Review of atrial fibrillation outcome trials of oral anticoagulant and antiplatelet agents.
ABSTRACT: Atrial fibrillation (AF) is strongly associated with cardioembolic stroke, and thromboprophylaxis is an established means of reducing stroke risk in patients with AF. Oral vitamin K antagonists such as warfarin have been the mainstay of therapy for stroke prevention in patients with AF. However, they are associated with a number of limitations, including excessive bleeding when not adequately controlled. Antiplatelet agents do not match vitamin K antagonists in terms of their preventive efficacy. Dual-antiplatelet therapy (clopidogrel and acetylsalicylic acid) or combined antiplatelet-vitamin K antagonist therapy in AF has also failed to provide convincing evidence of their additional benefit over vitamin K antagonists alone. Novel oral anticoagulants, including the direct thrombin inhibitor dabigatran and direct Factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban, have now been approved or are currently in late-stage clinical development in AF. These newer agents may provide a breakthrough in the optimal management of stroke risk.
Project description:Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug-drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice.
Project description:Patients with atrial fibrillation (AF) are at an approximately 0.5% to 3% increased risk of thromboembolism during and immediately after catheter ablation. Treatment guidelines recommend periprocedural oral anticoagulation plus unfractionated heparin during ablation. Rivaroxaban and dabigatran are the only non-vitamin K oral anticoagulants for which there are randomized controlled trials assessing uninterrupted anticoagulation in patients undergoing catheter ablation of AF. Edoxaban, a direct factor Xa inhibitor, is noninferior vs warfarin for the prevention of stroke or systemic embolism with less major bleeding in patients with nonvalvular AF. The ELIMINATE-AF (Evaluation of Edoxaban Compared With VKA in Subjects Undergoing Catheter Ablation of Nonvalvular Atrial Fibrillation) trial is a multinational, multicenter, prospective, randomized, open-label, parallel-group, blinded-endpoint evaluation (PROBE) study to assess the safety and efficacy of once-daily edoxaban 60?mg (30?mg in patients indicated for a dose reduction) vs vitamin K antagonists (VKA) in patients with nonvalvular AF undergoing catheter ablation (http://www.ClinicalTrials.gov: NCT02942576). A total of 560 patients are planned for randomization to edoxaban or VKA (2:1 ratio) to obtain 450 patients fully compliant with the protocol. Patients will complete 21 to 28?days of anticoagulation prior to the ablation and a 90-day post-ablation period. The primary efficacy endpoint is the composite of all-cause death, stroke, and major bleeding. The primary safety endpoint is major bleeding. A magnetic resonance imaging substudy will assess the incidence of silent cerebral lesions post-ablation. ELIMINATE-AF will define the efficacy and safety of edoxaban for uninterrupted oral anticoagulation during catheter ablation of AF.
Project description:Stroke prevention is central to the management of patients with atrial fibrillation (AF). Vitamin K antagonists (VKAs) are the established and long-standing option for stroke prevention therapy in patients with AF. However, non-VKA oral anticoagulants (NOACs) have recently been developed and demonstrated non-inferior efficacy vs VKA treatment, with fewer limitations in clinical practice and with reduced risks of major bleeding. In order to discuss the usage, efficacy and safety of NOACs, a satellite symposium was held at the Cardiostim/ EHRA Europace Congress in Nice in June 2014. At present, three NOACs, a direct thrombin inhibitor (dabigatran) and two direct factor Xa inhibitors (rivaroxaban and apixaban) have been approved in Europe for stroke prevention in patients with AF. In addition, the once-daily factor Xa inhibitor edoxaban has recently been evaluated in this setting in the phase III Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation - Thrombolysis In Myocardial Infarction Study 48 (ENGAGE AF-TIMI 48) that compared edoxaban 30 mg once daily (low-dose regimen) with dose-adjusted warfarin (international normalised ratio 2.0-3.0). ENGAGE AF-TIMI 48 was the largest trial with a NOAC to date, and demonstrated that both dosing regimens of once-daily edoxaban were non-inferior to well-managed warfarin treatment for the prevention of stroke or systemic embolism and also provided significant reductions in the risk of haemorrhagic stroke, cardiovascular mortality, major bleeding and intracranial bleeding. In summary, the recent availability of NOACs has enabled physicians to avoid the limitations of VKA therapy in clinical practice and tailor anticoagulant treatment to the individual patient. However, worldwide usage of oral anticoagulant therapy remains suboptimal compared with guideline recommendations, and further dissemination of its benefits may prove helpful.
