Development Of New Oral Anticoagulants Research Articles

Comparative Study between Rivaroxaban and Warfarin inTreatment of Patients with Recurrent Deep Venous Thrombosis

AbstractBackground: Venous Thrombo-Embolism (VTE) manifestsas Deep Venous Thrombosis (DVT) and/or Pulmonary Em-bolism (PE). Per 1000 persons in the general population, theannual incidence is 1 to 2 cases. For decades, the gold standard of anti-thrombotic therapy has been based on heparins and Vitamin K Antagonists (VKAs), their narrow therapeutic range and multiple interactions led to the development of New Oral Anticoagulants (NOACs) beginning in 2003. Two types of new anticoagulants have been developed: Direct factor Xa inhibitors (Rivaroxaban) and direct factor IIa (thrombin) inhibitors.Aim of Study: The aim of this study was to comparerivaroxaban versus warfarin in treatment of recurrent DVTas regard efficacy, safety and complications.Patients and Methods: This was a prospective studyconducted on 30 patients suffering from recurrent deep venousthrombosis. The studied cases were divided into two groups,Group A treated by rivaroxaban, while group B treated bywarfarin over a period of 6 months. All cases were subjectedto full history taking, complete general and local examination,routine laboratory investigations and Duplex Scanning.Results: No statistically significant differences amongrivaroxaban and warfarin groups as regards presence of riskfactors, DVT extension, duplex results and incidence ofcomplications, while there was significant difference as regardsduration till symptoms relief.Conclusion: Rivaroxaban seems to have same efficacyas warfarin with advantage being earlier in symptoms relief/days, recanalization and patient compliance. In addition,warfarin users need to be monitored regularly.

Comparison of Safety Profiles of New Oral Anticoagulants with Warfarin Using the Japanese Spontaneous Reporting Database

The development of new oral anticoagulants (NOACs) has led to an alternative to treatment with warfarin. However, real-world data on comparing safety profiles of NOACs and warfarin are insufficient. The purpose of this study was to compare safety profiles of warfarin and NOACs using a spontaneous reporting system database. Adverse event reports spontaneously submitted to the Pharmaceuticals and Medical Devices Agency (Japan) between April 2011 and January 2017 were analysed. We performed disproportionality analyses, calculating the reporting odds ratio (ROR) with 95% confidence interval (CI). The database comprised 3445 reports associated with warfarin, and 14,269 reports with NOACs. A large number of bleeding complications were detected with the use of both warfarin and NOACs. As for cerebral haemorrhage, the signal scores were greater for NOACs as a class (ROR 25.1, 95% CI 23.3-27) and individual agents (edoxaban: ROR 23.6, 95% CI 18.6-29.9; rivaroxaban ROR 23.9, 95% CI 21.4-26.8; apixaban ROR 28.1, 95% CI 25.4-31.1) than for warfarin (ROR 18.9, 95% CI 16.4-21.7), but showed the lowest value for dabigatran (ROR 9.26, 95% CI 7.76-11). Gastrointestinal haemorrhage had stronger signals for NOACs (ROR 19.4, 95% CI 17.8-21.1) than warfarin (ROR 12.2, 95% CI 10.2-14.6). With respect to calciphylaxis, the association with warfarin was noteworthy (ROR 190; 95% CI, 126-287), but no reports were detected involving NOACs. Our results may provide useful information for treatment with oral anticoagulants, although further studies with more data are needed.

Rationale for Development of New Oral Anticoagulants.

The development of new or direct oral anticoagulants was triggered by the disadvantages of classic oral anticoagulation, which was isolated in Link's laboratory in 1940. Some of these limitations are the individual variation in response to these drugs, drug interaction and the need for regular laboratory monitoring. With increasing comorbidity and life expectancy in populations these limitations led to interruption of treatment or even underuse of treatment in light of potential side effects. With the introduction of novel oral anticoagulants some of these drawbacks are targeted whereas even these drugs also have some limitations and should be given with cautions and not to all patients having an indication for anticoagulation.

