Practical Considerations in the Use of Novel Oral Anticoagulants for Stroke Prevention in Nonvalvular Atrial Fibrillation

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia associated with an increased risk of stroke. The role of anticoagulation therapy in the prevention of thrombosis and stroke is of critical importance for patients with AF. Limitations with vitamin K antagonists (VKAs), the current standard of care, have led to the development of novel oral anticoagulants (NOACs) that target either thrombin (dabigatran etexilate) or activated factor X (rivaroxaban, apixaban, and edoxaban). In comparison with traditional VKAs such as warfarin, these NOACs offer several pharmacologic advantages, including rapid onset of action, no significant food interactions, low potential for drug–drug interactions, and no requirement for routine coagulation monitoring. Completed phase‐III clinical trials have demonstrated the therapeutic potential of dabigatran, rivaroxaban, and apixaban in comparison with warfarin for stroke prevention in patients with nonvalvular AF (NVAF). While the future utility of NOACs in preventing stroke in patients with NVAF looks promising, several practical issues, including the current lack of a reversal strategy and use of these agents in older patients with renal dysfunction, must be considered. Clinician and patient understanding of such issues will be important for the safe and effective use of NOACs.     

Improving Stroke Risk Stratification in Atrial Fibrillation

Risk factors for stroke and thromboembolism in patients with atrial fibrillation used in current risk stratification schema are derived largely from analyses of clinical trial cohorts, and the available data depend on the comprehensiveness of trial reports and whether specific risk factors were sought. The most commonly used schema is the Cardiac failure, Hypertension, Age, Diabetes, Stroke [Doubled] (CHADS₂) score. Although simple and well validated, some limitations of CHADS₂ this schema are apparent. A more recent approach to risk stratification of patients with nonvalvular atrial fibrillation defines “major (definitive)” risk factors (eg, previous stroke/transient ischemic attack and age ≥ 75 years) and “clinically relevant non-major” risk factors (eg, heart failure, hypertension, diabetes, female gender, age 65-75 years, and atherosclerotic vascular disease). This scheme can be expressed as an acronym, CHA₂DS₂-VASc, denoting Cardiac failure or dysfunction, Hypertension, Age ≥ 75 [Doubled], Diabetes, Stroke [Doubled]-Vascular disease, Age 65-74, and Sex category [Female]), whereby 2 points are assigned for a history of stroke or age 75 years or more and 1 point each is assigned for age 65 to 74 years, a history of hypertension, diabetes, cardiac failure, and vascular disease. Patients with 1 definitive risk factor or a patient with a CHA₂DS₂-VASc score of 1 or more could be considered for oral anticoagulation, but a patient with a CHA₂DS₂-VASc score of 0 is truly low risk and could be managed with no antithrombotic therapy. This would simplify our approach to thromboprophylaxis in patients with atrial fibrillation.     

Comparative Stroke,Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation

BackgroundNonvitamin K antagonist oral anticoagulants (NOACs) are alternatives to warfarin in patients with nonvalvular atrial fibrillation. Randomized trials compared NOACs with warfarin, but none have compared individual NOACs against each other for safety and effectiveness.MethodsWe performed a retrospective new-user cohort study of patients with nonvalvular atrial fibrillation enrolled in US Medicare who initiated warfarin (n = 183,318), or a standard dose of dabigatran (150 mg twice daily; n = 86,198), rivaroxaban (20 mg once daily; n = 106,389), or apixaban (5 mg twice daily; n = 73,039) between October 2010 and September 2015. Propensity score-adjusted Cox proportional hazards regression was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the outcomes of thromboembolic stroke, intracranial hemorrhage, major extracranial bleeding, and all-cause mortality, comparing each NOAC with warfarin, and with each other NOAC.ResultsCompared with warfarin, each NOAC was associated with reduced risks of thromboembolic stroke (20%-29% reduction; P = .002 [dabigatran], P < 0.001 [rivaroxaban, apixaban]), intracranial hemorrhage (35%-62% reduction; P < 0.001 [each NOAC]), and mortality (19%-34% reduction; P < .001 [each NOAC]). The NOACs were similar for thromboembolic stroke but rivaroxaban was associated with increased risks of intracranial hemorrhage (vs dabigatran: HR = 1.71; 95% CI, 1.35-2.17), major extracranial bleeding (vs dabigatran: HR = 1.32; 95% CI, 1.21-1.45; vs apixaban: HR = 2.70; 95% CI, 2.38-3.05), and death (vs dabigatran: HR = 1.12; 95% CI, 1.01-1.24; vs apixaban: HR = 1.23; 95% CI, 1.09-1.38). Dabigatran was associated with reduced risk of intracranial hemorrhage (HR = 0.70; 95% CI ,0.53-0.94) and increased risk of major extracranial bleeding (HR = 2.04; 95% CI, 1.78-2.32) compared with apixaban.ConclusionsAmong patients treated with standard-dose NOAC for nonvalvular atrial fibrillation and warfarin users with similar baseline characteristics, dabigatran, rivaroxaban, and apixaban were associated with a more favorable benefit–harm profile than warfarin. Among NOAC users, dabigatran and apixaban were associated with a more favorable benefit–harm profile than rivaroxaban.     

