Abnormal vaginal bleeding in women with venous thromboembolism treated with apixaban or warfarin.

PubMed

Brekelmans, Marjolein P A; Scheres, Luuk J J; Bleker, Suzanne M; Hutten, Barbara A; Timmermans, Anne; Büller, Harry R; Middeldorp, Saskia

2017-04-03

Abnormal vaginal bleeding can complicate direct oral anticoagulant (DOAC) treatment. We aimed to investigate the characteristics of abnormal vaginal bleeding in patients with venous thromboembolism (VTE) receiving apixaban or enoxaparin/warfarin. Data were derived from the AMPLIFY trial. We compared the incidence of abnormal vaginal bleeding between patients in both treatment arms and collected information on clinical presentation, diagnostic procedures, management and outcomes. In the AMPLIFY trial, 1122 women were treated with apixaban and 1106 received enoxaparin/warfarin. A clinically relevant non-major (CRNM) vaginal bleeding occurred in 28 (2.5 %) apixaban and 24 (2.1 %) enoxaparin/warfarin recipients (odds ratio [OR] 1.2, 95 % confidence interval [CI] 0.7-2.0). Of all CRNM bleeds, 28 of 62 (45 %) and 24 of 120 (20 %) were of vaginal origin in the apixaban and enoxaparin/warfarin group, respectively (OR 3.4; 95 % CI 1.8-6.7). Premenopausal vaginal bleeds on apixaban were characterised by more prolonged bleeding (OR 2.3; 95 %CI 0.5-11). In both pre- and postmenopausal vaginal bleeds, diagnostic tests were performed in six (21 %) and in seven (29 %) apixaban and enoxaparin/warfarin treated patients, respectively. Medical treatment was deemed not necessary in 16 (57 %) apixaban and 16 (67 %) enoxaparin/warfarin recipients. The severity of clinical presentation and course of the bleeds was mild in 75 % of the cases in both groups. In conclusion, although the absolute number of vaginal bleeding events is comparable between apixaban and enoxaparin/warfarin recipients, the relative occurrence of vaginal bleeds is higher in apixaban-treated women. The characteristics and severity of bleeding episodes were comparable in both treatment arms.

Apixaban versus enoxaparin in the prevention of venous thromboembolism following total knee arthroplasty: a single-centre, single-surgeon, retrospective analysis.

PubMed

King, D A L; Pow, R E; Dickison, D M; Vale, P R

2016-09-01

There is a high risk of developing venous thromboembolism (VTE) following total knee arthroplasty (TKA). Conventional thromboprophylactic agents have limitations, such as route of administration, the need for monitoring, narrow therapeutic windows and interactions. Apixaban is a new oral anticoagulant with the potential to overcome these limitations. To report the efficacy and safety of apixaban and low-molecular-weight heparin, enoxaparin, in VTE prophylaxis following TKA. This single-centre, single-surgeon, retrospective analysis included 506 consecutive patients who underwent TKA between 2009 and 2015 and received enoxaparin or apixaban as thromboprophylaxis. Baseline characteristics of patients, in-hospital rates of VTE, total DVT, proximal or distal DVT, pulmonary embolism, bleeding outcomes and mortality were compared between the two groups. In-hospital VTE occurred in 22 (8.9%) patients in the enoxaparin group and 11 (4.5%) patients in the apixaban group (P = 0.049). Nine (3.6%) patients in the enoxaparin group and one (0.4%) in the apixaban group experienced a postoperative drop in haemoglobin ≥20 g/L that either necessitated transfusion of ≥2 units blood, caused haemodynamic instability or both (P = 0.020). Thirty-five patients experienced other bleeding events, with 25 (9.9%) in the enoxaparin group and 10 (4.0%) in the apixaban group (P = 0.009). There were no statistically significant differences in rates of total DVT, proximal or distal DVT, pulmonary embolism or mortality between the groups. Compared with enoxaparin, thromboprophylaxis with apixaban resulted in a lower VTE incidence and fewer haemorrhagic complications. © 2016 Royal Australasian College of Physicians.

Economic impact of enoxaparin versus unfractionated heparin for venous thromboembolism prophylaxis in patients with acute ischemic stroke: a hospital perspective of the PREVAIL trial.

PubMed

Pineo, Graham; Lin, Jay; Stern, Lee; Subrahmanian, Tarun; Annemans, Lieven

2012-03-01

The PREVAIL (Prevention of VTE [venous thromboembolism] after acute ischemic stroke with LMWH [low-molecular-weight heparin] and UFH [unfractionated heparin]) study demonstrated a 43% VTE risk reduction with enoxaparin versus UFH in patients with acute ischemic stroke (AIS). A 1% rate of symptomatic intracranial and major extracranial hemorrhage was observed in both groups. To determine the economic impact, from a hospital perspective, of enoxaparin versus UFH for VTE prophylaxis after AIS. A decision-analytic model was constructed and hospital-based costs analyzed using clinical information from PREVAIL. Total hospital costs were calculated based on mean costs in the Premier™ database and from wholesalers acquisition data. Costs were also compared in patients with severe stroke (National Institutes of Health Stroke Scale [NIHSS] score ≥14) and less severe stroke (NIHSS score <14). The average cost per patient due to VTE or bleeding events was lower with enoxaparin versus UFH ($422 vs $662, respectively; net savings $240). The average anticoagulant cost, including drug-administration cost per patient, was lower with UFH versus enoxaparin ($259 vs $360, respectively; net savings $101). However, when both clinical events and drug-acquisition costs were considered, the total hospital cost was lower with enoxaparin versus UFH ($782 vs $922, respectively; savings $140). Hospital cost-savings were greatest ($287) in patients with NIHSS scores ≥14. The higher drug cost of enoxaparin was offset by the reduction in clinical events as compared to the use of UFH for VTE prophylaxis after an AIS, particularly in patients with severe stroke. Copyright © 2011 Society of Hospital Medicine.

Correlation of missed doses of enoxaparin with increased incidence of deep vein thrombosis in trauma and general surgery patients.

PubMed

Louis, Scott G; Sato, Misa; Geraci, Travis; Anderson, Ross; Cho, S David; Van, Philbert Y; Barton, Jeffrey S; Riha, Gordon M; Underwood, Samantha; Differding, Jerome; Watters, Jennifer M; Schreiber, Martin A

2014-04-01

Enoxaparin sodium is widely used for deep vein thrombosis (DVT) prophylaxis, yet DVT rates remain high in the trauma and general surgery populations. Missed doses during hospitalization are common. To determine if missed doses of enoxaparin correlate with DVT formation. Data were prospectively collected among 202 trauma and general surgery patients admitted to a level I trauma center. Deep vein thrombosis screening was performed using a rigorous standardized protocol. The overall incidence of DVT was 15.8%. In total, 58.9% of patients missed at least 1 dose of enoxaparin. The DVTs occurred in 23.5% of patients who missed at least 1 dose and in 4.8% of patients who did not (P < .01). On univariate analysis, the need for mechanical ventilation (71.8% vs 44.1%), the performance of more than 1 operation (59.3% vs 40.0%), and male sex (75% vs 56%) were associated with DVT formation (P < .05 for all). A bivariate logistic regression was then performed, which revealed age 50 years or older and interrupted enoxaparin therapy as the only independent risk factors for DVT formation. The DVT rate did not differ between trauma and general surgery populations or in patients receiving once-daily vs twice-daily dosing regimens. Interrupted enoxaparin therapy and age 50 years or older are associated with DVT formation among trauma and general surgery patients. Missed doses occur commonly and are the only identified risk factor for DVT that can be ameliorated by physicians. Efforts to minimize interrupted enoxaparin prophylaxis in patients at risk for DVT should be optimized.

A cost-utility analysis of dabigatran, enoxaparin, and usual care for venous thromboprophylaxis after hip or knee replacement surgery in Thailand.

PubMed

Kotirum, Surachai; Chongmelaxme, Bunchai; Chaiyakunapruk, Nathorn

2017-02-01

To analyze the cost-utility of oral dabigatran etexilate, enoxaparin sodium injection, and no intervention for venous thromboembolism (VTE) prophylaxis after total hip or knee replacement (THR/TKR) surgery among Thai patients. A cost-utility analysis using a decision tree model was conducted using societal and healthcare payers' perspectives to simulate relevant costs and health outcomes covering a 3-month time horizon. Costs were adjusted to year 2014. The willingness-to-pay threshold of THB 160,000 (USD 4926) was used. One-way sensitivity and probabilistic sensitivity analyses using a Monte Carlo simulation were performed. Compared with no VTE prophylaxis, dabigatran and enoxaparin after THR and TKR surgery incurred higher costs and increased quality adjusted life years (QALYs). However, their incremental cost-effectiveness ratios were high above the willingness to pay. Compared with enoxaparin, dabigatran for THR/TKR lowered VTE complications but increased bleeding cases; dabigatran was cost-saving by reducing the costs [by THB 3809.96 (USD 117.30) for THR] and producing more QALYs gained (by 0.00013 for THR). Dabigatran (vs. enoxaparin) had a 98 % likelihood of being cost effective. Dabigatran is cost-saving compared to enoxaparin for VTE prophylaxis after THR or TKR under the Thai context. However, both medications are not cost-effective compared to no thromboprophylaxis.

Effects of aspirin and enoxaparin in a rat model of liver fibrosis.

PubMed

Li, Chen-Jie; Yang, Zhi-Hui; Shi, Xiao-Liu; Liu, De-Liang

2017-09-21

To examine the effects of aspirin and enoxaparin on liver function, coagulation index and histopathology in a rat model of liver fibrosis. METHODS Forty-five male Sprague-Dawley rats were randomly divided into the control group (n = 5) and model group (n = 40). Thioacetamide (TAA) was used to induce liver fibrosis in the model group. TAA-induced fibrotic rats received TAA continuously (n = 9), TAA + low-dose aspirin (n = 9), TAA + high-dose aspirin (n = 9) or TAA + enoxaparin (n = 9) for 4 wk. All rats were euthanized after 4 wk, and both hematoxylin-eosin and Masson staining were performed to observe pathological changes in liver tissue. Liver fibrosis was assessed according to the METAVIR score. Compared with untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the low-dose aspirin, high-dose aspirin and enoxaparin treated groups, especially in the high-dose aspirin treated group. Alanine aminotransferase and total bilirubin were higher, albumin was lower and both prothrombin time and international normalized ratio were prolonged in the four treatment groups compared to controls. No significant differences among the four groups were observed. Aspirin and enoxaparin can alleviate liver fibrosis in this rat model.

Goal directed enoxaparin dosing provides superior chemoprophylaxis against deep vein thrombosis.

PubMed

Kopelman, Tammy R; Walters, Jarvis W; Bogert, James N; Basharat, Usmaan; Pieri, Paola G; Davis, Karole M; Quan, Asia N; Vail, Sydney J; Pressman, Melissa A

2017-05-01

Optimal enoxaparin dosing for deep venous thrombosis (DVT) prophylaxis remains elusive. Prior research demonstrated that trauma patients at increased risk for DVT based upon Greenfield's risk assessment profile (RAP) have DVT rates of 10.8% despite prophylaxis. The aim of this study was to determine if goal directed prophylactic enoxaparin dosing to achieve anti-Xa levels of 0.3-0.5IU/ml would decrease DVT rates without increased complications. Retrospective review of trauma patients having received prophylactic enoxaparin and appropriately timed anti-Xa levels was performed. Dosage was adjusted to maintain an anti-Xa level of 0.3-0.5IU/ml. RAP was determined on each patient. A score of ≥5 was considered high risk for DVT. Sub-analysis was performed on patients who received duplex examinations subsequent to initiation of enoxaparin therapy to determine the incidence of DVT. 306 patients met inclusion criteria. Goal anti-Xa levels were met initially in only 46% of patients despite dosing of >40mg twice daily in 81% of patients; however, with titration, goal anti-Xa levels were achieved in an additional 109 patients (36%). An average enoxaparin dosage of 0.55mg/kg twice daily was required for adequacy. Bleeding complications were identified in five patients (1.6%) with three requiring intervention. There were no documented episodes of HIT. Subsequent duplex data was available in 197 patients with 90% having a RAP score >5. Overall, five DVTs (2.5%) were identified and all occurred in the high-risk group. All patients were asymptomatic at the time of diagnosis. An increased anti-Xa range of 0.3-0.5IU/ml was attainable but frequently required titration of enoxaparin dosage. This produced a lower rate of DVT than previously published without increased complications. Copyright © 2016 Elsevier Ltd. All rights reserved.

Neurological outcomes in patients with ischemic stroke receiving enoxaparin or heparin for venous thromboembolism prophylaxis: subanalysis of the Prevention of VTE after Acute Ischemic Stroke with LMWH (PREVAIL) study.

PubMed

Kase, Carlos S; Albers, Gregory W; Bladin, Christopher; Fieschi, Cesare; Gabbai, Alberto A; O'Riordan, William; Pineo, Graham F

2009-11-01

The Prevention of VTE after Acute Ischemic Stroke with LMWH (PREVAIL) study demonstrated that enoxaparin was superior to unfractionated heparin (UFH) in preventing venous thromboembolism in patients with ischemic stroke and was associated with a small but statistically significant increase in extracranial hemorrhage rates. In this PREVAIL subanalysis, we evaluate the long-term neurological outcomes associated with the use of enoxaparin compared with UFH. We also determine predictors of stroke progression. Acute ischemic stroke patients aged >or=18 years, who could not walk unassisted, were randomized to receive enoxaparin (40 mg once daily) or UFH (5000 U every 12 hours) for 10 days. Patients were stratified according to baseline stroke severity using the National Institutes of Health Stroke Scale score. End points for this analysis included stroke progression (>or=4-point increase in National Institutes of Health Stroke Scale score), neurological outcomes up to 3 months postrandomization (assessed using National Institutes of Health Stroke Scale score and modified Rankin Scale score), and incidence of intracranial hemorrhage. Stroke progression occurred in 45 of 877 (5.1%) patients in the enoxaparin group and 42 of 872 (4.8%) of those receiving UFH. Similar improvements in National Institutes of Health Stroke Scale and modified Rankin Scale scores were observed in both groups over the 90-day follow-up period. Incidence of intracranial hemorrhage was comparable between groups (20 of 877 [2.3%] and 22 of 872 [2.5%] in enoxaparin and UFH groups, respectively). Baseline National Institutes of Health Stroke Scale score, hyperlipidemia, and Hispanic ethnicity were independent predictors of stroke progression. The clinical benefits associated with use of enoxaparin for venous thromboembolism prophylaxis in patients with acute ischemic stroke are not associated with poorer long-term neurological outcomes or increased rates of symptomatic intracranial hemorrhage compared with UFH.

Treatment and follow-up of venous thrombosis in the neonatal intensive care unit: A retrospective study

PubMed Central

Bohnhoff, James C.; DiSilvio, Stefanie A.; Aneja, Rajesh K.; Shenk, Jennifer R.; Domnina, Yuliya A.; Brozanski, Beverly S.; Good, Misty

2016-01-01

Objective The critically ill, premature patients of neonatal intensive care units are susceptible to venous thrombosis, an adverse event associated with short- and long-term morbidity. Venous thrombosis is frequently treated with low molecular weight heparins (LMWH) such as enoxaparin, but optimal dosing of LMWH must balance the morbidity of venous thrombosis with the potential adverse affects of anticoagulation. The optimal dosing of enoxaparin for premature infants is unclear. The objective of this study was to describe enoxaparin therapy and follow-up in critically ill neonates diagnosed with venous thrombosis. Study Design Retrospective medical record review in the neonatal intensive care unit (NICU) in a single tertiary care institution. Infants with venous thrombosis diagnosed in the NICU were identified using pre-existing quality improvement lists and medical records. Results Twenty-six infants with 30 venous thromboses were identified with a median gestational age of 31 weeks at birth. Eighteen (69%) infants received enoxaparin for venous thrombosis during their hospitalization, beginning with a median dose of 1.5 mg/kg every 12h. This dose was increased to a median 2.1 mg/kg every 12h to achieve target anti-factor Xa levels. The target dose was significantly higher in patients with a postmenstrual age less than 37 weeks. Enoxaparin treatment was documented after discharge in 12 patients, continuing for a median of 99 days. Four patients died during hospitalization and their deaths were not attributable to venous thrombosis or anticoagulation complication. Follow-up documentation between 6 and 24 months after venous thrombosis diagnosis revealed no major morbidity of venous thrombosis or enoxaparin therapy. Conclusions Our data reinforces the relative safety and necessity of enoxaparin doses above 1.5 mg/kg per 12 hours in most neonates. This was particularly true for infants at lower postmenstrual age. PMID:27906197

Cost-utility of enoxaparin compared with unfractionated heparin in unstable coronary artery disease

PubMed Central

Nicholson, Tricia; McGuire, Alistair; Milne, Ruairidh

2001-01-01

Background Low molecular weight heparins hold several advantages over unfractionated heparin including convenience of administration. Enoxaparin is one such heparin licensed in the UK for use in unstable coronary artery disease (unstable stable angina and non-Q wave myocardial infarction). In these patients, two large randomised controlled trials and their meta-analysis showed small benefits for enoxaparin over unfractionated heparin at 30–43 days and potentially at one year. We found no relevant published full economic evaluations, only cost studies, one of which was conducted in the UK. The other studies, from the US, Canada and France, are difficult to interpret since their resource use and costs may not reflect UK practice. Methods We aimed to compare the benefits and costs of short-term treatment (two to eight days) with enoxaparin and unfractionated heparin in unstable coronary artery disease. We used published data sources to estimate the incremental cost per quality adjusted life year (QALY), adopting a NHS perspective and using 1998 prices. Results The base case was a 0.013 QALY gain and net cost saving of £317 per person treated with enoxaparin instead of unfractionated heparin. All but one sensitivity analysis showed net savings and QALY gains, the exception (the worst case) being a cost per QALY of £3,305. Best cases were a £495 saving and 0.013 QALY gain, or a £317 saving and 0.014 QALY gain per person. Conclusions Enoxaparin appears cost saving compared with unfractionated heparin in patients with unstable coronary artery disease. However, cost implications depend on local revascularisation practice. PMID:11701090

Short-term therapy with enoxaparin or unfractionated heparin for venous thromboembolism in hospitalized patients: utilization study and cost-minimization analysis.

PubMed

Argenta, Catia; Ferreira, Maria Angélica Pires; Sander, Guilherme Becker; Moreira, Leila Beltrami

2011-01-01

To evaluate the direct costs of venous thromboembolism (VTE) treatment with unfractionated heparin (UFH) and low-molecular weight heparin, from the institutional perspective. This is a real-world cohort study that included inpatients treated with UFH or enoxaparin for deep venous thromboembolism or pulmonary embolism in a tertiary public hospital. To estimate medical costs we computed the acquisition costs of drugs, supplies for administration, laboratory tests, and hospitalization cost according to the patient ward. One hundred sixty-seven patients aged 18 to 92 years were studied (50 treated with UFH and 117 with enoxaparin). The median of days in use of heparin was the same in both groups. Activated partial thromboplastin time was monitored in 98% of patients using UFH and 56.4% using enoxaparin. Nonstatistically significant differences were observed between groups in the number of bleeding events (10.0% and 9.4%; P = 1.00); blood transfusion (2.0% and 2.6%; P = 1.00); death (8.0% and 3.4%; P = 0.24); and recurrent VTE, bleeding, or death (20.0% and 14.5%; P = 0.38). Daily mean cost per patient was US$12.63 ± $4.01 for UFH and US$9.87 ± $2.44 for enoxaparin (P < 0.001). The total costs considering the mean time of use were US$88.39 and US$69.11. The treatment of VTE with enoxaparin provided cost savings in a large teaching hospital located in southern Brazil. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Comparison of minor bleeding complications using dabigatran or enoxaparin after cemented total hip arthroplasty.

PubMed

Gombár, Csaba; Horvath, Gyöngyi; Gálity, Hristifor; Sisák, Krisztián; Tóth, Kálmán

2014-04-01

Orally administered chemical thromboprophylactic agents for total hip replacement (THR) have become popular in recent years. Certain clinical trials suggest that the efficacy and the risk of major bleeding after administration of direct thrombin inhibitor dabigatran etexilate are equivalent to the clinical trial comparator, subcutaneous low-molecular-weight heparin enoxaparin. Our aim was to compare and evaluate the incidence of minor haemorrhagic and soft-tissue adverse effects of enoxaparin and dabigatran. 122 patients who were treated by elective cemented primary THR were enrolled in our quasi-randomised study. Two groups were formed according to which perioperative thromboprophylactic agent was used: 61 patients in enoxaparin group versus 61 patients in dabigatran group. Thigh volume changes, calculated perioperative blood loss, area of haematoma, wound bleeding, duration of wound discharge and intensity of serous wound discharge on postoperative day 3 and day 7 were recorded. The duration and intensity of serous wound discharge differed significantly between the two groups. Duration of wound discharge after drain removal was 2.2 (±2.7) days in the dabigatran group and 1.2 (±1.9) days in the enoxaparin group (p < 0.05). Significant increase in serous discharge was found in the dabigatran group (p < 0.05) on third and seventh postoperative days compared to the enoxaparin group. Both thromboprophylactic agents were found to have appropriate antithrombotic effects after THR. However, dabigatran was associated with an increased incidence of prolonged serous wound discharge, which might cause longer hospitalization and might instigate the use of prolonged antibiotic prophylaxis.

Enoxaparin can be used safely in patients with severe thrombocytopenia due to intensive chemotherapy regimens.

PubMed

Herishanu, Yair; Misgav, Mudi; Kirgner, Ilya; Ben-Tal, Ofira; Eldor, Amiram; Naparstek, Ella

2004-07-01

Treatment with intensive chemotherapy regimens is frequently complicated by severe thrombocytopenia. During the period of severe thrombocytopenia, anticoagulant treatment is not uncommonly indicated for thromboembolic events or thromboprophylaxis in these patients. We report 10 hematological patients treated with intensive chemotherapy protocols that were anticoagulated with enoxaparin for catheter related central venous thrombosis and thromboprophylaxis. During the period of severe thrombocytopenia the dosages of enoxaparin were reduced and no major bleeding occurred. Based on our experience we suggest that reduced dosages of low molecular weight heparins may be used relatively safely during transient severe thrombocytopenia.

Exploration of hydrophobic modification degree of chitosan-based nanocomplexes on the oral delivery of enoxaparin.

PubMed

Wang, Linlin; Li, Liang; Sun, Yujiao; Tian, Ye; Li, Ying; Li, Conghao; Junyaprasert, Varaporn B; Mao, Shirui

2013-11-20

The objective of this paper is to elucidate the influence of lipophilic modification degree of chitosan on the peroral absorption of enoxaparin. A series of novel chitosan grafted glyceryl monostearate (GM) copolymers with different GM substitution degree were synthesized and the successful synthesis was confirmed by (1)H NMR, FTIR and X-ray diffraction. Enoxaparin loaded nanocomplexes with different carriers were prepared by self-assembly process. Influence of GM substitution degree and chitosan molecular weight in the copolymer on the properties of the nanocomplexes was investigated. Morphology of the nanocomplexes was observed by atomic force microscopy. Mucoadhesive properties of the nanocomplexes were characterized using mucin particle method. Initially, mucoadhesion of the nanocomplexes increased with the increase of GM substitution degree and it started to decrease when the substitution degree was up to 18.6%. A good linear relationship between GM substitution degree and in vivo absorption of enoxaparin in fasted rats was established in the substitution degree range of 0-11.1%. In agreement with mucoadhesion data, further increasing GM substitution degree to 18.6% caused a decrease in oral absorption. In conclusion, oral bioavailability of enoxaparin can be enhanced by structure modification of the carriers and the bioavailability is hydrophobic modification degree dependent. Copyright © 2013 Elsevier B.V. All rights reserved.

Effect of thrombocytopenia on outcomes following treatment with either enoxaparin or unfractionated heparin in patients presenting with acute coronary syndromes.

PubMed

Yeh, Robert W; Wiviott, Stephen D; Giugliano, Robert P; Morrow, David A; Shui, Amy; Qin, Jie; Scirica, Benjamin; Bradner, James E; Jang, Ik-Kyung; Gibson, C Michael; Antman, Elliott M

2007-12-15

Thrombocytopenia is associated with an increased risk for adverse cardiac events and bleeding in patients presenting with acute coronary syndromes (ACS) treated with unfractionated heparin (UFH). Enoxaparin has been shown to improve outcomes in ACS; however, its effect on the development of thrombocytopenia in this population is not well documented. This study was conducted to examine the incidence and clinical importance of thrombocytopenia in patients presenting with non-ST-elevation ACS randomized to treatment with enoxaparin or UFH. Thrombocytopenia was defined as a platelet count <100 x 10(9)/L or a >50% decrease from baseline. Thrombocytopenia developed in a total of 93 of 3,910 patients during the follow-up period of 14 days; the incidence was similar between study arms. The development of thrombocytopenia was associated with more frequent death, nonfatal myocardial infarction, and urgent revascularization during the study period (odds ratio 2.96, p = 0.001). This association was independent of assignment to treatment with enoxaparin or UFH (p for interaction = 0.47). Major bleeding was also more common in patients with thrombocytopenia regardless of treatment. In conclusion, thrombocytopenia is a significant correlate of adverse events in patients presenting with non-ST-elevation ACS treated with either enoxaparin or UFH.

Structure and haemostatic effects of generic versions of enoxaparin available for clinical use in Brazil: similarity to the original drug.

PubMed

Glauser, Bianca F; Vairo, Bruno C; Oliveira, Stephan-Nicollas M C G; Cinelli, Leonardo P; Pereira, Mariana S; Mourão, Paulo A S

2012-02-01

Patent protection for enoxaparin has expired. Generic preparations are developed and approved for clinical use in different countries. However, there is still skepticism about the possibility of making an exact copy of the original drug due to the complex processes involved in generating low-molecular-weight heparins. We have undertaken a careful analysis of generic versions of enoxaparin available for clinical use in Brazil. Thirty-three batches of active ingredient and 70 of the final pharmaceutical product were obtained from six different suppliers. They were analysed for their chemical composition, molecular size distribution, in vitro anticoagulant activity and pharmacological effects on animal models of experimental thrombosis and bleeding. Clearly, the generic versions of enoxaparin available for clinical use in Brazil are similar to the original drug. Only three out of 33 batches of active ingredient from one supplier showed differences in molecular size distribution, resulting from a low percentage of tetrasaccharide or the presence of a minor component eluted as monosaccharide. Three out of 70 batches of the final pharmaceutical products contained lower amounts of the active ingredient than that declared by the suppliers. Our results suggest that the generic versions of enoxaparin are a viable therapeutic option, but their use requires strict regulations to ensure accurate standards.

Clinical presentation and course of bleeding events in patients with venous thromboembolism, treated with apixaban or enoxaparin and warfarin. Results from the AMPLIFY trial.

PubMed

Bleker, Suzanne M; Cohen, Alexander T; Büller, Harry R; Agnelli, Giancarlo; Gallus, Alexander S; Raskob, Gary E; Weitz, Jeffrey I; Curto, Madelyn; Sisson, Melanie; Middeldorp, Saskia

2016-11-30

Apixaban, a direct acting oral anticoagulant (DOAC), was found to be non-inferior to and safer as enoxaparin followed by warfarin for treatment of venous thromboembolism (VTE) in the AMPLIFY trial. Information is needed on how bleeding events with DOACs present and develop. In this post-hoc analysis, the clinical presentation and course of all major and clinically relevant non major (CRNM) bleeding events in the AMPLIFY trial were blindly classified by three investigators, using pre-designed classification schemes containing four categories. Odds ratios (OR) for classifying as category three or four (representing a more severe clinical presentation and course) were calculated between apixaban and enoxaparin/warfarin. In total, 63 major and 311 CRNM bleeding events were classified. Of the major bleeds, a more severe clinical presentation occurred in 28.5 % of apixaban versus 44.9 % of enoxaparin/warfarin related recipients (OR 0.49, 95 % confidence interval [CI] 0.14-1.78). A severe clinical course was observed in 14.3 % and in 12.2 %, respectively (OR 1.19, 95 %CI 0.21-6.69). Of the CRNM bleeding events, a more severe clinical presentation and extent of clinical care was found in 25 % of apixaban recipients compared to 22.7 % in the enoxaparin/warfarin group (OR 1.13, 95 %CI 0.65-1.97). The clinical presentation and course of major and CRNM bleeds were similar in apixaban and enoxaparin/warfarin treated patients. This finding should reassure physicians and patients that even in the absence of a specific reversal agent, apixaban is a convenient and safe choice for VTE.

Gold Medal Forum Winner. Unfractionated heparin three times a day versus enoxaparin in the prevention of deep vein thrombosis in trauma patients.

PubMed

Arnold, Joshua D; Dart, Benjamin W; Barker, Donald E; Maxwell, Robert A; Burkholder, Hans C; Mejia, Vicente A; Smith, Philip W; Longley, Joy M

2010-06-01

Venous thromboembolic disease is a significant source of morbidity and mortality in hospitalized trauma patients. Multiple drugs and dosing regimens have been suggested for pharmacoprophylaxis. In this study, we compared efficacy, complications, and cost of unfractionated heparin administered subcutaneously three times a day with standard-dosed enoxaparin for prophylaxis of deep venous thrombosis (DVT) in adult trauma patients over 1 year. Patients admitted for greater than 72 hours who received pharmacoprophylaxis as part of a comprehensive DVT protocol were included. A change was made in the protocol from enoxaparin (30 mg twice a day or 40 mg per day) to heparin (5000 U three times a day) at midyear. Surveillance lower extremity venous ultrasound was performed according to established institutional guidelines. Data, including demographics, associated injuries, complications, and cost, were collected and analyzed. Four hundred seventy-six patients met inclusion criteria. Two hundred thirty-seven (49.8%) patients received enoxaparin and 239 (50.2%) received heparin. Proximal lower extremity DVTs were detected in 16 (6.75%) patients in the enoxaparin group and 17 (7.11%) in the heparin group (P = 0.999). Risk factors for DVT in these patients included spinal cord injury (P = 0.001) and closed head injury (P = 0.031). There was no difference between the incidence of pulmonary emboli and bleeding. There was an estimated yearly pharmacy cost savings of $135,606. In trauma patients, subcutaneous heparin dosed three times a day may be as effective as standard-dosed enoxaparin for prophylaxis of venous thromboembolism without increased complications. Heparin three times a day for venous thromboembolism prophylaxis was associated with significant pharmaceutical cost savings.

Residual Enoxaparin Activity, Anti-Xa Levels, and Concerns About the American Society of Regional Anesthesia and Pain Medicine Anticoagulation Guidelines.

PubMed

Henshaw, Daryl S; Turner, James D; Forest, Daniel J; Thompson, Garrett R; Weller, Robert S

Currently, the American Society of Regional Anesthesia and Pain Medicine (ASRA) anticoagulation guidelines recommend that before the performance of a neuraxial procedure a minimum of 24 hours should elapse following a treatment dose of enoxaparin (1 mg/kg twice daily or 1.5 mg/kg once daily). The guidelines have since their inception also consistently recommended against the routine use of anti-Xa level monitoring for patients receiving enoxaparin. However, we noted in our clinical practice that anti-Xa levels were frequently still elevated despite patients meeting the time-based recommendation for treatment dose enoxaparin. To further investigate the possibility that residual anticoagulant activity may persist longer than 24 hours after a treatment dose of enoxaparin, we assessed anti-Xa level activity in patients presenting for elective surgery. Despite nearly universal compliance with ASRA's anticoagulation guidelines (1 sample was drawn at 23.25 hours), anti-Xa activity was found to be elevated in 11 of 19 patients. While 10 patients had an anti-Xa level within the peak prophylactic range (0.2-0.5 IU/mL), 1 patient's level was found to still be in the peak therapeutic range (0.5-1.0 IU/mL). These findings suggest that significant anticoagulant activity may persist longer than previously appreciated after the last treatment dose of enoxaparin and that the current time-based ASRA recommendation may not be conservative enough. Further research is needed to delineate the level of anti-Xa activity below which it is likely safe to proceed with a neuraxial procedure, but it may be time to reconsider the utility of anti-Xa level monitoring when it is available.

Cost in the use of enoxaparin compared with unfractionated heparin in patients with atrial fibrillation undergoing a transesophageal echocardiography-guided cardioversion (from Assessment of Cardioversion using Transesophageal Echocardiography [ACUTE] II randomized multicenter study).

PubMed

Zhao, Liping; Zhang, Zefeng; Kolm, Paul; Jasper, Susan; Lewis, Cheryl; Klein, Allan; Weintraub, William

2008-02-01

The ACUTE II study demonstrated that transesophageal echocardiographically guided cardioversion with enoxaparin in patients with atrial fibrillation was associated with shorter initial hospital stay, more normal sinus rhythm at 5 weeks, and no significant differences in stroke, bleeding, or death compared with unfractionated heparin (UFH). The present study evaluated resource use and costs in enoxaparin (n=76) and UFH (n=79) during 5-week follow-up. Resources included initial and subsequent hospitalizations, study drugs, outpatient services, and emergency room visits. Two costing approaches were employed for the hospitalization costing. The first approach was based on the UB-92 formulation of hospital bill and diagnosis-related group. The second approach was based on UB-92 and imputation using multivariable linear regression. Costs for outpatient and emergency room visits were determined from the Medicare fee schedule. Sensitivity analysis was performed to assess the robustness of the results. A bootstrap resample approach was used to obtain the confidence interval (CI) for the cost differences. Costs of initial and subsequent hospitalizations, outpatient procedures, and emergency room visits were lower in the enoxaparin group. Average total costs remained significantly lower for the enoxaparin group for the 2 costing approaches ($5,800 vs $8,167, difference $2,367, 95% CI 855 to 4,388, for the first approach; $7,942 vs $10,076, difference $2,134, 95% CI 437 to 4,207, for the second approach). Sensitivity analysis showed that cost differences between strategies are robust to variation of drug costs. In conclusion, the use of enoxaparin as a bridging therapy is a cost-saving strategy (similar clinical outcomes and lower costs) for atrial fibrillation.

Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE.

PubMed

Lassen, M R; Fisher, W; Mouret, P; Agnelli, G; George, D; Kakkar, A; Mismetti, P; Turpie, A G G

2012-05-01

Semuloparin is a novel ultra-low-molecular-weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE-KNEE), elective hip replacement (SAVE-HIP1) and hip fracture surgery (SAVE-HIP2). All studies were multinational, randomized and double-blind. Semuloparin and enoxaparin were administered for 7-10 days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non-fatal pulmonary embolism or all-cause death. Safety outcomes included major bleeding, clinically relevant non-major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). In total, 1150, 2326 and 1003 patients were randomized in SAVE-KNEE, SAVE-HIP1 and SAVE-HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE-HIP1. In SAVE-HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE-KNEE and SAVE-HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles. © 2012 International Society on Thrombosis and Haemostasis.

Economic and clinical evaluation of fondaparinux vs. enoxaparin for thromboprophylaxis following general surgery.

PubMed

Farias-Eisner, Robin; Horblyuk, Ruslan; Franklin, Meg; Lunacsek, Orsolya E; Happe, Laura E

2009-05-01

Patients undergoing general surgical procedures are at increased risk for venous thromboembolism (VTE). Compliance rates with established guidelines for VTE thromboprophylaxis in patients at moderate-to-high risk are notably low. Recent literature has demonstrated that fondaparinux is associated with lower costs and fewer VTEs than enoxaparin in patients undergoing major orthopedic surgery (MOS), but data are limited in patients undergoing general surgery. This study was conducted to evaluate the cost implications and relative real-world effectiveness of fondaparinux vs. enoxaparin in general surgery patients. Data were obtained from inpatient billing records from over 500 hospitals using Premier's Perspective Comparative Database. Patients hospitalized for general surgery between July 1, 2003 and January 31, 2006 were eligible for inclusion. Eligible patients were included if they received fondaparinux or enoxaparin after their general surgery date. Patients were excluded if they received both anticoagulants on their first day of therapy, were <18 years of age on the surgery date, or did not have data 6 months prior and 1 month post hospitalization. Included patients were stratified into two cohorts based on their first anticoagulant, fondaparinux or enoxaparin. Patients were matched in each group on 1:1 case-control matching based on propensity scores. A total of 5364 patients were included (n = 2682 for each cohort) from 326 unique hospitals. Average total costs per patient for the fondaparinux group were significantly lower than the enoxaparin group ($15 156 vs. 17 741, p < 0.0001). Patients receiving fondaparinux were significantly less likely to experience a VTE (2.80 vs. 3.77%, p = 0.046, a 35% relative risk reduction). No significant differences in bleeding events between the cohorts were observed (p = 0.6047), and no significant differences in all-cause inpatient death were noted (p = 0.3673). Fondaparinux was associated with significantly lower costs and fewer VTEs compared to enoxaparin without an increase in bleed rates or all-cause inpatient mortality. The findings from this study are limited by the retrospective study design and should only be generalized to a similar patient population.

Massive Spontaneous Retroperitoneal Hemorrhage Induced by Enoxaparin and Subsequent Abdominal Compartment Syndrome Requiring Surgical Decompression: A Case Report and Literature Review

DTIC Science & Technology

2011-08-01

No No No No No Abbreviations: DVT ppx - Deep Vein thrombosis prophylaxis; ASA - Aspirin; RF - renal failure; W - warfarin ; ACS...A. Surgical management of enoxaparin-and /or warfarin - induced massive retroperitoneal bleeding: report of a case and review of the literature

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

Impact of age on the efficacy and safety of extended-duration thromboprophylaxis in medical patients. Subgroup analysis from the EXCLAIM randomised trial.

PubMed

Yusen, Roger D; Hull, Russell D; Schellong, Sebastian M; Tapson, Victor F; Monreal, Manuel; Samama, Meyer-Michel; Chen, Min; Deslandes, Bruno; Turpie, Alexander G G

2013-12-01

The EXCLAIM study enrolled hospitalised acutely ill medical patients with age >40 years and recently-reduced mobility into a trial of extended-duration anticoagulant thromboprophylaxis. This post-hocanalysis evaluated the impact of age on patient outcomes. After completion of open-label therapy with enoxaparin 40 mg once-daily (10 ± 4 days), eligible patients underwent randomisation to receive double-blind therapy of enoxaparin (n=2,975) or placebo (n=2,988) for 28 ± 4 days. During follow-up, the venous thromboembolism (VTE) risk increased with age in both treatment groups. In patients with age >75 years, those who received extended-duration enoxaparin had lower incidence of VTE (2.5% vs 6.7%; absolute difference [AD] [95% confidence interval]: -4.2% [-6.5, -2.0]), proximal deep-vein thrombosis (2.5% vs 6.6%; AD -4.1% [-6.2, -2.0]), and symptomatic VTE (0.3% vs 1.5%; AD -1.2% [-2.2, -0.3]), in comparison to those who received placebo. In patients with age ≤75 years, those who received enoxaparin had reduced VTE (2.4% vs 2.8%; AD -0.4% [-1.5, 0.7]) and symptomatic VTE (0.2% vs 0.7%; AD -0.6% [-1.0, -0.1]) in comparison to those who received placebo. In both age subgroups, patients who received enoxaparin had increased rates of major bleeding versus those who received placebo: age >75 years (0.6% vs 0.2%; AD +0.3% [-0.2, 0.9], respectively); age ≤75 years (0.7% vs 0.2%; AD +0.5% [0.1, 0.9]). Patients in both age subgroups that received enoxaparin had similar low bleeding rates (0.6% and 0.7%, respectively). VTE risk increased with age, though the bleeding risk did not. Patients with age >75 years had a more favourable benefit-to-harm profile than younger patients.

Opposing effects of low molecular weight heparins on the release of inflammatory cytokines from peripheral blood mononuclear cells of asthmatics.

PubMed

Shastri, Madhur D; Stewart, Niall; Eapen, Mathew; Peterson, Gregory M; Zaidi, Syed Tabish R; Gueven, Nuri; Sohal, Sukhwinder Singh; Patel, Rahul P

2015-01-01

T-cell-mediated inflammatory cytokines, such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF-α), play an important role in the initiation and progression of inflammatory airways diseases. Low-molecular-weight heparins (LMWHs), widely used anticoagulants, possess anti-inflammatory properties making them potential treatment options for inflammatory diseases, including asthma. In the current study, we investigated the modulating effects of two LMWHs (enoxaparin and dalteparin) on the release of cytokines from stimulated peripheral blood mononuclear cells (PBMCs) of asthmatic subjects to identify the specific components responsible for the effects. PBMCs from asthmatic subjects (consist of ~75% of T-cells) were isolated from blood taken from ten asthmatic subjects. The PBMCs were pre-treated in the presence or absence of different concentrations of LMWHs, and were then stimulated by phytohaemagglutinin for the release of IL-4, IL-5, IL-13 and TNF-α. LMWHs were completely or selectively desulfated and their anticoagulant effect, as well as the ability to modulate cytokine release, was determined. LMWHs were chromatographically fractionated and each fraction was tested for molecular weight determination along with an assessment of anticoagulant potency and effect on cytokine release. Enoxaparin inhibited cytokine release by more than 48%, whereas dalteparin increased their release by more than 25%. The observed anti-inflammatory effects of enoxaparin were independent of their anticoagulant activities. Smaller fractions, in particular dp4 (four saccharide units), were responsible for the inhibitory effect of enoxaparin. Whereas, the larger fractions, in particular dp22 (twenty two saccharide units), were associated with the stimulatory effect of dalteparin. Enoxaparin and dalteparin demonstrated opposing effects on inflammatory markers. These observed effects could be due to the presence of structurally different components in the two LMWHs arising from different methods of depolymerisation. This study provides a platform for further studies investigating the usefulness of enoxaparin in various inflammatory diseases.

Population Pharmacokinetics of Enoxaparin in Pediatric Patients.

PubMed

Moffett, Brady S; Lee-Kim, YoungNa; Galati, Marianne; Mahoney, Donald; Shah, Mona D; Teruya, Jun; Yee, Donald

2018-02-01

There are no studies evaluating the pharmacokinetics of enoxaparin in the hospitalized pediatric patient population. To characterize the pharmacokinetics of enoxaparin in pediatric patients. A retrospective review of inpatients 1 to 18 years of age admitted to our institution who received enoxaparin with anti-factor Xa activity level monitoring was performed. Demographic variables, enoxaparin dosing, and anti-factor Xa activity levels were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. Simulation (n = 10 000) was performed to determine the percentage who achieved targeted anti-Xa levels at various doses. A total of 853 patients (male 52.1%, median age = 12.2 years; interquartile range [IQR] = 4.6-15.8 years) received a mean enoxaparin dose of 0.86 ± 0.31 mg/kg/dose. A median of 3 (IQR = 1-5) anti-factor Xa levels were sampled at 4.4 ± 1.3 hours after a dose, with a mean anti-factor Xa level of 0.52 ± 0.23 U/mL. A 1-compartment model best fit the data, and significant covariates included allometrically scaled weight, serum creatinine, and hematocrit on clearance, and platelets on volume of distribution. Simulations were run for patients both without and with reduced kidney function (creatinine clearance of ≤30 mL/min/1.73 m 2 ). A dose of 1 mg/kg/dose every 12 hours had the highest probability (72.3%) of achieving an anti-Xa level within the target range (0.5-1 U/mL), whereas a dose reduction of ~30% achieved the same result in patients with reduced kidney function. Pediatric patients should initially be dosed at 1-mg/kg/dose subcutaneously every 12 hours for treatment of thromboembolism followed by anti-Xa activity monitoring. Dose reductions of ~30% for creatinine clearance ≤30 mL/min/1.73 m 2 are required.

Bioactivity of enoxaparin in critically ill patients with normal renal function

PubMed Central

Gouya, Ghazaleh; Palkovits, Stefan; Kapiotis, Stylianos; Madl, Christian; Locker, Gottfried; Stella, Alexander; Wolzt, Michael; Heinz, Gottfried

2012-01-01

Aim In critically ill patients, reduced anti-FXa plasma activity following subcutaneous administration of enoxaparin or nadroparin has been described. In this study, we aimed to investigate the bioactivity of enoxaparin in critically ill patients and controls. Methods A prospective, controlled, open label study was performed on a medical intensive care unit (ICU) and a general medical ward. Fifteen ICU patients (male = 12, median age 52 years [IQR 40−65], with a median Simplified Acute Physiology Score of 30 [IQR 18−52]) and sex- and age-matched medical ward patients were included. The anti-FXa plasma activity was measured after a single subcutaneous dose of 40 mg enoxaparin. The thrombus size of a clot formed in an ex vivo perfusion chamber and endogenous thrombin potential (ETP) were measured. Results The anti-FXa plasma activity increased significantly after enoxaparin administration, with peak levels at 3 h after treatment, but was comparable between the ICU and medical ward groups (median 0.16 IU ml−1[IQR 0−0.22 IU ml−1]vs. 0.2 IU ml−1[IQR 0.15−0.27 IU ml−1], respectively, P= 0.13). The area under the anti-FXa activity curve from 0–12 h was similar between the groups (median 0.97 IU ml−1 h [IQR 0.59−2.1] and 1.48 IU ml−1 h1[IQR 0.83−1.62], P= 0.42 for the ICU group compared with the control group, respectively). The ETP was lower in the ICU group (P < 0.05) at baseline, but it was comparable at 3 h between the groups. Thrombus size decreased at 3 h compared with predose (P= 0.029) and was not different between the groups. Conclusion Similar bioactivity was achieved with a standard dose of subcutaneous enoxaparin in this selected cohort of ICU and general ward patients with normal renal function. PMID:23227470

Thromboelastogram-guided enoxaparin dosing does not confer protection from deep venous thrombosis: a randomized controlled pilot trial.

PubMed

Louis, Scott G; Van, Philbert Y; Riha, Gordon M; Barton, Jeffrey S; Kunio, Nicholas R; Underwood, Samantha J; Differding, Jerome A; Rick, Elizabeth; Ginzburg, Enrique; Schreiber, Martin A

2014-04-01

The incidence of deep venous thrombosis (DVT) remains high in general surgery and trauma patients despite widespread prophylaxis with enoxaparin. A recent study demonstrated decreased incidence of DVT if patients on enoxaparin had a change in R time (ΔR) of greater than 1 minute when heparinase-activated thromboelastography (TEG) was compared with normal TEG. We hypothesized that using ΔR-guided dosing would result in decreased DVT rates. A prospective, randomized controlled trial was performed at a Level 1 trauma center. Both trauma and general surgery patients were included. Upon enrollment, demographic data including age, sex, body mass index, and Acute Physiology and Chronic Health Evaluation II score were obtained. Enrolled patients were randomized to standard (30 mg twice a day) or TEG-guided dosing. Dose-adjusted patients underwent daily enoxaparin titration to achieve an ΔR of 1 minute to 2 minutes. Venous thromboembolism screening was performed per institutional protocol. Antithrombin III (AT-III) and anti-Xa levels were drawn at peak enoxaparin concentrations. A total of 87 patients were enrolled. There was no difference in demographic data between the groups. No pulmonary emboli were identified. The control group had a DVT rate of 16%, while the experimental group had a rate of 14% (p = nonsignificant). The experimental group's median enoxaparin dosage, 50 mg twice a day, was significantly higher than that of the control (p < 0.01). TEG ΔR was not different between the control and experimental groups. Beginning at Day 3, anti-Xa levels were higher in the experimental group (p < 0.05). There was no difference in AT-III activity between the two groups; 67% of the patients demonstrated AT-III deficiency. TEG adjusted enoxaparin dosing led to significant increases in anti-Xa activity, which did not correlate with a decreased DVT rate. Failure to reduce the DVT rate and increase ΔR despite increased dosing and increased anti-Xa activity is consistent with the high rate of AT-III deficiency detected in this study cohort. These data suggest that the future of DVT prevention may not lie in the optimization of low molecular weight heparin therapy but rather in compounds that increase antithrombin directly or operate independently of the AT-III pathway. Therapeutic study, level III.