The new oral anticoagulants: clinical use and reversal agent development

Warfarin has been the centre of oral anticoagulant therapy for over 60 years. Recent development of new oral anticoagulants (NOACs) has provided a safe and effective alternative for stroke prevention in patients with atrial fibrillation and for prevention of venous thromboembolism. Determination of their use in acute coronary syndrome has been hampered by increases in bleeding events in most large trials, especially when used with antiplatelet therapy. NOACs have equal or superior efficacy and safety profiles compared to warfarin, fewer drug interactions; no dietary restrictions; predictable responses that eliminates monitoring; a rapid onset eliminates bridging with parenteral anticoagulants; and a potential reduction in mortality in patients with atrial fibrillation. There are reports of bleeding events and deaths associated with NOACs. Haemorrhage associated with dabigatran and warfarin were the most common safety issues for anticoagulants reported to the United States Food and Drug Administration in 2012. The lack of a NOAC reversal agent is a significant clinical concern for many physicians. Current reversal agents for unfractionated heparin, low molecular weight heparins and warfarin are less than optimal, and there are no effective reversal agents for NOACs. Development programs for anticoagulant reversal of the NOACs have three approaches: multiple coagulation factor replacement, large molecules (recombinant antibodies or altered coagulation factors) that either bind to or substitute for the coagulation factor while the anticoagulant itself is either being excreted or metabolized, and a small molecule specifically designed to bind to the NOACs and heparins and prevent them from binding to the coagulation factor targets.

Zymogen-like FXa Is a Potent Bypassing Agent for Reversal of Direct FXa Inhibitors in Vivo

The pharmacokinetic challenges of warfarin therapy have led to the development of new oral anticoagulants (NOACs) that directly inhibit coagulation factor Xa (FXa). While these new drugs (including rivaroxaban and apixaban) have many benefits over warfarin, no approved strategy exists to reverse their anticoagulant effects in the event of life-threatening bleeding or emergent need for surgery. The most promising reversal strategy in clinical development is a catalytically inactive form of FXa (Gla-domainless FXaS195A, GD-FXaS195A) that binds the NOAC with high affinity to relieve inhibition of endogenous FXa. In principle, removing the inhibitor through molecular engagement is attractive, especially when administered before bleeding begins (e.g. pre-surgery), and there is in vivo evidence to support the efficacy of GD-FXaS195A as a pre-injury antidote for direct FXa inhibitors. However, since GD-FXaS195A is a scavenger of the inhibitor and not a pro-hemostatic agent, GD-FXaS195A may not be effective if given after a bleeding episode has begun. Moreover, its mechanism of action necessitates a 1:1 ratio of GD-FXaS195A to neutralize the inhibitor. Thus, high doses (hundreds of milligrams of protein) will likely be required in humans.We hypothesized that a pro-hemostatic bypassing agent might be able to reverse the effects of direct FXa inhibitors no matter when it is administered, and with high potency. To evaluate this, we used a variant of FXa (FXaI16L) that is more zymogen-like than wild-type (wt)-FXa. This “zymogen-like” variant has lower catalytic activity in in vitro assays compared to wt-FXa due to impaired active site maturation. It is also resistant to active site inhibitors including plasma protease inhibitors, resulting in an extension of its plasma half-life (>30 minutes vs ~1 minute for wt-FXa). Importantly, its activity is rescued upon binding to its cofactor FVa in vivo, and we have previously shown that FXaI16L bypasses the intrinsic pathway defect in hemophilic mice. Here we evaluated whether FXaI16L might also be able to bypass direct FXa inhibitors using in vitro thrombin generation assays (TGAs) and two in vivo injury models in mice, and directly compared FXaI16L to GD-FXaS195A. In TGA experiments, 500 nM rivaroxaban decreased peak thrombin generation to 23% of that observed in normal human plasma (NHP). This decreased thrombin generation could be reversed by the addition of 3 nM human (h)FXaI16L which normalized peak thrombin generation. In comparative studies, hFXaI16L was 300-fold more potent than GD-FXaS195A in TGA assays.These data highlight that differences in mechanism of action (pro-hemostatic vs. scavenger) will have a huge impact on amounts of protein needed to revive thrombin generation. This was further reflected in in vivo studies. In invivo experiments with wild-type mice using 7.5% FeCl3 to induce carotid artery thrombosis, 1 mg/kg rivaroxaban prevented formation of occlusive thrombi. 30 minutes after the initial FeCl3 injury to rivaroxaban-treated mice, infusion of 0.25 mg/kg murine (m)FXaI16L normalized the phenotype, causing rapid occlusion at the injury site within 5 minutes. In contrast, we did not observe carotid artery occlusion with administration of up to 25 mg/kg GD-FXaS195A 30 minutes after the injury to rivaroxaban-treated mice (Fig. 1). When both rivaroxaban and the reversal agent were given prior to the injury, both mFXaI16L (0.5 mg/kg) and GD-FXaS195A (25 mg/kg) were effective at reversing the inhibition. Furthermore, using intravital microscopy to examine thrombus formation at the site of laser injury to mouse cremasteric arterioles, we found that 1 mg/kg rivaroxaban completely abrogated fibrin deposition and substantially reduced platelet accumulation. Treatment with1 mg/kg mFXaI16L substantially increased platelet and fibrin deposition at the site of laser injury. [Display omitted] Taken together, these data provide strong support for the in vivo efficacy and potency of FXaI16L as a potential pro-hemostatic bypass agent to reverse direct FXa inhibitors. The data also illustrate that antidotes like GD-FXaS195A may not be as effective as pro-hemostatic agents like FXaI16L following an injury, and we predict that effective reversal of NOACs will require a nuanced approach that uses an antidote or a bypassing agent depending on the clinical scenario. DisclosuresJasuja:Pfizer: Employment. Patel-Hett:Pfizer: Employment. Fruebis:Pfizer: Employment. Pittman:Pfizer: Employment. Camire:Pfizer: Consultancy, Patents & Royalties, Research Funding.

