Although the efficacy of clopidogrel plus aspirin for treating acute coronary syndromes (ACS) is well established, considerable uncertainty remains about dosing. Investigators for the manufacturer-sponsored CURRENT–OASIS 7 trial employed a 2x2 factorial design to examine the effects of doubling the standard loading dose and first-week maintenance dose of clopidogrel (from 300 to 600 mg and from 75 to 150 mg, respectively), and compared the effects of high-dose (300–325 mg/day) versus low–dose (75–100 mg/day) aspirin. All 25,086 patients (mean age, 61; 27% women) had ACS and were scheduled for coronary angiography with percutaneous coronary intervention (PCI) as indicated within 72 hours after randomization, and all received a loading aspirin dose of >300 mg. The primary 30-day outcome was a composite of cardiovascular death, myocardial infarction (MI), and stroke. The study had 80% power to detect a 16% reduction in risk.

In the clopidogrel comparison, the rate of the primary outcome was similar in the double-dose and standard-dose groups (4.2% and 4.4%, respectively; hazard ratio, 0.94; 95% confidence interval, 0.83–1.06). Major bleeding, as determined by increased red-cell transfusion, was more common in the double-dose group (2.5% vs. 2.0%; HR, 1.24; 95% CI, 1.05–1.46; P=0.01). In the aspirin comparison, the rates of the primary outcome in both groups were the same as in the clopidogrel comparison, but the between-group bleeding rates were also similar.

In a prespecified analysis involving the 17,263 participants who underwent PCI (95% received a stent), a primary endpoint occurred in 3.9% of the double-dose clopidogrel group compared with 4.5% of the standard-dose clopidogrel group (HR, 0.86; 95% CI, 0.74–0.99; P=0.04); the difference was mostly attributable to the difference in MI rate. The stent thrombosis rate was significantly lower in the double-dose group than in the standard-dose group (1.6% vs. 2.3%; HR, 0.68; 95% CI, 0.55–0.85). The rate of major bleeding was higher in the double-dose group (1.6% vs. 1.1%; HR, 1.41; 95% CI, 1.09–1.83).

Comment: This study failed to show a benefit of high-dose clopidogrel or high-dose aspirin in patients with ACS who were expected to undergo cardiac catheterization. However, benefits were found in those who did undergo PCI, albeit at the cost of an increase in major bleeding. These findings were significant, although they were not adjusted for multiple comparisons. The comparison in the PCI recipients, as an expanded subgroup analysis, cannot bear the same weight as the full trial in the body of evidence. Interpretation of the aspirin results is problematic because the effect of the loading dose lasts for a week or more, and many patients on the higher dose also received a proton-pump inhibitor. The best antiplatelet regimen for PCI, therefore, remains uncertain.

— Harlan M. Krumholz, MD, SM

Published in Journal Watch Cardiology September 1, 2010