Conditions: Saphenous Vein Graft Disease
Keywords: Saphenous vein graft disease Coronary artery bypass graft surgery Antiplatelet therapy Coronary artery disease Secondary prevention Graft patency
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 250
Healthy volunteers: no

Brief summary:
Saphenous vein graft disease remains an unresolved medical problem. Many vein grafts occlude in the first year after bypass surgery, leading to adverse cardiovascular outcomes, including recurrent angina, myocardial infarction, and the need for repeat coronary intervention. While aspirin is the standard antiplatelet treatment after CABG surgery, 10-20% of vein grafts continue to occlude despite contemporary secondary preventative therapy. Compared to aspirin and other antiplatelet therapies like clopidogrel, ticagrelor treatment leads to a more pronounced platelet inhibition, and may substantially improve graft patency following CABG compared to aspirin. No data has yet to be collected regarding the impact of ticagrelor on saphenous vein graft patency following CABG. In this context, the investigators seek to compare vein graft patency between patients randomized to receive aspirin therapy, the current standard of care, or ticagrelor treatment, starting in the early postoperative period, and continuing for 2 years after CABG.

Detailed description:
This clinical trial will be a randomized double-blind study focusing on ticagrelor antiplatelet therapy as a means of improving vein graft patency after CABG. Patients will be eligible if they have received at least 1 vein bypass graft at time of surgery. Patients will be randomized to receive either aspirin 81 mg bid or ticagrelor 90 mg bid. The aspirin and ticagrelor medications will be prepared in blinded capsules. Patients recovering from surgery will be eligible for study randomization within the first 5 postoperative days. Treatment will continue for 1 year, at which time patients will undergo a CT coronary angiogram to assess graft patency. Patients will then be invited to continue participating in the trial for 1 more year, and a repeat CT coronary angiogram will be performed at the 2 year postoperative time-point.

Arms:
arm 1: One aspirin 81 mg capsule 2 times per day arm 2: One ticagrelor 90 mg capsule 2 times per day

Interventions: intervention 1: Aspirin intervention 2: Ticagrelor
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
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Ticagrelor Antiplatelet Therapy to Reduce Graft 
Events and Thrombosis (TARGET Trial): 
Does Ticagrelor Improve Graft Patency after 
Coronary Bypass? 
  
 
 
 
Study Number – Brilinta ISSBRIL0220 
Version 4 – October 17, 2013 
  
 
Principal Investigator: 
Alexander Kulik, MD MPH 
Lynn Heart and Vascular Institute 
Boca Raton Regional Hospital 
800 Meadows Road 
Boca Raton, Florida, 33486 
 
Drug Manufacturer:  
AstraZeneca LP 
1800 Concord Pike 
 
 
 
 
Wilmington, Delaware, 19850 
 
 
 
 
 
 
 
 
 
 


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Introduction 
 
Background 
Coronary artery bypass graft surgery (CABG) is the definitive surgical approach 
for the treatment of ischemic heart disease, with >400,000 procedures performed 
annually in the United States alone [1].  Despite the increasing use of arterial 
grafts during CABG, the saphenous vein remains an important conduit that is still 
used for more than 70% of grafts, due to its ease of use and ready availability [2].  
While convenient as a conduit however, the saphenous vein is severely limited 
by the progressive development of saphenous vein graft disease.  With important 
clinical sequalae, saphenous vein graft disease remains an unresolved medical 
problem, as up to 20% of venous grafts occlude in the first year after bypass 
surgery [3].  Between 1 and 6 years, the graft attrition rate is 1% to 2% per year, 
and between 6 and 10 years it rises to 4% per year.  By 10 years after surgery, 
only 60% of grafts are patent and only 50% of patent vein grafts are free of 
significant stenosis.  In addition, native coronary artery disease (CAD) 
progresses in 5% of patients annually [4-7].  As a result of graft and native vessel 
attrition, this population is at high risk for subsequent ischemic events, including 
myocardial infarction (MI) and death [6].  Further revascularization, either 
reoperation or percutaneous coronary intervention (PCI), is required in 4% of 
patients by 5 years, 19% of patients by 10 years, and 31% of patients by 12 
years after the initial bypass surgery [2, 8]. 
 
Saphenous vein graft disease is composed of three discrete stages: thrombosis, 
intimal hyperplasia, and atherosclerosis.  These processes are interlinked 
pathologically in the evolution of vein graft disease [5-6, 8-10].  Early thrombosis 
is a major cause of vein graft attrition during the first month after CABG.  Even 
when preformed under optimal conditions, the harvesting of venous conduits is 
associated with focal endothelial disruption that results in the accumulation of 
fibrin on the luminal surface, the adherence and aggregation of platelets, and the 
activation of the extrinsic coagulation cascade by subendothelium tissue factor 
[11-12].  Grafts that survive this early period develop a progressive thickening of 
the media with neointimal formation that begins within days of implantation.  This 
continues over the subsequent months, and forms a template for the 
development of superimposed atherosclerotic changes [9-10]. 
 
Aspirin is recommended for secondary prevention after CABG because of its 
effects on early patency and reduction in cardiac events [13-16].  By decreasing 
thromboxane-A2 production, aspirin prevents platelet aggregation [14].  When 
administered within 48 hours following cardiac surgery, aspirin is associated with 
a lower risk of death and ischemic complications of the heart, brain, kidneys, and 
gastrointestinal tract [17].  Several randomized controlled trials have 
demonstrated that aspirin significantly improves graft patency after CABG [18-
21].  In the largest trial on the subject, the Veterans Administration Cooperative 
Study enrolled 772 CABG patients, noting that, compared to placebo, aspirin at a 
dose of 325 mg/day or higher increased vein graft patency both at 60 days [22] 


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and 1 year after surgery [23].  Despite its established benefit in patients with 
CAD, aspirin therapy does have limitations.  It is a relatively weak antiplatelet 
agent and does not inhibit platelet aggregation by thromboxane A2-independent 
pathways (e.g. ADP or collagen stimulation).  Even with aspirin therapy for 
secondary prevention, a large number of recurrent events occur [24].  Moreover, 
a significant proportion of patients undergoing CABG may be aspirin resistant, as 
defined as undetectable platelet inhibition after 1 week of therapy [25-26].   
Depending on the population studied and the specific definition of aspirin 
resistance, anywhere from 10-40% of patients have an inadequate antiplatelet 
response to aspirin [25, 27].  Such patients appear to be at increased risk for the 
development of vascular events.  In theory, these aspirin-resistant patients may 
derive particular benefit from alternative antiplatelet therapy (such as ticagrelor) 
instead of aspirin [28]. 
 