Which drug should we use for stroke prevention in atrial fibrillation?

Oral anticoagulation (OAC) remains the mainstay for prevention of ischaemic stroke in atrial fibrillation. This article reviews the latest evidence and development of new oral anticoagulants for the prevention of ischaemic stroke, as well as bleeding risk assessment, mitigation and management. Decision-making for stroke prevention has evolved towards the initial identification of 'low-risk' patients who do not need any antithrombotic therapy. Subsequent to this step, patients with at least 1 stroke risk factor can be offered effective stroke prevention, which is OAC. There is increased morbidity and mortality amongst warfarin users, if time in therapeutic range is poor. New oral anticoagulants (such as dabigatran, rivaroxaban, apixaban and edoxaban) offer relative efficacy, safety and convenience compared to warfarin, in relation to stroke prevention in atrial fibrillation. Bleeding risk can be assessed by HAS-BLED score, whereas the new SAMe-TT2R2 score can predict the patient's suitability for vitamin K antagonists. The landscape for stroke prevention in atrial fibrillation has greatly changed. It is no longer a question of 'if we treat' but more of 'how to treat', as the presence of one or more stroke risk factors in atrial fibrillation confers a risk of fatal and devastating strokes. OAC use, whether as well controlled vitamin K antagonists or nonvitamin K antagonists oral anticoagulant, will reduce the burden of stroke in atrial fibrillation.

Consistency of safety and efficacy of new oral anticoagulants across subgroups of patients with atrial fibrillation.

