Benefits of double-dose clopidogrel post-ACS unclear
MedWire News: Results from the CURRENT-OASIS 7 study suggest that neither a double-dose of clopidogrel in the first week, nor high-dose aspirin, after acute coronary syndrome (ACS) reduces the risk for cardiovascular (CV) events compared with standard doses of each drug in patients referred for invasive treatment.
However, results from a sub-analysis of the study suggest that the 30-day risk for CV events and stent thrombosis may be reduced among patients undergoing primary coronary intervention (PCI) if double-dose clopidogrel is taken.
The findings published in separate papers in the New England Journal of Medicine and The Lancet, were initially presented at the European Society of Cardiology (ESC) 2009 Congress, and reported by MedWire News at the time.
Shamir Mehta (McMaster University, Hamilton, Ontario, Canada) and colleagues randomly assigned 25,086 ACS patients referred for PCI to receive double-dose (600-mg loading dose on day 1, 150 mg daily on days 2-7, then 75 mg daily until day 30) or standard-dose clopidogrel (300-mg loading dose, then 75 mg daily until day 30).
All patients were also randomly allocated to receive high-dose (300 to 325 mg daily) or standard-dose (75 to 100 mg daily) aspirin in addition to their assigned clopidogrel dose.
The team found no significant difference in the primary endpoint of CV death, myocardial infarction, or stroke at 30 days between patients taking double- and standard-dose clopidogrel, at 4.2% and 4.4%, respectively (hazard ratio [HR]=0.94; 95% confidence interval [CI]: 0.83-1.06).
Major bleeding, however, occurred more frequently among patients taking double-dose compared with those taking standard-dose clopidogrel, at 2.5% versus 2.0%, respectively (HR=1.24, 95% CI: 1.05-1.46; p=0.01).
Similar results were observed for the effects of high-dose aspirin, with the primary endpoint occurring at a rate of 4.2% and 4.4% among the patients taking high-dose and standard-dose aspirin, respectively (HR=0.97; 95% CI: 0.86-1.09). Major bleeding rates were no different, at 2.3% among both those taking high- and low-dose aspirin, but minor bleeding was slightly more frequent in the high-dose group, at a HR of 1.13 (p=0.04).
The sub-analysis of 17,263 patients who underwent PCI showed that double-dose clopidogrel was associated with a lower 30-day rate of stent thrombosis than standard-dose clopidogrel, at 0.7% versus 1.3%, respectively (HR=0.54, 95% CI: 0.39-0.74; p=0.0001).
A slight decrease in the primary CV-event endpoint was also observed among patients taking double-dose clopidogrel compared with those taking a standard clopidogrel dose, at 3.9% and 4.5%, respectively (HR=0.86, 95% CI: 0.74-0.99; p=0.036).
This effect was not seen with high-dose aspirin, however.
In a related editorial in The Lancet, Gregg Stone (Columbia University Medical Center, New York, USA) emphasized the importance of further study looking specifically at the possibility of a detrimental clopidogrel-aspirin interaction that could occur if used together at higher doses in a clinical setting.
In another editorial in the New England Journal of Medicine, Valentin Fuster (Mount Sinai School of Medicine, New York) highlighted discrepancies between the published study findings and the 2009 presentation in which "significantly reduced major CV events" were reported in patients taking double-dose clopidogrel.
"The conclusions reported at the meeting led many cardiologists to adopt the double-dose clopidogrel strategy, thus leading to more clopidogrel being prescribed.
"This outcome underscores the need for simultaneous publication of high-impact clinical trials when they are presented at international meetings," he concluded.
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By Lauretta Ihonor