Trial of apixaban with single and combination antiplatelet therapy in ACS stopped early due to observed increase in major bleeding events
Full-dose anticoagulation, in combination with antiplatelet therapy of any kind in patients with acute coronary syndrome, results in substantial bleeding without any clear additional benefit and should only be considered when required for another condition.
Post-acute coronary syndrome (ACS) treatment with apixaban didn't reduce cardiovascular events compared to placebo, but it increased bleeding regardless of concomitant therapy with aspirin alone or aspirin plus clopidogrel, according to a study that was stopped early because of bleeding events.
The study examined high-risk ACS patients who were treated with aspirin or aspirin plus clopidogrel as part of a post-hoc analysis from Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2). APPRAISE-2 was a double-blind clinical trial of 7,392 patients at 858 sites from 39 countries. Patients were included if they had ACS within the previous 7 days, symptoms of myocardial ischemia at rest, elevated cardiac biomarkers, and dynamic ST-segment changes on electrocardiogram, and if they received aspirin or aspirin plus a P2Y12 receptor inhibitor. Patients were also required to have 2 or more risk factors: age 65 or older, diabetes, myocardial infarction (MI) within the previous 5 years, cerebrovascular disease, peripheral artery disease, clinical heart failure or a left ventricular ejection fraction below 40% associated with the index event, creatinine clearance below 60 mL/min, or no revascularization after the index event.
Patients were randomized to apixaban (5 mg twice daily or 2.5 mg twice daily for a creatinine clearance <40 mL/min) versus placebo. Other treatment decisions, including the use, choice, and duration of antiplatelet therapy, were left to the discretion of treating clinicians. The primary efficacy endpoint for APPRAISE-2 and for this analysis was a composite endpoint of cardiovascular death, MI, and ischemic stroke. Secondary efficacy outcomes included cardiovascular death and all-cause mortality. Thrombolysis in myocardial infarction (TIMI) major bleeding was the primary safety endpoint, with TIMI major or minor bleeding assessed as a secondary safety outcome.
The trial was stopped early by the independent data monitoring committee due to increased bleeding events with apixaban without any offsetting reduction in ischemic events. Results were published online Aug. 10 by the Journal of the American College of Cardiology and will appear the Aug. 18 print issue.
At baseline, 16.3% of patients (n=1,202) were on aspirin alone, and 79.0% (n=5,814) were on aspirin plus clopidogrel. There were 19.2% (n=1,415) of patients who switched antiplatelet therapy at least once during follow-up. No differential effect of apixaban versus placebo was seen for the composite endpoint in patients taking aspirin (12.21 per 100 patient-years vs. 13.21 per 100 patient-years; adjusted hazard ratio [HR], 0.91; 95% CI, 0.62 to 1.32) or aspirin plus clopidogrel (13.22 vs. 14.24; adjusted HR, 0.95; 95% CI, 0.78 to 1.14; P=0.84). Compared with placebo, apixaban increased TIMI major bleeding in patients taking aspirin (1.48 vs. 0.25; adjusted HR, 6.62; 95% CI, 0.75 to 51.73) and in patients taking aspirin plus clopidogrel (2.58 vs. 1.02; adjusted HR, 2.44; 95% CI, 1.34 to 4.45; P=0.41).
The researchers noted that there were similar results with subgroup and marginal structure model analyses to account for antiplatelet therapy switching during follow-up. They wrote, “These data suggest that use of novel oral anticoagulants with a strategy of concomitant aspirin alone compared with aspirin plus clopidogrel might not improve the safety of these agents.”
An editorial noted that the results further clarify the existing evidence that full-dose anticoagulation, in combination with antiplatelet therapy of any kind in patients with ACS, results in substantial bleeding without any clear additional benefit and should only be considered when required for another condition. The editorial continued, “How to optimize such an antithrombotic regimen, especially in light of the myriad of new options, including 4 approved NOACs [novel oral anticoagulants] and the more potent antiplatelet therapies (prasugrel, ticagrelor, vorapaxar) not included in the previously mentioned studies, is critically important and the subject of ongoing investigation.”