Gallus, Alexander S.; Wittkowsky, Ann; Crowther, Mark; Hylek, Elaine M.; Palareti, Gualtiero
Background: The objective of this article is to summarize the published literature concerning the pharmacokinetics and pharmacodynamics of oral anticoagulant drugs that are currently available for clinical use and other aspects related to their management. Methods: We carried out a standard review of published articles focusing on the laboratory and clinical characteristics of the vitamin K antagonists; the direct thrombin inhibitor, dabigatran etexilate; and the direct factor Xa inhibitor, rivaroxaban Results: The antithrombotic effect of each oral anticoagulant drug, the interactions, and the monitoring of anticoagulation intensity are described in detail and discussed without providing specific recommendations. Moreover, we describe and discuss the clinical applications and optimal dosages of oral anticoagulant therapies, practical issues related to their initiation and monitoring, adverse events such as bleeding and other potential side effects, and available strategies for reversal. Conclusions: There is a large amount of evidence on laboratory and clinical characteristics of vitamin K antagonists. A growing body of evidence is becoming available on the first new oral anticoagulant drugs available for clinical use, dabigatran and rivaroxaban. PMID:22315269
Garcia, David; Libby, Edward; Crowther, Mark A
Although their first application in clinical practice occurred in the 1940s, vitamin K antagonists remain the only form of oral anticoagulant medication approved for long-term use. Although the available vitamin K antagonists are highly effective for the prevention and/or treatment of most thrombotic disease, the significant interpatient and intrapatient variability in dose-response, the narrow therapeutic index, and the numerous drug and dietary interactions associated with these agents have led clinicians, patients, and investigators to search for alternative agents. Three new orally administered anticoagulants (apixaban, dabigatran, and rivaroxaban) are in the late stages of development and several others are just entering (or moving through) earlier phases of investigation. These novel anticoagulant medications are being studied for the prevention and treatment of venous thromboembolism, the treatment of acute coronary syndromes and the prevention of stroke in patients with atrial fibrillation. This review summarizes published clinical trial data pertinent to apixaban, dabigatran, and rivaroxaban. PMID:19880491
Daly, Ann K; King, Barry P
There is wide interindividual variation in oral anticoagulant dose requirement, which is partly genetically determined. Several cytochrome P450s contribute to oxidative metabolism of oral anticoagulants. The most important of these is CYP2C9, which hydroxylates the S-enantiomers of warfarin, acenocoumarol and phenprocoumon with high catalytic activity. In at least eight separate clinical studies, possession of the CYP2C9*2 or CYP2C9*3 variant alleles, which result in decreased enzyme activity, has been associated with a significant decrease in a mean warfarin dose requirement. Several studies also suggest that possession of a CYP2C9 variant allele is associated with an increased risk of adverse events, such as bleeding. Possession of the CYP2C9*3 variant also appears to be associated with a low acenocoumarol dose requirement. Other genetic factors, such as polymorphisms in the cytochromes P450 that metabolize the R-enantiomers of warfarin and acenocoumarol, may also be relevant to anticoagulant dose. The molecular basis of anticoagulant resistance where a higher than normal dose of anticoagulant is required remains unclear, but could be due to unusually high CYP2C9 activity (pharmacokinetic resistance) or to an abnormality in the target enzyme vitamin K epoxide reductase (pharmacodynamic resistance). PMID:12724615
Reiffel, James A
Warfarin has a proven record as an oral anticoagulant; almost every study, however, has found that it is not prescribed for 40-60% of patients who are eligible and should receive it, and of those who do receive it, serum warfarin levels only achieved a time in therapeutic range (TTR) equal to INR 2-3 about 55-60% of the time (online video available at: http://education.amjmed.com/video.php?event_id=445&stage_id=5&vcs=1). This means that only about 1 in 4 patients are adequately anticoagulated with warfarin, and thus there is a large unmet need for achieving better anticoagulation in these patients. Although physicians have sometimes tried to use antiplatelet therapy (aspirin, plus or minus clopidogrel) for anticoagulation, this may result in as much as a doubling of the risk of thromboembolic events. Recently 2 new classes of oral anticoagulant agents have appeared: direct thrombin inhibitors (DTIs) and factor Xa inhibitors. This review sequentially examines the recent clinical trial evidence for the 3 approved NOACs in the 2 classes, highlighting that all 3 share a class effect of being noninferior to warfarin for reducing risk of stroke and systemic embolization and reducing risk of bleeding, with a relative risk of mortality consistently reduced by 10% per year. In addition, all of the NOACs have a significantly lower risk of intracranial/intracerebral bleeding than warfarin, an important clinical consideration, since that is the most feared bleeding risk and may be sufficient reason to consider switching patients from warfarin to a NOAC, even if they seem to be doing well on warfarin. Finally in addition to reviewing the overall benefits of these NOACs over traditional therapy, the clinical application differences between the classes and between the agents are reviewed. PMID:24655744
Bellasi, Antonio; Di Lullo, Luca; Melfa, Gianvincenzo; Minoretti, Claudio; Ratti, Carlo; Campana, Carlo; Volpi, Maurizio; Mangano, Stefano; Di Iorio, Biagio; Cozzolino, Mario
The new or direct oral anticoagulants [new oral anticoagulants (NOAC) or direct oral anticoagulants (DOAC)] were launched in the Italian market in 2013. Although these compounds share common pharmacological indications with vitamin K antagonists (warfarin or acenocumarol), they have different mechanisms of action, do not require a constant anticoagulant monitoring but are more efficacious and safer than vitamin K antagonists. The use of these molecules (Dabigatran, Apixaban, Rivaroxaban, Betrixaban, Edoxaban) is constantly rising in daily practice. However, while available data suggest that NOAC/DOAC use is safe, dosage should be adjusted based on renal or liver function. It should be acknowledged that commonly available blood tests [Prothrombin Time (PT) and partial thromboplastin time (PTT)] are not indicated to monitor the anticoagulant activity of these compounds. With the exception of dabigatran, we currently lack of an antidote to reverse the anticoagulant effect of NOAC/DOAC. We herein review available evidence on NOAC/DOAC pharmacokinetic, risk factors for bleeding, interventions to reverse the anticoagulant activity in case of hemorrhages or need of urgent surgery and/or NOAC/DOAC overdose or side effects. PMID:27545637
McMahon, Sean R; Brummel-Ziedins, Kathleen; Schneider, David J
Despite advances in interventional and pharmacologic therapy, survivors of myocardial infarction remain at an increased risk of subsequent cardiovascular events. Initial pharmacological management includes both platelet inhibition and parenteral anticoagulation, whereas long-term pharmacological therapy relies on antiplatelet therapy for prevention of thrombotic complications. Biomarkers showing ongoing thrombin generation after acute coronary syndromes suggest that anticoagulants may provide additional benefit in reducing cardiovascular events. We review the pharmacokinetics of novel anticoagulants, clinical trial results, the role of monitoring, and future directions for the use of novel oral anticoagulants in the treatment of coronary artery disease. Clinical trials have shown that long-term use of oral anticoagulants decreases the risk of cardiovascular events, but they do so at a cost of an increased risk of bleeding. Future studies will need to identify optimal treatment combinations for selected patients and conditions that address both the appropriate combination of therapy and the appropriate dosage of each agent when used in combination. PMID:27228186
Abo-Salem, Elsayed; Becker, Richard C
The development of a new generation of non-vitamin K oral anticoagulants represents a potential breakthrough in the management of patients with thrombotic diseases, disorders and conditions. While a large and growing body of evidence from large-scale clinical trials and registries supports a favorable safety profile, having a means to rapidly reverse their anticoagulant effects represents an unmet need among practicing clinicians. Several targeted reversal agents are currently in development and the early results are promising. Idarucizumab is a monoclonal antibody that can immediately and specifically reverse dabigatran. Andexanet alfa is a recombinant modified factor Xa that can bind and reverse oral and parenteral factor Xa inhibitors, including rivaroxaban, apixaban and edoxaban, and low molecular weight heparin. Aripazine is a small molecule that can reverse the action of factor Xa inhibitors and possibly dabigatran as well through non-covalent binding and charge-charge interactions. PMID:26939028
Barnes, Geoffrey D; Nallamothu, Brahmajee K; Sales, Anne E; Froehlich, James B
Anticoagulation clinics were initially developed to provide safe and effective care for warfarin-treated patients with atrial fibrillation, venous thromboembolism, and mechanical valve replacement. Traditionally, these patients required ongoing laboratory monitoring and warfarin dose adjustment by expert providers. With the introduction of direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, and edoxaban), many have questioned the need for anticoagulation clinic. However, we think that the growing number of oral anticoagulant choices creates an urgent need for expanding the traditional role of the anticoagulation clinic. We outline 3 key purposes that a reimagined anticoagulation clinic would serve: (1) to assist patients and clinicians with selecting the most appropriate drug and dose from a growing list of anticoagulant options (including warfarin), (2) to help patients minimize the risk of serious bleeding complications with careful long-term monitoring and peri-procedural management, and (3) to encourage ongoing adherence to these life-saving medications. We also describe how repurposing anticoagulation clinics as broader medication safety clinics would promote safe and effective care across a range of cardiovascular conditions for high-risk medications (eg, spironolactone, amiodarone). Finally, we highlight a few existing health systems that are overcoming key challenges to implementing a reimagined anticoagulation or medication safety clinic structure. PMID:26933047
Godier, A; Martin, A-C; Rosencher, N; Susen, S
Direct oral anticoagulants (DOAC) are recommended for stroke prevention in atrial fibrillation and for the treatment of venous thromboembolism. However, they are associated with hemorrhagic complications. Management of DOAC-induced bleeding remains challenging. Activated or non-activated prothrombin concentrates are proposed, although their efficacy to reverse DOAC is uncertain. Therapeutic options also include antidotes: idarucizumab, antidote for dabigatran, has been approved for use whereas andexanet alpha, antidote for anti-Xa agents, and aripazine, antidote for all DOAC, are under development. Other options include hemodialysis for the treatment of dabigatran-associated bleeding and administration of oral charcoal if recent DOAC ingestion. DOAC plasma concentration measurement is necessary to guide DOAC reversal. We propose an update on DOAC-associated bleeding, integrating the availability of dabigatran antidote and the critical place of DOAC concentration measurements. PMID:27297642
Francis, Charles W
Polymorphisms in CYP2C9, a critical cytochrome P-450 enzyme in the metabolism of warfarin, alters its clearance and affects dosing. CYP*1 has higher activity than either the *2 or *3 variants, and patients with the *2 or *3 variants require a lower dose. VKORC1 is the enzyme inhibited by warfarin, and its levels are affected by several polymorphisms that can be divided into high or low level haplotypes, and patients with high level haplotypes require higher warfarin doses. The use of algorithms for dosing that incorporate pharmacogenomic information perform better than those using clinical data alone. Considerable effort is ongoing to develop new oral anticoagulants as alternatives to warfarin, and three agents are in advanced development. Dabigatran is an oral direct thrombin inhibitor that has been compared with enoxaparin for prevention of VTE following hip or knee replacement. Based on non-inferiority results in European trials, it has now been approved for marketing in Europe. Phase III trials with a new oral Xa inhibitor, rivaroxaban, have been completed in hip or knee replacement, and rivaroxaban was superior to enoxaparin in prevention of VTE with no increase in bleeding complications. Phase III studies with apixaban, another oral Xa inhibitor, are in progress. These agents are also being evaluated in large studies for prevention of stroke in atrial fibrillation and for VTE treatment. PMID:19074093
Franchini, Massimo; Mannucci, Pier Mannuccio
Venous thromboembolism (VTE), consisting of deep vein thrombosis and pulmonary embolism, is a major clinical concern associated with significant morbidity and mortality. The cornerstone of management of VTE is anticoagulation, and traditional anticoagulants include parenteral heparins and oral vitamin K antagonists. Recently, new oral anticoagulant drugs have been developed and licensed, including direct factor Xa inhibitors (e.g. rivaroxaban, apixaban and edoxaban) and thrombin inhibitors (e.g. dabigatran etexilate). This narrative review focusses on the characteristics of these direct anticoagulants and the main results of published clinical studies on their use in the prevention and treatment of VTE. PMID:27581829
Kamali, Farhad; Pirmohamed, Munir
Coumarins are the mainstay of oral anticoagulation for the treatment and prophylaxis of thromboembolic disorders. They have a narrow therapeutic index and regular monitoring is therefore required to avoid serious adverse effects. There is wide interindividual variability in dosage requirements, which makes anticoagulation response unpredictable. Current dosing titrations are haphazard and inconvenient and poor initial control leads to morbidity, and occasional mortality, because of bleeding and further thromboembolism. Recent discoveries have helped to characterize the factors that contribute to the interindividual variability in responses to coumarins. Patient and environmental factors that affect anticoagulation response to coumarins include age, body size, dietary vitamin K status, concurrent disease and drug interactions. More recently, single nucleotide polymorphisms in the 2C9 isoform of cytochrome P450 (CYP2C9) and vitamin K epoxide reductase (VKOR) have been shown to make significant contributions to the variability in coumarin dosage requirements. Polymorphisms in other genes that mediate the actions of coumarins may also contribute to this variability. Racial and cultural differences influence dosage requirements, which can be explained, at least in part, by genetic and dietary factors. Incorporation of genetic and environmental factors could help in the prediction of more individualized loading and maintenance doses for safer anticoagulation therapy. PMID:16722840
Wittkowsky, Ann K
The complexities of oral anticoagulation with warfarin have led to the search for more practical alternative agents. Novel direct factor IIa inhibitors and direct factor Xa inhibitors currently in development can be administered at a fixed dose and do not require routine coagulation monitoring and ongoing dosage adjustment to ensure their effectiveness and safety. A number of phase III trials of these agents for the prevention of venous thromboembolism associated with orthopedic surgery and acute medical illness, for the treatment of venous thromboembolism, and for stroke prevention in patients with atrial fibrillation have been completed, with almost universally positive results. If these novel agents are approved for use in the United States, the future of oral anticoagulant therapy will allow a more nuanced approach to drug selection than has been available in the past. Attention to drug interactions and renal function will be required, as methods to measure the presence of these agents are not precise, cannot quantify the degree of anticoagulant present, and are influenced by the changes in serum drug concentrations during the dosing interval. In the future, patient preferences and the pharmacokinetic and pharmacodynamic characteristics of individual drugs will be able to be matched to optimize therapy. These new agents represent a new paradigm for anticoagulation that promises to improve patient care in the long term. PMID:22122180
How, Choon How
Anticoagulation therapy is effective in preventing primary and secondary thromboembolic events due to atrial fibrillation. Warfarin, which was approved by the United States in 1954, was the only long-term oral anticoagulation therapy till the approval of dabigatran in 2010, and of rivaroxaban and other direct factor Xa inhibitors from 2011, forming a group known as novel oral anticoagulants (NOAC). NOAC have fewer food and drug interactions compared to warfarin; hence, the patient will require fewer clinic visits. However, the short half-life of NOAC means that twice-a-day dosing is needed and there is higher risk of a prothrombotic state when doses are missed. Other disadvantages are the lack of long-term data on NOAC, their high cost and the current lack of locally available antidotes. PMID:26702159
Karthikeyan, Ganesan; Eikelboom, John W; Hirsh, Jack
The results of 3 large randomized trials of activated factor X inhibitors, for the prevention of venous thromboembolism, recently became available. Similar data for orally active thrombin inhibitors is also available from recent trials. In this review, we attempt to provide a balanced perspective on the relative merits and demerits of the new, orally active anticoagulants, and speculate on the future of these agents in clinical practice. PMID:19341179
Patel, Anand; Goddeau Jr, Richard P.; Henninger, Nils
Warfarin is very effective in preventing stroke in patients with atrial fibrillation. However, its use is limited due to fear of hemorrhagic complications, unpredictable anticoagulant effects related to multiple drug interactions and dietary restrictions, a narrow therapeutic window, frequent difficulty maintaining the anticoagulant effect within a narrow therapeutic window, and the need for inconvenient monitoring. Several newer oral anticoagulants have been approved for primary and secondary prevention of stroke in patients with non-valvular atrial fibrillation. These agents have several advantages relative to warfarin therapy. As a group, these direct oral anticoagulants (DOAC), which include the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), are more effective than dose adjusted warfarin for prevention of all-cause stroke (including both ischemic and hemorrhagic stroke), and have an overall more favorable safety profile. Nevertheless, an increased risk of gastrointestinal bleeding (with the exception of apixaban), increased risk for thrombotic complication with sudden discontinuation, and inability to accurately assess and reverse anticoagulant effect require consideration prior to therapy initiation, and pose a challenge for decision making in acute stroke therapy. PMID:27347226
Turpie, Alexander G G
Atrial fibrillation (AF) is a major risk factor for stroke. Currently, acetylsalicylic acid (a platelet inhibitor) and vitamin K antagonists (VKAs; oral anticoagulants), including warfarin, are the only approved antithrombotic therapies for stroke prevention in patients with AF. Although effective, VKAs have unpredictable pharmacological effects, requiring regular coagulation monitoring and dose adjustment to maintain effects within the therapeutic range. The clinical development pathway for novel anticoagulants often involves evaluation of efficacy and safety in a short-term indication, such as the prevention of venous thrombo-embolism (VTE), followed by longer-term VTE treatment studies, and finally chronic indications, including stroke prevention studies in patients with AF. The coagulation pathway provides many targets for novel anticoagulants, including Factor Xa (FXa) and Factor IIa (thrombin). Numerous oral, direct FXa inhibitors are in various stages of clinical development, including rivaroxaban, LY517717, YM150, DU-176b, apixaban, and betrixaban, and are anticipated to overcome the limitations of VKAs. Dabigatran is the only oral direct thrombin inhibitor in late-stage development. Studies of these agents for stroke prevention in patients with AF are planned or ongoing. If approved, they may represent the next generation of anticoagulants, by providing new therapeutic options for stroke prevention in patients with AF. PMID:18096568
Giebl, A; Gürtler, K
New oral anticoagulants (NOAC) inhibit factor Xa (Stuart-Prower factor) or factor IIa (thrombin) and are alternatives to vitamin K antagonists. Perioperative indications are deep vein thrombosis prophylaxis for prosthetic hip and knee replacement, therapeutic anticoagulation for deep vein thrombosis as well as the prophylaxis of stroke for patients with atrial fibrillation. Patients on NOACs pose multiple perioperative challenges for all medical disciplines involved. For non-emergency surgery, patients should be evaluated by an anesthesiolgist as early as possible to assess an optimal appointment for surgery and bridging strategy. Management of emergency procedures for patients on NOACs requires an interdisciplinary approach. The individual risk for uncontrolled bleeding versus the urgency for surgery needs to be evaluated on an individual basis. The determination of drug serum levels enables a rough estimation of anticoagulant activity. Emergency procedures in coagulopathy due to active bleeding are treated with the unspecific administration of blood products and coagulation factor concentrates. PMID:24696299
Pengo, Vittorio; Pegoraro, Cinzia; Cucchini, Umberto; Iliceto, Sabino
A multicenter, observational, retrospective, cross-sectional study of patients, receiving oral anticoagulation therapy (OAT) for stroke prophylaxis in chronic non-valvular atrial fibrillation (NVAF) was conducted in the US, Canada, France, Italy and Spain according to their predominant model of care [routine medical care (RMC) or Anticoagulation Clinic care (ACC)]. The study objectives were to assess anticoagulation control (time in target range), and to describe the features of the local model of care. Consecutive patients were recruited on the basis of a minimum of 60 days of oral anticoagulant treatment over a 12 month period, and clinic and physician details were captured by means of a structured face-to-face or telephone interview. Time in therapeutic range (TTR) was calculated by using linear interpolation between INR values. A total of 1511 patients were recruited, of whom 1445 were included in the analysis of TTR. TTR was higher in ACC (69.5% and 64.9% for Italy and Spain, respectively) with respect to RMC (58.1%, 62.8% and 59.3% for the US, Canada and France, respectively). Mean intervals between INR determinations were between 3 and 4 weeks. Dose changes in case of INR outside therapeutic range were more frequent in Spain and less frequent in France. Striking differences were observed in type of VKA used, specialists involved in patient management, and dosage instructions. Studying of anticoagulation management based on local models of care highlights important discrepancies among countries and suggests further standardization of the management of this important therapy is necessary. PMID:16475046
Hamada, Yukihiro; Kawasumi, Noriyo; Hirai, Jun; Yamagishi, Yuka; Mikamo, Hiroshige
Voriconazole (VRCZ), a broad-spectrum triazole, is served in two dosage forms-injection and oral. VRCZ is difference dosage of oral and intravenous administration writing a medical package insert in Japan. 6 mg/kg intravenous injection (IV) twice daily for first day as initial loading dose, followed by 3-4 mg/kg IV twice daily between meals is recommended. 300 mg orally twice daily for first day as initial loading dose, followed by 150-200 mg orally twice daily between meals is recommended. Patients weighing over 40 kg, 200 mg orally twice daily between meals is recommended. Patients weighing under 40 kg, 100 mg orally twice daily between meals is recommended, increase to 150 mg twice daily if inadequate response. This study evaluated VRCZ trough concentration and oral dosage in the 23 cases which administered VRCZ to analysis for TDM in Aichi University Hospital. Spearman rank correlation coefficient was calculated to examine relationships among variables. The level of statistical significance was set at p=0.05. All data were analyzed and processed on JMP 8 (SAS Institute Japan). There was a significant positive correlation between VRCZ trough concentration and dose/weight (r=0.47 p<0.05). In this result, VRCZ oral dosage is appropriate to administer dose/weight (mg/kg) twice a day as same as IV. PMID:25566590
de Moerloose, P; Casini, A; Boehlen, F; Fontana, P
Physicians are confronted with many new antithrombotic drugs, either antiplatelet agents or new oral anticoagulants (NOAC). Targets of NOAC are specific (either anti-IIa or antiXa) and clinical studies have shown that NOAC are as efficacious and as safe as "old" anticoagulants (heparin, low molecular weight heparin, vitamin K antagonists); moreover they present some advantages. Indeed, NOAC have a wide therapeutic window and do not require laboratory monitoring. Therefore, it is very tempting to prescribe them on a large scale basis in patients at risk or having thromboembolic diseases. However, things are not so simple in the day-to-day practice and this review aims at answering in a brief and simplified manner to some questions. PMID:23409645
Laroia, Sandeep T; Morales, Steven; Laroia, Archana T
New oral anticoagulants (NOAC) are the latest addition to anticoagulant armamentarium. Unlike traditional anti-coagulants like warfarin, lab monitoring and management of bleeding complications secondary to these agents is different. As more and more patients are being switched to these drugs, interventional radiologists in particular will benefit from a clinical review of NOAC. PMID:26752818
Munson, C F; Reid, A J
Novel oral anticoagulants (NOACs) have emerged as a good alternative to warfarin in the prevention of stroke for patients with atrial fibrillation. NOAC use is increasing rapidly; therefore, greater understanding of their use in the perioperative period is important for optimal care. Studies and reviews that reported on the use of NOACs were identified, with particular focus on the perioperative period. PubMed was searched for relevant articles published between January 2000 and August 2015. The inevitable rise in the use of NOACs such as rivaroxaban (Xarelto™), apixaban (Eliquis™), edoxaban (Lixiana™) and dabigatran (Pradaxa™) may present a simplified approach to perioperative anticoagulant management due to fewer drug interactions, rapidity of onset of action and relatively short half-lives. Coagulation status, however, cannot reliably be monitored and no antidotes are currently available. When planning for discontinuation of NOACs, special consideration of renal function is required. Advice regarding the management of bleeding complications is provided for consideration in emergency surgery. In extreme circumstances, haemodialysis may be considered for bleeding with the use of dabigatran. NOACs will increasingly affect operative planning in plastic surgery. In order to reduce the incidence of complications associated with anticoagulation, the management of NOACs in the perioperative period requires knowledge of the time of last dose, renal function and the bleeding risk of the planned procedure. Consideration of these factors will allow appropriate interpretation of the current guidelines. PMID:27013144
Kaczorowska, Beata; Pawełczyk, Małgorzata; Przybyła, Monika
Brain stroke is a grave society problem. About 20% ischemic strokes are cardiac related problems. Atrial fibrillation (AF) is the most common cause of ischemic strokes. Decision to deploy anticoagulant treatment with AF patient depends on bleeding and thrombo-embolic risk which summerise scale CHA(2)DS(2)VASc and HAS-BLED. Past recent years in AF treatment anticoagulants from the group of vitamin K antagonist were used. At present in brain stroke prevention and systemic emboilment, new oral anticoagulants (NOA) which weren't worst than vitamin K antagonists, and they are recomendet in most cases of AF unrelated with heart valve defets. Useing NOA causes lower risk of bleeding, including intracranial heamorrhage. It is believed that this is related to the selective inhibition of specific coagulation factors, and respect other hemostatic mechanisms. Results from clinical studies NOA are encouraging, but still lacks clear answers regarding, among other things: long-term safety of treatment and economically viable in everyday clinical practice. In addition, to date there is no specific antidote for this group of drugs. PMID:27234866
Garcia, D; Barrett, Y C; Ramacciotti, E; Weitz, J I
In contrast to vitamin K antagonists, which reduce the functional levels of several coagulation factors, the new oral anticoagulants specifically target either thrombin or factor Xa. These new agents have such predictable pharmacokinetics and pharmacodynamics that routine coagulation monitoring is unnecessary. However, there are still some situations in which measurement of anticoagulant effect may be required. The coagulation assays that are used to monitor heparin derivatives or vitamin K antagonists may not always accurately reflect the anticoagulant activity of the new oral anticoagulants, and specialized assays may be needed. In this article, we: (i) identify situations in which assessment of anticoagulant effect may aid treatment decisions; (ii) describe the effects of the new oral anticoagulants on the various coagulation tests; (iii) review the specialized coagulation assays that have been developed to measure the anticoagulant effects of the new oral anticoagulants; and (iv) provide a clinical perspective on the role of coagulation testing in the clinical management of patients treated with the new oral anticoagulants. PMID:23216682
Gallego, Pilar; Roldán, Vanessa; Lip, Gregory Y H
Nonvalvular atrial fibrillation (AF) confers an increased risk of thromboembolism, with a 5-fold higher risk of ischemic stroke. Oral anticoagulation (OAC) has shown to be highly effective in preventing stroke and mortality compared to placebo and is also used in patients without AF for both treatment and prophylaxis of venous thromboembolism. The OAC halts the coagulation by different mechanisms. Until recently, the only option was the vitamin K antagonists (VKAs), but their inherent limitations have promoted the development of novel oral anticoagulants (NOACs), which may offer efficacious and safer alternatives. Patients should be carefully selected to receive the most suitable treatment for each one. As the VKA efficacy and safety largely rely on the time the patient remains within the therapeutic range, this could be a useful selection criterion. Bleeding remains the main complication of all OACs. Although clinical trials of stroke prevention in AF have shown a significant reduction in hemorrhagic stroke and intracranial bleeding with the NOACs, as prescriptions are increasing, clinicians need to be prepared to accurate management of bleeding complications. Withholding the drug is usually enough for most cases of mild bleeding, but in patients with major, life-threatening bleeding, other measures, such as fluid replacement and blood transfusion, might be necessary while waiting for specific reversal agents that may reach the market soon. In case of acute bleeding, the accurate estimation of anticoagulant effect could also be needed, but the currently available coagulation tests only offer a qualitative measure. While awaiting long-term safety data, the choice between all these available therapies should be based on patient preferences, compliance, and ease of administration as well as on local factors affecting cost-effectiveness. But the increasing variety of therapeutic options when chronic OAC is needed can only improve the provided health care. PMID
Ciurus, Tomasz; Sobczak, Sebastian; Cichocka-Radwan, Anna