Because of the concerns regarding aspirin resistance [25, 27], and the high vein 
graft occlusion rate noted in recent trials [3], several investigators have sought to 
evaluate the role of clopidogrel after CABG.  A thienopyridine that irreversibly 
inhibits the platelet P2Y12 adenosine diphosphate receptor, clopidogrel has been 
shown to have important antithrombotic effects [29] and clinical benefits in 
several CAD trials [30-31].  Following CABG surgery however, observational and 
clinical trials have failed to convincingly demonstrate that its use improves clinical 
outcomes [32-35] or postoperative graft patency [36-39] compared to aspirin 
therapy.  To date, 4 clinical trials involving 659 patients have evaluated the 
impact of clopidogrel on the process of vein graft disease after CABG (with 
cardiopulmonary bypass) [36-39].  Only one of these trials found a benefit in 
terms of vein graft patency with clopidogrel treatment.  Nevertheless, this study 
was limited by the lack of blinding and placebo-control, and the control arm 
received a fairly low dose of aspirin (100 mg) [38].  Using a higher dose of 
aspirin, Kulik et al. performed a randomized double-blind placebo-controlled trial 
comparing 162 mg aspirin daily to aspirin 162 mg plus clopidogrel 75 mg daily, 
and no difference in vein graft patency was noted [39]. 
 
Overall, the experience with clopidogrel after CABG has been unimpressive in 
terms of improving graft patency or clinical outcomes.  In keeping with the 
American Heart Association guidelines [40-41], the current standard of care for 
postoperative antiplatelet therapy is isolated aspirin therapy, in doses of 100-325 
mg daily.  Interestingly, a favorable experience with ticagrelor was recently noted 
after CABG.  Like clopidogrel, ticagrelor inhibits the platelet P2Y12 adenosine 
diphosphate receptor, but has a more rapid onset of action and more consistent 
and pronounced platelet inhibition than clopidogrel [42-43].  In the PLATO study, 
18,624 patients with acute coronary syndrome were randomized for 1-year 
treatment with aspirin plus ticagrelor 90 mg twice daily or aspirin plus clopidogrel 
75 mg daily.  The primary end point of the study (cardiovascular death, MI, or 
stroke) was significantly reduced by ticagrelor compared to clopidogrel (9.8% 
versus 11.7%, ticagrelor versus clopidogrel, P<0.001) [42].  In a subsequent sub-
group analysis of the 1,261 PLATO patients who underwent CABG, ticagrelor 


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treatment led to a non-significant reduction in the primary end-point at 1 year 
(10.6% versus 13.1%, ticagrelor versus clopidogrel, P=0.29), and a significant 
reduction in cardiovascular mortality (4.1% versus 7.9%, ticagrelor versus 
clopidogrel, P<0.01) [43]. 
 
To date, no data is available regarding the impact of ticagrelor on saphenous 
vein graft patency following CABG.  Even with routine aspirin use after CABG, 
10-20% of vein grafts occlude within 1 year after surgery, placing these patients 
at high risk for future myocardial events.  In contrast to clopidogrel, ticagrelor 
treatment leads to a more pronounced platelet inhibition, and may substantially 
improve graft patency following CABG compared to aspirin therapy.  We 
therefore propose a randomized controlled trial to compare postoperative graft 
patency between patients treated after CABG with aspirin therapy, the current 
standard of care, to those treated with ticagrelor starting in the early 
postoperative period. 
 
Research Hypothesis 
The hypothesis of this clinical trial is that ticagrelor treatment will improve 
postoperative saphenous vein graft patency 1 and 2 years after CABG surgery, 
as compared to standard aspirin therapy. 
 
Study Rationale 
Saphenous vein graft disease remains an unresolved medical problem.  Many 
vein grafts occlude in the first year after bypass surgery, leading to adverse 
cardiovascular outcomes, including recurrent angina, myocardial infarction, and 
the need for repeat coronary intervention.  While aspirin is the standard 
antiplatelet treatment after CABG surgery, 10-20% of vein grafts continue to 
occlude despite contemporary secondary preventative therapy. Compared to 
aspirin and other antiplatelet therapies like clopidogrel, ticagrelor treatment leads 
to a more pronounced platelet inhibition, and may substantially improve graft 
patency following CABG compared to aspirin.  No data has yet to be collected 
regarding the impact of ticagrelor on saphenous vein graft patency following 
CABG.  In this context, we seek to compare vein graft patency between patients 
randomized to receive aspirin therapy, the current standard of care, or ticagrelor 
treatment, starting in the early postoperative period, and continuing for 2 years 
after CABG. 
 
Benefits, Risks and Ethical Assessment 
It is anticipated that ticagrelor will improve vein graft patency in this clinical trial.  
To maximize the benefits and minimize the risks associated with ticagrelor, 
concomitant aspirin treatment will not be administered to patients randomized to 
receive ticagrelor in order to prevent bleeding complications associated with dual 
antiplatelet therapy.  Patients who are randomized to aspirin treatment will 
receive 162 mg daily in keeping with current clinical guidelines, since a lower 
daily dose of 81 mg daily may be under-treatment and insufficient for antiplatelet 
therapy after CABG.  In addition to graft patency at 1 and 2 years after surgery, 


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major adverse cardiovascular events and adverse bleeding events will be 
recorded in the 2-year interval after surgery.  The study will be conducted with 
the highest ethical standards, in accordance with the applicable United States 
Food and Drug Administration (FDA) regulations and institutional review board 
requirements.  This trial will be submitted to the FDA for review.  Moreover, 
research ethics approval will be sought from the Western Institutional Review 
Board (WIRB). 
 
 
Study Objectives 
 
Primary Objective 
The primary objective of this clinical trial will be to evaluate whether, as compared 
to usual aspirin treatment, ticagrelor early after CABG prevents saphenous vein 
graft occlusion 1 year after surgery, as assessed by computed tomography (CT) 
coronary angiography, as well as 2 years after surgery via study extension. 
 
