Prasugrel for Prevention of Early Saphenous Vein Graft Thrombosis

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.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Bypass
• Intervention / Treatment: Drug: Prasugrel; Drug: Placebo

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94121
      • San Francisco VA Medical Center, San Francisco, CA
  • Florida
    • Gainesville, Florida, United States, 32608
      • North Florida/South Georgia Veterans Health System, Gainesville, FL
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Jesse Brown VA Medical Center Community-Based Outpatient Clinic Lake Side Divison, Chicago, IL
  • Texas
    • Dallas, Texas, United States, 75216
      • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Prasugrel; prasugrel 10 mg by mouth daily	Drug: Prasugrel; one 10 mg tablet by mouth daily; Other Names: Effient
Placebo Comparator: Arm 2: Placebo; placebo by mouth once daily	Drug: Placebo; placebo similar in appearance to prasugrel

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Shuaib M. Abdullah, MD, VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2013
• Primary Completion (Actual): April 30, 2018
• Study Completion (Actual): May 31, 2018

Study Registration Dates

• First Submitted: March 16, 2012
• First Submitted That Met QC Criteria: March 20, 2012
• First Posted (Estimate): March 22, 2012

Study Record Updates

• Last Update Posted (Actual): October 30, 2019
• Last Update Submitted That Met QC Criteria: October 17, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: prasugrel; thrombosis; Coronary Artery Bypass
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride
• Other Study ID Numbers: CLIN-007-11F

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No