New anticoagulant treatments to protect against stroke in atrial fibrillation

Warfarin has long been the 'gold standard' of oral anticoagulation for stroke prevention in atrial fibrillation (AF). Recently, the oral direct thrombin inhibitors and direct factor Xa inhibitors have emerged as attractive alternatives to warfarin and have already changed the landscape of stroke prevention in AF. The new anticoagulants have important advantages over warfarin. Despite their impressive performance in clinical trials, their long-term efficacy and safety still require evaluation in 'real-world' clinical practice. In this review, the emerging role of the new oral anticoagulants for stroke prevention in patients with AF is discussed.     

Alternatives to chronic warfarin therapy for the prevention of stroke in patients with atrial fibrillation

Atrial fibrillation (AF) is associated with a fivefold increased risk for stroke due to thromboembolic events. Warfarin remains the standard medical therapy for decades in these patients but is difficult to use safely and conveniently. Chronic warfarin therapy is contraindicated in 14% to 44% of patients with AF who are at risk for stroke. In clinical practice, warfarin is prescribed to only 15% to 60% of patients with AF who are at high risk for thromboembolic events and have no clear contraindication to their use. Alternatives to warfarin include (i) antiplatelet therapy; (ii) new oral anticoagulants; and (iii) exclusion of the left atrial appendage (LAA) as a major embolic source. Dual antiplatelet therapy with aspirin and clopidogrel was superior to aspirin alone in reducing the risk of stroke in patients unsuitable to warfarin. Furthermore, a number of newer oral anticoagulants are currently under investigation for stroke prevention in AF. Oral direct thrombin or factor Xa inhibitors are in the most advanced stages of development. Given that about 90% of the source of thromboembolism occurs in the LAA in patients with non-valvular AF, occlusion of flow into the LAA may prevent thrombus formation in the appendage and hence reduction of stroke. Recently, several devices have been employed percutaneously with encouraging results in selected patients. Current review summarizes the latest clinical trial data pertinent to dual-antiplatelet therapy, several newer antithrombotic agents and LAA occlusion.     

New oral anticoagulants in atrial fibrillation.

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.     

Neue Antikoagulanzien zur Schlaganfallpr?vention bei Vorhofflimmern

Oral anticoagulation with vitamin K antagonists (warfarin, phenprocoumon) is successful in both primary and secondary stroke prevention for patients with atrial fibrillation (AF), yielding a 60-70% relative reduction in stroke risk compared with placebo and a mortality reduction of 26%. However, these agents have a number of well documented shortcomings. This review describes the current landscape and developments in stroke prevention in patients with AF with special reference to secondary prevention. A number of new drugs for oral anticoagulation that do not exhibit the limitations of vitamin K antagonists are under investigation. These include direct factor Xa inhibitors and direct thrombin inhibitors. Recent studies (RE-LY, ROCKET-AF, AVERROES, ARISTOTLE) provide promising results for these new agents including higher efficacy and significantly lower incidences of intracranial bleeding compared with warfarin. The new substances show similar results in secondary as well as in primary stroke prevention in patients with AF. The new anticoagulants add to the therapeutic options for patients with AF and offer a number of advantages over warfarin for both clinician and patient, including a favorable bleeding profile and convenience of use. Consideration of these new anticoagulants will improve clinical decision-making.     

Antithrombotic therapy for stroke prevention in atrial fibrillation and mechanical heart valves

Cardioembolic strokes account for one-sixth of all strokes and are an important potentially preventable cause of morbidity and mortality. Vitamin K antagonists (e.g., warfarin) are effective for the prevention of cardioembolic stroke in patients with atrial fibrillation (AF) and in those with mechanical heart valves but because of their inherent limitations are underutilized and often suboptimally managed. Antiplatelet therapies have been the only alternatives to warfarin for stroke prevention in AF but although they are safer and more convenient they are much less efficacious. The advent of new oral anticoagulant drugs offers the potential to reduce the burden of cardioembolic stroke by providing access to effective, safe, and more convenient therapies. New oral anticoagulants have begun to replace warfarin for stroke prevention in some patients with AF, based on the favorable results of recently completed phase III randomized controlled trials, and provide for the first time an alternative to antiplatelet therapy for patients deemed unsuitable for warfarin. The promise of the new oral anticoagulants in patients with mechanical heart valves is currently being tested in a phase II trial. If efficacy and safety are demonstrated, the new oral anticoagulants will provide an alternative to warfarin for patients with mechanical heart valves and may also lead to increased use of mechanical valves for patients who would not have received them in the past because of the requirement for long term warfarin therapy.     

