similar rates of VTE patients were hospitalized in the rivaroxaban and enoxaparin/VKA treatment groups, 189/405 (47%) and 193/401 (48%), respectively. In hospitalized VTE patients, rivaroxaban treatment produced a 1.6-day mean reduction in LOS (median = 1 day) compared with enoxaparin/VKA (mean = 4.5 vs 6.1; median = 3 vs 4), translating to total costs that were $3419 lower in rivaroxaban-treated patients. In hospitalized North American patients with VTE, treatment with rivaroxaban produced a statistically significant reduction in LOS. When treating DVT and PE patients, clinicians should consider newer anti-coagulants with less complex treatment regimens.

Adherence to Rivaroxaban, Dabigatran, and Apixaban for Stroke Prevention for Newly Diagnosed and Treatment-Naive Atrial Fibrillation Patients: An Update Using 2013–2014 Data

PubMed Central

Brown, Joshua D.; Shewale, Anand R.; Talbert, Jeffery C.

2017-01-01

BACKGROUND Few studies have assessed adherence to non-vitamin K antagonist oral anticoagulants (NOACs), especially using contemporary data now that multiple NOACs are available. OBJECTIVE To compare adherence and treatment patterns among NOACs for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). METHODS Incident and treatment-naive NVAF patients were identified during 2013–2014 from a large claims database in this retrospective cohort study. Patients were included who initiated rivaroxaban, dabigatran, or apixaban within 30 days after diagnosis. Adherence to the index medication and adherence to any oral anticoagulant was assessed using the proportion of days covered (PDC) at 3, 6, and 9 months. The number of switches and gaps in therapy were also evaluated. Analyses were stratified by stroke risk scores, and a logistic regression model was used to control for factors that may predict high adherence. RESULTS Dabigatran had lower adherence (PDC = 0.76, 0.64, 0.57) compared with rivaroxaban (PDC = 0.83, 0.73, 0.66; P < 0.001) and apixaban (PDC = 0.82, 0.72, 0.66; P < 0.001) at 3, 6, and 9 months of follow-up and twice the number of switches to either other anticoagulants or antiplatelet therapy. Adherence was higher overall as stroke risk increased, and dabigatran had consistently lower adherence compared with the other NOACs. Multivariable logistic regression predicting PDC ≥ 0.80 showed rivaroxaban users with higher odds of high adherence compared with dabigatran or rivaroxaban across all time periods. Adjusted analyses showed that increasing age and comorbid hypertension and diabetes were associated with higher adherence. CONCLUSIONS In this real-world analysis of adherence to NOACs, rivaroxaban and apixaban had favorable unadjusted adherence profiles compared with dabigatran, while rivaroxaban users had higher odds of high adherence (PDC ≥ 0.80) among the NOACs in adjusted analyses. Clinicians and managed care organizations should consider the implications of lower adherence on clinical outcomes and quality assessment. PMID:28854077

Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin. A propensity score matched analysis.

PubMed

Lip, Gregory Y H; Keshishian, Allison; Kamble, Shital; Pan, Xianying; Mardekian, Jack; Horblyuk, Ruslan; Hamilton, Melissa

2016-10-28

In addition to warfarin, there are four non-vitamin K antagonist oral anticoagulants (NOACs) available for stroke prevention in non valvular atrial fibrillation (NVAF). There are limited data on the comparative risks of major bleeding among newly anticoagulated NVAF patients who initiate warfarin, apixaban, dabigatran, or rivaroxaban, when used in 'real world' clinical practice. The study used the Truven MarketScan ® Commercial & Medicare supplemental US claims database. NVAF patients aged ≥18 years newly prescribed an oral anticoagulant 01JAN2013-31DEC2014, with a ≥1-year baseline period, were included (study period: 01JAN2012-31DEC2014). Major bleeding was defined as bleeding requiring hospitalisation. Propensity score matching (PSM) was used to balance age, sex, region, baseline comorbidities, and comedications. Cox proportional hazards models were used to estimate the PSM hazard ratio (HR) of major bleeding. Among 45,361 newly anticoagulated NVAF patients, 15,461 (34.1 %) initiated warfarin, 7,438 (16.4 %) initiated apixaban, 17,801 (39.2 %) initiated rivaroxaban, and 4,661 (10.3 %) initiated dabigatran. Compared to matched warfarin initiators, apixaban (HR: 0.53; 95 % CI: 0.39-0.71) and dabigatran (HR: 0.69; 95 % CI: 0.50-0.96) initiators had a significantly lower risk of major bleeding. Patients initiating rivaroxaban (HR: 0.98; 95 % CI: 0.83-1.17) had a non-significant difference in major bleeding risk compared to matched warfarin patients. When comparisons were made between NOACs, matched rivaroxaban patients had a significantly higher risk of major bleeding (HR: 1.82; 95 % CI: 1.36-2.43) compared to apixaban patients. The differences for apixaban-dabigatran and dabigatran-rivaroxaban matched cohorts were not statistically significant. Among newly anticoagulated NVAF patients in the real-world setting, apixaban and dabigatran initiation was associated with significantly lower risk of major bleeding compared to warfarin initiation. When compared to apixaban, rivaroxaban initiation was associated with significantly higher risk of major bleeding.

Major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin: a "real-world" observational study in the United States.

PubMed

Lip, Gregory Y H; Pan, Xianying; Kamble, Shital; Kawabata, Hugh; Mardekian, Jack; Masseria, Cristina; Bruno, Amanda; Phatak, Hemant

2016-09-01

Limited data are available about the real-world safety of non-vitamin K antagonist oral anticoagulants (NOACs). To compare the major bleeding risk among newly anticoagulated non-valvular atrial fibrillation (NVAF) patients initiating apixaban, warfarin, dabigatran or rivaroxaban in the United States. A retrospective cohort study was conducted to compare the major bleeding risk among newly anticoagulated NVAF patients initiating warfarin, apixaban, dabigatran or rivaroxaban. The study used the Truven MarketScan(®) Commercial & Medicare supplemental US database from 1 January 2013 through 31 December 2013. Major bleeding was defined as bleeding requiring hospitalisation. Cox model estimated hazard ratios (HRs) of major bleeding were adjusted for age, gender, baseline comorbidities and co-medications. Among 29 338 newly anticoagulated NVAF patients, 2402 (8.19%) were on apixaban; 4173 (14.22%) on dabigatran; 10 050 (34.26%) on rivaroxaban; and 12 713 (43.33%) on warfarin. After adjusting for baseline characteristics, initiation on warfarin [adjusted HR (aHR): 1.93, 95% confidence interval (CI): 1.12-3.33, P=.018] or rivaroxaban (aHR: 2.19, 95% CI: 1.26-3.79, P=.005) had significantly greater risk of major bleeding vs apixaban. Dabigatran initiation (aHR: 1.71, 95% CI: 0.94-3.10, P=.079) had a non-significant major bleeding risk vs apixaban. When compared with warfarin, apixaban (aHR: 0.52, 95% CI: 0.30-0.89, P=.018) had significantly lower major bleeding risk. Patients initiating rivaroxaban (aHR: 1.13, 95% CI: 0.91-1.41, P=.262) or dabigatran (aHR: 0.88, 95% CI: 0.64-1.21, P=.446) had a non-significant major bleeding risk vs warfarin. Among newly anticoagulated NVAF patients in the real-world setting, initiation with rivaroxaban or warfarin was associated with a significantly greater risk of major bleeding compared with initiation on apixaban. When compared with warfarin, initiation with apixaban was associated with significantly lower risk of major bleeding. Additional observational studies are required to confirm these findings. © 2016 The Authors International Journal of Clinical Practice Published by John Wiley & Sons Ltd.

A cross-country comparison of rivaroxaban spontaneous adverse event reports and concomitant medicine use with the potential to increase the risk of harm.

PubMed

McDonald, Cameron J; Kalisch Ellett, Lisa M; Barratt, John D; Caughey, Gillian E

2014-12-01

Concerns with the safety profiles of the newer anticoagulants have been raised because of differences in treatment populations between pre-marketing studies (randomized controlled trials) and clinical practice. Little is known about the potential safety issues and the reporting in spontaneous adverse event databases associated with rivaroxaban. To analyse spontaneous adverse event reports associated with the oral anticoagulant rivaroxaban from Australia, Canada and the USA; and to examine concomitant medicine use that may increase the risk of adverse events. Spontaneous adverse event report databases from Australia, Canada and the USA were examined for all reports of adverse events associated with rivaroxaban and concomitant medicines from 1 August 2005 to 31 March 2013. Disproportionality analysis (the proportional reporting ratio [PRR] and reporting odds ratio [ROR]) was conducted for quantitative detection of signals, using the US database. There were 244 spontaneous adverse event reports associated with rivaroxaban from Australia, 536 from Canada and 1,638 from the USA. Reporting of haemorrhage (any type) was common, ranging from 30.7% for Australia to 37.5% for Canada. Gastrointestinal haemorrhage was the most commonly reported haemorrhage, accounting for 13.9% of Australian, 16.4% of Canadian and 11.1% of US adverse event reports. Positive signals were confirmed in the US data (haemorrhage [any type] PRR 11.93, χ (2) 4,414.78 and ROR 13.41, 95% confidence interval [CI] 12.13-14.81; gastrointestinal haemorrhage PRR 12.52, χ (2) 2,018.48 and ROR 13.15, 95% CI 11.36-15.21). Reporting of concomitant use of medicines with the potential to increase bleeding risk ranged from 63.7% in Australia to 89.2% in Canada. A large proportion of adverse event reports for rivaroxaban were associated with use of concomitant medicines, which may have increased the risk of adverse events-in particular, haemorrhage. Increased awareness of a patient's comorbidity and associated medicine use is needed when rivaroxaban is used in clinical practice.

Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial).

PubMed

Bansilal, Sameer; Bloomgarden, Zachary; Halperin, Jonathan L; Hellkamp, Anne S; Lokhnygina, Yuliya; Patel, Manesh R; Becker, Richard C; Breithardt, Günter; Hacke, Werner; Hankey, Graeme J; Nessel, Christopher C; Singer, Daniel E; Berkowitz, Scott D; Piccini, Jonathan P; Mahaffey, Kenneth W; Fox, Keith A A

2015-10-01

The prevalence of both atrial fibrillation (AF) and diabetes mellitus (DM) are rising, and these conditions often occur together. Also, DM is an independent risk factor for stroke in patients with AF. We aimed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial. We stratified the ROCKET AF population by DM status, assessed associations with risk of outcomes by DM status and randomized treatment using Cox proportional hazards models, and tested for interactions between randomized treatments. For efficacy, primary outcomes were stroke (ischemic or hemorrhagic) or non-central nervous system embolism. For safety, the primary outcome was major or nonmajor clinically relevant bleeding. The 5,695 patients with DM (40%) in ROCKET AF were younger, were more obese, and had more persistent AF, but fewer had previous stroke (the CHADS2 score includes DM and stroke). The relative efficacy of rivaroxaban and warfarin for prevention of stroke and systemic embolism was similar in patients with (1.74 vs 2.14/100 patient-years, hazard ratio [HR] 0.82) and without (2.12 vs 2.32/100 patient-years, HR 0.92) DM (interaction P = .53). The safety of rivaroxaban vs warfarin regarding major bleeding (HRs 1.00 and 1.12 for patients with and without DM, respectively; interaction P = .43), major or nonmajor clinically relevant bleeding (HRs 0.98 and 1.09; interaction P = .17), and intracerebral hemorrhage (HRs 0.62 and 0.72; interaction P = .67) was independent of DM status. Adjusted exploratory analyses suggested 1.3-, 1.5-, and 1.9-fold higher 2-year rates of stroke, vascular mortality, and myocardial infarction in DM patients. The relative efficacy and safety of rivaroxaban vs warfarin was similar in patients with and without DM, supporting use of rivaroxaban as an alternative to warfarin in diabetic patients with AF. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF.

PubMed

Jones, William Schuyler; Hellkamp, Anne S; Halperin, Jonathan; Piccini, Jonathan P; Breithardt, Gunter; Singer, Daniel E; Fox, Keith A A; Hankey, Graeme J; Mahaffey, Kenneth W; Califf, Robert M; Patel, Manesh R

2014-01-01

Vascular disease is included in a risk scoring system to predict stroke in patients with non-valvular atrial fibrillation (AF). This post hoc analysis of ROCKET AF aimed to determine the absolute rates of stroke and bleeding, and the relative effectiveness and safety of rivaroxaban vs. warfarin in patients with and without peripheral artery disease (PAD). Peripheral artery disease was defined on the case-report form as the presences of intermittent claudication, amputation for arterial insufficiency, vascular reconstruction, bypass surgery, or percutaneous intervention to the extremities, or previously documented abdominal aortic aneurysm. ROCKET AF was a double-blind, double-dummy, randomized-controlled trial comparing rivaroxaban and warfarin for the prevention of stroke or systemic embolism. A total of 839 (5.9%) patients in ROCKET AF had PAD. Patients with and without PAD had similar rates of stroke or systemic embolism [HR: 1.04, 95% CI (0.72, 1.50), P = 0.84] and major or non-major clinically relevant (NMCR) bleeding [HR: 1.11, 95% CI (0.96, 1.28), P = 0.17], respectively. The efficacy of rivaroxaban when compared with warfarin for the prevention of stroke or systemic embolism was similar in patients with PAD (HR: 1.19, 95% CI: 0.63-2.22) and without PAD (HR: 0.86, 95% CI: 0.73-1.02; interaction P = 0.34). There was a significant interaction for major or NMCR bleeding in patients with PAD treated with rivaroxaban compared with warfarin (HR: 1.40, 95% CI: 1.06-1.86) compared with those without PAD (HR: 1.03, 95% CI: 0.95-1.11; interaction P = 0.037). Patients with PAD in ROCKET AF did not have a statistically significant higher risk of stroke or systemic embolism than patients without PAD, and there were similar efficacy outcomes in patients treated with rivaroxaban and warfarin. In PAD patients, there was a higher risk of major bleeding or NMCR bleeding with rivaroxaban when compared with warfarin (interaction P = 0.037). Further investigation is warranted to validate this subgroup analysis and determine the optimal treatment in this high-risk cohort of AF patients with PAD.

Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF).

PubMed

Sherwood, Matthew W; Douketis, James D; Patel, Manesh R; Piccini, Jonathan P; Hellkamp, Anne S; Lokhnygina, Yuliya; Spyropoulos, Alex C; Hankey, Graeme J; Singer, Daniel E; Nessel, Christopher C; Mahaffey, Kenneth W; Fox, Keith A A; Califf, Robert M; Becker, Richard C

2014-05-06

During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI. In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non-central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3-30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36-1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80-2.00]; P=0.32). TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation. http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation).

PubMed

Goodman, Shaun G; Wojdyla, Daniel M; Piccini, Jonathan P; White, Harvey D; Paolini, John F; Nessel, Christopher C; Berkowitz, Scott D; Mahaffey, Kenneth W; Patel, Manesh R; Sherwood, Matthew W; Becker, Richard C; Halperin, Jonathan L; Hacke, Werner; Singer, Daniel E; Hankey, Graeme J; Breithardt, Gunter; Fox, Keith A A; Califf, Robert M

2014-03-11

This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin. The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model. The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, ≥75 years; pinteraction = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) ≥90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk. Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Cardiac Tamponade Associated with Rivaroxaban.

PubMed

Boone, Stephen

2015-07-01

Rivaroxaban is an oral anticoagulant approved for prevention of stroke, as well as for the treatment and prevention of venous thromboembolic disease. Hemopericardium is a serious complication of anticoagulant use, which has been reported with oral vitamin-K antagonists and newer oral anticoagulants. At the time of this report, to my knowledge, there are no published reports of hemorrhagic effusion leading to tamponade associated with a Factor Xa Inhibitor. I report a case of hemopericardium with associated tamponade in a patient who developed pericarditis while being treated with Rivaroxaban. The case highlights an important adverse effect of a newer anticoagulant, as well as the particular dangers of medication co-administration in the elderly.

Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study.

PubMed

Weitz, Jeffrey I; Bauersachs, Rupert; Beyer-Westendorf, Jan; Bounameaux, Henri; Brighton, Timothy A; Cohen, Alexander T; Davidson, Bruce L; Holberg, Gerlind; Kakkar, Ajay; Lensing, Anthonie W A; Prins, Martin; Haskell, Lloyd; van Bellen, Bonno; Verhamme, Peter; Wells, Philip S; Prandoni, Paolo

2015-08-31

Patients with unprovoked venous thromboembolism (VTE) are at high risk for recurrence. Although rivaroxaban is effective for extended VTE treatment at a dose of 20 mg once daily, use of the 10 mg dose may further improve its benefit-to-risk ratio. Low-dose aspirin also reduces rates of recurrent VTE, but has not been compared with anticoagulant therapy. The EINSTEIN CHOICE study is a multicentre, randomised, double-blind, active-controlled, event-driven study comparing the efficacy and safety of two once daily doses of rivaroxaban (20 and 10 mg) with aspirin (100 mg daily) for the prevention of recurrent VTE in patients who completed 6-12 months of anticoagulant therapy for their index acute VTE event. All treatments will be given for 12 months. The primary efficacy objective is to determine whether both doses of rivaroxaban are superior to aspirin for the prevention of symptomatic recurrent VTE, while the principal safety outcome is the incidence of major bleeding. The trial is anticipated to enrol 2,850 patients from 230 sites in 31 countries over a period of 27 months. In conclusion, the EINSTEIN CHOICE study will provide new insights into the optimal antithrombotic strategy for extended VTE treatment by comparing two doses of rivaroxaban with aspirin (clinicaltrials.gov NCT02064439).

Whole blood clots are more resistant to lysis than plasma clots--greater efficacy of rivaroxaban.

PubMed

Varin, Rémi; Mirshahi, Shahsultan; Mirshahi, Pezhman; Klein, Christophe; Jamshedov, Jovid; Chidiac, Jean; Perzborn, Elisabeth; Mirshahi, Massoud; Soria, Claudine; Soria, Jeannette

2013-03-01

Defective thrombolysis, a thrombotic risk factor, can be attributed to the formation of a compact clot poorly accessible to fibrinolytic enzymes. Venous thrombi, rich in red blood cells (RBCs), and arterial thrombi containing various amounts of RBCS, plasma and whole blood (WB) clot permeability and degradability were compared. The effect of rivaroxaban, a potent direct factor Xa inhibitor, was also evaluated. Fibrin permeability was determined by flow measurement through the clot. Clot degradability was evaluated by the amount of D-dimer generated by clot perfusion with plasminogen and tissue plasminogen activator. Fibrin clot structure was assessed by confocal microscopy. WB clot permeability (KS) and degradability were 6.7- and 38-fold lower, respectively, compared with plasma clots. This is attributed to 1) occlusion of fibrin pores by RBCs and 2) a consistent increase in thrombin generation due to platelets and RBCs inducing formation of a tighter clot. Rivaroxaban added to plasma or WB before clotting, in reducing thrombin generation, led to the formation of a looser clot that is more degradable by fibrinolytic enzymes. Permeability and degradability of whole blood clots formed in the presence of rivaroxaban were very similar to those of plasma clots. The resistance to fibrinolysis of WB clots was reduced considerably when clots were formed with rivaroxaban. These results may have implications for the development of antithrombotic agents. Copyright © 2012 Elsevier Ltd. All rights reserved.

Retroperitoneal haematoma in a postoperative ALIF patient taking rivaroxaban for atrial fibrillation.

PubMed

Deekonda, Praveena; Stokes, Oliver M; Chan, Daniel

2016-11-02

Novel oral anticoagulants (NOACs) are being increasingly used in the secondary prevention of thromboembolic stroke in patients with atrial fibrillation. Patients taking NOACs are difficult to manage perioperatively, and several unexpected complications have been reported in these patients. We report a case of a rivaroxaban-induced retroperitoneal haematoma in a 72-year-old man who underwent an L5/S1 anterior lumbar interbody fusion (ALIF) for grade 1 spondylolytic spondylolisthesis. The patient suffered from atrial fibrillation and was taking rivaroxaban, a factor Xa inhibitor, for thromboembolic risk reduction. In accordance with perioperative Novel Oral Anticoagulant (NOAC) guidelines, rivaroxaban was stopped 2 days preoperatively and restarted on the third postoperative day. The patient presented on the ninth postoperative day, complaining of severe left iliac fossa pain, nausea, and vomiting, accompanied by swelling and bruising around the surgical site. A computed tomography (CT) scan showed a large expanding retroperitoneal haematoma. The patient was taken back to theatre for an evacuation of the haematoma and subsequently recovered without any further complications. This is the first case of a rivaroxaban-induced retroperitoneal haematoma reported in the literature, secondary to elective spinal surgery. This report adds to the body of evidence on the risk of postoperative bleeding in patients taking NOACs. If patients on NOACs present with abdominal symptoms following anterior approach to the lumbar spine, treating clinicians should have a high index of suspicion for retroperitoneal haematoma.

Resolution of massive left atrial appendage thrombi with rivaroxaban before balloon mitral commissurotomy in severe mitral stenosis: A case report and literature review.

PubMed

Li, Yuechun; Lin, Jiafeng; Peng, Chen

2016-12-01

Data on nonvitamin K antagonist oral anticoagulant being used for the treatment of LAA thrombi are limited only in nonvalvular atrial fibrillation. There are no data on the antithrombotic efficacy and safety of nonvitamin K antagonist oral anticoagulant in the resolution of left atrial appendage (LAA) thrombi in patients with rheumatic mitral stenosis. A 49-year-old woman with known rheumatic mitral stenosis and atrial fibrillation was referred for percutaneous transvenous mitral commissurotomy because of progressive dyspnea on exertion over a period of 3 months. Transesophageal echocardiography (TEE) demonstrated a large LAA thrombus protruding into left atria cavity before the procedure. Direct factor Xa (FXa) inhibitor rivaroxaban (20 mg/d) was started for the patient. After 3 weeks of rivaroxaban treatment TEE showed a relevantly decreased thrombus size, and a complete thrombus resolution was achieved after 5 weeks of anticoagulant therapy with the FXa inhibitor. To the best of our knowledge, this is the first documented case of large LAA thrombus resolution with nonvitamin K antagonist oral anticoagulant in severe mitral stenosis, and in which percutaneous transvenous mitral commissurotomy was performed subsequently. The report indicated that rivaroxaban could be a therapeutic option for mitral stenosis patients with LAA thrombus. Further study is required before the routine use of rivaroxaban in patients with rheumatic mitral stenosis and atrial fibrillation.

Rivaroxaban vs. warfarin for stroke prevention in patients with nonvalvular atrial fibrillation.

PubMed

Darby-Stewart, Andrea; Dachs, Robert; Graber, Mark A

2012-03-15

Patients with nonvalvular atrial fibrillation and a CHADS2 score of 2 points or more should be placed on warfarin anticoagulation. If they do not meet the CHADS2 criteria for warfarin, then they should receive therapy with aspirin. If a patient's condition is well-controlled on warfarin, this study does not support transitioning him or her to rivaroxaban, the more expensive alternative. Home monitoring of INR should be considered for patients who are capable and motivated to perform self-monitoring. Rivaroxaban has no reversal agent and has significant drug interactions (P-glycoprotein inducers and CYP3A4 inhibitors increase the risk of bleeding; P-glycoprotein inducers reduce effectiveness).

Rivaroxaban in the treatment of venous thromboembolism and the prevention of recurrences: a practical approach.

PubMed

Arcelus, Juan I; Domènech, Pere; Fernández-Capitan, Ma Del Carmen; Guijarro, Ricardo; Jiménez, David; Jiménez, Sonia; Lozano, Francisco S; Monreal, Manel; Nieto, José A; Páramo, José A

2015-05-01

Anticoagulation therapy is the standard treatment of patients with symptomatic venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. Until recently, treatment of VTE was based on parenteral or low-molecular-weight heparin for initial therapy (5-10 days) and oral vitamin K antagonists for long-term therapy. Those treatments have some limitations, including parenteral administration (heparins), the need for frequent monitoring and dose adjustments, interactions with several medications, and dietary restrictions (vitamin K antagonists). Rivaroxaban is a new oral direct factor Xa inhibitor with a wide therapeutic window, predictable anticoagulant effect, no food interactions, and few drug interactions. Consequently, no periodic monitoring of anticoagulation is needed, and fixed doses can be prescribed. EINSTEIN program demonstrated that rivaroxaban was as effective as and significantly safer than standard therapy for treatment of VTE. Rivaroxaban was recently authorized so doubts exist about how to use it in daily clinical practice. This document aims to clarify common questions formulated by clinicians regarding the use of this new drug. © The Author(s) 2014.

Risk of stroke/systemic embolism, major bleeding and associated costs in non-valvular atrial fibrillation patients who initiated apixaban, dabigatran or rivaroxaban compared with warfarin in the United States Medicare population.

PubMed

Amin, Alpesh; Keshishian, Allison; Trocio, Jeffrey; Dina, Oluwaseyi; Le, Hannah; Rosenblatt, Lisa; Liu, Xianchen; Mardekian, Jack; Zhang, Qisu; Baser, Onur; Vo, Lien

2017-09-01

To compare the risk and cost of stroke/systemic embolism (SE) and major bleeding between each direct oral anticoagulant (DOAC) and warfarin among non-valvular atrial fibrillation (NVAF) patients. Patients (≥65 years) initiating warfarin or DOACs (apixaban, rivaroxaban, and dabigatran) were selected from the Medicare database from 1 January 2013 to 31 December 2014. Patients initiating each DOAC were matched 1:1 to warfarin patients using propensity score matching to balance demographics and clinical characteristics. Cox proportional hazards models were used to estimate the risks of stroke/SE and major bleeding of each DOAC vs. warfarin. Two-part models were used to compare the stroke/SE- and major-bleeding-related medical costs between matched cohorts. Of the 186,132 eligible patients, 20,803 apixaban-warfarin pairs, 52,476 rivaroxaban-warfarin pairs, and 16,731 dabigatran-warfarin pairs were matched. Apixaban (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.31, 0.53) and rivaroxaban (HR = 0.72; 95% CI 0.63, 0.83) were significantly associated with lower risk of stroke/SE compared to warfarin. Apixaban (HR = 0.51; 95% CI 0.44, 0.58) and dabigatran (HR = 0.79; 95% CI 0.69, 0.91) were significantly associated with lower risk of major bleeding; rivaroxaban (HR = 1.17; 95% CI 1.10, 1.26) was significantly associated with higher risk of major bleeding compared to warfarin. Compared to warfarin, apixaban ($63 vs. $131) and rivaroxaban ($93 vs. $139) had significantly lower stroke/SE-related medical costs; apixaban ($292 vs. $529) and dabigatran ($369 vs. $450) had significantly lower major bleeding-related medical costs. Among the DOACs in the study, only apixaban is associated with a significantly lower risk of stroke/SE and major bleeding and lower related medical costs compared to warfarin.

Meta-Analysis of Effectiveness and Safety of Oral Anticoagulants in Atrial Fibrillation With Focus on Apixaban.

PubMed

Bai, Ying; Shi, Xu-Bo; Ma, Chang-Sheng; Lip, Gregory Y H

2017-11-01

We performed a meta-analysis of data on the effectiveness and safety of apixaban compared with other oral anticoagulants (warfarin or rivaroxaban or dabigatran or edoxaban) for stroke prevention in atrial fibrillation (AF) in different settings of randomized controlled trials, real-world studies, and radiofrequency ablation (RFA). Thirty studies were searched in PubMed, the Cochrane Library, and Clinicaltrials.gov databases reporting comparative effectiveness and safety of apixaban with warfarin (n = 23), rivaroxaban (n = 12), dabigatran (n = 13), or edoxaban (n = 2) for stroke prevention in AF. In real-world estimates, apixaban was similar to warfarin for the prevention of stroke or systematic thromboembolism (hazard ratio 0.93, 95% CI 0.71 to 1.14, I 2  = 82.9%, N = 7), and safer than warfarin in the risks of major bleeding (hazard ratio 0.62, 95% CI 0.54 to 0.70, I 2  = 18.7%, N = 9) in patients with AF. The risk of stroke or thromboembolism with apixaban was similar to rivaroxaban, dabigatran, and edoxaban in the settings of real-world studies and RFA. Major bleeding with apixaban was generally lower than rivaroxaban (relative risks 0.45, 95% CI 0.38 to 0.53, I 2  = 0%, N = 5) and similar to dabigatran in real-world studies (relative risks 1.44, 95% CI 0.33 to 6.30, I 2  = 97.7%, N = 5), but similar to rivaroxaban, dabigatran, and edoxaban in RFA. In conclusion, our meta-analysis provides a comprehensive estimate of the effectiveness and safety of apixaban compared with other oral anticoagulants (warfarin, rivaroxaban, dabigatran, and edoxaban) in patients with AF in different settings of randomized controlled trial, real-world studies, and RFA. Copyright © 2017 Elsevier Inc. All rights reserved.

Factors Associated With Major Bleeding Events

PubMed Central

Goodman, Shaun G.; Wojdyla, Daniel M.; Piccini, Jonathan P.; White, Harvey D.; Paolini, John F.; Nessel, Christopher C.; Berkowitz, Scott D.; Mahaffey, Kenneth W.; Patel, Manesh R.; Sherwood, Matthew W.; Becker, Richard C.; Halperin, Jonathan L.; Hacke, Werner; Singer, Daniel E.; Hankey, Graeme J.; Breithardt, Gunter; Fox, Keith A. A.; Califf, Robert M.

2014-01-01

Objectives This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). Background The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin. Methods The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model. Results The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, ≥75 years; pinteraction = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) ≥90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk. Conclusions Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767) PMID:24315894

Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.

PubMed

Mega, J L; Braunwald, E; Mohanavelu, S; Burton, P; Poulter, R; Misselwitz, F; Hricak, V; Barnathan, E S; Bordes, P; Witkowski, A; Markov, V; Oppenheimer, L; Gibson, C M

2009-07-04

Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Evaluation of the efficacy and safety of rivaroxaban using a computer model for blood coagulation.

PubMed

Burghaus, Rolf; Coboeken, Katrin; Gaub, Thomas; Kuepfer, Lars; Sensse, Anke; Siegmund, Hans-Ulrich; Weiss, Wolfgang; Mueck, Wolfgang; Lippert, Joerg

2011-04-22

Rivaroxaban is an oral, direct Factor Xa inhibitor approved in the European Union and several other countries for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is in advanced clinical development for the treatment of thromboembolic disorders. Its mechanism of action is antithrombin independent and differs from that of other anticoagulants, such as warfarin (a vitamin K antagonist), enoxaparin (an indirect thrombin/Factor Xa inhibitor) and dabigatran (a direct thrombin inhibitor). A blood coagulation computer model has been developed, based on several published models and preclinical and clinical data. Unlike previous models, the current model takes into account both the intrinsic and extrinsic pathways of the coagulation cascade, and possesses some unique features, including a blood flow component and a portfolio of drug action mechanisms. This study aimed to use the model to compare the mechanism of action of rivaroxaban with that of warfarin, and to evaluate the efficacy and safety of different rivaroxaban doses with other anticoagulants included in the model. Rather than reproducing known standard clinical measurements, such as the prothrombin time and activated partial thromboplastin time clotting tests, the anticoagulant benchmarking was based on a simulation of physiologically plausible clotting scenarios. Compared with warfarin, rivaroxaban showed a favourable sensitivity for tissue factor concentration inducing clotting, and a steep concentration-effect relationship, rapidly flattening towards higher inhibitor concentrations, both suggesting a broad therapeutic window. The predicted dosing window is highly accordant with the final dose recommendation based upon extensive clinical studies.

Evaluation of the Efficacy and Safety of Rivaroxaban Using a Computer Model for Blood Coagulation

PubMed Central

Burghaus, Rolf; Coboeken, Katrin; Gaub, Thomas; Kuepfer, Lars; Sensse, Anke; Siegmund, Hans-Ulrich; Weiss, Wolfgang; Mueck, Wolfgang; Lippert, Joerg

2011-01-01

Rivaroxaban is an oral, direct Factor Xa inhibitor approved in the European Union and several other countries for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is in advanced clinical development for the treatment of thromboembolic disorders. Its mechanism of action is antithrombin independent and differs from that of other anticoagulants, such as warfarin (a vitamin K antagonist), enoxaparin (an indirect thrombin/Factor Xa inhibitor) and dabigatran (a direct thrombin inhibitor). A blood coagulation computer model has been developed, based on several published models and preclinical and clinical data. Unlike previous models, the current model takes into account both the intrinsic and extrinsic pathways of the coagulation cascade, and possesses some unique features, including a blood flow component and a portfolio of drug action mechanisms. This study aimed to use the model to compare the mechanism of action of rivaroxaban with that of warfarin, and to evaluate the efficacy and safety of different rivaroxaban doses with other anticoagulants included in the model. Rather than reproducing known standard clinical measurements, such as the prothrombin time and activated partial thromboplastin time clotting tests, the anticoagulant benchmarking was based on a simulation of physiologically plausible clotting scenarios. Compared with warfarin, rivaroxaban showed a favourable sensitivity for tissue factor concentration inducing clotting, and a steep concentration–effect relationship, rapidly flattening towards higher inhibitor concentrations, both suggesting a broad therapeutic window. The predicted dosing window is highly accordant with the final dose recommendation based upon extensive clinical studies. PMID:21526168

Trends in oral anticoagulant use in Qatar: a 5-year experience.

PubMed

Elewa, Hazem; Alhaddad, Amani; Al-Rawi, Safa; Nounou, Amir; Mahmoud, Hesham; Singh, Rajvir

2017-04-01

In Qatar, dabigatran was introduced in 2011 followed by rivaroxaban in 2014. In this study, we aim to explore the trends in oral anticoagulant use in Qatar over the past 5 years and to what extent did DOACs replace warfarin. We also explored the extent of switching between different anticoagulants (from warfarin to DOACs and vice versa). We collected all anticoagulant prescriptions dispensed as in- or out-patient from 2011 to 2015 in all Hamad Medical Corporation (HMC) hospitals. Overall number of patients using warfarin, dabigatran and rivaroxaban over the last 5 years collectively was calculated. Per each calendar year, we calculated the number of all 3 OAC used (warfarin, dabigatran and rivaroxaban), frequency of use of each one of the OAC prescribed and compared the change in proportion of DOACs to warfarin prescriptions over the years. Overall, 6961 patients were using OAC over the past 5 years among which 5849 (84%) used warfarin, 496 (7.1%) used dabigatran and 616 (8.8%) used rivaroxaban. Oral anticoagulants use increased gradually from 2091 in 2011 to 3688 in 2015. Number of patients receiving DOACs increased significantly compared to warfarin [11 (0.5%) in 2011 vs. 849 (23%) in 2015 (p < 0.0001)]. Since its introduction in 2014, number of rivaroxaban users increased significantly compared to dabigatran [212 (40.9%) in 2014 vs. 544 (64.1%) in 2015]. DOACs have been gradually replacing warfarin in Qatar and the trend of their use is similar to that reported in other countries. Warfarin remains the most commonly used oral anticoagulant.

[Critical haematuria after prostate biopsies with RIVAROXABAN. Case report].

PubMed

Olivier, J; Yakoubi, R; Gras, S; Van Agt, G; Delepaul, B

2013-10-01

Managing patients with new oral anticoagulants in perioperative period is not yet well protocolized. We report a clinical case of a critical haematuria after prostate biopsies to a patient treated with RIVAROXABAN. Monitoring and treatment of the haematuria have been difficult due to the lack of biological control and antidote for this treatment. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Photodegradation of novel oral anticoagulants under sunlight irradiation in aqueous matrices.

PubMed

Yassine, Montaha; Fuster, Laura; Dévier, Marie-Hélène; Geneste, Emmanuel; Pardon, Patrick; Grélard, Axelle; Dufourc, Erick; Al Iskandarani, Mohamad; Aït-Aïssa, Selim; Garric, Jeanne; Budzinski, Hélène; Mazellier, Patrick; Trivella, Aurélien S

2018-02-01

Kinetics of photodegradation of novel oral anticoagulants dabigatran, rivaroxaban, and apixaban were studied under simulated solar light irradiation in purified, mineral, and river waters. Dabigatran and rivaroxaban underwent direct photolysis with polychromatic quantum yields of 2.2 × 10 -4 and 4.4 × 10 -2 , respectively. The direct photodegradation of apixaban was not observed after 19 h of irradiation. Kinetics of degradation of rivaroxaban was not impacted by the nature of the aqueous matrix while photosensitization from nitrate ions was observed for dabigatran and apixaban dissolved in a mineral water. The photosensitized reactions were limited in the tested river water (Isle River, Périgueux, France) certainly due to the hydroxyl radical scavenging effect of the dissolved organic matter. The study of photoproduct structures allowed to identify two compounds for dabigatran. One of them is the 4-aminobenzamidine while the second one is a cyclization product. In the case of rivaroxaban, as studied by very high field NMR, only one photoproduct was observed i.e. a photoisomer. Finally, seven photoproducts were clearly identified from the degradation of apixaban under simulated solar light. Copyright © 2017 Elsevier Ltd. All rights reserved.

Adherence to Rivaroxaban, Dabigatran, and Apixaban for Stroke Prevention in Incident, Treatment-Naïve Nonvalvular Atrial Fibrillation.

PubMed

Brown, Joshua D; Shewale, Anand R; Talbert, Jeffery C

2016-11-01

Non-vitamin K antagonist oral anticoagulants (NOACs) are widely used for prevention of stroke secondary to nonvalvular atrial fibrillation (NVAF). Increased use of NOACs is partially a result of simplified regimens compared with warfarin, which has been associated with poor adherence and persistence to therapy. Few studies have assessed adherence to NOACs, especially using contemporary data now that multiple NOACs are available. To evaluate adherence to NOACs in a cohort of newly diagnosed NVAF patients who are commercially insured. Incident, treatment-naïve NVAF patients were identified in 2013 from a large claims database. Patients were included who initiated rivaroxaban, dabigatran, or apixaban within 30 days after diagnosis. Subjects were required to have 12 months of pre-index information to assess demographic and clinical characteristics (comorbidities, CHA 2 DS 2 -VASc, and HAS-BLED scores). Adherence to the index medication and adherence to any oral anticoagulant was assessed using proportion of days covered (PDC) at 3, 6, and 9 months. The number of switches and gaps in therapy were also evaluated. Analyses were stratified by stroke risk scores, and a logistic regression model was used to control for factors that may predict high adherence (PDC ≥ 0.80). A total of 3,455 rivaroxaban, 1,264 dabigatran, and 504 apixaban users were included with no major clinical or demographic differences between groups. At 3, 6, and 9 months of follow-up, dabigatran had lower adherence (PDC = 0.77, 0.67, and 0.62) compared with rivaroxaban (PDC = 0.84, 0.75, and 0.70; P < 0.001) and apixaban (PDC = 0.82, 0.75, and 0.71; P < 0.001), as well as nearly twice the number of switches to either other anticoagulants or antiplatelet therapy. At 9 months, 55.0% of rivaroxaban initiators had PDC ≥ 0.80, which was comparable with 56.8% for apixaban and significantly greater than 46.7% for dabigatran (P < 0.001). Adherence was higher overall as stroke risk increased and showed dabigatran had consistently lower adherence compared with the other NOACs. Overall adherence to any oral anticoagulants, allowing for switches to another NOAC or warfarin, was not dependent on the index medication (9-month PDC = 0.74, 0.71, and 0.74 for rivaroxaban, dabigatran, and apixaban initiators). Adjusted analyses showed that increasing age and comorbid hypertension and diabetes were associated with higher adherence. Compared with rivaroxaban, dabigatran initiators had nearly 30% lower odds of being adherent to their index medication, and no differences were observed between apixaban and rivaroxaban. At 9 months, there were no differences between NOACs for overall adherence to oral anticoagulants. In this real-world analysis of adherence to NOACs, rivaroxaban and apixaban had favorable profiles compared with dabigatran, and rivaroxaban appeared to have higher overall adherence among the NOACs. Clinicians and managed care organizations should consider the implications of lower adherence on clinical outcomes as well as quality assessment. The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1TR000117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Brown reports receiving a training fellowship from Human and Pfizer. Study concept and design were contributed by Brown and Shewale. Talbert took the lead in data collection, along with Brown, and data interpretation was primarily performed by Brown, along with Shewale. The manuscript was written primarily by Brown, along with Shewale, and revised by all the authors.

Risk of Myocardial Infarction in Patients with Long-Term Non-Vitamin K Antagonist Oral Anticoagulant Treatment.

PubMed

Tornyos, Adrienn; Kehl, Dániel; D'Ascenzo, Fabrizio; Komócsi, András

2016-01-01

The relative cardiovascular (CV) safety of oral anticoagulants continues to be debated, and in particular concerns for risk of myocardial infarction (MI) have been raised. We analyzed the risk of MI in patients treated long term with oral anticoagulants (vitamin K antagonists [VKA], direct thrombin inhibitors or activated X factor antagonist) for atrial fibrillation, deep vein thrombosis or pulmonary embolism using a network meta-analysis (NMA). Randomized, phase 3 trials comparing novel anticoagulants to VKA were searched. Information on study design and clinical outcomes was extracted. The primary end-point of the analysis was the occurrence of MI or acute coronary syndrome. A Bayesian multiple treatment analysis was performed using fixed-effect and random-effects modeling. Twelve trials including 100,524 randomized patients were analyzed. The odds for MI in NMA were worse with dabigatran when compared to VKA, rivaroxaban, apixaban, and edoxaban (OR: 0.66 CI: 0.49-0.87; OR: 0.56 CI: 0.38-0.82, OR: 0.59 CI 0.40-0.88, and OR: 0.71 CI: 0.50-1.0, respectively).The posterior probability of being the first best choice of treatment was 53.5% for rivaroxaban, 33.8% for apixaban, 9.5% for ximelagatran, 2.0% for edoxaban, 1.2% for VKA, and 0.007% for dabigatran. There is a considerable heterogeneity regarding CV safety among oral anticoagulants. Differences in risk of MI may influence the choice of treatment. Multiple treatment NMA found 29%-44% higher odds of MI with dabigatran supporting the concerns regarding its CV safety. Copyright © 2015 Elsevier Inc. All rights reserved.

Anticoagulant management in the cardiovascular setting.

PubMed

Verheugt, Freek W A

2012-02-01

Vitamin K antagonists have been used as oral anticoagulants (OACs) for over five decades, yet their use in real-world practice is problematic primarily because of their narrow therapeutic window, exacerbated by extensive food and drug interactions, necessitating regular coagulation monitoring and dose adjustment. Around half of patients receiving warfarin are within the therapeutic range, exposing them to the dangers of under-anticoagulation (i.e. thrombosis formation) or over-anticoagulation (i.e. bleeding). A new generation of OACs with improved pharmacology promises to revolutionize antithrombotic management. Rivaroxaban, apixaban (both oral direct Factor Xa inhibitors) and dabigatran (a direct thrombin inhibitor) all exhibit predictable anticoagulant responses and few drug-drug interactions and do not require routine coagulation monitoring. © 2011 The Author Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.

Cost comparison of continued anticoagulation with rivaroxaban versus placebo based on the 1-year EINSTEIN-Extension trial efficacy and safety results.

PubMed

Wells, Philip S; Lensing, Anthonie W A; Haskell, Lloyd; Levitan, Bennett; Laliberté, François; Durkin, Michael; Ashton, Veronica; Xiao, Yongling; Crivera, Concetta; Lejeune, Dominique; Schein, Jeff; Lefebvre, Patrick

2018-06-01

The EINSTEIN-Extension trial (EINSTEIN-EXT) found that continued treatment with rivaroxaban for an additional 6 or 12 months (vs placebo) after 6-12 months of initial anticoagulation significantly reduced the risk of recurrent venous thromboembolism (VTE) with a small non-significant increased risk of major bleeding (none fatal or in critical site). This study aimed to compare total healthcare cost between rivaroxaban and placebo, based on the EINSTEIN-EXT event rates. Total healthcare cost was calculated as the sum of treatment and clinical event costs from a US managed care perspective. Treatment duration and event rates were obtained from the EINSTEIN-EXT study. Adjustment on treatment duration was made by assuming a 10% non-adherence rate. Drug costs were based on wholesale acquisition costs. Cost estimates for clinical events (i.e. recurrent deep vein thrombosis [DVT], recurrent pulmonary embolism, major bleeding, clinically relevant non-major bleeding) were determined from the literature. Results were examined over a ±20% range of each cost component and over 95% confidence intervals (CIs) of event rate differences in deterministic (one-way) and probabilistic sensitivity analyses (PSA). Total healthcare cost was $1,454 lower for rivaroxaban-treated (vs placebo-treated) patients in the base-case, with a lower clinical event cost fully offsetting drug cost. The cost savings of recurrent DVT alone (-$3,102) was greater than drug cost ($2,723). Total healthcare cost remained lower for rivaroxaban in the majority (73%) of PSA (cost difference [95% CI] = -$1,454 [-$2,396, $1,231]). This study was conducted over the 1-year observation period of the EINSTEIN-EXT trial, which limited "real-world" applicability and examination of long-term economic impact. Assumptions on drug and clinical event costs were US-based and, thus, not applicable to other healthcare systems. Total healthcare costs were estimated to be lower for patients continuing rivaroxaban therapy compared to those receiving placebo in VTE patients who had completed 6-12 months of VTE treatment.

Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D).

PubMed

Young, Annie M; Marshall, Andrea; Thirlwall, Jenny; Chapman, Oliver; Lokare, Anand; Hill, Catherine; Hale, Danielle; Dunn, Janet A; Lyman, Gary H; Hutchinson, Charles; MacCallum, Peter; Kakkar, Ajay; Hobbs, F D Richard; Petrou, Stavros; Dale, Jeremy; Poole, Christopher J; Maraveyas, Anthony; Levine, Mark

2018-05-10

Purpose Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer. Patient and Methods In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ± 4.5%, assuming a VTE recurrence rate at 6 months of 10%. Results A total of 203 patients were randomly assigned to each group, 58% of whom had metastases. Twenty-six patients experienced recurrent VTE (dalteparin, n = 18; rivaroxaban, n = 8). The 6-month cumulative VTE recurrence rate was 11% (95% CI, 7% to 16%) with dalteparin and 4% (95% CI, 2% to 9%) with rivaroxaban (hazard ratio [HR], 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate of major bleeding was 4% (95% CI, 2% to 8%) for dalteparin and 6% (95% CI, 3% to 11%) for rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). Corresponding rates of CRNMB were 4% (95% CI, 2% to 9%) and 13% (95% CI, 9% to 19%), respectively (HR, 3.76; 95% CI, 1.63 to 8.69). Conclusion Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin.

Bleeding risk of apixaban, dabigatran, and low-dose rivaroxaban compared with warfarin in Japanese patients with non-valvular atrial fibrillation: a propensity matched analysis of administrative claims data.

PubMed

Kohsaka, Shun; Murata, Tatsunori; Izumi, Naoko; Katada, Jun; Wang, Feng; Terayama, Yasuo

2017-11-01

There is scarce evidence comparing novel oral anticoagulants (NOACs) with warfarin in real-world settings in Japan. This study compared the risk of bleeding events among patients with non-valvular atrial fibrillation (NVAF) initiating treatment with NOACs versus warfarin. A retrospective cohort study was conducted using a de-identified electronic health record based database of health claims and Diagnosis Procedure Combination data from 275 consenting hospitals in Japan. NVAF patients newly initiated on oral anticoagulants were eligible. Based on the first prescription, patients were assigned to 5/2.5 mg BID apixaban, 150/110 mg BID dabigatran, 15/10 mg QD rivaroxaban (approved dose lower in Japan compared to Western countries [20/15 mg QD]) or warfarin groups. One-to-one propensity score matching (PSM) was used to balance patient characteristics between warfarin and each NOAC. Patients were followed up to 1 year post-first prescription. Among 38,662 eligible patients, a total of 5977, 5090, and 6726 matched pairs were identified for warfarin versus apixaban, warfarin versus dabigatran, and warfarin versus rivaroxaban, respectively after PSM. Compared to warfarin, apixaban (hazard ratio [HR] 0.586; 95% CI 0.421-0.815), dabigatran (HR 0.617; 0.425-0.895) and rivaroxaban (HR 0.693; 0.514-0.933) were associated with a significantly lower risk of major bleeding. The risk of any bleeding was significantly lower for apixaban (HR 0.782; 0.682-0.896), but not for dabigatran (HR 0.988; 0.860-1.135) or rivaroxaban (HR 0.938; 0.832-1.057) when comparing to warfarin. Among Japanese patients with NVAF, treatment with apixaban 5/2.5 mg BID was associated with a significantly lower risk of major bleeding and any bleeding when compared to warfarin. Treatment with dabigatran 150/110 mg BID or rivaroxaban 15/10 mg QD was associated with a significantly lower risk of major bleeding, but not any bleeding, than warfarin. The potential benefit of individual NOACs in real-world practice needs to be assessed further.

Peri-procedural interrupted oral anticoagulation for atrial fibrillation ablation: comparison of aspirin, warfarin, dabigatran, and rivaroxaban

PubMed Central

Winkle, Roger A.; Mead, R. Hardwin; Engel, Gregory; Kong, Melissa H.; Patrawala, Rob A.

2014-01-01

Aims Atrial fibrillation ablation requires peri-procedural oral anticoagulation (OAC) to prevent thromboembolic events. There are several options for OAC. We evaluate peri-procedural AF ablation complications using a variety of peri-procedural OACs. Methods and results We examined peri-procedural OAC and groin, bleeding, and thromboembolic complications for 2334 consecutive AF ablations using open irrigated-tip radiofrequency (RF) catheters. Pre-ablation OAC was warfarin in 1113 (47.7%), dabigatran 426 (18.3%), rivaroxaban 187 (8.0%), aspirin 472 (20.2%), and none 136 (5.8%). Oral anticoagulation was always interrupted and intraprocedural anticoagulation was unfractionated heparin (activated clotting time, ACT = 237 ± 26 s). Pre- and post-OAC drugs were the same for 1591 (68.2%) and were different for 743 (31.8%). Following ablation, 693 (29.7%) were treated with dabigatran and 291 (12.5%) were treated with rivaroxaban. There were no problems changing from one OAC pre-ablation to another post-ablation. Complications included 12 (0.51%) pericardial tamponades [no differences for dabigatran (P = 0.457) or rivaroxaban (P = 0.163) compared with warfarin], 12 (0.51%) groin complications [no differences for rivaroxaban (P = 0.709) and fewer for dabigatran (P = 0.041) compared with warfarin]. Only 5 of 2334 (0.21%) required blood transfusions. There were two strokes (0.086%) and no transient ischaemic attacks (TIAs) in the first 48 h post-ablation. Three additional strokes (0.13%), and two TIAs (0.086%) occurred from 48 h to 30 days. Only one stroke had a residual deficit. Compared with warfarin, the neurologic event rate was not different for dabigatran (P = 0.684) or rivaroxaban (P = 0.612). Conclusion Using interrupted OAC, low target intraprocedural ACT, and irrigated-tip RF, the rate of peri-procedural groin, haemorrhagic, and thromboembolic complications was extremely low. There were only minimal differences between OACs. Low-risk patients may remain on aspirin/no OAC pre-ablation. There are no problems changing from one OAC pre-ablation to another post-ablation. PMID:25115168

Efficacy and Safety of Rivaroxaban Versus Warfarin in Patients Taking Nondihydropyridine Calcium Channel Blockers for Atrial Fibrillation (from the ROCKET AF Trial).

PubMed

Washam, Jeffrey B; Hellkamp, Anne S; Lokhnygina, Yuliya; Piccini, Jonathan P; Berkowitz, Scott D; Nessel, Christopher C; Becker, Richard C; Breithardt, Günter; Fox, Keith A A; Halperin, Jonathan L; Hankey, Graeme J; Mahaffey, Kenneth W; Singer, Daniel E; Patel, Manesh R

2017-08-15

Non-dihydropyridine calcium channel blockers (non-DHP CCBs) possess combined P-glycoprotein and moderate CYP3A4 inhibition, which may lead to increased exposure of medications that are substrates for these metabolic pathways, such as rivaroxaban. We evaluated the use and outcomes of non-DHP CCBs in patients with atrial fibrillation (AF) in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). We assessed clinical outcomes in patients who received non-DHP CCBs and the impact on the efficacy and safety of rivaroxaban compared with warfarin. Stroke or noncentral nervous system (CNS) systemic embolism (SE), major or nonmajor clinically relevant (NMCR) bleeding, all-cause death, and major bleeding were compared according to non-DHP CCB use. At randomization, 1,308 patients (9.2%) were taking a non-DHP CCB. They were more likely to be women, have diabetes and COPD, and less likely to have heart failure and had a lower mean CHADS 2 score (3.3 vs 3.5). Non-DHP CCB use was not associated with an increased risk of stroke/non-CNS SE (p = 0.11) or the composite outcome of NMCR or major bleeding (p = 0.087). Non-DHP CCB use was associated with an increased risk of major bleeding (adjusted hazard ratio 1.50, 95% CI 1.11 to 2.04) and intracranial hemorrhage (adjusted hazard ratio 2.84, 95% CI 1.53 to 5.29). No significant difference was observed in the primary efficacy (stroke or non-CNS SE; adjusted interaction p value = 0.38) or safety outcome (NMCR or major bleeding; adjusted interaction p value = 0.14) between rivaroxaban and warfarin with non-DHP CCB use. In conclusion, although the overall use of non-DHP CCBs was associated with an increased risk of major bleeding and intracranial hemorrhage, the use was not associated with a significant change in the safety or efficacy of rivaroxaban compared with warfarin observed in ROCKET AF. Copyright © 2017 Elsevier Inc. All rights reserved.

Outcomes of Temporary Interruption of Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation

PubMed Central

Sherwood, Matthew W.; Douketis, James D.; Patel, Manesh R.; Piccini, Jonathan P.; Hellkamp, Anne S.; Lokhnygina, Yuliya; Spyropoulos, Alex C.; Hankey, Graeme J.; Singer, Daniel E.; Nessel, Christopher C.; Mahaffey, Kenneth W.; Fox, Keith A. A.; Califf, Robert M.; Becker, Richard C.

2014-01-01

Background During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI. Methods and Results In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non–central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3–30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36–1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80–2.00]; P=0.32). Conclusions TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767. PMID:24552831

Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants.

PubMed

Cuker, Adam; Siegal, Deborah M; Crowther, Mark A; Garcia, David A

2014-09-16

Non-vitamin K oral anticoagulants (NOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations. This study's objective was to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban. We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2). We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R(2) = 0.92 to 0.99) and ecarin-based assays (R(2) = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. For rivaroxaban and apixaban, anti-Xa activity is linear (R(2) = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification. Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in NOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Possible Rivaroxaban Failure during the Postpartum Period.

PubMed

Rudd, Kelly M; Winans, Amanda R McFee; Panneerselvam, Narmadha

2015-11-01

Rivaroxaban, a factor Xa inhibitor, is a direct-acting oral anticoagulant (DOAC) indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for reducing the risk of DVT and PE recurrence. To our knowledge, no data are presently available to guide DOAC dosing in the postpartum period when pharmacokinetic and pharmacodynamic changes induced by pregnancy have an impact on drug clearance and increase hypercoagulability for a period of 6-8 weeks after delivery. We describe the case of a 35-year-old postpartum woman who presented to the emergency department with a diagnosis of a new multiple segmental PE 5 days after starting rivaroxaban therapy for a diagnosis of DVT. No precipitating cause, including noncompliance, was identified as a source of thrombosis embolization or extension. The patient was admitted, a heparin infusion was started for the management of PE, and rivaroxaban was discontinued. She was transitioned to enoxaparin 1 mg/kg (90 mg) subcutaneously every 12 hours the next day, bridged to warfarin, and discharged home on the overlapping regimen with close follow-up by the pharmacist-managed outpatient Anticoagulation Management Service. To our knowledge, this is the first case report of potential failure associated with rivaroxaban therapy in the postpartum period, possibly due to pharmacokinetic alterations seen in the postpartum period contributing to decreased drug exposure, yielding reduced anticoagulant efficacy. Clinicians should carefully weigh the risks and benefits of DOAC therapy in postpartum patients or other special populations requiring anticoagulation therapy. This report also highlights the need for further research identifying the impact of pharmacokinetic changes induced by special populations and the need to develop monitoring assays for such clinical situations. © 2015 Pharmacotherapy Publications, Inc.

Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system.

PubMed

Raschi, Emanuel; Poluzzi, Elisabetta; Koci, Ariola; Salvo, Francesco; Pariente, Antoine; Biselli, Maurizio; Moretti, Ugo; Moore, Nicholas; De Ponti, Fabrizio

2015-08-01

We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS). We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications. DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively). The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury. © 2015 The British Pharmacological Society.

Incidence and characteristics of major bleeding among rivaroxaban users with renal disease and nonvalvular atrial fibrillation

PubMed Central

Patel, Manesh R.; Peacock, W. Frank; Tamayo, Sally; Sicignano, Nicholas; Hopf, Kathleen P.; Yuan, Zhong

2018-01-01

Objective Patients with nonvalvular atrial fibrillation (AF) and renal disease (RD) who receive anticoagulation therapy appear to be at greater risk of major bleeding (MB) than AF patients without RD. As observed in past studies, anticoagulants are frequently withheld from AF patients with RD due to concerns regarding bleeding. The objective of this study was to evaluate the incidence and pattern of MB in those with RD, as compared to those without RD, in a population of rivaroxaban users with nonvalvular AF. Methods Electronic medical records of over 10 million patients from the Department of Defense Military Health System were queried to identify rivaroxaban users with nonvalvular AF. A validated algorithm was used to identify MB-related hospitalizations. RD was defined through diagnostic codes present within 6 months prior to the bleeding date for MB cases and end of study participation for non-MB patients. Data were collected on patient characteristics, comorbidities, MB management, and outcomes. Results Overall, 44,793 rivaroxaban users with nonvalvular AF were identified. RD was present among 6,921 patients (15.5%). Patients with RD had a higher rate of MB than those without RD, 4.52 per 100 person-years versus 2.54 per 100 person-years, respectively. The fatal bleeding outcome rate (0.09 per 100 person-years) was identical between those with and without RD. Conclusion In this post-marketing study of 44,793 rivaroxaban users with nonvalvular AF, RD patients experienced a higher MB rate than those without RD. The higher rate of MB among those with RD may be due to the confounding effects of comorbidities. PMID:29618192

ROCKET AF adds more concerns about Digoxin safety in patients with atrial fibrillation

PubMed Central

ElMaghawry, Mohamed

2015-01-01

In a recent article in the Journal, we have reviewed the adverse cardiovascular outcomes observed with digoxin use in the PALLAS study.1 The PALLAS study was designed to determine if dronedarone would reduce major vascular events in patients with permanent atrial fibrillation (AF).2 However the study was stopped early because of safety reasons, as a significant number of patients on the dronedarone arm reached the co-primary end point composite of stroke, myocardial infarction, systemic embolism, or cardiovascular death. Data sub-analyses suggested that digoxin-dronedarone interaction was responsible for the higher arrhythmic death rate observed in the trial. These observations are consistent with several other studies that demonstrate the potential hazard of the use of digoxin in heart failure and/or atrial fibrillation. A more recent article published in the Lancet studied the use and outcomes of digoxin in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism in Atrial Fibrillation (ROCKET AF) trial.3 The investigators concluded that digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. PMID:26779514

[Ultrasound dynamics lysis apex thrombus as an objective criterion of effectiveness of anticoagulation therapy in venous thrombosis].

PubMed

Kalinin, R E; Suchkov, I A; Pshennikov, A S; Agapov, A B

2016-01-01

To assess the effectiveness of anticoagulant therapy (ACT) for the treatment of patients with deep venous thrombosis (DVT) of the lower extremities. The study considered ultrasonic characteristics of lysis of the proximal part of thrombus: localization and nature of venous thrombosis, the length and diameter of the proximal floating part of the thrombus, and duration of the venous thrombosis. Depending on the ACT options patients were divided into 3 groups: Group 1 (18 patients) received rivaroxaban, group 2 (19 patients) received enoxaparin sodium with subsequent transition to warfarin, and 3 group (19 patietns) received enoxaparin sodium, followed by administration of rivaroxaban. Treatment with rivaroxaban was preferable over standard ACT with enoxaparin/warfarin with regards to the lysis of thrombus when duration of thrombosis did not exceed 10 days. In 10.5% of patients who received warfarin flotation of thrombi remained for 14 days; the length of the floating part of the thrombi did not exceed 3 cm. Such circumstances and inability to reach a therapeutic INR value required cava filter placement. Treatment with enoxaparin sodium followed by the administration of rivaroxaban was found to be the most efficient ACT regimen as there was no negative dynamics of ultrasound characteristics of lysis of thrombi at any duration of the disease.

Adherence to Rivaroxaban Compared with Other Oral Anticoagulant Agents Among Patients with Nonvalvular Atrial Fibrillation.

PubMed

McHorney, Colleen A; Ashton, Veronica; Laliberté, François; Germain, Guillaume; Wynant, Willy; Crivera, Concetta; Schein, Jeffrey R; Lefebvre, Patrick; Peterson, Eric D

2017-09-01

Adherence to oral anticoagulant (OAC) agents is important for patients with nonvalvular atrial fibrillation (NVAF) to prevent potentially severe adverse events. To compare real-world adherence rates and time to discontinuation for rivaroxaban versus other OACs (apixaban, dabigatran, and warfarin) among patients with NVAF using claims-based data. Health care claims from the IMS Health Real-World Data Adjudicated Claims database (July 2012-June 2015) were analyzed. Adherence rate was defined as the percentage of patients with proportion of days covered (PDC) ≥ 0.80 and ≥ 0.90. Discontinuation was defined as a gap of more than 30 days between the end of a dispensing days of supply and the start date of the next fill, if any. Patients were included if they had ≥ 2 dispensings of rivaroxaban, apixaban, dabigatran, or warfarin at least 180 days apart (the first was considered the index date), had > 60 days of supply, had ≥ 6 months of pre-index eligibility, had ≥ 1 atrial fibrillation (AF) diagnosis pre-index or at index date, and had no valvular involvement. A logistic regression model was used to evaluate adherence to OAC therapy, while a Cox model was used to compare time to discontinuation; both models adjusted for baseline confounders. A total of 13,645 rivaroxaban, 6,304 apixaban, 3,360 dabigatran, and 13,366 warfarin patients were identified. A significantly higher proportion of rivaroxaban users (80.1%) was adherent to therapy (PDC ≥ 0.80 at 6 months) versus apixaban (75.8%), dabigatran (69.2%), and warfarin users (64.5%). After adjustment, the proportion of patients adherent to therapy remained significantly higher for rivaroxaban users versus apixaban (absolute difference [AD] = 5.8%), dabigatran (AD = 9.5%), and warfarin users (AD = 13.6%; all P < 0.001). More pronounced differences were found with a PDC ≥0.90. In addition, rivaroxaban users were significantly less likely to discontinue therapy compared with other OACs after adjustments (all P < 0.05). Among NVAF patients, rivaroxaban was associated with significantly higher adherence rates relative to other OACs whether using either a PDC of > 0.80 or > 0.90. Such differences in adherence could translate into improved patient outcomes and lower health care costs. This research was funded by Janssen Scientific Affairs. Ashton, Crivera, and Schein are employees and stockholders of Janssen Scientific Affairs. Laliberté, Germain, Wynant, and Lefebvre are employees of Analysis Group, a consulting company that received research grants from Janssen Scientific Affairs in connection with this study. McHorney is an employee of Evidera, a consulting company that received research grants from Janssen Scientific Affairs in connection with this study. Peterson received research grants from Janssen Scientific Affairs in connection with this study. All authors contributed to concept and design. The data were collected by Germain, Wynant, Laliberté, and Lefebvre and interpreted primarily by McHorney and Peterson, with the assistance of Lefebvre, Laliberté, Ashton, Crivera, and Schein. The manuscript was written primarily by Laliberté, Germain, and Lefebvre, with the assistance of Wynant. Revisions were made primarily by Ashton, Crivera, McHorney, Schein, and Peterson.

