Clinical trial NCT01560780
Conditions: Coronary Artery Bypass
Keywords: Coronary Artery Bypass thrombosis prasugrel
Sponsor: VA Office of Research and Development
Start date: 2013-02-01; Completion date: 2018-05-31
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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)

Arms: arm 1: prasugrel 10 mg by mouth daily arm 2: placebo by mouth once daily
Interventions: intervention 1: Prasugrel intervention 2: Placebo
Intervention descriptions: intervention 1: one 10 mg tablet by mouth daily intervention 2: placebo similar in appearance to prasugrel

Protocol documents:
Prot_SAP_000.pdf: 
Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 1 of 16 
 
        
 
 
 
                         
INVESTIGATOR’S ABBREVIATED PROTOCOL 
1. TITLE:  Prasugrel for prevention of early saphenous vein graft thrombosis 
 
2. PRINCIPAL INVESTIGATOR: Emmanouil Brilakis, MD, PhD 
CO-INVESTIGATOR:  Subhash Banerjee, MD 
KEY MEMBERS: Bavana V. Rangan  
 
 
 
 
         Wanda Frey 
          
 
 
         K. Michelle Harper 
 
 
 
 
         Raul E. Ramirez  
         Michele Roesle 
 
 
 
 
        Ameka Catchings 
 
 
 
 
        Aristotelis Papayannis 
 
 
 
 
        Tesfaldet Michael 
 
 
3. SPONSOR OF THE STUDY: VA Merit, VA OR&D 
 
4.  IND/ IDE:  Not Applicable 
  
5. PURPOSE OF THE STUDY, INCLUDING HYPOTHESIS TO BE TESTED: 
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. 
We 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. 
 
 
 
 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 2 of 16 
 
        
 
 
 
                         
Figure 1. Impact of early SVG failure on subsequent 
clinical outcomes in the PREVENT IV trial. Patients with 
early SVG failure had significantly higher risk driven 
mainly by significant increase in the need for repeat 
coronary revascularization (D=death, MI=myocardial 
infarction, Revasc=coronary revascularization) 
Figure 2.  Saphenous vein graft (SVG) and internal 
mammary artery (IMA) patency rates after CABG in VA 
Cooperative Studies #207/297/364.  
6. BACKGROUND AND RESULTS OF PREVIOUS RELATED RESEARCH: 
 
Saphenous vein graft failure 
Coronary artery disease (CAD) is the leading cause of 
morbidity and mortality in the US population and is 
highly prevalent among veterans. Obstructive CAD 
often requires coronary revascularization, which can be 
achieved either with percutaneous coronary 
intervention (PCI) or with coronary artery bypass graft 
surgery (CABG). In spite of a decline in surgical 
volume over time,1 CABG is still one of the most 
frequently performed surgical procedures: during 2006, 
444,000 (14.9 per 10,000 population) CABG 
operations were performed in nonfederal USA 
hospitals that participated in the National Hospital 
Discharge Survey.2  
 
First used by Rene Favaloro in 1968, saphenous vein 
bypass grafts (SVGs) continue to be used in almost all 
CABG operations today for several reasons: first, 
because of their relatively large diameter and wall 
characteristics, they are technically easy to use; second, 
they are plentiful, and therefore can be used to perform 
multiple grafts; third, they are long and can reach 
any coronary artery; and fourth, they are easily 
harvested.3 However, SVG have high rates of both 
early and late failure. 
 
Early SVG failure occurred in 46% of 1929 patients 
in the Project of Ex-vivo Vein Graft Engineering via 
Transfection IV (PREVENT IV) trial4 and in 29-
37% of 2203 patients included in the Randomized 
On/Off Bypass (ROOBY) Study.5 In the PREVENT 
IV trial, the composite of death, myocardial 
infarction, or coronary revascularization occurred 
more frequently among patients who developed 
early SVG failure compared with those who did not 
[adjusted hazard ratio (HR) 1.79, 95% confidence 
intervals (CI) 1.40-2.28; P<0.001) (Figure 1).6 
 
Early SVG failure may also predispose to late (>1 
year) SVG failure, which occurred in 39% of SVGs 
at 10-years in three VA Cooperative Studies 
(#207/297/364) (Figure 2)7 and in 50% of SVGs at 
≥15 years in another study of 1,388 patients.8 As 
treatment of occluded9  or severely stenosed10 
SVGs is challenging and costly, prevention of early 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 3 of 16 
 
        
 
 
 
                         
Figure 4. Identification of intraluminal thrombus formation in SVGs 
immediately after harvesting using optical coherence tomography 
(panel A) or by direct visualization (panel B).
SVG failure is critically important.  
 