AimsThe well-known limitations of vitamin K antagonists (VKA) led to development of new oral anticoagulants (NOAC) in non-valvular atrial fibrillation (NVAF). The aim of this meta-analysis was to determine the consistency of treatment effects of NOAC irrespective of age, comorbidities, or prior VKA exposure.Methods and ResultsAll randomized, controlled phase III trials comparing NOAC to VKA up to October 2012 were eligible provided their results (stroke/systemic embolism (SSE) and major bleeding (MB)) were reported according to age (≤ or >75 years), renal function, CHADS2 score, presence of diabetes mellitus or heart failure, prior VKA use or previous cerebrovascular events. Interactions were considered significant at p <0.05. Three studies (50,578 patients) were included, respectively evaluating apixaban, rivaroxaban, and dabigatran versus warfarin. A trend towards interaction with heart failure (p = 0.08) was observed with respect to SSE reduction, this being greater in patients not presenting heart failure (RR = 0.76 [0.67–0.86]) than in those with heart failure (RR = 0.90 [0.78–1.04]); Significant interaction (p = 0.01) with CHADS2 score was observed, NOAC achieving a greater reduction in bleeding risk in patients with a score of 0–1 (RR 0.67 CI 0.57–0.79) than in those with a score ≥2 (RR 0.85 CI 0.74–0.98). Comparison of MB in patients with (RR 0.97 CI 0.79–1.18) and without (RR 0.76 CI 0.65–0.88) diabetes mellitus showed a similar trend (p = 0.06). No other interactions were found. All subgroups derived benefit from NOA in terms of SSE or MB reduction.ConclusionsNOAC appeared to be more effective and safer than VKA in reducing SSE or MB irrespective of patient comorbidities. Thromboembolism risk, evaluated by CHADS2 score and, to a lesser extent, diabetes mellitus modified the treatment effects of NOAC without complete loss of benefit with respect to MB reduction.

Treatment of Venous Thromboembolism

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common, potentially lethal condition with acute morbidity. To review the etiology of VTE and the 3 phases of VTE treatment: acute (first 5-10 days), long-term (from end of acute treatment to 3-6 months), and extended (beyond 3-6 months). Cochrane reviews, meta-analyses, and randomized controlled trials, as well as other clinical trials for topics not covered by the former, were reviewed. Literature searches using broad terms were used to find meta-analyses published in the last 15 years. The ninth edition of the American College of Chest Physicians Antithrombotic Therapy Guidelines was used to supplement the literature search. Guidelines from specialty organizations were consulted when relevant. The Canadian Agency for Drugs and Technologies in Health was searched for relevant cost-effectiveness studies. We also searched our own literature database of 8386 articles for relevant research. Low-molecular-weight heparin (LMWH) along with with vitamin K antagonists and the benefits and proven safety of ambulation have allowed for outpatient management of most cases of DVT in the acute phase. Development of new oral anticoagulants further simplifies acute-phase treatment and 2 oral agents can be used as monotherapy, avoiding the need for LMWH. Patients with PE can also be treated in the acute phase as outpatients, a decision dependent on prognosis and severity of PE. Thrombolysis is best reserved for severe VTE; inferior vena cava filters, ideally the retrievable variety, should be used when anticoagulation is contraindicated. In general, DVT and PE patients require 3 months of treatment with anticoagulants, with options including LMWH, vitamin K antagonists, or direct factor Xa or direct factor IIa inhibitors. After this time, decisions for further treatment are based on balancing the risk of VTE recurrence, determined by etiology of the VTE (transient risk factors, unprovoked or malignancy associated), against the risk of major hemorrhage from treatment. Better prediction tools for major hemorrhage are needed. Experience with new oral anticoagulants as acute, long-term, and extended therapy options is limited as yet, but as a class they appear to be safe and effective for all phases of treatment. The mainstay of VTE treatment is anticoagulation, while interventions such as thrombolysis and inferior vena cava filters are reserved for limited circumstances. Multiple therapeutic modes and options exist for VTE treatment with small but nonetheless important differential effects to consider. Anticoagulants will probably always increase bleeding risk, necessitating tailored treatment strategies that must incorporate etiology, risk, benefit, cost, and patient preference. Although great progress has been made, further study to understand individual patient risks is needed to make ideal treatment decisions.

