Non-vitamin-K oral anticoagulants (NOACs) for the prevention of secondary stroke

ABSTRACT

Introduction: In patients with atrial fibrillation (AF), oral anticoagulation with vitamin K antagonists (VKA) (warfarin, phenprocoumon) is effective both for primary and secondary stroke prevention with a 60–70% relative reduction in stroke risk compared with placebo. Mortality is reduced by 26%. VKA have a number of well-documented shortcomings which were overcome by non-vitamin-K oral anticoagulants (NOACs).

Areas covered: Results of randomized trials for four NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) have been published (ARISTOTLE, RE-LY, ENGAGE, ROCKET-AF). In this review, the authors discuss the results in subgroups of patients with prior transient ischemic attacks or ischemic stroke. In aggregate, the NOACs are superior to warfarin for secondary prevention and result in a 50% reduction in intracerebral hemorrhage. Apixaban was superior to aspirin in the AVERROES trial and had a similar rate of major bleeding complications.

Expert opinion: NOACs add to the therapeutic options for secondary stroke prevention in patients with AF and offer advantages over warfarin including a favorable bleeding profile and convenience of use. Aspirin should no longer be used for secondary stroke prevention in patients with AF.     

Edoxaban for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation

Introduction: Oral anticoagulation is central to the management of patients with atrial fibrillation (AF) and at least one additional stroke risk factor. For decades, the vitamin K antagonists (e.g. warfarin) remained the only oral anticoagulant available for stroke prevention in AF. The non-vitamin K oral anticoagulants (NOACs) are now available, and these drugs include the direct thrombin inhibitors and factor Xa inhibitors. The latter class includes edoxaban, which has recently been approved for stroke prevention in AF by the United States Food and Drug Administration and the European Medicine Agency. In line with other NOACs, edoxaban avoids the many limitations of warfarin associated with variability of anticoagulation effect and multiple food and drug interactions.

Areas covered: In this review, the currently available evidence on edoxaban in patients with non-valvular AF is discussed. The pharmacology, efficacy and safety, and current aspects of use of edoxaban in patients with non-valvular AF for stroke and thromboembolism prevention are reviewed.

Expert opinion: Phase III trials on edoxaban for stroke prevention in non-valvular AF confirms non-inferiority of edoxaban compared to well-managed warfarin both in terms of efficacy and safety. Currently ongoing and future trials as well as real-world data are warranted to confirm its effectiveness and safety for chronic anticoagulation and improve evidence in other areas which are lacking evidence where NOAC use remains controversial.     

Changing anticoagulant paradigms for atrial fibrillation: dabigatran,apixaban and rivaroxaban

Introduction: Vitamin K antagonists (VKAs) are the main therapeutic agents used to prevent embolic events in patients with atrial fibrillation (AF). Despite their proven efficacy, VKAs are underused and have several limitations. In recent years, there has been great interest in the development of new oral anticoagulants with a more efficient pharmacological profile, first tested in venous thromboembolism prevention and later in AF.

Areas covered: The authors review the pharmacological differences between dabigatran, rivaroxaban and apixaban, and potential subgroups of patients in whom these new drugs would constitute a possible alternative to VKA therapy. Pharmacodynamic and pharmacokinetic data from each compound are analyzed in respect to their potential use in AF. This article provides an exhaustive review of the current status of this topic and the controversies still regarding each drug.

Expert opinion: Apixaban and rivaroxaban are under evaluation for thromboembolic prevention in AF; dabigatran was recently approved for this indication. Therefore, it is important to know the characteristics of these drugs as a potential alternative to VKAs.     

Consensus in cardiology on non-vitamin-K oral anticoagulants for patients with atrial fibrillation

Introduction: Non-vitamin-K oral anticoagulants (NOACs) are known to have advantages over vitamin K antagonists (VKAs) for patients with atrial fibrillation (AF). However, more than half of patients are still treated with VKAs. The absence of direct comparisons amongst NOACs and the insufficient evidence in some clinical situations could explain, at least in part, this predominance of VKAs. The aims of our study were: 1) to analyze the opinion of an expert panel on the role of NOACs in different clinical scenarios; 2) to elaborate specific consensus recommendations for the management of NOACs for each one of these situations.

Patients and methods: An online survey was created covering distinct aspects of the use of oral anticoagulants in various clinical settings. A two-round modified Delphi approach was used.