Mechanisms leading to saphenous vein graft failure 
SVG failure is the result of 3 consecutive and inter-related processes: thrombosis, intimal hyperplasia, 
and atherosclerosis (Figure 3).11, 12  Immediately post CABG thrombus forms in SVGs due to 
endothelial disruption during harvesting and implantation. If the SVGs remain patent during this 
period, they develop a platelet-mediated progressive thickening of the vessel wall, which involves 
smooth muscle cell proliferation and extracellular matrix protein synthesis. Atherosclerosis 
subsequently develops on the ground of intimal hyperplasia, leading to decreased antegrade flow or 
eventually SVG occlusion.  
Figure 3. Evolution of saphenous vein graft lesion development. After coronary artery bypass SVGs either 
occlude early or develop intimal thickening (panel 1), which forms the ground for moderate lesion development 
(panel 2). Moderate SVG lesions have high rates of progression to severe, symptom-causing lesions (panel 3), 
and eventually occlusion (panel 4). 
SVG harvesting during CABG can cause 
significant injury, both at the time of removal 
from the leg and during SVG flushing to 
prepare the conduit for grafting.13 SVG wall 
injury may predispose to intraluminal platelet 
thrombus formation, which was observed in 
68% of SVGs examined by OCT immediately 
post harvesting (Figure 4).13 Several factors 
may affect the severity of SVG injury, such as 
the mode of harvesting (endoscopic vs. open), 
manual high-pressure intraluminal distension, 
and the presence of baseline SVG disease. Lack 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 4 of 16 
 
        
 
 
 
                         
of heparinization during SVG harvesting was associated with a trend for higher SVG occlusion rates 
one week post CABG, highlighting the risk for early SVG thrombosis.14 
 
Several other factors are associated with decreased SVG patency, such as multiple distal SVG 
anastomoses15 and off-pump surgery,5 that is why SVGs with multiple anastomosis will be excluded 
from the present study; nearly all coronary bypass graft surgeries are performed on-pump at our 
institution. 
 
Platelet thrombus formation is critical for promoting subsequent SVG neointima hyperplasia 
formation.16 Administration of antiplatelet agents, such as clopidogrel has been shown to decrease 
intimal proliferation in animal models.17, 18 
 
SVG atherosclerosis forms on the ground of intimal hyperplasia, likely due to a combination of lipid 
accumulation and thrombus formation.19 SVG atherosclerosis is usually diffuse, concentric, and friable 
with a poorly developed or absent fibrous cap and little evidence of calcification, whereas native 
vessel atheroma is proximal, focal, eccentric, and nonfriable with a well-developed fibrous cap and 
frequent calcification.11  Histologically, SVG atheromas tend to have more foam cells and 
inflammatory cells, including multinucleate giant cells, than native coronary atheromas.11  SVGs have 
a more powerful system of lipid biosynthesis and uptake, that may in part account for the accelerated 
formation of SVG atherosclerosis and forms the basis of using aggressive lipid lowering therapies to 
prevent SVG failure.11 
 
In summary thrombus formation occurs frequently during the early period post implantation and plays 
a critical role both in early SVG occlusion and in the formation of intimal hyperplasia and subsequent 
SVG atherosclerosis. Therefore, strategies that can decrease early SVG thrombus formation could be 
beneficial in preventing SVG atherosclerosis development and SVG failure.  
 
 
Current therapies for SVG failure prevention  
At present, the only treatments proven to prevent SVG failure are aspirin and lipid-lowering agents, 
mainly statins.11, 20  
 
Aspirin significantly reduces the rates of graft occlusion and clinical complications after CABG.21 In a 
meta-analysis from the Antiplatelet Trialists' Collaboration, low-dose aspirin was associated with 
improved graft patency, as assessed by coronary angiography, at one year after surgery.21 The pooled 
odds reduction for SVG closure was 41 percent (8 percent absolute risk reduction) with low-dose 
aspirin (75 to 325 mg/day) compared to placebo or control therapy. The benefit was similar to that 
seen with higher and more gastrotoxic doses of aspirin. Aspirin should be started either preoperative or 
within 6 hours from CABG22 and continued indefinitely. 
 
Lipid lowering therapy can significantly reduce atherosclerosis risk in a variety of high and low-risk 
populations.  Four trials have specifically examined the role of lipid-lowering therapy in SVGs: (1) the 
Post-Coronary Artery Bypass Graft (POST-CABG)23, 24 trial evaluated lovastatin and if needed, 
cholestyramine; (2) the Lopid Coronary Angiography Trial (LOCAT)25 evaluated gemfibrozil; (3) the 
Cholesterol Lowering Atherosclerotic Study (CLAS)26 evaluated colestipol and niacin; and (4) the 
study by Makuuchi et al evaluated pravastatin vs placebo.27  The first 3 trials showed reduction in the 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 5 of 16 
 
        
 
 
 
                         
angiographic progression of SVG disease. The POST-CABG and the CLAS trials also demonstrated a 
reduction in clinical events. 
 
Although administration of aspirin and statins is the current standard of care for preventing early SVG 
failure, 29-46% of patients experience SVG failure during the first year post CABG.4, 5 Therefore, 
additional therapies are needed to further decrease the SVG failure risk of those patients. 
 
 
Investigative therapies for early SVG failure prevention 
Several therapies are currently being evaluated to prevent early SVG failure. Those therapies address 
different stages of the SVG disease process, starting at the time of CABG surgery and continuing 
through the initial year post implantation.  
 
