Apixaban associated with more bleeding, no change in ischemic events

A phase 3 trial of apixaban, a new factor Xa inhibitor, was halted after the drug was found to increase major bleeding in patients taking it after acute coronary syndrome.

The double-blind trial included more than 7,000 patients who had recent acute coronary syndrome and at least two risk factors for recurrent ischemic events and were receiving standard antiplatelet therapy. The participants were randomized to receive either apixaban, 5 mg twice daily, or placebo, and the primary end point was cardiovascular death, myocardial infarction or ischemic stroke. However, after a median follow-up of 241 days, the trial was stopped due to differences between groups in the primary safety outcome—major bleeding. Such bleeding occurred in 1.3% (46 people) of those who received apixaban, compared to 0.5% (18 people) of those on placebo (hazard ratio, 2.59; P=0.001). There were also more intracranial and fatal bleeds in the active group.

No significant difference was found between the groups in rates of cardiovascular death, myocardial infarction or ischemic stroke. The combined outcome occurred in 7.5% of apixaban users compared to 7.9% of placebo users (P=0.51). The study authors noted that phase 2 trials of apixaban and another factor Xa inhibitor, rivaroxaban, had found increases in bleeding but also reductions in ischemic events. The early discontinuation of this trial—at a lower number of ischemic events than expected—leaves some uncertainty about whether a benefit to the drug could have been found in this study, they said.

The results could also be different in other patient populations, the study authors suggested. This trial included high-risk patients, many with diabetes, heart failure or renal insufficiency, but no differences were seen among the subgroups in the study, such as those receiving aspirin plus clopidogrel versus aspirin alone or those who had or didn't have revascularization.

Still, the results of this trial, combined with those of other interventions, such as vitamin K antagonists, “raise doubt about whether meaningful incremental efficacy can be achieved with an acceptable risk of bleeding by combining a long-term oral anticoagulant with both aspirin and a P2Y12-receptor antagonist in patients with coronary disease,” the authors concluded. The study was funded by Bristol-Myers Squibb and Pfizer and was published online by the New England Journal of Medicine on July 24.