Rivaroxaban Noninferior to Warfarin in Reducing Risk of Stroke

For people at increased risk for ischemic stroke, warfarin has been shown to reduce the risk in patients with nonvalvular atrial fibrillation. However, possible food and drug interactions require frequent monitoring of coagulation to make adjustments in dose; this need for monitoring makes it difficult for many patients to use warfarin and other vitamin K antagonists. According to researchers, rivaroxaban, a direct factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. Standard therapy regimen includes enoxaparin followed by warfarin to prevent venous thromboembolism in patients undergoing orthopedic surgery; rivaroxaban has been shown to be more effective compared with enoxaparin in those patients. Rivaroxaban has also been shown to be noninferior to enoxaparin followed by warfarin in patients with established venous thrombosis. The researchers recently conducted a trial to compare a regimen of once-daily rivaroxaban with dose-adjusted warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation at moderate-to-high risk for stroke. The researchers reported trial results online first in the New England Journal of Medicine [2011;doi:10.1066/NEJMoa1009638]. ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention for Stroke and Embolism Trial in Atrial Fibrillation) was a multicenter, randomized, double-blind, double-dummy, event-driven trial conducted at 1178 sites in 45 countries. The primary efficacy end point was a composite of stroke (ischemic or hemorrhagic) and systemic embolism. Secondary efficacy end points were a composite of stroke, systemic embolism, death from cardiovascular causes, or myocardial infarction; and individual components of the composite end points. The researchers randomly assigned 14,264 patients with nonvalvular atrial fibrillation at increased risk for stroke to 1 of 2 groups: those receiving a daily dose of 20 mg of rivaroxaban (n=7131) or those receiving dose-adjusted warfarin (n=7133). Median duration of treatment was 590 days; median follow-up was 707 days. Median age of participants was 73 years, 39.7% were female, 90.5% had substantial rates of coexisting illnesses (hypertension, heart failure, diabetes), and 54.8% had a previous stroke, systemic embolism, or transient ischemic attack. In the patients included in the primary efficacy analysis (per-protocol population), stroke or systemic embolism occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 patients in the warfarin group (2.2% per year) (hazard ratio [HR] in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66-0.96; P<.001 for noninferiority). In the as-treated safety population, primary events occurred in 189 patients in the rivaroxaban group (1.7% per year) and in 243 patients in the warfarin group (2.2% per year) (HR, 0.79; 95% CI, 0.65-0.95; P=.01 for superiority). Among all randomized patients in the intention-to-treat analysis, 269 patients in the rivaroxaban group experienced primary events (2.1% per year) compared with 306 patients in the warfarin group (2.4% per year) (HR, 0.88; 95% CI, 0.74-1.03; P<.001 for noninferiority; P=.12 for superiority). Major and clinically relevant nonmajor bleeding occurred in 14.9% (n=1475) of patients in the rivaroxaban group and 14.5% (n=1449) of those in the warfarin group (HR in the rivaroxaban group, 1.03; 95% CI, 0.96-1.11; P=.44). Rates of major bleeding were also similar between the 2 groups. There were significant reductions in intracranial hemorrhage and fatal bleeding in the rivaroxaban group compared with the warfarin group (0.5% vs 0.7%; P=.02 and 0.2% vs 0.5%, P=.003, respectively). In summary, the researchers stated, “In patients with nonvalvular atrial fibrillation who were at moderate-to-high risk for stroke, rivaroxaban was noninferior to warfarin for the prevention of subsequent stroke or systemic embolism. There were no significant differences in rates of major bleeding and clinically relevant nonmajor bleeding between the 2 study groups, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.”