Intraoperative treatments that are under investigation include: (a) bathing of SVGs before 
implantation in short oligomers of L-arginine that can cross the membrane of the endothelial cells 
comprising the vessel wall and are cleaved inside the endothelial cells to provide an effective 
intracellular source of monomeric L-arginine. The delivery of L-arginine results in increased nitric 
oxide release leading to reduced intimal hyperplasia (NCT00264706 and NCT01313533); (b) bathing 
of SVGs in peptides or small molecules, such as novel anti-c-myc antisense drug (AVI-5126, 
NCT00451256). However the results of the PREVENT IV trial that evaluated pre-implantation 
bathing of SVGs in edifoligide (e2F decoy) did not show any benefit at 12-18 month follow-up 
angiography4; (c) endoscopic saphenous vein harvesting to minimize vessel trauma (NCT01121341); 
(d) intra-operative imaging of SVGs (with fluorescence angiography in the GRIIP trial 
(NCT00187421) or with standard angiography in a hybrid catheterization laboratory/operating room28) 
with immediate surgical or percutaneous treatment of suboptimal grafts (12% of total grafts in one 
study28); (e) use of SVG sheaths (such as the eSVS mesh, NCT00777777) that may minimize intimal 
hyperplasia by providing external SVG support; and (f) use of the “no touch” SVG harvesting 
technique, that aims to minimize SVG trauma (Improving the Results of Heart Bypass Surgery Using 
New Approaches to Surgery and Medication – SUPERIOR SVG - NCT01047449). 
 
Treatments for the first year after CABG that are currently under evaluation include (a) P2Y12 
inhibitors such as ticagrelor (NCT01373411), (b) fish oil (as part of the SUPERIOR SVG trial); and 
(c) monthly infusion of a recombinant human monoclonal antibody against P-selectin during the first 8 
months post CABG (NCT01245634). Another study (NCT00481806) is attempting to evaluate the role 
of thrombin in angiographic SVG occlusion during the first year post CABG. 
 
In summary there are multiple clinical trials evaluating different options for optimizing early SVG 
patency, highlighting the large clinical need for improvements in this area, that has not changed for 
several years.3  
 
 
Thienopyridine administration for early SVG failure prevention 
Five studies evaluating thienopyrifines for the prevention of early SVG failure have been published to 
date with conflicting results (Table 1).  
Limet et al randomized 173 patients to ticlopidine vs. placebo and performed graft angiography at 3 
time points (10, 180, and 360 days).29 Graft patency was higher in the ticlopidine group at all time 
points. 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 6 of 16 
 
        
 
 
 
                         
 
Two Chinese studies have been published (the first author is Gao in both studies): 
 
Gao et al randomized 197 patients to aspirin + clopidogrel vs. aspirin alone. Using computed 
tomography they reported similar 1 and 12-month SVG patency rate (98.1% and 98.2% at 1 month 
and 93.5% and 96.3% at 12 months for aspirin and the combination, respectively, p=non-significant).30 
 
Gao et al randomized 249-patients to aspirin + clopidogrel vs. aspirin alone. Using computed 
tomography they reported higher 3-month SVG patency rate in patients receiving clopidogrel (91.6% 
vs. 85.7%, p=0.043).31  
 
In contrast, the Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) trial randomized 
113 patients to aspirin + clopidogrel vs. aspirin + placebo for 1 year. Follow-up angiography and 
IVUS evaluation showed no difference in 12-month SVG patency (95% in both groups, p=1.0) or in 
SVG intimal area hyperplasia (4.5±2.1 mm2 vs. 4.1±2.0 mm2, p=0.44).12  
 
Finally, the Preoperative Aspirin and Postoperative Antiplatelets in Coronary Artery Bypass Grafting 
(PAPA-CABG) study randomized 100 patients undergoing CABG to placebo or clopidogrel for 30 
days. Patients subsequently underwent computed tomography for bypass graft patency evaluation.32 
Overall, similar proportion of patients in the placebo and clopidogrel group had at least one SVG 
occlusion (23.1% vs. 17.5%, p=0.54), but radial artery occlusion occurred less frequently in the 
clopidogrel group (43.8% vs. 10.5%, p=0.05). Although more potent antiplatelet therapy could 
increase the risk of bleeding, no significant difference in bleeding was observed in the above studies, 
yet these studies were underpowered to detect such differences. 
 
Table 1. Studies assessing the effect of thienopyridine administration post CABG on bypass graft 
patency. 
Study 
Thienopyridine 
N 
Time of 
assessment 
Primary endpoint 
Findings 
Limet et al29 
ticlopidine 
173 
10, 180, and 
360 days 
Graft patency, as 
assessed by coronary 
angiography 
Higher graft patency 
in the ticlopidine 
group at day 10 
(84.4% vs. 66.7%, p 
< 0.05), day 180 
(74.4% vs. 52.3%, p 
< 0.05) and day 360 
(75.0% vs. 52.5%, p 
< 0.05). 
 
