For years, warfarin has been the only oral anticoagulant approved for the prevention of stroke in patients with atrial fibrillation.1 However; warfarin treatment is difficult because of numerous food and drug interactions, which requires frequent monitoring of therapy. Rivaroxaban is a new oral factor Xa inhibitor that has stable pharmacokinetics and pharmacodynamic properties, making it a more desirable alternative to warfarin therapy.2
The ROCKET-AF trial was a multicenter, randomized, double-blind, double-dummy, non-inferiority trial comparing rivaroxaban 20mg daily (15mg daily for patients with CrCl 30-49 mL/min) to warfarin targeting an INR of 2-3 in patients with nonvalvular atrial fibrillation at moderate to high risk for stroke (CHADS2 score > 2). The primary endpoint in the study was a composite of stroke (ischemic and hemorrhagic) and systemic embolism. The principal safety endpoint was a composite of major and non-major bleeding events. Major bleeding events were defined as fatal bleeding, bleeding at critical anatomic sites, fall in hemoglobin ≥ 2 g/dL, transfusions of ≥2 units of whole blood or packed red blood cells, or bleeding causing permanent disability.2
There were 14,264 patients randomized to treatment for a median duration of 590 days, with a median follow-up time of 707 days. The median age was 73 years, the mean CHADS2 score was 3.5, and 54.8% of patients had a history of transient ischemic attack, stroke, or systemic embolism. Mean time in therapeutic range for patients receiving warfarin was 55%. Rivaroxaban was shown to be non-inferior to warfarin in three separate prespecified analyses for the primary endpoint.2,3 Rivaroxaban was not found to be superior to warfarin using the intention-to-treat analysis which showed an event rate of 2.1% per year for rivaroxaban compared to 2.4% for warfarin (P=0.12). After study discontinuation, more events were seen in patients who received rivaroxaban compared to warfarin during the first month after randomized treatment was discontinued (22 vs. 7, respectively, P=0.008). No difference was seen for the principal safety endpoint with a bleeding rate of 14.9% per year with rivaroxaban compared to 14.5% per year with warfarin (P=0.44). Intracranial hemorrhages and fatal bleeding rates were significantly lower in the rivaroxaban group compared to the warfarin group (0.5% vs. 0.7% per year, P=0.02 for intracranial hemorrhage; 0.2% vs. 0.5% per year, P=0.003 for fatal bleeding). Significantly more major gastrointestinal bleeds (P<0.001), decrease in hemoglobin > 2 g/dL (P=0.02), and transfusions (P=0.04) were seen in the rivaroxaban group compared to the warfarin group.2
This trial showed that rivaroxaban was non-inferior to warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation with moderate to high risk of stroke. Limitations of the study include the time in therapeutic range for the warfarin group of 55%, which is lower than previously described in other studies such as the RE-LY trial (time in therapeutic range >60%).2 If time in therapeutic range was improved, fewer primary events may have been observed ...