Project description: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; e.g., 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 (e.g., those with renal impairment) and other specific clinical situations.
Project description:Background:Until the approval of dabigatran etexilate, treatment choices for stroke prevention in patients with atrial fibrillation (AF) were vitamin K antagonists (VKAs) or antiplatelet drugs. This analysis explored whether availability of non-vitamin K antagonist oral anticoagulants post-dabigatran approval was associated with changing treatment patterns in China. Methods:Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) collected data on antithrombotic therapy choices for patients with newly diagnosed nonvalvular AF at risk for stroke. In China, enrollment in phase 1 (before dabigatran approval) and phase 2 (after dabigatran approval) occurred from 2011 to 2013 and 2013 to 2014, respectively. Analyses were restricted to sites within China that contributed patients to both phases. The weighted average of the site-specific results was estimated for standardization. Sensitivity analyses used multiple regression. Results:Thirteen sites participated in both phase 1 (419 patients) and phase 2 (276 patients), 76.1% and 16.0% were known to be at high risk for stroke (CHA2DS2-VASc ?2) and bleeding (HAS-BLED ?3); 55.5% were male. In phase 1, 16.7%, 61.6%, and 21.7% of patients were prescribed oral anticoagulants (OACs), antiplatelet agents, and no treatment, respectively. Respective proportions were 26.4%, 40.6%, and 33.0% in phase 2. The absolute increase in the site-standardized proportion of patients prescribed OACs after dabigatran availability was 9.9% (95% confidence interval [CI]: 3.7%-16.0%). There was a standardized 17.3% (95% CI: -24.3% to -10.4%) absolute decrease in antiplatelet agent use. Conclusions:There was an increase in OAC and decrease in antiplatelet agent prescription since dabigatran availability in China. However, a large proportion of AF patients at risk for stroke remained untreated.
Project description:Data on the management of atrial fibrillation (AF) in the Balkan Region are limited. The Serbian AF Association (SAFA) prospectively investigated contemporary 'real-world' AF management in clinical practice in Albania, Bosnia&Herzegovina, Bulgaria, Croatia, Montenegro, Romania and Serbia through a 14-week (December 2014-February 2015) prospective, multicentre survey of consecutive AF patients. We report the results pertinent to stroke prevention strategies. Of 2712 enrolled patients, 2663 (98.2%) with complete data were included in this analysis (mean age 69.1?±?10.9 years, female 44.6%). Overall, 1960 patients (73.6%) received oral anticoagulants (OAC) and 762 (28.6%) received antiplatelet drugs. Of patients given OAC, 17.2% received non-vitamin K antagonist oral anticoagulants (NOACs). CHA2DS2-VASc score was not significantly associated with OAC use. Of the 'truly low-risk' patients (CHA2DS2-VASc?=?0 [males], or 1 [females]) 56.5% received OAC. Time in Therapeutic Range (TTR) was available in only 18.7% of patients (mean TTR: 49.5%?±?22.3%). Age???80 years, prior myocardial infarction and paroxysmal AF were independent predictors of OAC non-use. Our survey shows a relatively high overall use of OAC in AF patients, but with low quality of vitamin K antagonist therapy and insufficient adherence to AF guidelines. Additional efforts are needed to improve AF-related thromboprophylaxis in clinical practice in the Balkan Region.
Project description:AIMS:Edoxaban is a direct factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF). Uninterrupted edoxaban therapy in patients undergoing AF ablation has not been tested. METHODS AND RESULTS:The ELIMINATE-AF trial, a multinational, multicentre, randomized, open-label, parallel-group study, was conducted to assess the safety and efficacy of once-daily edoxaban 60?mg (30?mg in patients indicated for dose reduction) vs. vitamin K antagonists (VKAs) in AF patients undergoing catheter ablation. Patients were randomized 2:1 to edoxaban vs. VKA. The primary endpoint (per-protocol population) was time to first occurrence of all-cause death, stroke, or International Society of Thrombosis and Haemostasis-defined major bleeding during the period from the end of the ablation procedure to end of treatment (90?days). Overall, 632 patients were enrolled, 614 randomized, and 553 received study drug and underwent ablation; 177 subjects underwent brain magnetic resonance imaging to assess silent cerebral infarcts. The primary endpoint (only major bleeds occurred) was observed in 0.3% (1 patient) on edoxaban and 2.0% (2 patients) on VKA [hazard ratio (95% confidence interval): 0.16 (0.02-1.73)]. In the ablation population (modified intent-to-treat population including patients with ablation), the primary endpoint was observed in 2.7% of edoxaban (N?=?10) and 1.7% of VKA patients (N?=?3) between start of ablation and end of treatment. There were one ischaemic and one haemorrhagic stroke, both in patients on edoxaban. Cerebral microemboli were detected in 13.8% (16) patients who received edoxaban and 9.6% (5) patients in the VKA group (nominal P?=?0.62). CONCLUSION:Uninterrupted edoxaban therapy represents an alternative to uninterrupted VKA treatment in patients undergoing AF ablation.