Gao et al30 
clopidogrel 
197 
1 and 12 
months 
SVG patency, as 
assessed by 
computed 
tomography 
 
Similar SVG patency 
in both study groups. 
Gao et al31 
clopidogrel 
249 
3 months 
SVG patency, as 
assessed by 
computed 
tomography 
Higher SVG patency 
in clopidogrel group: 
91.6% vs. 85.7%, 
p=0.043 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 7 of 16 
 
        
 
 
 
                         
 
CASCADE12 
clopidogrel 
113 
12 months 
SVG intimal area at 
follow-up IVUS 
4.5±2.1 mm2 in 
placebo vs. 4.1±2.0 
mm2 in clopidogrel, 
p=0.44 
 
PAPA CABG33 
clopidogrel 
100 
30 days 
SVG occlusion, as 
assessed by 
computed 
tomography 
23.1% in placebo vs. 
17.5% in clopidogrel 
groups had ≥1 
occluded graft 
(p=0.54). Radial 
graft occlusion was 
lower in the 
clopidogrel arm 
(43.8% vs. 10.5%, 
p=0.05). 
 
 
 
In addition to the above studies an analysis of the Clopidogrel in Unstable angina to prevent Recurrent 
ischemic Events (CURE) trial, showed that patients who underwent CABG had a trend for lower 
incidence of the primary endpoint (composite of cardiovascular death, myocardial infarction, or 
stroke) at 12 months [14.5% for clopidogrel 16.2% for placebo; relative risk (RR), 0.89; 95% CI, 0.71 
to 1.11].32  
 
In summary 2 of the 5 published trials demonstrated benefit with thienopyridine on bypass graft 
patency and 3 did not. There are multiple possible explanations for these conflicting results. One 
explanation is that SVG thrombus is not important for maintaining early SVG patency, however this 
would contradict studies showing association of baseline SVG thrombus with subsequent SVG 
failure.14 A second possible explanation is that clopidogrel does not provide adequate platelet 
inhibition to successfully prevent SVG thrombus formation. Several studies have demonstrated 
variable antiplatelet response to clopidogrel depending on genetic factors and concomitant medication 
administration.34 A third possible explanation is that the surrogate endpoint used in the CASCADE 
trial (intimal hyperplasia) may not be the best surrogate endpoint, and surrogate endpoints that directly 
assess SVG thrombus (such as OCT) may be more accurate. 
 
7. Definition of the Population to Which the Study is Directed, with Justification: 
 Study subjects will be recruited from the group of patients who are referred for 
coronary artery bypass graft surgery the Dallas VA Medical Center. The study we 
propose is significant because: (a) it would affect many veterans, (b) the consequences of 
early SVG failure are grave, (c) treatment of severe/total SVGs lesions is challenging, 
and (d) outcomes after treatment of severe/total SVG lesions are poor. 
 
(a) CABG is one of the most commonly performed operations with nearly a half 
million operations performed annually in the US.2 Early SVG graft failure is 
common with 29%-46% of patients undergoing CABG developing failure of at 
least one SVG during the first postoperative year.4, 5 
 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 8 of 16 
 
        
 
 
 
                         
(b) Early SVG failure is associated with significantly higher rates of death, 
myocardial infarction, or coronary revascularization.6 
 
(c) Treatment options for severe SVG lesions or SVG occlusion are limited. 
Although percutaneous coronary intervention is currently the preferred treatment 
for severe SVG lesions,50 it is limited by high-rates of peri-procedural myocardial 
infarction (approximately 10%, even when embolic protection devices are used51) 
and by high rates of in-stent restenosis, requiring repeat procedures,52 which may 
be reduced by drug-eluting stent implantation.10 Repeat CABG is technically 
difficult, has higher mortality compared to initial CABG, and provides less 
symptomatic improvement.8 Percutaneous coronary intervention of a native 
coronary artery instead of the diseased SVG is an option, but outcomes were 
similar to SVG interventions in a series of 142 patients from our institution.53 We 
recently proposed retrograde percutaneous coronary intervention of native 
coronary artery chronic total occlusions to treat acutely thrombosed SVGs, 
however this approach is  technically demanding and its long term outcomes are 
unknown.54 
 
(d) Clinical outcomes after SVG interventions are poor,53 especially if SVGs are 
occluded at presentation. We recently reviewed the outcomes of 34 consecutive 
patients undergoing percutaneous intervention for acute SVG occlusion at our 
institution and found 86% procedural success compared to 99% success in native 
coronary artery lesions.9 At 1 and 3 years, mortality was 8% and 42%, an acute 
coronary syndrome occurred in 15% and 41%, and repeat coronary 
revascularization was required in 28% and 38%, respectively.9 Approximately 
half of the deaths were cardiac, and the remainder were non-cardiac (cancer, 
infection, stroke), which is likely explained by their advanced age and multiple 
comorbidities.  
 
In summary, early SVG failure is common and carries significant morbidity and 
mortality. If prasugrel can prevent early SVG failure, it could significantly improve the 
quality and duration of life of patients undergoing CABG, reduce the need for repeat 
revascularization procedures, and potentially reduce their healthcare costs. 
 