The diagnosis and treatment of venous thromboembolism

Venous thromboembolism (VTE) is a common condition that can lead to complications such as postphlebitic syndrome, chronic pulmonary artery hypertension, and death. The approach to the diagnosis of has evolved over the years and an algorithm strategy combining pretest probability, D-dimer testing, and diagnostic imaging now allows for safe, convenient, and cost-effective investigation of patients. Patients with low pretest probability and a negative D-dimer can have VTE excluded without the need for imaging. The mainstay of treatment of VTE is anticoagulation, whereas interventions such as thrombolysis and inferior vena cava filters are reserved for special situations. Low-molecular-weight heparin has allowed for outpatient management of most patients with deep vein thrombosis at a considerable cost savings to the health care system. Patients with malignancy-associated VTE benefit from decreased recurrent rates if treated with long-term low-molecular-weight heparin. The development of new oral anticoagulants further simplifies treatment. The duration of anticoagulation is primarily influenced by underlying cause of the VTE (whether provoked or not) and consideration of the risk for major hemorrhage. Testing for genetic and acquired thrombophilia may provide insight as to the cause of a first idiopathic deep vein thrombosis, but the evidence linking most thrombophilias to an increased risk of recurrent thrombosis is limited.

Mechanical antithrombotic intervention by LAA occlusion in atrial fibrillation

Stroke in patients with atrial fibrillation (AF) is often associated with substantial morbidity and mortality. Oral anticoagulation remains the first-line approach to stroke prevention in such individuals; however, for a considerable proportion of patients, traditional treatment using warfarin is limited by a number of factors, such as the inconvenience of frequent therapeutic monitoring and the risk of haemorrhage. The development of new oral anticoagulants with improved efficacy and safety profiles has provided viable options for oral anticoagulation therapy in patients with nonvalvular (nonrheumatic AF). Nonetheless, in patients who have an increased risk of major haemorrhage, a nonpharmacological approach to antithrombotic therapy remains an attractive alternative. The left atrial appendage (LAA) has been found to be the source of >90% of thrombi in patients with nonvalvular AF; thus, prevention of thrombus formation via transcatheter mechanical LAA occlusion is a novel therapeutic target for stroke prevention in this patient population. In this Review, we present the rationale for LAA occlusion in patients with AF, the available occlusion devices and their clinical evidence to date. We also discuss the roles of various imaging techniques in device implantation and the management strategy for associated procedural complications.

Safety of new oral anticoagulant drugs: a perspective.

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.

NEW ORAL ANTICOAGULANT DRUGS IN ATRIAL FIBRILLATION AND ACUTE CORONARY SYNDROME

After an acute coronary syndrome, patients remain at risk of recurrent ischemic events despite the use of antiplatelet therapy. In order to reduce the risk of recurrent ischemia in the treatment of patients with acute coronary syndromes, standard oral anticoagulants, such as vitamin K antagonists, have been introduced. These drugs have an important role in preventing stroke and systemic embolism in patients with atrial fibrillation. Vitamin K antagonists (e.g., warfarin) reduce the risk of recurrent cardiovascular events and stroke but increase the risk of bleeding. In addition, the traditional anticoagulants have other significant drawbacks. Therefore, modulation of the coagulation process represents an important target in the development of new oral anticoagulants today. The new oral anticoagulants selectively target thrombin (dabigatran etexilate) or factor Xa (rivaroxaban, apixaban, edoxaban). Unlike traditional anticoagulants, these drugs have rapid onset of action and a relatively wide therapeutic range, do not require routine prothrombin time (PT) monitoring and have low potential for food and drug interaction. Dabigatran etexilate and rivaroxaban have been already approved in many countries for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The third phase of clinical studies in which rivaroxaban was investigated in patients with acute coronary syndrome has been successfully completed. Acta Medica Medianae 2013;52(3):42-48.