Secondary Objective 
The secondary objective of this clinical trial will be to evaluate whether, as 
compared to usual aspirin treatment, ticagrelor early after CABG prevents 
saphenous vein graft stenosis, defined as >50% narrowing of the graft, 1 year after 
surgery, as assessed by computed tomography (CT) coronary angiography, as 
well as 2 years after surgery via study extension. 
 
Exploratory Objectives 
Additional exploratory objectives of this clinical trial will include the impact of 
ticagrelor treatment, as compare to aspirin, on the incidence of major adverse 
cardiovascular events (mortality, myocardial infarction, cerebrovascular accident, 
hospitalization for coronary ischemia, and need for coronary intervention) and 
bleeding events in the first year and second year study after CABG (Appendix B).  
It is recognized that the study will be under-powered in the evaluation of these 
outcomes, which will be defined using the previously published definitions from the 
CURE and CASCADE trials [30, 39, 44].  Specifically, major bleeding episodes will 
be defined as substantially disabling bleeding, intraocular bleeding leading to the 
loss of vision, or bleeding necessitating the transfusion of at least 2 units of blood.  
Major bleeding is classified as life-threatening if the bleeding episode is fatal, leads 
to a reduction in the hemoglobin level of at least 5 grams per deciliter or to 
substantial hypotension requiring the use of intravenous inotropic agents, if it 
necessitates a surgical intervention, if it is a symptomatic intracranial hemorrhage, 
or if it necessitates the transfusion of four or more units of blood.  Minor bleeding 
episodes will include other hemorrhages (i.e. nose bleeds) that lead to the 
interruption of the study medication. 
 
 
 
 


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Study Plan and Procedures 
 
Overall Study Design 
 
This clinical trial will be a randomized double-blind study comparing two 
postoperative antiplatelet regimens after CABG.  The trial will be conducted over 
a 4 year period in order to achieve the study objectives.  Patients will be recruited 
during the first and second years of the study.  Graft evaluation will be performed 
during the second, third and fourth years of the study.  Each patient will 
participate in the trial for 1 year following surgery, at which point a CT coronary 
angiogram will assess graft patency.  Patients will then be invited to continue 
participating in the study for a second year (study extension).  A CT coronary 
angiogram will subsequently asses 2-year graft patency. 
 
AstraZeneca LP (Wilmington, Delaware) will provide the ticagrelor tablets for the 
study (Appendix C).  The ticagrelor tablets will be submitted by AstraZeneca to 
Compounding Docs Pharmacy (Boca Raton, Florida), a pharmaceutical custom 
compounding company.  The aspirin drug for the study will be provided by 
Compounding Docs.  The ticagrelor and aspirin study drug will be crushed and 
compounded into capsules for the trial.  The compounding process does not 
affect the bioavailability of ticagrelor or aspirin, and the bioavailability of the 
capsules will be confirmed through independent biochemical analysis.  A bullet 
pulverizer will be used to crush a pool of 300 tablets at a time (aspirin or 
ticagrelor).  A ProFiller 3600 capsule filling system will then prepare 300 capsules 
containing the active powder (aspirin or ticagrelor), with inert microcrystalline 
cellulose used to fill the remaining capsule space.  The crushed tablets will not 
be used beyond the expiration of the original product. 
 
Compounding Docs will prepare identical capsules containing either 81 mg of 
aspirin or 90 mg of ticagrelor.  These prepared capsules will appear identical for 
the purpose of blinding in this study.  Patients in the trial will be assigned to 
receive either one aspirin 81 mg capsule 2 times per day (Arm A – aspirin) or one 
ticagrelor 90 mg capsule 2 times per day (Arm B – ticagrelor).  Compounding 
Docs will prepare pill bottles containing 180 capsules to cover for a 3-month 
supply.  The blinded capsules will be stored at room temperature (25°C), as 
indicated on the bottle container label.  These pill bottles will then be submitted to 
the Boca Raton Regional Hospital (BRRH) pharmacy.  Ordering and dispensing 
of the blinded study medication will be coordinated by the BRRH pharmacy.  
Shipment of study medication to the second recruitment site at the University of 
Ottawa Heart Institute (Ottawa, Ontario, Canada) will also be coordinated by the 
BRRH pharmacy.  After surgery, each trial participant will be provided with a 3-
month supply of study medication, and a new pill bottle will be provided to each 
patient every 3 months over the course of the 1- or 2-year trial enrollment. 
 
 
The study population will include all patients undergoing CABG over the study 
period at the Lynn Heart and Vascular Institute of the Boca Raton Regional 


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Hospital in Boca Raton, Florida, and the University of Ottawa Heart Institute in 
Ottawa, Ontario, Canada.  Patients undergoing on-pump or off-pump CABG will 
be eligible for this study, as long as at least one saphenous vein graft is used.  
Patients undergoing concurrent valve repair or replacement surgery will also be 
eligible, unless postoperative warfarin anticoagulation is anticipated (i.e. 
mechanical prosthetic valve).  CABG patients will be pre-screened and evaluated 
for study eligibility in the perioperative period (Appendix A).  Study eligible 
patients will be selected and approached by the study coordinator to explain the 
trial.  Consent and randomization will occur within 5 days after surgery.  
Randomization will be stratified based on the surgical site, the presence of 
diabetes mellitus, and the use of cardiopulmonary bypass (on-pump or off-
pump). 
 
Prior to trial enrollment, in the early postoperative period, patients will be treated 
with usual aspirin antiplatelet therapy (typically 325 mg daily) starting within 24 
hours after surgery, in keeping with current clinical guidelines [41].  At the time of 
randomization following surgery, this standard aspirin treatment will be 
discontinued.  Patients will be randomized into an aspirin group (Arm A - aspirin 
81 mg bid) or a ticagrelor group (Arm B - ticagrelor 90 mg bid).  The study 
capsules will be identical to ensure blinding.  Medication administration and data 
collection will be performed in a double-blind manner, such that neither the 
patient nor the healthcare personnel will be aware of the medication assignment. 
 