Oral direct inhibitors of thrombin and activated factor Xa are approved as new anticoagulant drugs. In contrast to vitamin K antagonists (VKA) and heparins, the new agents have single targets in the coagulation cascade and more predictable pharmacokinetics, but they lack validated and available antidotes. Unlike VKA, they do not require routine monitoring of coagulation. However, the measurement of their pharmacologic effects might be of value in selected patients. They interfere with the routine coagulation tests, which should be interpreted with caution. Specific tests exist and can be used in case of emergencies. Adequate supportive care and temporary removal of all antithrombotic agents constitute the basis for management of serious bleeding complications. The administration of coagulation factors, such as fresh frozen plasma, prothrombin complex concentrates or recombinant activated FVII, can benefit in life-threatening bleeding or emergency surgery. Specific antidotes for non-vitamin K oral anticoagulants are in clinical development. This review aims at answering in a brief and simplified manner some clinical questions. PMID:26336492
Grissinger, Matthew; Gaunt, Michael J; Rich, Darryl S
Medication errors involving oral anticoagulants have led to serious adverse events, including hemorrhage, treatment failures leading to thromboembolic events, and death. This article will highlight medication errors that may arise during the use of oral anticoagulants and provide risk-reduction strategies to address the potential for error and patient harm. PMID:27250070
Costopoulos, Charis; Niespialowska-Steuden, Maria; Kukreja, Neville; Gorog, Diana A
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide with a prevalence that has now reached pandemic levels as a consequence of the rapid modernization of the developing world. Its presentation as an acute coronary syndrome (ACS) is a frequent reason for hospital admission and of profound implications for personal, societal and global health. Despite improvements in the management of ACS with anti-platelet and anticoagulant therapy and revascularization techniques, many patients continue to suffer recurrent ischemic events. The need to reduce future cardiovascular events has led to the development of novel therapies to prevent coronary thrombosis, targeting thrombin-mediated pathways. These include direct Xa inhibitors (apixaban, rivaroxaban and darexaban), direct thrombin inhibitors (dabigatran) and PAR 1 antagonists (vorapaxar and atopaxar). This article critically reviews the comparative mechanisms of action, the risks and benefits, together with the clinical evidence base for the use of these novel oral agents in the management of ACS patients. PMID:22989603
Capranzano, Piera; Miccichè, Eligio; D'Urso, Lucia; Privitera, Fiorella; Tamburino, Corrado
For decades, warfarin has remained the standard oral anticoagulation for stroke prevention in atrial fibrillation (AF). Three novel oral anticoagulants (NOACs) have been recently approved for stroke prevention in non-valvular AF: dabigatran, rivaroxaban and apixaban. Better pharmacological and clinical profiles make these newcomers a preferable alternative over warfarin. Current AF guidelines do not endorse NOACs over warfarin, or one NOAC over another. Indeed, choice of the anticoagulation regimen should be personalized based on the relative efficacy and safety of different agents across subgroups stratified by thrombotic and bleeding risk, as well as on other clinical factors, including anticoagulation control on warfarin, drug interactions, compliance and need for coagulation monitoring. This review appraises i) the randomized evidence on approved NOACs versus warfarin in AF across subgroups stratified by risk factors of stroke and bleeding and by the anticoagulation level reached on warfarin; and ii) clinical factors impacting on the anticoagulation regimen selection. PMID:23957907
Myers, B; Neal, R; Myers, O; Ruparelia, M
Direct oral anticoagulants (DOACs or NOACs -non-vitamin K oral anticoagulants), as the name suggests, are oral anticoagulants with a direct inhibitory action either against factor X or factor II (thrombin). Pregnant women were excluded from participating in all the large trials of the DOACs and they are considered contra-indicated in pregnancy and breast feeding. We present a case of inadvertent exposure to rivaroxaban in a woman who presented at 25 weeks' gestation. The management of her pregnancy and delivery is described, and the previous published case reports are reviewed with a discussion about the use of DOACs in woman of childbearing age. PMID:27512489
Sunkara, Gangadhar; Bende, Girish; Mendonza, Anisha E; Solar-Yohay, Susan; Biswal, Shibadas; Neelakantham, Srikanth; Wagner, Robert; Flarakos, Jimmy; Zhang, Yiming; Jarugula, Venkateswar
The oral bioavailability of valsartan from extemporaneous suspension and solution formulations were evaluated relative to tablet formulation in two separate open-label, randomized crossover studies in healthy adults. In both studies, the plasma concentrations of valsartan after oral administration were analyzed using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods, and the corresponding pharmacokinetic parameters were estimated using noncompartmental analysis. The peak plasma concentration (Cmax ) and area under the concentration time-curves (AUC(0-∞) ) of valsartan from the extemporaneous suspension were higher by 1.93- and 1.56-fold, respectively, relative to the tablet formulation (P < .001). The Cmax and AUC(0-∞) of valsartan from the oral solution were higher by 2.21- and 1.74-fold, respectively, relative to the tablet formulation (P < .001). These results indicate that both rate and extent of absorption of valsartan are higher in the two liquid dosage forms (extemporaneous suspension and solution formulations) relative to the solid oral dosage form (tablet formulation). PMID:27128457
New, non-vitamin K antagonist oral anticoagulants (NOACs) have been developed to overcome the limitations of warfarin. These include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. In the US, rivaroxaban and apixaban are licensed for thromboprophylaxis after elective hip or knee arthroplasty, and rivaroxaban and dabigatran are approved for treatment of venous thromboembolism. Dabigatran, rivaroxaban, and apixaban also are licensed for stroke prevention in eligible patients with atrial fibrillation. Designed to be given in fixed doses without routine coagulation monitoring, the NOACs are more convenient to administer than warfarin. Phase III clinical trials have shown that the NOACs are at least as effective as warfarin and are associated with less intracranial bleeding. This article compares the pharmacological properties of the NOACs with those of warfarin, describes the clinical trial data with the NOACs in the approved indications, outlines the unmet medical needs that the NOACs address, highlights the potential limitations of the NOACs, and provides guidance on the optimal use of the NOACs. PMID:25374671
Pinto, Ian; Giri, Anshu; Arshad, Umbreen; Gajra, Ajeet
The advent of new oral anticoagulants (NOAC) has increased the armamentarium against thromboembolic diseases but has given rise to a conundrum on their reversal. NOAC's have comparable efficacy to traditional vitamin K antagonists with similar rates of major bleeding. However there is no standardized method for reversal of these agents and no specific antidote. This is of concern not only in acute bleeding episodes but also in clinical scenarios where emergency surgery is required. Recent studies have investigated reversal of dabigatran, rivaroxaban, and apixaban using prothrombin complex concentrates (PCC), recombinant factor VIIa, and in the case of dabigatran, a monoclonal antibody. These studies have been encouraging in showing improvement of bleeding times and blood loss in most models, especially with the use of PCCs and the dabigatran antibody. Of note the majority of common currently used coagulation assays may not correlate with clinical reversal. The management of overt bleeding with NOACs is difficult due to the lack of clinical trials. Current animal trials, case reports and hemostatic testing on human blood have shown some promise; provide guidance but warrant further investigation. PMID:25877809
Liakoni, Evangelia; Rätz Bravo, Alexandra E; Krähenbühl, Stephan
Case reports and analyses of clinical studies and of pharmacovigilance data suggest that new oral anticoagulants (NOACs) are associated with a small risk for hepatotoxicity. The objective of this publication is to summarize the current data about this subject, with a special emphasis on pharmacovigilance data in the World Health Organization (WHO) Global Individual Case Safety Reports (ICSR) database and on potential mechanisms of hepatotoxicity. For that, all available case reports as well as published analyses of clinical studies were obtained with a detailed search in PubMed. In addition, pharmacovigilance data from VigiBase(®), the WHO Global ICRS database, were extracted and analyzed. The data show that liver injury associated with NOACs was reported in clinical studies and in pharmacovigilance databases. Several case reports described potentially life-threatening hepatotoxicity in patients treated with rivaroxaban or dabigatran. For rivaroxaban, most affected patients were symptomatic and liver injury was most often hepatocellular or mixed. The frequency was between 0.1 and 1 % in clinical studies and was by trend lower than for comparators (mostly enoxaparin or warfarin). Comparing the pharmacovigilance reports for the individual NOACs, more hepatic adverse events were reported for rivaroxaban than for dabigatran or apixaban. With the exception of edoxaban, for which only few reports are available, patients with acute liver failure have been reported for every NOAC, but most patients had concomitant drugs or diseases. So far, there are no clear mechanisms explaining the hepatotoxicity of these drugs. We conclude that hepatotoxicity appears to be associated with all NOACs currently on the market. Hepatotoxicity associated with NOACs is idiosyncratic; it appears at therapeutic doses, is rare and the mechanism is not related to the pharmacological action of these drugs. Prescribers should inform patients about possible symptoms of hepatotoxicity and stop these
Koenig-Oberhuber, V; Filipovic, M
In our daily anaesthetic practice, we are confronted with an increasing number of patients treated with either antiplatelet or anticoagulant agents. During the last decade, changes have occurred that make the handling of antithrombotic medication a challenging part of anaesthetic perioperative management. In this review, the authors discuss the most important antiplatelet and anticoagulant drugs, the perioperative management, the handling of bleeding complications, and the interpretation of some laboratory analyses related to these agents. PMID:27566810
Scott, Alun; Gibson, John; Crighton, Alexander
Recently, new oral anticoagulants have been introduced as alternatives to warfarin. While national guidelines for treatment of dental patients taking warfarin as an anticoagulant are well-established, no such information is available for these novel therapeutic agents. At present, the local guidance available is contradictory between different health boards/health planning units, and liaison with the medical practitioner managing the individual patient's anticoagulation is imperative if any invasive procedure is proposed. This paper examines the available evidence regarding these drugs and sets out proposals for clinical guidance of dental practitioners treating these patients in primary dental care. PMID:25668377
Obamiro, Kehinde O.; Chalmers, Leanne; Bereznicki, Luke R. E.
Background Assessing and improving patients’ anticoagulation knowledge can lead to better treatment outcomes. While validated knowledge instruments exist for use in people taking warfarin, these tools are not necessarily applicable to patients taking direct-acting oral anticoagulants. Objective To develop and validate an oral anticoagulation knowledge instrument that is applicable to all oral anticoagulant medications. Methods Ten anticoagulation experts participated in the development of the Anticoagulation Knowledge Tool to ensure content validity. The knowledge instrument was administered to three groups of participants comprising of 44 pharmacists, 50 patients and 50 members of the general public. A subgroup of participants in the patient and pharmacist group were retested approximately 2–3 months after the initial testing. Statistical tests were conducted to determine the validity and reliability of the scale, and item analysis was used to determine the performance of individual questions. Results The 28-item instrument developed had a scale content validity index of 0.92, supporting content validity. The pharmacist group’s mean score was significantly higher than that of the patient group, and the patient group scored significantly higher than the general public group (94% vs 62% vs 20%, respectively; p<0.001), supporting construct validity. Internal consistency reliability was acceptable with a Cronbach’s α value of > 0.7 across the three groups, and the test–retest reliability was confirmed with a Pearson’s correlation coefficient of 0.72 and 0.78 for the pharmacist and patient groups, respectively. Conclusion The Anticoagulation Knowledge Tool is a valid and reliable instrument that can be used in routine clinical practice to assess patients’ anticoagulation knowledge. PMID:27351746
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Pluym, Mark; Howell, Gregory
The target-specific oral anticoagulants have recently been introduced as alternatives to warfarin for both prophylactic and therapeutic indications. Although their efficacy and side-effect profiles have been favorable, there is significant concern about management of hemorrhage with these agents as there is no direct reversal agent available. It is important for clinicians to be aware of these agents and the issues that surround them. Most of the management of hemorrhage is based on expert opinion and case reviews. Given the potentially catastrophic consequences of acute hemorrhage while patients are on anticoagulation, specific treatments are needed. Some methods that have been described include activated charcoal, hemodialysis, prohemostatic agents, and transfusions. Target-specific therapies have been shown to be effective in early studies in animal models; however, the effects in humans are still under investigation. More investigation is needed on the management of bleeding complications from target-specific oral anticoagulants. PMID:25255409
Calenda, Emile; Genevois, Olivier; Cardon, Annie; Muraine, Marc
AIM To check the safety of continuation of oral anticoagulants in ophthalmic procedures requiring a peribulbar anesthesia. METHOD A prospective case control study included 750 patients with oral anticoagulants in group A and 750 patients who had never been treated with oral anticoagulant in group B. Hemorrhages were graded as follows: 1) spot ecchymosis of eyelid and or subconjunctival hemorrhage; 2) eyelid ecchymosis involving half of the lid surface area; 3) eyelid ecchymosis all around the eye, no increase in intraocular pressure; 4) retrobulbar hemorrhage with increased intraocular pressure. RESULTS In group A, grade 1 was observed in 13 patients (1.74%) and grade 2 in 2 patients (0.26%). In group B, grade 1 was observed in 12 patients (1.6%) and grade 2 was absent. No 3 or 4 hemorrhage grade was encountered in both groups. There was not significant difference in grade 1 hemorrhage between both groups (P=0.21). CONCLUSION Oral anticoagulants were not associated with a significant increase in potentially sight-threatening local anesthetic complications. PMID:24634874
Enriquez, Andres; Lip, Gregory Y H; Baranchuk, Adrian
In recent years, non-vitamin K oral anticoagulants (NOACs) have emerged as an alternative to warfarin for the prevention and treatment of thrombo-embolic disease. Large randomized trials have demonstrated that these agents, which act by directly targeting thrombin (dabigatran) and factor Xa (rivaroxaban, apixaban, and edoxaban), are at least as effective as warfarin, with lower rates of bleeding and fewer interactions with food and drugs. In addition, NOACs have a more predictable anticoagulant effect, allowing a fixed dose regimen and obviating the need for routine anticoagulation monitoring. Since the introduction of NOACs, one of the major concerns for clinicians has been the lack of specific agents to reverse their anticoagulant effect in case of life-threatening haemorrhagic complications or emergency surgery, which have limited their use in patients deemed at a higher risk of bleeding. New specific antidotes (e.g. idarucizumab, andexanet alfa, and ciraparantag) show promising data, and may soon become available for clinical use. In this article, we review the pharmacology of these agents, the incidence and outcomes of haemorrhagic complications, the available strategies for anticoagulation reversal, and the more recent advances for the development of specific antidotes. PMID:25816811
Feher, Gergely; Illes, Zsolt; Komoly, Samuel; Hargroves, David
Cerebral venous thrombosis (CVT) is an uncommon cause of stroke with extremely diverse clinical features, predisposing factors, brain imaging findings, and outcome. Anticoagulation is the cornerstone of CVT management, however, it is not supported by high-quality evicence. Novel oral anticoagulants (NOACs) have been extensively studied in patients with deep vein thrombosis, pulmonary embolism and non-valvular atrial fibrillation. The aim of our work was to review the available evidence for NOACs in the treatment of CVT. Based on our literature search there is insufficient evidence to support the use of NOACs in CVT, although case series with rivaroxaban and dabigatran have showed promising results. PMID:25994451
Anticoagulation control is imperative for individuals who are prescribed long-term oral anticoagulation therapy. Therapeutic international normalized ratios decrease the risk of the thromboembolic complications that are associated with oral anticoagulation therapy. Individuals on oral anticoagulation therapy are often asked to make lifestyle modifications that can become barriers to medication adherence. The application of the theory of planned behavior to oral anticoagulation therapy can be used to assist advanced practice nurses in assessing individuals for the perceived barriers or obstacles that might interfere with the behavioral changes necessary to successfully comply with the recommended treatment plan. PMID:19298315
Testa, Sophie; Paoletti, Oriana; Zimmermann, Anke; Bassi, Laura; Zambelli, Silvia; Cancellieri, Emilia
Anticoagulation Clinics (ACs) are services specialized in management of patients on anticoagulant treatment. At present, ACs manage patients chiefly on antivitamin K antagonists (AVKs), but patient population has already changed in the last few years, because of an increase of treatments with other anticoagulant drugs, which require different management systems. The strong increase in the number of patients at AC, mainly on long-term treatment, has determined the development of web management, through telemedicine systems, improving the quality of life and maintaining the same clinical quality levels. New oral anticoagulants (NOAs) have shown to be as effective as AVK antagonists in stroke prevention in atrial fibrillation and for treatment of venous thromboembolism in addition to VTE prophylaxis in orthopaedic surgery, when administered at a fixed dose, but patient adherence and compliance are crucial for good quality treatment. At present, lacking data from the real world, an oversimplification of treatment with NOAs could cause unjustified risks for patients and also a possible future underuse of good drugs. For these reasons the vigilance must be high and ACs can have a crucial role in defining which is the best management for NOA patients and how to do it, as it happened for AVKs. PMID:23097696
Mickley, Frank; Geigenmüller, Grit; Schinköthe, Claudia
Equal safety and efficacy of direct oral anticoagulants as compared to vitamin K antagonists have been shown in elderly and very old patients. The use of these seem to have certain advantages in this special patient cohort: higher drug safety, no need for lab monitoring, less drug-drug interactions and a lower rate of intracranial hemorrhages. However, more data is needed to quantify the exact bleeding risk for geriatric patients. Elderly patients suffer quite frequently from significant comorbidities, such as renal failure, dementia, vision loss etc., which might put them at higher risk to suffer from medication side effects, especially bleeding complications. Routine clinical examinations combined with monitoring of renal function are therefore of paramount importance. Regarding these precautions the use of the new oral anticoagulants in the elderly is hence quite justified and rising. PMID:26625228
Fareau, Sarah; Baumstarck, Karine; Farcet, Anaïs; Molines, Catherine; Auquier, Pascal; Retornaz, Frédérique
Atrial fibrillation (AF) is the most common arrhythmia. Its prevalence increases with age and increases the risk of stroke and systemic embolism. Few data are currently available on the quality of life (QOL) of anticoagulated patients with the advent of direct oral anticoagulants (DOAC). Our study aims to describe levels of QOL in elderly patients with AF receiving oral anticoagulants and compare QOL of patients treated with vitamin K antagonists (VKA) and DOAC. This prospective study included patients of 65 years and over, receiving anticoagulants for AF (VKA or DOAC) from general practice (n=70) or cardiac practice (n=30). The patients completed a self-administered questionnaire that included demographic, geriatric data and a QOL standardized scale: the anti-clot treatment scale (ACTS) 17 items exploring two dimensions "Burdens" and "Benefits". Eighty-nine patients were enrolled: 61 were taking VKA and 28 taking DOAC. Our two groups were comparable for all demographic and clinical characteristics studied. Our patients' mean scores were 48.6±12.1 on Burdens and 9.7±3.8 on Benefits. Burdens and Benefits scores were significantly better for patients treated with DOAC compared to patients with VKA (p<0.0001 and p<0.01, respectively). Anticoagulation in the elderly should be encouraged given the high thrombotic risk of AF. No matter what kind of molecule is chosen if in accordance to good guidance. Patients treated with ACOD seem to have a better QOL, but these results should be confirmed through larger randomized studies. PMID:25786423
da Silva, Rose M.F.L.
Atrial fibrillation is the most frequent arrhythmia in clinical practice, reaching 2% of the people in the world and is associated with systemic embolism. Thus, the use of anticoagulants is indicated if CHA2DS2-VASc score ≥2 or in patients with previous transient ischemic attack or stroke. For decades, warfarin, a vitamin K antagonist, was the only choice for chronic oral anticoagulation. Recently, novel oral anticoagulants (NOACs) have been introduced, offering similar (or better) effectiveness, safety, and convenience to the vitamin K antagonists. Dabigatran was the first NOAC approved and is a direct thrombin inhibitor. Rivaroxaban and apixaban are factor Xa inhibitors. They display rapid onset of action, more predictable of pharmacological profile, less interactions with other drugs, lack of significant effects in the diet, and less risk of intracranial hemorrhage than warfarin. Despite that dose adjustment is necessary for patients with chronic kidney disease or according to body weight, these new drugs do not require regular monitoring. There are recommendations for the start and follow-up therapy with NOACs, planning for cardioversion, ablation and surgical interventions and the management of bleeding. This article is a review of the major studies of the NOACs. The clinical use of these drugs in patients with non-valvular atrial fibrillation is presented. PMID:25470147
Skelley, Jessica W; Kyle, Jeffrey A; Roberts, Rachel A
To review the use of the novel oral anticoagulant (NOAC) agents for the treatment of heparin-induced thrombocytopenia (HIT) from relevant clinical trial data. A MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, and Google-Scholar searches (1966-March 2016) were conducted using the keywords: thrombocytopenia, NOACs, dabigatran, apixaban, rivaroxaban, edoxaban, Xa inhibitor, direct thrombin inhibitor. Articles evaluating the new oral anticoagulants for thrombocytopenia published in English and using human subjects were selected. Eight clinical trials were identified. References cited in identified articles were used for additional citations. Approximately 12 million hospitalized patients each year are exposed to heparin for thromboprophylaxis. HIT, an immune-mediated, prothrombotic adverse reaction is a potential complication of heparin therapy. As a result, heparin products must be immediately withdrawn and replaced by alternative anticoagulants to compensate for the thrombotic risk associated with HIT. Limitations exist with the only currently FDA approved heparin alternative, argatroban. NOACs have been considered as potential alternatives to traditional agents based on their pharmacologic activity. Case reports have indicated positive results in patients, with clinical outcomes and tolerability supporting the use of the NOACs as alternative agents in the treatment of HIT. Positive results have been reported for the use of NOACs in the treatment of HIT. Further robust studies are needed for definitive decision making by clinicians. PMID:27102287
Hu, Tiffany Y; Vaidya, Vaibhav R; Asirvatham, Samuel J
Novel oral anticoagulants (NOACs) are increasingly used in clinical practice, but lack of commercially available reversal agents is a major barrier for mainstream use of these therapies. Specific antidotes to NOACs are under development. Idarucizumab (aDabi-Fab, BI 655075) is a novel humanized mouse monoclonal antibody that binds dabigatran and reverses its anticoagulant effect. In a recent Phase III study (Reversal Effects of Idarucizumab on Active Dabigatran), a 5 g intravenous infusion of idarucizumab resulted in the normalization of dilute thrombin time in 98% and 93% of the two groups studied, with normalization of ecarin-clotting time in 89% and 88% patients. Two other antidotes, andexanet alfa (PRT064445) and ciraparantag (PER977) are also under development for reversal of NOACs. In this review, we discuss commonly encountered management issues with NOACs such as periprocedural management, laboratory monitoring of anticoagulation, and management of bleeding. We review currently available data regarding specific antidotes to NOACs with respect to pharmacology and clinical trials. PMID:26937198
Summers, Richard L; Sterling, Sarah A
Direct oral anticoagulants (DOACs) offer clinical advantages over warfarin, such as minimal medication and food interactions and fixed dosing without the need for routine monitoring of coagulation status. As with all anticoagulants, bleeding, either spontaneous or provoked, is the most common complication. The long-term use of these drugs is increasing, and there is a crucial need for emergency medicine service professionals to understand the optimal management of associated bleeding. This review aims to describe the indications and pharmacokinetics of available DOACs; to discuss the risk of bleeding; to provide a treatment algorithm to manage DOAC-associated emergency bleeding; and to discuss future directions in bleeding management, including the role of specific reversal agents, such as the recently approved idarucizumab for reversal of the direct thrombin inhibitor dabigatran. Because air medical personnel are increasingly likely to encounter patients receiving DOACs, it is important that they have an understanding of how to manage patients with emergent bleeding. PMID:27255877
Di Minno, Giovanni; Russolillo, Anna; Ventre, Itala; Di Minno, Alessandro; Prisco, Domenico
In phase III studies, some oral inhibitors of both thrombin (dabigatran etexilate) and activated factor X (rivaroxaban, apixaban) have been employed as new anticoagulant drugs in patients with atrial fibrillation or acute coronary syndromes. Such new drugs have overcome a series of limitations of the standard-of-care warfarin, and argue for the possibility of an easy, widespread use of anticoagulation in vascular medicine. However, to this end, we need information on management of bleeding in patients receiving these drugs. Dabigatran etexilate, rivaroxaban and apixaban affect major laboratory tests for clotting. However, at present we do not know whether and how this information may be clinically useful. Their high cost is another major issue, and newer pharmacoeconomic studies are needed to evaluate their cost-effectiveness ratio vs warfarin. PMID:23160017
Fitzgerald, John Leonard; Howes, Laurence Guy
In recent years, new direct-acting oral anticoagulants (DOACs) have been introduced into clinical practice that specifically inhibit either factor Ia or Xa. These drugs have, to a large extent, replaced warfarin for the treatment of venous thrombosis, pulmonary embolism, and non-valvular atrial fibrillation. They have potential advantages over warfarin in providing more stable anticoagulation and the lack of a need for regular venesection to monitor activity. They also have the promise of less drug and food interactions. All of these drugs are substrates for the permeability glycoprotein (P-gp) excretion system, and several are metabolised, in part, by cytochrome P450 (CYP) 3A4. This current article assesses the interactions that do or may occur with the DOACs, particularly with respect to the P-gp and CYP3A4 systems. PMID:27435452
Saeed, Wajeeha; Burke, James F; Mirrani, Ghazi; Sirinivasa, Minisha; Nabi, Usman; Hayat, Umar; Khan, Zubair; Sardar, Muhammad Rizwan
Atrial fibrillation (AF) is the most common arrhythmia and represents one-third of the arrhythmia-related hospital admissions in the developed countries. Embolic strokes associated with AF are more severe and disabling. Thromboembolic stroke prevention is a major goal in treatment of AF and Warfarin has successfully served this purpose for many years. Drug-drug interaction and regular monitoring with Warfarin pose a significant challenge where health care system has limited resources; and lack of a well-structured health system, hinders regular International Normalized Ratio (INR) monitoring. Novel oral anticoagulants (NOACs) have opened up a new exciting chapter in the field of anticoagulation in non-valvular atrial fibrillation (NVAF). This review discussed the landmark trials that led to the development of NOACs and explored the potentials of these new agents with simultaneous comparison of Warfarin. PMID:27504556
Fontana, Pierre; Robert-Ebadi, Helia; Bounameaux, Henri; Boehlen, Françoise; Righini, Marc
In recent years, small oral compounds that specifically block activated coagulation factor X (FXa) or thrombin (FIIa) have become alternatives to the anticoagulants that had been used for several decades. As of today, these direct oral anticoagulants (DOACs) include dabigatran etexilate (thrombin inhibitor) and apixaban, edoxaban and rivaroxaban (inhibitors of FXa). While there is no doubt that DOACs represent a major step forward in the management of patients with venous thromboembolic disease and atrial fibrillation, new challenges have arisen. They need to be addressed with the necessary pragmatism on the basis of evidence. Indeed, a better understanding of the management of these last-generation antithrombotics will favour safer use and increase confidence of the practitioner for the prescription of these drugs. The aim of this article is to present practical suggestions for the prescription and use of these drugs in everyday clinical practice, based on clinical experience and recently updated recommendations of the European Heart Rhythm Association and the American College of Chest Physicians among other scientific organisations. We address issues such as pharmacokinetics, dosing, side effects, limitations of use, drug interactions, switching from and to other anticoagulants, renal function, concomitant administration of antiplatelet agents and perioperative use. We also address the issue of monitoring and reversal, taking advantage of the most recent development in this latter area. Rather than being one additional set of recommendations, our narrative review aims at assisting the practicing physician in his or her daily handling of these novel anticoagulant compounds, based on frequently asked questions to the authors, a group of experienced specialists in the field who have, however, no commitment to issue guidelines. PMID:26964028
Rudd, Kelly M.; Phillips, Elizabeth (Lisa) M.