Oral anticoagulant persistence in patients with non-valvular atrial fibrillation: A cohort study using primary care data in Germany

PubMed Central

Lefèvre, Cinira; Evans, David; Hack, Guido; Stynes, Gillian; Maguire, Andrew

2017-01-01

This study examined characteristics and treatment persistence among patients prescribed oral anticoagulants (OACs) for stroke prevention in non-valvular atrial fibrillation (NVAF). We identified 15,244 patients (51.8% male, 72.7% aged ≥70) with NVAF and no prior OAC therapy who were prescribed apixaban (n = 1,303), rivaroxaban (n = 5,742), dabigatran (n = 1,622) or vitamin-K antagonists (VKAs, n = 6,577) between 1-Dec-2012 and 31-Oct-2014 in German primary care (IMS® Disease Analyzer). We compared OAC persistence using Cox regression over patients’ entire follow-up and using a data-driven time-partitioned approach (before/after 100 days) to handle non-proportional hazards. History of stroke risk factors (stroke/transient ischaemic attack [TIA] 15.2%; thromboembolism 14.1%; hypertension 84.3%) and high bleeding risk (HAS-BLED score≥3 68.4%) was common. Apixaban-prescribed patients had more frequent history of stroke/TIA (19.7%) and high bleeding risk (72.6%) than other OACs. 12-month persistence rates were: VKA 57.5% (95% confidence interval (CI) 56.0–59.0%), rivaroxaban 56.6% (54.9–58.2%), dabigatran 50.1% (47.2–53.1%), apixaban 62.9% (58.8–67.0%). Over entire follow-up, compared to VKA, non-persistence was similar with apixaban (adjusted hazard ratio 1.08, 95% CI 0.95–1.24) but higher with rivaroxaban (1.21, 1.14–1.29) and dabigatran (1.53, 1.40–1.68). Using post-hoc time-partitioned approach: in first 100 days, non-persistence was higher with apixaban (1.37, 1.17–1.59), rivaroxaban (1.41, 1.30–1.53) and dabigatran (1.91, 1.70–2.14) compared to VKA. Compared to apixaban, rivaroxaban non-persistence was similar (1.03, 0.89–1.20), dabigatran was higher (1.39, 1.17–1.66). After 100 days, apixaban non-persistence was lower than VKA (0.66, 0.52–0.85); rivaroxaban (0.97, 0.87–1.07) and dabigatran (1.10, 0.95–1.28) were similar to VKA. Furthermore, rivaroxaban (1.46, 1.13–1.88) and dabigatran (1.67, 1.26–2.19) non-persistence was higher than apixaban. This study describes real-world observations on OAC use, particularly early apixaban use following approval for NVAF, in Germany. We identified potential differential OAC prescribing and higher persistence with apixaban than other OACs after 100 days’ treatment. Larger studies are needed with longer follow-up to establish long-term patterns. PMID:29016695

Antithrombotic treatment in elderly patients with atrial fibrillation.

PubMed

Suárez Fernández, C; Camafort, M; Cepeda Rodrigo, J M; Díez-Manglano, J; Formiga, F; Pose Reino, A; Tiberio, G; Mostaza, J M

2015-04-01

Atrial fibrillation (AF) in the elderly is a complex condition due to the high number of frequently associated comorbidities, such as cardiovascular and kidney disease, cognitive disorders, falls and polypharmacy. Except when contraindicated, anticoagulation is necessary for preventing thromboembolic events in this population. Both vitamin K antagonists and direct oral anticoagulants (dabigatran, rivaroxaban and apixaban) are indicated in this context. Renal function should be closely monitored for this age group when these drugs are used. In recent years, various clinical practice guidelines have been published on patients with AF. The majority of these guidelines make specific recommendations on the clinical characteristics and treatment of elderly patients. In this update, we review the specific comments on the recommendations concerning antithrombotic treatment in elderly patients with nonvalvular AF. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Evaluation of the antithrombotic abilities of non-vitamin K antagonist oral anticoagulants using the Total Thrombus-formation Analysis System®.

PubMed

Idemoto, Yoshiaki; Miura, Shin-Ichiro; Norimatsu, Kenji; Suematsu, Yasunori; Hitaka, Yuka; Shiga, Yuhei; Morii, Joji; Imaizumi, Satoshi; Kuwano, Takashi; Iwata, Atsushi; Zhang, Bo; Ogawa, Masahiro; Saku, Keijiro

2017-03-01

The Total Thrombus-formation Analysis System (T-TAS ® ) is a novel automated microchip flow-chamber system for the quantitative evaluation of thrombus formation under blood flow conditions. T-TAS ® uses two types of microchip to evaluate thrombus formation: the AR-chip quantifies white thrombus formation and the PL-chip quantifies platelet thrombus formation. We assessed the antithrombotic abilities of various non-vitamin K antagonist oral anticoagulants (NOACs) using T-TAS ® . One hundred and three consecutive patients who were hospitalized with cardiovascular diseases were enrolled. We divided the patients into 2 groups; a control group that did not receive an anticoagulant (non-AC group) and an anticoagulant group (AC group). The AC group was further divided into warfarin, dabigatran, rivaroxaban and apixaban groups. We performed common coagulation tests and evaluated the area under the flow pressure curve (AR-AUC and PL-AUC) to quantify antithrombotic ability using T-TAS ® at the trough. There were no significant differences in patient characteristics between the non-AC and AC groups. Only 55.1 % of patients in the AC group achieved the target blood pressure (BP) of less than 130/80 mmHg. Compared with the non-AC group, AR-AUC was significantly decreased in the AC, warfarin, dabigatran and apixaban groups. Only the rivaroxaban group did not show a significant decrease in AR-AUC. NOACs showed a significant decrease in PL-AUC compared with the non-AC group. In conclusion, T-TAS ® was a useful tool for evaluating anticoagulation activity. NOACs was significantly effective as an antiplatelet agent. BP control should be a higher priority than the selection of an anticoagulant drug, especially NOACs.

[Recanalization of lower-limb deep veins as an index of efficacy of treatment for acute venous thrombosis].

PubMed

Kuznetsov, M R; Sapelkin, S V; Boldin, B V; Leont'ev, S G; Neskhodimov, L A

The authors analysed the results of examination and treatment of a total of 102 patients presenting with iliofemoral venous thrombosis. During treatment, ultrasonographic duplex scanning was used to determine the localization of the proximal margin of thrombotic masses, the time of appearing of the first signs of recanalization, its degree at various levels of the deep venous system, as well as alteration in velocity of the venous blood flow in the deep veins of the lower limbs. The dynamics of clinical symptoms was assessed by the visual analogue scale. Clinical and instrumental examination was performed on day 10, and then 1, 3, 6 and 12 months after the beginning of treatment. The patients were subdivided into three groups. Group One comprised 38 patients receiving therapy with low-molecular-weight heparin (enoxaprin) followed by switching to indirect anticoagulants (warfarin) combined with venotonics (original highly-purified diosmin 600 mg once daily). Group Two was composed of 33 patients receiving rivaroxaban at a dose of 15 mg twice daily for 3 weeks, followed by 20 mg once daily. Group Tree patients (n=31) were also given rivaroxaban according to the above-described standard regimen but in combination with venotonics (original highly-purified diosmin 600 mg once daily). The obtained findings showed that prescribing rivaroxaban to patients from the first day of the disease made it possible to considerably improve and accelerate the processes of restoration of patency of deep veins of lower extremities as compared with the patients taking vitamin K antagonists (warfarin). In patients receiving rivaroxaban, there were no cases of residual thrombotic occlusions of the major veins, and recanalization in three fourths of patients was assessed as good and in the remaining third as moderate. In the warfarin group, occlusion in the iliac veins was noted to persist persisted in 13% of patients, with good recanalization observed only in half of the patients. Addition of venotonics (original highly-purified diosmin) to anticoagulants from the first day demonstrated safety of this therapeutic regimen (with no cases of clinically significant haemorrhagic complications revealed) and its high efficacy as compared with monotherapy with rivaroxaban. A combination of diosmin with rivaroxaban turned out more efficient than a combination of diosmin with warfarin.

Rivaroxaban for the treatment of saphenous vein graft thrombosis.

PubMed

Marmagkiolis, Konstantinos; Cilingiroglu, Mehmet

2016-01-01

Thrombus formafigtion plays a significant role in disease of saphenous vein bypass grafts. Use of oral anticoagulants has not been tested in treatment of thrombotic occlusion of saphenous vein graft (SVG) disease. Here we describe the use of the novel oral anticoagulant rivaroxaban in the treatment of occlusive SVG disease with intraluminal thrombus, leading to successful recanalization. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Management of rivaroxaban in relation to bodyweight and body mass index

PubMed Central

Uprichard, James

2016-01-01

Being overweight or obese is associated with a higher individual risk of venous thromboembolism and poorer postprocedural outcomes after hip or knee replacement surgery. In addition, there is evidence that obesity represents a significant driving factor for the current and projected prevalence of atrial fibrillation. Rivaroxaban and other direct oral anticoagulants offer fixed-dose regimens for these indications. They do not require therapeutic drug monitoring or dose adjustment according to the weight of the patient. However, primary care physicians seem to be hesitant to accept the concept of a fixed-dose regimen for patients at extremes of weight, perhaps because of familiarity with weight-based dosing of other drugs including low molecular weight heparins. The main concerns related to unadjusted dosing are increased exposure in underweight patients leading to a risk of excessive bleeding and conversely to underanticoagulation of overweight patients. Rivaroxaban has shown similar efficacy and a similar or better safety profile compared with standard treatment for several venous and arterial indications, including venous thromboembolism, nonvalvular atrial fibrillation, and acute coronary syndrome. Prespecified subgroup analyses of patients stratified by weight or body mass index demonstrated outcomes that were consistent with the overall analysis and within each weight and body mass index group. The results suggest that standard-dose rivaroxaban can be safely prescribed in adult patients of all weights. PMID:27090286

Multicenter Trial of Rivaroxaban for Early Discharge of Pulmonary Embolism From the Emergency Department (MERCURY PE): Rationale and Design.

PubMed

Singer, Adam J; Xiang, Jim; Kabrhel, Christopher; Merli, Gino J; Pollack, Charles; Tapson, Victor F; Wildgoose, Peter; Peacock, W Frank

2016-11-01

Traditionally, patients with pulmonary embolism (PE) are admitted from the emergency department and treated with low-molecular-weight heparin followed by warfarin. Several studies now demonstrate that it is possible to identify low-risk PE patients that can safely be treated as outpatients. The advent of the direct-acting oral anticoagulants such as rivaroxaban has made it easier than ever to manage patients outside of the hospital. This article describes the design of a randomized controlled trial aimed at testing the hypothesis that low-risk PE patients can be safely and effectively managed at home using rivaroxaban, resulting in fewer days of hospitalization than standard-of-care treatment. We have initiated a multicenter, open-label, randomized clinical trial in which low-risk adult PE patients (identified by the Hestia criteria) are randomized to outpatient management with oral rivaroxaban 15 mg twice daily for 21 days followed by 20 mg once daily for 90 days versus standard care, determined by the treating physician and based on local practices. The primary clinical endpoint will be the total number of inpatient hospital days (including the index admission) for venous thromboembolic or bleeding-related events during the first 30 days after randomization. A total of 150 subjects per group will provide 82% power to detect a difference of 1 day or greater in the primary outcome. Patient enrollment is ongoing at present in 45 of 60 planned sites. No interim analysis is planned and the study is being monitored by a data safety management board. The MERCURY PE study is designed to test the hypothesis that outpatient management of low-risk PE patients with rivaroxaban reduces the number of hospitalization days from venous thromboembolism and bleeding compared with standard care. This article describes the rationale and methodology for this study. © 2016 by the Society for Academic Emergency Medicine.

Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants.

PubMed

Schmitz, E M H; Boonen, K; van den Heuvel, D J A; van Dongen, J L J; Schellings, M W M; Emmen, J M A; van der Graaf, F; Brunsveld, L; van de Kerkhof, D

2014-10-01

Three novel direct oral anticoagulants (DOACs) have recently been registered by the Food and Drug Administration and European Medicines Agency Commission: dabigatran, rivaroxaban, and apixaban. To quantify DOACs in plasma, various dedicated coagulation assays have been developed. To develop and validate a reference ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) method and to evaluate the analytical performance of several coagulation assays for quantification of dabigatran, rivaroxaban, and apixaban. The developed UPLC-MS/MS method was validated by determination of precision, accuracy, specificity, matrix effects, lower limits of detection, carry-over, recovery, stability, and robustness. The following coagulation assays were evaluated for accuracy and precision: laboratory-developed (LD) diluted thrombin time (dTT), Hemoclot dTT, Pefakit PiCT, ECA, Liquid anti-Xa, Biophen Heparin (LRT), and Biophen DiXal anti-Xa. Agreement between the various coagulation assays and UPLC-MS/MS was determined with random samples from patients using dabigatran or rivaroxaban. The UPLC-MS/MS method was shown to be accurate, precise, sensitive, stable, and robust. The dabigatran coagulation assay showing the best precision, accuracy and agreement with the UPLC-MS/MS method was the LD dTT test. For rivaroxaban, the anti-factor Xa assays were superior to the PiCT-Xa assay with regard to precision, accuracy, and agreement with the reference method. For apixaban, the Liquid anti-Xa assay was superior to the PiCT-Xa assay. Statistically significant differences were observed between the various coagulation assays as compared with the UPLC-MS/MS reference method. It is currently unknown whether these differences are clinically relevant. When DOACs are quantified with coagulation assays, comparison with a reference method as part of proficiency testing is therefore pivotal. © 2014 International Society on Thrombosis and Haemostasis.

The EXPAND study: Efficacy and safety of rivaroxaban in Japanese patients with non-valvular atrial fibrillation.

PubMed

Shimokawa, Hiroaki; Yamashita, Takeshi; Uchiyama, Shinichiro; Kitazono, Takanari; Shimizu, Wataru; Ikeda, Takanori; Kamouchi, Masahiro; Kaikita, Koichi; Fukuda, Koji; Origasa, Hideki; Sakuma, Ichiro; Saku, Keijiro; Okumura, Yasuo; Nakamura, Yuichiro; Morimoto, Hideo; Matsumoto, Naoki; Tsuchida, Akihito; Ako, Junya; Sugishita, Nobuyoshi; Shimizu, Shogo; Atarashi, Hirotsugu; Inoue, Hiroshi

2018-05-01

The EXPAND study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF). This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients ≥20 years of age (mean, 71.6 ± 9.4 years) who were being or about to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for an average of 897.1 (±206.8) days with a high follow-up rate (99.65%). The mean CHADS 2 score at baseline was 2.1 (1.3) (0-1, 37%; 2, 29%; ≥3, 34%). The total incidence rate of symptomatic stroke and SE (primary efficacy endpoint) was 1.0%/year, and 0.5%, 0.9%, and 1.7%/year for those with CHADS 2 scores of 0-1, 2, and ≥3, respectively. Cumulative incidence rates for major bleeding (primary safety endpoint) and non-major bleeding (secondary safety endpoint) were 1.2%/year and 4.9%/year, respectively. Differences were noted between new and current users only for major bleeding event rate (1.7% vs. 1.1%/year, P = 0.0024). Comparisons with previous studies suggested that rivaroxaban is effective and safe for low-risk patients (0-1 CHADS 2 ), as shown for warfarin in the XANTUS international prospective post-marketing study. The EXPAND study demonstrated that low dosages of rivaroxaban for Japanese NVAF patients in real-world clinical practice, including those with CHADS 2 scores 0-1, resulted in low rates of stroke and SE, and major and non-major bleeding. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban.

PubMed

Willmann, Stefan; Becker, Corina; Burghaus, Rolf; Coboeken, Katrin; Edginton, Andrea; Lippert, Jörg; Siegmund, Hans-Ulrich; Thelen, Kirstin; Mück, Wolfgang

2014-01-01

Venous thromboembolism has been increasingly recognised as a clinical problem in the paediatric population. Guideline recommendations for antithrombotic therapy in paediatric patients are based mainly on extrapolation from adult clinical trial data, owing to the limited number of clinical trials in paediatric populations. The oral, direct Factor Xa inhibitor rivaroxaban has been approved in adult patients for several thromboembolic disorders, and its well-defined pharmacokinetic and pharmacodynamic characteristics and efficacy and safety profiles in adults warrant further investigation of this agent in the paediatric population. The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for rivaroxaban doses of 10 and 20 mg in adults and to scale this model to the paediatric population (0-18 years) to inform the dosing regimen for a clinical study of rivaroxaban in paediatric patients. Experimental data sets from phase I studies supported the development and qualification of an adult PBPK model. This adult PBPK model was then scaled to the paediatric population by including anthropometric and physiological information, age-dependent clearance and age-dependent protein binding. The pharmacokinetic properties of rivaroxaban in virtual populations of children were simulated for two body weight-related dosing regimens equivalent to 10 and 20 mg once daily in adults. The quality of the model was judged by means of a visual predictive check. Subsequently, paediatric simulations of the area under the plasma concentration-time curve (AUC), maximum (peak) plasma drug concentration (C max) and concentration in plasma after 24 h (C 24h) were compared with the adult reference simulations. Simulations for AUC, C max and C 24h throughout the investigated age range largely overlapped with values obtained for the corresponding dose in the adult reference simulation for both body weight-related dosing regimens. However, pharmacokinetic values in infants and preschool children (body weight <40 kg) were lower than the 90 % confidence interval threshold of the adult reference model and, therefore, indicated that doses in these groups may need to be increased to achieve the same plasma levels as in adults. For children with body weight between 40 and 70 kg, simulated plasma pharmacokinetic parameters (C max, C 24h and AUC) overlapped with the values obtained in the corresponding adult reference simulation, indicating that body weight-related exposure was similar between these children and adults. In adolescents of >70 kg body weight, the simulated 90 % prediction interval values of AUC and C 24h were much higher than the 90 % confidence interval of the adult reference population, owing to the weight-based simulation approach, but for these patients rivaroxaban would be administered at adult fixed doses of 10 and 20 mg. The paediatric PBPK model developed here allowed an exploratory analysis of the pharmacokinetics of rivaroxaban in children to inform the dosing regimen for a clinical study in paediatric patients.

Signals of bleeding among direct-acting oral anticoagulant users compared to those among warfarin users: analyses of the post-marketing FDA Adverse Event Reporting System (FAERS) database, 2010-2015.

PubMed

Alshammari, Thamir M; Ata, Sondus I; Mahmoud, Mansour Adam; Alhawassi, Tariq M; Aljadhey, Hisham S

2018-01-01

To analyze and compare the signals of bleeding from the use of direct-acting oral anticoagulants (DOACs) in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database over 5 years. Reports of bleeding and of events with related terms submitted to the FAERS between October 2010 and September 2015 were retrieved and then analyzed using the reporting odds ratio (ROR). The signals of bleeding associated with DOAC use were compared with the signals of bleeding associated with warfarin use utilizing the FAERS databases. A total of 1,518 reports linked dabigatran to bleeding, accounting for 2.7% of all dabigatran-related reports, whereas 93 reports linked rivaroxaban to bleeding, which accounted for 4.4% of all rivaroxaban-related reports. The concurrent proportion of bleeding-related reports for warfarin was 3.6%, with a total of 654 reports. The association of bleeding and of related terms with the use of all three medications was significant, albeit with different degrees of association. The ROR was 12.30 (95% confidence interval [CI] 11.65-12.97) for dabigatran, 15.61 (95% CI 14.42-16.90) for warfarin, and 18.86 (95% CI 15.31-23.23) for rivaroxaban. The signals of bleeding varied among the DOACs, and the bleeding signal was higher for rivaroxaban and lower for dabigatran compared to that for warfarin.

Simple and rapid assay for effect of the new oral anticoagulant (NOAC) rivaroxaban: preliminary results support further tests with all NOACs

PubMed Central

2014-01-01

Background New oral anticoagulant (NOAC) drugs are known to influence the results of some routine hemostasis tests. Further data are needed to enable routine assessment of the effects of NOAC on clotting parameters in some special circumstances. Methods Following administration of rivaroxaban to patients, at the likely peak and trough activity times, we assessed the effects on prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and clotting time using Russell’s viper venom, and in the presence of phospholipids and calcium reagent available as DVVreagent® and DVVconfirm®. The data were used to determine an adequate NOAC plasma level based on anticoagulant activities expressed as a ratio (patients/normal, R-C). Results DVVconfirm as R-C could be rapidly performed, and the results were reasonably sensitive for rivaroxaban and probably for other FX inhibitors. This assay is not influenced by lupus anticoagulant and heparin, does not require purified NOAC as control, and will measure whole-plasma clotting activity. Conclusions We propose a cut-off R-C value of 4.52 ± 0.33 for safety, but clinical studies are needed to establish whether this cut-off is useful for identifying patients at increased risk of hemorrhage or exhibiting low anticoagulation effect. It also seems possible that normal R-C could indicate an absence of anticoagulant activity when rivaroxaban is discontinued due to episodes of uncontrolled bleeding during anticoagulation or for emergency surgery. PMID:24656069

Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation-Related Mild Ischemic Stroke: A Randomized Clinical Trial.

PubMed

Hong, Keun-Sik; Kwon, Sun U; Lee, Sang Hun; Lee, Ji Sung; Kim, Yong-Jae; Song, Tae-Jin; Kim, Young Dae; Park, Man-Seok; Kim, Eung-Gyu; Cha, Jae-Kwan; Sung, Sang Min; Yoon, Byung-Woo; Bang, Oh Young; Seo, Woo-Keun; Hwang, Yang-Ha; Ahn, Seong Hwan; Kang, Dong-Wha; Kang, Hyun Goo; Yu, Kyung-Ho

2017-10-01

In atrial fibrillation (AF)-related acute ischemic stroke, the optimal oral anticoagulation strategy remains unclear. To test whether rivaroxaban or warfarin sodium is safer and more effective for preventing early recurrent stroke in patients with AF-related acute ischemic stroke. A randomized, multicenter, open-label, blinded end point evaluation, comparative phase 2 trial was conducted from April 28, 2014, to December 7, 2015, at 14 academic medical centers in South Korea among patients with mild AF-related stroke within the previous 5 days who were deemed suitable for early anticoagulation. Analysis was performed on a modified intent-to-treat basis. Participants were randomized 1:1 to receive rivaroxaban, 10 mg/d for 5 days followed by 15 or 20 mg/d, or warfarin with a target international normalized ratio of 2.0-3.0, for 4 weeks. The primary end point was the composite of new ischemic lesion or new intracranial hemorrhage seen on results of magnetic resonance imaging at 4 weeks. Primary analysis was performed in patients who received at least 1 dose of study medications and completed follow-up magnetic resonance imaging. Key secondary end points were individual components of the primary end point and hospitalization length. Of 195 patients randomized, 183 individuals (76 women and 107 men; mean [SD] age, 70.4 [10.4] years) completed magnetic resonance imaging follow-up and were included in the primary end point analysis. The rivaroxaban group (n = 95) and warfarin group (n = 88) showed no differences in the primary end point (47 [49.5%] vs 48 [54.5%]; relative risk, 0.91; 95% CI, 0.69-1.20; P = .49) or its individual components (new ischemic lesion: 28 [29.5%] vs 31 of 87 [35.6%]; relative risk, 0.83; 95% CI, 0.54-1.26; P = .38; new intracranial hemorrhage: 30 [31.6%] vs 25 of 87 [28.7%]; relative risk, 1.10; 95% CI, 0.70-1.71; P = .68). Each group had 1 clinical ischemic stroke, and all new intracranial hemorrhages were asymptomatic hemorrhagic transformations. Hospitalization length was reduced with rivaroxaban compared with warfarin (median, 4.0 days [interquartile range, 2.0-6.0 days] vs 6.0 days [interquartile range, 4.0-8.0]; P < .001). In mild AF-related acute ischemic stroke, rivaroxaban and warfarin had comparable safety and efficacy. clinicaltrials.gov Identifier: NCT02042534.

Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation.

PubMed

Namba, Sayaka; Yamaoka-Tojo, Minako; Kakizaki, Ryota; Nemoto, Teruyoshi; Fujiyoshi, Kazuhiro; Hashikata, Takehiro; Kitasato, Lisa; Hashimoto, Takuya; Kameda, Ryo; Meguro, Kentaro; Shimohama, Takao; Tojo, Taiki; Ako, Junya

2017-08-01

In recent years, direct oral anticoagulants (DOACs) of dabigatran, rivaroxaban, apixaban, edoxaban, which are all alternatives to warfarin, have been released. The use of DOACs is becoming more widespread in the clinical management of thrombotic stroke risk in patients with atrial fibrillation (AF). In large-scale clinical trials of each drug, DOACs were reported to inhibit intracranial hemorrhage, stroke, and death compared to warfarin. Warfarin is an endogenous vitamin K antagonist; therefore, patients who are taking warfarin must be prohibited from taking vitamin K. Vitamin K is an essential cofactor required for the ɤ-carboxylation of vitamin K-dependent proteins including coagulation factors, osteocalcin (OC), matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6). OC is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification in the vessel wall. GAS6 prevents the apoptosis of vascular smooth muscle cells. Therefore, decrease of blood vitamin K levels may cause osteoporosis, vascular calcification, and the inhibition of vessels angiogenesis. This study aimed to evaluate the effects of changing from warfarin to rivaroxaban on bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. We studied 21 consecutive patients with persistent or chronic AF, who were treated with warfarin at least for 12 months. Warfarin administration was changed to rivaroxaban (10 or 15 mg/day) in all patients. Osteopontin (OPN), bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were measured. Pulse wave velocity (PWV) and augmentation index (AI) were also measured as atherosclerosis assessments. All measurements were done before and six months after the rivaroxaban treatment. There was a significant increase in serum level of BAP compared to baseline (12.5 ± 4.6 to 13.4 ± 4.1 U/L, P < 0.01). In contrast, there was a significant decrease in the serum level of ucOC (9.5 ± 5.0 to 2.7 ± 1.3 ng/ml, P < 0.01). Also, in the ucOC levels, there was a significant negative correlation between baseline values and baseline to 6-months changes in high ucOC group (r = -0.97, P < 0.01). The atherosclerosis- and osteoporosis-related biomarker, serum level of OPN were significantly decreased compared to baseline (268.3 ± 46.8 to 253.4 ± 47.1 ng/ml, P < 0.01). AI and PWV were significantly decreased after 6 months of treatment with rivaroxaban (33.9 ± 18.4 to 24.7 ± 18.4%, P = 0.04; 1638.8 ± 223.0 to 1613.0 ± 250.1 m/s, P = 0.03, respectively). Switching to rivaroxaban from warfarin in patients with atrial fibrillation was associated with an increase of bone formation markers and a decrease of bone resorption markers, and also improvements of PWV and AI.

Major Bleeding Risk During Anticoagulation with Warfarin, Dabigatran, Apixaban, or Rivaroxaban in Patients with Nonvalvular Atrial Fibrillation.

PubMed

Adeboyeje, Gboyega; Sylwestrzak, Gosia; Barron, John J; White, Jeff; Rosenberg, Alan; Abarca, Jacob; Crawford, Geoffrey; Redberg, Rita

2017-09-01

The use of non-vitamin K oral anticoagulants (NOACs) has increased steadily following marketing approval; however, their relative safety in nonvalvular atrial fibrillation (NVAF) patients in real-world clinical practice remains unclear. To compare the risk of major bleeding during anticoagulation therapy between warfarin and NOACs. This retrospective cohort study analyzed administrative claims data on new NVAF users of warfarin, dabigatran, apixaban, or rivaroxaban in routine clinical care from November 2010 to February 2015 in a commercially insured population in the United States. The primary outcome was time to first major bleeding event requiring hospitalization. Patients were followed until discontinuation or switch of anticoagulants, health plan disenrollment, death, or end of study. All patient characteristics were balanced after propensity score inverse probability of treatment (IPT) weighting. Event rates by type of anticoagulant exposure were compared using IPT-weighted Cox proportional hazards models. The study cohort comprised 44,057 patients who used warfarin (n = 23,431), dabigatran (n = 8,539), apixaban (n = 3,689), and rivaroxaban (n = 8,398). Overall mean (SD) age was 70 (12) years, and 41% of the patients were women. A total of 2,337 major bleeding events occurred during 36,636.2 person-years of follow-up. The unadjusted rate of major bleeding with warfarin was 6.0 per 100 person-years versus 2.8 with dabigatran, 3.3 with apixban, and 5.0 with rivaroxaban. Relative to warfarin, major bleeding risk was lower with dabigatran (HR = 0.67, 95% CI = 0.60-0.76) and apixaban (HR = 0.52, 95% CI = 0.41-0.67). Compared with rivaroxaban, major bleeding risk was also lower with dabigatran (HR = 0.67, 95% CI = 0.58-0.78) and apixaban (HR = 0.52, 95% CI = 0.40-0.68). Major bleeding risk was similar for rivaroxaban and warfarin. Relative to apixaban, dabigatran was associated with a significantly higher risk of major gastrointestinal bleeding (HR = 1.43, 95% CI = 1.09-1.88). Study results were consistent with safety findings from pivotal clinical trials comparing NOACs with warfarin and added the perspective of a large real-world observational study that compared bleeding risks associated with NOACs during anticoagulation therapy. Apixaban and dabigatran were associated with lower major bleeding risk compared with warfarin or rivaroxaban; however, apixaban had a lower risk of major gastrointestinal bleeding than dabigatran. These findings can help inform the choice of an optimal agent, which must balance effectiveness and bleeding risk in complex patients. This study was funded by Anthem. Adeboyeje, Sylwestrzak, and Barron are employees of HealthCore, a wholly owned and independently operated subsidiary of Anthem. White, Rosenberg, Abarca, and Crawford are employees of Anthem. Study concept and design were primarily contributed by Adeboyeje and Sylwestrzak, along with the other authors. Adeboyeje took the lead in data collection, along with Sylwestrzak and Barron. Data interpretation was performed primarily by Rosenberg, Crawford, and Redberg, with assistance from the other authors. The manuscript was written by all the authors and revised primarily by White, Abarca, and Redberg, along with the other authors.

Adherence to non-vitamin-K-antagonist oral anticoagulant medications based on the Pharmacy Quality Alliance measure.

PubMed

McHorney, Colleen A; Crivera, Concetta; Laliberté, François; Nelson, Winnie W; Germain, Guillaume; Bookhart, Brahim; Martin, Silas; Schein, Jeffrey; Lefebvre, Patrick; Deitelzweig, Steven

2015-12-01

CMS Star Ratings help inform beneficiaries about the performance of health and drug plans. Medication adherence is currently weighted at nearly half of a Part D plan's Star Ratings. Including the adherence to non-vitamin-K-antagonist oral anticoagulants (NOACs) as a measure in the Star Ratings program may increase a plan's incentives to improve patient adherence. To assess the adherence to medication of patients who used the NOACs rivaroxaban, dabigatran, or apixaban in 2014 based on the Pharmacy Quality Alliance (PQA) adherence measure. Healthcare claims from the Humana database between July 2013 and December 2014 were analyzed. Adult patients with ≥2 dispensings of NOAC agents in 2014, at least 180 days apart, with >60 days of supply, and ≥180 days of continuous enrollment prior to the index NOAC were identified. The PQA measure was calculated as the percentage of patients who had a proportion of days covered (PDC) ≥0.8. Multivariate logistic regression analyses were also conducted adjusting for baseline confounders. A total of 11,095 rivaroxaban, 6548 dabigatran, and 3532 apixaban users were identified. Based on the PQA adherence measure (PDC ≥0.8), a significantly higher proportion of rivaroxaban users (72.7%) was found to be adherent compared to dabigatran (67.2%: p < 0.001) and apixaban (69.5%: p < 0.001) users. Compared to apixaban users, the adjusted likelihood of being adherent was significantly higher for rivaroxaban users (unadjusted OR [95% CI]: 1.17 [1.08-1.27], p < 0.001; adjusted OR [95% CI]: 1.20 (1.10-1.31), p < 0.001) and significantly lower for dabigatran users (unadjusted OR [95% CI]: 0.90 [0.82-0.98], p = 0.019; adjusted OR [95% CI]: 0.85 [0.77-0.93], p < 0.001). Limitations of the study are potential inaccuracies in claims data, possible change in patterns over time, and the impossibility of knowing whether all supplied tablets were taken. Using the PQA's adherence measure, rivaroxaban users were found to have significantly higher adherence compared to apixaban and dabigatran users.

Comparative risk of major bleeding with new oral anticoagulants (NOACs) and phenprocoumon in patients with atrial fibrillation: a post-marketing surveillance study.

PubMed

Hohnloser, Stefan H; Basic, Edin; Nabauer, Michael

2017-08-01

Non-vitamin K antagonist oral anticoagulants (NOACs) are at least as effective and safe as vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF). All pivotal trials have compared NOACs to warfarin. However, other VKAs are commonly used, for instance phenprocoumon. A retrospective cohort study using a German claims database assessed the comparative risks of bleeding leading to hospitalization during therapy with NOACs and phenprocoumon in AF patients. Endpoints consisted of major bleeding, gastrointestinal bleeding, and any bleeding. Data were collected from January 1, 2013 to March 31, 2015. Patients newly initiated on dabigatran, apixaban, rivaroxaban, or phenprocoumon were included. Hazard Ratios for bleeding events were derived from Cox proportional hazard models, adjusting for differences in baseline characteristics. Propensity score matching was performed as a sensitivity analysis. A total of 35,013 patients were identified, including 3138 on dabigatran, 3633 on apixaban, 12,063 on rivaroxaban, and 16,179 on phenprocoumon. Patients prescribed apixaban or phenprocoumon were older compared to those on dabigatran or rivaroxaban and had a higher CHA 2 DS 2 -VASc score. After adjusting for baseline confounders, apixaban was associated with lower risks of major bleeding (HR 0.68, 95% CI 0.51-0.90, p = 0.008), gastrointestinal bleeding (HR 0.53, 95% CI 0.39-0.72, p < 0.001), and any bleeding (HR 0.80, 95% CI 0.70-0.92, p = 0.002) compared to phenprocoumon. There were no significant differences in bleeding risk between dabigatran and phenprocoumon. Rivaroxaban was associated with more gastrointestinal bleeding (HR 1.39, 95% CI 1.21-1.60, p < 0.001) and any bleeding (HR 1.19, 95% CI 1.10-1.28, p < 0.001). Sensitivity analysis using propensity score matching confirmed these observations. Apixaban therapy is associated with a significantly reduced risk of bleeding compared to phenprocoumon. Bleeding risk with dabigatran was similar to that of phenprocoumon but bleeding risk with rivaroxaban was higher.

Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation.

PubMed

Hankey, Graeme J; Stevens, Susanna R; Piccini, Jonathan P; Lokhnygina, Yuliya; Mahaffey, Kenneth W; Halperin, Jonathan L; Patel, Manesh R; Breithardt, Günter; Singer, Daniel E; Becker, Richard C; Berkowitz, Scott D; Paolini, John F; Nessel, Christopher C; Hacke, Werner; Fox, Keith A A; Califf, Robert M

2014-05-01

Intracranial hemorrhage (ICH) is a life-threatening complication of anticoagulation. We investigated the rate, outcomes, and predictors of ICH in 14 264 patients with atrial fibrillation from Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Cox proportional hazards modeling was used. During 1.94 years (median) of follow-up, 172 patients (1.2%) experienced 175 ICH events at a rate of 0.67% per year. The significant, independent predictors of ICH were race (Asian: hazard ratio, 2.02; 95% CI, 1.39-2.94; black: hazard ratio, 3.25; 95% CI, 1.43-7.41), age (1.35; 1.13-1.63 per 10-year increase), reduced serum albumin (1.39; 1.12-1.73 per 0.5 g/dL decrease), reduced platelet count below 210×10(9)/L (1.08; 1.02-1.13 per 10×10(9)/L decrease), previous stroke or transient ischemic attack (1.42; 1.02-1.96), and increased diastolic blood pressure (1.17; 1.01-1.36 per 10 mm Hg increase). Predictors of a reduced risk of ICH were randomization to rivaroxaban (0.60; 0.44-0.82) and history of congestive heart failure (0.65; 0.47-0.89). The ability of the model to discriminate individuals with and without ICH was good (C-index, 0.69; 95% CI, 0.64-0.73). Among patients with atrial fibrillation treated with anticoagulation, the risk of ICH was higher among Asians, blacks, the elderly, and in those with previous stroke or transient ischemic attack, increased diastolic blood pressure, and reduced platelet count or serum albumin at baseline. The risk of ICH was significantly lower in patients with heart failure and in those who were randomized to rivaroxaban instead of warfarin. The external validity of these findings requires testing in other atrial fibrillation populations.

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients

PubMed Central

Yoshioka, Hideki; Sato, Hiromi; Hatakeyama, Hiroto

2018-01-01

The noninferiority of direct oral factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban) in treatment of atrial fibrillation were demonstrated compared with warfarin by several large clinical trials; however, subsequent meta-analyses reported a higher risk of major bleeding with rivaroxaban than with the other FXa inhibitors. In the present study, we first estimated the changes of prothrombin time (PT) in 5 randomized trials based on reported population pharmacokinetic and pharmacodynamic models and then carried out a model-based meta-analysis to obtain models describing the relationship between PT changes and the event rates of ischemic stroke/systemic embolism (SE) and of major bleeding. By using the models, we simulated the optimal therapeutic doses for each FXa inhibitor. It was suggested that dose reduction of rivaroxaban from the current 20 mg/d to 10 mg/d would decrease patient deaths from major bleeding (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.64-0.74) with little increase in those for ischemic stroke/SE (HR, 1.11; 95% CI, 1.07-1.20). The overall decrease in the mortality caused by both events was estimated as 5.81 per 10 000 patient-years (95% CI, 3.92-8.16), with an HR of 0.87 (95% CI, 0.83-0.91). For apixaban and edoxaban, no distinct change in the overall mortality was simulated by dose modification. This study suggested that the current dose of rivaroxaban might be excessive and would need to be reduced to decrease the excess risk of major bleeding. PMID:29760204

Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials.

PubMed

Prins, Martin H; Lensing, Anthonie W A; Brighton, Tim A; Lyons, Roger M; Rehm, Jeffrey; Trajanovic, Mila; Davidson, Bruce L; Beyer-Westendorf, Jan; Pap, Ákos F; Berkowitz, Scott D; Cohen, Alexander T; Kovacs, Michael J; Wells, Philip S; Prandoni, Paolo

2014-10-01

Patients with venous thromboembolism and cancer have a substantial risk of recurrent venous thromboembolism and bleeding during anticoagulant therapy. Although monotherapy with low-molecular-weight heparin is recommended in these patients, in clinical practice many patients with venous thromboembolism and cancer do not receive this treatment. We aimed to assess the efficacy and safety of a single-drug regimen with oral rivaroxaban compared with enoxaparin followed by vitamin K antagonists, in the subgroup of patients with cancer enrolled in the EINSTEIN-DVT and EINSTEIN-PE randomised controlled trials. We did a subgroup analysis of patients with active cancer (either at baseline or diagnosed during the study), a history of cancer, or no cancer who were enrolled in the EINSTEIN-DVT and EINSTEIN-PE trials. Eligible patients with deep-vein thrombosis (EINSTEIN-DVT) or pulmonary embolism (EINSTEIN-PE) were randomly assigned in a 1:1 ratio to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy (enoxaparin 1·0 mg/kg twice daily and warfarin or acenocoumarol; international normalised ratio 2·0-3·0). Randomisation with a computerised voice-response system was stratified according to country and intended treatment duration (3, 6, or 12 months). The prespecified primary efficacy and safety outcomes of both the trials and this subanalysis were symptomatic recurrent venous thromboembolism and clinically relevant bleeding, respectively. We did efficacy and mortality analyses in the intention-to-treat population, and bleeding analyses for time spent receiving treatment plus 2 days in the safety population (all patients who received at least one dose of study drug). The EINSTEIN-DVT and EINSTEIN-PE studies are registered at ClinicalTrials.gov, numbers NCT00440193 and NCT00439777. In patients with active cancer (diagnosed at baseline or during treatment), recurrent venous thromboembolism occurred in 16 (5%) of 354 patients allocated to rivaroxaban and 20 (7%) of 301 patients allocated to enoxaparin and vitamin K antagonist (hazard ratio [HR] 0·67, 95% CI 0·35 to 1·30). Clinically relevant bleeding occurred in 48 (14%) of 353 patients receiving rivaroxaban and in 49 (16%) of 298 patients receiving standard therapy (HR 0·80, 95% CI 0·54 to 1·20). Major bleeding occurred in eight (2%) of 353 patients receiving rivaroxaban and in 15 (5%) of 298 patients receiving standard therapy (HR 0·42, 95% CI 0·18 to 0·99). The overall frequency of recurrent venous thromboembolism in patients with only a history of cancer (five [2%] of 233 patients in the rivaroxaban group vs five [2%] of 236 in the standard therapy group; HR 0·98, 95% CI 0·28-3·43) was similar to that of patients without cancer (65 [2%] of 3563 vs 70 [2%] of 3594, respectively; HR 0·93, 95% CI 0·66-1·30), but the frequency was increased in patients with active cancer at baseline (six [2%] of 258 vs eight [4%] of 204, respectively; HR 0·62, 95% CI 0·21-1·79) and most markedly increased in patients whose diagnosis of cancer was made during the study (ten [10%] of 96 vs 12 [12%] of 97, respectively; HR 0·80, 95% CI 0·34-1·88). The overall frequency of major bleeding in patients with only a history of cancer (one [<1%] patient in the rivaroxaban group vs four [2%] patients in the standard therapy group; HR 0·23, 95% CI 0·03-2·06) was similar to that of patients without cancer (31 [1%] vs 53 [1%], respectively; HR 0·58, 95% CI 0·37-0·91), but was increased in patients with active cancer at baseline (five [2%] vs eight [4%], respectively; HR 0·47, 95% CI 0·15-1·45) and was highest in those with cancer diagnosed during the study (three [3%] vs seven [7%], respectively; HR 0·33, 95% CI 0·08-1·31). In patients with active cancer and venous thromboembolism, rivaroxaban had similar efficacy to prevent recurrence of venous thromboembolism and reduced the number major bleeding events compared with treatment with enoxaparin and a vitamin K antagonist, although there was no difference between groups for clinically relevant bleeding. Based on these results, a head-to-head comparison of rivaroxaban with long-term low-molecular-weight heparin in patients with cancer is warranted. Bayer HealthCare Pharmaceuticals and Janssen Research & Development. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Efficacy of using rivaroxaban for treatment of heat-induced thrombosis after endovenous laser ablation].

PubMed

Fokin, A A; Borsuk, D A; Kazachkov, E L

The study was aimed at assessing efficacy of using rivaroxaban for treatment of endothermal heat-induced thrombosis (EHIT) after endovenous laser ablation (EVLA) of saphenous veins. Our prospective study included a total of 1,326 patients subjected to 1,514 EVLAs. In 1,091 (72.1%) cases the great saphenous vein (GSV) was ablated, in 124 (8.2%) cases the anterior accessory vein (AAV) was treated and in 299 (19.7%) cases the small saphenous vein (SSV) was treated. Heat-induced thrombosis developed in 21 (1.4%) cases: in 19 cases in the basin of the great saphenous vein and in 2 cases in the anterior accessory saphenous vein. No heat-induced thromboses in the basin of the small saphenous vein were observed. In 9 (0.6%) cases there was class 1 EHIT (according to the Kabnick classification), class 2 EHIT was noted in 10 (0.7%) cases and class 3 EHIT was observed in 2 (0.1%) cases. All patients with EHIT were given rivaroxaban: patients with class 1 EHIT received it at a single daily dose of 20 mg, patients with class 2 and 3 EHIT - at a dose of 15 mg twice daily. In one (4.8%) case the drug had to be discontinued on day two due to the development of dyspeptic events. All patients were found to have complete regression of the heat-induced thrombus within 6-25 days. No cases of clinical manifestations of pulmonary artery thromboembolism were observed. A conclusion was drawn that in clinical practice EHIT is an important and insufficiently studied problem. Rivaroxaban may be used as an oral agent for treatment of heat-induced thromboses after EVLA. Further studies are required to examine its efficacy and safety profile.

Comparative effectiveness of dabigatran and rivaroxaban versus warfarin for the treatment of non-valvular atrial fibrillation

PubMed Central

Bengtson, Lindsay GS; Lutsey, Pamela L.; Chen, Lin Y.; MacLehose, Richard F.; Alonso, Alvaro

2016-01-01

Background Effectiveness data on novel oral anticoagulants (NOACs) versus warfarin for stroke prevention in non-valvular atrial fibrillation (NVAF) by prior warfarin use are limited. Methods We used data from the US MarketScan databases from 2009–2012. NVAF patients initiating dabigatran or rivaroxaban were matched with up to 5 warfarin users. Propensity score-adjusted Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (95%CI) for relevant endpoints in NOACs versus warfarin users. Separate analyses were conducted to compare anticoagulant-naïve users of NOACs and those switching from warfarin. Results Among 32,918 dabigatran, 3,301 rivaroxaban, and 109,447 warfarin users with NVAF, 225 intracranial bleeds, 1035 ischemic strokes, 958 myocardial infarctions, and 1842 gastrointestinal bleeds were identified. Compared to warfarin users, patients initiating NOACs had similar ischemic stroke rates and lower intracranial bleeding rates, while the gastrointestinal bleeding rate was higher in dabigatran users than warfarin users. Associations of dabigatran with ischemic stroke risk differed between anticoagulant-naïve initiators and patients switching from warfarin; dabigatran was associated with lower ischemic stroke rates in naïve users (HR 0.65, 95%CI 0.52–0.82) but not in switchers (HR 1.20, 95%CI 0.95–1.51), compared to warfarin. Risk of stroke and bleeding was not different between rivaroxaban and warfarin users. Conclusions Real-world effectiveness of NOACs (compared to warfarin) for diverse outcomes was comparable to efficacy reported in published clinical trials. However, harms and benefits of switching from warfarin to dabigatran need to be evaluated. PMID:27889397

Cost-effectiveness of Apixaban Versus Other Oral Anticoagulants for the Initial Treatment of Venous Thromboembolism and Prevention of Recurrence.

PubMed

Lanitis, Tereza; Leipold, Robert; Hamilton, Melissa; Rublee, Dale; Quon, Peter; Browne, Chantelle; Cohen, Alexander T

2016-03-01

To assess the cost-effectiveness of apixaban versus rivaroxaban, low-molecular-weight heparin (LMWH)/dabigatran, and LMWH/vitamin K antagonist (VKA) for the initial treatment and prevention of recurrent thromboembolic events in patients with venous thromboembolism (VTE). A Markov model was developed to evaluate the pharmacoeconomic effect of 6 months of treatment with apixaban versus other anticoagulants over a lifetime horizon. Network meta-analyses were conducted using the results of the Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy (AMPLIFY), EINSTEIN-pooled, and RE-COVER I and II trials for the following end points: recurrent VTE, major bleeds, clinically relevant non-major bleeds, and treatment discontinuations. The analysis was conducted from the perspective of the United Kingdom National Health Service. The outcomes evaluated were the number of events avoided in a 1000-patient cohort, total costs, life years, quality-adjusted life years (QALYs), and cost per QALY gained over a patient's lifetime. Treatment for 6 months with apixaban was projected to result in fewer recurrent VTE and bleeding events in comparison to rivaroxaban, LMWH/dabigatran, and LMWH/VKA. Apixaban was cost-effective compared with LMWH/VKA at an incremental cost-effectiveness ratio of £2520 per QALY gained and was a dominant (ie, lower costs and higher QALYs) alternative to either rivaroxaban or LMWH/dabigatran. Sensitivity analysis indicated that results were robust over a wide range of inputs. The assessment of the effects and costs of apixaban in this study predicted that apixaban is a dominant alternative to rivaroxaban and LMWH/dabigatran and a cost-effective alternative to LMWH/VKA for 6 months of treatment of VTE and the prevention of recurrence. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Real-World Use of Apixaban for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Meta-Analysis.

PubMed

Proietti, Marco; Romanazzi, Imma; Romiti, Giulio Francesco; Farcomeni, Alessio; Lip, Gregory Y H

2018-01-01

The use of oral anticoagulant therapy for stroke prevention in atrial fibrillation has been transformed by the availability of the nonvitamin K antagonist oral anticoagulants. Real-world studies on the use of nonvitamin K antagonist oral anticoagulants would help elucidate their effectiveness and safety in daily clinical practice. Apixaban was the third nonvitamin K antagonist oral anticoagulants introduced to clinical practice, and increasing real-world studies have been published. Our aim was to summarize current evidence about real-world studies on apixaban for stroke prevention in atrial fibrillation. We performed a systematic review and meta-analysis of all observational real-world studies comparing apixaban with other available oral anticoagulant drugs. From the original 9680 results retrieved, 16 studies have been included in the final meta-analysis. Compared with warfarin, apixaban regular dose was more effective in reducing any thromboembolic event (odds ratio: 0.77; 95% confidence interval: 0.64-0.93), but no significant difference was found for stroke risk. Apixaban was as effective as dabigatran and rivaroxaban in reducing thromboembolic events and stroke. The risk of major bleeding was significantly lower for apixaban compared with warfarin, dabigatran, and rivaroxaban (relative risk reduction, 38%, 35%, and 46%, respectively). Similarly, the risk for intracranial hemorrhage was significantly lower for apixaban than warfarin and rivaroxaban (46% and 54%, respectively) but not dabigatran. The risk of gastrointestinal bleeding was lower with apixaban when compared with all oral anticoagulant agents ( P <0.00001 for all comparisons). Use of apixaban in real-life is associated with an overall similar effectiveness in reducing stroke and any thromboembolic events when compared with warfarin. A better safety profile was found with apixaban compared with warfarin, dabigatran, and rivaroxaban. © 2017 American Heart Association, Inc.

Quality of life with rivaroxaban in patients with non-valvular atrial fibrilation by therapeutic compliance.

PubMed

Márquez-Contreras, Emilio; Martell-Claros, Nieves; Gil-Guillén, Vicente; De la Figuera-Von Wichmann, Mariano; Sánchez-López, Eugenio; Gil-Gil, Ines; Márquez-Rivero, Sara

2017-03-01

To assess the quality of life (QOL) with rivaroxaban in patients with non-valvular atrial fibrilation (NVAF) related to therapeutic compliance. Prospective, longitudinal, multicenter study was developed in 160 Spanish primary or specialized care centers. We included 412 patients treated with rivaroxaban, prescribed for stroke prevention. Three visits were conducted: baseline, 6 and 12 months. Compliance was measured by electronic monitoring systems. QOL was measured by a specific questionnaire. We calculated the percentage of compliance means, the percentage of daily compliers and the score of QOL. Three hundred and seventy patients finished the study (mean age 75.19 SD: 7.5 years). Daily compliance was 83.5% (CI 78.53-88.57%) (n = 309) and 80% (CI 74.65-85.35%) at 6 and 12 months, respectively. Average QOL rating was 112.85 (SD 29.31) in non-compliant and 111.80 (SD 29.31) in the compliant group (p = Not significant), and after 12 months of 124.67 (SD 30.78) and 83.47 (SD 26.44), respectively (p < 0.0001), with a decrease in the score compliers (p < 0.01) and an increase in non-compliant group (p < 0.05). A higher number of drugs consumed, as well as the number of diseases/conditions suffered, the older age of the patients and having been previously treated with VKA were associated with a higher overall score (worse QOL). QOL in NVAF patients treated with rivaroxaban improved significantly over the study group at the expense of compliers. A worse QOL was associated with pluripathology, polymedication, older patients and previous treatment with VKA.

Left atrial thrombus and dense spontaneous echocardiographic contrast in patients on continuous direct oral anticoagulant therapy undergoing catheter ablation of atrial fibrillation: Comparison of dabigatran, rivaroxaban, and apixaban.

PubMed

Wu, Michael; Gabriels, James; Khan, Mohammad; Shaban, Nada; D'Amato, Salvatore; Liu, Christopher F; Markowitz, Steven M; Ip, James E; Thomas, George; Singh, Parmanand; Lerman, Bruce; Patel, Apoor; Cheung, Jim W

2018-04-01

Left atrial thrombus (LAT) and dense spontaneous echocardiographic contrast (SEC) detected by transesophageal echocardiography (TEE) in patients on continuous direct oral anticoagulants (DOAC) therapy before catheter ablation of atrial fibrillation (AF) or atrial flutter (AFL) have been described. We sought to compare rates of TEE-detected LAT and dense SEC among patients taking different DOACs. We evaluated 609 consecutive patients from 3 tertiary hospitals (median age 65 years; interquartile range 58-71 years; 436 (72%) men) who were on ≥4 weeks of continuous DOAC therapy (dabigatran, n = 166 [27%]; rivaroxaban, n = 257 [42%]; or apixaban, n = 186 [31%]) undergoing TEE before catheter ablation of AF/AFL. Demographic, clinical, and TEE data were collected for each patient. Despite ≥4 weeks of continuous DOAC therapy, 17 patients (2.8%) had LAT and 15 patients (2.5%) had dense SEC detected by TEE. The rates of LAT were 3.0%, 3.5%, and 1.6% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .482). The rates of dense SEC were 1.2%, 3.5%, and 2.2% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .299). Congestive heart failure (odds ratio 4.4; 95% confidence interval 1.6-12; P = .003) and moderate/severe left atrial enlargement (odds ratio 3.1; 95% confidence interval 1.1-8.6; P = .026) were independent predictors of LAT. In this study, ∼3% of patients on continuous DOAC therapy had LAT detected before catheter ablation of AF/AFL. Specific DOAC therapy did not significantly affect the rates of LAT detection. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Low-Molecular-Weight Heparin and the Relative Risk of Surgical Site Bleeding Complications: Results of a Systematic Review and Meta-Analysis of Randomized Controlled Trials of Venous Thromboprophylaxis in Patients After Total Joint Arthroplasty.

PubMed

Suen, Kary; Westh, Roger N; Churilov, Leonid; Hardidge, Andrew J

2017-09-01

Venous thromboembolism causes significant morbidity and mortality in patients after total joint arthroplasty. Although network meta-analyses have demonstrated a benefit of various thromboprophylactic agents, there remains a concern in the surgical community regarding the resulting wound complications. There is currently no systematic review of the surgical site bleeding complications of thromboprophylactic agents. The aim of this study was to systematically review the surgical site bleeding outcomes of venous thromboembolism prophylaxis in this population. A systematic review and meta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized controlled trials comparing more than one of low-molecular-weight heparin (LMWH), warfarin, rivaroxaban, apixaban, dabigatran, aspirin, or no pharmacologic treatment in patients after total hip or knee arthroplasty were selected for inclusion. Five meta-analyses were performed to compare LMWH with control, warfarin, apixaban, rivaroxaban, and dabigatran. Forty-five randomized controlled trials of 56,730 patients were included. LMWH had a significantly increased relative risk of surgical site bleeding in comparison with control (relative risk, 2.32; 95% confidence interval, 1.40-3.85) and warfarin (1.54; 1.23-1.94). The relative risk of LMWH trended higher than apixaban (1.27; 1.00-1.63) and was similar to rivaroxaban (0.95; 0.74-1.23). Only 1 study reported the risk of surgical site bleeding in LMWH vs dabigatran (5.97; 2.08-17.11). LMWH increased the risk of surgical site bleeding compared with control, warfarin. and dabigatran and trended toward an increased risk compared with apixaban. The risk of surgical site bleeding was similar with LMWH and rivaroxaban. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison of estimated glomerular filtration rate equations for dosing new oral anticoagulants in patients with atrial fibrillation.

PubMed

Manzano-Fernández, Sergio; Andreu-Cayuelas, José M; Marín, Francisco; Orenes-Piñero, Esteban; Gallego, Pilar; Valdés, Mariano; Vicente, Vicente; Lip, Gregory Y H; Roldán, Vanessa

2015-06-01

New oral anticoagulants require dosing adjustment according to renal function. We aimed to determine discordance in hypothetical recommended dosing of these drugs using different estimated glomerular filtration rate equations in patients with atrial fibrillation. Cross-sectional analysis of 910 patients with atrial fibrillation and an indication for oral anticoagulation. The glomerular filtration rate was estimated using the Cockcroft-Gault, Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations. For dabigatran, rivaroxaban, and apixaban we identified dose discordance when there was disagreement in the recommended dose based on different equations. Among the overall population, relative to Cockcroft-Gault, discordance in dabigatran dosage was 11.4% for Modification of Diet in Renal Disease and 10% for Chronic Kidney Disease Epidemiology Collaboration, discordance in rivaroxaban dosage was 10% for Modification of Diet in Renal Disease and 8.5% for the Chronic Kidney Disease Epidemiology Collaboration. The lowest discordance was observed for apixaban: 1.4% for Modification of Diet in Renal Disease and 1.5% for the Chronic Kidney Disease Epidemiology Collaboration. In patients with Cockcroft-Gault<60mL/min or elderly patients, discordances in dabigatran and rivaroxaban dosages were higher, ranging from 13.2% to 30.4%. Discordance in apixaban dosage remained<5% in these patients. Discordance in new oral anticoagulation dosages using different equations is frequent, especially among elderly patients with renal impairment. This discordance was higher in dabigatran and rivaroxaban dosages than in apixaban dosages. Further studies are needed to clarify the clinical importance of these discordances and the optimal anticoagulant dosages depending on the use of different equations to estimate renal function. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Beyond Stroke Prevention in Atrial Fibrillation: Exploring Further Unmet Needs with Rivaroxaban.

PubMed

Gibson, C M; Hankey, G J; Nafee, T; Welsh, R C

2018-03-22

With improved life expectancy and the aging population, the global burden of atrial fibrillation (AF) continues to increase, and with AF comes an estimated fivefold increased risk of ischaemic stroke. Prophylactic anticoagulant therapy is more effective in reducing the risk of ischaemic stroke in AF patients than acetylsalicylic acid or dual-antiplatelet therapy combining ASA with clopidogrel. Non-vitamin K antagonist oral anticoagulants are the standard of care for stroke prevention in patients with non-valvular AF. The optimal anticoagulant strategy to prevent thromboembolism in AF patients who are undergoing percutaneous coronary intervention and stenting, those who have undergone successful transcatheter aortic valve replacement and those with embolic stroke of undetermined source are areas of ongoing research. This article provides an update on three randomized controlled trials of rivaroxaban, a direct, oral factor Xa inhibitor, that are complete or are ongoing, in these unmet areas of stroke prevention: oPen-label, randomized, controlled, multicentre study explorIng twO treatmeNt stratEgiEs of Rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in patients with Atrial Fibrillation who undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) trial; the New Approach riVaroxaban Inhibition of factor Xa in a Global trial vs Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS) trial and the Global study comparing a rivAroxaban-based antithrombotic strategy to an antipLatelet-based strategy after transcatheter aortIc vaLve rEplacement to Optimize clinical outcomes (GALILEO) trial. The data from these studies are anticipated to help address continuing challenges for a range of patients at risk of stroke. Schattauer.

New oral anticoagulants in patients with cancer: current state of evidence.

PubMed

Sardar, Partha; Chatterjee, Saurav; Herzog, Eyal; Pekler, Gerald; Mushiyev, Savi; Pastori, Luciano J; Visco, Ferdinand; Aronow, Wilbert S

2015-01-01

Effectiveness of new oral anticoagulants (NOAC) in patients with cancer is not clearly defined. There remain concerns of doubtful benefit and chances of potential harm with newer agents. In this meta-analysis, we evaluated the efficacy and safety of NOAC in patients with cancer. PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched from January 01, 2001 through February 28, 2013. Randomized controlled trials reporting efficacy and safety data of NOACs (rivaroxaban, dabigatran, and apixaban) with control (low-molecular-weight heparin/vitamin K antagonists/placebo) for patients with cancer were included. Primary efficacy outcome was venous thromboembolism (VTE) or VTE-related death, and primary safety outcome was clinically relevant bleeding. We used random-effects models. Six trials randomized 19,832 patients, and 1197 patients had cancer. Risk of VTE or VTE-related death was not significantly different with NOAC versus control [odds ratio (OR), 0.80; 95% confidence interval (CI), 0.39-1.65] in patients with cancer. Separate analysis for individual effects showed similar results for rivaroxaban (OR, 1.08; 95% CI, 0.60-1.94) and dabigatran (OR, 0.91; 95% CI, 0.21-3.91). Clinically relevant bleeding was not higher with NOAC compared with control (OR, 1.49; 95% CI, 0.82-2.71); individual effect of rivaroxaban showed similar results. No statistically significant difference of efficacy and safety with NOAC was found between patients with and without cancer. Rivaroxaban might be equally effective and safe as vitamin K antagonist in patients with cancer. Dabigatran is as effective as comparator; however, safety profile of dabigatran is unknown. Randomized trials of new anticoagulants specific to the cancer population are necessary, and NOAC also need to be evaluated against low-molecular-weight heparin.

In vitro dissolution method fitted to in vivo absorption profile of rivaroxaban immediate-release tablets applying in silico data.

PubMed

Wingert, Nathalie R; Dos Santos, Natália O; Campanharo, Sarah C; Simon, Elisa S; Volpato, Nadia M; Steppe, Martin

2018-05-01

This study aimed to develop and validate an in vitro dissolution method based on in silico-in vivo data to determine whether an in vitro-in vivo relationship could be established for rivaroxaban in immediate-release tablets. Oral drugs with high permeability but poorly soluble in aqueous media, such as the anticoagulant rivaroxaban, have a major potential to reach a high level of in vitro-in vivo relationship. Currently, there is no study on scientific literature approaching the development of RIV dissolution profile based on its in vivo performance. Drug plasma concentration values were modeled using computer simulation with adjustment of pharmacokinetic properties. Those values were converted into drug fractions absorbed by the Wagner-Nelson deconvolution approach. Gradual and continuous dissolution of RIV tablets was obtained with a 30 rpm basket on 50 mM sodium acetate +0.2% SDS, pH 6.5 medium. Dissolution was conducted for up to 180 min. The fraction absorbed was plotted against the drug fraction dissolved, and a linear point-to-point regression (R 2  = 0.9961) obtained. The in vitro dissolution method designed promoted a more convenient dissolution profile of RIV tablets, whereas it suggests a better relationship with in vivo performance.

Medical costs in the US of clinical events associated with oral anticoagulant (OAC) use compared to warfarin among non-valvular atrial fibrillation patients ≥75 and <75 years of age, based on the ARISTOTLE, RE-LY, and ROCKET-AF trials.

