Pilot Study to Determine Feasibility of a Randomized Trial of Screening for Coronary Artery Disease in Kidney Transplant Candidates
Phase: NA
Conditions: End Stage Renal Disease, Coronary Artery Disease
Sponsor: University of British Columbia

Gill, John: A randomized trial of screening for coronary artery disease in kidney transplant candidates, 
Study Protocol. 
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Initial Protocol Date: Sept 13 2013 
Amendment 1: Sept 22 2014 
Amendment 2: Oct 21 2014 
Amendment 3: Dec 3 2014 
Amendment 4: Aug 15 2016 
 
 
 
Protocol Title: 
 
 
A randomized trial of screening for  
Coronary Artery Disease  
in Kidney Transplant Candidates 
Pilot Study 
 
NCT02082483 
 
 
 
 
 
 
 
 
 
 
A multi-center pilot study to inform the feasibility of a definitive trial to 
determine if a non-use of screening tests (i.e. Myocardial Perfusion 
Scintigraphy or Dobutamine Stress Echo) is non-inferior to screening all 
asymptomatic wait-listed patients at regular intervals as described in 
transplant specific guidelines  

Gill, John: A randomized trial of screening for coronary artery disease in kidney transplant candidates, 
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Study Chairs: Dr. John Gill and Dr Greg Knoll 
 
Study Vice Chair:  Dr. Joseph Kim 
 
Central Study Coordinator: Angela Ogniben 
 
Sponsor, Co-ordinating Centre and Data Co-ordinating Centre: 
Dr. John Gill  
University of British Columbia and Providence Health Care 
JGill@providencehealth.bc.ca 
Angela Ogniben  
Clinical Research Coordinator 
Kidney Transplant Research Office 
1081 Burrard St, Howe Site 4th floor 
Vancouver, BC V6Z 1Y6 
(T) 604-682-2344 ext 64707 
(F) 604-806-8856 
 
Data Co-ordinating Centre:  
Louise LeBel 
Clinical Research Coordinator 
Ottawa Hospital Research Institute 
Centre for Practice-Changing Research, Room L1295  
501 Smyth Rd, Box 201B  
Ottawa, ON   K1H 8L6 
Tel: 613-737-8899 ext 74639 
Fax: 613-739-6938  
 
Funding Agency: 
Canadian Institutes of Health Research 
MOP 133509 
 
Trial Registration:  http://www.clinicaltrials.gov/ 
 
 
 
This protocol has been developed by the Study Steering Committee and its contents are the 
confidential intellectual property of this group. It is an offence to reproduce or use the 
information and data in this protocol for any purpose other than the Cardiac Screening in 
Kidney Transplant Candidates Pilot Study without prior approval from the Study Co-
ordinating Centre. 
 

Gill, John: A randomized trial of screening for coronary artery disease in kidney transplant candidates, 
Study Protocol. 
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Gill, John: A randomized trial of screening for coronary artery disease in kidney transplant candidates, 
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* Each site will determine the estimated time to transplantation based on PRA and ABO 
blood type.  The site investigator will complete Table 3 which will be used to estimate a 
potential participants time to transplantation. Patients who require a routine cardiac 
screening test (see Figure 1) to determine regular screening schedule for patients (based 
on cardiac history) before the estimated date of transplantation, are eligible for study 
participation.   
 