Pharmacology,benefits, unaddressed questions,and pragmatic issues of the newer oral anticoagulants for stroke prophylaxis in non-valvular atrial fibrillation and proposal of a management algorithm

This systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral direct thrombin and factor Xa inhibitors, which have emerged for the first time in ~ 60 years as cogent alternatives to warfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most common clinical scenarios with several unsolved questions and areas of uncertainty that may play a role in physicians' reluctance to prescribe the newer oral anticoagulants such as 1) patients with renal failure; 2) the elderly; 3) patients presenting with atrial fibrillation and acute coronary syndromes and/or undergoing coronary stenting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspects presented in current guidelines are covered and we also propose an evidence-based anticoagulation management algorithm.     

Stroke prevention in patients with atrial fibrillation—anticoagulation strategy 2012

Vitamin K antagonists have been recommended as the only available oral anticoagulants for stroke prevention in patients with atrial fibrillation for many years. Despite their proved effectiveness, there are several limitations and drawbacks of this therapy. Recently three major clinical trials of novel oral anticoagulants clinical trials have been published. Dabigatran, a direct thrombin inhibitor, as well as rivaroxaban and apixaban, direct Xa factor inhibitors, were found to have at least noninferior efficacy and safety in comparison to vitamin K antagonists for stroke prevention in patients with non-valvular fibrillation. These novel oral anticoagulants may constitute a valuable alternative to vitamin K antagonists.     

Long-Term Clinical Outcomes of Underdosed Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Atrial Flutter

BackgroundAlthough direct oral anticoagulants (DOACs) have been shown to be effective at reducing the risk of stroke in patients with atrial fibrillation/flutter (AF), they are sometimes underdosed off-label to mitigate their associated higher bleeding risk. We sought to evaluate frequency and clinical outcomes of inappropriate underdosing of DOACS in patients with AF.MethodsWe conducted a study of subjects with AF who had a clinical indication for stroke prophylaxis (with a congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 47 years, sex category [CHA₂DS₂-VASc] of 2 or greater) and were prescribed 1 of the 4 clinically approved DOACs (apixaban, rivaroxaban, dabigatran, or edoxaban). We compared all-cause mortality, composite of stroke and systemic embolism, composite of myocardial infarction (MI), acute coronary syndromes (ACS), and coronary revascularization, and major bleeding between patients appropriately dosed and inappropriately underdosed.ResultsA total of 8125 patients met inclusion criteria, with a mean follow up of 2.2 ± 2 years. Of those, 1724 patients (21.2%) were inappropriately dosed. After adjusting for baseline variables, there was no difference in all-cause mortality, risk of stroke or systemic embolism, International Society on Thrombosis and Haemostasis (ISTH) major bleeding, or composite of myocardial infarction, acute coronary syndromes, or coronary revascularization between patients appropriately dosed and inappropriately underdosed. In subgroup analysis, only apixaban demonstrated an increased incidence all-cause mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.03-1.49) with inappropriate underdosing. There was no difference in the remaining clinical outcomes noted on subgroup analysis.ConclusionUnderdosing of DOACs did not minimize risk of bleeding, systemic embolization or all-cause mortality in patients with AF. Inappropriate underdosing with apixaban in particular was associated with increased all-cause mortality.     

Dabigatran and Warfarin for Secondary Prevention of Stroke in Atrial Fibrillation Patients: A Nationwide Cohort Study

Background

This register-based observational study compares dabigatran to warfarin for secondary stroke prevention in atrial fibrillation patients among both “new starters” on dabigatran and “switchers” to dabigatran from warfarin.

