Elsevier

The Lancet

Volume 383, Issue 9921, 15–21 March 2014, Pages 955-962
The Lancet

Articles
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials

https://doi.org/10.1016/S0140-6736(13)62343-0Get rights and content

Summary

Background

Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes.

Methods

We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71 683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF–TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity.

Findings

42 411 participants received a new oral anticoagulant and 29 272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73–0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38–0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85–0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39–0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01–1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59–0·81 vs 0·93, 0·76–1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84–1·27; p=0·74), and a more favourable bleeding profile (0·65, 0·43–1·00; p=0·05), but significantly more ischaemic strokes (1·28, 1·02–1·60; p=0·045).

Interpretation

This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk–benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.

Funding

None.

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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