Anticoagulation therapy is mandatory in patients with pulmonary embolism to prevent significant morbidity and mortality. The mainstay of therapy has been vitamin-K antagonist therapy bridged with parenteral anticoagulants. The recent approval of new oral anticoagulants (NOACs: apixaban, dabigatran, and rivaroxaban) has generated significant interest in their role in managing venous thromboembolism, especially pulmonary embolism due to their improved pharmacokinetic and pharmacodynamic profiles, predictable anticoagulant response, and lack of required efficacy monitoring. This paper addresses the available literature, on-going clinical trials, highlights critical points, and discusses potential advantages and disadvantages of the new oral anticoagulants in patients with pulmonary embolism. PMID:23691304
Merli, Geno J
Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA
Vílchez, Juan Antonio; Gallego, Pilar
The recent development of new oral anticoagulants (NOACs) offers the possibility of efficacy, relative safety and convenience compared with warfarin. This could lead to greater patient compliance, with easier management and improved provision of thromboprophylaxis. Safety whilst using NOACs should be focused on bleeding cases, surgery or on the management of patients receiving anticoagulant therapy with concomitant impairment of renal function, especially since many NOACs are dependent on renal excretion. Thus, if the clearance creatinine indicates severe renal impairment, NOACS will be contraindicated or their dose needs to be changed. In patients who need surgery, there are published protocols of management, depending on the severity of the intervention and renal function. In the case of severe hemorrhage, requiring rapid reversal of the anticoagulant effect and in the absence of specific antidotes, alternatives such as one of the nonspecific haemostatic agents must be considered. Clinical evaluation in bleeding situations and a meticulous risk–benefit appraisal for NOACs is needed, and these procoagulant agents and patients must be monitored closely. This article provides an overview of the pharmacology and potential risks, as well as the efficacy and safety of NOACs. PMID:25083259
Pollack, Charles V
Long-term oral anticoagulant (OAC) therapy is used for the treatment and prevention of thrombosis and thromboembolism. As OAC use is so widespread, emergency physicians are likely to encounter patients on anticoagulant therapy in the emergency department (ED) on a regular basis, either for the same reasons as the population in general or as a result of the increased bleeding risk that OAC use entails. The vitamin K antagonist warfarin has been the standard OAC for several decades, but recently, the newer agents dabigatran etexilate, rivaroxaban and apixaban (collectively, novel OACs, non-vitamin K OACs, or simply ‘NOACs’) have become available for long-term use. Protocols for assessing and managing warfarin-treated patients in the ED are well established and include international normalised ratio (INR) testing, which helps guide patient management. However, the INR does not give an accurate evaluation of coagulation status with NOACs, and alternative tests are therefore needed for use in emergency settings. This paper discusses what information the INR provides for a patient taking warfarin and which coagulation tests can guide the physician when treating patients on one of the NOACs, as well as other differences in emergency anticoagulation management. PMID:25987596
Davis, Estella M; Uhlmeyer, Erin M; Schmidt, David P; Schardt, Greg L
The direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban are US Food and Drug Administration (FDA)-approved target-specific oral anticoagulants (TSOACs) that have emerged onto the market for use in some indications similar to those for warfarin; in addition, edoxaban is seeking FDA approval. Similar indications include reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation for all 3 agents, for the prevention of deep vein thrombosis that may lead to pulmonary embolism in patients undergoing hip or knee surgery for rivaroxaban and apixaban, and for the treatment and prevention of deep vein thrombosis and pulmonary embolism. As anticoagulants, they are all associated with a risk of bleeding, and, unfortunately, there are no approved antidotes for reversal of these agents. A number of small studies in human subjects and in human/animal models exposed to TSOACs have evaluated the use of activated charcoal, hemodialysis for dabigatran, or clotting factor concentrates for their ability to neutralize the anticoagulant effects or reduce drug concentrations of TSOACs. Clotting factor concentrates that have been used include prothrombin complex concentrates and recombinant factor VII. This review examines studies and case reports evaluating these strategies for expedited or emergent reversal of TSOACs. PMID:25485923
Pollack, Charles V
Long-term oral anticoagulant (OAC) therapy is used for the treatment and prevention of thrombosis and thromboembolism. As OAC use is so widespread, emergency physicians are likely to encounter patients on anticoagulant therapy in the emergency department (ED) on a regular basis, either for the same reasons as the population in general or as a result of the increased bleeding risk that OAC use entails.The vitamin K antagonist warfarin has been the standard OAC for several decades, but recently, the newer agents dabigatran etexilate, rivaroxaban and apixaban (collectively, novel OACs, non-vitamin K OACs, or simply 'NOACs') have become available for long-term use. Protocols for assessing and managing warfarin-treated patients in the ED are well established and include international normalised ratio (INR) testing, which helps guide patient management. However, the INR does not give an accurate evaluation of coagulation status with NOACs, and alternative tests are therefore needed for use in emergency settings. This paper discusses what information the INR provides for a patient taking warfarin and which coagulation tests can guide the physician when treating patients on one of the NOACs, as well as other differences in emergency anticoagulation management. PMID:25987596
Hogg, Kerstin; Panag, Ajit; Worster, Andrew; Thachil, Jecko
The direct oral anticoagulants (DOACs) are the mainstay for stroke prophylaxis in nonvalvular atrial fibrillation and treatment of acute venous thrombosis. They are attractive alternatives to warfarin because of their efficacy, ease of prescription and safety profile. The emergency department has gained expertise in the management of DOAC bleeding complications, but has been slower to adopt prescription decisions. Emergency clinicians are in a unique position to identify patients who are prescribed DOACs and are at high risk of impending bleeding. This is a practical guide for the emergency clinician on how to prescribe DOACs, the red flags for DOAC patients in the emergency department and advances in the treatment of bleeding. PMID:27116543
Numerous factors have been identified as risk factors for instability of oral anticoagulation, including variability in vitamin K intake. However few studies have directly tested the feasibility of manipulating dietary vitamin K to achieve stable oral anticoagulation. Recent findings from a rando...
... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Monensin oral dosage forms. 520.1448 Section 520.1448 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... starting line). The loss on drying is not more than 10 percent when dried in vacuum at 60 °C for 2 hours....
... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Monensin oral dosage forms. 520.1448 Section 520.1448 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... starting line). The loss on drying is not more than 10 percent when dried in vacuum at 60 °C for 2 hours....
... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Monensin oral dosage forms. 520.1448 Section 520.1448 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... starting line). The loss on drying is not more than 10 percent when dried in vacuum at 60 °C for 2 hours....
... HUMAN SERVICES Food and Drug Administration 21 CFR Part 520 Oral Dosage Form New Animal Drugs... Administration (FDA) is amending the animal drug regulations to reflect approval of a new animal drug application (NADA) filed by Novartis Animal Health US, Inc. The NADA provides for the veterinary prescription use...
... HUMAN SERVICES Food and Drug Administration 21 CFR Part 520 Oral Dosage Form New Animal Drugs... Administration (FDA) is amending the animal drug regulations to reflect the original approval of a new animal.... 801-808. List of Subjects in 21 CFR Part 520 Animal drugs. 0 Therefore, under the Federal Food,...
Toth, Peter P
Background Patients who have had a venous thromboembolic event are generally advised to receive anticoagulant treatment for 3 months or longer to prevent a recurrent episode. Current guidelines recommend initial heparin and an oral vitamin K antagonist (VKA) for long-term anticoagulation. However, because of the well-described disadvantages of VKAs, including extensive food and drug interactions and the need for regular anticoagulation monitoring, novel oral anticoagulants (NOACs) have become an attractive option in recent years. These agents are given at fixed doses and do not require routine coagulation-time monitoring. The NOACs are discussed in this review with regard to the needs of patients on long-term anticoagulation. Methods Current guidelines from Europe and North America that refer to the treatment of deep vein thrombosis and/or pulmonary embolism are included, as well as published randomized Phase III clinical trials of NOACs. PubMed searches were used for sourcing case studies of long-term anticoagulant treatment, and results were filtered for human application and screened for relevance. Conclusion NOAC-based therapy showed a similar efficacy and safety profile to heparins/VKAs but without the need for regular anticoagulation monitoring or dietary adjustments, and can be taken as a fixed-dose regimen once or twice daily. This represents a significant step forward in facilitating the management of long-term anticoagulation therapy. Furthermore, in the EINSTEIN studies, improved patient satisfaction was documented with the NOAC rivaroxaban, which may result in better adherence to therapy and an overall reduction in the incidence of recurrent venous thromboembolism. PMID:26929637
Sarich, Troy C; Seltzer, Jonathan H; Berkowitz, Scott D; Costin', James; Curnutte, John T; Gibson, C Michael; Hoffman, Maureane; Kaminskas, Edvardas; Krucoff, Mitchell W; Levy, Jerrold H; Mintz, Paul D; Reilly, Paul A; Sager, Philip T; Singer, Daniel E; Stockbridge, Norman; Weitz, Jeffrey I; Kowey, Peter R
This white paper provides a summary of presentations and discussions that were held at an Anticoagulant-Induced Bleeding and Reversal Agents Think Tank co-sponsored by the Cardiac Safety Research Consortium and the US Food and Drug Administration (FDA) at the FDA's White Oak Headquarters on April 22, 2014. Attention focused on a development pathway for reversal agents for the novel oral anticoagulants (NOACs). This is important because anticoagulation is still widely underused for stroke prevention in patients with atrial fibrillation. Undertreatment persists, although NOACs, in general, overcome some of the difficulties associated with anticoagulation provided by vitamin K antagonists. One reason for the lack of a wider uptake is the absence of NOAC reversal agents. As there are neither widely accepted academic and industry standards nor a definitive regulatory policy on the development of such reversal agents, this meeting provided a forum for leaders in the fields of cardiovascular clinical trials and cardiovascular safety to discuss the issues and develop recommendations. Attendees included representatives from pharmaceutical companies; regulatory agencies; end point adjudication specialist groups; contract research organizations; and active, academically based physicians. There was wide and solid consensus that NOACs overall offer improvements in convenience, efficacy, and safety compared with warfarin, even without reversal agents. Still, it was broadly accepted that it would be helpful to have reversal agents available for clinicians to use. Because it is not feasible to do definitive outcomes studies demonstrating a reversal agent's clinical benefits, it was felt that these agents could be approved for use in life-threatening bleeding situations if the molecules were well characterized preclinically, their pharmacodynamic and pharmacokinetic profiles were well understood, and showed no harmful adverse events in early human testing. There was also consensus
Briasoulis, Alexandros; Kottam, Anupama; Khan, Mazhar; Afonso, Luis
Recent trials on novel oral anticoagulants (NOAC) in patients undergoing cardioversion showed that NOACs are as safe and effective as treatment with vitamin K antagonists in patients with atrial fibrillation undergoing electric or pharmacological cardioversion. We conducted an EMBASE and MEDLINE search for studies in which patients undergoing cardioversion were assigned to treatment with NOACs versus VKAs. We identified one prospective randomized study and three post hoc analysis of randomized trials which enrolled 2,788 controls that received NOACs and 1,729 patients that received VKAs. NOACs and VKAs had comparable effects on the rates of stroke/thromboembolism, major bleeding events and all-cause mortality. NOACs are safe and effective alternatives to VKA in patients with AF undergoing cardioversion. PMID:25542262
Pulignano, Giovanni; Tinti, Maria Denitza; Tolone, Stefano; Musto, Carmine; De Lio, Lucia; Pino, Paolo Giuseppe; Minardi, Giovanni; Violini, Roberto; Uguccioni, Massimo
Left ventricular noncompaction (LVNC) is characterized by left ventricular (LV) hypertrabeculations and is associated with heart failure, arrhythmias and embolism. We report the case of a 67-year-old LVNC patient, under oral anticoagulation (OAC) therapy for apical thrombosis. After she discontinued OAC, the thrombus involved almost the whole of the left ventricle; in a few months her condition worsened, requiring hospitalization, and despite heparin infusion she experienced myocardial infarction (MI), caused by embolic occlusion of the left anterior descending artery. Although infrequent as a complication of LVNC, and usually attributable to microvascular dysfunction, in this case MI seems due to coronary thromboembolism from dislodged thrombotic material in the left ventricle. PMID:26162290
Douketis, James; Bell, Alan David; Eikelboom, John; Liew, Aaron
Abstract Objective To compare key features of the new oral anticoagulants (NOACs)—dabigatran, rivaroxaban, and apixaban—and to address questions that arise when comparing the NOACs. Sources of information PubMed was searched for recent (January 2008 to week 32 of 2013) clinical studies relating to NOAC use for stroke prevention in atrial fibrillation (AF) and for the treatment of acute venous thromboembolism (VTE). Main message All NOACs are at least as effective as warfarin for stroke prevention in patients with nonvalvular AF, and are at least as safe in terms of bleeding risk according to 3 large trials. Meta-analyses of these trials have shown that, compared with warfarin therapy, NOACs reduced total mortality, cardiovascular mortality, and intracranial bleeding, and there was a trend toward less overall bleeding. Practical advantages of NOACs over warfarin include fixed once- or twice-daily oral dosing without the need for coagulation monitoring, and few known or defined drug or food interactions. Potential drawbacks of NOACs include a risk of bleeding that might be increased in patients older than 75 years, increased major gastrointestinal bleeding with high-dose dabigatran, increased dyspepsia with dabigatran, the lack of a routine laboratory test to reliably measure anticoagulant effect, and the lack of an antidote for reversal. No direct comparisons of NOACs have been made in randomized controlled trials, and the choice of NOAC is influenced by individual patient characteristics, including risk of stroke or VTE, risk of bleeding, and comorbidity (eg, renal dysfunction). Conclusion The NOACs represent important alternatives in the management of patients with AF and VTE, especially for patients who have difficulty accessing regular coagulation monitoring. The companion to this article addresses common “what if” questions that arise in the long-term clinical follow-up and management of patients receiving NOACs. PMID:25392438
Lentz, S R
Despite rapid growth in the use of direct oral anticoagulants (DOACs), warfarin remains a widely prescribed anticoagulant drug. It is likely that the overall use of warfarin will continue to decline, but not completely disappear, as indications for DOACs expand. This changing anticoagulation landscape, along with the likelihood that personalized genomic information will become increasingly available, has several implications for the future of warfarin dosing strategies. PMID:27178490
... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Imprinting of solid oral dosage form drug products... AS SAFE AND EFFECTIVE AND NOT MISBRANDED General Provisions § 330.3 Imprinting of solid oral dosage form drug products. A requirement to imprint an identification code on solid oral dosage form...
... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Imprinting of solid oral dosage form drug products... AS SAFE AND EFFECTIVE AND NOT MISBRANDED General Provisions § 330.3 Imprinting of solid oral dosage form drug products. A requirement to imprint an identification code on solid oral dosage form...
... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Imprinting of solid oral dosage form drug products... AS SAFE AND EFFECTIVE AND NOT MISBRANDED General Provisions § 330.3 Imprinting of solid oral dosage form drug products. A requirement to imprint an identification code on solid oral dosage form...
... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Imprinting of solid oral dosage form drug products... AS SAFE AND EFFECTIVE AND NOT MISBRANDED General Provisions § 330.3 Imprinting of solid oral dosage form drug products. A requirement to imprint an identification code on solid oral dosage form...
... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Imprinting of solid oral dosage form drug products... AS SAFE AND EFFECTIVE AND NOT MISBRANDED General Provisions § 330.3 Imprinting of solid oral dosage form drug products. A requirement to imprint an identification code on solid oral dosage form...
Petruševska, Marija; Berglez, Sandra; Krisch, Igor; Legen, Igor; Megušar, Klara; Peternel, Luka; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Kopp, Sabine; Langguth, Peter; Mehta, Mehul; Polli, James E; Shah, Vinod P; Dressman, Jennifer
Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system (BCS). Levetiracetam's therapeutic use, its wide therapeutic index, and its favorable pharmacokinetic properties make levetiracetam a valid candidate for the BCS-based biowaiver approach. Further, no BE studies with levetiracetam IR formulations in which the test formulation failed to show BE with the comparator have been reported in the open literature. On the basis of the overall evidence, it appears unlikely that a BCS-based biowaiver approach for levetiracetam IR solid oral dosage forms formulated with established excipients would expose patients to undue risks. Thus, the BCS-based biowaiver approach procedure is recommended for IR solid oral dosage form containing levetiracetam, provided the excipients in the formulation are also present in products that have been approved in countries belonging to or associated with the International Committee on Harmonization and are used in their usual quantities, and provided the dissolution profiles of the test and reference product comply with the current requirements for BCS-based biowaivers. PMID:25663270
Cappelleri, Gianluca; Fanelli, Andrea
The use of direct oral anticoagulants including apixaban, rivaroxaban, and dabigatran, which are approved for several therapeutic indications, can simplify perioperative and postoperative management of anticoagulation. Utilization of regional neuraxial anesthesia in patients receiving anticoagulants carries a relatively small risk of hematoma, the serious complications of which must be acknowledged. Given the extensive use of regional anesthesia in surgery and the increasing number of patients receiving direct oral anticoagulants, it is crucial to understand the current clinical data on the risk of hemorrhagic complications in this setting, particularly for anesthesiologists. We discuss current data, guideline recommendations, and best practice advice on effective management of the direct oral anticoagulants and regional anesthesia, including in specific clinical situations, such as patients undergoing major orthopedic surgery at high risk of a thromboembolic event, or patients with renal impairment at an increased risk of bleeding. PMID:27290980
MIRANDA, M.; BOLLERO, P.; D’OVIDIO, N.; MARSANGO, V.; BARLATTANI, A.
SUMMARY Objectives. This work aims to assess the risks both thromboembolic that bleeding of a management protocol “non-conservative” in patients on oral anticoagulant therapy (OAT) to be undergoing implant surgery. Materials and methods. We decided to take a surgical “non-conservative” protocol, to insert four implants in the aesthetic zone, without using flapless surgery and the surgical template. In accordance with the hematologist, the value of INR is lowered and warfarin was replaced with heparin low molecular weight, to have a better coagulation’s control. Results. The modern guidelines impose a protocol of conservative management in patients with OAT, with minimally invasive surgery, flapless, and use of surgical template to reduce the risk of uncontrolled bleeding. This, thanks to the team-work between dentist and hematologist, thanks to careful adjustment of INR and the use of local haemostatic agents, were not encountered any problems with bleeding or intra or postoperative. Conclusion. Surgical treatment of patients with OAT is a real problem for the oral surgeon, to treat every time in association with the hematologist. Applying this type of surgical procedure, different from today’s guidelines, in our experience there were no post-operative complications (bleeding or bleeding); osseointegration has not been compromised and the prosthetic rehabilitation was completed successfully. PMID:25694802
Cohen, Alexander; Jeyaindran, Sinnadurai; Kim, Jae Yeol; Park, Kihyuk; Sompradeekul, Suree; Tambunan, Karmel L; Tran, Huyen; Tsai, I-Chen; Ward, Christopher; Wong, Raymond
Pulmonary embolism (PE) is the principal preventable cause of in-hospital deaths. Prevalence of PE in Asians is uncertain but undoubtedly underestimated. Asians and Caucasians have similar non-genetic risk factors for PE, and there is mounting evidence that PE affects Asians much more commonly than previously supposed; incidence, especially among high-risk patients, may approach that in Caucasians. Furthermore, PE incidence in Asia is increasing, due to both increased ascertainment, and also population ageing and growing numbers of patients with predisposing risk factors. Despite being warranted, thromboprophylaxis for high-risk patients is not routine in Pacific Asian countries/regions. There also appears to be scope to implement venous thromboembolism (VTE) management guidelines more assiduously. Anticoagulants, primarily heparins and warfarin, have been the mainstays of VTE management for years; however, these agents have limitations that complicate routine use. The complexity of current guidelines has been another barrier to applying evidence-based recommendations in everyday practice. Updated management approaches have considerable potential to improve outcomes. New oral anticoagulants that are easier to administer, require no, or much less, monitoring or dose-adjustment and have a favourable risk/benefit profile compared with conventional modalities, may offer an alternative with the potential to simplify VTE management. However, more information is required on practical management and the occurrence and treatment of bleeding complications. Increasing recognition of the burden of PE and new therapeutic modalities are altering the VTE management landscape in Pacific Asia. Consequently, there is a need to further raise awareness and bridge gaps between the latest evidence and clinical practice. PMID:26139085
Children generally reject taking medicine which does not have a favorable shape, taste, flavor, etc. However, if a child who needs to take a medicine, rejects taking it, he might never recover from his condition. When a child is unable to take medicine orally, it is intravenously administered, and he and his caregivers then may experience stress. Syrups and suspensions are considered as favorable types of dosage forms in which to orally administer medicine to infants and children. However, they may have disadvantages such as solubility, a bad taste, portability problems or required refrigerator storage. World Health Organization (WHO) currently favors that infants and children be treated with oral solid medicines. New oral solid tablets, such as a mini-tablet, instead of liquid medicines are proposed for this group, however, there are a few reports that mini-tablets are suitable for infants and children. Palatability is one of the main elements of patient acceptability of an oral pediatric medicine. Palatability is defined as the overall appreciation of an oral medicinal product in relation to its smell, taste, aftertaste and feeling in the mouth. Design of the formulation of an oral pediatric medicine should be considered together with its palatability. PMID:25747220
Pettifor, J. M.; Benson, R.
Reported are case histories of three infants with congenital malformations (including defective formation of the nose and hands) associated with ingestion of oral anticoagulants during the first trimester of pregnancy. (CL)
Spivak, Inna E
Anticoagulation is an important strategy for the prevention of stroke associated with atrial fibrillation. Development of new oral agents has created a need to educate nurses to administer these medications and provide patient education. PMID:26306367
There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (<11 mg/week, 11–21 mg/week, >21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in
Tong, Hoi Y; Dávila-Fajardo, Cristina Lucía; Borobia, Alberto M; Martínez-González, Luis Javier; Lubomirov, Rubin; Perea León, Laura María; Blanco Bañares, María J; Díaz-Villamarín, Xando; Fernández-Capitán, Carmen; Cabeza Barrera, José; Carcas, Antonio J
There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (<11 mg/week, 11-21 mg/week, >21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in
Sherwood, Matthew W.; Becker, Richard C.