Title 
A randomized trial of screening for coronary artery disease in kidney transplant 
candidates: Pilot Study 
Project Office 
SPH  
Study Size 
144 
Study Design 
Multi-center, open label, randomized controlled trial of regular screening versus no-
regular screening for coronary artery disease in kidney transplant candidates 
Primary 
objective 
To determine the feasibility of a definitive trial. Feasibility is determined by 1) 
protocol adherence 2) enrolment rates 3) consent rates.  A patient will be 
considered adherent if they were adherent to their allocated screening strategy 
(regular versus no regular screening) over the 24 month treatment period. 
Enrolment rates will be assessed monthly during the six month enrolment period.  
Consent rates will be defined as the proportion of patients enrolled among eligible 
patients approached for enrolment and will be defined after completion of the six 
month enrolment period. 
Secondary 
Objective 
To record the composite outcome of cardiac death and non-fatal myocardial 
infarction (i.e. the proposed primary outcome in the definitive trial). These 
outcomes will be adjudicated by a blinded clinical endpoints committee using 
criteria from the POISE Trial 
Tertiary 
Objective 
To record transplant events, wait-list holds, and wait-list removals including the 
indication. To ascertain health care encounters related to the diagnosis and 
management of CAD.  
Inclusion/ 
Exclusion 
Criteria 
 Inclusion criteria: a) adult patients ≥ 18 years of age, able to provide informed 
consent; b) patients with dialysis-dependent renal failure and active on the 
deceased donor transplant waiting list; c) patients expected to require further 
screening for CAD prior to transplantation by the current standard of care; d) 
investigator consented and signed off on patient eligibility; e) patients anticipated 
to undergo transplantation more than 12 months from the date of enrolment. 
Exclusion criteria: a) patients with signs or symptoms suggestive of active cardiac 
disease such as unstable coronary syndromes, decompensated heart failure, 
uncontrolled arrhythmia, and severe valvular heart disease; b) patient who have 
been put “on hold” for  transplantation due to a medical problem (e.g. an infection); 
c) prior extra-renal transplant recipients; d) multi-organ transplant candidates (e.g. 
kidney pancreas transplant candidates); e) patients with a planned living donor 
transplant; f) patients receiving dialysis in a non-local unit; g) patients with a non-
approved requirement for surveillance echocardiography.  
Treatment 
Patients randomized to routine screening will undergo non-invasive testing for CAD 
according the 2005 National Kidney Foundation Guidelines (Figure 1 study 
manual).(7) Patients randomized to no regular screening will not undergo regular 
non-invasive testing for CAD in the absence of symptoms. Patients in both groups 
who develop symptoms of angina or an angina equivalent, will be investigated 
according to the local standard of care which may include the use of non-invasive or 
invasive cardiac testing. 