Results: Forty-eight experts responded to the survey. Consensus was reached on 58% (48/83) of the items. The panelists concluded that the term non-valvular AF should be avoided. In most clinical settings NOACs were preferred over VKAs. Once daily NOACs were preferred in elderly patients to improve therapeutic compliance and, in those over the age of 85, edoxaban could be the best choice. Edoxaban and apixaban were the favorites for patients with AF and moderate chronic kidney disease (CKD). In the case of patients on triple antithrombotic therapy due to AF and acute coronary syndrome (ACS) the lowest effective NOAC dose should be used.

Conclusion: Our study emphasizes that there are several clinical circumstances in patients with AF requiring complex decisions about anticoagulation treatment and offers some recommendations based on the consensus reached by an expert panel.     

Oral anticoagulant use in cardiovascular disorders: a perspective on present and potential indications for rivaroxaban

Background: Four non-vitamin-K-antagonist oral anticoagulants (NOACs) have been approved for use in various cardiovascular indications. The direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors apixaban, edoxaban and rivaroxaban are now increasingly used in clinical practice. For some of these agents, available data from real-world studies support the efficacy and safety data in phase III clinical trials.

Objectives: This review aims to summarize the current status of trials and observational studies of oral anticoagulant use over the spectrum of cardiovascular disorders (excluding venous thrombosis), provide a reference source beyond stroke prevention for atrial fibrillation (AF) and examine the potential for novel applications in the cardiovascular field.

Methods: We searched the recent literature for data on completed and upcoming trials of oral anticoagulants with a particular focus on rivaroxaban.

Results: Recent data in specific patient subgroups, such as patients with AF undergoing catheter ablation or cardioversion, have led to an extended approval for rivaroxaban, whereas the other NOACs have ongoing or recently completed trials in this setting. However, there are unmet medical needs for several arterial thromboembolic-related conditions, including patients with: AF and acute coronary syndrome, AF and coronary artery disease undergoing elective percutaneous coronary intervention, coronary artery disease and peripheral artery disease, implanted cardiac devices, and embolic stroke of unknown source.

Conclusion: NOACs may provide alternative treatment options in areas of unmet need, and numerous studies are underway to assess their benefit–risk profiles in these settings.     

The factor xa inhibitor edoxaban for the prevention of stroke and systemic embolism in patients with atrial fibrillation

Introduction: With the rising prevalence of nonvalvular atrial fibrillation (NVAF) in the general population, the development of new drugs for prevention of thromboembolic events is essential. Non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to present a number of advantages over conventionally used agents, such as predictable pharmacokinetics and no requirement for continuous anticoagulant monitoring. The most recently approved NOAC for the NVAF indication is edoxaban. Several subgroup analyses from the edoxaban phase III ENGAGE AF-TIMI 48 trial have now been published, alongside meta-analysis data comparing the four currently approved NOACs. Consequently, an updated review of the literature is merited.

Areas covered: A PubMed search using the terms ‘edoxaban’, ‘non-vitamin K antagonist oral anticoagulant’, ‘ENGAGE AF-TIMI 48’, and ‘atrial fibrillation’ was performed and results screened for the most relevant English language publications. The market position, pharmacological profile, clinical efficacy, safety and tolerability of edoxaban are presented and discussed.

Expert commentary: Edoxaban has been shown to have an efficacy similar or superior to that of warfarin, with a potentially lower risk of major bleeding and predictable, dose-dependent pharmacology. In order to clarify its position within the NOAC market, head-to-head comparative studies are required.     

Clopidogrel hydrogen sulphate for atrial fibrillation

Introduction: Atrial fibrillation is a common cardiac rhythm abnormality with a considerable cardiovascular disease burden worldwide. It is an independent major risk factor for stroke. Stroke prevention with anticoagulation or antiplatelet agents has been an important area of clinical research. Warfarin is the most widely used antithrombotic therapy for stroke prophylaxis for last several years, and now dabigatran (150 mg b.i.d.) is more effective than warfarin in stroke prevention in individuals at increased of stroke. In addition, several studies have evaluated the efficacy of clopidogrel for stroke prophylaxis either alone or in combination with aspirin.

Areas covered: This review summarizes the key findings of the trials looking at the efficacy of clopidogrel in stroke prevention. A literature search was performed using PubMed and Google Scholar. The trials that evaluated the efficacy of clopidogrel in preventing atherothrombotic events or stroke were also included.

