Comparison of the Efficacy and Safety of New Oral Anticoagulants With Warfarin in Patients With Atrial Fibrillation: A Meta-Analysis of Randomised Trials

Study Questions:

What is the relative benefit of new oral anticoagulants for stroke prevention in patients with atrial fibrillation in key subgroups, and their effects on important secondary outcomes?


The investigators searched Medline from January 1, 2009, to November 19, 2013, limiting searches to phase 3 randomized trials of patients with atrial fibrillation who were randomized to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. They 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, ischemic stroke, hemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial hemorrhage, and gastrointestinal bleeding. They calculated relative risks (RRs) and 95% confidence intervals (CIs) for each outcome. They did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. The authors used a random-effects model to compare pooled outcomes, and tested for heterogeneity.


A total of 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 hemorrhagic stroke (RR, 0.49; 95% CI, 0.38-0.64; p < 0.0001). New oral anticoagulants also significantly reduced all-cause mortality (RR, 0.90; 95% CI, 0.85-0.95; p = 0.0003) and intracranial hemorrhage (RR, 0.48; 95% CI, 0.39-0.59; p < 0.0001), but increased gastrointestinal bleeding (RR, 1.25; 95% CI, 1.01-1.55; p = 0.04). The investigators 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 center-based time in therapeutic range was <66% than when it was ≥66% (RR, 0.69; 95% CI, 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 (RR, 1.03; 95% CI, 0.84-1.27; p = 0.74), and a more favorable bleeding profile (RR, 0.65; 95% CI, 0.43-1.00; p = 0.05), but significantly more ischemic strokes (RR, 1.28; 95% CI, 1.02-1.60; p = 0.045).


The authors concluded that new oral anticoagulants had a favorable risk–benefit profile, with significant reductions in stroke, intracranial hemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding.


This study reported that stroke and systemic embolic events were significantly reduced in patients receiving new oral anticoagulants for stroke prevention in atrial fibrillation. This benefit was mainly driven by substantial protection against hemorrhagic stroke, which was reduced by half. The relative efficacy and safety of the anticoagulants was consistent across a wide range of patients with atrial fibrillation. These findings may offer clinicians a more comprehensive picture of the new oral anticoagulants as an option to reduce the risk of stroke in this patient population. Note that the current meta-analysis does not really answer which novel oral anticoagulant is best, whether from an efficacy or safety perspective, and future prospective trials with head-to-head comparisons between the new agents are indicated to assess that.

Clinical Topics: Anticoagulation Management

Keywords: Risk, Myocardial Infarction, Stroke, Intracranial Hemorrhages, Warfarin, Confidence Intervals, Hemorrhage

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