Atrial fibrillation is a common arrhythmia. One of the important aspects of the management of atrial fibrillation is stroke prevention. Warfarin has been the longstanding anticoagulant used for stroke prevention in patients with atrial fibrillation. There are now three novel oral anticoagulants, which have been studied in randomized controlled trials and subsequently approved by the Federal Drug Administration for stroke prevention in patients with atrial fibrillation. Special patient populations, including renal insufficiency, elderly, prior stroke, and extreme body weights, were represented to varying degrees in the clinical trials of the novel oral anticoagulants. Furthermore, there is variation in the pharmacokinetics and pharmacodynamics of each anticoagulant, which affect the patient populations differently. Patients and clinicians are faced with the task of selecting among the available anticoagulants, and this review is designed to be a tool for clinical decision-making. PMID:23846737
Rahmat, Nur A; Lip, Gregory Y H
In the last decade, we have witnessed the emergence of the oral non-vitamin K oral anticoagulants (NOACs), which have numerous advantages compared with the vitamin K antagonists, particularly their lack of need for monitoring; as a result their use is increasing. Nonetheless, the NOACs face two major challenges: the need for reliable laboratory assays to assess their anticoagulation effect, and the lack of approved antidotes to reverse their action. This article provides an overview of monitoring the anticoagulant effect of NOACs and their potential specific antidotes in development. PMID:26835107
Gosselin, R C; Adcock, D M
The introduction of direct oral anticoagulant (DOAC) therapy into clinical use in the past 5 years has had significant impact on the clinical laboratory. Clinicians' desire to determine plasma drug presence or measure drug concentration, and more recent observations regarding the limitations and utility of coagulation testing in the setting of DOAC treatment, suggest that early published recommendations regarding laboratory testing should be reassessed. These initial recommendations, furthermore, were often based on drug-spiked plasma studies, rather than samples from patients receiving DOAC therapy. We have demonstrated that reagent sensitivity varies significantly whether drug-spiked samples or samples from DOAC-treated patients are tested. Data from drug-enriched samples must therefore be interpreted with caution or be used as a guide only. We present laboratory assays that can be used to determine drug presence and to measure drug concentration, and provide recommended testing algorithms. As DOAC therapy may significantly impact on specialty coagulation assays, we review those tests with the potential to give false-positive and false-negative results. PMID:26791879
Yeh, Calvin H; Hogg, Kerstin; Weitz, Jeffrey I
The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges. PMID:25792448
Baber, Usman; Mastoris, Ioannis; Mehran, Roxana
Vitamin K antagonists (VKAs) have long been the standard of care for treatment of venous thromboembolism (VTE), and thromboprophylaxis in atrial fibrillation (AF). Despite their efficacy, their use requires frequent monitoring and is complicated by drug-drug interactions and the need to maintain a narrow therapeutic window. Since 2009, novel oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, have become alternative options to VKAs owing to their predictable and safe pharmacological profiles. The overall clinical effect of these drugs, which is a balance between ischaemic benefit and bleeding harm, varies according to the clinical scenario. As adjunctive therapy to dual antiplatelet therapy in patients with acute coronary syndrome, NOACs are associated with incremental bleeding risks and modest benefits. For treatment of VTE, NOACs have a safer profile than VKAs and a similar efficacy. In thromboprophylaxis in AF, NOACs are associated with the greatest benefits by reducing both ischaemic events and haemorrhagic complications and might reduce mortality compared with VKAs. The role of NOACs continues to evolve as these drugs are evaluated in different patient populations, including those with renal impairment or with AF and undergoing percutaneous coronary intervention. PMID:25367652
Başaran, Özcan; Dogan, Volkan; Beton, Osman; Tekinalp, Mehmet; Aykan, Ahmet Cağri; Kalaycioğlu, Ezgi; Bolat, Ismail; Taşar, Onur; Şafak, Özgen; Kalcik, Macit; Yaman, Mehmet; İnci, Sinan; Altintaş, Bernas; Kalkan, Sedat; Kirma, Cevat; Biteker, Murat
Abstract This study aimed to investigate the potential misuse of novel oral anticoagulants (NOACs) and the physicians’ adherence to current European guideline recommendations in real-world using a large dataset from Real-life Multicenter Survey Evaluating Stroke Prevention Strategies in Turkey (RAMSES Study). RAMSES study is a prospective, multicenter, nationwide registry (ClinicalTrials.gov identifier NCT02344901). In this subgroup analysis of RAMSES study, patients who were on NOACs were classified as appropriately treated (AT), undertreated (UT), and overtreated (OT) according to the European Society of Cardiology (ESC) guidelines. The independent predictors of UT and OT were determined by multivariate logistic regression. Of the 2086 eligible patients, 1247 (59.8%) received adequate treatment. However, off-label use was detected in 839 (40.2%) patients; 634 (30.4%) patients received UT and 205 (9.8%) received OT. Independent predictors of UT included >65 years of age, creatinine clearance ≥50 mL/min, urban living, existing dabigatran treatment, and HAS-BLED score of <3, whereas that of OT were creatinine clearance <50 mL/min, ongoing rivaroxaban treatment, and HAS-BLED score of ≥3. The suboptimal use of NOACs is common because of physicians’ poor compliance to the guideline recommendations in patients with nonvalvular atrial fibrillation (NVAF). Older patients who were on dabigatran treatment with good renal functions and low risk of bleeding were at risk of UT, whereas patients who were on rivaroxaban treatment with renal impairment and high risk of bleeding were at risk of OT. Therefore, a greater emphasis should be given to prescribe the recommended dose for the specified patients. PMID:27583892
Douketis, James; Bell, Alan David; Eikelboom, John; Liew, Aaron
Abstract Objective To address common “what if” questions that arise relating to the long-term clinical follow-up and management of patients receiving the new oral anticoagulants (NOACs). Sources of information For this narrative review, we searched the PubMed database for recent (January 2008 to week 32 of 2013) clinical studies relating to NOAC use for stroke prevention in atrial fibrillation and for the treatment of acute venous thromboembolism. We used this evidence base to address prespecified questions relating to NOAC use in primary care settings. Main message Dabigatran and rivaroxaban should be taken with meals to decrease dyspepsia and increase absorption, respectively. There are no dietary restrictions with any of the NOACs, beyond moderating alcohol intake, and rivaroxaban and apixaban can be crushed if required. The use of acid suppressive therapies does not appear to affect the efficacy of the NOACs. As with warfarin, patients taking NOACs should avoid long-term use of nonsteroidal anti-inflammatory and antiplatelet drugs. For patients requiring surgery, generally NOACs should be stopped 2 to 5 days before the procedure, depending on bleeding risk, and the NOAC should usually be resumed at least 24 hours after surgery. Preoperative coagulation testing is generally unnecessary. In patients who develop bleeding, minor bleeding typically does not require laboratory testing or discontinuation of NOACs; with major bleeding, the focus should be on local measures to control the bleeding and supportive care, and coagulation testing should be performed. There are currently no antidotes to reverse NOACs. The NOACs should not be used in patients with valvular heart disease, prosthetic heart valves, cancer-associated deep vein thrombosis, or superficial thrombophlebitis. Conclusion Management of “what if” scenarios for patients taking NOACs have been proposed, but additional study is needed to address these issues, especially periprocedural management and
Zikria, Jennifer; Ansell, Jack
Vitamin K antagonists (VKA), such as warfarin, have been the only available oral anticoagulants despite their many limitations. The greatest medical need is to find a replacement for warfarin for long-term therapy, particularly for stroke prevention in atrial fibrillation (AF) patients. Emerging oral anticoagulants are free from many of warfarin's drawbacks and may offer a convenient alternative. Drugs in advanced development target factor Xa (rivaroxaban, apixaban) or thrombin (dabigatran etexilate). Recently, the RE-LY phase III study found dabigatran etexilate was an effective and convenient alternative to warfarin in stroke prevention for AF patients. Within the next two years, similar studies comparing rivaroxaban and apixaban versus warfarin in AF patients will become available. This paper reviews warfarin's limitations, discusses the pharmacokinetics of emerging anticoagulants in advanced development, and summarizes trials with an emphasis on head-to-head studies comparing novel anticoagulants to warfarin. PMID:20040270
Blann, A D
Disadvantages with traditional anticoagulants (vitamin K antagonists and heparinoids) have led to the development on non-vitamin K antagonist oral anticoagulants (NOACs). These agents are set to replace the traditional anticoagulants in situations such as following orthopaedic surgery, in atrial fibrillation, and in the prevention and treatment of venous thromboembolism. Although superior to vitamin K antagonists and heparinoids in several aspects, NOACs retain the ability to cause haemorrhage and, despite claims to the contrary, may need monitoring. This review aims to summarise key aspects of the NOACs of relevance to the laboratory. PMID:25562993
Egea-Guerrero, J J; Quintana Díaz, M
The high incidence of trauma, especially in elderly people anticoagulated with new oral anticoagulants (NOAs), has become a major challenge, particularly in critical situations with life-threatening bleeding. Under these circumstances, urgent NOA reversion becomes mandatory. Prothrombin complex has become a frequent indication in critical situations in which rapid reversal of anticoagulation is needed and where the use of fresh frozen plasma is limited. This study offers our point of view regarding the usefulness of NOAs, not only in the prevention of cardioembolic events but also as regards their emergent reversion in cases of severe bleeding associated to trauma. PMID:25510394
Kreuter, Michael; Wijsenbeek, Marlies S; Vasakova, Martina; Spagnolo, Paolo; Kolb, Martin; Costabel, Ulrich; Weycker, Derek; Kirchgaessler, Klaus-Uwe; Maher, Toby M
Procoagulant and antifibrinolytic activity has been associated with idiopathic pulmonary fibrosis (IPF); however, investigation of anticoagulant therapy in IPF has suggested deleterious effects. This post hoc analysis evaluated the effect of medically indicated anticoagulation on mortality and other clinical outcomes in IPF.Patients randomised to placebo (n=624) from three controlled trials in IPF were analysed by oral anticoagulant use. End-points included all-cause and IPF-related mortality, disease progression, hospitalisation, and adverse events, over 1 year.At baseline, 32 (5.1%) patients randomised to placebo were prescribed anticoagulants for non-IPF indications, 29 (90.6%) of whom received warfarin. Unadjusted analyses demonstrated significantly higher all-cause and IPF-related mortality at 1 year in baseline anticoagulant users versus nonusers (15.6% versus 6.3%, p=0.039 and 15.6% versus 3.9%, p=0.002, respectively). In multivariate analyses, baseline use of anticoagulants was an independent predictor of IPF-related mortality (hazard ratio 4.7, p=0.034), but not other end-points. Rates of bleeding and cardiac events did not differ significantly between groups. In an exploratory analysis, anticoagulant use at any time during the study was an independent predictor of all end-points.This post hoc analysis suggests that anticoagulants used for non-IPF indications may have unfavourable effects in IPF patients. Future studies are needed to explore this relationship further. PMID:27103382
Obamiro, Kehinde O; Chalmers, Leanne; Bereznicki, Luke R E
Atrial fibrillation (AF) is a growing public health concern and remains an independent risk factor for ischemic stroke. Warfarin, a commonly used oral anticoagulant, is associated with a 60-70 % relative reduction in stroke risk and a reduction in mortality of 26 %. However, warfarin has several limitations, including a narrow therapeutic window, variable dose response, multiple interactions with other drugs and concurrent illnesses, and the need for frequent laboratory monitoring. In recent years, the direct acting oral anticoagulants (DOACs), including dabigatran, rivaroxaban, apixaban and edoxaban, have been developed to overcome the limitations of warfarin therapy. These treatment strategies are either comparable or superior to warfarin in stroke prevention in AF. Despite the documented effectiveness of oral anticoagulants in AF, patients may not derive optimal benefit if they fail to adhere or fail to continue with their medication. This may lead to treatment failure, increased hospitalization and mortality. This review summarizes the literature regarding adherence and persistence (or discontinuation) rates with oral anticoagulants in the management of AF; the impact of non-adherence and non-persistence on treatment outcomes; and the effectiveness of strategies to improve adherence and persistence with oral anticoagulant therapy. PMID:27262433
... gums or nosebleeds. Oral Medications These mainly include aspirin or clopidogrel (Plavix) and warfarin (Coumadin). These medications ... will decide which one is right for you. Aspirin tends to cause fewer bleeding complications than clopidogrel ...
Bosch, Luis Ángel Bermúdez
Warfarin is the current standard of care in oral anticoagulation therapy. It is commonly prescribed to treat venous thromboembolism, pulmonary embolism, acute myocardial infarction, and to decrease the risk of stroke in atrial fibrillation. Warfarin therapy is challenging because of marked and often unpredictable inter-individual dosing variations that effectively reach and maintain adequate anticoagulation. Several researchers have developed pharmacogenetic-guided maintenance dose algorithms that incorporate genetics and individual patient characteristics. However, there is limited information available concerning dosing during warfarin initiation. This is considered the most clinically challenging therapeutic phase. In such, the risk of recurrent thromboembolism and hemorrhage are elevated. The objective of this retrospective study is to predict the individual initial doses for Puerto Rican patients (n=175) commencing anticoagulation therapy at Veterans Affairs Caribbean Healthcare System (VACHS) using pharmacogenetic/pharmacokinetic-driven model. A pharmacogenetic driven model (R2=0.4809) was developed in Puerto Rican patients and combined with pharmacokinetic formulas that enabled us to predict the individual initial doses for patients (n=121) commencing anticoagulation therapy. WinNonlin® pharmacokinetic-pharmacodynamic simulations were carried out to determine the predictability of this model. This model demonstrated promising results with few (n=10) simulations outside of their respective therapy range. A customized pharmacogenetic-based warfarin maintenance dose algorithm (R2=0.7659) was developed in a derivation cohort of 131 patients. The predictability of this developed pharmacogenetic algorithm was compared with the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm and it demonstrated superior predictability within our study population. PMID:25285240
Stabile, Eugenio; Izzo, Raffaele; Rozza, Francesco; Losi, Maria Angela; Coscioni, Enrico; Trimarco, Bruno
Vitamin K-dependent antagonists (VKAs) are the most commonly used oral anticoagulants. Non-VKA oral anticoagulants (NOACs), directly target factor IIa (dabigatran) or Xa (rivaroxaban, apixaban, and edoxaban) have predictable pharmacological effects and relatively few drug and food interactions compared with VKA. Among NOACs, dabigatran has been extensively tested for stroke prevention in patients with non-valvular atrial fibrillation eligible for oral anticoagulation with VKA. Dabigatran is at least as effective as warfarin at preventing stroke with advantages of less serious bleeding except for gastrointestinal bleeding, which occurs more often than with warfarin. The findings of dabigatran use in randomized trials, post market registries and specific clinical settings are discussed in this article. PMID:27207360
Haustein, K O
Anticoagulants of the cumarin-type (warfarin, phenprocoumon, and acenocoumarol) are drugs for the long-term treatment and prevention of thromboembolic disorders. Because of their narrow therapeutic range, many patients have bleedings of variable severity or have recurrent thrombotic events. For this reason, the study of the pharmacokinetic parameters of phenprocoumon (PPC), considering its influence on blood clotting factors, is of high interest. The elimination kinetics of PPC, its interaction with phytomenadion (vitamin K), and the pharmacokinetic behavior of the anticoagulant under steady-state conditions have been investigated in studies with healthy volunteers and patients taking anticoagulants. The maintenance dose and the plasma levels of PPC were correlated with prothrombin time (PT) in 89 patients treated with PPC. Varying parameters in each patient (e.g., elimination kinetics of PPC, activity of the cumarin-dependent blood-clotting factors, endogenous phytomenadion stores), render it impossible to use a different means of monitoring than that of PT determination. PMID:10327214
Wharin, Caitlin; Tagalakis, Vicky
Patients with cancer are at high risk for venous thromboembolism (VTE). Most clinical guidelines agree that low-molecular-weight heparins (LMWHs) are the preferred anticoagulants for the prevention and treatment of VTE in cancer patients. However, LMWHs require daily injections, weight-adjustment of dose, and can be associated with heparin-induced thrombocytopenia; all of which are important considerations in managing cancer-associated VTE. Comparatively, the new oral anticoagulants offer a more attractive option because of their oral administration, fixed-dose, and lack of routine laboratory monitoring. The results of phase III trials support the efficacy and safety of the new oral anticoagulants in the management of VTE. However, generalizing these findings to cancer patients with VTE is difficult since very few cancer patients were included. In this comprehensive review, we provide an overview of the current treatment of VTE, explore anticoagulant thromboprophylaxis in ambulatory cancer patients, and summarize existing evidence on the efficacy and safety of the new oral anticoagulants for the management of VTE in both non-cancer and cancer populations. PMID:24360911
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Riva, Nicoletta; Ageno, Walter
Anticoagulant treatment can be currently instituted with two different classes of drugs: the vitamin K antagonists (VKAs) and the newer, "novel" or non-vitamin K antagonist oral anticoagulant drugs (NOACs). The NOACs have several practical advantages over VKAs, such as the rapid onset/offset of action, the lower potential for food and drug interactions, and the predictable anticoagulant response. However, the VKAs currently have a broader spectrum of indications, a standardized monitoring test, and established reversal strategies. The NOACs emerged as alternative options for the prevention and treatment of venous thromboembolism and for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Nevertheless, there remain some populations for whom the VKAs remain the most appropriate anticoagulant drug. This article discusses the advantages and disadvantages of VKAs and NOACs. PMID:25703519
Werth, Sebastian; Breslin, Tomás; NiAinle, Fionnuala; Beyer-Westendorf, Jan
Modern direct-acting anticoagulants are rapidly replacing vitamin K antagonists (VKA) in the management of millions of patients worldwide who require anticoagulation. These drugs include agents that inhibit activated factor X (FXa) (such as apixaban and rivaroxaban) or thrombin (such as dabigatran), and are collectively known today as non-VKA oral anticoagulants (NOACs). Since bleeding is the most common and most dangerous side effect of long-term anticoagulation, and because NOACs have very different mechanisms of action and pharmacokinetics compared with VKA, physicians are naturally concerned about the lack of experience regarding frequency, management and outcome of NOAC-associated bleeding in daily care. This review appraises trial and registry (or "real-world") data pertaining to bleeding complications in patients taking NOACs and VKA and provides practical recommendations for the management of acute bleeding situations. PMID:25940651
Arihiro, Shoji; Todo, Kenichi; Yamagami, Hiroshi; Kimura, Kazumi; Furui, Eisuke; Terasaki, Tadashi; Shiokawa, Yoshiaki; Kamiyama, Kenji; Takizawa, Shunya; Okuda, Satoshi; Okada, Yasushi; Kameda, Tomoaki; Nagakane, Yoshinari; Hasegawa, Yasuhiro; Mochizuki, Hiroshi; Ito, Yasuhiro; Nakashima, Takahiro; Takamatsu, Kazuhiro; Nishiyama, Kazutoshi; Kario, Kazuomi; Sato, Shoichiro; Koga, Masatoshi; Nagatsuka, K; Minematsu, K; Nakagawara, J; Akiyama, H; Shibazaki, K; Maeda, K; Shibuya, S; Yoshimura, S; Endo, K; Miyagi, T; Osaki, M; Kobayashi, J; Okata, T; Tanaka, E; Sakamoto, Y; Takizawa, H; Takasugi, J; Tokunaga, K; Homma, K; Kinoshita, N; Matsuki, T; Higashida, K; Shiozawa, M; Kanai, H; Uehara, S
Background Large clinical trials are lack of data on non‐vitamin K antagonist oral anticoagulants for acute stroke patients. Aim To evaluate the choice of oral anticoagulants at acute hospital discharge in stroke patients with nonvalvular atrial fibrillation and clarify the underlying characteristics potentially affecting that choice using the multicenter Stroke Acute Management with Urgent Risk‐factor Assessment and Improvement‐NVAF registry (ClinicalTrials.gov NCT01581502). Method The study included 1192 acute ischemic stroke/transient ischemic attack patients with nonvalvular atrial fibrillation (527 women, 77·7 ± 9·9 years old) between September 2011 and March 2014, during which three nonvitamin K antagonist oral anticoagulant oral anticoagulants were approved for clinical use. Oral anticoagulant choice at hospital discharge (median 23‐day stay) was assessed. Results Warfarin was chosen for 650 patients, dabigatran for 203, rivaroxaban for 238, and apixaban for 25. Over the three 10‐month observation periods, patients taking warfarin gradually decreased to 46·5% and those taking nonvitamin K antagonist oral anticoagulants increased to 48·0%. As compared with warfarin users, patients taking nonvitamin K antagonist oral anticoagulants included more men, were younger, more frequently had small infarcts, and had lower scores for poststroke CHADS 2, CHA 2 DS 2‐VASc, and HAS‐BLED, admission National Institutes of Health stroke scale, and discharge modified Rankin Scale. Nonvitamin K antagonist oral anticoagulants were started at a median of four‐days after stroke onset without early intracranial hemorrhage. Patients starting nonvitamin K antagonist oral anticoagulants earlier had smaller infarcts and lower scores for the admission National Institutes of Health stroke scale and the discharge modified Rankin Scale than those starting later. Choice of nonvitamin K antagonist oral anticoagulants was independently associated with 20‐day or
Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide. Strokes that occur as a complication of AF are usually more severe and associated with a higher disability or morbidity and mortality rate compared with non-AF-related strokes. The risk of stroke in AF is dependent on several risk factors; AF itself acts as an independent risk factor for stroke. The combination of effective anticoagulation therapy, risk stratification (based on stroke risk scores, such as CHADS2 and CHA2DS2-VASc), and recommendations provided by guidelines is essential for decreasing the risk of stroke in patients with AF. Although effective in preventing the occurrence of stroke, vitamin K antagonists (VKAs; eg, warfarin) are associated with several limitations. Therefore, direct oral anticoagulants, such as apixaban, dabigatran etexilate, edoxaban, and rivaroxaban, have emerged as an alternative to the VKAs for stroke prevention in patients with nonvalvular AF. Compared with the VKAs, these agents have more favorable pharmacological characteristics and, unlike the VKAs, they are given at fixed doses without the need for routine coagulation monitoring. It remains important that physicians use these direct oral anticoagulants responsibly to ensure optimal safety and effectiveness. This article provides an overview of the existing data on the direct oral anticoagulants, focusing on management protocols for aiding physicians to optimize anticoagulant therapy in patients with nonvalvular AF, particularly in special patient populations (eg, those with renal impairment) and other specific clinical situations. PMID:26089678
Ansell, Jack E
The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin. PMID:26872887
Tummala, Ramyashree; Kavtaradze, Ana; Gupta, Anjan; Ghosh, Raktim Kumar
The Vitamin K antagonist warfarin was the only oral anticoagulant available for decades for the treatment of thrombosis and prevention of thromboembolism until Direct Oral Anticoagulants (DOACs); a group of new oral anticoagulants got approved in the last few years. Direct thrombin inhibitor: dabigatran and factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban directly inhibit the coagulation cascade. DOACs have many advantages over warfarin. However, the biggest drawback of DOACs has been the lack of specific antidotes to reverse the anticoagulant effect in emergency situations. Activated charcoal, hemodialysis, and activated Prothrombin Complex Concentrate (PCC) were amongst the nonspecific agents used in a DOAC associated bleeding but with limited success. Idarucizumab, the first novel antidote against direct thrombin inhibitor dabigatran was approved by US FDA in October 2015. It comprehensively reversed dabigatran-induced anticoagulation in a phase I study. A phase III trial on Idarucizumab also complete reversal of anticoagulant effect of dabigatran. Andexanet alfa (PRT064445), a specific reversal agent against factor Xa inhibitors, showed a complete reversal of anticoagulant activity of apixaban and rivaroxaban within minutes after administration without adverse effects in two recently completed parallel phase III trials ANNEXA-A and ANNEXA-R respectively. It is currently being studied in ANNEXA-4, a phase IV study. Aripazine (PER-977), the third reversal agent, has shown promising activity against dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH. This review article summarizes pharmacological characteristics of these novel antidotes, coagulation's tests affected, available clinical and preclinical data, and the need for phase III and IV studies. PMID:27082776
Albert, Nancy M
Atrial fibrillation (AF), a common arrhythmia, increases the risk of ischemic stroke. Stroke and bleeding scores for patients with AF can help to stratify risk and determine the need for antithrombotic therapy, for which warfarin has been the gold standard. Although highly effective, warfarin has several limitations that can lead to its underuse. Data from randomized, Phase III clinical trials of the novel oral anticoagulants, dabigatran, a direct thrombin inhibitor, and rivaroxaban and apixaban, both factor Xa inhibitors, indicate these drugs are at least noninferior to warfarin for the prevention of stroke and systemic embolism. They are easier to administer, and have an equivalent or lower risk of bleeding versus warfarin. A better understanding of the risks and benefits of the novel oral anticoagulants, and their use in clinical practice, will prepare clinicians to anticipate and address educational and clinical needs of AF patients and their families, and promote evidence-based prescription of appropriate and safe anticoagulation therapy. PMID:24373340
Comerota, Anthony J; Ramacciotti, Eduardo
Venous thromboembolism (VTE) is a prevalent, potentially fatal health problem. Although standard anticoagulant therapy is effective when compared with the newer direct oral anticoagulants (DOACs), it has disadvantages. Heparin and its derivatives must be administered parenterally, whereas use of oral vitamin K antagonists is complicated by unpredictable pharmacokinetics and pharmacodynamics, drug-food and drug-drug interactions and the requirement for frequent laboratory monitoring. Randomized phase 3 trials have demonstrated that patients receive similarly effective anticoagulation with the DOACs dabigatran, edoxaban, rivaroxaban and apixaban when compared with warfarin, with similar or reduced risk of bleeding. Extended therapy trials have consistently demonstrated superior effectiveness for DOAC treatment when compared with placebo in preventing VTE recurrence. This article presents a comprehensive review of the pharmacokinetics, pharmacodynamics and accumulated clinical trial evidence for each DOAC for short-term, long-term and extended VTE therapy, and it considers the potential implications these agents have for the clinical management of VTE. PMID:27432042
Goodarzi, Navid; Barazesh Morgani, Ahmadreza; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Langguth, Peter; Mehta, Mehul U; Polli, James E; Shah, Vinod P; Dressman, Jennifer B
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing ribavirin are reviewed. Ribavirin is highly soluble, but its permeability characteristics are not well defined. Therefore according to the Biopharmaceutical Classification System, and taking a "worst case" approach, ribavirin should be assigned to class III. As ribavirin is transported across the brush border membrane of the human jejunum by hCNT2, it shows saturable uptake in the intestine. However, no common excipients have been shown to compete for ribavirin absorption, nor have problems with BE of immediate release ribavirin formulations containing different excipients and produced by different manufacturing methods been reported in the open literature. So the risk of bioinequivalence caused by these factors appears to be low. Ribavirin is considered a narrow therapeutic index drug, as judged by comparing the minimum effective concentration and minimum toxic concentrations in blood. Although ribavirin would not be eligible for approval via a Biopharmaceutical Classification System-based biowaiver procedure according to today's guidances due to its narrow therapeutic index, the risks of biowaiving should be weighed against the considerable risks associated with studying BE of ribavirin products in healthy subjects. PMID:26952879
This review discusses the basic pharmacology of new oral anticoagulants that are used for prevention of thromboembolism in patients with atrial fibrillation. It presents available evidence, and provides recommendations for the management of patients requiring invasive procedures in dental practice. PMID:26835072
Zeus, Tobias; Kelm, Malte; Bode, Christoph
Thrombo-embolic prophylaxis is a key element within the therapy of atrial fibrillation/atrial flutter. Besides new oral anticoagulants the concept of left atrial appendage occlusion has approved to be a good alternative option, especially in patients with increased risk of bleeding. PMID:26261929
Galanis, Taki; Keiffer, Gina; Merli, Geno
Background Several novel oral anticoagulants have been studied for the prevention and treatment of venous thromboembolism (VTE) in different patient populations. Clinicians will increasingly encounter scenarios in which they must choose among these and conventional anticoagulants for the treatment of this potentially fatal condition. Objective To review the results of Phase III clinical trials that investigated the novel oral anticoagulants for the treatment of deep vein thrombosis and pulmonary embolism. Potential advantages and disadvantages of these anticoagulant agents with respect to each other and conventional therapy will also be explored through a case-based approach. Methods A literature search in PubMed was conducted that identified Phase III clinical trials investigating the novel oral anticoagulant agents for the treatment of VTE. Results The new oral anticoagulant agents have been shown to be as safe and effective for the treatment of VTE as conventional therapies. Conclusions These novel, oral anticoagulant agents are legitimate options for the treatment of VTE. A careful assessment of a patient׳s comorbidities, medication use, and laboratory results should be undertaken before prescribing the new oral anticoagulant agents for patients with VTE. PMID:25352938
Kirley, Kate; Qato, Dima M.; Kornfield, Rachel; Stafford, Randall S.; Alexander, G. Caleb
Background Little is known regarding the adoption of direct thrombin inhibitors in clinical practice. We examine trends in oral anticoagulation for the prevention of thromboembolism in the United States. Methods and Results We used the IMS Health National Disease and Therapeutic Index, a nationally representative audit of office-based providers, to quantify patterns of oral anticoagulant use among all subjects and stratified by clinical indication. We quantified oral anticoagulant expenditures using the IMS Health National Prescription Audit. Between 2007 and 2011, warfarin treatment visits declined from approximately 2.1 million [M] quarterly visits to approximately 1.6M visits. Dabigatran use increased from 0.062M quarterly visits (2010Q4) to 0.363M visits (2011Q4), reflecting its increasing share of oral anticoagulant visits from 3.1% to 18.9%. In contrast to warfarin, the majority of dabigatran visits have been for atrial fibrillation, though this proportion decreased from 92% (2010Q4) to 63% (2011Q4), with concomitant increases in dabigatran’s off-label use. Among atrial fibrillation visits, warfarin use decreased from 55.8% of visits (2010Q4) to 44.4% (2011Q4), while dabigatran use increased from 4.0% to 16.9%. Of atrial fibrillation visits, the fraction not treated with any oral anticoagulants has remained unchanged at approximately 40%. Expenditures related to dabigatran increased rapidly from $16M in 2010Q4 to $166M in 2011Q4, exceeding expenditures on warfarin ($144M) in 2011Q4. Conclusions Dabigatran has been rapidly adopted into ambulatory practice in the United States, primarily for treatment of atrial fibrillation, but increasingly for off-label indications. We did not find evidence that it has increased overall atrial fibrillation treatment rates. PMID:22949490
Madan, Shivanshu; Shah, Shenil; Partovi, Sasan
The increasing availability of novel oral anticoagulants (NOAC) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) offers alternatives for patients currently prescribed warfarin. This article provides a brief overview on the mechanism and clinical use of these drugs as well as a review of the pivotal clinical trials providing the basis for each agent’s safety and efficacy. While these agents are currently Food and Drug Administration (FDA) approved for anticoagulation of patients with nonvalvular AF, additional studies continually emerge offering further insight into the application of these agents in other areas. PMID:25276617
New oral anticoagulants (NOACs) have been introduced to improve anticoagulant therapy worldwide, but safe implementation may require additional measures. First, optimization of dose adjustment based on therapeutic levels of the drug may be more appropriate than fixed dose therapy. The development and implementation in quantitative laboratory assays will enable further dose optimization. Second, non-adherence to medication is a potential threat to the safe use of NOACs. Since cardiovascular medication may not be optimally used in about 50% of patients, procedures to improve adherence are imperative, also for NOAC therapy and in particular in elderly patients. PMID:23809888
Pannach, Sven; Beyer-Westendorf, Jan
Anti-coagulated patients often undergo endoscopic procedures and non-vitamin-K-antagonist oral anticoagulants (NOAC) are increasingly prescribed. Consequently, a comprehensive knowledge about the adequate peri-interventional handling of these substances is required. A standardized approach needs to be planned for elective and emergency situations. As a result of their pharmacokinetics, the peri-endoscopic management of NOAC is relatively easy - an heparin "bridging"/"switching" is usually not required. In case of a severe NOAC bleeding endoscopic treatment must be considered at an early stage. PMID:26261933
Satger, Bernadette; Blaise, Sophie; Fontaine, Michèle; Yver, Jacqueline; Allenet, Benoît; Baudrant, Magali; Pernod, Gilles; Bosson, Jean-Luc
The vitamin K antagonists (VKA) remain to this day the only oral form of therapeutic anticoagulation. Approximately 1% of the French population, mainly elderly, is treated with these anticoagulants. Oral anticoagulants have significant risks of iatrogenic complications; indeed they are the leading cause of such drug-induced complications, predominantly hemorrhages. AFSSAPS (French Drug and Medical Products Agency) clinical practice recommendations, repeatedly disseminated, emphasize the education of patients receiving VKAs. Managing oral anticoagulant treatment is challenging, with a significant risk of under- or overdosing and consequently, thrombosis or hemorrhage. The therapeutic window is narrow, multiple drug-interactions are possible, and the specific dose required for a particular individual to achieve appropriate International Normalized Ratio (INR) levels is unpredictable. The literature contains few randomized controlled trials about the efficacy of education for patients treated with oral anticoagulants. These education programs are not standardized and are therefore varied and difficult to compare. Nevertheless, studies demonstrate the importance of patient education programs in reducing the risk of hemorrhage and achieving better treatment stability. The Grenoble region hospital-community network for vascular diseases (GRANTED) has developed an education program for these patients, consisting of individual sessions for the patient and/or a friend or family member (either at a health care facility or at the patient's home), telephone support and group sessions, and using educational tools and supports. There is also a link with the general practitioner who receives a report. This approach makes it possible to adapt the educational message to individual patients and their daily lives, as well as directly involving them in the management of their treatment. PMID:19815369
Messerschmidt, Cory; Friedman, Richard J
Anticoagulant medications help to reduce the risk of thromboembolic events after total hip arthroplasty and total knee arthroplasty. Traditionally, this has been accomplished with medications, such as low-molecular-weight heparin and warfarin. However, these traditional anticoagulants possess a variety of shortcomings that leave much room for improvement. A new class of oral anticoagulants is now available, and present a more convenient option for safe and efficacious thromboprophylaxis in post arthroplasty patients, particularly in the outpatient setting. This review focuses on the direct thrombin inhibitor, dabigatran, and the selective factor Xa inhibitors, rivaroxaban and apixaban, and the clinical data to date about their use in total hip arthroplasty and total knee arthroplasty patients. PMID:25767271
Reisenwitz, T H; Wimbish, G J
The capsule dosage form in nonprescription pharmaceuticals persists as being one of the most vulnerable to product tampering. This study examines consumer preference toward three solid oral dosage forms (capsules, caplets, and tablets) in nonprescription products. Thirteen independent variables representing dosage form attributes are measured on semantic differential scales. The data are analyzed using analysis of variance (ANOVA) and factor analysis. Implications for the pharmaceutical marketer are noted. Future directions for research are also outlined. PMID:10159645
Chang, Jeremy B.; Quinnies, Kayla M.; Realubit, Ronald; Karan, Charles; Rand, Jacob H.; Tatonetti, Nicholas P.
