Prasugrel for Prevention of Early Saphenous Vein Graft Thrombosis

Study Overview
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Brief Summary
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This is a randomized-controlled clinical 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. The primary goal of the study is to determine whether prasugrel administration will prevent thrombus (clot) formation within a saphenous vein graft at 12 months, as examined by optical coherence tomography.

Detailed Description
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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: Reduction of the prevalence of intragraft thrombus at 12-month follow-up optical coherence tomography imaging (primary efficacy endpoint) Similar incidence of severe bleeding using the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria (primary safety endpoint) 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) Reduction of major adverse cardiac events, defined as the composite of death, acute coronary syndrome, or coronary revascularization) during follow-up (secondary endpoints)

Official Title
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Prasugrel for Prevention of Early Saphenous Vein Graft Thrombosis

Conditions
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Coronary Artery Bypass

Intervention / Treatment
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* Drug: Prasugrel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Prasugrel<br>prasugrel 10 mg by mouth daily | Drug: Prasugrel<br>* one 10 mg tablet by mouth daily<br>* Other names: Effient;|
| Placebo Comparator: Arm 2: Placebo<br>placebo by mouth once daily | Drug: Placebo<br>* placebo similar in appearance to prasugrel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of Intragraft Thrombus at 12-month Follow-up Optical Coherence Tomography Imaging | Number of patients with intragraft thrombus seen at 12 month follow-up by optical coherence tomography in imaged saphenous vein graft | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Severe Bleeding Using the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) Criteria | Number of patients with major bleeding defined by the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries criteria. | 12 months | 
| Number of Patients With Angiographic Saphenous Vein Graft Failure | Number of patients with angiographic saphenous vein graft failure (defined as =75% SVG diameter stenosis in at least one saphenous vein graft) | 12 months | 
| Total Target Saphenous Vein Graft Atheroma Volume, as Assessed by Intravascular Ultrasonography | Total target saphenous vein graft atheroma volume (mm3) as assessed by Intravascular ultrasound imaging in imaged saphenous vein grafts. | 12 months | 
| Saphenous Vein Graft Lipid Core Burden Index, as Assessed at Near-infrared Intracoronary Spectroscopy | Lipid core burden as measured by Lipid Core Burden Index on near infrared intracoronary spectroscopy imaging of saphenous vein graft. Lipid Core Burden Index is defined as the fraction of pixels within the scanned region with a probability >0.60 that a lipid core plaque is present (calculated by an algorithm developed to identify the NIRS signals associated with the molecular structure of lipids), multiplied by 1000 using EchoPlaque software (INDEC Medical Systems; Los Altos, CA) . Thus, the lipid core burden index (LCBI) is a quantitative summary metric of the probability of the presence of lipid within the scanned region, with a range of 0-1000, with higher indices indicating a higher proportion of pixels with a >0.6 probability of lipid being present in the pullback of the catheter along the length of the entire vessel. | 12 months | 
| Major Adverse Cardiac Events, Defined as the Composite of Death, Acute Coronary Syndrome, or Coronary Revascularization) During Follow-up | Number of patients with the composite outcome of death, acute coronary syndrome, or coronary revascularization. | 12 months | 
| Normalized Total Target Saphenous Vein Graft Atheroma Volume, as Assessed by Intravascular Ultrasonography | On IVUS images, atheroma volume was defined as the sum of the cross-sectional areas between the leading edges of the lumen and external elastic membrane. Total Target SVG atheroma volume was calculated as: ∑(EEM area - Lumen area). Normalized atheroma volume represents the atheroma volume corrected for pullback length, and this parameter was calculated as: ∑(EEM area - Lumen area)/number of frames in pullback | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary Artery Bypass, thrombosis, prasugrel