Enoxaparin Treatment of Spontaneous Deep Vein Thrombosis in a Chronically Catheterized Rhesus Macaque (Macaca mulatta)

PubMed Central

Wathen, Asheley B; Myers, Daniel D; Zajkowski, Paul; Flory, Graham; Hankenson, F Claire

2009-01-01

A chronically catheterized 14-y-old male rhesus macaque (Macaca mulatta) was reported for recurrent scrotal swelling. The scrotum was enlarged and warm to touch, and associated skin was noted to be lichenified on physical examination. The penis could not be extruded due to preputial swelling. Results from the following diagnostic tests were all unremarkable or within normal limits: scrotal aspirate, hematology, serum biochemistries, urinalysis, and radiography of the thorax, scrotum, and abdomen. Ultrasonography of lower extremities identified thrombi in bilateral iliac veins and left femoral vein. Collateral circulation surrounding the left femoral vein permitted some compensatory venous return. The left femoral vein of this animal had been catheterized approximately 2 mo before initial presentation. A coagulation panel revealed a positive D-dimer test, indicative of elevated levels of fibrin degradation products due to active thrombus breakdown. Enoxaparin sodium, a low-molecular-weight heparin for human use, was administered at 20 mg subcutaneously once daily for 10 d to treat occlusive venous thrombi. After enoxaparin treatment, the edema was greatly decreased. To achieve complete resolution, a second course of enoxaparin was administered 2 months after the first. Ultrasonography of the pelvic vasculature 6 mo after completion of therapy showed marked thrombus resolution, allowing for bilateral patency in the iliac and femoral veins. Follow-up evaluation revealed that D-dimer values were negative as well. This case demonstrates the novel application of the human medication enoxaparin to treat clinical signs of deep vein thrombosis in a chronically catheterized rhesus macaque. PMID:19807974

Incidence of deep vein thrombosis is increased with 30 mg twice daily dosing of enoxaparin compared with 40 mg daily.

PubMed

Riha, Gordon M; Van, Philbert Y; Differding, Jerome A; Schreiber, Martin A

2012-05-01

The purpose of this study was to analyze whether 2 standard dosing regimens of enoxaparin (30 mg twice daily vs 40 mg once daily) would result in different deep vein thrombosis (DVT) rates and anti-factor Xa activity (anti-Xa) in surgical patients. Patients who required enoxaparin for prophylaxis were followed prospectively. Demographics were recorded. Patients underwent standardized duplex screening. Peak anti-Xa levels were drawn on 4 consecutive days. Sixty-three patients were followed up (28 patients on 30 mg twice daily, 35 patients on 40 mg once daily). There was no significant difference in demographics between groups. Twenty-five percent of patients on 30 mg twice daily developed a DVT, whereas 2.9% of patients on 40 mg once daily developed a DVT. Patients on 30 mg twice daily had significantly lower anti-Xa levels. The incidence of DVT is increased in surgical patients who receive 30 mg twice daily dosing of enoxaparin compared with 40 mg daily. Dosing of 40 mg once daily results in significantly higher peak anti-Xa levels compared with 30 mg twice daily. Copyright © 2012 Elsevier Inc. All rights reserved.

Comparison of Low-Molecular-Weight Heparins Prepared From Bovine Lung Heparin and Porcine Intestine Heparin.

PubMed

Guan, Yudong; Xu, Xiaohui; Liu, Xinyue; Sheng, Anran; Jin, Lan; Linhardt, Robert J; Chi, Lianli

2016-06-01

Currently porcine intestine is the only approved source for producing pharmaceutical heparin in most countries. Enoxaparin, prepared by benzylation and alkaline depolymerization from porcine intestine heparin, is prevalent in the anticoagulant drug market. It is predicted that porcine intestine heparin-derived enoxaparin (PIE) will encounter shortage, and expanding its production from heparins obtained from other animal tissues may, therefore, be inevitable. Bovine lung heparin is a potential alternative source for producing enoxaparin. Critical processing parameters for producing bovine lung heparin-derived enoxaparin (BLE) are discussed. Three batches of BLEs were prepared and their detailed structures were compared with PIEs using modern analytical techniques, including disaccharide composition, intact chain mapping by liquid chromatography-mass spectrometry and 2-dimensional nuclear magnetic resonance spectroscopy. The results suggested that the differences between PIEs and BLEs mainly result from N-acetylation differences derived from the parent heparins. In addition, bioactivities of BLEs were about 70% of PIEs based on anti-factor IIa and Xa chromogenic assays. We conclude that BLE has the potential to be developed as an analogue of PIE, although some challenges still remain. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial.

PubMed

Groom, Katie M; McCowan, Lesley M; Mackay, Laura K; Lee, Arier C; Said, Joanne M; Kane, Stefan C; Walker, Susan P; van Mens, Thijs E; Hannan, Natalie J; Tong, Stephen; Chamley, Larry W; Stone, Peter R; McLintock, Claire

2017-03-01

Preeclampsia and small-for-gestational-age pregnancy are major causes of maternal and perinatal morbidity and mortality. Women with a previous pregnancy affected by these conditions are at an increased risk of recurrence in a future pregnancy. Past trials evaluating the effect of low-molecular-weight heparin for the prevention of recurrence of preeclampsia and small-for-gestational-age pregnancy have shown conflicting results with high levels of heterogeneity displayed when trials were compared. We sought to assess the effectiveness of enoxaparin in addition to high-risk care for the prevention of preeclampsia and small-for-gestational-age pregnancy in women with a history of these conditions. This was an open-label randomized controlled trial in 5 tertiary care centers in 3 countries. Women with a viable singleton pregnancy were invited to participate between >6 +0 and <16 +0 weeks if deemed to be at high risk of preeclampsia and/or small for gestational age based on their obstetric history. Eligible participants were randomly assigned in a 1-to-1 ratio to standard high-risk care or standard high-risk care plus enoxaparin 40 mg (4000 IU) by subcutaneous injection daily from recruitment until 36 +0 weeks or delivery, whichever occurred sooner. Standard high-risk care was defined as care coordinated by a high-risk antenatal clinic service, aspirin 100 mg daily until 36 +0 weeks, and-for women with prior preeclampsia-calcium 1000-1500 mg daily until 36 +0 weeks. In a subgroup of participants serum samples were taken at recruitment and at 20 and 30 weeks' gestation and later analyzed for soluble fms-like tyrosine kinase-1, soluble endoglin, endothelin-1, placental growth factor, and soluble vascular cell adhesion molecule 1. The primary outcome was a composite of preeclampsia and/or small-for-gestational-age <5th customized birthweight percentile. All data were analyzed on an intention-to-treat basis. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12609000699268). Between July 26, 2010, and Oct. 28, 2015, a total of 156 participants were enrolled and included in the analysis. In all, 149 participants were included in the outcome analysis (72 receiving standard high-risk care plus enoxaparin and 77 receiving standard high-risk care only). Seven women who miscarried <16 weeks' gestation were excluded. The majority of participants (151/156, 97%) received aspirin. The addition of enoxaparin had no effect on the rate of preeclampsia and/or small-for-gestational-age <5th customized birthweight percentile: enoxaparin 18/72 (25%) vs no enoxaparin 17/77 (22.1%) (odds ratio, 1.19; 95% confidence interval, 0.53-2.64). There was also no difference in any of the secondary outcome measures. Levels of soluble fms-like tyrosine kinase-1 and soluble endoglin increased among those who developed preeclampsia, but there was no difference in levels of these antiangiogenic factors (nor any of the other serum analytes measured) among those treated with enoxaparin compared to those receiving standard high-risk care only. The use of enoxaparin in addition to standard high-risk care does not reduce the risk of recurrence of preeclampsia and small-for-gestational-age infants in a subsequent pregnancy. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Unfractionated heparin-clopidogrel combination in ST-elevation myocardial infarction not receiving reperfusion therapy.

PubMed

Bugiardini, Raffaele; Dorobantu, Maria; Vasiljevic, Zorana; Kedev, Sasko; Knežević, Božidarka; Miličić, Davor; Calmac, Lucian; Trninic, Dijana; Daullxhiu, Irfan; Cenko, Edina; Ricci, Beatrice; Puddu, Paolo Emilio; Manfrini, Olivia; Koller, Akos; Badimon, Lina

2015-07-01

We sought explore the relative benefits of unfractionated heparin (UFH) compared with enoxaparin, alone or in combination with clopidogrel, in ST-segment elevation myocardial infarction (STEMI) patients not undergoing reperfusion therapy. This is a propensity score study from The International Survey on Acute Coronary Syndromes in Transition Countries (ISACS-TC/NCT01218776) on patients admitted between October 2010-June 2013. There were a total of 1175 STEMI patients who did not receive mechanical or pharmacological reperfusion. Of these, 1063 were eligible for the aim of the study, being treated with UFH (522/1175; 44.4%) or enoxaparin (541/1175; 46%). Clopidogrel in combination with UFH or enoxaparin was given to 751 (63.9%) patients. The primary endpoint was in-hospital mortality. Secondary endpoints were intracranial hemorrhages, and clinically relevant bleedings. After adjustment for any confounders, UFH was associated with a lower risk of in-hospital mortality in clopidogrel users (multivariate adjusted regression analysis: odds ratio [OR]: 0.62, 95% Confidence Interval [CI] 0.41-0.94) as compared with clopidogrel non-users (OR: 0.94, 95% CI 0.55-1.60). The observed effect was not associated with combined enoxaparin and clopidogrel therapy. Major bleeding events were comparable in the enoxaparin group and UFH group (0.4% and 1.5% respectively, p = 0.06). The risk of major hemorrhage was nearly similar with combined UFH-clopidogrel therapy (1.4%) as compared with UFH alone (1.9%), p = 0.67. UFH - Clopidogrel combination was associated with a large mortality reduction in STEMI patients not undergoing reperfusion therapy and did not significantly increase the risk of major bleeding. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Determination of enoxaparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent.

PubMed

Schaden, Eva; Schober, Andreas; Hacker, Stefan; Spiss, Christian; Chiari, Astrid; Kozek-Langenecker, Sibylle

2010-04-01

Drug monitoring of low molecular weight heparin is generally not recommended, but could be reasonable in critically ill patients, whose risk for bleeding or thrombosis shows a high interpatient variability. Anti-Xa assays are not available around the clock even in central hospitals, whereas rotational thrombelastometry (ROTEM) becomes increasingly used at the bedside. Prothrombinase-induced clotting time (PiCT) reagent allows determination of factor Xa-inhibition in plasma. The aim of our study was to evaluate enoxaparin determination in whole blood with the ROTEM using specific test modifications, including PiCT. After ethics committee's approval, citrated whole blood obtained from overall 16 healthy volunteers was incubated with enoxaparin at 16 different anti-Xa concentrations. Main endpoint was the clotting time (CT) in ROTEM representing initial activation of clot formation. CT was determined in the new PiCT-ROTEM test, in a low-tissue factor-activated modification (LowTF-ROTEM) as well as in the commercially available heparin-sensitive ROTEM assays (HEPTEM and INTEM). In the absence of enoxaparin, CT values were 168.6 +/- 6.1 s (PiCT-ROTEM), 247.3 +/- 18.6 s (LowTF-ROTEM), and -6.2 +/- 7.9 s (INTEM-HEPTEM). A linear dependency (P < 0.01) between anti-Xa concentration and CT was found for PiCT-ROTEM, LowTF-ROTEM, and for INTEM-HEPTEM with correlation coefficients of 0.93 for PiCT-ROTEM, 0.94 for LowTF-ROTEM, and 0.81 for INTEM-HEPTEM. This in-vitro experiment demonstrates a strong correlation between enoxaparin anti-Xa concentrations and specific ROTEM tests. These promising assays should be further evaluated for monitoring anticoagulation in high-risk patients in clinical studies.

Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand.

PubMed

Permsuwan, Unchalee; Chaiyakunapruk, Nathorn; Nathisuwan, Surakit; Sukonthasarn, Apichard

2015-09-01

Non-ST elevation acute coronary syndrome (NSTE-ACS) imposes a significant health and economic burden on a society. Anticoagulants are recommended as standard therapy by various clinical practice guidelines. Fondaparinux was introduced and evaluated in a number of large randomised, controlled trials. This study therefore aimed to determine the cost-effectiveness of fondaparinux versus enoxaparin in the treatment of NSTE-ACS in Thailand. A two-part construct model comprising a one-year decision tree and a Markov model was developed to capture short and long-term costs and outcomes from the perspective of provider and society. Effectiveness data were derived from OASIS-5 trial while bleeding rates were derived from the Thai Acute Coronary Syndrome Registry (TACSR). Costs data were based on a Thai database and presented in the year of 2013. Both costs and outcomes were discounted by 3% annually. A series of sensitivity analyses were performed. The results showed that compared with enoxaparin, fondaparinux was a cost-saving strategy (lower cost with slightly higher effectiveness). Cost of revascularisation with major bleeding had a greater impact on the amount of cost saved both from societal and provider perspectives. With a threshold of 160,000 THB ((4,857.3 USD) per QALY in Thailand, fondaparinux was about 99% more cost-effective compared with enoxaparin. Fondaparinux should be considered as a cost-effective alternative when compared to enoxaparin for NSTE-ACS based on Thailand's context, especially in the era of limited healthcare resources. Copyright © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial.

PubMed

Agnelli, G; Buller, H R; Cohen, A; Gallus, A S; Lee, T C; Pak, R; Raskob, G E; Weitz, J I; Yamabe, T

2015-12-01

The AMPLIFY trial compared apixaban with enoxaparin followed by warfarin for the treatment of acute venous thromboembolism (VTE). To perform a subgroup analysis to compare the efficacy and safety of apixaban and enoxaparin followed by warfarin for the treatment of VTE in patients with cancer enrolled in AMPLIFY. Patients with symptomatic VTE were randomized to a 6-month course of apixaban or enoxaparin followed by warfarin. The primary efficacy outcome and principal safety outcome were recurrent VTE or VTE-related death and major bleeding, respectively. Of the 5395 patients randomized, 169 (3.1%) had active cancer at baseline, and 365 (6.8%) had a history of cancer without active cancer at baseline. Among patients with active cancer, recurrent VTE occurred in 3.7% and 6.4% of evaluable patients in the apixaban and enoxaparin/warfarin groups, respectively (relative risk [RR] 0.56, 95% confidence interval [CI] 0.13-2.37); major bleeding occurred in 2.3% and 5.0% of evaluable patients, respectively (RR 0.45, 95% CI 0.08-2.46). Among patients with a history of cancer, recurrent VTE occurred in 1.1% and 6.3% of evaluable patients in the apixaban and enoxaparin/warfarin groups, respectively (RR 0.17, 95% CI 0.04-0.78); major bleeding occurred in 0.5% and 2.8% of treated patients, respectively (RR 0.20, 95% CI 0.02-1.65). The results of this subgroup analysis suggest that apixaban is a convenient option for cancer patients with VTE. However, additional studies are needed to confirm this concept and to compare apixaban with low molecular weight heparin in these patients. © 2015 International Society on Thrombosis and Haemostasis.

Fondaparinux and acute coronary syndromes: update on the OASIS 5-6 studies.

PubMed

Schiele, François

2010-04-15

Anticoagulant therapy is a major component in the management of acute coronary syndromes (ACS). Four anticoagulant agents are currently commercially available for ACS, namely unfractionated heparin (UFH), enoxaparin, bivalirudin and fondaparinux. We describe the advantages of fondaparinux and the reasons that have hampered its uptake into routine management of ACS. Fondaparinux was shown to be efficacious in the prevention of deep vein thrombosis vs low-molecular-weight heparins, while in the setting of venous thrombo-embolic disease, it was shown to be noninferior to enoxaparin and UFH. Two pivotal studies have demonstrated the efficacy of fondaparinux as an anticoagulant in the setting of ACS, namely OASIS-5 in non-ST elevation ACS, and OASIS-6 in ST elevation myocardial infarction (MI). In OASIS-5, fondaparinux was shown to be noninferior to enoxaparin in terms of death, MI or refractory ischemia at 9 days. Furthermore, a 50% reduction in bleeding complications was obtained with fondaparinux vs enoxaparin, leading to a risk reduction for death. In OASIS-6, fondaparinux was shown to be superior to the comparator (UFH or placebo). European and North American guidelines give fondaparinux a Grade 1A and 1B recommendation respectively, but uptake of fondaparinux in routine practice has been slow. We explore reasons for this, such as prevailing doubts about the efficacy of fondaparinux in the setting of angioplasty, the problem of catheter thrombosis, and the lack of antidote in case of bleeding complications. With the exception of primary angioplasty, fondaparinux is as effective as enoxaparin or UFH, but is also associated with a considerable reduction in bleeding complications, and thus, an undeniable net clinical benefit.

[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.

Catheter-related thrombosis: biological and clinical evidence for risk with currently available anticoagulants.

PubMed

Montalescot, Gilles; Walenga, Jeanine M

2009-01-01

Anticoagulants used during percutaneous coronary intervention (PCI) should not only prevent coronary events, but also minimize the risk of periprocedural complications. Current anticoagulation therapies for PCI include unfractionated heparin (UFH), enoxaparin, fondaparinux, and bivalirudin. UFH and enoxaparin have good efficacy and safety profiles in PCI; furthermore, associated periprocedural complications such as catheter thrombosis are rare. Although newer anticoagulants seem safe and effective in patients with acute coronary syndrome, clinical trial data suggest that some pure factor Xa (FXa) inhibitors are associated with increased rates of catheter thrombosis, compared with heparin-based agents. Experimental systems show that polytherapeutic agents, including UFH and enoxaparin, are more effective anticoagulants than certain single-target agents. More studies are needed to assess whether catheter thrombosis is a class-, drug-, or dose-related effect, and how best to prevent it. Future trials should report the rates of periprocedural complications when assessing the safety of novel anticoagulation therapies in PCI.

Comparison of Low-Molecular-Weight Heparins Prepared From Bovine Heparins With Enoxaparin.

PubMed

Liu, Xinyue; St Ange, Kalib; Fareed, Jawed; Hoppensteadt, Debra; Jeske, Walter; Kouta, Ahmed; Chi, Lianli; Jin, Caijuan; Jin, Yongsheng; Yao, Yiming; Linhardt, Robert J

2017-09-01

Heparin and its low-molecular-weight heparin (LMWH) derivatives are widely used clinical anticoagulants. These drugs are critical for the practice of medicine in applications including kidney dialysis, cardiopulmonary bypass, and in the management of venous thromboembolism. Currently, these drugs are derived from livestock, primarily porcine intestine. The worldwide dependence on a single animal species has made the supply chain for this critical drug quite fragile, leading to the search for other sources of these drugs, including bovine tissues such as bovine intestine or lung. A number of laboratories are currently examining the similarities and differences between heparins prepared from porcine and bovine tissues. The current study is designed to compare LMWH prepared from bovine heparins through chemical β-elimination, a process currently used to prepare the LMWH, enoxaparin, from porcine heparin. Using top-down, bottom-up, compositional analysis and bioassays, LMWHs, derived from bovine lung and intestine, are shown to closely resemble enoxaparin.

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.

A feasible strategy for preventing blood clots in critically ill patients with acute kidney injury (FBI): study protocol for a randomized controlled trial.

PubMed

Robinson, Sian; Zincuk, Aleksander; Larsen, Ulla Lei; Ekstrøm, Claus; Toft, Palle

2014-06-13

Previous pharmacokinetic trials suggested that 40 mg subcutaneous enoxaparin once daily provided inadequate thromboprophylaxis for intensive care unit patients. Critically ill patients with acute kidney injury are at increased risk of venous thromboembolism and yet are often excluded from these trials. We hypothesized that for critically ill patients with acute kidney injury receiving continuous renal replacement therapy, a dose of 1 mg/kg enoxaparin subcutaneously once daily would improve thromboprophylaxis without increasing the risk of bleeding. In addition, we seek to utilize urine output prior to discontinuing dialysis, and low neutrophil gelatinase-associated lipocalin in dialysis-free intervals, as markers of renal recovery. In a multicenter, double-blind randomized controlled trial in progress at three intensive care units across Denmark, we randomly assign eligible critically ill adults with acute kidney injury into a treatment (1 mg/kg enoxaparin subcutaneously once daily) or control arm (40 mg enoxaparin subcutaneously once daily) upon commencement of continuous renal replacement therapy.We calculated that with 133 patients in each group, the study would have 80% power to show a 40% reduction in the relative risk of venous thromboembolism with 1 mg/kg enoxaparin, at a two-sided alpha level of 0.05. An interim analysis will be conducted after the first 67 patients have been included in each group.Enrolment began in March 2013, and will continue for two years. The primary outcome is the occurrence of venous thromboembolism. Secondary outcomes include anti-factor Xa activity, bleeding, heparin-induced thrombocytopenia, filter lifespan, length of stay, ventilator free days, and mortality. We will also monitor neutrophil gelatinase-associated lipocalin and urine volume to determine whether they can be used as prognostic factors for renal recovery. Critically ill unit patients with acute kidney injury present a particular challenge in the provision of thromboprophylaxis. This study hopes to add to the growing evidence that the existing recommendation of 40 mg enoxaparin is inadequate and that 1 mg/kg is both safe and effective for thromboprophylaxis.In addition, the study seeks to identify predictors of renal recovery allowing for the proper utilization of resources. EU Clinical Trials Register: EudraCT number: 2012-004368-23, 25 September 2012.

Effect of low molecular weight heparin (enoxaparin) on congenital cataract surgery.

PubMed

Caça, Ihsan; Sahin, Alparslan; Cingü, Abdullah Kürsat; Ari, Seyhmus; Alakuş, Fuat; Cinar, Yasin

2012-01-01

To assess the efficacy of intracameral enoxaparin (a low-molecular-weight heparin) infusion, in variable doses on postoperative inflammatory response in congenital cataract surgery. It is a prospective, randomized controlled trial. Eighty eyes of 53 children with congenital cataract were enrolled in this study. Every eye had primary posterior capsulorrhexis and intraocular lens (IOL) implantation after lens aspiration. The eyes were divided into 4 equal groups. In group 1 balanced salt solution (BSS) without enoxaparin was used as an irrigation solution. Whereas in group 2, 3 and 4, 40mg, 20mg and 10mg enoxaparin in 500mL BSS was used respectively. The inflammatory response in the anterior chamber was compared among the groups with slit-lamp biomicroscopy. The mean follow-up period was (17.75±3.95) months in group 1, (18.00±5.15) months in group 2, (19.20±5.47) months in group 3 and (18.65±5.16) months in group 4. Mean number of inflammatory cells in the anterior chamber in group 1 was significantly higher than that of group 2, 3, 4 (P<0.001). There was fibrin formation in the anterior chambers of 3 eyes in group 1 and one eye in group 4. There was synechiae formation in 3 eyes of group 1 and one eye of group 4. There was no significant difference among the groups by means of fibrin or synechiae formation (P>0.05). There were IOL precipitates in 4 eyes of group 1 and 2 eyes of group 4. IOL precipitate formation was significantly higher in group 1 than that of group 2 and 3 in which there was no IOL precipitate (P=0.048). There was IOL subluxation in only one eye of group 1, 3 and 4 while no subluxation was observed in group 2 (P>0.05). There was no statistically significant difference detected about IOL subluxation occurance in all 4 groups (P>0.05). Complications of cataract surgery in congenital cataract patients associated with postoperative inflammatory response found to be decreased with the use of enoxaparin in intraocular infusion solutions. Furthermore according to our results the anti-inflammatory effect of enoxaparin was dose dependant.

Effect of low molecular weight heparin (enoxaparin) on congenital cataract surgery

PubMed Central

Çaça, Ihsan; Şahin, Alparslan; Cingü, Abdullah Kürsat; Ari, Şeyhmus; Alakuş, Fuat; Çinar, Yasin

2012-01-01

AIM To assess the efficacy of intracameral enoxaparin (a low-molecular-weight heparin) infusion, in variable doses on postoperative inflammatory response in congenital cataract surgery. METHODS It is a prospective, randomized controlled trial. Eighty eyes of 53 children with congenital cataract were enrolled in this study. Every eye had primary posterior capsulorrhexis and intraocular lens (IOL) implantation after lens aspiration. The eyes were divided into 4 equal groups. In group 1 balanced salt solution (BSS) without enoxaparin was used as an irrigation solution. Whereas in group 2, 3 and 4, 40mg, 20mg and 10mg enoxaparin in 500mL BSS was used respectively. The inflammatory response in the anterior chamber was compared among the groups with slit-lamp biomicroscopy. RESULTS The mean follow-up period was (17.75±3.95) months in group 1, (18.00±5.15) months in group 2, (19.20±5.47) months in group 3 and (18.65±5.16) months in group 4. Mean number of inflammatory cells in the anterior chamber in group 1 was significantly higher than that of group 2, 3, 4 (P<0.001). There was fibrin formation in the anterior chambers of 3 eyes in group 1 and one eye in group 4. There was synechiae formation in 3 eyes of group 1 and one eye of group 4. There was no significant difference among the groups by means of fibrin or synechiae formation (P>0.05). There were IOL precipitates in 4 eyes of group 1 and 2 eyes of group 4. IOL precipitate formation was significantly higher in group 1 than that of group 2 and 3 in which there was no IOL precipitate (P=0.048). There was IOL subluxation in only one eye of group 1, 3 and 4 while no subluxation was observed in group 2 (P>0.05). There was no statistically significant difference detected about IOL subluxation occurance in all 4 groups (P>0.05). CONCLUSION Complications of cataract surgery in congenital cataract patients associated with postoperative inflammatory response found to be decreased with the use of enoxaparin in intraocular infusion solutions. Furthermore according to our results the anti-inflammatory effect of enoxaparin was dose dependant. PMID:23166871

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.

Alternative dosing of prophylactic enoxaparin in the trauma patient: is more the answer?

PubMed

Kopelman, Tammy R; O'Neill, Patrick J; Pieri, Paola G; Salomone, Jeffrey P; Hall, Scott T; Quan, Asia; Wells, Jordan R; Pressman, Melissa S

2013-12-01

Inadequate anti-factor Xa levels and increased venous thromboembolic events occur in trauma patients receiving standard prophylactic enoxaparin dosing. The aim of this study was to test the hypothesis that higher dosing (40 mg twice daily) would improve peak anti-Xa levels and decrease venous thromboembolism. A retrospective review was performed of trauma patients who received prophylactic enoxaparin and peak anti-Xa levels over 27 months. Patients were divided on the basis of dose: group A received 30 mg twice daily, and group B received 40 mg twice daily. Demographics and rates of venous thromboembolism were compared between dose groups and patients with inadequate or adequate anti-Xa levels. One hundred twenty-four patients were included, 90 in group A and 34 in group B. Demographics were similar, except that patients in group B had a higher mean body weight. Despite this, only 9% of group B patients had inadequate anti-Xa levels, compared with 33% of those in group A (P = .01). Imaging studies were available in 69 patients and revealed 8 venous thromboembolic events (P = NS, group A vs group B) with significantly more venous thromboembolic events occurring in patients with low anti-Xa levels (P = .02). Although higher dosing of enoxaparin led to improved anti-Xa levels, this did not equate to a statistical decrease in venous thromboembolism. Copyright © 2013 Elsevier Inc. All rights reserved.

Thrombelastography-Based Dosing of Enoxaparin for Thromboprophylaxis in Trauma and Surgical Patients: A Randomized Clinical Trial.

PubMed

Connelly, Christopher R; Van, Philbert Y; Hart, Kyle D; Louis, Scott G; Fair, Kelly A; Erickson, Anfin S; Rick, Elizabeth A; Simeon, Erika C; Bulger, Eileen M; Arbabi, Saman; Holcomb, John B; Moore, Laura J; Schreiber, Martin A

2016-10-19

Prophylactic enoxaparin is used to prevent venous thromboembolism (VTE) in surgical and trauma patients. However, VTE remains an important source of morbidity and mortality, potentially exacerbated by antithrombin III or anti-Factor Xa deficiencies and missed enoxaparin doses. Recent data suggest that a difference in reaction time (time to initial fibrin formation) greater than 1 minute between heparinase and standard thrombelastogram (TEG) is associated with a decreased risk of VTE. To evaluate the effectiveness of TEG-adjusted prophylactic enoxaparin dosing among trauma and surgical patients. This randomized clinical trial, conducted from October 2012 to May 2015, compared standard dosing (30 mg twice daily) with TEG-adjusted enoxaparin dosing (35 mg twice daily) for 185 surgical and trauma patients screened for VTE at 3 level I trauma centers in the United States. The incidence of VTE, bleeding complications, anti-Factor Xa deficiency, and antithrombin III deficiency. Of the 185 trial participants, 89 were randomized to the control group (median age, 44.0 years; 55.1% male) and 96 to the intervention group (median age, 48.5 years; 74.0% male). Patients in the intervention group received a higher median enoxaparin dose than control patients (35 mg vs 30 mg twice daily; P < .001). Anti-Factor Xa levels in intervention patients were not higher than levels in control patients until day 6 (0.4 U/mL vs 0.21 U/mL; P < .001). Only 22 patients (11.9%) achieved a difference in reaction time greater than 1 minute, which was similar between the control and intervention groups (10.4% vs 13.5%; P = .68). The time to enoxaparin initiation was similar between the control and intervention groups (median [range] days, 1.0 [0.0-2.0] vs 1.0 [1.0-2.0]; P = .39), and the number of patients who missed at least 1 dose was also similar (43 [48.3%] vs 54 [56.3%]; P = .30). Rates of VTE (6 [6.7%] vs 6 [6.3%]; P > .99) were similar, but the difference in bleeding complications (5 [5.6%] vs 13 [13.5%]; P = .08) was not statistically significant. Antithrombin III and anti-Factor Xa deficiencies and hypercoagulable TEG parameters, including elevated coagulation index (>3), maximum amplitude (>74 mm), and G value (>12.4 dynes/cm2), were prevalent in both groups. Identified risk factors for VTE included older age (61.0 years vs 46.0 years; P = .04), higher body mass index (calculated as weight in kilograms divided by height in meters squared; 30.6 vs 27.1; P = .03), increased Acute Physiology and Chronic Health Evaluation II score (8.5 vs 7.0; P = .03), and increased percentage of missed doses per patient (14.8% vs 2.5%; P = .05). The incidence of VTE was low and similar between groups; however, few patients achieved a difference in reaction time greater than 1 minute. Antithrombin III deficiencies and hypercoagulable TEG parameters were prevalent among patients with VTE. Low VTE incidence may be due to an early time to enoxaparin initiation and an overall healthier and less severely injured study population than previously reported. clinicaltrials.gov Identifier: NCT00990236.

Clinical and economic benefits of extended treatment with apixaban for the treatment and prevention of recurrent venous thromboembolism in Canada.

PubMed

Quon, Peter; Le, Hoa H; Raymond, Vincent; Mtibaa, Mondher; Moshyk, Andriy

2016-06-01

Background and objective Venous thromboembolism (VTE) is associated with long-term clinical and economic burden. Clinical guidelines generally recommend at least 3 months of anticoagulation, but, in clinical practice, concerns over bleeding risk often limit extended treatment. Apixaban was studied for extended VTE treatment in the AMPLIFY-EXT trial, demonstrating superiority to placebo in VTE reduction without increasing risk of major bleeding. This study assessed the long-term clinical and economic benefits of extending treatment with apixaban when clinical equipoise exists compared to standard of care with enoxaparin/warfarin and other novel oral anti-coagulants (NOACs) for the treatment and prevention of recurrent VTE in Canada. Methods A Markov model was developed to follow patients with VTE over their lifetimes. Efficacy and safety for apixaban and enoxaparin/warfarin were based on AMPLIFY and AMPLIFY-EXT, while relative efficacy to other NOACs was synthesized by network meta-analysis (NMA). Dosages for NOACs and enoxaparin/warfarin were based on their respective trials and were given up to 18 months and up to 6 months, followed by no treatment, respectively. Patient quality adjusted life years (QALYs) were based on published studies, and costs for resource utilization were from a Ministry of Health perspective, expressed as 2014 CAD ($). Results Extended treatment with apixaban compared to enoxaparin/warfarin resulted in fewer recurrent VTEs, VTE-related deaths, and bleeding events, but at slightly increased cost. The incremental cost-effectiveness ratio was $4828 per QALY gained. Compared to other NOACs, apixaban had the fewest bleeding events, similar recurrent VTE events, and the lowest overall cost, which was driven by the strong bleeding profile. In scenario analyses of acute and lifetime treatments, apixaban was cost-effective against all strategies. Conclusions Extended treatment with apixaban can offer substantial clinical benefits and is a cost-effective alternative to enoxaparin/warfarin and other NOACs.

Low-molecular-weight heparin and mortality in acutely ill medical patients.

PubMed

Kakkar, Ajay K; Cimminiello, Claudio; Goldhaber, Samuel Z; Parakh, Rajiv; Wang, Chen; Bergmann, Jean-François

2011-12-29

Although thromboprophylaxis reduces the incidence of venous thromboembolism in acutely ill medical patients, an associated reduction in the rate of death from any cause has not been shown. We conducted a double-blind, placebo-controlled, randomized trial to assess the effect of subcutaneous enoxaparin (40 mg daily) as compared with placebo--both administered for 10±4 days in patients who were wearing elastic stockings with graduated compression--on the rate of death from any cause among hospitalized, acutely ill medical patients at participating sites in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia. Inclusion criteria were an age of at least 40 years and hospitalization for acute decompensated heart failure, severe systemic infection with at least one risk factor for venous thromboembolism, or active cancer. The primary efficacy outcome was the rate of death from any cause at 30 days after randomization. The primary safety outcome was the rate of major bleeding during and up to 48 hours after the treatment period. A total of 8307 patients were randomly assigned to receive enoxaparin plus elastic stockings with graduated compression (4171 patients) or placebo plus elastic stockings with graduated compression (4136 patients) and were included in the intention-to-treat population. The rate of death from any cause at day 30 was 4.9% in the enoxaparin group as compared with 4.8% in the placebo group (risk ratio, 1.0; 95% confidence interval [CI], 0.8 to 1.2; P=0.83). The rate of major bleeding was 0.4% in the enoxaparin group and 0.3% in the placebo group (risk ratio, 1.4; 95% CI, 0.7 to 3.1; P=0.35). The use of enoxaparin plus elastic stockings with graduated compression, as compared with elastic stockings with graduated compression alone, was not associated with a reduction in the rate of death from any cause among hospitalized, acutely ill medical patients. (Funded by Sanofi; LIFENOX ClinicalTrials.gov number, NCT00622648.).

SCI with Brain Injury: Bedside-to-Bench Modeling for Developing Treatment and Rehabilitation Strategies

DTIC Science & Technology

2012-10-01

GLUCONATE 1 SIMVASTATIN 2 SIMVASTATIN 1 METOPROLOL 1 METOPROLOL 1 Discharge  Medications Note that the length of stay in rehabilitation is shorter in SCVMC...ENOXAPARIN 3 ENOXAPARIN 3 GABAPENTIN 3 GABAPENTIN 2 DOXYCYCLINE 3 DOXYCYCLINE 1 LISINOPRIL 3 LISINOPRIL 1 CHLORHEXIDINE 2 CHLORHEXIDINE 2 METOPROLOL 2... METOPROLOL 2 DEXTROSE 2 DEXTROSE 1 MICONAZOLE 2 MICONAZOLE 1 HEPARIN 1 HEPARIN 3 FENTANYL 1 FENTANYL 2 BACLOFEN 1 BACLOFEN 1 FERROUS  SULFATE 1 FERROUS

Effects of enoxaparin and unfractionated heparin in prophylactic and therapeutic doses on the fertility of female Wistar rats.

PubMed

Figueiró-Filho, Ernesto Antonio; Aydos, Ricardo Dutra; Senefonte, Flávio Renato de Almeida; Ferreira, Cristiane Munaretto; Pereira, Erica Freire de Vasconcelos; Oliveira, Vanessa Marcon de; Menezes, Giovanna Pádoa de; Bósio, Marco Antonio Costa

2014-07-01

To evaluate the effects of exposure of enoxaparin and unfractionated heparin (UFH) in prophylactic and therapeutic doses on the fertility rates of pregnant healthy Wistar rats. Enoxaparin and UFH were administered in prophylactic doses 1 mg/Kg/day 72 UI/Kg/day, and in therapeutic doses at 2 mg/kg/day 400UI/Kg/day. The rats were divided into five groups. The number of live and dead foetuses was quantified. The uterine horns were dissected and the presence of early and late reabsorptions (abortions) was determined. A p<0.05 was considered statistically significant. We did not observe statistically significant differences between groups when comparing the average weight of the foetuses and placentas, rate of female VS males, rates of pre-implantation loss (RPL), rates of efficiency implantation (REI), rates of post-implantation loss (RPIL) and rates of foetal viability (RFV). There was no significant effect on fertility with the use of anticoagulant drugs in pregnant healthy Wistar rats.

The economic impact of enoxaparin versus unfractionated heparin for prevention of venous thromboembolism in acute ischemic stroke patients

PubMed Central

Pineo, Graham F; Lin, Jay; Annemans, Lieven

2012-01-01

Venous thromboembolism (VTE) is a common complication after acute ischemic stroke that can be prevented by the use of anticoagulants. Current guidelines from the American College of Chest Physicians recommend that patients with acute ischemic stroke and restricted mobility receive prophylactic low-dose unfractionated heparin or a low-molecular-weight heparin. Results from clinical studies, most recently from PREVAIL (PREvention of Venous Thromboembolism After Acute Ischemic Stroke with LMWH and unfractionated heparin), suggest that the low-molecular-weight heparin, enoxaparin, is preferable to unfractionated heparin for VTE prophylaxis in patients with acute ischemic stroke and restricted mobility. This is due to a better clinical benefit-to-risk ratio, with the added convenience of once-daily administration. In line with findings from modeling studies and real-world data in acutely ill medical patients, recent economic data indicate that the higher drug cost of enoxaparin is offset by the reduction in clinical events as compared with the use of unfractionated heparin for the prevention of VTE after acute ischemic stroke, particularly in patients with severe stroke. With national performance measures highlighting the need for hospitals to examine their VTE practices, the relative costs of different regimens are of particular importance to health care decision-makers. The data reviewed here suggest that preferential use of enoxaparin over unfractionated heparin for the prevention of VTE after acute ischemic stroke may lead to reduced VTE rates and concomitant cost savings in clinical practice. PMID:22570556

Effect of subcutaneous Enoxaparin injection duration on bruising size in acute coronary syndrome patients.

PubMed

Dehghani, Khadije; Najari, Zahra; Dehghani, Hamideh

2014-11-01

Bruising is an unpleasant result of subcutaneous injection of Enoxaparin, which causes physical discomfort, limitation of injection site, patient's refusal of treatment, and distrust in nurses' ability. The application of techniques which reduce patients' fear, anxiety, and physical damage is one of the tasks of nurses. This clinical trial investigated the effect of duration of subcutaneous Enoxaparin injection on the bruising size in acute coronary syndrome patients. Seventy 35-75-year-old acute coronary syndrome patients hospitalized in Coronary Care Units were selected randomly. Each subject received 10- and 30-sec duration of injections by a single researcher on both sides of the abdomen in 12-h intervals. The bruising size was measured using a transparent millimeter measuring paper, 24 and 48 h after each injection. Data were gathered by a data recording form (demographic and measurements data) and analyzed by descriptive statistics and non-parametric tests through SPSS. Results showed that the mean bruising sizes at 24 h after 10- and 30-sec injection were 33.26 mm(2) (72.77) and 48.96 mm(2) (99.91), respectively, and at 48 h were 15.61 mm(2) (142.02) and 52.48 mm(2) (143), respectively. There was no significant relationship between the two techniques (P > 0.05), although the effect of age on bruising size was significant (P = 0.01). According to the findings of the present study, length of Enoxaparin subcutaneous injection has no effect on the bruising size.

Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis

PubMed Central

Büller, Harry R.; Bethune, Claudette; Bhanot, Sanjay; Gailani, David; Monia, Brett P.; Raskob, Gary E.; Segers, Annelise; Verhamme, Peter; Weitz, Jeffrey I.

2015-01-01

BACKGROUND Experimental data indicate that reducing factor XI levels attenuates thrombosis without causing bleeding, but the role of factor XI in the prevention of postoperative venous thrombosis in humans is unknown. FXI-ASO (ISIS 416858) is a second-generation antisense oligonucleotide that specifically reduces factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty. METHODS In this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS Around the time of surgery, the mean (±SE) factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively. CONCLUSIONS This study showed that factor XI contributes to postoperative venous thromboembolism; reducing factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. (Funded by Isis Pharmaceuticals; FXI-ASO TKA ClinicalTrials.gov number, NCT01713361.) PMID:25482425

Top-down and bottom-up analysis of commercial enoxaparins.

PubMed

Liu, Xinyue; St Ange, Kalib; Lin, Lei; Zhang, Fuming; Chi, Lianli; Linhardt, Robert J

2017-01-13

A strategy for the comprehensive analysis of low molecular weight (LMW) heparins is described that relies on using an integrated top-down and bottom-up approach. Liquid chromatography-mass spectrometry, an essential component of this approach, is rapid, robust, and amenable to automated processing and interpretation. Nuclear magnetic resonance spectroscopy provides complementary top-down information on the chirality of the uronic acid residues comprising a low molecular weight heparin. Using our integrated approach four different low molecular weight heparins prepared from porcine heparin through chemical β-eliminative cleavage were comprehensively analyzed. Lovenox™ and Clexane™, the innovator versions of enoxaparin marketed in the US and Europe, respectively, and two generic enoxaparins, from Sandoz and Teva, were analyzed. The results which were supported by analysis of variation (ANOVA), while showing remarkable similarities between different versions of the product and good lot-to-lot consistency of each product, also detects subtle differences that may result from differences in their manufacturing processes or differences in the source (or parent) porcine heparin from which each product is prepared. Copyright © 2016 Elsevier B.V. All rights reserved.

Safety and efficacy of periprocedural anticoagulation with enoxaparin in patients undergoing peripheral endovascular revascularization.

PubMed

Brodmann, Marianne; Dorr, A; Hafner, F; Gary, T; Froehlich, H; Kvas, E; Deutschmann, H; Pilger, E

2014-07-01

Periprocedural anticoagulation is primarily used in endovascular procedures to prevent acute reocclusion of the target vessel, but periprocedural anticoagulation might also have an impact on long-term outcome. Consecutive bleeding events are feared complications. Despite changes in peripheral endovascular revascularizations (EVRs), the periprocedural management has remained unchanged for years. Unfractionated heparin is still the treatment of choice during and immediately after EVR. We performed a prospective, single-center, open-label phase III study comparing 2 different regimes of enoxaparin peri-interventional to peripheral EVR stratified into low- and high-risk groups according to the acute and long-term reocclusion risk due to their vessel morphology. In both groups, 0.5 mg/kg of enoxaparin as a bolus was administered intravenously 10 to 15 minutes before the start of the procedure. In the low-risk group, 40 mg of enoxaparin were administered once daily for 7 days; whereas in the high-risk group, 1 mg/kg of enoxaparin was administered subcutaneously (sc) 2 times a day for 48 hours after the procedure and afterward 40 mg of enoxaparin was administered sc once daily for 5 days. For the analysis of the per protocol population, 44 patients remained in the low-risk group and 140 in the high-risk group. Concerning the primary safety end point, a total of 25 (13.59%) bleeding events occurred until day 30; 5 (11.36%) of them in the low-risk group and 20 (14.29%) in the high-risk group (P = .809 for low vs high risk). None of the bleeding events observed were major according to Thrombolysis In Myocardial Infarction criteria. Concerning our primary efficacy end point, none of the patients showed an acute reocclusion classified as a significant decrease in ankle-brachial index (ABI) or elevated peak systolic velocity ratio confirmed by duplex sonography until day 30. Concerning the second end point of prevention of chronic reobstruction, at day 180 ABI has decreased in the low-risk group from mean 0.94 at day 30 to mean 0.89 and from 1.28 at day 30 to 0.85 after 6 months in the high-risk group. No significant reobstruction was found in the low-risk group, whereas 5 significant reobstruction events were objectified in the high-risk group, all of them in the femoropopliteal arterial segment at day 180. We conclude that low-molecular-weight heparin either in a low-dose or high-dose regime during a peripheral EVR is safe concerning bleeding complications and acute reobstructions. The long-term follow-up showed no significant difference between our high- and low-risk groups concerning reobstruction. The periprocedural anticoagulation seems to have no influence on the long-term patency rate after peripheral EVR. © The Author(s) 2013.

Fondaparinux versus Enoxaparin - Which is the Best Anticoagulant for Acute Coronary Syndrome? - Brazilian Registry Data.

PubMed

Soeiro, Alexandre de Matos; Silva, Pedro Gabriel Melo de Barros E; Roque, Eduardo Alberto de Castro; Bossa, Aline Siqueira; César, Maria Cristina; Simões, Sheila Aparecida; Okada, Mariana Yumi; Leal, Tatiana de Carvalho Andreucci Torres; Pedroti, Fátima Cristina Monteiro; Oliveira, Múcio Tavares de

2016-09-01

Recent studies have shown fondaparinux's superiority over enoxaparin in patients with non-ST elevation acute coronary syndrome (ACS), especially in relation to bleeding reduction. The description of this finding in a Brazilian registry has not yet been documented. To compare fondaparinux versus enoxaparin in in-hospital prognosis of non-ST elevation ACS. Multicenter retrospective observational study. A total of 2,282 patients were included (335 in the fondaparinux group, and 1,947 in the enoxaparin group) between May 2010 and May 2015. Demographic, medication intake and chosen coronary treatment data were obtained. Primary outcome was mortality from all causes. Secondary outcome was combined events (cardiogenic shock, reinfarction, death, stroke and bleeding). Comparison between the groups were done through Chi-Square test and T test. Multivariate analysis was done through logistic regression, with significance values defined as p < 0.05. With regards to treatment, we observed the performance of a percutaneous coronary intervention in 40.2% in the fondaparinux group, and in 35.1% in the enoxaparin group (p = 0.13). In the multivariate analysis, we observed significant differences between fondaparinux and enoxaparin groups in relation to combined events (13.8% vs. 22%. OR = 2.93, p = 0.007) and bleeding (2.3% vs. 5.2%, OR = 4.55, p = 0.037), respectively. Similarly to recently published data in international literature, fondaparinux proved superior to enoxaparin for the Brazilian population, with significant reduction of combined events and bleeding. Estudos recentes têm apresentado superioridade do fondaparinux em relação à enoxaparina em pacientes com síndrome coronariana aguda (SCA) sem supradesnivelamento de ST, principalmente relacionada à redução de sangramentos. A descrição desse achado em registro brasileiro ainda não foi documentada. Comparar fondaparinux versus enoxaparina no prognóstico intrahospitalar em SCA sem supradesnivelamento de ST. Estudo retrospectivo, multicêntrico e observacional. Foram incluídos 2.282 pacientes (335 no grupo fondaparinux e 1.947 no grupo enoxaparina) entre maio de 2.010 e maio de 2.015. Foram obtidos dados demográficos, medicações utilizadas e tratamento coronariano adotado. O desfecho primário foi mortalidade por todas as causas. O desfecho secundário foi eventos combinados (choque cardiogênico, reinfarto, morte, acidente vascular cerebral e sangramentos). A comparação entre os grupos foi realizada por meio de Q-quadrado e teste-T. A análise multivariada foi realizada por regressão logística, sendo considerado significativo p < 0,05. Em relação ao tratamento, observou-se realização de intervenção coronária percutânea em 40,2% no grupo fondaparinux e 35,1% no grupo enoxaparina (p = 0,13). Na análise multivariada, observaram-se diferenças significativas entre os grupos fondaparinux e enoxaparina em relação a eventos combinados (13,8% vs. 22%, OR = 2,93, p = 0,007) e sangramentos (2,3% vs. 5,2%, OR = 4,55, p = 0,037), respectivamente. Semelhante aos dados recentemente publicados na literatura mundial, fondaparinux mostrou-se superior à enoxaparina para a população brasileira, com redução significativa de eventos combinados e sangramentos.

How useful is determination of anti-factor Xa activity to guide bridging therapy with enoxaparin? A pilot study.

