Novel Oral Anticoagulants in Atrial Fibrillation: A Meta‐analysis of Large, Randomized, Controlled Trials vs Warfarin

Background: Warfarin reduces ischemic stroke in atrial fibrillation, but has numerous limitations. Novel oral anticoagulants provide more predictable anticoagulation with fewer shortcomings. Hypothesis: Novel oral anticoagulants are superior to warfarin to prevent stroke or systemic embolism. Methods: Phase III randomized warfarin-controlled trials enrolling >3000 patients that reported clinical efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation were identified from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through October 2012. Two reviewers extracted data; differences were resolved by consensus. The end points analyzed were stroke or systemic embolism (primary efficacy composite); all-cause mortality, ischemic stroke, systemic embolism (individually, secondary efficacy); and hemorrhagic stroke, major bleeding (individually, safety). The Mantel-Haenszel method was used to calculate pooled relative risk (RR) and 95% confidence intervals (CI) from fixed-effects (if homogenous) or random-effects models (if heterogeneous). Results: In 5 studies of 51895 patients, the composite of stroke or systemic embolism (RR: 0.82; 95% CI: 0.69–0.98; P = 0.03) and all-cause mortality (RR: 0.91; 95% CI: 0.85-0.96; P = 0.0026, respectively) were reduced with the novel agents. Factor Xa inhibitors significantly reduced the primary composite (RR: 0.84; 95% CI: 0.74-0.94; P = 0.004) and all-cause mortality (RR: 0.91; 95% CI: 0.84 - 0.98; P = 0.01). Direct thrombin inhibitor achieved results similar to the overall meta-analysis (drug class–outcome interactions P = 0.47 for primary outcome, P = 1.00 for mortality). Compared with warfarin, novel anticoagulants markedly reduced hemorrhagic stroke (RR: 0.51; 95% CI: 0.41-0.64; P < 0.0001). Conclusions: Novel oral anticoagulants may be superior to warfarin in patients with atrial fibrillation, reducing the composite of stroke or systemic embolism and lowering all-cause mortality. The benefit is largely due to fewer hemorrhagic strokes. Ernesto Paolasso, MD, is a national lead investigator for a clinical trial sponsored by Daiichi-Sankyo investigating a novel oral anticoagulant. Robert Giugliano, MD, SM, is a member of the TIMI Study Group, which has received research grant support from Johnson & Johnson and from Daiichi-Sankyo related to clinical trials of anticoagulants. Dr. Giugliano has received honoraria for consultation/lectures from Bristol-Myers Squibb, Daiichi-Sankyo, Johnson & Johnson, and Sanofi-Aventis. The authors have no other funding, financial relationships, or conflicts of interest to disclose.