Expert opinion: Clopidogrel prevents more vascular events, including stroke, in patients with a recent myocardial infarction, stroke or peripheral vascular disease than aspirin. Combination of clopidogrel and aspirin provides a greater reduction of stroke than aspirin or clopidogrel monotherapy, but at an increased risk of bleeding. Dual antiplatelet therapy (clopidogrel and aspirin) is inferior to warfarin in primary stroke prevention for patient with atrial fibrillation and thus should be considered for stroke prophylaxis only in patients ineligible for warfarin. However, with the advent of newer agents, like direct thrombin inhibitors and Factor Xa inhibitors, the role of antiplatelet therapy for stroke prevention in atrial fibrillation remains unclear.     

Acute stroke in patients on new direct oral anticoagulants: how to manage,how to treat?

Introduction: For a long time, vitamin K antagonists (VKA) were the only available oral anticoagulants for clinical use. It is conceivable that the number of patients treated with novel direct oral anticoagulants (NOAC) will increase, due to the easy handling and the favorable risk–benefit profile compared with VKA. It is, therefore, expected that clinicians will be increasingly confronted with the question on how to treat acute ischemic stroke (AIS) if there is an indication for thrombolysis or how to manage intracranial bleedings.

Areas covered: In this review, we discuss controversies on thrombolysis in patients anticoagulated with NOAC, the dilemma of when to restart anticoagulation after AIS, and whether (and when) to re-institute oral anticoagulation after a brain hemorrhage. We provide suggestions for the management of these situations.

Expert opinion: Thrombolysis for patients with ischemic stroke who were given warfarin at subtherapeutic International normalized ratio values (≤ 1.7) may be considered according to guideline. Thrombolysis is contraindicated if intake of NOAC is reported in a patient, but no other information is available on-time of last intake of NOAC. Prothrombin complex concentrate have been proposed as a plausible, but unproven therapy to reverse the anticoagulant effects of NOACs.     

Minimizing the risk of hemorrhagic stroke during anticoagulant therapy for atrial fibrillation

Introduction: Oral anticoagulation (OAC) is given for ischemic stroke prevention in patients with nonvalvular atrial fibrillation. OAC’s most serious complications are major bleeding and, in particular, hemorrhagic stroke. Together with vitamin K antagonists (VKAs), direct oral anticoagulants (DOAC) are now available which have a more rapid onset/offset of action and more predictable anticoagulant effect. The advent of DOAC has given to the clinician an opportunity to tailor OAC therapy in order to maximize advantages and minimize complications.

Areas covered: This review covers data published in literature regarding the risk of hemorrhagic stroke in patients taking OAC. Bleeding risk assessment is discussed and different bleeding risk factors are presented. The paper will also review clinical studies comparing DOAC against standard anticoagulation, in regard to the risk of hemorrhagic stroke.

Expert opinion: Bleeding assessment is mandatory in order to select patients at high hemorrhagic risk who will benefit the most from close monitoring. Blood pressure, alcohol intake, concomitant medication and comorbidities should be constantly evaluated and treated accordingly. During VKA therapy, adherence and intensity of anticoagulation must be strictly monitored. DOAC are associated with lower risk of hemorrhagic stroke than VKA. However, periodic hepatic and renal checks as well as careful evaluation of time adherence are necessary to reduce the risk of bleeding.     

Clinical relevance of pharmacokinetic and pharmacodynamic properties of edoxaban when treating patients with atrial fibrillation and heart failure

Introduction: Atrial fibrillation (AF) is an independent risk factor for stroke. It is most prevalent in the elderly and frequently coexists with heart failure (HF). The joint occurrence of AF and HF further worsens prognosis. The prevention of thromboembolism is crucial in the management of AF. In recent years, new oral anticoagulants (NOACs) have been licensed for the prevention of stroke and systemic embolism in patients with AF.

Areas covered: This article reviews the key published studies on the pharmacology, clinical efficacy and safety of edoxaban, the latest NOAC to receive approval for the AF indication. This potent and selective inhibitor of factor Xa shows predictable pharmacokinetic and pharmacodynamic profiles. Its efficacy and safety have been demonstrated in the pivotal, phase III, warfarin-controlled ENGAGE AF-TIMI 48 trial in 21,105 AF patients.