Recruitment and written consent will be performed either prior to surgery or 
within 5 days after surgery.  This interval of time after surgery will enable subjects 
to recover from anesthesia and the occasional confusion associated with 
postoperative narcotic use, in order to provide informed consent.  Randomization 
will occur following surgery.  Patients who are requiring high levels of 
hemodynamic support (more than 2 inotropes) within 48 hours after surgery will 
not be randomized into the study.  Patients requiring postoperative 
anticoagulation with warfarin will also not be recruited.  Following surgery, the 
study medication will be administered daily via nasogastric tube (if patient is 
intubated) or orally, starting on postoperative days 1-5, for the duration of 1-2 
years. 
 
Treatment will continue for 1 year, at which time patients will undergo a CT 
coronary angiogram to assess graft patency.  Patients will then be invited to 
continue participating in the trial for 1 more year with the same study treatment.  
A repeat CT coronary angiogram will subsequently be performed for another 
graft evaluation at the 2-year time point after surgery.  Because cholesterol levels 
can impact postoperative graft patency, current clinical guidelines recommend 
lipid-lowering therapy after CABG to achieve low-density lipoprotein (LDL) levels 
<100 mg/dL [41].  As such, patients in this trial will undergo lipid level evaluation 
at baseline before surgery and every 3 months during study enrollment.  This 
information will be made available to clinicians involved in the care of study 
subjects to facilitate modification of lipid-lowering therapy, as needed, in keeping 


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with guideline recommendations.   A creatinine level will be obtained before the 
1-year and 2-year CT coronary angiogram, given the potential renal toxic effects 
associated with intravenous contrast. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Trial Timeline 
 
CABG Patient Consented Pre-op or Within 5 Days after Surgery 
 
Double-Blind Randomization based on Stratification factors 
 
Initiate Aspirin 81 mg bid or Ticagrelor 90 mg bid  
Within 5 days post-CABG 
 
Discharge from hospital 
With supply of meds for 3 months 
 
Physician follow-up  
Within 1 month  
 
Research Coordinator follow-up  
Lipid profile  
Assessment of major adverse cardiovascular and safety events 
Resupply study medication  
At 3, 6, 9 and 12 months 
 
CT coronary angiogram, Creatinine level 
Consent for study extension (year 2)  
At 12 months 
 
Research Coordinator follow-up  
Lipid profile  
Assessment of major adverse cardiovascular and safety events 
Resupply study medication  
At 15, 18, and 21 months  
 
Lipid profile  
Assessment of major adverse cardiovascular and safety events 
CT coronary angiogram, Creatinine level  
At 24 months 


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Rationale for Study Design and Doses 
The TARGET study will be a randomized double-blind controlled trial, which will 
generate the highest quality data regarding the potential patency benefits 
associated with ticagrelor after CABG.  The study design will ensure that ticagrelor 
patients do not receive aspirin, to prevent bleeding complications associated with 
dual antiplatelet therapy.  For the control patients who receive aspirin, 81 mg bid 
(162 mg daily) will be used.  This relates to the fact that post-CABG patients have 
relative aspirin resistance postoperatively, and 81 mg of aspirin daily may be 
insufficient as the sole antiplatelet therapy.  This relative aspirin resistance of post-
CABG patients constitutes yet another biologic basis for investigating of the use of 
ticagrelor after bypass surgery.  A higher dose of aspirin (162 mg daily) will ensure 
that aspirin patients receive adequate antiplatelet treatment after CABG, in keeping 
with current clinical guidelines [41].  At 1- and 2-years after surgery, graft patency 
will be evaluated by CT coronary angiography.  Compared to conventional 
coronary angiography, CT angiography is a non-invasive diagnostic test that does 
not require an arterial puncture or catheter manipulation within the aorta, native 
coronary arteries, or bypass grafts.  In a meta-analysis of 14 studies, CT coronary 
angiography was shown to have a sensitivity of 97.6% and a specificity of 98.5% 
for the assessment of graft occlusion, as compared to conventional coronary 
angiography [45]. 
 
Subject Selection Criteria 
Inclusion Criteria 
For inclusion in the study, subjects should fulfill the following criteria: 
1. Provision of informed consent prior to any study specific procedures 
2. Female and/or male patients aged 18-90 years 
3. Patients undergoing first-time CABG with at least 1 saphenous vein graft, 
irrespective of concurrent valve surgery 
 
Exclusion Criteria 
Subjects should not enter the study if any of the following exclusion criteria are 
fulfilled: 
1. Inability to provide informed consent 
2. Pregnancy or seeking pregnancy 
3. Patients undergoing redo-CABG 
4. Serum creatinine >1.8 mg/dL (need for contrast with CT coronary angiogram) 
5. Hypersensitivity or allergy to aspirin or ticagrelor 
6. Anticipated need for postoperative anticoagulation with coumadin, dabigatran 
or rivaroxaban (mechanical valve, chronic atrial fibrillation, DVT/PE) 
7. History of gastrointestinal hemorrhage 
8. Active pathological bleeding 
9. History of intracranial hemorrhage 


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10. Severe hepatic impairment 
11. Current or anticipated use of strong CYP3A4 inhibitors (e.g. ketoconazole, 
clarithromycin, nefazadone, ritonavir, and atazanavir) 
 
Study Conduct 
Restrictions during the Study 
Patients who require long-term anticoagulation (chronic atrial fibrillation, 
mechanical valve) will not be recruited into the TARGET trial, due to the higher 
risk of bleeding complications associated with the combination of both ticagrelor 
and coumadin.  Despite this exclusion, subjects who are recruited into the trial 
may subsequently develop an indication for anticoagulation after study 
enrollment.  As an example, anticoagulation may be necessary starting 10 days 
after surgery for a TARGET participant who has developed new-onset 
postoperative atrial fibrillation or deep vein thrombosis.  In this scenario, the trial 
subject will discontinue the blinded study medication (aspirin or ticagrelor) and 
receive open label treatment as indicated by the clinicians involved in the 
patient’s care (i.e. open label 81 mg aspirin daily plus coumadin).  When 
anticoagulation is no longer needed (resolved atrial fibrillation), or the course of 
coumadin has been completed, open label treatment will cease, and the trial 
subject will resume the blinded study medication.  The subject will continue to 
followed as part of the trial and undergo CT graft evaluation irrespective of study 
medication interruptions.  
 