PubMed

Deitelzweig, Steve; Amin, Alpesh; Jing, Yonghua; Makenbaeva, Dinara; Wiederkehr, Daniel; Lin, Jay; Graham, John

2013-09-01

Based on clinical trials the oral anticoagulants (OACs) apixaban, dabigatran, and rivaroxaban are efficacious for reducing stroke risk for non-valvular atrial fibrillation (NVAF) patients. Based on the clinical trials, this study evaluated the medical costs for clinical events among NVAF patients ≥75 and <75 years of age treated with individual OACs vs warfarin. Rates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients receiving warfarin or each of the OACs were determined for NVAF populations aged ≥75 years and <75 years of age from the OAC vs warfarin trials. One-year incremental costs among patients with clinical events were obtained from published literature and inflation adjusted to 2010 costs. Medical costs, excluding medication costs, for clinical events associated with each OAC and warfarin were then estimated and compared. Among NVAF patients aged ≥75, compared to warfarin, use of either apixaban or rivaroxaban was associated with a reduction in medical costs per patient year (apixaban = -$825, rivaroxaban =-$23), while dabigatran use was associated with increased medical costs of $180 per patient year. Among NVAF patients <75 years of age medical costs per patient year were estimated to be reduced -$254, -$367, and -$88, for apixaban, dabigatran, and rivaroxaban, respectively, in comparison to warfarin. This economic analysis was based on clinical trial data and, therefore, the direct application of the results to routine clinical practice will require further assessment. Difference in medical costs between OAC and warfarin treated NVAF patients vary by age group and individual OACs. Although reductions in medical costs for NVAF patients aged ≥75 and <75 were observed for those using either apixaban or rivaroxaban vs warfarin, the reductions were greater per patient year for both the older and younger NVAF populations using apixaban.

Medical cost reductions associated with the usage of novel oral anticoagulants vs warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF, and ARISTOTLE trials.

PubMed

Deitelzweig, Steve; Amin, Alpesh; Jing, Yonghua; Makenbaeva, Dinara; Wiederkehr, Daniel; Lin, Jay; Graham, John

2012-01-01

The randomized clinical trials, RE-LY, ROCKET-AF, and ARISTOTLE, demonstrate that the novel oral anticoagulants (NOACs) are effective options for stroke prevention among non-valvular atrial fibrillation (AF) patients. This study aimed to evaluate the medical cost reductions associated with the use of individual NOACs instead of warfarin from the US payer perspective. Rates for efficacy and safety clinical events for warfarin were estimated as the weighted averages from the RE-LY, ROCKET-AF and ARISTOTLE trials, and event rates for NOACs were determined by applying trial hazard ratios or relative risk ratios to such weighted averages. Incremental medical costs to a US health payer of an AF patient experiencing a clinical event during 1 year following the event were obtained from published literature and inflation adjusted to 2010 cost levels. Medical costs, excluding drug costs, were evaluated and compared for each NOAC vs warfarin. Sensitivity analyses were conducted to determine the influence of variations in clinical event rates and incremental costs on the medical cost reduction. In a patient year, the medical cost reduction associated with NOAC usage instead of warfarin was estimated to be -$179, -$89, and -$485 for dabigatran, rivaroxaban, and apixaban, respectively. When clinical event rates and costs were allowed to vary simultaneously, through a Monte Carlo simulation, the 95% confidence interval of annual medical costs differences ranged between -$424 and +$71 for dabigatran, -$301 and +$135 for rivaroxaban, and -$741 and -$252 for apixaban, with a negative number indicating a cost reduction. Of the 10,000 Monte-Carlo iterations 92.6%, 79.8%, and 100.0% were associated with a medical cost reduction >$0 for dabigatran, rivaroxaban, and apixaban, respectively. Usage of the NOACs, dabigatran, rivaroxaban, and apixaban may be associated with lower medical (excluding drug costs) costs relative to warfarin, with apixaban having the most substantial medical cost reduction.

Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a 'real world' atrial fibrillation population: a modelling analysis based on a nationwide cohort study.

PubMed

Banerjee, Amitava; Lane, Deirdre A; Torp-Pedersen, Christian; Lip, Gregory Y H

2012-03-01

The concept of net clinical benefit has been used to quantify the balance between risk of ischaemic stroke (IS) and risk of intracranial haemorrhage (ICH) with the use oral anticoagulant therapy (OAC) in the setting of non-valvular atrial fibrillation (AF), and has shown that patients at highest risk of stroke and thromboembolism gain the greatest benefit from OAC with warfarin. There are no data for the new OACs, that is, dabigatran, rivaroxaban and apixaban, as yet. We calculated the net clinical benefit balancing IS against ICH using data from the Danish National Patient Registry on patients with non-valvular AF between 1997-2008, for dabigatran, rivaroxaban and apixaban on the basis of recent clinical trial outcome data for these new OACs. In patients with CHADS(2)=0 but at high bleeding risk, apixaban and dabigatran 110 mg bid had a positive net clinical benefit. At CHA(2)DS(2)-VASc=1, apixaban and both doses of dabigatran (110 mg and 150 mg bid) had a positive net clinical benefit. In patients with CHADS(2) score≥1 or CHA(2)DS(2)-VASc≥2, the three new OACs (dabigatran, rivaroxaban and apixaban) appear superior to warfarin for net clinical benefit, regardless of risk of bleeding. When risk of bleeding and stroke are both high, all three new drugs appear to have a greater net clinical benefit than warfarin. In the absence of head-to-head trials for these new OACs, our analysis may help inform decision making processes when all these new OACs become available to clinicians for stroke prevention in AF. Using 'real world' data, our modelling analysis has shown that when the risk of bleeding and stroke are both high, all three new drugs appear to have a greater net clinical benefit compared to warfarin.

Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin: ROCKET AF Trial.

PubMed

Sherwood, Matthew W; Nessel, Christopher C; Hellkamp, Anne S; Mahaffey, Kenneth W; Piccini, Jonathan P; Suh, Eun-Young; Becker, Richard C; Singer, Daniel E; Halperin, Jonathan L; Hankey, Graeme J; Berkowitz, Scott D; Fox, Keith A A; Patel, Manesh R

2015-12-01

Gastrointestinal (GI) bleeding is a common complication of oral anticoagulation. This study evaluated GI bleeding in patients who received at least 1 dose of the study drug in the on-treatment arm of the ROCKET AF (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial. The primary outcome was adjudicated GI bleeding reported from first to last drug dose + 2 days. Multivariable modeling was performed with pre-specified candidate predictors. Of 14,236 patients, 684 experienced GI bleeding during follow-up. These patients were older (median age 75 years vs. 73 years) and less often female. GI bleeding events occurred in the upper GI tract (48%), lower GI tract (23%), and rectum (29%) without differences between treatment arms. There was a significantly higher rate of major or nonmajor clinical GI bleeding in rivaroxaban- versus warfarin-treated patients (3.61 events/100 patient-years vs. 2.60 events/100 patient-years; hazard ratio: 1.42; 95% confidence interval: 1.22 to 1.66). Severe GI bleeding rates were similar between treatment arms (0.47 events/100 patient-years vs. 0.41 events/100 patient-years; p = 0.39; 0.01 events/100 patient-years vs. 0.04 events/100 patient-years; p = 0.15, respectively), and fatal GI bleeding events were rare (0.01 events/100 patient-years vs. 0.04 events/100 patient-years; 1 fatal events vs. 5 fatal events total). Independent clinical factors most strongly associated with GI bleeding were baseline anemia, history of GI bleeding, and long-term aspirin use. In the ROCKET AF trial, rivaroxaban increased GI bleeding compared with warfarin. The absolute fatality rate from GI bleeding was low and similar in both treatment arms. Our results further illustrate the need for minimizing modifiable risk factors for GI bleeding in patients on oral anticoagulation. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Rivaroxaban to Prevent Pulmonary Embolism after Hip or Knee Replacement

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Direct oral anticoagulants: An update.

PubMed

Franco Moreno, Ana Isabel; Martín Díaz, Rosa María; García Navarro, María José

2017-12-30

Vitamin K antagonists were the only choice for chronic oral anticoagulation for more than half a century. Over the past few years, direct oral anticoagulants have emerged, including one direct thrombin inhibitor (dabigatran etexilate) and three factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). In randomised controlled trials comparing direct oral anticoagulants with traditional vitamin K antagonists, the direct oral anticoagulants all showed a favourable benefit-risk balance in their safety and efficacy profile, in prevention of thromboembolic events in patients with atrial fibrillation and in the prevention and treatment of venous thromboembolism and acute coronary syndrome. In 2008, dabigatran was the first direct oral anticoagulant approved by the European Medicine Agency. Subsequently, rivaroxaban, apixaban and edoxaban were also authorised. This article reviews the evidence related to the use of these drugs. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Evaluating the impact of new anticoagulants in the hospital setting

PubMed Central

Braidy, Nady; Bui, Khai; Bajorek, Beata

2010-01-01

The short-comings of current anticoagulants have led to the development of newer, albeit more expensive, oral alternatives. Objective To explore the potential impact the new anticoagulants dabigatran and rivaroxaban in the local hospital setting, in terms of utilisation and subsequent costing. Method A preliminary costing analysis was performed based on a prospective 2-week clinical audit (29th June - 13th July 2009). Data regarding current anticoagulation management were extracted from the medical files of patients admitted to Ryde Hospital. To model potential costing implications of using the newer agents, the reported incidence of VTE/stroke and bleeding events were obtained from key clinical trials. Results Data were collected for 67 patients treated with either warfarin (n=46) or enoxaparin (n=21) for prophylaxis of VTE/stroke. At least two-thirds of all patients were deemed suitable candidates for the use of newer oral anticoagulants (by current therapy: warfarin: 65.2% (AF), 34.8% (VTE); enoxaparin: 100%, (VTE)). The use of dabigatran in VTE/stroke prevention was found to be more cost- effective than warfarin and enoxaparin due to significantly lower costs of therapeutic monitoring and reduced administration costs. Rivaroxaban was more cost-effective than warfarin and enoxaparin for VTE/stroke prevention when supplier-rebates (33%) were factored into costing. Conclusion This study highlights the potential cost- effectiveness of newer anticoagulants, dabigatran and rivaroxaban, compared to warfarin and enoxaparin. These agents may offer economic advantages, as well as clinical benefits, in the hospital-based management of anticoagulated patients. PMID:25132883

Outcome of Secondary Stroke Prevention in Patients Taking Non-Vitamin K Antagonist Oral Anticoagulants.

PubMed

Nakase, Taizen; Moroi, Junta; Ishikawa, Tatsuya

2018-05-01

Since non-vitamin K antagonist oral anticoagulants (NOACs) were released for clinical use, many studies have investigated its effectiveness in stroke prevention. In this study, to determine whether or not there is a difference in outcome in secondary stroke prevention between warfarin and NOACs, patients with embolic stroke with newly prescribed anticoagulants were prospectively analyzed. Patients with acute ischemic stroke, who newly started anticoagulant therapy, were consecutively asked to participate in this study. Enrolled patients (76.3 ± 11.0 years old) were classified into warfarin (n = 48), dabigatran (n = 73), rivaroxaban (n = 49), and apixaban (n = 65). The outcome in 1 year was prospectively investigated at outpatient clinic or telephone interview. Recurrence of stroke and death was considered as the critical incidence. The prevalence of risk factors was not different among all medicines. Patients with dabigatran showed significantly younger onset age (P < .001: 72.2 years old) and milder neurologic deficits than patients on other medicines (P < .001). Cumulative incident rates were 7.1%, 15.3%, 19.0%, and 29.7% for dabigatran, apixaban, rivaroxaban, and warfarin, respectively. Dabigatran showed relatively better outcome compared with warfarin (P = .069) and rivaroxaban (P = .055). All patients on NOACs presented lower cumulative stroke recurrence compared with warfarin. Even in the situation of secondary stroke prevention, noninferiority of NOACs to warfarin might be demonstrated. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

A review of apixaban for stroke prevention in atrial fibrillation: insights from ARISTOTLE.

PubMed

Hess, Connie N; Al-Khatib, Sana M; Granger, Christopher B; Lopes, Renato

2013-09-01

Atrial fibrillation (AF) is associated with significant mortality and morbidity, and stroke represents the most-feared complication. Consequently, AF treatment has focused on thromboprophylaxis, with warfarin as the mainstay of therapy. However, concerns over ease of use and safety have limited its use. Three novel oral anticoagulants have been approved for use in stroke prevention in AF based on randomized data: 1) dabigatran, studied in Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY); 2) rivaroxaban, studied in Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF); and 3) apixaban, studied in Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE). In this review, we focus on apixaban and discuss subgroup analyses that have been performed in the three trials comparing novel oral anticoagulants with warfarin. We conclude with recommendations regarding further investigations.

Cost-effectiveness of rivaroxaban for stroke prevention in atrial fibrillation in the Portuguese setting.

PubMed

Morais, João; Aguiar, Carlos; McLeod, Euan; Chatzitheofilou, Ismini; Fonseca Santos, Isabel; Pereira, Sónia

2014-09-01

To project the long-term cost-effectiveness of treating non-valvular atrial fibrillation (AF) patients for stroke prevention with rivaroxaban compared to warfarin in Portugal. A Markov model was used that included health and treatment states describing the management and consequences of AF and its treatment. The model's time horizon was set at a patient's lifetime and each cycle at three months. The analysis was conducted from a societal perspective and a 5% discount rate was applied to both costs and outcomes. Treatment effect data were obtained from the pivotal phase III ROCKET AF trial. The model was also populated with utility values obtained from the literature and with cost data derived from official Portuguese sources. The outcomes of the model included life-years, quality-adjusted life-years (QALYs), incremental costs, and associated incremental cost-effectiveness ratios (ICERs). Extensive sensitivity analyses were undertaken to further assess the findings of the model. As there is evidence indicating underuse and underprescription of warfarin in Portugal, an additional analysis was performed using a mixed comparator composed of no treatment, aspirin, and warfarin, which better reflects real-world prescribing in Portugal. This cost-effectiveness analysis produced an ICER of €3895/QALY for the base-case analysis (vs. warfarin) and of €6697/QALY for the real-world prescribing analysis (vs. mixed comparator). The findings were robust when tested in sensitivity analyses. The results showed that rivaroxaban may be a cost-effective alternative compared with warfarin or real-world prescribing in Portugal. Copyright © 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Spotlight on unmet needs in stroke prevention: The PIONEER AF-PCI, NAVIGATE ESUS and GALILEO trials.

PubMed

Hemmrich, Melanie; Peterson, Eric D; Thomitzek, Karen; Weitz, Jeffrey I

2016-09-28

Atrial fibrillation (AF) is a major healthcare concern, being associated with an estimated five-fold risk of ischaemic stroke. In patients with AF, anticoagulants reduce stroke risk to a greater extent than acetylsalicylic acid (ASA) or dual antiplatelet therapy (DAPT) with ASA plus clopidogrel. Non-vitamin K antagonist oral anticoagulants (NOACs) are now a widely-accepted therapeutic option for stroke prevention in non-valvular AF (NVAF). There are particular patient types with NVAF for whom treatment challenges remain, owing to sparse clinical data, their high-risk nature or a need to harmonise anticoagulant and antiplatelet regimens if co-administered. This article focuses on three randomised controlled trials (RCTs) that are investigating the utility of rivaroxaban, a direct, oral, factor Xa inhibitor, in additional areas of stroke prevention where data for anticoagulants are lacking: oPen-label, randomized, controlled, multicentre study explorIng twO treatmeNt stratEgiEs of Rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment (PIONEER AF-PCI); New Approach riVaroxoban Inhibition of factor Xa in a Global trial vs Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS); and Global study comparing a rivAroxaban-based antithrombotic strategy to an antipLatelet-based strategy after transcatheter aortIc vaLve rEplacement to Optimize clinical outcomes (GALILEO). Data from these studies present collaborative efforts to build upon existing registrational Phase III data for rivaroxaban, driving the need for effective and safe treatment of a wider range of patients for stroke prevention.

The effect of bariatric surgery on direct-acting oral anticoagulant drug levels.

PubMed

Rottenstreich, Amihai; Barkai, Aviv; Arad, Ariela; Raccah, Bruria Hirsh; Kalish, Yosef

2018-03-01

To determine direct-acting oral anticoagulant (DOAC) blood levels in post-bariatric surgery (BS) patients treated with long-term anticoagulation therapy. We identified from medical records patients who underwent BS during 2005-2016 and who were treated with DOACs. We offered testing DOAC blood levels to these patients and to age, sex, body mass index, and serum creatinine-matched individuals treated by DOACs who did not undergo BS. Overall, 36 individuals were enrolled, 18 post-BS patients and 18 control subjects. Of the post-BS patients, 12 underwent laparoscopic sleeve gastrectomy, 4 laparoscopic adjustable gastric banding and 2 laparoscopic Roux-en-Y gastric bypass surgery. Median time lapsed from surgery until study inclusion was 4.9years. Five post-BS patients had peak drug levels below expected levels compared to none of the control subjects (P=0.05). For patients who used apixaban (n=9) and dabigatran (n=2), peak drug levels were within the expected range. In contrast, for the 7 patients who used rivaroxaban, levels were below the expected range in 5, including all four who underwent sleeve gastrectomy and one following adjustable gastric banding. Peak rivaroxaban levels were significantly lower in the post-BS than the control group (P=0.02). This preliminary study suggests that all DOACs, particularly rivaroxaban, be cautiously used following BS, if used at all. Given that vitamin-K antagonists can be easily monitored, they may be a better choice, until more data on DOAC use in this patient population are available. Copyright © 2017 Elsevier Ltd. All rights reserved.

Direct comparative effectiveness and safety between non-vitamin K antagonist oral anticoagulants for stroke prevention in nonvalvular atrial fibrillation: a systematic review and meta-analysis of observational studies.

PubMed

Li, Guowei; Lip, Gregory Y H; Holbrook, Anne; Chang, Yaping; Larsen, Torben B; Sun, Xin; Tang, Jie; Mbuagbaw, Lawrence; Witt, Daniel M; Crowther, Mark; Thabane, Lehana; Levine, Mitchell A H

2018-06-08

The non-vitamin K antagonist oral anticoagulants (NOACs) have been increasingly prescribed in clinical practice for stroke prevention in patients with nonvalvular atrial fibrillation (AF). Direct comparisons between NOACs in trials are lacking, leaving an important clinical decision-making gap. We aimed to perform a systematic review and meta-analysis to summarize the evidence of observational studies for direct comparative effectiveness and safety amongst NOACs in patients with AF. Conference proceedings and electronic databases including MEDLINE, CINAHL, EMBASE and PUBMED were systematically searched. We included observational studies directly comparing individual NOACs in patients with nonvalvular AF who were aged ≥ 18 years for stroke prevention. Primary outcome included effectiveness outcome (stroke or systemic embolism) and safety outcome (major bleeding). Data were extracted in duplicated by two reviewers independently. A random-effects meta-analysis was conducted to synthesize the data from included observational studies. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to rate the overall quality of evidence for each outcome. Fifteen studies were included for qualitative synthesis, twelve studies for meta-analyses. It was found that rivaroxaban and dabigatran were similar with regard to risk of stroke or systemic embolism (Hazard ratio [HR] = 1.00, 95% CI 0.91-1.10; evidence quality: low), but rivaroxaban was associated with higher risk of major bleeding (HR = 1.39, 95% CI 1.28-1.50; evidence quality: moderate). Compared with apixaban, a significantly higher risk of major bleeding was observed with rivaroxaban (HR = 1.71, 95% CI 1.51-1.94; evidence quality: low). Apixaban was associated with lower risk of major bleeding, in comparison with dabigatran (HR = 0.80, 95% CI 0.68-0.95; evidence quality: low). No differences in risk of stroke or systemic embolism was observed between rivaroxaban versus apixaban, and apixaban versus dabigatran. In this study, apixaban was found to have the most favorable safety profile amongst the three NOACs. No significant difference was observed in risk of stroke or systemic embolism between the NOACs. Such findings may provide some decision-making support for physicians regarding their choices amongst NOACs in patients with AF.Registration PROSPERO (identifier: CRD42016052908).

Impact of BMI on clinical outcomes of NOAC therapy in daily care - Results of the prospective Dresden NOAC Registry (NCT01588119).

PubMed

Tittl, L; Endig, S; Marten, S; Reitter, A; Beyer-Westendorf, I; Beyer-Westendorf, J

2018-07-01

Direct acting non-Vitamin K antagonist oral anticoagulants (NOAC) are characterized by a fixed dosing regimen. Despite the potential for relative underdosing due to large distribution volumes, dose adjustments for patients with high body mass index (BMI) are not recommended. Since efficacy and safety data in obese patients are scarce, we evaluated the impact of BMI on clinical outcomes in daily care patients treated with NOAC for stroke prevention in atrial fibrillation or venous thromboembolism. Using prospectively collected data from a non-interventional registry, cardiovascular (CV), major bleeding events (MB) and all-cause mortality were evaluated according to BMI classes. All outcome events were centrally adjudicated using standard scientific definitions. Between November 1st 2011 and December 31st 2016, 3432 patients were enrolled into the registry (61.3% rivaroxaban; 20% apixaban; 10.1% dabigatran, 8.6% edoxaban; mean follow-up 998.1 ± 542.9 days; median 1004 days). With increasing BMI (range 13.7-57.2 kg/m 2 ), the proportion of patients receiving standard (vs. reduced) NOAC dose increased from 64.7% (underweight) to 78.9% (obesity). Although obese patients had more cardiovascular risk factors compared to normal weight patients, on-treatment rates of clinical outcomes (CV, MB, all-cause-mortality) were lowest in overweight and obese patients. In a large set of real-life NOAC recipients we found no indication that high BMI is associated with inferior NOAC effectiveness or safety, which is in line with recent epidemiological data of a "BMI paradox" that indicates a somewhat protective effect of higher BMI regarding unfavourable outcomes also in patients receiving fixed dose NOAC anticoagulation without dose adjustment for higher BMI. Copyright © 2018 Elsevier B.V. All rights reserved.

Advances in Clinical Cardiology 2016: A Summary of the Key Clinical Trials.

PubMed

Gray, Alastair; McQuillan, Conor; Menown, Ian B A

2017-07-01

The findings of many new cardiology clinical trials over the last year have been published or presented at major international meetings. This paper aims to describe and place in context a summary of the key clinical trials in cardiology presented between January and December 2016. The authors reviewed clinical trials presented at major cardiology conferences during 2016 including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), European Association for the Study of Diabetes (EASD), Transcatheter Cardiovascular Therapeutics (TCT), and the American Heart Association (AHA). Selection criteria were trials with a broad relevance to the cardiology community and those with potential to change current practice. A total of 57 key cardiology clinical trials were identified for inclusion. Here we describe and place in clinical context the key findings of new data relating to interventional and structural cardiology including delayed stenting following primary angioplasty, contrast-induced nephropathy, management of jailed wires, optimal duration of dual antiplatelet therapy (DAPT), stenting vs bypass for left main disease, new generation stents (BioFreedom, Orsiro, Absorb), transcatheter aortic valve implantation (Edwards Sapien XT, transcatheter embolic protection), and closure devices (Watchman, Amplatzer). New preventative cardiology data include trials of bariatric surgery, empagliflozin, liraglutide, semaglutide, PCSK9 inhibitors (evolocumab and alirocumab), and inclisiran. Antiplatelet therapy trials include platelet function monitoring and ticagrelor vs clopidogrel for peripheral vascular disease. New data are also presented in fields of heart failure (sacubitril/valsartan, aliskiren, spironolactone), atrial fibrillation (rivaroxaban in patients undergoing coronary intervention, edoxaban in DC cardioversion), cardiac devices (implantable cardioverter defibrillator in non-ischemic cardiomyopathy), and electrophysiology (cryoballoon vs radiofrequency ablation). This paper presents a summary of key clinical cardiology trials during the past year and should be of practical value to both clinicians and cardiology researchers.

Novel venous thromboembolic disease (VTED) prophylaxis for total knee arthroplasty—aspirin and fish oil

PubMed Central

Sodhi, Nipun; Patel, Yatindra H.; Sultan, Assem A.; Khlopas, Anton; Chughtai, Morad; Kolisek, Frank R.; Williams, Nick; Mont, Michael A.

2017-01-01

Background Despite the demonstrated success of multiple anticoagulation therapies for post-operative prophylaxis of thromboembolic disease in lower extremity arthroplasties, each modality comes with a unique set of limitations. Thus, the ideal anticoagulation medication which provides adequate therapy with minimal cost, complications, or added patient work is yet to be defined. One promising novel thrombophylactic supplement is fish oil, as many preliminary clinical trials have demonstrated a protective effect of fish oil against thrombosis in multiple clinical settings. In addition, others have demonstrated synergistic effect when combined with aspirin. However, there are paucity of studies that compared combined aspirin and fish oil therapy for venous thromboembolism prophylaxis with other pharmacological agents, especially in the field of orthopaedics. Therefore, this study evaluated: (I) risk of post-operative deep vein thrombosis (DVT) and pulmonary embolism (PE), and (II) bleeding complications; among patients who had primary total knee arthroplasty (TKA) and received one of the following regimens: (i) 325 mg aspirin and mechanical pulsatile stocking; (ii) rivaroxaban; or (iii) 325 mg aspirin and 1,000 mg fish oil. Methods This was a 6-year prospective study analyzing the postoperative thromboembolic prophylaxis received by patients who underwent primary TKA. Patients who had a previous history of thromboembolic disease were excluded from the study due to an increased risk of recurrent clot formation. A total of 850 patients were enrolled. A total of 300 patients enrolled between October 2011 and June 2013 received 325 mg aspirin and mechanical pulsatile stocking, while 250 patients enrolled between June 2013 and December 2014 received rivaroxaban. A total of 300 patients enrolled between January 2015 and July 2017 received 325 mg aspirin and 1,000 mg fish oil. Major venous thromboembolic events (VTEs) and bleeding complications within the first 90 days post-operatively were recorded in each cohort. The odds ratios (ORs) and 95% confidence intervals (CIs), for thromboembolic and bleeding events were calculated and compared between the aspirin and fish oil cohort vs. aspirin and pulsatile stocking cohort, and aspirin and fish oil cohort vs. rivaroxaban cohort. A P value of <0.05 was used to determine statistical significance. Results A total of 25 DVT events were recorded including 1 of 300 (0.33%) in the aspirin and fish oil cohort, 22 of 300 (7.33%) in the aspirin and pulsatile stocking cohort and 2 of 250 (0.8%) in the rivaroxaban cohort. When comparing ORs, patients who received aspirin and fish oil demonstrated significantly lower risk for thromboembolic events when compared to the aspirin and pulsatile stocking group (OR: 0.045; 95% CI: 0.0061–0.3394; P<0.05). When compared to the rivaroxaban cohort the ORs did not differ significantly (OR: 0.416; 95% CI: 0.0376–4.6223; P>0.05). In addition, no PE events were recorded in any of the cohorts. When compared to rivaroxaban, the fish oil and aspirin cohort demonstrated significantly lower incidence of bleeding episodes (1 of 300, 0.33% vs. 30 of 250 patients, 12%; OR: 0.0278; 95% CI: 0.0038–0.2051; P<0.05). No bleeding events were recorded in the aspirin and pulsatile stocking cohort. Conclusions This study demonstrated the potentially synergistic anti-thromboembolic effect of aspirin and fish oil in the prevention of post-operative venous thromboembolism in primary TKA patients. Based on the results from this study, the authors conclude that the combination of aspirin and fish oil maybe an excellent thromboprophylactic modality for patients to use after TKA. These results warrant further, larger prospective studies analyzing the use of fish oil supplements in VTE prophylaxis. PMID:29299477

Novel venous thromboembolic disease (VTED) prophylaxis for total knee arthroplasty-aspirin and fish oil.

PubMed

Bonutti, Peter M; Sodhi, Nipun; Patel, Yatindra H; Sultan, Assem A; Khlopas, Anton; Chughtai, Morad; Kolisek, Frank R; Williams, Nick; Mont, Michael A

2017-12-01

Despite the demonstrated success of multiple anticoagulation therapies for post-operative prophylaxis of thromboembolic disease in lower extremity arthroplasties, each modality comes with a unique set of limitations. Thus, the ideal anticoagulation medication which provides adequate therapy with minimal cost, complications, or added patient work is yet to be defined. One promising novel thrombophylactic supplement is fish oil, as many preliminary clinical trials have demonstrated a protective effect of fish oil against thrombosis in multiple clinical settings. In addition, others have demonstrated synergistic effect when combined with aspirin. However, there are paucity of studies that compared combined aspirin and fish oil therapy for venous thromboembolism prophylaxis with other pharmacological agents, especially in the field of orthopaedics. Therefore, this study evaluated: (I) risk of post-operative deep vein thrombosis (DVT) and pulmonary embolism (PE), and (II) bleeding complications; among patients who had primary total knee arthroplasty (TKA) and received one of the following regimens: (i) 325 mg aspirin and mechanical pulsatile stocking; (ii) rivaroxaban; or (iii) 325 mg aspirin and 1,000 mg fish oil. This was a 6-year prospective study analyzing the postoperative thromboembolic prophylaxis received by patients who underwent primary TKA. Patients who had a previous history of thromboembolic disease were excluded from the study due to an increased risk of recurrent clot formation. A total of 850 patients were enrolled. A total of 300 patients enrolled between October 2011 and June 2013 received 325 mg aspirin and mechanical pulsatile stocking, while 250 patients enrolled between June 2013 and December 2014 received rivaroxaban. A total of 300 patients enrolled between January 2015 and July 2017 received 325 mg aspirin and 1,000 mg fish oil. Major venous thromboembolic events (VTEs) and bleeding complications within the first 90 days post-operatively were recorded in each cohort. The odds ratios (ORs) and 95% confidence intervals (CIs), for thromboembolic and bleeding events were calculated and compared between the aspirin and fish oil cohort vs. aspirin and pulsatile stocking cohort, and aspirin and fish oil cohort vs. rivaroxaban cohort. A P value of <0.05 was used to determine statistical significance. A total of 25 DVT events were recorded including 1 of 300 (0.33%) in the aspirin and fish oil cohort, 22 of 300 (7.33%) in the aspirin and pulsatile stocking cohort and 2 of 250 (0.8%) in the rivaroxaban cohort. When comparing ORs, patients who received aspirin and fish oil demonstrated significantly lower risk for thromboembolic events when compared to the aspirin and pulsatile stocking group (OR: 0.045; 95% CI: 0.0061-0.3394; P<0.05). When compared to the rivaroxaban cohort the ORs did not differ significantly (OR: 0.416; 95% CI: 0.0376-4.6223; P>0.05). In addition, no PE events were recorded in any of the cohorts. When compared to rivaroxaban, the fish oil and aspirin cohort demonstrated significantly lower incidence of bleeding episodes (1 of 300, 0.33% vs . 30 of 250 patients, 12%; OR: 0.0278; 95% CI: 0.0038-0.2051; P<0.05). No bleeding events were recorded in the aspirin and pulsatile stocking cohort. This study demonstrated the potentially synergistic anti-thromboembolic effect of aspirin and fish oil in the prevention of post-operative venous thromboembolism in primary TKA patients. Based on the results from this study, the authors conclude that the combination of aspirin and fish oil maybe an excellent thromboprophylactic modality for patients to use after TKA. These results warrant further, larger prospective studies analyzing the use of fish oil supplements in VTE prophylaxis.

Methodological challenges in assessment of current use of warfarin among patients with atrial fibrillation using dispensation data from administrative health care databases.

PubMed

Sinyavskaya, Liliya; Matteau, Alexis; Johnson, Sarasa; Durand, Madeleine

2018-06-05

Algorithms to define current exposure to warfarin using administrative data may be imprecise. Study objectives were to characterize dispensation patterns, to measure gaps between expected and observed refill dates for warfarin and direct oral anticoagulants (DOACs). Retrospective cohort study using administrative health care databases of the Régie de l'assurance-maladie du Québec. We identified every dispensation of warfarin, dabigatran, rivaroxaban, or apixaban for patients with AF initiating oral anticoagulants between 2010 and 2015. For each dispensation, we extracted date and duration. Refill gaps were calculated as difference between expected and observed dates of successive dispensation. Refill gaps were summarized using descriptive statistics. To account for repeated observations nested within patients and to assess the components of variance of refill gaps, we used unconditional multilevel linear models. We identified 61 516 new users. Majority were prescribed warfarin (60.3%), followed by rivaroxaban (16.4%), dabigatran (14.5%), apixaban (8.8%). Most frequent recorded duration of dispensation was 7 days, suggesting use of pharmacist-prepared weekly pillboxes. The average refill gap from multilevel model was higher for warfarin (9.28 days, 95%CI:8.97-9.59) compared with DOACs (apixaban 3.08 days, 95%CI: 2.96-3.20, dabigatran 3.70, 95%CI: 3.56-3.84, rivaroxaban 3.15, 95%CI: 3.03-3.27). The variance of refill gaps was greater among warfarin users than among DOAC users. Greater refill gaps for warfarin may reflect inadequate capture of the period covered by the number of dispensed pills recorded in administrative data. A time-dependent definition of exposure using dispensation data would lead to greater misclassification of warfarin than DOACs use. Copyright © 2018 John Wiley & Sons, Ltd.

Cost-effectiveness of non-vitamin K antagonist oral anticoagulants for atrial fibrillation in Portugal.

PubMed

Costa, João; Fiorentino, Francesca; Caldeira, Daniel; Inês, Mónica; Lopes Pereira, Catarina; Pinheiro, Luís; Vaz-Carneiro, António; Borges, Margarida; Gouveia, Miguel

2015-12-01

Recently, three novel non-vitamin K antagonist oral anticoagulants received approval for reimbursement in Portugal for patients with non-valvular atrial fibrillation (AF). It is therefore important to evaluate the relative cost-effectiveness of these new oral anticoagulants in Portuguese AF patients. A Markov model was used to analyze disease progression over a lifetime horizon. Relative efficacy data for stroke (ischemic and hemorrhagic), bleeding (intracranial, other major bleeding and clinically relevant non-major bleeding), myocardial infarction and treatment discontinuation were obtained by pairwise indirect comparisons between apixaban, dabigatran and rivaroxaban using warfarin as a common comparator. Data on resource use were obtained from the database of diagnosis-related groups and an expert panel. Model outputs included life years gained, quality-adjusted life years (QALYs), direct healthcare costs and incremental cost-effectiveness ratios (ICERs). Apixaban provided the most life years gained and QALYs. The ICERs of apixaban compared to warfarin and dabigatran were €5529/QALY and €9163/QALY, respectively. Apixaban was dominant over rivaroxaban (greater health gains and lower costs). The results were robust over a wide range of inputs in sensitivity analyses. Apixaban had a 70% probability of being cost-effective (at a threshold of €20 000/QALY) compared to all the other therapeutic options. Apixaban is a cost-effective alternative to warfarin and dabigatran and is dominant over rivaroxaban in AF patients from the perspective of the Portuguese national healthcare system. These conclusions are based on indirect comparisons, but despite this limitation, the information is useful for healthcare decision-makers. Copyright © 2015 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Safety and Efficacy of Novel Oral Anticoagulants vs Low Molecular Weight Heparin for Thromboprophylaxis in Large-Volume Liposuction and Body Contouring Procedures.

PubMed

Morales, Rolando; Ruff, Eric; Patronella, Christopher; Mentz, Henry; Newall, Germán; Hustak, Kristi L; Fortes, Paul; Bush, Amelia

2016-04-01

Preventing venous thromboembolism (VTE) remains an important topic in the plastic surgery community. However, there is little consensus regarding appropriate VTE prophylaxis for patients undergoing common body contouring procedures. This study compared the use of two novel oral anticoagulants (Rivaroxaban and Apixiban) vs low molecular weight heparin (LMWH) for postoperative chemical prophylaxis in body contouring plastic surgery procedures. A single center retrospective chart review of 1572 patients who underwent body contouring plastic surgery procedures from January 2012 to February 2015 was performed. Major complications associated with chemical prophylaxis were reviewed including hematomas requiring surgical evacuation, acute blood loss anemia requiring transfusions, and thrombotic or hemorrhagic events. Drug-related adverse events occurred in 1.27% (n = 20) of patients. The complications encountered by the 454 patients on LMWH consisted of 0.88% (n = 4) with hematomas requiring surgical evacuation, 0.44% (n = 2) with decreased hemoglobin requiring transfusions, and 0.22% (n = 1) with a deep vein thrombosis (DVT). The complications encountered by 703 patients on with Rivaroxaban consisted of 1.3% (n = 9) with hematomas requiring surgical evacuation, 0.43% (n = 3) with decreased hemoglobin requiring transfusions, and 0.1% (n = 1) with a DVT and pulmonary embolism. The complications encountered by 415 patients on with Apixaban consisted of 0.48% (n = 2) with a DVT. Novel oral anticoagulants (Rivaroxaban and Apixiban) are comparable to LMWH for chemical prophylaxis after body contouring procedures with similar rates of drug-related complications. Further investigation is warranted with more clinical cases in order to recommend the use of this medication for routine postoperative chemical prophylaxis after body contouring procedures. 3 Therapeutic. © 2016 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.

Factor Xa Inhibitor Suppresses the Release of Phosphorylated HSP27 from Collagen-Stimulated Human Platelets: Inhibition of HSP27 Phosphorylation via p44/p42 MAP Kinase

PubMed Central

Tsujimoto, Masanori; Kuroyanagi, Gen; Matsushima-Nishiwaki, Rie; Kito, Yuko; Enomoto, Yukiko; Iida, Hiroki; Ogura, Shinji; Otsuka, Takanobu; Tokuda, Haruhiko; Kozawa, Osamu; Iwama, Toru

2016-01-01

Selective inhibitors of factor Xa (FXa) are widely recognized as useful therapeutic tools for stroke prevention in non-valvular atrial fibrillation or venous thrombosis. Thrombin, which is rapidly generated from pro-thrombin through the activation of factor X to FXa, acts as a potent activator of human platelets. Thus, the reduction of thrombin generation by FXa inhibitor eventually causes a suppressive effect on platelet aggregation. However, little is known whether FXa inhibitors directly affect the function of human platelets. We have previously reported that collagen induces the phosphorylation of heat shock protein 27 (HSP27), a low-molecular weight heat shock protein via Rac-dependent activation of p44/p42 mitogen-activated protein (MAP) kinase in human platelets, eventually resulting in the release of HSP27. In the present study, we investigated the direct effect of FXa inhibitor on the collagen-induced human platelet activation. Rivaroxaban as well as edoxaban significantly reduced the collagen-induced phosphorylation of both HSP27 and p44/p42 MAP kinase without affecting the platelet aggregation. Rivaroxaban significantly inhibited the release of phosphorylated HSP27 from collagen-stimulated platelets but not the secretion of platelet derived growth factor-AB. In patients administrated with rivaroxaban, the collagen-induced levels of phosphorylated HSP27 were markedly diminished after 2 days of administration, which failed to affect the platelet aggregation. These results strongly suggest that FXa inhibitor reduces the collagen-stimulated release of phosphorylated HSP27 from human platelets due to the inhibition of HSP27 phosphorylation via p44/p42 MAP kinase. PMID:26867010

Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use

PubMed Central

Lensing, Anthonie W. A.; Middeldorp, Saskia; Levi, Marcel; Beyer-Westendorf, Jan; van Bellen, Bonno; Bounameaux, Henri; Brighton, Timothy A.; Cohen, Alexander T.; Trajanovic, Mila; Gebel, Martin; Lam, Phuong; Wells, Philip S.; Prins, Martin H.

2016-01-01

Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an “unacceptable health risk” during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence densities in percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs off) as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% confidence interval [CI], 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding (on vs off hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR, 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration. PMID:26696010

Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use.

PubMed

Martinelli, Ida; Lensing, Anthonie W A; Middeldorp, Saskia; Levi, Marcel; Beyer-Westendorf, Jan; van Bellen, Bonno; Bounameaux, Henri; Brighton, Timothy A; Cohen, Alexander T; Trajanovic, Mila; Gebel, Martin; Lam, Phuong; Wells, Philip S; Prins, Martin H

2016-03-17

Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an "unacceptable health risk" during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence densities in percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs off) as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% confidence interval [CI], 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding (on vs off hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR, 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration. © 2016 by The American Society of Hematology.

Impact of Variations in Kidney Function on Nonvitamin K Oral Anticoagulant Dosing in Patients With Atrial Fibrillation and Recent Acute Heart Failure.

PubMed

Andreu-Cayuelas, José M; Pastor-Pérez, Francisco J; Puche, Carmen M; Mateo-Martínez, Alicia; García-Alberola, Arcadio; Flores-Blanco, Pedro J; Valdés, Mariano; Lip, Gregory Y H; Roldán, Vanessa; Manzano-Fernández, Sergio

2016-02-01

Renal impairment and fluctuations in renal function are common in patients recently hospitalized for acute heart failure and in those with atrial fibrillation. The aim of the present study was to evaluate the hypothetical need for dosage adjustment (based on fluctuations in kidney function) of dabigatran, rivaroxaban and apixaban during the first 6 months after hospital discharge in patients with concomitant atrial fibrillation and heart failure. An observational study was conducted in 162 patients with nonvalvular atrial fibrillation after hospitalization for acute decompensated heart failure who underwent creatinine determinations during follow-up. The hypothetical recommended dosage of dabigatran, rivaroxaban and apixaban according to renal function was determined at discharge. Variations in serum creatinine and creatinine clearance and consequent changes in the recommended dosage of these drugs were identified during 6 months of follow-up. Among the overall study population, 44% of patients would have needed dabigatran dosage adjustment during follow-up, 35% would have needed rivaroxaban adjustment, and 29% would have needed apixaban dosage adjustment. A higher proportion of patients with creatinine clearance < 60 mL/min or with advanced age (≥ 75 years) would have needed dosage adjustment during follow-up. The need for dosage adjustment of nonvitamin K oral anticoagulants during follow-up is frequent in patients with atrial fibrillation after acute decompensated heart failure, especially among older patients and those with renal impairment. Further studies are needed to clarify the clinical importance of these needs for drug dosing adjustment and the ideal renal function monitoring regime in heart failure and other subgroups of patients with atrial fibrillation. Copyright © 2015 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Factor Xa Inhibitor Suppresses the Release of Phosphorylated HSP27 from Collagen-Stimulated Human Platelets: Inhibition of HSP27 Phosphorylation via p44/p42 MAP Kinase.

PubMed

Tsujimoto, Masanori; Kuroyanagi, Gen; Matsushima-Nishiwaki, Rie; Kito, Yuko; Enomoto, Yukiko; Iida, Hiroki; Ogura, Shinji; Otsuka, Takanobu; Tokuda, Haruhiko; Kozawa, Osamu; Iwama, Toru

2016-01-01

Selective inhibitors of factor Xa (FXa) are widely recognized as useful therapeutic tools for stroke prevention in non-valvular atrial fibrillation or venous thrombosis. Thrombin, which is rapidly generated from pro-thrombin through the activation of factor X to FXa, acts as a potent activator of human platelets. Thus, the reduction of thrombin generation by FXa inhibitor eventually causes a suppressive effect on platelet aggregation. However, little is known whether FXa inhibitors directly affect the function of human platelets. We have previously reported that collagen induces the phosphorylation of heat shock protein 27 (HSP27), a low-molecular weight heat shock protein via Rac-dependent activation of p44/p42 mitogen-activated protein (MAP) kinase in human platelets, eventually resulting in the release of HSP27. In the present study, we investigated the direct effect of FXa inhibitor on the collagen-induced human platelet activation. Rivaroxaban as well as edoxaban significantly reduced the collagen-induced phosphorylation of both HSP27 and p44/p42 MAP kinase without affecting the platelet aggregation. Rivaroxaban significantly inhibited the release of phosphorylated HSP27 from collagen-stimulated platelets but not the secretion of platelet derived growth factor-AB. In patients administrated with rivaroxaban, the collagen-induced levels of phosphorylated HSP27 were markedly diminished after 2 days of administration, which failed to affect the platelet aggregation. These results strongly suggest that FXa inhibitor reduces the collagen-stimulated release of phosphorylated HSP27 from human platelets due to the inhibition of HSP27 phosphorylation via p44/p42 MAP kinase.

Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Asian Patients With Atrial Fibrillation.

PubMed

Cha, Myung-Jin; Choi, Eue-Keun; Han, Kyung-Do; Lee, So-Ryoung; Lim, Woo-Hyun; Oh, Seil; Lip, Gregory Y H

2017-11-01

There are limited real-world data comparing the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in Asians with nonvalvular atrial fibrillation. We aimed to compare the effectiveness and safety between NOACs and warfarin users in the Korean atrial fibrillation population, with particular focus on high-risk patients. Using the Korean National Health Insurance Service database, we analyzed the risk of ischemic stroke, intracranial hemorrhage (ICH) events, and all-cause death in NOAC users (n=11 611 total, n=5681 taking rivaroxaban, n=3741 taking dabigatran, and n=2189 taking apixaban) compared with propensity score-matched warfarin users (n=23 222) among patients with high-risk atrial fibrillation (CHA 2 DS 2 -VASc score ≥2) between 2014 and 2015. NOAC treatment was associated with similar risk of ischemic stroke and lower risk of ICH and all-cause mortality compared with warfarin. All 3 NOACs were associated with a similar risk of ischemic stroke and a lower risk of ICH compared with warfarin. Dabigatran and apixaban were associated with a lower risk of total mortality and the composite net clinical outcome (ischemic stroke, ICH, and all-cause death) compared with warfarin, whereas this was nonsignificant for rivaroxaban. Among previously oral anticoagulant-naive patients (n=23 262), dabigatran and apixaban were superior to warfarin for ICH prevention, whereas rivaroxaban and warfarin were associated with similar risk of ICH. In real-world practice among a high-risk Asian atrial fibrillation population, all 3 NOACs demonstrated similar risk of ischemic stroke and lower risk of ICH compared with warfarin. All-cause mortality was significantly lower only with dabigatran and apixaban. © 2017 American Heart Association, Inc.

Possible role of rivaroxaban in attenuating pressure-overload-induced atrial fibrosis and fibrillation.

PubMed

Kondo, Hidekazu; Abe, Ichitaro; Fukui, Akira; Saito, Shotaro; Miyoshi, Miho; Aoki, Kohei; Shinohara, Tetsuji; Teshima, Yasushi; Yufu, Kunio; Takahashi, Naohiko

2018-03-01

Coagulation factor Xa (FXa) promotes thrombus formation and exacerbates inflammation via activation of protease-activated receptor (PAR)-2. We tested the hypothesis of whether administration of direct oral anticoagulant, rivaroxaban, would attenuate transverse aortic constriction (TAC)-induced atrial inflammatory fibrosis and vulnerability to atrial fibrillation (AF) in mice. Ten-week-old male CL57/B6 mice were divided into a sham-operation (CNT) group and TAC-surgery group. These two groups were then subdivided into vehicle (VEH) and rivaroxaban (RVX) treatment (30μg/g/day) groups. We assessed PAR-2 expression in response to TAC-related stimulation using rat cultured cells. TAC-induced left atrial thrombus formation was not observed in the TAC-RVX group. Cardiac PAR-2 upregulation was observed in both TAC groups. In the quantitative analysis of mRNA levels, cardiac PAR-2 upregulation was attenuated in the TAC-RVX group compared to TAC-VEH group. In histological evaluation, the TAC-VEH group showed cardiac inhomogeneous interstitial fibrosis and abundant infiltration of macrophages, which were attenuated by RVX administration. Electrophysiological examination revealed that AF duration in the TAC group was shortened by RVX administration. TAC-induced protein overexpression of monocyte chemoattractant protein-1, and mRNA overexpression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 in the left atrium was suppressed by RVX treatment. In cardiac fibroblasts, persistent intermittent stretch upregulated PAR-2, which was suppressed by RVX pre-incubation. These observations demonstrate that coagulation FXa inhibitor probably has a cardioprotective effect against pressure-overload-induced atrial remodeling. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial

PubMed Central

Steinberg, Benjamin A.; Hellkamp, Anne S.; Lokhnygina, Yuliya; Patel, Manesh R.; Breithardt, Günter; Hankey, Graeme J.; Becker, Richard C.; Singer, Daniel E.; Halperin, Jonathan L.; Hacke, Werner; Nessel, Christopher C.; Berkowitz, Scott D.; Mahaffey, Kenneth W.; Fox, Keith A.A.; Califf, Robert M.; Piccini, Jonathan P.

2015-01-01

Aim Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation (AF). We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation. Methods and results Patients randomized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (n = 14 264) were grouped by baseline AF category: paroxysmal or persistent. Multivariable adjustment was performed to compare thrombo-embolic events, bleeding, and death between groups, in high-risk subgroups, and across treatment assignment (rivaroxaban or warfarin). Of 14 062 patients, 11 548 (82%) had persistent AF and 2514 (18%) had paroxysmal AF. Patients with persistent AF were marginally older (73 vs. 72, P = 0.03), less likely female (39 vs. 45%, P < 0.0001), and more likely to have previously used vitamin K antagonists (64 vs. 56%, P < 0.0001) compared with patients with paroxysmal AF. In patients randomized to warfarin, time in therapeutic range was similar (58 vs. 57%, P = 0.94). Patients with persistent AF had higher adjusted rates of stroke or systemic embolism (2.18 vs. 1.73 events per 100-patient-years, P = 0.048) and all-cause mortality (4.78 vs. 3.52, P = 0.006). Rates of major bleeding were similar (3.55 vs. 3.31, P = 0.77). Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment (rivaroxaban vs. warfarin, Pinteraction = 0.6). Conclusion In patients with AF at moderate-to-high risk of stroke receiving anticoagulation, those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF. PMID:25209598

Use and Outcomes of Antiarrhythmic Therapy in Patients with Atrial Fibrillation Receiving Oral Anticoagulation: Results from the ROCKET AF Trial

PubMed Central

Steinberg, Benjamin A.; Hellkamp, Anne S.; Lokhnygina, Yuliya; Halperin, Jonathan L.; Breithardt, Günter; Passman, Rod; Hankey, Graeme J.; Patel, Manesh R.; Becker, Richard C.; Singer, Daniel E.; Hacke, Werner; Berkowitz, Scott D.; Nessel, Christopher C.; Mahaffey, Kenneth W.; Fox, Keith A.A.; Califf, Robert M.; Piccini, Jonathan P.

2014-01-01

Background Antiarrhythmic drugs (AAD) and anticoagulation are mainstays of atrial fibrillation (AF) treatment. Objective We aimed to study the use and outcomes of AAD therapy in anticoagulated AF patients. Methods Patients in the ROCKET AF trial (n=14,264) were grouped by AAD use at baseline: amiodarone, other AAD, or no AAD. Multivariable adjustment was performed to compare stroke, bleeding, and death across groups, as well as across treatment assignment (rivaroxaban or warfarin). Results Of 14,264 patients randomized, 1681 (11.8%) were treated with an AAD (1144 [8%] with amiodarone, 537 [3.8%] with other AADs). Amiodarone-treated patients were less-often female (38% vs. 48%), had more persistent AF (64% vs. 40%), and more concomitant heart failure (71% vs. 41%) than patients receiving other AADs. Patients receiving no AAD more closely-resembled amiodarone-treated patients. Time in therapeutic range was significantly lower in warfarin-treated patients receiving amiodarone versus no AAD (50% vs. 58%, p<0.0001). Compared with no AAD, neither amiodarone (adjusted HR 0.98, 95% CI 0.74–1.31, p=0.9) nor other AADs (adjusted HR 0.66, 95% CI 0.37–1.17, p=0.15) were associated with increased mortality. Similar results were observed for embolic and bleeding outcomes. Rivaroxaban treatment effects in patients not on an AAD were consistent with the overall trial (primary endpoint adjusted HR 0.82, 95% CI 0.68–0.98, pinteraction=0.06; safety endpoint adjusted HR 1.12, 95% CI 0.90–1.24, pinteraction=0.33). Conclusion Treatment with AADs was not associated with increased morbidity or mortality in anticoagulated patients with AF. The influence of amiodarone on outcomes in patients receiving rivaroxaban requires further study. PMID:24833235

Direct-Acting Oral Anticoagulants: Practical Considerations for Emergency Medicine Physicians

PubMed Central

Peacock, W. Frank; Rafique, Zubaid; Singer, Adam J.

2016-01-01

Nonvalvular atrial fibrillation- (NVAF-) related stroke and venous thromboembolism (VTE) are cardiovascular diseases associated with significant morbidity and economic burden. The historical standard treatment of VTE has been the administration of parenteral heparinoid until oral warfarin therapy attains a therapeutic international normalized ratio. Warfarin has been the most common medication for stroke prevention in NVAF. Warfarin use is complicated by a narrow therapeutic window, unpredictable dose response, numerous food and drug interactions, and requirements for frequent monitoring. To overcome these disadvantages, direct-acting oral anticoagulants (DOACs)—dabigatran, rivaroxaban, apixaban, and edoxaban—have been developed for the prevention of stroke or systemic embolic events (SEE) in patients with NVAF and for the treatment of VTE. Advantages of DOACs include predictable pharmacokinetics, few drug-drug interactions, and low monitoring requirements. In clinical studies, DOACs are noninferior to warfarin for the prevention of NVAF-related stroke and the treatment and prevention of VTE as well as postoperative knee and hip surgery VTE prophylaxis, with decreased bleeding risks. This review addresses the practical considerations for the emergency physician in DOAC use, including dosing recommendations, laboratory monitoring, anticoagulation reversal, and cost-effectiveness. The challenges of DOACs, such as the lack of specific laboratory measurements and antidotes, are also discussed. PMID:27293895

Left ventricular hypertrophy diagnosed after a stroke: a case report.

PubMed

Umeojiako, Wilfred Ifeanyi; Kanyal, Ritesh

2018-03-22

Stroke is a recognized clinical course of hypertrophic cardiomyopathy. This interesting case showed notable difference on the electrocardiogram of a patient 4 months prior to suffering a stroke and 10 days after suffering a stroke. The pre-stroke electrocardiogram showed atrial fibrillation with a narrow QRS complex, while the post-stroke electrocardiogram showed marked left ventricular hypertrophy. Left ventricular hypertrophy was diagnosed using the Sokolow-Lyon indices. The development of left ventricular hypertrophy a few days after suffering a stroke has not previously been reported. An 83-year-old white British woman with a background history of permanent atrial fibrillation, hypertension, and previous stroke attended the emergency department with a 2-day history of exertional dyspnea, and chest tightness. On examination, she had bibasal crepitations with a systolic murmur loudest at the apex. In-patient investigations include an electrocardiogram, blood tests, chest X-ray, contrast echocardiogram, coronary angiogram, and cardiovascular magnetic resonance imaging. An electrocardiogram showed atrial fibrillation, with inferolateral T wave inversion, and left ventricular hypertrophy. A chest X-ray showed features consistent with pulmonary edema. A contrast echocardiogram showed marked hypertrophy of the mid to apical left ventricle, appearance consistent with apical hypertrophic cardiomyopathy. Coronary angiography showed eccentric shelf-type plaque with non-flow-limiting stenosis in the left coronary artery main stem. Cardiovascular magnetic resonance imaging reported findings highly suggestive of apical hypertrophic cardiomyopathy. Our patient was treated and discharged on rivaroxaban, bisoprolol, and atorvastatin with a follow-up in the cardiomyopathy outpatient clinic. Electrocardiogram diagnosis of left ventricular hypertrophy led to the diagnosis of apical hypertrophic cardiomyopathy in this patient. Left ventricular hypertrophy was only evident a few days after our patient suffered a stroke. The underlying mechanisms responsible for this remain unclear. Furthermore, differential diagnosis of hypertrophic cardiomyopathy should be considered in people with electrocardiogram criteria for left ventricular hypertrophy. Cardiovascular magnetic resonance imaging is an important diagnostic tool in identifying causes of left ventricular hypertrophy. Family screening should be recommended in patients with new diagnosis of hypertrophic cardiomyopathy.

Rare case of losartan-induced cough complicated by rectus sheath haematoma: in a patient on rivaroxaban therapy.

PubMed

Talari, Goutham; Talari, Preetham; Sweigart, Joseph; Ahmed, Sadiq

2016-12-23

Spontaneous rectus sheath haematomas and cough secondary to losartan are individually rare conditions. Abdominal wall haematomas present with abdominal pain and abdominal mass. Most patients are managed conservatively; Surgery or embolisation is indicated for shock, infection, rupture into the peritoneum or intractable pain. This is a man aged 65 years presented with dry cough and right-sided abdominal pain. He started losartan a few weeks prior to the onset of cough and had been on rivaroxaban for prior deep venous thrombosis. The right side of his abdomen was distended, bruised and tender. His haemoglobin dropped from 13.3to 9.5 g/dL. CT abdomen/pelvis showed a large 14.5×9.1×4.5 cm haematoma within the right lateral rectus muscle. His only risk factor for developing rectus sheath haematoma was cough in the setting of anticoagulation. Dry cough due to angiotensin receptor blockers is rare, but can have very serious consequences. 2016 BMJ Publishing Group Ltd.

Oral Anticoagulant Therapy

PubMed Central

Gallus, Alexander S.; Wittkowsky, Ann; Crowther, Mark; Hylek, Elaine M.; Palareti, Gualtiero

2012-01-01

Background: The objective of this article is to summarize the published literature concerning the pharmacokinetics and pharmacodynamics of oral anticoagulant drugs that are currently available for clinical use and other aspects related to their management. Methods: We carried out a standard review of published articles focusing on the laboratory and clinical characteristics of the vitamin K antagonists; the direct thrombin inhibitor, dabigatran etexilate; and the direct factor Xa inhibitor, rivaroxaban Results: The antithrombotic effect of each oral anticoagulant drug, the interactions, and the monitoring of anticoagulation intensity are described in detail and discussed without providing specific recommendations. Moreover, we describe and discuss the clinical applications and optimal dosages of oral anticoagulant therapies, practical issues related to their initiation and monitoring, adverse events such as bleeding and other potential side effects, and available strategies for reversal. Conclusions: There is a large amount of evidence on laboratory and clinical characteristics of vitamin K antagonists. A growing body of evidence is becoming available on the first new oral anticoagulant drugs available for clinical use, dabigatran and rivaroxaban. PMID:22315269

Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis.

PubMed

Castellucci, Lana A; Cameron, Chris; Le Gal, Grégoire; Rodger, Marc A; Coyle, Doug; Wells, Philip S; Clifford, Tammy; Gandara, Esteban; Wells, George; Carrier, Marc

2014-09-17

Many anticoagulant strategies are available for the treatment of acute venous thromboembolism, yet little guidance exists regarding which drug is most effective and safe. To summarize and compare the efficacy and safety outcomes associated with 8 anticoagulation options (unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], or fondaparinux in combination with vitamin K antagonists); LMWH with dabigatran or edoxaban; rivaroxaban; apixaban; and LMWH alone) for treatment of venous thromboembolism. A systematic literature search was conducted using MEDLINE, EMBASE, and the evidence-based medicine reviews from inception through February 28, 2014. Eligible studies were randomized trials reporting rates of recurrent venous thromboembolism and major bleeding in patients with acute venous thromboembolism. Of the 1197 studies identified, 45 trials including 44,989 patients were included in the analyses. Two reviewers independently extracted trial-level data including number of patients, duration of follow-up, and outcomes. The data were pooled using network meta-analysis. The primary clinical and safety outcomes were recurrent venous thromboembolism and major bleeding, respectively. Compared with the LMWH-vitamin K antagonist combination, a treatment strategy using the UFH-vitamin K antagonist combination was associated with an increased risk of recurrent venous thromboembolism (hazard ratio [HR], 1.42; 95% credible interval [CrI], 1.15-1.79). The proportion of patients experiencing recurrent venous thromboembolism during 3 months of treatment were 1.84% (95% CrI, 1.33%-2.51%) for the UFH-vitamin K antagonist combination and 1.30% (95% CrI, 1.02%-1.62%) for the LMWH-vitamin K antagonist combination. Rivaroxaban (HR, 0.55; 95% CrI, 0.35-0.89) and apixaban (HR, 0.31; 95% CrI, 0.15-0.62) were associated with a lower risk of bleeding than was the LMWH-vitamin K antagonist combination, with a lower proportion of patients experiencing a major bleeding event during 3 months of anticoagulation: 0.49% (95% CrI, 0.29%-0.85%) for rivaroxaban, 0.28% (95% CrI, 0.14%-0.50%) for apixaban, and 0.89% (95% CrI, 0.66%-1.16%) for the LMWH-vitamin K antagonist combination. Using meta-analytic pooling, there were no statistically significant differences for efficacy and safety associated with most treatment strategies used to treat acute venous thromboembolism compared with the LMWH-vitamin K antagonist combination. However, findings suggest that the UFH-vitamin K antagonist combination is associated with the least effective strategy and that rivaroxaban and apixaban may be associated with the lowest risk for bleeding.

Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).

PubMed

Washam, Jeffrey B; Stevens, Susanna R; Lokhnygina, Yuliya; Halperin, Jonathan L; Breithardt, Günter; Singer, Daniel E; Mahaffey, Kenneth W; Hankey, Graeme J; Berkowitz, Scott D; Nessel, Christopher C; Fox, Keith A A; Califf, Robert M; Piccini, Jonathan P; Patel, Manesh R

2015-06-13

Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767. In 14,171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events per 100 patients-years; hazard ratio 1·17; 95% CI 1·04-1·32; p=0·0093), vascular death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03-1·39, p=0·0201), and sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08-1·70, p=0·0076). Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed. Janssen Research & Development and Bayer HealthCare AG. Copyright © 2015 Elsevier Ltd. All rights reserved.

Direct oral anticoagulants: analysis of worldwide use and popularity using Google Trends.

PubMed

Lippi, Giuseppe; Mattiuzzi, Camilla; Cervellin, Gianfranco; Favaloro, Emmanuel J

2017-08-01

Four direct oral anticoagulants (DOACs) have been approved for clinical use by many medicines regulatory agencies around the world. Due to increasing use of these drugs in routine practice, we planned an original study to investigate their worldwide diffusion using a popular Web-search engine. Two electronic searches were performed using Google Trends, the former using the keywords "warfarin" AND "heparin" AND "fondaparinux", and the latter using the keywords "warfarin" AND "dabigatran" AND "rivaroxaban" AND "apixaban" AND "edoxaban", both using the search criterion "prescription drug". No language restriction was applied, and the searches were carried out from the first date available in Google Trends (January 1 st , 2004) to present time (June 1 st , 2017). The median Google Trends score of warfarin (i.e., 86) was consistently higher than that of heparin (54; P<0.001), fondaparinux (6; P<0.001), dabigatran (11; P<0.001), rivaroxaban (5; P<0.001), apixaban (1; P<0.001) and edoxaban (1; P<0.001). Specific analysis of the trends shows that the score of warfarin exhibits a highly significant decrease over time (r=-0.40; P<0.001), whilst that of heparin has remained virtually unchanged (r=0.12; P=0.127), and that of fondaparinux has marginally increased (r=0.16; P=0.038). As regards DOACs, the scores of these drugs significantly increased during the search period (dabigatran, r=0.79; rivaroxaban, r=0.99; apixaban, r=0.98; edoxaban, r=0.78; all P<0.001). When the analysis was limited to the past five years, the dabigatran score significantly decreased (r=-0.57; P<0.001), whereas that of the other DOACs exhibited an even sharper increase. Most Google searches for DOACs were performed in North America, central-eastern Europe and Australia. The results of our analysis suggest that the popularity of DOACs is constantly increasing around the world, whereas that of warfarin has exhibited a constant and inexorable decline.