Expert opinion: NOACs will likely improve the management of AF, with or without HF. Edoxaban has a favorable pharmacokinetic profile that supports its use in special patient populations, including patients aged ≥75 years, with HF, renal impairment, poor adherence, and on polypharmacy. Proven strategies of edoxaban dose-reduction for optimal use in the presence of moderate renal impairment, and/or use of strong P-gp inhibitors are available.     

Suspected adverse drug reaction reports with oral anticoagulants in Portugal: a pharmacovigilance study

Objective: In this pharmacovigilance study, we aimed to determine the incidence of spontaneously reported suspected adverse drug reactions (ADRs) related to oral anticoagulants: non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, rivaroxaban) and vitamin K antagonists (VKA)

Research design and methods: In this retrospective observational study, we extracted all the individual case safety reports related to oral anticoagulants recorded in the Portuguese Pharmacovigilance Database (January 2010 to April 2015). The annual incidence of suspected ADRs was estimated using drug exposure data. Disproportionality of reporting ADR was addressed through reporting odds ratio (ROR) and 99% confidence intervals.

Results: We appraised 794 suspected ADR (78% related to NOACs). The annual number of ADRs increased overtime with 9 ADRs/million Defined Daily Dose (DDD) at the end of 2014. The incidence of NOACs ADRs decreased from 2012 onwards. VKA showed a disproportion in ‘Investigation’ (ROR 0.10, 99%CI 0.05–0.22) and ‘Injury, poisoning and procedural complications’ (ROR 0.36, 99%CI 0.19–0.69) ADRs compared with NOACs. NOACs had a higher significant disproportion of ‘Nervous system disorders’ related ADRs (ROR 3.98, 99%CI 1.50–10.53).

Conclusions: Reporting of ADRs associated with oral anticoagulants (mainly NOACs), is increasing. Exploratory disproportion analyses showed an increase of reports of nervous system ADRs with NOACs, and INR-related ADRs with VKA.     

Stroke prevention in atrial fibrillation patients

Importance of the field: Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and is associated with an increased risk of stroke, mortality and significant morbidity. Given the rapidly increasing incidence and prevalence of AF, and the resulting public health burden of the consequences associated with this arrhythmia, stroke prevention is an extremely important topic.

Areas covered in this review: This review covers the epidemiology of AF, the pathophysiology of ischemic stroke in AF and current antithrombotic therapy choices for stroke prevention in this condition. In addition, this article discusses important topics such as the assessment of stroke risk stratification and bleeding risk assessment, which are key issues in deciding upon thromboprophylaxis for AF patients. Finally, the review highlights the advent of new anticoagulant therapies and discusses the future challenges for researchers in this area.

What the reader will gain: This review summarizes all of the major antithrombotic trials conducted in AF patients over the last twenty years and highlights the importance of anticoagulation therapy for the prevention of stroke, after appropriate individual stroke and bleeding risk assessment.

Take home message: Assessment of individual stroke risk and bleeding risk is key in determining appropriate thromboprophylaxis for AF patients, given the associated thromboembolic and hemorrhagic complications. The availability of newer, safer and more convenient drugs will mean that oral anticoagulation is available for a larger proportion of AF patients who may benefit from it.     

New anticoagulants for venous thromboembolism and atrial fibrillation: what the future holds

Introduction: The field of anticoagulation has seen impressive progress over the last decade. The introduction of the Non Vitamin K Oral Anticoagulants (NOACs) has revolutionized practice surrounding thromboprophylaxis, treatment of thromboembolic disease and stroke prevention in atrial fibrillation (AF). However, the search for the ‘holy grail’ of anticoagulation, an agent that combines optimal efficacy with minimal bleeding diathesis, continues.

Areas covered: In this paper we aim to summarize the current evidence from pre-clinical studies and early phase clinical trials, presenting the pharmacodynamic and pharmacokinetic properties as well as the safety and efficacy profiles of the most important antithrombotic agents in development.

Expert opinion: Research focused on the development of new anticoagulation agents is rapidly expanding. Although the exploration of antithrombotic agents that act on well-established targets such factor Xa and thrombin remains the mainstay, attention has also shifted to other factors in the coagulation cascade. The evidence emerging from clinical research is growing, generating exciting possibilities in the field of anticoagulation.     