Nouveaux anticoagulants oraux dans la fibrillation atriale non valvulaire

Vitamin K antagonists (VKA) had several decades of proven efficacy in AF-related stroke prevention but the drug's numerous limitations make its implementation difficult for practitioners and patients. The drawbacks of VKA have prompted the development of new oral anticoagulants (NOAC) that are at least as efficacious and safe as warfarin in phase III trials. Dabigatran (220and 300mg/day), rivaroxaban (20mg/day) and apixaban (10mg/day) were proved to be non-inferior compared with warfarin in the prevention of bleeding, stroke and systemic embolism. Dabigatran 300mg/day and apixaban were found to be statistically superior to warfarin in stroke reduction. All these drugs reduced the risk of intracranial bleeding compared to warfarin. Dabigatran 220mg/day and apixaban decreased the risk of major bleeding. The limitation of NOAC was an increase of gastrointestinal bleeding by dabigatran 300mg/j and rivaroxaban and myocardial infarction by dabigatran. Practitioners must also be aware of the disadvantages of these new drugs when choosing NOAC for their patients with unstable INR.

The changing face of oral anticoagulants

Warfarin has been the established oral anticoagulant for the last 50 years, being effective in the prevention and treatment of venous and arterial thromboembolic disorders. However, the frequent requirement for INR monitoring, multiple drug and food interactions have fuelled the need for development of new oral anticoagulants. Dabigatran is the first of a series of new oral anticoagulants that are emerging as the successors to warfarin. This new group of anticoagulants is rapidly gaining FDA and NICE approval and has proven non-inferiority to warfarin and viable alternatives to warfarin in the coming years. Given the obvious impact of this on dental treatment in the primary care and hospital setting this article aims to increase familiarisation with this new medicine group.

Anticoagulation beyond direct thrombin and factor Xa inhibitors: indications for targeting the intrinsic pathway?

Antithrombotic drugs like vitamin K antagonists and heparin have been the gold standard for the treatment and prevention of thromboembolic disease for many years. Unfortunately, there are several disadvantages of these antithrombotic drugs: they are accompanied by serious bleeding problems, it is necessary to monitor the therapeutic window, and there are various interactions with food and other drugs. This has led to the development of new oral anticoagulants, specifically inhibiting either thrombin or factor Xa. In terms of effectiveness, these drugs are comparable to the currently available anticoagulants; however, they are still associated with issues such as bleeding, reversal of the drug and complicated laboratory monitoring. Vitamin K antagonists, heparin, direct thrombin and factor Xa inhibitors have in common that they target key proteins of the haemostatic system. In an attempt to overcome these difficulties we investigated whether the intrinsic coagulation factors (VIII, IX, XI, XII, prekallikrein and high-molecular-weight kininogen) are superior targets for anticoagulation. We analysed epidemiological data concerning thrombosis and bleeding in patients deficient in one of the intrinsic pathway proteins. Furthermore, we discuss several thrombotic models in intrinsic coagulation factor-deficient animals. The combined results suggest that intrinsic coagulation factors could be suitable targets for anticoagulant drugs.

Oral Direct Factor Xa Inhibitors

Vitamin K antagonists, such as warfarin, have been the mainstay of oral anticoagulation for many decades. Although effective, warfarin has numerous limitations, including a variable dose requirement from patient to patient because of differences in dietary vitamin K intake, common genetic polymorphisms, and multiple drug interactions that affect its pharmacodynamics and metabolism. Consequently, warfarin requires frequent monitoring to ensure that a therapeutic anticoagulant effect has been achieved because excessive anticoagulation can lead to bleeding, and because insufficient anticoagulation can result in thrombosis. Such monitoring is burdensome for patients and physicians and is costly for the health care system. These limitations have prompted the development of new oral anticoagulants that target either factor Xa or thrombin. Although the path to the development of these drugs has been long, the new drugs are at least as effective and safe as warfarin, but they streamline clinical care because they can be administered in fixed doses without routine coagulation monitoring. This article focuses on rivaroxaban, apixaban, and edoxaban, the oral factor Xa inhibitors in the most advanced stages of development. After 20 years of discovery research, these agents are already licensed for several indications. Thus, the long path to finding replacements for warfarin has finally reached fruition. Therefore, development of the oral factor Xa inhibitors represents a translational science success story.