Managing bleeding and emergency reversal of newer oral anticoagulants: a review for primary care providers.

PubMed

Peacock, W Frank

2014-10-01

The therapeutic landscape for anticoagulation management is undergoing a shift from the use of traditional anticlotting agents such as heparins and warfarin as the only options to the growing adoption of newer target-specific oral anticoagulants (TSOACs) with novel mechanisms of action. Dabigatran, the first TSOAC approved for use in the United States, is a direct competitive inhibitor of thrombin. It has predictable kinetics, with an elimination half-life of 12 to 17 hours in healthy volunteers. Apixaban and rivaroxaban are selective inhibitors of factor Xa, and also display first-order kinetics. In younger healthy individuals, apixaban has an apparent half-life of approximately 12 hours, whereas rivaroxaban has an elimination half-life of 5 to 9 hours. Understanding the pharmacologic properties of these newer drugs can lead to better insights regarding their respective safety and efficacy profiles and their application in clinical practice. Laboratory assessments have been developed to measure the anticoagulant efficacy of these newer agents. However, the results of these tests can be highly variable, and are therefore not always useful for monitoring the anticoagulation effects of these agents. In addition, several strategies have been documented for the potential reversal of the anticoagulant effects of these drugs, from the temporary discontinuation of an agent before elective surgery to suggested emergency procedures in the case of major bleeding events. New, specific reversal agents for dabigatran, apixaban, and rivaroxaban are currently being developed, and dabigatran has received fast-track designation from the US Food and Drug Administration. Until comprehensive clinical guidelines are developed, institutions involved in emergency care should establish their own procedures for the management of patients undergoing anticoagulation who require emergency treatment. These protocols should include appropriate laboratory testing to assess anticoagulant activity as part of the inpatient workup if time allows, and the potential use of hemodialysis, prohemostatic agents, and reversal agents when available.

Novel anticoagulants for stroke prevention in atrial fibrillation: a systematic review of cost-effectiveness models.

PubMed

Limone, Brendan L; Baker, William L; Kluger, Jeffrey; Coleman, Craig I

2013-01-01

To conduct a systematic review of economic models of newer anticoagulants for stroke prevention in atrial fibrillation (SPAF). We searched Medline, Embase, NHSEED and HTA databases and the Tuft's Registry from January 1, 2008 through October 10, 2012 to identify economic (Markov or discrete event simulation) models of newer agents for SPAF. Eighteen models were identified. Each was based on a lone randomized trial/new agent, and these trials were clinically and methodologically heterogeneous. Dabigatran 150 mg, 110 mg and sequentially-dosed were assessed in 9, 8, and 9 models, rivaroxaban in 4 and apixaban in 4. Warfarin was a first-line comparator in 94% of models. Models were conducted from United States (44%), European (39%) and Canadian (17%) perspectives. Models typically assumed patients between 65-73 years old at moderate-risk of stroke initiated anticoagulation for/near a lifetime. All models reported cost/quality-adjusted life-year, 22% reported using a societal perspective, but none included indirect costs. Four models reported an incremental cost-effectiveness ratio (ICER) for a newer anticoagulant (dabigatran 110 mg (n = 4)/150 mg (n = 2); rivaroxaban (n = 1)) vs. warfarin above commonly reported willingness-to-pay thresholds. ICERs vs. warfarin ranged from $3,547-$86,000 for dabigatran 150 mg, $20,713-$150,000 for dabigatran 110 mg, $4,084-$21,466 for sequentially-dosed dabigatran and $23,065-$57,470 for rivaroxaban. Apixaban was found economically-dominant to aspirin, and dominant or cost-effective ($11,400-$25,059) vs. warfarin. Indirect comparisons from 3 models suggested conflicting comparative cost-effectiveness results. Cost-effectiveness models frequently found newer anticoagulants cost-effective, but the lack of head-to-head trials and the heterogeneous characteristics of underlying trials and modeling methods make it difficult to determine the most cost-effective agent.

Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants: A Systematic Review.

PubMed

Samuelson, Bethany T; Cuker, Adam; Siegal, Deborah M; Crowther, Mark; Garcia, David A

2017-01-01

Direct oral anticoagulants (DOACs) are the treatment of choice for most patients with atrial fibrillation and/or noncancer-associated venous thromboembolic disease. Although routine monitoring of these agents is not required, assessment of anticoagulant effect may be desirable in special situations. The objective of this review was to summarize systematically evidence regarding laboratory assessment of the anticoagulant effects of dabigatran, rivaroxaban, apixaban, and edoxaban. PubMed, Embase, and Web of Science were searched for studies reporting relationships between drug levels and coagulation assay results. We identified 109 eligible studies: 35 for dabigatran, 50 for rivaroxaban, 11 for apixaban, and 13 for edoxaban. The performance of standard anticoagulation tests varied across DOACs and reagents; most assays, showed insufficient correlation to provide a reliable assessment of DOAC effects. Dilute thrombin time (TT) assays demonstrated linear correlation (r 2  = 0.67-0.99) across a range of expected concentrations of dabigatran, as did ecarin-based assays. Calibrated anti-Xa assays demonstrated linear correlation (r 2  = 0.78-1.00) across a wide range of concentrations for rivaroxaban, apixaban, and edoxaban. An ideal test, offering both accuracy and precision for measurement of any DOAC is not widely available. We recommend a dilute TT or ecarin-based assay for assessment of the anticoagulant effect of dabigatran and anti-Xa assays with drug-specific calibrators for direct Xa inhibitors. In the absence of these tests, TT or APTT is recommended over PT/INR for assessment of dabigatran, and PT/INR is recommended over APTT for detection of factor Xa inhibitors. Time since last dose, the presence or absence of drug interactions, and renal and hepatic function should impact clinical estimates of anticoagulant effect in a patient for whom laboratory test results are not available. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Systematic Review of Cost-Effectiveness Models

PubMed Central

Limone, Brendan L.; Baker, William L.; Kluger, Jeffrey; Coleman, Craig I.

2013-01-01

Objective To conduct a systematic review of economic models of newer anticoagulants for stroke prevention in atrial fibrillation (SPAF). Patients and Methods We searched Medline, Embase, NHSEED and HTA databases and the Tuft’s Registry from January 1, 2008 through October 10, 2012 to identify economic (Markov or discrete event simulation) models of newer agents for SPAF. Results Eighteen models were identified. Each was based on a lone randomized trial/new agent, and these trials were clinically and methodologically heterogeneous. Dabigatran 150 mg, 110 mg and sequentially-dosed were assessed in 9, 8, and 9 models, rivaroxaban in 4 and apixaban in 4. Warfarin was a first-line comparator in 94% of models. Models were conducted from United States (44%), European (39%) and Canadian (17%) perspectives. Models typically assumed patients between 65–73 years old at moderate-risk of stroke initiated anticoagulation for/near a lifetime. All models reported cost/quality-adjusted life-year, 22% reported using a societal perspective, but none included indirect costs. Four models reported an incremental cost-effectiveness ratio (ICER) for a newer anticoagulant (dabigatran 110 mg (n = 4)/150 mg (n = 2); rivaroxaban (n = 1)) vs. warfarin above commonly reported willingness-to-pay thresholds. ICERs vs. warfarin ranged from $3,547–$86,000 for dabigatran 150 mg, $20,713–$150,000 for dabigatran 110 mg, $4,084–$21,466 for sequentially-dosed dabigatran and $23,065–$57,470 for rivaroxaban. Apixaban was found economically-dominant to aspirin, and dominant or cost-effective ($11,400–$25,059) vs. warfarin. Indirect comparisons from 3 models suggested conflicting comparative cost-effectiveness results. Conclusions Cost-effectiveness models frequently found newer anticoagulants cost-effective, but the lack of head-to-head trials and the heterogeneous characteristics of underlying trials and modeling methods make it difficult to determine the most cost-effective agent. PMID:23626785

Use of concomitant aspirin in patients with atrial fibrillation: Findings from the ROCKET AF trial.

PubMed

Shah, Rohan; Hellkamp, Anne; Lokhnygina, Yuliya; Becker, Richard C; Berkowitz, Scott D; Breithardt, Günter; Hacke, Werner; Halperin, Jonathan L; Hankey, Graeme J; Fox, Keith A A; Nessel, Christopher C; Mahaffey, Kenneth W; Piccini, Jonathan P; Singer, Daniel E; Patel, Manesh R

2016-09-01

We aimed to investigate the relationship between aspirin use and clinical outcomes in patients enrolled in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), in particular, those with known coronary artery disease (CAD). Patients in ROCKET AF, comparing rivaroxaban and warfarin, were analyzed. Aspirin use was assessed at baseline. Stroke and systemic embolism, myocardial infarction, death, and major or nonmajor clinically relevant (NMCR) bleeding were compared between groups. Multivariable modeling was done adjusting for baseline risk factors. A total of 5,205 (36.5%) patients were receiving aspirin at baseline (mean dose 99.2mg); 30.6% of those had known CAD. Patients receiving aspirin were more likely to have prior myocardial infarction (22% vs 14%; P<.001) and heart failure (68% vs 59%; P<.001). Relative efficacy of rivaroxaban versus warfarin was similar with and without aspirin use for both stroke/systemic embolism (P=.95 for interaction), and major or NMCR bleeding (P=.76 for interaction). After adjustment, aspirin use was associated with similar rates of stroke/systemic embolism (hazard ratio [HR] 1.16, 95% CI 0.98-1.37; P=.094) but higher rates of all-cause death (HR 1.27, 95% CI 1.13-1.42; P<.0001) and major or NMCR bleeding (HR 1.32, 95% CI 1.21-1.43; P<.0001). There was a significant interaction between no CAD at baseline and aspirin for all-cause death (P=.009). Aspirin use at baseline was associated with an increased risk for bleeding and all-cause death in ROCKET AF, a risk most pronounced in patients without known CAD. Although these findings may reflect unmeasured clinical factors, further investigation is warranted to determine optimal aspirin use in patients with AF. Copyright © 2016 Elsevier Inc. All rights reserved.

Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial.

PubMed

Steinberg, Benjamin A; Hellkamp, Anne S; Lokhnygina, Yuliya; Patel, Manesh R; Breithardt, Günter; Hankey, Graeme J; Becker, Richard C; Singer, Daniel E; Halperin, Jonathan L; Hacke, Werner; Nessel, Christopher C; Berkowitz, Scott D; Mahaffey, Kenneth W; Fox, Keith A A; Califf, Robert M; Piccini, Jonathan P

2015-02-01

Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation (AF). We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation. Patients randomized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (n = 14 264) were grouped by baseline AF category: paroxysmal or persistent. Multivariable adjustment was performed to compare thrombo-embolic events, bleeding, and death between groups, in high-risk subgroups, and across treatment assignment (rivaroxaban or warfarin). Of 14 062 patients, 11 548 (82%) had persistent AF and 2514 (18%) had paroxysmal AF. Patients with persistent AF were marginally older (73 vs. 72, P = 0.03), less likely female (39 vs. 45%, P < 0.0001), and more likely to have previously used vitamin K antagonists (64 vs. 56%, P < 0.0001) compared with patients with paroxysmal AF. In patients randomized to warfarin, time in therapeutic range was similar (58 vs. 57%, P = 0.94). Patients with persistent AF had higher adjusted rates of stroke or systemic embolism (2.18 vs. 1.73 events per 100-patient-years, P = 0.048) and all-cause mortality (4.78 vs. 3.52, P = 0.006). Rates of major bleeding were similar (3.55 vs. 3.31, P = 0.77). Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment (rivaroxaban vs. warfarin, Pinteraction = 0.6). In patients with AF at moderate-to-high risk of stroke receiving anticoagulation, those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

A Decision Analysis of Percutaneous Left Atrial Appendage Occlusion Relative to Novel and Traditional Oral Anticoagulation for Stroke Prevention in Patients with New-Onset Atrial Fibrillation.

PubMed

Micieli, Andrew; Wijeysundera, Harindra C; Qiu, Feng; Atzema, Clare L; Singh, Sheldon M

2016-04-01

Percutaneous left atrial appendage occlusion (LAAO) is a nonpharmacologic approach for stroke prevention in nonvalvular atrial fibrillation (NVAF). No direct comparisons to novel oral anticoagulants (OACs) exists, limiting decision making on the optimal strategy for stroke prevention in NVAF patients. Addressing this gap in knowledge is timely given the recent debate by the US Food and Drug Administration regarding the effectiveness of LAAO. To assess the cost-effectiveness of LAAO and novel OACs relative to warfarin in patients with new-onset NVAF without contraindications to OAC. A cost-utility analysis using a patient-level Markov micro-simulation decision analytic model was undertaken to determine the lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) of LAAO and all novel OACs relative to warfarin. Effectiveness and utility data were obtained from the published literature and cost from the Ontario Drug Benefits Formulary and Case Costing Initiative. Warfarin had the lowest discounted QALY (5.13 QALYs), followed by dabigatran (5.18 QALYs), rivaroxaban and LAAO (5.21 QALYs), and apixaban (5.25 QALYs). The average discounted lifetime costs were $15 776 for warfarin, $18 280 for rivaroxaban, $19 156 for apixaban, $20 794 for dabigatran, and $21 789 for LAAO. Apixaban dominated dabigatran and LAAO and demonstrated extended dominance over rivaroxaban. The ICER for apixaban relative to warfarin was $28 167/QALY. Apixaban was preferred in 40.2% of simulations at a willingness-to-pay threshold of $50 000/QALY. Assumptions regarding clinical and methodological differences between published studies of each therapy were minimized. Apixaban is the most cost-effective therapy for stroke prevention in patients with new-onset NVAF without contraindications to OAC. Uncertainty around this conclusion exists, highlighting the need for further research. © The Author(s) 2015.

Safety of 4-factor prothrombin complex concentrate (4F-PCC) for emergent reversal of factor Xa inhibitors.

PubMed

Tao, Jing; Bukanova, Elena N; Akhtar, Shamsuddin

2018-01-01

Although factor Xa inhibitors have become a popular choice for chronic oral anticoagulation, effective drug reversal remains difficult due to a lack of specific antidote. Currently, 4-factor prothrombin complex concentrate (4F-PCC) is considered the treatment of choice for factor Xa inhibitor-related major bleeding. However, safety of 4F-PCC and its risk of thrombosis when used for this off-label purpose remain unclear. The purpose of this retrospective study is to determine the rate of thromboembolism when 4F-PCC is used for the emergent reversal of factor Xa inhibitors. We conducted a single-center retrospective review of medical records between 2013 and 2017. Patients were included if they received 4F-PCC to reverse rivaroxaban, apixaban, or edoxaban for emergent invasive procedures or during episodes of major bleeding defined as bleeding with hemodynamic instability, fall in hemoglobin of 2 g/dL, or bleeding requiring blood transfusion. Thrombotic events including myocardial infarction, pulmonary embolism, deep vein thrombosis, cerebral vascular accident, and arterial thrombosis of the limb or mesentery were recorded if they occurred within 14 days of 4F-PCC administration. Data was analyzed using point and interval estimation to approximate the rate and confidence interval of thromboembolic events. Forty-three patients were identified in our review. Doses of 4F-PCC were determined by the treating physician and mainly ranged from 25 to 50 IU/kg. Twenty-two patients (51.2%) received both sequential compression devices (SCDs) and subcutaneous heparin for DVT prophylaxis. Twenty-one patients (48.8%) were placed on SCDs only. Three patients received concomitant FFP. Thrombotic events within 14 days of 4F-PCC administration occurred in 1 out of 43 patients (2.1%, 95% CI [0.1-12.3]). This thrombotic event was an upper extremity DVT which occurred 1 day after the patient received 1325 IU (25 IU/kg) of 4F-PCC to reverse rivaroxaban for traumatic intracranial hemorrhage. The patient was taken for emergent decompressive craniotomy after rivaroxaban reversal. In patients who did not undergo surgery or who underwent minor invasive procedures, no thrombotic events were noted. Based on our preliminary data, the thromboembolic rate of 4F-PCC when given at a dose of 25-50 IU/kg to emergently reverse rivaroxaban and apixaban appears acceptable. Since many patients who require 4F-PCC to emergently reverse factor Xa inhibitors will be at high risk of developing thrombotic events, practitioners should be highly vigilant of these complications. Large, multicenter prospective trials are needed to further determine this risk.

New oral anticoagulants--a review.

PubMed

Ghanima, Waleed; Atar, Dan; Sandset, Per Morten

2013-10-01

Dabigatran, rivaroxaban and apixaban are three new oral anticoagulants that have recently been approved in Norway. The aim of this article is to provide an overview of the mechanisms of action, the most important indications and practical advice on the use of these drugs. The review is based on published phase 3 studies, a literature search in PubMed and the authors' clinical experience. Indications for use of the new anticoagulants include thromboprophylaxis after total hip and knee replacement surgery (all three), prevention of stroke and systemic embolism in non-valvular atrial fibrillation (all three), treatment of acute venous thrombosis and secondary prophylaxis after venous thrombosis (currently only rivaroxaban). For the aforementioned indications, these drugs have proven to be non-inferior to standard established anticoagulation therapy. For atrial fibrillation, all three drugs have also shown a lower incidence of intracranial bleeding compared with standard treatment. It is important to limit the use of these drugs to approved indications, to select patients who show good compliance, to rule out contraindications and to identify drug interactions. Monitoring of coagulation is not required, but patients should be followed up regularly to detect conditions that may lead to changes in the expected efficacy or safety.

The Perils of Inhibiting Deficient Factors.

PubMed

Sayar, Zara; Speed, Victoria; Patel, Jignesh P; Patel, Raj K; Arya, Roopen

2018-06-08

We report a case of a previously undiagnosed factor X deficiency in an 83-year old man, who had no previous bleeding history despite multiple haemostatic challenges. He was anticoagulated with warfarin for atrial fibrillation (AF) without bleeding complications; however, major haemorrhage occurred soon after a switch to rivaroxaban. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin.

PubMed

Davidson, Bruce L; Verheijen, Sara; Lensing, Anthonie W A; Gebel, Martin; Brighton, Timothy A; Lyons, Roger M; Rehm, Jeffrey; Prins, Martin H

2014-06-01

Combined anticoagulant and aspirin therapy is associated with increased bleeding risk in patients with atrial fibrillation, but the bleeding risk of combined use of anticoagulant and nonsteroidal anti-inflammatory drugs (NSAIDs) is poorly documented. To estimate the bleeding risk of combined anticoagulant (rivaroxaban or enoxaparin-vitamin K antagonist [VKA]) and NSAID or aspirin therapy in patients with venous thromboembolism. Prospective analysis of observational data from the EINSTEIN deep vein thrombosis and pulmonary embolism clinical trials comparing rivaroxaban with enoxaparin-VKA treatment, trials performed in hospitals and clinics in 8246 patients enrolled from 2007 to 2009. Bleeding event rates during exposure to NSAID and aspirin therapy were compared to time without exposure. Days of NSAID or aspirin use and nonuse, clinically relevant bleeding event and major bleeding event rates by patient-years, and hazard ratios. During NSAID-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 37.5 per 100 patient-years vs 16.6 per 100 patient-years during anticoagulant use only (hazard ratio [HR], 1.77 [95% CI, 1.46-2.14]). Major bleeding during NSAID-anticoagulant treatment occurred with an event rate of 6.5 per 100 patient-years, compared to 2.0 per 100 patient-years during nonuse (HR, 2.37 [95% CI, 1.51-3.75]). For aspirin-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 36.6 per 100 patient-years, compared to 16.9 per 100 patient-years during aspirin nonuse (HR, 1.70 [95% CI, 1.38-2.11]). Major bleeding in aspirin-anticoagulant-treated patients occurred with an event rate of 4.8 per 100 patient-years, compared to 2.2 per 100 patient-years during aspirin nonuse (HR, 1.50 [95% CI, 0.86-2.62]). Increases in risk for clinically relevant and major bleeding were similar for rivaroxaban and enoxaparin-VKA anticoagulation regimens. Among patients with venous thromboembolism receiving anticoagulant therapy, concomitant use of an NSAID or aspirin is associated with an increased risk of clinically relevant and major bleeding.

Real-life Use of Anticoagulants in Venous Thromboembolism With a Focus on Patients With Exclusion Criteria for Direct Oral Anticoagulants.

PubMed

Moustafa, Farès; Pesavento, Raffaele; di Micco, Pierpaolo; González-Martínez, José; Quintavalla, Roberto; Peris, Maria-Luisa; Porras, José Antonio; Falvo, Nicolas; Baños, Pilar; Monreal, Manuel

2018-04-01

We assessed the real-life use of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and exclusion criteria for randomized trials. From 2013 to 2016, 3,578 of 18,853 patients (19%) had exclusion criteria. Irrespective of which anticoagulant was chosen, they had more VTE recurrences (hazard ratio (HR): 3.10; 95% confidence interval (CI): 2.47-3.88), major bleeds (HR: 4.10; 95% CI: 3.38-4.96), and deaths (HR: 9.47; 95% CI: 8.46-10.6) than those without exclusion criteria. During initial therapy, no patient with exclusion criteria on DOACs (n = 115) recurred, but those on rivaroxaban bled less often (adjusted HR: 0.18; 95% CI: 0.04-0.79) than those on unfractionated heparin (n = 224) and similar to those (n = 3,172) on low-molecular-weight (LMWH) heparin. For long-term therapy, patients on rivaroxaban (n = 151) had nonsignificantly fewer VTE recurrences (adjusted HR: 0.74; 95% CI: 0.08-1.32) and major bleeds (adjusted HR: 0.41; 95% CI: 0.15-1.15) than those on LMWH (n = 2,071). The efficacy and safety of DOACs were similar to standard therapy. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Coagulation Management in Jersey Calves: An ex vivo Study.

PubMed

Gröning, Sabine; Maas, Judith; van Geul, Svenja; Rossaint, Rolf; Steinseifer, Ulrich; Grottke, Oliver

2017-01-01

Jersey calves are frequently used as an experimental animal model for in vivo testing of cardiac assist devices or orthopedic implants. In this ex vivo study, we analyzed the coagulation system of the Jersey calves and the potential of human-based coagulation management to circumvent perioperative bleeding complications during surgery. Experimental Procedure: Blood from 7 Jersey calves was subjected to standard laboratory tests and thromboelastometry analysis. An ex vivo model of dilutional coagulopathy was used to study the effects of fibrinogen or prothrombin complex concentrate supplementation. Fibrinolysis was induced with tissue plasminogen activator to identify potential therapeutic strategies involving tranexamic acid or aprotinin. Furthermore, anticoagulation strategies were evaluated by incubating the blood samples with dabigatran or rivaroxaban. Baseline values for thromboelastometry and standard laboratory parameters, including prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin III, and D-dimers, were established. Fifty percent diluted blood showed a statistically significant impairment of hemostasis. The parameters significantly improved after the administration of fibrinogen or prothrombin complex concentrate. Tranexamic acid and aprotinin ameliorated tissue plasminogen activator-induced fibrinolysis. Both dabigatran and rivaroxaban significantly prolonged the coagulation parameters. In this ex vivo study, coagulation factors, factor concentrate, antifibrinolytic reagents, and anticoagulants regularly used in the clinic positively impacted coagulation parameters in Jersey calf blood. © 2017 S. Karger AG, Basel.

Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts.

PubMed

Piccini, Jonathan P; Stevens, Susanna R; Chang, YuChiao; Singer, Daniel E; Lokhnygina, Yuliya; Go, Alan S; Patel, Manesh R; Mahaffey, Kenneth W; Halperin, Jonathan L; Breithardt, Günter; Hankey, Graeme J; Hacke, Werner; Becker, Richard C; Nessel, Christopher C; Fox, Keith A A; Califf, Robert M

2013-01-15

We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R(2)CHADS(2)) improved net reclassification index by 6.2% compared with CHA(2)DS(2)VASc (C statistic=0.578) and by 8.2% compared with CHADS(2) (C statistic=0.575). The inclusion of creatinine clearance <60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R(2)CHADS(2) in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS(2). In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00403767.

[Prevention and treatment of venous thromboembolism: the place of new oral anticoagulants].

PubMed

Reis, Abílio

2012-04-01

Venous thromboembolism (VTE) is still an important problem of Public Health, due to its impact in terms of morbidity, mortality, resource allocation and associated costs. In the prevention and treatment of VTE, pharmacological therapy is well defined and efficacious but has some inconveniences that leave space for improvement. Several new oral anticoagulants are being developed and tested for the prevention and treatment of VTE. The better studied are the selective Factor Xa inhibitors apixaban, rivaroxaban and edoxaban, and the thrombin antagonist dabigatran. They all are orally administrated, don't have important interactions with food or other drugs, have a convenient fixed-dose regimen and a predictable action, and dispense routine monitoring of their anticoagulant effect. The major part of them has phase III studies concluded and published. Some of them are already approved by de European Medicines Agency (EMA) and the Food and Drug Administration (FDA) and recommended by the international guidelines. Rivaroxaban is approved by the EMA for the treatment of deep venous thrombosis (DVT) and for the prevention of recurrences of DVT and pulmonary embolism. In this article the available evidences are reviewed, the place of the new oral anticoagulants is discussed and future perspectives regarding the prevention and treatment of VTE are outlined. Copyright © 2012 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Direct oral anticoagulants and its implications in dentistry. A review of literature.

PubMed

Lanau, Neus; Mareque, Javier; Giner, Lluis; Zabalza, Michel

2017-11-01

Four novel direct oral anticoagulants (DOACs) named dabigatran, rivaroxaban, edoxaban and apixaban have been recently introduced to overcome some of the drawbacks of existing anticoagulants. They have less interactions and do not require routine monitoring. However, there is not enough scientific data about the protocol to apply in these patients on DOACs undergoing dental treatment. Thus is necessary to evaluate the potential bleeding risk of these drugs, the possibility of thromboembolic events occurring if they are withdrawn or the need to change to heparin previously. A comprehensive search of the PubMed, Scopus and ISI Web of Science databases was conducted to identify studies that evaluated the relationship between direct oral anticoagulants and dental procedures. The quality of the reported information was assessed following the PRISMA statement. Eleven studies that met the inclusion criteria were included in the review: 2 randomized clinical trials, 3 prospective studies, 3 retrospective studies, 2 case series and 1 case report. DOACs are safe drugs in terms of bleeding. The possible postoperative bleeding complications are manageable with conventional haemostasis measurements. The bridging approach with heparin does not seem to be recommended. Consensus among the professionals involved in the management of the patient is fundamental in invasive dental treatments and in complex patients. Key words: Oral anticoagulants, DOAC, NOAC, dabigatran, rivaroxaban, apixaban, edoxaban, bleeding, oral surgery.

Confirmation of model-based dose selection for a Japanese phase III study of rivaroxaban in non-valvular atrial fibrillation patients.

PubMed

Kaneko, Masato; Tanigawa, Takahiko; Hashizume, Kensei; Kajikawa, Mariko; Tajiri, Masahiro; Mueck, Wolfgang

2013-01-01

This study was designed to confirm the appropriateness of the dose setting for a Japanese phase III study of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF), which had been based on model simulation employing phase II study data. The previously developed mixed-effects pharmacokinetic/pharmacodynamic (PK-PD) model, which consisted of an oral one-compartment model parameterized in terms of clearance, volume and a first-order absorption rate, was rebuilt and optimized using the data for 597 subjects from the Japanese phase III study, J-ROCKET AF. A mixed-effects modeling technique in NONMEM was used to quantify both unexplained inter-individual variability and inter-occasion variability, which are random effect parameters. The final PK and PK-PD models were evaluated to identify influential covariates. The empirical Bayes estimates of AUC and C(max) from the final PK model were consistent with the simulated results from the Japanese phase II study. There was no clear relationship between individual estimated exposures and safety-related events, and the estimated exposure levels were consistent with the global phase III data. Therefore, it was concluded that the dose selected for the phase III study with Japanese NVAF patients by means of model simulation employing phase II study data had been appropriate from the PK-PD perspective.

[Clinical experience with the use of rivaroxaban in the treatment of cancer patients with venous thrombosis].

PubMed

Kravtsov, P F; Katorkin, S E; Melnicov, M A

The urgency of the problem. The incidence of various thromboembolic complications in patients with oncopathology reaches 5-12%. When treating VTE in patients with oncology it is necessary to choose between two generally recognized alternatives. The recommended two-component scheme of the initiating phase of anticoagulant therapy with subsequent long-term admission of VKA is fraught with the development of clinically significant bleeding during the initial selection of the dose of warfarin and an increased risk of recurrence of VTE. Long-term parenteral use of LMWH is often negatively treated by patients and adversely affects compliance. For these reasons, enteral administration of new oral anticoagulants is promising for prolonged anticoagulant therapy in this category of patients. The paper cites three clinical cases of treatment of patients with acute venous thrombosis of deep veins against a background of different oncological processes. In the first case - the operated previously for cancer, in the second case - to be treated over oncological process and in the third case - in the primary cancer detection. The results of the studies of EINSTEIN-DVT and EINSTEIN-PE allow us to consider the use of rivaroxaban in the treatment of patients with VTE on the background of oncopathology. The possibility of its use from the first day, in our opinion, is a significant advantage, since it allows us to reveal the clinical effectiveness of anticoagulant therapy already during the first stage of treatment, since NOAKs does not imply the possibility of laboratory monitoring.

All-Cause, Stroke/Systemic Embolism-, and Major Bleeding-Related Health-Care Costs Among Elderly Patients With Nonvalvular Atrial Fibrillation Treated With Oral Anticoagulants.

PubMed

Deitelzweig, Steve; Luo, Xuemei; Gupta, Kiran; Trocio, Jeffrey; Mardekian, Jack; Curtice, Tammy; Hlavacek, Patrick; Lingohr-Smith, Melissa; Menges, Brandy; Lin, Jay

2018-05-01

In this study, all-cause, stroke/systemic embolism (SE)-related, and major bleeding (MB)-related health-care costs among elderly patients with nonvalvular atrial fibrillation (NVAF) initiating treatment with different oral anticoagulants (OACs) were compared. Patients ≥65 years of age initiating OACs, including apixaban, rivaroxaban, dabigatran, and warfarin, were identified from the Humana Research Database between January 1, 2013, and September 30, 2015. Propensity score matching was used to separately match the different OAC cohorts with the apixaban cohort. All-cause health-care costs and stroke/SE-related and MB-related medical costs per patient per month (PPPM) were compared using generalized linear or 2-part regression models. Compared to apixaban, rivaroxaban was associated with significantly higher all-cause health-care costs (US$2234 vs US$1846 PPPM, P < .001) and MB-related medical costs (US$106 vs US$47 PPPM, P < .001), dabigatran was associated with significantly higher all-cause health-care costs (US$1980 vs US$1801 PPPM, P = .007), and warfarin was associated with significantly higher all-cause health-care costs (US$2386 vs US$1929 PPPM, P < .001), stroke/SE-related medical costs (US$42 vs US$18 PPPM, P < .001), and MB-related medical costs (US$132 vs US$51 PPPM, P < .001). Among elderly patients with NVAF, other OACs were associated with higher all-cause health-care costs than apixaban.

Anticoagulation by factor Xa inhibitors.

PubMed

Orfeo, T; Butenas, S; Brummel-Ziedins, K E; Gissel, M; Mann, K G

2010-08-01

Therapeutic agents that regulate blood coagulation are critical to the management of thrombotic disorders, with the selective targeting of factor (F) Xa emerging as a promising approach. To assess anticoagulant strategies targeting FXa. A deterministic computational model of tissue factor (Tf)-initiated thrombin generation and two empirical experimental systems (a synthetic coagulation proteome reconstruction using purified proteins and a whole blood model) were used to evaluate clinically relevant examples of the two available types of FXa-directed anticoagulants [an antithrombin (AT)-dependent agent, fondaparinux, and an AT-independent inhibitor, Rivaroxaban] in experimental regimens relevant to long-term (suppression of new Tf-initiated events) and acute (suppression of ongoing coagulation processes) clinical applications. Computational representations of each anticoagulant's efficacy in suppressing thrombin generation over a range of anticoagulant concentrations in both anticoagulation regimens were validated by results from corresponding empirical reconstructions and were consistent with those recommended for long-term and acute clinical applications, respectively. All three model systems suggested that Rivaroxaban would prove more effective in the suppression of an ongoing coagulation process than fondaparinux, reflecting its much higher reactivity toward the prothrombinase complex. The success of fondaparinux in acute settings in vivo is not explained solely by its properties as an FXa inhibitor. We have reported that FIXa contributes to the long-term capacity of clot-associated catalysts to restart a coagulation process, suggesting that the enhanced anti-FIXa activity of fondaparinux-AT may be critical to its success in acute settings in vivo. © 2010 International Society on Thrombosis and Haemostasis.

Neck-to-shoulder pain as an unusual presentation of pulmonary embolism in a patient with cervical spinal cord injury: A case report.

PubMed

Lee, Dong Gyu; Chang, Min Cheol

2017-10-01

Information on referred pain can be helpful for diagnosing diseases of the visceral organs. Here, the authors report a patient with cervical spinal cord injury (SCI) who had referred pain at the right side from the neck to shoulder, as a presentation of pulmonary embolism (PE). A 55-year-old man with complete tetraplegia, due to cervical SCI after C5 and C6 vertebral body fracture, complained of right neck-to-shoulder pain (numerical scale rating: 6). Despite pain medication (meloxicam 15 mg, gabapentin 400 mg, and propacetamol HCl 1 g), the pain was not reduced. Along with right neck-to-shoulder pain, he presented mild fever (37.8°C) and mildly elevated respiratory rate (20 breaths/min). D-dimer level was also mildly elevated to 6.09 mg/mL (normal value: < 0.5 mg/mL). Computed tomography pulmonary angiography revealed PE in the right lower lobe pulmonary artery. For managing PE, rivaroxaban was administered for three days. After the administration of rivaroxaban, the patient's pain completely disappeared. This study shows that pain at the neck-to-shoulder area can occur following unexpected causes such as PE. Not limited to PE, the evaluation of diseases in the thoracic or abdominal organs is recommended if patients with cervical SCI present refractory pain in the dermatomes innervated by high cervical nerve roots.

Lack of rivaroxaban influence on a prothrombinase-based assay for the detection of activated C protein resistance: an Italian ex vivo and in vitro study in normal subjects and factor V Leiden carriers.

PubMed

Gessoni, G; Valverde, S; Valle, L; Gessoni, F; Caruso, P; Valle, R

2017-08-01

Activated protein C resistance (APCr) leads to hypercoagulability and is due, often but not exclusively, to Factor V Leiden (FVL). The aim of this study was to assess the ex vivo and in vitro interference of the direct factor Xa inhibitor rivaroxaban (RIV) on a prothrombinase-based assay for APCr detection. An ex vivo study was performed on fresh plasma samples obtained from 44 subjects with FV wild-type and seven with FVL heterozygous, all treated with RIV. An in vitro study was performed on 15 plasma samples (six from normal subjects, six from heterozygous, and three from homozygous FVL carriers, all frozen specimens) spiked with RIV. RIV concentration was evaluated using a chromogenic assay, and APCr was evaluated by a prothrombinase-based assay. No significant interference of RIV on APCr results obtained by a prothrombinase-based assay was observed for drug concentrations up to 400 ng/mL in FV wild-type and FVL carriers (homozygous and heterozygous). These results were confirmed both ex vivo and in vitro. RIV did not significantly interfere with the prothrombinase-based assay used for the assessment of APCr, and this was observed to occur independently of FV status. However, only concentrations up to 400 ng/mL were tested and, therefore, what occurs in the presence of higher doses remains to be investigated. © 2017 John Wiley & Sons Ltd.

Representativeness of the dabigatran, apixaban and rivaroxaban clinical trial populations to real-world atrial fibrillation patients in the United Kingdom: a cross-sectional analysis using the General Practice Research Database

PubMed Central

Lee, Sally; Monz, Brigitta U; Clemens, Andreas; Brueckmann, Martina; Lip, Gregory Y H

2012-01-01

Objective Three oral anticoagulants have reported study results for stroke prevention in patients with atrial fibrillation (AF) (dabigatran etexilate, rivaroxaban and apixaban); all demonstrated superiority or non-inferiority compared with warfarin (RE-LY, ARISTOTLE and ROCKET-AF). This study aimed to assess the representativeness for the real-world AF population, particularly the population eligible for anticoagulants. Design A cross-sectional database analysis. Setting Dataset derived from the General Practice Research Database (GPRD). Primary and secondary outcomes measure The proportion of real-world patients with AF who met the inclusion/exclusion criteria for RE-LY, ARISTOTLE and ROCKET-AF were compared. The results were then stratified by risk of stroke using CHADS2 and CHA2DS2-VASc. Results 83 898 patients with AF were identified in the GPRD. For the population at intermediate or high risk of stroke and eligible for anticoagulant treatment (CHA2DS2-VASc ≥1; n=78 783 (94%)), the proportion eligible for inclusion into RE-LY (dabigatran etexilate) was 68% (95% CI 67.7% to 68.3%; n=53 640), compared with 65% (95% CI 64.7% to 65.3%; n=51 163) eligible for ARISTOTLE (apixaban) and 51% (95% CI 50.7% to 51.4%; n=39 892) eligible for ROCKET-AF (rivaroxaban). Using the CHADS2 method of risk stratification, for the population at intermediate or high risk of stroke and eligible for anticoagulation treatment (CHADS2 ≥1; n=71 493 (85%)), the proportion eligible for inclusion into RE-LY was 74% (95% CI 73.7% to 74.3%; n=52 783), compared with 72% (95% CI 71.7% to 72.3%; n=51 415) for ARISTOTLE and 56% (95% CI 55.6% to 56.4%; n=39 892) for ROCKET-AF. Conclusions Patients enrolled within RE-LY and ARISTOTLE were more reflective of the ‘real-world’ AF population in the UK, in contrast with patients enrolled within ROCKET-AF who were a more narrowly defined group of patients at higher risk of stroke. Differences between trials should be taken into account when considering the applicability of findings from randomised clinical trials. However, assessing representativeness is not a substitute for assessing generalisibility, that is, how well clinical trial results would translate into effectiveness and safety in everyday routine care. PMID:23242482

A meta-analysis of phase III randomized controlled trials with novel oral anticoagulants in atrial fibrillation: comparisons between direct thrombin inhibitors vs. factor Xa inhibitors and different dosing regimens.

PubMed

Providência, Rui; Grove, Erik Lerkevang; Husted, Steen; Barra, Sérgio; Boveda, Serge; Morais, João

2014-12-01

Previous studies evaluating the ability of novel oral anticoagulants (NOAC) to prevent thromboembolism in patients with non-valvular atrial fibrillation (AF) have identified differences between the efficacy and safety of the drugs tested. Whether these differences reflect differences in direct thrombin or Xa inhibition, different dosing regimens or specific aspects of each agent or trial has not yet been explored. A search was performed on MEDLINE, EMBASE and COCHRANE, and ongoing studies were tracked on clinicaltrials.gov. Phase III randomized controlled trials of direct thrombin inhibitors (DTI) and factor Xa inhibitors (FXaI) vs. warfarin in patients with AF were eligible. Data were pooled using random-effects, according to the Mantel-Haenszel model. Sensitivity analyses were performed on DTI, FXaI, once-daily and twice-daily regimens. Seven studies were pooled, including a total of 80,290 patients. Both DTI and FXaI outperformed warfarin regarding stroke or systemic embolism, intracranial bleeding, total and cardiovascular mortality. No significant differences were found between DTI and FXaI or between once-daily and twice-daily regimens. Some drugs performed worse than warfarin regarding some secondary endpoints, including: edoxaban 30 mg bid on ischaemic stroke, dabigatran on acute myocardial infarction, dabigatran 150 mg bid and rivaroxaban 20mgod on gastrointestinal bleeding. Our pooled data do not support the hypothesis of a significant class-effect of DTI or FXaI, nor the benefit of once-daily vs. twice-daily dosing in the setting of AF, reinforcing that the choice of NOAC should be adapted to the specific patient and focused on the agent itself, rather than the pharmacological class or dosing regimen.

Hospitalizations in patients with atrial fibrillation: an analysis from ROCKET AF.

PubMed

DeVore, Adam D; Hellkamp, Anne S; Becker, Richard C; Berkowitz, Scott D; Breithardt, Guenter; Hacke, Werner; Halperin, Jonathan L; Hankey, Graeme J; Mahaffey, Kenneth W; Nessel, Christopher C; Singer, Daniel E; Fox, Keith A A; Patel, Manesh R; Piccini, Jonathan P

2016-08-01

The high costs associated with treatment for atrial fibrillation (AF) are primarily due to hospital care, but there are limited data to understand the reasons for and predictors of hospitalization in patients with AF. The ROCKET AF trial compared rivaroxaban with warfarin for stroke prophylaxis in AF. We described the frequency of and reasons for hospitalization during study follow-up and utilized Cox proportional hazards models to assess for baseline characteristics associated with all-cause hospitalization. Of 14 171 patients, 14% were hospitalized at least once. Of 2614 total hospitalizations, 41% were cardiovascular including 4% for AF; of the remaining, 12% were for bleeding. Compared with patients not hospitalized, hospitalized patients were older (74 vs. 72 years), and more frequently had diabetes (46 vs. 39%), prior MI (23 vs. 16%), and paroxysmal AF (19 vs. 17%), but less frequently had prior transient ischaemic attack/stroke (49 vs. 56%). After multivariable adjustment, lung disease [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.29-1.66], diabetes [1.22, (1.11-1.34)], prior MI [1.27, (1.13-1.42)], and renal dysfunction [HR 1.07 per 5 unit GFR < 65 mL/min, (1.04-1.10)] were associated with increased hospitalization risk. Treatment assignment was not associated with differential rates of hospitalization. Nearly 1 in 7 of the moderate-to-high-risk patients with AF enrolled in this trial was hospitalized within 2 years, and both AF and bleeding were rare causes of hospitalization. Further research is needed to determine whether care pathways directed at comorbid conditions among AF patients could reduce the need for and costs associated with hospitalization. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

The treatment of missing data in a large cardiovascular clinical outcomes study.

PubMed

Little, Roderick J; Wang, Julia; Sun, Xiang; Tian, Hong; Suh, Eun-Young; Lee, Michael; Sarich, Troy; Oppenheimer, Leonard; Plotnikov, Alexei; Wittes, Janet; Cook-Bruns, Nancy; Burton, Paul; Gibson, C Michael; Mohanty, Surya

2016-06-01

The potential impact of missing data on the results of clinical trials has received heightened attention recently. A National Research Council study provides recommendations for limiting missing data in clinical trial design and conduct, and principles for analysis, including the need for sensitivity analyses to assess robustness of findings to alternative assumptions about the missing data. A Food and Drug Administration advisory committee raised missing data as a serious concern in their review of results from the ATLAS ACS 2 TIMI 51 study, a large clinical trial that assessed rivaroxaban for its ability to reduce the risk of cardiovascular death, myocardial infarction or stroke in patients with acute coronary syndrome. This case study describes a variety of measures that were taken to address concerns about the missing data. A range of analyses are described to assess the potential impact of missing data on conclusions. In particular, measures of the amount of missing data are discussed, and the fraction of missing information from multiple imputation is proposed as an alternative measure. The sensitivity analysis in the National Research Council study is modified in the context of survival analysis where some individuals are lost to follow-up. The impact of deviations from ignorable censoring is assessed by differentially increasing the hazard of the primary outcome in the treatment groups and multiply imputing events between dropout and the end of the study. Tipping-point analyses are described, where the deviation from ignorable censoring that results in a reversal of significance of the treatment effect is determined. A study to determine the vital status of participants lost to follow-up was also conducted, and the results of including this additional information are assessed. Sensitivity analyses suggest that findings of the ATLAS ACS 2 TIMI 51 study are robust to missing data; this robustness is reinforced by the follow-up study, since inclusion of data from this study had little impact on the study conclusions. Missing data are a serious problem in clinical trials. The methods presented here, namely, the sensitivity analyses, the follow-up study to determine survival of missing cases, and the proposed measurement of missing data via the fraction of missing information, have potential application in other studies involving survival analysis where missing data are a concern. © The Author(s) 2016.

Benefit, risk and cost of new oral anticoagulants and warfarin in atrial fibrillation; A multicriteria decision analysis.

PubMed

Mendoza-Sanchez, Jose; Silva, Federico; Rangel, Lady; Jaramillo, Linda; Mendoza, Leidy; Garzon, Jenny; Quiroga, Andrea

2018-01-01

Warfarin and new oral anticoagulants are effective in reducing stroke in atrial fibrillation; however, the benefits and risks rates in clinical trials show heterogeneity for each anticoagulant, and is unknown the cost influence on a model considering most of the treatment consequences. We designed a benefit-risk and cost assessment of oral anticoagulants. We followed the roadmap proposed by IMI-PROTECT and the considerations of emerged good practice to perform Multi-Criteria Decision Analysis (MCDA). The roadmap defines the following steps: (1) planning, (2) evidence gathering and data preparation, (3) analyses, (4) explorations, and (5) conclusions. We defined two reference points (0-100) to allocate numerical values for scores and weights, and used an analogue numeric scale to assess physicians' preferences. As benefits of the anticoagulant therapy, we included reductions in stroke and all-cause mortality; intracranial haemorrhage, gastrointestinal haemorrhage, minor bleeding and myocardial infarction were considered risks. We also made an estimation of the annual drug cost per person. The scores were: Apixaban 33, Dabigatrán 25, warfarin 18 and Rivaroxaban 14 this score reveals the most preferred up to the less preferred option, considering the benefit-risk ratio and drug costs altogether. The relative model weights were: 51.1% for risks, 40.4% for benefits and 8.5% for cost. The sensitivity analysis confirms the model robustness. From this analysis, apixaban should be considered as the preferred anticoagulant option -due to a better benefit-risk balance and a minor cost influence- followed by dabigatran, warfarin and rivaroxaban.

Direct oral anticoagulants and digestive bleeding: therapeutic management and preventive measures.

PubMed

Deutsch, David; Boustière, Christian; Ferrari, Emile; Albaladejo, Pierre; Morange, Pierre-Emmanuel; Benamouzig, Robert

2017-06-01

The use of direct oral anticoagulants (DOACs) was an important step forward in the management of atrial fibrillation and venous thromboembolism (VTE). The DOACs, anti-IIa for dabigatran and anti-Xa for rivaroxaban, apixaban and edoxaban, all have a rapid onset of action and a short half life. There is no need for routine hemostasis testing for treatment monitoring of a DOAC. Compared with vitamin K antagonists (VKAs), DOACs may increase the risk of gastrointestinal bleeding (relative risk 1.25). Withholding the DOAC treatment, evaluating the time of the last intake and estimating the patient's renal function are the first steps in the management of gastrointestinal bleeding. For patients without impaired renal function, achieving low coagulation takes around 24 h after the last intake of a DOAC. The use of DOAC antagonists will be helpful in controlling bleeding in the most severe and urgent situations. Idarucizumab is available for clinical use for dabigatran and andexanet is currently being reviewed by drug agencies for rivaroxaban, apixaban and edoxaban. It is important to assess the bleeding risk associated with the planned procedure, and the patient's renal function before withholding DOAC therapy for a scheduled intervention. It is mandatory to strengthen the local hemostasis strategies in DOAC-treated patients undergoing a therapeutic endoscopic procedure. Resuming or not resuming anticoagulation with a DOAC after bleeding or a risky procedure depends on the thrombotic and bleeding risk as well as the procedure involved. This discussion should always involve the cardiologist and decisions should be taken by a pluridisciplinary team.

New Target-Specific Oral Anticoagulants and Intracranial Bleeding: Management and Outcome in a Single-Center Case Series.

PubMed

Senger, Sebastian; Keiner, Dörthe; Hendrix, Philipp; Oertel, Joachim

2016-04-01

New target-specific anticoagulants such as the direct thrombin inhibitor dabigatran and the factor Xa inhibitor rivaroxaban are used in an increasing number of patients. Several studies comparing these new oral anticoagulants with vitamin K antagonists revealed a lower risk of severe bleeding complications and reduced thromboembolic events. However, the lack of antidotes is a challenging issue in the treatment of traumatic or spontaneous intracranial hemorrhage. A retrospective analysis of patients with intracranial bleeding under new oral anticoagulants was performed; these patients were admitted to our department between January 2011 and November 2014. Treatment, reversal management of blood coagulopathy, and outcome of the patients were analyzed. Seventeen patients were included. The median age was 80.4 years. Seven patients were treated with dabigatran and 10 with rivaroxaban. Eight patients had traumatic intracranial bleeding and 9 patients had spontaneous intracranial hemorrhage. Complex perioperative hematologic treatment followed. In 9 cases, the clinical outcome was devastating with severe neurologic deficits (n = 2), comatose status (n = 4), or death (n = 3). Patients with the indication for acute surgical treatment had a high risk for a critical clinical outcome. Only a few case reports have analyzed the clinical course and the outcome after intracranial bleeding under new target-specific oral anticoagulants. Here, one of the first larger series is presented. Because of the lack of reversibility of the anticoagulative effects and the overall risks with geriatric patients, surgical treatment should be delayed as long as possible and comorbidities have to be considered. Copyright © 2016 Elsevier Inc. All rights reserved.

The use of frozen plasma samples in thromboelastometry.

PubMed

Schoergenhofer, Christian; Buchtele, Nina; Schwameis, Michael; Bartko, Johann; Jilma, Bernd; Jilma-Stohlawetz, Petra

2017-11-01

Thromboelastometry is increasingly used in the clinical and scientific setting. The use of frozen plasma samples may be useful in overcoming certain limitations such as local and timely availability. Whole blood (WB) samples of 20 healthy volunteers were obtained, and plasma was generated. NATEM (n = 20), EXTEM (n = 20) and INTEM (n = 8) analyses were performed in WB, fresh plasma and frozen and thawed plasma. Dabigatran (500, 1000 ng/ml), rivaroxaban (100, 200 ng/ml) or alteplase (333 ng/ml) were added ex vivo to WB, and thromboelastometry was performed in WB and in frozen and thawed plasma samples. Clot formation time, mean clot firmness and the area under the curve were significantly altered in plasma compared to WB. In INTEM and EXTEM analysis, clotting time (CT) was comparable between WB (100%) and fresh (INTEM 114% and EXTEM 93%, ratio of the means) and frozen plasma samples (85 and 99%), whereas in NATEM analysis, the CT increased in fresh (193%) and frozen plasma samples (130%). Dabigatran dose-dependently increased the CT approximately 5- and 9-fold in WB and even more pronounced 10- and 26-fold in plasma. Accordingly, rivaroxaban dose-dependently increased the CT 2- and 2.7-fold in WB, and 3.5- and 4-fold in plasma samples. Hyperfibrinolysis was achieved by addition of alteplase in all WB samples and was reproducible in plasma samples. In conclusion, thromboelastometry, especially INTEM and EXTEM analyses, is possible using frozen and stored plasma samples with comparable results to the corresponding whole blood samples.

[Atrial fibrillation in elderly].

PubMed

Arquizan, Caroline

2012-11-01

Atrial fibrilation (AF) is frequent and a strong risk factor for ischemic stroke in elderly. Ischemic stroke in patients with AF are more severe. Vitamine K antagonist therapy is highly effective for stroke prevention but is associated with hemorrhagic risk. The new oral anticoagulants (direct thrombin inhibitor [dabigatran], and direct factor Xa inhibitors [rivaroxaban and apixaban]) have all shown non inferiority or superiority, with better safety, considering the risk of intracranial haemorrhage. On this basis, it is justified to give them in priority in the vast majority of patients with AF, the choice of the drug and the dose is individual.

Disadvantages of VKA and requirements for novel anticoagulants.

PubMed

Shameem, Raji; Ansell, Jack

2013-06-01

Vitamin K antagonists have been in wide use for over 70 years. Warfarin, the most commonly used vitamin K antagonist, has been shown to be highly effective in treating and preventing thrombosis. Despite this, warfarin has many disadvantages, which has led to the development of a new class of oral anticoagulants targeted to specific coagulation factors designated as target-specific oral anticoagulants (TSOAs). TSOAs include the thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban). This chapter reviews the disadvantages of warfarin and evaluates both the advantages and disadvantages of the new oral anticoagulants. © 2013 Elsevier Ltd. All rights reserved.

Cost-effectiveness analysis of left atrial appendage occlusion compared with pharmacological strategies for stroke prevention in atrial fibrillation.

PubMed

Lee, Vivian Wing-Yan; Tsai, Ronald Bing-Ching; Chow, Ines Hang-Iao; Yan, Bryan Ping-Yen; Kaya, Mehmet Gungor; Park, Jai-Wun; Lam, Yat-Yin

2016-08-31

Transcatheter left atrial appendage occlusion (LAAO) is a promising therapy for stroke prophylaxis in non-valvular atrial fibrillation (NVAF) but its cost-effectiveness remains understudied. This study evaluated the cost-effectiveness of LAAO for stroke prophylaxis in NVAF. A Markov decision analytic model was used to compare the cost-effectiveness of LAAO with 7 pharmacological strategies: aspirin alone, clopidogrel plus aspirin, warfarin, dabigatran 110 mg, dabigatran 150 mg, apixaban, and rivaroxaban. Outcome measures included quality-adjusted life years (QALYs), lifetime costs and incremental cost-effectiveness ratios (ICERs). Base-case data were derived from ACTIVE, RE-LY, ARISTOTLE, ROCKET-AF, PROTECT-AF and PREVAIL trials. One-way sensitivity analysis varied by CHADS2 score, HAS-BLED score, time horizons, and LAAO costs; and probabilistic sensitivity analysis using 10,000 Monte Carlo simulations was conducted to assess parameter uncertainty. LAAO was considered cost-effective compared with aspirin, clopidogrel plus aspirin, and warfarin, with ICER of US$5,115, $2,447, and $6,298 per QALY gained, respectively. LAAO was dominant (i.e. less costly but more effective) compared to other strategies. Sensitivity analysis demonstrated favorable ICERs of LAAO against other strategies in varied CHADS2 score, HAS-BLED score, time horizons (5 to 15 years) and LAAO costs. LAAO was cost-effective in 86.24 % of 10,000 simulations using a threshold of US$50,000/QALY. Transcatheter LAAO is cost-effective for prevention of stroke in NVAF compared with 7 pharmacological strategies. The transcatheter left atrial appendage occlusion (LAAO) is considered cost-effective against the standard 7 oral pharmacological strategies including acetylsalicylic acid (ASA) alone, clopidogrel plus ASA, warfarin, dabigatran 110 mg, dabigatran 150 mg, apixaban, and rivaroxaban for stroke prophylaxis in non-valvular atrial fibrillation management.

Emergency Coagulation Assessment During Treatment With Direct Oral Anticoagulants: Limitations and Solutions.

PubMed

Ebner, Matthias; Birschmann, Ingvild; Peter, Andreas; Härtig, Florian; Spencer, Charlotte; Kuhn, Joachim; Blumenstock, Gunnar; Zuern, Christine S; Ziemann, Ulf; Poli, Sven

2017-09-01

In patients receiving direct oral anticoagulants (DOACs), emergency treatment like thrombolysis for acute ischemic stroke is complicated by insufficient availability of DOAC-specific coagulation tests. Conflicting recommendations have been published concerning the use of global coagulation assays for ruling out relevant DOAC-induced anticoagulation. Four hundred eighty-one samples from 96 DOAC-treated patients were tested using prothrombin time (PT), activated partial thromboplastin time (aPTT) and thrombin time (TT), DOAC-specific assays (anti-Xa activity, diluted TT), and liquid chromatography-tandem mass spectrometry. Sensitivity and specificity of test results to identify DOAC concentrations <30 ng/mL were calculated. Receiver operating characteristic analyses were used to define reagent-specific cutoff values. Normal PT and aPTT provide insufficient specificity to safely identify DOAC concentrations <30 ng/mL (rivaroxaban/PT: specificity, 77%/sensitivity, 94%; apixaban/PT: specificity, 13%/sensitivity, 94%, dabigatran/aPTT: specificity, 49%/sensitivity, 91%). Normal TT was 100% specific for dabigatran, but sensitivity was 26%. In contrast, reagent-specific PT and aPTT cutoffs provided >95% specificity and a specific TT cutoff enhanced sensitivity for dabigatran to 84%. For apixaban, no cutoffs could be established. Even if highly DOAC-reactive reagents are used, normal results of global coagulation tests are not suited to guide emergency treatment: whereas normal PT and aPTT lack specificity to rule out DOAC-induced anticoagulation, the low sensitivity of normal TT excludes the majority of eligible patients from treatment. However, reagent-specific cutoffs for global coagulation tests ensure high specificity and optimize sensitivity for safe emergency decision making in rivaroxaban- and dabigatran-treated patients. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02371044 and NCT02371070. © 2017 American Heart Association, Inc.

Optical profiling of anticoagulation status (Conference Presentation)

NASA Astrophysics Data System (ADS)

Tshikudi, Diane M.; Tripathi, Markandey M.; Hajjarian, Zeinab; Nadkarni, Seemantini K.

2016-02-01

Defective blood coagulation resulting from excessive procoagulant activity often leads to thrombotic disorders such as stroke and myocardial infarction. A variety of oral and injectable anticoagulant drugs are prescribed to prevent or treat life-threatening thrombosis. However, due to bleeding complications often associated with anticoagulant treatment, routine monitoring and accurate dosing of anticoagulant therapy is imperative. We have developed Optical thromboelastography (OTEG), a non-contact approach that utilizes a drop of whole blood to measure blood coagulation status in patients. Here, we demonstrate the capability of OTEG for rapidly monitoring anticoagulation in whole blood samples. OTEG monitors coagulation status by assessing changes in blood viscosity from temporal intensity fluctuations of laser speckle patterns during clotting. In OTEG a blood drop is illuminated with coherent light and the blood viscosity is measured from the speckle intensity autocorrelation curve, g2 (t). The metrics, clotting time (R+k), clot progression (angle) and maximum clot stiffness (MA) are then extracted. The aim of the current study was to evaluate the accuracy of OTEG in assessing anticoagulation status of common anticoagulants including heparin, argatroban and rivaroxaban status. A dose-dependent prolongation of R+k was observed in anticoagulated blood, which closely corresponded with standard-reference Thromboelastography (TEG) (r 0.87-0.99, P>0.01 for all cases). OTEG angle was unaltered by anticoagulation whereas TEG angle presented a dose-dependent diminution probably linked to clot rupture. In both OTEG and TEG, MA was unaffected by heparin, argatroban or rivaroxaban. We conclude that OTEG can accurately monitor anticoagulation status following treatment, potentially providing a powerful tool for routine monitoring of patients in the doctor's office or in the home setting.

Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial.

PubMed

Kasner, Scott E; Lavados, Pablo; Sharma, Mukul; Wang, Yongjun; Wang, Yilong; Dávalos, Antoni; Shamalov, Nikolay; Cunha, Luis; Lindgren, Arne; Mikulik, Robert; Arauz, Antonio; Lang, Wilfried; Czlonkowska, Anna; Eckstein, Jens; Gagliardi, Rubens; Amarenco, Pierre; Ameriso, Sebastián F; Tatlisumak, Turgut; Veltkamp, Roland; Hankey, Graeme J; Toni, Danilo S; Bereczki, Daniel; Uchiyama, Shinichiro; Ntaios, George; Yoon, Byung-Woo; Brouns, Raf; DeVries Basson, M M; Endres, Matthias; Muir, Keith; Bornstein, Natan; Ozturk, Serefnur; O'Donnell, Martin; Mundl, Hardi; Pater, Calin; Weitz, Jeffrey; Peacock, W Frank; Swaminathan, Balakumar; Kirsch, Bodo; Berkowitz, Scott D; Peters, Gary; Pare, Guillaume; Themeles, Ellison; Shoamanesh, Ashkan; Connolly, Stuart J; Hart, Robert G

2018-06-01

The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS. We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus. Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe. NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Antithrombotic Therapy for VTE Disease

PubMed Central

Kearon, Clive; Comerota, Anthony J.; Prandoni, Paolo; Bounameaux, Henri; Goldhaber, Samuel Z.; Nelson, Michael E.; Wells, Philip S.; Gould, Michael K.; Dentali, Francesco; Crowther, Mark; Kahn, Susan R.

2012-01-01

Background: This article addresses the treatment of VTE disease. Methods: We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence. Results: For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C). Conclusion: Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences. PMID:22315268

[Consensus statement: Management of oral anticoagulation for stroke prevention in patients with nonvalvular atrial fibrillation].

PubMed

Helms, Thomas Maria; Silber, Sigmund; Schäfer, Andreas; Masuhr, Florian; Palm, Frederick; Darius, Harald; Schrör, Karsten; Bänsch, Dietmar; Bramlage, Peter; Hankowitz, Johannes; Karle, Christoph A; Stargardt, Tom; Weil, Joachim; Geller, Johann Christoph

2016-09-01

With the introduction of edoxaban last year in Germany, four nonvitamin K antagonist oral anticoagulants are now available for stroke prevention in patients with nonvalvular atrial fibrillation. These novel oral anticoagulants (NOAC) represent an attractive new option compared to vitamin K antagonists (e.g., warfarin or phenprocoumon) due to simple use and fewer interactions with other drugs or food. Therefore, no INR monitoring and dosage adjustments are required for NOAC. The compelling clinical advantage of NOAC is the dramatic risk reduction of hemorhagic stroke and intracranial bleeding compared to current standard. In addition, total mortality is significantly reduced by 10 %. These effects are demonstrated for all four NOAC (dabigatran, rivaroxaban, apixaban and edoxaban). Therefore, current national and international guidelines recommend NOAC as the preferred option or at least as an attractive alternative compared to the former standard of vitamin K antagonists. The economic impact and reimbursement by Statutory Health Insurance (GKV) is of major importance for treatment in an outpatient setting. For apixaban and edoxaban, an additional benefit was granted by the institution of G‑BA and IQWiG in this clinical setting, whereas dabigatran and rivaroxaban were not assessed due to market entrance prior to 2011 before the AMNOG procedure was initiated. The members of this consensus paper recommend NOAC as the preferred option for patients with nonvalvular atrial fibrillation who are currently not treated with anticoagulant drugs in spite of clear indication for anticoagulation. For new patients with nonvalvular fibrillation, it should be decided on an individual basis which treatment option is adequate for the patient with their respective comorbidities.

Risk of renal failure with the non-vitamin K antagonist oral anticoagulants: systematic review and meta-analysis.

PubMed

Caldeira, Daniel; Gonçalves, Nilza; Pinto, Fausto J; Costa, João; Ferreira, Joaquim J

2015-07-01

Vitamin K antagonists (VKA)-related nephropathy is a novel entity characterized by acute kidney injury related to International Normalized Ratio supratherapeutic levels. Non-vitamin K antagonists oral anticoagulants (NOACs) have a predictable dose-response relationship and an improved safety profile. We hypothesized that these drugs do not have an increased risk of incident renal failure, which may be detrimental for the use of NOACs. Systematic review and meta-analysis of phase III randomized controlled trials (RCTs). Trials were searched through Medline, Cochrane Library and public assessment reports in August 2014. Primary outcome was renal failure. NOACs were evaluated against any comparator. Random-effects meta-analysis was performed by default, and pooled estimates were expressed as Risk Ratio (RR) and 95%CI. Heterogeneity was evaluated with I(2) test. Ten RCTs fulfilled inclusion criteria (one apixaban RCT, three dabigatran RCTs, and six rivaroxaban RCTs), enrolling 75 100 patients. Overall NOACs did not increase the risk of renal failure with an RR 0.96, 95%CI 0.88-1.05 compared with VKA or Low-molecular weight heparin (LMWH), without significant statistical heterogeneity (I(2)  = 3.5%). Compared with VKA, NOACs did not increase the risk of renal failure (RR 0.96, 95%CI 0.87-1.07; I(2)  = 17.8%; six RCTs). Rivaroxaban did not show differences in the incidence of renal failure compared with LMWH (RR 1.20, 95%CI 0.37-3.94; four trials), but there was an increased risk of creatinine elevation RR 1.25, 95%CI 1.08-1.45; I(2)  = 0%. NOACs had a similar risk of renal failure compared with VKA/LMWH in phase III RCTs. Post-marketing surveillance should be warranted. Copyright © 2015 John Wiley & Sons, Ltd.

