Abstract & Commentary
Comment by Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams is on the Editorial Board of Clinical Cardiology Alert.
Synopsis: In patients 75 years of age or younger who have myocardial infarction with ST-segment elevation and who receive aspirin and a standard fibrinolytic regimen, the addition of clopidogrel improves the patency rate of the infarct-related artery and reduces ischemic complications.
Source: Sabatine MS, et al. Addition of Clopidogrel to Aspirin and Fibrinolytic Therapy for Myocardial Infarction with ST-Segment Elevation. N Engl J Med. 2005 (online edition).
In the Clopidogrel as Adjunctive Perfusion Therapy trial, 3500 STEMI patients in 23 countries given fibrinolytic therapy, ASA and heparin, were randomized to clopidrogrel (C) 300 mg or placebo (P), then 75mg daily or placebo. The primary end point was TIMI 0-1 flow on coronary angiography at day 2-8, death, or MI at time of angiogram.
Results: C decreased TIMI 0-1 flow, death, or recurrent MI by 36%, P = 0.000003 (22% P; 15% C), with infarct related artery patency the major achieved end point. At 30 days, there was a 20% decrease in CV death, MI, and need for revascularization, P = 0.03 (P 14%; C 11.6%). No increase in serious bleeding was observed.
The randomized, placebo-controlled trial of adding clopidogrel to aspirin in 46,000 acute MI patients, was a 5-year study of Clopidogrel (C) 75 mg vs placebo (P) in acute ST elevation MI, given within 24 hours in 1250 centers in China. Thrombolytic therapy was given in 50%; 70% within 12 hours. There was also an IV metoprolol arm (2 x 2 factorial design).
Results: The primary end point of death, recurrent MI, or stroke at 28 days was reduced by 9% (10.1% P vs 9.3% C; P = 0.002). Mortality decreased by 7% (P =.03), recurrent MI by 13% (P = 0.02), and stroke by 14% (NS). Again, there was no increase in major bleeding.
These 2 trials, involving almost 50,000 subjects with acute STEMI, convincingly establishes early clopidogrel therapy as being effective in improving infarct patency and decreasing adverse clinical events, when given early after acute STEMI. Two major issues include the dose differential between the studies, and the absence of primary or direct angioplasty in either study. Most to all acute MI subjects undergoing direct angioplasty receive clopidogrel at the time of intervention, thus, the results of CLARITY and COMMIT/CCS2 suggest that a benefit should also accrue to all primary angioplasty patients. Bleeding risk, however, while acceptable in these 2 trials, would be expected to increase with early clopidogrel in acute, with early intervention. Nevertheless, there is now compelling evidence to include dual anti-platelet therapy early after presentation with acute STEMI. The best initial dosage is also unclear. Does a 300mg loading dose provide better outcomes than starting at 75mg/dL?