A central challenge in designing and administering effective anticoagulants is achieving the proper therapeutic window and dosage for each patient. The Hill coefficient, nH, which measures the steepness of a dose-response relationship, may be a useful gauge of this therapeutic window. We sought to measure the Hill coefficient of available anticoagulants to gain insight into their therapeutic windows. We used a simple fluorometric in vitro assay to determine clotting activity in platelet poor plasma after exposure to various concentrations of anticoagulants. The Hill coefficient for argatroban was the lowest, at 1.7 ± 0.2 (95% confidence interval, CI), and the Hill coefficient for fondaparinux was the highest, at 4.5 ± 1.3 (95% CI). Thus, doubling the dose of fondaparinux from its IC50 would decrease coagulation activity by nearly a half, whereas doubling the dose of argatroban from its IC50 would decrease coagulation activity by merely one quarter. These results show a significant variation among the Hill coefficients, suggesting a similar variation in therapeutic windows among anticoagulants in our assay. PMID:27439480
Peacock, W Frank
The therapeutic landscape for anticoagulation management is undergoing a shift from the use of traditional anticlotting agents such as heparins and warfarin as the only options to the growing adoption of newer target-specific oral anticoagulants (TSOACs) with novel mechanisms of action. Dabigatran, the first TSOAC approved for use in the United States, is a direct competitive inhibitor of thrombin. It has predictable kinetics, with an elimination half-life of 12 to 17 hours in healthy volunteers. Apixaban and rivaroxaban are selective inhibitors of factor Xa, and also display first-order kinetics. In younger healthy individuals, apixaban has an apparent half-life of approximately 12 hours, whereas rivaroxaban has an elimination half-life of 5 to 9 hours. Understanding the pharmacologic properties of these newer drugs can lead to better insights regarding their respective safety and efficacy profiles and their application in clinical practice. Laboratory assessments have been developed to measure the anticoagulant efficacy of these newer agents. However, the results of these tests can be highly variable, and are therefore not always useful for monitoring the anticoagulation effects of these agents. In addition, several strategies have been documented for the potential reversal of the anticoagulant effects of these drugs, from the temporary discontinuation of an agent before elective surgery to suggested emergency procedures in the case of major bleeding events. New, specific reversal agents for dabigatran, apixaban, and rivaroxaban are currently being developed, and dabigatran has received fast-track designation from the US Food and Drug Administration. Until comprehensive clinical guidelines are developed, institutions involved in emergency care should establish their own procedures for the management of patients undergoing anticoagulation who require emergency treatment. These protocols should include appropriate laboratory testing to assess anticoagulant activity
Lassen, Michael R
For many years, vitamin K antagonists, unfractionated heparins, low-molecular-weight heparins and a pentasaccharide were the only anticoagulant drugs available for the prevention of venous thromboembolism after surgery. However, their benefits were associated with disadvantages, such as their subcutaneous route of administration or the need for coagulation monitoring. Research was challenged to develop new drugs that would simplify thromboprophylaxis while showing equivalent or better efficacy. Rivaroxaban and dabigatran are now available in some countries for the prevention of venous thromboembolism after total hip or knee replacement in adults. Apixaban is also undergoing trials for this indication. Additionally, these drugs show potential for stroke prevention in atrial fibrillation, treatment of venous thromboembolism and prevention of secondary events in acute coronary syndrome. PMID:19548861
Verheugt, Freek W A; Granger, Christopher B
In patients with non-valvular atrial fibrillation, oral anticoagulation with vitamin K antagonists reduces the risk of stroke by more than 60%. But vitamin K antagonists have limitations, including causing serious bleeding such as intracranial haemorrhage and the need for anticoagulation monitoring. In part related to these limitations, they are used in only about half of patients who should be treated according to guideline recommendations. In the past decade, oral agents have been developed that directly block the activity of thrombin (factor IIa), as well as drugs that directly inhibit activated factor X (Xa), which is the first protein in the final common pathway to the activation of thrombin. These novel non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to be at least as good as warfarin for stroke prevention in atrial fibrillation and they have proved to have better safety profiles. Their net advantage is underscored by significantly lower all-cause mortality compared with warfarin in large clinical trials. Because of these features and their ease of use, they are recommended for stroke prevention in atrial fibrillation. They have also a fast onset and offset of action, but they currently lack specific antidotes. This paper addresses the role of anticoagulation for stroke prevention in atrial fibrillation in the era of NOACs, with a focus on special situations including management in the event of bleeding and around the time of procedures including cardioversion, catheter ablation, and device implantation. Also their use in patients with concomitant coronary artery disease, with advanced age, with chronic kidney disease, or with valvular heart disease will be discussed as well as the interaction of NOACs with other cardiac medication, and switching between anticoagulants. PMID:25777666
Kowalski, Zbigniew; Kowalski, Piotr; Grzegorek, Damian
The optimal and the most effective treatment of pulmonary embolism is still a matter of concern and each day sees a new set of challenges for the world of medicine. The progress, has been made in recent years, improved quality of life and caused much better treatment results. This is difficult issue in patients, receiving anticoagulant therapy, because they require an individual approach and adjustability to the therapeutic possibilities. The benefits of long-term anticoagulant therapy, which decreases relapses of idiopathic venous thromboembolism and diminishes risk of thromboembolic complications, should be taking under consideration. It is still a matter of dispute the time of carrying out of treatment, especially after the first life idiopathic episode of pulmonary embolism. The purpose of this paper is an overview and a summary of the foregoing achievements concerned the standards of idiopathic pulmonary embolism treatment, expecting benefits flowing with using new oral anticoagulants, as an alternative to known for decades Vitamin K antagonist drugs. A lot of information about new oral anticoagulants speaks in favor of their use, but unknown safety of the drugs caused searching the best strategy of pulmonary embolism treatment all the time. PMID:27590653
Chan, Noel C; Eikelboom, John W; Weitz, Jeffrey I
The direct oral anticoagulants (DOACs) represent a major advance in oral anticoagulant therapy and have replaced the vitamin K antagonists as the preferred treatment for many indications. By simplifying long-term anticoagulant therapy and improving its safety, the DOACs have the potential to reduce the global burden of thrombosis. Postmarketing studies suggest that the favorable results achieved with DOACs in the randomized controlled trials can be readily translated into practice, but highlight the need for appropriate patient, drug and dose selection, and careful follow-up. Leveraging on their success to date, ongoing studies are assessing the utility of DOACs for the prevention of thrombosis in patients with embolic stroke of unknown source, heart failure, coronary artery disease, peripheral artery disease, antiphospholipid syndrome, and cancer. The purpose of this article is to (1) review the pharmacology of the DOACs, (2) describe the advantages of the DOACs over vitamin K antagonists, (3) summarize the experience with the DOACs in established indications, (4) highlight current challenges and limitations, (5) highlight potential new indications; and (6) identify future directions for anticoagulant therapy. PMID:27126650
Ernestus, R I; Speder, B; Pakos, P; Hildebrandt, G; Klug, N
Intracerebral hemorrhage (ICH) during oral anticoagulation is a serious complication, which is mostly fatal for the multimorbid patient. In the present retrospective study of 53 patients with ICH during treatment with a cumarin derivative (Phenoprocoumon, Marcumar), we investigated the relationship between therapy and preexisting parameters such as age, location, level of consciousness, additional bleeding risks, and the degree of anticoagulation, which were assumed to be of prognostic relevance. The therapeutic management of ICH during treatment with anticoagulants was determined predominantly by location of the hematoma, patient's age, and additional bleeding risks, but less by level of consciousness and initial thromboplastin time (Quick's test). As a consequence of the individual analysis of these 5 parameters, age over 60 years, location of hematoma in the midline or ventricles, coma, additional bleeding risks such as arterial hypertension and trauma, and Quick's test below 15% at the time of bleeding were supposed to be responsible for poor prognosis. Mortality increased with a rising number of poor prognostic factors, independently of surgical or conservative treatment. In consequence, prognosis of ICH during oral anticoagulation is predominantly influenced by the number of such disadvantageous indicators and only little by therapy. PMID:8053274
Kowalski, Zbigniew; Kowalski, Piotr; Grzegorek, Damian
The optimal and the most effective treatment of pulmonary embolism is still a matter of concern and each day sees a new set of challenges for the world of medicine. The progress, has been made in recent years, improved quality of life and caused much better treatment results. This is difficult issue in patients, receiving anticoagulant therapy, because they require an individual approach and adjustability to the therapeutic possibilities. The benefits of long-term anticoagulant therapy, which decreases relapses of idiopathic venous thromboembolism and diminishes risk of thromboembolic complications, should be taking under consideration. It is still a matter of dispute the time of carrying out of treatment, especially after the first life idiopathic episode of pulmonary embolism. The purpose of this paper is an overview and a summary of the foregoing achievements concerned the standards of idiopathic pulmonary embolism treatment, expecting benefits flowing with using new oral anticoagulants, as an alternative to known for decades Vitamin K antagonist drugs. A lot of information about new oral anticoagulants speaks in favor of their use, but unknown safety of the drugs caused searching the best strategy of pulmonary embolism treatment all the time. PMID:27591448
Burnett, Allison E; Mahan, Charles E; Vazquez, Sara R; Oertel, Lynn B; Garcia, David A; Ansell, Jack
Venous thromboembolism (VTE) is a serious medical condition associated with significant morbidity and mortality, and an incidence that is expected to double in the next forty years. The advent of direct oral anticoagulants (DOACs) has catalyzed significant changes in the therapeutic landscape of VTE treatment. As such, it is imperative that clinicians become familiar with and appropriately implement new treatment paradigms. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance for VTE treatment with the DOACs. When possible, guidance statements are supported by existing published evidence and guidelines. In instances where evidence or guidelines are lacking, guidance statements represent the consensus opinion of all authors of this manuscript and are endorsed by the Board of Directors of the Anticoagulation Forum.The authors of this manuscript first developed a list of pivotal practical questions related to real-world clinical scenarios involving the use of DOACs for VTE treatment. We then performed a PubMed search for topics and key words including, but not limited to, apixaban, antidote, bridging, cancer, care transitions, dabigatran, direct oral anticoagulant, deep vein thrombosis, edoxaban, interactions, measurement, perioperative, pregnancy, pulmonary embolism, reversal, rivaroxaban, switching, \\thrombophilia, venous thromboembolism, and warfarin to answer these questions. Non- English publications and publications > 10 years old were excluded. In an effort to provide practical information about the use of DOACs for VTE treatment, answers to each question are provided in the form of guidance statements, with the intent of high utility and applicability for frontline clinicians across a multitude of care settings. PMID:26780747
Dennis, V C; Thomas, B K; Hanlon, J E
Concomitant therapy with warfarin and nonsteroidal antiinflammatory drugs (NSAIDs) is of concern due to the potential for increased bleeding. Nonsteroidal antiinflammatory drugs may alter patient response to warfarin by pharmacodynamic or pharmacokinetic interactions. A man receiving long-term, stable warfarin therapy experienced a significant increase in international normalized ratio 1 week after nabumetone was added to his regimen. Despite prompt reduction of the warfarin dosage, he experienced hemarthrosis of his right knee. Previous reports suggested lack of interaction between nabumetone and warfarin. Caution and close monitoring are advisable when the two agents are administered concomitantly. PMID:10678303
Cuker, Adam; Siegal, Deborah M.; Crowther, Mark A.; Garcia, David A.
Background The target-specific oral anticoagulant agents (TSOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations. Objectives This study’s objective is to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban. Methods We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Results We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R2 0.92–0.99) and ecarin-based assays (R2 0.92–1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. In terms of rivaroxaban and apixaban, anti-Xa activity is linear (R2 0.89–1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification. Conclusions Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in TSOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed. PMID:25212648
Schaefer, Jordan K; McBane, Robert D; Wysokinski, Waldemar E
The novel oral anticoagulants or direct oral anticoagulants (DOAC) are becoming more common in clinical practice for the prevention of stroke in non-valvular atrial fibrillation (NVAF). The availability of several agents with similar efficacy and safety for stroke prevention in NVAF patients offers more selection, but at the same time requires certain knowledge to make a good choice. This comparative analysis provides an appraisal of the respective clinical trials and highlights much of what remains unknown about four FDA-approved agents: dabigatran, apixaban, rivaroxaban, and edoxaban. It details how the DOACs compare to warfarin and to one another summarizes pharmacologic and pharmacodynamic properties, and drug interactions from the stand point of practical consequences of these findings. Common misconceptions and reservations are addressed. The practical application of this data is intended to help choosing the most appropriate agent for individual NVAF patient. PMID:26658769
Stoltenberg, I; Breitkreutz, J
The new European regulations on paediatric medicines and recent WHO recommendations have induced an increased need for research into novel child-appropriate dosage forms. The aim of this study was the development of orally disintegrating mini-tablets (ODMTs) as a suitable dosage form for paediatric patients. The suitability of five commercially available ready-to-use tableting excipients, Ludiflash, Parteck ODT, Pearlitol Flash, Pharmaburst 500 and Prosolv ODT, to be directly compressed into mini-tablets, with 2 mm in diameter, was examined. All of the excipients are based on co-processed mannitol. Drug-free ODMTs and ODMTs with a child-appropriate dose of hydrochlorothiazide were investigated. ODMTs could be produced with all investigated excipients. ODMTs with a sufficient crushing strength >7 N and a low friability <1% could be obtained, as well as ODMTs with a short simulated wetting test-time <5 s. ODMTs made of Ludiflash showed the best results with crushing strengths from 7.8 N up to 11.8 N and excellent simulated wetting test-times from 3.1 s to 5.0 s. For each excipient, ODMTs with accordance to the pharmacopoeial specification content uniformity could be obtained. The promising results indicate that orally disintegrating mini-tablets may serve as a novel platform technology for paediatrics in future. PMID:21324357
Reiffel, James A
For clinicians, atrial fibrillation (AFib) is not a disease that will probably be "cured" at some point during their professional lifetime. (online video available at: http://education.amjmed.com/video.php?event_id=445&stage_id=5&vcs=1). AFib is a condition that occurs in association with aging, affecting as many as 1 in 10 patients by the time they reach age 85, and therefore all physicians who read The American Journal of Medicine should be aware of AFib-its etiology, how to recognize it, and with some idea of how it is treated. Perhaps the most important aspect of AFib, however, is as a risk factor for systemic embolism and stroke, which means that almost all patients with AFib will need to receive anticoagulation therapy, probably for the rest of their lives. For the past several decades the only oral anticoagulant agent has been warfarin. Warfarin is an effective anticoagulant, but for many reasons (patient adherence, physician reluctance, warfarin's narrow therapeutic efficacy), less than half of the patients who should be anticoagulated are prescribed warfarin (dropping to less than a third in older patients), and of those who are prescribed and apparently adherent, less than a third maintain serum warfarin levels in the narrow therapeutic range of INR 2-3. Thus, it is clear that the traditional prescription of warfarin for patients with AFib has failed to meet an important need for reducing risk of systemic embolism and stroke. Fortunately, however, within the last couple of years a new generation of novel oral anticoagulant (NOAC) agents has proven successful in randomized clinical trials and has been passing through the regulatory approval process. For physicians this represents both a challenge-to learn and understand the evidence base for these new anticoagulant therapies-and the opportunity now to treat their aging patients who are increasingly likely to present with cerebrovascular disease risks and who are depending on their physicians to treat them
Johnson, Stacy A.; Yarbrough, Peter M.; Rose, Richard S.; Lanspa, Michael J.
Target-specific oral anticoagulants have been rapidly adopted into clinical practice for stroke prophylaxis and venous thromboembolism treatment, raising concerns about off-label prescribing practices. We conducted a retrospective review of consecutive patients prescribed dabigatran, rivaroxaban or apixaban prior to inpatient hospitalization over an 18-month period to examine the off-label prescribing frequency, contraindications and related complications. Chart review included baseline demographics, hospital admitting service, outpatient prescribing service, renal function, therapeutic indication, echocardiographic findings, contraindications, major bleeding events and vital status. We identified 160 patients who received a target-specific oral anticoagulant prior to hospitalization. Over half (53.1%) of the patients received rivaroxaban, 43.7% received dabigatran and 3.1% received apixaban. Atrial fibrillation (68.1%) and venous thromboembolism treatment (25.6%) were the most common indications. Ninety percent of patients had a U.S. Foods and Drugs Administration (FDA)-approved indication for therapy. Major bleeding events occurred in 4.4% of patients. Cardiology was the most common prescribing and admitting service (43.8 and 31.3%), and more frequently adhered to FDA-approved indications (97 vs. 84%, P = 0.01). There were no significant differences between prescribing services regarding major contraindications (P = 0.14) and major bleeding events (P = 0.77). Off-label prescription rates for target-specific oral anticoagulants were infrequent and not associated with increased adverse events. PMID:26414695
Faraoni, David; Levy, Jerrold H; Albaladejo, Pierre; Samama, Charles-Marc
Perioperative management of patients treated with the non-vitamin K antagonist oral anticoagulants is an ongoing challenge. Due to the lack of good clinical studies involving adequate monitoring and reversal therapies, management requires knowledge and understanding of pharmacokinetics, renal function, drug interactions, and evaluation of the surgical bleeding risk. Consideration of the benefit of reversal of anticoagulation is important and, for some low risk bleeding procedures, it may be in the patient's interest to continue anticoagulation. In case of major intra-operative bleeding in patients likely to have therapeutic or supra-therapeutic levels of anticoagulation, specific reversal agents/antidotes would be of value but are currently lacking. As a consequence, a multimodal approach should be taken which includes the administration of 25 to 50 U/kg 4-factor prothrombin complex concentrates or 30 to 50 U/kg activated prothrombin complex concentrate (FEIBA®) in some life-threatening situations. Finally, further studies are needed to clarify the ideal therapeutic intervention. PMID:25925382
Eriksson, Bengt I; Quinlan, Daniel J
Current anticoagulant provision is dominated by parenteral heparin and oral warfarin, which act by inhibiting several steps of the coagulation pathway indirectly. Recent research efforts have focused on the identification of small molecule inhibitors of the coagulation enzymes as novel therapies for thrombotic disorders. There has been particular success in developing nonpeptidic, orally available, small molecules to directly inhibit the key proteases, factor IIa and factor Xa. Of the new oral anticoagulants in development, the two agents in the most advanced stage are dabigatran etexilate (BIBR 1048) and rivaroxaban (BAY 59-7939), which inhibit factor IIa and factor Xa, respectively. Other agents in the early stages of development include several Xa inhibitors (LY-517717, YM150, DU-176b and apixaban [BMS-562247]), a factor IXa inhibitor (TTP889), and an orally active glycosaminoglycan enhancer (odiparcil [SB-424323]), which indirectly enhances thrombin inhibition via heparin cofactor II. Results have been reported from important, phase II dose-finding studies, and a number of registration-track phase III studies have been initiated, reflecting the drive towards potentially more effective, but primarily safer and more convenient therapies for the prevention and treatment of venous and arterial thrombosis. Indeed, two unmet needs for anticoagulation that can be easily identified are safety and ease of use. Safety relates primarily to the incidence of major bleeding and this remains the key concern of orthopaedic surgeons, over and above any efficacy advantage, and convenience of use, which centres on oral administration replacing the need for injections. The clinical development of these new anticoagulants is following the well tested strategy of dose-ranging and registration studies in major orthopaedic surgery, prior to development in arterial indications. There are a number of subtle issues, including the timing of the first perioperative dose, duration of
Rubboli, Andrea; Becattini, Cecilia; Verheugt, Freek WA
Bleeding is the most important complication of oral anticoagulation (OAC) with vitamin K-antagonists. Whilst bleeding is unavoidably related to OAC, it may have a great impact on the prognosis of treated subjects by leading to discontinuation of treatment, permanent disability or death. The yearly incidence of bleeding during OAC is 2%-5% for major bleeding, 0.5%-1% for fatal bleeding, and 0.2%-0.4% for intracranial bleeding. While OAC interruption and/or antagonism, as well as administration of coagulation factors, represent the necessary measures for the management of bleeding, proper stratification of the individual risk of bleeding prior to start OAC is of paramount importance. Several factors, including advanced age, female gender, poor control and higher intensity of OAC, associated diseases and medications, as well as genetic factors, have been proven to be associated with an increased risk of bleeding. Most of these factors have been included in the development of bleeding prediction scores, which should now be used by clinicians when prescribing and monitoring OAC. Owing to the many limitations of OAC, including a narrow therapeutic window, cumbersome management, and wide inter- and intra-individual variability, novel oral anticoagulants, such as factor Xa inhibitors and direct thrombin inhibitors, have been recently developed. These agents can be given in fixed doses, have little interaction with foods and drugs, and do not require regular monitoring of anticoagulation. While the novel oral anticoagulants show promise for effective thromboprophylaxis in atrial fibrillation and venous thromboembolism, definitive data on their safety and efficacy are awaited. PMID:22125670
New oral anticoagulants (NOAC) are approved for several indications for prophylaxis and treatment of venous thromboembolism and for prevention of embolism in atrial fibrillation at fixed daily doses without need of laboratory guided dose adjustment. Due to their low molecular weight of about 500 to 600 Dalton and their hydrophilicity free anticoagulant is excreted immediately through glomerular filtration into the urine. Impairment of renal function may increase the plasma concentration of the anticoagulants and lowered creatinine clearance is a declared contraindication. In contrast to the initial aim of development the anticoagulant effect is required to be determined in special clinical situations. Several specific and non-specific assays using plasma samples are currently undergoing standardization. As all NOACs are excreted into the urine, specific assays were developed for this matrix to determine them quantitatively of qualitatively. Urine samples can be easily and repetitively obtained avoiding problems and risks associated with blood sampling. The qualitative assay can be performed as a point of care test (POC) also by the patient by judging the different colours for the absence or presence of the drugs with the naked eye. The test is rapid (results available within 15 min), sensitive, specific and accurate and does not require a purified NOAC as control. The tests may be a tool for clinicians who need to know for treatment decisions if a NOAC is on board or not. As the tests are specific for oral direct thrombin inhibitors and for oral direct factor Xa inhibitors, the indication does not interfere with other qualitative POC test in development using clotting systems. The test may be indicated for patients at acute hospitalization, before surgery or central nervous system puncture anaesthesia, if fibrinolytic therapy is indicated, acute deterioration of renal function, and for control of adherence to therapy. PMID:23915217
Amin, Alpesh; Marrs, Joel C
Anticoagulation therapy is central to the management of thromboembolic disorders, and the use of direct oral anticoagulants offers several advantages over standard therapy with parenteral heparins and vitamin K antagonists. In phase III clinical trials, the direct oral anticoagulants (given once or twice daily) all demonstrated favorable benefit-risk profiles compared with conventional standard therapy for the treatment and secondary prevention of venous thromboembolism and for stroke prevention in patients with nonvalvular atrial fibrillation. In clinical practice, many factors may influence overall clinical outcomes in patients receiving anticoagulant therapy, including adherence and persistence to the prescribed therapy, which becomes particularly important during long-term therapy. When choosing an anticoagulant for an individual patient, the pharmacological and clinical profile of the anticoagulant, its dosing regimen, and the patient's clinical characteristics (eg, renal function and comorbidities) and preferences should be considered. This review examines the rationale for and clinical evidence of the selected dosing regimens of the direct oral anticoagulants for the treatment of venous thromboembolism and stroke prevention in nonvalvular atrial fibrillation. The potential influence of dosing strategies (eg, once- or twice-daily dosing) and other factors on patient adherence and therapy persistence are also discussed. PMID:26316518
Vandenbroucke, V; Bousquet-Melou, A; De Backer, P; Croubels, S
The first aim of the study was to investigate the pharmacokinetics of eight anticoagulant rodenticides (brodifacoum, bromadiolone, chlorophacinone, coumatetralyl, difenacoum, difethialone, flocoumafen and warfarin) in plasma and liver of the mouse after single oral administration. Eight groups of mice dosed orally with a different anticoagulant rodenticide in a dose equal to one-half the lethal dose 50 (LD(50)), were killed at various times up to 21 days after administration. The eight anticoagulant rodenticides were assayed in plasma and liver by an LC-ESI-MS/MS method. Depending on the compound, the limit of quantification was set at 1 or 5 ng/mL in plasma. In liver, the limit of quantification was set at 250 ng/g for coumatetralyl and warfarin and at 100 ng/g for the other compounds. The elimination half-lives in plasma for first-generation rodenticides were shorter than those for second-generation rodenticides. Coumatetralyl, a first-generation product, had a plasma elimination half-life of 0.52 days. Brodifacoum, a second-generation product, showed a plasma elimination half-life of 91.7 days. The elimination half-lives in liver varied from 15.8 days for coumatetralyl to 307.4 days for brodifacoum. The second aim of the study was to illustrate the applicability of the developed method in a clinical case of a dog suspected of rodenticide poisoning. PMID:19000263
Venous thromboembolism (VTE) is associated with a risk of recurrence that depends on factors specific to index event and patient. A first unprovoked VTE increases the risk of a recurrent event, particularly during the first year after anticoagulation cessation. Determining a strategy for the long-term prevention of recurrent VTE poses challenges that stem from a lack of agreement on recommended therapy duration and varying treatment burden for the patient. Oral anticoagulants, including vitamin K antagonists and non-vitamin K antagonist oral anticoagulants (NOACs), are the main treatment options for the long-term prevention of recurrent VTE. However, the risk of VTE recurrence must be balanced against the risk of bleeding in each patient. Phase III clinical trials have evaluated rivaroxaban, apixaban and dabigatran for extended treatment and prevention of VTE versus placebo, and versus warfarin in the case of dabigatran. Compared with placebo treatment, each NOAC showed superior efficacy together with an acceptable safety profile during extended treatment periods of 6-18months. Patients receiving long-term NOAC therapy will still require regular risk factor assessment, but these agents may permit longer treatment duration with an improved benefit-risk profile. PMID:27263046
