Correspondence Cleveland Clinic, Department of Cardiovascular Medicine, 9500 Euclid Avenue, Desk F25, Cleveland, OH 44195, USA

Email bhattd@ccf.org

Original article

Chen et al.; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group (2005) Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366: 1607–1621   PubMed

Synopsis

Background

Findings have indicated that aspirin and clopidogrel could reduce the occurrence of adverse events in patients with ST-segment elevation myocardial infarction (STEMI); however, the overall effect on mortality and morbidity is not known.

Objectives

To determine whether treatment with aspirin plus clopidogrel reduces mortality and major morbidity when compared with aspirin alone in patients with STEMI.

Design

From August 1999 to February 2005, COMMIT, a randomized, placebo-controlled multicenter trial, studied patients with STEMI in an emergency setting. To be eligible for the trial, patients had to have left bundle branch block, ST-segment elevation or ST-segment depression within 24 h of suspected acute myocardial infarction symptom onset. Exclusion criteria included contraindications to aspirin or clopidogrel and the need for percutaneous coronary intervention.

Intervention

Eligible patients were randomly assigned to treatment with 162 mg aspirin and 75 mg clopidogrel daily, or 162 mg aspirin and placebo daily. Both treatment regimens were continued for 4 weeks, unless the patient had died or had been discharged from hospital, at which point the treatment was stopped. A questionnaire detailing the compliance with study medication, any major adverse events and, if the patient had died, the cause of death, was completed by all patients at 28 days or at hospital discharge, if earlier. All analyses were done on the basis of intention to treat.

Outcome measures

The two joint primary outcomes were all-cause death, and the composite of reinfarction, stroke or death.

Results

Of the 45,852 patients enrolled in COMMIT (mean age 61 years and 28% women), 22,961 received aspirin and clopidogrel therapy and 22,891 received aspirin and placebo. The COMMIT investigators found that the group who received aspirin plus clopidogrel had significantly fewer reinfarctions, strokes and deaths than the group given aspirin and clopidogrel; only 2,212 (9.2%) patients receiving clopidogrel had such an event compared with 2,310 (10.1%) patients receiving placebo (9% proportional risk reduction, 95% CI 3–14%, P = 0.002). Furthermore, all-cause mortality was significantly lower in the aspirin–clopidogrel group than in the aspirin–placebo group; 1,726 (7.5%) patients died in the clopidogrel group compared with 1,845 (8.1%) in the placebo group (7% proportional risk reduction, 95% CI 1–13%, P = 0.03). Although the subgroup analysis was not sufficiently powered, the beneficial effect of clopidogrel on the joint primary outcomes did not differ between patient subgroups. Notably, clopidogrel did not significantly increase the risk of bleeding in the overall treatment period, in patients aged more than 70 years or in those taking fibrinolytic therapy (overall, 134 [0.58%] patients with clopidogrel compared with 125 [0.55%] patients with placebo, P = 0.59).

Conclusion

Clopidogrel should be routinely added to aspirin and standard therapy in patients with STEMI because it can safely and effectively reduce mortality and the occurrence of major adverse vascular events.

Commentary

Outside the US and Western Europe, pharmacologic reperfusion is the mainstay of therapy for STEMI. Second generation fibrinolytics were shown to be superior to first generation lytics, and although subsequent generations have had advantages in terms of convenience of dosing, they have not significantly decreased mortality. Interestingly, intravenous glycoprotein IIb/IIIa inhibitors, which have an important role in the management of non-ST-segment elevation acute coronary syndrome patients, were found to improve TIMI flow when combined with a reduced dose of lytic drugs; however, large, phase III trials found that these inhibitors did not reduce mortality in STEMI patients. Thus, to date, the preferred chemical reperfusion strategy consists of aspirin, unfractionated heparin or low-molecular-weight heparin, and a fibrinolytic agent.¹

With the publication of COMMIT, we witness a major advance in pharmacologic reperfusion therapy. In this trial, the 7% relative risk reduction in all-cause mortality in patients treated with clopidogrel compared with those who were not is considerable, especially as this reduction in mortality was incremental to other standard therapies. The mechanistic data describing how clopidogrel might work in this setting was provided by the CLARITY trial, which demonstrated a significant improvement in arterial patency, with the addition of clopidogrel to aspirin, anticoagulation and lysis.² The superior efficacy shown by angiographic results from the CLARITY trial has now been extended to a benefit in mortality with the COMMIT findings.

Notably, starting on the first day of COMMIT, an early increase in the benefit of clopidogrel was seen. Moreover, the sooner treatment was started after symptom onset the greater the benefit of clopidogrel. This pattern is particularly surprising considering that a loading dose was not employed. Studies that used a loading dose of clopidogrel showed a consistent early reduction in ischemic events. Loading doses of 300 mg have been most widely studied, but there are data to suggest that 600 mg is more effective at suppressing platelet aggregation.

Importantly, elderly patients were enrolled in COMMIT and aspirin plus clopidogrel did not appear to increase the risk of intracranial hemorrhage. Even in patients older than 75 years of age who were receiving a lytic agent, addition of clopidogrel did not significantly increase bleeding rates (Z Chen, personal communication). When considering the safety data, it should be noted again that patients did not receive a loading dose of clopidogrel; the safety of a 300 mg loading dose (or higher) in combination with a lytic agent in patients over 75 years of age has not yet been tested and cannot currently be recommended.

Questions remain regarding the optimum duration of clopidogrel therapy after presentation with STEMI. While not strictly evidence-based, it is logical to extrapolate from the CURE study findings of patients with non-ST-segment elevation acute coronary syndromes and continue dual antiplatelet therapy with aspirin and clopidogrel for at least 1 year.³ Whether therapy should be continued beyond 1 year in patients with established cardiovascular disease is being investigated in the CHARISMA trial.⁴ The validation of ADP-receptor blockade as a therapeutic target has spawned a number of clinical trials evaluating compounds such as prasugrel, AZD6140 and cangrelor.⁵ The relative efficacy and bleeding hazard of these compounds will need to be carefully evaluated, but they hold potential for further advances in pharmacologic reperfusion for STEMI. At present, in the absence of major bleeding contraindications, adding clopidogrel to aspirin and other reperfusion therapies should be considered the standard of care for patients with STEMI.

Acknowledgments

The synopsis was written by Hannah Camm, Associate Editor, Nature Clinical Practice.

References

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Subject areas under which this article appears: Acute coronary syndromes | Therapy | Thrombosis