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Table of Contents   
1.0 INTRODUCTION AND RATIONALE 
6 
1.1 PRINCIPAL RESEARCH QUESTION 
7 
1.2 NEED FOR THE TRIAL 
8 
1.2.1 WAIT-LISTED PATIENTS ARE INCREASING IN NUMBER AND MEDICAL COMPLEXITY 
8 
1.2.2 LONGER WAITING TIMES AND CHANGING DONOR CHARACTERISTICS INCREASE CAD RISK 
8 
1.2.3 WAIT-LISTED PATIENTS ARE AT HIGH RISK FOR CAD BUT ARE COMMONLY ASYMPTOMATIC 
9 
1.2.4 THE STANDARD OF CARE IS NOT EVIDENCE BASED AND EXPENSIVE 
9 
1.2.5 THE CURRENT STANDARD OF CARE MAY BE HARMFUL 
10 
1.3 SYSTEMATIC LITERATURE REVIEW 
10 
1.3.1 NON-INVASIVE SCREENING TESTS HAVE LIMITED PREDICTIVE ABILITY FOR CAD 
11 
1.3.2 RANDOMIZED STUDIES IN ASYMPTOMATIC NON-RENAL FAILURE SURGICAL CANDIDATES HAVE NOT   DEMONSTRATED 
A BENEFIT OF REVASCULARIZATION PRIOR TO ELECTIVE SURGERY 
11 
1.3.3 TRANSPLANT SPECIFIC GUIDELINES CONTRADICT GUIDELINES FOR THE GENERAL PUBLIC 
11 
1.3.4 NO-REGULAR USE OF SCREENING TESTS MAY BE SAFE IN WAIT-LISTED PATIENTS 
11 
1.3.5 SUMMARY WHY THE CARDIAC SCREENING TRIAL IS NEEDED 
12 
2.0 PLAN OF INVESTIGATION 
12 
2.1 TRIAL OBJECTIVES 
12 
2.1.1 PRIMARY OUTCOMES 
13 
2.1.2 SECONDARY OUTCOMES 
13 
2.1.3 TERTIARY OUTCOMES 
13 
2.2 SAMPLE SIZE 
13 
3.0 ELIGIBILITY CRITERIA 
13 
3.1 INCLUSION CRITERIA 
14 
3.2 EXCLUSION CRITERIA 
14 
4.0 PATIENT RECRUITMENT AND INFORMED CONSENT 
15 
4.1 INCIDENT PATIENT  IDENTIFICATION AND ENROLMENT 
16 
4.2 PREVALENT PATIENT IDENTIFICATION AND ENROLMENT 
16 
4.3 INFORMED CONSENT 
16 
4.4 RANDOMIZATION 
16 
5.0 TRIAL MANAGEMENT OF PATIENT RANDOMIZED TO REGULAR AND NO-REGULAR SCREENING 
17 
5.1 SCREENING TEST SCHEDULE 
17 
5.2 TYPE OF NON-INVASIVE CARDIAC SCREENING TEST 
17 
5.3 INVESTIGATION AND MANAGEMENT OF AN ABNORMAL SCREENING TEST 
17 
5.4 MANAGEMENT OF PATIENTS WHO DEVELOP CLINICAL SYMPTOMS OF CAD 
17 
5.5 PERMITTED INVESTIGATIONS IN RANDOMIZED STUDY PATIENTS 
18 
5.6 OTHER STUDY MANOEUVRES 
18 
5.7 METHODS TO PROTECT AGAINST CONTAMINATION 
18 
6.0 FOLLOW UP 
19 
7.0 TRIAL OUTCOME ASCERTAINMENT 
19 
8.0 OUTCOMES ADJUDICATION 
21 
9.0 DATA ANALYSES 
21 
10.0 DATA SAFETY MONITORING BOARD 
21 
11.0 TRIAL MANAGEMENT 
21 
11.1 WHAT ARE THE ARRANGEMENTS FOR THE DAY TO DAY MANAGEMENT OF THE TRIAL? 
21 
11.2 METHODS FOR PROTECTING AGAINST SOURCES OF BIAS 
22 
11.3 TRIAL OVERSIGHT 
23 
11.4 TRIAL STEERING COMMITTEE  
24 
11.5 MONITORING 
24 
11.5.1 SITE MONITORING 
24 
11.5.2 TIMING AND FREQUENCY OF MONITORING VISITS 
24 
11.5.3 MONITORING PROCEDURES 
25 
11.6 ENSURING DATA QUALITY 
25 
 

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1.0 INTRODUCTION AND RATIONALE 
     Kidney transplantation is the preferred treatment for end-stage renal disease (ESRD) as 
it prolongs survival, improves quality of life, and is less costly than dialysis.(1-3) However, 
the demand for kidney transplantation exceeds the organ supply, and Canadians routinely 
wait on dialysis for 3 to 8 years for a deceased donor kidney transplant.(4) ESRD patients 
are at high risk for the development or progression of coronary artery disease (CAD). As 
such, the very risk of CAD can exclude patients from consideration of transplantation, or 
result in death before or after transplantation.(5, 6) CAD is difficult to diagnose in ESRD 
patients who may not develop the classic symptoms of angina because of uremia, diabetes 
and other factors.  
     The current standard of care described in transplant guidelines includes two phases of 
screening for CAD i) prior to acceptance onto the waiting list, and ii) screening at regular 
intervals (i.e. annually) after wait-listing.(7) The aim of screening is to identify CAD by non-
invasive tests (i.e. Myocardial Perfusion Scintigraphy or Dobutamine Stress Echo), identify 
critical coronary stenoses by angiography, and prophylactically revascularize diseased 
patients with the aim of prolonging survival before and after transplantation. Although this 
is the standard of care, only one randomized trial performed in 1992 involving 26 diabetic 
patients has ever been performed to evaluate this strategy.(8) This study was prematurely 
terminated because of slow recruitment and an unexpected imbalance in CAD events 
favoring treatment.  
     Ironically screening for CAD may paradoxically increase morbidity and mortality by i) 
exposing patients to the risk of angiography and revascularization procedures or ii) by 
delaying or excluding patients from life saving transplantation. Indeed, screening is not 
beneficial in most non-ESRD surgical candidates and is not routinely recommended. (9) 
However, the goals of screening transplant surgical candidates differ from those in non-
ESRD surgical candidates and include not only prevention of peri-operative cardiac events, 
but also maintenance of transplant eligibility during wait-listing, and long-term post 
transplant survival. These differences and the lack of evidence in the transplant setting 
have led to confusion about the optimal management of transplant candidates: The two 
main issues of uncertainty are 1) whether to screen asymptomatic patients for occult CAD, 
and 2) whether the usual approach of revascularizing coronary stenoses in asymptomatic 
patients is of benefit. 
     Canadian transplant physicians are unwilling to forgo screening for CAD prior to 
acceptance onto the waiting list, because these tests are considered essential to determine 
initial transplant eligibility. However, the largest health services burden is related to 
screening after wait-listing, and there is clinical equipoise to determine the utility of 
screening after wait-listing in a clinical trial. The current application is for a pilot trial to 
determine the feasibility of a definitive randomized controlled trial to test the hypothesis 
that selective use of cardiac screening tests is non-inferior with respect to the composite 
endpoint of non-fatal MI and cardiac death compared to the current standard of care that 
involves screening all asymptomatic wait-listed patients at regular intervals. Physicians 
would investigate patients in both groups if they develop symptoms of CAD. With over 
100,000 kidney transplant candidates in North America, Australia, and New Zealand a 
defintive trial is need to inform optimal care.  The definitive trial findings will either a) save 
valuable resources by averting needless and potentially harmful tests, or b) validate 