Tompson, Alice; Heneghan, Carl; Fitzmaurice, David; Sutton, Stephen; Harrison, Sian; Ward, Alison
Background Clinical trials suggest that oral anticoagulation therapy (OAT) self-monitoring is safe and effective, however little is known about the patient experience of this process. There is a lack of understanding about how best to train and support patients embarking on OAT self-monitoring. Aim To collect in-depth information about patients’ experiences of OAT self-monitoring outside of clinical trial conditions and to produce a set of recommendations on how best to support such patients. Design and setting Semi-structured qualitative interviews with patients who self-monitor and live in England. Method In total, 26 of the 267 (9.7%) who participated in the Cohort study of Anticoagulation Self-Monitoring (CASM) and were still self-monitoring after 12 months’ follow-up were interviewed. Topics discussed included experiences of OAT self-monitoring, healthcare support, training, and decision making. Framework analysis was used. Results Following initial problems using the monitoring device, interviewees described a mostly positive experience. Although less effort was expended attending monitoring appointments with health professionals, effort was required to conduct self-monitoring tests and to interpret and act on the results. Desire to self-manage was variable, especially when dosing advice systems worked promptly and reliably. Interviewees overcame patchy healthcare system knowledge and support of self-monitoring by educating themselves. Family and friends provided support with learning to use the monitor and managing OAT dosage adjustments. Conclusion Better, more-consistent training and health-service support would have alleviated a number of problems encountered by these patients who were self-monitoring. This training and support will become even more important if self-monitoring becomes more accessible to the general population of people on OAT. PMID:26077266
Lippi, Giuseppe; Favaloro, Emmanuel J; Mattiuzzi, Camilla
The recent development and marketing of novel direct oral anticoagulants (DOACs) represents a paradigm shift in the management of patients requiring long-term anticoagulation. The advantages of these compounds over traditional therapy with vitamin K antagonists include a reportedly lower risk of severe hemorrhages and the limited need for laboratory measurements. However, there are several scenarios in which testing should be applied. The potential for drug-to-drug interaction is one plausible but currently underrecognized indication for laboratory assessment of the anticoagulant effect of DOACs. In particular, substantial concern has been raised during Phase I studies regarding the potential interaction of these drugs with some antibiotics, especially those that interplay with permeability glycoprotein (P-gp) and cytochrome 3A4 (CYP3A4). A specific electronic search on clinical trials published so far confirms that clarithromycin and rifampicin significantly impair the bioavailability of dabigatran, whereas clarithromycin, erythromycin, fluconazole, and ketoconazole alter the metabolism of rivaroxaban in vivo. Because of their more recent development, no published data were found for apixaban and edoxaban, or for potential interactions of DOACs with other and widely used antibiotics. It is noteworthy, however, that an online resource based on Food and Drug Administration and social media information, reports several hemorrhagic and thrombotic events in patients simultaneously taking dabigatran and some commonly used antibiotics such as amoxicillin, cephalosporin, and metronidazole. According to these reports, the administration of antibiotics in patients undergoing therapy with DOACs would seem to require accurate evaluation as to whether dose adjustments (personalized or antibiotic class driven) of the anticoagulant drug may be advisable. This might be facilitated by direct laboratory assessments of their anticoagulant effect ex vivo. PMID:24919144
Anticoagulation therapy is essential for the effective treatment and secondary prevention of venous thromboembolism (VTE). For many years, anticoagulation for acute VTE was limited to the use of initial parenteral heparin, overlapping with and followed by a vitamin K antagonist. Although highly effective, this regimen has several limitations and is particularly challenging when given in an ambulatory setting. Current treatment pathways for most patients with deep-vein thrombosis typically involve initial hospital or community-based ambulatory care with subsequent follow-up in a secondary care setting. With the introduction of non-vitamin K antagonist oral anticoagulants (NOACs) into routine clinical practice, it is now possible for the initial acute management of patients with deep-vein thrombosis to be undertaken by primary care. As hospital admissions associated with VTE become shorter, primary care will play an increasingly important role in the long-term management of these patients. Although the NOACs can potentially simplify patient management and improve clinical outcomes, primary care physicians may be less familiar with these new treatments compared with traditional therapy. To assist primary care physicians in further understanding the role of the NOACs, this article outlines the main differences between NOACs and traditional anticoagulation therapy and discusses the benefit–risk profile of the different NOACs in the treatment and secondary prevention of recurrent VTE. Key considerations for the use of NOACs in the primary care setting are highlighted, including dose transition, risk assessment and follow-up, duration of anticoagulant therapy, how to minimize bleeding risks, and the importance of patient education and counseling. PMID:27217793
Sarah, Lessire; Anne-Sophie, Dincq; Jonathan, Douxfils; Bérangère, Devalet; Jean-Baptiste, Nicolas; Anne, Spinewine; Anne-Sophie, Larock; Jean-Michel, Dogné; Maximilien, Gourdin; François, Mullier
Dabigatran etexilate (DE), rivaroxaban, and apixaban are nonvitamin K antagonist oral anticoagulants (NOACs) that have been compared in clinical trials with existing anticoagulants (warfarin and enoxaparin) in several indications for the prevention and treatment of thrombotic events. All NOACs presented bleeding events despite a careful selection and control of patients. Compared with warfarin, NOACs had a decreased risk of intracranial hemorrhage, and apixaban and DE (110 mg BID) had a decreased risk of major bleeding from any site. Rivaroxaban and DE showed an increased risk of major gastrointestinal bleeding compared with warfarin. Developing strategies to minimize the risk of bleeding is essential, as major bleedings are reported in clinical practice and specific antidotes are currently not available. In this paper, the following preventive approaches are reviewed: improvement of appropriate prescription, identification of modifiable bleeding risk factors, tailoring NOAC's dose, dealing with a missed dose as well as adhesion to switching, bridging and anesthetic procedures. PMID:25032218
Jones, W J; Francis, J J
Softgels, which contain a liquid formulation of a drug, often provide clinical benefit over other solid oral dosage forms and may represent an attractive alternative to them. A consumer preference survey of softgels versus other solid forms investigated four areas: (1) identification of various dosage forms; (2) perception of therapeutic benefit (easiest to swallow, faster-acting, work longer); (3) impact of individual product characteristics on overall product selection; and (4) market impact in terms of premiums consumers would pay on the basis of dosage form. The 300 survey participants strongly preferred clear softgels over other dosage forms in virtually every area. Softgels were perceived as easy to swallow and fast-acting, with a duration of action second only to that of a two-piece capsule. Overall preference was driven by ease of swallowing, and softgels were rated first by the majority of respondents. Consumers would be interested in various products if these were available as softgels rather than in their current oral dosage forms and may be willing to pay a premium for softgel products. This survey confirms consumer preferences for particular dosage forms and for softgels over other solid forms. Pharmaceutical scientists and marketers should consider softgels as alternative dosage forms when developing new compounds or considering life-cycle management of existing products. PMID:11186141
Wypasek, E; Mazur, P; Bochenek, M; Awsiuk, M; Grudzien, G; Plincer, D; Undas, A
Warfarin dosage estimation using the pharmacogenetic algorithms has been shown to improve the quality of anticoagulation control in patients with atrial fibrillation. We sought to assess the genetic, demographic and clinical factors that determine the quality of anticoagulation in patients following aortic valve replacement (AVR). We studied 200 consecutive patients (130 men) aged 63 ± 12.3 years, undergoing AVR, in whom warfarin dose was established using a pharmacogenetic algorithm. The quality of anticoagulation within the first 3 months since surgery was expressed as the time of international normalized ratio (INR) in the therapeutic range (TTR). The median TTR in the entire cohort was 59.6% (interquartile range, 38.7 - 82.7). Ninety-nine (49.5%) patients with TTR ≥ 60% did not differ from those with poor anticoagulation control (TTR < 60%) with regard to demographic and cardiovascular risk factors. Coronary artery disease (n = 84, 42%) and previous stroke (n = 5, 2.5%) predicted higher TTR, while possession of CYP2C9*2 variant allele (n = 49, 25%) was associated with lower TTR (P = 0.01). In turn, VKORC1 c.-1639A, CYP2C9*2 and *3 variants were independently associated with actual warfarin dose (P < 0.0001). In AVR patients better anticoagulation control is observed in patients with coronary artery disease and history of stroke, which might result in part from previous lifestyle modification and therapy. Possession of CYP2C9*2 and/or CYP2C9*3 allele variants is associated with lower TTR values and warfarin dose variations in AVR patients, the latter affected also by VKORC1 c.-1693G>A polymorphism. PMID:27511999
Turagam, Mohit K; Velagapudi, Poonam; Flaker, Greg C
Stroke prevention in elderly atrial fibrillation patients remains a challenge. There is a high risk of stroke and systemic thromboembolism but also a high risk of bleeding if anticoagulants are prescribed. The elderly have increased chronic kidney disease, coronary artery disease, polypharmacy, and overall frailty. For all these reasons, anticoagulant use is underutilized in the elderly. In this manuscript, the benefits of non-vitamin K antagonist oral anticoagulants compared with warfarin in the elderly patient population with multiple comorbid conditions are reviewed. PMID:26366064
Harris, K; Mant, J
Aim Anticoagulant prophylaxis with vitamin K antagonists (such as warfarin) is effective in reducing the risk of stroke in patients with atrial fibrillation (AF). New oral anticoagulants have emerged as potential alternatives to traditional oral agents. The purpose of this review was to summarise the effectiveness and safety of rivaroxaban, dabigatran and apixaban in stroke prevention in patients with AF in phase III trials, evaluate their cost-effectiveness and consider the implications for primary care. Methodology A literature search was performed between 2007 and 2012, selecting all phase III trials (ROCKET AF, RE-LY and ARISTOTLE) of new oral anticoagulants and relevant cost–benefit studies. Results Evidence shows that all three agents are at least as effective as warfarin in the prevention of stroke and systemic emboli, with similar safety profiles. Cost–benefit studies of rivaroxaban and dabigatran further confirm their potential use as alternatives to warfarin in clinical practice. These observations may allow stratification of the general practice AF population, to help prioritise which patients may benefit from receiving a new oral anticoagulant. Conclusion The clinical and economic benefits of the new oral anticoagulants, along with appropriate risk stratification, may enable a higher number of patients with AF to receive effective and convenient prophylaxis for stroke prevention. PMID:23621153
Bacchus, Farzana; Schulman, Sam
Four non-vitamin K antagonist oral anticoagulants, apixaban, dabigatran, edoxaban, and rivaroxaban, have been evaluated in phase III clinical trials for the treatment of acute venous thromboembolism, and all except edoxaban have also been studied for extended secondary prophylaxis after venous thromboembolism. Rivaroxaban, and recently also dabigatran, has been approved for this indication, and it is therefore timely to review the characteristics, efficacy, and safety of these drugs with emphasis on patients with venous thromboembolism. This review focuses on the clinical results from the phase III trials, separately for each of the drugs as compared with vitamin K antagonists. We also address the results from meta-analyses that were published recently. Finally, the results in some special groups of interest-renal impairment, elderly patients, and patients with cancer-are reviewed, although they only comprised small minorities of the study populations. All 4 drugs demonstrated noninferiority against vitamin K antagonists in the acute treatment and clear superiority against placebo in the extended treatment (not performed with edoxaban). The risk of bleeding was generally lower with non-vitamin K antagonist oral anticoagulants, and the reduction of risk of intracranial hemorrhage seems to mirror the experience from atrial fibrillation trials. In conclusion, during the past 30 years we have moved from a week of hospitalization and intravenous heparin therapy, via low-molecular-weight heparin injections subcutaneously and early discharge from the hospital, to the possibility of only oral outpatient therapy without coagulation monitoring, yet safe for patients with acute venous thromboembolism. PMID:25717178
Gehrie, Eric; Tormey, Christopher
Warfarin, the most commonly used of the vitamin K antagonists, has been a mainstay of oral anticoagulation for decades. However, its usage is limited by morbidity and mortality secondary to bleeding as well as a cumbersome therapeutic monitoring process. In the past several years, a number of competing novel oral anticoagulants (NOACs) have been developed, each of which aspires to match or exceed warfarin's effectiveness while mitigating bleeding risk and eliminating therapeutic monitoring requirements. At present, 1 oral direct thrombin inhibitor and 2 direct factor Xa inhibitors are approved by the US Food and Drug Administration. Here, we compare the clinical efficacy and safety profiles of these new drugs. In addition, we discuss various laboratory assays that may be useful to measure these drugs in certain clinical circumstances. Finally, we discuss emerging strategies to reverse these agents in an emergency. The purpose of this article is to provide a framework for practicing pathologists to advise clinicians on NOAC laboratory measurement and management of NOAC-associated bleeding. PMID:25927153
von Vajna, Erika; Alam, Ruhaniyah; So, Tsz-Yin
Common treatment options for deep vein thrombosis and venous thromboembolism in the pediatric population include unfractionated heparin, low molecular weight heparin, and warfarin. Other alternatives are bivalirudin, argatroban, and fondaparinux. Warfarin is the only approved oral option, but an oral agent without frequent monitoring would be optimal for pediatric patients. Thus, there is an increasing need for new anticoagulation options in this population. None of the current direct oral anticoagulants have FDA-approved indications and dosing in children. The two classes of DOACs and the drugs they are comprised of are factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) and direct thrombin inhibitor (dabigatran). Off-label usage of these agents is largely based on adult doses. By far, rivaroxaban and dabigatran have the most published data and ongoing trials in pediatric patients compared to edoxaban and apixaban. After evaluating the current literature available on these agents, it is, however, still too early to make any definitive recommendations on their usage in this special population. PMID:26739579
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Al-Gousous, Jozef; Langguth, Peter
Since its inception in the 1930s, disintegration testing has become an important quality control (QC) test in pharmaceutical industry, and disintegration test procedures for various dosage forms have been described by the different pharmacopoeias, with harmonization among them still not quite complete. However, because of the fact that complete disintegration does not necessarily imply complete dissolution, much more research has been focused on dissolution rather than on disintegration testing. Nevertheless, owing to its simplicity, disintegration testing seems to be an attractive replacement to dissolution testing as recognized by the International Conference on Harmonization guidelines, in some cases. Therefore, with proper research being carried out to overcome the associated challenges, the full potential of disintegration testing could be tapped saving considerable efforts allocated to QC testing and quality assurance. PMID:25546430
Miesbach, Wolfgang; Seifried, Erhard
To date, clinical studies show that the incidence of spontaneous bleeding with new direct oral anticoagulants (DOAs) is comparable to that of established anticoagulants. However, unlike vitamin K antagonists, there are currently no clinically available antidotes or approved reversal agents for new DOAs. Restoring normal coagulation is important in many cases, such as emergency surgeries, serious bleedings, or anticoagulant overdosing. Attempts have been made to restore normal coagulation after treatment with new DOAs using compounds such as recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), or FEIBA (factor eight inhibitor bypassing activity). Limited pre-clinical data and even less clinical evidence are available on the usefulness of these methods in restoring normal coagulation for the emergency management of critical bleeding episodes. Evaluating the utility of DOAs is further complicated by the fact that it is unknown how predictive established test systems are of the bleeding risks. Clinical practice requires further evaluation of the emergency management options for the new DOAs to define the agents and the doses that are most useful. Furthermore, patients receiving long-term treatment with a DOA are likely to undergo elective surgery at some point, and there is lack of evidence regarding perioperative treatment regimens under such conditions. This review summarises potential bleeding management options and available data on the new DOAs. PMID:22782297
Yeh, Calvin H.; Gross, Peter L.
The new oral anticoagulants (NOACs), which include dabigatran, rivaroxaban, apixaban, and edoxaban, are poised to replace warfarin for treatment of the majority of patients with venous thromboembolism (VTE). With a rapid onset of action and the capacity to be administered in fixed doses without routine coagulation monitoring, NOACs streamline VTE treatment. In phase 3 trials in patients with acute symptomatic VTE, NOACs have been shown to be noninferior to conventional anticoagulant therapy for prevention of recurrence and are associated with less bleeding. Rivaroxaban and dabigatran are already licensed for VTE treatment in the United States, and apixaban and edoxaban are under regulatory consideration for this indication. As the number of approved drugs increases, clinicians will need to choose the right anticoagulant for the right VTE patient. To help with this decision, this review (1) compares the pharmacologic profiles of the NOACs, (2) outlines the unique design features of the phase 3 trials that evaluated the NOACs for VTE treatment, (3) reviews the results of these trials highlighting similarities and differences in the findings, (4) provides perspective about which VTE patients should receive conventional treatment or are candidates for NOACs, and (5) offers suggestions about how to choose among the NOACs. PMID:24923298
Mullier, François; Douxfils, Jonathan; Tamigniau, Anne; Dogné, Jean-Michel; Horellou, Marie-Hélène; Flaujac, Claire; Chatelain, Bernard; Goffinet, Catherine; Samama, Meyer-Michel; Gouin-Thibault, Isabelle
Non-VKA oral anticoagulants (NOACs), thanks to their ease of use and their similar or superior safety/efficacy profiles versus warfarin, have now widely reached the lucrative market of anticoagulation. However, while the marketing authorization holders always claim, in a quite unclear way that no monitoring is required, accumulative evidence and cases of major bleeding have been described in the literature and reported by spontaneous reporting systems at the regulator's level. These compounds are usually given at fixed doses without routine coagulation monitoring. However, new data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of, at least dabigatran. Therefore, in certain patient populations, i.e. acute or chronic renal impairment or multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This article aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice. PMID:25857818
Mani, Helen; Minet, Valentine; Devalet, Bérangère; Chatelain, Bernard; Dogné, Jean-Michel
Non-VKA oral anticoagulants (NOACs) have now widely reached the lucrative market of anticoagulation. While the marketing authorization holders claimed that no routine monitoring is required and that these compounds can be given at fixed doses, several evidences arisen from the literature tend to demonstrate the opposite. New data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of at least dabigatran. Information regarding the association of rivaroxaban and apixaban exposure and the bleeding risk is available in the drug approval package on the FDA website. These reviews suggest that accumulation of these compounds increases the risk of experiencing a bleeding complication. Therefore, in certain patient populations such as patients with acute or chronic renal impairment or with multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This paper aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice. PMID:26090400
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Eckman, Mark H
Until recently, vitamin K antagonists, warfarin being the most commonly used agent in the United States, have been the only oral anticoagulant therapies available to prevent stroke in patients with atrial fibrillation (AF). In the last 5 years four new, non-vitamin K oral anticoagulants, the so-called NOACs or novel oral anticoagulants, have come to market and been approved by the Federal Drug Administration. Despite comparable if not superior efficacy in preventing AF-related stroke, and generally lower risks of major hemorrhage, particularly intracranial bleeding, the uptake of these agents has been slow. A number of barriers stand in the way of the more widespread use of these novel agents. Chief among them is concern about the lack of antidotes or reversal agents. Other concerns include the need for strict medication adherence, since missing even a single dose can lead to a non-anticoagulated state; out-of-pocket costs for patients; the lack of easily available laboratory tests to quantitatively assess the level of anticoagulant activity when these agents are being used; contraindications to use in patients with severe chronic kidney disease; and black-box warnings about the increased risk of thromboembolic events if these agents are discontinued prematurely. Fortunately, a number of reversal agents are in the pipeline. Three reversal agents, idarucizumab, andexanet alfa, and aripazine, have already progressed to human studies and show great promise as either antidotes for specific drugs or as universal reversal agents. The availability of these reversal agents will likely increase the clinical use of the non-vitamin K oral anticoagulants. In light of the many complex and nuanced issues surrounding the choice of an optimal anticoagulant for any AF patient, a patient-centered/shared decision-making approach will be useful. PMID:26343041
Lippi, Giuseppe; Sanchis-Gomar, Fabian; Favaloro, Emmanuel J
Despite direct oral anticoagulants becoming a mainstay of anticoagulant therapy, the effective, timely, and safe reversal of their anticoagulant effect remains challenging. Emerging evidence attests that andexanet, a recombinant and inactive variant of native factor X (FXa), competitively inhibits and counteracts the anticoagulant effect of many inhibitors of native activated FXa. PMID:27048885
Dincq, Anne-Sophie; Dogné, Jean-Michel; Gourdin, Maximilien
The field of oral anticoagulation has evolved with the arrival of non-vitamin K antagonist oral anticoagulants (NOACs) including an anti-IIa agent (dabigatran etexilate) and anti-Xa agents (rivaroxaban and apixaban). The main specificities of these drugs are predictable pharmacokinetics and pharmacodynamics but special attention should be paid in the elderly, in case of renal dysfunction and in case of emergency. In addition, their perioperative management is challenging, especially with the absence of specific antidotes. Effectively, periods of interruption before surgery or invasive procedures depend on half-life and keeping a permanent balance between bleeding and thromboembolic risks. In addition, few data regarding the link between plasma concentrations and their effects are provided. Routine laboratory tests are altered by NOACs and quantitative measurements are not widely performed. This paper provides a review on the management of NOACs in the perioperative setting, including the estimation of the bleeding and thrombotic risk, the periods of interruption, the indication of heparin bridging, the usefulness of laboratory tests before surgery or invasive procedure, and the time of resuming. Most data are based on expert's opinions. PMID:25276784
Diener, Hans-Christoph; Kleinschnitz, Christoph
Non-vitamin-K oral anticoagulants (NOACs) represent a major advance in the prevention of stroke in patients with atrial fibrillation (AF), offering a similar, if not superior, efficacy and safety profile and several practical advantages over oral vitamin K antagonists (VKAs). The rapid onset of action of the NOACs, their relatively short half-live, and the availability of specific reversal agents may be advantageous when managing acute ischemic strokes, and in the post-stroke, post-transient ischemic attack, and post-intracranial hemorrhage settings. In this review article, we offer practical guidance on the use of NOACs in these settings, focusing on managing the acute event and on initiating or resuming anticoagulation for secondary prevention. We also assess the use of NOACs to prevent stroke and bleeding in patients with AF who have chronic kidney disease, are elderly, or cognitively impaired, and we offer guidance on optimizing the use of NOACs and VKAs in these patient groups in the absence of evidence-based guidelines. PMID:27165264
Stöllberger, Claudia; Finsterer, Josef
Atrial fibrillation (AF) is a frequent cause of stroke. Secondary prophylaxis by oral anticoagulants (OAC) is recommended after stroke in AF-patients. OAC can be achieved by vitamin-K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) like dabigatran, rivaroxaban, apixaban or edoxaban. Seizures are frequent after stroke, and antiepileptic drugs (AEDs) are indicated. The review, based on a literature research, aims to give an overview about pharmacokinetic knowledge and clinical data about drug-drug interactions (DDIs) between NOACs and AED. Carbamazepine, levetiracetam, phenobarbital, phenytoin and valproic acid might decrease the effect of NOACs by inducing P-glycoprotein (P-gp) activity. Carbamazepine, oxcarbazepine, phenytoin, phenobarbital and topiramate might decrease the effect of NOACs by inducing CYP3A4 activity. Controversial data - inhibition as well as induction of CYP3A4 - were found about valproic acid. The relevance of these DDIs is largely unknown since there are only sporadic case reports available. To increase the knowledge about DDIs between NOACs and AEDs we suggest subgroup analyses addressing effects and safety of VKAs versus NOACs in patients with AF on AEDs, in case they have been included in previously completed or still ongoing trials or registries. This could be easily feasible and would be desirable in view of the large data already accumulated. PMID:27450623
Beukenhorst, A L; Arts, D L; Lucassen, W; Jager, K J; van der Veer, S N
Guidelines provide recommendations for antithrombotic treatment to prevent stroke in people with atrial fibrillation, but oral anticoagulant prescriptions in Dutch primary care are often discordant with these recommendations. Suboptimal guideline features (i.e. format and content) have been suggested as a potential explanatory factor for this type of discordance. Therefore, we systematically appraised features of the Dutch general practitioners' (NHG) atrial fibrillation guideline to identify guidelinerelated barriers that may hamper its use in practice. We appraised the guideline's methodological rigour and transparency using the Appraisal of Guidelines, Research and Evaluation (AGREE) II tool. Additionally, we used the Guideline Implementability Appraisal (GLIA) tool to assess the key recommendations on oral anticoagulant prescription. The editorial independence of the guideline group scored highly (88%); scores for other aspects of the guideline's methodological quality were acceptable, ranging from 53% for stakeholder involvement to 67% for clarity of presentation. At the recommendation level, the main implementation obstacles were lack of explicit statements on the quality of underlying evidence, lack of clarity around the strength of recommendations, and the use of ambiguous terms which may hamper operationalisation in electronic systems. Based on our findings we suggest extending stakeholder involvement in the guideline development process, standardising the layout and language of key recommendations, providing monitoring criteria, and preparing electronic implementation parallel with guideline development. We expect this to contribute to optimising the NHG atrial fibrillation guideline, facilitating its implementation in practice, and ultimately to improving antithrombotic treatment and stroke prevention in people with atrial fibrillation. PMID:27185775
Vacas, M; Fernández, M A; Martínez-Brotons, F; Lafuente, P J; Ripoll, F; Alvarez, C; Iriarte, J A
The aim of this study was to evaluate the accuracy of the portable coagulometer CoaguChek (Roche Diagnostics) as a prothrombin time (PT) monitor, and to correlate capillary blood results with those of three different routine methods used for monitoring oral anticoagulant therapy (OAT): capillary, plasma and whole blood samples. Three hospitals participated in the study with a total of 235 patients on OAT. The international normalized ratio (INR) results obtained with CoaguChek were compared with those obtained using each of the routine methods. The study presents a good correlation between the PT monitor and the three methods studied: r = 0.9745 (hospital A), r = 0.9283 (hospital B), r = 0.9136 (hospital C). A simplified concordance test of the methods results in a nine-field comparison table showing concordances of 87.2, 85.7 and 68.4%, respectively. The absolute difference (mean +/- SD) between laboratory A and CoaguChek INRs was 0.0571 +/- 0.2042, with values of 0.04286 +/- 0.3906 for laboratory B and 0.6986 +/- 0.6170 for laboratory C. These results confirm that CoaguChek could be used as a new method for oral anticoagulant monitoring, and is in best agreement with the capillary blood PT system. PMID:11408745
Peacock, W. Frank; Rafique, Zubaid; Singer, Adam J.