 
8. SUBJECT SELECTION, INCLUSION AND EXCLUSION CRITERIA:  
Patients undergoing clinically-indicated CABG will be identified by a study investigator 
or coordinator and will be screened for eligibility for the study using the following 
criteria: 
 
Inclusion criteria: 
1. Age 18 years or greater 
2. Willing and able to give informed consent. The patients must be able to comply 
with study procedures and follow-up. 
3. Undergoing clinically-indicated coronary artery bypass graft surgery 
 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 9 of 16 
 
        
 
 
 
                         
Exclusion criteria: 
1. Known allergy to aspirin or prasugrel 
2. Need for concomitant cardiac procedure, such as valve repair or replacement 
3. Increased risk of bleeding [need for warfarin or oral Xa inhibitor or thrombin 
inhibitor administration, recent (within 30 days) major bleed, known bleeding 
diathesis or coagulation disorder] 
4. Positive pregnancy test or breast-feeding 
5. Coexisting conditions that limit life expectancy to less than 12 months or that 
could affect a patient's compliance with the protocol 
6. Serum creatinine > 2.5 mg/dL 
7. Severe peripheral arterial disease limiting vascular access 
8. Prior stroke or transient ischemic attack 
9. Weight <60 kg or age >75 years 
10. Multiple distal SVG anastomoses 
11. Postoperative complications prolonging hospitalization (including, but not limited 
to bleeding, prolonged intubation, infection, deep venous thrombosis or 
pulmonary embolism) 
 
9. NUMBER OF SUBJECTS IN THE STUDY: 
Approximately 120 patients will be randomized into this study at the Dallas VA Medical 
Center.  
 
10. JUSTIFICATION FOR THE USE OF SPECIAL SUBJECT POPULATIONS: 
Not applicable. 
 
11. STUDY DESIGN:  
The primary efficacy objective is to compare the prevalence of SVG thrombus as 
detected by optical coherence tomography of a target SVG between patients receiving 
prasugrel vs. placebo.  We hypothesize that prasugrel will be superior to placebo in 
reducing the prevalence of SVG thrombus at 12-month follow-up OCT imaging.  
The primary safety endpoint is the incidence of severe bleeding as defined using 
the GUSTO study criteria.67 We hypothesize that patients receiving prasugrel will have 
similar incidence of severe bleeding compared to patients receiving placebo during the 
12-month study period. 
 
The secondary endpoints will be: (1) incidence of angiographic SVG failure 
(defined as ≥75% SVG diameter stenosis in at least one SVG); the total and normalized 
total SVG atheroma volume within at least 40 mm of the target SVG, as assessed by 
intravascular ultrasonography; the lipid core burden index of the target SVG, as assessed 
by near-infrared intracoronary spectroscopy; and (2) the incidence of major adverse 
cardiac events and moderate bleeding during the 12-month study period.   


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 10 of 16 
 
        
 
 
 
                         
The proposed study is a phase 3, single-center, randomized, double-blind, 
controlled, parallel-group study of prasugrel vs. matching placebo in patients with recent 
CABG, starting at the time of hospital dismissal from CABG (Figure 13). All patients 
will be receiving aspirin, as per standard current practice. 
 
Figure 13: Flowchart of the proposed study design. 
CABG = coronary artery bypass graft surgery; OCT = optical coherence tomography; IVUS = 
intravascular ultrasound; NIRS= near-infrared spectroscopy; R = randomization; m = month; 
FU = follow-up. 
 
12. DESCRIPTION OF PROCEDURES TO BE PERFORMED: 
The study design will be explained to the patients and if they agree to participate 
they will be asked to sign an informed consent form and they will receive a copy of the 
consent form. They will subsequently be randomized to prasugrel or placebo, as 
described below. 
Randomization and Treatment 
Randomization will be performed based on computer-generated random numbers, 
and will be blocked with block sizes of 4-10, varying randomly. Subjects will be assigned 
on a 1:1 basis to prasugrel (Effient®), Daiichi Sankyo and Eli Lilly) at a dose of 10 mg 
daily or matching placebo. The patients and study coordinators will be blinded to the 
study medication. Angiographic, OCT, IVUS, NIRS and angiographic analyses will also 
be done blinded to study-arm allocation. Breaking the blind will be possible for any 
patient who develops a complication or whose clinical care requires knowledge of the 
study group allocation. 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 11 of 16 
 
        
 
 
 