In the case of a serious bleeding event (i.e. gastrointestinal bleeding requiring 
hospitalization) while enrolled in TARGET, a study subject will permanently 
discontinue the study medication.  The patient will continue to be followed for the 
duration of trial enrollment, but the subject will receive open label treatment as 
indicated by the clinicians involved in the patient’s care (i.e. open label 81 mg 
aspirin daily). 
 
Subject Enrollment and Randomization 
CABG patients will be evaluated by the study coordinator for pre-screening and 
trial eligibility in the perioperative period.  Consent and randomization will occur 
within 5 days after surgery.  Randomization will be stratified based on the 
surgical site, the presence of diabetes mellitus, and the use of cardiopulmonary 
bypass (on-pump or off-pump).  A block randomization technique will ensure an 
equal distribution of diabetic patients in both arms of the trial, in addition to an 
equal distribution of on-pump and off-pump CABG patients.  The randomization 
schedule will be generated using SAS 9.1 software (SAS, Cary, NC).  All patients 
and study personnel will be blinded to the treatment assignment which will be 
performed by hospital pharmacies at the Boca Raton Regional Hospital or 


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University of Ottawa Heart Institute.  While consent may be performed before 
surgery, randomization will not be performed until after surgery when clinical 
stability has been ensured (patients who are requiring high levels of 
hemodynamic support and are at high risk of perioperative death will not be 
randomized into the study).  At the time of randomization following surgery, 
standard aspirin treatment will be discontinued.  Patients will be randomized into 
an aspirin group (Arm A - aspirin 81 mg bid) or a ticagrelor group (Arm B - 
ticagrelor 90 mg bid).   
 
Procedures for Randomization 
Once a patient has been identified and consented, the pharmacy will be notified 
that the patient needs to be randomized.  A Randomization Form will be 
completed and faxed to the pharmacy.  In addition, protocol orders will be 
entered into the patient’s medical record.  The hospital pharmacist will refer to 
the randomization schedule and assign the patient to the appropriate group.  In 
addition, a second pharmacist will be required to sign off on the Randomization 
Form to confirm that the patient was assigned to the appropriate group. 
 
Procedures for Handling Subjects Incorrectly Randomized 
The Randomization Form will be designed in a manner that the subgroups will be 
clearly identified.  In addition, the process of utilizing a second pharmacist during 
the randomization phase will avoid incorrect assignments.  If a subject has been 
incorrectly enrolled, the unblinded pharmacist will be notified and the 
randomization number will be corrected.  The patient will remain on the same 
blinded study medication. 
  
Blinding and Procedures for Unblinding the Study 
The study personnel will be blinded, with the exception of the pharmacy staff 
involved in randomizing the trial subjects.  Only unblinded pharmacy personnel 
will have access to any unblinded patient logs.  Unblinded pharmacy personnel 
will be notified by the Principal Investigator or his designee that a patient requires 
unblinding.  A patient should not be unblinded without the authorization of the 
Principal Investigator.  Any requests for unblinding should be directed to the 
Principal Investigator and/or the research coordinator.  Upon approval of the 
Principal Investigator, a patient may be unblinded if this information is essential in 
determining the continued care of the patient. 
 
Methods for Ensuring Blinding 
The study personnel will not have access to any of the unblinded patient logs.  
This includes patient assignment logs and/or drug accountability logs.  These 
logs will be maintained in the pharmacy. 
 
 


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Treatments 
 
Investigational 
product 
Dosage form and 
strength 
Provider 
Aspirin 
81 mg PO bid 
Compounding Docs 
Ticagrelor (Brilinta) 
90 mg PO bid 
AstraZeneca 
 
Doses and Treatment Regimens 
Patients randomized into Arm A will be treated twice daily with blinded aspirin 
capsules containing aspirin 81 mg.  Patients randomized into Arm B will be 
treated twice daily with blinded ticagrelor capsules containing ticagrelor 90 mg. 
Labeling 
The label will include the following information: Facility Name, Patient Name, 
Dose (1 capsule bid), Prescription Number, and Dispensing Date.  In addition, 
the drug name will be included as “Investigational Drug: Ticagrelor 90 mg versus 
Aspirin 81 mg”.  The bottle container label will also note that the capsules need to 
be stored at room temperature (25°C). 
 
Storage 
The investigational drug will be stored in the hospital pharmacy.  This area has 
limited and restricted access. 
 
Concomitant and Post-Study Treatments 
Patients will receive concomitant therapies in both groups as recommended by 
the current American College of Cardiology / American Heart Association 
guidelines.  This will include smoking cessation counseling and the 
administration of beta blockers, angiotensin converting enzyme inhibitors, and 
lipid-lowering medications as indicated [41, 46-47].  Target LDL values (less than 
100 mg/dL) will be those recommended as per current guidelines.  In the 
absence of specific contraindications, all patients will be on postoperative lipid 
lowering therapy, and lipid profiles will be assessed every 3 months following 
surgery.  Diabetic patients will have aggressive perioperative glycemic control, 
including an intravenous insulin infusion both in the operating room and in the 
intensive care unit, and a subcutaneous insulin sliding scale while recovering on 
the surgical ward.  Once drinking well, diabetic patients will be restarted on their 
original preoperative diabetic regimens (oral agents and/or insulin therapy).  The 
treatment of diabetes during this study will be closely monitored in collaboration 
with endocrinologists. 
 
Treatment Compliance 
The research coordinators involved in the trial and the Principal Investigator will 
answer questions, assess patient compliance with the trial protocol, and evaluate 


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safety issues throughout trial enrollment.  Telephone calls by the research 
coordinator will be performed every 3 months after surgery.  Additionally, trial 
participants will meet with a research coordinator every 3 months to receive a 
new 3-month supply of the study medication.  These visits and telephone calls 
will help in the retention of study subjects.  Patient compliance will be evaluated 
through personal interviews and the counting of remaining pills at 3-month 
intervals (at the time that new study medication is provided to patients). 
 
Accountability 
The research coordinator will count remaining investigational drug at the time of 
study drug return.  This information will be maintained in the study patient’s chart.  
In addition, patient assignment logs and drug accountability logs will be 
maintained in the hospital pharmacy.  These logs will be maintained by unblinded 
pharmacy personnel. 
 