Nonvalvular atrial fibrillation- (NVAF-) related stroke and venous thromboembolism (VTE) are cardiovascular diseases associated with significant morbidity and economic burden. The historical standard treatment of VTE has been the administration of parenteral heparinoid until oral warfarin therapy attains a therapeutic international normalized ratio. Warfarin has been the most common medication for stroke prevention in NVAF. Warfarin use is complicated by a narrow therapeutic window, unpredictable dose response, numerous food and drug interactions, and requirements for frequent monitoring. To overcome these disadvantages, direct-acting oral anticoagulants (DOACs)—dabigatran, rivaroxaban, apixaban, and edoxaban—have been developed for the prevention of stroke or systemic embolic events (SEE) in patients with NVAF and for the treatment of VTE. Advantages of DOACs include predictable pharmacokinetics, few drug-drug interactions, and low monitoring requirements. In clinical studies, DOACs are noninferior to warfarin for the prevention of NVAF-related stroke and the treatment and prevention of VTE as well as postoperative knee and hip surgery VTE prophylaxis, with decreased bleeding risks. This review addresses the practical considerations for the emergency physician in DOAC use, including dosing recommendations, laboratory monitoring, anticoagulation reversal, and cost-effectiveness. The challenges of DOACs, such as the lack of specific laboratory measurements and antidotes, are also discussed. PMID:27293895
Bujanda, L; Sarasqueta, C; Lanas, Á; Quintero, E; Cubiella, J; Hernandez, V; Morillas, J D; Perez-Fernández, T; Salas, D; Andreu, M; Carballo, F; Bessa, X; Portillo, I; Jover, R; Balaguer, F; Cosme, A; Castells, A
Background: We aimed to evaluate whether oral anticoagulants (OACs) alter faecal immunochemical test (FIT) performance in average-risk colorectal cancer (CRC) screening. Methods: Individuals aged 50–69 years were invited to receive one FIT sample (cutoff 75 ng ml–1) between November 2008 and June 2011. Results: Faecal immunochemical test was positive in 9.3% (21 out of 224) of users of OAC and 6.2% (365 out of 5821) of non-users (P-trend=0.07). The positive predictive value (PPV) for advanced neoplasia (AN) in non-users was 50.4% vs 47.6% in users (odds ratio, 0.70; 95% CI, 0.3–1.8; P=0.5). The PPV for AN in OAC more antiplatelets (aspirin or clopidogrel) was 75% (odds ratio, 2; 95% CI, 0.4–10.8; P=0.4). Conclusions: Oral anticoagulant did not significantly modify the PPV for AN in this population-based colorectal screening program. The detection rate of advanced adenoma was higher in the combination OAC more antiplatelets. PMID:24496455
Alegret, Josep M.; Viñolas, Xavier; Arias, Miguel A.; Martínez-Rubio, Antoni; Rebollo, Pablo; Ràfols, Carles; Martínez-Sande, José L.
New oral anticoagulants (NOAC) have demonstrated their efficacy as an alternative to vitamin K antagonists (VKA) in the prophylaxis of cardioembolic events in patients with atrial fibrillation (AF). However, evidence on the benefits of NOAC in health-related quality of life (HRQoL) is lacking.We evaluated changes in HRQoL related to oral anticoagulation therapy employing a specific questionnaire in a cohort of 416 patients with AF undergoing electrical cardioversion. In terms of HRQoL, we observed a progressive adaptation to treatment with VKA; satisfaction with NOAC remained constant. Older age, higher left ventricular ejection fraction and NOAC were associated with better HRQoL. PMID:24843316
Alegret, Josep M; Viñolas, Xavier; Arias, Miguel A; Martínez-Rubio, Antoni; Rebollo, Pablo; Ràfols, Carles; Martínez-Sande, José L
New oral anticoagulants (NOAC) have demonstrated their efficacy as an alternative to vitamin K antagonists (VKA) in the prophylaxis of cardioembolic events in patients with atrial fibrillation (AF). However, evidence on the benefits of NOAC in health-related quality of life (HRQoL) is lacking.We evaluated changes in HRQoL related to oral anticoagulation therapy employing a specific questionnaire in a cohort of 416 patients with AF undergoing electrical cardioversion. In terms of HRQoL, we observed a progressive adaptation to treatment with VKA; satisfaction with NOAC remained constant. Older age, higher left ventricular ejection fraction and NOAC were associated with better HRQoL. PMID:24843316
Stalker, D J; Welshman, I R; Pollock, S R
The bioavailability of three formulations of medroxyprogesterone acetate (MPA) was assessed in 30 healthy male volunteers in a three-way, open-label, cross-over-designed trial. Each subject received one Provera 500-mg tablet, one Farlutal 500-mg tablet, and one Provera 500-mg granule packet according to a randomized schedule, with each treatment separated by a 21-day washout period. Serum MPA levels were determined using both radioimmunoassay (RIA) and high-performance liquid chromatography techniques. Based on the results of RIA analysis, Farlutal tablets produced significantly lower serum MPA concentrations compared with Provera tablets at most sampling times, resulting in statistically lower AUC0-144 for the Farlutal tablet (544 vs 768 ng.hr/ml; -29.2%). The Farlutal tablet also had a significantly lower maximum concentration than the Provera tablet (27.8 vs 47.4 ng/ml; -41.4%). However, there was no significant difference in time of maximum concentration between the tablet formulations (3.71 vs 3.41 hr), indicating that the rates of absorption of the two tablet formulations were comparable. Provera granules provided significantly higher serum MPA levels than Provera tablets at 0.5, 1, 1.5, 2, and 6 hours, and the AUC0-144 for Provera granules was higher by 5.47% (810 vs 768 ng.hr/ml). There were no differences in terminal elimination rate constants among the dosage forms. No significant adverse events were noted during the trial. The relative bioavailabilities of Provera granules and Farlutal tablets were 105% and 71.2%, respectively, compared with Provera tablets. PMID:1388093
Guentert, T W; Stebler, T; Banken, L; Defoin, R; Schmitt, M
The bioavailability of tenoxicam (Ro 12-0068, Tilcotil, CAS 59804-37-4) from an effervescent tablet and an instant milk drink formulation relative to the commercial 20 mg tablet was investigated in a randomized cross-over study. Twelve healthy male volunteers (age 18-35 years; weight 63-95 kg) received on three different occasions a single oral tablet, an effervescent tablet or an instant milk drink (dissolved in water) with each dose containing 20 mg of tenoxicam. The wash-out period between two consecutive treatments was at least 5 weeks. Plasma concentrations after dosing were determined with a specific HPLC method. With the effervescent tablet and the milk drink, maximum concentrations were obtained at the same time (0.5-3.0 h) as with the reference tablet (0.5-4.0 h). Plasma peak concentrations appeared highest after the commercial tablet (mean +/- SD: Cmax 2.8 +/- 0.55 mg/l), but the difference to the effervescent tablet (2.7 +/- 0.41 mg/l) and the milk formulation (2.5 +/- 0.41 mg/l) was negligible. Similar mean elimination half-lives of 73, 77, and 77 h were obtained with the effervescent tablet, the milk drink, and the commercial tablet, respectively. Average bioavailability relative to the tablet was for the effervescent tablet and for the milk drink 96% with a coefficient of variation of 8%. The 90%-confidence intervals of the mean differences between the test and standard preparations in log-transformed AUC0-infinity and Cmax were within 20% around the respective mean parameter value calculated for the standard preparation allowing to conclude bioequivalence of the three oral formulations. PMID:7986242
Over the past few years, three novel oral anticoagulants, dabigatran, rivaroxaban, and apixaban, have been approved in the USA and Europe to reduce the risk of stroke or systemic embolism in patients with nonvalvular atrial fibrillation, and the results of a Phase III trial for a fourth novel oral anticoagulant, edoxaban, have recently been published. The aim of this review is to examine this indication from a clinician’s perspective, highlighting efficacy and safety results from the major trials with these novel oral agents. Clinical issues regarding bleeding, monitoring, and reversal are discussed, along with requirements to consider when interrupting treatment with a novel oral anticoagulant for the purpose of transitioning to another anticoagulant and prior to cardioversion, ablation, percutaneous coronary intervention, or emergency surgery. The cost-effectiveness of each of the approved novel oral anticoagulants is reviewed, and the author provides recommendations for selecting appropriate patients for these agents. PMID:25187724
Labarère, José; Yver, Jacqueline; Satger, Bernadette; Allenet, Benoit; Berremili, Touffek; Fontaine, Michèle; Franco, Guy; Bosson, Jean Luc
Background Long-term oral anticoagulation treatment is associated with potential morbidity. Insufficient patient education is linked to poorly controlled anticoagulation. However the impact of a specific educational program on anticoagulation related morbidity remains unknown. Objective To evaluate the effect of an oral anticoagulation patient education program in reducing both hemorrhagic and recurrent thrombotic complications. Design/Participants We conducted a prospective, multicenter open randomized study, comparing an interventional group who received a specific oral anticoagulation treatment educational program with a control group. Eligible patients were older than 18 and diagnosed as having deep vein thrombosis or pulmonary embolism requiring therapy with a vitamin K antagonist for 3 months or more. Our primary outcome was the occurrence of hemorrhagic or thromboembolic events. Results During the 3-month follow-up the main outcome criteria were observed 20 times (6.6% of patients), 5 (3.1%) in the experimental and 15 (10.6%) in the control group. Consequently, in multivariate analysis, the cumulative risk reduction in the experimental group was statistically significant (OR 0.25, 95% CI 0.1 – 0.7, < 0.01). Conclusions Patient education using an educational program reduced VKA-related adverse event rates. PMID:18566863
Sakata, Osamu; Onishi, Hiraku; Machida, Yoshiharu
A semisolid dosage form of clonazepam (CZP), administered to the oral cavity between the lower gum and bottom lip with small volume of saline, was developed to obtain the stable dosage which can replace the injection dosage form. Semisolid dosage forms were prepared using a mixture of CZP/(polyethylene glycol 1500 (PEG))/(oleic acid (OA)) at the ratios of 1/39/0, 1/37/2 and 2/36/2 (w/w), named CZP1-PEG, CZP1-PEG-OA and CZP2-PEG-OA, respectively, and were evaluated in vitro and in vivo. No crystal of CZP was observed in CZP1-PEG-OA for at least 8 days, while CZP crystal appeared before administration for CZP2-PEG-OA. When a small volume of saline was added to CZP1-PEG-OA just before the oral cavity administration, more than 80% (w/w) was found to exist in the soluble form. Each semisolid dosage form (40 mg) was administered to the oral cavity in rats, and CZP 1 mg suspension in 0.5% (w/v) sodium carboxymethylcellulose aqueous solution was administered into rat stomach as a control. CZP1-PEG-OA gave the plasma concentrations of more than 5 ng/ml and 12 ng/ml at 30 min and 1 h after administration, respectively, which might be near the plasma levels effective for the suppression of epileptic seizures in human, while the plasma concentration was less than 5 ng/ml at 30 min or did not reach 10 ng/ml at 1 h for the other formulations. It is proposed that the semisolid dosage form CZP1-PEG-OA should be a possibly useful preparation for the antiepileptic or sedative medication. PMID:20046075
Siewert, Ryan; Hostetter, Jeff
Yes. Dabigatran, rivaroxaban, and apixaban are safe and effective compared with warfarin for preventing stroke in patients with nonvalvular atrial fibrillation. These novel oral anticoagulants (NOACs) are noninferior in reducing the number of strokes and systemic emboli and in lowering all-cause mortality while not increasing major bleeding complications and hemorrhagic events. PMID:27474824
Michielsen, Dirk P.J.; Coomans, Danny; Van Lersberghe, Caroline; Braeckman, Johan G.
Introduction The aim of study is comparing the haemostatic properties of conventional monopolar resection (TURP) and bipolar transurethral resection in saline (TURIS) of the prostate in patients under chronic oral anticoagulants. Material and methods Out of a cohort group of 550 endoscopic resections for bladder outlet obstruction, 176 patients on chronic oral anticoagulant therapy required endoscopic resection either by monopolar TURP or bipolar TURIS technology. Changes in haemoglobin, blood transfusion, and clot retention were compared between both groups. Results Mean postoperative change in haemoglobin level was –1.21 ±0.92 mg/dl in the TURP group compared to –1.29 ±0.99 mg/dl in the TURIS group (p = 0.603). The need for blood transfusions and the mean numbers of units transfused did not significantly differ between the 2 groups. Clot retention appeared in 12 patients (15%) in the TURP group compared to 13 patients (13%) in the TURIS group (p = 0.828). Conclusions Despite promising experimental results of better haemostasis and deeper coagulation depth, bipolar technology does not permit one to reduce the amount of blood loss when compared to patients treated by conventional monopolar technology in this study group of patients on oral anticoagulation therapy. Patients on oral anticoagulants suffer more incidents of clot retention, which sometimes results in re-hospitalisation. PMID:22291832
Morais, João; De Caterina, Raffaele
Atrial fibrillation (AF) is a common heart rhythm disturbance; its incidence increases with age, and it is also an independent risk factor for stroke. Anticoagulation has been proven as the most effective way to reduce the risk of stroke in patients with AF, and vitamin K antagonists have been used for decades as the gold standard treatment. Vitamin K antagonists have a narrow therapeutic window in addition to variable pharmacokinetics and pharmacodynamics, and they frequently interact with food and other drugs, requiring coagulation monitoring to ensure balance between safety and efficacy. The novel oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban selectively target either thrombin or Factor Xa and have predictable pharmacologic profiles, removing the need for routine coagulation monitoring. This article summarizes phase III data in patient subtypes and discusses controversies surrounding AF management with these agents. Results indicate that NOACs in non-valvular AF have an overall improved efficacy-safety profile compared with warfarin. Significantly fewer fatal bleeding events were observed in patients randomized to rivaroxaban, apixaban, or edoxaban compared with those on warfarin, and significant reductions in the incidence of life-threatening bleeding were observed in patients randomized to dabigatran. All four pivotal trials testing the NOACs against warfarin showed significantly lower rates of intracranial bleeding in patients administered NOACs. These results suggest that wider use of NOACs has the potential to improve outcomes for most patients with AF. PMID:26780749
Ru San, Tan; Chan, Mark Yan Yee; Wee Siong, Teo; Kok Foo, Tang; Kheng Siang, Ng; Lee, Sze Huar; Chi Keong, Ching
Unlike vitamin K antagonists (VKAs), the new oral anticoagulants (NOACs)—direct thrombin inhibitor, dabigatran, and direct activated factor X inhibitors, rivaroxaban, and apixaban—do not require routine INR monitoring. Compared to VKAs, they possess relatively rapid onset of action and short halflives, but vary in relative degrees of renal excretion as well as interaction with p-glycoprotein membrane transporters and liver cytochrome P450 metabolic enzymes. Recent completed phase III trials comparing NOACs with VKAs for stroke prevention in atrial fibrillation (AF)—the RE-LY, ROCKET AF, and ARISTOTLE trials—demonstrated at least noninferior efficacy, largely driven by significant reductions in haemorrhagic stroke. Major and nonmajor clinically relevant bleeding rates were acceptable compared to VKAs. Of note, the NOACs caused significantly less intracranial haemorrhagic events compared to VKAs, the mechanisms of which are not completely clear. With convenient fixed-dose administration, the NOACs facilitate anticoagulant management in AF in the community, which has hitherto been grossly underutilised. Guidelines should evolve towards simplicity in anticipation of greater use of NOACs among primary care physicians. At the same time, the need for caution with their use in patients with severely impaired renal function should be emphasised. PMID:22997573
Stebelski, L; Brichant, J F; Piérard, L; Peters, P; Sénard, M
New oral anticoagulants (NOACs) are a major step forward in the field of anticoagulation. As a consequence, the number of patients treated with NOACs that have to undergo surgery constantly increases. The optimal management of such patients is not clearly determined so far as scientifically established data are lacking. A first proposal is to mimic the perioperative management of patients on vitamin-K antagonists. When the risk of perioperative bleeding is low, NOAC intake is stopped 24 hours before surgery. If the risk of postoperative hemorrhage is moderate or high, NOAC treatment is interrupted 5 days before surgery with a low molecular weight heparin bridging whenever necessary. A second option is based on pharmacokinetic data. When the risk of perioperative bleeding is low, NOAC intake is stopped the day before surgery. If the risk of perioperative bleeding is higher, NOAC intake is suspended for 5 half lives before surgery, 48-72 hours or more. This interruption should be for a longer period in the presence of renal failure. When an unforeseen surgery is needed, the procedure must be delayed as late as possible. In case of emergency, non specific pro-hemostatic agents such as prothrombin complexes or recombinant factor VIIa have not strongly proven useful and must only be used in last ditch effort. PMID:25796785
Cervellin, Gianfranco; Benatti, Mario; Bonfanti, Laura; Lippi, Giuseppe
The direct oral anticoagulants (DOACs) are increasingly used in patients with atrial fibrillation and venous thromboembolism. The decision making of clinicians and especially emergency physicians for the appropriate management of patients taking DOACs entails a thorough understanding of pharmacologic profile, practical guidance on their usage, and management of bleeding and/or thrombotic events. The available evidence suggests that the bleeding complications observed in patients taking DOACs are less frequent and potentially less severe than those in patients taking vitamin K antagonists or heparins. This should be regarded as an advantage for emergency physicians, since it would decrease the admission rate of anticoagulated patients and probably require a less aggressive treatment in the emergency department (ED). The greatest challenge of DOACs is so far represented by the lack of clinically usable antidotes, since these (i.e., idarucizumab, andexanet alfa, and aripazine) are in different phases of development. A second major concern is the current lack of consensus about laboratory monitoring for these drugs. Although there is widespread perception that patients on DOACs do not require dose adjustment based on laboratory testing, in some selected clinical situations, laboratory testing may be taken into consideration in the ED. The type of laboratory diagnostics needed for emergency management should hence include tests that are promptly available, affordable to all stat laboratories, and cost effective. The aim of this article is to provide a personal overview on quality and safety issues of DOACs with an ED perspective. PMID:25839867
Baumann, Stefan; Huseynov, Aydin; El-Battrawy, Ibrahim; Renker, Matthias; Akin, Ibrahim
New oral anticoagulants (NOACs) are becoming available as alternatives to vitamin K antagonists (VKAs) to prevent systemic embolism in patients with non-valvular atrial fibrillation for the prevention and treatment of venous thromboembolism and pulmonary embolism. A comprehensive understanding of the basic concepts of hemostaseology, the underlying pharmacology, drug interactions and management of potential complications is essential for the selection of suitable patients to receive NOACs, for correct prescription and for optimal patient treatment. Furthermore, the use of NOACs in a perioperative setting is crucial, as it requires knowledge of time and dose of last intake of drug, current renal function and the planned procedure in order to assess the overall risk of bleeding. Although no antidote exists to reverse the effects of these novel drugs, selective substitution of coagulation factors and dialysis may be necessary. Therefore, choosing the most beneficial alternative to VKAs on an individual basis can be challenging for physicians. In conclusion, the recent introduction of NOACs represents an opportunity for anticoagulative treatment regimes, while the benefits, risks and limitations should be reflected carefully. The purpose of this systematic review is to highlight features and to provide practical guidance of NOACs in comparison with VKAs that should be considered in a multifaceted decision making process to improve efficacy and safety. PMID:26666330
Increasing age and renal impairment are risk factors for venous thrombosis but also for anticoagulant-induced bleeding. In large-scale phase III trials, non-VKA oral anticoagulants (NOACs) were at least as effective and safe for the treatment of acute venous thromboembolism as warfarin. Here, we review the efficacy and safety of dabigatran, rivaroxaban, apixaban and edoxaban in the subgroups of elderly patients (≥75 years) and patients with impaired renal function (creatinine clearance ≤50 ml/min). In all phase III trials, the efficacy of NOACs in the prevention of recurrent VTE was conserved both in the elderly subgroup and in the subgroup with impaired renal function. In a meta-analysis of the pooled results, NOACs reduced VTE recurrence compared with warfarin in elderly patients. In elderly patients and patients with impaired renal function, the safety of NOACs was in line with the results of the overall study. NOACs may offer an effective, safer and more convenient alternative for VKAs also in the elderly. However, the efficacy/safety profile of NOACs in the aged population needs to be confirmed in real-life. PMID:25650285
New oral anticoagulants, including dabigatran, rivaroxaban, and apixaban, have been recently approved for primary and secondary prophylaxis of thromboembolic conditions. However, there is no clear strategy for managing and reversing their anticoagulant effects. We aimed to summarize the available evidence for clinical management and reversal of bleeding associated with new oral anticoagulants. Using a systematic review approach, we aimed to identify studies describing reversal strategies for dabigatran, rivaroxaban, and apixaban. The search was conducted using Medline, EMBASE, HealthSTAR, and grey literature. We included laboratory and human studies. We included 23 studies reported in 37 out of 106 potentially relevant references. Four studies were conducted in humans and the rest were in vitro and in vivo studies. The majority of the studies evaluated the use of prothrombinase complex concentrate (PCC), either activated or inactivated, and recombinant activated factor VII (rFVIIa). Other interventions were also identified. Laboratory studies suggest that hemostatic parameters and bleeding might be partially or completely corrected by PCC for rivaroxaban better than dabigatran. Studies in humans suggest that PCC might reverse the effects of rivaroxaban better than dabigatran assessed by hemostatic tests. We were not able to locate studies evaluating the clinical efficacy of these agents. The best available evidence suggests that PCC (activated or inactivated) might be the best option for reversing new anticoagulants. Evidence for rFVIIa is less compelling. There might be differences in the efficacy of reversing agents for different anticoagulants. Studies assessing the clinical efficacy of these reversal agents are urgently needed. PMID:23806169
Monem, Mohammed; Iskandarani, Mohamad Khalid; Gokaraju, Kishan
We discuss the case of an independent 80-year-old Caucasian woman, being treated with new oral anticoagulants for a previous deep vein thrombosis, who had fallen on her right shoulder. She made a delayed presentation to the emergency department with a wrist drop in her right dominant hand. She had right arm bruising with good distal pulses but had a global neurological deficit in the hand. Plain radiographs of the shoulder, humerus, elbow, forearm and wrist demonstrated no fractures. MRI showed a significant right axillary lesion distorting the surrounding soft tissues, including the brachial plexus, and CT with contrast confirmed this to be a large axillary pseudoaneurysm. This was treated with an endovascular stent resulting in slightly improved motor function, but the significant residual deficit required subsequent rehabilitation to improve right upper limb function. PMID:27535738
Esmon, Charles T.