Rivaroxaban real-world evidence: Validating safety and effectiveness in clinical practice.

PubMed

Beyer-Westendorf, Jan; Camm, A John; Coleman, Craig I; Tamayo, Sally

2016-09-28

Randomised controlled trials (RCTs) are considered the gold standard of clinical research as they use rigorous methodologies, detailed protocols, pre-specified statistical analyses and well-defined patient cohorts. However, RCTs do not take into account the complexity of real-world clinical decision-making. To tackle this, real-world data are being increasingly used to evaluate the long-term safety and effectiveness of a given therapy in routine clinical practice and in patients who may not be represented in RCTs, addressing key clinical questions that may remain. Real-world evidence plays a substantial role in supporting the use of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) in clinical practice. By providing data on patient profiles and the use of anticoagulation therapies in routine clinical practice, real-world evidence expands the current awareness of NOACs, helping to ensure that clinicians are well-informed on their use to implement patient-tailored clinical decisions. There are various issues with current anticoagulation strategies, including under- or overtreatment and frequent monitoring with VKAs. Real-world studies have demonstrated that NOAC use is increasing (Dresden NOAC registry and Global Anticoagulant Registry in the FIELD-AF [GARFIELD-AF]), as well as reaffirming the safety and effectiveness of rivaroxaban previously observed in RCTs (XArelto on preveNtion of sTroke and non-central nervoUS system systemic embolism in patients with non-valvular atrial fibrillation [XANTUS] and IMS Disease Analyzer). This article will describe the latest updates in real-world evidence across a variety of methodologies, such as non-interventional studies (NIS), registries and database analyses studies. It is anticipated that these studies will provide valuable clinical insights into the management of thromboembolism, and enhance the current knowledge on anticoagulant use and outcomes for patients.

Life-threatening haematuria caused by vancomycin-induced thrombocytopenia

PubMed Central

Lobo, Niyati; Ejiofor, Kandi; Thurairaja, Ramesh; Khan, Muhammad Shamim

2015-01-01

Thrombocytopenia is a rare side effect of vancomycin, an antibiotic that is often used to treat Gram-positive bacterial infections. A 67-year-old man developed bilateral pulmonary emboli and hospital-acquired pneumonia following left ureteric reimplantation. He was anticoagulated with rivaroxaban and started on intravenous vancomycin and gentamicin for treatment of pneumonia. After five doses of vancomycin, his platelet count dropped to a nadir of 0×109/L (baseline: 314×109/L) manifesting as visible heavy haematuria and haemodynamic instability due to excessive blood loss. Reversal of the thrombocytopenia was achieved with intravenous immunoglobulin, methylprednisolone and continuous platelet transfusions. PMID:25716041

Acute management of bleeding in patients on novel oral anticoagulants.

PubMed

Siegal, Deborah M; Crowther, Mark A

2013-02-01

Novel oral anticoagulants that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban) are currently available for prevention of venous thromboembolism (VTE) after orthopaedic surgery, treatment of acute VTE, and prevention of arterial thromboembolism in non-valvular atrial fibrillation. These agents offer advantages over VKAs, including rapid onset, shorter half-lives, fewer drug interactions, and lack of need for routine monitoring. However, there are no established agents to reverse their anticoagulant effect. We review the risk of bleeding with the novel oral anticoagulants and the limitations of conventional coagulation assays for measuring anticoagulant effect. We provide an approach to the management of patients with bleeding complications with evidence for various interventions for reversal, where available.

[Dysphagia and tonsillitis in a 25-year-old male patient : The nearly forgotten severe complication of a common ailment].

PubMed

Murray, A; Rath, T; Wördehoff, L; Schuler-Lüttmann, S; Baumgärtel, M W

2018-05-01

We report the case of a patient with a severe dysphagia accompanying progressive tonsillitis. The clinical examination supported the possibility of a severe septic soft tissue infection. The blood cultures revealed a largely anaerobic sepsis with Fusobacterium necrophorum. This unusual pathogen is the most common cause of Lemierre's syndrome. A duplex sonogram and magnetic resonance imaging (MRI) of the neck region and vessels suggested a thrombophlebitis of the left internal jugular vein with partial occlusion, so that Lemierre's syndrome could be diagnosed. The patient was treated with appropriate antibiotics according to the resistogram and also with rivaroxaban.

Comparing the Cost Effectiveness of Non-vitamin K Antagonist Oral Anticoagulants with Well-Managed Warfarin for Stroke Prevention in Atrial Fibrillation Patients at High Risk of Bleeding.

PubMed

Hospodar, Alexa R; Smith, Kenneth J; Zhang, Yuting; Hernandez, Inmaculada

2018-05-09

Several studies have compared the cost effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin using results from clinical trials evaluating NOACs. However, the time in therapeutic range (TTR) of warfarin groups ranged across clinical trials, and all were below the therapeutic goal of 70%. We compared the cost effectiveness of edoxaban 60 mg, apixaban 5 mg, dabigatran 150 mg, dabigatran 110 mg, rivaroxaban 20 mg, and well-managed warfarin with a TTR of 70% in preventing stroke among patients with atrial fibrillation at high risk of bleeding. For the six treatments, we used a Markov state-transition model to quantify lifetime costs in $US and effectiveness in quality-adjusted life-years (QALYs). We simulated relative risk ratios of clinical events with each NOAC versus warfarin with a TTR of 70% using published regression models that predict how the incidence of thrombotic or hemorrhagic events changes for each unit change in TTR. We re-ran our analysis for two other estimates of TTR: 65 and 75%. Treatment with edoxaban 60 mg cost $US127,520/QALY gained compared with warfarin with a TTR of 70% and cost $US41,860/QALY gained compared with warfarin with a TTR of 65%. However, warfarin with a TTR of 75% was more effective and less expensive than all NOACs. For three levels of TTR, apixaban 5 mg, dabigatran 150 mg, dabigatran 110 mg, and rivaroxaban 20 mg were dominated strategies. The comparative cost effectiveness of edoxaban and warfarin is highly sensitive to TTR. At the $US100,000/QALY willingness-to-pay threshold, our results suggest that warfarin is the most cost-effective treatment for patients who can achieve a TTR of 70%.

A mobile compression device for thrombosis prevention in hip and knee arthroplasty.

PubMed

Colwell, Clifford W; Froimson, Mark I; Anseth, Scott D; Giori, Nicholas J; Hamilton, William G; Barrack, Robert L; Buehler, Knute C; Mont, Michael A; Padgett, Douglas E; Pulido, Pamela A; Barnes, C Lowery

2014-02-05

Venous thromboembolic events, either deep venous thrombosis or pulmonary embolism, are important complications in patients undergoing knee or hip arthroplasty. The purpose of this study was to evaluate the effectiveness of a mobile compression device (ActiveCare+S.F.T.) with or without aspirin compared with current pharmacological protocols for prophylaxis against venous thromboembolism in patients undergoing elective primary unilateral arthroplasty of a lower-extremity joint. A multicenter registry was established to capture the rate of symptomatic venous thromboembolic events following primary knee arthroplasty (1551 patients) or hip arthroplasty (1509 patients) from ten sites. All patients were eighteen years of age or older with no known history of venous thromboembolism, coagulation disorder, or solid tumor. Use of the compression device began perioperatively and continued for a minimum of ten days. Patients with symptoms of deep venous thrombosis or pulmonary embolism underwent duplex ultrasonography and/or spiral computed tomography. All patients were evaluated at three months postoperatively to document any evidence of deep venous thrombosis or pulmonary embolism. Of 3060 patients, twenty-eight (0.92%) had venous thromboembolism (twenty distal deep venous thrombi, three proximal deep venous thrombi, and five pulmonary emboli). One death occurred, with no autopsy performed. Symptomatic venous thromboembolic rates observed in patients who had an arthroplasty of a lower-extremity joint using the mobile compression device were noninferior (not worse than), at a margin of 1.0%, to the rates reported for pharmacological prophylaxis, including warfarin, enoxaparin, rivaroxaban, and dabigatran, except in the knee arthroplasty group, in which the mobile compression device fell short of the rate reported for rivaroxaban by 0.06%. Use of the mobile compression device with or without aspirin for patients undergoing arthroplasty of a lower-extremity joint provides a noninferior risk for the development of venous thromboembolism compared with current pharmacological protocols.

Antithrombotic therapy in patients with non-valvular atrial fibrillation undergoing percutaneous coronary intervention: should we change our practice after the PIONEER AF-PCI and RE-DUAL PCI trials?

PubMed

Duerschmied, D; Brachmann, J; Darius, H; Frey, N; Katus, H A; Rottbauer, W; Schäfer, A; Thiele, H; Bode, C; Zeymer, Uwe

2018-04-20

The number of patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) is increasing. Since these patients have a CHA 2 DS 2 -VASc score of 1 or higher, they should be treated with oral anticoagulation to prevent stroke. However, combination therapy with oral anticoagulation for prevention of embolic stroke and dual platelet inhibition for prevention of coronary thrombosis significantly increases bleeding complications. The optimal combination, intensity and duration of antithrombotic combination therapy is still not known. In the rather small randomized WOEST trial, the combination of a vitamin K antagonist (VKA) and clopidogrel decreased bleeding compared to the conventional triple therapy with VKA, clopidogrel and aspirin. In the PIONEER AF-PCI trial, two rivaroxaban-based treatment regimens significantly reduced bleeding complications compared to conventional triple therapy without increasing embolic or ischemic complications following PCI. Dual therapy with rivaroxaban and clopidogrel appeared to provide an optimal risk-benefit ratio. In the RE-DUAL PCI trial, dual therapy with dabigatran also reduced bleeding complications compared to conventional triple therapy. With respect to the composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization dabigatran-based dual therapy was non-inferior to VKA-based triple therapy. The upcoming trials AUGUSTUS with apixaban and ENTRUST-PCI with edoxaban will further examine the use of NOACs in this setting. While recent guidelines recommend NOAC-based dual therapy in only a subset of patients (those who are at increased risk of bleeding), the available data now suggest that this should be the preferred choice for the majority of patients. Adding aspirin to this primary choice for up to 4 weeks in patients at especially high ischemic risk would likely prevent atherothrombotic events, but this needs further investigation. Taken together, it is time to adjust our practice and move to dual therapy consisting of a NOAC plus clopidogrel in most patients.

Reduced Anticoagulant Effect of Dabigatran in a Patient Receiving Concomitant Phenytoin.

PubMed

Wiggins, Barbara S; Northup, Amanda; Johnson, Dominic; Senfield, Jeffrey

2016-02-01

Dabigatran, a direct thrombin inhibitor, is an oral anticoagulant indicated for the prevention of stroke in patients with atrial fibrillation (AF) and for the treatment and prevention of deep vein thrombosis and pulmonary embolism. Dabigatran, as well as the other new anticoagulants-rivaroxaban, apixaban, and edoxaban-are substrates for P-glycoprotein (P-gp). Although the U.S. labeling for rivaroxaban and apixaban states to avoid concomitant use with phenytoin, a known P-gp inducer, the U.S. labeling for dabigatran and edoxaban are less clear. We describe the first case report, to our knowledge, documenting a drug interaction between phenytoin and dabigatran by using laboratory measurements of dabigatran serum concentrations. A 45-year-old African-American man was admitted to the inpatient cardiology service following defibrillations from his implantable cardioverter defibrillator. The patient was evaluated and received appropriate antitachycardia pacing for atrial tachyarrhythmias for an episode of ventricular tachycardia (VT), and antiarrhythmic therapy with sotalol was initiated to reduce both his AF and VT burden. On review of the patient's medications for potential interactions, it was discovered that the patient was taking both dabigatran and phenytoin. To determine the magnitude of this drug interaction prior to making a change in his anticoagulation regimen, a dabigatran serum concentration was measured. This concentration was undetectable, indicating that phenytoin had a significant influence on dabigatran's metabolism and that this patient was at high risk for stroke. Clinicians should be aware of this interaction between phenytoin and dabigatran as well as with all other new oral anticoagulants. In patients taking phenytoin who require an anticoagulant, only warfarin should be prescribed to minimize the risk of stroke. In addition, the prescribing information for dabigatran should be updated to include other medications that result in a significant reduction in dabigatran serum concentrations, such as phenytoin. © 2016 Pharmacotherapy Publications, Inc.

New anticoagulants for the prevention of stroke in atrial fibrillation.

PubMed

Höchtl, Thomas; Huber, Kurt

2012-02-01

Oral anticoagulation in atrial fibrillation is obligatory to lower the risk of spontaneous cerebrovascular and systemic thromboembolism. For this purpose, vitamin K antagonists (coumarins) have been recommended as the most effective drugs for a long time. However, problems with the practical use of these agents, e.g. the need for frequent and regular coagulation controls, the inter-individual differences in maintaining a stable therapeutic range, as well as drug or food interactions, have led to the search and investigation of alternative compounds characterized by a more simple use (e.g. without regular controls of therapeutic levels), high efficacy, as well as low risk of bleeding. The direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban and apixaban have recently been investigated to prove whether they fulfill the high expectancy of an ideal anticoagulant with respect to a more favorable efficacy/safety profile and without the need for coagulation controls, thereby improving quality of life. Dabigatran (RE-LY) achieved an impressive reduction in stroke and non-central nervous system (non-CNS) embolism (110 mg: 1.5%/year; 150 mg: 1.1%/year) in contrast to warfarin (1.7%/year; P = 0.34 and P < 0.001) with a favorable action on bleeding hazards. The results of rivaroxaban which were obtained in the ROCKET AF study (on treatment analysis: stroke and non-CNS embolism: 1.7%/year vs. 2.15%/year with warfarin; P = 0.015; primary safety endpoint major and minor bleeding: 14.91 vs. 14.52%; P = 0.442) point in the same direction. And finally, compared to aspirin, apixaban reduced the combined primary efficacy endpoint by 52% with comparable rates of bleeding (AVERROES). This review gives a summary of the current knowledge about these agents and their potential future importance. © 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.

Stroke prevention in patients with atrial fibrillation in France: comparative cost-effectiveness of new oral anticoagulants (apixaban, dabigatran, and rivaroxaban), warfarin, and aspirin.

PubMed

Lanitis, T; Cotté, F E; Gaudin, A F; Kachaner, I; Kongnakorn, T; Durand-Zaleski, I

2014-08-01

To conduct an economic evaluation of the currently prescribed treatments for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) including warfarin, aspirin, and novel oral anticoagulants (NOACs) from a French payer perspective. A previously published Markov model was adapted in accordance to the new French guidelines of the Commission for Economic Evaluation and Public Health (CEESP), to adopt the recommended efficiency frontier approach. A cohort of patients with NVAF eligible for stroke preventive treatment was simulated over lifetime. Clinical events modeled included strokes, systemic embolism, intracranial hemorrhage, other major bleeds, clinically relevant non-major bleeds, and myocardial infarction. Efficacy and bleeding data for warfarin, apixaban, and aspirin were obtained from ARISTOTLE and AVERROES trials, whilst efficacy data for other NOACs were from published indirect comparisons. Acute medical costs were obtained from a dedicated analysis of the French national hospitalization database (PMSI). Long-term medical costs and utility data were derived from the literature. Univariate and probabilistic sensitivity analyses were performed to assess the robustness of the model projections. Warfarin and apixaban were the two optimal treatment choices, as the other five treatment strategies including aspirin, dabigatran 110 mg, dabigatran in sequential dosages, dabigatran 150 mg, and rivaroxaban were strictly dominated on the efficiency frontier. Further, apixaban was a cost-effective alternative vs warfarin with an incremental cost of €2314 and an incremental quality-adjusted life year (QALY) of 0.189, corresponding to an incremental cost-effectiveness ratio (ICER) of €12,227/QALY. Apixaban may be the most economically efficient alternative to warfarin in NVAF patients eligible for stroke prevention in France. All other strategies were dominated, yielding apixaban as a less costly yet more effective treatment alternative. As formally requested by the CEESP, these results need to be verified in a French clinical setting using stroke reduction and bleeding safety observed in real-life patient cohorts using these anticoagulants.

[Clinical characteristics of patients with atrial fibrillation treated with direct oral anticoagulants attended in primary care setting. The SILVER-AP study].

PubMed

de la Figuera, Mariano; Cinza, Sergio; Marín, Nuria; Egocheaga, Isabel; Prieto, Miguel Angel

To analyse the clinical characteristics and management of patients with non-valvular atrial fibrillation (NVAF) treated with direct oral anticoagulants (DOAC). Observational, cross-sectional and multicentre study. Autonomous Communities in which the general practitioner can prescribe DOAC (n=9). The study included a total of 790 patients on chronic treatment with anticoagulants, and on whom therapy was changed, as well as being currently on treatment with DOAC for at least for 3 months. A record was made of the sociodemographic and clinical management date. Mean age was 78.6±8.4 years, and 50.5% of patients were men. Mean CHADS 2 score was 2.6±1.2, mean CHA 2 DS 2 -VASc score was 4.3±1.6, and the mean HAS-BLED score was 2.3±1.0. Mean duration of treatment with DOAC was 15.8±12.5 months. Rivaroxaban was the DOAC most frequently prescribed (57.8%), followed by dabigatran (23.7%), and apixaban (18.5%). Of the patients receiving rivaroxaban, 70.2% were taking the dose of 20mg/daily. Of the patients receiving dabigatran, 41.7% were taking the dose of 150mg twice daily, and in the case of apixaban, 56.2% were taking the dose of 5mg twice daily. Satisfaction (ACTS Burdens scale 52.0±7.2 and ACTS Benefits scale 12.1±2.2), and therapeutic adherence (97.8% of patients took their medication regularly) with DOAC were high. Patients treated with DOAC in Spain have a high thromboembolic risk. A significant proportion of patients receive a lower dose of DOAC than that recommended according to their clinical profile. Satisfaction and medication adherence are high. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Discrepancies between the use of MDRD-4 IDMS and CKD-EPI equations, instead of the Cockcroft-Gault equation, in the determination of the dosage of direct oral anticoagulants in patients with non-valvular atrial fibrillation.

PubMed

Pérez Cabeza, Alejandro Isidoro; Chinchurreta Capote, Pedro Antonio; González Correa, Jose Antonio; Ruiz Mateas, Francisco; Rosas Cervantes, Gabriel; Rivas Ruiz, Francisco; Valle Alberca, Almudena; Bravo Marqués, Rafael

2018-02-09

Direct oral anticoagulants (DOACs) require dose adjustment according to estimated clearance creatinine (eClCr) using the Cockcroft-Gault (CG) equation. There are discrepancies with the equations that estimate glomerular filtration rate (eGFR). We analyse how the use of the CKD-EPI and MDRD-4 IDMS equations affect the recommended dosage for ACODs. Retrospective study of patients with non-valvular atrial fibrillation seen at a cardiology clinic between November 2012 and August 2014. Patients were reclassified according to the recommended dosage for dabigatran, rivaroxaban, apixaban and edoxaban, based on the eGFR equation used. Other clinical factors are taken into account, according to the product label. We analysed the percentage of discordance. Four hundred and fifty-four patients, 53.3% men, with a mean age of 68.7±13.8 years were studied. The mean intra-individual differences recorded for the CG equation were 3.9ml/min/1.73m 2 with MDRD-4 IDMS (95% CI 1.4-6.4, P=.003) and 11.3ml/min/1.73m 2 with CKD-EPI (95% CI 8.9-13.7, P<.001). A gradient is observed in the discordance of the posology (apixaban 1.1%, dabigatran 3.5%, edoxaban 5.7%, rivaroxaban 8.4% with MDRD-4 IDMS). Differences were limited to patients with eClCr<60ml/min and were more evident in≥75 years in which the eGFR equations overestimate renal function. In patients with non-valvular atrial fibrillation, especially with renal failure and in the elderly, eGFR equations tend to overestimate renal function relative to CG and therefore suggest an overdose of DOACs. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Use of Dual Antiplatelet Therapy and Patient Outcomes in Those Undergoing Percutaneous Coronary Intervention: The ROCKET AF Trial.

PubMed

Sherwood, Matthew W; Cyr, Derek D; Jones, W Schuyler; Becker, Richard C; Berkowitz, Scott D; Washam, Jeffrey B; Breithardt, Günter; Fox, Keith A A; Halperin, Jonathan L; Hankey, Graeme J; Singer, Daniel E; Piccini, Jonathan P; Nessel, Christopher C; Mahaffey, Kenneth W; Patel, Manesh R

2016-08-22

The authors assessed the use of dual antiplatelet therapy (DAPT) and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). The frequency, patterns, and outcomes when adding DAPT to non-vitamin K antagonist oral anticoagulants in the setting of PCI in patients with AF are largely unknown. The study population included all patients in the treatment group of the ROCKET AF trial divided by the receipt of PCI during follow-up. Clinical characteristics, PCI frequency, and rates of DAPT were reported. Clinical outcomes were adjudicated independently as part of the trial. Among 14,171 patients, 153 (1.1%) underwent PCI during a median 806 days of follow-up. Patients treated with rivaroxaban were significantly less likely to undergo PCI compared with warfarin-treated patients (61 vs. 92; p = 0.01). Study drug was continued during PCI in 81% of patients. Long-term DAPT (≥30 days) was used in 37% and single antiplatelet therapy in 34%. A small number switched from DAPT to monotherapy within 30 days of PCI (n = 19 [12.3%]) and 15% of patients received no antiplatelet therapy after PCI. Rates of stroke/systemic embolism and major bleeding events were high in post-PCI patients (4.5/100 patient-years and 10.2/100 patient-years) in both treatment groups. In patients with AF at moderate to high risk for stroke, PCI occurred in <1% per year. DAPT was used in a variable manner, with the majority of patients remaining on study drug after PCI. Rates of both thrombotic and bleeding events were high after PCI, highlighting the need for studies to determine the optimal antithrombotic therapy. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Setting priorities in the health care sector - the case of oral anticoagulants in nonvalvular atrial fibrillation in Denmark.

PubMed

Poulsen, Peter Bo; Johnsen, Søren Paaske; Hansen, Morten Lock; Brandes, Axel; Husted, Steen; Harboe, Louise; Dybro, Lars

2017-01-01

Resources devoted to health care are limited, therefore setting priorities is required. It differs between countries whether decision-making concerning health care technologies focus on broad economic perspectives or whether focus is narrow on single budgets ("silo mentality"). The cost perspective as one part of the full health economic analysis is important for decision-making. With the case of oral anticoagulants in patients with nonvalvular atrial fibrillation (NVAF), the aim is to discuss the implication of the use of different cost perspectives for decision-making and priority setting. In a cost analysis, the annual average total costs of five oral anticoagulants (warfarin and non-vitamin K oral anticoagulants [NOACs; dabigatran, rivaroxaban, apixaban, and edoxaban]) used in daily clinical practice in Denmark for the prevention of stroke in NVAF patients are analyzed. This is done in pairwise comparisons between warfarin and each NOAC based on five potential cost perspectives, from a "drug cost only" perspective up to a "societal" perspective. All comparisons of warfarin and NOACs show that the cost perspective based on all relevant costs, ie, total costs perspective, is essential for the choice of therapy. Focusing on the reimbursement costs of the drugs only, warfarin is the least costly option. However, with the aim of therapy to prevent strokes and limit bleedings, including the economic impact of this, all NOACs, except rivaroxaban, result in slightly lower health care costs compared with warfarin. The same picture was found applying the societal perspective. Many broad cost-effectiveness analyses of NOACs exist. However, in countries with budget focus in decision-making this information does not apply. The present study's case of oral anticoagulants has shown that decision-making should be based on health care or societal cost perspectives for optimal use of limited resources. Otherwise, the risk is that suboptimal decisions will be likely.

Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation.

PubMed

Königsbrügge, Oliver; Weigel, Günter; Quehenberger, Peter; Pabinger, Ingrid; Ay, Cihan

2018-02-07

The effect of direct oral anticoagulants (DOACs) on turbidimetric measurements of plasma clot formation and susceptibility to fibrinolysis may facilitate a comparison between different classes of anticoagulants in plasma samples. We obtained 424 citrate plasma samples from 226 atrial fibrillation patients on anticoagulation and 24 samples without anticoagulation serving as controls. As comparators, we measured the international normalized ratio (INR) for phenprocoumon samples (N = 166), anti-Xa for low molecular weight heparin (LMWH) samples (N = 42), and DOAC levels with mass spectrometry (dabigatran N = 40, rivaroxaban N = 110, apixaban N = 42). Plasma clot formation and lysis were recorded continuously on a photometer after addition of an activation mix (tissue factor 2 pmol/l and tissue plasminogen activator 333 ng/ml). We used linear regression and ANCOVA for correlation analysis. Clot formation lag phase was prolonged in the presence of anticoagulants in a concentration-dependent manner for DOACs (dabigatran Spearman r = 0.74; rivaroxaban r = 0.78; apixaban r = 0.72, all p < 0.0001), INR dependent for phenprocoumon (r = 0.59, p < 0.0001), anti-Xa level dependent in LMWH samples (r = 0.90, p < 0.0001). Maximum rate of clot formation and peak clot turbidity were reduced in the presence of anticoagulants, but correlated only moderately with the comparator measures of anticoagulation. The clot lysis time was inversely correlated with DOAC concentrations in the presence of recombinant thrombomodulin. A direct ex vivo comparison between the effects of different classes of anticoagulants is possible with turbidimetric measurement of plasma clot formation and lysis. Anticoagulation inhibited clot formation in a plasma concentration manner for DOACs, INR dependent for phenprocoumon, and anti-Xa dependent for LMWH. Susceptibility to fibrinolysis increased with increasing DOAC concentrations.

Thrombosis prevention in lower extremity arthroplasty: mobile compression device or pharmacological therapy.

PubMed

Colwell, Clifford W

2014-11-01

Venous thromboembolic (VTE) events, either deep vein thromboses (DVT) or pulmonary emboli (PE), are important complications in patients undergoing knee or hip arthroplasty. Symptomatic VTE rates observed in total joint arthroplasty patients using the mobile compression device with home use capability were non-inferior to rates reported for pharmacological prophylaxis, including warfarin, enoxaparin, rivaroxaban, and dabigatran. Major bleeding in total hip arthroplasty was less using the mobile compression device than using low molecular weight heparin. A cost analysis demonstrated a cost savings based on decreased major bleeding. Use of a mobile compression device with or without aspirin for patients undergoing total joint arthroplasty provides a non-inferior risk for developing VTE compared with current pharmacological protocols.

Pharmacogenetics of novel oral anticoagulants: a review of identified gene variants & future perspectives.

PubMed

Ašić, Adna; Marjanović, Damir; Mirat, Jure; Primorac, Dragan

2018-05-16

Novel oral anticoagulants (NOACs) are becoming a therapy of choice in everyday clinical practice after almost 50 years during which warfarin and related coumarin derivatives were used as the main anticoagulants. Advantages of NOACs over standard anticoagulants include their predictable pharmacodynamics and pharmacokinetics, stable plasma concentrations and less drug-drug and food-drug interactions. However, pharmacogenetics has its place in administration of NOACs, as considerable interindividual variations have been detected. In this review, previous findings in pharmacogenetics of dabigatran, rivaroxaban, apixaban and edoxaban are summarized, along with recommendations for studying genes encoding metabolically important enzymes for four selected NOACs. Future directions include identification of clinically relevant SNPs, and change in optimum dosage for patients who are carriers of significant variants.

Novel oral anticoagulants for atrial fibrillation.

PubMed

How, Choon How

2015-12-01

Anticoagulation therapy is effective in preventing primary and secondary thromboembolic events due to atrial fibrillation. Warfarin, which was approved by the United States in 1954, was the only long-term oral anticoagulation therapy till the approval of dabigatran in 2010, and of rivaroxaban and other direct factor Xa inhibitors from 2011, forming a group known as novel oral anticoagulants (NOAC). NOAC have fewer food and drug interactions compared to warfarin; hence, the patient will require fewer clinic visits. However, the short half-life of NOAC means that twice-a-day dosing is needed and there is higher risk of a prothrombotic state when doses are missed. Other disadvantages are the lack of long-term data on NOAC, their high cost and the current lack of locally available antidotes.

Comparing new anticoagulants.

PubMed

Wooten, James M

2012-12-01

For years, the pharmaceutical industry has been trying to find a safe and effective drug to replace warfarin. Although warfarin is an effective anticoagulant, its pharmacology, adverse effects, and risk profiles dictate that patients taking this medication must be monitored judiciously. The US Food and Drug Administration has approved two drugs for commercial use, dabigatran and rivaroxaban, that will compete directly with warfarin for use in specific indications. Because of direct marketing to patients, physicians are being asked to comment on these new medications. This brief review illustrates the data available for the two new drugs when compared to warfarin for the specified indications. For some patients, these drugs may be highly beneficial and offer an excellent alternative to warfarin. For others, warfarin may still be the preferred drug.

Novel oral anticoagulants for atrial fibrillation

PubMed Central

How, Choon How

2015-01-01

Anticoagulation therapy is effective in preventing primary and secondary thromboembolic events due to atrial fibrillation. Warfarin, which was approved by the United States in 1954, was the only long-term oral anticoagulation therapy till the approval of dabigatran in 2010, and of rivaroxaban and other direct factor Xa inhibitors from 2011, forming a group known as novel oral anticoagulants (NOAC). NOAC have fewer food and drug interactions compared to warfarin; hence, the patient will require fewer clinic visits. However, the short half-life of NOAC means that twice-a-day dosing is needed and there is higher risk of a prothrombotic state when doses are missed. Other disadvantages are the lack of long-term data on NOAC, their high cost and the current lack of locally available antidotes. PMID:26702159

Study protocol for the dabigatran, apixaban, rivaroxaban, edoxaban, warfarin comparative effectiveness research study.

PubMed

Krumme, Alexis A; Pawar, Ajinkya; Schneeweiss, Sebastian; Glynn, Robert J; Choudhry, Niteesh K; Kulldorff, Martin; Ortiz, Adrian Santiago; Avorn, Jerome; Gagne, Joshua J

2018-01-01

Since 2010, four oral anticoagulants have been approved for marketing in addition to warfarin for treatment of thromboembolic disease. Limited head-to-head data exist comparing these treatments, leaving patients and clinicians with little guidance for selecting a strategy that balances recurrence reduction with bleeding risk. In the dabigatran, apixaban, rivaroxban, edoxaban and warfarin comparative effectiveness research study, we compare all five currently available oral anticoagulant agents for the extended treatment of deep venous thrombosis and pulmonary embolism, as well as no extended treatment, and evaluate whether results differ in specific sub-populations. As our population includes Medicare novel anticoagulant users and large numbers of commercially insured and Medicaid patients, our results will likely be transportable to the majority of US patients experiencing a DVT or pulmonary embolism. NCT03271450.

Direct oral anticoagulants: analysis of worldwide use and popularity using Google Trends

PubMed Central

Mattiuzzi, Camilla; Cervellin, Gianfranco; Favaloro, Emmanuel J.

2017-01-01

Background Four direct oral anticoagulants (DOACs) have been approved for clinical use by many medicines regulatory agencies around the world. Due to increasing use of these drugs in routine practice, we planned an original study to investigate their worldwide diffusion using a popular Web-search engine. Methods Two electronic searches were performed using Google Trends, the former using the keywords “warfarin” AND “heparin” AND “fondaparinux”, and the latter using the keywords “warfarin” AND “dabigatran” AND “rivaroxaban” AND “apixaban” AND “edoxaban”, both using the search criterion “prescription drug”. No language restriction was applied, and the searches were carried out from the first date available in Google Trends (January 1st, 2004) to present time (June 1st, 2017). Results The median Google Trends score of warfarin (i.e., 86) was consistently higher than that of heparin (54; P<0.001), fondaparinux (6; P<0.001), dabigatran (11; P<0.001), rivaroxaban (5; P<0.001), apixaban (1; P<0.001) and edoxaban (1; P<0.001). Specific analysis of the trends shows that the score of warfarin exhibits a highly significant decrease over time (r=−0.40; P<0.001), whilst that of heparin has remained virtually unchanged (r=0.12; P=0.127), and that of fondaparinux has marginally increased (r=0.16; P=0.038). As regards DOACs, the scores of these drugs significantly increased during the search period (dabigatran, r=0.79; rivaroxaban, r=0.99; apixaban, r=0.98; edoxaban, r=0.78; all P<0.001). When the analysis was limited to the past five years, the dabigatran score significantly decreased (r=−0.57; P<0.001), whereas that of the other DOACs exhibited an even sharper increase. Most Google searches for DOACs were performed in North America, central-eastern Europe and Australia. Conclusions The results of our analysis suggest that the popularity of DOACs is constantly increasing around the world, whereas that of warfarin has exhibited a constant and inexorable decline. PMID:28861419

Time trends in intracranial bleeding associated with direct oral anticoagulants: a 5-year cohort study

PubMed Central

Hogg, Kerstin; Bahl, Bharat; Latrous, Meriem; Scaffidi Argentina, Sarina; Thompson, Jesse; Chatha, Aasil Ayyaz; Castellucci, Lana; Stiell, Ian G.

2015-01-01

Background: Over the past 5 years, dabigatran, rivaroxaban and apixaban were approved for stroke prevention. Phase III studies have shown a lower risk of intracranial bleeding with these direct oral anticoagulants than with warfarin; however, there is a lack of real-life data to validate this. We analyzed time trends in atraumatic intracranial bleeding from 2009 to 2013 among patients prescribed oral anticoagulants and those not prescribed oral anticoagulants. Methods: We used ICD-10-CA (enhanced Canadian version of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems) codes to identify all patients with atraumatic intracranial bleeding who presented to our neurosurgical centre (serving a population of more than 1.2 million). Trained researchers extracted data on anticoagulant medications used in the week before diagnosis of the intracranial bleed. Provincial prescription data for oral anticoagulants were obtained from IMS Brogan CompuScript Market Dynamics. The primary outcome was the time trend in incident intracranial bleeds associated with oral anticoagulation during the period 2009-2013. The secondary outcomes were the time trend in intracranial bleeds not associated with oral anticoagulation and the provincial prescribing patterns for oral anticoagulants during the same period. Results: A total of 2050 patients presented with atraumatic intracranial bleeds during the study period. Of the 371 (18%) prescribed an anticoagulant in the week before presentation, 335 were prescribed an oral anticoagulant. There was an increasing time trend in intracranial bleeding associated with oral anticoagulants (p = 0.009; 6 additional events per year) and in intracranial bleeding not associated with oral anticoagulation (p = 0.06). During 2013, prescriptions for warfarin decreased to 70% of all oral anticoagulant prescriptions in the province, whereas those for dabigatran and rivaroxaban increased to 17% and 12%, respectively. Interpretation: We observed increasing time trends in intracranial bleeding, both associated with and not associated with oral anticoagulants, over the study period. Although aggregate provincial data showed increased prescribing of oral anticoagulants, other more likely explanations for our findings include an aging population or increasing frailty. PMID:26770966

Pharmacological thromboprophylaxis and its impact on venous thromboembolism following total knee and hip arthroplasty in Korea: A nationwide population-based study

PubMed Central

Lee, Juhyun; Lee, Ji Yun; Lee, Jeong-Ok

2017-01-01

Background Limited data is available regarding the pharmacological prophylaxis for venous thromboembolism (VTE) in Asian patients undergoing total knee arthroplasty or total hip arthroplasty (TKA/THA). Methods We performed a population-based epidemiological study using the Health Insurance Review and Assessment Service database to estimate the rate of pharmacological thromboprophylaxis and its impact on VTE in Korean patients who underwent TKA/THA between 2009 and 2013. Results We identified 306,912 cases (TKA, 261,260; THA, 45,652). The pharmacological thromboprophylaxis rate was 57.16% (TKA, 58.32%; THA, 50.51%), which increased from 42.81% in 2009 to 65.92% in 2013 (P = 0.0165). Both low-molecular-weight-heparin (22.42%) and rivaroxaban (22.71%) were the most common drugs for prophylaxis. The number of patients aged ≥ 60 years (87.31% vs. 81.01%, P < 0.0001), cases requiring general anesthesia (20.70% vs. 18.37%, P < 0.0001), and cases requiring long hospital stay (median, 13 days vs. 12 days, P < 0.0001) were significantly greater in the pharmacological prophylaxis group. The incidence of VTE within 3 months of surgery was 1.52% (TKA, 1.46%; THA, 1.87%). Patients with pharmacological prophylaxis had higher VTE rates (TKA, 1.69% vs. 1.14%; THA, 2.30% vs. 1.43%) than those without prophylaxis, with advanced age, use of general anesthesia, and a longer hospital stay increasing the risk of VTE. However, rivaroxaban significantly reduced the incidence of VTE following TKA (0.82% vs. 1.14%; odd ratio [OR], 0.72; 95% CI, 0.65–0.79). Moreover, ≥ 10 days of pharmacological thromboprophylaxis was significantly associated with lower incidence of VTE after TKA (1.33% vs. 1.52%; OR, 0.87; 95% CI, 0.81–0.94). Conclusion This represents the largest epidemiological study showing a gradual increase in the use of pharmacological prophylaxis in Korean patients undergoing TKA/THA. Although the incidence of VTE is still low without pharmacological prophylaxis, this study demonstrates that the incidence of VTE can be reduced further using appropriate pharmacological thromboprophylaxis strategies. PMID:28542415

Point-of-Care Coagulation Tests Monitoring of Direct Oral Anticoagulants and Their Reversal Therapy: State of the Art.

PubMed

Iapichino, Giacomo E; Bianchi, Paolo; Ranucci, Marco; Baryshnikova, Ekaterina

2017-06-01

Direct oral anticoagulants (DOACs) exert similar anticoagulant effects to vitamin K antagonists and are increasingly used worldwide. Nevertheless, an evidence-based approach to patients receiving DOACs when any unplanned urgent surgery or bleeding (either spontaneous or traumatic) occurs is still missing. In this review, we investigate the role of point-of-care coagulation tests when other, more specific tests are not available. Indeed, thromboelastography and activated clotting time can detect dabigatran-induced coagulopathy, while their accuracy is limited for apixaban and rivaroxaban, mostly in cases of low drug plasma concentrations. These tests can also be used to guide the reversal of DOAC-induced coagulopathy providing a quick, before-and-after picture in case of therapeutic use of hemostatic compounds. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Effects of novel oral anticoagulants on left atrial and left atrial appendage thrombi: an appraisal.

PubMed

Marsico, Fabio; Cecere, Milena; Parente, Antonio; Paolillo, Stefania; de Martino, Fabiana; Dellegrottaglie, Santo; Trimarco, Bruno; Perrone Filardi, Pasquale

2017-02-01

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and predisposes to an increased risk of thromboembolic events. Patients affected by AF exhibit an increased risk of stroke compared with those in sinus rhythm, with the most common location of thrombi in the left atrial appendage. Until 2009, warfarin and other vitamin K antagonists were the only class of oral anticoagulants available. More recently, dabigatran, rivaroxaban, apixaban, and edoxaban have been approved by regulatory authorities for prevention of stroke in patients with non-valvular AF. Few data are available about the efficacy of novel oral anticoagulants for the treatment of left atrial and left atrial appendage thrombosis. Aim of this review is to summarize available evidence regarding the effectiveness of novel oral anticoagulants on left atrial appendage thrombosis.

Advances in the management of venous thromboembolism.

PubMed

Schulman, Sam

2012-09-01

The past decade has witnessed important advances in the diagnosis and treatment of venous thromboembolism with excellent opportunities to apply evidence-based medicine for many of the steps in the management of the disease. This review discusses the clinical prediction rules that should be used to reduce utilization of imaging diagnosis for deep vein thrombosis or pulmonary embolism and the risk stratification for thrombolytic therapy or outpatient management of pulmonary embolism. The treatment options have increased and include low-molecular-weight heparin (LMWH), intravenous or subcutaneous unfractionated heparin - the latter either monitored or not monitored, fondaparinux and rivaroxaban for the initial phase. Thereafter, vitamin K antagonists (VKAs), LMWH, oral factor Xa or thrombin inhibitors are or will soon become available. The VKAs have been subjected to many randomised trial addressing the initiation, intensity, monitoring and self-management. Extended anticoagulation and the selection for that is finally reviewed. Copyright © 2012. Published by Elsevier Ltd.

Risk-adapted management of pulmonary embolism.

PubMed

Barco, Stefano; Konstantinides, Stavros V

2017-03-01

The presence and severity of right ventricular (RV) dysfunction is a key determinant of prognosis in the acute phase of pulmonary embolism (PE). Risk-adapted treatment strategies continue to evolve, tailoring initial management to the clinical presentation and the functional status of the RV. Beyond pharmacological and, if necessary, mechanical circulatory support, systemic thrombolysis remains the mainstay of treatment for hemodynamically unstable patients; in contrast, it is not routinely recommended for intermediate-risk PE. Catheter-directed pharmacomechanical reperfusion treatment represents a promising option for minimizing bleeding risk; for reduced-dose intravenous thrombolysis, the data are still preliminary. Non-vitamin K-dependent oral anticoagulants, directly inhibiting factor Xa (rivaroxaban, apixaban, edoxaban) or thrombin (dabigatran), have simplified initial and long-term anticoagulation for PE while reducing major bleeding risk. Use of vena cava filters should be restricted to selected patients with absolute contraindications to anticoagulation, or PE recurrence despite adequately dosed anticoagulants. © 2017 Elsevier Ltd. All rights reserved.

Cost-effectiveness of pharmacogenetics-guided warfarin therapy vs. alternative anticoagulation in atrial fibrillation.

PubMed

Pink, J; Pirmohamed, M; Lane, S; Hughes, D A

2014-02-01

Pharmacogenetics-guided warfarin dosing is an alternative to standard clinical algorithms and new oral anticoagulants for patients with nonvalvular atrial fibrillation. However, clinical evidence for pharmacogenetics-guided warfarin dosing is limited to intermediary outcomes, and consequently, there is a lack of information on the cost-effectiveness of anticoagulation treatment options. A clinical trial simulation of S-warfarin was used to predict times within therapeutic range for different dosing algorithms. Relative risks of clinical events, obtained from a meta-analysis of trials linking times within therapeutic range with outcomes, served as inputs to an economic analysis. Neither dabigatran nor rivaroxaban were cost-effective options. Along the cost-effectiveness frontier, in relation to clinically dosed warfarin, pharmacogenetics-guided warfarin and apixaban had incremental cost-effectiveness ratios of £13,226 and £20,671 per quality-adjusted life year gained, respectively. On the basis of our simulations, apixaban appears to be the most cost-effective treatment.

Clinical utility of apixaban in the prevention and treatment of venous thromboembolism: current evidence

PubMed Central

Zalpour, Ali; Oo, Thein Hlaing

2014-01-01

Anticoagulation with heparin and vitamin K antagonist has been the mainstay of prevention and treatment of venous thromboembolism (VTE) for many years. In recent years, novel oral anticoagulants such as dabigatran etexilate (a direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (a direct factor Xa inhibitor) have emerged for the prevention and treatment of VTE. Novel oral anticoagulants have been shown to be noninferior to vitamin K antagonist or heparin in the prevention and treatment of VTE. This review specifically examines the role of apixaban in the prevention and treatment of VTE based on the available literature. The management of apixaban in the perioperative setting is also explored because some patients on apixaban may require surgical intervention. Finally, we discuss the management of apixaban-induced major bleeding complications, the relevance of drug–drug interactions, and patient education. PMID:25395835

Prothrombin complex concentrate and fatal thrombotic adverse events: A complication to keep in mind.

PubMed

Tabet, Rabih; Shammaa, Youssef; Karam, Boutros; Yacoub, Harout; Lafferty, James

2018-05-13

Thromboembolic events such as deep vein thrombosis and pulmonary embolism are well-known complications that can occur after prothrombin complex concentrate therapy. However, acute myocardial infarction is a very rare but potentially life-threatening complication that was exclusively described in patients with bleeding disorders who received chronic and recurrent concentrate infusions. We report the case of a 70 year-old male patient with cholangiocarcinoma who was admitted to our hospital with worsening fatigue and weakness. His stay was complicated by uncontrolled bleeding secondary to rivaroxaban use and advanced liver disease. By the end of the prothrombin complex concentrate infusion used to reverse his coagulopathy, patient developed ST-segment elevation myocardial infarction with cardiogenic shock and passed away. This is the first reported case of acute myocardial infarction that occurs in a patient without hemophilia and after the first prothrombin complex concentrate infusion.

[Perioperative management of new oral anticoagulants].

PubMed

Samama, Charles-Marc; Pernod, Gilles; Albaladejo, Pierre; Sie, Pierre

2014-06-01

New oral anticoagulants do represent a major step forward as compared to low molecular weight heparins and vitamin K antagonists. Several issues deserve attention regarding their perioperative management. Three (and very soon four or five) active molecules are available on the market, adding to the major intra- and inter-individual variability, to the high number of drug-drug interactions, and to the interferences of renal function and many other parameters. New tests are available including the diluted thrombin time for dabigatran and a specific anti-Xa test for rivaroxaban and apixaban. No antidote is approved yet. Scheduled surgery: the safest suggestion is to mimic the perioperative management of vitamin K antagonist, with a 5-day interruption and low molecular weight heparin bridging whenever necessary. Emergency procedures: several suggestions issued from the Groupe d'Intérêt en Hémostase Péri-opératoire are proposed. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Cannabis arteritis: ever more important to consider.

PubMed

Santos, Rui Pedro; Resende, Cristina Isabel Pinho; Vieira, Ana Paula; Brito, Celeste

2017-03-13

Cannabis arteritis (CA) is a major and underdiagnosed cause of peripheral arterial disease in young patients. A 34-year-old man, daily smoker of 20 cigarettes and two cannabis cigarettes for 14 years, presented with a necrotic plaque of left hallux for 3 weeks. The Doppler ultrasound and angiography were compatible with severe Buerger's disease. Submitted to a revascularisation procedure and hypocoagulation with rivaroxaban. He had ceased smoking but maintained consumption of cannabis. Owing to the persistence of distal necrosis, amputation of the hallux was performed with good evolution. CA is a subtype of Buerger's disease. It is poorly known but increasingly prevalent and manifests in cannabis users regardless of tobacco use. The drug is considered at least a cofactor of the arteriopathy. The most effective treatment is cessation of consumption. Being cannabis one of the most consumed drugs, its mandatory to ask about its use in all young patients with arteriopathy. 2017 BMJ Publishing Group Ltd.

Current Status of New Anticoagulants in the Management of Venous Thromboembolism

PubMed Central

Montoya, Roberto C.; Gajra, Ajeet

2012-01-01

Venous Thromboembolism, manifested as deep venous thrombosis and pulmonary embolism, is a common problem associated with significant morbidity, mortality, and resource expenditure. Unfractionated heparin, low-molecular-weight heparin, and vitamin K antagonists are the most common treatment and prophylaxis, and have demonstrated their efficacy in a vast number of previous studies. Despite their broad use, these agents have important limitations that have led to the development of new drugs in a bid to overcome the disadvantages of the old ones without decreasing their therapeutic effect. These novel medications, some approved and others in different stages of development, include direct thrombin inhibitors like dabigatran etexilate, and direct activated factor X inhibitors like rivaroxaban. The current paper will review the characteristics, clinical trial results, and current and potential therapeutic uses of these new agents with a focus on the categories of direct thrombin inhibitors and activated factor X inhibitors. PMID:22496694

Inherited antithrombin deficiency and anabolic steroids: a risky combination.

PubMed

Choe, Hannah; Elfil, Mohamed; DeSancho, Maria T

2016-09-01

A 20-year-old male with asymptomatic inherited type 1 antithrombin deficiency and a family history of thrombosis started injecting himself with testosterone 250 mg intramuscularly twice weekly for 5 weeks. He presented to the hospital with progressive dyspnea on exertion, chest pain and hemoptysis. Workup revealed bilateral submassive pulmonary embolism and proximal right lower extremity deep vein thrombosis. He was treated with intravenous (IV) unfractionated heparin and underwent catheter-directed thrombolysis with alteplase to the main pulmonary arteries. Postprocedure, he remained on IV alteplase infusion for 24 h and unfractionated heparin in the intensive care unit. Concomitantly he received plasma-derived antithrombin concentrate. He was transitioned to subcutaneous enoxaparin twice daily and discharged from the hospital on oral rivaroxaban 15 mg twice a day. This case highlights the heightened thrombogenic effect of anabolic steroids in the setting of underlying thrombophilia especially in younger subjects.

The use of novel oral anticoagulants for thromboprophylaxis after elective major orthopedic surgery

PubMed Central

Rachidi, Saleh; Aldin, Ehab Saad; Greenberg, Charles; Sachs, Barton; Streiff, Michael; Zeidan, Amer M

2014-01-01

Venous thromboembolism is a common cause of morbidity and mortality among patients undergoing elective orthopedic surgery. Due to the high incidence of venous thromboembolism in this setting, perioperative anticoagulation is the recommended approach for thromboprophylaxis. Low molecular weight heparin (LMWH), fondaparinux and warfarin are the agents commonly used for thromboprophylaxis. The well-recognized limitations of warfarin and the inconvenience and discomfort associated with the subcutaneous administration of low molecular weight heparin and fondaparinux inspired intense investigation to develop novel oral anticoagulants (NOACs) with more predictable pharmacokinetics, fewer drug interactions and no need for regular laboratory monitoring. Three NOACs have been demonstrated to be effective for thromboprophylaxis after total hip arthroplasty (THA) and total knee arthroplasty (TKA) in large randomized controlled trials. Here we review the pharmacology of rivaroxaban, dabigatran, and apixaban, summarize the major clinical trials of these agents in thromboprophylaxis after THA and TKA, and discuss the clinical factors to be considered by providers when selecting a NOAC for their patients. PMID:24219550

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-06-01

(+)-Dapoxetine hydrochloride; Abatacept, Adalimumab, Agalsidase beta, Alemtuzumab, Alglucosidase alfa, Aliskiren fumarate, Ambrisentan, Amlodipine, Aripiprazole, Atrasentan, Azacitidine, Azelnidipine; Belotecan hydrochloride, Bevacizumab, Bilastine, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, CG-100649, Cinacalcet hydrochloride, Clindamycin phosphate/ benzoyl peroxide; Dasatinib, Denosumab, Duloxetine hydrochloride, Dutasteride, Dutasteride/tamsulosin; Ecogramostim, Eculizumab, Eltrombopag olamine, EndoTAG-1, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe; FAHF-2, Fondaparinux sodium; Gefitinib, Golimumab; HEV-239, HSV-TK; Imatinib mesylate, Indium 111 ((111)In) ibritumomab tiuxetan, Influenza vaccine(surface antigen, inactivated, prepared in cell culture), Insulin glargine; Kisspeptin-54; Lidocaine/prilocaine, Lomitapide; Maraviroc, Mirodenafil hydrochloride, MK-8141, MVA-Ag85A; Nilotinib hydrochloride monohydrate; Olmesartan medoxomil; Paclitaxel-eluting stent, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pitavastatin calcium, Prasugrel; Recombinant human relaxin H2, RHAMM R3 peptide, Rivaroxaban, Rosuvastatin calcium, RRz2; Sagopilone, Salinosporamide A, SB-509, Serlopitant, Sirolimus-eluting stent, Sorafenib, Sunitinib malate; Tadalafil, Temsirolimus, Teriparatide, TG-4010, Tositumomab/iodine (I131) tositumomab; Velusetrag Hydrochloride; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Elevated serum erythropoietin in a patient with polycythaemia vera presenting with Budd-Chiari syndrome

PubMed Central

Jones, Catherine; Levy, Yair; Tong, Alex W

2014-01-01

Polycythaemia vera (PV) is a clonal disorder of bone marrow stem cells characterised by erythrocytosis. Diagnosis of PV requires exclusion of secondary causes of polycythaemia. It has been held that an elevated erythropoietin (Epo) level strongly indicates secondary erythrocytosis and excludes PV diagnosis, to the extent that the reduced serum Epo level is currently listed as a minor criterion in the WHO classification scheme for PV. However, patients with PV who co-present with Budd-Chiari syndrome have been documented with elevated serum Epo levels. For these patients, identification of the Janus kinase 2 (JAK2) V617F point mutation along with the transient nature of the Epo elevation provides certainty of PV diagnosis, as illustrated by the proband. In this case report, the patient's positive response to cytoreductive therapy (hydroxyurea 500 mg daily) and phlebotomy (750 mL over three phlebotomies) further supports validity of PV diagnosis with elevated Epo. The patient remains on rivaroxaban (Xarelto) for treatment of her portal vein thrombosis. PMID:25452296

Oral and parenteral anticoagulants: new kids on the block.

PubMed

Aditya, S

2012-01-01

Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms "anticoagulants", "blood coagulation inhibitors", "anticoagulants and venous thromboembolism", "anticoagulants and atrial fibrillation", and "'antithrombins." Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened.

To Bleed or Not to Bleed: That is the Question. The Side Effects of Apixaban.

PubMed

Ciccone, Marco Matteo; Zito, Annapaola; Devito, Fiorella; Maiello, Maria; Palmiero, Pasquale

2018-01-01

Apixaban is a new oral anticoagulant (NOACs: Novel Oral Anticoagulant), like dabigatran, rivaroxaban, and edoxaban. All of them are prescribed to patients with non valvular atrial fibrillation or venous thromboembolism, to replace warfarin, because of the lower probability of bleeding, however they can cause bleeding by themselves. Bleeding is an adverse event in patients taking anticoagulants. It is associated with a significant increase of morbidity and risk of death. However, these drugs should be used only for the time when anticoagulation is strictly required, especially when used for preventing deep vein thrombosis. Prolonged use increases the risk of bleeding. In the ARISTOTLE Trial Apixaban, compared with warfarin, was associated with a lower rate of intracranial hemorrhages and less adverse consequences following extracranial hemorrhage. Many physicians still have limited experience with new oral anticoagulants and about bleeding risk managment. We reviewed the available literature on extracranial and intracranial bleeding concerning apixaban. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review.

PubMed

Poudel, Dilli Ram; Ghimire, Sushil; Dhital, Rashmi; Forman, Daniel A; Warkentin, Theodore E

2017-09-01

Recently published reports have established a heparin-induced thrombocytopenia (HIT)-mimicking thromboembolic disorder without proximate heparin exposure, called spontaneous HIT syndrome. Although the pathophysiology remains unclear, anti-platelet factor 4 (PF4)/heparin antibodies possibly triggered by exposure to knee cartilage glycosaminoglycans or other non-heparin polyanions found on bacterial surfaces and nucleic acids have been postulated. We present a 53-year-old female receiving antithrombotic prophylaxis with aspirin following right total knee replacement surgery (without perioperative or any previous lifetime heparin exposure) who acutely presented with high-risk pulmonary embolism (PE) and right great saphenous vein thrombophlebitis on postoperative day (POD) 14; her platelet count at presentation was 13 × 10 9 /L. Prior to diagnostic consideration of spontaneous HIT syndrome, the patient briefly received unfractionated heparin (UFH) and one dose of enoxaparin. The patient's serum tested strongly positive for anti-PF4/heparin antibodies by two different PF4-dependent enzyme-linked immunosorbent assays (ELISAs) and by serotonin release assay (SRA). Failure of fondaparinux anticoagulation (persisting HIT-associated disseminated intravascular coagulation) prompted switching to argatroban. Severe thrombocytopenia persisted (platelet count nadir, 12 × 10 9 /L, on POD21), and 9 days after starting argatroban symptomatic right leg deep-vein thrombosis (DVT) occurred, prompting switch to rivaroxaban. Thereafter, her course was uneventful, although platelet count recovery was prolonged, reaching 99 × 10 9 /L by POD45 and 199 × 10 9 /L by POD79. The patient's serum elicited strong serotonin release in the absence of heparin (seen even with 1/32 serum dilution) that was enhanced by pharmacological concentrations of UFH (0.1 and 0.3 IU/mL) and fondaparinux (0.1-1.2 μg/mL, i.e., in vitro fondaparinux "cross-reactivity"). Ultimately, platelet count recovery was associated with seroreversion to a negative SRA (documented at POD151). Our literature review identified joint replacement surgery, specifically knee replacement, to be a relatively common trigger of spontaneous HIT syndrome. Further, including our patient case, 5 of 7 patients with spontaneous HIT syndrome post-orthopedic surgery who received treatment with argatroban developed new and/or progressive lower-limb DVT or recurrent PE despite anticoagulation with this parenteral direct thrombin inhibitor, suggesting that this patient population is at high risk of breakthrough thrombotic events despite treatment with this HIT treatment-approved anticoagulant. Our case also illustrates successful outcome with rivaroxaban for treatment of spontaneous HIT syndrome, consistent with emerging literature supporting safety and efficacy of direct oral anticoagulant therapy for treatment of acute HIT.

Secondary prevention of recurrent venous thromboembolism after initial oral anticoagulation therapy in patients with unprovoked venous thromboembolism.

PubMed

Robertson, Lindsay; Yeoh, Su Ern; Ramli, Ahmad

2017-12-15

Currently, little evidence is available on the length and type of anticoagulation used for extended treatment for prevention of recurrent venous thromboembolism (VTE) in patients with unprovoked VTE who have completed initial oral anticoagulation therapy. To compare the efficacy and safety of available oral therapeutic options (aspirin, warfarin, direct oral anticoagulants (DOACs)) for extended thromboprophylaxis in adults with a first unprovoked VTE, to prevent VTE recurrence after completion of an acceptable initial oral anticoagulant treatment period, as defined in individual studies. For this review, the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (March 2017) as well as the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2). We also searched trials registries (March 2017) and reference lists of relevant articles. We included randomised controlled trials in which patients with a first, symptomatic, objectively confirmed, unprovoked VTE, who had been initially treated with anticoagulants, were randomised to extended prophylaxis (vitamin K antagonists (VKAs), antiplatelet agents, or DOACs) versus no prophylaxis or placebo. We also included trials that compared one type of extended prophylaxis versus another type of extended prophylaxis. Two review authors independently selected studies, assessed quality, and extracted data. We resolved disagreements by discussion. Six studies with a combined total of 3436 participants met the inclusion criteria. Five studies compared extended prophylaxis versus placebo: three compared warfarin versus placebo, and two compared aspirin versus placebo. One study compared one type of extended prophylaxis (rivaroxaban) versus another type of extended prophylaxis (aspirin). For extended prophylaxis versus placebo, we downgraded the quality of the evidence for recurrent VTE and all-cause mortality to moderate owing to concerns arising from risks of selection and performance bias in individual studies. For all other outcomes in this review, we downgraded the quality of the evidence to low owing to concerns arising from risk of bias for the studies stated above, combined with concerns over imprecision. For extended prophylaxis versus other extended prophylaxis, we downgraded the quality of the evidence for recurrent VTE and major bleeding to moderate owing to concerns over imprecision. Risk of bias in the individual study was low.Meta-analysis showed that extended prophylaxis was no more effective than placebo in preventing VTE-related mortality (odds ratio (OR) 0.98, 95% confidence interval (CI) 0.14 to 6.98; 1862 participants; 4 studies; P = 0.98; low-quality evidence), recurrent VTE (OR 0.63, 95% CI 0.38 to 1.03; 2043 participants; 5 studies; P = 0.07; moderate-quality evidence), major bleeding (OR 1.84, 95% CI 0.87 to 3.85; 2043 participants; 5 studies; P = 0.86; low-quality evidence), all-cause mortality (OR 1.00, 95% CI 0.63 to 1.57; 2043 participants; 5 studies; P = 0.99; moderate-quality evidence), clinically relevant non-major bleeding (OR 1.78, 95% CI 0.59 to 5.33; 1672 participants; 4 studies; P = 0.30; low-quality evidence), stroke (OR 1.15, 95% CI 0.39 to 3.46; 1224 participants; 2 studies; P = 0.80; low-quality evidence), or myocardial infarction (OR 1.00, 95% CI 0.35 to 2.87; 1495 participants; 3 studies; P = 1.00; low-quality evidence).One study showed that the novel oral anticoagulant rivaroxaban was associated with fewer recurrent VTEs than aspirin (OR 0.28, 95% CI 0.15 to 0.54; 1389 participants; P = 0.0001; moderate-quality evidence). Data show no clear differences in the incidence of major bleeding between rivaroxaban and aspirin (OR 3.06, 95% CI 0.37 to 25.51; 1389 participants; P = 0.30; moderate-quality evidence) nor in the incidence of clinically relevant non-major bleeding (OR 0.84, 95% CI 0.37 to 1.94; 1389 participants; 1 study; P = 0.69; moderate-quality evidence). Data on VTE-related mortality, all-cause mortality, stroke, and myocardial infarction were not yet available for participants with unprovoked VTE and will be incorporated in future versions of the review. Evidence is currently insufficient to permit definitive conclusions concerning the effectiveness and safety of extended thromboprophylaxis in prevention of recurrent VTE after initial oral anticoagulation therapy among participants with unprovoked VTE. Additional good-quality large-scale randomised controlled trials are required before firm conclusions can be reached.

International Council for Standardization in Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral Anticoagulants.

PubMed

Gosselin, Robert C; Adcock, Dorothy M; Bates, Shannon M; Douxfils, Jonathan; Favaloro, Emmanuel J; Gouin-Thibault, Isabelle; Guillermo, Cecilia; Kawai, Yohko; Lindhoff-Last, Edelgard; Kitchen, Steve

2018-03-01

This guidance document was prepared on behalf of the International Council for Standardization in Haematology (ICSH) for providing haemostasis-related guidance documents for clinical laboratories. This inaugural coagulation ICSH document was developed by an ad hoc committee, comprised of international clinical and laboratory direct acting oral anticoagulant (DOAC) experts. The committee developed consensus recommendations for laboratory measurement of DOACs (dabigatran, rivaroxaban, apixaban and edoxaban), which would be germane for laboratories assessing DOAC anticoagulation. This guidance document addresses all phases of laboratory DOAC measurements, including pre-analytical (e.g. preferred time sample collection, preferred sample type, sample stability), analytical (gold standard method, screening and quantifying methods) and post analytical (e.g. reporting units, quality assurance). The committee addressed the use and limitations of screening tests such as prothrombin time, activated partial thromboplastin time as well as viscoelastic measurements of clotting blood and point of care methods. Additionally, the committee provided recommendations for the proper validation or verification of performance of laboratory assays prior to implementation for clinical use, and external quality assurance to provide continuous assessment of testing and reporting method. Schattauer GmbH Stuttgart.

Apixaban for the treatment of cerebral venous thrombosis: A case series.