Project description:Atrial fibrillation is the most common arrhythmia in the elderly. It is responsible for significant morbidity and mortality from cardioembolic complications like stroke. As a result, atrial fibrillation patients are risk-stratified using the CHADS2 or CHA2DS2-VASc scoring systems. Those at intermediate-to-high risk have traditionally been treated with therapeutic anticoagulation with warfarin for stroke prevention. Although effective, warfarin use is fraught with multiple concerns, such as a narrow therapeutic window, drug-drug and drug-food interactions, and excessive bleeding. Novel oral anticoagulant agents have recently become available as viable alternatives for warfarin therapy. Direct thrombin inhibitor dabigatran and factor Xa inhibitors like rivaroxaban and apixaban have already been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation. Edoxaban is the latest oral direct factor Xa inhibitor studied in the largest novel oral anticoagulant trial so far: ENGAGE AF-TIMI 48. Treatment with a 30 mg or 60 mg daily dose of edoxaban was found to be noninferior to dose-adjusted warfarin in reducing the rate of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, with a lower incidence of bleeding complications and cardiovascular deaths. Edoxaban was recently reviewed by an FDA advisory committee and recommended as a stroke-prophylaxis agent. Once approved, it promises to provide another useful alternative to warfarin therapy.
Project description: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.
Project description:The goal of this study was to compare the safety and effectiveness of individual antiembolic interventions in nonvalvular atrial fibrillation (AF): novel oral anticoagulants (NOACs) (apixaban, dabigatran, edoxaban, and rivaroxaban); vitamin K antagonists (VKA); aspirin; and the Watchman device.A network meta-analysis of randomized, clinical trials (RCTs) was performed. RCTs that included patients with prosthetic cardiac valves or mitral stenosis, mean or median follow-up <6 months, <200 participants, without published report in English language, and NOAC phase II studies were excluded. The placebo/control arm received either placebo or no treatment. The primary efficacy outcome was the combination of stroke (of any type) and systemic embolism. All-cause mortality served as a secondary efficacy outcome. The primary safety outcome was the combination of major extracranial bleeding and intracranial hemorrhage. A total of 21 RCTs (96 017 nonvalvular AF patients; median age, 72 years; 65% males; median follow-up, 1.7 years) were included. In comparison to placebo/control, use of aspirin (odds ratio [OR], 0.75 [95% CI, 0.60-0.95]), VKA (0.38 [0.29-0.49]), apixaban (0.31 [0.22-0.45]), dabigatran (0.29 [0.20-0.43]), edoxaban (0.38 [0.26-0.54]), rivaroxaban (0.27 [0.18-0.42]), and the Watchman device (0.36 [0.16-0.80]) significantly reduced the risk of any stroke or systemic embolism in nonvalvular AF patients, as well as all-cause mortality (aspirin: OR, 0.82 [0.68-0.99]; VKA: 0.69 [0.57-0.85]; apixaban: 0.62 [0.50-0.78]; dabigatran: 0.62 [0.50-0.78]; edoxaban: 0.62 [0.50-0.77]; rivaroxaban: 0.58 [0.44-0.77]; and the Watchman device: 0.47 [0.25-0.88]). Apixaban (0.89 [0.80-0.99]), dabigatran (0.90 [0.82-0.99]), and edoxaban (0.89 [0.82-0.96]) reduced risk of all-cause death as compared to VKA.The entire spectrum of therapy to prevent thromboembolism in nonvalvular AF significantly reduced stroke/systemic embolism events and mortality.