                         
Patients randomized to the treatment arm will receive prasugrel at a dose of 10 mg 
daily. Patients randomized to placebo will receive one placebo tablet. To minimize the 
potential for side effects during the study period patients with an increased  risk of 
bleeding [need for warfarin or oral Xa inhibitor or thrombin inhibitor administration, recent 
(within 30 days) major bleed, known bleeding diathesis or coagulation disorder], will be 
excluded from the present study.  
To minimize the possibility of study medication discontinuation, adherence with 
the study medication will be assessed during every follow-up visit. Patients will be asked 
to return all unused medications and study containers. The number of tables issued minus 
the number of tablets returned will be used to calculate the number of tablets taken. From 
this information compliance will be calculated as: (number of capsules dispensed – 
number of capsules returned) / (number of days between visits x number of tablets per 
daily dose). Patients with <80% compliance with the study medication will be counseled 
on the importance of taking their medications. 
Catheterization, OCT, IVUS, and NIRS  
 One SVG will be examined in each patient. The target intermediate SVG lesion 
will be selected by the interventional cardiologist performing the procedure as the longest 
and least-angulated SVG amenable to intravascular imaging. After intragraft 
administration of 200 µg of nitroglycerin, an OCT catheter (DragonFly, St Jude Medical, 
Minneapolis, Minnesota) will be advanced 40-50 mm distal to the SVG proximal 
anastomosis and will be pulled back proximal to the lesion using a motorized system at a 
speed of 20 mm/sec. The OCT images will be written on CD-R or DVD for subsequent 
off-line analysis. Subsequently, a 45-MHz, 3.2F, rotational IVUS catheter (Revolution, 
Volcano therapeutics, Rancho Cordova, California, USA) will be advanced into the target 
SVG and the transducer will be advanced as distal as possible within the SVG and will 
then be pulled back to the SVG aortic ostium using a motorized pull-back system at a 
speed of 0.5 mm/s. During pullback, gray-scale IVUS will be recorded at a rate of 30 
frames per second. The gray-scale IVUS movie will be written on CD-R or DVD for 
subsequent off-line analysis. Similarly, a 3.2-F near-infrared spectroscopy catheter 
(Lipiscan IVUS, InfraReDx, Burlington, Massachusetts) will be advanced into the target 
SVG and positioned to the same location where the IVUS catheter was previously placed, 
if feasible. The catheter will then be pulled back to the aortic ostium using a motorized 
pull-back system at a speed of 0.5 cm/s. A chemogram of the artery will be obtained, as 
shown in Figures 10-12. The near-infrared spectroscopy data will also be recorded in CD-
R or DVD for subsequent analysis. 
Examination of the target SVG lesion with angiography, OCT, IVUS, and NIRS 
will be obtained at 12 months post CABG. If the patient undergoes clinically-indicated 
graft angiography before the 12-month planned angiography, then: (a) if ≥10 months 
have elapsed from enrollment in the study, then angiography, OCT, IVUS, and NIRS of a 
target SVG will be performed; or (b) if <10 months have elapsed from enrollment, then 
prasugrel will be continued and the patient will be asked to return for the planned 12-
month angiography, OCT, IVUS and NIRS.  
 
Follow-Up: Study procedures and follow-up assessments are summarized in the below 
table 2. 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 12 of 16 
 
        
 
 
 
                         
 
Table 2. Schedule of observations and laboratory assessments. 
 
 
Treatment period 
 
Test 
0 
1m 
+/- 5 
days 
3m +/- 
10 days 
(phone 
FU)  
6m+/- 
10 
days 
9m +/- 
10 days 
(phone 
FU) 
12m 
+/- 30 
days 
Post-
Treatment 
Follow-up 
Contact 
(30  days 
after 12 
month 
visit – 
Phone 
FU) 
Inclusion/Exclusion 
criteria reviewed  
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Medical history  
X 
X 
X 
X 
X 
X 
X 
Physical examination/ 
Vital Signs  
X 
X 
 
X 
 
X 
 
Medication adherence 
 
X 
X 
X 
X 
X 
 
Electrocardiogram 
X 
 
 
 
 
X 
 
SVG angiography, 
OCT, IVUS and NIRS  
 
 
 
 
 
X 
 
FU=follow-up; SVG=saphenous vein graft; IVUS=intravascular ultrasonography; NIRS = 
near-infrared spectroscopy; OCT = optical coherence tomography 
 
 
13. ANTICIPATED DATA AND DATA ANALYSIS: 
Expected treatment effect 
A recent study demonstrated the presence of thrombus in 25% of SVGs examined 
early post CABG.47 Given the potent antiplatelet effect of prasugrel, we anticipate 80% 
reduction in the prevalence of thrombus in SVGs, as assessed by OCT.  
   
Sample size calculation 
Assuming that thrombus will be detected by OCT in 25% of patients in the 
placebo group vs. 5% of patients in the prasugrel group (80% relative reduction), the 
sample size required to detect the specified difference with 80% power and a 2-sided α 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 13 of 16 
 
        
 
 
 
                         
level of .05 is 48 patients per group, which was increased to 60 patients to allow for 20% 
dropout.  
Assuming 48 patients are evaluable in each group, the power of the study 
assuming a prevalence of thrombus by OCT in the control arm of 20%, 25%, and 30% 
will be 67%, 80%, and 89%, respectively.  
Enrolling 40 patients per year for three consecutive years will require enrollment 
of 25 % of the eligible patients at our institution. Enrollment rate in the SOS trial which 
also required angiographic and IVUS follow-up62 was 56%, suggesting that enrollment of 
the projected number of patients is feasible in our setting. 
 
