Prasugrel for Prevention of Early Saphenous Vein Graft Thrombosis

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT01560780
• Collaborator: (none)
• Enrollment: 84
• Locations: 4
• Arms: 2
• Actual Duration (Months): 63.9
• Patients Per Site: 21
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Bypass	Drug: Prasugrel; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 84 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Prasugrel for Prevention of Early Saphenous Vein Graft Thrombosis
• Actual Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Apr 30, 2018
• Actual Study Completion Date: May 31, 2018

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Prevalence of Intragraft Thrombus at 12-month Follow-up Optical Coherence Tomography Imaging [12 months]

   Number of patients with intragraft thrombus seen at 12 month follow-up by optical coherence tomography in imaged saphenous vein graft

Secondary Outcome Measures

1. Number of Patients With Severe Bleeding Using the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) Criteria [12 months]

   Number of patients with major bleeding defined by the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries criteria.

2. Number of Patients With Angiographic Saphenous Vein Graft Failure [12 months]

   Number of patients with angiographic saphenous vein graft failure (defined as =75% SVG diameter stenosis in at least one saphenous vein graft)

3. Total Target Saphenous Vein Graft Atheroma Volume, as Assessed by Intravascular Ultrasonography [12 months]

   Total target saphenous vein graft atheroma volume (mm3) as assessed by Intravascular ultrasound imaging in imaged saphenous vein grafts.

4. Saphenous Vein Graft Lipid Core Burden Index, as Assessed at Near-infrared Intracoronary Spectroscopy [12 months]

   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.

5. Major Adverse Cardiac Events, Defined as the Composite of Death, Acute Coronary Syndrome, or Coronary Revascularization) During Follow-up [12 months]

   Number of patients with the composite outcome of death, acute coronary syndrome, or coronary revascularization.

6. Normalized Total Target Saphenous Vein Graft Atheroma Volume, as Assessed by Intravascular Ultrasonography [12 months]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	San Francisco VA Medical Center, San Francisco, CA	San Francisco	California	United States	94121
2	North Florida/South Georgia Veterans Health System, Gainesville, FL	Gainesville	Florida	United States	32608
3	Jesse Brown VA Medical Center Community-Based Outpatient Clinic Lake Side Divison, Chicago, IL	Chicago	Illinois	United States	60611
4	VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX	Dallas	Texas	United States	75216

Sponsors and Collaborators

• 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 Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 12, 2012

More Information

Publications

None provided.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT01560780
• Other Study ID Numbers: CLIN-007-11F
• First Posted: Mar 22, 2012
• Last Update Posted: Oct 30, 2019
• Last Verified: Oct 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Keywords provided by VA Office of Research and Development: Coronary Artery Bypass; thrombosis; prasugrel
• Additional relevant MeSH terms: Thrombosis; Prasugrel Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Arm 1: Prasugrel	Arm 2: Placebo
Arm/Group Description	prasugrel 10 mg by mouth daily Prasugrel: one 10 mg tablet by mouth daily	placebo by mouth once daily Placebo: placebo similar in appearance to prasugrel
Period Title: Overall Study
STARTED	42	42
Clinical Follow-Up at 12 Months	42	42
Completed Study Drug for 12 Months	27	27
COMPLETED	29	30
NOT COMPLETED	13	12

Baseline Characteristics

Arm/Group Title	Arm 1: Prasugrel	Arm 2: Placebo	Total
Arm/Group Description	prasugrel 10 mg by mouth daily Prasugrel: one 10 mg tablet by mouth daily	placebo by mouth once daily Placebo: placebo similar in appearance to prasugrel	Total of all reporting groups
Overall Participants	42	42	84
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65 (7)	64 (6)	64 (6)
Sex: Female, Male (Count of Participants)
Female	1 2.4%	1 2.4%	2 2.4%
Male	41 97.6%	41 97.6%	82 97.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 2.4%	1 1.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	10 23.8%	8 19%	18 21.4%
White	31 73.8%	32 76.2%	63 75%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 2.4%	1 2.4%	2 2.4%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

In the prasugrel arm, 29 of the 42 patients underwent SVG angiography at 12 months (2 died, 11 did not want to undergo SVG angiography). Of these, 25 had interpretable OCT. In the placebo arm, 30 of the 42 patients underwent SVG angiography at 12 months (1 died, 11 did not wish to undergo SVG angiography). Of these, 28 had interpretable OCT.

Arm/Group Title	Arm 1: Prasugrel	Arm 2: Placebo
Arm/Group Description	prasugrel 10 mg by mouth daily Prasugrel: one 10 mg tablet by mouth daily	placebo by mouth once daily Placebo: placebo similar in appearance to prasugrel
Measure Participants	25	28
Count of Participants [Participants]	14 33.3%	14 33.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Prasugrel, Arm 2: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Number of Patients With Severe Bleeding Using the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) Criteria
Description	Number of patients with major bleeding defined by the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries criteria.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Prasugrel	Arm 2: Placebo
Arm/Group Description	prasugrel 10 mg by mouth daily Prasugrel: one 10 mg tablet by mouth daily	placebo by mouth once daily Placebo: placebo similar in appearance to prasugrel
Measure Participants	42	42
Count of Participants [Participants]	1 2.4%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Prasugrel, Arm 2: Placebo
	Comments
	Type of Statistical Test	Equivalence
	Comments	safety end-point with p-value of <0.05
Statistical Test of Hypothesis	p-Value	>0.99
	Comments
	Method	Log Rank
	Comments

3. Secondary Outcome

Title	Number of Patients With Angiographic Saphenous Vein Graft Failure
Description	Number of patients with angiographic saphenous vein graft failure (defined as =75% SVG diameter stenosis in at least one saphenous vein graft)
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

In the prasugrel arm, 29 of the 42 patients underwent SVG angiography at 12 months (2 died, 11 did not want to undergo SVG angiography). In the placebo arm, 30 of the 42 patients underwent SVG angiography at 12 months (1 died, 11 did not wish to undergo SVG angiography).

