Early aortocoronary saphenous vein bypass graft (SVG) failure is common and is associated with high morbidity and mortality. Aspirin significantly reduces the incidence of early saphenous vein graft failure, whereas clopidogrel use provided conflicting results in small randomized studies. Prasugrel is a novel thienopyridine that provides more rapid, consistent, and intense platelet inhibition than clopidogrel. However, in patients who undergo coronary artery bypass graft surgery, it remains unknown whether prasugrel may decrease thrombus formation in saphenous vein grafts during the first postoperative year, leading to less saphenous vein graft wall thickening, less lipid deposition in the saphenous vein graft wall and fewer clinical events without increasing the risk for severe bleeding. We hypothesize that in patients undergoing clinically-indicated coronary artery bypass graft surgery, administration of prasugrel starting at dismissal from the index coronary bypass graft surgery hospitalization will result in lower prevalence of thrombus formation in a target SVG, as assessed by optical coherence tomography performed 12 months post surgery compared to placebo, with similar incidence of major bleeding. We propose a phase III, single-center, double-blind trial that will randomize 120 patients undergoing clinically-indicated coronary artery bypass graft surgery to prasugrel at a dose of 10 mg daily or matching placebo for 12 months, starting at the time of hospital dismissal from surgery. All patients will receive aspirin. Coronary angiography, optical coherence tomography, intravascular ultrasonography, and near-infrared spectroscopy of one target saphenous vein graft will be performed at 12 months. The specific objectives of the proposed study are to determine whether compared to placebo, prasugrel administration will result in: (1) reduction of the prevalence of intragraft thrombus at 12-month follow-up optical coherence tomography imaging (primary efficacy endpoint); (2) similar incidence of severe bleeding using the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria (primary safety endpoint); (3) reduction of total and normalized total target saphenous vein graft atheroma volume and reduction of saphenous vein graft lipid core burden index as assessed by near-infrared intracoronary spectroscopy at 12-month follow-up saphenous vein graft imaging (secondary endpoints); and (4) reduction of major adverse cardiac events, defined as the composite of death, acute coronary syndrome, or coronary revascularization) during follow-up (secondary endpoints). PUBLIC HEALTH RELEVANCE: The Potential Impact on Veterans Health Care is the identification of a novel therapy (prasugrel) that could prevent the early failure of saphenous vein bypass grafts in our veteran patients with coronary artery disease.