Statistical Analysis of primary endpoints 
All endpoints (primary and secondary) will be analyzed with an intent-to-treat 
approach.  
The prevalence of thrombus within the target SVG at 12-month OCT imaging (primary 
efficacy endpoint) will be analyzed using the Fisher’s exact test.  In view of the relatively 
small sample size of the trial, multivariable logistic regression analyses will be performed 
to adjust the findings for any potential differences in the baseline characteristics of the 
two study groups, which are known to influence the occurrence of SVG failure. Such 
characteristics are: patient age, prior myocardial infarction; total cholesterol and HDL-
cholesterol levels; minimum graft diameter; mean arterial pressure; ejection fraction; 
male gender; and current smoking.69  The significant characteristics will be incorporated 
in the calculation of an adjusted odds ratio representing the association between treatment 
and the prevalence of thrombus, along with 95% confidence intervals.  Because off-pump 
and endoscopic SVG harvesting may be associated with higher rates of SVG failure, 
randomization will be stratified by (a) on vs. off pump and (b) endoscopic vs. open 
harvesting). 
The time elapsed to the incidence of severe bleeding, defined using the GUSTO 
criteria67 (primary safety endpoint) will evaluated using Kaplan-Meier survival curves 
and compared between the 2 study groups using the log-rank test. 
 
Statistical Analysis of secondary endpoints:  
The differences in angiographic SVG failure, in total and normalized total SVG 
atheroma volume and in lipid core burden index at 12-month SVG imaging will be 
compared between the 2 study groups using Fisher’s exact test. A logistic regression 
model will be developed to evaluate the treatment effect on this outcome adjusting for 
patient age, prior myocardial infarction; total cholesterol and HDL-cholesterol levels; 
minimum graft diameter; mean arterial pressure; ejection fraction; male gender; and 
current smoking.69. 
The incidence of major adverse cardiovascular events (composite of death, acute 
coronary syndrome, and coronary revascularization) at 12 months will be compared 
between the two study groups using the chi-square test. Kaplan-Meier survival curves 
and the log-rank test will be used to compare time-to-event of major adverse cardiac 
events in the two study groups.  
 
All tests will be two-sided. The critical level for the primary and four secondary 
outcomes will be 0.05. No adjustments will be made for multiple secondary endpoints 
 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 14 of 16 
 
        
 
 
 
                         
14. PROVISIONS FOR MANAGING ADVERSE REACTIONS: 
For safety monitoring, any emergency adverse event resulting from participation 
in the study will be treated at the Dallas VA Medical Center. Dr. Brilakis will evaluate all 
adverse events and determine the appropriate course of action. 
If a patient develops severe bleeding during the study period, prasugrel will be 
temporarily held and will be discontinued if the patient is considered to be at increased 
risk for recurrent bleeding. If a patient develops an indication for receiving oral 
anticoagulation therapy with warfarin or dabigatran during his or her participation in the 
study, prasugrel administration will be discontinued to minimize the risk of bleeding. 
If any subjects are hospitalized for an acute coronary syndrome or undergo 
coronary angiography at an outside hospital, the hospitalization records will be obtained 
and reviewed by the clinical events committee. The Universal definition of myocardial 
infarction will be used for diagnosing myocardial infarction. Bleeding will be assessed 
with the use of the GUSTO criteria.67 Severe bleeding will be defined as fatal bleeding, 
intracranial hemorrhage, or bleeding causing hemodynamic compromise requiring blood 
or fluid replacement, inotropes, or surgery.67 The frequencies of moderate bleeding, 
defined as bleeding requiring transfusion not characterized as severe, and 
moderate/severe and severe bleeding will also be analyzed. Information on (surgical or 
percutaneous) coronary revascularization will also be collected. Data will be entered on 
paper-based case report forms and will be double-entered into a secure, password 
protected database, accessible only by study personnel. Subjects will be identified by a 
unique study number in the database.  
Additionally a Data Safety Monitoring Board will be appointed to review the 
study periodically (every 12 months, or sooner if required).  
 
15. RISK/ BENEFIT ASSESSMENT: 
Although participation in our study carries some risk (related to administration of 
prasugrel and to invasive follow-up SVG imaging) we will make every effort to minimize 
it. To minimize the risk associated with prasugrel, patients at high risk for adverse 
reactions (patients at increased risk of bleeding, patients receiving oral anticoagulants, 
patients with prior stroke or transient ischemic attack and patients with weight <60 kg or 
age >75 years) will be excluded from the study. Also patients will be monitored closely 
with clinic visits or phone follow-up, at 1, 3, 6, 9, and 12 months from enrollment. To 
minimize the risk from cardiac catheterization and invasive SVG assessment, patients at 
high risk for complications, such as patients with peripheral vascular disease and renal 
failure, will be excluded. All angiographic SVG imaging procedures will be performed 
by experienced, high-volume, interventional cardiologists. 
 
Relevance to Veterans health (Potential Benefit) 
Ischemic heart disease is the leading cause of death in men over 40 years of age.  The 
predominantly male, older VA population with its high incidence of hyperlipidemia, 
hypercholesterolemia, hypertension and cigarette smoking represents a highly susceptible 
population for this disease.55 Frequently the preferred or only possible revascularization 
treatment for ischemic heart disease is coronary artery bypass graft surgery. Every year, 
about 5,300 coronary artery bypass procedures are performed in the VA system alone 
with a total budget of approximately $222,600,000 per year ($42,000 per operation), 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 15 of 16 
 
        
 
 
 
                         
according to VA Decision Support System (DSS) data. Veterans are at particular risk for 
early SVG failure, as they often have advanced diffuse coronary artery disease and rapid 
SVG atherosclerosis progression9, 10, 53 and would greatly benefit from successful 
completion of the proposed study.  
 