Arm/Group Title	Arm 1: Prasugrel	Arm 2: Placebo
Arm/Group Description	prasugrel 10 mg by mouth daily Prasugrel: one 10 mg tablet by mouth daily	placebo by mouth once daily Placebo: placebo similar in appearance to prasugrel
Measure Participants	29	30
Count of Participants [Participants]	7 16.7%	12 28.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Prasugrel, Arm 2: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	Fisher Exact
	Comments

4. Secondary Outcome

Title	Total Target Saphenous Vein Graft Atheroma Volume, as Assessed by Intravascular Ultrasonography
Description	Total target saphenous vein graft atheroma volume (mm3) as assessed by Intravascular ultrasound imaging in imaged saphenous vein grafts.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

In the prasugrel arm, 29 of the 42 patients underwent SVG angiography at 12 months (2 died, 11 did not want to undergo SVG angiography). Of these, 25 had interpretable IVUS. In the placebo arm, 30 of the 42 patients underwent SVG angiography at 12 months (1 died, 11 did not wish to undergo SVG angiography). Of these, 27 had interpretable IVUS.

Arm/Group Title	Arm 1: Prasugrel	Arm 2: Placebo
Arm/Group Description	prasugrel 10 mg by mouth daily Prasugrel: one 10 mg tablet by mouth daily	placebo by mouth once daily Placebo: placebo similar in appearance to prasugrel
Measure Participants	25	27
Mean (Standard Deviation) [mm3]	349 (189)	358 (175)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Prasugrel, Arm 2: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.85
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Saphenous Vein Graft Lipid Core Burden Index, as Assessed at Near-infrared Intracoronary Spectroscopy
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

In the prasugrel arm, 29 of the 42 patients underwent SVG angiography at 12 months (2 died, 11 did not want to undergo SVG angiography). Of these, 12 had interpretable NIRS. In the placebo arm, 30 of the 42 patients underwent SVG angiography at 12 months (1 died, 11 did not wish to undergo SVG angiography). Of these, 20 had interpretable NIRS.

Arm/Group Title	Arm 1: Prasugrel	Arm 2: Placebo
Arm/Group Description	prasugrel 10 mg by mouth daily Prasugrel: one 10 mg tablet by mouth daily	placebo by mouth once daily Placebo: placebo similar in appearance to prasugrel
Measure Participants	13	20
Mean (Standard Deviation) [units on a scale]	7.5 (9.3)	7.4 (15.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Prasugrel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Major Adverse Cardiac Events, Defined as the Composite of Death, Acute Coronary Syndrome, or Coronary Revascularization) During Follow-up
Description	Number of patients with the composite outcome of death, acute coronary syndrome, or coronary revascularization.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Prasugrel	Arm 2: Placebo
Arm/Group Description	prasugrel 10 mg by mouth daily Prasugrel: one 10 mg tablet by mouth daily	placebo by mouth once daily Placebo: placebo similar in appearance to prasugrel
Measure Participants	42	42
Count of Participants [Participants]	8 19%	4 9.5%

7. Secondary Outcome

Title	Normalized Total Target Saphenous Vein Graft Atheroma Volume, as Assessed by Intravascular Ultrasonography
Description	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
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

In the prasugrel arm, 29 of the 42 patients underwent SVG angiography at 12 months (2 died, 11 did not want to undergo SVG angiography). Of these, 25 had interpretable IVUS. In the placebo arm, 30 of the 42 patients underwent SVG angiography at 12 months (1 died, 11 did not wish to undergo SVG angiography). Of these, 27 had interpretable IVUS.

Arm/Group Title	Arm 1: Prasugrel	Arm 2: Placebo
Arm/Group Description	prasugrel 10 mg by mouth daily Prasugrel: one 10 mg tablet by mouth daily	placebo by mouth once daily Placebo: placebo similar in appearance to prasugrel
Measure Participants	25	27
Mean (Standard Deviation) [mm3/frame]	0.093 (0.045)	0.079 (0.035)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Prasugrel, Arm 2: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	12 months
Arm/Group Title	Arm 1: Prasugrel		Arm 2: Placebo
Arm/Group Description	prasugrel 10 mg by mouth daily Prasugrel: one 10 mg tablet by mouth daily		placebo by mouth once daily Placebo: placebo similar in appearance to prasugrel
All Cause Mortality
	Arm 1: Prasugrel		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/42 (4.8%)		1/42 (2.4%)
Serious Adverse Events
	Arm 1: Prasugrel		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/42 (21.4%)		4/42 (9.5%)
Blood and lymphatic system disorders
Severe GUSTO bleeding	1/42 (2.4%)		0/42 (0%)
Cardiac disorders
Acute coronary syndrome	2/42 (4.8%)		2/42 (4.8%)
Percutaneous Coronary Intervention	6/42 (14.3%)		2/42 (4.8%)
General disorders
Death	2/42 (4.8%)		1/42 (2.4%)
Other (Not Including Serious) Adverse Events
	Arm 1: Prasugrel		Arm 2: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/42 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.