Decision-Making in Clinical Practice: Oral Anticoagulant Therapy in Patients with Non-valvular Atrial Fibrillation and a Single Additional Stroke Risk Factor

Approximately 1 in 3–4 patients presenting with an ischemic stroke will also have atrial fibrillation (AF), and AF-related strokes can be effectively prevented using oral anticoagulant therapy (OAC), either with well-controlled vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs). In addition, OAC use (both VKAs and NOACs) is associated with a 26% reduction in all-cause mortality (VKAs) or an additional 10% mortality reduction with NOACs relative to VKAs. The decision to use OAC in individual AF patient is based on the estimated balance of the benefit from ischemic stroke reduction against the risk of major OAC-related bleeding [essentially intracranial hemorrhage (ICH)]. Better appreciation of the importance of VKAs’ anticoagulation quality [a target time in therapeutic range (TTR) of ≥70%] and the availability of NOACs (which offer better safety compared to VKAs) have decreased the estimated threshold for OAC treatment in AF patients towards lower stroke risk levels. Still, contemporary registry-based data show that OAC is often underused in AF patients at increased risk of stroke. The uncertainty whether to use OAC may be particularly pronounced in AF patients with a single additional stroke risk factor, who are often (mis)perceived as having a “borderline” or insufficient stroke risk to trigger the use of OAC. However, observational data from real-world AF cohorts show that the annual stroke rates in such patients are higher than in patients with no additional stroke risk factors, and OAC use has been associated with reduction in stroke, systemic embolism, or death in comparison to no therapy or aspirin, with no increase in the risk of bleeding relative to aspirin. In this review article, we summarize the basic principles of stroke risk stratification in AF patients and discuss contemporary real-world evidence on OAC use and outcomes of OAC treatment in AF patients with a single additional stroke risk factor in various real-world AF cohorts.     

Challenges of stroke prevention in patients with atrial fibrillation in clinical practice

Strokes and transient ischaemic attacks in patients with atrial fibrillation (AF) can be largely prevented. Risk stratification and appropriate prophylactic regimens help to alleviate the burden of AF-related thromboembolism. Guidelines recommend routine anticoagulation with oral vitamin K antagonists (VKAs) for patients at moderate-to-high risk of stroke, and acetylsalicylic acid (ASA) for those at low risk of stroke. ASA is less effective at reducing the risk of stroke than VKAs; however, ASA does not require monitoring or dose adjustment. Trials of anticoagulants show consistent benefits of oral VKAs for primary and secondary stroke prevention in patients with AF. Nevertheless, VKAs do require frequent coagulation monitoring and dose adjustment because of their variable dose-response profile, narrow therapeutic window, increased risk for bleeding complications and numerous food and drug interactions. This review aims to provide an overview of the clinical challenges of anticoagulant therapy for the prevention of stroke in patients with AF.     

房颤患者华法林抗凝治疗177例

目的回顾性分析心房颤动（房颤）患者的抗凝治疗与卒中情况。 方法调查2015年8月1日至2017年6月30日苏北人民医院住院房颤患者301例的病例资料,记录性别、年龄、主要诊断、合并疾病情况、CHA2DS2-VASc评分、HAS-BLED评分、INR值、华法林剂量、新型口服抗凝剂（NOAC）、阿司匹林使用情况、血栓栓塞事件、出血事件情况,分析抗凝治疗的规范性及其与临床后果的关系。 结果住院房颤患者平均年龄（72±11）岁,房颤类型以非瓣膜型房颤为主,占93.7%（282/301）,58.8%的房颤患者采用口服华法林抗凝治疗,4%接受NOAC抗凝治疗。华法林抗凝治疗组缺血性卒中发生率显著低于未抗凝治疗组差异具有统计学意义（13.0% vs 20.5%,P=0.025）。瓣膜型和非瓣膜型房颤患者华法林抗凝治疗后INR达标（INR 2.0~3.0）的比率分别为15.8%和7.1%。 结论为了达到更好的房颤患者卒中预防效果,需进一步加强华法林抗凝治疗的教育和监测。     

