CURE, Clopidogrel, and Aspirin: Good Study, Nice Adjunct, and the Real Deal
Abstract & Commentary
Source: Peters RJ, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: Observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003;108:1682-1687.
The authors studied the benefits and risks of adding clopidogrel to different doses of aspirin in the treatment of patients with acute coronary syndrome (ACS). Patients with ACS who were using daily aspirin of varying doses were randomized to receive clopidogrel or placebo for up to one year. The patients were divided into three groups based on the daily dose of aspirin—up to 100 mg, 101-199 mg, and 200 mg or more. Patients were eligible for inclusion if they had ACS symptoms without ST segment elevation, class IV heart failure, or recent therapeutic cardiac catheterization or coronary artery bypass grafting. The patients needed to have evidence of ischemia other than ST segment elevation, or cardiac enzymes (including troponin) of at least twice the normal level.
Clopidogrel was given as a loading dose of 200 mg orally followed by 75 mg per day for 3-12 months. The dose of the aspirin was left up to the discretion of the local investigator. The outcome measured was the combined incidence of cardiovascular death, myocardial infarction, or stroke. This combined outcome measure was reduced by clopidogrel regardless of aspirin dose, as follows: up to 100 mg, 10.5% vs. 8.6% (relative risk [RR], 0.81 [95% CI, 0.68-0.97]); 101-199 mg, 9.8% vs. 9.5% (RR, 0.97 [95% CI, 0.77-1.22]); and 200 mg or more, 13.6% vs. 9.8% (RR, 0.71 [95% CI, 0.59-0.85]).
The incidence of major bleeding increased with increasing aspirin dose both in the placebo group (1.9%, 2.8%, and 3.7%, respectively; P = 0.0001) and the clopidogrel group (3.0%, 3.4%, and 4.9%, respectively; P = 0.0009); thus, the excess risk with clopidogrel was 1.1%, 1.2%, and 1.2%, respectively. The adjusted hazard ratio for major bleeding for the highest vs. the lowest dose of aspirin was 1.9 (95% CI, 1.29-2.72) in the placebo group, 1.6 (95% CI 1.19-2.23) in the clopidogrel group, and 1.7 (95% CI 1.36-2.20) in the combined group.
In patients with ACS, adding clopidogrel to aspirin is beneficial regardless of aspirin dose. However, bleeding risks increase with increasing aspirin dose, regardless of the clopidogrel. Higher doses of aspirin are no more effective than lower doses in prevention of the combined outcome measure. These findings suggest that with orwithout clopidogrel, the optimal daily dose of aspirin may be between 75 mg and 100 mg. Overall, the greatest improvement in outcome measures was seen at the lowest dose of aspirin and clopidogrel, although the latter had only a fractional effect.
Commentary by Richard J. Hamilton, MD, FAAEM, ABMT
Clopidogrel is an adenosine 5´-diphosphate (ADP) inhibitor and is classified as an antiplatelet agent. Recently, experts and consensus panels have been suggesting its use in the patient suspected of acute coronary syndrome.1 In addition, Clinical Evidence Concise suggests that clopidogrel is likely to be beneficial in unstable angina patients.2 I was interested in this article because I have yet to become completely comfortable with its use in the emergency department (ED). This study provided me with some fairly helpful data to guide safety issues in using clopidogrel and—more importantly—aspirin. I will be using the "baby" dose (81 mg) of aspirin and clopidogrel to maximum benefit for my patients. By the way, Clinical Evidence Concise lists only aspirin as proven to be beneficial. I think everyone in the ED who has any complaint remotely related to ACS should be given a baby aspirin. Aspirin is the horse that pulls the risk reduction cart in ACS—everything else is just helping out.
Dr. Hamilton, Associate Professor of Emergency Medicine, Residency Program Director, Department of Emergency Medicine, Drexel University College of Medicine, Philadelphia, PA, is on the Editorial Board of Emergency Medicine Alert.
References
1. Pollack CV Jr., et al. 2002 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency department practice (special contribution). Ann Emerg Med 2003; 41:355-369.
2. Natarajan M. Angina (unstable). Clinical Evidence Concise, Issue 9. London: BMJ Publishing Group; 2003:8.
The authors studied the benefits and risks of adding clopidogrel to different doses of aspirin in the treatment of patients with acute coronary syndrome.
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