Elsevier

The Lancet

Volume 376, Issue 9748, 9–15 October 2010, Pages 1233-1243
The Lancet

Articles
Double-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

https://doi.org/10.1016/S0140-6736(10)61088-4Get rights and content

Summary

Background

Clopidogrel and aspirin are the most commonly used antiplatelet therapies for percutaneous coronary intervention (PCI). We assessed the effect of various clopidogrel and aspirin regimens in prevention of major cardiovascular events and stent thrombosis in patients undergoing PCI.

Methods

The CURRENT-OASIS 7 trial was undertaken in 597 centres in 39 countries. 25 086 individuals with acute coronary syndromes and intended early PCI were randomly assigned to double-dose (600 mg on day 1, 150 mg on days 2–7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clopidogrel, and high-dose (300–325 mg daily) versus low-dose (75–100 mg daily) aspirin. Randomisation was done with a 24 h computerised central automated voice response system. The clopidogrel dose comparison was double-blind and the aspirin dose comparison was open label with blinded assessment of outcomes. This prespecified analysis is of the 17 263 individuals who underwent PCI. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Analyses were by intention to treat, adjusted for propensity to undergo PCI. This trial is registered with ClinicalTrials.gov, number NCT00335452.

Findings

8560 patients were assigned to double-dose and 8703 to standard-dose clopidogrel (8558 and 8702 completed 30-day follow-up, respectively), and 8624 to high-dose and 8639 to low-dose aspirin (8622 and 8638 completed 30-day follow-up, respectively). Compared with the standard dose, double-dose clopidogrel reduced the rate of the primary outcome (330 events [3·9%] vs 392 events [4·5%]; adjusted hazard ratio 0·86, 95% CI 0·74–0·99, p=0·039) and definite stent thrombosis (58 [0·7%] vs 111 [1·3%]; 0·54 [0·39–0·74], p=0·0001). High-dose and low-dose aspirin did not differ for the primary outcome (356 [4·1%] vs 366 [4·2%]; 0·98, 0·84–1·13, p=0·76). Major bleeding was more common with double-dose than with standard-dose clopidogrel (139 [1·6%] vs 99 [1·1%]; 1·41, 1·09–1·83, p=0·009) and did not differ between high-dose and low-dose aspirin (128 [1·5%] vs 110 [1·3%]; 1·18, 0·92–1·53, p=0·20).

Interpretation

In patients undergoing PCI for acute coronary syndromes, a 7-day double-dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose. Efficacy and safety did not differ between high-dose and low-dose aspirin. A double-dose clopidogrel regimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended early PCI.

Funding

Sanofi-Aventis and Bristol-Myers Squibb.

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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