Methods

We identified, in nationwide Danish registries, 2398 patients with atrial fibrillation and a history of stroke/transient ischemic attack, making a first-time purchase of dabigatran 110 mg twice a day (bid; D110) and 150 mg bid (D150). Patients were categorized as either vitamin K antagonist (VKA) naive or experienced. Warfarin controls were identified using a complete (for VKA-naive dabigatran patients) or matched sampling approach (for VKA-experienced dabigatran patients). Subjects were followed for an average of 12.6 months for stroke and transient ischemic attacks. Confounder-adjusted Cox regression models were used to compare event rates between treatments.

Results

Among patients with a history of stroke/transient ischemic attack and prior VKA experience, switching to dabigatran was associated with an increased stroke/transient ischemic attack rate for both dabigatran doses compared with continuing on warfarin (D110 hazard ratio [HR] 1.99; 95% confidence interval [CI], 1.42-2.78; D150 HR 2.34; 95% CI, 1.60-3.41). Among prior stroke/transient ischemic attack patients who were new starters on dabigatran or warfarin, the rate of stroke/transient ischemic attack for both doses of dabigatran was similar to or lower than warfarin (D110 HR 0.64; 95% CI, 0.50-0.80; D150 HR 0.92l; 95% CI, 0.73-1.15).

Conclusions

In this register-based study, VKA-experienced patients with a history of stroke or transient ischemic attack who switched to dabigatran therapy had an increased rate of stroke compared with patients persisting with warfarin therapy.     

Concomitant Use of Direct Oral Anticoagulants with Antiplatelet Agents and the Risk of Major Bleeding in Patients with Nonvalvular Atrial Fibrillation

Purpose

Patients with nonvalvular atrial fibrillation commonly have comorbidities requiring concurrent use of oral anticoagulants and antiplatelets. There are no real-world data on the comparative safety of concomitant antithrombotic treatments in the era of direct oral anticoagulant (DOACs). Thus, we compared the incidence of intracranial hemorrhage, gastrointestinal bleeding, and other major bleeding between concomitant DOAC-antiplatelet use and concomitant vitamin K antagonist (VKA)-antiplatelet use in patients with nonvalvular atrial fibrillation.

Efficacy and Safety Outcomes of Direct Oral Anticoagulants and Amiodarone in Patients with Atrial Fibrillation

Background

Direct oral anticoagulants (DOACs) and amiodarone are widely used in the treatment of nonvalvular atrial fibrillation. The DOACs are P-glycoprotein (P-gp) and cytochrome p-450 (CYP3A4) substrates. Direct oral anticoagulant levels may be increased by the concomitant use of potent dual P-gp/CYP3A4 inhibitors, such as amiodarone, which can potentially translate into adverse clinical outcomes. We aimed to assess the efficacy and safety of drug–drug interaction by the concomitant use of DOACs and amiodarone.

高血压合并房颤患者卒中危险因素的分析

目的：：探讨高血压合并房颤患者随访2年的卒中发生率及其危险因素。方法：分析高血压合并房颤患者资料,根据2年随访事件中是否发生卒中分为卒中组和非卒中组。用单因素和多因素Cox回归模型分析影响高血压合并房颤患者卒中发生的独立危险因素。结果：入选568例高血压合并房颤患者,其中卒中组53例,非卒中组515例,2年卒中发生率为9．3%。卒中组年龄显著高于非卒中组(P<0．01);卒中组女性、既往卒中史所占比例均高于非卒中组(P<0．05);非卒中组接受抗高血压、抗凝、他汀类药物治疗比例均高于卒中组( P<0．05);多因素Cox回归模型分析显示,年龄( HR=1．044,95%CI1．011~1．077)、女性(HR =1．893,95%CI1．169~3．121)、未接受抗高血压治疗(HR =1．966,95%CI1．009~3．801)、既往卒中史(HR=1．679,95%CI1．073~2．614)是高血压合并房颤患者2年卒中发生的独立危险因素。结论：年龄、女性、未接受抗高血压治疗和既往卒中史是高血压合并房颤患者2年卒中发生的独立危险因素。     

Advances in Stroke Prevention in Atrial Fibrillation: Enhanced Risk Stratification Combined With the Newer Oral Anticoagulants

