ArticlesDouble-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial
Introduction
Percutaneous coronary intervention (PCI) is an important advance in the treatment of patients with acute coronary syndromes with or without ST-segment elevation.1, 2, 3 Despite the benefits of PCI in reduction of major cardiovascular events, the risk of thrombotic complications remains an important concern.4, 5, 6, 7 Aspirin, in combination with clopidogrel—a thienopyridine adenosine diphosphate receptor antagonist—prevents major thrombotic events in patients undergoing PCI8, 9, 10 and has been the standard of care for more than a decade.11, 12, 13, 14, 15 However, with increased early use of PCI in patients presenting with acute coronary syndromes,11, 12, 13, 14, 15, 16 attention has focused on development of antiplatelet regimens that have a rapid onset of action and that achieve high levels of platelet inhibition. Findings from several studies suggest that doubling of the clopidogrel loading dose (from 300 mg to 600 mg) and maintenance dose (from 75 mg to 150 mg daily) results in a faster onset of action and greater inhibition of platelet aggregation than lower doses can achieve.17, 18, 19, 20, 21, 22, 23, 24 This more intense dose regimen could further protect against ischaemic events and stent thrombosis in patients with acute coronary syndromes.25
Observational studies have suggested that high-dose aspirin (≥300 mg daily) does not confer a reduced risk of ischaemic events compared with low-dose aspirin (75–100 mg daily), and might be associated with an increased risk of major bleeding.26, 27 However, the dose of aspirin varies greatly worldwide.26 In North America, high doses of aspirin (≥300 mg) are commonly used and recommended (particularly after PCI),11 whereas in Europe, lower doses (≤100 mg) are favoured.13 This variation in practice is partly due to the fact that no large randomised comparisons of aspirin dose have been done in acute coronary syndromes and PCI since its routine use three decades ago.
The CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Symptoms) trial assessed whether doubling of the loading and maintenance dose of clopidogrel for 7 days was better than the standard dose, and whether high-dose aspirin was better than low-dose aspirin in patients undergoing PCI.28 The objective of this prespecified subgroup analysis of the CURRENT-OASIS 7 trial was to assess the efficacy and safety outcomes in patients who received the intended PCI procedure.
Section snippets
Study design and patients
The CURRENT-OASIS 7 trial was a 2×2 factorial trial undertaken between June, 2006, and July, 2009, at 597 centers in 39 countries in North America, South America, Europe, Asia, South Africa, Australia, and New Zealand. The study design and overall results of the clopidogrel and aspirin dose comparisons have been previously reported.28, 29
Patients were eligible for inclusion in the trial if they had symptoms compatible with acute coronary syndromes (with or without ST-segment elevation) and
Results
25 086 patients with acute coronary syndromes (with or without ST-segment elevation) were enrolled and randomly assigned treatment in the CURRENT-OASIS 7 trial, of whom 24 835 underwent coronary angiography and 17 263 received PCI (figure 1). Median time from randomisation to PCI was 0·5 h (IQR 0·3–1·0) in those with STEMI and 3·2 h (0·9–19·6) in those with non-ST-segment elevation acute coronary syndromes. Baseline characteristics were well matched between the randomised groups (table 1).
Discussion
Results from this prespecified subanalysis of the CURRENT-OASIS 7 trial show that a 7-day double-dose regimen of clopidogrel was more effective than was the standard-dose regimen in prevention of the primary outcome of cardiovascular death, myocardial infarction, or stroke, and stent thrombosis for patients who underwent PCI. High-dose aspirin did not differ significantly from low-dose aspirin in prevention of these outcomes. Double-dose clopidogrel increased the risk of major bleeding, but the
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Committees listed at end of paper and investigators listed in webappendix