APPRAISE-2: Apixaban failed to meet primary efficacy, safety endpoints

Alexander J. N Engl J Med. 2011;doi:10.1056/NEJMoa1105819.

Issue: September 2011

The oral direct factor Xa inhibitor apixaban did not significantly improve the primary efficacy endpoint of patients with an acute coronary syndrome and substantially increased the risk for major bleeding, resulting in the early termination of the APPRAISE-2 trial.

“The results of the current trial 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 researchers wrote.

The Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2) trial was a double blind, placebo-controlled trial in which 7,392 patients with a recent ACS and at least two additional risk factors for recurrent ischemic events were randomly assigned to twice-daily 5 mg apixaban (Bristol-Myers Squibb, Pfizer; n=3,705) or placebo (n=3,687), besides standard antiplatelet therapy.

During follow-up (median, 241 days), the primary efficacy outcome of a composite of CV death, MI or ischemic stroke was not significantly improved in the apixaban group (HR=0.95; P=.51). Further analysis indicated that the study’s primary safety endpoint of major bleeding, as stated in the Thrombolysis in Myocardial Infarction definition, occurred significantly more often among those given apixaban (HR=2.59; P=.001), with a greater number of intracranial and fatal bleeding events reported vs. placebo.

“(The findings) definitively confirm the increases in bleeding observed in the phase 2 trials of factor Xa inhibitors administered in addition to antiplatelet therapy,” the researchers concluded. “Unfortunately, the reductions in ischemic events suggested in the phase 2 trial were not observed in this larger phase 3 trial.”

The trial was funded by Bristol-Myers Squibb and Pfizer.

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