 
16. DATA SAFETY MONITORING PLAN: 
 
A Data and Safety Monitoring Board (DSMB) will be appointed to periodically 
review the conduct of the proposed trial for safety. The committee members will include 
cardiologists with experience in clinical research who will not be participating in the trial 
as investigators.  Potential financial or intellectual conflicts of interest will be assessed 
prior to appointing the members. The DSMB will meet prior to the enrollment of the first 
subject to review the trial protocol, informed consent documents and plans for safety and 
data monitoring of the study. The DSMB will determine the risks and benefits to research 
subjects, protection and safety of the subjects and to offer suggestions for improving the 
study design. In addition, the DSMB will determine which data will be required for 
periodic review. The DSMB will meet every 12 months to: determine adherence to study 
plan; review interim analysis, if applicable, and determine specific data to be analyzed; 
review protocol violations and deviations to assess adequacy of study; ensure 
documentation of informed consent; review enrollment followed eligibility criteria, 
enrollment numbers, visit compliance, or screening failure information; discuss 
investigator or key personnel changes; review completeness and quality of data collection 
forms; evaluate the aggregate analysis of adverse events/serious adverse events; review 
vital signs, clinical tests, etc.; and review confidentiality. At the end of each meeting the 
DSMB will give a recommendation to continue the trial unchanged, modify the protocols 
and/or consent form, or terminate the trial. 
 
17. PROCESS FOR OBTAINING INFORMED CONSENT AND PROTECTING 
SUBJECT PRIVACY:   
Before the subject undergoes procedures specific to the protocol, the informed consent 
and HIPAA authorization will be signed and dated by the subject and the member of the 
study team performing the Informed Consent procedures. Following referral and 
notification that a patient meets initial pre-screening criteria, the PI and/ member of the 
study team will present the option to participate in the research study to the patient and 
any family/ friend that the patient wishes to include. Study subjects will be recruited by 
study staff (PI, co-investigator, research nurse/coordinator) from patients who present for 
Coronary Artery Bypass Surgery once it is deemed appropriate to approach patient per 
good clinical practice guidelines. If the patient expresses interest, then the informed 
consent, HIPAA authorization (including risks and benefits) will be discussed in detail 
and an opportunity will be provided to ask questions. Patient will also be provided the 
opportunity to discuss with family/ friend, as he/she deems fit.   After all required 
signatures have been obtained; a copy of the consent and HIPAA authorization will be 
provided to the subject and scanned into the subject’s medical record.   
 
18. DOCUMENTATION OF INFORMED CONSENT: 


Version 12/12/12 
Source: Full Protocol Version 3, dated 12/12/12                                                
                                   Page 16 of 16 
 
        
 
 
 
                         
Following the study subjects’ enrollment a research enrollment note documenting the 
procedure of informed consent will be entered in CPRS by a member of the research team. 
Notes will include a brief description of the study, procedures for obtaining consent and 
HIPAA authorization, study personnel and contact numbers. A copy of the signed informed 
consent and HIPAA authorization form will be provided to the research office for scanning 
into the patient’s records.  
 
19. PAYMENT TO SUBJECTS FOR THEIR PARTICIPATION: 
Study participants will be paid $50 for 1 month and 6 month, and $200 for 12 month 
follow-up visits, to assist with the cost of transportation. 
 
20. PROVISIONS FOR DATA STORAGE AND CONFIDENTIALITY: 
Confidentiality of subject data will be maintained in accordance with VA, IRB 
and HIPAA regulations.  Physician investigators, study coordinators and study team 
members will have access to the subjects’ medical records and the results of all 
examinations undertaken.   
In accordance with HIPAA, the consent form and HIPAA authorization describes 
to the subject what protected health information will be obtained and/or stored and for 
what purpose, as well as a list of who may have access to this data, including outside 
agencies.  All records will be maintained in a locked cabinet in the research team’s 
locked office in the CRU.  Computerized data will be de-identified and stored on a 
password protected computer in a locked office of the research team.  Additionally 
patient logs and identifiable computerized data will be stored on the study team’s limited 
access shared research folder located on the secure VA server. 
In accordance with VA guidelines, all records of this research study will continue 
to be securely maintained in accordance with VHA Record Control Schedule.  The 
records will be kept in a locked file cabinet or locked room with limited access.  If the PI 
leaves the VA facility, the research records will be retained by the institution. 
 
21. PROVISIONS FOR STORAGE/ ANALYSIS OF RESEARCH SPECIMENS: 
Not Applicable. 
. 
22. DISSEMINATION OF RESEARCH RESULTS 
The results from this research will be published in medical journals and presented at 
medical meetings. 
 
23. MULTI-CENTER RESEARCH. 
Not applicable. 
 
REFERENCES, APPENDICES and TABLES:  
Please see attached Sponsor’s Protocol.