New oral anticoagulants versus vitamin K antagonists before cardioversion of atrial fibrillation: a meta-analysis of data from 4 randomized trials

Background: Scarce data are available about efficacy and safety of new oral anticoagulants (NOACs) for cardioversion (CV) of atrial fibrillation (AF). We performed a meta-analysis of data from randomized studies reporting outcomes of patients receiving NOACs, as compared to vitamin K antagonists (VKAs), and undergoing CV of AF. Methods: Data from four studies were selected, including 4268 CVs. The primary endpoints were the incidence of stroke or systemic embolism and the incidence of major bleeding within 30 days. Results: There was not any significant difference in the incidence of stroke or systemic embolism between NOACs and VKAs (RR 0.73, p = 0.47) nor in the incidence of major bleeding (RR 1.39, p = 0.13). Conclusions: We found no evidence of differential outcomes after CV of AF according to treatment with NOACs or VKAs. This finding warrants confirmation in larger clinical series and in the setting of properly powered randomized trials of newly diagnosed AF.     

New anticoagulation drugs for atrial fibrillation

Atrial fibrillation (AF) confers an increased risk of ischemic stroke or thromboembolism that is reduced by long-term oral anticoagulant therapy. Until recently, the latter has typically been one from the vitamin K antagonist (VKA) class of drugs. Although highly effective, VKAs have limitations, and their use is challenging for both patients and clinicians. A new generation of oral anticoagulant drugs is emerging, including several drugs that appear to be viable alternatives to VKAs in AF patients.     

The increasing need for anticoagulant therapy to prevent stroke in patients with atrial fibrillation

Ischemic stroke, a major complication of atrial fibrillation (AF), is believed to result from atrial thrombus formation caused by ineffective atrial contraction. Oral anticoagulant therapy effectively reduces the risk of ischemic stroke in patients with AF; this therapy is recommended for patients with any frequency or duration of AF and other risk factors for stroke, such as increased age (>75 years), hypertension, prior stroke, left ventricular dysfunction, diabetes, or heart failure. Recently published data comparing rate-control and rhythm-control strategies in AF emphasized the importance of maintaining an international normalized ratio higher than 2.0 during warfarin therapy and the need for continuing anticoagulant therapy to prevent stroke in high-risk patients, even if the strategy is rhythm control. Hemorrhagic complications can be minimized by stringent control of the international normalized ratio (particularly in elderly patients) and appropriate therapy for comorbidities such as hypertension, gastric ulcer, and early-stage cancers. Undertreatment of patients with AF is a continuing problem, particularly in the elderly population. Patients perceived as likely to be noncompliant, such as the functionally impaired, are less likely to receive warfarin therapy. However, stroke prevention with anticoagulants is cost-effective and improves quality of life, despite the challenges of maintaining appropriate anticoagulation with monitoring and warfarin dose titration. New medications in development with more predictable dosing and fewer drug-drug interactions may reduce the complexities of achieving optimal anticoagulation and increase the practicality of long-term anticoagulant therapy for patients with AF at risk of stroke.     

New oral anticoagulants in the ED setting: a review

Background

Emergency department (ED) clinicians are not typically involved in the long-term management of patients' anticoagulation therapy, but they are responsible for decision making for emergency conditions requiring anticoagulation, such as acute venous thromboembolism (VTE). In addition, emergency physicians are often faced with patients who present first to the ED with conditions that may prompt long-term anticoagulation upon hospital discharge, such as atrial fibrillation (AF), or who have acute or potential bleeding complications from anticoagulation.

Objective

In this review, clinical trials of new oral anticoagulants evaluated for treatment of VTE and stroke prophylaxis in AF, as well as practical management aspects, will be discussed. In addition, clinical trials evaluating the adjunctive use of the new oral anticoagulants with antiplatelet therapy in patients who have experienced acute coronary syndrome will be explored.