Anticoagulation management in clinical practice: preventing stroke in patients with atrial fibrillation

Atrial fibrillation (AF) is a major and widely recognized risk factor for cardioembolic stroke. Prophylactic therapy for the prevention of stroke in patients with AF is often achieved through oral anticoagulation, specifically with warfarin, which has been used for this purpose for more than 50 years. Although warfarin therapy is effective when implemented appropriately, it is often underutilized and requires consistent monitoring to ensure both safety in avoiding bleeding and efficacy in preventing strokes. Because the burden of AF-related stroke continues to rise, healthcare professionals need to understand the strengths and limitations of current and emerging treatment options. This review outlines current practices for managing the risk of stroke with anticoagulation in patients with AF, and discusses how new oral anticoagulants may affect clinical practice.     

新型Xa抑制剂——沙班类药物在心房颤动患者脑卒中预防中的作用

心房颤动是缺血性脑卒中的主要因素,心房颤动伴发缺血性脑卒中患者的病死率约为非瓣膜性心房颤动患者的2倍,且心房颤动所致脑卒中具有高致残率和高复发率的特点.华法林是维生素K拮抗剂,一直以来作为非瓣膜性心房颤动患者预防脑卒中和系统性血栓的首选药物,但由于华法林存在治疗窗口窄、药物之间相互作用、频繁的实验监测等问题,使其临床应用受到限制.目前研究开发的一系列新型Xa因子抑制剂,能安全且有效地预防脑卒中及体循环栓塞,并降低出血风险.现将系统回顾新型Xa因子抑制剂--沙班类药物用于心房颤动患者脑卒中预防的临床研究.     

Emerging oral anticoagulants for stroke prevention in patients with non-valvular atrial fibrillation

In patients with atrial fibrillation (AF) warfarin has been the mainstay therapy for stroke prevention. In recent randomized clinical trials (RCTs) oral direct thrombin inhibitor (Dabigatran) and factor Xa inhibitors (Rivaroxaban and Apixaban) challenged the efficacy and safety benchmarks set by warfarin. These drugs boast a rapid onset of action, shorter half-life and fewer drug and dietary interactions. Moreover, these new anticoagulants do not require monitoring, titration or dose adjustments. These agents have already been approved for prevention of stroke or systemic embolism in patients with AF. Uncertainty regarding suitability, efficacy and safety in certain patient subsets and issues related to the ability effectively monitor the pharmacodynamic effects and reverse the therapeutic effects of these drugs should be addressed as we engage in a widespread use of these agents in various patient subsets.     

非瓣膜病房颤缺血性脑卒中的预防

非瓣膜病房颤缺血性脑卒及体动脉栓塞的发病率很高,预防这一事件的发生现已成为国内外研究的热题。抗凝治疗无疑是卒中预防中重要环节之一,新型口服抗凝剂相较华法林可能对亚洲房颤人群血栓栓塞的预防效果更好,不良事件发生率更低,正在成为一种全新的选择。随着左心耳封堵技术日渐成熟,给不适合抗凝治疗的房颤患者带来了福音。许多大型临床研究显示射频消融不仅可以恢复窦律,还可以降低房颤负荷,减少血栓栓塞事件的发生,对于栓塞风险较高的病人来说,新型口服抗凝药联合射频消融对卒中预防效果可能会更好。肥胖、吸烟、嗜酒、高血压、糖尿病等危险因素在房颤病程进展中扮演了重要角色,包括房颤危险因素在内的综合管理对缺血性脑卒中的预防效果更佳。     

Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation

New oral anticoagulants, including apixaban, dabigatran, and rivaroxaban, have been developed as alternatives to warfarin, the standard oral anticoagulation therapy for patients with atrial fibrillation (AF). A systematic review and meta-analysis of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants to those of warfarin in patients with AF. The published research was systematically searched for randomized controlled trials of >1 year in duration that compared new oral anticoagulants to warfarin in patients with AF. Random-effects models were used to pool efficacy and safety data across randomized controlled trials. Three studies, including 44,563 patients, were identified. Patients randomized to new oral anticoagulants had a decreased risk for all-cause stroke and systemic embolism (relative risk [RR] 0.78, 95% confidence interval [CI] 0.67 to 0.92), ischemic and unidentified stroke (RR 0.87, 95% CI 0.77 to 0.99), hemorrhagic stroke (RR 0.45, 95% CI 0.31 to 0.68), all-cause mortality (RR 0.88, 95% CI 0.82 to 0.95), and vascular mortality (RR 0.87, 95% CI 0.77 to 0.98). Randomization to a new oral anticoagulant was associated with a lower risk for intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66). Data regarding the risks for major bleeding (RR 0.88, 95% CI 0.71 to 1.09) and gastrointestinal bleeding (RR 1.25, 95% CI 0.91 to 1.72) were inconclusive. In conclusion, the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favorable safety profile, making them promising alternatives to warfarin.     

New Approaches to Stroke Prevention in Atrial Fibrillation

It is estimated that atrial fibrillation (AF) is responsible for almost 15% of all strokes. Several randomized clinical trials have demonstrated the superiority of adjusted-dose warfarin over aspirin for stroke prevention in AF patients, particularly in high-risk individuals. Current national guidelines from the American Heart Association/American Stroke Association recommend the use of adjusted-dose warfarin with an international normalized ratio goal of 2.0 to 3.0 for patients with ischemic stroke or transient ischemic attack with persistent or paroxysmal AF, and aspirin for those who cannot take oral anticoagulants. However, the use of warfarin may be challenging in some patients, and there is a need for alternative treatments. We describe alternative treatments for AF and provide an overview on emerging therapies.     

Are the novel anticoagulants better than warfarin for patients with atrial fibrillation?

Atrial fibrillation (AF) is associated with significant morbidity and mortality related to stroke due to thromboembolism. Several novel oral anticoagulants (NOACs) have been developed that dose-dependently inhibit thrombin or activated factor X (factor Xa). These new agents offer potential advantages over vitamin K antagonists, however, several limitations exist. We will review the four large randomized trials comparing the efficacy and safety of new oral anticoagulants with warfarin for stroke prevention in patients with AF as well as assess “real world” data and discuss the limitations of the new agents.     

Target-specific oral anticoagulants in atrial fibrillation: results of phase III trials and comments on sub-analyses

Dabigatran, rivaroxaban, apixaban and edoxaban administered in fixed doses and without routine laboratory monitoring have been compared to warfarin for the prevention of stoke in patients with nonvalvular atrial fibrillation (AF). Phase III data is currently available for dabigatran, rivaroxaban and apixaban. It is derived from three randomized controlled trials: RE-LY, ROCKET AF and ARISTOTLE. Dabigatran and apixaban appeared to be superior to warfarin for the primary endpoint of stroke or systemic embolism, while rivaroxaban was deemed non-inferior. The risk of major bleeding was modestly decreased overall with the new agents, while the risk of intracranial hemorrhage was substantially reduced. The results of ENGAGE AF-TIMI 48 comparing edoxaban to warfarin are still pending. Large, well designed clinical trials support the use of three new target-specific oral anticoagulants for the prevention of stroke in individuals with nonvalvular AF.     

Anticoagulation. Modern concepts

An effective oral anticoagulation with vitamin K antagonists is currently a successfully used standard therapy in patients with atrial fibrillation (AF) yielding a 60-70% relative reduction in stroke risk compared with placebo, when an international normalized ratio (INR) value between 2.0 and 3.0 is maintained. However, these agents have a number of well documented shortcomings which partially result in a reduced compliance as well as an insufficient INR adjustment. A number of new drugs for oral anticoagulation including direct factor Xa inhibitors, such as rivaroxaban and direct thrombin inhibitors, such as dabigatran have shown promising results, including higher efficacy and significantly lower incidences of intracranial bleeding compared with warfarin. The new substances show similar results in secondary as well as in primary stroke prevention in patients with AF and therefore offer a number of advantages over warfarin, including a favorable bleeding profile and convenience of use. Consideration of these new anticoagulants might be a good option.     

