Group Terminates Study of Apixaban in High-Risk Patients with Acute Coronary Syndrome

A trial evaluating whether adding apixaban to antiplatelet therapy can prevent recurrent ischemic events in high-risk patients ended prematurely after the data monitoring safety committee expressed concern about the frequency of major bleeding events and corresponding lack of efficacy associated with the direct factor Xa inhibitor. Of particular concern were the significantly higher rates of fatal bleeding, intracranial bleeding, and transfusions for apixaban-treated patients. In reporting findings from the APPRAISE-2 (Apixaban for Prevention of Acute Ischemic Events 2) trial, the authors cautioned that the high rate of discontinuation in the apixaban arm and the trial’s abrupt termination compromised any conclusions drawn about apixaban’s efficacy [N Engl J Med. 2011;365(8):699-708]. From March 2009 until the phase 3 trial’s closure in November 2010, the APPRAISE-2 investigators enrolled 7392 patients from 39 countries. Patients were selected for their high risk of a recurrent ischemic event, having received a diagnosis of acute coronary syndrome (ACS) a week or less before enrollment. The most common index ACS events among participants were myocardial infarction with or without ST-segment elevation (40% vs 42%, respectively) and unstable angina (18%). Eligibility was restricted to clinically stable individuals receiving standard treatment, such as aspirin (97%) or aspirin and a P2Y12-receptor antagonist (81%). Participants had to have at least 2 specified high-risk characteristics; more than half met ≥3 of the following criteria: age ≥65 years (median age, 67 years); no revascularization for their index ACS event; diabetes mellitus; heart failure or left ventricular ejection fraction 50% of patients received statins, beta-blockers, or angiotensin-converting enzyme inhibitors. Baseline, disease, and treatment characteristics were well balanced between the arms. When APPRAISE-2 ended, data showed 279 patients (7.5%) in the apixaban group had experienced an event included in the composite primary end point—cardiovascular death, myocardial infarction, or ischemic stroke—compared with 293 patients (7.9%) in the placebo arm. Rates were similar between the subgroup of patients taking concomitant aspirin and the subgroup taking aspirin combined with another antiplatelet therapy. Apixaban was associated with a rate of major bleeding events that was more than double the rate observed with placebo (1.3% vs 0.5%, respectively). Bleeding events caused the death of 5 apixaban users; none of the patients taking placebo had a fatal bleed. Altogether, the apixaban arm reported more than twice as many bleeding events as the placebo arm (679 vs 305, respectively), as well as a higher number of intracranial bleeds (12 vs 3, respectively) and major or clinically relevant nonmajor bleeding episodes (117 vs 45, respectively). Apixaban was also associated with a higher rate of blood transfusions than placebo (3.9% vs 2.0%, respectively). Although apixaban was associated with a slightly lower rate of recurrent ischemic events than placebo at the time APPRAISE-2 was halted, the degree of benefit was not sufficient to justify apixaban’s continued use in light of the serious bleeding problems. The authors said these outcomes “raise doubt about whether meaningful incremental efficacy can be achieved with an acceptable risk of bleeding” when administering a long-term oral anticoagulant with aspirin and a P2Y12-receptor antagonist to patients with coronary disease. Ongoing trials are investigating different doses of apixaban in ACS patients with a lower risk profile.—Christin Melton