PubMed

Hammerstingl, Christoph; Omran, Heyder; Tripp, Christian; Poetzsch, Bernd

2009-02-01

Low-molecular-weight heparins (LMWH) are commonly used as peri-procedural bridging anticoagulants. The usefulness of measurement of anti-factor Xa activity (anti-Xa) to guide bridging therapy with LMWH is unknown. It was the objective of this study to determine levels of anti-Xa during standard bridging therapy with enoxaparin, and to examine predictors for residual anti-Xa. Consecutive patients receiving enoxaparin at a dosage of 1 mg/kg body weight/12 hours for temporary interruption of phenprocoumon were prospectively enrolled to the study. Blood-samples were obtained 14 hours after LMWH-application immediately pre- procedurally. Procedural details, clinical and demographic data were collected and subsequently analyzed. Seventy patients were included (age 75.2 +/- 10.8 years, Cr Cl 55.7 +/- 21.7ml/min, body mass index [BMI] 27.1 +/- 4.9). LMWH- therapy was for a mean of 4.2 +/- 1.6 days; overall anti-Xa was 0.58 +/- 0.32 U/ml. In 37 (52.8%) of patients anti-Xa was > or U/ml, including 10 (14.3%) patients with anti-Xa > 1U/ml. Linear regression analysis of single variables and logistic multivariable regression analysis failed to prove a correlation between anti-Xa and single or combined factors. No major bleeding, no thromboembolism and four (5.7%) minor haemorrhages were observed. When bridging OAC with therapeutic doses of enoxaparin a high percentage of patients undergo interventions with high residual anti-Xa. The levels of anti-Xa vary largely and are independent of single or combined clinical variables. Since the anti-Xa-related outcome of patients receiving bridging therapy with LMWH is not investigated, no firm recommendation on the usefulness of monitoring of anti-Xa can be given at this stage.

Weight-based enoxaparin dosing and deep vein thrombosis in hospitalized trauma patients: A double-blind, randomized, pilot study.

PubMed

Kay, Annika Bickford; Majercik, Sarah; Sorensen, Jeffrey; Woller, Scott C; Stevens, Scott M; White, Thomas W; Morris, David S; Baldwin, Margaret; Bledsoe, Joseph R

2018-04-23

Venous thromboembolism is a cause of morbidity and mortality in trauma patients. Chemoprophylaxis with low-molecular-weight heparin at a standardized dose is recommended. Conventional chemoprophylaxis may be inadequate. We hypothesized that a weight-adjusted enoxaparin prophylaxis regimen would reduce the frequency of venous thromboembolism in hospitalized trauma patients and at 90-day follow-up. This prospective, randomized pilot study enrolled adult patients admitted to a level 1 trauma center between July 2013 and January 2015. Subjects were randomized to receive either standard (30 mg subcutaneously every 12 hours) or weight-based (0.5mg/kg subcutaneously every 12 hours) enoxaparin. Surveillance duplex ultrasound for lower extremity deep vein thrombosis was performed on hospital days 1, 3, and 7, and weekly thereafter. The primary outcome was deep vein thrombosis during hospitalization. Secondary outcomes included venous thromboembolism at 90 days and significant bleeding events. Two hundred thirty-four (124 standard, 110 weight-based) subjects were enrolled. There was no difference between standard and weight-based regarding age, body mass index, percentage female gender, injury severity score, or percentage that had surgery. There was a trend toward less in-hospital deep vein thrombosis in weight-based (12 [9.7%] standard vs 4 [3.6%] weight-based, P = .075). At 90 days, there was no difference in venous thromboembolism (12 [9.7%] standard vs 6 [5.5%] weight-based, P =.34). There was 1 bleeding event, which occurred in a standard subject. Weight-based enoxaparin dosing for venous thromboembolism chemoprophylaxis in trauma patients may provide better protection against venous thromboembolism than standard. A definitive study is necessary to determine whether weight-based dosing is superior to standard. Copyright © 2018 Elsevier Inc. All rights reserved.

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.

Use of Enoxaparin in Obese Adolescents During Bariatric Surgery--a Pilot Study.

PubMed

Mushtaq, Alvina; Vaughns, Janelle D; Ziesenitz, Victoria C; Nadler, Evan P; van den Anker, John N

2015-10-01

Obese patients have a higher risk of venous thromboembolism when immobilized due to surgery. The objective of this study was to assess anti-factor Xa activity in adolescent bariatric surgical patients receiving prophylactic enoxaparin. Four morbidly obese adolescents undergoing laparoscopic sleeve gastrectomy were enrolled. Enoxaparin was administered (40 mg subcutaneous (SC) if BMI ≤50 kg/m(2) or 60 mg SC if BMI >50 kg/m(2)) for prevention of venous thromboembolism every 12 h starting after induction of anesthesia until discharge. Plasma anti-factor Xa activity was assessed over 12 h after the first dose and used as a surrogate marker for enoxaparin levels. Non-compartmental analysis of anti-factor Xa activity levels was performed and compared with previously published studies. Patients recruited were 16 to 18 years of age with a mean BMI of 52.6 ± 5.8 kg/m(2) (>99th BMI percentile). Peak anti-factor Xa activity ranged from 0.20 to 0.23 IU/mL in our study population, compared to 0.38 to 0.53 IU/mL in the cited lean comparator groups. Our current dosing practice of 40 mg SC for individuals with a BMI ≤50 kg/m(2) and 60 mg for individuals with a BMI ≥50 kg/m(2) resulted in anti-factor Xa activity that was sufficient for adequate thromboprophylaxis in adolescent bariatric surgical patients. Our data also demonstrates lower drug exposures in the obese when compared to lean patients. Therefore, randomized controlled efficacy and safety studies are urgently needed to guide the use of low-molecular-weight heparins in the pediatric and adolescent obese population.

Analysis of sulfates on low molecular weight heparin using mass spectrometry: structural characterization of enoxaparin.

PubMed

Gupta, Rohitesh; Ponnusamy, Moorthy P

2018-05-31

Structural characterization of low molecular weight heparin (LMWH) is critical to meet biosimilarity standards. In this context, the review focuses on structural analysis of labile sulfates attached to the side-groups of LMWH using mass spectrometry. A comprehensive review of this topic will help readers to identify key strategies for tackling the problem related to sulfate loss. At the same time, various mass spectrometry techniques are presented to facilitate compositional analysis of LMWH, mainly enoxaparin. Areas covered: This review summarizes findings on mass spectrometry application for LMWH, including modulation of sulfates, using enzymology and sample preparation approaches. Furthermore, popular open-source software packages for automated spectral data interpretation are also discussed. Successful use of LC/MS can decipher structural composition for LMWH and help evaluate their sameness or biosimilarity with the innovator molecule. Overall, the literature has been searched using PubMed by typing various search queries such as 'enoxaparin', 'mass spectrometry', 'low molecular weight heparin', 'structural characterization', etc. Expert commentary: This section highlights clinically relevant areas that need improvement to achieve satisfactory commercialization of LMWHs. It also primarily emphasizes the advancements in instrumentation related to mass spectrometry, and discusses building automated software for data interpretation and analysis.

Biosensors for brain trauma and dual laser doppler flowmetry: enoxaparin simultaneously reduces stroke-induced dopamine and blood flow while enhancing serotonin and blood flow in motor neurons of brain, in vivo.

PubMed

Broderick, Patricia A; Kolodny, Edwin H

2011-01-01

Neuromolecular Imaging (NMI) based on adsorptive electrochemistry, combined with Dual Laser Doppler Flowmetry (LDF) is presented herein to investigate the brain neurochemistry affected by enoxaparin (Lovenox(®)), an antiplatelet/antithrombotic medication for stroke victims. NMI with miniature biosensors enables neurotransmitter and neuropeptide (NT) imaging; each NT is imaged with a response time in milliseconds. A semiderivative electronic reduction circuit images several NT's selectively and separately within a response time of minutes. Spatial resolution of NMI biosensors is in the range of nanomicrons and electrochemically-induced current ranges are in pico- and nano-amperes. Simultaneously with NMI, the LDF technology presented herein operates on line by illuminating the living brain, in this example, in dorso-striatal neuroanatomic substrates via a laser sensor with low power laser light containing optical fiber light guides. NMI biotechnology with BRODERICK PROBE(®) biosensors has a distinct advantage over conventional electrochemical methodologies both in novelty of biosensor formulations and on-line imaging capabilities in the biosensor field. NMI with unique biocompatible biosensors precisely images NT in the body, blood and brain of animals and humans using characteristic experimentally derived half-wave potentials driven by oxidative electron transfer. Enoxaparin is a first line clinical treatment prescribed to halt the progression of acute ischemic stroke (AIS). In the present studies, BRODERICK PROBE(®) laurate biosensors and LDF laser sensors are placed in dorsal striatum (DStr) dopaminergic motor neurons in basal ganglia of brain in living animals; basal ganglia influence movement disorders such as those correlated with AIS. The purpose of these studies is to understand what is happening in brain neurochemistry and cerebral blood perfusion after causal AIS by middle cerebral artery occlusion in vivo as well as to understand consequent enoxaparin and reperfusion effects actually while enoxaparin is inhibiting blood clots to alleviate AIS symptomatology. This research is directly correlated with the medical and clinical needs of stroke victims. The data are clinically relevant, not only to movement dysfunction but also to the depressive mood that stroke patients often endure. These are the first studies to image brain neurotransmitters while any stroke medications, such as anti-platelet/anti-thrombotic and/or anti-glycoprotein are working in organ systems to alleviate the debilitating consequences of brain trauma and stroke/brain attacks.

Biosensors for Brain Trauma and Dual Laser Doppler Flowmetry: Enoxaparin Simultaneously Reduces Stroke-Induced Dopamine and Blood Flow while Enhancing Serotonin and Blood Flow in Motor Neurons of Brain, In Vivo

PubMed Central

Broderick, Patricia A.; Kolodny, Edwin H.

2011-01-01

Neuromolecular Imaging (NMI) based on adsorptive electrochemistry, combined with Dual Laser Doppler Flowmetry (LDF) is presented herein to investigate the brain neurochemistry affected by enoxaparin (Lovenox®), an antiplatelet/antithrombotic medication for stroke victims. NMI with miniature biosensors enables neurotransmitter and neuropeptide (NT) imaging; each NT is imaged with a response time in milliseconds. A semiderivative electronic reduction circuit images several NT’s selectively and separately within a response time of minutes. Spatial resolution of NMI biosensors is in the range of nanomicrons and electrochemically-induced current ranges are in pico- and nano-amperes. Simultaneously with NMI, the LDF technology presented herein operates on line by illuminating the living brain, in this example, in dorso-striatal neuroanatomic substrates via a laser sensor with low power laser light containing optical fiber light guides. NMI biotechnology with BRODERICK PROBE® biosensors has a distinct advantage over conventional electrochemical methodologies both in novelty of biosensor formulations and on-line imaging capabilities in the biosensor field. NMI with unique biocompatible biosensors precisely images NT in the body, blood and brain of animals and humans using characteristic experimentally derived half-wave potentials driven by oxidative electron transfer. Enoxaparin is a first line clinical treatment prescribed to halt the progression of acute ischemic stroke (AIS). In the present studies, BRODERICK PROBE® laurate biosensors and LDF laser sensors are placed in dorsal striatum (DStr) dopaminergic motor neurons in basal ganglia of brain in living animals; basal ganglia influence movement disorders such as those correlated with AIS. The purpose of these studies is to understand what is happening in brain neurochemistry and cerebral blood perfusion after causal AIS by middle cerebral artery occlusion in vivo as well as to understand consequent enoxaparin and reperfusion effects actually while enoxaparin is inhibiting blood clots to alleviate AIS symptomatology. This research is directly correlated with the medical and clinical needs of stroke victims. The data are clinically relevant, not only to movement dysfunction but also to the depressive mood that stroke patients often endure. These are the first studies to image brain neurotransmitters while any stroke medications, such as anti-platelet/anti-thrombotic and/or anti-glycoprotein are working in organ systems to alleviate the debilitating consequences of brain trauma and stroke/brain attacks. PMID:22346571

Ecchymosis and/or haematoma formation after prophylactic administration of subcutaneous enoxaparin in the abdomen or arm of the critically ill patient.

PubMed

Jareño-Collado, R; Sánchez-Sánchez, M M; Fraile-Gamo, M P; García-Crespo, N; Barba-Aragón, S; Bermejo-García, H; Sánchez-Izquierdo, R; Sánchez-Muñoz, E I; López-López, A; Arias-Rivera, S

Ecchymosis and/or haematoma are the most common adverse events after subcutaneous administration of low molecular weight heparin. There is no strong recommendation as to the puncture site. To evaluate the adverse events, ecchymosis and/or haematoma after the administration of prophylactic subcutaneous enoxaparin in the abdomen vs the arm in the critically ill patient. A randomised, two-arm clinical trial (injection in the abdomen vs the arm), performed between July 2014 and January 2017, in an 18-bed, polyvalent intensive care unit. Patients receiving prophylactic enoxaparin, admitted >72h, with no liver or haematological disorders, a body mass index (BMI) >18.5, not pregnant, of legal age and with no skin lesions which would impede assessment were included. We excluded patients who died or who were transferred to another hospital before completing the evaluation. We gathered demographic and clinical variables, and the onset of ecchymosis and/or haematomas at the injection site after 12, 24, 48 and 72hours. A descriptive analysis was undertaken, with group comparison and logistic regression. The study was approved by the ethics committee with the signed consent of patients/families. 301 cases (11 excluded): 149 were injected in the abdomen vs 141 in the arm. There were no significant differences in demographic and clinical variables, BMI, enoxaparin dose or antiplatelet administration [ecchymosis, abdomen vs arm, n(%): 66(44) vs 72(51), P=.25] [haematoma abdomen vs arm, n(%): 9(6) vs 14(10), P=.2]. Statistical significance was found in the size of the haematomas after 72h: [area of haematoma (mm 2 ) abdomen vs arm, median (IQR): 2(1-5.25) vs 20(5.25-156), P=.027]. In our patient cohort, prophylactic subcutaneous enoxaparin administered in the abdomen causes fewer haematomas after 72hours, than when administered in the arm. The incidence rate of ecchymosis and haematoma was lower than the published incidence in critically ill patients, although patients receiving anti-platelet agents present a higher risk of injury. No relationship was observed in relation to BMI. Copyright © 2017 Sociedad Española de Enfermería Intensiva y Unidades Coronarias (SEEIUC). Publicado por Elsevier España, S.L.U. All rights reserved.

Factors predicting recurrence of chronic subdural haematoma: the influence of intraoperative irrigation and low-molecular-weight heparin thromboprophylaxis.

PubMed

Tahsim-Oglou, Yasemin; Beseoglu, Kerim; Hänggi, Daniel; Stummer, Walter; Steiger, Hans-Jakob

2012-06-01

Burr-hole drainage has become the accepted treatment of choice for chronic subdural haematoma (cSDH), although still burdened with a major recurrence rate. The current analysis was initiated to determine management-related risk factors for recurrence, i.e. postoperative low-molecular-weight heparin thromboprophylaxis, and the importance of rinsing the subdural space. Two-hundred and forty-seven patients with computerised tomography (CT) defined symptomatic cSDH were managed by two burr-hole trepanations and drainage between January 2005 and November 2008. Postoperative thromboprophylaxis with 40 mg enoxaparine daily was given only during the first half of the study period. For the current analysis the amount of rinsing fluid, postoperative low-dose thromboprophylaxis, as well as age and gender, bilaterality, preoperative and postoperative blood coagulation studies, platelet counts and decrease of subdural fluid on early postoperative CT, were recorded and correlated with recurrence. Statistical calculation was done by univariate and multivariate analysis. A total of 62 of 247 patients needed revision surgery for recurrence (25.1 %). Recurrence rates were significantly lower in the patients treated without postoperative enoxaparine (18.84 %) than in the group with postoperative low-dose enoxaparine thromboprophylaxis (32.11 %) and enoxaparine was administered in a higher proportion of the patients suffering recurrence (P = 0.013). A median intraoperative irrigation volume of 863 ml saline was used in the patients suffering recurrence and 1,500 ml in patients without recurrence (P < 0.001). The median age was slightly higher in the patients suffering from recurrence. Male gender predominated in both groups but was slightly more pronounced in the recurrence group. Preoperative and postoperative platelet counts and plasmatic coagulation indices did not differ significantly between the groups. Relative residual subdural fluid collection on early postoperative CT remained larger in patients finally suffering recurrence (P = 0.03). Multivariate analysis confirmed a small amount of rinsing fluid, male gender and the use of enoxaparine as the most important risk factors for recurrence, although that latter factor did not reach statistical significance in the multivariate analysis. The investigation provides evidence that copious intraoperative irrigation and avoidance of postoperative low-molecular-weight heparin thromboprophylaxis may reduce the recurrence rate of cSDH.

Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients.

PubMed

Cohen, Alexander T; Harrington, Robert A; Goldhaber, Samuel Z; Hull, Russell D; Wiens, Brian L; Gold, Alex; Hernandez, Adrian F; Gibson, C Michael

2016-08-11

Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.).

Quantitative PCR and disaccharide profiling to characterize the animal origin of low-molecular-weight heparins.

PubMed

Houiste, Céline; Auguste, Cécile; Macrez, Céline; Dereux, Stéphanie; Derouet, Angélique; Anger, Pascal

2009-02-01

Low-molecular-weight heparins (LMWHs) are widely used in the management of thrombosis and acute coronary syndromes. They are obtained by the enzymatic or chemical depolymerization of porcine intestinal heparin. Enoxaparin sodium, a widely used LMWH, has a unique and reproducible oligosaccharide profile which is determined by the origin of the starting material and a tightly controlled manufacturing process. Although other enoxaparin-like LMWHs do exist, specific release criteria including the origin of the crude heparin utilized for their production, have not been established. A quantitative polymerase chain reaction method has been developed to ensure the purity of the porcine origin of crude heparin, with a DNA detection limit as low as 1 ppm for bovine, or 10 ppm for ovine contaminants. This method is routinely used as the release acceptance criterion during enoxaparin sodium manufacturing. Furthermore, when the process removes DNA, other analytical techniques can be used to assess any contamination. Disaccharide profiling after exhaustive depolymerization can determine the presence of at least 10% bovine or 20% ovine material; multivariate analysis is useful to perform the data analysis. Consistent with the availability of newer technology, these methods should be required as acceptance criteria for crude heparins used in the manufacture of LMWHs to ensure their safety, quality, and immunologic profile.

Low molecular weight heparin use in unexplained recurrent miscarriage

PubMed Central

Yuksel, Halide; Kayatas, Semra; Boza, Aysen Telce; Api, Murat; Ertekin, A. Aktug; Cam, Cetin

2014-01-01

Objective: The aim of the study was to investigate whether the use of low molecular weight heparin (LMWH) improve live birth rates when compared with control group in patients with unexplained recurrent miscarriages (URM). Methods: In this prospective observational study 150 women with a history of two or more previous unexplained first trimester pregnancy loss who received LMWH; either enoxaparin (n=50), tinzaparin (n=50) or nothing (n=50) were followed for the pregnancy outcome measures. Only the patients who have used standardized dosage of LMWH (4000 IU/day enoxaparin or 3500 IU/day tinzaparin ) were included to the study. The primary end point was the live birth rate and secondary end points were the side effects, late pregnancy complications and neonatal outcome in the study cohorts. Results: Live birth was achieved 85% of the LMWH group and 66% of the control group (p=0.007). According to the subgroup analysis; live birth rates did not differ significantly between the enoxaparin and tinzaparin group (84% and 86%, respectively). Maternal and neonatal side effects were not statistically significant among the study participants. Conclusion: Thromboprophylaxis with LMWH resulted in a improved live-birth rate in patient with 2 or more consecutive unexplained recurrent pregnancy loss. Nevertheless these findings need to be confirmed in larger randomized trials. PMID:25674114

Design and rationale of the MICHELANGELO Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-5 trial program evaluating fondaparinux, a synthetic factor Xa inhibitor, in patients with non-ST-segment elevation acute coronary syndromes.

PubMed

Mehta, Shamir R; Yusuf, Salim; Granger, Christopher B; Wallentin, Lars; Peters, Ron J G; Bassand, Jean-Pierre; Budaj, Andrzej; Joyner, Campbell; Chrolavicius, Susan; Fox, Keith A A

2005-12-01

Factor Xa plays a central role in the generation of thrombin, making it a novel target for treatment of arterial thrombosis. Fondaparinux, a synthetic pentasaccharide, is a factor Xa inhibitor, which has been shown to be superior to enoxaparin for the prevention of venous thrombosis. We designed a large, phase III, randomized trial to evaluate the efficacy and safety of fondaparinux compared with enoxaparin in acute coronary syndromes. The OASIS-5 trial is a randomized, double-blind trial of fondaparinux versus enoxaparin in 20,000 patients with unstable angina or non-ST-segment elevation myocardial infarction. The primary objective is to determine whether fondaparinux is noninferior to enoxaparin in preventing the composite of death, new myocardial infarction, and refractory ischemia at 9 days (primary outcome) and at 30 days (secondary outcome) after randomization. There will be additional follow-up of all patients for 3 to 6 months after randomization. If noninferiority is established at 9 days, superiority will be tested. The primary safety outcome is to evaluate the rates of major bleeds in the 2 groups with the balance of benefit and risk assessed by comparing the impact on the composite of the primary and safety outcomes. Secondary outcomes are each component of the composite primary outcome separately at days 9, 30, and up to 6 months. The TIMACS, a major substudy using a partial 2x2 factorial design evaluating whether early angiography and intervention (within 24 hours) are superior to a more delayed approach (after 36 hours) in reducing major ischemic events at 6 months after randomization. The MICHELANGELO OASIS 5 program will provide a comprehensive and reliable evaluation of fondaparinux in a broad spectrum of patients with ACS.

Incidence of symptomatic venous thromboembolism in 2372 knee and hip replacement patients after discharge: data from a thromboprophylaxis registry in Montreal, Canada.

PubMed

Senay, Andréa; Trottier, Milanne; Delisle, Josée; Banica, Andreea; Benoit, Benoit; Laflamme, G Yves; Malo, Michel; Nguyen, Hai; Ranger, Pierre; Fernandes, Julio C

2018-01-01

Low-molecular-weight heparin (LMWH) is a recommended anticoagulant for thromboprophylaxis after major orthopedic surgery. Dabigatran etexilate is an oral anticoagulant recognized as noninferior to LMWH. We aimed to assess the incidence of symptomatic venous thromboembolic events (VTEs) after discharge in patients who underwent joint replacement, using a hospital registry. Patients who underwent total knee and hip arthroplasty between September 2011 and March 2015 were selected. Subcutaneous enoxaparin (30 mg twice daily) was given during hospitalization. At discharge, patients received either enoxaparin 30 mg twice daily/40 mg once daily or dabigatran 220 mg/150 mg once daily. Patients were seen or called at 2, 6, and 12 weeks after surgery. Outcomes were the number of VTEs, including deep venous thrombosis, pulmonary embolism, and the number of major/minor bleeding events after discharge. After discharge, 1468 patients were prescribed enoxaparin and 904 dabigatran (1396 total knee arthroplasty and 976 total hip arthroplasty patients). Mean age was 66±10 years, and 60% were female. The cumulative incidence of VTEs during the 12-week follow-up was 0.7%. One patient sustained a VTE during the switch window. Seven patients sustained a pulmonary embolism (0.3%). There was no statistical difference between the total knee arthroplasty and total hip arthroplasty groups. The incidence of major and minor bleeding events during follow-up was 0.3% and 30.3%, respectively. These events had a higher incidence in the dabigatran group compared to the enoxaparin group after discharge ( p <0.05), but not between knee and hip replacement groups for major bleeding events. A pharmaceutical prophylaxis protocol using LMWH and dabigatran during the post-discharge period resulted in low incidences of VTE and equivalence between treatments. However, the increased number of major and minor bleeding events in patients taking dabigatran is of concern regarding the safety and needs to be evaluated using analyses adjusted for risk factors.

Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial.

PubMed

Goette, Andreas; Merino, Jose L; Ezekowitz, Michael D; Zamoryakhin, Dmitry; Melino, Michael; Jin, James; Mercuri, Michele F; Grosso, Michael A; Fernandez, Victor; Al-Saady, Naab; Pelekh, Natalya; Merkely, Bela; Zenin, Sergey; Kushnir, Mykola; Spinar, Jindrich; Batushkin, Valeriy; de Groot, Joris R; Lip, Gregory Y H

2016-10-22

Edoxaban, an oral factor Xa inhibitor, is non-inferior for prevention of stroke and systemic embolism in patients with atrial fibrillation and is associated with less bleeding than well controlled warfarin therapy. Few safety data about edoxaban in patients undergoing electrical cardioversion are available. We did a multicentre, prospective, randomised, open-label, blinded-endpoint evaluation trial in 19 countries with 239 sites comparing edoxaban 60 mg per day with enoxaparin-warfarin in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. The dose of edoxaban was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, low bodyweight [≤60 kg], or concomitant use of P-glycoprotein inhibitors) were present. Block randomisation (block size four)-stratified by cardioversion approach (transoesophageal echocardiography [TEE] or not), anticoagulant experience, selected edoxaban dose, and region-was done through a voice-web system. The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, analysed by intention to treat. The primary safety endpoint was major and clinically relevant non-major (CRNM) bleeding in patients who received at least one dose of study drug. Follow-up was 28 days on study drug after cardioversion plus 30 days to assess safety. This trial is registered with ClinicalTrials.gov, number NCT02072434. Between March 25, 2014, and Oct 28, 2015, 2199 patients were enrolled and randomly assigned to receive edoxaban (n=1095) or enoxaparin-warfarin (n=1104). The mean age was 64 years (SD 10·54) and mean CHA 2 DS 2 -VASc score was 2·6 (SD 1·4). Mean time in therapeutic range on warfarin was 70·8% (SD 27·4). The primary efficacy endpoint occurred in five (<1%) patients in the edoxaban group versus 11 (1%) in the enoxaparin-warfarin group (odds ratio [OR] 0·46, 95% CI 0·12-1·43). The primary safety endpoint occurred in 16 (1%) of 1067 patients given edoxaban versus 11 (1%) of 1082 patients given enoxaparin-warfarin (OR 1·48, 95% CI 0·64-3·55). The results were independent of the TEE-guided strategy and anticoagulation status. ENSURE-AF is the largest prospective randomised clinical trial of anticoagulation for cardioversion of patients with non-valvular atrial fibrillation. Rates of major and CRNM bleeding and thromboembolism were low in the two treatment groups. Daiichi Sankyo provided financial support for the study. Copyright © 2016 Elsevier Ltd. All rights reserved.

The relationship of renal function to outcome: A post hoc analysis from the EdoxabaN versus warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) study.

PubMed

Lip, Gregory Y H; Al-Saady, Naab; Ezekowitz, Michael D; Banach, Maciej; Goette, Andreas

2017-11-01

The ENSURE-AF study (NCT 02072434) of anticoagulation for electrical cardioversion in nonvalvular atrial fibrillation (NVAF) showed comparable low rates of bleeding and thromboembolism between the edoxaban and the enoxaparin-warfarin treatment arms. This post hoc analysis investigated the relationship between renal function and clinical outcomes. ENSURE-AF was a multicenter, PROBE evaluation trial of edoxaban 60 mg, or dose reduced to 30 mg/d for weight≤60 kg, creatinine clearance (CrCl; Cockcroft-Gault) ≤50 mL/min, or concomitant P-glycoprotein inhibitors compared with therapeutically monitored enoxaparin-warfarin in 2,199 NVAF patients undergoing electrical cardioversion. Efficacy and safety outcomes and time in therapeutic range in the warfarin arm were analyzed in relation to CrCl in prespecified ranges ≥15 and ≤30, >30 and ≤50, >50 and <80, and ≥80 mL/min, and an exploratory ≥95-mL/min analysis. A total of 1,095 subjects were randomized to edoxaban and 1,104 to enoxaparin-warfarin. Mean age was 64.3±10 and 64.2±11 years. Mean time in therapeutic range was progressively lower with reducing CrCl strata, being 66.8% in those with CrCl >30 to ≤50 compared with 71.8% in those with CrCl ≥80. The odds ratios for the primary efficacy and safety end points were comparable for the different predefined renal function strata; given the small numbers, the 95% CI included 1.0. In the subset of those with CrCl ≥95, the odds ratios showed consistency with the other CrCl strata. When CrCl was assessed as a continuous variable, there was a nonsignificant trend toward higher major or clinically relevant nonmajor bleeding with reducing CrCl levels, with no significant differences between the 2 treatment arms. When we assessed CrCl at baseline compared with end of treatment, there were no significant differences in CrCl change between the edoxaban and enoxaparin-warfarin arms. The proportions with worsening of renal function (defined as a decrease of >20% from baseline) were similar in the 2 treatment arms. Given the small number of events in ENSURE-AF, no effect of renal (dys)function was demonstrated in comparing edoxaban to enoxaparin-warfarin for cardioversion; efficacy and safety of edoxaban remained consistent even in patients with normal or supranormal renal function. Copyright © 2017 Elsevier Inc. All rights reserved.

Bilateral orbital haematomas in an anticoagulated patient with severe H1N1 influenza.

PubMed

Mansurali, Naseem; Maclaren, Graeme; Sundar, Gangadhara

2011-03-01

A previously healthy woman was admitted to the intensive care unit (ICU) with severe H1N1 influenza. She had prolonged hospital stay due to multiple complications of critical illness, including pelvic deep vein thrombosis (DVT), which was treated with subcutaneous enoxaparin. The patient was referred to the ophthalmology service for bilateral proptosis. On examination, she had bilateral tense proptosis, worse on the left side with exposure keratopathy. Laboratory tests showed that she had thrombocytopenia and raised activated partial thromboplastin time (APTT). A CT scan revealed well-circumscribed soft tissue density lesions in the superolateral orbits and was reported as bilateral lacrimal gland enlargement. However, based on a clinical suspicion of subperiosteal hematoma collection, a diagnostic tap was performed. Following aspiration of six mls of dark blood from the left superior orbit, there was a reduction of proptosis with improvement in chemosis and resolution of exposure keratopathy. Enoxaparin is one of several antithrombotic agents which are increasingly being used for DVT prophylaxis in severely compromised patients. Furthermore, ICU patients ventilated for prolonged periods are at risk of developing chemosis and exposure keratopathy. Thus, the clinician should maintain a high index of suspicion in identifying subperiosteal hematomas, when managing such cases. The spontaneous bilateral vision threatening subperiosteal hematoma was probably caused by a combination of enoxaparin therapy and prolonged ventilation.

Apixaban: A Review in Venous Thromboembolism.

PubMed

Greig, Sarah L; Garnock-Jones, Karly P

2016-10-01

Apixaban (Eliquis ® ) is an oral, direct factor Xa inhibitor that is available for use in the treatment and secondary prevention of venous thromboembolism (VTE). Like other direct oral anticoagulants (DOACs), apixaban has generally predictable pharmacological properties and does not require routine anticoagulation monitoring. In large phase III trials, oral apixaban was noninferior to subcutaneous enoxaparin sodium overlapped with and followed by oral warfarin (enoxaparin/warfarin) in the treatment of adults with acute VTE over 6 months with regard to the incidence of recurrent VTE or VTE-related death (AMPLIFY), and was significantly more effective than placebo in the prevention of recurrent VTE or all-cause mortality over 12 months in patients who had completed 6-12 months' anticoagulation treatment for VTE (AMPLIFY-EXT). Apixaban was generally well tolerated in these trials; the risks of major bleeding and the composite endpoint of major or clinically relevant nonmajor (CRNM) bleeding with apixaban were significantly lower than enoxaparin/warfarin in AMPLIFY and not significantly different from that of placebo in AMPLIFY-EXT. Similarly, in Japanese adults with acute VTE (AMPLIFY-J), apixaban was associated with a significantly lower risk of major or CRNM bleeding than unfractionated heparin plus warfarin, and no cases of recurrent VTE or VTE-related death over 24 weeks. Thus, apixaban is useful therapeutic alternative for the management of adults with VTE.

Fucus Vesiculosus

MedlinePlus

... type of brown seaweed. People use the whole plant to make medicine. People use Fucus vesiculosus for ... diclofenac (Voltaren, Cataflam, others), ibuprofen (Advil, Motrin, others), naproxen (Anaprox, Naprosyn, others), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, ...

Long-term efficacy and safety of once-daily enoxaparin plus warfarin for the outpatient ambulatory treatment of lower-limb deep vein thrombosis in the TROMBOTEK trial.

PubMed

Kurtoglu, Mehmet; Koksoy, Cuneyt; Hasan, Ekim; Akcalı, Yigit; Karabay, Ozalp; Filizcan, Ugur

2010-11-01

The present study was designed to evaluate the long-term efficacy and safety of once-daily enoxaparin plus warfarin for the outpatient ambulatory treatment of lower-limb deep venous thrombosis (DVT). A total of 246 patients, comprising 128 men (mean age, 54.28±16.48 years) and 118 women (mean age, 50.11±16.47 years) with symptomatic lower extremity DVT, were included in this open-label, single-arm, multicenter, phase IV clinical trial conducted at 14 centers in Turkey. All patients were administered subcutaneous enoxaparin (1.5 mg/kg, once-daily) until international normalized ratio (INR) levels reached to 2 to 3, followed by oral warfarin (5 mg/d) for at least 3 months and elastic compression stockings (30-40 mm Hg). Clinical signs (leg circumference), symptoms (edema, pain, tenderness), recanalization rates upon duplex ultrasound examination, laboratory findings (D-dimer and INR levels), and postthrombotic syndrome status with CEAP classification were the efficacy parameters evaluated every 3 months during 18 months of follow-up. Safety end points included minor and major bleeding as well as serious adverse events. Ambulatory treatment with enoxaparin plus warfarin significantly reduced physical symptoms, including tenderness, edema, pain (P<.001), and the circumference of the affected leg (P<.001). The leg circumference difference in almost all patients was <1.5 cm at the end of 18 months (P<.001). Recanalization rates for occluded iliofemoral vein were 76.1% at 3 months and 86.5% at 18 months (P<.001). An early and significant decrease obtained in D-dimer levels on day 10 continued to decline significantly until month 6 and remained unchanged afterwards (P<.001). Of four patients diagnosed with major bleeding during oral anticoagulant use, three recovered with conservative treatment (reduction in hemoglobin levels in 2 developed at visit 2 [day 10] and intracranial bleeding in 1 developed at visit 3 [day 30]), and one patient required a hysterectomy after menorrhagia developed at visit 7 (month 18). Two of the 65 (9.9%) adverse events documented were serious adverse events, but none of the serious adverse events leading to death were related to the study medications. Ambulatory treatment with enoxaparin plus warfarin seems to be effective in symptomatic healing and in clinical improvement by reducing thrombus formation and organization at all levels of lower extremity venous system with DVT, without a significant major bleeding risk. Therefore, the results of our conventional conservative treatment are in line with 1A level evidence reported in the recent American College of Chest Physicians guideline. Copyright © 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

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.

Enoxaparin Injection

MedlinePlus

... as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in ...

Device Interventions for Stroke Prevention in Atrial Fibrillation

MedlinePlus

... complex LAA are not suitable because of the design of the LARIAT. The above information is correct ... days before the procedure and replaced with enoxaparin shots (injections). What to Expect the Day of the ...

Yerba Mate

MedlinePlus

Mate is a plant. The leaves are used to make medicine. Mate is used as a stimulant to relieve mental and physical tiredness ( ... diclofenac (Voltaren, Cataflam, others), ibuprofen (Advil, Motrin, others), naproxen (Anaprox, Naprosyn, others), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, ...

Siberian Ginseng

MedlinePlus

Siberian ginseng is a plant. People use the root of the plant to make medicine. Siberian ginseng is often called an "adaptogen." This is a ... diclofenac (Voltaren, Cataflam, others), ibuprofen (Advil, Motrin, others), naproxen (Anaprox, Naprosyn, others), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, ...

Application of Adaptive DP-optimality to Design a Pilot Study for a Clotting Time Test for Enoxaparin.

PubMed

Gulati, Abhishek; Faed, James M; Isbister, Geoffrey K; Duffull, Stephen B

2015-10-01

Dosing of enoxaparin, like other anticoagulants, may result in bleeding following excessive doses and clot formation if the dose is too low. We recently showed that a factor Xa based clotting time test could potentially assess the effect of enoxaparin on the clotting system. However, the test did not perform well in subsequent individuals and effectiveness of an exogenous phospholipid, Actin FS, in reducing the variability in the clotting time was assessed. The aim of this work was to conduct an adaptive pilot study to determine the range of concentrations of Xa and Actin FS to take forward into a proof-of-concept study. A nonlinear parametric function was developed to describe the response surface over the factors of interest. An adaptive method was used to estimate the parameters using a D-optimal design criterion. In order to provide a reasonable probability of observing a success of the clotting time test, a P-optimal design criterion was incorporated using a loss function to describe the hybrid DP-optimality. The use of adaptive DP-optimality method resulted in an efficient estimation of model parameters using data from only 6 healthy volunteers. The use of response surface modelling identified a range of sets of Xa and Actin FS concentrations, any of which could be used for the proof-of-concept study. This study shows that parsimonious adaptive DP-optimal designs may provide both precise parameter estimates for response surface modelling as well as clinical confidence in the potential benefits of the study.

Effect of switching unfractionated heparin to low-molecular-weight heparin on serum potassium in hemodialysis patients.

PubMed

Ezzatzadegan Jahromi, Shahrokh; Mahmoodi, Mohammad Saleh; Behroozi, Fatemeh; Roozbeh, Jamshid; Emamghoreishi, Fatemeh

2014-11-01

Unfractionated (UF) heparin is the most common anticoagulant used during hemodialysis. Failure of the kidneys to excrete potassium as well as heparin-induced reduction of aldosterone synthesis put hemodialysis patients at risk of hyperkalemia. It has not yet been clearly known whether hyperkalemia is also induced by low-molecular-weight (LMW) heparins. This study aimed to evaluate the effect of switching UF heparin to LMW heparin enoxaparin, as an anticoagulant during hemodialysis, on serum potassium level in patients on hemodialysis. In two hemodialysis units, 58 patients were randomly assigned into two groups, to receive two different anticoagulation protocols for 3 weeks; one group continued to receive their routine dose of UF heparin, 5000 units, and the other received enoxaparin, 0.5 mg/kg, at the beginning of each hemodialysis session. While there was no significant difference between baseline blood measurements of the two groups in terms of kidney function tests and electrolytes, following 3 weeks of the study, the mean serum potassium level decreased from 4.9 ± 0.8 mEq/L to 4.5 ± 0.5 mEq/L in the LMW heparin group (P = .001); however, there was no change in the mean serum potassium level in those who continued to receive their usual dose of UF heparin. In a subgroup analysis, diabetic patients in the enoxaparin group did not experience significant reduction in serum potassium levels. Our study revealed the role of LMW heparins as a potential alternative to UF heparins in the hemodialysis patients with hyperkalemia.

Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a prior history - an open-label randomised trial (the EPPI trial): study protocol.

PubMed

Groom, K M; McCowan, L M; Stone, P R; Chamley, L C; McLintock, C

2016-11-22

Preeclampsia and intrauterine fetal growth restriction (IUGR) are two of the most common causes of maternal and perinatal morbidity and mortality. Current methods of predicting those at most risk of these conditions remain relatively poor, and in clinical practice past obstetric history remains the most commonly used tool. Aspirin and, in women at risk of preeclampsia only, calcium have been demonstrated to have a modest effect on risk reduction. Several observational studies and randomised trials suggest that low molecular weight heparin (LMWH) therapy may confer some benefit. This is a multicentre open label randomised controlled trial to determine the effect of the LMWH, enoxaparin, on the prevention of recurrence of preeclampsia and/or IUGR in women at high risk due to their past obstetric history in addition to standard high risk care for all participants. A singleton pregnancy >6 +0 and <16 +0 weeks gestation with most recent prior pregnancy with duration >12 weeks having; (1) preeclampsia delivered <36 +0 weeks, (2) Small for gestational age (SGA) infant <10 th customised birthweight centile delivered <36 +0 weeks or, (3) SGA infant ≤3 rd customised birthweight centile delivered at any gestation. Randomisation is stratified for maternal thrombophilia status and women are randomly assigned to 'standard high risk care' or 'standard high risk care' plus enoxaparin 40 mg from recruitment until 36 +0 weeks or delivery, whichever occurs sooner. Standard high risk care includes the use of aspirin 100 mg daily and calcium 1000-1500 mg daily (unless only had previous SGA with no preeclampsia). The primary outcome is preeclampsia and/or SGA <5 th customised birthweight centile. Analysis will be by intention to treat. The EPPI trial has more focussed and clinically relevant inclusion criteria than other randomised trials with a more restricted composite primary outcome. The inclusion of standard use of aspirin (and calcium) for all participants will help to ensure that any differences observed in outcome are likely to be related to enoxaparin use. These data will make a significant contribution to future meta-analyses and systematic reviews on the use of LMWH for the prevention of placental mediated conditions. ACTRN12609000699268 Australian New Zealand Clinical Trials Registry. Date registered 13/Aug/2009 (prospective registration).

Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran.

PubMed

Agnelli, G; Eriksson, B I; Cohen, A T; Bergqvist, D; Dahl, O E; Lassen, M R; Mouret, P; Rosencher, N; Andersson, M; Bylock, A; Jensen, E; Boberg, B

2009-01-01

Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.

In vitro and in vivo characterization of a reversible synthetic heparin analog.

PubMed

Whelihan, Matthew F; Cooley, Brian; Xu, Yongmei; Pawlinski, Rafal; Liu, Jian; Key, Nigel S

2016-02-01

The global supply of unfractionated heparin (UFH) and all commercially available low molecular weight heparins (LMWH) remain dependent on animal sources, such as porcine intestine or bovine lung. Recent experience has shown that contamination of the supply chain (with over-sulfated chondroitin sulfates) can result in lethal toxicity. Fondaparinux is currently the only commercially available synthetic analog of heparin. We recently described a new class of chemoenzymatically synthesized heparin analogs. One of these compounds (S12-mer) is a dodecasaccharide consisting of an antithrombin-binding moiety with repeating units of IdoA2S-GlcNS6S and two 3-O-sulfate groups that confer the ability to bind protamine. We sought to further characterize this new compound in vitro using biochemical and global coagulation assays and in vivo using thrombosis and hemostasis assays. The anticoagulant activities of the Super 12-mer (S12-mer) and Enoxaparin in anti-factor Xa and plasma-based thrombin generation assays were roughly equivalent with a 50% reduction in peak thrombin generation occurring at approximately 325nM. When protamine was titrated against a fixed concentration of S12-mer in plasma or blood, the S12-mer displayed a significant restitution of thrombin generation and clot formation. In vivo, S12-mer inhibited venous thrombosis to a similar extent as Enoxaparin, with similar bleeding profiles. These data show that the S12-mer has almost identical efficacy to Enoxaparin in terms of FXa inhibition, while displaying significant reversibility with protamine. Taken together with the ability to ensure purity and homogeneity from batch to batch, the S12-mer is a promising new synthetic heparin analog with a potentially enhanced safety profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

Four Thrombotic Events Over 5 Years, Two Pulmonary Emboli and Two Deep Venous Thrombosis, When Testosterone-HCG Therapy Was Continued Despite Concurrent Anticoagulation in a 55-Year-Old Man With Lupus Anticoagulant.

PubMed

Glueck, Charles J; Lee, Kevin; Prince, Marloe; Jetty, Vybhav; Shah, Parth; Wang, Ping

2016-01-01

When exogenous testosterone or treatments to elevate testosterone (human chorionic gonadotropin [HCG] or Clomid) are prescribed for men who have antecedent thrombophilia, deep venous thrombosis and pulmonary embolism often occur and may recur despite adequate anticoagulation if testosterone therapy is continued. A 55-year-old white male was referred to us because of 4 thrombotic events, 3 despite adequate anticoagulation over a 5-year period. We assessed interactions between thrombophilia, exogenous testosterone therapy, and recurrent thrombosis. In 2009, despite low-normal serum testosterone 334 ng/dL (lower normal limit [LNL] 300 ng/dL), he was given testosterone (TT) cypionate (50 mg/week) and human chorionic gonadotropin (HCG; 500 units/week) for presumed hypogonadism. Ten months later, with supranormal serum T (1385 ng/dL, upper normal limit [UNL] 827 ng/dL) and estradiol (E2) 45 pg/mL (UNL 41 pg/mL), he had a pulmonary embolus (PE) and was then anticoagulated for 2 years (enoxaparin, then warfarin). Four years later, on TT-HCG, he had his first deep venous thrombosis (DVT). TT was stopped and HCG continued; he was anticoagulated (enoxaparin, then warfarin, then apixaban, then fondaparinux). One year after his first DVT, on HCG, still on fondaparinux, he had a second DVT (5/315), was anticoagulated (enoxaparin + warfarin), with a Greenfield filter placed, but 8 days later had a second PE. Thrombophilia testing revealed the lupus anticoagulant. After stopping HCG, and maintained on warfarin, he has been free of further DVT-PE for 9 months. When DVT-PE occur on TT or HCG, in the presence of thrombophilia, TT-HCG should be stopped, lest DVT-PE reoccur despite concurrent anticoagulation.

[Low molecular weight heparin and non valvular atrial fibrillation].

PubMed

Ederhy, S; Di Angelantonio, E; Meuleman, C; Janower, S; Boccara, F; Cohen, A

2006-12-01

Low molecular weight heparin (LMWH) are obtained through chemical or enzyme depolymerisation of unfractioned heparins (UFH). LMWHs present several advantages over UFH: they exhibit a smaller interindividual variability of the anticoagulant effect, they have a greater bioavailability, a longer plasma half-life and do not require monitoring of the anticoagulant effect. LMWH have restrictive indications in AF patients, cardioversion (II level C and TEE for ACC/AHA/ESC and 2C for ACCP guidelines) or use as a bridge therapy (IIB, level C for ACC/AHA/ESC). The ACE study (Anticoagulation for cardioversion using enoxaparin), showed a reduction, though not statistically significant, of 42% of the composite end point (embolic event, major bleeding and death) 2.8% under enoxaparin vs. 4.8 % under conventional treatment, relative risk 0.58, CI 95% 0.23-1.46). Other studies, using dalteparin, confirmed that an anticoagulant treatment using LMWH followed by warfarin was at least as good as conventional management. ACUTE II (Assessment of cardioversion using transesophageal echochardiography), a randomized multicenter trial, compared the efficacy and tolerance of enoxaparin (1 mg/kg every 12 hours) and UFH in 155 patients eligible for a TEE-guided cardioversion. These patients were administered LMWH or UFH for 24 hours before TEE or cardioversion. There were no significative differences regarding the incidence of the study end points, in particular stroke and bleeding, and no death occurred. HAEST (Heparin in acute embolic stroke trial), a randomized, placebo-controlled, double blind trial failed to show the LMWH superiority over aspirin in patients with acute ischemic stroke and atrial fibrillation. Finally, LMWH have been proposed as a bridge therapy in patients under chronic VKA prior to surgery or invasive procedures. This strategy resulted in a low rate of thromboembolic events and major bleedings.

Reproducibility of the anti-Factor Xa and anti-Factor IIa assays applied to enoxaparin solution.

PubMed

Martinez, Céline; Savadogo, Adama; Agut, Christophe; Anger, Pascal

2013-01-01

Enoxaparin is a widely used subcutaneously administered antithrombotic agent comprising a complex mixture of glycosaminoglycan chains. Owing to this complexity, its antithrombotic potency cannot be defined by physicochemical methods and is therefore evaluated using an enzymatic assay of anti-Xa and anti-IIa activity. Maintaining consistent anti-Xa activity in the final medicinal product allows physicians to ensure administration of the appropriate dosage to their patients. Bioassays are usually complex and display poorer reproducibility than physicochemical tests such as HPLC assays. Here, we describe the implementation of a common robotic platform and standard release potency testing procedures for enoxaparin sodium injection (Lovenox, Sanofi, Paris, France) products at seven quality control sites within Sanofi. Qualification and analytical procedures, as well as data handling, were optimized and harmonized to improve assay reproducibility. An inter-laboratory study was performed in routine-release conditions. The coefficients of variation for repeatability and reproducibility in assessments of anti-Xa activity were 1.0% and 1.2%, respectively. The tolerance interval in reproducibility precision conditions, expressed as percentage potency, was 96.8-103.2% of the drug product target of 10,000 IU/ml, comparing favorably with the United States of America Pharmacopeia specification (90-110%). The maximum difference between assays in two different laboratories is expected to be 4.1%. The reproducibility characteristics of anti-IIa activity assessments were found to be similar. These results demonstrate the effectiveness of the standardization process established and allow for further improvements to quality control in Lovenox manufacture. This process guarantees closeness between actual and target potencies, as exemplified by the results of release assays obtained during a three-year period. Copyright © 2013 Elsevier B.V. All rights reserved.

