Comparison of Double Dose of Clopidogrel with Standard Dose in Patients with Acute Coronary Syndromes

Although clopidogrel and aspirin are commonly used agents for patients with cardiovascular disease, uncertainty about the optimal dose for each agent has resulted in wide geographic variations in practice patterns for patients with acute coronary syndromes, as well as for those undergoing percutaneous coronary intervention (PCI). Studies have established that compared with the standard dose used in early trials, doubling the loading and maintenance doses of clopidogrel results in greater, more rapid, and more uniform platelet inhibition, leading to improved clinical outcomes. Although indirect comparisons in trials evaluating varying doses of aspirin versus placebo have shown reductions in vascular events, observational analyses have suggested a dose-dependent increase in the risk of bleeding association with aspirin. The CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes) trial was designed to address 2 issues: (1) whether a doubling of the loading and initial maintenance doses of clopidogrel is superior to the standard dose regimen, and (2) whether higher-dose aspirin (300-325 mg daily) is superior to lower-dose aspirin (75-100 mg daily) in patients with acute coronary syndromes referred for an early invasive strategy. Results were reported in the New England Journal of Medicine [2010;363(10):930-942]. The international randomized trial was conducted between June 2006 and July 2009. The primary outcome was time to cardiovascular death, myocardial infarction, or stroke, whichever occurred first, up to day 30. Secondary outcomes included the composite of death from cardiovascular causes, myocardial infarction, stroke, or recurrent ischemia; the individual components of the primary outcome; and death from any cause. The trial included 25,086 patients with an acute coronary syndrome who had been referred for an invasive surgery. In the first component, the participants were randomly assigned, in a 2-by-2 factorial design to either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter). In the second component, patients were randomly assigned in an open-label fashion to either higher- or lower-dose aspirin. Of the 25,086 patients, 24,835 had coronary angiography and 17,263 had PCI. Of the 7823 patients who did not have PCI, 45.0% (n=3520) had no clinically significant coronary artery disease, 23.8% (n=1859) underwent coronary artery bypass grafting, and 31.2% (n=2444) were not candidates for any type of revascularization. The primary outcome occurred in 4.2% (n=522) of patients in the double-dose clopidogrel group at 30 days, compared with 4.4% (n=557) in the standard dose group (hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.83-1.06; P=.30). Major bleeding occurred in 2.5% (n=313) of patients in the double-dose clopidogrel group, compared with 2.0% (n=255) in the standard dose group (HR, 1.24; 95% CI, 1.05-1.46; P=.01). In the subgroup of patients who underwent PCI (n=17,623), double-dose clopidogrel was associated with a significant reduction in the rate of stent thrombosis (1.6% vs 2.3%; HR, 0.68; 95% CI, 0.55-0.85; P=.001). There was no significant difference between higher-and lower-dose aspirin in terms of the primary outcome or major bleeding. Of the patients in the higher-dose aspirin group, 4.2% (n=530) had a primary outcome event at 30 days, compared with 4.4% (n=549) of patients in the lower-dose group (HR, 0.97; 95% CI, 0.86-1.09; P=.61). As defined by the study criteria, major bleeding occurred in 2.3% (n=282) of the patients in the higher-dose group and 2.3% (n=286) in the lower-dose group (HR, 0.99; 95% CI, 0.84-1.17; P=.90). In conclusion, the researchers said that “in patients with an acute coronary syndrome who were referred for an invasive surgery, there was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, myocardial infarction, or stroke.”