PubMed

Rao, Shishir Keekana; Ibrahim, Mohammad; Hanni, Claudia M; Suchdev, Kushak; Parker, Dennis; Rajamani, Kumar; Mohamed, Wazim

2017-10-15

Venous thrombosis affecting cerebral veins and sinuses (CVT) is an uncommon neurological condition. Traditionally patients are treated with intravenous heparin followed by an oral vitamin K antagonist like warfarin. Direct oral anticoagulants (DOACs) may offer advantages over warfarin. There is evidence to demonstrate the effectiveness of both dabigatran and rivaroxaban. No data, however, has been published describing the use of apixaban in patients with CVT. Report of three cases of CVT and review literature on available treatment options; efficacy and safety of novel oral anticoagulants in patients with systemic thrombosis. All patients presented with typical features of CVT. After confirming the diagnosis, they were acutely treated with heparin and later discharged on apixaban. During follow up visits, they tolerated apixaban well and did not have any bleeding complications. Follow up scans showed resolution of the thrombus and recanalization. CVT is an uncommon neurological condition and is often complicated by associated intraparenchymal hemorrhage. Although not recommended in current guidelines, apixaban may be a safe and effective option for the treatment of CVT. Copyright © 2017 Elsevier B.V. All rights reserved.

Controversies regarding the new oral anticoagulants for stroke prevention in patients with atrial fibrillation.

PubMed

Mohanty, Bibhu D; Looser, Patrick M; Gokanapudy, Lakshmi R; Handa, Rishi; Mohanty, Sudipta; Choi, Sharon S; Goldman, Martin E; Fuster, Valentin; Halperin, Jonathan L

2014-06-01

Increasing use of the new oral anticoagulants (NOACs) - dabigatran, rivaroxaban, and apixaban - has prompted considerable discussion in the medical community even as warfarin remains the mainstay of therapy. This article raises 10 controversial issues regarding the use of NOACs for stroke prevention in patients with atrial fibrillation, and offers a review of the latest available evidence. We provide a brief overview of the mechanism and dosing of these drugs, as well as a summary of the key clinical trials that have brought them into the spotlight. Comparative considerations relative to warfarin such as NOAC safety, efficacy, bleeding risk, reversibility, drug-transitioning and use in patients well controlled on warfarin are addressed. Use in select populations such as the elderly, those with coronary disease, renal impairment, or on multiple anti-platelet drugs is also discussed. Finally, we consider such specific issues as comparative efficacy, off-label use, cost, rebound and management during events. Ultimately, the rise of the NOACs to mainstream use will depend on further data and clinical experience amongst the medical community. © The Author(s) 2014.

[Treatment with inhibitors of new oral direct anticoagulants in patients with severe bleedings or urgent surgical procedures. The new dabigatran antidote: the place of idarucizumab in clinical practice].

PubMed

Boda, Zoltán

2016-03-20

Only vitamin K antagonists could be applied as oral anticoagulants over the past six decades. Coumarols have narrow therapeutic range, and unpredictable anticoagulant effects are resulted by multiple drug interactions. Therefore, regular routine monitoring of the international normalized ratio is necessary. There are two groups of factor-specific anticoagulants: molecules with anti-FIIa (dabigatran) and anti-FXa (rivaroxaban, apixaban and edoxaban) effect. Author summarizes the most important clinical features of the new oral anticoagulants, their indications and the possibilities of laboratory controls. Bleedings are the most important side effects of anticoagulants. This review summarizes the current published evidences for new oral anticoagulants reversal (non-specific and specific) agents, especially in cases with severe acute bleedings or urgent surgery procedures. It reports on how to use inhibitors, the recommended doses and the most important clinical results. The review focuses on idarucizumab - already approved by the U.S. Food and Drug Administration and the European Medicines Agency - which has a key role as the first specific inhibitor of dabigatran.

Novel oral anticoagulants for stroke prevention in patients with atrial fibrillation: dawn of a new era.

PubMed

Contractor, Tahmeed; Levin, Vadim; Martinez, Matthew W; Marchlinski, Francis E

2013-01-01

Atrial fibrillation (AF) is an important cause of ischemic stroke and is the underlying cause of > 20% of all strokes, with increasing age being a risk factor. Until recently, warfarin was the only available oral anticoagulant used to decrease this risk in patients with AF. However, there are several disadvantages of warfarin use, such as the requirement for monitoring the international normalized ratio, its wide range of drug-food interactions, and its narrow therapeutic index. Thus, there has been a strong impetus for the development of newer oral anticoagulants with predictable pharmacokinetics that obviate the need for monitoring the international normalized ratio. The US Food and Drug Administration has approved a direct thrombin inhibitor (dabigatran) and 2 factor Xa inhibitors (rivaroxaban and apixaban) for stroke prevention in patients with nonvalvular AF. There are several other new oral anticoagulant agents on the horizon, including the factor Xa inhibitor edoxaban. This review article discusses the pharmacological properties, clinical trial data, and practical issues associated with the use of these novel oral anticoagulants.

Novel anticoagulants for stroke prevention in patients with atrial fibrillation.

PubMed

Jalota, A; Scarabelli, T M; Saravolatz, L; Bakhsh, M U; Agrawal, P; Jalota, R; Chen-Scarabelli, C; Fuster, V; Halperin, J

2014-06-01

Atrial fibrillation (AF) is the most common cardiac arrhythmia that can potentially result in stroke. Vitamin K antagonists (VKA) like warfarin were for many decades the only oral anticoagulants available for stroke prevention in patients with non-valvular atrial fibrillation (AF) at high risk of stroke. Recently, new oral anticoagulants (NOACS) have been introduced that act via direct inhibition of thrombin (dabigatran) or activated factor X (edoxaban, rivaroxaban and apixaban). Unlike VKAs, these anticoagulants do not require routine INR monitoring and posses favorable pharmacological properties. NOACs act rapidly, and have a stable and predictable dose-related anticoagulant effect with few clinically relevant drug-drug interactions. Phase III trials comparing these agents to warfarin for stroke prevention in patients with non-valvular AF demonstrated that they are at least as efficacious and safe as warfarin. Evolution of clinical guidelines to incorporate the new anticoagulants for stroke prevention in non-valvular AF may result in a reduction in the incidence of AF-related strokes. Safe and effective use of these new drugs in clinical practice requires understanding of their distinct pharmacological properties.

Cardiovascular risk factors among college students: Knowledge, perception, and risk assessment.

PubMed

Tran, Dieu-My T; Zimmerman, Lani M; Kupzyk, Kevin A; Shurmur, Scott W; Pullen, Carol H; Yates, Bernice C

2017-04-01

To assess college students' knowledge and perception of cardiovascular risk factors and to screen for their cardiovascular risks. The final sample that responded to recruitment consisted of 158 college students from a midwestern university. A cross-sectional, descriptive study was performed using convenience sampling. College students were knowledgeable about cardiovascular risk factors but did not perceive themselves at risk for cardiovascular disease (CVD). Knowledge of cardiovascular risk factors was correlated with the lifetime risk estimates (ρ = .17, p = .048), and perception of cardiovascular risk was positively associated with 30-year CVD risk estimates (ρ = .16, p = .048). More than 50% of the participants had 1 or more cardiovascular risk factors. High knowledge level of cardiovascular risk factors was not sufficient to lower cardiovascular risks within this study population, but changing perception of cardiovascular risk factors may play a bigger role in reducing long-term cardiovascular risks.

Cardiovascular Diseases in HIV-infected Subjects (HIV-HEART Study)

ClinicalTrials.gov

2010-05-07

Detection of Frequency, Severity and Progression of Cardiovascular Diseases in Patients With HIV-infection.; Effect on Cardiovascular Risk and Life Quality by Age, Gender, Classic Cardiovascular Risk Factors,; HIV-specific Cardiovascular Risk Factors, Cardiovascular Medication, Antiretroviral Medication

21 CFR 870.4500 - Cardiovascular surgical instruments.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiovascular surgical instruments. 870.4500... (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Surgical Devices § 870.4500 Cardiovascular surgical instruments. (a) Identification. Cardiovascular surgical instruments are surgical instruments that...

21 CFR 870.4500 - Cardiovascular surgical instruments.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiovascular surgical instruments. 870.4500... (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Surgical Devices § 870.4500 Cardiovascular surgical instruments. (a) Identification. Cardiovascular surgical instruments are surgical instruments that...

21 CFR 870.2100 - Cardiovascular blood flowmeter.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiovascular blood flowmeter. 870.2100 Section... (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Monitoring Devices § 870.2100 Cardiovascular blood flowmeter. (a) Identification. A cardiovascular blood flowmeter is a device that is...

Editor's Choice - Acute Cardiovascular Care Association Position Paper on Intensive Cardiovascular Care Units: An update on their definition, structure, organisation and function.

PubMed

Bonnefoy-Cudraz, Eric; Bueno, Hector; Casella, Gianni; De Maria, Elia; Fitzsimons, Donna; Halvorsen, Sigrun; Hassager, Christian; Iakobishvili, Zaza; Magdy, Ahmed; Marandi, Toomas; Mimoso, Jorge; Parkhomenko, Alexander; Price, Susana; Rokyta, Richard; Roubille, Francois; Serpytis, Pranas; Shimony, Avi; Stepinska, Janina; Tint, Diana; Trendafilova, Elina; Tubaro, Marco; Vrints, Christiaan; Walker, David; Zahger, Doron; Zima, Endre; Zukermann, Robert; Lettino, Maddalena

2018-02-01

Acute cardiovascular care has progressed considerably since the last position paper was published 10 years ago. It is now a well-defined, complex field with demanding multidisciplinary teamworking. The Acute Cardiovascular Care Association has provided this update of the 2005 position paper on acute cardiovascular care organisation, using a multinational working group. The patient population has changed, and intensive cardiovascular care units now manage a large range of conditions from those simply requiring specialised monitoring, to critical cardiovascular diseases with associated multi-organ failure. To describe better intensive cardiovascular care units case mix, acuity of care has been divided into three levels, and then defining intensive cardiovascular care unit functional organisation. For each level of intensive cardiovascular care unit, this document presents the aims of the units, the recommended management structure, the optimal number of staff, the need for specially trained cardiologists and cardiovascular nurses, the desired equipment and architecture, and the interaction with other departments in the hospital and other intensive cardiovascular care units in the region/area. This update emphasises cardiologist training, referring to the recently updated Acute Cardiovascular Care Association core curriculum on acute cardiovascular care. The training of nurses in acute cardiovascular care is additionally addressed. Intensive cardiovascular care unit expertise is not limited to within the unit's geographical boundaries, extending to different specialties and subspecialties of cardiology and other specialties in order to optimally manage the wide scope of acute cardiovascular conditions in frequently highly complex patients. This position paper therefore addresses the need for the inclusion of acute cardiac care and intensive cardiovascular care units within a hospital network, linking university medical centres, large community hospitals, and smaller hospitals with more limited capabilities.

Diabetes Drugs and Cardiovascular Safety

PubMed Central

2016-01-01

Diabetes is a well-known risk factor of cardiovascular morbidity and mortality, and the beneficial effect of improved glycemic control on cardiovascular complications has been well established. However, the rosiglitazone experience aroused awareness of potential cardiovascular risk associated with diabetes drugs and prompted the U.S. Food and Drug Administration to issue new guidelines about cardiovascular risk. Through postmarketing cardiovascular safety trials, some drugs demonstrated cardiovascular benefits, while some antidiabetic drugs raised concern about a possible increased cardiovascular risk associated with drug use. With the development of new classes of drugs, treatment options became wider and the complexity of glycemic management in type 2 diabetes has increased. When choosing the appropriate treatment strategy for patients with type 2 diabetes at high cardiovascular risk, not only the glucose-lowering effects, but also overall benefits and risks for cardiovascular disease should be taken into consideration. PMID:27302713

Understanding cardiovascular risk in hemophilia: A step towards prevention and management.

PubMed

Sousos, Nikolaos; Gavriilaki, Eleni; Vakalopoulou, Sofia; Garipidou, Vasileia

2016-04-01

Advances in hemophilia care have led to increased life expectancy and new challenges in the management of the aging hemophilia population, including cardiovascular risk. Despite the deep knowledge into cardiovascular disease in terms of pathophysiology, risk prediction, prevention, early detection and management gained over the last decades, studies in hemophiliacs are scarce and mainly descriptive. As a growing amount of evidence points towards a similar or increased prevalence of traditional cardiovascular risk factors in hemophilia compared to the general population, the role of non-traditional, disease-related and treatment-related cardiovascular risk factors remains under investigation. Better understanding of cardiovascular risk in hemophilia is mandatory for proper cardiovascular risk prevention and management. Therefore, this review aims to summarize current knowledge on cardiovascular risk in hemophilia patients focusing on a) cardiovascular risk factors (traditional, non-traditional, disease-related and treatment-related), b) cardiovascular morbidity and mortality and c) cardiovascular prevention and management. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Cardiovascular Effects of Antidiabetic Therapies].

PubMed

Laubner, Katharina; Seufert, Jochen

2017-05-01

Type 2- diabetes mellitus (T2DM) represents a major risk factor for cardiovascular complications and mortality. Strict glucose control in the early course of the disease prevents cardiovascular complications only in the long run. Non-medical therapies (diet, exercise, body weight reduction) bear little evidence for positive cardiovascular effects.Bariatric surgery is not number one choice in therapy of T2DM. Metformin seems to provide positive cardiovascular effects. Insulin seems to be cardiovascular neutral, as well as the DPP4-inhibitors Saxagliptin, Sitagliptin and Alogliptin. Concerning GLP-1-RAs, Lixisenatide has a neutral cardiovascular effect, whereas Liraglutide and Semaglutide reduce cardiovascular outcomes. The SGLT2-inhibitor Empagliflozin reduces cardiovascular mortality, total mortality and hospitalization by heart failure. © Georg Thieme Verlag KG Stuttgart · New York.

Physiological Changes to the Cardiovascular System at High Altitude and Its Effects on Cardiovascular Disease.

PubMed

Riley, Callum James; Gavin, Matthew

2017-06-01

Riley, Callum James, and Matthew Gavin. Physiological changes to the cardiovascular system at high altitude and its effects on cardiovascular disease. High Alt Med Biol. 18:102-113, 2017.-The physiological changes to the cardiovascular system in response to the high altitude environment are well understood. More recently, we have begun to understand how these changes may affect and cause detriment to cardiovascular disease. In addition to this, the increasing availability of altitude simulation has dramatically improved our understanding of the physiology of high altitude. This has allowed further study on the effect of altitude in those with cardiovascular disease in a safe and controlled environment as well as in healthy individuals. Using a thorough PubMed search, this review aims to integrate recent advances in cardiovascular physiology at altitude with previous understanding, as well as its potential implications on cardiovascular disease. Altogether, it was found that the changes at altitude to cardiovascular physiology are profound enough to have a noteworthy effect on many forms of cardiovascular disease. While often asymptomatic, there is some risk in high altitude exposure for individuals with certain cardiovascular diseases. Although controlled research in patients with cardiovascular disease was largely lacking, meaning firm conclusions cannot be drawn, these risks should be a consideration to both the individual and their physician.

HIV and Cardiovascular Disease

MedlinePlus

... Select a Language: Fact Sheet 652 HIV and Cardiovascular Disease HIV AND CARDIOVASCULAR DISEASE WHY SHOULD PEOPLE WITH HIV CARE ABOUT CVD? ... OF CVD? WHAT ABOUT CHANGING MEDICATIONS? HIV AND CARDIOVASCULAR DISEASE Cardiovascular disease (CVD) includes a group of problems ...

Ideal cardiovascular health in young adult populations from the United States, Finland, and Australia and its association with cIMT: The International Childhood Cardiovascular Cohort Consortium

USDA-ARS?s Scientific Manuscript database

The goals for cardiovascular disease prevention were set by the American Heart Association in 2010 for the concept of cardiovascular health. Ideal cardiovascular health is defined by senen cardiovascular health metrics: blood pressure, glucose, cholesterol, body mass index, and physical activity on ...

The Applicability of Nonlinear Systems Dynamics Chaos Measures to Cardiovascular Physiology Variables

NASA Technical Reports Server (NTRS)

Hooker, John C.

1991-01-01

Three measures of nonlinear chaos (fractal dimension, Approximate Entropy (ApEn), and Lyapunov exponents) were studied as potential measures of cardiovascular condition. It is suggested that these measures have potential in the assessment of cardiovascular condition in environments of normal cardiovascular stress (normal gravity on the Earth surface), cardiovascular deconditioning (microgravity of space), and increased cardiovascular stress (lower body negative pressure (LBNP) treatments).

Depression, anxiety, and the cardiovascular system: the psychiatrist's perspective.

PubMed

Roose, S P

2001-01-01

It is becoming clear that the comorbidity of depression and cardiovascular disease does not occur by chance but rather is an inevitable consequence of the relationship between the conditions. Depression in patients with cardiovascular disease is a significant risk factor for developing symptomatic and fatal ischemic heart disease. Moreover, depressed patients have a higher than expected rate of sudden cardiovascular death. Therefore, appropriate treatment of patients with depression and cardiovascular disease cannot be restricted to considerations of either depression or cardiovascular disease in isolation. The tricyclic antidepressants (TCAs) have various effects on the cardiovascular system, including Type IA antiarrhythmic activity that has been associated with an increased risk of mortality in post-myocardial infarction patients. The selective serotonin reuptake inhibitors (SSRIs) are not associated with adverse cardiac effects. The SSRI paroxetine was compared with a therapeutic level of the TCA nortriptyline in a randomized, controlled study and demonstrated a benign cardiovascular profile, while the TCA induced a significantly higher rate of serious adverse cardiovascular events. On the basis of this favorable cardiovascular profile, the SSRIs should therefore be the preferred choice for the treatment of most patients with comorbid depression and cardiovascular disease. Investigation of putative pathophysiologic mechanisms linking depression and cardiovascular mortality, such as the role of platelet activation, will form the basis for further investigation of antidepressant treatments in order to establish if the antidepressants have a beneficial effect on the prognosis of cardiovascular diseases.

Ideal cardiovascular health influences cardiovascular disease risk associated with high lipoprotein(a) levels and genotype: The EPIC-Norfolk prospective population study.

PubMed

Perrot, Nicolas; Verbeek, Rutger; Sandhu, Manjinder; Boekholdt, S Matthijs; Hovingh, G Kees; Wareham, Nicholas J; Khaw, Kay-Tee; Arsenault, Benoit J

2017-01-01

Lipoprotein(a) (Lp[a]) is a strong genetic risk factor for cardiovascular disease (CVD). The American Heart Association has prioritised seven cardiovascular health metrics to reduce the burden of CVD: body mass index, healthy diet, physical activity, smoking status, blood pressure, diabetes and cholesterol levels (together also known as ideal cardiovascular health). Our objective was to determine if individuals with high Lp(a) levels could derive cardiovascular benefits if characterized by ideal cardiovascular health. A total of 14,051 participants of the EPIC-Norfolk study were stratified according to the cardiovascular health score (based on the number of health metrics with an ideal, intermediate or poor status). Of them, 1732 had a CVD event during a mean follow-up of 11.5 years. Cox proportional hazards models were used to describe the association between the cardiovascular health score and Lp(a) level or genotype (as estimated by the rs10455872 variant) with the risk of CVD. We observed little or no differences in serum Lp(a) levels across the seven cardiovascular health metric categories. Among participants with high serum Lp(a) levels ≥50 mg/dl), those in the highest (i.e. healthiest) cardiovascular health score category (10-14) had an adjusted hazard ratio for cardiovascular disease of 0.33 (95% CI = 0.17-0.63, p = 0.001) compared to participants in the lowest (i.e. unhealthiest) cardiovascular health score category(0-4). Similar results were obtained when we replaced Lp(a) with rs10455872. Although Lp(a) levels are only slightly influenced by cardiovascular health metrics, an ideal cardiovascular health could substantially reduce CVD risk associated with high Lp(a) levels or genotype. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Supply and Demand of the Cardiovascular Workforce

PubMed Central

Narang, Akhil; Sinha, Shashank S.; Rajagopalan, Bharath; Ijioma, Nkechinyere N.; Jayaram, Natalie; Kithcart, Aaron P.; Tanguturi, Varsha K.; Cullen, Michael W.

2017-01-01

As the burden of cardiovascular disease in the United States continues to increase, uncertainty remains on how well-equipped the cardiovascular workforce is to meet the challenges that lie ahead. In a time when health care is rapidly shifting, numerous factors affect the supply and demand of the cardiovascular workforce. This Council Commentary critically examines several factors that influence the cardiovascular workforce. These include current workforce demographics and projections, evolving health care and practice environments, and the increasing burden of cardiovascular disease. Finally, we propose 3 strategies to optimize the workforce. These focus on cardiovascular disease prevention, the effective utilization of the cardiovascular care team, and alterations to the training pathway for cardiologists. PMID:27712782

The cardiovascular macrophage: a missing link between gut microbiota and cardiovascular diseases?

PubMed

Chen, X; Zheng, L; Zheng, Y-Q; Yang, Q-G; Lin, Y; Ni, F-H; Li, Z-H

2018-03-01

The prevalence of cardiovascular diseases is on the rise. Interventions that would aid prevention or treatment of these diseases are essential. The microbes residing in the gut, collectively called "gut microbiota", produce a plethora of compounds that enter the bloodstream and affect the cardiovascular system. Signals ascending from gut microbiome are believed to modulate differentiation and functional activity of macrophages residing in perivascular tissue, atherosclerotic plaques, and perivascular areas of the brain. Cardiovascular macrophages may be the key players that transform the signals ascending from gut microbiome into increased predisposition to cardiovascular diseases. The present review summarizes the knowledge to date on potential relationships between gut microbiota, cardiovascular macrophages, and cardiovascular diseases.

Cardiovascular Health Promotion in Children: Challenges and Opportunities for 2020 and Beyond: A Scientific Statement From the American Heart Association.

PubMed

Steinberger, Julia; Daniels, Stephen R; Hagberg, Nancy; Isasi, Carmen R; Kelly, Aaron S; Lloyd-Jones, Donald; Pate, Russell R; Pratt, Charlotte; Shay, Christina M; Towbin, Jeffrey A; Urbina, Elaine; Van Horn, Linda V; Zachariah, Justin P

2016-09-20

This document provides a pediatric-focused companion to "Defining and Setting National Goals for Cardiovascular Health Promotion and Disease Reduction: The American Heart Association's Strategic Impact Goal Through 2020 and Beyond," focused on cardiovascular health promotion and disease reduction in adults and children. The principles detailed in the document reflect the American Heart Association's new dynamic and proactive goal to promote cardiovascular health throughout the life course. The primary focus is on adult cardiovascular health and disease prevention, but critical to achievement of this goal is maintenance of ideal cardiovascular health from birth through childhood to young adulthood and beyond. Emphasis is placed on the fundamental principles and metrics that define cardiovascular health in children for the clinical or research setting, and a balanced and critical appraisal of the strengths and weaknesses of the cardiovascular health construct in children and adolescents is provided. Specifically, this document discusses 2 important factors: the promotion of ideal cardiovascular health in all children and the improvement of cardiovascular health metric scores in children currently classified as having poor or intermediate cardiovascular health. Other topics include the current status of cardiovascular health in US children, opportunities for the refinement of health metrics, improvement of health metric scores, and possibilities for promoting ideal cardiovascular health. Importantly, concerns about the suitability of using single thresholds to identify elevated cardiovascular risk throughout the childhood years and the limits of our current knowledge are noted, and suggestions for future directions and research are provided. © 2016 American Heart Association, Inc.

21 CFR 870.3375 - Cardiovascular intravascular filter.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiovascular intravascular filter. 870.3375... Cardiovascular intravascular filter. (a) Identification. A cardiovascular intravascular filter is an implant that... and Revision of 2/12/90 (K90-1)” and (ii) “Guidance for Cardiovascular Intravascular Filter 510(k...

21 CFR 870.3375 - Cardiovascular intravascular filter.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiovascular intravascular filter. 870.3375... Cardiovascular intravascular filter. (a) Identification. A cardiovascular intravascular filter is an implant that... and Revision of 2/12/90 (K90-1)” and (ii) “Guidance for Cardiovascular Intravascular Filter 510(k...

21 CFR 870.3375 - Cardiovascular intravascular filter.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiovascular intravascular filter. 870.3375... Cardiovascular intravascular filter. (a) Identification. A cardiovascular intravascular filter is an implant that... and Revision of 2/12/90 (K90-1)” and (ii) “Guidance for Cardiovascular Intravascular Filter 510(k...

21 CFR 870.3375 - Cardiovascular intravascular filter.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiovascular intravascular filter. 870.3375... Cardiovascular intravascular filter. (a) Identification. A cardiovascular intravascular filter is an implant that... and Revision of 2/12/90 (K90-1)” and (ii) “Guidance for Cardiovascular Intravascular Filter 510(k...

21 CFR 870.3375 - Cardiovascular intravascular filter.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiovascular intravascular filter. 870.3375... Cardiovascular intravascular filter. (a) Identification. A cardiovascular intravascular filter is an implant that... and Revision of 2/12/90 (K90-1)” and (ii) “Guidance for Cardiovascular Intravascular Filter 510(k...

75 FR 47819 - Workshop on Optimizing Clinical Trial Design for the Development of Pediatric Cardiovascular Devices

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-09

...] Workshop on Optimizing Clinical Trial Design for the Development of Pediatric Cardiovascular Devices AGENCY... (AAP), the American College of Cardiology (ACC), and the Society for Cardiovascular Angiography and... Development of Pediatric Cardiovascular Devices.'' The topic to be discussed is pediatric cardiovascular...

76 FR 47143 - Approval for Manufacturing Authority, Foreign-Trade Zone 153; Abbott Cardiovascular Systems, Inc...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-04

... Authority, Foreign-Trade Zone 153; Abbott Cardiovascular Systems, Inc., (Cardiovascular Devices), Riverside... of Abbott Cardiovascular Systems, Inc., within Sites 11-13 of FTZ 153, located in Riverside County... behalf of Abbott Cardiovascular Systems, Inc., as described in the application and Federal Register...

Matters of the heart: cardiovascular disease in U.S. women.

PubMed

Bybee, Kevin A; Stevens, Tracy L

2013-01-01

Cardiovascular disease is the leading cause of death in United States women and accounts for approximately 500,000 deaths annually. Over half of cardiovascular disease-related deaths in women result from coronary artery disease including acute coronary syndromes. This paper reviews gender specific issues in women as they relate to current cardiovascular disease epidemiology, trends in cardiovascular disease epidemiology, coronary artery disease detection, risk factor modification, and prevention of cardiovascular disease-related events.

Obesity and Cardiovascular Disease: a Risk Factor or a Risk Marker?

PubMed

Mandviwala, Taher; Khalid, Umair; Deswal, Anita

2016-05-01

In the USA, 69 % of adults are either overweight or obese and 35 % are obese. Obesity is associated with an increased incidence of various cardiovascular disorders. Obesity is a risk marker for cardiovascular disease, in that it is associated with a much higher prevalence of comorbidities such as diabetes, hypertension, and metabolic syndrome, which then increase the risk for cardiovascular disease. However, in addition, obesity may also be an independent risk factor for the development of cardiovascular disease. Furthermore, although obesity has been shown to be an independent risk factor for several cardiovascular diseases, it is often associated with improved survival once the diagnosis of the cardiovascular disease has been made, leading to the term "obesity paradox." Several pathways linking obesity and cardiovascular disease have been described. In this review, we attempt to summarize the complex relationship between obesity and cardiovascular disorders, in particular coronary atherosclerosis, heart failure, and atrial fibrillation.

Insulin and Its Cardiovascular Effects: What Is the Current Evidence?

PubMed

Dongerkery, Sahana Pai; Schroeder, Pamela R; Shomali, Mansur E

2017-10-23

In this article, we examine the nature of the complex relationship between insulin and cardiovascular disease. With metabolic abnormalities comes increased risk for cardiovascular complications. We discuss the key factors implicated in development and progression of cardiovascular disease, its relationship to insulin therapy, and what can be learned from large, recent cardiovascular outcome studies. Preclinical studies suggest that insulin has positive effects of facilitating glucose entry into cells and maintaining euglycemia and negative effects of favoring obesity and atherogenesis under certain conditions. Confounding this relationship is that cardiovascular morbidity is linked closely to duration and control of diabetes, and insulin is often used in patients with diabetes of longer duration. However, more recent clinical studies examining the cardiovascular safety of insulin therapy have been reassuring. Diabetes and cardiovascular outcomes are closely linked. Many studies have implicated insulin resistance and hyperinsulinemia as a major factor for poor cardiovascular outcomes. Additional studies link the anabolic effects of therapeutic insulin to weight gain, along with hypoglycemia, which may further aggravate cardiovascular risk in this population. Though good glycemic control has been shown to improve microvascular risks in type 1 and type 2 diabetes, what are the known cardiovascular effects of insulin therapy? The ORIGIN trial suggests at least a neutral effect of the basal insulin glargine on cardiovascular outcomes. Recent studies have demonstrated that ultra-long-acting insulin analogs like insulin degludec are non-inferior to insulin glargine with regard to cardiovascular outcomes.

Psoriasis as a cardiovascular risk factor: updates and algorithmic approach.

PubMed

Cozzani, Emanuele; Rosa, Gianmarco; Burlando, Martina; Parodi, Aurora

2018-04-19

Although psoriasis is predominantly a chronic inflammatory skin disorder, it has been known to be associated with cardiovascular disease. Patients with psoriasis, particularly with moderate to severe forms, present an increased rate of cardiovascular mortality, myocardial infarction and stroke. However the pathophysiology of the relationship between psoriasis and cardiovascular risk and comorbidities has not yet completely known. Chronic inflammation may be considered a solid link between psoriasis and related cardiovascular events. Several cytokines and inflammatory cells play a pivotal role in the development of psoriatic lesions, resulting in angiogenesis and endothelial dysfunction. Furthermore, the imbalance between oxidative stress and anti-oxidant mechanisms in psoriatic patients may contribute to explain the pathogenesis of increased reactive oxygen species and the formation of atherosclerotic plaque. Other mechanistic pathways which may be involved in this relationship include cardiovascular effects of medications, a common genetic background and a higher prevalence of cardiovascular risk factors, which are often under-diagnosed and under-treated in psoriatic patients. Indeed, the early detection of specific markers of cardiovascular impairment, such as N-terminal pro B-type natriuretic peptide, homocysteine and YKL-40, may enable psoriatic patients at higher cardiovascular risk to be identified as soon as possible. This review examines the increased cardiovascular risk profile and high prevalence of cardiovascular disease associated with psoriasis, focusing on pathogenic links between psoriasis and atherosclerosis, serological markers of cardiovascular involvement and the implications of anti-psoriatic therapies on cardiovascular risk and proposes a flow chart, that every dermatologist should follow to screen psoriatic patients.

Leisure-Time Physical Activity, but not Commuting Physical Activity, is Associated with Cardiovascular Risk among ELSA-Brasil Participants.

PubMed

Pitanga, Francisco José Gondim; Matos, Sheila M A; Almeida, Maria da Conceição; Barreto, Sandhi Maria; Aquino, Estela M L

2018-01-01

Despite reports in the literature that both leisure-time physical activity (LTPA) and commuting physical activity (CPA) can promote health benefits, the literature lacks studies comparing the associations of these domains of physical activity with cardiovascular risk scores. To investigate the association between LTPA and CPA with different cardiovascular risk scores in the cohort of the Longitudinal Study of Adult Health ELSA-Brasil. Cross-sectional study with data from 13,721 participants of both genders, aged 35-74 years, free of cardiovascular disease, from ELSA Brazil. Physical activity was measured using the International Physical Activity Questionnaire (IPAQ). Five cardiovascular risk scores were used: Framingham score - coronary heart disease (cholesterol); Framingham score - coronary heart disease (LDL-C); Framingham score - cardiovascular disease (cholesterol); Framingham score - cardiovascular disease (body mass index, BMI); and pooled cohort equations for atherosclerotic cardiovascular disease (ASCVD). Associations adjusted for confounding variables between physical activity and different cardiovascular risk scores were analyzed by logistic regression. Confidence interval of 95% (95%CI) was considered. LTPA is inversely associated with almost all cardiovascular risk scores analyzed, while CPA shows no statistically significant association with any of them. Dose-response effect in association between LTPA and cardiovascular risk scores was also found, especially in men. LTPA was shown to be associated with the cardiovascular risk scores analyzed, but CPA not. The amount of physical activity (duration and intensity) was more significantly associated, especially in men, with cardiovascular risk scores in ELSA-Brasil.

Psoriasis and cardiovascular risk. Assessment by different cardiovascular risk scores.

PubMed

Fernández-Torres, R; Pita-Fernández, S; Fonseca, E

2013-12-01

Psoriasis is an inflammatory disease associated with an increased risk of cardiovascular morbidity and mortality. However, very few studies determine cardiovascular risk by means of Framingham risk score or other indices more appropriate for countries with lower prevalence of cardiovascular risk factors. To determine multiple cardiovascular risk scores in psoriasis patients, the relation between cardiovascular risk and psoriasis features and to compare our results with those in the literature. We assessed demographic data, smoking status, psoriasis features, blood pressure and analytical data. Cardiovascular risk was determined by means of Framingham, SCORE, DORICA and REGICOR scores. A total of 395 patients (59.7% men and 40.3% women) aged 18-86 years were included. The proportion of patients at intermediate and high risk of suffering a major cardiovascular event in the next 10 years was 30.5% and 11.4%, respectively, based on Framingham risk score; 26.9% and 2.2% according to DORICA and 6.8% and 0% using REGICOR score. According to the SCORE index, 22.1% of patients had a high risk of death due to a cardiovascular event over the next 10 years. Cardiovascular risk was not related to psoriasis characteristics, except for the Framingham index, with higher risk in patients with more severe psoriasis (P = 0.032). A considerable proportion of patients had intermediate or high cardiovascular risk, without relevant relationship with psoriasis characteristics and treatment schedules. Therefore, systematic evaluation of cardiovascular risk scores in all psoriasis patients could be useful to identify those with increased cardiovascular risk, subsidiary of lifestyle changes or therapeutic interventions. © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.

The year 2012 in the European Heart Journal-Cardiovascular Imaging: Part I.

PubMed

Edvardsen, Thor; Plein, Sven; Saraste, Antti; Knuuti, Juhani; Maurer, Gerald; Lancellotti, Patrizio

2013-06-01

The new multi-modality cardiovascular imaging journal, European Heart Journal - Cardiovascular Imaging, was started in 2012. During its first year, the new Journal has published an impressive collection of cardiovascular studies utilizing all cardiovascular imaging modalities. We will summarize the most important studies from its first year in two articles. The present 'Part I' of the review will focus on studies in myocardial function, myocardial ischaemia, and emerging techniques in cardiovascular imaging.

FGF-23 and cardiovascular disease: review of literature.

PubMed

Batra, Jasveen; Buttar, Rupinder Singh; Kaur, Pardeep; Kreimerman, Jacqueline; Melamed, Michal L

2016-12-01

This review examines associations between fibroblast growth factor 23 (FGF-23) and cardiovascular disease. FGF-23 is a hormone produced by osteocytes and osteoblasts that aids with phosphate excretion by the kidney and acts as a negative feedback regulator for activated vitamin D synthesis. Recent studies have found associations between elevated FGF-23 levels and a number of cardiovascular diseases, including hypertension, left ventricular hypertrophy, endothelial dysfunction, cardiovascular events and mortality. Recent studies have explored the possible effects of FGF-23 on the cardiovascular system. In animal and observational human studies, there is a link between elevated FGF-23 levels and multiple cardiovascular outcomes, including hypertension, left ventricular hypertrophy and cardiovascular events and mortality. Further studies are required to evaluate whether decreasing FGF-23 levels improves cardiovascular outcomes.

New horizons in anticoagulation: Direct oral anticoagulants and their implications in oral surgery

PubMed Central

Ripollés-de Ramón, Jorge; Collado-Yurrita, Luis; Vaello-Checa, Iris; Colmenero-Ruiz, Constantino; Helm, Alexandra; Ciudad-Cabañas, Maria-José; Serrano-Cuenca, Victoriano

2017-01-01

Background Thrombotic disorders remain a leading cause of death in the Western World. For decades, vitamin K antagonists used in the prevention of this pathology, such as warfarin or sintrom, were the only oral agents available for long-term anticoagulation, in spite of their disadvantages. Material and Methods An electronic database search was carried out on MedLine and The Cochrane Library Plus, without restrictions on the type of study nor dates, in English and Spanish. Abstracts were reviewed, and complete articles if necessary, considering all articles that included recommendations on DOACs and oral surgery. Results In recent years, the so-called “new oral anticoagulants” have been introduced in clinical practice to treat those patients whose medical conditions require long-term anticoagulant treatment, replacing traditional oral anticoagulants. Conclusions The new oral anticoagulants represent new therapeutic options, with a number of advantages such as poor interaction with food, minor drug interactions, and do not require periodic dose adjustments or routine controls. The purpose of this review is to establish an update on the new oral anticoagulants: Dabigatran, Rivarozaban, Apixaban and Edoxaban. Key words:Novel oral anticoagulants, Dabigatran, Rivaroxaban, Apixaban, Edoxaban, bleeding management, oral surgery, Anti-IIa, Anti Xa. PMID:28809374

Hospital length of stay in patients initiated on direct oral anticoagulants versus warfarin for venous thromboembolism: a real-world single-center study.

PubMed

Badreldin, Hisham

2018-07-01

This study was conducted to describe the real-world hospital length of stay in patients treated with all of the U.S. Food and Drug Administration approved direct oral anticoagulants (DOACs) versus warfarin for new-onset venous thromboembolism (VTE) at a large, tertiary, academic medical center. A retrospective cohort analysis of all adult patients diagnosed with acute onset VTE was conducted. Of the 441 patients included, 261 (57%) patients received DOACs versus 180 (41%) patients received warfarin. In the DOAC group, a total of 92 (35%) patients received rivaroxaban, followed by 83 (32%) patients received apixaban, 50 (19%) patients received dabigatran, and 36 (14%) patients received edoxaban. Patients initiated on DOACs had a statistically significant shorter hospital length of stay compared to patients initiated on warfarin (median 3 days, [IQR 0-5] vs. 8 days [IQR 5-11], P < 0.05). Despite the shorter hospital length of stay in patients receiving DOACs, the overall reported differences between the DOACs group and the warfarin group in terms of recurrent VTE, major bleeding, intracranial bleeding, and gastrointestinal bleeding at 3 and 6 months were deemed to be statistically insignificant.

[Concepts in anticoagulant therapy - past, present, and future].

PubMed

Graf, L

2012-11-01

The understanding of the clotting system emerged in parallel to the development of anticoagulants. In contrast to vitamin K-antagonists and heparins that where discovered by chance, new anticoagulants have been systematically designed to specifically inhibit single clotting factors. Both clotting factors Xa (FXa) and thrombin play a crucial role within the new cell-based model of hemostasis. Thus it is obvious that FXa and thrombin turned out to be ideal targets for anticoagulation. The proof of the concept of selective inhibition of thrombin and FXa has been provided by hirudin and fondaparinux, respectively. By now, a whole group of new oral anticoagulants has been licensed: the direct FXa-inhibitors rivaroxaban, apixaban, and edoxaban as well as the direct thrombin dabigatran etexilate. Furthermore, a bundle of FXa- and thrombin-inhibitors that differ from the so far licensed products mainly in pharmacokinetics are in an advanced phase of development. A further innovative concept of anticoagulation that entered its clinical phase of development is the inhibition of factor VIII. Other new concepts such as inhibition of initiation of coagulation by blocking factor VIIa, inhibition of contact factor XII, or inhibition of factor IX are in an early phase of development.

Risk of gastrointestinal bleeding during anticoagulant treatment.

PubMed

Lanas-Gimeno, Aitor; Lanas, Angel

2017-06-01

Gastrointestinal bleeding (GIB) is a major problem in patients on oral anticoagulation therapy. This issue has become even more pressing since the introduction of direct oral anticoagulants (DOACs) in 2009. Areas covered: Here we review current evidence related to GIB associated with oral anticoagulants, focusing on randomized controlled trials, meta-analyses, and post-marketing observational studies. Dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily increase the risk of GIB compared to warfarin. The risk increase with edoxaban is dose-dependent, while apixaban shows apparently, no increased risk. We summarize what is known about GIB risk factors for individual anticoagulants, the location of GIB in patients taking these compounds, and prevention strategies that lower the risk of GIB. Expert opinion: Recently there has been an important shift in the clinical presentation of GIB. Specifically, upper GIB has decreased with the decreased incidence of peptic ulcers due to the broad use of proton pump inhibitors and the decreased prevalence of H. pylori infections. In contrast, the incidence of lower GIB has increased, due in part to colonic diverticular bleeding and angiodysplasia in the elderly. In this population, the addition of oral anticoagulation therapy, especially DOACs, seems to increase the risk of lower GIB.

Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation.

PubMed

Bruins Slot, Karsten Mh; Berge, Eivind

2018-03-06

Factor Xa inhibitors and vitamin K antagonists (VKAs) are now recommended in treatment guidelines for preventing stroke and systemic embolic events in people with atrial fibrillation (AF). This is an update of a Cochrane review previously published in 2013. To assess the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for preventing cerebral or systemic embolic events in people with AF. We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (August 2017), MEDLINE (1950 to April 2017), and Embase (1980 to April 2017). We also contacted pharmaceutical companies, authors and sponsors of relevant published trials. We used outcome data from marketing authorisation applications of apixaban, edoxaban and rivaroxaban that were submitted to regulatory authorities in Europe and the USA. We included randomised controlled trials (RCTs) that directly compared the effects of long-term treatment (lasting more than four weeks) with factor Xa inhibitors versus VKAs for preventing cerebral and systemic embolism in people with AF. The primary efficacy outcome was the composite endpoint of all strokes and systemic embolic events. Two review authors independently extracted data, and assessed the quality of the trials and the risk of bias. We calculated a weighted estimate of the typical treatment effect across trials using the odds ratio (OR) with 95% confidence interval (CI) by means of a fixed-effect model. In case of moderate or high heterogeneity of treatment effects, we used a random-effects model to compare the overall treatment effects. We also performed a pre-specified sensitivity analysis excluding any open-label studies. We included data from 67,688 participants randomised into 13 RCTs. The included trials directly compared dose-adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux, idrabiotaparinux, or rivaroxaban. The majority of the included data (approximately 90%) was from apixaban, edoxaban, and rivaroxaban.The composite primary efficacy endpoint of all strokes (both ischaemic and haemorrhagic) and non-central nervous systemic embolic events was reported in all of the included studies. Treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose-adjusted warfarin in participants with AF (OR 0.89, 95% CI 0.82 to 0.97; 13 studies; 67,477 participants; high-quality evidence).Treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.78, 95% CI 0.73 to 0.84; 13 studies; 67,396 participants; moderate-quality evidence). There was, however, statistically significant and high heterogeneity (I 2 = 83%). When we repeated this analysis using a random-effects model, it did not show a statistically significant decrease in the number of major bleedings (OR 0.88, 95% CI 0.66 to 1.17). A pre-specified sensitivity analysis excluding all open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.75, 95% CI 0.69 to 0.81), but high heterogeneity was also observed in this analysis (I 2 = 72%). The same sensitivity analysis using a random-effects model also showed a statistically significant decrease in the number of major bleedings in participants treated with factor Xa inhibitors (OR 0.76, 95% CI 0.60 to 0.96).Treatment with a factor Xa inhibitor significantly reduced the risk of intracranial haemorrhages (ICHs) compared with warfarin (OR 0.50, 95% CI 0.42 to 0.59; 12 studies; 66,259 participants; high-quality evidence). We observed moderate, but statistically significant heterogeneity (I 2 = 55%). The pre-specified sensitivity analysis excluding open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.47, 95% CI 0.40 to 0.56), with low, non-statistically significant heterogeneity (I 2 = 27%).Treatment with a factor Xa inhibitor also significantly reduced the number of all-cause deaths compared with warfarin (OR 0.89, 95% 0.83 to 0.95; 10 studies; 65,624 participants; moderate-quality evidence). Treatment with factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin in people with AF. The absolute effect of factor Xa inhibitors compared with warfarin treatment was, however, rather small. Factor Xa inhibitors also reduced the number of ICHs, all-cause deaths and major bleedings compared with warfarin, although the evidence for a reduction in the latter is less robust.

Cardiovascular health promotion for elementary school children. The Heart Smart Program.

PubMed

Berenson, G S; Arbeit, M L; Hunter, S M; Johnson, C C; Nicklas, T A

1991-01-01

Models of health promotion directed to cardiovascular disease prevention are becoming increasingly important, based on the wealth of behavioral and physiologic data that examine the determinants, distributions, and interrelationships and trends over time of cardiovascular risk factors in children. The epidemiologic studies of children of cardiovascular risk factors and of life-styles provide the foundation to address intervention strategies beginning at the school age. Cardiovascular health promotion programs in elementary schools have tremendous potential for the prevention of adult cardiovascular diseases in our nation.

Applications of 3D printing in cardiovascular diseases.

PubMed

Giannopoulos, Andreas A; Mitsouras, Dimitris; Yoo, Shi-Joon; Liu, Peter P; Chatzizisis, Yiannis S; Rybicki, Frank J

2016-12-01

3D-printed models fabricated from CT, MRI, or echocardiography data provide the advantage of haptic feedback, direct manipulation, and enhanced understanding of cardiovascular anatomy and underlying pathologies. Reported applications of cardiovascular 3D printing span from diagnostic assistance and optimization of management algorithms in complex cardiovascular diseases, to planning and simulating surgical and interventional procedures. The technology has been used in practically the entire range of structural, valvular, and congenital heart diseases, and the added-value of 3D printing is established. Patient-specific implants and custom-made devices can be designed, produced, and tested, thus opening new horizons in personalized patient care and cardiovascular research. Physicians and trainees can better elucidate anatomical abnormalities with the use of 3D-printed models, and communication with patients is markedly improved. Cardiovascular 3D bioprinting and molecular 3D printing, although currently not translated into clinical practice, hold revolutionary potential. 3D printing is expected to have a broad influence in cardiovascular care, and will prove pivotal for the future generation of cardiovascular imagers and care providers. In this Review, we summarize the cardiovascular 3D printing workflow, from image acquisition to the generation of a hand-held model, and discuss the cardiovascular applications and the current status and future perspectives of cardiovascular 3D printing.

Cardiovascular safety of biologic therapies for the treatment of RA.

PubMed

Greenberg, Jeffrey D; Furer, Victoria; Farkouh, Michael E

2011-11-15

Cardiovascular disease represents a major source of extra-articular comorbidity in patients with rheumatoid arthritis (RA). A combination of traditional cardiovascular risk factors and RA-related factors accounts for the excess risk in RA. Among RA-related factors, chronic systemic inflammation has been implicated in the pathogenesis and progression of atherosclerosis. A growing body of evidence--mainly derived from observational databases and registries--suggests that specific RA therapies, including methotrexate and anti-TNF biologic agents, can reduce the risk of future cardiovascular events in patients with RA. The cardiovascular profile of other biologic therapies for the treatment of RA has not been adequately studied, including of investigational drugs that improve systemic inflammation but alter traditional cardiovascular risk factors. In the absence of large clinical trials adequately powered to detect differences in cardiovascular events between biologic drugs in RA, deriving firm conclusions on cardiovascular safety is challenging. Nevertheless, observational research using large registries has emerged as a promising approach to study the cardiovascular risk of emerging RA biologic therapies.

Brachial-Ankle PWV: Current Status and Future Directions as a Useful Marker in the Management of Cardiovascular Disease and/or Cardiovascular Risk Factors.

PubMed

Tomiyama, Hirofumi; Matsumoto, Chisa; Shiina, Kazuki; Yamashina, Akira

2016-01-01

Since 2001, brachial-ankle pulse wave velocity (brachial-ankle PWV) measurement has been applied for risk stratification of patients with atherosclerotic cardiovascular disease and/or its risk factors in Japan. Measurement of the brachial-ankle PWV is simple and well standardized, and its reproducibility and accuracy are acceptable. Several cross-sectional studies have demonstrated a significant correlation between the brachial-ankle PWV and known risk factors for cardiovascular disease; the correlation is stronger in subjects with cardiovascular disease than in those without cardiovascular disease. We conducted a meta-analysis, which demonstrated that the brachial-ankle PWV is an independent predictor of future cardiovascular events. Furthermore, the treatment of cardiovascular risk factors and lifestyle modifications have been shown to improve the brachial-ankle PWV. Thus, at present, brachial-ankle PWV is close to being considered as a useful marker in the management of atherosclerotic cardiovascular disease and/or its risk factors.

[TECOS: confirmation of the cardiovascular safety of sitaliptin].

PubMed

Scheen, A J; Paquot, N

2015-10-01

The cardiovascular safety of sitagliptin has been evaluated in TECOS ("Trial Evaluating Cardiovascular Outcomes with Sitagliptin"). TECOS recruited patients with type 2 diabetes and a history of cardiovascular disease who received, as add-on to their usual therapy, either sitagliptin (n = 7.257) or placebo (n = 7.266), with a median follow-up of 3 years. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% confidence interval, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). The cardiovascular safety of sitagliptin, which was already shown in meta-analyses of phase II-III randomised controlled trials and in observational cohort studies in real life, is now confirmed in the landmark prospective cardiovascular outcome study TECOS.

Status of cardiovascular health among adults in a rural area of Northwest China

PubMed Central

Zhao, Yaling; Yan, Hong; Yang, Ruihai; Li, Qiang; Dang, Shaonong; Liu, Ruru; Pei, Leilei; Cao, Lei; Marshall, Roger J.; Wang, Duolao

2016-01-01

Abstract The aim of this study was to assess the status of cardiovascular health among a rural population in Northwest China and to determine the associated factors for cardiovascular health. A population-based cross-sectional study was conducted in the rural areas of Hanzhong in Northwest China. Interview, physical examination, and fasting blood glucose and lipid measurements were completed for 2693 adults. The construct of cardiovascular health and the definitions of cardiovascular health metrics proposed by the American Heart Association were used to assess cardiovascular health. The proportions of subjects with cardiovascular health metrics were calculated, adjusting for age and sex. The multiple logistic regression model was used to evaluate the association between ideal cardiovascular health and its associated factors. Only 0.5% (0.0% in men vs 0.9% in women, P = 0.002) of the participants had ideal cardiovascular health, whereas 33.8% (18.0% in men vs 50.0% in women, P < 0.001) and 65.7% (82.0% in men vs 49.1% in women, P < 0.001) of the participants had intermediate and poor cardiovascular health, respectively. The prevalence of poor cardiovascular health increased with increasing age (P < 0.001 for trend). Participants fulfilled, on average, 4.4 (95% confidence interval: 4.2–4.7) of the ideal cardiovascular health metrics. Also, 22.2% of the participants presented with 3 or fewer ideal metrics. Only 19.4% of the participants presented with 6 or more ideal metrics. 24.1% of the participants had all 4 ideal health factors, but only 1.1% of the participants had all 4 ideal health behaviors. Women were more likely to have ideal cardiovascular health, whereas adults aged 35 years or over and those who had a family history of hypertension were less likely to have ideal cardiovascular health. The prevalence of ideal cardiovascular health was extremely low among the rural population in Northwest China. Most adults, especially men and the elderly, had a poor cardiovascular health status. To improve cardiovascular health among the rural population, efforts, especially lifestyle improvements, education and interventions to make healthier food choices, reduce salt intake, increase physical activities, and cease smoking, will be required at the individual, population, and social levels. PMID:27428234

Risk Factors and Causes of Syncope

MedlinePlus

... Risk Factors & Causes of Syncope Risk Factors for Cardiovascular Syncope The risk of cardiovascular syncope increases with ... Long QT syndrome and Brugada Syndrome Signs of Cardiovascular Syncope Cardiovascular syncope usually is sudden. There may ...

The Various Applications of 3D Printing in Cardiovascular Diseases.

PubMed

El Sabbagh, Abdallah; Eleid, Mackram F; Al-Hijji, Mohammed; Anavekar, Nandan S; Holmes, David R; Nkomo, Vuyisile T; Oderich, Gustavo S; Cassivi, Stephen D; Said, Sameh M; Rihal, Charanjit S; Matsumoto, Jane M; Foley, Thomas A

2018-05-10

To highlight the various applications of 3D printing in cardiovascular disease and discuss its limitations and future direction. Use of handheld 3D printed models of cardiovascular structures has emerged as a facile modality in procedural and surgical planning as well as education and communication. Three-dimensional (3D) printing is a novel imaging modality which involves creating patient-specific models of cardiovascular structures. As percutaneous and surgical therapies evolve, spatial recognition of complex cardiovascular anatomic relationships by cardiologists and cardiovascular surgeons is imperative. Handheld 3D printed models of cardiovascular structures provide a facile and intuitive road map for procedural and surgical planning, complementing conventional imaging modalities. Moreover, 3D printed models are efficacious educational and communication tools. This review highlights the various applications of 3D printing in cardiovascular diseases and discusses its limitations and future directions.

Thyroid and the Heart

PubMed Central

Grais, Ira Martin; Sowers, James R.

2015-01-01

Thyroid hormones modulate every component of the cardiovascular system necessary for normal cardiovascular development and function. When cardiovascular disease is present, thyroid function tests are characteristically indicated to determine if overt thyroid disorders or even subclinical dysfunction exists. As hypothyroidism, hypertension and cardiovascular disease all increase with advancing age monitoring of TSH, the most sensitive test for hypothyroidism, is important in this expanding segment of our population. A better understanding of the impact of thyroid hormonal status on cardiovascular physiology will enable health care providers to make decisions regarding thyroid hormone evaluation and therapy in concert with evaluating and treating hypertension and cardiovascular disease. The goal of this review is to access contemporary understanding of the effects of thyroid hormones on normal cardiovascular function and the potential role of overt and subclinical hypothyroidism and hyperthyroidism in a variety of cardiovascular diseases. PMID:24662620

[Subclinical hypothyroidism and cardiovascular risk].

PubMed

López Rubio, María Antonia; Tárraga López, Pedro Juan; Rodríguez Montes, José Antonio; Frías López, María del Carmen; Solera Albero, Juan; Bermejo López, Pablo

2015-05-01

To assess whether subclinical hypothyroidism can behave as a cardiovascular risk factor or a modifier thereof, identifying epidemiological variables and estimated in a sample of patients diagnosed in the province of Albacete (Spain) cardiovascular risk. Observational, descriptive study was carried out in Albacete during the first half of January 2012 in patients of both genders with subclinical hypothyroidism. The following variables were analyzed: Fasting glucose , total cholesterol , HDL cholesterol, LDL cholesterol , triglycerides , TSH , T4 , weight, height, Body Mass Index , blood pressure, a history of cardiovascular disease , cardiovascular risk factors and estimated cardiovascular risk. 326 patients younger than 65 years at 78% without cardiovascular risk factors in 48.61 %, with female predominance (79.2 %). The prevalence of cardiovascular risk factors was identified: smoking (33.2 %), diabetes mellitus (24.9%), hypertension (23.4 %), lipid abnormalities (28.9%) and atrial fibrillation (4,9%). No association between subclinical hypothyroidism and most lipid profile parameters that determine a pro- atherogenic profile, except with hypertriglyceridemia was found. Likewise, neither association with increased cardiovascular risk was found. The profile of patients with subclinical hypothyroidism is a middle-aged woman with no cardiovascular risk factors in half of cases. It has been found relationship between subclinical hypothyroidism and hypertriglyceridemia, but not with the other parameters of lipid profile, other cardiovascular risk factors or with increased risk. However, 25% of diabetics and 22% of non-diabetics are at moderate to high cardiovascular risk. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

A Systematic Review of Cardiovascular Disease in Sexual Minorities

PubMed Central

Brody, Abraham; Luscombe, Rachel E.; Primiano, Jillian E.; Marusca, Peter; Sitts, Edward M.; Chyun, Deborah

2017-01-01

Background: Mental health and HIV disparities are well documented among sexual minorities, but there is a dearth of research on other chronic conditions. Cardiovascular disease remains the leading cause of death worldwide. Although sexual minorities have high rates of several modifiable risk factors for cardiovascular disease (including stress, tobacco use, and alcohol consumption), there is a paucity of research in this area. Objectives: In this systematic review, we synthesized and critiqued the existing evidence on cardiovascular disease among sexual minority adults. Search Methods: We conducted a thorough literature search of 6 electronic databases for studies published between January 1985 and December 2015 that compared cardiovascular disease risk or prevalence between sexual minority and heterosexual adults. Selection Criteria: We included peer-reviewed English-language studies that compared cardiovascular disease risk or diagnoses between sexual minority and heterosexual individuals older than 18 years. We excluded reviews, case studies, and gray literature. A total of 31 studies met inclusion criteria. Data Collection and Analysis: At least 2 authors independently abstracted data from each study. We performed quality assessment of retrieved studies using the Crowe Critical Appraisal Tool. Main Results: Sexual minority women exhibited greater cardiovascular disease risk related to tobacco use, alcohol consumption, illicit drug use, poor mental health, and body mass index, whereas sexual minority men experienced excess risk related to tobacco use, illicit drug use, and poor mental health. We identified several limitations in the extant literature. The majority of included studies were cross-sectional analyses that used self-reported measures of cardiovascular disease. Even though we observed elevated cardiovascular disease risk, we found few differences in cardiovascular disease diagnoses (including hypertension, diabetes, and high cholesterol). Overall, 23 of the 26 studies that examined cardiovascular disease diagnoses used subjective measures. Only 7 studies used a combination of biomarkers and self-report measures to establish cardiovascular disease risk and diagnoses. Authors’ Conclusions: Social conditions appear to exert a negative effect on cardiovascular disease risk among sexual minorities. Although we found few differences in cardiovascular disease diagnoses, we identified an elevated risk for cardiovascular disease in both sexual minority men and women. There is a need for research that incorporates subjective and objective measures of cardiovascular disease risk. Public Health Implications: Cardiovascular disease is a major health concern for clinicians, public health practitioners, and policymakers. This systematic review supports the need for culturally appropriate interventions that address cardiovascular disease risk in sexual minority adults. PMID:28207331

Cardiovascular effects of anti-diabetes drugs

PubMed Central

Younk, Lisa M.; Lamos, Elizabeth M.

2016-01-01

Introduction Cardiovascular disease remains the major contributor to morbidity and mortality in diabetes. From the need to reduce cardiovascular risk in diabetes and to ensure that such risk is not exacerbated by drug treatments, governmental regulators and drug manufacturers have focused on clinical trials evaluating cardiovascular outcomes. Areas covered Findings from mechanistic and clinical trials of biguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose transporter 2 (SGLT-2) inhibitors will be reviewed. These drug classes will be compared within the context of available cardiovascular outcomes data. Clinical implications of new study regulations will be examined. Expert opinion Recent cardiovascular studies provide a more comprehensive evaluation of specific anti-diabetes therapy in individuals with high cardiovascular risk. Long-term effects of anti-hyperglycemic agents in patients with lower cardiovascular risk are still speculative. Historical data supports continued use of metformin as a first-line agent. DPP-4 inhibitors and GLP-1 receptor agonists appear to have neutral effects on cardiovascular outcomes. The significantly decreased cardiovascular risk associated with empagliflozin SGLT-2 inhibitor therapy is impressive and may change how practitioners prescribe add-on therapy to metformin. PMID:27268470

“How many times must a man look up before he can really see the sky?” Rheumatic cardiovascular disease in the era of multimodality imaging

PubMed Central

Mavrogeni, Sophie I; Markousis-Mavrogenis, George; Heutemann, David; van Wijk, Kees; Reiber, Hans J; Kolovou, Genovefa

2015-01-01

Cardiovascular involvement in rheumatic diseases (RD) is the result of various pathophysiologic mechanisms including inflammation, accelerated atherosclerosis, myocardial ischemia, due to micro- or macro-vascular lesions and fibrosis. Noninvasive cardiovascular imaging, including echocardiography, nuclear techniques, cardiovascular computed tomography and cardiovascular magnetic resonance, represents the main diagnostic tool for early, non-invasive diagnosis of heart disease in RD. However, in the era of multimodality imaging and financial crisis there is an imperative need for rational use of imaging techniques in order to obtain the maximum benefit at the lowest possible cost for the health insurance system. The oligo-asymptomatic cardiovascular presentation and the high cardiovascular mortality of RD necessitate a reliable and reproducible diagnostic approach to catch early cardiovascular involvement. Echocardiography remains the routine cornerstone of cardiovascular evaluation. However, a normal echocardiogram can not always exclude cardiac involvement and/or identify heart disease acuity and pathophysiology. Therefore, cardiovascular magnetic resonance is a necessary adjunct complementary to echocardiography, especially in new onset heart failure and when there are conflicting data from clinical, electrocardiographic and echocardiographic evaluation of RD patients. PMID:26413486

Long-term insulin glargine therapy in type 2 diabetes mellitus: a focus on cardiovascular outcomes

PubMed Central

Joseph, Joshua J; Donner, Thomas W

2015-01-01

Cardiovascular disease is the leading cause of mortality in type 2 diabetes mellitus. Hyperinsulinemia is associated with increased cardiovascular risk, but the effects of exogenous insulin on cardiovascular disease progression have been less well studied. Insulin has been shown to have both cardioprotective and atherosclerosis-promoting effects in laboratory animal studies. Long-term clinical trials using insulin to attain improved diabetes control in younger type 1 and type 2 diabetes patients have shown improved cardiovascular outcomes. Shorter trials of intensive diabetes control with high insulin use in higher risk patients with type 2 diabetes have shown either no cardiovascular benefit or increased all cause and cardiovascular mortality. Glargine insulin is a basal insulin analog widely used to treat patients with type 1 and type 2 diabetes. This review focuses on the effects of glargine on cardiovascular outcomes. Glargine lowers triglycerides, leads to a modest weight gain, causes less hypoglycemia when compared with intermediate-acting insulin, and has a neutral effect on blood pressure. The Outcome Reduction With Initial Glargine Intervention (ORIGIN trial), a 6.2 year dedicated cardiovascular outcomes trial of glargine demonstrated no increased cardiovascular risk. PMID:25657589

Leveraging model-informed approaches for drug discovery and development in the cardiovascular space.

PubMed

Dockendorf, Marissa F; Vargo, Ryan C; Gheyas, Ferdous; Chain, Anne S Y; Chatterjee, Manash S; Wenning, Larissa A

2018-06-01

Cardiovascular disease remains a significant global health burden, and development of cardiovascular drugs in the current regulatory environment often demands large and expensive cardiovascular outcome trials. Thus, the use of quantitative pharmacometric approaches which can help enable early Go/No Go decision making, ensure appropriate dose selection, and increase the likelihood of successful clinical trials, have become increasingly important to help reduce the risk of failed cardiovascular outcomes studies. In addition, cardiovascular safety is an important consideration for many drug development programs, whether or not the drug is designed to treat cardiovascular disease; modeling and simulation approaches also have utility in assessing risk in this area. Herein, examples of modeling and simulation applied at various stages of drug development, spanning from the discovery stage through late-stage clinical development, for cardiovascular programs are presented. Examples of how modeling approaches have been utilized in early development programs across various therapeutic areas to help inform strategies to mitigate the risk of cardiovascular-related adverse events, such as QTc prolongation and changes in blood pressure, are also presented. These examples demonstrate how more informed drug development decisions can be enabled by modeling and simulation approaches in the cardiovascular area.