Differentiation of parenteral anticoagulants in the prevention and treatment of venous thromboembolism.

PubMed

Fareed, Jawed; Adiguzel, Cafer; Thethi, Indermohan

2011-03-28

The prevention of venous thromboembolism has been identified as a leading priority in hospital safety. Recommended parenteral anticoagulant agents with different indications for the prevention and treatment of venous thromboembolism include unfractionated heparin, low-molecular-weight heparins and fondaparinux. Prescribing decisions in venous thromboembolism management may seem complex due to the large range of clinical indications and patient types, and the range of anticoagulants available. MEDLINE and EMBASE databases were searched to identify relevant original articles. Low-molecular-weight heparins have nearly replaced unfractionated heparin as the gold standard antithrombotic agent. Low-molecular-weight heparins currently available in the US are enoxaparin, dalteparin, and tinzaparin. Each low-molecular-weight heparin is a distinct pharmacological entity with different licensed indications and available clinical evidence. Enoxaparin is the only low-molecular-weight heparin that is licensed for both venous thromboembolism prophylaxis and treatment. Enoxaparin also has the largest body of clinical evidence supporting its use across the spectrum of venous thromboembolism management and has been used as the reference standard comparator anticoagulant in trials of new anticoagulants. As well as novel oral anticoagulant agents, biosimilar and/or generic low-molecular-weight heparins are now commercially available. Despite similar anticoagulant properties, studies report differences between the branded and biosimilar and/or generic agents and further clinical studies are required to support the use of biosimilar low-molecular-weight heparins. The newer parenteral anticoagulant, fondaparinux, is now also licensed for venous thromboembolism prophylaxis in surgical patients and the treatment of acute deep-vein thrombosis; clinical experience with this anticoagulant is expanding. Parenteral anticoagulants should be prescribed in accordance with recommended dose regimens for each clinical indication, based on the available clinical evidence for each agent to assure optimal safety and efficacy.

Comparative immunological effect of anticoagulant and antioxidant therapy in the prevention of abortion in mice.

PubMed

Junovich, Gisela; Dubinsky, Valeria; Gentile, Teresa; Sarto, Adriana; Pasqualini, Sergio; Gutiérrez, Gabriela

2011-02-01

Considering the potential adverse effects of anticoagulation in abortion treatment, we investigate whether antioxidants might exert the same immunoprotection. Although the fertility properties of Vitamin E have been associated with its antioxidant capacity, its effect on cytokine balance during pregnancy is still unknown. Pregnant females from CBA/J × DBA/2 abortion model were orally supplemented with Vitamin E or inoculated intraperitoneally with enoxaparin. Foeto-placental units were scored at 14.5 days of pregnancy, and abortion rate was calculated. Cytokine placental levels were determined by enzyme-linked immunosorbent assay. Vitamin E (15 mg/day) has been able to decrease abortion rate and to increase IL-6 placental levels, while both treatments increased vascular endothelial growth factor (VEGF) placental levels. Vitamin E and enoxaparin are able not only to prevent foetal wastage but also to balance IL-6 and VEGF placental levels, presenting a new potential therapeutic alternative for patients with recurrent abortion not associated with thrombophilias. © 2010 John Wiley & Sons A/S.

Thromboprophylaxis after vaginal delivery: a district general hospital experience.

PubMed

Potdar, N; Jabbar, B; Burrell, S J

2006-01-01

The Confidential Enquiries into Maternal Deaths (RCOG 2001) recommends risk assessment and appropriate thromboprophylaxis after vaginal delivery. This study examines the risk group and the need for thromboprophylaxis after vaginal delivery in our local population and the cost implications for the same. It is a retrospective study of women who delivered in the month of November 2003. There were 307 deliveries, of these 251 (81.7%) were vaginal deliveries. Confidential Enquiries into Maternal Deaths (CEMD) risk classification was possible for 243 women. A total of 170 women were low risk, 66 (27.16%) moderate risk and 7 (2.88%) high risk. The costs of thromboprophylaxis for the year in our unit were calculated as pound7,339.71 for unfractionated heparin (UFH) 5,000 IU twice daily and pound7,098.27 for 40 mg enoxaparin once daily. A total of 30% of our District General Hospital population were classified as moderate or high risk for thromboprophylaxis after vaginal delivery. It is less expensive to use enoxaparin compared with unfractionated heparin for thromboprophylaxis.

Cost effectiveness of enoxaparin as prophylaxis against venous thromboembolic complications in acutely ill medical inpatients: modelling study from the hospital perspective in Germany.

PubMed

Schädlich, Peter K; Kentsch, Michael; Weber, Manfred; Kämmerer, Wolfgang; Brecht, Josef Georg; Nadipelli, Vijay; Huppertz, Eduard

2006-01-01

To estimate, from the hospital perspective in Germany, the cost effectiveness of the low-molecular-weight heparin (LMWH) subcutaneous enoxaparin sodium 40 mg once daily (ENOX) relative to no pharmacological prophylaxis (NPP) and relative to subcutaneous unfractionated heparin (UFH) 5,000 IU three times daily (low-dose UFH [LDUFH]). Each is used in addition to elastic bandages/compression stockings and physiotherapy in the prevention of venous thromboembolic events (VTE) in immobilised acutely ill medical inpatients without impaired renal function or extremes of body weight. The incremental cost-effectiveness ratios (ICERs) of the 'additional cost for ENOX per clinical VTE avoided versus NPP' and 'additional cost for ENOX per episode of major bleeding avoided versus LDUFH' were chosen as target variables. The target variables were quantified using a modelling approach based on the decision-tree technique. Resource use during thromboprophylaxis, diagnosis and treatment of VTEs, episode of major bleeding and secondary pneumonia after pulmonary embolism (PE) was collected from a hospital survey. Costs were exclusively those to hospitals incurred by staff expenses, drugs, devices, disposables, laboratory tests and equipment for diagnostic procedures. These costs were determined by multiplying utilised resource items by the price or tariff of each item as of the first quarter of 2003. Safety and efficacy values of the comparators were taken from the MEDENOX (prophylaxis in MEDical patients with ENOXaparin) and the THE-PRINCE (THromboEmbolism-PRevention IN Cardiac or respiratory disease with Enoxaparin) trials and from a meta-analysis. The evaluation encompassed 8 (6-14) days of thromboprophylaxis plus time to treat VTE and episode of major bleeding in hospital. Point estimates of all model parameters were applied exclusively in the base-case analysis. There were incremental costs of euro 1,106 for ENOX per clinical VTE avoided versus NPP (1 euro approximately equals 1.07 US dollars; average of the first quarter of 2003). ENOX dominated LDUFH: cost savings of euro 55,825 were obtained and 7.7 episodes of major bleeding were avoided by ENOX compared with LDUFH, each per 1000 patients. In comprehensive sensitivity analyses, the robustness of the model and its results was shown. Results of this evaluation suggest that, in immobilised acutely ill medical inpatients, ENOX may offer hospitals in Germany a very cost-effective option for thromboprophylaxis compared with NPP and a cost-saving alternative compared with LDUFH.

SCI with Brain Injury: Bedside-to-Bench Modeling for Developing Treatment and Rehabilitation Strategies

DTIC Science & Technology

2012-10-01

SIMVASTATIN 2 SIMVASTATIN 1 METOPROLOL 1 METOPROLOL 1 Discharge  Medications Note that the length of stay in rehabilitation is shorter in SCVMC, a...ENOXAPARIN 3 GABAPENTIN 3 GABAPENTIN 2 DOXYCYCLINE 3 DOXYCYCLINE 1 LISINOPRIL 3 LISINOPRIL 1 CHLORHEXIDINE 2 CHLORHEXIDINE 2 METOPROLOL 2 METOPROLOL 2

Liquid chromatography-diode array detection-mass spectrometry for compositional analysis of low molecular weight heparins.

PubMed

Wang, Zhangjie; Li, Daoyuan; Sun, Xiaojun; Bai, Xue; Jin, Lan; Chi, Lianli

2014-04-15

Low molecular weight heparins (LMWHs) are important artificial preparations from heparin polysaccharide and are widely used as anticoagulant drugs. To analyze the structure and composition of LMWHs, identification and quantitation of their natural and modified building blocks are indispensable. We have established a novel reversed-phase high-performance liquid chromatography-diode array detection-electrospray ionization-mass spectrometry approach for compositional analysis of LMWHs. After being exhaustively digested and labeled with 2-aminoacridone, the structural motifs constructing LMWHs, including 17 components from dalteparin and 15 components from enoxaparin, were well separated, identified, and quantified. Besides the eight natural heparin disaccharides, many characteristic structures from dalteparin and enoxaparin, such as modified structures from the reducing end and nonreducing end, 3-O-sulfated tetrasaccharides, and trisaccharides, have been unambiguously identified based on their retention time and mass spectra. Compared with the traditional heparin compositional analysis methods, the approach described here is not only robust but also comprehensive because it is capable of identifying and quantifying nearly all components from lyase digests of LMWHs. Copyright © 2014 Elsevier Inc. All rights reserved.

Mechanism of action of antiplatelet drugs on decompression sickness in rats: a protective effect of anti-GPIIbIIIa therapy.

PubMed

Lambrechts, Kate; Pontier, Jean-Michel; Mazur, Aleksandra; Theron, Michaël; Buzzacott, Peter; Wang, Qiong; Belhomme, Marc; Guerrero, François

2015-05-15

Literature highlights the involvement of disseminated thrombosis in the pathophysiology of decompression sickness (DCS). We examined the effect of several antithrombotic treatments targeting various pathways on DCS outcome: acetyl salicylate, prasugrel, abciximab, and enoxaparin. Rats were randomly assigned to six groups. Groups 1 and 2 were a control nondiving group (C; n = 10) and a control diving group (CD; n = 30). Animals in Groups 3 to 6 were treated before hyperbaric exposure (HBE) with either prasugrel (n = 10), acetyl salicylate (n = 10), enoxaparin (n = 10), or abciximab (n = 10). Blood samples were taken for platelet factor 4 (PF4), thiobarbituric acid reactive substances (TBARS), and von Willebrand factor analysis. Onset of DCS symptoms and death were recorded during a 60-min observation period after HBE. Although we observed fewer outcomes of DCS in all treated groups compared with the CD, statistical significance was reached in abciximab only (20% vs. 73%, respectively, P = 0.007). We also observed significantly higher levels of plasmatic PF4 in abciximab (8.14 ± 1.40 ng/ml; P = 0.004) and enoxaparin groups (8.01 ± 0.80 ng/ml; P = 0.021) compared with the C group (6.45 ± 1.90 ng/ml) but not CD group (8.14 ± 1.40 ng/ml). Plasmatic levels of TBARS were significantly higher in the CD group than the C group (49.04 ± 11.20 μM vs. 34.44 ± 5.70 μM, P = 0.002). This effect was prevented by all treatments. Our results suggest that abciximab pretreatment, a powerful glycoprotein IIb/IIIa receptor antagonist, has a strong protective effect on decompression risk by significantly improving DCS outcome. Besides its powerful inhibitory action on platelet aggregation, we suggest that abciximab could also act through its effects on vascular function, oxidative stress, and/or inflammation. Copyright © 2015 the American Physiological Society.

Thrombus Burden of Deep Vein Thrombosis and Its Association with Thromboprophylaxis and D-Dimer Measurement: Insights from the APEX Trial.

PubMed

Chi, Gerald; Goldhaber, Samuel Z; Hull, Russell D; Hernandez, Adrian F; Kerneis, Mathieu; Al Khalfan, Fahad; Cohen, Alexander T; Harrington, Robert A; Gibson, C Michael

2017-12-01

Background The aim of this study was to evaluate the effect of betrixaban on the occurrence of deep vein thrombosis (DVT) and also the extent of thrombus and to assess the association of baseline D-dimer with subsequent thrombus burden. Methods In the APEX trial (ClinicalTrials.gov: NCT01583218), 7,513 acutely ill hospitalized medical patients were randomly assigned to extended-duration betrixaban (35–42 days) or enoxaparin (10 ± 4 days). D-dimer concentration was measured at baseline, and mandatory lower-extremity compression ultrasonography (CUS) was performed at 35 to 42 days. The thrombus burden of DVT was assessed by the number of non-compressible vascular segments in six target proximal veins and compared between treatment groups and D-dimer categories (≥2 × upper limit of normal [ULN] versus <2 × ULN). Results Compared with enoxaparin, extended-duration betrixaban reduced the DVT risk at 35 to 42 days (any-dose: relative risk [RR] = 0.76 [95% confidence interval: 0.61–0.94]; p = 0.013; full-dose: RR = 0.70 [0.55–0.90]; p = 0.005). Patients who received betrixaban were more likely to have a lower thrombus burden (p = 0.012 for any-dose and p = 0.001 for full-dose). Elevated D-dimer at baseline was independently associated with a 2.12-fold increased risk of developing DVT (p < 0.001). A greater thrombus burden was also observed in those with D-dimer ≥ 2 × ULN compared with <2 × ULN (p < 0.0001). Conclusion Extended-duration betrixaban reduced the number of venous segments with thrombosis at 35 to 42 days compared with enoxaparin. A positive D-dimer was associated with a greater extent of thrombus burden among acutely ill medical patients who developed DVT despite receiving thromboprophylaxis.

Deep vein thrombosis associated with dengue fever.

PubMed

Roy, Amrita; Chaudhuri, Jasodhara; Chakraborty, Swapna

2013-11-08

Hemorrhagic manifestations are common with Dengue but thrombotic events are uncommonly reported. 11-year-old boy who presented with ileo-femoral deep vein thrombosis associated with serologically confirmed infection with DEN1 dengue virus. There was no other history or investigation suggestive of a procoagulant state. Successfully treated with enoxaparin and warfarin. Thrombotic complications are possible with dengue infection.

National Trauma Institute: A National Coordinating Center for Trauma Research Funding

DTIC Science & Technology

2016-12-01

comparing the effectiveness of modern ventilator modalities upon patients with ARDS/ALI does not exist. Low-tidal volume ventilation (ARDSNet...associated with better oxygenation , less sedative usage, and less ventilator -associated pneumonia compared with other ventilator modes. However, questions...hypercoagulable at baseline, and that further investigations into the effects of platelet activation and obesity, time-to-enoxaparin administration, and

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.

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.).

Pentasaccharides in the prophylaxis and treatment of venous thromboembolism: a systematic review.

PubMed

Nijkeuter, M; Huisman, M V

2004-09-01

The aim of this review is to perform a critical analysis of all completed studies evaluating pentasaccharides-synthetically derived, selective inhibitors of activated factor X-in prophylaxis in major orthopedic surgery and the treatment of venous thromboembolism. Venous thromboembolism is a disorder with considerable morbidity when left untreated. New antithrombotic agents have been developed that selectively inhibit components of the coagulation system, thereby avoiding the difficulties associated with current anticoagulants. The pentasaccharides fondaparinux and idraparinux are the first of a new class of synthetic selective inhibitors of activated factor X. Fondaparinux has been extensively investigated in two areas: orthopedic surgery and venous thromboembolism. It is clear from four thromboprophylaxis studies in major orthopedic surgery that fondaparinux is 50% more effective in reducing venous thromboembolism than enoxaparin. This superior efficacy led to an overall increase in major bleeding, which was however primarily due to more fondaparinux-treated patients with bleeding indexes of 2 or greater. The incidence of fatal bleeding, critical organ bleeding, or bleeding leading to reoperation did not differ significantly between the two groups. In the initial treatment of patients with proximal vein thrombosis and pulmonary embolism, fondaparinux was equally effective as low molecular weight heparins and unfractionated heparin, respectively, without a different incidence in major bleeding in fondaparinux and comparator heparin groups. Fondaparinux, one of the first of a new class of synthetic selective factor Xa inhibitors, is overall 50% more effective in reducing venous thromboembolism than enoxaparin in major orthopedic surgery, with an overall 1% increased rate of major bleeding, when compared with enoxaparin. The incidence of fatal bleeding, critical organ bleeding, or bleeding leading to reoperation did not differ significantly between the two treatment groups. Fondaparinux is equally effective as low molecular weight heparins and unfractionated heparin in the initial treatment of patients with proximal vein thrombosis and pulmonary embolism, respectively. Finally, as with any new drug, fondaparinux should be used cautiously and only in patients who reflect the population of the clinical trials in which the drug was evaluated.

A capillary electrophoretic method for fingerprinting low molecular weight heparins.

PubMed

King, J Timothy; Desai, Umesh R

2008-09-15

Clinically used low molecular weight heparins (LMWH) are anticoagulants of choice and are phenomenally complex mixtures of millions of distinct natural and unnatural polymeric sequences. The FDA recommends that each LMWH be considered as an independent drug with its own activity profile, placing significant importance on the biophysical characterization of each intact LMWH. We report a robust protocol for fingerprinting these pharmaceutical agents. Capillary electrophoresis of three LMWHs, enoxaparin, tinzaparin, and a Sigma preparation, under reverse polarity conditions in the presence of selected linear alkyl polyamines gives an electrophoretic pattern that is characteristic of the nature of the starting material. The buffers that best provided optimal resolution without compromising sensitivity and speed of analysis were 50 mM sodium phosphate, pH 2.3, and 100 mM ammonium formate, pH 3.5. Resolution was strongly dependent on the structure of polyamine with pentaethylenehexamine being most effective for enoxaparin and Sigma LMWH. In contrast, tinzaparin could be best resolved with tetraethylenepentamine. Cyclic polyamines were ineffective. Resolution was also dependent on the concentration of resolving agents and displayed a narrow window that provides optimal resolution. These features suggest a strong structural origin of the fingerprint pattern. Overall, the simple protocol will find special use in assessing LMWH quality and batch-to-batch variability.

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.

Prediction of One-Year Survival in High-Risk Patients with Acute Coronary Syndromes: Results from the SYNERGY Trial

PubMed Central

Yang, Qinghong; Pieper, Karen S.; Antman, Elliott M.; White, Harvey D.; Goodman, Shaun G.; Cohen, Marc; Kleiman, Neal S.; Langer, Anatoly; Aylward, Philip E.; Col, Jacques J.; Reist, Craig; Ferguson, James J.; Califf, Robert M.

2008-01-01

BACKGROUND Despite advances in pharmacologic therapy and invasive management strategies for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), these patients still suffer substantial morbidity and mortality. OBJECTIVE The objective of this study was to analyze independent predictors of 1-year mortality in patients with high-risk NSTE ACS. DESIGN AND PARTICIPANTS A total of 9,978 patients were assigned to receive enoxaparin or unfractionated heparin (UFH) in this prospective, randomized, open-label, international trial. MEASUREMENTS Vital status at 1 year was collected. Univariable and multivariable predictors of 1-year mortality were identified. Three different multivariable regression models were constructed to identify: (1) predictors of 30-day mortality; (2) predictors of 1-year mortality; (3) predictors of 1-year mortality in 30-day survivors. The last model is the focus of this paper. RESULTS Overall, 9,922 (99.4%) of patients had 1-year follow-up. Of the 56 patients (37 UFH-assigned and 19 enoxaparin-assigned) without 1-year data, 11 patients were excluded because of withdrawal of consent, and 45 could not be located. One-year mortality was 7.5% (7.7% enoxaparin-assigned patients; 7.3% UFH-assigned patients; P = 0.4). In patients surviving 30 days after enrollment, independent predictors of 1-year mortality included factors known at baseline such as increased age, male sex, decreased weight, having ever smoked, decreased creatinine clearance, ST-segment depression, history of diabetes, history of angina, congestive heart failure, coronary artery bypass grafting, increased heart rate, rales, increased hematocrit, lowered hemoglobin, and higher platelet count. Factors predictive of mortality during the hospitalization and 30-day follow-up period were decreased weight at 30 days from baseline, atrial fibrillation, decreased nadir platelet, no use of beta-blockers and statins up to 30 days, and not receiving an intervention (c-index = 0.82). CONCLUSIONS Easily determined baseline clinical characteristics can be used to predict 1-year mortality with reasonable discriminative power. These models corroborate prior work in a contemporary aggressively managed population. A model to predict 1-year mortality in patients surviving at least 30 days may be quite helpful to healthcare providers in setting expectations and goals with patients after ACS. PMID:18196350

Comparative study of Factor Xa fluorogenic substrates and their influence on the quantification of LMWHs.

PubMed

Castro-López, Vanessa; Harris, Leanne F; O'Donnell, James S; Killard, Anthony J

2011-01-01

Low molecular weight heparins (LMWHs) are recognised as the preferred anticoagulants in the prevention and treatment of venous thromboembolism. Anti-Factor Xa (anti-FXa) levels are used to monitor the anticoagulant effect of LMWHs and such assays are routinely employed in hospital diagnostic laboratories. In this study, a fluorogenic anti-FXa assay was developed using a commercially available fluorogenic substrate with an attached 6-amino-1-naphthalene-sulfonamide (ANSN) fluorophore and was used for the determination of two LMWHs, enoxaparin and tinzaparin and the heparinoid, danaparoid. The assay was based on the complexation of heparinised plasma with 100 nM exogenous FXa and 25 μM of the fluorogenic substrate Mes-D-LGR-ANSN (C(2)H(5))(2) (SN-7). The assay was tested with pooled plasma samples spiked with anticoagulant concentrations in the range 0-1.6 U mL(-1). The statistically sensitive assay range was 0-0.4 U mL(-1) for enoxaparin and tinzaparin and 0-0.2 U mL(-1) for danaparoid, with assay variation typically below 10.5%. This assay was then compared with a previously published fluorogenic anti-FXa assay developed with the peptide substrate, methylsulfonyl-D: -cyclohexylalanyl-glycyl-arginine-7-amino-4-methylcoumarin acetate (Pefafluor FXa). Both assays were compared in terms of fluorescence intensity, lag times and sensitivity to anticoagulants.

Brief communication: Preoperative anticoagulant activity after bridging low-molecular-weight heparin for temporary interruption of warfarin.

PubMed

O'Donnell, Martin J; Kearon, Clive; Johnson, Judy; Robinson, Marlene; Zondag, Michelle; Turpie, Irene; Turpie, Alexander G

2007-02-06

Preoperative low-molecular-weight heparin (LMWH) is often used when warfarin therapy is interrupted for surgery. To determine the preoperative anticoagulant activity of LMWH following a standardized "bridging" regimen. Prospective cohort study. Single university hospital. Consecutive patients who had warfarin therapy interrupted before an invasive procedure. Enoxaparin, 1 mg/kg of body weight, twice daily. The last dose was administered the evening before surgery. Blood anti-factor Xa heparin levels measured shortly before surgery. Preoperative anti-Xa heparin levels were obtained in 80 patients at an average of 14 hours after the last dose of enoxaparin was administered. The average anti-Xa heparin level was 0.6 U/mL. The anti-Xa heparin level, measured shortly before surgery, was 0.5 U/mL or greater in 54 (68%) patients and 1.0 U/mL or greater in 13 (16%) patients. A shorter interval since the last dose (P < 0.001) and a higher body mass index (P = 0.001) were associated with higher preoperative anti-Xa heparin levels. The small sample size limits accurate estimates of the frequency of the clinical outcomes. A single regimen of LMWH was evaluated. Anti-Xa heparin levels often remain high at the time of surgery if a last dose of a twice-daily regimen of LMWH is given the evening before surgery.

Characterization of currently marketed heparin products: key tests for LMWH quality assurance.

PubMed

Ye, Hongping; Toby, Timothy K; Sommers, Cynthia D; Ghasriani, Houman; Trehy, Michael L; Ye, Wei; Kolinski, Richard E; Buhse, Lucinda F; Al-Hakim, Ali; Keire, David A

2013-11-01

During the 2007-2008 heparin crisis it was found that the United States Pharmacopeia (USP) testing monograph for heparin sodium or low molecular weight heparins did not detect the presence of the contaminant, oversulfated chondroitin sulfate (OSCS). In response to this concern, new tests and specifications were developed by the Food and Drug Administration (FDA) and USP and put in place to detect not only the contaminant OSCS, but also to improve assurance of quality and purity of these drug products. The USP monographs for the low molecular weight heparins (LMWHs) approved for use in the United States (dalteparin, tinzaparin and enoxaparin) are also undergoing revision to include many of the same tests used for heparin sodium, including; one-dimensional (1D) 500 MHz (1)H NMR, SAX-HPLC, percent galactosamine in total hexosamine and anticoagulation time assays with purified Factor IIa or Factor Xa. These tests represent orthogonal approaches for heparin identification, measurement of bioactivity and for detection of process impurities or contaminants in these drug products. Here we describe results from a survey of multiple lots from three types of LMWHs in the US market which were collected after the 2009 heparin sodium monograph revision. In addition, innovator and generic versions of formulated enoxaparin products purchased in 2011 are compared using these tests and found to be highly similar within the discriminating power of the assays applied. Published by Elsevier B.V.

Enoxaparin vs. unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction in elderly and younger patients: results from ExTRACT-TIMI 25.

PubMed

White, Harvey D; Braunwald, Eugene; Murphy, Sabina A; Jacob, Ashok J; Gotcheva, Nina; Polonetsky, Leonid; Antman, Elliott M

2007-05-01

To determine the effects of age on outcomes in patients with STEMI treated with a strategy of enoxaparin (ENOX) vs. unfractionated heparin (UFH). In the ExTRACT-TIMI 25 trial, 20,479 patients with STEMI were randomized in a double-blind fashion to UFH or ENOX. A novel reduced dose of ENOX was administered to patients >or=75 years, and a reduced dose in those with an estimated creatinine clearance of < 30 mL/min. Anti-Xa levels were measured in a subset of patients (n = 73). The exposure to anti-Xa over time was lower in the elderly (AUC(0-12 h) P < 0.0001; AUC(steady-state) P = 0.0046). The relative risk reduction (RR) with ENOX on the primary endpoint, i.e. death or non-fatal recurrent myocardial infarction, was greater in patients < 75 years (20%) than > 75 years (6%), but the absolute benefits were similar. When compared with UFH, ENOX was associated with an RR of 1.67 for major bleeding, but the magnitude of the excess risk tended to be lower (RR = 1.15) in patients >or= 75 years assigned to ENOX. A dose reduction of ENOX in the elderly appears to be helpful in ameliorating bleeding risk. A strategy of ENOX was superior to UFH in both young and elderly patients with STEMI treated with fibrinolysis.

Factors associated with thromboembolic events following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

PubMed

Rottenstreich, Amihai; Kalish, Yosef; Kleinstern, Geffen; Yaacov, Almog Ben; Dux, Joseph; Nissan, Aviram

2017-12-01

We investigated the risk factors, incidence, and role of thromboprophylaxis in the development of thrombosis following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We reviewed data of patients with CRS/HIPEC in three hospitals. Overall, 192 patients underwent CRS/HIPEC during 2007-2016. Mechanical (thigh-length pneumatic compression stockings) and pharmacologic thromboprophylaxis (40 mg enoxaparin daily, starting 12 h before surgery until discharge) was provided for all patients; and 116 (60.4%) also received an extended course of enoxaparin for 2-4 weeks after discharge. Twenty-six patients experienced thrombotic complications (13.5%) including portal-splenic-mesenteric venous thrombosis (n = 11, 5.7%), pulmonary embolism (n = 10, 5.2%), and deep vein thrombosis (n = 5, 2.6%); most (n = 21, 80.8%) occurred after hospital discharge. Univariate analysis identified Peritoneal Cancer Index, intraoperative transfusion requirement, operative blood loss, operative time, lengths of hospital, and intensive care unit stay, and lack of administration of anticoagulation at discharge as significantly associated with thrombosis. With multivariate analysis, only the lack of anticoagulation therapy at discharge remained significantly associated with thrombosis (P = 0.0001). Thromboembolic complications are common following CRS/HIPEC. As significantly lower rates of thrombosis were found in patients who received an extended course of anticoagulation, we support its use for at least 2 weeks after discharge. © 2017 Wiley Periodicals, Inc.

Hydrophilic interaction chromatography-multiple reaction monitoring mass spectrometry method for basic building block analysis of low molecular weight heparins prepared through nitrous acid depolymerization.

PubMed

Sun, Xiaojun; Guo, Zhimou; Yu, Mengqi; Lin, Chao; Sheng, Anran; Wang, Zhiyu; Linhardt, Robert J; Chi, Lianli

2017-01-06

Low molecular weight heparins (LMWHs) are important anticoagulant drugs that are prepared through depolymerization of unfractionated heparin. Based on the types of processing reactions and the structures of the products, LMWHs can be divided into different classifications. Enoxaparin is prepared by benzyl esterification and alkaline depolymerization, while dalteparin and nadroparin are prepared through nitrous acid depolymerization followed by borohydride reduction. Compositional analysis of their basic building blocks is an effective way to provide structural information on heparin and LMWHs. However, most current compositional analysis methods have been limited to heparin and enoxaparin. A sensitive and comprehensive approach is needed for detailed investigation of the structure of LMWHs prepared through nitrous acid depolymerization, especially their characteristic saturated non-reducing end (NRE) and 2,5-anhydro-d-mannitol reducing end (RE). A maltose modified hydrophilic interaction column offers improved separation of complicated mixtures of acidic disaccharides and oligosaccharides. A total of 36 basic building blocks were unambiguously identified by high-resolution tandem mass spectrometry (MS). Multiple reaction monitoring (MRM) MS/MS quantification was developed and validated in the analysis of dalteparin and nadroparin samples. Each group of building blocks revealed different aspects of the properties of LMWHs, such as functional motifs required for anticoagulant activity, the structure of heparin starting materials, cleavage sites in the depolymerization reaction, and undesired structural modifications resulting from side reactions. Copyright © 2016 Elsevier B.V. All rights reserved.

Low-molecular-weight heparin use in the obese, elderly, and in renal insufficiency.

PubMed

Clark, N P

2008-01-01

Superior bioavailability and simple weight-based dosing have made low-molecular-weight heparins (LMWH) the preferred agents for treatment and prevention of venous thromboembolism (VTE) for most indications. Despite improved pharmacokinetics, there remain populations where appropriate LMWH dose intensity and frequency are open to question. Obese patients have a lower proportion of lean body mass as a percentage of total body weight. As a result, LMWH dosing based on total body weight could cause supra-therapeutic anticoagulation. Elderly patients also have less lean body mass in addition to a higher incidence of age-related renal disease and increased risk of bleeding. Renal insufficiency presents a risk of LMWH accumulation as well as increased risk of bleeding. Among LMWH products, only dalteparin labeling recommends a maximum dose. Prospective data call into question the validity of this dose limitation. Additionally, because obese patients are already at higher risk of VTE recurrence, they may be particularly sensitive to subtherapeutic anticoagulation. Prospective data evaluating LMWH use in elderly patients have been limited to in-patient treatment. Few recommendations can be made in this population other than close monitoring. Renal insufficiency is a risk for bleeding during LMWH use. Available evidence supports the potential for enoxaparin accumulation, but not tinzaparin. Enoxaparin dose adjustment, either empiric or based on anti-Xa monitoring, has insufficient data to support widespread implementation. Unfractionated heparin is not reliant on renal elimination and is a sensible option for VTE treatment in patients with a creatinine clearance<30 ml/min.

Acute renal infarction from a cardiac thrombus.

PubMed

Nasser, Nicola J; Abadi, Sobhi; Azzam, Zaher S

2007-11-01

A 53-year-old man presented to hospital 2 hours after the abrupt onset of left upper abdominal pain. He was treated with analgesics and discharged after 4 hours of observation, but presented to another hospital 2 hours later with severe left abdominal pain. His past medical history included ischemic dilated cardiomyopathy due to recurrent myocardial infarction. Physical examination, electrocardiography, laboratory investigations, contrast-enhanced computed tomography, and transesophageal echocardiography. Renal artery thromboembolism resulting from dilated cardiomyopathy, severely reduced cardiac function and an intracardiac thrombus. Anticoagulation with unfractionated heparin followed by enoxaparin and warfarin.

Computer-Based Training Methods for Surgical Training

DTIC Science & Technology

2009-10-07

c1J:Ptollmottetv 1an-2cm _,round the J»’l~l.a. Slightly ft ex.the knee " "d lt!move the ooep Ulird of 100 fat Pid. Rtt Pc1lell• Gimbe either everted...pcrtormed to restore norma l fum:tio n o f the musculosk~let£~1 system a lter acute injury ( eg fracture of a bone ). or to treat long standing defom1ities...Enoxaparin in the Prevention of Deep Vein Thrombosis and Symptomatic Pulmonary Embolism After Elective Hip Replacement or Revision Total Hip

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.

Venous thromboembolism prophylaxis for patients receiving regional anesthesia following injury in Iraq and Afghanistan.

PubMed

Holley, Aaron B; Petteys, Sarah; Mitchell, Joshua D; Holley, Paul R; Hostler, Jordanna M; Clark, Paul; Collen, Jacob F

2014-01-01

Soldiers with combat-related traumatic injury are at high risk for venous thromboembolism (VTE) and often require regional anesthesia (RA) for pain control. We evaluated whether the recommended reduction in chemoprophylaxis in the presence of RA increases VTE rates. We collected data each hospital day for all soldiers admitted to the Walter Reed Army Medical Center following injury in Iraq or Afghanistan. We analyzed thromboprophylaxis and RA rates and assessed risk factors for VTE. We separated outcomes by whether RA was central neuraxial (cNAB) or peripheral blockade. Among 1,259 patients, 323 received RA for a median of 12 days (5-27 days). Those with RA were younger and more likely to have been injured in combat or by an improvised explosive device. They also received more packed red blood cell transfusions and had longer admissions. Patients with RA spent a greater percentage of days on enoxaparin 40 mg daily compared with those without RA (34.4% vs. 22.0%, p < 0.001) and more hospital days without any chemoprophylaxis (2.0 [1.0-6.0] vs. 1.0 [0.0-3.0], p < 0.001). Patients with cNAB were less likely to be placed on enoxaparin 30 mg twice daily. Patients with RA in place had mechanical prophylaxis ordered at the same rate as those without RA. Neither the presence of any RA nor cNAB specifically was associated with an increased risk for VTE. No bleeding or neurologic complications occurred in those receiving RA. Despite changes to chemoprophylaxis, soldiers wounded in combat who receive RA are not at increased risk for VTE. Therapeutic study, level III.

Fragment profiling of low molecular weight heparins using reversed phase ion pair liquid chromatography-electrospray mass spectrometry.

PubMed

Xu, Xiaohui; Li, Daoyuan; Chi, Lequan; Du, Xuzhao; Bai, Xue; Chi, Lianli

2015-04-30

Low molecular weight heparins (LMWHs) are linear and highly charged carbohydrate polymers prepared by chemical or enzymatic depolymerization of heparin. Compared to unfractionated heparin (UFH), LMWHs are prevalently used as clinical anticoagulant drugs due to their lower side effects and better bioavailability. The work presented herein provides a rapid and powerful fragment mapping method for structural characterization of LMWHs. The chain fragments of two types of LMWHs, enoxaparin and nadroparin, were generated by controlled enzymatic digestion with each of heparinase I (Hep I, Enzyme Commission (EC) # 4.2.2.7), heparinase II (Hep II, no EC # assigned) and heparinase III (Hep III, EC # 4.2.2.8). Reversed phase ion pair high performance liquid chromatography (RPIP-HPLC) coupled with electrospray ion trap time-of-flight mass spectrometry (ESI-IT-TOF-MS) was used to profile the oligosaccharide chains ranging from disaccharides to decasaccharides. A database containing all theoretical structural compositions was established to assist the mass spectra interpretation. The six digests derived by three enzymes from two types of LMWHs exhibited distinguishable fingerprinting patterns. And a total of 94 enoxaparin fragments and 109 nadroparin fragments were detected and identified. Besides the common LMWH oligosaccharides, many components containing characteristic LMWH structures such as saturated L-idopyranosuronic acid, 2,5-anhydro-D-mannitol, 1,6-anhydro-D-aminopyranose, as well as odd number oligosaccharides were also revealed. Quantitative comparison of major components derived from innovator and generic nadroparin products was presented. This approach to profile LMWHs' fragments offers a highly reproducible, high resolution and information-rich tool for evaluating the quality of this category of anticoagulant drugs or comparing structural similarities among samples from various sources. Copyright © 2015 Elsevier Ltd. All rights reserved.

The safety of low molecular-weight heparin after blunt liver and spleen injuries.

PubMed

Rostas, Jack W; Manley, Justin; Gonzalez, Richard P; Brevard, Sidney B; Ahmed, Naveed; Frotan, Mohammad Amin; Mitchell, Ellen; Simmons, Jon D

2015-07-01

Anticoagulation is routinely administered to all trauma patients owing to the high incidence of venous thromboembolism (VTE). However, the timing of administration of anticoagulation is not clearly defined when patients have blunt spleen or liver injuries because of the perceived risk of hemorrhage with early administration. A retrospective chart review was performed of all blunt trauma patients who sustained blunt liver and/or spleen injuries during the 5-year period from 2007 to 2011. Data were collected for all patients managed with nonoperative therapy for these injuries while also receiving routine prophylactic anticoagulation with low molecular-weight heparin. Patients were categorized based on the initiation of enoxaparin therapy after injury: early (<48 hours), intermediate (48 to 72 hours), and late (>72 hours). Primary and secondary outcomes were designated as need for operative or radiologic intervention secondary to spleen or liver hemorrhage, number of transfusions, and incidence of VTE. Three hundred and twenty-eight patients were included. There were no enoxaparin-related hemorrhagic complications or hemorrhage necessitating operative intervention. Patients in the early, intermediate, and late groups received an average of .9, .93, and 1.55 units of blood, respectively. There was 1 pulmonary embolism in the early group, and there were 6 VTE complications in the late group (3 deep venous thromboses and 3 pulmonary embolisms). There are currently no standards for the initiation of prophylactic anticoagulation in trauma patients with blunt liver and spleen injuries. Early administration may be safe and reduce the incidence of thrombotic complications in patients with blunt spleen and liver injuries. Prospective studies in this area are warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

Switch-backs associated with generic drugs approved using product-specific determinations of therapeutic equivalence.

PubMed

Gagne, Joshua J; Polinski, Jennifer M; Jiang, Wenlei; Dutcher, Sarah K; Xie, Jing; Lii, Joyce; Fulchino, Lisa A; Kesselheim, Aaron S

2016-08-01

US Food and Drug Administration approval for generic drugs relies on demonstrating pharmaceutical equivalence and bioequivalence; however, some drug products have unique attributes that necessitate product-specific approval pathways. We evaluated rates of patients' switching back to brand-name versions from generic versions of four drugs approved via such approaches. We used data from Optum LifeSciences Research Database to identify patients using a brand-name version of a study drug (acarbose tablets, salmon calcitonin nasal spray, enoxaparin sodium injection, and venlafaxine extended release tablets) or a control drug. We followed patients to identify switching to generic versions and then followed those who switched to identify whether they switched back to brand-name versions. We calculated switch and switch-back rates and used Kaplan-Meier and log-rank tests to compare rates between study and control drugs. Our cohort included 201 959 eligible patients. Brand-to-generic switch rates ranged from 66 to 106 switches per 100 person-years for study drugs and 80 to 110 for control drugs. Rates of switch-back to brand-name versions ranged from 5 to 37 among study drugs and 3 to 53 among control drugs. Switch-back rates were higher for venlafaxine vs. sertraline (p < 0.01) and calcitonin vs. alendronate (p = 0.01). Switch-back rates were lower for venlafaxine vs. paroxetine (p < 0.01) and acarbose vs. nateglinide (p < 0.01). Rates were similar for acarbose vs. glimepiride (p = 0.97) and for enoxaparin vs. fondiparinux (p = 0.11). As compared to control drugs, patients were not more likely to systematically switch back from generic to brand-name versions of the four study drugs. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Nomenclature and traceability debate for biosimilars: small-molecule surrogates lend support for distinguishable nonproprietary names.

PubMed

Chao, Jingdong; Skup, Martha; Alexander, Emily; Tundia, Namita; Macaulay, Dendy; Wu, Eric; Mulani, Parvez

2015-03-01

The purpose of the present study was to investigate the traceability of adverse events (AEs) for branded and generic drugs with identical nonproprietary names and to consider potential implications for the traceability of AEs for branded and biosimilar biologics. Adverse event reports in the Food and Drug Administration AE Reporting System (FAERS) were compared with those in a commercial insurance claims database (Truven Health MarketScan(®)) for 2 drugs (levetiracetam and enoxaparin sodium) with manufacturing or prescribing considerations potentially analogous to those of some biosimilars. Monthly rates of branded- and generic-attributed AEs were estimated pre- and post-generic entry. Post-entry branded-to-generic AE relative rate ratios were calculated. In FAERS, monthly AE rate ratios during the post-generic period showed a pattern in which AE rates for the branded products were greater than for the generic products. Differences in rates of brand- and generic-attributed AEs were statistically significant for both study drugs; the AE rate for the branded products peaked at approximately 10 times that of the generic levetiracetam products and approximately 4 times that of the generic enoxaparin sodium products. In contrast, monthly ratios for the MarketScan data were relatively constant over time. Use of the same nonproprietary name for generic and branded products may contribute to poor traceability of AEs reported in the FAERS database due to the significant misattribution of AEs to branded products (when those AEs were in fact associated with patient use of generic products). To ensure accurate and robust safety surveillance and traceability for biosimilar products in the United States, improved product identification mechanisms, such as related but distinguishable nonproprietary names for biosimilars and reference biologics, should be considered.

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.

Thrombogenesis with continuous blood flow in the inferior vena cava. A novel mouse model.

PubMed

Diaz, José A; Hawley, Angela E; Alvarado, Christine M; Berguer, Alexandra M; Baker, Nichole K; Wrobleski, Shirley K; Wakefield, Thomas W; Lucchesi, Benedict R; Myers, Daniel D

2010-08-01

Several rodent models have been used to study deep venous thrombosis (DVT). However, a model that generates consistent venous thrombi in the presence of continuous blood flow, to evaluate therapeutic agents for DVT, is not available. Mice used in the present study were wild-type C57BL/6 (WT), plasminogen activator inhibitor-1 (PAI-1) knock out (KO) and Delta Cytoplasmic Tail (DCT). An electrolytic inferior vena cava (IVC) model (EIM) was used. A 25G stainless-steel needle, attached to a silver coated copper wire electrode (anode), was inserted into the exposed caudal IVC. Another electrode (cathode) was placed subcutaneously. A current of 250 muAmps over 15 minutes was applied. Ultrasound imaging was used to demonstrate the presence of IVC blood flow. Analyses included measurement of plasma soluble P-selectin (sP-Sel), thrombus weight (TW), vein wall morphometrics, P-selectin and Von Willebrand factor (vWF) staining, transmission electron microscopy (TEM), scanning electron microscopy (SEM); and the effect of enoxaparin on TW was evaluated. A current of 250 muAmps over 15 minutes consistently promoted thrombus formation in the IVC. Plasma sP-Sel was decreased in PAI-1 KO and increased in DCT vs. WT (WT/PAI-1: p=0.003, WT/DCT: p=0.0002). Endothelial activation was demonstrated by SEM, TEM, P-selectin and vWF immunohistochemistry and confirmed by inflammatory cell counts. Ultrasound imaging demonstrated thrombus formation in the presence of blood flow. Enoxaparin significantly reduced the thrombus size by 61% in this model. This EIM closely mimics clinical venous disease and can be used to study endothelial cell activation, leukocyte migration, thrombogenesis and therapeutic applications in the presence of blood flow.

A caution regarding the use of low-molecular weight heparin in pediatric otogenic lateral sinus thrombosis.

PubMed

Shah, Udayan K; Jubelirer, Tracey F; Fish, Jonathan D; Elden, Lisa M

2007-02-01

Lateral sinus thrombosis (LST), a rare complication of otitis media, is managed by antibiotics, surgery and anticoagulation. Traditionally, post-operative anticoagulation has been achieved by intravenous unfractionated heparin followed by oral warfarin. Fractionated, or low-molecular weight heparin derivatives (LMWH) have been introduced recently. There has been minimal literature to date regarding their use for the management of LST. We present use of the LMWH enoxaparin (Lovenox) for otogenic LST in two children, both of whom experienced hemorrhagic complications. On this basis and in the context of a literature review, we urge caution when using LMWH for pediatric otogenic LST.

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

Extended thromboprophylaxis in the acutely ill medical patient after hospitalization - a paradigm shift in post-discharge thromboprophylaxis.

PubMed

Mahan, Charles E; Burnett, Allison E; Fletcher, Meghan L; Spyropoulos, Alex C

2018-02-01

Venous thromboembolism (VTE) is a significant healthcare burden with approximately 900,000 events annually in the United States, over half of which are healthcare-associated. This number is anticipated to double by 2050. Group prophylaxis strategies confined to the inpatient setting appear to have minimal impact on the reduction of post-discharge VTE in medically ill patients due to shortened lengths of stay and a heterogenous population that includes patients at low risk for VTE. In accordance with current guideline recommendations, very few (<5%) medically ill patients are discharged with extended prophylaxis, which potentially creates a clinical gap for at-risk patients as VTE risk has been shown to persist for up to 90 days. Initial studies of extended thromboprophylaxis in acutely ill medical patients with enoxaparin, rivaroxaban and apixaban showed little to no benefit towards VTE reduction that was consistently outweighed by increased bleeding. The more recent APEX study that compared betrixaban to enoxaparin in an enriched patient population at high-risk for VTE was the first study of extended thromboprophylaxis that showed similar efficacy in VTE prevention without an increase in major bleeding. Based on the APEX results, betrixaban recently gained FDA approval for extended thromboprophylaxis in acutely ill medical patients. Recognition that up to half of medically ill patients are not at sufficient risk to warrant thromboprophylaxis has driven extensive research towards development of scientifically derived and validated VTE risk assessment models intended to identify patients who do not warrant prophylaxis, as well as those at high risk who may derive benefit from extended thromboprophylaxis. This article will review prior and ongoing extended thromboprophylaxis studies, VTE and bleed risk assessment models, incorporation of biomarkers in VTE risk assessment and key issues in the paradigm shift towards individualized VTE prophylaxis in acutely ill medical patients.

Global outcomes of ST-elevation myocardial infarction: comparisons of the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction study 25 (ExTRACT-TIMI 25) registry and trial.

PubMed

Steinberg, Benjamin A; Moghbeli, Nazanin; Buros, Jacqueline; Ruda, Mikhail; Parkhomenko, Alexander; Raju, B Soma; García-Castillo, Armando; Janion, Marianna; Nicolau, José C; Fox, Keith A A; Morrow, David A; Gibson, C Michael; Antman, Elliott M

2007-07-01

Outcomes in patients with ST-elevation myocardial infarction (STEMI) differ between those in clinical trials and those in routine practice, as well as across different regions. We hypothesized that adjustment for baseline risk would minimize such variations. The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction (ExTRACT-TIMI) 25 registry was an observational study of patients with STEMI presenting to hospitals participating in the ExTRACT-TIMI 25 randomized clinical trial. Consecutive patients with STEMI who were not enrolled in the trial were entered into the registry. Demographics, in-hospital therapies, and in-hospital events were collected. Baseline risk was assessed using the TIMI Risk Index for STEMI. To adjust for differences among the countries from which the patients presented, the gross national income per annum per capita (GNI) was used. A total of 3726 patients were registered from 109 sites in 25 countries. Patients in the registry had a higher baseline risk than those in the trial; they had more extensive prior cardiac histories and more comorbidities. Unadjusted in-hospital mortality was higher in the registry (8.3%) than in the trial (6.6%) (hazard ratio, 1.30; P < .001); however, after adjusting for TIMI Risk Index, mortality was similar (hazard ratio(adj), 1.00; P = .97). The GNI was not significantly predictive of in-hospital mortality in the multivariable model of the registry. Patients in the registry had higher mortality than those in the trial. This difference could be explained by the higher baseline risk of patients in the registry. After adjusting for baseline risk, the GNI of the country in which the patient presented did not contribute to predicting in-hospital mortality.