Discussion

Both dabigatran etexilate and rivaroxaban have successfully completed phase III trials for acute VTE treatment and are currently approved for the reduction of risk of stroke and systemic embolism in patients with nonvalvular AF. In a recently completed phase III trial, apixaban also demonstrated promising efficacy and safety in that indication. Rivaroxaban represents the only new anticoagulant to date to have shown promising phase III results as an adjunct to antiplatelet therapy after acute coronary syndrome.

Conclusion

Knowledge of the appropriate clinical use and safety concerns of the new anticoagulants is imperative as they become more frequently prescribed, and their potential uses in the ED setting represent an important aspect of continuing education for emergency physicians.     

Novel Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: Focus on Apixaban

Stroke prevention in atrial fibrillation (AF) has been challenging over decades, mostly due to a number of difficulties associated with oral vitamin K antagonists (VKAs), which have been the most effective stroke prevention treatment for a long time. The oral direct thrombin inhibitors (e.g., dabigatran) and oral direct inhibitors of factor Xa (e.g., rivaroxaban, apixaban) have emerged recently as an alternative to VKAs for stroke prevention in AF. These drugs act rapidly, and have a predictable and stable dose-related anticoagulant effect with a few clinically relevant drug-drug interactions. The novel oral anticoagulants are used in fixed doses with no need for regular laboratory monitoring of anticoagulation intensity. However, each of these drugs has distinct pharmacological properties that could influence optimal use in clinical practice. The following phase 3 randomized trials with novel oral anticoagulants versus warfarin for stroke prevention in AF have been completed: the Randomized Evaluation of Long-term Anticoagulant therapy (RE-LY) trial with dabigatran, the Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial with rivaroxaban, and the Apixaban for Reduction of Stroke and Other Thromboembolism Events in Atrial Fibrillation (ARISTOTLE) trial with apixaban. Moreover, the Apixaban Versus Acetylsalicylic Acid to prevent Strokes (AVERROES) trial included patients with AF who have failed or were unsuitable for warfarin, and compared apixaban versus aspirin for stroke prevention in AF. Overall, apixaban has two large trials for stroke prevention in AF showing benefits not only over warfarin, but also over aspirin among those patients who have failed or refused warfarin. In the ARISTOTLE trial, apixaban was superior to warfarin in the reduction of stroke or systemic embolism, major bleeding, intracranial hemorrhage, and all-cause mortality, with a similar reduction in the rate of ischemic stroke and better tolerability. When compared with aspirin in the AVERROES trial, apixaban was associated with more effective reduction of stroke, a similar risk of major bleeding, and better tolerability. In this review article, the authors summarize the current knowledge on novel oral anticoagulants and discuss the clinical aspects of their use for stroke prevention in AF, with particular emphasis on apixaban.     

Ximelagatran for stroke prevention in atrial fibrillation

Atrial fibrillation is the most common sustained cardiac arrhythmia and the most frequently encountered cause of embolic stroke. Vitamin K antagonists (such as warfarin) have represented the cornerstone of anticoagulation practice for the last 60 years. Although highly effective in preventing thromboembolic events among patients with atrial fibrillation, warfarin therapy is limited by a multitude of potential problems. Hence, warfarin is significantly underused in clinical practice, with only half of warfarin-treated patients actually achieving therapeutic anticoagulation in routine clinical practice. Consequently, there is an overwhelming need for an alternative oral anticoagulant for patients with atrial fibrillation that is safer, more practical and effective. Ximelagatran (Exanta, AstraZeneca) is a novel oral direct thrombin inhibitor that is rapidly converted to the active compound melagatran after oral absorption. It has a low potential for drug interactions, anticoagulation monitoring is not required, and it is administered at a fixed twice-daily dose. The Stroke Prevention using the ORal Thrombin Inhibitor in patients with nonvalvular atrial Fibrillation (SPORTIF) III and V trials have together demonstrated the noninferiority of ximelagatran relative to warfarin for the prevention of stroke and embolic events in atrial fibrillation. Unfortunately, initial optimism has been tempered by serious concerns over its safety data in view of its propensity to cause elevation in liver enzymes.     

