A double-blind, randomized trial of clopidogrel 300 mg loading dose and aspirin 325 mg followed by clopidogrel 75 mg and aspirin daily compared with placebo loading dose followed by clopidogrel 75 mg and aspirin daily for the prevention of vascular events and all-cause mortality in patients undergoing percutaneous coronary intervention.

Study Sponsor: Sanofi Recherché and Bristol-Myers Squibb
Principle Investigator: Tony Chou, M.D.
Co-Investigators: Thomas Ports, M.D., Andrew Michaels, M.D., Fady Malik, M.D., Morgan Lin, M.D.
Study Coordinator: Alisa Gaskin, R.N., M.S., C.C.R.N.

Purpose:
To evaluate the effect of study treatment on the composite of death (all-cause), MI or urgent target vessel revascularization at Day 28. All randomized subjects will be followed for 12 months to determine the efficacy of prolonged (12-month) combination therapy of clopidogrel 75 mg plus ASA daily versus placebo (after day 28) plus ASA daily. Also, the safety of short term (28 day) versus long term administration of clopidogrel will be compared.

Mechanism of Action of Clopidogrel:
Clopidogrel is a new thienopyridine derivative, chemically related to ticlopidine, yet shown in animal studies to be more effective at inhibiting platelet formation. Clopidogrel prevents arterial as well as venous thrombosis and reduces atherogenesis in several animal species. Clopidogrel blocks activation of platelets by adenosine diphosphate (ADP) by selectively and irreversibly inhibiting the binding of this agonist to its platelet receptor, thereby affecting ADP-dependent activation of the GP IIb-IIIa complex, the major receptor for fibrinogen present on the platelet surface. In clinical pharmacology studies, clopidogrel 75 mg once daily produces inhibition of ADP-induced platelet aggregation equivalent to that of ticlopidine 250 mg twice daily.

Clinical Trials:
Clinical pharmacology studies have confirmed the inhibition of ADP-induced aggregation and confirmed clopidogrel's antithrombotic activity using an ex vivo model of thrombosis. Clopidogrel has been compared against ASA in one large trial. CAPRIE (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events) was a randomized, blind, active-controlled trial designed to assess the efficacy of clopidogrel and ASA in the reduction of ischemic stroke, myocardial infarction, or vascular death. Nineteen-thousand one-hundred and eighty-five patients were studied. It was found that long-term administration of clopidogrel to patients with atherosclerotic vascular disease was significantly more effective than ASA in reducing the combined risk of these end-points.

Most Common Side Effects:
GI upset (27.1%), macular/papular rash (4.9%), diarrhea (4.5%), neutropenia (<1.0%), low risk of serious GI (2.0%) or intracerebral hemorrhage (<1.0%), bruising (0.04%), pruritis (0.02%).

Population:
Patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention.

Treatment Procedures:
Loading dose of clopidogrel (300 mg) given 6-24 hours pre-procedure, then 75 mg QD plus ASA versus Placebo loading dose, then clopidogrel 75 mg given for 28 days plus ASA, then placebo plus ASA given for 11 months.

Who to Contact: If you have any questions, feel free to contact
Andrew D. Michaels (UCSF Co-Director of the Cath Lab; 415-514-2104)