Rivaroxaban Treatment for Patients with a Recent Acute Coronary Syndrome

Standard medical therapy following an acute coronary syndrome includes long-term antiplatelet therapy with aspirin and an adenosine diphosphate receptor inhibitor. Despite this therapy, patients remain at risk for recurrent cardiovascular events, due perhaps to excess thrombin generation that persists beyond the acute presentation in such patients. The risk of recurrent cardiovascular events has brought attention to the role of oral anticoagulants following an acute coronary syndrome. Patients treated with warfarin plus aspirin had improved cardiovascular outcomes, but widespread use of warfarin has been limited by the challenges posed by drug administration and the risk of bleeding associated with warfarin. Post–myocardial-infarction treatment with the factor IIa inhibitor ximelagatran also showed cardiovascular benefits, but that drug has been associated with hepatotoxicity. Rivaroxaban is an oral anticoagulant that directly and selectively inhibits factor Xa. Since factor Xa plays a central role in thrombosis, researchers hypothesized that treatment with low-dose rivaroxaban was thought to improve cardiovascular outcomes in patients with recent acute coronary syndrome. Researchers recently designed a trial to evaluate twice-daily rivaroxaban at 2.5 mg and 5 mg as adjunctive therapy in patients with a recent acute coronary syndrome. They reported trial results online in the New England Journal of Medicine [10.1056/NEJMoa1112277]. The phase 3, double-blind, placebo-controlled trial was conducted from November 2008 through September 2011. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. The secondary efficacy end point was death from any cause, myocardial infarction, or stroke. Patients at 766 sites in 44 countries were randomized to receive twice-daily doses of either 2.5 mg (n=5114) or 5 mg of rivaroxaban (n=5115) or placebo (n=5113) for a mean of 13.1 months. The index event was an ST-segment elevation myocardial infarction (STEMI) in 50.3% of the cohort, a non-STEMI in 25.6%, and unstable angina in 24.0%. Baseline characteristics of the patients were similar among the 3 study groups. Premature discontinuation of the study drug occurred in 26.9% of patients in the 2.5-mg group, 29.4% in the 5-mg group, and 26.4% in the placebo group. Patient choice and adverse events were the most common reasons for discontinuation of the study drug. The rate of the primary end point with rivaroxaban was reduced significantly compared with placebo (8.9% vs 10.7%, respectively; hazard ratio, 0.84; 95% confidence interval [CI], 0.74-0.96; P=.008). The intention-to-treat analysis yielded similar results. The researchers also analyzed the effect of rivaroxaban on the individual components of the end point. Rivaroxaban versus placebo had a hazard ratio of 0.80 (P=.04) for death from cardiovascular causes, 0.85 (P=.047) for myocardial infarction, and 1.24 (P=.25) for stroke. The study drug reduced the rate of the secondary efficacy end point, compared with placebo (9.2% vs 11.0%; hazard ratio, 0.84; 95% CI, 0.74-0.95; P=.006). Rivaroxaban also reduced the risk of stent thrombosis compared with placebo (2.3% vs 2.9%; hazard ratio, 0.69; 95% CI, 0.51-0.93; P=.002). In analyses comparing the 2 doses of the study drug, each of the 2 doses reduced the primary efficacy end point as compared with placebo. Compared with placebo, the twice-daily dose of 2.5 mg of rivaroxaban reduced the rate of death from cardiovascular causes (2.7% vs 4.1%; hazard ratio, 0.66; 95% CI, 0.51-0.86; P=.002) as well as from any cause (2.9% vs 4.5%; hazard ratio, 0.68; 95% CI, 0.53-0.87; P=.002), a survival benefit not seen in the twice-daily 5-mg group. Rivaroxaban increased the rates of major bleeding not related to coronary artery bypass grafting (2.1% vs 0.6%; hazard ratio, 3.96; 95% CI, 2.46-6.38; P<.001) and intracranial hemorrhage, compared with placebo (0.6% vs 0.2%; P=.009); there was no significant increase in the rate of fatal bleeding or other adverse events. There were fewer fatal bleeding events in the twice-daily 2.5-mg group than in the twice-daily 5-mg group (0.1% vs 0.4%; P=.04).