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.

A new therapeutic strategy for electrical cardioversion of atrial fibrillation.

PubMed

de Luca, I; Sorino, M; Del Salvatore, B; de Luca, L

2001-11-01

The conventional approach to cardioversion of atrial fibrillation includes a period of anticoagulation with oral anticoagulant therapy (OAT) extending from 3 weeks precardioversion to 4 weeks postcardioversion. The protocol of rapid anticoagulation (such as that of the ACUTE study) consists of a precardioversion transesophageal echocardiography (TEE) followed by OAT for 4 weeks. In the last few years low-molecular-weight heparins have established themselves as a safe and efficacious alternative to traditional antithrombotic therapies. The aim of this study was to demonstrate that the exclusion of thrombi by precardioversion TEE together with the exclusion of atrial stunning by a second TEE performed after 1 week, to date not suggested in the literature, could reduce to 7 days the period of pericardioversion anticoagulation. This therapy would be carried out using low-molecular-weight heparins with no need for biological monitoring and with the possibility of self-administration. We have studied 57 consecutive patients who had atrial fibrillation or flutter with a history of atrial fibrillation lasting > 48 hours. All patients received enoxaparin at a dosage of 100 IU antiXa/kg twice daily before undergoing multiplane TEE. Previous informed consent and ethical committee authorization had been obtained. Twenty-four hours following TEE, in the absence of thrombi and/or spontaneous moderate/severe echocontrast in the atrial chambers, the patients underwent electrical cardioversion and were discharged within 24 hours of sinus rhythm restoration. These patients were prescribed enoxaparin at the indicated dosage twice daily until TEE, performed in an outpatients setting 7 days following cardioversion. In the absence of thrombi and/or atrial and/or left atrial appendage stunning, OAT was terminated. Enoxaparin was associated with OAT for the following 3 weeks if any of the following signs of stunning were present: A wave inferior to the normal value for age at transmitral Doppler; a left atrial appendage emptying velocity < 40 cm/s; the appearance or increase in the severity of spontaneous echocontrast. For all patients, clinical and electrocardiographic follow-up was carried out at 1 month. In one patient TEE was not tolerated and one refused it. In 7 patients cardioversion was not performed: 4 because of the presence of thrombi, 1 because of moderate/severe spontaneous echocontrast and 2 owing to spontaneous cardioversion. Of the remaining 48 patients, cardioversion proved to be efficacious in 38, with sustained sinus rhythm at 1 week in 33 patients. One of these refused the second TEE and of the remaining 32 patients, 24 (75%) showed no signs of stunning at the second TEE and so anticoagulation was terminated. Thus, after 1 week, 75% (24/33) of patients in sinus rhythm could benefit from a shortened anticoagulation therapy which lasted for a mean of only 8.5 days. No patients showed signs of a thromboembolic accident at 1 and 2 months of follow-up. Most patients undergoing electrical cardioversion for atrial fibrillation could benefit from a shorter period of anticoagulation with low-molecular-weight heparins for 1 week if TEE precardioversion and 7 days postcardioversion excludes thrombi and atrial stunning. The management of patients with atrial fibrillation would be greatly simplified.

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.

Characterization of Low-Molecular-Weight Heparins by Strong Anion-Exchange Chromatography.

PubMed

Sadowski, Radosław; Gadzała-Kopciuch, Renata; Kowalkowski, Tomasz; Widomski, Paweł; Jujeczka, Ludwik; Buszewski, Bogusław

2017-11-01

Currently, detailed structural characterization of low-molecular-weight heparin (LMWH) products is an analytical subject of great interest. In this work, we carried out a comprehensive structural analysis of LMWHs and applied a modified pharmacopeial method, as well as methods developed by other researchers, to the analysis of novel biosimilar LMWH products; and, for the first time, compared the qualitative and quantitative composition of commercially available drugs (enoxaparin, nadroparin, and dalteparin). For this purpose, we used strong anion-exchange (SAX) chromatography with spectrophotometric detection because this method is more helpful, easier, and faster than other separation techniques for the detailed disaccharide analysis of new LMWH drugs. In addition, we subjected the obtained results to statistical analysis (factor analysis, t-test, and Newman-Keuls post hoc test).

[Renal impairment in patients with thromboembolic event: prevalence and clinical implications. A systematic review of the literature].

PubMed

Wilke, Thomas; Wehling, Martin; Amann, Steffen; Bauersachs, Rupert M; Böttger, Björn

2015-08-01

The assessment of the renal function of patients with a deep vein thrombosis/pulmonary embolism (VTE patients) is of utmost importance for the selection/dosage of an agent in the initial anticoagulation management of these patients because the majority of available anticoagulants are cleared renally. Specifically, there is a high risk of drug accumulation and subsequent bleedings in patients with severe renal insufficiency. Consequently, specific recommendations have been made for the initial anticoagulation management of these patients in both product labels and AWMF treatment recommendations: some drugs should not be used in these patients, for other drugs a careful use, intensified screening (anti-Xa), or, in the case of enoxaparin, a dose-adjustment are recommended.This literature review aimed to answer the following questions: · What is the prevalence of renal insufficiency in VTE patients?. · Which data are available with regard to the real-world initial anticoagulation management and corresponding clinical outcomes (recurrent VTE events, bleedings, mortality) of these patients? We did a systematic review of existing publications in german or english published in 2004-2014. Only quantitative analyses have been included in the review. We identified 1,135 publications, 37 of them were included in our review. The prevalence of renal insufficiency in VTE patients, defined as CrCl < 60 ml / min, was reported to be 12.3 %-71.9 % related to all VTE patients. The prevalence of severe renal insufficiency, defined as CrCl < 30 ml / min, was reported to be 3,3 %-13,6 %. The substantial ranges in reported prevalences are mainly due to differences in the characteristics of patients addressed in the different publications.A CrCl < 30 ml / min is an independent predictor for both mortality and lethal recurrent pulmonary embolism, possibly also for severe bleedings in VTE patients. In addition to that, a severe renal insufficiency may also be a predictor for the probability that a first VTE event occurs.Several anticoagulants approved for the initial anticoagulation management of VTE patients face the risk of drug accumulation in renally insufficent patients. So, for example, a standard enoxaparin dosage was shown to be associated with elevated bleeding risk compared to adjusted enoxaparin dosage in renally insufficient patients. However, similar data do not exist for other low molecular weight heparins (LMWHs) or unfractioned heparins (UFHs). Only for two LMWHs, Certoparin and Tinzaparin, safety data with regard to renally insufficient patients have been published so far.None of the included studies showed advantages of UFH therapy in comparison to LMWH therapy in initial anticoagulation management of VTE patients. In contrast to that, available evidence shows disadvantageous efficacy/safety of UFH in comparison to LMWH treatment. However, this evidence is not based on head-to-head comparisons but is derived from registry and observational study data only. A detailed knowledge of product labels is of utmost importance in the inital anticoagulation treatment of VTE patients because several agents may not be used in the addressed patients with severe renal insufficiency at all while others may be used based on specific dosage/surveillance schemes only. We also recommend to critically appraise the current AWMF treatment guideline because it still recommends initial anticoagulation management with UFHs in VTE patients with severe renal insufficiency. Available data do not support that recommendation. © Georg Thieme Verlag KG Stuttgart · New York.

Preliminary clinical evaluation of a noninvasive device for the measurement of coagulability in the elderly.

PubMed

Lerman, Yaffa; Werber, Moshe M; Fine, Ilya; Kemelman, Polina

2011-01-01

The feasibility of the noninvasive assessment of blood 'coagulability' (the tendency to coagulate) has been tested by using a novel device, the Thrombo-Monitor. It monitors, by using the principles of near infra-red (NIR) dynamic light scattering, the tendency of blood to create clots. The Thrombo-Monitor observes the very initial changes of blood viscosity, which occurs due to the temporarily induced stasis of capillary blood of the finger. One hundred and fifteen patients aged >65 years (matched by age and sex) participated in the study. Patients were initially divided into four groups based on the patient's medical therapy. The study groups were: warfarin, enoxaparin, aspirin and/or clopidogrel, and a control group. The medications were given according to the patient's comorbidities (eg, atrial fibrillation [AF], status post pulmonary embolism [S/p PE], status post cerebrovascular accident [S/p CVA]). The Thrombo-Monitor Index (TMI) is a noninvasive index, derived on the basis of laboratory test results of international normalized ratio (INR) and prothrombin time (PT) values. For the group of patients who were treated only with warfarin, TMI was adjusted by using the jackknife statistical approach to create maximum correlation and linearity with INR and PT values that ranged from 1.1 to 5.0. For all warfarin patients (N = 35) the TMI was found to have a good correlation with INR and PT values (R(2) = 0.64, P < 0.00001); mean TMI = 1.86 (SD = 0.91); mean INR and PT = 2.3 (SD = 0.91). The calibration curve thus generated was used to calculate the TMI for all other groups: aspirin group, mean TMI = 1.3 (SD = 0.14, N = 23), corresponding approximately to INR and PT values of 1.036; enoxaparin group (N = 24), mean TMI = 1.34 (SD = 0.304), corresponding to mean INR and PT values of 1.07 (SD = 0.3); control group, INR and PT ≥ 1 (N = 32), mean TMI = 1.24 (SD = 0.32). R(2) of all control and warfarin patients (N = 67) was 0.55 (P < 0.00001). In summary, the newly introduced TMI index is significantly correlated with INR and PT values.

Mesenteric ischemia-reperfusion injury: clearly improved hemodynamics but only minor protection of the rat small intestine by (sub)therapeutic heparin sodium and enoxaparin doses.

PubMed

Walensi, Mikolaj; de Groot, Herbert; Schulz, Rainer; Hartmann, Matthias; Petrat, Frank

2013-01-01

Tissue protection against ischemia (I)/reperfusion (R) injury by heparins can be due to their anticoagulant and/or non-anticoagulant properties. Here we studied the protective potential of the anticoagulant and the non-anticoagulant features of heparin sodium (HepSo) and enoxaparin (Enox) against mesenteric I/R injury in a rat model. Mesenteric I/R was induced in rats (n = 6 per group) by superior mesenteric artery occlusion (SMAO; 90 min) and reopening (120 min). Therapeutic/clinical and subtherapeutic/non-anticoagulant doses of HepSo (0.25 mg/kg bolus + 0.25 mg/kg × h; 0.05 mg/kg bolus + 0.1 mg/kg × h) or Enox (0.5 mg/kg bolus + 0.5 mg/kg × h; 0.05 mg/kg bolus + 0.1 mg/kg × h) were administered intravenously starting 30 min before SMAO to the end of reperfusion. Systemic/vital and intestinal microcirculatory parameters were measured during the whole experimental procedure, those of small intestine injury at the end. During intestinal reperfusion, mean arterial blood pressure and heart rates were significantly increased by HepSo and, less effectively, by Enox, in a dose-dependent manner. Intestinal microcirculation was only affected by the therapeutic HepSo dose, which decreased the microvascular flow and S(O2) during reperfusion. The subtherapeutic Enox treatment, as opposed to any HepSo dose, most effectively diminished I/R-induced intestinal hemorrhages, myeloperoxidase activity (as a measure of neutrophil invasion), and histopathological changes. Therapeutic but, to a lesser extent, also the subtherapeutic doses of both HepSo and Enox clearly improve hemodynamics during mesenteric reperfusion, while intestinal protection is exclusively provided by Enox, especially at its subtherapeutic dose. Alterations in intestinal microcirculation are not responsible for these effects. Thus, non-anticoagulant Enox doses and, preferably, heparin(oid)s unable to affect coagulation, could diminish clinical risks of I/R-induced gastrointestinal complications. Copyright © 2013 Elsevier Inc. All rights reserved.

Cardiac implantable electronic device hematomas: Risk factors and effect of prophylactic pressure bandaging.

PubMed

Koh, Youlin; Bingham, Nicholas E; Law, Natalie; Le, Dustin; Mariani, Justin A

2017-07-01

Cardiac implantable electronic device (CIED) hematomas are associated with many adverse outcomes. We examined the incidence and risk factors associated with hematoma formation post-CIED implantation, and explored the preventative effect of prophylactic pressure bandaging (PPB) in a large tertiary center. 1,091 devices were implanted during October 2011-December 2014. Clinically significant hematomas (CSH) were those that necessitated prolonged admission, including those due to reoperation, and clinically suspicious hematomas were swellings noted by medical/nursing staff. We screened for variables affecting hematoma incidence prior to conducting multivariate logistic regression analyses, one for all hematomas and one for CSH. 61 hematomas were identified (5.6% of patients), with 12 of those clinically significant (1.1% of patients). Factors significantly increasing the odds of developing any hematoma were stage 2 (odds ratio [OR] = 2.93, 95% confidence interval [CI] [1.08-7.94], P = 0.034) and 3 chronic kidney disease (CKD) (OR = 3.39 [1.20-9.56], P = 0.021), unfractionated heparin/therapeutic enoxaparin (OR = 3.15 [1.22-8.14], P = 0.018), and dual antiplatelets-aspirin + clopidogrel (OR = 2.95 [1.14-7.65], P = 0.026) + other combinations. Body Mass index (BMI) 25.0-29.9 (OR 0.52 [0.28-0.98], P = 0.044) and >30 were associated with decreased hematoma risk (OR 0.43 [0.20-0.91], P = 0.028). Factors significant for CSH formation were unfractionated heparin/therapeutic enoxaparin (OR = 9.55 [1.83-49.84], P = 0.007) and aspirin + clopidogrel (OR = 7.19 [1.01-50.91], P = 0.048). PPB nonsignificantly increased the odds of total hematoma development (OR = 1.53 [0.87-2.69], P = 0.135), and reduced CSH (OR = 0.67 [0.18-2.47], P = 0.547). Heparin and dual antiplatelet use remain strong predictors of overall hematoma formation. CKD is a comparatively moderate predictor. BMI > 25 may decrease the risk of hematoma formation. PPB had nonsignificant effects on hematoma development. © 2017 Wiley Periodicals, Inc.

Extended-duration versus short-duration pharmacological thromboprophylaxis in acutely Ill hospitalized medical patients: a systematic review and meta-analysis of randomized controlled trials.

PubMed

Liew, Aaron Y L; Piran, Siavash; Eikelboom, John W; Douketis, James D

2017-04-01

Extended-duration pharmacological thromboprophylaxis, for at least 28 days, is effective for the prevention of symptomatic venous thromboembolism (VTE) in high-risk surgical patients but is of uncertain benefit in hospitalized medical patients. We aimed to evaluate the efficacy and safety of extended-duration thromboprophylaxis in hospitalized medical patients. We conducted a systematic PubMed, Medline and EMBASE literature search until June 2016 and a meta-analysis of randomized controlled trials which compared extended-duration with short-duration thromboprophylaxis in hospitalized medical patients. Four randomized controlled trials comparing extended-duration prophylaxis (24-47 days) with short-duration prophylaxis (6-14 days) in a total of 34,068 acutely ill hospitalized medical patients were included. When compared with short-duration prophylaxis, extended-duration prophylaxis was associated with a decrease in symptomatic proximal or distal deep vein thrombosis (DVT) [relative risk (RR) = 0.52; 95% confidence interval (Cl): 0.35-0.77: p = 0.001; absolute risk reduction (ARR) = 0.32%, number needed to treat (NNT) = 313], and symptomatic non-fatal pulmonary embolism (RR = 0.61; 95% Cl 0.38-0.99: p = 0.04; ARR = 0.16%; NNT = 625), an increase in major bleeding (RR = 2.08; 95% Cl 1.50-2.90: p < 0.0001, absolute risk increase = 0.41%, number needed to harm = 244), and no significant reduction in VTE-related mortality (RR = 0.69; 95% Cl 0.45-1.06: p = 0.09) or all-cause mortality (RR = 1.00; 95% CI 0.89-1.12; p = 0.95). There was heterogeneity for major bleeding due to results from the APEX trial (no difference between betrixaban and enoxaparin). Compared with short-duration thromboprophylaxis, extended-duration treatment reduces the risk for symptomatic DVT and non-fatal pulmonary embolism. Extended treatment with apixaban, enoxaparin and rivaroxaban but not betrixaban increases the risk for major bleeding.

Obscure Severe Infrarenal Aortoiliac Stenosis With Severe Transient Lactic Acidosis

PubMed Central

Nantsupawat, Teerapat; Mankongpaisarnrung, Charoen; Soontrapa, Suthipong; Limsuwat, Chok

2013-01-01

A 57-year-old man presented with sudden onset of leg pain, right-sided weakness, aphasia, confusion, drooling, and severe lactic acidosis (15 mmol/L). He had normal peripheral pulses and demonstrated no pain, pallor, poikilothermia, paresthesia, or paralysis. Empiric antibiotics, aspirin, full-dose enoxaparin, and intravenous fluid were initiated. Lactic acid level decreased to 2.5 mmol/L. The patient was subsequently extubated and was alert and oriented with no complaints of leg or abdominal pain. Unexpectedly, the patient developed cardiac arrest, rebound severe lactic acidosis (8.13 mmol/L), and signs of acute limb ischemia. Emergent computed tomography of the aorta confirmed infrarenal aortoiliac thrombosis. Transient leg pain and transient severe lactic acidosis can be unusual presentations of severe infrarenal aortoiliac stenosis. When in doubt, vascular studies should be implemented without delay to identify this catastrophic diagnosis. PMID:26425569

Non-ST-segment elevation syndromes. Pharmacologic management, conservative versus early invasive approach.

PubMed

Santiago, Patrick; Tadros, Peter

2002-07-01

Many advances have been made in the treatment of acute coronary syndromes. Patients with intermediate-risk or high-risk features should receive treatment with the newer pharmacologic agents--enoxaparin, statins and, in selected cases, clopidogrel--in addition to established standard therapies (i.e., aspirin, beta-blockers, nitroglycerin, and oxygen). Use of GpIIb-IIIa inhibitors should also be strongly considered, especially in an early invasive approach. However, there is no substitute for a good physician who has the big picture and knows the individual patient in totality. This physician can best judge the dangers of the patient's acute cardiac condition against the comorbidities that may be exacerbated by revascularization procedures. The ability to weigh the risks of the patient's acute coronary syndrome against the risks of an aggressive invasive approach ultimately provides the best care for each patient.

Upper extremity deep vein thrombosis in a triathlete: Again intense endurance exercise as a thrombogenic risk.

PubMed

Sancho-González, Ignacio; Bonilla-Hernández, María Vicenta; Ibañez-Muñoz, David; Vicente-Campos, Davinia; Chicharro, José López

2017-05-01

Triathlon followers increase each year and long-distance events have seen major growth worldwide. In the cycling phase, athletes must maintain an aerodynamic posture on the bike for long periods of time. We report a case of a 38-year-old triathlete with symptoms of an axillary vein thrombosis 48h after a long triathlon competition. After 3days of hospitalization with a treatment consisted on enoxaparin anticoagulant and acenocumarol, the patient was discharged with instructions to continue treatment under home hospitalization with acetaminophen. Four weeks after the process, the patient was asymptomatic and the diameter of his arm was near normality. Due to the growing popularity of events based on endurance exercise, it is necessary more research to determine the etiopathogeny of deep venous thrombosis in athletes. Copyright © 2016 Elsevier Inc. All rights reserved.

Penile Mondor's disease after anterolateral retroperitoneal approach for lumbar fracture.

PubMed

Dobran, Mauro; Benigni, Roberta; Nasi, Davide; Cantoro, Daniele

2017-11-01

This is a rare case of thrombosis of the dorsal vein of the penis (Mondor's disease) occurred after an anterior-lateral retroperitoneal approach for a vertebral stabilisation in thoracolumbar vertebral fracture. Potential causes are traumatism, neoplasms, excessive sexual activity or abstinence. Although penile Mondor's disease is a clinical diagnosis, ultrasound imaging is the gold standard to confirm it. In the reported case, 1 week after neurosurgical retroperitoneal procedure of vertebral stabilisation, the patient complained of a painful cord-like mass midshaft of penis. The diagnosis was made by clinical evaluation and ultrasound images. After 2 weeks of therapy with enoxaparin sodium, the patient recovered. The authors report this case evaluating the possible correlation between the anterior-lateral retroperitoneal approach and the development of the rare Mondor's disease. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Bacteremia in Preterm Infants Receiving Probiotics; Throbbing Headache Associated with Enoxaparin Use; DRESS Reaction Following Isoniazid Treatment; SIADH Associated with Glimepiride; Mania Associated with Bortezomib Administration

PubMed Central

Mancano, Michael A.

2015-01-01

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration’s (FDA’s) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA’s MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner. PMID:26405333

Historical perspective and contemporary management of acute coronary syndromes: from MONA to THROMBINS2.

PubMed

Kline, Kristopher P; Conti, C Richard; Winchester, David E

2015-01-01

Acute coronary syndrome (ACS) remains a major burden on morbidity and mortality in the United States. Medical professionals and students often use the mnemonic 'MONA' (morphine, oxygen, nitroglycerin and aspirin) to recall treatments for ACS; however, this list of therapies is outdated. We provide a historical perspective on 'MONA,' attempt to uncover its origin in the medical literature, and demonstrate the myriad changes that have occurred over the last 50 years of ACS management. We have developed a novel mnemonic, 'THROMBINS2' (thienopyridines, heparin/enoxaparin, renin-angiotensin system blockers, oxygen, morphine, beta blocker, intervention, nitroglycerin, statin/salicylate) to help bedside clinicians recall all the elements of contemporary ACS management. We demonstrate the mortality benefit for each component of contemporary ACS management, correlating the continued improvement with historical data on mortality after myocardial infarction. We encourage providers to utilize this mnemonic to explore options and guide treatments in ACS patients.

Structural Characterization of the Low-Molecular-Weight Heparin Dalteparin by Combining Different Analytical Strategies.

PubMed

Bisio, Antonella; Urso, Elena; Guerrini, Marco; de Wit, Pauline; Torri, Giangiacomo; Naggi, Annamaria

2017-06-24

A number of low molecular weight heparin (LMWH) products are available for clinical use and although all share a similar mechanism of action, they are classified as distinct drugs because of the different depolymerisation processes of the native heparin resulting in substantial pharmacokinetic and pharmacodynamics differences. While enoxaparin has been extensively investigated, little information is available regarding the LMWH dalteparin. The present study is focused on the detailed structural characterization of Fragmin ® by LC-MS and NMR applied both to the whole drug and to its enzymatic products. For a more in-depth approach, size homogeneous octasaccharide and decasaccharide components together with their fractions endowed with high or no affinity toward antithrombin were also isolated and their structural profiles characterized. The combination of different analytical strategies here described represents a useful tool for the assessment of batch-to-batch structural variability and for comparative evaluation of structural features of biosimilar products.

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.

A decision model to estimate a risk threshold for venous thromboembolism prophylaxis in hospitalized medical patients.

PubMed

Le, P; Martinez, K A; Pappas, M A; Rothberg, M B

2017-06-01

Essentials Low risk patients don't require venous thromboembolism (VTE) prophylaxis; low risk is unquantified. We used a Markov model to estimate the risk threshold for VTE prophylaxis in medical inpatients. Prophylaxis was cost-effective for an average medical patient with a VTE risk of ≥ 1.0%. VTE prophylaxis can be personalized based on patient risk and age/life expectancy. Background Venous thromboembolism (VTE) is a common preventable condition in medical inpatients. Thromboprophylaxis is recommended for inpatients who are not at low risk of VTE, but no specific risk threshold for prophylaxis has been defined. Objective To determine a threshold for prophylaxis based on risk of VTE. Patients/Methods We constructed a decision model with a decision-tree following patients for 3 months after hospitalization, and a lifetime Markov model with 3-month cycles. The model tracked symptomatic deep vein thromboses and pulmonary emboli, bleeding events and heparin-induced thrombocytopenia. Long-term complications included recurrent VTE, post-thrombotic syndrome and pulmonary hypertension. For the base case, we considered medical inpatients aged 66 years, having a life expectancy of 13.5 years, VTE risk of 1.4% and bleeding risk of 2.7%. Patients received enoxaparin 40 mg day -1 for prophylaxis. Results Assuming a willingness-to-pay (WTP) threshold of $100 000/ quality-adjusted life year (QALY), prophylaxis was indicated for an average medical inpatient with a VTE risk of ≥ 1.0% up to 3 months after hospitalization. For the average patient, prophylaxis was not indicated when the bleeding risk was > 8.1%, the patient's age was > 73.4 years or the cost of enoxaparin exceeded $60/dose. If VTE risk was < 0.26% or bleeding risk was > 19%, the risks of prophylaxis outweighed benefits. The prophylaxis threshold was relatively insensitive to low-molecular-weight heparin cost and bleeding risk, but very sensitive to patient age and life expectancy. Conclusions The decision to offer prophylaxis should be personalized based on patient VTE risk, age and life expectancy. At a WTP of $100 000/QALY, prophylaxis is not warranted for most patients with a 3-month VTE risk below 1.0%. © 2017 International Society on Thrombosis and Haemostasis.

Reversed-phase ion-pair ultra-high-performance-liquid chromatography-mass spectrometry for fingerprinting low-molecular-weight heparins.

PubMed

Langeslay, Derek J; Urso, Elena; Gardini, Cristina; Naggi, Annamaria; Torri, Giangiacomo; Larive, Cynthia K

2013-05-31

Heparin is a complex mixture of sulfated linear carbohydrate polymers. It is widely used as an antithrombotic drug, though it has been shown to have a myriad of additional biological activities. Heparin is often partially depolymerized in order to decrease the average molecular weight, as it has been shown that low molecular weight heparins (LMWH) possess more desirable pharmacokinetic and pharmacodynamic properties than unfractionated heparin (UFH). Due to the prevalence of LMWHs in the market and the emerging availability of generic LMWH products, it is important that analytical methods be developed to ensure the drug quality. This work explores the use of tributylamine (TrBA), dibutylamine (DBA), and pentylamine (PTA) as ion-pairing reagents in conjunction with acetonitrile and methanol modified mobile phases for reversed-phase ion-pairing ultraperformance liquid chromatography coupled to mass spectrometry (RPIP-UPLC-MS) for fingerprint analysis of LMWH preparations. RPIP-UPLC-MS fingerprints are presented and compared for tinzaparinand enoxaparin. Copyright © 2013 Elsevier B.V. All rights reserved.

Early pregnancy cerebral venous thrombosis and status epilepticus treated with levetiracetam and lacosamide throughout pregnancy.

PubMed

Ylikotila, Pauli; Ketola, Raimo A; Timonen, Susanna; Malm, Heli; Ruuskanen, Jori O

2015-11-01

Cerebral venous thrombosis (CVT) is an uncommon cause of stroke, accounting to less than 1% of all strokes. We describe a pregnant woman with a massive CVT in early pregnancy, complicated by status epilepticus. The mother was treated with levetiracetam, lacosamide, and enoxaparin throughout pregnancy. A male infant was born on pregnancy week 36, weighing 2.2kg. Both levetiracetam and and lacosamide were present in cord blood in levels similar to those in maternal blood. The infant was partially breast-fed and experienced poor feeding and sleepiness, starting to resolve after two first weeks. Milk samples were drawn 5 days after the delivery and a blood sample from the infant 3 days later. Lacosamide level in milk was low, resulting in an estimated relative infant dose of 1.8% of the maternal weight-adjusted daily dose in a fully breast-fed infant. This is the first case describing lacosamide use during pregnancy and lactation. Copyright © 2015 Elsevier Inc. All rights reserved.

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis: Factor XI as a Target for New Anticoagulants.

PubMed

Weitz, Jeffrey I; Fredenburgh, James C

2018-02-01

The goal of anticoagulant therapy is to attenuate thrombosis without compromising hemostasis. Although the direct oral anticoagulants are associated with less intracranial hemorrhage than vitamin K antagonists, bleeding remains their major side effect. Factor XI has emerged as a promising target for anticoagulants that may be safer than those currently available. The focus on factor XI stems from epidemiological evidence of its role in thrombosis, the observation of attenuated thrombosis in factor XI-deficient mice, identification of novel activators, and the fact that factor XI deficiency is associated with only a mild bleeding diathesis. Proof-of-concept comes from the demonstration that compared with enoxaparin, factor XI knockdown reduces venous thromboembolism without increasing bleeding after elective knee arthroplasty. This article rationalizes the selection of factor XI as a target for new anticoagulants, reviews the agents under development, and outlines a potential path forward for their development. © 2017 American Heart Association, Inc.

A highly regular fucan sulfate from the sea cucumber Stichopus horrens.

PubMed

Ustyuzhanina, Nadezhda E; Bilan, Maria I; Dmitrenok, Andrey S; Borodina, Elizaveta Yu; Nifantiev, Nikolay E; Usov, Anatolii I

2018-02-01

A highly regular fucan sulfate SHFS was isolated from the sea cucumber Stichopus horrens by extraction of the body walls in the presence of papain followed by ion-exchange and gel permeation chromatography. SHFS had MW of about 140 kDa and contained fucose and sulfate in the molar ratio of about 1:1. Chemical and NMR spectroscopic methods were applied for the structural characterization of the polysaccharide. SHFS was shown to have linear molecules built up of 3-linked α-l-fucopyranose 2-sulfate residues. Anticoagulant properties of SHFS were assessed in vitro in comparison with the LMW heparin (enoxaparin) and totally sulfated 3-linked α-l-fucan. SHFS was found to have the lowest activity, and hence, both sulfate groups at O-2 and O-4 of fucosyl units seem to be important for anticoagulant effect of sulfated homo-(1 → 3)-α-l-fucans. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mapping of low molecular weight heparins using reversed phase ion pair liquid chromatography-mass spectrometry.

PubMed

Li, Daoyuan; Chi, Lequan; Jin, Lan; Xu, Xiaohui; Du, Xuzhao; Ji, Shengli; Chi, Lianli

2014-01-01

Low molecular weight heparins (LMWHs) are structurally complex, highly sulfated and negatively charged, linear carbohydrate polymers prepared by chemical or enzymatic depolymerization of heparin. They are widely used as anticoagulant drugs possessing better bioavailability, longer half-life, and lower side effects than heparin. Comprehensive structure characterization of LMWHs is important for drug quality assurance, generic drug application, and new drug research and development. However, fully characterization of all oligosaccharide chains in LMWHs is not feasible for current available analytical technologies due to their structure complexity and heterogeneity. Fingerprinting profiling is an efficient way for LMWHs' characterization and comparison. In this work, we present a simple, sensitive, and powerful analytical approach for structural characterization of LMWHs. Two different LMWHs, enoxaparin and nadroparin, were analyzed using reversed phase ion pair electrospray ionization mass spectrometry (RPIP-ESI-MS). More than 200 components were identified, including major structures, minor structures, and process related impurities. This approach is robust for high resolution and complementary fingerprinting analysis of LMWHs. Copyright © 2013 Elsevier Ltd. All rights reserved.

Profiling analysis of low molecular weight heparins by multiple heart-cutting two dimensional chromatography with quadruple time-of-flight mass spectrometry.

PubMed

Ouyang, Yilan; Zeng, Yangyang; Rong, Yinxiu; Song, Yue; Shi, Lv; Chen, Bo; Yang, Xinlei; Xu, Naiyu; Linhardt, Robert J; Zhang, Zhenqing

2015-09-01

Low molecular weight heparins (LMWHs) are polydisperse and microheterogenous mixtures of polysaccharides used as anticoagulant drugs. Profiling analysis is important for obtaining deeper insights into the structure of LMWHs. Previous oligosaccharide mapping methods are relatively low resolution and are unable to show an entire picture of the structural complexity of LMWHs. In the current study a profiling method was developed relying on multiple heart-cutting, two-dimensional, ultrahigh performance liquid chromatography with quadruple time-of-flight mass spectrometry. This represents an efficient, automated, and robust approach for profiling LMWHs. Using size-exclusion chromatography and ion-pairing reversed-phase chromatography in a two-dimensional separation, LMW components of different sizes and LMW components of the same size but with different charges and polarities can be resolved, providing a more complete picture of a LMWH. Structural information on each component was then obtained with quadrupole time-of-flight mass spectrometry. More than 80 and 120 oligosaccharides were observed and unambiguously assigned from the LMWHs, nadroparin and enoxaparin, respectively. This method might be useful for quality control of LMWHs and as a powerful tool for heparin-related glycomics.

A photoacoustic tool for therapeutic drug monitoring of heparin (Conference Presentation)

NASA Astrophysics Data System (ADS)

Wang, Junxin; Hartanto, James; Jokerst, Jesse V.

2017-03-01

Heparin is used broadly in cardiac, pulmonary, surgical, and vascular medicine to treat thrombotic disorders with over 500 million doses per year globally. Despite this widespread use, it has a narrow therapeutic window and is one of the top three medication errors. The active partial thromboplastin time (PTT) monitors heparin, but this blood test suffers from long turnaround times, a variable reference range, and limited utility with low molecular weight heparin. Here, we describe an imaging technique that can monitor heparin concentration and activity in real time using photoacoustic spectroscopy via methylene blue as a simple and Federal Drug Agency-approved contrast agent. We found a strong correlation between heparin concentration and photoacoustic signal measured in phosphate buffered saline (PBS) and blood (R2>0.90). Clinically relevant concentrations were detected in blood with a heparin detection limit of 0.28 U/mL and a low molecular weight heparin (enoxaparin) detection limit of 72 μg/mL. We validated this imaging approach by correlation to the PTT (Pearson's r = 0.86; p<0.05) as well as with protamine sulfate treatment. To the best of our knowledge, this is the first report to use imaging data to monitor anticoagulation.

Bruises on the ears and body.

PubMed

Sarmiento, Diana M; Northrup, Thomas F; Wah, Yu

2017-09-01

Over the course of a month, this 34-year-old woman had sought care at our facility--and another--on 3 separate occasions for painful bruises (visits #1 and #3) and deep vein thrombosis (visit #2). The bruises first appeared acutely on her arms, prompting her first visit to our ED and leading to a hospital stay. Several weeks later, the patient developed new bruise-like lesions on her earlobes, face, trunk, and lower extremities. In between these 2 visits, the patient was seen in another ED (and admitted) for right upper extremity DVT and was started on enoxaparin, followed by warfarin. The patient had no history of trauma, but did have a 7-year history of cocaine abuse. The initial bruises appeared one week after using cocaine from a different dealer. On her most recent visit, her vitals and physical examination were unremarkable, apart from the skin findings. Her complete blood count, complete metabolic panel, and urinalysis were unremarkable. On her previous admissions, the patient's urine drug test had been positive for cocaine. She'd also tested positive for cytoplasmic antineutrophil cytoplasmic antibodies, antinuclear antibodies, anti-double stranded DNA, and anticardiolipin IgM. WHAT IS YOUR DIAGNOSIS? HOW WOULD YOU TREAT THIS PATIENT?

The ischemic liver cirrhosis theory and its clinical implications.

PubMed

Mancuso, Andrea

2016-09-01

The canonical pathway theory of cirrhosis addresses inflammation as the main driver of hepatic fibrogenesis in hepatitis, so needing a further hypothesis for etiologies missing inflammation, for which parenchymal extinction is postulated. The present paper reports an alternative hypothesis suggesting a central role of micro-vascular ischemia in fibrogenesis and cirrhosis development, whatever is the aetiology of liver chronic injury. In fact, since chronic liver injury could finally result in endothelial damage and micro-vascular thrombosis, leading to a trigger of inappropriate hepatocyte proliferation and fibrosis, finally cirrhosis development could arise from chronic micro-vascular ischemia. Recently, some important confirmation of this hypothesis has been reported. In fact, in a murine experimental model of congestive hepatopathy, it was found that chronic hepatic congestion leads to sinusoidal thrombosis and strain, which in turn promote hepatic fibrosis. Furthermore, a study on a murine model of cirrhosis reported enoxaparin to reduce hepatic vascular resistance and portal pressure by having a protective role against fibrogenesis. In conclusion, the hypothesis giving a central role of micro-vascular ischemia in fibrogenesis and cirrhosis development could change the clinical scenario of chronic liver disease and have several main implications on management of various liver disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

GlycCompSoft: Software for Automated Comparison of Low Molecular Weight Heparins Using Top-Down LC/MS Data

PubMed Central

Li, Lingyun; Zhang, Fuming; Hu, Min; Ren, Fuji; Chi, Lianli; Linhardt, Robert J.

2016-01-01

Low molecular weight heparins are complex polycomponent drugs that have recently become amenable to top-down analysis using liquid chromatography-mass spectrometry. Even using open source deconvolution software, DeconTools, and automatic structural assignment software, GlycReSoft, the comparison of two or more low molecular weight heparins is extremely time-consuming, taking about a week for an expert analyst and provides no guarantee of accuracy. Efficient data processing tools are required to improve analysis. This study uses the programming language of Microsoft Excel™ Visual Basic for Applications to extend its standard functionality for macro functions and specific mathematical modules for mass spectrometric data processing. The program developed enables the comparison of top-down analytical glycomics data on two or more low molecular weight heparins. The current study describes a new program, GlycCompSoft, which has a low error rate with good time efficiency in the automatic processing of large data sets. The experimental results based on three lots of Lovenox®, Clexane® and three generic enoxaparin samples show that the run time of GlycCompSoft decreases from 11 to 2 seconds when the data processed decreases from 18000 to 1500 rows. PMID:27942011

Streptococcus gallolyticus subsp. pasteurianus meningitis complicated by venous sinus thrombosis: A case report.

PubMed

Wardle, Martin; Mu, Andre; Tong, Steven Y C

2018-06-01

A case of Streptococcus gallolyticus subsp. pasteurianus meningitis, unusually occurring in a splenectomized patient and complicated by cerebral venous thrombosis, is described. Following presentation with meningism and diagnosis and management of S. gallolyticus meningitis, the patient presented again with a further 4days of fevers and subsequently developed left-sided paresthesias. Cerebral imaging revealed a venous thrombus in the right frontal cortical veins and left sigmoid sinus. The patient recovered following 4 weeks of intravenous ceftriaxone and anticoagulation with enoxaparin and then warfarin. Apart from the splenectomy, no underlying cause was found. The patient was commenced on life-long prophylactic amoxicillin, given appropriate vaccinations, and anticoagulated with warfarin. After initial difficulties, identification of the causative organism to the subspecies level was confirmed by analysis of short-read whole genome sequencing data. This case demonstrates two features that have not previously been reported for S. gallolyticus subsp. pasteurianus infections: splenectomy as a potential risk factor and that infection may be complicated by cerebral venous thrombosis. The resolution provided by whole genome sequencing was valuable in accurately identifying the bacterial subspecies. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

New Insights in Thrombin Inhibition Structure-Activity Relationships by Characterization of Octadecasaccharides from Low Molecular Weight Heparin.

PubMed

Mourier, Pierre A J; Guichard, Olivier Y; Herman, Fréderic; Sizun, Philippe; Viskov, Christian

2017-03-08

Low Molecular Weight Heparins (LMWH) are complex anticoagulant drugs that mainly inhibit the blood coagulation cascade through indirect interaction with antithrombin. While inhibition of the factor Xa is well described, little is known about the polysaccharide structure inhibiting thrombin. In fact, a minimal chain length of 18 saccharides units, including an antithrombin (AT) binding pentasaccharide, is mandatory to form the active ternary complex for LMWH obtained by alkaline β-elimination (e.g., enoxaparin). However, the relationship between structure of octadecasaccharides and their thrombin inhibition has not been yet assessed on natural compounds due to technical hurdles to isolate sufficiently pure material. We report the preparation of five octadecasaccharides by using orthogonal separation methods including size exclusion, AT affinity, ion pairing and strong anion exchange chromatography. Each of these octadecasaccharides possesses two AT binding pentasaccharide sequences located at various positions. After structural elucidation using enzymatic sequencing and NMR, in vitro aFXa and aFIIa were determined. The biological activities reveal the critical role of each pentasaccharide sequence position within the octadecasaccharides and structural requirements to inhibit thrombin. Significant differences in potency, such as the twenty-fold magnitude difference observed between two regioisomers, further highlights the importance of depolymerisation process conditions on LMWH biological activity.

Qualitative and quantitative analysis of heparin and low molecular weight heparins using size exclusion chromatography with multiple angle laser scattering/refractive index and inductively coupled plasma/mass spectrometry detectors.

PubMed

Ouyang, Yilan; Zeng, Yangyang; Yi, Lin; Tang, Hong; Li, Duxin; Linhardt, Robert J; Zhang, Zhenqing

2017-11-03

Heparin, a highly sulfated glycosaminoglycan, has been used as a clinical anticoagulant over 80 years. Low molecular weight heparins (LMWHs), heparins partially depolymerized using different processes, are widely used as clinical anticoagulants. Qualitative molecular weight (MW) and quantitative mass content analysis are two important factors that contribute to LMWH quality control. Size exclusion chromatography (SEC), relying on multiple angle laser scattering (MALS)/refractive index (RI) detectors, has been developed for accurate analysis of heparin MW in the absence of standards. However, the cations, which ion-pair with the anionic polysaccharide chains of heparin and LMWHs, had not been considered in previous reports. In this study, SEC with MALS/RI and inductively coupled plasma/mass spectrometry detectors were used in a comprehensive analytical approach taking both anionic polysaccharide and ion-paired cations heparin products. This approach was also applied to quantitative analysis of heparin and LMWHs. Full profiles of MWs and mass recoveries for three commercial heparin/LMWH products, heparin sodium, enoxaparin sodium and nadroparin calcium, were obtained and all showed higher MWs than previously reported. This important improvement more precisely characterized the MW properties of heparin/LMWHs and potentially many other anionic polysaccharides. Copyright © 2017 Elsevier B.V. All rights reserved.

A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa.

PubMed

Lu, Genmin; DeGuzman, Francis R; Hollenbach, Stanley J; Karbarz, Mark J; Abe, Keith; Lee, Gail; Luan, Peng; Hutchaleelaha, Athiwat; Inagaki, Mayuko; Conley, Pamela B; Phillips, David R; Sinha, Uma

2013-04-01

Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin-activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non-protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.

National survey on thromboprophylaxis and anticoagulant or antiplatelet management in neurosurgical and neurocritical patients.

PubMed

Vázquez-Alonso, E; Fábregas, N; Rama-Maceiras, P; Ingelmo Ingelmo, I; Valero Castell, R; Valencia Sola, L; Iturri Clavero, F

2015-12-01

To determine the protocols used by Spanish anaesthesiologists for thromboprophylaxis and anticoagulant or antiplatelet drugs management in neurosurgical or neurocritical care patients. An online survey with 22 questions, with one or multiple options, launched by the Neuroscience Subcommittee of the Spanish Anaesthesia Society and available between June and October 2012. Of the 73 hospitals included in the National Hospitals Catalogue, a valid response to the online questionnaire was received by 41 anaesthesiologists from 37 sites (response rate 50.7%). Only one response per site was used. A specific protocol was available in 27% of these centres. Mechanical thromboprophylaxis is used, intraoperatively or postoperatively, in 80%, and pharmacological treatment is used by 75% of respondents. Enoxaparin was the most frequent heparin used in craniotomy patients (78%). Craniotomies were performed maintaining acetylsalicylic acid treatment in patients with coronary stents and double anti-platelet treatment in a half of the centres. Mechanical thromboprophylaxis is used more frequently than the pharmacological approach in neurosurgical or neurocritical populations in Spanish hospitals. Management of patients under previous anticoagulant treatment was highly heterogeneous among hospitals included in this survey. Previous antiplatelet treatment is modified depending on primary or secondary prescription. Copyright © 2014 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

Development of hydrophilic interaction chromatography with quadruple time-of-flight mass spectrometry for heparin and low molecular weight heparin disaccharide analysis.

PubMed

Ouyang, Yilan; Wu, Chengling; Sun, Xue; Liu, Jianfen; Linhardt, Robert J; Zhang, Zhenqing

2016-01-30

Heparin and low molecular weight heparin (LMWH) are widely used as clinical anticoagulants. The determination of their composition and structural heterogeneity still challenges analysts. Disaccharide compositional analysis, utilizing heparinase-catalyzed depolymerization, is one of the most important ways to evaluate the sequence, structural composition and quality of heparin and LMWH. Hydrophilic interaction chromatography coupled with quadruple time-of-flight mass spectrometry (HILIC/QTOFMS) has been developed to analyze the resulting digestion products. HILIC shows good resolution and excellent MS compatibility. Digestion products of heparin and LMWHs afforded up to 16 compounds that were separated using HILIC and analyzed semi-quantitatively. These included eight common disaccharides, two disaccharides derived from chain termini, three 3-O-sulfo-group-containing tetrasaccharides, along with three linkage region tetrasaccharides and their derivatives. Structures of these digestion products were confirmed by mass spectral analysis. The disaccharide compositions of a heparin, two batches of the LMWH, enoxaparin, and two batches of the LMWH, nadroparin, were compared. In addition to identifying disaccharides, 3-O-sulfo-group-containing tetrasaccharides, linkage region tetrasaccharides were observed having slightly different compositions and contents in these heparin products suggesting that they had been prepared using different starting materials or production processes. Thus, compositional analysis using HILIC/QTOFMS offers a unique insight into different heparin products. Copyright © 2015 John Wiley & Sons, Ltd.

Structural analysis of low molecular weight heparin by ultraperformance size exclusion chromatography/time of flight mass spectrometry and capillary zone electrophoresis.

PubMed

Zhang, Qianqian; Chen, Xi; Zhu, Zhijia; Zhan, Xueqiang; Wu, Yanfang; Song, Lankun; Kang, Jingwu

2013-02-05

Although low molecular weight heparins (LMWHs) have been used as anticoagulant agents for over 2 decades, their structures have not been fully characterized. In this work, we propose a new strategy for the comprehensive structural analysis of LMWHs based on the combination of ultraperformance size exclusion chromatography/electrospray quadruple time-of-flight-mass spectrometry (UPSEC/Q-TOF-MS) and capillary zone electrophoresis (CZE). More than 70 components, including oligosaccharides with special structures such as 1,6-anhydro rings, saturated uronic acid at the nonreducing end and odd-numbered saccharides units were identified with UPSEC/Q-TOF-MS. Furthermore, a more detailed compositional analysis was accomplished by CZE analysis. PEG10000 and MgCl(2) were added to the background electrolyte to separate those saccharides with the nearly same charge-to-mass ratio. Baseline separation and quantification of all the building blocks of the most complex LMWH, namely, enoxaparin, which include 10 disaccharides, 1 trisaccharide, 2 tetrasaccharides, and, of particular importance, 4 1,6-anhyro derivatives, was achieved using CZE for the first time. Additionally, the peaks of oligosaccharides, in the absence of commercially available standards, were assigned on the basis of the linear correlation between the electrophoretic mobilities of oligosaccharides and their charge-to-mass ratios. These two approaches are simple and robust for structural analysis of LMWHs.

Heparin concentration is critical for cell culture with human platelet lysate.

PubMed

Hemeda, Hatim; Kalz, Jana; Walenda, Gudrun; Lohmann, Michael; Wagner, Wolfgang

2013-09-01

Culture media for mesenchymal stromal cells (MSCs) are generally supplemented with fetal bovine serum. Human platelet lysate (hPL) has been proven to be a very effective alternative without the risk of xenogeneic infections or immune reactions. In contrast to fetal bovine serum, hPL comprises plasma, and anticoagulants-usually unfractionated heparin (UFH)-need to be added to prevent gel formation. Cultures of MSCs in hPL media with various concentrations of UFH and enoxaparin, a low-molecular-weight heparin (LMWH), were systematically compared with regard to proliferation, fibroblastoid colony-forming unit frequency, immunophenotype and in vitro differentiation. At least 0.61 IU/mL UFH or 0.024 mg/mL LMWH was necessary for reliable prevention of coagulation of hPL pools used in this study. Higher concentrations impaired cellular proliferation in a dose-dependent manner even without benzyl alcohol, which is commonly added to heparins as a bacteriostatic agent. Colony-forming unit frequency was also reduced at higher heparin concentrations, particularly with LMWH, whereas no significant effect was observed on cellular morphology or immunophenotype. High concentrations of heparins reduced the in vitro differentiation toward adipogenic and osteogenic lineages. Heparin concentration is critical for culture of MSCs in hPL media; this is of particular relevance for cellular therapy where cell culture procedures need to be optimized and standardized. Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

First Indian study evaluating role of biochemical investigations and diagnostic tools in detection of adverse drug reactions.

