The addition of apixaban, at a dose of 5 mg twice-daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome (ACS) increased the number of major bleeding events without a significant reduction in recurrent ischemic events, according to the APPRAISE-2 trial, published online July 24 in the New England Journal of Medicine.

Apixaban, approved in the EU with the trade name Eliquis (Bristol-Myers Squibb/Pfizer), an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an ACS. The study was conducted in 40 countries and was coordinated by Duke Clinical Research Institute in Durham, N.C., and Uppsala Clinical Research Center in Sweden.

John H. Alexander, MD, a cardiologist and associate professor of medicine at Duke University Medical Center in Durham, N.C., and colleagues conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, a 5 mg twice-daily dose, with placebo, in addition to standard antiplatelet therapy, in patients with a recent ACS and at least two additional risk factors for recurrent ischemic events.

According to the APPRAISE-2 investigators, the trial was terminated prematurely after the recruitment of 7,392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events.

With a median follow-up of 241 days, the primary end point of cardiovascular death, MI or ischemic stroke occurred in 7.5 percent of the 3,705 patients assigned to apixaban (13.2 events per 100 patient-years) and in 7.9 percent of the 3,687 patients assigned to placebo (14 events per 100 patient-years).

The primary safety outcome of major bleeding according to the Thrombolysis in MI (TIMI) definition occurred in 1.3 percent of the 3,673 patients who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 0.5 percent of the 3,642 patients who received at least one dose of placebo (0.9 events per 100 patient-years). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo.

“The findings from the APPRAISE-2 trial definitively confirm the increases in bleeding observed in the Phase II trials of factor Xa inhibitors administered in addition to antiplatelet therapy,” Alexander and colleagues wrote. “Unfortunately, the reductions in ischemic events suggested in the phase II trial were not observed in this larger Phase III trial. Because this trial was stopped early owing to the increase in bleeding events, with fewer events having occurred than the number planned, uncertainty remains regarding the effect of apixaban on ischemic events.”

Therefore, they concluded that treatment with apixaban, as compared with placebo, was associated with a significant increase in the risk of bleeding, without a significant effect on the incidence of recurrent ischemic events.

“Because of the early termination of the trial, with accrual of two-thirds of the expected events and a median follow-up of eight months, some uncertainty regarding efficacy remains,” said Alexander, during the trial presentation July 24 at the 57th Congress of the International Society on Thrombosis and Haemostasis in Kyoto, Japan. “The addition of an anticoagulant to currently recommended antiplatelet treatment post-ACS should be used cautiously and only in patients with clear indications for both anticoagulant and antiplatelet therapy.”

Further research is needed to explore different antithrombotic combinations and doses, according to the researchers, that might have a different risk-benefit balance.

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