The European Association of Preventive Cardiology Exercise Prescription in Everyday Practice and Rehabilitative Training (EXPERT) tool: A digital training and decision support system for optimized exercise prescription in cardiovascular disease. Concept, definitions and construction methodology.

PubMed

Hansen, Dominique; Dendale, Paul; Coninx, Karin; Vanhees, Luc; Piepoli, Massimo F; Niebauer, Josef; Cornelissen, Veronique; Pedretti, Roberto; Geurts, Eva; Ruiz, Gustavo R; Corrà, Ugo; Schmid, Jean-Paul; Greco, Eugenio; Davos, Constantinos H; Edelmann, Frank; Abreu, Ana; Rauch, Bernhard; Ambrosetti, Marco; Braga, Simona S; Barna, Olga; Beckers, Paul; Bussotti, Maurizio; Fagard, Robert; Faggiano, Pompilio; Garcia-Porrero, Esteban; Kouidi, Evangelia; Lamotte, Michel; Neunhäuserer, Daniel; Reibis, Rona; Spruit, Martijn A; Stettler, Christoph; Takken, Tim; Tonoli, Cajsa; Vigorito, Carlo; Völler, Heinz; Doherty, Patrick

2017-07-01

Background Exercise rehabilitation is highly recommended by current guidelines on prevention of cardiovascular disease, but its implementation is still poor. Many clinicians experience difficulties in prescribing exercise in the presence of different concomitant cardiovascular diseases and risk factors within the same patient. It was aimed to develop a digital training and decision support system for exercise prescription in cardiovascular disease patients in clinical practice: the European Association of Preventive Cardiology Exercise Prescription in Everyday Practice and Rehabilitative Training (EXPERT) tool. Methods EXPERT working group members were requested to define (a) diagnostic criteria for specific cardiovascular diseases, cardiovascular disease risk factors, and other chronic non-cardiovascular conditions, (b) primary goals of exercise intervention, (c) disease-specific prescription of exercise training (intensity, frequency, volume, type, session and programme duration), and (d) exercise training safety advices. The impact of exercise tolerance, common cardiovascular medications and adverse events during exercise testing were further taken into account for optimized exercise prescription. Results Exercise training recommendations and safety advices were formulated for 10 cardiovascular diseases, five cardiovascular disease risk factors (type 1 and 2 diabetes, obesity, hypertension, hypercholesterolaemia), and three common chronic non-cardiovascular conditions (lung and renal failure and sarcopaenia), but also accounted for baseline exercise tolerance, common cardiovascular medications and occurrence of adverse events during exercise testing. An algorithm, supported by an interactive tool, was constructed based on these data. This training and decision support system automatically provides an exercise prescription according to the variables provided. Conclusion This digital training and decision support system may contribute in overcoming barriers in exercise implementation in common cardiovascular diseases.

Burn mortality in patients with preexisting cardiovascular disease.

PubMed

Knowlin, Laquanda; Reid, Trista; Williams, Felicia; Cairns, Bruce; Charles, Anthony

2017-08-01

Burn shock, a complex process, which develops following burn leads to severe and unique derangement of cardiovascular function. Patients with preexisting comorbidities such as cardiovascular diseases may be more susceptible. We therefore sought to examine the impact of preexisting cardiovascular disease on burn outcomes. A retrospective analysis of patients admitted to a regional burn center from 2002 to 2012. Independent variables analyzed included basic demographics, burn mechanism, presence of inhalation injury, TBSA, pre-existing comorbidities, and length of ICU/hospital stay. Bivariate analysis was performed and Poisson regression modeling was utilized to estimate the incidence of being in the ICU and mortality. There were a total of 5332 adult patients admitted over the study period. 6% (n=428) had a preexisting cardiovascular disease. Cardiovascular disease patients had a higher mortality rate (16%) compared to those without cardiovascular disease (3%, p<0.001). The adjusted Poisson regression model to estimate incidence risk of being in intensive care unit in patients with cardiovascular disease was 33% higher compared to those without cardiovascular disease (IRR=1.33, 95% CI=1.22-1.47). The risk for mortality is 42% higher (IRR=1.42, 95% CI=1.10-1.84) for patients with pre-existing cardiovascular disease compared to those without cardiovascular disease after controlling for other covariates. Preexisting cardiovascular disease significantly increases the risk of intensive care unit admission and mortality in burn patients. Given the increasing number of Americans with cardiovascular diseases, there will likely be a greater number of individuals at risk for worse outcomes following burn. This knowledge can help with burn prognostication. Copyright © 2017 Elsevier Ltd and ISBI. All rights reserved.

Association Between Leisure Time Physical Activity, Cardiopulmonary Fitness, Cardiovascular Risk Factors, and Cardiovascular Workload at Work in Firefighters.

PubMed

Yu, Clare C W; Au, Chun T; Lee, Frank Y F; So, Raymond C H; Wong, John P S; Mak, Gary Y K; Chien, Eric P; McManus, Alison M

2015-09-01

Overweight, obesity, and cardiovascular disease risk factors are prevalent among firefighters in some developed countries. It is unclear whether physical activity and cardiopulmonary fitness reduce cardiovascular disease risk and the cardiovascular workload at work in firefighters. The present study investigated the relationship between leisure-time physical activity, cardiopulmonary fitness, cardiovascular disease risk factors, and cardiovascular workload at work in firefighters in Hong Kong. Male firefighters (n = 387) were randomly selected from serving firefighters in Hong Kong (n = 5,370) for the assessment of cardiovascular disease risk factors (obesity, hypertension, diabetes mellitus, dyslipidemia, smoking, known cardiovascular diseases). One-third (Target Group) were randomly selected for the assessment of off-duty leisure-time physical activity using the short version of the International Physical Activity Questionnaire. Maximal oxygen uptake was assessed, as well as cardiovascular workload using heart rate monitoring for each firefighter for four "normal" 24-hour working shifts and during real-situation simulated scenarios. Overall, 33.9% of the firefighters had at least two cardiovascular disease risk factors. In the Target Group, firefighters who had higher leisure-time physical activity had a lower resting heart rate and a lower average working heart rate, and spent a smaller proportion of time working at a moderate-intensity cardiovascular workload. Firefighters who had moderate aerobic fitness and high leisure-time physical activity had a lower peak working heart rate during the mountain rescue scenario compared with firefighters who had low leisure-time physical activities. Leisure-time physical activity conferred significant benefits during job tasks of moderate cardiovascular workload in firefighters in Hong Kong.

Global cardiovascular research output, citations, and collaborations: a time-trend, bibliometric analysis (1999-2008).

PubMed

Huffman, Mark D; Baldridge, Abigail; Bloomfield, Gerald S; Colantonio, Lisandro D; Prabhakaran, Poornima; Ajay, Vamadevan S; Suh, Sarah; Lewison, Grant; Prabhakaran, Dorairaj

2013-01-01

Health research is one mechanism to improve population-level health and should generally match the health needs of populations. However, there have been limited data to assess the trends in national-level cardiovascular research output, even as cardiovascular disease [CVD] has become the leading cause of morbidity and mortality worldwide. We performed a time trends analysis of cardiovascular research publications (1999-2008) downloaded from Web of Knowledge using a iteratively-tested cardiovascular bibliometric filter with >90% precision and recall. We evaluated cardiovascular research publications, five-year running actual citation indices [ACIs], and degree of international collaboration measured through the ratio of the fractional count of addresses from one country against all addresses for each publication. Global cardiovascular publication volume increased from 40 661 publications in 1999 to 55 284 publications in 2008, which represents a 36% increase. The proportion of cardiovascular publications from high-income, Organization for Economic Cooperation and Development [OECD] countries declined from 93% to 84% of the total share over the study period. High-income, OECD countries generally had higher fractional counts, which suggest less international collaboration, than lower income countries from 1999-2008. There was an inverse relationship between cardiovascular publications and age-standardized CVD morbidity and mortality rates, but a direct, curvilinear relationship between cardiovascular publications and Human Development Index from 1999-2008. Cardiovascular health research output has increased substantially in the past decade, with a greater share of citations being published from low- and middle-income countries. However, low- and middle-income countries with the higher burdens of cardiovascular disease continue to have lower research output than high-income countries, and thus require targeted research investments to improve cardiovascular health.

Cardiovascular Reactivity in Patients With Major Depressive Disorder With High- or Low-Level Depressive Symptoms: A Cross-Sectional Comparison of Cardiovascular Reactivity to Laboratory-Induced Mental Stress.

PubMed

Wang, Mei-Yeh; Chiu, Chen-Huan; Lee, Hsin-Chien; Su, Chien-Tien; Tsai, Pei-Shan

2016-03-01

Depression increases the risk of adverse cardiac events. Cardiovascular reactivity is defined as the pattern of cardiovascular responses to mental stress. An altered pattern of cardiovascular reactivity is an indicator of subsequent cardiovascular disease. Because depression and adverse cardiac events may have a dose-dependent association, this study examined the differences in cardiovascular reactivity to mental stress between patients with major depressive disorder (MDD) with high depression levels and those with low depression levels. Moreover, autonomic nervous system regulation is a highly plausible biological mechanism for the pattern of cardiovascular reactivity to mental stress. The association between cardiovascular reactivity and parameters of heart rate variability (HRV), an index for quantifying autonomic nervous system activity modulation, was thus examined. This study included 88 patients with MDD. HRV was measured before stress induction. The Stroop Color and Word Test and mirror star-tracing task were used to induce mental stress. We observed no significant association between depressive symptom level and any of the cardiovascular reactivity parameters. Cardiovascular reactivity to mental stress was comparable between patients with MDD with high-level depressive symptoms and those with low-level depressive symptoms. After adjusting for confounding variables, the high-frequency domain of HRV was found to be an independent predictor of the magnitude of heart rate reactivity (β = -.33, p = .002). In conclusion, the magnitude of cardiovascular reactivity may be independent of depression severity in patients with MDD. The autonomic regulation of cardiovascular responses to mental stress primarily influences heart rate reactivity in patients with MDD. © The Author(s) 2015.

Cumulative effect of psychosocial factors in youth on ideal cardiovascular health in adulthood: the Cardiovascular Risk in Young Finns Study.

PubMed

Pulkki-Råback, Laura; Elovainio, Marko; Hakulinen, Christian; Lipsanen, Jari; Hintsanen, Mirka; Jokela, Markus; Kubzansky, Laura D; Hintsa, Taina; Serlachius, Anna; Laitinen, Tomi T; Laitinen, Tomi; Pahkala, Katja; Mikkilä, Vera; Nevalainen, Jaakko; Hutri-Kähönen, Nina; Juonala, Markus; Viikari, Jorma; Raitakari, Olli T; Keltikangas-Järvinen, Liisa

2015-01-20

The American Heart Association has defined a new metric of ideal cardiovascular health as part of its 2020 Impact Goals. We examined whether psychosocial factors in youth predict ideal cardiovascular health in adulthood. Participants were 477 men and 612 women from the nationwide Cardiovascular Risk in Young Finns Study. Psychosocial factors were measured from cohorts 3 to 18 years of age at the baseline of the study, and ideal cardiovascular health was examined 27 years later in adulthood. The summary measure of psychosocial factors in youth comprised socioeconomic factors, emotional factors, parental health behaviors, stressful events, self-regulation of the child, and social adjustment of the child. There was a positive association between a higher number of favorable psychosocial factors in youth and greater ideal cardiovascular health index in adulthood (β=0.16; P<0.001) that persisted after adjustment for age, sex, medication use, and cardiovascular risk factors in childhood (β=0.15; P<0.001). The association was monotonic, suggesting that each increment in favorable psychosocial factors was associated with improvement in cardiovascular health. Of the specific psychosocial factors, a favorable socioeconomic environment (β=0.12; P<0.001) and participants' self-regulatory behavior (β=0.07; P=0.004) were the strongest predictors of ideal cardiovascular health in adulthood. The findings suggest a dose-response association between favorable psychosocial factors in youth and cardiovascular health in adulthood, as defined by the American Heart Association metrics. The effect seems to persist throughout the range of cardiovascular health, potentially shifting the population distribution of cardiovascular health rather than simply having effects in a high-risk population. © 2015 American Heart Association, Inc.

Cardiovascular disease in live related renal transplantation.

PubMed

Kaul, A; Sharm, R K; Gupta, A; Sinha, N; Singh, U

2011-11-01

Cardiovascular disease has become the leading cause of morbidity and mortality in renal transplant recipients, although its pathogenesis and treatment are poorly understood. Modifiable cardiovascular risk factors and graft dysfunction both play an important role in development of post transplant cardiovascular events. Prevalence of cardiovascular disease was studied in stable kidney transplant patients on cyclosporine based triple immunosuppression in relation to the various risk factors and post transplant cardiovascular events. Analysis of 562 post transplant patients with stable graft function for 6 months, the patients were evaluated for cardiovascular events in post transplant period. Pre and post transplant risk factors were analyzed using the COX proportional hazard model. 174 patients had undergone pre transplant coronary angiography, 15 of these patients underwent coronary revascularization (angioplasty in 12, CABG in 3). The prevalence of CAD was 7.2% in transplant recipients. Of 42 patients with CAD 31 (73.8%) had cardiovascular event in post transplant period. Age > or = 40 yrs, male sex, graft dysfunction, diabetes as primary renal disease, pre transplant cardiovascular event, chronic rejection showed significant correlation in univariate analysis and there was significant between age > or = 40 years (OR = 2.16 with 95% CI, 0.977-4.78) S creatinine > or = 1.4 mg % (OR = 2.40 with 95% CI, 1.20 - 4.82), diabetes as primary disease (OR with 95% CI 3.67, 3.2-14.82), PTDM (OR 3.67, 95% CI 1.45-9.40), pre-transplant cardiovascular disease (OR 4.14, 95% CI .38-13.15) with post transplant cardiovascular event on multivariate analysis. There was poor patient and graft survival among those who suffered post transplant cardiovascular event. The incidence of cardiovascular disease continues to be high after renal transplantation and modifiable risk factors should be identified to prevent occurrence of events in post transplant period.

Circulating endothelial progenitor cells and cardiovascular outcomes.

PubMed

Werner, Nikos; Kosiol, Sonja; Schiegl, Tobias; Ahlers, Patrick; Walenta, Katrin; Link, Andreas; Böhm, Michael; Nickenig, Georg

2005-09-08

Endothelial progenitor cells derived from bone marrow are believed to support the integrity of the vascular endothelium. The number and function of endothelial progenitor cells correlate inversely with cardiovascular risk factors, but the prognostic value associated with circulating endothelial progenitor cells has not been defined. The number of endothelial progenitor cells positive for CD34 and kinase insert domain receptor (KDR) was determined with the use of flow cytometry in 519 patients with coronary artery disease as confirmed on angiography. After 12 months, we evaluated the association between baseline levels of endothelial progenitor cells and death from cardiovascular causes, the occurrence of a first major cardiovascular event (myocardial infarction, hospitalization, revascularization, or death from cardiovascular causes), revascularization, hospitalization, and death from all causes. A total of 43 participants died, 23 from cardiovascular causes. A first major cardiovascular event occurred in 214 patients. The cumulative event-free survival rate increased stepwise across three increasing baseline levels of endothelial progenitor cells in an analysis of death from cardiovascular causes, a first major cardiovascular event, revascularization, and hospitalization. After adjustment for age, sex, vascular risk factors, and other relevant variables, increased levels of endothelial progenitor cells were associated with a reduced risk of death from cardiovascular causes (hazard ratio, 0.31; 95 percent confidence interval, 0.16 to 0.63; P=0.001), a first major cardiovascular event (hazard ratio, 0.74; 95 percent confidence interval, 0.62 to 0.89; P=0.002), revascularization (hazard ratio, 0.77; 95 percent confidence interval, 0.62 to 0.95; P=0.02), and hospitalization (hazard ratio, 0.76; 95 percent confidence interval, 0.63 to 0.94; P=0.01). Endothelial progenitor-cell levels were not predictive of myocardial infarction or of death from all causes. The level of circulating CD34+KDR+ endothelial progenitor cells predicts the occurrence of cardiovascular events and death from cardiovascular causes and may help to identify patients at increased cardiovascular risk. Copyright 2005 Massachusetts Medical Society.

Effects of education and income on cardiovascular outcomes: A systematic review and meta-analysis.

PubMed

Khaing, Win; Vallibhakara, Sakda A; Attia, John; McEvoy, Mark; Thakkinstian, Ammarin

2017-07-01

Objective Previous studies have reported discrepancy effects of education and income on cardiovascular diseases. This systematic review and meta-analysis was therefore conducted which aimed to summarize effects of education and income on cardiovascular diseases. Methods Studies were identified from Medline and Scopus until July 2016. Cohorts were eligible if they assessed associations between education/income and cardiovascular diseases, had at least one outcome including coronary artery diseases, cardiovascular events, strokes and cardiovascular deaths. A multivariate meta-analysis was applied to pool risk effects of these social determinants. Results Among 72 included cohorts, 39, 19, and 14 were studied in Europe, USA, and Asia. Pooled risk ratios of low and medium versus high education were 1.36 (95% confidence interval: 1.11-1.66) and 1.21 (1.06-1.40) for coronary artery diseases, 1.50 (1.17-1.92) and 1.27 (1.09-1.48) for cardiovascular events, 1.23 (1.06-1.43) and 1.17 (1.01-1.35) for strokes, and 1.39 (1.26-1.54) and 1.21 (1.12-1.30) for cardiovascular deaths. The effects of education on all cardiovascular diseases were still present in US and Europe settings, except in Asia this was present only for cardiovascular deaths. Effects of low and medium income versus high on these corresponding cardiovascular diseases were 1.49 (1.16-1.91) and 1.27 (1.10-1.47) for coronary artery diseases, 1.17 (0.96-1.44) and 1.05 (0.98-1.13) for cardiovascular events, 1.30 (0.99-1.72) and 1.24 (1.00-1.53) for strokes, and 1.76 (1.45-2.14) and 1.34 (1.17-1.54) for cardiovascular deaths. Conclusion Social determinants are risk factors of cardiovascular diseases in developed countries, although high heterogeneity in pooling. Data in Asia countries are still needed to update pooling.

Cardiovascular actions of L-cysteine and L-cysteine sulfinic acid in the nucleus tractus solitarius of the rat.

PubMed

Takemoto, Yumi

2014-07-01

The sulfur-containing excitatory amino acid (EAA) L-cysteine sulfinic acid (CSA), a neurotransmitter candidate, is endogenously synthesized from L-cysteine (Cys). Exogenous Cys administration into the brain produces cardiovascular effects; these effects likely occur via synaptic stimulation of central nervous system (CNS) neurons that regulate peripheral cardiovascular function. However, the cardiovascular responses produced by CNS Cys administration could result from CSA biosynthesized in synapse. The present study examined the role of CSA in Cys-induced cardiovascular responses within the nucleus tractus solitarius (NTS) of anesthetized rats. The NTS receives input from various visceral afferents that gate autonomic reflexes, including cardiovascular reflexes. Within the NTS, both Cys and CSA microinjections produced decrease responses in arterial blood pressure and heart rate that were similar to those produced by L-glutamate. Co-injection of the ionotropic EAA receptor antagonist kynurenic acid abolished Cys-, but not CSA-, induced cardiovascular responses. This finding suggests that only Cys-induced cardiovascular responses are mediated by kynurenate-sensitive receptors. This study provides the first demonstration that Cys- and CSA-induced cardiovascular responses occur via different mechanisms in the NTS of rats. Further, this study also indicates that Cys-induced cardiovascular responses do not occur via CSA. Thus, within the NTS, endogenous Cys and/or CSA might be involved in cardiovascular regulation.

Urine albumin/creatinine ratio, high sensitivity C-reactive protein and N-terminal pro brain natriuretic peptide--three new cardiovascular risk markers--do they improve risk prediction and influence treatment?

PubMed

Olsen, Michael H; Sehestedt, Thomas; Lyngbaek, Stig; Hansen, Tine W; Rasmussen, Susanne; Wachtell, Kristian; Torp-Pedersen, Christian; Hildebrandt, Per R; Ibsen, Hans

2010-01-01

In order to prioritize limited health resources in a time of increasing demands optimal cardiovascular risk stratification is essential. We tested the additive prognostic value of 3 relatively new, but established cardiovascular risk markers: N-terminal pro brain natriuretic peptide (Nt-proBNP), related to hemodynamic cardiovascular risk factors, high sensitivity C-reactive protein (hsCRP), related to metabolic cardiovascular risk factors and urine albumin/creatinine ratio (UACR), related to hemodynamic as well as metabolic risk factors. In healthy subjects with a 10-year risk of cardiovascular death lower than 5% based on HeartScore and therefore not eligible for primary prevention, the actual 10-year risk of cardiovascular death exceeded 5% in a small subgroup of subjects with UACR higher than the 95-percentile of approximately 1.6 mg/mmol. Combined use of high UACR or high hsCRP identified a larger subgroup of 16% with high cardiovascular risk in which primary prevention may be advised despite low-moderate cardiovascular risk based on HeartScore. Furthermore, combined use of high UACR or high Nt-proBNP in subjects with known cardiovascular disease or diabetes identified a large subgroup of 48% with extremely high cardiovascular risk who should be referred for specialist care to optimize treatment.

Cardiovascular hospitalizations and associations with environmental quality

EPA Science Inventory

Cardiovascular disease has been identified as a condition that may be associated with environmental factors. Air pollution in particular has been demonstrated to be associated with cardiovascular disease and atherosclerosis, which can increase the likelihood of cardiovascular eve...

Erectile dysfunction in the cardiovascular patient.

PubMed

Vlachopoulos, Charalambos; Jackson, Graham; Stefanadis, Christodoulos; Montorsi, Piero

2013-07-01

Erectile dysfunction is common in the patient with cardiovascular disease. It is an important component of the quality of life and it also confers an independent risk for future cardiovascular events. The usual 3-year time period between the onset of erectile dysfunction symptoms and a cardiovascular event offers an opportunity for risk mitigation. Thus, sexual function should be incorporated into cardiovascular disease risk assessment for all men. A comprehensive approach to cardiovascular risk reduction (comprising of both lifestyle changes and pharmacological treatment) improves overall vascular health, including sexual function. Proper sexual counselling improves the quality of life and increases adherence to medication. This review explores the critical connection between erectile dysfunction and cardiovascular disease and evaluates how this relationship may influence clinical practice. Algorithms for the management of patient with erectile dysfunction according to the risk for sexual activity and future cardiovascular events are proposed.

The Brain Norepinephrine System, Stress and Cardiovascular Vulnerability

PubMed Central

Wood, Susan K.; Valentino, Rita J.

2016-01-01

Chronic exposure to psychosocial stress has adverse effects on cardiovascular health, however the stress-sensitive neurocircuitry involved remains to be elucidated. The anatomical and physiological characteristics of the locus coeruleus (LC)-norepinephrine (NE) system position it to contribute to stress-induced cardiovascular disease. This review focuses on cardiovascular dysfunction produced by social stress and a major theme highlighted is that differences in coping strategy determine individual differences in social stress-induced cardiovascular vulnerability. The establishment of different coping strategies and cardiovascular vulnerability during repeated social stress has recently been shown to parallel a unique plasticity in LC afferent regulation, resulting in either excitatory or inhibitory input to the LC. This contrasting regulation of the LC would translate to differences in cardiovascular regulation and may serve as the basis for individual differences in the cardiopathological consequences of social stress. The advances described suggest new directions for developing treatments and/or strategies for decreasing stress-induced cardiovascular vulnerability. PMID:27131968

Role of Adipokines in Atherosclerosis: Interferences with Cardiovascular Complications in Rheumatic Diseases

PubMed Central

Scotece, Morena; Conde, Javier; Gómez, Rodolfo; López, Verónica; Pino, Jesús; González, Antonio; Lago, Francisca; Gómez-Reino, Juan J.; Gualillo, Oreste

2012-01-01

Patients with rheumatic diseases have an increased risk of mortality by cardiovascular events. In fact, several rheumatic diseases such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis are associated with a higher prevalence of cardiovascular diseases (CVDs). Although traditional cardiovascular risk factors have been involved in the pathogenesis of cardiovascular diseases in rheumatic patients, these alterations do not completely explain the enhanced cardiovascular risk in this population. Obesity and its pathologic alteration of fat mass and dysfunction, due to an altered pattern of secretion of proinflammatory adipokines, could be one of the links between cardiovascular and rheumatic diseases. Indeed, the incidence of CVDs is augmented in obese individuals with rheumatic disorders. Thus, in this paper we explore in detail the relationships among adipokines, rheumatic diseases, and cardiovascular complications by giving to the reader a holistic vision and several suggestions for future perspectives and potential clinical implications. PMID:22910888

Socioeconomic status and parenting during adolescence in relation to ideal cardiovascular health in Black and White men.

PubMed

Matthews, Karen A; Boylan, Jennifer M; Jakubowski, Karen P; Cundiff, Jenny M; Lee, Laisze; Pardini, Dustin A; Jennings, J Richard

2017-07-01

American Heart Association (AHA) developed a new metric to evaluate ideal cardiovascular health based on optimal levels of 7 cardiovascular risk factors and health behaviors. We evaluated the relationships of parenting characteristics and academic achievement in adolescence in relation to ideal cardiovascular health in midlife men. We measured cardiovascular risk factors in 171 Black and 136 White men and their ideal cardiovascular health score was constructed based on AHA guidelines. When the participants were 13-16 years old, annual measures of parent-child communication, positive relationship, parental monitoring, family cohesion, boys' involvement in family activities, and academic achievement were recorded and averaged. Confirmatory factor analysis of adolescent parenting measures revealed a single Parenting Composite. Multiple linear regressions showed a significant Race by Parenting Composite interaction term, β = -.19, p = .03; better parenting was significantly related to more ideal cardiovascular health in Blacks only, β = -.23, p = .004, which remained after adjustments for adolescent and adult socioeconomic status (SES). Academic achievement was related to ideal cardiovascular health, β = -.13, but was no longer significant after controls for adult SES. Adult SES was a strong correlate of ideal cardiovascular health in Black and White men. Black men exposed to positive parenting during adolescence had more ideal cardiovascular health based on AHA guidelines. Improving academic achievement in adolescence may indirectly benefit adult cardiovascular health through improving adult SES. This is the first study of adolescent family predictors of the extent of ideal cardiovascular health. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Knowledge and perception of cardiovascular disease risk among patients with rheumatoid arthritis.

PubMed

Boo, Sunjoo; Oh, Hyunjin; Froelicher, Erika S; Suh, Chang-Hee

2017-01-01

Patients with rheumatoid arthritis are at increased risk for cardiovascular disease. The prerequisites for reducing the risk of cardiovascular disease are adequate levels of knowledge and being aware of the risk. In this study, the levels of knowledge about cardiovascular disease among patients with rheumatoid arthritis and the perception were evaluated in relation to their actual 10-year risk of cardiovascular disease. This cross-sectional study of 200 patients with rheumatoid arthritis was conducted in a university-affiliated hospital in South Korea. The patients' actual risk of cardiovascular disease was estimated using the Framingham Risk Score. The most common risk factor was physical inactivity, with 77% of the patients not engaging in regular exercise. The patients lacked knowledge about the effects of physical inactivity and anti-inflammatory medication on the development of cardiovascular disease. Misperceptions about the risk of cardiovascular disease were common, i.e., 19.5% of the patients underestimated their risk and 41% overestimated. Hypertension, diabetes, obesity, and smoking were the most prevalent among the patients who underestimated their risk, and these same patients had the lowest level of knowledge about cardiovascular disease. This study demonstrated the rheumatoid arthritis patients' lack of knowledge about the effects of physical inactivity and anti-inflammatory medications on the development of cardiovascular disease, and their misperception of cardiovascular risk was common. As a preventive measure, educational programs about cardiovascular disease should be tailored specifically for patients with rheumatoid arthritis, and behavioral interventions, including routine exercise, should be made available at the time of diagnosis.

Cardiovascular disease in menopause: does the obstetric history have any bearing?

PubMed

Mahendru, Amita A; Morris, Edward

2013-09-01

Cardiovascular disease remains a leading cause of morbidity and mortality in menopausal women in spite of the overall reduction in age-adjusted mortality from the disease in the last few years. It is now clear that mechanisms of cardiovascular disease in menopausal women are similar to men and rather than midlife acceleration of cardiovascular disease in women, the final impact of cardiovascular disease in later life may be a reflection of cardiovascular changes during reproductive years as a result of woman's obstetric history. A decade after the Women's Health Initiative trial, there is upcoming evidence to suggest that hormone replacement therapy in young recently menopausal women has a cardioprotective effect. Cardiovascular changes during normal pregnancy or pregnancy complications such as preeclampsia may affect a woman's long-term cardiovascular health. Therefore, it is plausible that the cardioprotective benefit of hormone replacement therapy depends on occult pre-existing cardiovascular risks in women in relation to their previous obstetric history. In this review, we describe the cardiovascular changes during and after pregnancy in obstetric complications such as recurrent miscarriage, preeclampsia, intrauterine growth restriction, preterm labour and gestational diabetes; existing evidence regarding their association with cardiovascular disease later in life, and hypothesize possible mechanisms. Our aim is to improve the understanding and highlight the importance of including obstetric history in risk assessment in menopausal women and individualizing their risks before prescribing hormone replacement therapy. Future research in risk benefit assessment of hormone replacement therapy should also account for a woman's background cardiovascular risk in the light of her obstetric history.

C-reactive protein and cardiovascular risk in bipolar disorder patients: A systematic review.

PubMed

Marshe, Victoria S; Pira, Shamira; Mantere, Outi; Bosche, Bert; Looper, Karl J; Herrmann, Nathan; Müller, Daniel J; Rej, Soham

2017-10-03

New research is revealing a strong association between inflammatory markers with bipolar disorder (BD), potentially due to the high prevalence of cardiovascular disease and cardiovascular risk factors in BD. We aimed to synthesize the literature examining the association between the clinically most relevant inflammatory marker, C-reactive protein (CRP) and cardiovascular disease and cardiovascular risk factors in patients with BD. MEDLINE, Embase and PsychInfo were systematically searched for all relevant English language articles published prior to April 2017. Articles were included if they examined the association between CRP and cardiovascular risk factors/disease in BD. Fifteen relevant articles were retrieved. Studies were mostly cross-sectional and heterogeneous in the cardiovascular risk factors investigated. Overall, elevated CRP was associated with increased risk of metabolic syndrome, elevated body mass index, higher waist circumference, and obesity. CRP was inconsistently associated with elevated fasting glucose, insulin levels, serum triglycerides, total cholesterol levels, and low high density lipoprotein (HDL) levels. Atypical antipsychotic use may mediate some of these effects. No study examined CRP's association with actual cardiovascular disease (e.g. coronary artery disease) in BD. In BD, CRP is associated with increases in several cardiovascular risk factors, suggesting that systemic inflammation could be a shared driving force for both outcomes of BD and cardiovascular risk. Further longitudinal research is needed in this area to verify causality, including an examination of actual cardiovascular disease. Non-pharmacological and pharmacological treatments with anti-inflammatory effects should also be investigated, particularly in patients with increased CRP, for their potential to reduce cardiovascular risk in BD. Copyright © 2017 Elsevier Inc. All rights reserved.

Mortality of mothers from cardiovascular and non-cardiovascular causes following pregnancy complications in first delivery.

PubMed

Lykke, Jacob A; Langhoff-Roos, Jens; Lockwood, Charles J; Triche, Elizabeth W; Paidas, Michael J

2010-07-01

The combined effects of preterm delivery, small-for-gestational-age offspring, hypertensive disorders of pregnancy, placental abruption and stillbirth on early maternal death from cardiovascular causes have not previously been described in a large cohort. We investigated the effects of pregnancy complications on early maternal death in a registry-based retrospective cohort study of 782 287 women with a first singleton delivery in Denmark 1978-2007, followed for a median of 14.8 years (range 0.25-30.2) accruing 11.6 million person-years. We employed Cox proportional hazard models of early death from cardiovascular and non-cardiovascular causes following preterm delivery, small-for-gestational-age offspring and hypertensive disorders of pregnancy. We found that preterm delivery and small-for-gestational-age were both associated with subsequent death of mothers from cardiovascular and non-cardiovascular causes. Severe pre-eclampsia was associated with death from cardiovascular causes only. There was a less than additive effect on cardiovascular mortality hazard ratios with increasing number of pregnancy complications: preterm delivery 1.90 [95% confidence intervals 1.49, 2.43]; preterm delivery and small-for-gestational-age offspring 3.30 [2.25, 4.84]; preterm delivery, small-for-gestational-age offspring and pre-eclampsia 3.85 [2.07, 7.19]. Thus, we conclude that, separately and combined, preterm delivery and small-for-gestational-age are strong markers of early maternal death from both cardiovascular and non-cardiovascular causes, while hypertensive disorders of pregnancy are markers of early death of mothers from cardiovascular causes.

Beat to beat variability in cardiovascular variables: noise or music?

NASA Technical Reports Server (NTRS)

Appel, M. L.; Berger, R. D.; Saul, J. P.; Smith, J. M.; Cohen, R. J.

1989-01-01

Cardiovascular variables such as heart rate, arterial blood pressure, stroke volume and the shape of electrocardiographic complexes all fluctuate on a beat to beat basis. These fluctuations have traditionally been ignored or, at best, treated as noise to be averaged out. The variability in cardiovascular signals reflects the homeodynamic interplay between perturbations to cardiovascular function and the dynamic response of the cardiovascular regulatory systems. Modern signal processing techniques provide a means of analyzing beat to beat fluctuations in cardiovascular signals, so as to permit a quantitative, noninvasive or minimally invasive method of assessing closed loop hemodynamic regulation and cardiac electrical stability. This method promises to provide a new approach to the clinical diagnosis and management of alterations in cardiovascular regulation and stability.

Hepatitis C virus and cardiovascular: A review.

PubMed

Petta, Salvatore

2017-03-01

Chronic hepatitis C virus (HCV) infection is a systemic disease that leads to increased risks of cirrhosis and its complications, as well as extrahepatic disturbances, including immune-related disorders and metabolic alterations such as insulin resistance and steatosis. Recent accumulating evidence suggests that HCV infection can increase cardiovascular risk, and that viral eradication can improve cardiovascular outcomes in the clinical setting. These data are strengthened by evidence identifying potential mechanisms (in)directly linking HCV infection to vascular damage. However, the high prevalence of both HCV infection and cardiovascular alterations, as well as the presence of contrasting results not identifying any association between HCV infection and cardiovascular dysfunction, provides uncertainty about a direct association of HCV infection with cardiovascular risk. Further studies are needed to clarify definitively the role of HCV infection in cardiovascular alterations, as well as the impact of viral eradication on cardiovascular outcomes. These features are now more attractive, considering the availability of new, safe, and very effective interferon-free antiviral agents for the treatment of HCV infection. This review aims to discuss carefully available data on the relationship between HCV infection and cardiovascular risk.

Physical activity in primary and secondary prevention of cardiovascular disease: Overview updated.

PubMed

Alves, Alberto J; Viana, João L; Cavalcante, Suiane L; Oliveira, Nórton L; Duarte, José A; Mota, Jorge; Oliveira, José; Ribeiro, Fernando

2016-10-26

Although the observed progress in the cardiovascular disease treatment, the incidence of new and recurrent coronary artery disease remains elevated and constitutes the leading cause of death in the developed countries. Three-quarters of deaths due to cardiovascular diseases could be prevented with adequate changes in lifestyle, including increased daily physical activity. New evidence confirms that there is an inverse dose-response relationship between physical activity and cardiovascular disease and mortality risk. However, participation in moderate to vigorous physical activity may not fully attenuate the independent effect of sedentary activities on increased risk for cardiovascular diseases. Physical activity also plays an important role in secondary prevention of cardiovascular diseases by reducing the impact of the disease, slowing its progress and preventing recurrence. Nonetheless, most of eligible cardiovascular patients still do not benefit from secondary prevention/cardiac rehabilitation programs. The present review draws attention to the importance of physical activity in the primary and secondary prevention of cardiovascular diseases. It also addresses the mechanisms by which physical activity and regular exercise can improve cardiovascular health and reduce the burden of the disease.

Serum C-reactive protein in the prediction of cardiovascular diseases: Overview of the latest clinical studies and public health practice.

PubMed

Avan, Amir; Tavakoly Sany, Seyedeh Belin; Ghayour-Mobarhan, Majid; Rahimi, Hamid Reza; Tajfard, Mohammad; Ferns, Gordon

2018-06-22

Cardiovascular disease is the most common cause of morbidity and mortality globally. Epidemiological studies using high-sensitivity assays for serum C-reactive protein have shown a consistent association between cardiovascular disease risk and serum C-reactive protein concentrations. C-reactive protein is a biomarker for inflammation, and has been established in clinical practice as an independent risk factor for cardiovascular disease events. There is evidence that serum C-reactive protein is an excellent biomarker of cardiovascular disease and is also an independent and strong predictor of adverse cardiovascular events. Further characterization of the impact and influence of lifestyle exposures and genetic variation on the C-reactive protein response to cardiovascular disease events may have implications for the therapeutic approaches to reduce cardiovascular disease events. This review summarizes the studies that have examined the association between serum C-reactive protein and the risk of cardiovascular disease. We also discuss the impact of independent factors and C-reactive protein genetic polymorphisms on baseline plasma C-reactive protein levels. © 2018 Wiley Periodicals, Inc.

75 FR 5335 - Workshop on Pediatric Neurological and Neurocognitive Assessments for Cardiovascular Devices...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-02

...] Workshop on Pediatric Neurological and Neurocognitive Assessments for Cardiovascular Devices; Public... Neurocognitive Assessments for Cardiovascular Devices.'' The purpose of the public workshop is to solicit... various neurological and neurocognitive assessments for pediatric patients implanted with cardiovascular...

Cardiovascular risk in women with polycystic ovary syndrome.

PubMed

Cho, L W; Atkin, S L

2007-12-01

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women that has received an immense amount of attention in the recent years due to the possible associated risk of cardiovascular disease. Women with PCOS demonstrate an adverse cardiovascular profile characteristic of the cardiometabolic syndrome and an established risk of progression to type 2 diabetes. Despite the presence of cardiovascular risk factors and increased surrogate markers of cardiovascular disease, it is unclear if they develop accelerated atherosclerosis. This article summarized the recent development and findings of cardiovascular risk in women with PCOS, and finally the therapeutic options will be discussed.

Aquaporins in Cardiovascular System.

PubMed

Tie, Lu; Wang, Di; Shi, Yundi; Li, Xuejun

2017-01-01

Recent studies have shown that some aquaporins (AQPs ), including AQP1, AQP4, AQP7 and AQP9, are expressed in endothelial cells, vascular smooth muscle cells and heart of cardiovascular system. These AQPs are involved in the cardiovascular function and in pathological process of related diseases, such as cerebral ischemia , congestion heart failure , hypertension and angiogenesis. Therefore, it is important to understand the accurate association between AQPs and cardiovascular system, which may provide novel approaches to prevent and treat related diseases. Here we will discuss the expression and physiological function of AQPs in cardiovascular system and summarize recent researches on AQPs related cardiovascular diseases.

[Strategies for cardiovascular disease prevention].

PubMed

Gabus, Vincent; Wuerzner, Grégoire; Saubade, Mathieu; Favre, Lucie; Jacot Sadowski, Isabelle; Nanchen, David

2018-02-28

Atherosclerosis is a disease which develops very gradually over decades. Under the influence of modifiable cardiovascular risk factors, such as blood pressure, LDL-cholesterol level, smoking or lifestyle, clinical symptoms of atherosclerosis manifest more or less early in life. When cardiovascular risk factors accumulate, the risk of having a cardiovascular event increases and the benefits of prevention measures are greater. This article summarizes existing strategies for controlling modifiable cardiovascular risk factors in primary prevention. The physician can rely on an interprofessional network of cardiovascular prevention. Managing risk factors while respecting the autonomy and priorities of the patient will bring the greatest benefit.

[Association of cardiovascular autonomic neuropathy and prolonged QT interval with cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus].

PubMed

Ticse Aguirre, Ray; Villena, Jaime E

2011-03-01

In order to evaluate the relationship between cardiovascular autonomic neuropathy and corrected QT interval (QTc) with cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus, we followed up for 5 years 67 patients attending the outpatient Endocrinology Service. 82% completed follow-up and cardiovascular events occurred in 16 patients. We found that long QTc interval was the only variable significantly associated with cardiovascular morbidity and mortality in the multiple logistic regression analysis (RR: 13.56, 95% CI: 2.01-91.36) (p = 0.0074).

A review of the epidemiologic literature on the role of environmental arsenic exposure and cardiovascular diseases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, C.-H.; Hsiao, C.K.; Chen, C.-L.

2007-08-01

Cardiovascular disease is the leading cause of mortality worldwide. Arsenic is a ubiquitous metalloid in the crust of the earth. Chronic arsenic poisoning is becoming an emerging epidemic in Asia. Epidemiological studies have shown that chronic arsenic poisoning through ingestion of arsenic-contaminated water is associated with various cardiovascular diseases in dose-response relationships. These cardiovascular disorders include carotid atherosclerosis detected by ultrasonography, impaired microcirculation, prolonged QT interval and increased QT dispersion in electrocardiography, and clinical outcomes such as hypertension, blackfoot disease (a unique peripheral vascular disease endemic in southwestern Taiwan), coronary artery disease and cerebral infarction. Chronic arsenic poisoning is anmore » independent risk factor for cardiovascular disease. The adverse cardiovascular effects of long-term arsenic exposure may be persistent and/or irreversible. Arsenic-induced cardiovascular diseases in human population may result from the interaction among genetic, environment and nutritional factors. The major adverse cardiovascular effect of chronic arsenic poisoning has been established qualitatively and quantitatively in the high arsenic exposure areas, but the low-dose effect of arsenic on cardiovascular diseases remains to be explored. Cardiovascular death is the major cause of mortality worldwide, and a small increased risk may imply a large quantity of excess mortality.« less

ISPD Cardiovascular and Metabolic Guidelines in Adult Peritoneal Dialysis Patients Part I - Assessment and Management of Various Cardiovascular Risk Factors.

PubMed

Wang, Angela Yee Moon; Brimble, K Scott; Brunier, Gillian; Holt, Stephen G; Jha, Vivekanand; Johnson, David W; Kang, Shin-Wook; Kooman, Jeroen P; Lambie, Mark; McIntyre, Chris; Mehrotra, Rajnish; Pecoits-Filho, Roberto

2015-01-01

Cardiovascular disease contributes significantly to the adverse clinical outcomes of peritoneal dialysis (PD) patients. Numerous cardiovascular risk factors play important roles in the development of various cardiovascular complications. Of these, loss of residual renal function is regarded as one of the key cardiovascular risk factors and is associated with an increased mortality and cardiovascular death. It is also recognized that PD solutions may incur significant adverse metabolic effects in PD patients. The International Society for Peritoneal Dialysis (ISPD) commissioned a global workgroup in 2012 to formulate a series of recommendations regarding lifestyle modification, assessment and management of various cardiovascular risk factors, as well as management of the various cardiovascular complications including coronary artery disease, heart failure, arrhythmia (specifically atrial fibrillation), cerebrovascular disease, peripheral arterial disease and sudden cardiac death, to be published in 2 guideline documents. This publication forms the first part of the guideline documents and includes recommendations on assessment and management of various cardiovascular risk factors. The documents are intended to serve as a global clinical practice guideline for clinicians who look after PD patients. The ISPD workgroup also identifies areas where evidence is lacking and further research is needed. Copyright © 2015 International Society for Peritoneal Dialysis.

Sleep restriction undermines cardiovascular adaptation during stress, contingent on emotional stability.

PubMed

Lü, Wei; Hughes, Brian M; Howard, Siobhán; James, Jack E

2018-02-01

Sleep loss is associated with increased cardiovascular disease, but physiological mechanisms accounting for this relationship are largely unknown. One possible mechanism is that sleep restriction exerts effects on cardiovascular stress responses, and that these effects vary between individuals. Emotional stability (ES) is a personality trait pertinent to sleep restriction and stress responding. However, no study to date has explored how ES and sleep-restriction interactively affect cardiovascular stress responses or processes of adaptation during stress. The present study sought to investigate the association between ES and impact of sleep restriction on cardiovascular function during stress, with particular regard to the trajectory of cardiovascular function change across time. Ninety female university students completed a laboratory vigilance stress task while undergoing continuous cardiovascular (SBP, DBP, HR, SV, CO, TPR) monitoring, after either a night of partial sleep restriction (40% of habitual sleep duration) or a full night's rest. Individuals high in ES showed stable and adaptive cardiovascular (SBP, SV, CO) responses throughout stress exposure, regardless of sleep. In contrast, individuals low in ES exhibited cardiovascular adaptation during stress exposure while rested, but disrupted adaption while sleep-restricted. These findings suggest that sleep-restriction undermines healthful cardiovascular adaptation to stress for individuals low in ES. Copyright © 2017 Elsevier B.V. All rights reserved.

Cardiovascular risk profile in women and dementia.

PubMed

Dufouil, Carole; Seshadri, Sudha; Chêne, Geneviève

2014-01-01

There is growing evidence for the importance of cardiovascular risk factors in dementia development, including Alzheimer's disease. As cardiovascular risk profiles vary greatly by gender, with men suffering a greater burden of cardiovascular risk in midlife, this could lead to differences in dementia risk. To explore current evidence on the association between components of the cardiovascular risk profile and dementia risk in women and men, we reviewed all studies reporting the risk of dementia associated with cardiovascular risk factors stratified by gender and found 53 eligible articles out of over 4,000 published since the year 2000. Consistent results were found: 1) for exposures acting specifically in women: Overweight/obesity (harmful) and physical activity (protective), and 2) for exposures acting similarly in women and men: Moderate alcohol (protective) and hypertension, diabetes, and depression (harmful). A modified effect of tobacco or high cholesterol/statin use remained controversial. Available data do not allow us to assess whether selection of men with healthier cardiovascular profile (due to cardiovascular death in midlife) could lead in late life either to a difference in the distribution of risk factors or to a differential effect of these risk factors by gender. We recommend that results on dementia risk factors, especially cardiovascular ones, be reported systematically by gender in all future studies. More generally, as cardiovascular risk profiles evolve over time, more attention needs to be paid to the detection and correction of cardiovascular risk factors, as early as possible in the life course, and as actively in women as in men.

The impact of congenital cardiovascular malformations on the assessment and surgical management of infants with cleft lip and/or palate.

PubMed

Harry, Brian L; TeBockhorst, Seth; Deleyiannis, Frederic W-B

2013-05-01

The purpose of this study was to assess the cardiac evaluation of cleft lip and/or palate patients, characterize their cardiovascular malformations, and determine the impact of cardiovascular malformations on surgical management. A single-institution retrospective study of 329 consecutive cleft patients was performed. Cardiovascular malformations were categorized according to involvement of cardiac septa, vasculature, and valves. Their impact on the need for cardiac surgery, timing of cleft repair, need for subacute bacterial endocarditis (SBE) prophylaxis, and the perioperative experience was evaluated. Ten percent (33/329) of cleft patients had a cardiovascular malformation, and 3% underwent cardiac surgery prior to cleft repair. Malformations of the septa, vasculature, and valves were present in 9%, 6%, and 2% of cleft infants, respectively. Murmur as a sign of structural cardiovascular disease was 79% sensitive and 97% specific. Cleft palate repair was delayed by 2 months in patients with a cardiovascular malformation (P = .001). Subacute bacterial endocarditis prophylaxis was recommended, not recommended, or not specified by cardiology in 18%, 33%, and 48% of cleft patients with a cardiovascular malformation, respectively. Postoperative stay and surgical complications were not associated with cardiovascular malformation. Even in the absence of a murmur, echocardiographic screening should be considered in infants with nonspecific signs of cardiovascular disease. Greater awareness of the guidelines for SBE prophylaxis is needed. Most cleft patients with a cardiovascular malformation do not require cardiac surgery and do not experience an increased rate of complications associated with cleft surgery.

14 CFR 67.111 - Cardiovascular.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Cardiovascular. 67.111 Section 67.111... STANDARDS AND CERTIFICATION First-Class Airman Medical Certificate § 67.111 Cardiovascular. Cardiovascular... disease that has required treatment or, if untreated, that has been symptomatic or clinically significant...

14 CFR 67.311 - Cardiovascular.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Cardiovascular. 67.311 Section 67.311... STANDARDS AND CERTIFICATION Third-Class Airman Medical Certificate § 67.311 Cardiovascular. Cardiovascular... disease that has required treatment or, if untreated, that has been symptomatic or clinically significant...

14 CFR 67.211 - Cardiovascular.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Cardiovascular. 67.211 Section 67.211... STANDARDS AND CERTIFICATION Second-Class Airman Medical Certificate § 67.211 Cardiovascular. Cardiovascular... any of the following: (a) Myocardial infarction; (b) Angina pectoris; (c) Coronary heart disease that...

Cardiovascular Fitness Education for Elementary Students

ERIC Educational Resources Information Center

Jenkins, David

1978-01-01

This cardiovascular fitness program for grades 1-6 (with emphasis on grades 5 and 6) consists of (1) discussion classes and exercise experiments, (2) discussion of exercise effects during regular activity sessions, (3) required cardiovascular warmup exercises, and (4) evaluation of cardiovascular fitness. (Author/MJB)

Racial Differences in Ideal Cardiovascular Health Metrics Among Mississippi Adults, 2009 Mississippi Behavioral Risk Factor Surveillance System

PubMed Central

Gamble, Abigail; Mendy, Vincent

2013-01-01

Introduction Cardiovascular disease is a leading cause of death and health disparities in Mississippi. Identifying populations with poor cardiovascular health may help direct interventions toward those populations disproportionately affected, which may ultimately increase cardiovascular health and decrease prominent disparities. Our objective was to assess racial differences in the prevalence of cardiovascular health metrics among Mississippi adults. Methods We used data from the 2009 Mississippi Behavioral Risk Factor Surveillance System to determine age-standardized prevalence estimates and 95% confidence intervals of cardiovascular health metrics among 2,003 black and 5,125 white adults. Logistic regression models were used to evaluate the relationship between race and cardiovascular health metrics. The mean cardiovascular metrics score and percentage of the population with ideal and poor cardiovascular health were calculated by subgroup. Results Approximately 1.3% of blacks and 2.6% of whites exhibited ideal levels of all 7 cardiovascular health metrics. The prevalence of 4 of the 7 cardiovascular health metrics was significantly lower among the total population of blacks than among whites, including a normal body mass index (20.8% vs 32.3%, P < .001), no history of diabetes (85.1% vs 91.3%, P < .001), no history of hypertension (53.9% vs 67.9%, P < .001), and physical activity (52.8% vs 62.2%, P < .001). The logistic regression models revealed significant race-by-sex interactions; differences between blacks and whites for normal body mass index, no history of diabetes mellitus, and no current smoking were found among women but not among men. Conclusion Cardiovascular health is poor among Mississippi adults overall, and racial differences exist. PMID:24262026

Major adverse cardiovascular event reduction with GLP-1 and SGLT2 agents: evidence and clinical potential

PubMed Central

Røder, Michael E.

2017-01-01

Treatment of patients with type 2 diabetes is directed against treating symptoms of hyperglycemia, minimizing the risk of hypoglycemia, and the risk of microvascular and macrovascular complications. The majority of patients with type 2 diabetes die from cardiovascular or cerebrovascular disease. Future therapies should therefore focus on reducing cardiovascular morbidity in this high-risk population. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are two drug classes with proven antihyperglycemic effect in type 2 diabetes. However, these drugs seem to have other effects such as weight reduction, low risk of hypoglycemia, and blood pressure reduction. Emerging evidence suggests pleiotropic effects, which potentially could be important in reducing cardiovascular risk. Prompted by regulatory authorities demanding cardiovascular outcome trials (CVOTs) assessing the cardiovascular safety of new antihyperglycemic drug candidates, many CVOTs are ongoing and a few of these are finalized. Somewhat surprising recent CVOTs in both drug classes have shown promising data on cardiovascular morbidity and mortality in patients with a very high risk of cardiovascular events. It is uncertain whether this is a class effect of the two drug classes, and it is yet unproven whether long-term cardiovascular benefits of these drugs can be extrapolated to populations at lower risk of cardiovascular disease. The aim of the present review is to give an overview of our current knowledge of the GLP-1RA and SGLT2-i classes, with specific focus on mechanisms of action, effects on cardiovascular risk factors and cardiovascular morbidity and mortality from the CVOTs presently available. The clinical potential of these data is discussed. PMID:29344329

Nutraceuticals in cardiovascular prevention: lessons from studies on endothelial function.

PubMed

Zuchi, Cinzia; Ambrosio, Giuseppe; Lüscher, Thomas F; Landmesser, Ulf

2010-08-01

An "unhealthy" diet is considered as a main cause of increased atherosclerotic cardiovascular disease in the industrialized countries. There is a substantial interest in the potential cardiovascular protective effects of "nutraceuticals," that is food-derived substances that exert beneficial health effects. The correct understanding of cardiovascular effects of these compounds will have important implications for cardiovascular prevention strategies. Endothelial dysfunction is thought to play an important role in development and progression of atherosclerosis, and the characterization of the endothelial effects of several nutraceuticals may provide important insights into their potential role in cardiovascular prevention. At the same time, the analysis of the endothelial effects of nutraceuticals may also provide valuable insights into mechanisms of why certain nutraceuticals may not be effective in cardiovascular prevention, and it may aid in the identification of food-derived substances that may have detrimental cardiovascular effects. These findings further support the notion that nutraceuticals do need support from large clinical outcome trials with respect to their efficacy and safety profile for cardiovascular prevention, before their widespread use can be recommended. In fact, the term nutraceutical was coined to encourage an extensive and profound research activity in this field, and numerous large-scale clinical outcome trials to examine the effects of nutraceuticals on cardiovascular events have now been performed or are still ongoing. Whereas it is possible that single nutraceuticals may be effective in cardiovascular prevention, this field of research provides also valuable insights into which food components may be particularly important for cardiovascular prevention, to further advice the composition of a particularly healthy diet. The present review summarizes recent studies on the endothelial effects of several nutraceuticals, that have been intensely studied.

Childhood Lifestyle and Clinical Determinants of Adult Ideal

PubMed Central

Laitinen, Tomi T.; Pahkala, Katja; Venn, Alison; Woo, Jessica G; Oikonen, Mervi; Dwyer, Terence; Mikkilä, Vera; Hutri-Kähönen, Nina; Smith, Kylie J.; Gall, Seana L.; Morrison, John A.; Viikari, Jorma S.A.; Raitakari, Olli T.; Magnussen, Costan G.; Juonala, Markus

2013-01-01

Background The American Heart Association recently defined ideal cardiovascular health by simultaneous presence of seven health behaviors and factors. The concept is associated with cardiovascular disease incidence, and cardiovascular disease and all-cause mortality. To effectively promote ideal cardiovascular health already early in life, childhood factors predicting future ideal cardiovascular health should be investigated. Our aim was thus to comprehensively explore childhood determinants of adult ideal cardiovascular health in population based cohorts from three continents. Methods The sample comprised a total of 4409 participants aged 3–19 years at baseline from the Cardiovascular Risk in Young Finns Study (YFS; N=1883) from Finland, Childhood Determinants of Adult Health Study (CDAH; N=1803) from Australia and Princeton Follow-up Study (PFS; N=723) from the United States. Participants were re-examined 19–31 years later when aged 30–48 years. Results In multivariable analyses, independent childhood predictors of adult ideal cardiovascular health were family socioeconomic status (P<0.01; direct association) and BMI (P<0.001; inverse association) in all cohorts. In addition, blood pressure (P=0.007), LDL-cholesterol (P<0.001) and parental smoking (P=0.006) in the YFS, and own smoking (P=0.001) in CDAH were inversely associated with future ideal cardiovascular health. Conclusions Among several lifestyle and clinical indicators studied, higher family socioeconomic status and non-smoking (parental/own) in childhood independently predict ideal cardiovascular health in adulthood. As atherosclerotic cardiovascular diseases are rooted in childhood, our findings suggest that special attention could be paid to children who are from low socioeconomic status families, and who smoke or whose parents smoke, to prevent cardiovascular disease morbidity and mortality. PMID:24075574

Primary prevention of cardiovascular disease in patients with systemic lupus erythematosus: case series and literature review.

PubMed

Fasano, S; Margiotta, D P; Navarini, L; Pierro, L; Pantano, I; Riccardi, A; Afeltra, A; Valentini, G

2017-12-01

Background Systemic lupus erythematosus is associated with an increased risk of cardiovascular disease. Low-dose aspirin, hydroxychloroquine and statins have been suggested to play a prophylactic role of cardiovascular events. This study is devoted to reviewing the literature on the topic and assessing the effects of these drugs in preventing a first cardiovascular event in a two-centre Italian series. Methods A PubMed search on cardiovascular prevention in systemic lupus erythematosus was performed. Moreover, systemic lupus erythematosus patients admitted to two centres from 2000-2015, who at admission had not experienced any cardiovascular event, were investigated. Aspirin, hydroxychloroquine and statin use, and the occurrence of any cardiovascular event, were recorded at each visit. Kaplan-Meier and Cox regression analyses were performed to evaluate the role of traditional, disease-related cardiovascular risk factors and of each of the three drugs in the occurrence of new cardiovascular events. Results The literature search produced conflicting results. Two hundred and ninety-one systemic lupus erythematosus patients were included in the study and followed for a median of eight years. During follow-up, 16 cardiovascular events occurred. At multivariate analysis, taking aspirin (hazard ratio: 0.24) and hydroxychloroquine for more than five years (hazard ratio: 0.27) reduced, while antiphospholipid antibody positivity (hazard ratio: 4.32) increased, the risk of a first cardiovascular event. No effect of statins emerged. Conclusion Our study confirms an additive role of aspirin and hydroxychloroquine in the primary prophylaxis of cardiovascular events in Italian patients with systemic lupus erythematosus. The lack of any detected effect in previous reports may depend on the design of studies and their short follow-up period.

Maintained intentional weight loss reduces cardiovascular outcomes: results from the Sibutramine Cardiovascular OUTcomes (SCOUT) trial.

PubMed

Caterson, I D; Finer, N; Coutinho, W; Van Gaal, L F; Maggioni, A P; Torp-Pedersen, C; Sharma, A M; Legler, U F; Shepherd, G M; Rode, R A; Perdok, R J; Renz, C L; James, W P T

2012-06-01

The Sibutramine Cardiovascular OUTcomes trial showed that sibutramine produced greater mean weight loss than placebo but increased cardiovascular morbidity but not mortality. The relationship between 12-month weight loss and subsequent cardiovascular outcomes is explored. Overweight/obese subjects (N = 10 744), ≥55 years with cardiovascular disease and/or type 2 diabetes mellitus, received sibutramine plus weight management during a 6-week Lead-in Period before randomization to continue sibutramine (N = 4906) or to receive placebo (N = 4898). The primary endpoint was the time from randomization to first occurrence of a primary outcome event (non-fatal myocardial infarction, non-fatal stroke, resuscitated cardiac arrest or cardiovascular death). For the total population, mean weight change during Lead-in Period (sibutramine) was -2.54 kg. Post-randomization, mean total weight change to Month 12 was -4.18 kg (sibutramine) or -1.87 kg (placebo). Degree of weight loss during Lead-in Period or through Month 12 was associated with a progressive reduction in risk for the total population in primary outcome events and cardiovascular mortality over the 5-year assessment. Although more events occurred in the randomized sibutramine group, on an average, a modest weight loss of approximately 3 kg achieved in the Lead-in Period appeared to offset this increased event rate. Moderate weight loss (3-10 kg) reduced cardiovascular deaths in those with severe, moderate or mild cardiovascular disease. Modest weight loss over short-term (6 weeks) and longer-term (6-12 months) periods is associated with reduction in subsequent cardiovascular mortality for the following 4-5 years even in those with pre-existing cardiovascular disease. While the sibutramine group experienced more primary outcome events than the placebo group, greater weight loss reduced overall risk of these occurring in both groups. © 2011 Blackwell Publishing Ltd.

Suboptimal primary and secondary cardiovascular disease prevention in HIV-positive individuals on antiretroviral therapy.

PubMed

van Zoest, Rosan A; van der Valk, Marc; Wit, Ferdinand W; Vaartjes, Ilonca; Kooij, Katherine W; Hovius, Joppe W; Prins, Maria; Reiss, Peter

2017-08-01

Background We aimed to identify the prevalence of cardiovascular risk factors, and investigate preventive cardiovascular medication use and achievement of targets as per Dutch cardiovascular risk management guidelines among human immunodeficiency virus (HIV)-positive and HIV-negative individuals. Design The design was a cross-sectional analysis within an ongoing cohort study. Methods Data on medication use and cardiovascular disease prevalence were available for 528 HIV-positive and 521 HIV-negative participants. We identified cardiovascular risk factors and applied cardiovascular risk management guidelines, mainly focusing on individuals eligible for (a) primary prevention because of high a priori cardiovascular risk, or for (b) secondary prevention. Results One hundred and three (20%) HIV-positive and 77 (15%) HIV-negative participants were classified as having high cardiovascular risk; 53 (10%) HIV-positive and 27 (5%) HIV-negative participants were eligible for secondary prevention. Of HIV-positive individuals 57% at high cardiovascular risk and 42% of HIV-positive individuals eligible for secondary prevention had systolic blood pressures above guideline-recommended thresholds. Cholesterol levels were above guideline-recommended thresholds in 81% of HIV-positive individuals at high cardiovascular risk and 57% of HIV-positive individuals eligible for secondary prevention. No statistically significant differences were observed between HIV-positive and HIV-negative participants regarding achievement of targets, except for glycaemic control (glycated haemoglobin ≤ 53 mmol/mol) among individuals using diabetes medication (90% vs 50%, p = 0.017) and antiplatelet/anticoagulant use for secondary prevention (85% vs 63%, p = 0.045), which were both superior among HIV-positive participants. Conclusions Cardiovascular risk management is suboptimal in both HIV-positive and HIV-negative individuals and should be improved.

Suboptimal primary and secondary cardiovascular disease prevention in HIV-positive individuals on antiretroviral therapy

PubMed Central

van der Valk, Marc; Wit, Ferdinand W; Vaartjes, Ilonca; Kooij, Katherine W; Hovius, Joppe W; Prins, Maria; Reiss, Peter

2017-01-01

Background We aimed to identify the prevalence of cardiovascular risk factors, and investigate preventive cardiovascular medication use and achievement of targets as per Dutch cardiovascular risk management guidelines among human immunodeficiency virus (HIV)-positive and HIV-negative individuals. Design The design was a cross-sectional analysis within an ongoing cohort study. Methods Data on medication use and cardiovascular disease prevalence were available for 528 HIV-positive and 521 HIV-negative participants. We identified cardiovascular risk factors and applied cardiovascular risk management guidelines, mainly focusing on individuals eligible for (a) primary prevention because of high a priori cardiovascular risk, or for (b) secondary prevention. Results One hundred and three (20%) HIV-positive and 77 (15%) HIV-negative participants were classified as having high cardiovascular risk; 53 (10%) HIV-positive and 27 (5%) HIV-negative participants were eligible for secondary prevention. Of HIV-positive individuals 57% at high cardiovascular risk and 42% of HIV-positive individuals eligible for secondary prevention had systolic blood pressures above guideline-recommended thresholds. Cholesterol levels were above guideline-recommended thresholds in 81% of HIV-positive individuals at high cardiovascular risk and 57% of HIV-positive individuals eligible for secondary prevention. No statistically significant differences were observed between HIV-positive and HIV-negative participants regarding achievement of targets, except for glycaemic control (glycated haemoglobin ≤ 53 mmol/mol) among individuals using diabetes medication (90% vs 50%, p = 0.017) and antiplatelet/anticoagulant use for secondary prevention (85% vs 63%, p = 0.045), which were both superior among HIV-positive participants. Conclusions Cardiovascular risk management is suboptimal in both HIV-positive and HIV-negative individuals and should be improved. PMID:28578613

Real-world cardiovascular assessment of mirabegron treatment in patients with overactive bladder and concomitant cardiovascular disease: Results of a Japanese post-marketing study.