PubMed

Tandon, Vishal R; Khajuria, Vijay; Raina, Kapila; Mahajan, Vivek; Sharma, Aman; Gillani, Zahid

2014-09-01

To evaluate the role of biochemical investigations (BI) and diagnostic tools (DT) in ADR detection. An observational prospective cross-sectional study was done using suspected ADR data collection form. A total of 2381 ADR related events were recorded in two years. Total number/percentage of biochemical abnormalities (BA) related ADR detection rate was 14.57% and of DT was 1.091% in contrast to 84.33% recorded with clinical presentation. Maximum cases were inward patients (87.13%), 67.02% were recorded by active surveillance. ADR detection rate at one point & detection on follow up was 56.31% Vs 46.38%. ADR detection rate of ECG, endoscopy, X-ray were 0.57%, 0.22%, 0.22% and of CT scan, MRI, DEXA scan, USG and biopsy was 0.04% each. Maximum ADRs were severe/serious, latent and Type-A in nature. Anemia (4.6%), followed by liver dysfunction (2.8%), renal dysfunction, electrolyte imbalance, hyperglycemia (1.1% each), abnormal coagulation profile (1%), decrease platelet count (0.8%), hypoglycemia (0.7%) were the most common BAs. Anti retroviral drugs (ART), tirofiban and methotrexate accounted for anemia, ART and anti tubercular drugs for liver & renal dysfunction, insulin for hypoglycemia, tirofiban, paclitaxel, capecipabine and ifosfamide for thrombocytopenia, hematuria by enoxaparin & dyslipidemia with ART were common ADRs. BI and DT can play very important role in ADR detection.

Implementation of Pharmaceutical Practice Guidelines by a Project Model Based

PubMed Central

Mahmoudi, Laleh; Karamikhah, Razieh; Mahdavinia, Azadeh; Samiei, Hasan; Petramfar, Peyman; Niknam, Ramin

2015-01-01

Abstract All around the world a few studies have been found on the effect of guideline implementation on direct medications’ expenditure. The goal of this study was to evaluate cost savings of guideline implementation among patients who had to receive 3 costly medications including albumin, enoxaparin, and pantoprazole in a tertiary hospital in Shiraz, Iran. An 8-month prospective study was performed in 2 groups; group 1 as an observational group (control group) in 4 months from June to September 2014 and group 2 as an interventional group from October 2014 to January 2015. For group 1 the pattern of costly medications usage was determined without any intervention. For group 2, after guideline implementation, the economic impact was evaluated by making comparisons between the data achieved from the 2 groups. A total of 12,680 patients were evaluated during this study (6470 in group 1; 6210 in group 2). The reduction in the total value of costly administered drugs was 56% after guideline implementation. Such reduction in inappropriate prescribing accounts for the saving of 85,625 United States dollars (USD) monthly and estimated 1,027,500 USD annually. Guideline implementation could improve the adherence of evidence-based drug utilization and resulted in significant cost savings in a major teaching medical center via a decrease in inappropriate prescribing of costly medications. PMID:26496288

Anticoagulants in ischemia-guided management of non-ST-elevation acute coronary syndromes.

PubMed

Mayer, Martin

2017-03-01

The most recent joint guidelines from the American Heart Association (AHA) and American College of Cardiology (ACC) on the management of non-ST-elevation acute coronary syndromes (NSTE-ACS) are a result of a substantial and considered undertaking, and those involved deserve much recognition for their efforts. However, the handling of anticoagulants seems somewhat inadequate, and this is a highly-relevant matter when managing NSTE-ACS. Among areas of potential uncertainty, emergency medicine professionals might still be left wondering about the particulars of anticoagulant therapy when pursuing ischemia-guided management of NSTE-ACS (that is, managing NSTE-ACS without an intent for early invasive measures, such as coronary angiography and revascularization). This review seeks to provide insight into this question. Relevant clinical trials are appraised and translated into clinical context for emergency medicine professionals, including the implications of noteworthy advancements in the management of NSTE-ACS. Although current guidelines from the AHA and ACC suggest enoxaparin has better evidence than other anticoagulants in the setting of NSTE-ACS management, careful review of the evidence shows this is not actually clearly supported by the available evidence in the era of contemporary management. Unless and until better contemporary data emerge, emergency medicine professionals must carefully weigh the available evidence, its limitations, and the possible clinical implications of the various anticoagulant options when managing NSTE-ACS. Copyright © 2017 Elsevier Inc. All rights reserved.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2002-05-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables can be retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, abarelix, abciximab, acarbose, alefacept, alteplase, amisulpride, amoxicillin trihydrate, apomorphine hydrochloride, aprepitant, argatroban monohydrate, aspirin, atenolol; Betamethasone dipropionate, betamethasone valerate, bicalutamide, bleomycin sulfate; Calcium carbonate, candesartan cilexetil, celecoxib, cetirizine hydrochloride, cisplatin, clarithromycin, clavulanate potassium, clomethiazole edisilate, clopidogrel hydrogensulfate, cyclophosphamide, chorionic gonadotropin (human); Dalteparin sodium, desloratadine, dexamethasone, doxorubicin, DPC-083; Efalizumab, efavirenz, enoxaparin sodium, eprosartan mesilate, etanercept, etoposide, ezetimibe; Faropenem daloxate, fenofibrate, fluocinolone acetonide, flutamide, fluvastatin sodium, follitropin beta, fondaparinux sodium; Gabapentin, glibenclamide, goserelin, granisetron hydrochloride; Haloperidol, hydrochlorothiazide; Imiquimod, interferon beta-1a, irbesartan, iseganan hydrochloride; L-758298, lamivudine, lanoteplase, leflunomide, leuprorelin acetate, loratadine, losartan potassium; Melagatran, metformin hydrochloride, methotrexate, metronidazole, micafungin sodium, mitoxantrone hydrochloride; Nelfinavir mesilate, neutral insulin injection, nizatidine; Olopatadine hydrochloride, omeprazole, ondansetron hydrochloride; Pamidronate sodium, paracetamol, paroxetine hydrochloride, perindopril, pimecrolimus, pioglitazone hydrochloride, piroxicam, pleconaril, pralmorelin, pravastatin sodium, prednisolone, prednisone, propofol; Raloxifene hydrochloride, ranpirnase, remifentanil hydrochloride, risedronate sodium, risperidone, rofecoxib, ropinirole hydrochloride, rosuvastatin calcium; Sevoflurane, sildenafil citrate, simvastatin, somatropin; Tacrolimus, tamoxifen citrate, telmisartan, temozolomide, thiopental sodium, tinzaparin sodium, tirofiban hydrochloride, treosulfan, triamcinolone acetonide; Urokinase; Valsartan, vardenafil, vincristine; Warfarin sodium; Ximelagatran; Zidovudine.

[Evaluation of selected parameters of blood coagulation and fibrinolysis system in patients undergoing total hip replacement surgery with normovolemic hemodilution procedure and standard enoxaparine prophylaxis].

PubMed

Piecuch, Wiesław; Sokołowska, Bozena; Dmoszyńska, Anna; Furmanik, Franciszek

2003-01-01

The aim of the study was to evaluate selected blood coagulation and fibrinolysis parameters in patients undergoing total hip replacement surgery with normovolemic hemodilution and standard enoksaparine profilaxis. The study included 66 patients undergoing hip replacement surgery. The group consisted of 51 women and 15 men, within the age range of 47-78, the mean age was 64. In 32 (subgroup II) patients the surgery was performed with the use of normovolemic hemodilution, in 34 (subgroup I) the hemodilution procedure was not applied. The enoksaparine as prophylaxis started 12 hours prior to surgery and continued during hospitalisation. The examination of the coagulation system was performed: on the day of the operation in the morning, on the day of the operation in the evening and on the first day after operation. We determined the concentrations of TAT and PAP complexes, prothrombin fragments 1 + 2 (F1 + 2) and d-dimers (DD). 1) during total hip replacement surgery and particularly in the period of the first 12 hours after the procedure marked activation of coagulation and fibrinolysis occurRed; 2) the application of the hemodilution procedure does not influence significantly the degree of coagulation and fibrinolysis disorders in the perioperative period, but could reduced incidence of thromboembolic complications in the postoperative period.

Coltsfoot as a potential cause of deep vein thrombosis and pulmonary embolism in a patient also consuming kava and blue vervain.

PubMed

Freshour, Jessica E; Odle, Brian; Rikhye, Somi; Stewart, David W

2012-09-01

To report a case of deep vein thrombosis (DVT) with symptomatic pulmonary embolism (PE) possibly associated with the use of coltsfoot, kava, or blue vervain. A 27-year-old white male presented with leg pain and swelling, tachycardia, and pleuritic chest pain. He had no significant medical history. A medication history revealed extensive herbal medication use including: coltsfoot, passionflower, red poppy flower petals, wild lettuce, blue lily flowers, wild dagga flowers, Diviners Three Burning Blend® (comprised of salvia divinorum, blue lily, and wild dagga), kava-kava, St. John's Wort, blue vervain, and Dreamer's Blend® (comprised of Calea zacatechichi, vervain, Entada rheedii, wild lettuce, and Eschscholzia californica). Lower extremity Doppler ultrasound and computed topography (CT) of the chest revealed DVT and PE. A hypercoagulable work-up was negative. The patient was treated with enoxaparin and warfarin and was discharged home. While no distinct agent can be identified as a sole cause of this venous thromboembolic event, coltsfoot could potentially affect coagulation through its effect on vascular endothelial cells as they regulate nitric oxide. Nitric oxide is a known mediator of platelet activity and coagulation, particularly in the pulmonary vasculature. Kava and vervain have estrogenic properties. Of the medications consumed by this self-proclaimed "herbalist," coltsfoot is a potential cause of venous thromboembolic disease (VTE).

Therapeutic implications of coexisting severe pulmonary hemorrhage and pulmonary emboli in a case of Wegener granulomatosis.

PubMed

Dreyer, Gavin; Fan, Stanley

2009-05-01

Wegener granulomatosis classically involves the renal, respiratory, and ear, nose, and throat systems. Pulmonary hemorrhage is recognized as a severe respiratory complication. Untreated, the mortality rate approaches 90% at 2 years. We describe a case of Wegener granulomatosis with coexistent severe lung hemorrhage and pulmonary and deep vein thromboses. A 31-year-old man presented with features of vasculitis, including epistaxis, fever, and acute kidney injury with an increased serum creatinine level (3.27 mg/dL). Kidney biopsy confirmed pauci-immune crescentic glomerulonephritis, and antineutrophil cytoplasmic antibody showing a cytoplasmic staining pattern was strongly positive. Standard immunosuppression therapy (prednisolone and cyclophosphamide) was started. Eleven days later, the patient developed sudden dyspnea. A computed tomographic pulmonary angiogram showed pulmonary emboli, and ultrasound of the limbs showed ileofemoral thrombi bilaterally. Subcutaneous enoxaparin and warfarin therapy was started, but 8 days later, the patient had a massive pulmonary hemorrhage. Anticoagulation therapy was stopped, and plasma exchange was started to prevent further life-threatening hemorrhage. An inferior vena cava filter was inserted to prevent further pulmonary emboli during the period when anticoagulation was withheld. Kidney function improved, and pulmonary hemorrhage resolved after 5 plasma exchanges. Reintroduction of intravenous heparin and subsequently warfarin caused no further bleeding. We discuss the difficult management dilemma this combination of disease manifestations presents and review the current literature.

Induction of anti-PF4/heparin antibodies after arthroplasty for rheumatic diseases.

PubMed

Migita, Kiyoshi; Asano, Tomoyuki; Sato, Shuzo; Motokawa, Satoru

2018-04-17

Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. These pathogenic antibodies against PF4/heparin bind and activate cellular FcγRIIa on platelets to induce a hypercoagulable state culminating in thrombosis. Recent studies indicate several conditions, including joint surgery, induce spontaneous HIT, which can occur without exposure to heparin. To determine the real-world evidences concerning the incidences of venous thromboembolism (VTE) after total joint arthroplasty for rheumatic disease, we conducted a multicenter cohort study (J-PSVT) designed to document the VTE and seroconversion rates of anti-PF4/heparin antibody in 34 Japanese National hospital organization (NHO) hospitals. J-PSVT indicated that prophylaxis with fondaparinux, not enoxaparin, reduces the risk of deep vein thrombosis in patients undergoing arthroplasty. Multivariate analysis revealed that dynamic mechanical thromboprophylaxis (intermittent plantar device) was an independent risk factor for seroconversion of anti-PF4/heparin antibodies, which was also confirmed by propensity-score matching. Seroconversion rates of anti-PF4/heparin antibodies were significantly reduced in rheumatoid arthritis (RA) patients compared with osteoarthritis (OA) patients, which may link with the findings that IgG fractions isolated from RA patients not OA patients contained PF4. Our study indicated that a unique profile of anti-PF4/heparin antibodies is induced by arthroplasty for rheumatic diseases.

Monitoring of unfractionated heparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent (PiCT®).

PubMed

Schaden, E; Jilch, S; Hacker, S; Schober, A; Kozek-Langenecker, S

2012-12-24

To achieve sufficient and safe anticoagulation with unfractionated heparin (UFH) a close and reliable drug monitoring is necessary. In general, the activated partial thromboplastin time (APTT) is used for this purpose. In acute phase response, however, the APTT test procedure might be unreliable e.g. with false low results in the presence of elevated factor VIII. In this so called heparin resistance, measurement of anti-Xa activity is recommended over APTT to avoid potentially harmful dose escalation. A combination of anti-Xa measurement and global hemostatic testing with ROTEM® employing the anti-Xa sensitive PiCT® reagent showed high correlation with enoxaparin levels. This test modification could also be suitable for monitoring UFH. Aim of the study was to evaluate the correlation between PiCT®-ROTEM® and levels of UFH. In this in-vitro study blood samples from healthy volunteers were spiked with UFH and subjected to different ROTEM® tests. There was a linear correlation between UFH level and clotting time (CT) in the PiCT®-ROTEM® test with an excellent correlation coefficient of 0.92. Additional endpoints showed similar results (PiCT®-ROTEM® MaxVel r = -0.85 and PiCT®-ROTEM® t_MaxVel r = 0.88). As a point-of-care applicable tool ROTEM® is immediately at hand. If further clinical studies confirm sensitivity in heparin resistance, PiCT®-ROTEM® could permit rapid UFH dose adjustments especially required in critical illness with acute phase response. Copyright © 2012 Elsevier B.V. All rights reserved.

Double layer adhesive silicone dressing as a potential dermal drug delivery film in scar treatment.

PubMed

Mojsiewicz-Pieńkowska, Krystyna; Jamrógiewicz, Marzena; Żebrowska, Maria; Mikolaszek, Barbara; Sznitowska, Małgorzata

2015-03-15

The present studies focused on the evaluation of design of an adhesive silicone film intended for scar treatment. Developed silicone double layer film was examined in terms of its future relevance to therapy and applicability on the human skin considering properties which included in vitro permeability of water vapor and oxygen. In order to adapt the patches for medical use in the future there were tested such properties as in vitro adhesion and occlusion related to in vivo hydration. From the silicone rubbers double layer silicone film was prepared: a non-adhesive elastomer as a drug carrier (the matrix for active substances - enoxaparin sodium - low molecular weight heparin) and an adhesive elastomer, applied on the surface of the matrix. The novel adhesive silicone film was found to possess optimal properties in comparison to commercially available silicone dressing: adhesion in vivo, adhesion in vitro - 11.79N, occlusion F=85% and water vapor permeability in vitro - WVP=105g/m(2)/24h, hydration of stratum corneum in vivoH=61-89 (RSD=1.6-0.9%), oxygen permeation in vitro - 119-391 cm(3)/m(2)/24 (RSD=0.17%). In vitro release studies indicated sufficient LMWH release rate from silicone matrix. Developed novel adhesive silicone films were considered an effective treatment of scars and keloids and a potential drug carrier able to improve the effectiveness of therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

Cost Effectiveness of Antiplatelet and Antithrombotic Therapy in The Setting of Acute Coronary Syndrome: Current Perspective and Literature Review

PubMed Central

Fanari, Zaher; Weiss, Sandra; Weintraub, William S

2015-01-01

Acute Coronary Syndromes are associated with high rates of morbidity and mortality. The advances of antiplatelet and anticoagulation therapy over several years time have result in in improved in cardiac outcomes, but with increased health care costs. Multiple cost effectiveness studies have been performed to evaluate the use of available antiplatelet agents and anticoagulation in the setting of both ST Elevation myocardial infarction (STEMI) and Non–ST Elevation Acute Coronary Syndrome (NSTE-ACS). Early on the use of GPI prove to be economically attractive in the management of ACS, however the introduction of P2Y12 receptor antagonist limited their use to a bail out agents in complex interventions. Generic clopidogrel is probably still an economically attractive P2Y12 receptor antagonist choice especially in low risk ACS, while both ticagrelor and prasugrel present an economically attractive alternative option especially in high risk ACS and patients at risk for stent thrombosis. While enoxaparin presents an economically dominant alternative to heparin in NSTE-ACS, its role in STEMI in the contemporary era is unclear. During PCI, bivalirudin monotherapy was shown to be an economically dominant alternative to the combination of heparin and GPI in ACS. However, new studies may suggest that using heparin monotherapy may offer an attractive alternative. The comparative and cost effectiveness of different combinations of antiplatelet and antithrombotic therapy will be the focus of future expected clinical and economic assessments. PMID:26068886

Case study: Idiopathic hemothorax in a patient with status asthmaticus.

PubMed

Ricketti, Peter A; Unkle, David W; Lockey, Richard; Cleri, Dennis J; Ricketti, Anthony J

2016-09-01

Idiopathic spontaneous hemothorax has been rarely described in the literature. A case of status asthmaticus and spontaneous hemothorax is described in a 29-year-old female of African descent who presented to the emergency room after 2 days of severe cough productive of yellow sputum, otalgia, sore throat, subjective fevers, chills, headache, progressive wheezing, chest tightness and dyspnea. She had a history of 7 years of asthma and was non-adherent with her controller asthma medications. Prophylactic subcutaneous administration of enoxaparin 40 milligrams was initiated upon hospitalization. The patient initially had a normal chest radiograph but subsequently developed a large, left hemothorax that required tube thoracostomy placement followed by video-assisted thoracoscopic surgery (VATS). The patient was transferred to the Intensive Care Unit (ICU) and tube thoracostomy resulted in evacuation of 1,400 milliliters of blood-like fluid, which had a pleural fluid hematocrit greater than 50% of the serum hematocrit. A contrast-enhanced computed tomography (CT) scan of the chest did not reveal any source for the bleeding and a technetium bone scan of the chest was normal. The patient required transfusion of 5 units of packed red blood cells. She was then taken to the operating room for VATS because of continued chest tube drainage (3,200 milliliters of fluid over a 48-hour period). The etiology of the hemothorax was unknown despite surgical exploration but was felt to be secondary to cough and bronchospasm associated with status asthmaticus.

ST-segment resolution with bivalirudin versus heparin and routine glycoprotein IIb/IIIa inhibitors started in the ambulance in ST-segment elevation myocardial infarction patients transported for primary percutaneous coronary intervention: The EUROMAX ST-segment resolution substudy.

PubMed

Van't Hof, Arnoud; Giannini, Francesco; Ten Berg, Jurrien; Tolsma, Rudolf; Clemmensen, Peter; Bernstein, Debra; Coste, Pierre; Goldstein, Patrick; Zeymer, Uwe; Hamm, Christian; Deliargyris, Efthymios; Steg, Philippe G

2017-08-01

Myocardial reperfusion after primary percutaneous coronary intervention (PCI) can be assessed by the extent of post-procedural ST-segment resolution. The European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) trial compared pre-hospital bivalirudin and pre-hospital heparin or enoxaparin with or without GPIIb/IIIa inhibitors (GPIs) in primary PCI. This nested substudy was performed in centres routinely using pre-hospital GPI in order to compare the impact of randomized treatments on ST-resolution after primary PCI. Residual cumulative ST-segment deviation on the single one hour post-procedure electrocardiogram (ECG) was assessed by an independent core laboratory and was the primary endpoint. It was calculated that 762 evaluable patients were needed to show non-inferiority (85% power, alpha 2.5%) between randomized treatments. A total of 871 participated with electrocardiographic data available in 824 patients (95%). Residual ST-segment deviation one hour after PCI was 3.8±4.9 mm versus 3.9±5.2 mm for bivalirudin and heparin+GPI, respectively ( p=0.0019 for non-inferiority). Overall, there were no differences between randomized treatments in any measures of ST-segment resolution either before or after the index procedure. Pre-hospital treatment with bivalirudin is non-inferior to pre-hospital heparin + GPI with regard to residual ST-segment deviation or ST-segment resolution, reflecting comparable myocardial reperfusion with the two strategies.

Access to new cardiovascular therapies in Canadian hospitals: a national survey of the formulary process.

PubMed

Shalansky, Stephen J; Virk, Roohina; Ackman, Margaret; Jackevicius, Cynthia; Kertland, Heather; Tsuyuki, Ross; Humphries, Karin

2003-02-01

Access to new therapies in hospitals depends upon both clinical trial evidence and local Pharmacy and Therapeutics (P&T) committee approval. The process of formulary evaluation by P&T committees is not well-understood. To describe the formulary decision-making process in Canadian hospitals for cardiovascular medications recently made available on the Canadian market. Postal survey of hospital pharmacy directors in all Canadian hospitals with more than 50 beds. Target drugs included abciximab, enoxaparin, dalteparin, clopidogrel, eptifibatide and tirofiban. Of 428 surveys mailed, responses were received from 164 P&T committees representing 350 hospitals for an effective response rate of 82%. While physicians make up the largest proportion of committee membership, pharmacists play an influential role. Information most commonly cited as influencing formulary decisions included published clinical trials (97%), regional guidelines (90%), pharmacoeconomic data (84%), decisions at peer hospitals (73%) and local opinion leaders (60%). However, this information was often not required on formulary applications. Approval timelines varied widely for target medications but there were no regional, hospital or P&T committee characteristics that were independent predictors of early formulary application or approval. There is wide variability in the time taken for Canadian institutions to adopt new cardiovascular therapies, which is not explained by regional, hospital or P&T committee characteristics. Standardization of the formulary application and evaluation processes, including sharing of information amongst institutions, would lead to broader understanding of the applicable issues, more objectivity and improved efficiency.

[The best of thrombosis in 2002].

PubMed

Maillard, L

2003-01-01

In the area of myocardial infarction one is reminded of the publication of the CADILLAC study which has reopened the debate on the systematic use of GpIIbIIIa inhibitors in the acute phase of myocardial infarction complementing primary angioplasty with the placement of an endoprosthesis. New modalities for thrombolysis are in the course of evaluation, notably Eptibaphide Alteplase combination in the INTRO-AMI study and Tenecteplase Abciximab in association with enoxaparine or non-fractionated heparin in the TIMI 23 study. Several studies comparing angioplasty to lysis have been published. STOPAMI 2 evaluated myocardial salvage in the framework of primary angioplasty with placement of an endoprosthesis combined with abciximab infusion in comparison with half dose fibrinolysis associated with abciximab. CAPTIM is a strategy evaluation comparing the results of pre-hospital fibrinolysis with primary angioplasty. With the RITA 3 study the interventional approach definitely comes top in comparison with a conservative approach for the treatment of unstable angina. One is equally reminded of the changes in the ACC/AHA recommendations for the management of unstable angina. The debate continues on the indications for thrombolysis in submassive pulmonary embolus. In the therapeutic area, one is reminded of the update on the interactions between angiotensin converting enzymes and aspirin in treatment and long term coronary syndrome. Finally, at the end of 2001, the work of French teams was published concerning the evaluation of risk of relapse for cerebral vascular accident in the presence of a foramen ovale or an aneurysm of the inter-atrial septum.

A rare complication of pulmonary tuberculosis: a case report.

PubMed

Kumarihamy, Kulatunga Wijekoon Mudiyanselage Pramitha Prabhashini; Ralapanawa, Dissanayake Mudiyanselage Priyantha Udaya Kumara; Jayalath, Widana Arachchilage Thilak Ananda

2015-02-10

Pulmonary tuberculosis remains an important public health problem globally and one of the most prevalent infectious diseases in Sri Lanka. It can cause a wide variety of complications but hematological manifestations are rare. According to our literature survey, this is the first reported case of the disease associated with deep vein thrombosis in Sri Lanka. A 37 year old Sri Lankan Sinhalese female presented with fever of one month's duration with productive cough and two weeks painless left lower limb swelling. Chest X-ray showed bilateral inflammatory shadows with a cavitatory lesion on the right apical region. A computed tomographic pulmonary angiography scan excluded pulmonary embolism. She had rising mycoplasma antibody titre (four fold). Acute deep vein thrombosis of the left lower limb was confirmed by venous duplex. Pulmonary tuberculosis was confirmed with positive culture for Mycobacterium tuberculosis. She was treated with clarythromycin, enoxaparin, warfarin and anti tuberculus drugs. It was difficult to maintain her International Normalizing Ratio in the therapeutic range due to drug interactions and poor compliance. At five months of presentation she died of massive pulmonary embolism. Our case emphasizes that patients with severe pulmonary tuberculosis are at risk of developing thromboembolism and superadded infections. It should be noted that even though starting anti tuberculosis drugs improved haemostatic disturbances, achieving the target International Normalizing Ratio was difficult due to drug interactions. Therefore these patients should be closely followed up to prevent complications and death from pulmonary embolism.

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

LMWH in the prevention of preeclampsia and fetal growth restriction in women without thrombophilia. A systematic review and meta-analysis.

PubMed

Mastrolia, Salvatore Andrea; Novack, Lena; Thachil, Jecko; Rabinovich, Anat; Pikovsky, Oleg; Klaitman, Vered; Loverro, Giuseppe; Erez, Offer

2016-10-28

Placental mediated pregnancy complications such as preeclampsia and fetal growth restriction (FGR) are common, serious, and associated with increased morbidity and mortality. We conducted a systematic review and meta-analysis to determine the effect of treatment with low-molecular-weight heparins (LMWHs) for secondary prevention of these complications in non thrombophilic women. We searched the electronic databases PubMed, Scopus, and Cochrane Library for randomised controlled trials addressing this question. Five studies including 403 patients met the inclusion criteria, 68 developed preeclampsia and 118 FGR. The studies were very heterogeneous in terms of inclusion criteria, LMWH preparation, and dosage. Meta-analyses were performed using random-effect models. The overall use of LMWHs was associated with a risk reduction for preeclampsia (Relative risk (RR) 0.366; 95 % confidence interval (CI), 0.219-0.614) and FGR (RR 0.409; 95 % CI, 0.195-0.932) vs. no treatment. From the data available for analysis it appears that the use of Dalteparin is associated with a risk reduction for preeclampsia (p=0.002) and FGR (p<0.001); while Enoxaparin is associated with risk reduction for preeclampsia (p=0.013) but not for FGR (p=0.3). In spite of the small number of studies addressing the research question, and the high variability among them, our meta-analysis found a modest beneficial effect of LMWH for secondary prevention of preeclampsia and FGR. Further studies are needed to address these questions before a definite conclusion can be reached.

Successful medical treatment of glans ischemia after voluntary buprenorphine injection.

PubMed

Brecheteau, François; Grison, Pierre; Abraham, Pierre; Lebdai, Souhil; Kemgang, Steve; Souday, Vincent; Nedelcu, Cosmina; Culty, Thibaut; Larré, Stéphane; Azzouzi, Abdel Rahmene; Bigot, Pierre

2013-11-01

The diverted use of synthetic opioid buprenorphine by drug addicts can be responsible for serious ischemic and infectious complications, particularly in the case of intravenous injection. We present a case of serious glans ischemia after buprenorphine injection directly into the deep dorsal vein of the penis. Analysis using new medical imaging techniques and treatments is detailed below. A 26-year-old male drug addict presented with glans pain 4 days after self-injection of buprenorphine into the deep dorsal vein of the penis. The patient was apyretic and presented a urethral discharge. His glans was blue without discoloration on digital pressure. Additionally, his biologic and serologic tests were normal while bacteriology showed the presence of Enterobacter cloacae urethritis. After 48 hours of intravenous antibiotic treatment without improvement, a specific medical treatment using enoxaparin and ilomedin was initiated, with the assumption that there was an ischemic complication. Laser speckle contrast imaging allowed confirmation of the presence of distal penis ischemia and provided an accurate mapping of the ischemic zone. A 28-day treatment combining antibiotics, subcutaneous heparin at curative dose, antiplatelet drug, ilomedin, and hyperbaric oxygen therapy resulted in clinical improvement of the lesions with no functional complications. To date, no consensus exists on the proper diagnostic and treatment approach to severe glans ischemia due to buprenorphine injection into the deep dorsal vein of the penis. The results of laser speckle contrast imaging were of real interest during the process of diagnosis. In addition, the combination of ilomedin with hyperbaric oxygen therapy and anticoagulant and antiplatelet drugs appeared to be an effective therapy. © 2013 International Society for Sexual Medicine.

An economic evaluation of the costs and benefits of heparin rationalisation in a hospital pharmacy.

PubMed

Reeves, Penny; Cooke, Jonathan; Lloyd, Adam; Hutchings, Adam

2004-06-01

To estimate the costs and benefits for a UK hospital pharmacy of stocking a single low molecular weight heparin (LMWH), enoxaparin, compared to stocking unfractionated heparin (UFH) and stocking both UFH and multiple different LMWHs. A decision-tree model was developed which considered the use of heparins for five indications: prophylaxis against venous thromboembolism (VTE) in major orthopaedic surgery; VTE prophylaxis in major general surgery; VTE prophylaxis in acute medical inpatients; treatment of diagnosed VTE; and anticoagulation for patients with unstable angina and non-ST-elevation myocardial infarction (UA/NSTEMI). Previously published cost-effectiveness analyses for each indication were combined into a single model and updated to 2002 prices. The number of patients given heparin in each indication was estimated from the pharmacy records of a large UK teaching hospital. The model estimated the use of drugs, staff time, clinical events and resource use resulting from anti-coagulation. Costs were estimated from the perspective of the hospital and the UK National Health Service. Total annual cost was estimated to be pounds sterling 3.2 m (single LMWH), pounds sterling 4.4 m (UFH only) and pounds sterling 3.7 m (multiple heparins). The largest expected cost savings from using a single LMWH compared to UFH only resulted from reduced hospital stay for DVT treatment, reduced revascularisation in UA/NSTEMI and fewer VTE events in orthopaedic surgery. Expected cost savings from using a single LMWH compared to multiple heparins were more modest Sub-optimal choice of anticoagulants may result in substantial excess costs elsewhere in the hospital.

Delayed Catheter-Related Intracranial Hemorrhage After a Ventriculoperitoneal or Ventriculoatrial Shunt in Hydrocephalus.

PubMed

Qian, Zhouqi; Gao, Liang; Wang, Ke; Pandey, Sajan

2017-11-01

Delayed catheter-related intracranial hemorrhage is not rare after a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt for the treatment of hydrocephalus. Immediate postoperative catheter-related intracranial hemorrhage is possibly due to the procedure itself; however, delayed intracranial hemorrhage may have other underlying mechanisms. This study aimed to investigate the clinical characteristics and reveal the risk factors of delayed catheter-related intracranial hemorrhage after a VP or VA shunt. We did a retrospective study to review patients with hydrocephalus and underwent VP or VA shunt in our department from September 2011 to December 2015. We reviewed the clinical characteristics of the patients with delayed catheter-related intracranial hemorrhage, and its risk factors were analyzed with SPSS 16.0. Of the 218 patients enrolled in the study (145 male, 73 female), 17 (7.8%) patients experienced delayed catheter-related intracranial hemorrhage, including 11 of 151 (7.3%) patients with a VP shunt and 6 of 67 (9.0%) patients with a VA shunt. Additionally, 4 of the 16 patients with postoperative low-molecular-weight heparin (LMWH) therapy and 13 of the 202 patients without LMWH experienced bleeding, showing a significant difference (25% vs. 6.4%, P = 0.026). The relative risk was 4.8 (95% confidence interval: 1.4-17.1). Delayed catheter-related intracranial hemorrhage is not rare after a VP or VA shunt. However, most patients can be cured after appropriate treatment. Postoperative anticoagulation therapy with enoxaparin may be associated with an increased risk of bleeding. Copyright © 2017. Published by Elsevier Inc.

Venous Thromboembolism Risk and Adequacy of Prophylaxis in High Risk Pregnancy in the Arabian Gulf

PubMed Central

Alsayegh, Faisal; Al-Jassar, Waleed; Wani, Salima; Tahlak, Muna; Al-Bahar, Awatef; Al-Kharusi, Lamya; Al-Tamimi, Halima; El-Taher, Faten; Mahmood, Naeema; Al-Zakwani, Ibrahim

2016-01-01

Objectives: To estimate the prevalence of venous thromboembolism (VTE) risk factors in pregnancy and the proportion of pregnancies at risk of VTE that received the recommended prophylaxis according to the American College of Chest Physicians (ACCP) 2012 published guidelines in antenatal clinics in the Arabian Gulf. Methods: The evaluation of venous thromboembolism (EVE)-Risk project was a non-interventional, cross-sectional, multi-centre, multi-national study of all eligible pregnant women (≥17 years) screened during antenatal clinics from 7 centres in the Arabian Gulf countries (United Arab Emirates, Kuwait, Bahrain, Qatar and Oman). Pregnant women were recruited during a 3-month period between September and December 2012. Results: Of 4,131 screened pregnant women, 32% (n=1,337) had ≥1 risk factors for VTE. Common VTE risk factors included obesity (76%), multiparity (33%), recurrent miscarriages (9.1%), varicose veins (6.9%), thrombophilia (2.6%), immobilization (2.0%), sickle cell disease (2.8%) and previous VTE (1.6%). Only 8.3% (n=111) of the high risk patients were on the recommended VTE prophylaxis. Enoxaparin was used in 80% (n=89) of the cases followed by tinzaparin (4%; n=4). Antiplatelet agents were prescribed in 11% (n=149) of pregnant women. Of those on anticoagulants (n=111), 59% (n=66) were also co-prescribed antiplatelet agents. Side effects (mainly local bruising at the injection site) were reported in 12% (n=13) of the cases. Conclusion: A large proportion of pregnant women in the Arabian Gulf countries have ≥1 VTE risk factor with even a smaller fraction on prophylaxis. VTE risk assessment must be adopted to identify those at risk who would need VTE prophylaxis. PMID:26517701

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.

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.

Effect of the human chorionic gonadotropin diet on patient outcomes.

PubMed

Goodbar, Nancy H; Foushee, Jaime A; Eagerton, David H; Haynes, Katie B; Johnson, Amanda A

2013-05-01

To report a case of left lower extremity deep vein thrombosis (DVT) and bilateral pulmonary embolisms in a patient who initiated the human chorionic gonadotropin (HCG) diet 2 weeks prior to presentation. A 64-year-old white female presented with leg swelling and shortness of breath. Lower extremity ultrasound revealed left leg DVT, and a computed tomography angiogram revealed bilateral pulmonary embolisms. A complete history and physical examination were unremarkable for any risk factors for acute thrombosis, with the exception of the initiation of the HCG diet approximately 2 weeks prior to presentation; the patient was taking 20 sublingual drops of HCG twice daily. Results of her hypercoagulable workup were negative. Upon admission, therapy was started with enoxaparin 120 mg subcutaneously twice daily and warfarin 5 mg orally once daily. According to the Naranjo probability scale, initiation of the HCG diet was a probable cause of our patient's adverse effects. The HCG diet has very few efficacy studies and no significant safety studies associated with its use. Six relevant studies were identified for assessment of efficacy, and only 1 was associated with a significant weight reduction in the HCG diet study population. All of these studies evaluated the use of the HCG diet via injections of the hormone and significant calorie restriction, which is known as the Simeons method. Currently marketed HCG products include sublingual drops, lozenges, and pellets, but none of these methods has an evidence-based efficacy and safety standard. As popularity of the HCG diet continues to increase, so do the potential adverse events associated with the management of weight loss via an unproven strategy. Patient safety information regarding this dieting strategy should be recognized by medical professionals.

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.

Venous thromboembolism prophylaxis in the critically ill: a point prevalence survey of current practice in Australian and New Zealand intensive care units.

PubMed

Robertson, Megan S; Nichol, Alistair D; Higgins, Alisa M; Bailey, Michael J; Presneill, Jeffrey J; Cooper, D James; Webb, Steven A; McArthur, Colin; MacIsaac, Christopher M

2010-03-01

Critically ill patients are at high risk of morbidity and mortality caused by venous thromboembolism (VTE). In addition to premorbid predisposing conditions, critically ill patients may be exposed to prolonged immobility, invasive intravascular catheters and frequent operative procedures, and further may have contraindications to pharmaceutical prophylactic measures designed to attenuate VTE risk. There are limited data describing current VTE prophylaxis regimens in Australia and New Zealand. To document current Australian and New Zealand management of VTE prophylaxis in a large mixed cohort of critically ill patients. Prospective, multicentre point prevalence survey endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG). 30 public hospital ICUs in Australia and New Zealand surveyed on Wednesday 9 May 2007. For all patients in each ICU on the study day, demographic data, admission diagnosis and information on VTE prophylaxis were prospectively collected. 502 patients were included in the survey, and 431 of these (86%) received VTE prophylaxis. Of these, 64% (276/431) received pharmacological prophylaxis and 80% (345/431) received mechanical prophylaxis, with 44% (190/431) receiving both. Of those receiving pharmacological prophylaxis, unfractionated heparin was used in 74%, and enoxaparin (low molecular weight heparin) in 23%. Contraindications to pharmacological prophylaxis were reported in 122 patients. Overall, pharmacological prophylaxis was administered to 87% of potentially suitable patients. We observed a high prevalence of VTE prophylaxis, with many critically ill patients receiving two or more modalities of prophylaxis. These results show that the potential risk of VTE in critically ill patients is recognised in Australia and New Zealand, and strategies to mitigate this serious complication are widely implemented.

Perioperative management of vitamin K antagonists in patients with low thromboembolic risk undergoing elective surgery: A prospective experience.

PubMed

Becerra, Ana Florencia; Cornavaca, María Teresita; Revigliono, José Ignacio; Contreras, Alejandro; Albertini, Ricardo; Tabares, Aldo Hugo

2017-10-11

To quantify thromboembolic and bleeding events in patients with low thromboembolic risk, who were chronically receiving vitamin K antagonists and undergoing elective surgery. A descriptive, prospective, single-center study was conducted between December 2010 and July 2014. Patients aged over 18 years old, chronically anticoagulated with vitamin K antagonists and admitted for elective surgery were included in the study. We excluded patients with a creatinine clearance<30ml/min, a body weight>120kg, heparin-induced thrombocytopenia, pregnant women, carriers of an epidural catheter for analgesia, patients who underwent unscheduled surgery and high thromboembolic risk-patients. Vitamin K antagonists were discontinued 5 days prior to the procedure without administering anticoagulant enoxaparin. The NIR was measured 24h before the procedure. A single dose of 3mg of vitamin K was administered in cases of a NIR>1.5. Vitamin K antagonists was resumed according to the surgical bleeding risk. Events were registered between 5 days prior to the procedure until 30 days after it. A total of 75 procedures were included in the study. Fifty-six patients (74.7%) received vitamin K antagonists for atrial fibrillation, 15 suffered from venous thromboembolism (20%) and 4 had mechanical heart valves (5.3%). Twenty-six patients (34.5%) underwent high-bleeding risk surgeries and 49 (65.5%) underwent low risk procedures. No thromboembolic event was recorded. Four bleeding events (5.3%) were reported, 3 of which were considered major bleeding events (2 fatal). Suspending vitamin K antagonists with no bridging therapy performed in patients with a low thromboembolic risk does not expose such patients to a significant risk of embolic events. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

[Transport and treatment of patients with STEMI in rural Iceland--Only a few patients receive PPCI within 120 minutes].

PubMed

Sigmundsson, Thórir S; Arnarson, Daníel; Rafnsson, Arnar; Magnússon, Viðar; Gunnarsson, Gunnar Thór; Thorgeirsson, Gestur

2016-01-01

ST-segment Elevation Myocardial Infarction (STEMI) is a life-threatening disease and good outcome depends on early restoration of coronary blood flow. Primary percutaneous coronary intervention (PPCI) is the treatment of choice if performed within 120 minutes of first medical contact (FMC) but in case of anticipated long transport or delays, pre-hospital fibrinolysis is indicated. The aim was to study transport times and adherence to clinical guidelines in patients with STEMI transported from outside of the Reykjavik area to Landspitali University Hospital in Iceland. Retrospective chart review was conducted of all patients diagnosed with STEMI outside of the Reykjavik area and transported to Landspitali University Hospital in Reykjavik in 2011-2012. Descriptive statistical analysis and hypothesis testing was applied. Eighty-six patients had signs of STEMI on electrocardiogram (ECG) at FMC. In southern Iceland nine patients (21%) underwent PPCI within 120 minutes (median 157 minutes) and no patient received fibrinolysis. In northern Iceland and The Vestman Islands, where long transport times are expected, 96% of patients eligible for fibrinolysis (n=31) received appropriate therapy in a median time of 57 minutes. Significantly fewer patients received appropriate anticoagulation treatment with clopidogrel and enoxaparin in southern Iceland compared to the northern part. Mortality rate was 7% and median length of stay in hospital was 6 days. Time from FMC to PPCI is longer than 120 minutes in the majority of cases. Pre-hospital fibrinolysis should be considered as first line treatment in all parts of Iceland outside of the Reykjavik area. Directly electronically transmitted ECGs and contact with cardiologist could hasten diagnosis and decrease risk of unnecessary interhospital transfer. A STEMI database should be established in Iceland to facilitate quality control.

[Prevention of venous thromboembolic disease in the critical patient: an assessment of clinical practice in the Community of Madrid].

PubMed

García-Olivares, P; Guerrero, J E; Tomey, M J; Hernangómez, A M; Stanescu, D O

2014-01-01

To analyze measures referred to venous thromboembolic prophylaxis in critically ill patients. An epidemiological, cross-sectional (prevalence cut), multicenter study was performed using an electronic survey. Comparison of results with quality indexes of the Spanish Society of Intensive Care Medicine, the American College of Chest Physician guidelines and international studies. Intensive Care Units (ICUs) in the Community of Madrid (Spain). All patients admitted to the ICU on the day of the survey. General aspects of venous thromboembolic prophylaxis and protocols used (risk stratification and ultrasound screening). A descriptive analysis was performed, continuous data being expressed as the mean or median, and categorical data as percentages. A total of 234 patients in 18 ICUs were included. Eighteen percent (42/234) received no prophylaxis, and 55% had no contraindication to pharmacological prophylaxis. Of the 192 patients receiving prophylaxis, 84% received pharmacological prophylaxis, 14% mechanical prophylaxis and 2% combined prophylaxis. Low molecular weight heparin was the only pharmacological prophylaxis used, with a majority use of enoxaparin (17 of 18 ICUs). In patients with mechanical prophylaxis (31/192), antiembolic stockings were the most commonly used option (58%). Pharmacological prophylaxis contraindications were reported in 20% of the patients (46/234), the most frequent cause being thrombocytopenia (28% of the cases). Fifty percent of the ICUs used no specific venous thromboembolic prophylaxis protocol. Pharmacological prophylaxis with low molecular weight heparin was the most frequently used venous thromboembolic prophylactic measure. In patients with contraindications to pharmacological prophylaxis, mechanical measures were little used. The use of combined prophylaxis was anecdotal. Many of our ICUs lack specific prophylaxis protocols. Copyright © 2013 Elsevier España, S.L. and SEMICYUC. All rights reserved.

One step minilaparotomy-assisted transmesenteric portal vein recanalization combined with transjugular intrahepatic portosystemic shunt placement: A novel surgical proposal in pediatrics

PubMed Central

Pelizzo, Gloria; Quaretti, Pietro; Moramarco, Lorenzo Paolo; Corti, Riccardo; Maestri, Marcello; Iacob, Giulio; Calcaterra, Valeria

2017-01-01

Transjugular intrahepatic portosystemic shunt (TIPS) placement is a standard procedure for the treatment of portal hypertension complications. When this conventional approach is not feasible, alternative procedures for systemic diversion of portal blood have been proposed. A one-step interventional approach, combining minilaparotomy-assisted transmesenteric (MAT) antegrade portal recanalization and TIPS, is described in an adolescent with recurrent esophageal varice bleeding and portal cavernoma (PC). A 16-year-old girl was admitted to our Unit because of repeated bleeding episodes over a short period of time due to esophageal varices in the context of a PC. A portal vein recanalization through an ileocolic vein isolation with the MAT approach followed by TIPS during the same session was performed. In the case of failed portal recanalization, this approach, would also be useful for varice endovascular embolization. Postoperative recovery was uneventful. Treatment consisting of propanolol, enoxaparin and a proton pump inhibitor was prescribed after the procedure. One month post-op, contrast enhanced computed tomography confirmed the patency of the portal and intrahepatic stent grafts. No residual peritoneal fluid was detected nor opacification of the large varices. Endoscopy showed good improvement of the varices. Doppler ultrasound confirmed the accelerated flow in the portal stent and hepatopetal flow inside the intrahepatic portal branches. Three months post-op, TIPS maintained its hourglass shape despite a slight expansion. Portal hypertension and life threatening conditions related to PC would benefit from one-step portal recanalization. MAT-TIPS is feasible and safe for the treatment of PC even in children. This minimally invasive procedure avoids or delays surgical treatment or re-transplantation when necessary in pediatric patients. PMID:28487619

Are pharmacological properties of anticoagulants reflected in pharmaceutical pricing and reimbursement policy? Out-patient treatment of venous thromboembolism and utilization of anticoagulants in Poland.

PubMed

Bochenek, T; Czarnogorski, M; Nizankowski, R; Pilc, A

2014-06-01

Pharmacotherapy with vitamin K antagonists (VKA) and low-molecular-weight heparins (LMWH) is a major cost driver in the treatment of venous thromboembolism (VTE). Major representatives of anticoagulants in Europe include: acenocoumarol and warfarin (VKA), enoxaparin, dalteparin, nadroparin, reviparin, parnaparin and bemiparin (LMWH). Aim of this report is to measure and critically assess the utilization of anticoagulants and other resources used in the out-patient treatment of VTE in Poland. To confront the findings with available scientific evidence on pharmacological and clinical properties of anticoagulants. The perspectives of the National Health Fund (NHF) and the patients were adopted, descriptive statistics methods were used. The data were gathered at the NHF and the clinic specialized in treatment of coagulation disorders. Non-pharmacological costs of treatment were for the NHF 1.6 times higher with VKA than with LMWH. Daily cost of pharmacotherapy with LMWH turned out higher than with VKA (234 times for the NHF, 42 times per patient). Within both LMWH and VKA the reimbursement due for the daily doses of a particular medication altered in the manner inversely proportional to the level of patient co-payment. Utilization of long-marketed and cheap VKA was dominated by LMWH, when assessed both through the monetary measures and by the actual volume of sales. Pharmaceutical reimbursement policy favored the more expensive equivalents among VKA and LMWH, whereas in the financial terms the patients were far better off when remaining on a more expensive alternative. The pharmaceutical pricing and reimbursement policy of the state should be more closely related to the pharmacological properties of anticoagulants.

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.

Thromboprophylaxis and VTE rates in soldiers wounded in Operation Enduring Freedom and Operation Iraqi Freedom.