Patients with atrial fibrillation (AF) have an increased stroke risk compared with those in sinus rhythm, although the absolute risk for individual patients is modulated by the presence of various additional risk factors. Patient selection for oral anticoagulation for stroke prevention is based on risks of stroke and bleeding. Although CHADS₂ (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack) is the most widely used scheme for evaluating stroke risk in patients with AF, several other stroke risk factors are not included; therefore, many patients' stroke risk may be underestimated, contributing to the underuse of anticoagulants. Furthermore, a substantial proportion of patients are categorized as being at moderate risk (CHADS₂ = 1), and there has been some ambiguity regarding optimum thromboprophylaxis in this group. The refinement of CHADS₂, CHA₂DS₂‐VASc (Congestive heart failure, Hypertension, Age 75 years [2 points], Diabetes mellitus, Stroke or transient ischemic attack [2 points], Vascular disease, Age 65 to 74 years, Sex category [female]), considers additional risk factors. Its main advantage is its ability to identify patients truly at low risk of thromboembolism (CHA₂DS₂‐VASc = 0), who are unlikely to benefit from antithrombotic therapy. For all others, an oral anticoagulant may be the preferred approach, simplifying clinical decision making. Implementation of CHA₂DS₂‐VASc may also result in an increased proportion of patients receiving anticoagulation. The emergence of newer oral anticoagulants that can be given without routine coagulation monitoring, with improved benefit–risk profiles vs vitamin K antagonists, promises to simplify therapy for patients with AF at risk of stroke. This, coupled with advances in stroke risk stratification, is expected to improve patient outcomes and reduce the burden of AF‐related stroke.     

Underuse of Oral Anticoagulants in Atrial Fibrillation: A Systematic Review

Background

Atrial fibrillation is associated with substantial mortality and morbidity from stroke and thromboembolism. Despite an efficacious oral anticoagulation therapy (warfarin), atrial fibrillation patients at high risk for stroke are often under-treated. This systematic review compares current treatment practices for stroke prevention in atrial fibrillation with published guidelines.

Methods

Literature searches (1997-2008) identified 98 studies concerning current treatment practices for stroke prevention in atrial fibrillation. The percentage of patients eligible for oral anticoagulation due to elevated stroke risk was compared with the percentage treated. Under-treatment was defined as treatment of <70% of high-risk patients.

Results

Of 54 studies that reported stroke risk levels and the percentage of patients treated, most showed underuse of oral anticoagulants for high-risk patients. From 29 studies of patients with prior stroke/transient ischemic attack who should all receive oral anticoagulation according to published guidelines, 25 studies reported under-treatment, with 21 of 29 studies reporting oral anticoagulation treatment levels below 60% (range 19%-81.3%). Subjects with a CHADS₂ (congestive heart failure, hypertension, age >75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score ≥2 also were suboptimally treated, with 7 of 9 studies reporting treatment levels below 70% (range 39%-92.3%). Studies (21 of 54) using other stroke risk stratification schemes differ in the criteria they use to designate patients as “high risk,” such that direct comparison is not possible.

Conclusions

This systematic review demonstrates the underuse of oral anticoagulation therapy for real-world atrial fibrillation patients with an elevated risk of stroke, highlighting the need for improved therapies for stroke prevention in atrial fibrillation.     

Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation

The availability of 4 non–vitamin K oral anticoagulants (NOACs), that is, dabigatran, rivaroxaban, apixaban, and edoxaban, has changed the landscape of stroke prevention in patients with atrial fibrillation. This review article provides an overview of the 4 phase III studies that have compared these NOACs, examining major outcomes of efficacy and safety. A range of practical questions relating to the NOACs have emerged, including topics such as patient selection, treating patients with renal impairment, treating elderly patients, and combining anticoagulant therapy with antiplatelet drugs. We also address the interaction of various patient characteristics with the treatments and suggest the features can assist the physician in the choice of a particular NOAC for a particular patient(s).     

Efficacy and Safety of Apixaban Versus Warfarin in Patients with Atrial Fibrillation and a History of Cancer: Insights from the ARISTOTLE Trial

Background

Cancer is associated with a prothrombotic state and increases the risk of thrombotic events in patients with atrial fibrillation. We described the clinical characteristics and outcomes and assessed the safety and efficacy of apixaban versus warfarin in patients with atrial fibrillation and cancer in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.

Viewpoint: Stroke Prevention in Recent Guidelines for the Management of Patients with Atrial Fibrillation: An Appraisal

Formal guidelines play an important role in disseminating the best available evidence knowledge and are expected to provide simple and practical recommendations for the most optimal management of patients with various conditions. Such guidelines have important implications for many disease states, which thereby could be more professionally managed in everyday clinical practice by clinicians with divergent educational backgrounds, and also more easily implemented in wards or outpatient clinics, eliminating inequalities in health care management. In this brief Viewpoint we provide an appraisal on the recommendations pertinent to the prevention of atrial fibrillation–related stroke or systemic thromboembolism, as provided in recently published guidelines for the management of this arrhythmia.