Safety and efficacy of non-vitamin K oral anticoagulants in non-valvular atrial fibrillation: a Bayesian meta-analysis approach

Introduction: Choosing between different non-vitamin K antagonist oral anticoagulants (NOACs) in non-valvular atrial fibrillation (NVAF) is difficult due to the absence of head to head comparative studies. We performed a Bayesian meta-analysis to explore similarities and differences between different NOACs and to rank treatments overall for safety and efficacy outcomes.

Areas covered: Through a systematic literature search we identified randomized controlled Phase III trials of dabigatran, rivaroxaban, apixaban, and edoxaban versus adjusted-dose warfarin in patients with NVAF.

Expert opinion: Warfarin ranked worst for all-cause mortality and intracranial bleedings and had a nil probability of ranking first for any outcome. The risk of major bleeding versus warfarin was lower with apixaban, dabigatran 110 mg, and both doses of edoxaban. All agents reduced the risk of intracranial bleeding versus warfarin. Edoxaban 30 mg was the best among the treatments being compared for major and gastrointestinal bleeding. Dabigatran 150 mg was the best for stroke and systemic embolism. This study suggests that NOACs are generally preferable to warfarin in patients with NVAF. However, safety and efficacy differences do exist among NOACs, which might drive their use in specific subsets of AF patients, allowing prescribers to tailor treatment to distinct patient profiles.     

Anticoagulation in atrial fibrillation: the trials and tribulations of keeping within therapeutic range

ABSTRACT

Atrial fibrillation (AF) is a growing epidemic in the developed world that has attracted much attention due to the associated risk of stroke and thromboembolism. This article discusses the application of oral anticoagulation (OAC) therapy with vitamin K antagonists (VKA) in order to reduce these risks. The article provides an overview of OAC management and highlights the need for greater efforts to increase time within therapeutic range.     

Non-vitamin K oral anticoagulants versus vitamin K antagonists in the treatment of venous thromboembolic disease

Introduction: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in the western world. The approval of non-vitamin K oral anticoagulants (NOACs) as antithrombotic alternatives to vitamin K antagonists (VKAs) has offered more treatment options to physicians for the prevention of VTE recurrence, fatal pulmonary embolism (PE) and long-term complications. Four NOACs (dabigatran, rivaroxaban, apixaban and edoxaban) that have been approved for the treatment of acute VTE following large phase III trials, where NOACs demonstrated similar efficacy and superior safety profile compared to VKAs.

Areas covered: The purpose of this review article is to summarise current knowledge of oral anticoagulation for the treatment of acute VTE and to compare NOACs with VKAs, highlighting the factors that might influence the decisions of physicians. Data for this article were obtained through a search of PubMed for trials comparing NOACs with VKAs in acute VTE setting and articles or analyses that interpreted results from these trials.

Expert opinion: The NOACs have changed clinical practice regarding oral anticoagulation for acute VTE. Despite their advantages, ‘grey zones’ still remain and more studies are needed to provide evidence and confirm the superiority (or at least non-inferiority) of NOACs over VKAs. Real world data might give additional insights.     

Non-vitamin K antagonist oral anticoagulants: impact of non-adherence and discontinuation

Introduction: Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) are at least as effective as vitamin K antagonists (VKAs) reducing thromboembolism and mortality in atrial fibrillation (AF). These ‘fixed-dose regimen’ drugs are characterized by not requiring routine monitoring or dosage adjustment. Stroke prevention with OAC is indicated in AF patients with CHA₂DS₂-VASc ≥2 (≥3 in females) and NOACs are recommended in preference to VKAs. However, underuse, premature discontinuation of treatment and non-adherence to guidelines is common, and independently associated with higher stroke risk and all-cause mortality.

Areas covered: In this review, we provide an overview of the impact of under or overdosing NOACs in AF patients. We debate the current adherence to AF-guidelines, the reasons involved in non-adherence and discontinuation, as well as the limitations found by patients and physicians about the use of NOACs.

Expert opinion: The more convenient non-monitored and fixed-dose regimen of NOACs might improve patients’ adherence but may hinder the identification of patients with poor adherence or discontinuation. Since there are several reasons for OAC underuse, future strategies to improve adherence should be implemented, that include more and better education about AF and stroke risk, as well as and specific information about the potential consequences of non-adherence to OAC.     