PubMed

Holley, Aaron B; Petteys, Sarah; Mitchell, Joshua D; Holley, Paul R; Collen, Jacob F

2013-09-01

US soldiers suffer catastrophic injuries during combat. We sought to define risk factors and rates for VTE in this population. We gathered data each hospital day on all patients injured in Afghanistan or Iraq who were admitted to the Walter Reed Army Medical Center (WRAMC). We analyzed prophylaxis rates and efficacy and identified risk factors for VTE. We recorded data on 506 combat casualties directly admitted to WRAMC after medical air evacuation. The average injury severity score for the group was 18.4 ± 11.7, and the most common reason for air evacuation was injury by improvised explosive device (65%). As part of the initial resuscitation, patients received 4.7 ± 9.0 and 4.00 ± 7.8 units of packed RBCs and fresh frozen plasma, respectively, and 42 patients received factor VIIa. Forty-six patients (9.1%) were given a diagnosis of VTE prior to discharge, 18 (3.6%) during air evacuation, and 28 (5.5%) during the hospital stay. In Cox regression analysis, administration of 1 unit of packed RBCs was associated with a hazard ratio (HR) of 1.04 (95% CI, 1.02-1.07; P = .002), and enoxaparin, 30 mg bid, administered subcutaneously for the majority of hospital days was associated with a HR of 0.31 (95% CI, 0.11-0.86; P = .02) for VTE during the hospitalization. Patients who suffer traumatic injuries in combat overseas are at high risk for VTE during evacuation and recovery. Those with large resuscitations are at particularly high risk, and low-molecular-weight heparin is associated with a decrease in VTE.

[Prophylactic use of a recombinant activated factor VII in delivery haemorrhage by caesarean in a woman with major factor VII deficiency: a case report].

PubMed

Comes, Jean-François; Devignes, Jean; Thiebaugeorges, Olivier; Briquel, Marie-Elisabeth; Lecompte, Thomas

2011-01-01

Taking in charge the delivery of pregnant women with inherited major deficiency of factor VII (FVII) is poorly reported in literature. We report here the haemorrhagic prophylaxis of delivery by recombinant activated FVII (rFVIIa) in a 27-year-old women, gravida 1, para 0, with major deficiency FVII by missense mutation (p.Arg337Cys). Her parents, first germen, presented a FVII deficiency. She has four brothers and three sisters, of which only one brother has major FVII deficiency with hemorrhagic diathesis in childhood (hematochezia). At her birth, because of dystocia, a right sterno-cleido-mastoid muscle hematoma and left clavicle fracture occurred. The FVII concentration was 0.08 U/mL. At the age of fifteen, a surgery of appendicitis was performed with substitution by FVII from plasma donors without any haemorrhagic complication. Because of anatomic specificity (bifid uterus and vagina), caesarean was planned. After reviewing of the literature, caesarean was performed at 38th week of gestation with haemorrhagic prophylaxis consisting in administration of rFVIIa (eptacog alfa) at a dose of 20 μg/kg, 30 min before surgery, then every 3 h during 48 h. No haemorrhagic complication occurred. Thrombosis prophylaxis was ensured by enoxaparin (4000 UI a day subcutaneously started 6 h after surgery for 5 days). Clinical examination of the newborn was normal. In future, modalities of taking in charge have to be evaluated by prospective studies involving a sufficiently numerous group of woman with FVII major deficiency, or by retrospective studies with the means of national or European registers.

Initial Experience of the American Society of Regional Anesthesia and Pain Medicine Coags Regional Smartphone Application: A Novel Report of Global Distribution and Clinical Usage of an Electronic Decision Support Tool to Enhance Guideline Use.

PubMed

Gupta, Rajnish K; McEvoy, Matthew D

2016-01-01

Decision support tools have been demonstrated to improve adherence to medical guidelines; however, smartphone applications (apps) have not been studied in this regard. In a collaboration between Vanderbilt University and the American Society of Regional Anesthesia and Pain Medicine (ASRA), the ASRA Coags Regional app was created to be a decision support tool for the 2010 published guideline on regional anesthesia for patients receiving anticoagulation. This is a review of the distribution and usage of this app. The app was created to be a user-friendly version of the guideline. Download statistics were collected from April 2014 to October 2015, and app usage data were collected from October 2014 to October 2015. Usage data were analyzed for number of devices, number of search sessions, medications searched, and types of procedures. There were 8381 downloads, with 83% from North America. Of users who allowed data tracking, 4504 unique devices were identified with 30,003 separate search events. The most searched-for medications were rivaroxaban (n = 4427; 11%), clopidogrel (n = 4042; 10%), and enoxaparin, prophylactic twice daily dosing (n = 3249; 8%). Neuraxial procedures (n = 22,477; 78%) were the most commonly searched-for procedures and over half (n = 22,773; 52%) the users were interested in how long to hold a medication before performing a procedure. This is the first publication of download and usage data concerning medical smartphone apps. It provides a template for future app uptake and use in clinical practice. The app platform provides a new mechanism of rapidly disseminating guidelines and facilitating distribution of frequent updates.

Impact of a quality-assessment dashboard on the comprehensive review of pharmacist performance.

PubMed

Trinh, Long D; Roach, Erin M; Vogan, Eric D; Lam, Simon W; Eggers, Garrett G

2017-09-01

The impact of a quality-assessment dashboard and individualized pharmacist performance feedback on the adherence of order verification was evaluated. A before-and-after study was conducted at a 1,440-bed academic medical center. Adherence of order verification was defined as orders verified according to institution-derived, medication-related guidelines and policies. Formulas were developed to assess the adherence of verified orders to dosing guidelines using patient-specific height, weight, and serum creatinine clearance values from the electronic medical record at the time of pharmacist verification. A total of 5 medications were assessed by the formulas for adherence and displayed on the dashboard: ampicillin-sulbactam, ciprofloxacin, piperacillin-tazobactam, acyclovir, and enoxaparin. Adherence of order verification was assessed before (May 1-July 31, 2015) and after (November 1, 2015-January 31, 2016) individualized performance feedback was given based on trends identified by the quality-assessment dashboard. There was a significant increase in the overall adherence rate postintervention (90.1% versus 91.9%, p = 0.040). Among the 34 pharmacists who participated, the percentage of pharmacists with at least 90% overall adherence increased postintervention (52.9% versus 70.6%, p = 0.103). Time to verification was similar before and after the study intervention (median, 6.0 minutes; interquartile range, 3-13 minutes). The rate of documentation for nonadherent orders increased significantly postintervention (57.1% versus 68.5%, p = 0.019). The implementation of the quality-assessment dashboard, educational sessions, and individualized performance feedback significantly improved pharmacist order-verification adherence to institution-derived, medication-related guidelines and policies and the documentation rate of nonadherent orders. Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Comparison of the CoaguChek XS handheld coagulation analyzer and conventional laboratory methods measuring international normalised ratio (INR) values during the time to therapeutic range after mechanical valve surgery.

PubMed

Bardakci, Hasmet; Altıntaş, Garip; Çiçek, Omer Faruk; Kervan, Umit; Yilmaz, Sevinc; Kaplan, Sadi; Birincioglu, Cemal Levent

2013-05-01

To compare the international normalised ratio (INR) value of patients evaluated using the CoaguChek XS versus conventional laboratory methods, in the period after open-heart surgery for mechanical valve replacement until a therapeutic range is achieved using vitamin K antagonists (VKA) together with low molecular weight heparin (LMWH). One hundred and five patients undergoing open-heart surgery for mechanical valve replacement were enrolled. Blood samples were collected from patients before surgery, and on the second and fifth postoperative days, simultaneously for both the point of care device and conventional laboratory techniques. Patients were administered VKA together with LMWH at therapeutic doses (enoxaparin 100 IU/kg twice daily) subcutaneously, until an effective range was achieved on approximately the fifth day after surgery. The mean INR values using the CoaguChek XS preoperatively and on the second and fifth days postoperatively were 1.20 (SD ± 0.09), 1.82 (SD ± 0.45), and 2.55 (SD ± 0.55), respectively. Corresponding results obtained using conventional laboratory techniques were 1.18 (SD ± 0.1), 1.81 (SD ± 0.43), and 2.51 (SD ± 0.58). The correlation coefficient was r = 0.77 preoperatively, r = 0.981 on postoperative day 2, and r = 0.983 on postoperative day 5. Results using the CoaguChek XS Handheld Coagulation Analyzer correlated strongly with conventional laboratory methods, in the bridging period between open-heart surgery for mechanical valve replacement and the achievement of a therapeutic range on warfarin and LMWH. © 2013 Wiley Periodicals, Inc.

Comparison of thromboprophylaxis patterns in arthroplasty in public and private hospitals

PubMed Central

Cortada, Aline Pinheiro dos Santos; da Silva, Telma Gomes; da Silva, André Campos; Golmia, Ricardo Prado; Guerra, Renata Leborato; Takemoto, Maíra Libertad Soligo; Monteiro, Roberta Dyonisio Canaveira; Scheinberg, Morton Aaron

2015-01-01

Objective To compare therapy for prophylaxis of venous thromboembolism and costs related to hospitalization of patients undergoing total knee and hip replacement within the context of the Brazilian health system. Methods A retrospective study of patients undergoing arthroplasty in 2010 in a public hospital and two private hospitals in the state of São Paulo, conducted by means of medical record review. Costs were estimated based on the use of health care resources during hospitalization. A descriptive analysis was performed using frequency and mean (standard deviation) according to the type of care delivered (by public or private organization). Results A total of 215 patients were evaluated, and 56.3% were submitted to knee surgery and 43.7%, to hip replacement. Approximately 88% and 98% of patients from public and private health services, respectively, received some form of venous thromboembolism prophylaxis, and enoxaparin was the drug most widely used in both systems. The total cost of prophylaxis was R$ 1,873.01 (R$ 26.38 per patient) in the public service and R$ 21,559.73 (R$ 163.33 per patient) in the private service. For the individuals who presented with thromboembolism, the average cost of hospitalization was R$ 6,210.80 and R$ 43,792.59 per patient in public and private health services, respectively. Conclusion Thromboembolism prophylaxis in patients undergoing arthroplasty is most commonly used in the private health services than public organizations, despite its high costs in both services. The cost per patient with thrombosis during hospitalization was higher than the total cost of prophylaxis, suggesting that prevention is associated to better cost-benefit ratio. PMID:26313439

Is bariatric surgery safe in patients who refuse blood transfusion?

PubMed

Kitahama, Seiichi; Smith, Mark D; Rosencrantz, David R; Patterson, Emma J

2013-01-01

A small, but significant, number of patients undergoing bariatric surgery refuse blood transfusion for religious or other personal reasons. Jehovah's Witnesses number more than 1 million members in the United States alone. The reported rates of hemorrhage vary from .5% to 4% after bariatric surgery, with transfusion required in one half of these cases. Pharmacologic prophylaxis against venous thromboembolism could further increase the perioperative bleeding risk. Our objective was to report the perioperative outcomes of bariatric surgery who refuse blood transfusion at a bariatric center of excellence, private practice in the United States. A retrospective review of all patients who refused blood transfusion when undergoing bariatric surgery during a 10-year period was conducted. Patients were identified from a prospectively maintained database by the bloodless surgery program at Legacy Good Samaritan Hospital. Data were collected on demographics, co-morbidities, laboratory values, medication use, blood loss, and 30-day complications. Thirty-five bloodless surgery patients underwent bariatric surgery from 2000 to 2009. Of these 35 patients, 21 underwent laparoscopic adjustable gastric banding and 14 Roux-en-Y gastric bypass. Before 2006, only pneumatic compression devices were applied for venous thromboembolism prophylaxis (n = 6). Subsequently, combination venous thromboembolism prophylaxis was performed with fondaparinux sodium 2.5 mg for RYGB or enoxaparin 40 mg for LAGB (n = 29). One RYGB patient developed postoperative hemorrhage requiring reoperation. No venous thromboembolisms or deaths occurred. Bariatric surgery can be performed in patients who refuse blood transfusion with acceptable postoperative morbidity. Larger studies are necessary to confirm the safety of this approach and to examine the effect of pharmacologic thromboprophylaxis in this patient group. Copyright © 2013 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

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.

Self-aggregation of cationically modified poly(ε-caprolactone)2-co-poly(ethylene glycol) copolymers: Effect of cationic grafting ligand and poly(ε-caprolactone) chain length.

PubMed

Charoongchit, Pimchanok; Suksiriworapong, Jiraphong; Sripha, Kittisak; Mao, Shirui; Sapin-Minet, Anne; Maincent, Philippe; Junyaprasert, Varaporn Buraphacheep

2017-03-01

Cationic copolymers have been attractive to investigate due to their potential to complexation with anionic drugs and expected to use in the pharmaceutical application. In this study, the modified poly(ε-caprolactone) 2 -co-poly(ethylene glycol) copolymers (P(CL) 2 -PEG) were successfully synthesized by click reaction. The amount of small molecular cationic ligand, propargyltrimethyl ammonium iodide, was varied and grafted onto various mole ratios of P(CL) to PEG. The effects of P(CL) chain length and amount of the grafting cationic ligand on physicochemical properties of polymers and particles were studied. The number-average molecular weights of the copolymers grafted with cationic ligand were found ranging between 10,000 and 23,000g/mol as investigated by NMR. From DSC study, the results showed that the grafting ligand affected thermal behaviors of the copolymers by increasing the glass transition temperature and decreasing the melting temperature of the copolymers. Furthermore, these cationic copolymers could self-aggregate with their critical aggregation concentration depending on mole ratios of hydrophilic to hydrophobic portions. The particles containing higher amounts of the cationic ligand tended to aggregate in both acidic and basic pH environment and at high salt concentration. Additionally, particle size, size distribution (PdI), and morphology of self-assembling particles varied depending on P(CL) chain length and the amount of the grafting cationic ligand. The synthesized cationic copolymer showed a capability to encapsulate a high negatively charged drug, enoxaparin, with an encapsulation efficiency of 87%. After drug incorporation, the particles substantially changed in size, shape, PdI, and zeta potential to become more suitable for drug delivery. These cationic copolymers with flexible properties will be the candidate for further development as carriers for the delivery of negatively charged drugs. Copyright © 2016. Published by Elsevier B.V.

Venous thromboembolism after major venous injuries: Competing priorities.

PubMed

Frank, Brian; Maher, Zoё; Hazelton, Joshua P; Resnick, Shelby; Dauer, Elizabeth; Goldenberg, Anna; Lubitz, Andrea L; Smith, Brian P; Saillant, Noelle N; Reilly, Patrick M; Seamon, Mark J

2017-12-01

Venous thromboembolism (VTE) after major vascular injury (MVI) is particularly challenging because the competing risk of thrombosis and embolization after direct vessel injury must be balanced with risk of bleeding after surgical repair. We hypothesized that venous injuries, repair type, and intraoperative anticoagulation would influence VTE formation after MVI. A multi-institution, retrospective cohort study of consecutive MVI patients was conducted at three urban, Level I centers (2005-2013). Patients with MVI of the neck, torso, or proximal extremities (to elbows/knees) were included. Our primary study endpoint was the development of VTE (DVT or pulmonary embolism [PE]). The 435 major vascular injury patients were primarily young (27 years) men (89%) with penetrating (84%) injuries. When patients with (n = 108) and without (n = 327) VTE were compared, we observed no difference in age, mechanism, extremity injury, tourniquet use, orthopedic and spine injuries, damage control, local heparinized saline, or vascular surgery consultation (all p > 0.05). VTE patients had greater Injury Severity Score (ISS) (17 vs. 12), shock indices (1 vs. 0.9), and more torso (58% vs. 35%) and venous (73% vs. 48%) injuries, but less often received systemic intraoperative anticoagulation (39% vs. 53%) or postoperative enoxaparin (47% vs. 61%) prophylaxis (all p < 0.05). After controlling for ISS, hemodynamics, injured vessel, intraoperative anticoagulation, and postoperative prophylaxis, multivariable analysis revealed venous injury was independently predictive of VTE (odds ratio, 2.7; p = 0.002). Multivariable analysis of the venous injuries subset (n = 237) then determined that only delay in starting VTE chemoprophylaxis (odds ratio, 1.3/day; p = 0.013) independently predicted VTE after controlling for ISS, hemodynamics, injured vessel, surgical subspecialty, intraoperative anticoagulation, and postoperative prophylaxis. Overall, 3.4% of venous injury patients developed PE, but PE rates were not related to their operative management (p = 0.72). Patients with major venous injuries are at high risk for VTE, regardless of intraoperative management. Our results support the immediate initiation of postoperative chemoprophylaxis in patients with major venous injuries. Therapeutic/care management, level IV.

Dual Antiplatelet Therapy Does Not Increase the Risk of Bleeding After Carotid Endarterectomy: Results of a Prospective Study.

PubMed

Illuminati, Giulio; Schneider, Fabrice; Pizzardi, Giulia; Masci, Federica; Calio', Francesco G; Ricco, Jean-Baptiste

2017-04-01

The purpose of this study was to evaluate the risk of bleeding and other postoperative complications of carotid endarterectomy (CEA) in patients receiving dual antiplatelet therapy (DAPT). From January 2005 to December 2015, 188 consecutive patients undergoing CEA and receiving DAPT (aspirin 100 mg + clopidogrel 75 mg) were enrolled in a prospective study. All of them underwent coronary artery stenting with drug-eluting stents during the 6 months preceding CEA. In the entire series, DAPT was continued until the evening before CEA and resumed on the evening of the operation. All patients received intraoperative heparinization (5,000 IU before carotid clamping), which was reversed in 5 patients. In addition, all of them were given 2,000 units of enoxaparin every 12 hr after the operation, beginning 6 hr after completion of the operation, and until discharge. All the patients presented with carotid artery stenosis >70% (North American Symptomatic Carotid Endarterectomy Trial [NASCET] criteria), which was symptomatic in 42 patients (transient ischemic attack, n = 32; minor stroke, n = 10) and asymptomatic in 146. The CEA technique was standard, with prosthetic patch closure in 109 cases (58%) and eversion in 79 (42%). The primary endpoints of the study were occurrence of a postoperative cervical hematoma requiring surgical hemostasis and occurrence of cranial nerve injuries. The secondary endpoint was the combined rate of postoperative mortality, stroke, and myocardial ischemia. No postoperative cervical hematoma requiring surgical evacuation occurred in this series. One hypoglossal nerve palsy, regressive within 2 weeks, was observed. Postoperative mortality and neurologic and cardiac morbidity were nil. CEA under DAPT yields results comparable with those obtained in patients receiving a single antiplatelet treatment. No hemorrhagic complications were observed in this prospective series. Copyright © 2017 Elsevier Inc. All rights reserved.

Is thromboprophylaxis cost effective in ovarian hyperstimulation syndrome: A systematic review and cost analysis.

PubMed

Wormer, Kelly Comerford; Jangda, Ayesha A; El Sayed, Farah A; Stewart, Katherine I; Mumford, Sunni L; Segars, James H

2018-05-01

The majority of serious thromboembolic events occurring in assisted reproductive technologies (ART) are in women with ovarian hyperstimulation syndrome (OHSS). The purpose of this study was to present a thorough review and cost analysis regarding the use of venous thromboembolism (VTE) prophylaxis in OHSS to inform clinical management. Databases used were Pubmed and Embase, in addition to checking reference lists of retrieved articles (inception to November 2017). The systematic search strategy identified 365 titles and abstracts. Articles included in the qualitative synthesis had identified venous thrombosis incidence rates or ratios. A separate search for the cost model was conducted recognizing all associated complications of VTE. The decision tree was modeled to best fit the patient population and a sensitivity analysis was performed over a range of variables. The cost of VTE event per OHSS patient not on prophylaxis was €5940 (range €3405 to €38,727), versus €4134 (€2705 to €23,192) per event per patient on prophylaxis, amounting to a saving of (€19 to €23,192) per VTE per patient. Sensitivity analysis found VTE prophyaxis to be cost effective if the incidence of VTE in the OHSS population was greater than 2.79%. Prophylactic therapy was cost effective through 16 weeks of treatment. OHSS is infrequent and hence, the incidence of VTE in patients with OHSS is low; therefore, the data used to inform the incidence of VTE in OHSS in the model carry some uncertainty. Further, low molecular weight heparin (LMWH) has side effects therefore individualization of care must be considered. With the increasing incidence of infertility and requirement for ART, thromboembolism in OHSS poses a major health threat for patients. VTE prophylaxis using enoxaparin was cost effective in patients with severe OHSS over a wide range of costs and incidences. Prophylaxis was also cost effective through the completion of the first trimester of pregnancy. Copyright © 2018 Elsevier B.V. All rights reserved.

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.

Pharmacy Malpractice: The rate and prevalence of dispensing high-risk prescription-only medications at community pharmacies in Saudi Arabia.

PubMed

Alshammari, Thamir M; Alhindi, Salman A; Alrashdi, Ahmed M; Benmerzouga, Imaan; Aljofan, Mohamad

2017-07-01

To assess the compliance of community pharmacies with the regulations that prohibit the dispensing of prescription-only medications in the absence of a physician prescription in Saudi Arabia. A cross-sectional study was conducted in the period between October 2014 and January 2015. A list of 10 prescription-only medications were selected to be studied. 150 community pharmacies were visited across 6 major regions in Saudi Arabia to assess the prevalence of non-compliance among community pharmacies. Pharmacies were selected in random and researchers (disguised as patients) requested to purchase prescription-only medications in the absence of a prescription. Not all medications were purchased at once. Data were recorded per pharmacy, where pharmacies that approved dispense of the selected drug were scored as non-compliant and the pharmacies that rejected dispense of the selected drug were scored as compliant. Compliance rate was calculated per region per drug. Pharmacies based in governmental hospitals were visited in parallel. A total of 20 were visited. Data and statistical analysis were performed using Statistical Analyses Software (SAS 9.3). A total of 150 pharmacies were visited over a period of 3 months. On average, the percent approved dispense of prescription-only drugs across 6 regions in Saudi Arabia is 63% and the percent rejected dispense is 37% representing a significant non-compliance rate regarding the selected list of medications in this study. The frequency of dispense per medication across 6 major regions in Saudi Arabia is as follows: Isosorbide dinitrate (86%), Enoxaparin (82%), nitroglycerin (74%), Propranolol (73%), Verapamil (70%), Warfarin (65%), Methyldopa (64%), Ciprofloxacin (57%) and Codeine (4%). Non-compliance of community pharmacies with the law of pharmaceutical practice is at an alarming rate in the Kingdom of Saudi Arabia and authoritative figures must intervene to impede and combat such activities .

Percutaneous closure of the left atrial appendage for prevention of thromboembolism in atrial fibrillation for patients with contraindication to or failure of oral anticoagulation: a single-center experience.

PubMed

Faustino, Ana; Paiva, Luís; Providência, Rui; Trigo, Joana; Botelho, Ana; Costa, Marco; Leitão-Marques, António

2013-06-01

In non-valvular atrial fibrillation 90% of thrombi originate in the left atrial appendage (LAA). Percutaneous LAA closure has been shown to be non-inferior to warfarin for prevention of thromboembolism. To evaluate the initial experience of a single center in percutaneous LAA closure in patients with high thromboembolic risk and in whom oral anticoagulation was impractical or contraindicated or had failed. Patients with non-valvular atrial fibrillation and CHADS2 score ≥2 in whom oral anticoagulation was impractical or contraindicated or had failed underwent percutaneous LAA closure according to the standard technique. After the procedure, dual antiplatelet therapy was maintained for one month, followed by single antiplatelet therapy indefinitely. Patients were followed by clinical assessment and transthoracic and transesophageal echocardiography. The procedure was performed in 22 of the 23 selected patients (95.7%), mean age 70±9 years, CHADS2 score 3.2±0.9 and CHA2DS2-VASC score 4.7±1.4. Intraprocedural device replacement was necessary only in the first patient, due to oversizing. The following periprocedural complications were observed: one femoral pseudoaneurysm, three femoral hematomas and two minor oropharyngeal bleeds, resolved by local hemostatic measures. During a 12±8 month follow-up a mild peri-device flow and a thrombus adhering to the device, resolved under with enoxaparin therapy, were identified. The rate of transient ischemic attack (TIA)/stroke was lower than expected according to the CHADS2 score (0 vs. 6.7±2.2%). In our initial experience, this procedure proved to be a feasible, safe and effective alternative for atrial fibrillation patients in whom oral anticoagulation is not an option. Only relatively minor complications were observed, with a lower than expected TIA/stroke rate. Copyright © 2012 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Risk factors for deep vein thrombosis and pulmonary embolism after traumatic injury: A competing risks analysis.

PubMed

Van Gent, Jan-Michael; Calvo, Richard Yee; Zander, Ashley L; Olson, Erik J; Sise, C Beth; Sise, Michael J; Shackford, Steven R

2017-12-01

Venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism (PE), is typically reported as a composite measure of the quality of trauma center care. Given that recent data suggesting postinjury DVT and PE are distinct clinical processes, a better understanding may result from analyzing them as independent, competing events. Using competing risks analysis, we evaluated our hypothesis that the risk factors and timing of postinjury DVT and PE are different. We examined all adult trauma patients admitted to our Level I trauma center from July 2006 to December 2011 who received at least one surveillance duplex ultrasound of the lower extremities and who were at high risk or greater for DVT. Outcomes included DVT and PE events, and time-to-event from admission. We used competing risks analysis to evaluate risk factors for DVT while accounting for PE as a competing event, and vice versa. Of 2,370 patients, 265 (11.2%) had at least one venous thromboembolism event, 235 DVT only, 19 PE only, 11 DVT and PE. Within 2 days of admission, 38% of DVT cases had occurred compared with 26% of PE. Competing risks modeling of DVT as primary event identified older age, severe injury (Injury Severity Score, ≥ 15), mechanical ventilation longer than 4 days, active cancer, history of DVT or PE, major venous repair, male sex, and prophylactic enoxaparin and prophylactic heparin as associated risk factors. Modeling of PE as the primary event showed younger age, nonsevere injury (Injury Severity Score, < 15), central line placement, and prophylactic heparin as relevant factors. The risk factors for PE and DVT after injury were different, suggesting that they are clinically distinct events that merit independent consideration. Many DVT events occurred early despite prophylaxis, bringing into question the preventability of postinjury DVT. We recommend trauma center quality reporting program measures be revised to account for DVT and PE as unique events. Epidemiologic, level III.

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.).

Tinzaparin sodium: a review of its pharmacology and clinical use in the prophylaxis and treatment of thromboembolic disease.

PubMed

Cheer, Susan M; Dunn, Christopher J; Foster, Rachel

2004-01-01

Tinzaparin sodium (tinzaparin; innohep) is a low molecular weight heparin (LMWH) formed by the enzymatic degradation of porcine unfractionated heparin (UFH). In clinical trials, once-daily subcutaneous (SC) tinzaparin was effective and generally well tolerated in the prophylaxis and treatment of thromboembolic disease. SC tinzaparin 75 anti-Xa IU/kg/day showed similar thromboprophylactic efficacy to adjusted-dosage oral warfarin in patients undergoing total hip arthroplasty; in patients undergoing knee replacement, the incidence of deep vein thrombosis (DVT) was significantly lower with tinzaparin. The drug had similar efficacy to equivalent-dosage SC enoxaparin sodium in orthopaedic surgery. In patients undergoing general surgery, SC tinzaparin 3500 anti-Xa IU/day was of equivalent thromboprophylactic efficacy to SC UFH 5000IU twice daily. Encouraging preliminary results have been obtained with tinzaparin in the prevention of DVT in patients with complete motor paralysis. In the initial treatment of acute proximal DVT and pulmonary embolism, SC tinzaparin 175 anti-Xa IU/kg/day was at least as effective as adjusted-dosage intravenous (IV) UFH. In the outpatient treatment of venous thromboembolism, tinzaparin has demonstrated similar efficacy to dalteparin sodium (dalteparin) and warfarin. Tinzaparin was effective in preventing clotting in haemodialysis circuits; the anticoagulant efficacy of tinzaparin in patients undergoing haemodialysis was similar to that of SC dalteparin and similar to or less than (although in this case the tinzaparin dose was too low for sufficient anticoagulant efficacy) that of IV UFH. Advantages of tinzaparin over UFH and warfarin include ease of administration and lack of need for laboratory monitoring. Tinzaparin is more cost effective than UFH in the treatment of established thromboembolic disease, and home-based treatment with tinzaparin may offer greater cost benefits than hospital-based therapy. Tinzaparin is well tolerated, including in elderly patients and those with renal impairment receiving long-term treatment. Incidences of major bleeding complications were low and reports of heparin-induced thrombocytopenia were infrequent in clinical studies. In conclusion, tinzaparin is a valuable LMWH in the prophylaxis and management of thromboembolic disease.

Stent thrombosis and bleeding complications after implantation of sirolimus-eluting coronary stents in an unselected worldwide population: a report from the e-SELECT (Multi-Center Post-Market Surveillance) registry.

PubMed

Urban, Philip; Abizaid, Alexandre; Banning, Adrian; Bartorelli, Antonio L; Baux, Ana Cebrian; Džavík, Vladimír; Ellis, Stephen; Gao, Runlin; Holmes, David; Jeong, Myung Ho; Legrand, Victor; Neumann, Franz-Josef; Nyakern, Maria; Spaulding, Christian; Worthley, Stephen

2011-03-29

The aim of this study was to ascertain the 1-year incidence of stent thrombosis (ST) and major bleeding (MB) in a large, unselected population treated with sirolimus-eluting stents (SES). Stent thrombosis and MB are major potential complications of drug-eluting stent implantation. Their relative incidence and predisposing factors among large populations treated worldwide are unclear. The SES were implanted in 15,147 patients who were entered in a multinational registry. We analyzed the incidence of: 1) definite and probable ST as defined by the Academic Research Consortium; and 2) MB, with the STEEPLE (Safety and efficacy of Enoxaparin in PCI) definition, together with their relation to dual antiplatelet therapy (DAPT) and to 1-year clinical outcomes. The mean age of the sample was 62 ± 11 years, 30.4% were diabetic, 10% had a Charlson comorbidity index ≥3, and 44% presented with acute coronary syndrome or myocardial infarction. At 1 year, the reported compliance with DAPT as recommended by the European Society of Cardiology guidelines was 86.3%. Adverse event rates were: ST 1.0%, MB 1.0%, mortality 1.7%, myocardial infarction 1.9%, and target lesion revascularization 2.3%. Multivariate analysis identified 9 correlates of ST and 4 correlates of MB. Advanced age and a high Charlson index were associated with an increased risk of both ST and MB. After ST, the 7-day and 1-year all-cause mortality was 30% and 35%, respectively, versus 1.5% and 10% after MB. Only 2 of 13,749 patients (0.015%) experienced both MB and ST during the entire 1-year follow-up period. In this worldwide population treated with ≥1 SES, the reported compliance with DAPT was good, and the incidence of ST and MB was low. Stent thrombosis and MB very rarely occurred in the same patient. (The e-SELECT Registry: a Multicenter Post-Market Surveillance; NCT00438919). Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

The perioperative management of an inferior vena caval tumor thrombus in patients with renal cell carcinoma.

PubMed

Woodruff, Daniel Y; Van Veldhuizen, Peter; Muehlebach, Gregory; Johnson, Phillip; Williamson, Timothy; Holzbeierlein, Jeffrey M

2013-07-01

Inferior vena caval tumor thrombus (IVC-TT) occurs in 10% of patients diagnosed with renal cell carcinoma (RCC). The perioperative management of these patients remains challenging. Despite multiple publications outlining surgical approaches and outcomes there have been few studies detailing the best peri-operative management of patients with IVC-TT. Our goal was to define the optimal management of patients with RCC and IVC-TT. A review of all published literature regarding the management of RCC with IVC-TT was performed utilizing Pub Med and the Cochrane Database. Reviews were also made of all relevant literature regarding the need for cardiopulmonary bypass and recommendations regarding thrombus in any location in patients with malignancy. Specific items critically examined included: need for preoperative heart catheterization, need for anticoagulation and type of anticoagulation, need for additional studies such as lower extremity duplex or venogram, and indications for vena caval filter placement. The results were then presented to a multidisciplinary group made up of experts in the fields of Urology, Hematology, Oncology, Cardiothoracic Surgery, Interventional Radiology, and Pulmonary/Critical Care. Based on the available literature a best practice guidelines regarding the management of RCC with IVC-TT was established at our institution. Our institutional recommendations include (1) preoperative cardiac catheterization in all patients believed to require cardiopulmonary bypass for removal of the thrombus but only cardiac clearance for those who bypass is unlikely, (2) preoperative anticoagulation using a low molecular weight heparin such as enoxaparin unless contraindicated due to bleeding from the tumor or other contraindication, (3) avoidance of vena caval filters whenever possible is recommended due the potential for caval thrombosis and the difficulties they present during surgical resection. This study identified the available literature on the management of IVC-TT in association with RCC and was carefully reviewed by a multidisciplinary team. As a result, we have established a set of practice guidelines at our institution to help optimally manage patients with renal cell carcinoma and an inferior venal caval thrombus. Copyright © 2013 Elsevier Inc. All rights reserved.

The effect anticoagulation status on geriatric fall trauma patients.

PubMed

Coleman, Julia; Baldawi, Mustafa; Heidt, David

2016-12-01

This research study aims to identify the effect of anticoagulation status on hospital course, complications, and outcomes among geriatric fall trauma patients. The study design is a retrospective cohort study, looking at fall trauma among patients aged 60 to 80 years from 2009 to 2013 at a university hospital in the United States. The statistical analysis, conducted with SPSS software with a threshold for statistical significance of P < .05, was stratified by anticoagulation status and then further by type of anticoagulation (aspirin, warfarin, clopidogrel, enoxaparin, and dipyridamole). Outcomes variables include mortality, length of stay (LOS), intensive care unit (ICU) admission, and complications. The total number of patients included in this study was 1,121. Compared with patients not on anticoagulation, there was a higher LOS among patients on anticoagulation (6.3 ± 6.2 vs 4.9 ± 5.2, P = .001). A higher LOS (7.2 ± 6.8 vs 5.0 ± 5.3, P = .001) and days in the ICU (2.1 ± 5.4 vs 1.1 ± 3.8, P = .010) was observed in patients on warfarin. A higher mortality (7.1% vs 2.8%, P = .013), LOS (6.3 ± 6.2 vs 5.1 ± 5.396, P = .036), and complication rate (49.1 vs 36.7, P = .010) was observed among patients on clopidogrel. In this study, a higher mortality and complication rate were seen among clopidogrel, and a greater LOS and number of days in the ICU were seen in patients on warfarin. These differences are important, as they can serve as a screening tool for triaging the severity of a geriatric trauma patient's condition and complication risk. For patients on clopidogrel, it is essential that these patients are recognized early as high-risk patients who will need to be monitored more closely. For patients on clopidogrel or warfarin, bridging a patient's anticoagulation should be initiated as soon as possible to prevent unnecessary increased LOS. At last, these data also provide support against prescribing patients clopidogrel when other anticoagulation options are available. Published by Elsevier Inc.

Prospective Randomized Trial of Enoxaparin, Pentoxifylline and Ursodeoxycholic Acid for Prevention of Radiation-Induced Liver Toxicity

PubMed Central

Seidensticker, Max; Seidensticker, Ricarda; Damm, Robert; Mohnike, Konrad; Pech, Maciej; Sangro, Bruno; Hass, Peter; Wust, Peter; Kropf, Siegfried; Gademann, Günther; Ricke, Jens

2014-01-01

Background/Aim Targeted radiotherapy of liver malignancies has found to be effective in selected patients. A key limiting factor of these therapies is the relatively low tolerance of the liver parenchyma to radiation. We sought to assess the preventive effects of a combined regimen of pentoxifylline (PTX), ursodeoxycholic acid (UDCA) and low-dose low molecular weight heparin (LMWH) on focal radiation-induced liver injury (fRILI). Methods and Materials Patients with liver metastases from colorectal carcinoma who were scheduled for local ablation by radiotherapy (image-guided high-dose-rate interstitial brachytherapy) were prospectively randomized to receive PTX, UDCA and LMWH for 8 weeks (treatment) or no medication (control). Focal RILI at follow-up was assessed using functional hepatobiliary magnetic resonance imaging (MRI). A minimal threshold dose, i.e. the dose to which the outer rim of the fRILI was formerly exposed to, was quantified by merging MRI and dosimetry data. Results Results from an intended interim-analysis made a premature termination necessary. Twenty-two patients were included in the per-protocol analysis. Minimal mean hepatic threshold dose 6 weeks after radiotherapy (primary endpoint) was significantly higher in the study treatment-group compared with the control (19.1 Gy versus 14.6 Gy, p = 0.011). Qualitative evidence of fRILI by MRI at 6 weeks was observed in 45.5% of patients in the treatment versus 90.9% of the control group. No significant differences between the groups were observed at the 12-week follow-up. Conclusions The post-therapeutic application of PTX, UDCA and low-dose LMWH significantly reduced the extent and incidence fRILI at 6 weeks after radiotherapy. The development of subsequent fRILI at 12 weeks (4 weeks after cessation of PTX, UDCA and LMWH during weeks 1–8) in the treatment group was comparable to the control group thus supporting the observation that the agents mitigated fRILI. Trial Registration EU clinical trials register 2008-002985-70 ClinicalTrials.gov NCT01149304 PMID:25393877

Association of non-steroidal anti-inflammatory drugs with outcomes in patients with ST-segment elevation myocardial infarction treated with fibrinolytic therapy: an ExTRACT-TIMI 25 analysis.

PubMed

Gibson, C Michael; Pride, Yuri B; Aylward, Philip E; Col, Jacques J; Goodman, Shaun G; Gulba, Dietrich; Bergovec, Mijo; Kunadian, Vijayalakshmi; Zorkun, Cafer; Buros, Jacqueline L; Murphy, Sabina A; Antman, Elliott M

2009-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) may be prothrombotic, may worsen hypertension or congestive heart failure and obstruct access to the binding site of aspirin to cyclooxygenase-1 and thereby interfere with aspirin's mechanism of action in reducing death and recurrent myocardial infarction (MI). We hypothesized that treatment with NSAIDs prior to an index MI would be associated with an increase in the risk of death, heart failure and recurrent MI among patients with ST-segment elevation MI (STEMI) treated with fibrinolytic therapy. In ExTRACT-TIMI 25, patients with STEMI were treated with aspirin and fibrinolytic therapy and randomized to either enoxaparin or unfractionated heparin. We included patients who had received NSAIDs within 7 days of enrollment and evaluated the incidence of MI, the composite of death and MI and the composite of death, MI, severe heart failure and shock through 30 days. Of 20,479 patients enrolled, 572 (2.8%) received an NSAID within 7 days of enrollment. NSAID treatment prior to entry was associated with a higher incidence of 30-day death or nonfatal recurrent MI (15.9% vs. 10.8%, univariate P < 0.001). In multivariable models adjusting for randomization group and differences in baseline characteristics, NSAID use was associated with higher odds of MI (adjusted odds ratio [OR(adj)] 1.44, 95% confidence interval [CI] 1.01-2.07, P = 0.047), the composite of death and MI (OR(adj) 1.29, 95% CI 1.00-1.66, P = 0.051), and the composite of death, MI, severe heart failure and shock (OR(adj) 1.29, 95% CI 1.02-1.65, P = 0.037). Among STEMI patients treated with a fibrinolytic agent and aspirin, use of NSAIDs in the week preceding the incident event was associated with a higher incidence of MI, the composite of death and MI as well as the composite of death, MI, severe heart failure and shock at 30 days.

Death Associated with Inadequate Reassessment of Venous Thromboembolism Prophylaxis at and after Hospital Discharge.

PubMed

2015-01-01

Venous thromboembolism (VTE) prophylaxis, also known as thromboprophylaxis, reduces the risk of deep vein thrombosis, pulmonary embolism, and associated complications, including death, in high-risk patients. VTE prophylaxis is recommended for acutely ill, hospitalized medical patients at risk of thrombosis. Anticoagulants, the pharmacologic agents of choice to prevent VTE, are considered high-alert medications. By definition, therefore, anticoagulants bear a hightened risk of causing significant patient harm when they are used in error. As part of ongoing collaboration with a provincial death investigation service, ISMP Canada received a report of a fatal incident that involved continuation of VTE prophylaxis with enoxaparin for a patient discharge to a long-term care (LTC) facility from an acute care setting. The findings and recommendations from this case are charged to highlight the need to build routine reassessment of VTE prophylaxis into the process for discharging patients from the acute care setting and upon transfer to another facility or to primary care. The incident described in this bulletin highlights the importance of continually reassessing the need for VTE prophylaxis, especially at transitions of care, such as discharge from an acute care setting. Evidence and guidelines confirm the benefits of VTE prophylaxis in certain patients during a hospital stay for an acute illness, but the balance of benefits and risks may become unfavourable once the patient is discharged. Clear documentation from the acute care facility can assist the receiving facility and health-care providers, as well as family caregivers, when determining whether thromboprophylaxis is still warranted. Until clear guidance to continue thromboprophylaxis after acute care is available, health-care organizations and practitioners across the spectrum of care are urged to share and consider the strategies presented in this bulletin to ensure the safe use of VTE prophylaxis and improved communication among health-care providers. ISMP Canada will be integrating the learning from this case in an update of the Hospital-Self-Assessment for Anticoagulant Safety. This assessment is available on a complimentary basis to all facilities across Canada after sign up at HTTPS://mssa.ismp-canada.org/hsasas/.

Prognostic Significance of Bleeding Location and Severity Among Patients With Acute Coronary Syndromes

PubMed Central

Vavalle, John P.; Clare, Robert; Chiswell, Karen; Rao, Sunil V.; Petersen, John L.; Kleiman, Neal S.; Mahaffey, Kenneth W.; Wang, Tracy Y.

2013-01-01

Objectives This study sought to determine if there is an association between bleed location and clinical outcomes in acute coronary syndromes (ACS) patients. Background The prognostic significance of bleeding location among ACS patients undergoing cardiac catheterization is not well known. Methods We analyzed in-hospital bleeding events among 9,978 patients randomized in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) study. Bleeding events were categorized by location as access site, systemic, surgical, or superficial, and severity was graded using the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definition. We assessed the association of each bleeding location and severity with 6-month risk of death or myocardial infarction using a multicovariate-adjusted Cox proportional hazard model. Results A total of 4,900 bleeding events were identified among 3,694 ACS patients with in-hospital bleeding. Among 4,679 GUSTO mild/moderate bleeding events, only surgical and systemic bleeds were associated with an increased risk of 6-month death or myocardial infarction (adjusted hazard ratio [HR]: 2.52 [95% confidence interval (CI): 2.16 to 2.94, and 1.40 [95% CI: 1.16 to 1.69], respectively). Mild/moderate superficial and access-site bleeds were not associated with downstream risk (adjusted HR: 1.17 [95% CI: 0.97 to 1.40], and 0.96 [95% CI: 0.82 to 1.12], respectively). Among 221 GUSTO severe bleeds, surgical bleeds were associated with the highest risk (HR: 5.27 [95% CI: 3.80 to 7.29]), followed by systemic (HR: 4.48 [95% CI: 2.98 to 6.72]), and finally access-site bleeds (HR: 3.57 [95% CI: 2.35 to 5.40]). Conclusions Among ACS patients who develop in-hospital bleeding, systemic and surgical bleeding are associated with the highest risks of adverse outcomes regardless of bleeding severity. Although the most frequent among bleeds, GUSTO mild/moderate access-site bleeding is not associated with increased risk. These data underscore the importance of strategies to minimize overall bleeding risk beyond vascular access site management. PMID:23866183

Economic evaluation of bivalirudin with or without glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for early invasive management of acute coronary syndromes.

PubMed

Pinto, Duane S; Stone, Gregg W; Shi, Chunxue; Dunn, Elizabeth S; Reynolds, Matthew R; York, Meghan; Walczak, Joshua; Berezin, Ronna H; Mehran, Roxana; McLaurin, Brent T; Cox, David A; Ohman, E Magnus; Lincoff, A Michael; Cohen, David J

2008-11-25

The aim of this study was to determine the economic impact of several anticoagulation strategies for moderate- and high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients managed invasively. The ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial demonstrated that bivalirudin monotherapy yields similar rates of ischemic complications and less bleeding than regimens incorporating glycoprotein IIb/IIIa receptor inhibitors (GPI) for moderate- and high-risk NSTE-ACS. In ACUITY, 7,851 U.S. patients were randomized to: 1) heparin (unfractionated or enoxaparin) + GPI; 2) bivalirudin + GPI; or 3) bivalirudin monotherapy. Patients assigned to GPI were also randomized to upstream GPI before catheterization or selective GPI only with percutaneous coronary intervention. Resource use data were collected prospectively through 30-day follow-up. Costs were estimated with standard methods including resource-based accounting, hospital billing data, and the Medicare fee schedule. At 30 days, ischemic events were similar for all groups. Major bleeding was reduced with bivalirudin monotherapy compared with heparin + GPI or bivalirudin + GPI (p < 0.001). Length of stay was lowest with bivalirudin monotherapy or bivalirudin + catheterization laboratory GPI (p = 0.02). Despite higher drug costs, aggregate hospital stay costs were lowest with bivalirudin monotherapy (mean difference range: $184 to $1,081, p < 0.001 for overall comparison) and at 30 days (mean difference range: $123 to $938, p = 0.005). Regression modeling demonstrated that hospital savings were primarily due to less major and minor bleeding with bivalirudin ($8,658/event and $2,282/event, respectively). Among U.S. patients in the ACUITY trial, bivalirudin monotherapy compared with heparin + GPI resulted in similar protection from ischemic events, reduced bleeding, and shorter length of stay. Despite higher drug costs, aggregate hospital and 30-day costs were lowest with bivalirudin monotherapy. Thus bivalirudin monotherapy seems to be an economically attractive alternative to heparin + GPI for patients with moderate- and high-risk NSTE-ACS. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS]; NCT00093158).

