ArticlesComparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials
Introduction
Atrial fibrillation, the most common sustained cardiac arrhythmia, predisposes patients to an increased risk of embolic stroke and has a higher mortality than sinus rhythm.1, 2 Until 2009, warfarin and other vitamin K antagonists were the only class of oral anticoagulants available. Although these drugs are highly effective in prevention of thromboembolism, their use is limited by a narrow therapeutic index that necessitates frequent monitoring and dose adjustments resulting in substantial risk and inconvenience. This limitation has translated into poor patient adherence and probably contributes to the systematic underuse of vitamin K antagonists for stroke prevention.3, 4
Several new oral anticoagulants have been developed that dose-dependently inhibit thrombin or activated factor X (factor Xa) and offer potential advantages over vitamin K antagonists, such as rapid onset and offset of action, absence of an effect of dietary vitamin K intake on their activity, and fewer drug interactions. The predictable anticoagulant effects of the new anticoagulants enable the administration of fixed doses without the need for routine coagulation monitoring, thereby simplifying treatment. Individually, new oral anticoagulants are at least as safe and effective as warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation.5, 6, 7, 8 Dabigatran, rivaroxaban, and apixaban have been approved by regulatory authorities, whereas edoxaban has completed late-stage clinical assessment.
Although previously published meta-analyses have been done of trials comparing new oral anticoagulants with warfarin in patients with atrial fibrillation,9, 10, 11, 12, 13 this analysis is the first to include data from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48)8, 14 with edoxaban, the largest of the four trials. All four trials were powered to address their primary endpoints; however, the balance between efficacy and safety in important clinical subgroups needs better definition. We aimed to enhance precision in assessment of the relative benefit of new oral anticoagulants in key subgroups, and the effects of these drugs on important secondary outcomes, to offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in patients with atrial fibrillation.
Section snippets
Study selection
We undertook a prespecified analysis of the four phase 3, randomised trials comparing the efficacy and safety of new oral anticoagulants with warfarin for stroke prevention in patients with atrial fibrillation: Randomized Evaluation of Long Term Anticoagulation Therapy (RE-LY; dabigatran),5 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),6 Apixaban for Reduction in Stroke
Results
42 411 participants received a new oral anticoagulant and 29 272 participants received warfarin. The table shows baseline characteristics for each study. The average age of patients was similar between trials as was the proportion of women recruited (table). However, the underlying risk for stroke differed significantly across the trials as shown by the proportion of patients with CHADS2 scores of 3–6 (table). Median follow-up ranged from 1·8 years to 2·8 years and the median time in
Discussion
Our results show that stroke and systemic embolic events were significantly reduced in patients receiving new oral anticoagulants. This benefit was mainly driven by substantial protection against haemorrhagic stroke, which was reduced by half. Conceptually, haemorrhagic stroke is a complication of anticoagulant treatment even though it is part of the overall efficacy assessment of these drugs. Importantly, overall intracranial haemorrhage (which includes haemorrhagic stroke) was reduced by
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