Optimal doses for aspirin and clopidogrel

Despite the ubiquitous use of aspirin and clopidogrel in acute coronary syndromes for over a decade there remains a lack of consensus over optimal dosing strategies and a paucity of modern data to guide clinicians in this most pertinent of issues. As compared with the standard dose of clopidogrel used in early trials, more recent exploratory studies have shown that doubling the loading and maintenance doses of clopidogrel may lead to greater, more rapid, and more uniform platelet inhibition, which may further improve clinical outcomes. Similarly, uncertainty regarding the optimal dose of aspirin has resulted in wide geographic variations in practice with the European ESC guidelines recommending low doses of aspirin (≤100 mg daily) after PCI whereas the American AHA/ACC guidelines recommend 162 to 325 mg daily.

To attempt to resolve these issues, the CURRENT–OASIS 7 trial recruited 25 086 patients between 2006 and 2009, presenting with either a non-ST or ST elevation acute coronary syndrome and were scheduled to undergo PCI no later than 72 h after randomisation. In a 2-by-2 factorial design, patients were assigned 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) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke at 30 days. Secondary outcomes included probable or definite stent thrombosis and the main safety outcome was major bleeding.

The primary outcome occurred in 4.2% of patients on double-dose clopidogrel compared with 4.4% assigned to the standard-dose (HR, 0.94; 95% CI, 0.83 to 1.06; P=0.30). Major bleeding occurred in 2.5% of patients in the double-dose group and in 2.0% in the standard-dose group (HR, 1.24; 95% CI, 1.05 to 1.46; P=0.01). Double-dose clopidogrel was however associated with a significant reduction in the secondary outcome of stent thrombosis (1.6% vs 2.3%; HR, 0.68; 95% CI, 0.55 to 0.85; P=0.001). There was no significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome (4.2% vs 4.4%; HR, 0.97; 95% CI, 0.86 to 1.09; P=0.61) or major bleeding (2.3% vs 2.3%; HR, 0.99; 95% CI, 0.84 to 1.17; P=0.90).

Conclusions

While an initial loading dose of 600 mg of clopidogrel is likely to remain a part of standard clinical practice, CURRENT–OASIS 7 fails to support a place for a higher maintenance dose of 150 mg daily of clopidogrel and demonstrates a significant increase in bleeding with this regime. This study also demonstrates that there is no benefit from high maintenance doses of aspirin and provides support for European practice guidelines.

▶ Mehta SR, Bassand JP, Chrolavicius S, et al; CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med2010;363:930–42.

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