Orally active direct inhibitors of thrombin and factor Xa have now been approved for treatment or prevention of deep vein thrombosis, and stroke associated with atrial fibrillation. The factor Xa inhibitor, rivaroxaban, has shown promising results in the treatment of acute coronary syndrome but is not yet approved for that indication. These agents share a rapid onset and are cleared with half lives of approximately 10 hours. At present there is no approved antidote for either class of anticoagulant, making the treatment of life-threatening bleeding episodes problematic. These agents have fewer drug interactions than warfarin, have a predictable clearance, and hence do not require monitoring. Patients with renal insufficiency have delayed clearance and hence may have elevated levels of the drug leading to increased risk of bleeding. PMID:23026659
Pein, Miriam; Preis, Maren; Eckert, Carolin; Kiene, Florian E
Approaches to improve the taste of oral dosage forms that contain unpleasant tasting drugs are versatile. Likewise, the analytical in vitro and in vivo methods to assess taste-masking efficacy are diverse. Taste-masking has gained in importance since the EU legislation on medicines for children came into force in 2007, and taste-masking attributes are often required by regulatory authorities. However, standardized guidance for the analytical evaluation is still poor. Published protocols rarely consider real conditions, such as the volume of saliva or the residence time of solid oral dosage forms in the mouth. Methodological limitations and problems regarding time point of evaluation, sampling or sample pretreatment are hardly ever addressed. This critical review aims to evaluate and discuss published strategies in this context. PMID:24509066
Ferreira, Joana Lima; Wipf, Joyce E
Anticoagulants are beneficial for prevention and treatment of venous thromboembolism and stroke prevention in atrial fibrillation. The development of target-specific oral anticoagulants is changing the landscape of anticoagulation therapy and created growing interest on this subject. Understanding the pharmacology of different anticoagulants is the first step to adequately treat patients with best available therapy while avoiding serious bleeding complications. This article reviews the pharmacology of the main anticoagulant classes (vitamin K antagonists, direct oral anticoagulants, and heparins) and their clinical indications based on evidence-based data currently available in the literature. PMID:27235611
Vranckx, Pascal; Potpara, Tatjana; Dagres, Nikolaos; Heidbuchel, Hein
The purpose of this European Heart Rhythm Association survey was to assess the current practice concerning the use of oral anticoagulation in patients with post-operative atrial fibrillation (pre-existing or new-onset). The survey highlights the considerable heterogeneity of the type of anticoagulation, with 25% of the centres never using the non-vitamin K antagonist oral anticoagulants (NOACs) in this setting, as well the timing of oral anticoagulation initiation, the use and dosing of low-molecular-weight heparins, and the duration of anticoagulation when sinus rhythm is restored. One-third of the centres stated that they perceived that the risk of major pericardial bleeding requiring pericardiocentesis was higher when NOACs were used compared with vitamin K antagonists. Overall, the responding centres estimated the incidence of major pericardial haemorrhage to be 2.4%. More data are needed to inform practice guidelines in this field. PMID:27358360
Ezekowitz, Michael D; Spahr, Judy; Ghosh, Pradeepto; Corelli, Kathryn
Anticoagulation for stroke prevention in atrial fibrillation (AF) is effective. Pivotal trials RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE-AF TIMI 48 tested novel agents against warfarin (W). In RE-LY, an open-label trial, dabigatran 150 mg BID (D150) was superior (35%) and 110 mg BID (D110) was noninferior to W. D150 reduced ischemic strokes by 25% and intracerebral bleeds by 74%, but increased major GI bleeds by 0.5 % per year. In ROCKET AF, a double-blind study, rivaroxaban 20 mg daily, downtitrated to 15 mg daily (if CrCl was <49) was noninferior for efficacy and safety, with an increase in GI bleeds. In ARISTOTLE, a double-blind study, apixaban 5 mg BID (downtitrated to 2.5 mg BID if two of the following were present: age, >80; weight, <60 kg; or serum creatinine, >1.5 mg) was superior for safety (31%), efficacy (21%), and all-cause mortality (11%). In ENGAGE-AF TIMI 48, edoxaban 60 mg once daily (30 mg once daily if CrCl 30-50 ml/min, weight <60 kg, or concomitant verapamil or quinidine) was noninferior to W for efficacy, but reduced major bleeding (20%). To translate clinical trials to practice, understanding the disease and each anticoagulant is essential. For all novel agents, rapid anticoagulation, absence of monitoring, and a short half-life differentiate them from W. Bleed rates were either noninferior or lower than for W, without an antidote. Patient compliance is critical. Knowledge of renal function is essential and maintaining patients on therapy is key. PMID:24880227
Kim, Ji-young; Jeon, Ok-Cheol; Moon, Hyun Tae; Hwang, Seung Rim; Byun, Youngro
The preclinical safety of a newly developed oral anticoagulant, the low molecular weight heparin-deoxycholate conjugate (OH09208), was evaluated by a comprehensive evaluating program in compliance with standard guidelines. The single dose oral toxicity study in rats receiving 2000 and 5000 mg kg(-1) of OH09208 did not reveal any mortality, unusual body weight changes or necropsy findings. The results of the 4-week oral toxicity study with a 4-week recovery program in rats receiving OH09208 in doses of 100, 300 and 1000 mg kg(-1) day(-1) did not reveal any mortality, or indicate any unusual clinical signs, or show any toxicokinetic relationships to the administration of OH09208. Although the increase in liver enzymes in one male dog treated with 300 mg kg(-1) day(-1) and one female dog treated with 1000 mg kg(-1) day(-1) could not be excluded from the effect of the test substance, no other toxicologically significant changes were observed in the 4-week oral toxicity study with a 4-week recovery in beagle dogs. Thus, while the no-observed-adverse-effect level value from the 4-week study in both male and female rats was 1000 mg kg(-1) day(-1), those from the 4-week study in male and female beagle dogs were 300 and 1000 mg kg(-1) day(-1), respectively. Furthermore, OH09208 did not induce anaphylactic reactions in guinea pigs, micronucleated bone marrow cells in male ICR mice, chromosomal aberration in Chinese hamster lung cell lines, bacterial reverse mutation, and any abnormalities in hERG current assay, mouse central nervous system and dog cardiovascular studies. Overall, there were no unexpected toxicities in this preclinical study that might have precluded the safe administration of OH09208 to humans. PMID:25900269
Devabhakthuni, Sandeep; Yoon, Connie H; Pincus, Kathleen J
Anticoagulation therapy is often indicated for the treatment and prevention of venous thromboembolism (VTE). Despite advances in anticoagulant management with parenteral anticoagulants and vitamin K antagonists, limitations to their use still exists, leading to investigation of alternative anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors. To date, 3 target-specific oral anticoagulants (TSOACs) are Food and Drug Administration approved; several other agents are currently in development to optimize VTE management and minimize bleeding risks. The objective of this systematic review article is to provide clinicians an overview of the clinical evidence on the investigational TSOACs for the treatment and prevention of VTE. Of the agents in development, edoxaban holds the most promise due to robust data supporting its clinical benefit with a similar bleeding risk to currently approved agents. Clinicians should understand the TSOACs under investigation, since differences in pharmacokinetics and pharmacodynamics may influence clinical decision making and agent selection for management of VTE. Currently, no direct comparisons between TSOACs have been conducted. Agents under investigation have yet to overcome the major limitations of the currently existing TSOACs. Further studies are necessary to clarify which TSOAC agent is best for management of VTE in clinical practice. PMID:25634013
Objectives The first non-vitamin K antagonist oral anticoagulant (NOAC) introduced to the market in Japan was dabigatran in March 2011, and three more NOACs, rivaroxaban, apixaban, and edoxaban, have since become available. Randomized controlled trials of NOACs have revealed that intracranial hemorrhage (ICH) occurs less frequently with NOACs compared with warfarin. However, the absolute incidence of ICH associated with NOACs has increased with greater use of these anticoagulants, and we wanted to explore the incidence, clinical characteristics, and treatment course of patients with NOACs-associated ICH. Methods We retrospectively analyzed the characteristics of symptomatic ICH patients receiving NOACs between March 2011 and September 2014. Results ICH occurred in 6 patients (5 men, 1 woman; mean ± SD age, 72.8 ± 3.2 years). Mean time to onset was 146.2 ± 111.5 days after starting NOACs. Five patients received rivaroxaban and 1 patient received apixaban. None received dabigatran or edoxaban. Notably, no hematoma expansion was observed within 24 h of onset in the absence of infusion of fresh frozen plasma, activated prothrombin complex concentrate, recombinant activated factor VIIa or hemodialysis. When NOAC therapy was initiated, mean HAS-BLED and PANWARDS scores were 1.5 ± 0.5 and 39.5 ± 7.7, respectively. Mean systolic blood pressure was 137.8 ± 15.9 mmHg within 1 month before spontaneous ICH onset. Conclusion Six symptomatic ICHs occurred early in NOAC therapy but hematoma volume was small and did not expand in the absence of infusion of reversal agents or hemodialysis. The occurrence of ICH during NOAC therapy is possible even when there is acceptable mean systolic blood pressure control (137.8 ± 15.9 mmHg) and HAS-BLED score ≤ 2. Even stricter blood pressure lowering and control within the acceptable range may be advisable to prevent ICH during NOAC therapy. PMID:26171862
Charoo, Naseem; Cristofoletti, Rodrigo; Graham, Alexandra; Lartey, Paul; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James; Shah, Vinod P; Dressman, Jennifer
Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate release (IR) solid oral dosage forms containing fluconazole as the only active pharmaceutical ingredient (API) are reviewed. The decision is based on solubility, dissolution, permeability, therapeutic index, pharmacokinetic parameters, pharmacodynamic properties, and other relevant data. BE/bioavailability (BA) problems and drug-excipients interaction data were also reviewed and taken into consideration. According to the biopharmaceutics classification system (BCS), fluconazole in polymorphic forms II and III is a BCS class I drug and has a wide therapeutic index. BE of test formulations from many different manufacturers containing different excipients confirmed that the risk of bioinequivalence because of formulation and manufacturing factors is low. It was inferred that risk can be further reduced if in vitro studies are performed according to biowaiver guidelines. Thus, it is concluded that a biowaiver can be recommended for fluconazole IR dosage forms if (a) fluconazole is present as polymorphic form II or III or any other form/mixture showing high solubility, (b) the selection of excipients be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) countries for the same dosage form and used in their usual amounts, and (c) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving throughout the shelf life with similar dissolution profiles at pH 1.2, 4.5, and 6.8. PMID:25312492
Alturki, Abdulrahman; Alamri, Abdullah; Badawy, Mohamed; Teitelbaum, Jeanne
Options for anticoagulation have been expanding constantly during the past few years, providing a greater number of agents for prevention and management of thromboembolic disease. Although heparins and vitamin K antagonists (VKAs) has been used extensively for many decades, their narrow therapeutic range, interactions with other medications and food, and the need for routine monitoring of blood levels have led to the search for less problematic alternatives. Direct oral anticoagulants represent an important advance in anticoagulation therapy, directly inhibiting thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban) they represent an effective and safe alternatives to VKAs and heparins in the prevention and treatment of several thromboembolic disorders. DOCAs are associated with a low overall intracranial hemorrhage risk; however, life-threatening bleeding can occur. Reversal agents are approved for some and under development for others, concerns over the lack of antidotes or difficulty in obtaining them has tempered enthusiasm for their use because of the perception of better safety with heparins and VKAs as a result of the availability of effective reversal strategies. Appropriate use of these agents requires knowledge of their individual characteristics, mechanisms of action, pharmacokinetics, ways of monitoring, and when needed, manage patients in need of urgent surgery especially in life-threatening bleeds. This article provides a suggested comprehensive approach to manage patients with intracranial hemorrhage while on direct oral anticoagulants who require an urgent surgical intervention and who cannot wait for plasma concentration to decline. PMID:26960279
Use of oral anticoagulants is common in elderly persons. Oral anticoagulation can be used safely in the elderly if careful titration of the loading dose, careful changes in maintenance doses as well as consideration of drug interactions are taken into account. Frequent monitoring of the INR is essential, especially with changes in medical status and in co-medication. Correction of elevated INRs can be done following the recommendations. If vitamin K is used in stable patients, only small doses are required. In patients with atrial fibrillation, ischemic stroke risk and bleeding risk are predicted by overlapping factors. So patients who profit most from stroke risk reduction also show high bleeding risk. Risk stratification for ischemic stroke can be done easily with CHADS2-Score. Fall risk tends to be overestimated as a contraindication, whereas cognitive decline in combination with an unstable social network argues against anticoagulation. In the end, the decision to start or withhold anticoagulation has to be taken individually. PMID:20358518
Raschke, Carol G; Hatton, Randy C; Weaver, S Jay; Belgado, Bernadette S
The ability of electronic drug identification databases to identify solid oral dosage forms by their imprint codes was studied. The following seven commercially available electronic drug identification databases were selected to identify 500 solid oral dosage forms by their imprint codes: Clinical Pharmacology (Gold Standard Media, Tampa, FL), eFacts (Facts and Comparison, St. Louis, MO), Ident-A-Drug (Therapeutic Research, Stockton, CA), Identidex (Micromedex, Greenwood Village, CO), Clinical Reference Library (Lexi-Comp, Hudson, OH), Physicians' Desk Reference (PDR) Electronic Library (Medical Economics, Montvale, NJ), and RxList (RxList LLC, San Francisco, CA), Chi-square test was used to compare the percentages of medications identified by each of the seven electronic references. The ability of the databases to identify medication by specific characteristics, such as brand name versus generic, prescription versus nonprescription, commercially available for more than one year versus less than one year, colored versus white drug products, and controlled versus noncontrolled substances was evaluated. A logistic regression model was used to determine the probability of a drug product being identified by one of the electronic references based on these characteristics. All seven electronic databases combined identified 95.6% of the unknown medications by imprint code, color, shape, and scoring. Ident-A-Drug and Identidex identified the most drugs. The PDR Electronic Library and Facts and Comparisons Identified the least number of drugs. Solid oral dosage forms more likely to be identified were those that were on the market for more than a year, brand-name products, and prescription medications. Generic products on the market for less than a year and nonprescription products were particularly difficult to identify. A combination of electronic drug identification databases provides the best method of drug identification in an institutional setting. PMID:14503109
Stanisz, Beata J; Paszun, Sylwia K; Zalewska, Anna
Abstract: Cilazapril is a drug commonly used in management of heart failure in pediatric population. On pharmaceutical market it is available only in inconvenient for pediatric use tablet dosage forms. Until now, no oral liquid formulation containing cilazapril has been evaluated. Therefore, the aim of this study was to prepare easy to made and palatable 1 mg/mL oral liquid formulation with cilazapril (with consideration of original and generic cilazapril tablet and different packages) and subsequent investigation of physicochemical stability of these suspensions. Formulations were compounded using cilazapril obtained from original or generic cilazapril marketed tablet formulations and Ora-Blend" suspending agent. Stability of prepared suspensions stored in closed amber glass or amber plastic PET bottles in the temperature of 298 K was estimated throughout 28 day shelf-life period. Chemical stability was assessed by HPLC cilazapril stability indicating method. Physical stability was evaluated by appearance, taste, smell, pH and theological assessments. Cilazapril oral suspensions at concentration of 1 mg/mL demonstrated satisfactory stability over 28 day long storage at room temperature. Cilazapril concentrations remained within acceptable limit (+/- 10%) stored in closed amber bottles made of glass or PET material. Moreover, suspensions physical properties remained unaffected. Cilazapril - Ora-Blend* pediatric oral liquid is easy to made, palatable and stable when stored at room temperature for 28 days. Stability of cilazapril oral liquid remains unchanged while using cilazapril tablets produced by different manufacturers and bottles made of amber glass or PET material. PMID:25272892
Jacobs, Victoria; May, Heidi T; Bair, Tami L; Crandall, Brian G; Cutler, Michael J; Day, John D; Mallender, Charles; Osborn, Jeffrey S; Stevens, Scott M; Weiss, J Peter; Woller, Scott C; Bunch, T Jared
Direct oral anticoagulants (DOACs) have been used in clinical practice in the United States for the last 4 to 6 years. Although DOACs may be an attractive alternative to warfarin in many patients, long-term outcomes of use of these medications are unknown. We performed a propensity-matched analysis to report patient important outcomes of death, stroke/transient ischemic attack (TIA), bleeding, major bleeding, and dementia in patients taking a DOAC or warfarin. Patients receiving long-term anticoagulation from June 2010 to December 2014 for thromboembolism prevention with either warfarin or a DOAC were matched 1:1 by index date and propensity score. Multivariable Cox hazard regression was performed to determine the risk of death, stroke/TIA, major bleed, and dementia by the anticoagulant therapy received. A total of 5,254 patients were studied (2,627 per group). Average age was 72.4 ± 10.9 years, and 59.0% were men. Most patients were receiving long-term anticoagulation for AF management (warfarin: 96.5% vs DOAC: 92.7%, p <0.0001). Rivaroxaban (55.3%) was the most commonly used DOAC, followed by apixaban (22.5%) and dabigatran (22.2%). The use of DOACs compared with warfarin was associated with a reduced risk of long-term adverse outcomes: death (p = 0.09), stroke/TIA (p <0.0001), major bleed (p <0.0001), and bleed (p = 0.14). No significant outcome variance was noted in DOAC-type comparison. In the AF multivariable model patients taking DOAC were 43% less likely to develop stroke/TIA/dementia (hazard ratio 0.57 [CI 0.17, 1.97], p = 0.38) than those taking warfarin. Our community-based results suggest better long-term efficacy and safety of DOACs compared with warfarin. DOAC use was associated with a lower risk of cerebral ischemic events and new-onset dementia. PMID:27236255
Direct oral anticoagulant (DOAC) drugs (dabigatran, rivaroxaban, and apixaban) have emerged in the last decade to overcome some of the drawbacks of existing medications. To date, little is known about the dental management of patients taking these drugs. This study was undertaken to establish the evidence for the management of patients undergoing dental procedures while taking these medications. A rapid review approach was used to identify clinical and scientific research related to dental surgery performed in patients taking DOACs in order to produce an evidence summary. The rapid review did not identify any systematic reviews or original clinical trials and the overall quality of evidence found was poor. Most of the literature consisted of non-structured review articles and guidance documents based on assumptions from non-dental data and expert opinion, and recommendations on best practice varied throughout. The findings from the review of the literature varied considerably. Currently, recommendations are based on poor quality scientific data and clinical trials are required to establish best evidence-based practice guidance. PMID:26774397
Jespersen, Stine Funder; Christensen, Louisa M.; Christensen, Anders; Christensen, Hanne
Background. The knowledge is still sparse about patient related factors, influencing oral anticoagulation therapy (OAC) rates, in stroke patients with atrial fibrillation (AF). Aims. To assess the use of OAC in ischemic stroke patients diagnosed with AF and to identify patient related factors influencing the initiation of OAC. Methods. In the nationwide Danish Stroke Registry we identified 55,551 patients admitted with acute ischemic stroke from 2003 to 2011. Frequency analysis was used to assess the use of OAC in patients with AF, and logistic regression was used to determine independent predictors of OAC. Results. 17.1% (n = 9,482) of ischemic stroke patients had AF. OAC prescription rates were increasing, and in 2011 46.6% were prescribed OAC, 42.5% had a contraindication, and 3.7% were not prescribed OAC without a stated contraindication. Younger age, less severe stroke, and male gender were positive predictors of OAC, while excessive alcohol consumption, smoking, and institutionalization were negative predictors of OAC (P values < 0.05). Conclusions. Advanced age, severe stroke, female gender, institutionalization, smoking, and excessive alcohol consumption were associated with lower OAC rates. Contraindications were generally present in patients not in therapy, and the assumed underuse of OAC may be overestimated. PMID:24349774
Granziera, Serena; Hasan, Arjumand; Cohen, Alexander Ander T
Direct oral anticoagulants (DOACs) have been compared with standard therapy in large phase III studies to assess their safety and efficacy in the treatment of deep vein thrombosis and/or pulmonary embolism and in the secondary prevention of recurrent venous thromboembolism. Although the mean population age and the gross inclusion and exclusion criteria were similar across these studies, they differed in other aspects such as overall study design and acute treatment strategies. The 4 DOACs examined in phase III trials (apixaban, edoxaban, rivaroxaban, and dabigatran) showed noninferiority compared with standard therapy for the treatment of deep vein thrombosis and/or pulmonary embolism and for the prevention of recurrent venous thromboembolism. Furthermore, these DOACs exhibited a similar safety profile to standard therapy, with the risk of major bleeding significantly reduced in some of these studies. Rivaroxaban and apixaban were tested as a single-drug approach, whereas in the dabigatran and edoxaban studies, initial bridging with parenteral agents was employed. The purpose of this review is to compare the phase III studies of DOACs in this indication, to highlight the differences, and to discuss a series of clinically relevant issues, including the management of key patient subgroups (eg, fragile patients, those with cancer or renal impairment), extended treatment, use of comedications, heparin pretreatment versus a single-drug approach, and the bleeding profiles of the DOACs. PMID:26329910
Saint Etienne, Christophe; Angoulvant, Denis; Simeon, Edouard; Fauchier, Laurent
Long-term oral anticoagulant (OAC) and dual-antiplatelet therapy are commonly needed in patients with atrial fibrillation and in patients undergoing percutaneous coronary intervention (PCI), respectively. The combination of atrial fibrillation and PCI is frequent, and leads to a dilemma for antithrombotic therapy, where risk of stroke or stent thrombosis must be balanced with bleeding risk. In the WOEST study, 573 patients on OAC undergoing PCI were randomly assigned to receive clopidogrel alone or clopidogrel plus aspirin. The primary end point was the occurrence of any bleeding episode during 1-year follow-up. Clopidogrel alone administered to patients taking OAC after PCI was associated with a significantly lower rate of bleeding complications than clopidogrel plus aspirin. Moreover, a composite secondary end point of death, myocardial infarction and stent thrombosis was significantly lower in the dual-therapy group compared with the triple-therapy group. In spite of its limitations, the WOEST study constitutes a major breakthrough, showing that long-term aspirin after PCI may be obsolete in certain circumstances. This needs to be confirmed in further studies. PMID:24180531
Li Calzi, Mauro; Placci, Angelo; Lina, Daniela; Grassi, Francesca; Paoli, Giorgia; Bianconcini, Michele; Cattabiani, Maria Alberta; Menozzi, Alberto
We report the case of a 65--year-old woman admitted for inferior ST-segment elevation myocardial infarction complicated by complete atrioventricular block. The patient was under treatment with a novel oral anticoagulant (NOAC, rivaroxaban) because of a history of recurrent idiopathic pulmonary embolism. Emergency angiography showed complete acute thrombotic occlusion of the right coronary artery. After manual thrombectomy, there was no angiographic evidence of underlying atherosclerosis, therefore no further percutaneous coronary intervention was performed. Subsequent clinical course was uneventful. Laboratory tests demonstrated the presence of a heterozygous mutation of the factor II gene (G20210A), confirming the clinical evidence of a thrombophilic state. As rivaroxaban seemed to be ineffective in preventing spontaneous coronary thrombosis in this patient, antithrombotic therapy was shifted to warfarin plus low-dose aspirin. No further ischemic events occurred during the 1-year follow-up. It can be hypothesized that factor Xa inhibition by NOACs, such as rivaroxaban, could be insufficient in case of a thrombophilic state due to thrombin mutation. A brief review of the current literature on use of NOACs in acute coronary syndromes is also reported. PMID:27384603
Hägg, Lovisa; Johansson, Lars; Jansson, Jan-Håkan
Abstract Objective. An underuse of oral anticoagulants (OAC) in patients with atrial fibrillation (AF) has been suggested, as only 50% of all patients with AF receive OAC treatment. Whether this is due to contraindications, lack of an indication to treat, or an expression of underuse is sparsely investigated. This study therefore aimed to characterize individuals without OAC treatment in a real-life population of patients with AF. Design. Retrospective cross-sectional study. The medical records were scrutinized in order to identify the type of AF, risk factors for embolism and bleeding, and other factors of importance for OAC treatment. Setting. The municipalities of Skellefteå and Norsjö, northern Sweden. Subjects. A total of 2274 living residents with at least one verified episode of AF on or before December 31, 2010. Main outcome measures. Prevalence of treatment with OAC and documented reasons to withhold OAC treatment. Results. Among all 2274 patients with AF, 1187 (52%) were not treated with OAC. Of the untreated patients, 19% had no indication or had declined or had experienced adverse effects other than bleeding on warfarin treatment. The most common reason to withhold OAC was presence of risk factors for bleeding, found in 38% of all untreated patients. Furthermore, a documented reason could be identified to withhold OAC in 75%. Conclusions. Among patients with AF without OAC treatment a reason could be identified to withhold OAC in 75%. The underuse of OAC is estimated to be 25%. PMID:25464863
Brosens, I. A.; Robertson, W. B.; Van Assche, F. A.
Eighty-six women of proved fertility used an incremental dosage regimen of a combined oral contraceptive for a total of 570 cycles over one year. A daily tablet containing 50 μg of ethinyloestradiol and 50 μg D-norgestrel was taken for 11 days and a daily tablet containing 50 μg ethinyloestradiol and 125 μg D-norgestrel for the next 10 days. Withdrawal bleeding occurred during the tabletfree interval of seven days. The new preparation proved to be an efficient contraceptive, well tolerated, and with few side effects. Women who had gained weight while taking other oral contraceptives lost weight when they changed to the new preparation. The regimen allowed a significant reduction in the cycle dose of progestogen, and these results suggest that a further reduction in the cycle dose of both oestrogen and progestogen may be possible without losing contraceptive efficiency. PMID:4441832
De Caterina, Raffaele; Husted, Steen; Wallentin, Lars; Andreotti, Felicita; Arnesen, Harald; Bachmann, Fedor; Baigent, Colin; Collet, Jean-Philippe; Halvorsen, Sigrun; Huber, Kurt; Jespersen, Jørgen; Kristensen, Steen Dalby; Lip, Gregory Y H; Morais, João; Rasmussen, Lars Hvilsted; Ricci, Fabrizio; Sibbing, Dirk; Siegbahn, Agneta; Storey, Robert F; Ten Berg, Jurriën; Verheugt, Freek W A; Weitz, Jeffrey I
Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients, most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel. Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice. PMID:26952877
Verso, Melina; Agnelli, Giancarlo; Prandoni, Paolo
Patients with cancer account for 20 % of cases of venous thromboembolism (VTE). Cancer patients are at increased risk for VTE during the entire course of their disease, also in absence of traditional VTE risk factors. Furthermore, patients with VTE and cancer have an estimated risk of bleeding of 15-20 % per year while on anticoagulant treatment. For these reasons, treatment of acute VTE in patients with cancer remains a clinical challenge. In clinical studies, which included about 27,000 patients, new oral anticoagulants (NOACs) have been shown to be as effective and safe as conventional anticoagulation (heparin given with and followed by vitamin K antagonists) for the treatment of VTE. In these studies, 1227 patients with active cancer were enrolled. Preliminary results of subgroup analyses and meta-analyses of randomized clinical trials suggest that NOACs could represent an alternative to conventional anticoagulation in patients with active cancer. Further "ad hoc" studies evaluating the clinical benefit of treatment with NOACs in patients with VTE and cancer are needed. PMID:25840679
Raijada, Dhara; Müllertz, Anette; Cornett, Claus; Munk, Tommy; Sonnergaard, Jørn; Rantanen, Jukka
The present study introduces a miniaturized high-throughput platform to understand the influence of excipients on the performance of oral solid dosage forms during early drug development. Wet massing of binary mixtures of the model drug (sodium naproxen) and representative excipients was followed by sieving, drying, and compaction of the agglomerated material. The mini-compacts were subjected to stability studies at 25°C/5% relative humidity (RH), 25°C/60% RH and 40°C/75% RH for 3 months. The physical stability of the drug was affected by the storage condition and by the characteristics of the excipients, whereas all the samples were chemically stable. Force-distance curves obtained during the compression of agglomerated material were used for the comparison of compressibility of different drug-excipient mixtures. The agglomerated drug-excipient mixtures were also subjected to studies of the dissolution trend under sequential pH conditions to simulate pH environment of gastrointestinal tract. Major factors affecting the dissolution behavior were the diffusion layer pH of the binary mixtures and the ability of the excipients to alter the diffusion layer thickness. The proposed approach can be used for excipient selection and for early-stage performance testing of active pharmaceutical ingredient intended for oral solid dosage form. PMID:24436033
Vyas, Nimish B.; Rattner, Barnett A.
Avian risk assessments for rodenticides are often driven by the results of standardized acute oral toxicity tests without regards to a toxicant's mode of action and time course of adverse effects. First generation anticoagulant rodenticides (FGARs) generally require multiple feedings over several days to achieve a threshold concentration in tissue and cause adverse effects. This exposure regimen is much different than that used in the standardized acute oral toxicity test methodology. Median lethal dose values derived from standardized acute oral toxicity tests underestimate the environmental hazard and risk of FGARs. Caution is warranted when FGAR toxicity, physiological effects, and pharmacokinetics derived from standardized acute oral toxicity testing are used for forensic confirmation of the cause of death in avian mortality incidents and when characterizing FGARs' risks to free-ranging birds.
Ahmed, Zaheer; Hassan, Seemeen; Salzman, Gary A.
Warfarin was the only oral anticoagulant available for the treatment of venous thromboembolism for about half a century until the recent approval of novel oral agents dabigatran, rivoraxaban and apixaban. This presents new classes of medications less cumbersome to use. They do not require frequent laboratory monitoring or have nurmerous drug interactions. On the other hand it also poses a challenge to the physicians deciding which agent to use in specific patient populations, how to predict the bleeding risk compared to warfarin and between the different novel agents and how to manage bleeding with relatively recent discovery of few potential antidotes. This review summarizes the major trials that led to the approval of these agents and their exclusion criteria helping physicians understand which patient types might not benefit from these agents. It provides clinical pearls invaluable in everyday practice such as transitioning between traditional and novel anticoagulants, dose adjustments for high risk populations, drug interactions and cost analysis. Futhermore, the review provides direct comparisons with warfarin and indirect comparisons among the novel agents in terms of efficacy and bleeding risk narrating the numbers of patients with intracranial, gastrointestinal and fatal hemorrhages in each of the major trials. We hope that this review will help the physicians inform their patients about the benefits and risks of these agents and enable them to make an informed selection of the most appropriate anticoagulant.
Atrial fibrillation (AF) is a very common cardiac arrhythmia, and its prevalence is increasing along with aging in the developed world. This review discusses racial differences in the epidemiology and treatment of AF between African-American and Caucasian patients. Additionally, the effect of race on warfarin and novel oral anticoagulant use is discussed, as well as the role that physicians and patients play in achieving optimal treatment outcomes. Despite having a lower prevalence of AF compared with Caucasians, African-Americans suffer disproportionately from stroke and its sequelae. The possible reasons for this paradox include poorer access to health care, lower health literacy, and a higher prevalence of other stroke-risk factors among African-Americans. Consequently, it is important for providers to evaluate the effects of race, health literacy, access to health care, and cultural barriers on the use of anticoagulation in the management of AF. Warfarin-dose requirements vary across racial groups, with African-American patients requiring a higher dose than Caucasians to maintain a therapeutic international normalized ratio; the novel oral anticoagulants (dabigatran, rivaroxaban, and apixaban) seem to differ in this regard, although data are currently limited. Minority racial groups are not proportionally represented in either real-world studies or clinical trials, but as more information becomes available and other social issues are addressed, the treatment disparities between African-American and Caucasian patients should decrease. PMID:26056467
Samama, Meyer Michel; Gerotziafas, Grigoris T
Several newer anticoagulants are under clinical development. Recently two of them, Dabigatran etexilate/Pradaxa. and Rivaroxaban/Xarelto obtained marketing authorization in Europe and Canada for the prevention of thromboembolic events following major orthopedic surgery such as total hip and knee replacement. The results of Phase III clinical studies in thromboprophylaxis in major orthopedic surgery are highlighted and discussed in detail. Ongoing Phase II and III clinical trials assess their efficacy in the secondary prevention and treatment of deep vein thrombosis and pulmonary embolism, and in the long-term prevention of stroke in patients with non-valvular atrial fibrillation and in combination with aspirin and clopidogrel in patients with acute coronary syndromes. Many other small antithrombotic molecules including a new generation of low molecular weight heparins, are currently in different stages of clinical development. In addition to being administered orally, the newer anticoagulant agents have a more balanced benefit/risk ratio and wider therapeutic window. They have a rapid onset of action, a predictable anticoagulant effect that does not require routine laboratory monitoring. They have minor food and drug interactions, including those with cytochrome P450 and P.gp. They are highly specific and targeted to a single coagulation factor, and could carry similar or less hemorrhagic risks compared to the older anticoagulant agents. Finally, they may be used in a broader variety of patients, especially the medically ill patients with advanced cancer, and the elderly without any dosage adjustment, regardless of the patient age, gender, body weight, or in patients with mild renal impairment. Their use in the general world will hopefully confirm the promising results of clinical trials. PMID:19838770