Adding the oral anticoagulant rivaroxaban (Xarelto, Janssen) to standard therapy after myocardial infarction (MI) or unstable angina significantly reduced the risk for cardiovascular mortality, data reported in the New England Journal of Medicine and presented at the American Heart Association meeting indicate.

Patients assigned to 2.5 mg of rivaroxaban twice daily for 13 to 31 months were 34% less likely to die from cardiovascular disease than those in the placebo group (hazard ratio [HR]=0.66; 95% CI:0.51-0.86) and 32% less likely to die from any cause (HR=0.68, 95% CI:0.53-0.87; P =0.002 for both), according to Jessica L. Mega, MD, MPH, of Brigham and Women’s Hospital in Boston and colleagues.

They randomly assigned 15,526 patients to rivaroxaban 2.5 mg or 5 mg twice daily or matching placebo in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome (ATLAS-ACS 2 TIMI 51) trial.

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Overall, the rivaroxaban group had a 16% reduced risk for death (HR: 0.84; 95% CI: 0.74 to 0.96; P=0.008), but analysis revealed that the 5 mg rivaroxaban dose did not reduce this risk.

“If the data from ATLAS ACS 2 TIMI 51 were extrapolated into clinical practice, we could potentially see one life saved for every 56 patients treated with this combination of therapies over a two year period,” researcher C. Michael Gibson, MD, a Thrombolysis In Myocardial Infarction (TIMI) Study Group member, said in press release.

Hazard ratios for rivaroxaban vs. placebo were as follows for individual primary efficacy endpoint components:

  • Death from cardiovascular causes including those related to hemorrhage, HR= 0.80; P=0.04
  • Myocardial infarction, HR=0.85; P=0.47
  • Stroke, including stroke attributable to ischemic hemorrhage and uncertain causes, HR=1.24; P=0.25

Overall, major bleeding incidents were higher among the rivaroxaban group – 2.1% vs. 0.6% (P<0.001) for major bleeding events not related to bypass surgery, and 0.6% vs. 0.2% (P=0.009) for intracranial bleeding. However, rates for fatal bleeding events were similar between patients assigned to rivaroxaban and those assigned to placebo (0.3% vs. 0.2%; P=0.66), the researchers noted.

These findings are significant given that a phase 3 trial of apixaban, another anticoagulant belonging to the direct factor Xa inhibitor class, was discontinued last year due to bleeding risk. This past September, Astellas Pharmaceuticals also discontinued development of the anticoagulant darexaban maleate after reports of excess bleeding.

In the ATLAS-ACS 2 TIMI 51 trial, bleeding risk with rivaroxaban appeared to be dose-dependent, occurring more often at higher doses and after 180 days of treatment, Matthew T. Roe, MD, and E. Magnus Ohman, MB, FRCPI, from Duke Clinical Research Institute in Durham, N.C., wrote in an accompanying NEJM editorial.

Other factors that appeared to increase bleeding risk included lighter weight, older age, reduced renal function and being enrolled in North America.

“Given the exquisite balance between bleeding risks and ischemic benefits of treatment we need a better understanding of the role of rivaroxaban in higher-risk patients,” Roe and Ohman wrote.

Average patient age in the ATLAS-ACS 2 TIMI 51 trial was 63 years and about 75% were white men. About 50% had ST-elevation MI, 25% had non-ST-elevation MI and 25% had unstable angina. Sixty percent underwent revascularization with either coronary artery bypass graft or stenting.

Concurrent medications among study participants included aspirin (99%), thienopyridine (93%), statins (83%), beta blockers (66%), ACE inhibitor or ARB (39%) and calcium channel blockers (16%).

Mega JL et al. NEJM. 2011;doi:10.1056/NEJM0a1112277.

Roe MT, Ohman EM. NEJM. 2011;doi:10.1056/NEJMe1112770.

Gibson CM. # LBCT.01. Presented at: American Heart Association Scientific Sessions. Nov. 12-16, 2011. Orlando, FL.