PubMed

Katoh, Takao; Kuwamoto, Kana; Kato, Daisuke; Kuroishi, Kentarou

2016-12-01

To assess the effect of 25 or 50 mg mirabegron on cardiovascular end-points and adverse drug reactions in real-world Japanese patients with overactive bladder and cardiovascular disease. Participants had overactive bladder, a history of/coexisting cardiovascular disease and a 12-lead electrocardiogram carried out ≤7 days before initiating 4 weeks of mirabegron treatment. Patients with "serious cardiovascular disease" (class III or IV on the New York Heart Association functional classification and further confirmed by expert analysis) were excluded. Patient demographics, physical characteristics and cardiovascular history were recorded. After 4 weeks, patients underwent another electrocardiogram. Incidence of cardiovascular adverse drug reactions and change from baseline in electrocardiogram parameters (RR, PR, QRS intervals, Fridericia's corrected QT and heart rate) were assessed. Of 316 patients registered, 236 met criteria and had baseline/post-dose electrocardiograms: 61.9% male; 60.2% aged ≥75 years; 93.6% with coexisting cardiovascular disease, notably, arrhythmia (67.8%) and angina pectoris (19.1%). Starting mirabegron daily doses were 25 mg (19.9%) or 50 mg (80.1%). The incidence of cardiovascular adverse drug reactions was 5.51%. After 4 weeks, the mean heart rate increased by 1.24 b.p.m. (statistically significant, but clinically acceptable as per previous trials). No significant changes were observed in PR, QRS or Fridericia's corrected QT. No significant correlations in the total population or age-/sex-segregated subgroups were observed between baseline Fridericia's corrected QT and change at 4 weeks. No correlation for heart rate versus change from baseline heart rate with treatment was observed. Mirabegron was well tolerated in real-world Japanese patients with overactive bladder and coexisting cardiovascular disease. No unexpected cardiovascular safety concerns were observed. © 2016 The Japanese Urological Association.

Gout and rheumatoid arthritis, both to keep in mind in cardiovascular risk management: A primary care retrospective cohort study.

PubMed

Janssens, Hein J E M; Arts, Paul G J; Schalk, Bianca W M; Biermans, Marion C J

2017-01-01

To assess in one time window cardiovascular risks for both patients with gout and patients with rheumatoid arthritis in a Dutch primary care population. Retrospective matched cohort study with data from the electronic health records of 51 Dutch general practices. Participants were patients aged 30 years or older with an incident diagnosis of gout (n=2655) or rheumatoid arthritis (n=513), and matched non-disease controls (n=7891 and n=1850 respectively). At disease incidence date, patients and controls were compared for prevalence of hypertension, diabetes mellitus, hypercholesterolemia, and prior cardiovascular diseases. Patients without prior cardiovascular disease were followed for a first cardiovascular disease, and compared to controls using Kaplan-Meier survival curves and Cox proportional hazard analyses. Compared to controls, gout patients suffered more from hypertension (44.8%), diabetes (20.1%), hypercholesterolemia (13.7%), and prior cardiovascular disease (30%) (P<0.01), whereas rheumatoid arthritis patients (hypertension 28.5%; diabetes 11.7%; hypercholesterolemia 7.4%; prior cardiovascular disease 11.3%) did not (P>0.05). After adjustment, both gout and rheumatoid arthritis patients without prior cardiovascular disease were more likely to get a cardiovascular disease: hazard ratio (95% confidence interval) 1.44 (1.18 to 1.76), and 2.06 (1.34 to 3.16) respectively. This primary care study indicates that gout and rheumatoid arthritis are both independent risk factors for cardiovascular diseases, rheumatoid arthritis to some greater extent, whereas gout patients at first diagnosis had already an increased cardiovascular risk profile. It gives strong arguments for implementation of both rheumatic diseases in primary care guidelines on cardiovascular risk management. Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

The Cardiovascular Health in Ambulatory Care Research Team performance indicators for the primary prevention of cardiovascular disease: a modified Delphi panel study.

PubMed

Tu, Jack V; Maclagan, Laura C; Ko, Dennis T; Atzema, Clare L; Booth, Gillian L; Johnston, Sharon; Tu, Karen; Lee, Douglas S; Bierman, Arlene; Hall, Ruth; Bhatia, R Sacha; Gershon, Andrea S; Tobe, Sheldon W; Sanmartin, Claudia; Liu, Peter; Chu, Anna

2017-04-25

High-quality ambulatory care can reduce cardiovascular disease risk, but important gaps exist in the provision of cardiovascular preventive care. We sought to develop a set of key performance indicators that can be used to measure and improve cardiovascular care in the primary care setting. As part of the Cardiovascular Health in Ambulatory Care Research Team initiative, we established a 14-member multidisciplinary expert panel to develop a set of indicators for measuring primary prevention performance in ambulatory cardiovascular care. We used a 2-stage modified Delphi panel process to rate potential indicators, which were identified from the literature and national cardiovascular organizations. The top-rated indicators were pilot tested to determine their measurement feasibility with the use of data routinely collected in the Canadian health care system. A set of 28 indicators of primary prevention performance were identified, which were grouped into 5 domains: risk factor prevalence, screening, management, intermediate outcomes and long-term outcomes. The indicators reflect the major cardiovascular risk factors including smoking, obesity, hypertension, diabetes, dyslipidemia and atrial fibrillation. All indicators were determined to be amenable to measurement with the use of population-based administrative (physician claims, hospital admission, laboratory, medication), survey or electronic medical record databases. The Cardiovascular Health in Ambulatory Care Research Team indicators of primary prevention performance provide a framework for the measurement of cardiovascular primary prevention efforts in Canada. The indicators may be used by clinicians, researchers and policy-makers interested in measuring and improving the prevention of cardiovascular disease in ambulatory care settings. Copyright 2017, Joule Inc. or its licensors.

Advanced Tracers in PET Imaging of Cardiovascular Disease

PubMed Central

Zhang, Wei; Wu, Hua; Liu, Gang

2014-01-01

Cardiovascular disease is the leading cause of death worldwide. Molecular imaging with targeted tracers by positron emission tomography (PET) allows for the noninvasive detection and characterization of biological changes at the molecular level, leading to earlier disease detection, objective monitoring of therapies, and better prognostication of cardiovascular diseases progression. Here we review, the current role of PET in cardiovascular disease, with emphasize on tracers developed for PET imaging of cardiovascular diseases. PMID:25389529

Twenty-Four-Hour Central Pulse Pressure for Cardiovascular Events Prediction in a Low-Cardiovascular-Risk Population: Results From the Bordeaux Cohort.

PubMed

Cremer, Antoine; Boulestreau, Romain; Gaillard, Prune; Lainé, Marion; Papaioannou, Georgios; Gosse, Philippe

2018-02-23

Central blood pressure (BP) is a promising marker to identify subjects with higher cardiovascular risk than expected by traditional risk factors. Significant results have been obtained in populations with high cardiovascular risk, but little is known about low-cardiovascular-risk patients, although the differences between central and peripheral BP (amplification) are usually greater in this population. The study aim was to evaluate central BP over 24 hours for cardiovascular event prediction in hypertensive subjects with low cardiovascular risk. Peripheral and central BPs were recorded during clinical visits and over 24 hours in hypertensive patients with low cardiovascular risk (Systematic Coronary Risk Evaluation ≤5%). Our primary end point is the occurrence of a cardiovascular event during follow-up. To assess the potential interest in central pulse pressure over 24 hours, we performed Cox proportional hazard models analysis and comparison of area under the curves using the contrast test for peripheral and central BP. A cohort of 703 hypertensive subjects from Bordeaux were included. After the first 24 hours of BP measurement, the subjects were then followed up for an average of 112.5±70 months. We recorded 65 cardiovascular events during follow-up. Amplification was found to be significantly associated with cardiovascular events when added to peripheral 24-hour pulse pressure ( P =0.0259). The area under the curve of 24-hour central pulse pressure is significantly more important than area under the curve of office BP ( P =0.0296), and there is a trend of superiority with the area under the curve of peripheral 24-hour pulse pressure. Central pulse pressure over 24 hours improves the prediction of cardiovascular events for hypertensive patients with low cardiovascular risk compared to peripheral pulse pressure. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Office blood pressure or ambulatory blood pressure for the prediction of cardiovascular events.

PubMed

Mortensen, Rikke Nørmark; Gerds, Thomas Alexander; Jeppesen, Jørgen Lykke; Torp-Pedersen, Christian

2017-11-21

To determine the added value of (i) 24-h ambulatory blood pressure relative to office blood pressure and (ii) night-time ambulatory blood pressure relative to daytime ambulatory blood pressure for 10-year person-specific absolute risks of fatal and non-fatal cardiovascular events. A total of 7927 participants were included from the International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes. We used cause-specific Cox regression to predict 10-year person-specific absolute risks of fatal and non-fatal cardiovascular events. Discrimination of 10-year outcomes was assessed by time-dependent area under the receiver operating characteristic curve (AUC). No differences in predicted risks were observed when comparing office blood pressure and ambulatory blood pressure. The median difference in 10-year risks (1st; 3rd quartile) was -0.01% (-0.3%; 0.1%) for cardiovascular mortality and -0.1% (-1.1%; 0.5%) for cardiovascular events. The difference in AUC (95% confidence interval) was 0.65% (0.22-1.08%) for cardiovascular mortality and 1.33% (0.83-1.84%) for cardiovascular events. Comparing daytime and night-time blood pressure, the median difference in 10-year risks was 0.002% (-0.1%; 0.1%) for cardiovascular mortality and -0.01% (-0.5%; 0.2%) for cardiovascular events. The difference in AUC was 0.10% (-0.08 to 0.29%) for cardiovascular mortality and 0.15% (-0.06 to 0.35%) for cardiovascular events. Ten-year predictions obtained from ambulatory blood pressure are similar to predictions from office blood pressure. Night-time blood pressure does not improve 10-year predictions obtained from daytime measurements. For an otherwise healthy population sufficient prognostic accuracy of cardiovascular risks can be achieved with office blood pressure. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Design and rationale for the Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI 61) trial.

PubMed

Bohula, Erin A; Scirica, Benjamin M; Fanola, Christina; Inzucchi, Silvio E; Keech, Anthony; McGuire, Darren K; Smith, Steven R; Abrahamsen, Tim; Francis, Bruce H; Miao, Wenfeng; Perdomo, Carlos A; Satlin, Andrew; Wiviott, Stephen D; Sabatine, Marc S

2018-03-29

Lorcaserin, a selective serotonin 2C receptor agonist, is an effective pharmacologic weight-loss therapy that improves several cardiovascular risk factors. The long-term clinical cardiovascular and metabolic safety and efficacy in patients with elevated cardiovascular risk are unknown. CAMELLIA-TIMI 61 (NCT02019264) is a randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the safety and efficacy of lorcaserin with regard to major adverse cardiovascular events and progression to diabetes in overweight or obese patients at high cardiovascular risk. Overweight or obese patients either with established cardiovascular disease or with diabetes and at least 1 other cardiovascular risk factor were randomized in a 1:1 ratio to lorcaserin 10 mg twice daily or matching placebo. The primary safety objective is to assess for noninferiority of lorcaserin for the composite end point of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular event [MACE]) (with noninferiority defined as the upper bound of a 1-sided 97.5% CI excluding a hazard ratio of 1.4) compared with placebo assessed at an interim analysis with 460 adjudicated events. The efficacy objectives, assessed at study completion, will evaluate the superiority of lorcaserin for the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or any coronary revascularization (MACE+) and the key secondary end point of conversion to diabetes. Recruitment began in January 2014 and was completed in November 2015 resulting in a total population of 12,000 patients. The trial is planned to continue until at least 1,401 adjudicated MACE+ events are accrued and the median treatment duration exceeds 2.5 years. CAMELLIA-TIMI 61 is investigating the safety and efficacy of lorcaserin for MACEs and conversion to diabetes in overweight or obese patients with established cardiovascular disease or multiple cardiovascular risk factors. Copyright © 2018. Published by Elsevier Inc.

PFA-100-measured aspirin resistance is the predominant risk factor for hospitalized cardiovascular events in aspirin-treated patients: A 5-year cohort study.

PubMed

Chen, H Y; Chou, P

2018-04-01

Aspirin therapy is the clinical gold standard for the prevention of cardiovascular events. However, cardiovascular events still develop in some patients undergoing aspirin therapy. Many laboratory methods exist for measuring aspirin resistance. Using the platelet Function Analyzer (PFA)-100 system, we aimed to determine the effect of aspirin resistance on hospitalized cardiovascular events (hCVE) in a 5-year follow-up cohort. We also sought to determine the impact of aspirin resistance on the relationship between common cardiovascular risk factors and cardiovascular hospitalization. Aspirin resistance was evaluated in aspirin-treated patients from the outpatient department. A total of 465 patients during a 5-year follow-up period were included in this study. The primary endpoint of the study was hospitalization for any acute cardiovascular event. The prevalence and associated risk factors of acute cardiovascular events were evaluated. Aspirin resistance was prevalent in 91 (20.0%) of 465 patients. Prior hospitalization history of cardiovascular events was highly associated with aspirin resistance (P = .001). At the 5-year follow-up, cardiovascular events were found to have developed in 11 patients (8 stroke and 3 myocardial infarction) who exhibited aspirin resistance (12.1%) and in 9 (4 stroke and 5 myocardial infarction) patients who did not exhibit aspirin resistance (2.4%) (P < .001). At the 5-year follow-up, multivariate logistic regression analysis results showed a strong association between aspirin resistance and cardiovascular events (adjusted odds ratio 4.28; 95% CI: 1.64-11.20; P = .03). PFA-100 measurements of aspirin resistance correlate with hCVE, as evidenced by both the past medical history and the 5-year follow-up. The logistic regression analysis results showed that aspirin resistance plays a larger role in hospitalized cardiovascular disease than do other cardiovascular risk factors. © 2017 John Wiley & Sons Ltd.

75 FR 70933 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-19

...] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS... of Committee: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committees... appropriate clinical study design for thromboxane receptor antagonists for prevention of cardiovascular events...

Cardio-oncology: conflicting priorities of anticancer treatment and cardiovascular outcome.

PubMed

Tilemann, Lisa M; Heckmann, Markus B; Katus, Hugo A; Lehmann, Lorenz H; Müller, Oliver J

2018-04-01

This article about the emerging field of cardio-oncology highlights typical side effects of oncological therapies in the cardiovascular system, cardiovascular complications of malignancies itself, and potential preventive or therapeutic modalities. We performed a selective literature search in PubMed until September 2016. Cardiovascular events in cancer patients can be frequently attributed to oncological therapies or to the underlying malignancy itself. Furthermore, many patients with cancer have pre-existing cardiovascular diseases that can be aggravated by the malignancy or its therapy. Cardiovascular abnormalities in oncological patients comprise a broad spectrum from alterations in electrophysiological, laboratory or imaging tests to the occurrence of thromboembolic, ischemic or rhythmological events and the impairment of left ventricular function or manifest heart failure. A close interdisciplinary collaboration between oncologists and cardiologists/angiologists as well as an increased awareness of potential cardiovascular complications could improve clinical care of cancer patients and provides a basis for an improved understanding of underlying mechanisms of cardiovascular morbidity.

Advances in the study on endogenous sulfur dioxide in the cardiovascular system.

PubMed

Tian, Hong

2014-01-01

This review summarized the current advances in understanding the role of the novel gasotransmitter, sulfur dioxide (SO2), in the cardiovascular system. Articles on the advances in the study of the role of endogenous sulfur dioxide in the cardiovascular system were accessed from PubMed and CNKI from 2003 to 2013, using keywords such as "endogenous sulfur dioxide" and "cardiovascular system". Articles with regard to the role of SO2 in the regulation of cardiovascular system were selected. Recently, scientists discovered that an endogenous SO2 pathway is present in the cardiovascular system and exerts physiologically significant effects, such as regulation of the cardiac function and the pathogenesis of various cardiopulmonary diseases such as hypoxic pulmonary hypertension, hypertension, coronary atherosclerosis, and cardiac ischemia-reperfusion (I/R) injury, in the cardiovascular system. Endogenous SO2 is a novel member of the gasotransmitter family in addition to the nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). Studies indicated that it has a role in regulating the cardiovascular disease.

Oral contraceptives and cardiovascular risk in women with polycystic ovary syndrome.

PubMed

Carmina, E

2013-05-01

Because women affected by polycystic ovary syndrome (PCOS) present an increased cardiovascular risk, the safety of estroprogestin treatment is debated and contrasting data have been reported. However, cardiovascular risk is not the same in all PCOS women and individual cardiovascular risk should be assessed before staring any estroprogestin treatment. The available data show that products containing both 2nd-generation and 3rd-generation progestins (including drospirenone and cyproterone acetate) represent a safe treatment in PCOS patients with regular cardiovascular risk. In PCOS patients with increased cardiovascular risk, a careful choice of estroprogestin product is needed and cardiovascular risk should be monitored during treatment. In obese PCOS patients with normal glucose tolerance and lipid profile, products containing 2nd-generation progestins may be preferred because of lower venous thromboembolism risk. In PCOS patients with altered lipid profile or glucose intolerance, 3rd-generation progestins should be used but, during treatment, cardiovascular risk should be periodically re-assessed. In special situations, metformin or statins may be added to estroprogestin treatment.

Preeclampsia, prematurity and cardiovascular health in adult life.

PubMed

Lewandowski, Adam J; Leeson, Paul

2014-11-01

Investigations into how perinatal growth and intrauterine environment may 'programme' risk of later cardiovascular disease have been ongoing for over two decades. One of the more recent outcomes of these studies is the observation that certain pregnancy-related conditions, such as preterm birth, have an unusually large impact on the long-term cardiovascular health of the offspring. In the present paper, we review the current literature of how preterm birth affects the long-term cardiovascular structure and function of the offspring, considering three major areas of investigation: firstly, outlining the long-term cardiovascular phenotypic changes in preterm-born individuals; secondly, investigating factors related to preterm birth that may be modifying cardiovascular phenotype, such as preeclampsia, perinatal interventions, and physiological disturbances; and thirdly, the expected clinical relevance of these cardiovascular changes. This review discusses the importance of continued research focused on the mechanistic understanding of these cardiovascular alterations in order to develop specific primary prevention strategies. Copyright © 2014 Elsevier Ltd. All rights reserved.

Artificial Intelligence in Precision Cardiovascular Medicine.

PubMed

Krittanawong, Chayakrit; Zhang, HongJu; Wang, Zhen; Aydar, Mehmet; Kitai, Takeshi

2017-05-30

Artificial intelligence (AI) is a field of computer science that aims to mimic human thought processes, learning capacity, and knowledge storage. AI techniques have been applied in cardiovascular medicine to explore novel genotypes and phenotypes in existing diseases, improve the quality of patient care, enable cost-effectiveness, and reduce readmission and mortality rates. Over the past decade, several machine-learning techniques have been used for cardiovascular disease diagnosis and prediction. Each problem requires some degree of understanding of the problem, in terms of cardiovascular medicine and statistics, to apply the optimal machine-learning algorithm. In the near future, AI will result in a paradigm shift toward precision cardiovascular medicine. The potential of AI in cardiovascular medicine is tremendous; however, ignorance of the challenges may overshadow its potential clinical impact. This paper gives a glimpse of AI's application in cardiovascular clinical care and discusses its potential role in facilitating precision cardiovascular medicine. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

A literature review of the cardiovascular risk-assessment tools: applicability among Asian population.

PubMed

Liau, Siow Yen; Mohamed Izham, M I; Hassali, M A; Shafie, A A

2010-01-01

Cardiovascular diseases, the main causes of hospitalisations and death globally, have put an enormous economic burden on the healthcare system. Several risk factors are associated with the occurrence of cardiovascular events. At the heart of efficient prevention of cardiovascular disease is the concept of risk assessment. This paper aims to review the available cardiovascular risk-assessment tools and its applicability in predicting cardiovascular risk among Asian populations. A systematic search was performed using keywords as MeSH and Boolean terms. A total of 25 risk-assessment tools were identified. Of these, only two risk-assessment tools (8%) were derived from an Asian population. These risk-assessment tools differ in various ways, including characteristics of the derivation sample, type of study, time frame of follow-up, end points, statistical analysis and risk factors included. Very few cardiovascular risk-assessment tools were developed in Asian populations. In order to accurately predict the cardiovascular risk of our population, there is a need to develop a risk-assessment tool based on local epidemiological data.

Is Sex Good for Your Health? A National Study on Partnered Sexuality and Cardiovascular Risk Among Older Men and Women

PubMed Central

Liu, Hui; Waite, Linda; Shen, Shannon; Wang, Donna

2016-01-01

Working from a social relationship and life course perspective, we provide generalizable population-based evidence on partnered sexuality linked to cardiovascular risk in later life using national longitudinal data from the NSHAP (N=2204). We consider characteristics of partnered sexuality of older men and women, particularly sexual activity and sexual quality, as they affect cardiovascular risk. Cardiovascular risk is defined as hypertension, rapid heart rate, elevated CRP, and general cardiovascular events. We find that older men are more likely to report being sexually active, report having sex more often and more enjoyably than are older women. Results from cross-lagged models suggest that high frequency of sex is positively related to later risk of cardiovascular events for men but not women, whereas good sexual quality seems to protect women but not men from cardiovascular risk in later life. We find no evidence that poor cardiovascular health interferes with later sexuality for either gender. PMID:27601406

Regulation of the Cardiovascular System by Histamine.

PubMed

Hattori, Yuichi; Hattori, Kohshi; Matsuda, Naoyuki

2017-01-01

Histamine mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in the central nervous system. Histamine also exerts a series of actions upon the cardiovascular system but may not normally play a significant role in regulating cardiovascular function. During tissue injury, inflammation, and allergic responses, mast cells (or non-mast cells) within the tissues can release large amounts of histamine that leads to noticeable cardiovascular effects. Owing to intensive research during several decades, the distribution, function, and pathophysiological role of cardiovascular H 1 - and H 2 -receptors has become recognized adequately. Besides the recognized H 1 - and H 2 -receptor-mediated cardiovascular responses, novel roles of H 3 - and H 4 -receptors in cardiovascular physiology and pathophysiology have been identified over the last decade. In this review, we describe recent advances in our understanding of cardiovascular function and dysfunction mediated by histamine receptors, including H 3 - and H 4 -receptors, their potential mechanisms of action, and their pathological significance.

Aortic valve calcium independently predicts coronary and cardiovascular events in a primary prevention population.

PubMed

Owens, David S; Budoff, Matthew J; Katz, Ronit; Takasu, Junichiro; Shavelle, David M; Carr, J Jeffrey; Heckbert, Susan R; Otto, Catherine M; Probstfield, Jeffrey L; Kronmal, Richard A; O'Brien, Kevin D

2012-06-01

This study sought to test whether aortic valve calcium (AVC) is independently associated with coronary and cardiovascular events in a primary-prevention population. Aortic sclerosis is associated with increased cardiovascular morbidity and mortality among the elderly, but the mechanisms underlying this association remain controversial. Also, it is unknown whether this association extends to younger individuals. We performed a prospective analysis of 6,685 participants in MESA (Multi-Ethnic Study of Atherosclerosis). All subjects, ages 45 to 84 years and free of clinical cardiovascular disease at baseline, underwent computed tomography for AVC and coronary artery calcium scoring. The primary, pre-specified combined endpoint of cardiovascular events included myocardial infarctions, fatal and nonfatal strokes, resuscitated cardiac arrest, and cardiovascular death, whereas a secondary combined endpoint of coronary events excluded strokes. The association between AVC and clinical events was assessed using Cox proportional hazards regression with incremental adjustments for demographics, cardiovascular risk factors, inflammatory biomarkers, and subclinical coronary atherosclerosis. Over a median follow-up of 5.8 years (interquartile range: 5.6 to 5.9 years), adjusting for demographics and cardiovascular risk factors, subjects with AVC (n = 894, 13.4%) had higher risks of cardiovascular (hazard ratio [HR]: 1.50; 95% confidence interval [CI]: 1.10 to 2.03) and coronary (HR: 1.72; 95% CI: 1.19 to 2.49) events compared with those without AVC. Adjustments for inflammatory biomarkers did not alter these associations, but adjustment for coronary artery calcium substantially attenuated both cardiovascular (HR: 1.32; 95% CI: 0.98 to 1.78) and coronary (HR: 1.41; 95% CI: 0.98 to 2.02) event risk. AVC remained predictive of cardiovascular mortality even after full adjustment (HR: 2.51; 95% CI: 1.22 to 5.21). In this MESA cohort, free of clinical cardiovascular disease, AVC predicts cardiovascular and coronary event risk independent of traditional risk factors and inflammatory biomarkers, likely due to the strong correlation between AVC and subclinical atherosclerosis. The association of AVC with excess cardiovascular mortality beyond coronary atherosclerosis risk merits further investigation. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487). Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Cardiovascular Disease Risk in Children With Kidney Disease.

PubMed

Sethna, Christine B; Merchant, Kumail; Reyes, Abigail

2018-05-01

Cardiovascular disease is a major cause of death in individuals diagnosed with kidney disease during childhood. Children with kidney disease often incur a significant cardiovascular burden that leads to increased risk for cardiovascular disease. Evidence has shown that children with kidney disease, including chronic kidney disease, dialysis, kidney transplantation, and nephrotic syndrome, develop abnormalities in cardiovascular markers such as hypertension, dyslipidemia, left ventricular hypertrophy, left ventricular dysfunction, atherosclerosis, and aortic stiffness. Early identification of modifiable risk factors and treatment may lead to a decrease of long-term cardiovascular morbidity and mortality, but evidence in this population is lacking. Copyright © 2018 Elsevier Inc. All rights reserved.

Erectile dysfunction in patients with cardiovascular disease

PubMed Central

Ophuis, A.J.M. Oude; Nijeholt, A.A.B. Lycklama à

2006-01-01

Erectile dysfunction is a highly prevalent disease, especially in cardiovascular-compromised men. Many of the well-established risk factors for cardiovascular disease are also risk factors for erectile dysfunction. A correlation between erectile dysfunction and endothelial dysfunction is well established. It is postulated that erectile dysfunction with an arteriovascular aetiology can predate and be an indicator of potential coronary artery disease. In this paper we will attempt to increase awareness among cardiologists for the predictive value of erectile dysfunction for future cardiovascular disease in order to optimise cardiovascular risk management. The treatment of erectile dysfunction and cardiovascular interactions is also discussed in detail. ImagesFigure 1AFigure 1B PMID:25696612

Predictors of Cardiovascular Events After Liver Transplantation.

PubMed

Gallegos-Orozco, Juan F; Charlton, Michael R

2017-05-01

Indications for liver transplant have been extended, and older and sicker patients are undergoing transplantation. Infectious, malignant, and cardiovascular diseases account for the most posttransplant deaths. Cirrhotic patients can develop heart disease through systemic diseases affecting the heart and the liver, cirrhosis-specific heart disease, or common cardiovascular. No single factor can predict posttransplant cardiovascular complications. Patients with history of cardiovascular disease, and specific abnormalities on echocardiography, electrocardiography, or serum markers of heart disease seem to be at increased risk of complications. Pretransplant cardiovascular evaluation is essential to detecting these risk factors so their effects can be mitigated through appropriate intervention. Copyright © 2016 Elsevier Inc. All rights reserved.

Cardiovascular magnetic resonance in adults with previous cardiovascular surgery.

PubMed

von Knobelsdorff-Brenkenhoff, Florian; Trauzeddel, Ralf Felix; Schulz-Menger, Jeanette

2014-03-01

Cardiovascular magnetic resonance (CMR) is a versatile non-invasive imaging modality that serves a broad spectrum of indications in clinical cardiology and has proven evidence. Most of the numerous applications are appropriate in patients with previous cardiovascular surgery in the same manner as in non-surgical subjects. However, some specifics have to be considered. This review article is intended to provide information about the application of CMR in adults with previous cardiovascular surgery. In particular, the two main scenarios, i.e. following coronary artery bypass surgery and following heart valve surgery, are highlighted. Furthermore, several pictorial descriptions of other potential indications for CMR after cardiovascular surgery are given.

Cardiovascular health promotion in aging women: validating a population health approach.

PubMed

Sawatzky, Jo-Ann V; Naimark, Barbara J

2005-01-01

Although cardiovascular disease is the leading cause of death in North American women, most cardiovascular research has focused on men. In addition, while there has been a recent trend toward population health promotion (PHP) and a consequent focus on the broad determinants of health, there is still a dearth of research evidence related to the promotion of cardiovascular health within this context. The purpose of this study was to explore and describe the interrelationships between the determinants of health and individual cardiovascular health/risk behaviors in healthy women, within the context of a framework for PHP. A comprehensive inventory of factors affecting the cardiovascular health of women was operationalized in a survey questionnaire, the Cardiovascular Health Promotion Profile. Physical measures were also taken on each participant (n = 206). The multivariate analyses support significant interrelationships between the population health determinants and multiple individual cardiovascular health/risk behaviors in this cohort (p < 0.05). The evidence from this study provides foundational validation for a population health approach and population-based strategies for cardiovascular health promotion in women. Further research, within the context of a PHP framework, is central to building on the body of knowledge in this area.

Prevention of Cardiovascular Disease in Women.

PubMed

Saeed, Anum; Kampangkaew, June; Nambi, Vijay

2017-01-01

Cardiovascular diseases are the leading cause of morbidity and mortality among women worldwide. The pathophysiological basis of cardiovascular health among men and women is not identical. This leads to variable cardiovascular responses to stimulus and presentation of cardiovascular disease symptoms, both of which can have a direct effect on treatment outcomes. Traditionally, the enrollment of women in clinical trials has been minimal, resulting in a lack of gender-specific analysis of clinical trial data and, therefore, the absence of concrete risk factor assessment among women. However, scientific progress in the past decade has identified a spectrum of risk factors for cardiovascular diseases that may be specific to women. These risk factors, which may include menopause, hypertensive disease of pregnancy, and depression, confer additional risk in women besides the traditional risk factors. The current state of knowledge and awareness about these risk factors is suboptimal at this time. Therefore, although the treatment of cardiovascular diseases is similar in both genders, appropriate risk stratification may be limited in women compared to men. The purpose of this review is to describe the recent trends in identifying female-specific risk factors for cardiovascular diseases, their utility in risk stratification, and current pharmacological options for women with regard to cardiovascular disease prevention.

Cardiovascular disease risk factors in adolescents: do negative emotions and hypothalamic-pituitary-adrenal axis function play a role?

PubMed

Pajer, Kathleen A

2007-10-01

Negative emotions such as depression and hostility/anger are important risk factors for cardiovascular disease in adults, but are often neglected in treatment or prevention programs. Adolescence is a stage of life when negative emotions often first become problematic and is also a time when the pathogenesis of cardiovascular disease appears to accelerate. The literature on negative emotions and cardiovascular disease risk factors in adolescents is reviewed here. Research indicates that negative emotions are associated with cardiovascular disease risk factors in adolescence. Negative emotions are also associated with several types of hypothalamic-pituitary-adrenal axis dysregulation. Such dysregulation appears to have a facilitatory effect on cardiovascular disease development and progression in adults. Thus, it is possible that negative emotions in adolescents may be risk factors for the development of cardiovascular disease via dysregulation of the hypothalamic-pituitary-adrenal axis. Although this hypothesis has not been directly tested, some studies indirectly support the hypothesis. Negative emotions are associated with cardiovascular disease risk factors in adolescents; it is possible that hypothalamic-pituitary-adrenal axis dysregulation is an important mechanism. This hypothesis merits further research. If the hypothesis is valid, it has significant implications for early prevention of cardiovascular disease.

Evidence for sex differences in cardiovascular aging and adaptive responses to physical activity.

PubMed

Parker, Beth A; Kalasky, Martha J; Proctor, David N

2010-09-01

There are considerable data addressing sex-related differences in cardiovascular system aging and disease risk/progression. Sex differences in cardiovascular aging are evident during resting conditions, exercise, and other acute physiological challenges (e.g., orthostasis). In conjunction with these sex-related differences-or perhaps even as an underlying cause-the impact of cardiorespiratory fitness and/or physical activity on the aging cardiovascular system also appears to be sex-specific. Potential mechanisms contributing to sex-related differences in cardiovascular aging and adaptability include changes in sex hormones with age as well as sex differences in baseline fitness and the dose of activity needed to elicit cardiovascular adaptations. The purpose of the present paper is thus to review the primary research regarding sex-specific plasticity of the cardiovascular system to fitness and physical activity in older adults. Specifically, the paper will (1) briefly review known sex differences in cardiovascular aging, (2) detail emerging evidence regarding observed cardiovascular outcomes in investigations of exercise and physical activity in older men versus women, (3) explore mechanisms underlying the differing adaptations to exercise and habitual activity in men versus women, and (4) discuss implications of these findings with respect to chronic disease risk and exercise prescription.

Evidence for sex differences in cardiovascular aging and adaptive responses to physical activity

PubMed Central

Parker, Beth A.; Kalasky, Martha J.; Proctor, David N.

2010-01-01

There are considerable data addressing sex-related differences in cardiovascular system aging and disease risk/progression. Sex differences in cardiovascular aging are evident during resting conditions, exercise, and other acute physiological challenges (e.g., orthostasis). In conjunction with these sex-related differences—or perhaps even as an underlying cause—the impact of cardiorespiratory fitness and/or physical activity on the aging cardiovascular system also appears to be sex-specific. Potential mechanisms contributing to sex-related differences in cardiovascular aging and adaptability include changes in sex hormones with age as well as sex differences in baseline fitness and the dose of activity needed to elicit cardiovascular adaptations. The purpose of the present paper is thus to review the primary research regarding sex-specific plasticity of the cardiovascular system to fitness and physical activity in older adults. Specifically, the paper will (1) briefly review known sex differences in cardiovascular aging, (2) detail emerging evidence regarding observed cardiovascular outcomes in investigations of exercise and physical activity in older men versus women, (3) explore mechanisms underlying the differing adaptations to exercise and habitual activity in men versus women, and (4) discuss implications of these findings with respect to chronic disease risk and exercise prescription. PMID:20480371

Cardiovascular health in Brazilian state capitals 1.

PubMed

Matozinhos, Fernanda Penido; Felisbino-Mendes, Mariana Santos; Gomes, Crizian Saar; Jansen, Ann Kristine; Machado, Ísis Eloah; Lana, Francisco Carlos Félix; Malta, Deborah Carvalho; Velaquez-Melendez, Gustavo

2017-10-19

to estimate the prevalence of ideal cardiovascular health indicators in the Brazilian population, according to gender, age, education and region of residence. cross-sectional study that used data from 41,134 participants of the Surveillance System of Risk and Protective Factors for Chronic Diseases by Telephone Survey (Vigitel). The ideal cardiovascular health assessment considers four behavioral factors: not smoking; body mass index less than 25 kg/m2; practicing physical activity, eating fruits and vegetables five or more times per day; and two clinical factors (no diagnosis of diabetes or hypertension). The sum of factors at ideal levels results in a score ranging from zero (worse cardiovascular health) to six (ideal cardiovascular health). considering the six factors, only 3.4% of the studied population presented ideal levels of cardiovascular health, with the majority of participants (57.6%) presenting three or four ideal factors. Women had higher prevalence of ideal cardiovascular health (3.8% versus 2.9% for men) (p < 0.0001). the findings of this study are consistent with the elevated risk of mortality from cardiovascular disease, observed in the Brazilian population. This may contribute to a better understanding of the scenario of cardiovascular health in the urban population of the country.

Gender differences in developmental programming of cardiovascular diseases

PubMed Central

Dasinger, John Henry; Alexander, Barbara T.

2016-01-01

Hypertension is a risk factor for cardiovascular disease, the leading cause of death worldwide. Although multiple factors contribute to the pathogenesis of hypertension, studies by Dr. David Barker reporting an inverse relationship between birth weight and blood pressure led to the hypothesis that slow growth during fetal life increases blood pressure and the risk for cardiovascular disease in later life. It is now recognized that growth during infancy and childhood in addition to exposure to adverse influences during fetal life contribute to the developmental programming of increased cardiovascular risk. Numerous epidemiological studies support the link between influences during early life with later cardiovascular health; experimental models provide proof of principle and indicate that numerous mechanisms contribute to the developmental origins of chronic disease. Sex impacts the severity of cardiovascular risk in experimental models of developmental insult. Yet, few studies examine the influence of sex on blood pressure and cardiovascular health in low birth weight men and women. Fewer still assess how aging impacts sex differences in programmed cardiovascular risk. Thus, the aim of this review is to highlight current data regarding sex differences in the developmental programming of blood pressure and cardiovascular disease. PMID:26814204

All men with vasculogenic erectile dysfunction require a cardiovascular workup.

PubMed

Miner, Martin; Nehra, Ajay; Jackson, Graham; Bhasin, Shalender; Billups, Kevin; Burnett, Arthur L; Buvat, Jacques; Carson, Culley; Cunningham, Glenn; Ganz, Peter; Goldstein, Irwin; Guay, Andre; Hackett, Geoff; Kloner, Robert A; Kostis, John B; LaFlamme, K Elizabeth; Montorsi, Piero; Ramsey, Melinda; Rosen, Raymond; Sadovsky, Richard; Seftel, Allen; Shabsigh, Ridwan; Vlachopoulos, Charalambos; Wu, Frederick

2014-03-01

An association between erectile dysfunction and cardiovascular disease has long been recognized, and studies suggest that erectile dysfunction is an independent marker of cardiovascular disease risk. Therefore, assessment and management of erectile dysfunction may help identify and reduce the risk of future cardiovascular events, particularly in younger men. The initial erectile dysfunction evaluation should distinguish between predominantly vasculogenic erectile dysfunction and erectile dysfunction of other etiologies. For men believed to have predominantly vasculogenic erectile dysfunction, we recommend that initial cardiovascular risk stratification be based on the Framingham Risk Score. Management of men with erectile dysfunction who are at low risk for cardiovascular disease should focus on risk-factor control; men at high risk, including those with cardiovascular symptoms, should be referred to a cardiologist. Intermediate-risk men should undergo noninvasive evaluation for subclinical atherosclerosis. A growing body of evidence supports the use of emerging prognostic markers to further understand cardiovascular risk in men with erectile dysfunction, but few markers have been prospectively evaluated in this population. In conclusion, we support cardiovascular risk stratification and risk-factor management in all men with vasculogenic erectile dysfunction. Copyright © 2014 Elsevier Inc. All rights reserved.

Cardiovascular effects of variations in habitual levels of physical activity

NASA Technical Reports Server (NTRS)

Blomqvist, C. G.; Mitchell, J. H.

1975-01-01

Mechanisms involved in human cardiovascular adaption to stress, particularly adaption to different levels of physical activity are determined along with quantitative noninvasive methods for evaluation of cardiovascular function during stess in normal subjects and in individuals with latent or manifest cardiovascular disease. Results are summarized.

Behavioral Counseling to Promote a Healthful Diet and Physical Activity for CVD Prevention in Adults with Risk Factors

MedlinePlus

... Promote a Healthful Diet and Physical Activity for Cardiovascular Disease Prevention in Adults with Cardiovascular Risk Factors The ... Promote a Healthful Diet and Physical Activity for Cardiovascular Disease (CVD) Prevention in Adults with Cardiovascular Risk Factors. ...

Assessment of Cardiovascular Risk in Collegiate Football Players and Nonathletes

ERIC Educational Resources Information Center

Dobrosielski, Devon A.; Rosenbaum, Daryl; Wooster, Benjamin M.; Merrill, Michael; Swanson, John; Moore, J. Brian; Brubaker, Peter H.

2010-01-01

Collegiate American football players may be at risk for cardiovascular disease. Objective: To compare cardiovascular disease risk factors and cardiovascular structure and function parameters of football players, stratified by position, to a group of sedentary, nonathletes. Participants: Twenty-six collegiate football players and 13 nonathletes…

21 CFR 870.2100 - Cardiovascular blood flowmeter.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cardiovascular blood flowmeter. 870.2100 Section... Cardiovascular blood flowmeter. (a) Identification. A cardiovascular blood flowmeter is a device that is connected to a flow transducer that energizes the transducer and processes and displays the blood flow...

21 CFR 870.2100 - Cardiovascular blood flowmeter.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cardiovascular blood flowmeter. 870.2100 Section... Cardiovascular blood flowmeter. (a) Identification. A cardiovascular blood flowmeter is a device that is connected to a flow transducer that energizes the transducer and processes and displays the blood flow...

21 CFR 870.2100 - Cardiovascular blood flowmeter.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiovascular blood flowmeter. 870.2100 Section... Cardiovascular blood flowmeter. (a) Identification. A cardiovascular blood flowmeter is a device that is connected to a flow transducer that energizes the transducer and processes and displays the blood flow...

21 CFR 870.2100 - Cardiovascular blood flowmeter.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiovascular blood flowmeter. 870.2100 Section... Cardiovascular blood flowmeter. (a) Identification. A cardiovascular blood flowmeter is a device that is connected to a flow transducer that energizes the transducer and processes and displays the blood flow...

2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult – 2009 recommendations

PubMed Central

Genest, Jacques; McPherson, Ruth; Frohlich, Jiri; Anderson, Todd; Campbell, Norm; Carpentier, André; Couture, Patrick; Dufour, Robert; Fodor, George; Francis, Gordon A; Grover, Steven; Gupta, Milan; Hegele, Robert A; Lau, David C; Leiter, Lawrence; Lewis, Gary F; Lonn, Eva; Mancini, GB John; Ng, Dominic; Pearson, Glen J; Sniderman, Allan; Stone, James A; Ur, Ehud

2009-01-01

The present article represents the 2009 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult. PMID:19812802

Proceedings of the Symposium Teaching Cardiovascular Physiology Outside the Lecture Hall.

ERIC Educational Resources Information Center

Michael, Joel A.; Rovick, Allen A., Eds.

1983-01-01

Provided are 10 papers presented during a symposium on teaching cardiovascular physiology outside the lecture hall. Topics addressed include a mechanical model of the cardiovascular system for effective teaching, separate course for experiments in cardiovascular physiology, selective laboratory (alternative to cookbook experiments), cardiovascular…

78 FR 76307 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-17

...] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS...: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committee: To provide advice and... combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization. FDA intends...

Preventing Heart Attacks and Strokes: Increasing Awareness of the Adverse Cardiovascular Health Impacts of Air Pollution

EPA Science Inventory

Summary: Chronic cardiovascular disease imposes a significant health and economic burden on individuals and communities. Despite decades of improvement in cardiovascular mortality, cardiovascular disease and stroke remain the leading cause of death in the U.S. and disparities i...

Olive oil intake and risk of cardiovascular disease and mortality in the PREDIMED Study

PubMed Central

2014-01-01

Background It is unknown whether individuals at high cardiovascular risk sustain a benefit in cardiovascular disease from increased olive oil consumption. The aim was to assess the association between total olive oil intake, its varieties (extra virgin and common olive oil) and the risk of cardiovascular disease and mortality in a Mediterranean population at high cardiovascular risk. Methods We included 7,216 men and women at high cardiovascular risk, aged 55 to 80 years, from the PREvención con DIeta MEDiterránea (PREDIMED) study, a multicenter, randomized, controlled, clinical trial. Participants were randomized to one of three interventions: Mediterranean Diets supplemented with nuts or extra-virgin olive oil, or a control low-fat diet. The present analysis was conducted as an observational prospective cohort study. The median follow-up was 4.8 years. Cardiovascular disease (stroke, myocardial infarction and cardiovascular death) and mortality were ascertained by medical records and National Death Index. Olive oil consumption was evaluated with validated food frequency questionnaires. Multivariate Cox proportional hazards and generalized estimating equations were used to assess the association between baseline and yearly repeated measurements of olive oil intake, cardiovascular disease and mortality. Results During follow-up, 277 cardiovascular events and 323 deaths occurred. Participants in the highest energy-adjusted tertile of baseline total olive oil and extra-virgin olive oil consumption had 35% (HR: 0.65; 95% CI: 0.47 to 0.89) and 39% (HR: 0.61; 95% CI: 0.44 to 0.85) cardiovascular disease risk reduction, respectively, compared to the reference. Higher baseline total olive oil consumption was associated with 48% (HR: 0.52; 95% CI: 0.29 to 0.93) reduced risk of cardiovascular mortality. For each 10 g/d increase in extra-virgin olive oil consumption, cardiovascular disease and mortality risk decreased by 10% and 7%, respectively. No significant associations were found for cancer and all-cause mortality. The associations between cardiovascular events and extra virgin olive oil intake were significant in the Mediterranean diet intervention groups and not in the control group. Conclusions Olive oil consumption, specifically the extra-virgin variety, is associated with reduced risks of cardiovascular disease and mortality in individuals at high cardiovascular risk. Trial registration This study was registered at controlled-trials.com (http://www.controlled-trials.com/ISRCTN35739639). International Standard Randomized Controlled Trial Number (ISRCTN): 35739639. Registration date: 5 October 2005. PMID:24886626

Beneficial and adverse effects of testosterone on the cardiovascular system in men.

PubMed

Ruige, Johannes B; Ouwens, D Margriet; Kaufman, Jean-Marc

2013-11-01

The widespread use of T therapy, particularly in aging males, necessitates knowledge of the relationship between T and the cardiovascular system. The review is based on a 1970 to 2013 PubMed search with terms related to androgens in combination with cardiovascular disease, including T, dihydrotestosterone, trial, mortality, cardiovascular disease, myocardial infarction, blood pressure, endothelial function, dyslipidemia, thrombosis, ventricular function, and arrhythmia. Original articles, systematic reviews and meta-analyses, and relevant citations were screened. Low T has been linked to increased blood pressure, dyslipidemia, atherosclerosis, arrhythmia, thrombosis, endothelial dysfunction, as well as to impaired left ventricular function. On the one hand, a modest association is suggested between low endogenous T and incident cardiovascular disease or cardiovascular mortality, implying unrecognized beneficial T effects, residual confounding, or a relationship with health status. On the other hand, treatments with T to restore "normal concentrations" have so far not been proven to be beneficial with respect to cardiovascular disease; neither have they definitely shown specific adverse cardiovascular effects. The cardiovascular risk-benefit profile of T therapy remains largely evasive in view of a lack of well-designed and adequately powered randomized clinical trials. The important knowledge gap as to the exact relationship between T and cardiovascular disease would support a cautious, restrained approach to T therapy in aging men, pending clarification of benefits and risks by adequately powered clinical trials of sufficient duration.

Transforming growth factor beta signaling in adult cardiovascular diseases and repair

PubMed Central

Doetschman, Thomas; Barnett, Joey V.; Runyan, Raymond B.; Camenisch, Todd D.; Heimark, Ronald L.; Granzier, Henk L.; Conway, Simon J.; Azhar, Mohamad

2011-01-01

The majority of children with congenital heart disease now live into adulthood due to the remarkable surgical and medical advances that have taken place over the past half century. Because of this, the adults now represent the largest age group with adult cardiovascular diseases. They include patients with heart diseases that were not detected or not treated during childhood, those whose defects were surgically corrected but now need revision due to maladaptive responses to the procedure, those with exercise problems, and those with age-related degenerative diseases. Because adult cardiovascular diseases in this population are relatively new, they are not well understood. It is therefore necessary to understand the molecular and physiological pathways involved if we are to improve treatments. Since there is a developmental basis to adult cardiovascular disease, transforming growth factor beta (TGFβ) signaling pathways that are essential for proper cardiovascular development may also play critical roles in the homeostatic, repair and stress response processes involved in adult cardiovascular diseases. Consequently, we have chosen to summarize the current information on a subset of TGFβ ligand and receptor genes and related effector genes that when dysregulated are known to lead to cardiovascular diseases and adult cardiovascular deficiencies and/or pathologies. A better understanding of the TGFβ signaling network in cardiovascular disease and repair will impact genetic and physiologic investigations of cardiovascular diseases in elderly patients and lead to an improvement in clinical interventions. PMID:21953136

Usefulness of the d-ROMs test for prediction of cardiovascular events.

PubMed

Masaki, Nobuyuki; Sato, Atsushi; Horii, Syumpei; Kimura, Toyokazu; Toya, Takumi; Yasuda, Risako; Namba, Takayuki; Yada, Hirotaka; Kawamura, Akio; Adachi, Takeshi

2016-11-01

d-ROMs test developed to determine the degree of individual oxidative stress may predict cardiovascular events. 265 patients (204 men, 61 women; age, 65±13years) who had been treated for cardiovascular disease were divided evenly by quartile of baseline d-ROMs levels, and were followed up. During the observation periods of 2.66±1.47years, there were 14 (5%) deaths, 8 (3%) cardiovascular deaths, 13 (5%) major adverse cardiovascular events (MACEs), and 51 (19%) all cardiovascular events including heart failure, cardiovascular surgery, and revascularization. Log-rank tests demonstrated that the patients in the 4th quartile (d-ROMs≧395.00U.CARR) had a higher incidence rate of cardiovascular death than those in the 2nd quartile (d-ROMs 286.00-335.00, p=0.022). In multivariate Cox regression analysis, even after adjustment for age, sex, coronary risk factors, C-reactive protein, and renal function, high d-ROMs was a risk factor for all-cause death [adjusted HR of 4th vs. 1st quartile, 10.791 (95% confidence interval 1.032-112.805), p=0.047], and all cardiovascular events [HR of 4th vs. 1st quartile, 2.651 (95% confidence interval 1.138-6.177), p=0.024]. Our results suggest that d-ROMs is a useful oxidative stress marker to assess prognosis and risk of further cardiovascular events. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cardiovascular comorbidities of pediatric psoriasis among hospitalized children in the United States.

PubMed

Kwa, Lauren; Kwa, Michael C; Silverberg, Jonathan I

2017-12-01

Psoriasis has been shown to be associated with cardiovascular disease in adults. Little is known about cardiovascular risk in pediatric psoriasis. To determine if there is an association between pediatric psoriasis and cardiovascular comorbidities. Data were analyzed from the 2002-2012 Nationwide Inpatient Sample, which included 4,884,448 hospitalized children aged 0-17 years. Bivariate and multivariate survey logistic regression models were created to calculate the odds of psoriasis on cardiovascular comorbidities. In multivariate survey logistic regression models adjusting for age, sex, and race/ethnicity, pediatric psoriasis was significantly associated with 5 of 10 cardiovascular comorbidities (adjusted odds ratio [95% confidence interval]), including obesity (3.15 [2.46-4.05]), hypertension (2.63 [1.93-3.59]), diabetes (2.90 [1.90-4.42]), arrhythmia (1.39 [1.02-1.88]), and valvular heart disease (1.90 [1.07-3.37]). The highest odds of cardiovascular risk factors occurred in blacks and Hispanics and children ages 0-9 years, but there were no sex differences. The study was limited to hospitalized children. We were unable to assess the impact of psoriasis treatment or family history on cardiovascular risk. Pediatric psoriasis is associated with higher odds of multiple cardiovascular comorbidities among hospitalized patients. Strategies for mitigating excess cardiovascular risk in pediatric psoriasis need to be determined. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

GLP-1 Receptor Agonists and Cardiovascular Disease in Patients with Type 2 Diabetes

PubMed Central

Merino-Torres, Juan Francisco

2018-01-01

Diabetes mellitus is a chronic disease prevalence of which is high and continually growing. Cardiovascular disease continues to be the leading cause of death in patients with T2DM. The prevention of cardiovascular complications and the cardiovascular safety of treatments should be a primary objective when selecting treatment. Among all the drugs available, the compounds known as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) appear to be not just innocuous in terms of CVD but indeed to be beneficial. GLP-1 RA actions not only translate on an improvement of well-known cardiovascular risk factors such as glycaemic control, dyslipidaemia, weight, or arterial hypertension but also might show benefits on endothelial function, coronary ischaemia, and heart failure. On the other hand, recent clinical trials aimed at studying cardiovascular episodes have been conducted with GLP-1 RAs. Only liraglutide and semaglutide have shown superiority in cardiovascular benefit compared with placebo. Although many of the mechanisms by which liraglutide and semaglutide produce a cardiovascular benefit are still unknown it would be desirable for these benefits to be incorporated into the therapeutic algorithms routinely used in clinical practice. The purpose of this review is to explore GLP-1 RA actions not only in cardiovascular risk factors (glucose, weight, and hypertension) but also the possible effects on established cardiovascular disease.

Sleep: important considerations for the prevention of cardiovascular disease.

PubMed

Grandner, Michael A; Alfonso-Miller, Pamela; Fernandez-Mendoza, Julio; Shetty, Safal; Shenoy, Sundeep; Combs, Daniel

2016-09-01

Sleep plays many roles in maintenance of cardiovascular health. This review summarizes the literature across several areas of sleep and sleep disorders in relation to cardiometabolic disease risk factors. Insufficient sleep duration is prevalent in the population and is associated with weight gain and obesity, inflammation, cardiovascular disease, diabetes, and mortality. Insomnia is also highly present and represents an important risk factor for cardiovascular disease, especially when accompanied by short sleep duration. Sleep apnea is a well-characterized risk factor for cardiometabolic disease and cardiovascular mortality. Other issues are relevant as well. For example, sleep disorders in pediatric populations may convey cardiovascular risks. Also, sleep may play an important role in cardiovascular health disparities. Sleep and sleep disorders are implicated in cardiometabolic disease risk. This review addresses these and other issues, concluding with recommendations for research and clinical practice.

The Mediterranean diet, its components, and cardiovascular disease.

PubMed

Widmer, R Jay; Flammer, Andreas J; Lerman, Lilach O; Lerman, Amir

2015-03-01

One of the best-studied diets for cardiovascular health is the Mediterranean diet. This consists of fish, monounsaturated fats from olive oil, fruits, vegetables, whole grains, legumes/nuts, and moderate alcohol consumption. The Mediterranean diet has been shown to reduce the burden, or even prevent the development, of cardiovascular disease, breast cancer, depression, colorectal cancer, diabetes, obesity, asthma, erectile dysfunction, and cognitive decline. This diet is also known to improve surrogates of cardiovascular disease, such as waist-to-hip ratio, lipids, and markers of inflammation, as well as primary cardiovascular disease outcomes such as death and events in both observational and randomized controlled trial data. These enhancements easily rival those seen with more established tools used to fight cardiovascular disease such as aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, and exercise. However, it is unclear if the Mediterranean diet offers cardiovascular disease benefit from its individual constituents or in aggregate. Furthermore, the potential benefit of the Mediterranean diet or its components is not yet validated by concrete cardiovascular disease endpoints in randomized trials or observational studies. This review will focus on the effects of the whole and parts of the Mediterranean diet with regard to both population-based and experimental data highlighting cardiovascular disease morbidity or mortality and cardiovascular disease surrogates when hard outcomes are not available. Our synthesis will highlight the potential for the Mediterranean diet to act as a key player in cardiovascular disease prevention, and attempt to identify certain aspects of the diet that are particularly beneficial for cardioprotection. Copyright © 2015 Elsevier Inc. All rights reserved.

Uniform data collection in routine clinical practice in cardiovascular patients for optimal care, quality control and research: The Utrecht Cardiovascular Cohort.

PubMed

Asselbergs, Folkert W; Visseren, Frank Lj; Bots, Michiel L; de Borst, Gert J; Buijsrogge, Marc P; Dieleman, Jan M; van Dinther, Baukje Gf; Doevendans, Pieter A; Hoefer, Imo E; Hollander, Monika; de Jong, Pim A; Koenen, Steven V; Pasterkamp, Gerard; Ruigrok, Ynte M; van der Schouw, Yvonne T; Verhaar, Marianne C; Grobbee, Diederick E

2017-05-01

Background Cardiovascular disease remains the major contributor to morbidity and mortality. In routine care for patients with an elevated cardiovascular risk or with symptomatic cardiovascular disease information is mostly collected in an unstructured manner, making the data of limited use for structural feedback, quality control, learning and scientific research. Objective The Utrecht Cardiovascular Cohort (UCC) initiative aims to create an infrastructure for uniform registration of cardiovascular information in routine clinical practice for patients referred for cardiovascular care at the University Medical Center Utrecht, the Netherlands. This infrastructure will promote optimal care according to guidelines, continuous quality control in a learning healthcare system and creation of a research database. Methods The UCC comprises three parts. UCC-1 comprises enrolment of all eligible cardiovascular patients in whom the same information will be collected, based on the Dutch cardiovascular management guideline. A sample of UCC-1 will be invited for UCC-2. UCC-2 involves an enrichment through extensive clinical measurements with emphasis on heart failure, cerebral ischaemia, arterial aneurysms, diabetes mellitus and elevated blood pressure. UCC-3 comprises on-top studies, with in-depth measurements in smaller groups of participants typically based on dedicated project grants. All participants are followed up for morbidity and mortality through linkage with national registries. Conclusion In a multidisciplinary effort with physicians, patients and researchers the UCC sets a benchmark for a learning cardiovascular healthcare system. UCC offers an invaluable resource for future high quality care as well as for first-class research for investigators.

Elucidation of the Strongest Predictors of Cardiovascular Events in Patients with Heart Failure.

PubMed

Fukuda, Hiroki; Shindo, Kazuhiro; Sakamoto, Mari; Ide, Tomomi; Kinugawa, Shintaro; Fukushima, Arata; Tsutsui, Hiroyuki; Ito, Shin; Ishii, Akira; Washio, Takashi; Kitakaze, Masafumi

2018-06-20

In previous retrospective studies, we identified the 50 most influential clinical predictors of cardiovascular outcomes in patients with heart failure (HF). The present study aimed to use the novel limitless-arity multiple-testing procedure to filter these 50 clinical factors and thus yield combinations of no more than four factors that could potentially predict the onset of cardiovascular events. A Kaplan-Meier analysis was used to investigate the importance of the combinations. In a multi-centre observational trial, we prospectively enrolled 213 patients with HF who were hospitalized because of exacerbation, discharged according to HF treatment guidelines and observed to monitor cardiovascular events. After the observation period, we stratified patients according to whether they experienced cardiovascular events (rehospitalisation or cardiovascular death). Among 77,562 combinations of fewer than five clinical parameters, we identified 151 combinations that could potentially explain the occurrence of cardiovascular events. Of these, 145 combinations included the use of inotropic agents, whereas the remaining 6 included the use of diuretics without bradycardia or tachycardia, suggesting that the high probability of cardiovascular events is exclusively determined by these two clinical factors. Importantly, Kaplan-Meier curves demonstrated that the use of inotropes or of diuretics without bradycardia or tachycardia were independent predictors of a markedly worse cardiovascular prognosis. Patients treated with either inotropic agents or diuretics without bradycardia or tachycardia were at a higher risk of cardiovascular events. The uses of these drugs, regardless of heart rate, are the strongest clinical predictors of cardiovascular events in patients with HF. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Association of sedentary behavior time with ideal cardiovascular health: the ORISCAV-LUX study.

PubMed

Crichton, Georgina E; Alkerwi, Ala'a

2014-01-01

Recently attention has been drawn to the health impacts of time spent engaging in sedentary behaviors. No studies have examined sedentary behaviors in relation to the newly defined construct of ideal cardiovascular health, which incorporates three health factors (blood pressure, total cholesterol, fasting plasma glucose) and four behaviors (physical activity, smoking, body mass index, diet). The purpose of this study was to examine associations between sedentary behaviors, including sitting time, and time spent viewing television and in front of a computer, with cardiovascular health, in a representative sample of adults from Luxembourg. A cross-sectional analysis of 1262 participants in the Observation of Cardiovascular Risk Factors in Luxembourg study was conducted, who underwent objective cardiovascular health assessments and completed the International Physical Activity Questionnaire. A Cardiovascular Health Score was calculated based on the number of health factors and behaviors at ideal levels. Sitting time on a weekday, television time, and computer time (both on a workday and a day off), were related to the Cardiovascular Health Score. Higher weekday sitting time was significantly associated with a poorer Cardiovascular Health Score (p = 0.002 for linear trend), after full adjustment for age, gender, education, income and occupation. Television time was inversely associated with the Cardiovascular Health Score, on both a workday and a day off (p = 0.002 for both). A similar inverse relationship was observed between the Cardiovascular Health Score and computer time, only on a day off (p = 0.04). Higher time spent sitting, viewing television, and using a computer during a day off may be unfavorably associated with ideal cardiovascular health.

Ethnic differences in risk factors and total risk of cardiovascular disease based on the Norwegian CONOR study.

PubMed

Rabanal, Kjersti S; Lindman, Anja S; Selmer, Randi M; Aamodt, Geir

2013-12-01

Risk of cardiovascular disease varies between ethnic groups and the aim of this study was to investigate differences in cardiovascular risk factors, and total cardiovascular risk between ethnic groups in Norway. Cross-sectional study using data from the Cohort of Norway (CONOR). A sample of 62,145 participants, 40-65 years of age, originating from 11 geographical regions, were included in our study. Self-reported variables, blood samples and physical measurements were used to estimate age- and time-adjusted mean values of cardiovascular risk factors for different ethnic groups. The 10-year risks of cardiovascular mortality and cardiovascular events were calculated using the Framingham and NORRISK risk models. We observed differences between ethnic groups for cardiovascular risk factors and both Framingham and NORRISK risk scores. NORRISK showed significant differences by ethnicity in women only. Immigrants from the Indian subcontinent had the lowest high-density lipoprotein (HDL) levels, the highest levels of blood glucose, triglycerides, total cholesterol/HDL ratio, waist hip ratio and diabetes prevalence. Immigrants from the former Yugoslavia had the highest Framingham scores, high blood pressure, high total cholesterol/HDL ratio, overweight measures and smoking. Low cardiovascular risk was observed among East Asian immigrants. The previously reported excess cardiovascular risk among immigrants from the Indian subcontinent was supported in this study. We also showed that immigrants from the former Yugoslavian countries had a higher total 10-year risk of cardiovascular events than other ethnic groups. This study adds information about ethnic groups in Norway which needs to be addressed in further research and targeted prevention strategies.

42 CFR 410.17 - Cardiovascular disease screening tests.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 2 2011-10-01 2011-10-01 false Cardiovascular disease screening tests. 410.17... § 410.17 Cardiovascular disease screening tests. (a) Definition. For purposes of this subpart, the... Part B covers cardiovascular disease screening tests when ordered by the physician who is treating the...

42 CFR 410.17 - Cardiovascular disease screening tests.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 42 Public Health 2 2012-10-01 2012-10-01 false Cardiovascular disease screening tests. 410.17... § 410.17 Cardiovascular disease screening tests. (a) Definition. For purposes of this subpart, the... Part B covers cardiovascular disease screening tests when ordered by the physician who is treating the...