Discontinuation of Investigational Drug 
A recruited subject who subsequently develops an indication for anticoagulation 
(i.e. new-onset postoperative atrial fibrillation or deep vein thrombosis) will be 
asked to discontinue the TARGET blinded study medication.  The participant will 
then receive open label treatment as indicated by the clinicians involved in the 
patient’s care (i.e. open label 81 mg aspirin daily plus coumadin).  When 
anticoagulation is no longer needed (resolved atrial fibrillation), or the course of 
coumadin has been completed, open label treatment will cease, and the trial 
subject will be asked to resume the blinded study medication. 
 
In the case of a serious bleeding event (i.e. gastrointestinal bleeding requiring 
hospitalization) while enrolled in TARGET, a study subject will permanently 
discontinue the study medication. 
 
Procedures for Discontinuation of a Subject from Investigational Drug  
If it is determined that a patient will be discontinued from the investigational drug, 
then alternate medication will be prescribed, if applicable, by the Principal 
Investigator or the patient’s health care provider.  Attempts will be made to obtain 
any remaining investigational drug in the patient’s possession. 
 
Withdrawal from Study 
A patient may be withdrawn from study medication at any time by the study 
doctor or the sponsor without the patient’s consent.  For example: if it is in the 
patient’s best interest, if the patient has problems complying with study 
procedures, if the patient becomes pregnant, if the patient does not consent to 
continue in the study after being told of changes in the research, if the patient 
makes a request, if the patient has a serious adverse event (GI bleed), or for any 
other reason. 
 


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Collection of Study Variables 
Recording of Data 
Case report forms will be designed and utilized to collect all pertinent data. 
 
Data Collection at Enrollment and Follow-up 
Saphenous vein graft patency and stenosis will be assessed by CT coronary 
angiography at 1 year and 2 years after CABG.  The incidence of major adverse 
coronary events and safety outcomes will be documented during postoperative 
visit at 1 month after surgery and every 3 months thereafter.  A research 
coordinator will phone each patient every 3 months to document any other events 
and ensure study drug compliance.  This data will be recorded on the case report 
forms. 
Enrollment Procedures 
Patients undergoing CABG procedures will be pre-screened for eligibility in the 
study.  Inclusion and exclusion criteria will be reviewed.  The research 
coordinator will consult with the Principal Investigator or sub-investigator(s) 
regarding patient’s eligibility prior to enrollment.  Once a patient is deemed 
eligible for the study, the patient will be invited to participate. 
Follow-up Procedures 
Patients will be contacted by the research coordinator for all follow-up visits.  
Appointments will be scheduled and laboratory tests and/or CT scan will be 
completed.  Patients will receive a resupply of study drug at these appointments, 
if applicable.  The Principal Investigator and/or sub-investigator(s) will be 
informed of the patient’s status. 
 
 
Safety 
Definition of Adverse Events 
An adverse event (AE) is the development of an undesirable medical condition or 
the deterioration of a pre-existing medical condition following or during exposure 
to a pharmaceutical product, whether or not considered causally related to the 
product.  An undesirable medical condition can be symptoms (e.g. nausea, chest 
pain), signs (e.g. tachycardia, enlarged liver) or the abnormal results of an 
investigation (e.g. laboratory findings, electrocardiogram).  In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, even if no 
study treatment has been administered.  The term AE is used to include both 
serious and non-serious AEs. 
 


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Definitions of Serious Adverse Event 
A serious adverse event is an AE occurring during any study phase (i.e. follow-
up) that fulfils one or more of the following criteria: 
 
Results in death 
 
Is immediately life-threatening 
 
Requires in-patient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions 
 
Results in a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above 
The causality of serious adverse events (SAEs) and their relationship to the 
study treatment will be assessed by the investigators and communicated to 
AstraZeneca. 
 
Causality Assessment of Adverse Event to Treatment 
The investigator will assess the relationship of any AE to the use of the study 
drug, based on available information, using the following guidelines: 
 
Unlikely related – no temporal association, or the cause of the event has been 
identified, or the drug, biological or device cannot be implicated 
 
Possibly related – temporal association, but other etiologies are likely to be the 
cause; however involvement of the drug, biological, or device cannot be excluded 
 
Probably related – temporal association and other etiologies are possible but 
unlikely 
 
 
Recording of Adverse Events 
Adverse events will be recorded for study subjects while they are enrolled in the 
trial (maximum 2 year enrollment).  Serious adverse events that occur at any 
time after the inclusion of the subject in the study (defined as the time when the 
subject is randomized) up to 30 days after the subject completed or discontinued 
the study medication must be reported.  The subject is considered to have 
completed the study either after the completion of the last visit or contact (e.g. 
phone contact with the investigator or designee), or 30 days after the last dose of 
the study medication, whichever is later. 
As noted above, the incidence of major adverse cardiovascular events (mortality, 
myocardial infarction, cerebrovascular accident, hospitalization for coronary 
ischemia, and need for coronary intervention) and bleeding events will be 
recorded (and noted as adverse events) for trial subjects in the 2 year period 
after CABG.  If, during trial enrollment, a participant develops a major adverse 
cardiovascular event or major bleeding event, the TARGET blinded study 


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medication will be discontinued.  The participant will then receive open label 
treatment as indicated by the clinicians involved in the patient’s care. 
The following variables will be collected for each AE: 
 
Adverse event description 
 
The date when the AE started and stopped 
 
Whether the AE is serious or not 
 
Investigator causality rating against the study medication 
 
Action taken with regard to study medication 
 
Whether AE caused subject’s withdrawal from study 
 
Patient outcome 
 
In addition, the following variables will be collected for SAEs: 
 
Date AE met criteria for serious AE 
 
Date investigator became aware of serious AE 
 
Reason AE is serious (i.e. hospitalization, probable cause of death) 
 
Dates of hospitalization, discharge, and/or death 
 
Whether autopsy performed 
 
Investigator causality rating against the study medication or other 
medications 
 
Reporting of Serious Adverse Events  
Investigators and other site personnel will inform the FDA, via a MedWatch form, 
of any serious, unexpected, possibly related adverse events that occur in 
accordance with the reporting obligations of 21 CFR 312.32, and will concurrently 
forward all such reports to AstraZeneca.  A copy of the MedWatch report will be 
faxed to AstraZeneca at the time the event is reported to the FDA.  It is the 
responsibility of the investigator to compile all necessary information and ensure 
that the FDA receives a report according to the FDA reporting requirement 
timelines and to ensure that these reports are also submitted to AstraZeneca at 
the same time. 
 
