Dose comparisons of clopidogrel and aspirin in acute coronary syndromes
Insights
Double-dose clopidogrel (a P2Y12 inhibitor) did not significantly reduce major adverse cardiovascular events compared to standard-dose. However, higher-dose aspirin did not show significant differences versus lower-dose aspirin.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Clopidogrel and aspirin are standard treatments for acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI).
- Evidence-based dosing guidelines for these agents in ACS patients are lacking.
- Optimal antiplatelet therapy strategies require further investigation.
Purpose of the Study:
- To evaluate the efficacy and safety of double-dose versus standard-dose clopidogrel in ACS patients undergoing invasive procedures.
- To compare the effectiveness of higher-dose versus lower-dose aspirin in the same patient population.
- To determine the optimal antiplatelet regimen for preventing cardiovascular events post-ACS.
Main Methods:
- A 2x2 factorial randomized trial involving 25,086 ACS patients referred for an invasive strategy.
- Patients were assigned to double-dose (600mg loading, 150mg x 6 days, then 75mg) or standard-dose clopidogrel (300mg loading, then 75mg).
- Patients also received either higher-dose (300-325mg daily) or lower-dose (75-100mg daily) aspirin. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke at 30 days.
Main Results:
- No significant difference in the primary outcome between double-dose and standard-dose clopidogrel (4.2% vs. 4.4%, P=0.30).
- Major bleeding was higher with double-dose clopidogrel (2.5% vs. 2.0%, P=0.01).
- No significant difference in the primary outcome or major bleeding between higher-dose and lower-dose aspirin groups.
Conclusions:
- A 7-day double-dose clopidogrel regimen provided no significant benefit over standard-dose for the primary outcome in ACS patients.
- Higher-dose aspirin showed no advantage over lower-dose aspirin in reducing cardiovascular events or bleeding.
- The study did not establish evidence-based guidelines for clopidogrel or aspirin dosing in this high-risk population.
Background:
Clopidogrel and aspirin are widely used for patients with acute coronary syndromes and those undergoing percutaneous coronary intervention (PCI). However, evidence-based guidelines for dosing have not been established for either agent.
Methods:
We randomly assigned, in a 2-by-2 factorial design, 25,086 patients with an acute coronary syndrome who were referred for an invasive strategy 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 cardiovascular death, myocardial infarction, or stroke at 30 days.
Results:
The primary outcome occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (hazard ratio, 0.94; 95% confidence interval [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 (hazard ratio, 1.24; 95% CI, 1.05 to 1.46; P=0.01). Double-dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis among the 17,263 patients who underwent PCI (1.6% vs. 2.3%; hazard ratio, 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%; hazard ratio, 0.97; 95% CI, 0.86 to 1.09; P=0.61) or major bleeding (2.3% vs. 2.3%; hazard ratio, 0.99; 95% CI, 0.84 to 1.17; P=0.90).
Conclusions:
In patients with an acute coronary syndrome who were referred for an invasive strategy, 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. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00335452.)
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