• Myocardial Infarction
• Thrombotic Disorders Clinical Trials

The emergence of a series of novel oral anticoagulants with pharmacological advantages, relative to traditional vitamin-K antagonists, has allowed renewed investigation into the role of anticoagulation of various intensities for patients with acute coronary syndromes (ACS).

C. Michael Gibson, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA, reported results from the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) Trial [NCT00809965], which showed that rivaroxaban, an oral direct factor Xa inhibitor, significantly reduced the risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke in ACS patients. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage (ICH) but not the risk of fatal bleeding.

In this double-blind, placebo-controlled trial, 15,526 patients with a recent ACS (STEMI, NSTEMI, unstable angina; stabilized 1 to 7 days postindex event) were randomly assigned to receive twice-daily doses of either 2.5 mg (n=5174) or 5 mg (n=5176) rivaroxaban or placebo (n=5176) for a mean of 13 months, in addition to standard ACS antiplatelet therapies. Patients were excluded if they had an increased bleeding risk, current warfarin use, prior ICH, or prior ischemic stroke if on both aspirin (ASA) and a thienopyridine. The primary efficacy endpoint was a composite of death from CV causes, MI, or stroke (ischemic, hemorrhagic, or uncertain origin). TIMI major bleeding that was not associated with coronary artery bypass grafting (CABG) was the major safety assessment. The primary method of analysis was a log-rank test, stratified by thienopyridine use in the modified intent-to-treat (mITT) population with confirmation in an ITT analysis. Study endpoints were expressed as Kaplan-Meier estimates through 24 months.

Participants had a mean age of 62 years; 75% were male; and 32% were diabetic. Approximately 75% of the participants had an MI (50% STEMI; 26% NSTEMI). Ninety-three percent of the participants were treated with dual antiplatelet therapy at baseline, with a mean duration of treatment with thienopyridine of 13.3 months. The median time from the index event to randomization was 4.7 days.

Rivaroxaban (composite of both doses) significantly reduced the primary efficacy endpoint, as compared with placebo (8.9% vs 10.7%; HR, 0.84; 95% CI, 0.74 to 0.96; p=0.008 mITT; p=0.002 ITT), with significant reductions for both the twice-daily 2.5-mg (9.1% vs 10.7%; p=0.02) and the twice-daily 5-mg dose (8.8% vs 10.7%; p=0.03). The absolute risk reduction was 1.8%, with a number needed to treat for 2 years of 56. The twice-daily 2.5-mg dose reduced the rate of death from CV causes (2.7% vs 4.1%; p=0.002) and from any cause (2.9% vs 4.5%; p=0.002). Overall results were consistent, regardless of whether patients were on ASA plus a thienopyridine or ASA only (p-interaction 0.94). A survival benefit for CV death was not seen with the twice-daily 5-mg dose. Overall, rivaroxaban reduced the risk for composite CV death, MI, or stroke by 16% and reduced stent thrombosis by 31%.

The primary safety endpoint of non-CABG TIMI major bleeding was increased with rivaroxaban (2.1% vs 0.6%; HR, 3.96; 95% CI, 2.46 to 6.38; p<0.001), as were TIMI minor bleeding (p=0.003) and ICH (p=0.009). Bleeding was dose-dependent, with higher rates in the 5-mg rivaroxaban group, including non-CABG TIMI major bleeding (1.8% for the 2.5 mg group and 2.4% in the 5 mg group vs 0.6% for placebo patients; both p<0.001). However, there was no excess of fatal ICH or fatal bleeding and no evidence of hepatotoxicity or posttreatment rebound ischemic events with rivaroxaban.

Overall, these results demonstrate that low-level anticoagulation is effective for reducing recurrent events in patients with ACS, including mortality. One of the most important findings of this study is the importance of appropriate dosing for anticoagulation in post-ACS patients. Traditional intensity anticoagulation using a different oral Xa inhibitor, apixaban, was shown to be harmful in patients with ACS [Alexander JH et al. N Engl J Med 2011]. The current trial shows efficacy at doses of rivaroxaban that are significantly lower than that used for atrial fibrillation (20 mg daily), with the greatest efficacy at the lowest dose of 2.5 mg twice daily. These results will need to be integrated with those of other recent trials to determine the optimal overall combination of antithrombotic therapy for patients with ACS.

• © 2011 MD Conference Express®