Tissue factor-expressing monocytes inhibit fibrinolysis through a TAFI-mediated mechanism, and make clots resistant to heparins

PubMed Central

Semeraro, Fabrizio; Ammollo, Concetta T.; Semeraro, Nicola; Colucci, Mario

2009-01-01

Background Thrombin is the main activator of the fibrinolysis inhibitor TAFI (thrombin activatable fibrinolysis inhibitor) and heightened clotting activation is believed to impair fibrinolysis through the increase of thrombin activatable fibrinolysis inhibitor activation. However, the enhancement of thrombin generation by soluble tissue factor was reported to have no effect on plasma fibrinolysis and it is not known whether the same is true for cell-associated tissue factor. The aim of this study was to evaluate the effect of tissue factor-expressing monocytes on plasma fibrinolysis in vitro. Design and Methods Tissue factor expression by human blood mononuclear cells (MNC) and monocytes was induced by LPS stimulation. Fibrinolysis was spectrophotometrically evaluated by measuring the lysis time of plasma clots containing LPS-stimulated or control cells and a low concentration of exogenous tissue plasminogen activator. Results LPS-stimulated MNC (LPS-MNC) prolonged fibrinolysis time as compared to unstimulated MNC (C-MNC) in contact-inhibited but not in normal citrated plasma. A significantly prolonged lysis time was observed using as few as 30 activated cells/μL. Fibrinolysis was also impaired when clots were generated on adherent LPS-stimulated monocytes. The antifibrinolytic effect of LPS-MNC or LPS-monocytes was abolished by an anti-tissue factor antibody, by an antibody preventing thrombin-mediated thrombin activatable fibrinolysis inhibitor activation, and by a TAFIa inhibitor (PTCI). Assays of thrombin and TAFIa in contact-inhibited plasma confirmed the greater generation of these enzymes in the presence of LPS-MNC. Finally, the profibrinolytic effect of unfractionated heparin and enoxaparin was markedly lower (~50%) in the presence of LPS-MNC than in the presence of a thromboplastin preparation displaying an identical tissue factor activity. Conclusions Our data indicate that LPS-stimulated monocytes inhibit fibrinolysis through a tissue factor-mediated enhancement of thrombin activatable fibrinolysis inhibitor activation and make clots resistant to the profibrinolytic activity of heparins, thus providing an additional mechanism whereby tissue factor-expressing monocytes/macrophages may favor fibrin accumulation and diminish the antithrombotic efficacy of heparins. PMID:19377079

Measuring Anti–Factor Xa Activity to Monitor Low-Molecular-Weight Heparin in Obesity: A Critical Review

PubMed Central

Egan, Gregory; Ensom, Mary H H

2015-01-01

Background: The choice of whether to monitor anti–factor Xa (anti-Xa) activity in patients who are obese and who are receiving low-molecular-weight heparin (LMWH) therapy is controversial. To the authors’ knowledge, no systematic review of monitoring of anti-Xa activity in such patients has been published to date. Objective: To systematically ascertain the utility of monitoring anti-Xa concentrations for LMWH therapy in obese patients. Data Sources: MEDLINE (1946 to September 2014), the Cochrane Database of Systematic Reviews, Embase (1974 to September 2014), PubMed (1947 to September 2014), International Pharmaceutical Abstracts (1970 to September 2014), and Scopus were searched using the terms obesity, morbid obesity, thrombosis, venous thrombosis, embolism, venous thromboembolism, pulmonary embolism, low-molecular weight heparin, enoxaparin, dalteparin, tinzaparin, anti-factor Xa, anti-factor Xa monitoring, anti-factor Xa activity, and anti-factor Xa assay. The reference lists of retrieved articles were also reviewed. Study Selection and Data Extraction: English-language studies describing obese patients treated with LMWH or reporting anti-Xa activity were reviewed using a 9-step decision-making algorithm to determine whether monitoring of LMWH therapy by means of anti-Xa activity in obesity is warranted. Studies published in abstract form were excluded. Data Synthesis: The analysis showed that anti-Xa concentrations are not strongly associated with thrombosis or hemorrhage. In clinical studies of LMWH for thromboprophylaxis in bariatric surgery, orthopedic surgery, general surgery, and medical patients, and for treatment of venous thrombo embolism and acute coronary syndrome, anti-Xa activity can be predicted from dose of LMWH and total body weight; no difference in clinical outcome was found between obese and non-obese participants. Conclusions: Routinely determining anti-Xa concentrations in obese patients to monitor the clinical effectiveness of LMWH is not warranted on the basis of the current evidence. Circumstances where measurement of anti-Xa concentration may help in clinical decision-making in either obese or non-obese patients would be cases where elimination of LMWH is impaired or there is an unexpected clinical response, as well as to confirm compliance with therapy or to identify deviation from predicted pharmacokinetics. PMID:25762818

Determination of the molecular weight of low-molecular-weight heparins by using high-pressure size exclusion chromatography on line with a triple detector array and conventional methods.

PubMed

Bisio, Antonella; Mantegazza, Alessandra; Vecchietti, Davide; Bensi, Donata; Coppa, Alessia; Torri, Giangiacomo; Bertini, Sabrina

2015-03-19

The evaluation of weight average molecular weight (Mw) and molecular weight distribution represents one of the most controversial aspects concerning the characterization of low molecular weight heparins (LMWHs). As the most commonly used method for the measurement of such parameters is high performance size exclusion chromatography (HP-SEC), the soundness of results mainly depends on the appropriate calibration of the chromatographic columns used. With the aim of meeting the requirement of proper Mw standards for LMWHs, in the present work the determination of molecular weight parameters (Mw and Mn) by HP-SEC combined with a triple detector array (TDA) was performed. The HP-SEC/TDA technique permits the evaluation of polymeric samples by exploiting the combined and simultaneous action of three on-line detectors: light scattering detectors (LALLS/RALLS); refractometer and viscometer. Three commercial LMWH samples, enoxaparin, tinzaparin and dalteparin, a γ-ray depolymerized heparin (γ-Hep) and its chromatographic fractions, and a synthetic pentasaccharide were analysed by HP-SEC/TDA. The same samples were analysed also with a conventional HP-SEC method employing refractive index (RI) and UV detectors and two different chromatographic column set, silica gel and polymeric gel columns. In both chromatographic systems, two different calibration curves were built up by using (i) γ-Hep chromatographic fractions and the corresponding Mw parameters obtained via HP-SEC/TDA; (ii) the whole γ-Hep preparation with broad Mw dispersion and the corresponding cumulative distribution function calculated via HP-SEC/TDA. In addition, also a chromatographic column calibration according to European Pharmacopoeia indication was built up. By comparing all the obtained results, some important differences among Mw and size distribution values of the three LMWHs were found with the five different calibration methods and with HP-SEC/TDA method. In particular, the detection of the lower molecular weight components turned out to be the most critical aspect. Whereas HP-SEC/TDA may underestimate species under 2 KDa when present in low concentration, other methods appeared to emphasize their content.

Antiphospholipid Syndrome with Antiβ2glicoprotein-1 Antibodies as the Cause of Recurrent Tibial Vein Thrombosis in SAPHO syndrome.

PubMed

Przepiera-Będzak, Hanna; Brzosko, Marek

2016-12-01

The antiphospholipid antibody syndrome is defined by the presence of antiphospholipid antibodies in patients with recurrent venous or arterial thromboembolism (1). SAPHO syndrome is a rare disease, characterized by specific clinical manifestations of synovitis, acne pustulosis, hyperostosis, and osteitis. It is a disease that manifests with a combination of osseous and articular manifestations associated with skin lesions (2). Venous thrombosis complicating SAPHO syndrome seems to be uncommon with an unclear pathogenesis (3-9). Coexistence of antiphospholipid syndrome and SAPHO syndrome was not previously mentioned in literature. A 33-year-old white woman was diagnosed with SAPHO syndrome at the age of 31. The patient was previously diagnosed with polycystic ovary syndrome and depressive syndrome. She was treated with sulfasalazin (2 g daily) and methotrexate (20 mg weekly). Seven months before admission to our department she experienced an episode of deep vein thrombosis of the left leg, successfully treated with subcutaneous enoxaparin sodium (40 mg daily) that was continued for the following 6 months as secondary prophylaxis. Pustular skin changes on palmar surface of the hands and plantar surface of the feet (characteristic for palmo-plantar pustulosis), tenderness of sterno-clavicular joints, swelling and restricted motion of both wrists, and pain on motion in both elbows, shoulders, knees, and ankles were found on physical examination. There was also a moderate amount of effusion in her left knee. There was a 3-centimeter difference between the circumferences of the shins. The level of C reactive protein was increased (6.21 mg/L). The patient was positive for antiβ2glicoprotein-1 (anti-β2G-1) antibodies. Tests for anticardiolipin antibodies (aCL), antiannexin V antibodies, antiphosphatidylserine antibodies (aPS), and antiprothrombin antibodies (aPT) were negative. Prothrombin time, activated partial thromboplastin time, and D-dimer level were normal, and lupus anticoagulant was not present. Serum concentrations of protein C, protein S, factor V Leiden, and antiprothrombin III levels were normal. Tests for antinuclear antibodies, rheumatoid factor, and HLA-27 antigen were negative. Serum vascular endothelial growth factor (VEGF) level was 360 pg/mL, serum epidermal growth factor (EGF) level was 566 pg/mL. Bacteria culture of discharge from pustules was negative. Doppler ultrasound examination of the left leg confirmed thrombosis of one the posterior tibial veins at its lower third. Subcutaneous enoxaparin sodium was started and later replaced with acenocumarol. The dose of sulfasalazin was increased to 3.0 g daily, and azithromycin 1.0 g daily once a week (for 8 weeks) was added. After 3 months, the patient reported reduction of joint pain. The follow-up Doppler ultrasound examination of the left leg revealed resolution of thrombosis. Three months later, the anti-β2G-1 antibodies were positive, so the patient met the criteria of antiphospholipid syndrome (1). The treatment with acenocumarol was continued and hydroxychlorochine was started. Venous thrombosis complicating SAPHO syndrome seems to be uncommon with an unclear pathogenesis. There were reports of thrombosis of the following veins: subclavian, mediastinan, iliac, and the superior vena cava (3-8). We have diagnosed recurrent tibial vein thrombosis in a patient with SAPHO syndrome in the course of antiphospholipid syndrome. There were suggestions that the reason for some cases of vein thrombosis in SAPHO syndrome is a pressure of the hyperostotic skeleton or inflamed soft tissue on the vein walls (3,4,6,10), which was not the case in our patient. Legoupil et al. (6) suggested that the reason for iliac vein thrombosis in SAPHO syndrome was an impressive extension of the inflammatory process to the soft tissues within the lumbar spine. That patient was negative for aCL antibodies (6). Kawabata et al. (7) suspected that aCL antibodies could be the reason for thrombosis in this syndrome, but the patient with multiple venous thrombosis presented in his case report was negative for aCL antibodies; however, he was not tested for anti-β2G-1 antibodies. There was a paper demonstrating increased level of aCL antibodies in 5 of 12 patients with SAPHO syndrome (11). In our observations of 17 patients with SAPHO syndrome, only 1 had increased level of aCL antibodies without symptoms of thrombosis (12). That patient was negative for aCL antibodies, aPT antibodies, aPS antibodies, and antiphosphatidylserine antibodies, but she was positive twice for anti-β2G-1 antibodies. The presence of anti-β2G-1antibodies may be caused by an infectious agent, but in our case bacteria culture of the discharge from pustules was negative. One year after the first episode of deep vein thrombosis, our patient met the criteria of antiphospholipid syndrome. We conclude that antiphospholipid syndrome, especially the presence of anti-β2G-1 antibodies, could be the cause of increased risk of vein thrombosis in SAPHO syndrome.

Acute Pulmonary Embolism in Emergency Department Patients Despite Therapeutic Anticoagulation.

PubMed

Liu, Michelle Y; Ballard, Dustin W; Huang, Jie; Rauchwerger, Adina S; Reed, Mary E; Bouvet, Sean C; Vinson, David R

2018-05-01

Emergency department (ED) patients with acute pulmonary embolism (PE) despite therapeutic anticoagulation at the time of diagnosis are uncommonly encountered and present a diagnostic and management challenge. Their characterization and outcomes are poorly described. We sought to describe the prevalence and characteristics of therapeutically anticoagulated patients among a population of patients with acute PE in a community setting and to describe treatment changes and 30-day outcomes. From a large retrospective cohort of adults with acute, objectively-confirmed PE across 21 EDs between 01/2013 and 04/2015, we identified patients who arrived on direct oral or injectable anticoagulants, or warfarin with an initial ED international normalized ratio (INR) value ≥2.0. Patients were excluded from the larger cohort if they had received a diagnosis of venous thromboembolism (VTE) in the prior 30 days. We gathered demographic and clinical variables from electronic health records and structured manual chart review. We report discharge anticoagulation regimens and major 30-day adverse outcomes. Among 2,996 PE patients, 36 (1.2%) met study criteria. Mean age was 63 years. Eleven patients (31%) had active cancer and 25 (69%) were high risk on the PE Severity Index (Classes III-V), comparable to the larger cohort (p>0.1). Reasons for pre-arrival anticoagulation were VTE treatment or prevention (n=21), and atrial fibrillation or flutter (n=15). All patients arrived on warfarin and one was also on enoxaparin: 32 had a therapeutic INR (2.0-3.0) and four had a supratherapeutic INR (>3.0). Fifteen patients (42%) had at least one subtherapeutic INR (<2.0) in the 14 days preceding their diagnostic visit. Two patients died during hospitalization. Of the 34 ultimately discharged, 22 underwent a change in anticoagulation drug or dosing, 19 of whom received injectables, either to replace or to supplement warfarin. Four patients also received inferior vena cava filters. Thirty-day outcomes included one major hemorrhage and one additional death. No patients experienced recurrent or worsening VTE. We found a low prevalence of therapeutic anticoagulation at the time of acute PE diagnosis. Most patients with breakthrough PE underwent a change in therapy, though management varied widely. Subtherapeutic anticoagulation levels in the preceding weeks were common and support the importance of anticoagulation adherence.

Acute Pulmonary Embolism in Emergency Department Patients Despite Therapeutic Anticoagulation

PubMed Central

Liu, Michelle Y.; Ballard, Dustin W.; Huang, Jie; Rauchwerger, Adina S.; Reed, Mary E.; Bouvet, Sean C.

2018-01-01

Introduction Emergency department (ED) patients with acute pulmonary embolism (PE) despite therapeutic anticoagulation at the time of diagnosis are uncommonly encountered and present a diagnostic and management challenge. Their characterization and outcomes are poorly described. We sought to describe the prevalence and characteristics of therapeutically anticoagulated patients among a population of patients with acute PE in a community setting and to describe treatment changes and 30-day outcomes. Methods From a large retrospective cohort of adults with acute, objectively-confirmed PE across 21 EDs between 01/2013 and 04/2015, we identified patients who arrived on direct oral or injectable anticoagulants, or warfarin with an initial ED international normalized ratio (INR) value ≥2.0. Patients were excluded from the larger cohort if they had received a diagnosis of venous thromboembolism (VTE) in the prior 30 days. We gathered demographic and clinical variables from electronic health records and structured manual chart review. We report discharge anticoagulation regimens and major 30-day adverse outcomes. Results Among 2,996 PE patients, 36 (1.2%) met study criteria. Mean age was 63 years. Eleven patients (31%) had active cancer and 25 (69%) were high risk on the PE Severity Index (Classes III–V), comparable to the larger cohort (p>0.1). Reasons for pre-arrival anticoagulation were VTE treatment or prevention (n=21), and atrial fibrillation or flutter (n=15). All patients arrived on warfarin and one was also on enoxaparin: 32 had a therapeutic INR (2.0–3.0) and four had a supratherapeutic INR (>3.0). Fifteen patients (42%) had at least one subtherapeutic INR (<2.0) in the 14 days preceding their diagnostic visit. Two patients died during hospitalization. Of the 34 ultimately discharged, 22 underwent a change in anticoagulation drug or dosing, 19 of whom received injectables, either to replace or to supplement warfarin. Four patients also received inferior vena cava filters. Thirty-day outcomes included one major hemorrhage and one additional death. No patients experienced recurrent or worsening VTE. Conclusion We found a low prevalence of therapeutic anticoagulation at the time of acute PE diagnosis. Most patients with breakthrough PE underwent a change in therapy, though management varied widely. Subtherapeutic anticoagulation levels in the preceding weeks were common and support the importance of anticoagulation adherence. PMID:29760849

High prevalence of hepatitis B-antibody loss and a case report of de novo hepatitis B virus infection in a child after living-donor liver transplantation

PubMed Central

Sintusek, Palittiya; Posuwan, Nawarat; Wanawongsawad, Piyaporn; Jitraruch, Suttiruk; Poovorawan, Yong; Chongsrisawat, Voranush

2018-01-01

AIM To assess the seroprevalence of hepatitis B virus (HBV) immunity among previously vaccinated pediatric liver transplant recipients and present a case report of de novo hepatitis B infection after liver transplantation. METHODS This study focused on children with chronic liver diseases who received primary hepatitis B immunization and had a complete dataset of anti-HBs before and after liver transplantation between May 2001 and June 2017. Medical records were retrospectively reviewed for potential factors relating to HBV immunity loss. RESULTS In total, 50 children were recruited. The mean time from liver transplantation to anti-HBs testing was 2.53 ± 2.11 years. The mean anti-HBs levels before and after liver transplantation were 584.41 ± 415.45 and 58.56 ± 6.40 IU/L, respectively. The rate of non-immunity (anti-HBs < 10 IU/L) in the participants was 46% (n = 26) at one year, 57% (n = 7) at two years and 82% (n = 17) at > three years following liver transplantation. The potential factors relating to HBV immunity loss after liver transplantation were identified as anti-HBs (P = 0.002), serum albumin (P = 0.04), total bilirubin (P = 0.001) and direct bilirubin (P = 0.003) before liver transplantation. A five-year-old boy with biliary cirrhosis received 4 doses of HBV vaccine with an anti-HBs titer of > 1000 IU/L and underwent liver transplantation; his anti-HBc-negative father was the donor. After liver transplantation, the boy had stenosis of the hepatic artery up to the inferior vena cava anastomosis and underwent venoplasty three times. He also received subcutaneous injections of enoxaparin for 5 mo and 20 transfusions of blood components. Three years and ten months after the liver transplantation, transaminitis was detected with positive tests for HBsAg, HBeAg, and anti-HBc (2169.61, 1706 and 8.45, respectively; cutoff value: < 1.00) and an HBV viral load of 33212320 IU/mL. CONCLUSION The present study showed that loss of hepatitis B immunity after liver transplantation is unexpectedly common. In our case report, despite high levels of anti-HBs prior to transplantation, infection occurred at a time when, unfortunately, the child had lost immunity to hepatitis B after liver transplantation. PMID:29456414

Major bleeding risks of different low-molecular-weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis.

PubMed

van Rein, N; Biedermann, J S; van der Meer, F J M; Cannegieter, S C; Wiersma, N; Vermaas, H W; Reitsma, P H; Kruip, M J H A; Lijfering, W M

2017-07-01

Essentials Low-molecular-weight-heparins (LMWH) kinetics differ which may result in different bleeding risks. A cohort of 12 934 venous thrombosis patients on LMWH was followed until major bleeding. The absolute major bleeding risk was low among patients registered at the anticoagulation clinic. Once-daily dosing was associated with a lower bleeding risk as compared with twice-daily. Background Low-molecular-weight heparins (LMWHs) are considered members of a class of drugs with similar anticoagulant properties. However, pharmacodynamics and pharmacokinetics between LMWHs differ, which may result in different bleeding risks. As these agents are used by many patients, small differences may lead to a large effect on numbers of major bleeding events. Objectives To determine major bleeding risks for different LMWH agents and dosing schedules. Methods A cohort of acute venous thrombosis patients from four anticoagulation clinics who used an LMWH and a vitamin K antagonist were followed until they ceased LMWH treatment or until major bleeding. Exposures were classified according to different types of LMWHs and for b.i.d. and o.d. use. Cumulative incidences for major bleeding per 1000 patients and risk ratios were calculated and adjusted for study center. Results The study comprised 12 934 patients with a mean age of 59 years; 6218 (48%) were men. The cumulative incidence of major bleeding was 2.5 per 1000 patients (95% confidence interval [CI], 1.7-3.5). Enoxaparin b.i.d. or o.d. was associated with a relative bleeding risk of 1.7 (95% CI, 0.2-17.5) compared with nadroparin o.d. In addition, a nadroparin b.i.d. dosing schedule was associated with a 2.0-fold increased major bleeding risk (95% CI, 0.8-5.1) as compared with a nadroparin o.d. dosing schedule. Conclusions Absolute major bleeding rates were low for all LMWH agents and dosing schedules in a large unselected cohort. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with an increased major bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials. © 2017 International Society on Thrombosis and Haemostasis.

Ovarian hyperstimulation syndrome in a spontaneous singleton pregnancy.

PubMed

Cabar, Fábio Roberto

2016-05-24

The ovarian hyperstimulation syndrome is the combination of increased ovarian volume, due to the presence of multiple cysts and vascular hyperpermeability, with subsequent hypovolemia and hemoconcentration. We report a case of spontaneous syndrome in a singleton pregnancy. This was a spontaneous pregnancy with 12 weeks of gestational age. The pregnancy was uneventful until 11 weeks of gestational age. After that, the pregnant woman complained of progressive abdominal distention associated with abdominal discomfort. She did not report other symptoms. In the first trimester, a routine ultrasonography showed enlarged ovaries, multiples cysts and ascites. Upon admission, the patient was hemodynamically stable, her serum β-hCG was 24,487mIU/mL, thyroid-stimulating hormone was 2.2µUI/mL and free T4 was 1.8ng/dL. All results were within normal parameters. However, levels of estradiol were high (10,562pg/mL). During hospitalization, she received albumin, furosemide and prophylactic dose of enoxaparin. The patient was discharged on the sixth hospital day. RESUMO A síndrome de hiperestimulação ovariana é a combinação do aumento dos ovários, devido à presença de múltiplos cistos e de hiperpermeabilidade vascular, com subsequente hipovolemia e hemoconcentração. Relata-se um caso de síndrome espontânea em uma gestação única. Trata-se de gravidez espontânea com 12 semanas de idade gestacional. A gravidez ocorreu sem intercorrências até 11 semanas de idade gestacional. Após, a gestante passou a se queixar de distensão abdominal progressiva, associada com desconforto abdominal. A paciente não relatava outros sintomas. A ultrassonografia de rotina no primeiro trimestre mostrou ovários aumentados com múltiplos cistos e ascite. No momento da internação, a paciente apresentava-se hemodinamicamente estável, com β-hCG sérico de 24.487mUI/mL, hormônio estimulante da tireoide de 2,2µUI/m e T4 livre de 1,8ng/dL, ou seja, valores dentro dos parâmetros normais. Porém, os níveis de estradiol estavam elevados (10.562pg/mL). Durante a internação, a paciente recebeu albumina, furosemida e enoxaparina profilática. A alta hospitalar ocorreu no sexto dia de internação.

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.

Subcutaneous Administration of Low-Molecular-Weight Heparin to Horses Inhibits Ex Vivo Equine Herpesvirus Type 1-Induced Platelet Activation

PubMed Central

Stokol, Tracy; Serpa, Priscila B. S.; Brooks, Marjory B.; Divers, Thomas; Ness, Sally

2018-01-01

Equine herpesvirus type 1 (EHV-1) is a major cause of infectious respiratory disease, abortion and neurologic disease. Thrombosis in placental and spinal vessels and subsequent ischemic injury in EHV-1-infected horses manifests clinically as abortion and myeloencephalopathy. We have previously shown that addition of heparin anticoagulants to equine platelet-rich plasma (PRP) can abolish ex vivo EHV-1-induced platelet activation. The goal of this study was to test whether platelets isolated from horses treated with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) were resistant to ex vivo EHV-1-induced activation. In a masked, block-randomized placebo-controlled cross-over trial, 9 healthy adult horses received 4 subcutaneous injections at q. 12 h intervals of one of the following treatments: UFH (100 U/kg loading dose, 3 maintenance doses of 80 U/kg), 2 doses of LMWH (enoxaparin) 80 U/kg 24 h apart with saline at the intervening 12 h intervals, or 4 doses of saline. Blood samples were collected before treatment and after 36 h, 40 h (4 h after the last injection) and 60 h (24 h after the last injection). Two strains of EHV-1, Ab4 and RacL11, were added to PRP ex vivo and platelet membrane expression of P selectin was measured as a marker of platelet activation. Drug concentrations were monitored in a Factor Xa inhibition (anti-Xa) bioassay. We found that LMWH, but not UFH, inhibited platelet activation induced by low concentrations (1 × 106 plaque forming units/mL) of both EHV-1 strains at 40 h. At this time point, all horses had anti-Xa activities above 0.1 U/ml (range 0.15–0.48 U/ml) with LMWH, but not UFH. By 60 h, a platelet inhibitory effect was no longer detected and anti-Xa activity had decreased (range 0.03 to 0.07 U/ml) in LMWH-treated horses. Neither heparin inhibited platelet activation induced by high concentrations (5 × 106 plaque forming units/mL) of the RacL11 strain. We found substantial between horse variability in EHV-1-induced platelet activation at baseline and after treatment. Minor injection site reactions developed in horses given either heparin. These results suggest that LMWH therapy may prevent thrombotic sequelae of EHV-1, however further evaluation of dosage regimens is required. PMID:29892605

SR-90107 (Sanofi-Synthélabo).

PubMed

Liu, F; Bagley, W P; Carroll, R C

2000-09-01

SR-90107 is a synthetic pentasaccharide heparinoid Factor Xa antagonist and thrombokinase inhibitor in joint development by Sanofi-Synthelabo (formerly Sanofi) and Organon as a potential treatment and prophylaxis for deep vein thrombosis (DVT) and symptomatic pulmonary embolism following hip or knee surgery and as a potential treatment for coronary artery diseases [330073,359231]. The compound is in phase III clinical trials for the prevention of DVT and pulmonary embolism; phase III trials for the treatment of DVT and pulmonary embolism were expected to start in the first quarter of 2000 and phase IIb trials in cardiology indications are also underway. NDAs are planned to be submitted in Europe and the US in the third quarter of 2000 for the prevention of DVT and symptomatic pulmonary embolism, in 2002 for the treatment of DVT and pulmonary embolism and in 2004 for the treatment of coronary artery diseases [359231]. DVT AND PULMONARY EMBOLISM: The compound had entered phase III clinical trials by December 1998 for the prevention of thrombosis [320585]. By February 2000, four phase III trials in the prevention of DVT and pulmonary embolism following orthopaedic surgery were underway: the European PENTHIFRA trial, which involves 1707 patients with hip fracture; the US PENTATHLON trial, which involves 2200 patients undergoing hip replacements; the European EPHESUS trial, which involves 2200 patients undergoing hip replacements; and the US PENTAMAKS trial, which involves 1000 patients undergoing major knee surgery [359231]. Clinical data from these trials are expected to be available by June 2000 [359793]. By February 2000, preparations were also being made for two phase III trials of SR-90107 for the treatment of DVT and pulmonary embolism, both expected to be initiated in the first quarter of 2000; the MATISSE DVT trial, a double-blind trial of SR-90107 versus enoxaparin sodium in 2200 patients; and the MATISSE PE trial, an open study of SR-90107 versus unfractionated heparin in 2200 patients [359231]. CORONARY ARTERY DISEASES: By February 2000, SR-90107 was also under development for unstable angina, percutaneous transluminal coronary angioplasty, and acute myocardial infarction. At this time, the phase IIb PENTALYSE trial in thrombolyzed acute myocardial infarction patients had been completed, demonstrating a good safety/efficacy ratio, and the phase IIb PENTUA trial in unstable angina was ongoing [359231]. In October 1999, Merrill Lynch forecast sales of EUR 180 million in 2003, planning a review of this figure once clinical data were available [346209]. Also in October 1999, Lehman Brothers predicted that the product had a 70% chance of reaching the market with potential peak sales of US 700 million dollars in 2008 [346267].

Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.

PubMed

Aujesky, Drahomir; Roy, Pierre-Marie; Verschuren, Franck; Righini, Marc; Osterwalder, Joseph; Egloff, Michael; Renaud, Bertrand; Verhamme, Peter; Stone, Roslyn A; Legall, Catherine; Sanchez, Olivier; Pugh, Nathan A; N'gako, Alfred; Cornuz, Jacques; Hugli, Olivier; Beer, Hans-Jürg; Perrier, Arnaud; Fine, Michael J; Yealy, Donald M

2011-07-02

Although practice guidelines recommend outpatient care for selected, haemodynamically stable patients with pulmonary embolism, most treatment is presently inpatient based. We aimed to assess non-inferiority of outpatient care compared with inpatient care. We undertook an open-label, randomised non-inferiority trial at 19 emergency departments in Switzerland, France, Belgium, and the USA. We randomly assigned patients with acute, symptomatic pulmonary embolism and a low risk of death (pulmonary embolism severity index risk classes I or II) with a computer-generated randomisation sequence (blocks of 2-4) in a 1:1 ratio to initial outpatient (ie, discharged from hospital ≤24 h after randomisation) or inpatient treatment with subcutaneous enoxaparin (≥5 days) followed by oral anticoagulation (≥90 days). The primary outcome was symptomatic, recurrent venous thromboembolism within 90 days; safety outcomes included major bleeding within 14 or 90 days and mortality within 90 days. We used a non-inferiority margin of 4% for a difference between inpatient and outpatient groups. We included all enrolled patients in the primary analysis, excluding those lost to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00425542. Between February, 2007, and June, 2010, we enrolled 344 eligible patients. In the primary analysis, one (0·6%) of 171 outpatients developed recurrent venous thromboembolism within 90 days compared with none of 168 inpatients (95% upper confidence limit [UCL] 2·7%; p=0·011). Only one (0·6%) patient in each treatment group died within 90 days (95% UCL 2·1%; p=0·005), and two (1·2%) of 171 outpatients and no inpatients had major bleeding within 14 days (95% UCL 3·6%; p=0·031). By 90 days, three (1·8%) outpatients but no inpatients had developed major bleeding (95% UCL 4·5%; p=0·086). Mean length of stay was 0·5 days (SD 1·0) for outpatients and 3·9 days (SD 3·1) for inpatients. In selected low-risk patients with pulmonary embolism, outpatient care can safely and effectively be used in place of inpatient care. Swiss National Science Foundation, Programme Hospitalier de Recherche Clinique, and the US National Heart, Lung, and Blood Institute. Sanofi-Aventis provided free drug supply in the participating European centres. Copyright © 2011 Elsevier Ltd. All rights reserved.

Experimentally gained insight - based proposal apropos the treatment of osteonecrosis of the femoral head.

PubMed

Boss, J H; Misselevich, I; Bejar, J; Norman, D; Zinman, C; Reis, D N

2004-01-01

An impeded blood flow through the femoral head is incriminated in the etiopathogenesis of osteonecrosis of the femoral head. The disorder is either primary (idiopathic avascular osteonecrosis) or secondary to one condition or another, say, corticosteroid medication, fracture of the neck, coagulation defects, physical or thermal damage, storage disorders, alcoholism, and infectious, autoimmune as also marrow infiltrating diseases. In the wake of the necrosis, several mediators are released in increased amounts, prime among which is the vascular endothelial growth factor. The intermediates recruit endothelial progenitor cells, macrophages, osteoclasts, fibroblasts, and osteoblasts, which, pervading throughout the necrotic areas, initiate the reparative processes. The dead, soft and hard tissular debris is substituted by fibrous - later on by hematopoietic-fatty tissue - and bone. The newly formed, appositional and intramembranous bone is deficient in its mechanical properties. The ordinary load-carrying functions suffice to deform these weakened femoral heads so that osteoarthritic changes develop. Considering contemporary assumptions of the causes of osteonecrosis, oxygenation, revascularization, and core decompression are the realistic therapeutic interventions. Necrosis of rats' femoral heads is studied as a model of osteonecrosis in both adults and children. In view of rodents' lifelong persisting physeal cartilage, vascular deprivation-induced osteonecrosis in rats mimics children's Perthes disease. The experimental model, which is well suited to test treatment modalities, has been used to investigate the effects of exposure to hyperbaric oxygen with and without non-weight bearing, medication of enoxaparin, and creation of an intraosseous conduit on the remodeling of the avascular necrotic femoral head. Intriguingly, the shape of treated rats' femoral heads is disfigured to a greater degree than that of untreated animals. This is most likely due to the reduced yield strength and elastic modulus as well as the raised strain-to-failure of the recently formed bone making up the post-necrotic femoral heads. It follows that expedited osteogenesis is, counter intuition, detrimental to maintaining the hemispherical shape of the femoral head, and thus to an articulation with congruent load-bearing surfaces. If this is indeed the case, the remodeling of the necrotic femoral head should be delayed, rather than sped up, as the present day paradigm would have it. Bearing in mind that the dead osseous structures keep their mechanical attributes for quite a while, a slowed down new bone formation would favor the gradual replacement of the necrotic by living bone. Therefore, management of the adult patients with osteonecrosis and children with Perthes disease should focus on a slowly progressive substitution so that the decline of the bone's mechanical properties is kept to a minimum. One viable therapeutic mode is a medication of inhibitors of the vascular endothelial growth factor.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-06-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate, fluvastatin sodium, fondaparinux sodium; Gaboxadol, gamma-hydroxybutyrate sodium, gefitinib, gelclair, gemcitabine, gemfibrozil, glibenclamide, glyminox; Haloperidol, heparin sodium, HPV 16/HPV 18 vaccine, human insulin, human insulin; Icatibant, imatinib mesylate, indium 111 (111In) ibritumomab tiuxetan, infliximab, INKP-100, iodine (I131) tositumomab, IoGen, ipratropium bromide, ixabepilone; L-870810, lamivudine, lapatinib, laquinimod, latanoprost, levonorgestrel, licochalcone a, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, lorazepam, lovastatin; Maraviroc, maribavir, matuzumab, MDL-100907, melphalan, methotrexate, methylprednisolone, mitomycin, mitoxantrone hydrochloride, MK-0431, MN-001, MRKAd5 HIV-1 gag/pol/nef, MRKAd5gag, MVA.HIVA, MVA-BN Nef, MVA-Muc1-IL-2, mycophenolate mofetil; Nelfinavir mesilate, nesiritide, NSC-330507; Olanzapine, olmesartan medoxomil, omalizumab, oral insulin, osanetant; PA-457, paclitaxel, paroxetine, paroxetine hydrochloride, PCK-3145, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, perillyl alcohol, pexelizumab, pimecrolimus, pitavastatin calcium, porfiromycin, prasterone, prasugrel, pravastatin sodium, prednisone, pregabalin, prinomastat, PRO-2000, propofol, prostate cancer vaccine; Rasagiline mesilate, rhBMP-2/ACS, rhBMP-2/BCP, rhC1, ribavirin, rilpivirine, ritonavir, rituximab, Ro-26-9228, rosuvastatin calcium, rosuvastatin sodium, rubitecan; Selodenoson, simvastatin, sirolimus, sitaxsentan sodium, sorafenib, SS(dsFv)-PE38, St. John's Wort extract, stavudine; Tacrolimus, tadalafil, tafenoquine succinate, talaglumetad, tanomastat, taxus, tegaserod maleate, telithromycin, tempol, tenofovir, tenofovir disoproxil fumarate, testosterone enanthate, TH-9507, thalidomide, tigecycline, timolol maleate, tiotropium bromide, tipifarnib, torcetrapib, trabectedin, travoprost, travoprost/timolol, treprostinil sodium; Valdecoxib, vardenafil hydrochloride hydrate, varenicline, VEGF-2 gene therapy, venlafaxine hydrochloride, vildagliptin, vincristine sulfate, voriconazole, VRX-496, VX-385; Warfarin sodium; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, zidovudine. Copyright (c) 2005 Prous Science. All rights reserved.

US Emergency Department Visits for Outpatient Adverse Drug Events, 2013-2014.

PubMed

Shehab, Nadine; Lovegrove, Maribeth C; Geller, Andrew I; Rose, Kathleen O; Weidle, Nina J; Budnitz, Daniel S

2016-11-22

The Patient Protection and Affordable Care Act of 2010 brought attention to adverse drug events in national patient safety efforts. Updated, detailed, nationally representative data describing adverse drug events can help focus these efforts. To describe the characteristics of emergency department (ED) visits for adverse drug events in the United States in 2013-2014 and describe changes in ED visits for adverse drug events since 2005-2006. Active, nationally representative, public health surveillance in 58 EDs located in the United States and participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project. Drugs implicated in ED visits. National weighted estimates of ED visits and subsequent hospitalizations for adverse drug events. Based on data from 42 585 cases, an estimated 4.0 (95% CI, 3.1-5.0) ED visits for adverse drug events occurred per 1000 individuals annually in 2013 and 2014 and 27.3% (95% CI, 22.2%-32.4%) of ED visits for adverse drug events resulted in hospitalization. An estimated 34.5% (95% CI, 30.3%-38.8%) of ED visits for adverse drug events occurred among adults aged 65 years or older in 2013-2014 compared with an estimated 25.6% (95% CI, 21.1%-30.0%) in 2005-2006; older adults experienced the highest hospitalization rates (43.6%; 95% CI, 36.6%-50.5%). Anticoagulants, antibiotics, and diabetes agents were implicated in an estimated 46.9% (95% CI, 44.2%-49.7%) of ED visits for adverse drug events, which included clinically significant adverse events, such as hemorrhage (anticoagulants), moderate to severe allergic reactions (antibiotics), and hypoglycemia with moderate to severe neurological effects (diabetes agents). Since 2005-2006, the proportions of ED visits for adverse drug events from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased. Among children aged 5 years or younger, antibiotics were the most common drug class implicated (56.4%; 95% CI, 51.8%-61.0%). Among children and adolescents aged 6 to 19 years, antibiotics also were the most common drug class implicated (31.8%; 95% CI, 28.7%-34.9%) in ED visits for adverse drug events, followed by antipsychotics (4.5%; 95% CI, 3.3%-5.6%). Among older adults (aged ≥65 years), 3 drug classes (anticoagulants, diabetes agents, and opioid analgesics) were implicated in an estimated 59.9% (95% CI, 56.8%-62.9%) of ED visits for adverse drug events; 4 anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated. Medications to always avoid in older adults according to Beers criteria were implicated in 1.8% (95% CI, 1.5%-2.1%) of ED visits for adverse drug events. The prevalence of emergency department visits for adverse drug events in the United States was estimated to be 4 per 1000 individuals in 2013 and 2014. The most common drug classes implicated were anticoagulants, antibiotics, diabetes agents, and opioid analgesics.

Enhancement of trophoblast differentiation and survival by low molecular weight heparin requires heparin-binding EGF-like growth factor.

PubMed

Bolnick, Alan D; Bolnick, Jay M; Kohan-Ghadr, Hamid-Reza; Kilburn, Brian A; Pasalodos, Omar J; Singhal, Pankaj K; Dai, Jing; Diamond, Michael P; Armant, D Randall; Drewlo, Sascha

2017-06-01

Does low molecular weight heparin (LMWH) require heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) signaling to induce extravillous trophoblast differentiation and decrease apoptosis during oxidative stress? LMWH increased HBEGF expression and secretion, and HBEGF signaling was required to stimulate trophoblast extravillous differentiation, increase invasion in vitro and reduce trophoblast apoptosis during oxidative stress. Abnormal trophoblast differentiation and survival contribute to placental insufficiency syndromes, including preeclampsia and intrauterine growth restriction. Preeclampsia often manifests as a pro-thrombotic state, with unsuccessful transformation of the spiral arteries that reduces oxygen supply and can produce placental infarction. LMWH improves placental function by increasing blood flow. Recent data suggest that the actions of LMWH transcend its anti-coagulative properties, but the molecular mechanism is unknown. There is evidence that LMWH alters the expression of human HBEGF in trophoblast cells, which regulates human trophoblast pathophysiology. HBEGF, itself, is capable of increasing trophoblast survival and invasiveness. First-trimester placental explants and the HTR-8/SVneo cell line, established using extravillous trophoblast outgrowths from first-trimester villous explants, were treated in vitro with LMWH to examine the effects on HBEGF signaling and trophoblast function under normal physiological and pathological conditions. A highly specific antagonist of HBEGF and other inhibitors of HBEGF downstream signaling were used to determine the relationship between LMWH treatment and HBEGF. Placental tissues (n = 5) were obtained with IRB approval and patient consent from first-trimester terminations. Placental explants and HTR-8/SVneo cells were cultured on plastic or Matrigel™ and treated with a therapeutic dose of LMWH (Enoxaparin; 10 IU/ml), with or without CRM197, pan Erb-B2 Receptor Tyrosine Kinase (ERBB) inhibitor, anti-ERBB1 or ERBB4 blocking antibodies, or pretreatment of cells with heparitinase I. Extravillous differentiation was assessed by immunocytochemistry to determine the relative levels of integrins α6β4 and α1β1. Trophoblast invasiveness was assessed in villous explants by measuring outgrowth from villous tips cultured on Matrigel, and by invasion assays with HTR-8/SVneo cells cultured on Matrigel-coated transwell insert. Placental explants and HTR-8/SVneo cells were exposed to oxidative stress in a hypoxia-reoxygenation (H-R) model, measuring cell death by TUNEL assay, caspase 3 cleavage, and BCL-2α expression. LMWH induced extravillous differentiation, according to trophoblast invasion assays and integrin (α6β4-α1β1) switching. Treatment with LMWH rescued cytotrophoblasts and HTR-8/SVneo cells from apoptosis during exposure to reoxygenation injury, based on TUNEL, caspase 3 cleavage and BCL-2α expression. Experiments using CRM197, ERBB1 and ERBB4 blocking antibodies, pan-ERBB inhibitor and removal of cell surface heparin demonstrated that the effects of LMWH on trophoblast invasion and survival were dependent upon HBEGF signaling. N/A. The primary limitation of this study was the use of only in vitro experiments. Patient demographics from elective terminations were not available. These data provide new insights into the non-coagulation-related aspects of perinatal LMWH treatment in the management of placental insufficiency disorders. This research was supported by grants from the National Institutes of Health (HD071408 and HL128628), the March of Dimes, and the W. K. Kellogg Foundation. There were no conflicts or competing interests. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Restoration of ovarian function and natural fertility following the cryopreservation and autotransplantation of whole adult sheep ovaries

PubMed Central

Campbell, B.K.; Hernandez-Medrano, J.; Onions, V.; Pincott-Allen, C.; Aljaser, F.; Fisher, J.; McNeilly, A.S.; Webb, R.; Picton, H.M.

2014-01-01

STUDY QUESTION Is it possible to restore ovarian function and natural fertility following the cryopreservation and autotransplantation of whole ovaries, complete with vascular pedicle, in adult females from a large monovulatory animal model species (i.e. sheep)? SUMMARY ANSWER Full (100%) restoration of acute ovarian function and high rates of natural fertility (pregnancy rate 64%; live birth rate 29%), with multiple live births, were obtained following whole ovary cryopreservation and autotransplantation (WOCP&TP) of adult sheep ovaries utilizing optimized cryopreservation and post-operative anti-coagulant regimes. WHAT IS KNOWN ALREADY Fertility preservation by WOCP&TP requires successful cryopreservation of both the ovary and its vascular supply. Previous work has indicated detrimental effects of WOCP&TP on the ovarian follicle population. Recent experiments suggest that these deleterious effects can be attributed to an acute loss of vascular patency due to clot formation induced by damage to ovarian arterial endothelial cells. STUDY DESIGN, SIZE, DURATION Study 1 (2010–2011; N = 16) examined the effect of post-thaw perfusion of survival factors (angiogenic, antioxidant, anti-apoptotic; n = 7–8) and treatment with aspirin (pre-operative versus pre- and post-operative (n = 7–9)) on the restoration of ovarian function for 3 months after WOCP&TP. Study 2 (2011–2012; N = 16) examined the effect of cryoprotectant (CPA) perfusion time (10 versus 60 min; n = 16) and pre- and post-operative treatment with aspirin in combination with enoxaparine (Clexane®; n = 8) or eptifibatide (Integrilin®; n = 8) on ovarian function and fertility 11–23 months after WOCP&TP. PARTICIPANTS/MATERIALS, SETTING, METHODS Both studies utilized mature, parous, Greyface ewes aged 3–6 years and weighing 50–75 kg. Restoration of ovarian function was monitored by bi-weekly blood sampling and display of behavioural oestrus. Blood samples were assayed for gonadotrophins, progesterone, anti-Müllerian Hormone and inhibin A. Fertility restoration in Study 2 was quantified by pregnancy rate after a 3 month fertile mating period and was confirmed by ultrasound, hormonal monitoring and live birth. Ovarian function was assessed at sacrifice by ovarian appearance and vascular patency (Doppler ultrasound) and by follicular histology. MAIN RESULTS AND THE ROLE OF CHANCE In Study 1, survival factors were found to have no benefit, but the inclusion of pre-operative aspirin resulted in four ewes showing acute restoration of ovarian function within 3 weeks and a further six ewes showing partial restoration. The addition of post-operative aspirin alone had no clear benefit. In Study 2, combination of aspirin with additional post-operative anti-coagulants resulted in total acute restoration of ovarian function in 14/14 ewes within 3 weeks of WOCP&TP, with 9/14 ewes becoming pregnant and 4/14 giving birth to a total of seven normal lambs. There was no difference between anti-coagulants in terms of restoration of reproductive function and fertility. In contrast, the duration of CPA perfusion was highly significant with a 60 min perfusion resulting in ovaries of normal appearance and function with high rates of primordial follicle survival (70%) and an abundant blood supply, whereas ovaries perfused for 10 min had either resorbed completely and were vestigial (7/14) or were markedly smaller (P < 0.01). It is concluded that both the degree of CPA penetration and the maintenance of post-operative vascular patency are critical determinants of the success of WOCP&TP. LIMITATIONS, REASONS FOR CAUTION Before application of this technology to fertility preservation patients, it will be critical to optimize the CPA perfusion time for different sized human ovaries, determine the optimum period and level of anti-coagulant therapy, and confirm the normality of offspring derived from this procedure. WIDER IMPLICATIONS OF THE FINDINGS This technology holds promise for the preservation of fertility in women. It could also potentially be applied to the cryopreservation of other reproductive or even major organs (kidneys) where there are considerable difficulties in storing donated tissue. STUDY FUNDING/COMPETING INTEREST(S) Funding was received from the Medical Research Council, University of Nottingham. The authors confirm that they have no conflict of interest in relation to this work. PMID:24939954

Restoration of ovarian function and natural fertility following the cryopreservation and autotransplantation of whole adult sheep ovaries.

PubMed

Campbell, B K; Hernandez-Medrano, J; Onions, V; Pincott-Allen, C; Aljaser, F; Fisher, J; McNeilly, A S; Webb, R; Picton, H M

2014-08-01

Is it possible to restore ovarian function and natural fertility following the cryopreservation and autotransplantation of whole ovaries, complete with vascular pedicle, in adult females from a large monovulatory animal model species (i.e. sheep)? Full (100%) restoration of acute ovarian function and high rates of natural fertility (pregnancy rate 64%; live birth rate 29%), with multiple live births, were obtained following whole ovary cryopreservation and autotransplantation (WOCP&TP) of adult sheep ovaries utilizing optimized cryopreservation and post-operative anti-coagulant regimes. Fertility preservation by WOCP&TP requires successful cryopreservation of both the ovary and its vascular supply. Previous work has indicated detrimental effects of WOCP&TP on the ovarian follicle population. Recent experiments suggest that these deleterious effects can be attributed to an acute loss of vascular patency due to clot formation induced by damage to ovarian arterial endothelial cells. Study 1 (2010-2011; N = 16) examined the effect of post-thaw perfusion of survival factors (angiogenic, antioxidant, anti-apoptotic; n = 7-8) and treatment with aspirin (pre-operative versus pre- and post-operative (n = 7-9)) on the restoration of ovarian function for 3 months after WOCP&TP. Study 2 (2011-2012; N = 16) examined the effect of cryoprotectant (CPA) perfusion time (10 versus 60 min; n = 16) and pre- and post-operative treatment with aspirin in combination with enoxaparine (Clexane(®); n = 8) or eptifibatide (Integrilin(®); n = 8) on ovarian function and fertility 11-23 months after WOCP&TP. Both studies utilized mature, parous, Greyface ewes aged 3-6 years and weighing 50-75 kg. Restoration of ovarian function was monitored by bi-weekly blood sampling and display of behavioural oestrus. Blood samples were assayed for gonadotrophins, progesterone, anti-Müllerian Hormone and inhibin A. Fertility restoration in Study 2 was quantified by pregnancy rate after a 3 month fertile mating period and was confirmed by ultrasound, hormonal monitoring and live birth. Ovarian function was assessed at sacrifice by ovarian appearance and vascular patency (Doppler ultrasound) and by follicular histology. In Study 1, survival factors were found to have no benefit, but the inclusion of pre-operative aspirin resulted in four ewes showing acute restoration of ovarian function within 3 weeks and a further six ewes showing partial restoration. The addition of post-operative aspirin alone had no clear benefit. In Study 2, combination of aspirin with additional post-operative anti-coagulants resulted in total acute restoration of ovarian function in 14/14 ewes within 3 weeks of WOCP&TP, with 9/14 ewes becoming pregnant and 4/14 giving birth to a total of seven normal lambs. There was no difference between anti-coagulants in terms of restoration of reproductive function and fertility. In contrast, the duration of CPA perfusion was highly significant with a 60 min perfusion resulting in ovaries of normal appearance and function with high rates of primordial follicle survival (70%) and an abundant blood supply, whereas ovaries perfused for 10 min had either resorbed completely and were vestigial (7/14) or were markedly smaller (P < 0.01). It is concluded that both the degree of CPA penetration and the maintenance of post-operative vascular patency are critical determinants of the success of WOCP&TP. Before application of this technology to fertility preservation patients, it will be critical to optimize the CPA perfusion time for different sized human ovaries, determine the optimum period and level of anti-coagulant therapy, and confirm the normality of offspring derived from this procedure. This technology holds promise for the preservation of fertility in women. It could also potentially be applied to the cryopreservation of other reproductive or even major organs (kidneys) where there are considerable difficulties in storing donated tissue. Funding was received from the Medical Research Council, University of Nottingham. The authors confirm that they have no conflict of interest in relation to this work. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.