When reporting to AstraZeneca, a cover page will accompany the MedWatch 
form indicating the following: 
 
Investigator Sponsored Study (ISS) 
 
The investigator IND number assigned by the FDA 
 
The investigator’s name and address 
 
The trial title and AstraZeneca ISS reference number 
 
The investigative site will also indicate, either in the SAE report or the cover 
page, the causality of events in relation to all study medications as determined by 
the principal investigator. 
 
The SAE report and accompanying cover page will be sent by way of fax to 
AstraZeneca’s designated fax line: 1-866-984-7229. 
 


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Serious adverse events that do not require expedited reporting to the FDA will be 
reported to AstraZeneca using the MedDRA coding language for serious adverse 
events. 
 
All SAEs will be reported to AstraZeneca, whether or not considered causally 
related to the study drug.  All SAEs will be documented. 
 
The investigator will be responsible for informing the institutional review board 
(IRB) as soon as possible, in accordance with local laws and regulations.  All 
SAEs will be reported to the Western Institutional Review Board (WIRB).  The 
development of serious adverse events that might be attributable to the study 
medication will lead to the termination of the study drug.  
 
 
 
Ethical and Regulatory Requirements 
Ethical Conduct of the Study 
The TARGET trial will adhere to the highest research ethics standards, in 
accordance with the applicable FDA regulations and IRB requirements.  The 
study protocol will be reviewed by the Research Committee of the Boca Raton 
Regional Hospital.  Thereafter, the protocol, the Informed Consent Form (ICF), 
and relevant supporting information will be submitted to the Western Institutional 
Review Board (WIRB) for human research ethics approval.  The trial protocol will 
also be submitted to the United States Food and Drug Administration (FDA) to 
obtain exemption status from Investigational New Drug Application (IND) 
regulations. 
 
Patients will be approached before or after CABG surgery for enrollment in the 
trial.  As part of the consent process, patients will be explained the rationale of 
the trial and the potential adverse side effects associated with enrollment.  
Patients will be reminded that they are free to choose to either participate or not 
participate in the study. 
 
Ethics and Regulatory Review 
The TARGET trial will not begin subject recruitment until approval has been 
granted by WIRB and the FDA.  The investigator will be responsible for reporting 
to WIRB of the progress of the study at least once per year or as required.  In 
addition, the Investigator will be responsible for obtaining WIRB approval for any 
changes made to the protocol or Informed Consent prior to implementation, 
except where study subject safety is affected. 
The Investigator will promptly notify WIRB, AstraZeneca, and the FDA of all 
serious, unexpected, possibly related adverse events. 


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Informed Consent 
The Informed Consent will be approved by WIRB prior to subject enrollment. 
Patients will be consented in accordance with Good Clinical Practice guidelines, 
prior to enrollment in the trial. 
Changes to the Protocol and Informed Consent Form 
The Investigator will be responsible for obtaining WIRB approval for any changes 
made to the protocol or Informed Consent prior to implementation, except where 
the study subject safety is affected. AstraZeneca will be notified of any changes 
to the Protocol and/or Informed Consent. 
Audits and Inspections 
AstraZeneca will be notified of any audits or inspections conducted at the study 
locations.  The Principal Investigator and study staff will make themselves 
available, in accordance with federal guidelines. 
 
 
 
Study Management 
Training of Study Site Personnel 
All personnel will be properly trained in the protocol and procedures expected of 
them.  In addition, refresher training may be conducted, as needed.  Training 
logs will be kept in the study regulatory binders. 
Monitoring of the Study 
The sites will perform self monitoring of this study. 
Source Data 
All source documents will be maintained in the research chart for each subject.  
In addition, electronic medical records (EMR) may also be utilized by the study 
facility.  It is the practice of the research facility to allow EMR access to monitors 
or auditors, if requested. 
Study Timetable and End of Study 
Patient recruitment is expected to be completed within 2 years of initiating the 
study. Once the final patient has been recruited, follow-up will last for 2 additional 
years. The study duration is estimated at 4 years. 
 
During the time of enrollment, patients will be seen every three months. This 
includes the 3 month visit, 6 month visit, 9 month visit, and 12 month visit.  At the 
12 month visit, patients will be given the opportunity to continue in the study for 
an additional 12 months.  This would include the 15 month visit, 18 month visit, 
21 month visit, and 24 month visit. 
 


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Data Management 
All data will be recorded on preprinted case report forms (CRF) suitable for 
electronic data capture. The case report forms will be kept in the patient’s 
research chart.  The research charts will be stored in a locked, secure location. 
Data will be entered by qualified personnel at the conclusion of study. 
 
 
Statistical Methods 
 
Sample Size 
This trial will be a pilot study.  Outcome estimates will form the basis for assessing 
the feasibility of designing a future large and definitive trial.  One hundred fifty 
patients in each study arm will be enrolled (300 total patients).  Since each patient 
will receive 2 vein grafts, on average, there will be approximately 300 vein grafts 
in each group (600 vein grafts total).  This sample size will be large enough to 
detect whether a clinically important difference exists in terms of vein graft patency 
between the groups, but small enough that subject recruitment can be performed 
in an expedient manner, likely within the first 24 months of the study. 
 
This trial will not be designed or powered as a definitive clinical trial.  Based on 
several previously published clinical trials, it is anticipated that 10-20% of vein 
grafts will be documented as occluded at the 1-year time point after CABG.  Should 
ticagrelor improve graft patency and reduce vein occlusion from 20% to 10%, 
power calculations suggest that this pilot trial will have 96% power to detect a 
significant difference (P<0.05) between the groups.  Alternatively, if ticagrelor were 
to decrease the occlusion rate from 15% to 10%, the power will be approximately 
58%. 
 
