Elsevier

The Lancet

Volume 366, Issue 9497, 5–11 November 2005, Pages 1607-1621
The Lancet

Fast track — Articles
Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(05)67660-XGet rights and content

Summary

Background

Despite improvements in the emergency treatment of myocardial infarction (MI), early mortality and morbidity remain high. The antiplatelet agent clopidogrel adds to the benefit of aspirin in acute coronary syndromes without ST-segment elevation, but its effects in patients with ST-elevation MI were unclear.

Methods

45 852 patients admitted to 1250 hospitals within 24 h of suspected acute MI onset were randomly allocated clopidogrel 75 mg daily (n=22 961) or matching placebo (n=22 891) in addition to aspirin 162 mg daily. 93% had ST-segment elevation or bundle branch block, and 7% had ST-segment depression. Treatment was to continue until discharge or up to 4 weeks in hospital (mean 15 days in survivors) and 93% of patients completed it. The two prespecified co-primary outcomes were: (1) the composite of death, reinfarction, or stroke; and (2) death from any cause during the scheduled treatment period. Comparisons were by intention to treat, and used the log-rank method. This trial is registered with ClinicalTrials.gov, number NCT00222573.

Findings

Allocation to clopidogrel produced a highly significant 9% (95% CI 3–14) proportional reduction in death, reinfarction, or stroke (2121 [9·2%] clopidogrel vs 2310 [10·1%] placebo; p=0·002), corresponding to nine (SE 3) fewer events per 1000 patients treated for about 2 weeks. There was also a significant 7% (1–13) proportional reduction in any death (1726 [7·5%] vs 1845 [8·1%]; p=0·03). These effects on death, reinfarction, and stroke seemed consistent across a wide range of patients and independent of other treatments being used. Considering all fatal, transfused, or cerebral bleeds together, no significant excess risk was noted with clopidogrel, either overall (134 [0·58%] vs 125 [0·55%]; p=0·59), or in patients aged older than 70 years or in those given fibrinolytic therapy.

Interpretation

In a wide range of patients with acute MI, adding clopidogrel 75 mg daily to aspirin and other standard treatments (such as fibrinolytic therapy) safely reduces mortality and major vascular events in hospital, and should be considered routinely.

Introduction

About 10 million people have heart attacks every year worldwide and the incidence of myocardial infarction (MI) is rising in many developing countries.1 Although considerable improvements have been made in the emergency treatment of acute MI, appreciable risks of early mortality and morbidity remain, especially in populations with limited health resources. If simple and widely practicable treatments for acute MI can be shown reliably to produce even moderate improvements in outcome, then the worldwide benefits could be substantial.

Platelet activation and aggregation, which can be mediated by thromboxane or by ADP, play a key part in initiating and propagating coronary thrombosis, and are raised during MI (particularly after fibrinolytic therapy). Aspirin started soon after acute MI and continued for a few weeks has been shown to reduce 1 month mortality by about a quarter and the risks of non-fatal reinfarction and stroke by about half.2 Platelet aggregation is only inhibited in part by aspirin, which acts mainly by blocking the thromboxane-mediated aggregation pathway. Clopidogrel (like its predecessor ticlopidine) acts mainly by inhibiting the ADP-mediated aggregation pathway,3, 4 and has also been shown to be effective at preventing ischaemic events in patients with symptomatic atherothrombotic disease.5 Simultaneous inhibition of both of these pathways with the combination of clopidogrel (or ticlopidine) and aspirin should produce greater antiplatelet effects than either agent alone.6, 7

Compared with aspirin alone, results of randomised trials have shown that clopidogrel plus aspirin reduces the risk of ischaemic events in patients undergoing percutaneous coronary intervention (PCI), and in those with non-ST-elevation acute coronary syndromes.8, 9 More recently, the findings of a randomised trial of about 3500 patients with ST-elevation MI showed that adding clopidogrel to aspirin improved the patency of the infarct-related coronary artery after fibrinolytic therapy, and suggested some reduction in clinical events.10 But substantial uncertainty remained regarding the net effects on mortality and major morbidity of adding clopidogrel to aspirin in this setting. The aim of this study was to address these issues.

Section snippets

Methods

COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial; also Second Chinese Cardiac Study [CCS-2]) is a randomised placebo-controlled trial of the emergency treatment of patients with suspected acute MI. It used a 2×2 factorial design to allow separate assessment of the efficacy and safety of adding oral clopidogrel to aspirin and of using intravenous then oral metoprolol. Details of the study objectives, design, and methods have been reported previously,11 and are summarised below.

Results

45 852 patients with suspected acute MI were randomised from 1250 hospitals in China to receive aspirin 162 mg daily plus either clopidogrel 75 mg daily (n=22 961) or matching placebo (n=22 891) for up to 28 days in hospital. Follow-up to first hospital discharge or day 28 was available for all but two patients (figure 1). The qualifying MI was confirmed by the local investigators in 95·8% (n=22 002 clopidogrel and n=21 946 placebo) of randomised patients, with a further 1·8% (410 and 404)

Discussion

The findings of this large randomised trial show that addition of clopidogrel to aspirin reduces mortality and major morbidity in a wide range of patients with suspected acute MI, and these benefits seem to be largely independent of, and hence additional to, those of other standard treatments (such as fibrinolytic and anticoagulant therapy). The findings also show that such treatment is safe, with no apparent increase in life-threatening bleeds even when given with fibrinolytic therapy, or to

References (21)

There are more references available in the full text version of this article.

Cited by (1785)

  • The Role of Personalized Medicine in Companion Animal Cardiology

    2023, Veterinary Clinics of North America - Small Animal Practice
View all citing articles on Scopus

Collaborators and participating hospitals listed at end of paper

View full text