Novel oral anticoagulants in atrial fibrillation: a meta-analysis of large, randomized, controlled trials vs warfarin

Abstract

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.

Figure 1

Flow diagram of literature search. Abbreviations: RCTs, randomized controlled trials.

Figure 2

Overall analyses of the risk of stroke or systemic embolism. Studies are grouped as thrombin inhibitors vs warfarin (SPORTIF III/V and RE‐LY) and factor Xa inhibitors vs warfarin (ROCKET AF and ARISTOTLE). Single‐study random‐effects relative risks and 95% confidence intervals are shown by squares and horizontal lines. Overall and group pooled relative risks with 95% confidence intervals are shown by diamonds. Abbreviations: ARISTOTLE, Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; RE‐LY, Randomized Evaluation of Long‐Term Anticoagulant Therapy; ROCKET AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non‐Central Nervous System Systemic Embolism in Patients With Non‐Valvular Atrial Fibrillation; SPORTIF, Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation.

Figure 3

Trial sequential analysis monitoring boundaries for moderate evidence in the current meta‐analysis. The cumulative Z‐statistic crossed the monitoring boundaries before reaching the optimal information size (OIS).

Figure 4

Overall analyses of the risk of death from any cause. Studies are grouped as thrombin inhibitors vs warfarin (SPORTIF III/V and RE‐LY) and factor Xa inhibitors vs warfarin (ROCKET AF and ARISTOTLE). Single‐study fixed‐effects relative risks and 95% confidence interval estimates are shown by squares and horizontal lines. Overall and group pooled relative risks with 95% confidence intervals are shown by diamonds. Abbreviations: ARISTOTLE, Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; RE‐LY, Randomized Evaluation of Long‐Term Anticoagulant Therapy; ROCKET AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non‐Central Nervous System Systemic Embolism in Patients With Non‐Valvular Atrial Fibrillation; SPORTIF, Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation.

Figure 5

Trial sequential analysis monitoring boundaries for moderate evidence in the current meta‐analysis. The cumulative Z‐statistic crossed the monitoring boundaries before reaching the optimal information size (OIS).