Ximelagatran for stroke prevention in atrial fibrillation

Atrial fibrillation is the most common sustained cardiac arrhythmia and the most frequently encountered cause of embolic stroke. Vitamin K antagonists (such as warfarin) have represented the cornerstone of anticoagulation practice for the last 60 years. Although highly effective in preventing thromboembolic events among patients with atrial fibrillation, warfarin therapy is limited by a multitude of potential problems. Hence, warfarin is significantly underused in clinical practice, with only half of warfarin-treated patients actually achieving therapeutic anticoagulation in routine clinical practice. Consequently, there is an overwhelming need for an alternative oral anticoagulant for patients with atrial fibrillation that is safer, more practical and effective. Ximelagatran (Exanta®, AstraZeneca) is a novel oral direct thrombin inhibitor that is rapidly converted to the active compound melagatran after oral absorption. It has a low potential for drug interactions, anticoagulation monitoring is not required, and it is administered at a fixed twice-daily dose. The Stroke Prevention using the ORal Thrombin Inhibitor in patients with nonvalvular atrial Fibrillation (SPORTIF) III and V trials have together demonstrated the noninferiority of ximelagatran relative to warfarin for the prevention of stroke and embolic events in atrial fibrillation. Unfortunately, initial optimism has been tempered by serious concerns over its safety data in view of its propensity to cause elevation in liver enzymes.     

Non-Vitamin K Oral Anticoagulants for Stroke Prevention in Special Populations with Atrial Fibrillation

Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke or systemic embolism compared with normal sinus rhythm. These strokes may efficiently be prevented in patients with risk factors using oral anticoagulant therapy, with either vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) (i.e., direct thrombin inhibitors or direct factor Xa inhibitors). Owing to their specific risk profiles, some AF populations may have increased risks of both thromboembolic and bleeding events. These AF patients may be denied oral anticoagulants, whilst evidence shows that the absolute benefits of oral anticoagulants are greatest in patients at highest risk. NOACs are an alternative to VKAs to prevent stroke in patients with “non-valvular AF”, and NOACs may offer a greater net clinical benefit compared with VKAs, particularly in these high-risk patients. Physicians have to learn how to use these drugs optimally in specific settings. We review concrete clinical scenarios for which practical answers are currently proposed for use of NOACs based on available evidence for patients with kidney disease, elderly patients, women, patients with diabetes, patients with low or high body weight, and those with valve disease.     

Personalizing oral anticoagulant treatment in patients with atrial fibrillation

For decades, warfarin has remained the standard oral anticoagulation for stroke prevention in atrial fibrillation (AF). Three novel oral anticoagulants (NOACs) have been recently approved for stroke prevention in non-valvular AF: dabigatran, rivaroxaban and apixaban. Better pharmacological and clinical profiles make these newcomers a preferable alternative over warfarin. Current AF guidelines do not endorse NOACs over warfarin, or one NOAC over another. Indeed, choice of the anticoagulation regimen should be personalized based on the relative efficacy and safety of different agents across subgroups stratified by thrombotic and bleeding risk, as well as on other clinical factors, including anticoagulation control on warfarin, drug interactions, compliance and need for coagulation monitoring. This review appraises i) the randomized evidence on approved NOACs versus warfarin in AF across subgroups stratified by risk factors of stroke and bleeding and by the anticoagulation level reached on warfarin; and ii) clinical factors impacting on the anticoagulation regimen selection.     

Pharmacological and Non-pharmacological Treatments for Stroke Prevention in Patients with Atrial Fibrillation

Atrial fibrillation (AF) is associated with significant risk of stroke and other thromboembolic events, which can be effectively prevented using oral anticoagulation (OAC) with either vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, or edoxaban. Until recently, VKAs were the only available means for OAC treatment. NOACs had similar efficacy and were safer than or as safe as warfarin with respect to reduced rates of hemorrhagic stroke or other intracranial bleeding in the respective pivotal randomized clinical trials (RCTs) of stroke prevention in non-valvular AF patients. Increasing “real-world” evidence on NOACs broadly confirms the results of the RCTs. However, individual patient characteristics including renal function, age, or prior bleeding should be taken into account when choosing the OAC with best risk–benefit profile. In patients ineligible for OACs, surgical or interventional stroke prevention strategies should be considered. In patients undergoing cardiac surgery for other reasons, the left atrial appendage excision, ligation, or amputation may be the best option. Importantly, residual stumps or insufficient ligation may result in even higher stroke risk than without intervention. Percutaneous left atrial appendage occlusion, although requiring minimally invasive access, failed to demonstrate reduced ischemic stroke events compared to warfarin. In this review article, we summarize current treatment options and discuss the strengths and major limitations of the therapies for stroke risk reduction in patients with AF.     

