Perspective on COMMIT/CCS-2 Trial of Clopidogrel in STEMI Christopher Cannon, M.D. Brigham and Women’s Hospital Boston, MA

Milestones in the Evolution of Thrombolysis in Myocardial Infarction Mortality 1988 ISIS-2 SK 25% ↓ ASA 23% ↓ 1993 GUSTO-1 TPA 14%↓ 2005 COMMIT/ Clopidogrel7% ↓ CCS-2

Drugs that Failed to Show Mortality Reduction in STEMI in Past Decade Double-bolus t-PA TNK rPA nPA GP IIb/IIIa inhibition +lytic Oral GP IIb/IIIa Bivalirudin Hirudin Pexulizamab Magnesium Adenosine PSGL GIK etc….

ST Elevation MI: Clopidogrel Trials COMMIT/ CCS-2 46,000 Patients Mortality, D/MI/CVA AMI < 24 hrs Age up to 100 ~50% Lytic No loading dose China Non-invasive Strategy 3,500 Patients Infarct Artery Patency AMI < 12 hrs Age < % Fibrinolytic Loading dose Europe / N. Amer. Invasive Strategy

Special Considerations for Clinical Use Bolus vs. no bolus –Benefit on clinical endpoints in both trials emerged in first 24 hrs –CLARITY-TIMI 28: 20% benefit –COMMIT/CCS-2: 9% benefit (~13% in Pts <12 hrs) Elderly: evidence for benefit in COMMIT –In Pts > 75 years : no loading dose –In Pts < 75 years: 300 mg loading dose Worldwide public health benefit (1 month <$100 vs. t-PA $2,200) No excess major bleeding in CABG

Clopidogrel in STEMI Evidence from 2 large trials in ~ 50,000 patients Benefit in opening infarct-related artery, and in reducing mortality and morbidity No excess in major bleeding Low cost A new addition to treatment of STEMI

Clopidogrel Across Spectrum of CAD COMMIT(CCS-2) CAPRIE Lancet 1996 MI /S troke/PAD High-Risk Vascular Disease Up to 3.5 years STEMI Acute STEMI Long-term 2 o (1 o )prevention UA/NSTEMI PCI PCI NSTEMI / UA + Benefit 1 Year + Benefit 1-3 Years 30 Days + Benefit (ongoing)