Direct anticoagulant drugs to overcome limitations of vitamin K antagonists. A critical appraisal of data in atrial fibrillation patients

Introduction: The usefulness of anticoagulation in patients with atrial fibrillation (AF) is well known. However, the inherent limitations of vitamin K antagonists (VKAs) have made the development of new oral anticoagulants necessary. Drugs directed against thrombin or the factor Xa are currently available.

Areas covered: These molecules, being administered at fixed doses and not requiring laboratory monitoring, overcome one crucial problem associated with the use of VKAs. However, data about the bleeding risk related to the use of these molecules should be further analyzed.

Expert opinion: The efficacy of direct anticoagulants (DACs) in AF-related stroke prevention has been considered the primary outcome in all Phase III published trials. On the other hand, the reduction of the bleeding risk is an important goal achieved by the DACs as compared with VKAs. Besides data deriving from randomized trials, when talking about new drugs, the need of evidences from the ‘everyday clinical practice' are often requested. The aim of this literature revision is to report and analyze data from specific subgroups about which little is known. In particular, information about the use of DACs in oncologic patients, in patients receiving concomitant antiplatelet drugs and in the perioperative period is currently lacking. The parallel evaluation of all these data may lead to the identification of clinical and demographical criteria to choose when to switch to DACs.     

Impact of methodological choices on a meta-analysis of real-world evidence comparing non-vitamin-K antagonist oral anticoagulants with vitamin K antagonists for the treatment of patients with non-valvular atrial fibrillation

Objective: The aim of this study was to investigate the impact of methodological choices in a meta-analysis of real-world evidence (RWE) comparing three non-vitamin-K antagonist oral anticoagulants with vitamin K antagonists (VKAs) for the treatment of patients with non-valvular atrial fibrillation (NVAF).

Methods: The meta-analysis was based on a systematic review of RWE studies enrolling incident and prevalent patients aged ≥18 years with NVAF and receiving either rivaroxaban, dabigatran, apixaban or a VKA. Five different scenarios were considered to explore the impact of the initial meta-analysis assumptions: (1) using studies that involved only incident patients; (2) excluding studies that only reported crude values and did not consider any adjustment; (3) including all studies independently of possible database overlap; (4) using studies with data on different dosages for rivaroxaban and dabigatran; and (5) assigning quality weights to studies to assess quality of reporting. These scenarios were run on three outcomes: ischemic stroke (IS), myocardial infarction (MI) and intracranial hemorrhage (ICH).

Results: Across all scenarios, rivaroxaban was associated with significantly lower risks of IS and ICH than VKAs. In most scenarios, dabigatran was associated with significantly lower risks of IS and ICH. In all scenarios, apixaban was associated with a significantly lower risk of ICH.

Conclusions: Sensitivity analyses showed the impact of similar assumptions was different depending on the outcome and the drug considered. The development of recommendations and guidelines for the inclusion of RWE in meta-analyses could prove useful in evaluating the effectiveness of health care interventions.     

Novel oral anticoagulants: focus on the direct factor Xa inhibitor darexaban

Introduction: Inhibition of the pathways of anticoagulation is widely used for the prevention and treatment of arterial and venous thrombosis. Vitamin K antagonists (VKAs) have been the mainstay of oral anticoagulation for more than 60 years. Their safety and effectiveness have been established in multiple clinical trials, for a variety of clinical indications. However, there are several limitations to the use of VKAs including delayed onset of action and dosage titration, numerous food and drug interactions and need for regular laboratory monitoring. To overcome some of the limitations of traditional agents, new oral anticoagulants (OACs) have been developed and evaluated.

Areas covered: In the present review article, the pharmacokinetic properties of darexaban are presented, along with the available preliminary clinical data. The performance of darexaban in respect to safety and efficacy compared with its competitors is further discussed.

Expert opinion: Darexaban is a potent direct factor Xa inhibitor that demonstrated impressive pharmacokinetic properties in pre-clinical studies. It was further successfully evaluated in the ONYX program for the prevention of venous thromboembolism in patients undergoing hip replacement. Finally, in the Phase II RUBY-1 trial, darexaban was tested on the top of standard antiplatelet therapy for the prevention of ischemic events in acute coronary syndrome (ACS) patients. Despite the fact that darexaban had a relatively uneventful clinical evaluation program, its further development was recently discontinued. This decision could probably reflect the non-favorite results in commercially attractive indications, such as secondary prevention post-ACS and the increased competition for less common or short-term indications such stroke prevention in AF or VTE prophylaxis respectively.