Boston, MA - Platelet activation and aggregation play a key role in initiating and propagating coronary-artery thrombosis. Clopidogrel is an adenosine diphosphate-receptor antagonist that inhibits the activation and aggregation of platelets. A substantial proportion of patients receiving fibrinolytic therapy for myocardial infarction with ST-segment elevation have inadequate reperfusion or reocclusion of the infarct-related artery. Marc Sabatine, M.D., M.P.H. et al, from Harvard Medical School published a study in the March 8, 2005 issue of the New England Journal of Medicine demonstrating the benefit of adding clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. The study indicates the addition of clopidogrel improves the patency rate of the infarct-related artery and reduces ischemic complications.  

The study enrolled 3491 patients, ages 18 to 75, who presented within 12 hours after the onset of an ST-elevation myocardial infarction and randomly assigned them to receive clopidogrel or placebo. Patients taking clopidogrel started with a 300 mg loading dose followed by 75 mg once daily dose. All patients received a fibrinolytic agent, aspirin and, when necessary, heparin. Patients underwent angiography 48 to 192 hours after the start of the study medication. Patients were assessed for patency of the infarct-related artery and were followed for clinical end points. The primary efficacy end point was the composite of an occluded infarct-related artery, defined by a Thrombolysis in Myocardial Infarction (TIMI) flow grade of 0 or 1, on angiography. Death before the angiography or recurrent myocardial infarction before angiography were also primary efficacy end points. The primary safety end point was the rate of major bleeding by the end of the calendar day after angiography.  

The results of the study indicated the rates of primary efficacy end point as 21.7 percent in the placebo group and 15.0 percent in the clopidogrel group, that is a 36 % reduction in the odds of the end point with clopidogrel therapy (95 percent confidence interval, 24 to 47 percent; p<0.001). Clopidogrel has the greatest effect on the rate of an occluded infarct-related artery with a 41 percent reduction in the odds (p< 0.001). There was a 30% reduction in the rate of recurrent myocardial infarction (p= 0.08), but there was no significant effect on the rate of death from any cause (2.2 percent in the placebo group vs. 2.6 percent in the clopidogrel group, P=0.49). By 30 days, clopidogrel therapy reduced the odds of the composite end point of death from cardiovascular causes, recurrent myocardial infarction or recurrent ischemia leading to the need for urgent revascularization by 20 percent (from 14.1 to 11.6, p=0.03).  

This study demonstrates the benefit of adding clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. Arterial thrombi are composed of platelets and are resistant to fibrinolysis to induce reocclusion. Despite the actions of aspirin, platelet activation can still occur through thromboxane A₂-independent pathway, leading to platelet aggregation. Clopidogrel is an anti-platelet agent with synergistic effects with aspirin and fibrinolytic agents. Thus, in patients 75 years of age or younger who have myocardial infarction with ST-segment elevation and who receive fibrinolytic therapy, aspirin or heparin, clopidogrel is an effective, simple, inexpensive means of improving patency of the infarct-related artery and reducing the rate of ischemic complications.  

Co-authors: Christopher P. Cannon, M.D., C. Michael Gibson, M.D., Jose L. Lopez-Sendon, M.D., Gilles Montalescot, M.D., Pierre Theroux, M.D., Marc J. Claeys, M.D., Ph.D., Frank Cools, M.D., Karen A. Hill B.A., Allan M. Skene, Ph.D., Carolyn H. McCabe, B.S., and Eugene Braunwald, M.D.