Results of the highly anticipated ATLAS-ACS 2–TIMI 51 demonstrate that ACS patients receiving standard therapy, including dual antiplatelet therapy, may benefit from the addition of the factor Xa inhibitor rivaroxaban, although at the cost of some additional bleeding complications. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome trial was presented by C. Michael Gibson at the American Heart Association and published simultaneously in the New England Journal of Medicine.
15,526 patients with ACS were randomized to placebo or either 2.5 mg or 5 mg of rivaroxaban for 13 months. The rate of cardiovascular death, MI, or stroke was reduced in the patients taking rivaroxaban:
- 10.7% in the placebo group vs 8.9% in the rivaroxaban groups (HR for rivaroxaban 0.84, CI 0.74-0.96, p = 0.008)
Both doses of rivaroxaban were superior to placebo:
- 2.5 mg dose: 9.1% vs. 10.7%, p = 0.02
- 5 mg dose 8.8% vs. 10.7%, p= 0.03.
The lower dose of rivaroxaban resulted in a significant reduction in death from cardiovascular causes (2.7% vs. 4.1%, P = 0.002) and in all-cause mortality (2.9% vs. 4.5%, P = 0.002). These benefits were not observed in higher dose rivaroxaban, and the difference between the two doses of rivaroxaban was significant.
Rivaroxaban-treated patients experienced more major bleeding and intracranial hemorrhage than controls, but without a significant increase in fatal bleeding:
TIMI major bleeding not related to CABG:
- 2.1% for rivaroxaban vs. 0.6% for placebo, p<0.001
- 0.6% for rivaroxaban vs. 0.2% for placebo, p = 0.009
- 0.3% vs. 0.2%, p = 0.66
The benefits of rivaroxaban were observed across a wide range of subgroups, although the point estimate for patients who had previous stroke or TIA went in the opposite direction.
The authors concluded that “the addition of very-low-dose anticoagulation with rivaroxaban may represent a new treatment strategy in patients with a recent acute coronary syndrome.”
In an accompanying editorial, Matthew Roe and E. Magnus Ohman review the long and complicated history of efforts to incorporate anticoagulants into ACS therapy. They note that ATLAS-ACS 2 had relatively small percentages of elderly patients, female patients, and patients with impaired renal function, suggesting the results may not be entirely replicated with higher-risk patients in the real world. “We need a better understanding of the role of rivaroxaban in higher-risk patients,” they write. Nevertheless, they conclude, “a new era of secondary prevention after an acute coronary syndrome has begun and will be characterized by the need to balance ischemic versus bleeding risks when selecting the type, number, and duration of antithrombotic therapies for individual patients.”