Dual antiplatelet therapy has been the focus for secondary prevention of cardiovascular events following acute coronary syndrome (ACS).1 However, there remains a high residual risk of recurrent cardiovascular events with dual antiplatelet therapy as current outpatient management. In addition, oral anticoagulants for secondary prevention, while beneficial for secondary prevention after ACS, have been limited due to inconvenience of warfarin and bleeding risk.1-3 Therefore, newer oral anticoagulant agents, such as rivaroxaban, a new oral direct Factor Xa inhibitor, have been investigated for secondary prevention after ACS. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 46 (ATLAS ACS 2-TIMI 51) was conducted to determine the efficacy and safety of low-dose rivaroxaban among patients with ACS.2
Mega and colleagues performed a randomized, double-blind, placebo-controlled, event-driven trial in patients with a recent ACS to evaluate two doses of rivaroxaban added to standard therapy for a mean of 13 months. Adult patients were eligible for inclusion if they presented with symptoms associated with ACS and with a diagnosis of STEMI, non ST-segment elevation myocardial infarction (NSTEMI), or unstable angina. Patients were excluded if they had a previous intracranial or significant gastrointestinal hemorrhage or past medical history of a previous ischemic stroke or transient ischemic attack and taking dual antiplatelet therapy (aspirin and thienopyridine). Patients were assigned to twice-daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. All patients received standard outpatient therapy with low-dose aspirin and 93% of patients also received a thienopyridine. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. The secondary end point was death from any cause, myocardial infarction, or stroke. The primary safety end point was TIMI major bleeding not related to coronary-artery bypass grafting.2
A total of 15,526 patients underwent randomization with an index event of a STEMI in 50.3%, NSTEMI in 25.6%, and unstable angina in 24%. The mean patient age was 61 years with only 8.5-9.6% being over 75 years, approximately 75% were male, and more than 75% had normal renal function; the groups were well matched at baseline.2,3 When compared to placebo, rivaroxaban 2.5 and 5 mg significantly reduced the primary efficacy endpoint (10.7% vs. 8.9%, p=0.002, respectively) resulting in a number needed to treat (NNT) of 56. Rivaroxaban 2.5 mg decreased the rate of death from cardiovascular cause (2.7% vs. 4.1%, p=0.002) and death from any cause (2.9% vs. 4.5%, p=0.002) when compared to placebo, while rivaroxaban 5 mg was not significantly different than placebo. There was a benefit of rivaroxaban in all subgroups except those with a prior stroke or TIA. There was an increased risk of major bleeding (2.1% vs. 0.6%, p<0.001, numbers needed to harm, NNH 67), intracranial hemorrhage (0.6% vs. 0.2%, p=0.009, NNH 250) and minor bleeding with rivaroxaban compared to placebo, respectively; however the 2.5 mg dose had a lower risk of major bleeding and a significantly less risk of minor bleeding as compared with the 5 mg dose. There was no difference in fatal bleeds between rivaroxaban and placebo, and significantly less fatal bleeds with the 2.5 mg dose compared to the 5 mg dose. The authors concluded that rivaroxaban decreases the risk of death from cardiovascular causes, myocardial infarction, or stroke in patients with ACS, and rivaroxaban 2.5 mg was associated greater benefit with less bleeding compared with the 5 mg dose.2
Overall, rivaroxaban is a promising option for patients on standard therapy for secondary prevention following ACS. The ATLAS trial had a lower incidence of major bleeding compared to other trials evaluating oral factor Xa inhibitors; ...