Dabigatran

Atrial fibrillation (AF) affects more than 3 million Americans and is expected to reach epidemic proportions as the US population ages. The presence of AF increases lifetime stroke risk nearly 5-fold. Conventionally, patients at moderate or high risk of stroke have been prescribed antiplatelet agents or vitamin K antagonists to reduce the risk, but each has significant limitations. Accordingly, the development of new oral anticoagulants (direct thrombin inhibitors [DTIs] and factor Xa inhibitors) has attracted significant interest. The DTI dabigatran etexilate was recently shown to provide superior risk reduction to warfarin for stroke and systemic embolism for patients with nonvalvular AF and recently gained US Food and Drug Administration approval for this indication. Dabigatran etexilate is the first new agent for this indication in the United States in more than 50 years. Herein, we outline the options for stroke prevention in AF in the new oral anticoagulant era. The efficacy and practical obstacles surrounding the use of warfarin are summarized. We then review the mechanism of action, efficacy, and safety of dabigatran-including clinically relevant pharmacokinetics. Practical issues of initiation, conversion of anticoagulant therapy, and recommendations for dabigatran use in patients at high risk of bleeding and other special populations are discussed. We conclude by proposing a role for dabigatran in the armamentarium of drugs available for the management of stroke risk in AF.

Apixaban: Pharmakologie und klinisches Wirkprofil

Vitamin K antagonists are currently the most frequently used anticoagulants. However, practical limitations of their application, such as variability in dose response, a narrow therapeutic index and numerous drug and dietary interactions, have lead to development of new oral anticoagulants with better efficacy and safety profile. Recent advances included the development of orally active FXa inhibitors rivaroxaban and apixaban. Rivaroxaban received its marketing approval in September 2008. Apixaban has recently been approved for prevention of venous thromboembolism after total hip or knee replacement. This review describes the pharmacological properties of apixaban and discusses the latest findings from clinical trials.

Neue Antithrombotika

Vitamin K antagonists and heparins have been standard anticoagulation drugs over the past decades. They are effective and safe but they have several drawbacks which has led to the development of new oral anticoagulants. Dabigatran etexilate is a specific oral thrombin inhibitor and rivaroxaban and apixaban are oral inhibitors of factor Xa. These agents produce a predictable anticoagulant response after fixed-dose administration so that routine coagulation monitoring is unnecessary. Currently, dabigatran etexilate, rivaroxaban and apixaban are licensed for thromboprophylaxis after elective total hip or knee replacement surgery. Since august 2011, dabigatran etexilate is licensed for patients with atrial fibrillation, rivaroxaban will follow. However, indications will be expanded e.g. for therapy of venous thromboembolism. It is important to be aware of the pharmacokinetic and pharmacodynamic profiles of these new agents. The drugs considerably influence the global test of coagulation thus making an interpretation of test results difficult. Currently, there is a lack of suitable coagulation tests to monitor anticoagulation in emergency cases, such as bleeding. Specific antidotes are not yet available.

Dabigatran for stroke prevention in atrial fibrillation: the RE-LY trial

Oral anticoagulation is the mainstay of therapy for stroke prevention in patients with atrial fibrillation. Vitamin K antagonists such as warfarin reduce the risk of cardioembolic stroke by approximately two-thirds compared with no treatment, but are limited by their unpredictable anticoagulant effect and narrow therapeutic index. Warfarin therapy requires routine coagulation monitoring, which is inconvenient for patients and costly for the healthcare system. The limitations of the vitamin K agonists have spurred the development of new oral anticoagulants that selectively inhibit thrombin or factor Xa. The Randomized Evaluation of Long-Term Anticoagulation (RE-LY) trial of 18,113 patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke demonstrated that dabigatran etexilate given at a dose of 150 mg twice daily compared with warfarin, reduced the rate of stroke or systemic embolism by one-third with a similar rate of major bleeding, whereas dabigatran etexilate given at a dose of 110 mg twice daily compared with warfarin had a similar rate of stroke or systemic embolism and reduced the rate of major bleeding by one-fifth. Both doses of dabigatran etexilate reduced intracranial bleeding by approximately two-thirds compared with warfarin. Based on the results of the RE-LY trial, both the US FDA and Health Canada recently approved dabigatran etexilate for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.