Composite end point analyses of non-vitamin K antagonist oral anticoagulants compared with warfarin in patients with atrial fibrillation

Objective: Non-vitamin K antagonist oral anticoagulants (NOACs) have been proposed as alternatives to vitamin K antagonists (VKAs). The aim of this study is to examine the efficacy and safety of NOACs compared with warfarin with composite end points in patients with atrial fibrillation. Methods: This semi-systematic review performed a study of Phase III randomized controlled trials comparing NOACs with vitamin K antagonists (VKAs) in patient with atrial fibrillation using composite end points (combination of various clinical events). The use of composite end points allowed for combining efficacy and safety outcomes, thereby comparing the differences between NOAC and warfarin therapy from a clinical perspective. Results: Treatment with NOAC compared with warfarin was associated with a significant reduction in the sum of stroke or non-CNS, systemic embolism and major bleeding (odds ratio 0.87; 95% CI: 0.82–0.91). Conclusion: Generally, NOACs were associated with a more favorable efficacy and safety profile compared with warfarin with regard to composite end points.     

The next 10 years in personalized medicine in cardiology

In the majority of patients with non-valvular atrial fibrillation (AF) anticoagulation is required to reduce the risk of stroke. Although vitamin K antagonists effectively reduce the risk of stroke, they have many disadvantages that limit their use. Rivaroxaban is a new once-daily oral anticoagulant that overcomes some of these limitations (i.e., no monitoring of anticoagulant effect required and fixed doses can be prescribed). In recent AF studies, rivaroxaban was reported to be at least as effective as warfarin for the prevention of stroke or systemic embolism but with a lesser risk of fatal bleeding and intracranial hemorrhage. More recent data have confirmed the beneficial effects of rivaroxaban, as originally described, and irrespective of the history of previous stroke, heart failure, myocardial infarction, diabetes, moderate renal dysfunction or age. In the present review the authors discuss current evidence regarding the efficacy and safety of rivaroxaban in patients with non-valvular AF.     

Anticoagulation in atrial fibrillation

In this overview the actual guideline-recommendations for anticoagulation in atrial fibrillation and the problems of the currently available therapy are discussed. Furthermore an outlook over future developments in this field is given. Effective anticoagulation can prohibit thrombembolic events and is thus essential for the prognosis of patients suffering from atrial fibrillation. Until now vitamin-K-antagonists (VKAs) and acetylsalicylic acid (ASA) are available for oral anticoagulation in these patients. VKAs demonstrate a satisfying efficiency combined with rather high bleeding hazard. ASA on the other hand allows only moderate risk reduction with minimal side effects. Thus the guidelines recommend anticoagulation tailored to the individual risk, which can be evaluated by the CHADS2-Score. New therapeutic strategies, like the factor Xa inhibitor rivaroxaban or the factor II inhibitor dabigatran, are actually evaluated in phase III studies. These drugs bear the hope of higher efficiency combined with improved safety and much more comfortable use in the daily practice (e. g. no need for INR measurement, no dose adaptation).     

Left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation

The most severe consequence of atrial fibrillation (AF) is a cardioembolic stroke. The incidence of cardioembolic stroke increases significantly in patients with AF. Although warfarin has been the mainstay of the prevention of cardioembolic stroke, there are several limitations to the use of warfarin that hinder its effectiveness. This article provides the historical development of devices that exclude the left atrial appendage, their effectiveness and potential patient selection, as an alternative to warfarin and the novel oral anticoagulation therapy for the prevention of cardioembolic stroke in patients with AF.