Prasugrel for Prevention of Early Saphenous Vein Graft Thrombosis

Aortocoronary saphenous vein graft failure is common and is associated with high morbidity
and mortality. Thrombus formation plays a critical role in early saphenous vein graft
occlusion and may predispose to subsequent atherosclerosis formation. Optical coherence
tomography is a novel, high-resolution, intravascular imaging technique that can reliably
identify thrombus. Based on the findings of earlier VA Cooperative Studies, aspirin
significantly reduces the incidence of early saphenous vein graft failure and is currently
used in nearly all patients undergoing coronary bypass graft surgery. Administration of
clopidogrel for improving early saphenous vein graft patency has 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, and
whether this will result in 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.

Hypothesis: The investigators 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.

This is 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 to determine whether compared to placebo,
administration of prasugrel 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 in the incidence of angiographic SVG failure (defined as 75% SVG diameter
stenosis in at least one SVG); reduction in total and normalized total target saphenous
vein graft atheroma volume, as assessed by intravascular ultrasonography; and reduction
of saphenous vein graft lipid core burden index, as assessed at near-infrared
intracoronary spectroscopy at 12-month follow-up cardiac catheterization (secondary
endpoints)

4. Reduction of major adverse cardiac events, defined as the composite of death, acute
coronary syndrome, or coronary revascularization) during follow-up (secondary endpoints)

Inclusion Criteria:

- Age 18 years or greater

- Willing and able to give informed consent. The patients must be able to comply with
study procedures and follow-up.

- Undergoing clinically-indicated coronary artery bypass graft surgery

Exclusion Criteria:

- Known allergy to aspirin or prasugrel

- Need for concomitant cardiac procedure, such as valve repair or replacement

- Increased risk of bleeding, including need for warfarin or dabigatran administration

- Positive pregnancy test or breast-feeding

- Coexisting conditions that limit life expectancy to less than 12 months or that could
affect a patient's compliance with the protocol

- Serum creatinine > 2.5 mg/dL

- Severe peripheral arterial disease limiting vascular access

- Prior stroke or transient ischemic attack

- Weight <60 kg or age >75 years

- Multiple distal SVG anastomoses

- Postoperative complications prolonging hospitalization