Coronary Artery Bypass
Conditions
Keywords
Coronary Artery Bypass, thrombosis, prasugrel
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.
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)
Interventions
DRUGPrasugrel
one 10 mg tablet by mouth daily
DRUGPlacebo
placebo similar in appearance to prasugrel
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Prasugrel prasugrel 10 mg by mouth daily
Prasugrel: one 10 mg tablet by mouth daily | 42 |
| Arm 2: Placebo placebo by mouth once daily
Placebo: placebo similar in appearance to prasugrel | 42 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
| Overall Study | Patient Preference | 11 | 11 |
Baseline characteristics
| Characteristic | Arm 2: Placebo | Total | Arm 1: Prasugrel |
|---|---|---|---|
| Age, Continuous | 64 years STANDARD_DEVIATION 6 | 64 years STANDARD_DEVIATION 6 | 65 years STANDARD_DEVIATION 7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 18 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 32 Participants | 63 Participants | 31 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 41 Participants | 82 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 42 | 1 / 42 |
| other Total, other adverse events | 0 / 42 | 0 / 42 |
| serious Total, serious adverse events | 9 / 42 | 4 / 42 |
Outcome results
Primary
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
Time frame: 12 months
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Prasugrel | Prevalence of Intragraft Thrombus at 12-month Follow-up Optical Coherence Tomography Imaging | 14 Participants |
| Arm 2: Placebo | Prevalence of Intragraft Thrombus at 12-month Follow-up Optical Coherence Tomography Imaging | 14 Participants |
p-value: 0.78Fisher Exact
Secondary
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.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Prasugrel | Major Adverse Cardiac Events, Defined as the Composite of Death, Acute Coronary Syndrome, or Coronary Revascularization) During Follow-up | 8 Participants |
| Arm 2: Placebo | Major Adverse Cardiac Events, Defined as the Composite of Death, Acute Coronary Syndrome, or Coronary Revascularization) During Follow-up | 4 Participants |
Secondary
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
Time frame: 12 months
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Prasugrel | Normalized Total Target Saphenous Vein Graft Atheroma Volume, as Assessed by Intravascular Ultrasonography | 0.093 mm3/frame | Standard Deviation 0.045 |
| Arm 2: Placebo | Normalized Total Target Saphenous Vein Graft Atheroma Volume, as Assessed by Intravascular Ultrasonography | 0.079 mm3/frame | Standard Deviation 0.035 |
p-value: 0.97t-test, 2 sided
Secondary
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)
Time frame: 12 months
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Prasugrel | Number of Patients With Angiographic Saphenous Vein Graft Failure | 7 Participants |
| Arm 2: Placebo | Number of Patients With Angiographic Saphenous Vein Graft Failure | 12 Participants |
p-value: 0.19Fisher Exact
Secondary
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.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Prasugrel | Number of Patients With Severe Bleeding Using the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) Criteria | 1 Participants |
| Arm 2: Placebo | Number of Patients With Severe Bleeding Using the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) Criteria | 0 Participants |
p-value: >0.99Log Rank
Secondary
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.
Time frame: 12 months
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Prasugrel | Saphenous Vein Graft Lipid Core Burden Index, as Assessed at Near-infrared Intracoronary Spectroscopy | 7.5 units on a scale | Standard Deviation 9.3 |
| Arm 2: Placebo | Saphenous Vein Graft Lipid Core Burden Index, as Assessed at Near-infrared Intracoronary Spectroscopy | 7.4 units on a scale | Standard Deviation 15.5 |
p-value: 0.97t-test, 2 sided
Secondary
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.
Time frame: 12 months
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Prasugrel | Total Target Saphenous Vein Graft Atheroma Volume, as Assessed by Intravascular Ultrasonography | 349 mm3 | Standard Deviation 189 |
| Arm 2: Placebo | Total Target Saphenous Vein Graft Atheroma Volume, as Assessed by Intravascular Ultrasonography | 358 mm3 | Standard Deviation 175 |
p-value: 0.85t-test, 2 sided