Dabigatran,rivaroxaban, and apixaban are superior to warfarin in Asian patients with non-valvular atrial fibrillation: An updated meta-analysis

BACKGROUNDMost of the randomized clinical trials that led to the wide use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation (AF) originated from western countries. AIMTo systematically review and quantitatively synthesize the real-world data regarding the efficacy and safety of dabigatran, rivaroxaban, and apixaban compared to warfarin for stroke prevention in Asian patients with non-valvular AF.METHODSMedline, Cochrane, and ClinicalTrial.gov databases were reviewed. A random-effect model meta-analysis was used and I-square was utilized to assess the heterogeneity. The primary outcome was ischemic stroke. The secondary outcomes were all-cause mortality, major bleeding, intracranial hemorrhage, and gastrointestinal bleeding.RESULTSTwelve studies from East Asia or Southeast Asia and 441450 patients were included. Dabigatran, rivaroxaban, and apixaban were associated with a significant reduction in the incidence of ischemic stroke [hazard ratio (HR) = 0.78, 95% confidence interval (CI): 0.65-0.94; HR = 0.79, 95%CI: 0.74-0.85, HR = 0.70, 95%CI: 0.62-0.78; respectively], all-cause mortality (HR = 0.68, 95%CI: 0.56-0.83; HR = 0.66, 95%CI: 0.52-0.84; HR = 0.66, 95%CI: 0.49-0.90; respectively), and major bleeding (HR = 0.61, 95%CI: 0.54-0.69; HR = 0.70, 95%CI: 0.54-0.90; HR = 0.58, 95%CI: 0.43-0.78; respectively) compared to warfarin.CONCLUSIONDabigatran, rivaroxaban, and apixaban appear to be superior to warfarin in both efficacy and safety in Asians with non-valvular AF.     

Novel Oral Anticoagulants for Atrial Fibrillation

Three novel oral anticoagulants (NOACS)—dabigatran etexilate, rivaroxaban, and apixaban—have been approved in many countries for stroke prevention in atrial fibrillation, because they are associated with the same or lower rates of stroke, bleeding (particularly intracranially) and death compared with warfarin; and unlike warfarin, they can be given in fixed doses without routine coagulation monitoring. The effects of NOACs compared with warfarin are consistent in almost all populations and patient subgroups studied. Pharmacoeconomic analyses indicate that the NOACs are also cost-effective in Europe and North America. The lack of an antidote to the NOACs in patients who experience major bleeding has not been associated with a worse outcome among patients treated with NOACs compared with warfarin in secondary analyses. Multiple guidelines for the management of AF now recommend the NOACs for stroke prevention among atrial fibrillation (AF) patients at risk for stroke.     

Antikoagulation

An effective oral anticoagulation with vitamin K antagonists is currently a successfully used standard therapy in patients with atrial fibrillation (AF) yielding a 60–70% relative reduction in stroke risk compared with placebo, when an international normalized ratio (INR) value between 2.0 and 3.0 is maintained. However, these agents have a number of well documented shortcomings which partially result in a reduced compliance as well as an insufficient INR adjustment. A number of new drugs for oral anticoagulation including direct factor Xa inhibitors, such as rivaroxaban and direct thrombin inhibitors, such as dabigatran have shown promising results, including higher efficacy and significantly lower incidences of intracranial bleeding compared with warfarin. The new substances show similar results in secondary as well as in primary stroke prevention in patients with AF and therefore offer a number of advantages over warfarin, including a favorable bleeding profile and convenience of use. Consideration of these new anticoagulants might be a good option.     

Anticoagulación oral en la enfermedad renal crónica con fibrilación auricular

Chronic kidney disease (CKD) and atrial fibrillation (AF) frequently coexist, amplifying the risk of cardiovascular events and mortality. In patients with CKD stage 3 and non-valvular AF, direct oral anticoagulants (DOACs) have shown, compared to vitamin K antagonists (VKA), equal or greater efficacy in the prevention of stroke and systemic embolism, and greater safety. There are no randomized trials of the efficacy and safety of DOACs and VKA in advanced CKD. On the other hand, observational studies suggest that DOACs, compared to warfarin, are associated with a lower risk of acute kidney damage and generation/progression of CKD. This paper reviews the epidemiological and pathophysiological aspects of the CKD and AF association, the evidence of the efficacy and safety of warfarin and ACODs in various stages of CKD with AF as well as the comparison between warfarin and ACODs in efficacy and anticoagulant safety, and in its renal effects.