Statistical Analysis 
All study data will be collected in a blinded fashion during the course of the trial.  
At 1- and 2-years after surgery, the CT coronary angiograms will be read and 
interpreted by board-certified radiologists with expertise in cardiac CT imaging.  
The radiologists will be blinded to study treatment assignment.  The data analysis 
will also be performed in a blinded fashion, with un-blinding at the conclusion of 
the analysis.  Study outcomes will be compared on an intention-to-treat basis 
according to the randomization study-group assignment.  Vein graft occlusion, the 
primary outcome of the study, will be compared between the two randomization 
groups using a Fisher’s exact test.  To account for within-patient correlation and 
the possibility of multi-graft occlusion within individual patients, vein graft data will 
also be analyzed using logistic regression fit with generalized estimating equations 
methods.  For secondary outcomes, continuous data will be compared between 
the two groups using two-sided Student’s t tests, two-sample Wilcoxon rank-sum 
tests, or ANOVA, and a Fisher’s exact test will be used for categorical data.  Time 
to major adverse cardiovascular event will be determined for the study groups 
using the Kaplan-Meier method, and groups will be compared with a log-rank test.  
In accordance with intention-to-treat analysis, clinical and safety data will be 
analyzed for all randomized patients in the study.  This will include data collected 


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from subjects who have dropped out of the trial or who refuse postoperative CT 
coronary angiography (5% expected refusal). 
 
Study analysis will be performed at the 1-year and 2-year time-points.  The first 
analysis will be conducted when the last recruited patient has passed the 1-year 
time interval after surgery and has undergone CT angiography.  The second 
analysis will be performed when all recruited patients have crossed the 2-year 
time-point after surgery. 
 
 
 
Important Medical Procedures to be followed by the Investigator 
 
Overdose  
If an overdose on an AstraZeneca study drug occurs in the course of the study, 
then the investigators or other site personnel will inform appropriate AstraZeneca 
representatives within one day (i.e. immediately but no later than the end of the 
next business day) of when he or she becomes aware of it. 
 
The designated AstraZeneca representative will work with the Investigator to 
ensure that all relevant information is provided to the AstraZeneca Patient Safety 
data entry site. 
Pregnancy 
Patients who are pregnant or seeking to become pregnant will be excluded from 
trial recruitment.  All outcomes of pregnancy, should they occur, will be reported 
to AstraZeneca. 
 
 
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Appendix A - Study Inclusion and Exclusion Criteria 
 
 
Inclusion Criteria: 
 
- Patients undergoing first-time CABG with at 
least one saphenous vein graft 
 
- Female or male patients aged 18-90 years 
 
- On-pump or off-pump CABG 
 
- Concurrent valve repair or replacement 
 
 
 
Reason: 
 
- The population of clinical interest 
Exclusion Criteria: 
 
- Redo CABG 
 
 
- Serum creatinine >1.8 mg/dL 
 
 
- Hypersensitivity or allergy to aspirin or 
ticagrelor 
 
- Anticipated need for postoperative 
anticoagulation with coumadin, dabigatran or 
rivaroxaban (mechanical valve, chronic atrial 
fibrillation, DVT/PE) 
 
- History of gastrointestinal hemorrhage 
 
- Active pathological bleeding 
 
- History of intracranial hemorrhage 
 
- Severe hepatic impairment 
 
- Pregnancy or seeking pregnancy 
 
- Current or anticipated use of strong 
CYP3A4 inhibitors (e.g. ketoconazole, 
clarithromycin, nefazadone, ritonavir, and 
atazanavir) 
 
- Inability to provide informed consent 
 
- Postoperative low cardiac output syndrome 
requiring more than 2 inotropes 48 hours after
surgery 
Reason: 
 
- Higher risk of graft occlusion and poor long-
term outcome 
 
- Contraindication to use of postoperative CT 
coronary angiography 
 
- Contraindication to use of aspirin or ticagrelor 
 
 
- Contraindication to use of ticagrelor 
 
 
 
 
- Contraindication to use of ticagrelor 
 
- Contraindication to use of ticagrelor 
 
- Contraindication to use of ticagrelor 
 
- Contraindication to use of ticagrelor 
 
- Contraindication to use of ticagrelor 
 
- Contraindication to use of ticagrelor 
 
 
 
 
- Ineligible for research study enrollment 
 
- Unstable patient unlikely to benefit from 
treatment 
 
 


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Appendix B – Definitions of Outcomes 
As per the and CASCADE and CURE Trials [30, 39, 44] 
 
Death from Cardiovascular Cause 
Death from cardiovascular cause is defined as any death for which there is no clearly 
documented nonvascular cause. 
 
Myocardial Infarction 
Myocardial infarction is defined by the presence of at least two of the following: ischemic 
chest pain, the elevation of the serum levels of cardiac markers or enzymes (troponin, 
creatinine kinase, creatinine kinase MB isoenzyme, or other cardiac enzymes) to at least 
twice the upper limit of the normal reference range or three times the upper limit of normal 
within 48 hours after percutaneous coronary intervention or CABG (or to a level 20% 
higher than the previous value if the level has already been elevated because of an earlier 
myocardial infarction), and electrocardiographic changes compatible with infarction. 
 
Cerebrovascular Accident 
Stroke is defined as a new focal neurologic deficit of vascular origin lasting more than 24 
hours.  Stroke is further classified as the result of intracranial hemorrhage, ischemia (if a 
computed tomographic or magnetic resonance imaging scan is available), or uncertain 
cause. 
 
Angina 
Recurrent angina after surgery is defined by the Canadian Cardiovascular Society (CCS) 
classification and the need for anti-angina agents (i.e. nitrates).  Refractory ischemia after 
surgery is defined by re-hospitalization lasting at least 24 hours for unstable angina, with 
ischemic electrocardiographic changes. 
 
Bleeding 
Major bleeding episodes are defined as substantially disabling bleeding, intraocular 
bleeding leading to the loss of vision, or bleeding necessitating the transfusion of at least 
2 units of blood.  Major bleeding is classified as life-threatening if the bleeding episode is 
fatal, leads to a reduction in the hemoglobin level of at least 5 grams per deciliter or to 
substantial hypotension requiring the use of intravenous inotropic agents, if it necessitates 
a surgical intervention, if it is a symptomatic intracranial hemorrhage, or if it necessitates 
the transfusion of four or more units of blood.  Minor bleeding episodes included other 
hemorrhages that lead to the interruption of the study medication. 
 
 
 
 
 
 


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Appendix C – Ticagrelor Drug Information 
 


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