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current transplant practice and ensure optimal use of scarcely available deceased donor 
kidneys.  
 
1.1 Principal Research Question 
     For our definitive trial, we will determine if a strategy of non-use of regular screening 
tests (i.e. Myocardial Perfusion Scintigraphy or Dobutamine Stress Echo) is non-inferior 
with respect to the composite endpoint of non-fatal MI and cardiac death compared to 
screening all asymptomatic wait-listed patients at regular intervals as described in 
transplant specific guidelines published by the National Kidney Foundation (see Table 1 
below ).(7)  
Table 1. Frequency of screening for CAD in patients randomized to regular screening group 
Patient characteristics  
Frequency of Screening 
Diabetic patients 
Every 12 months 
Patients with prior coronary artery disease on coronary 
angiogram:  
If not revascularized  
If prior percutaneous intervention (angioplasty or stent) 
If prior coronary artery by-pass grafting (CABG) 
 
If prior CABG but incomplete revascularization  
 
 
Every 12 months 
Every 12 months 
3 years after revascularization 
and then every 12 months 
Every 12 months 
If high risk non-diabetic: 
More than 20% per 10 years cardiovascular event rate 
risk according to Framingham or 
known CAD (clinical, EKG, or other evidence of CAD but 
without angiographically visualized coronary stenosis), 
or PVD, or ejection fraction ≤ 40 %   
Every 24 months 
Non-diabetic low risk (includes all patients not included 
in the above categories) 
Every 36 months 
https://www.cvdriskchecksecure.com/FraminghamRiskScore.aspx    
 
     Before proceeding with a large multi-centre trial, feasibility will be assessed in a 
33 month pilot trial. In the pilot trial, feasibility is the primary outcome and will be 
assessed by protocol adherence, patient enrolment and consent rates.  
1) Protocol Adherence: A patient will be considered adherent if the observed number of 
screening tests performed equals the expected number of screening tests during the two 
year follow-up period (i.e. the expected number of tests in a diabetic patient who remains 
asymptomatic would be zero in the no-regular screening group, while the same patient 
would be expected to completed two screening tests during the 24 month treatment period 
in the pilot trial if randomized to regular screening). Our proposed sample size of 144 
patients will produce a 95% confidence interval equal to the sample adherence prevalence 
plus or minus 5% when the true prevalence of adherent patients is hypothesized to be 
90%.   
2) Enrolment of 24 patients per month during the six month enrolment period.  
3) Consent of 40% of eligible patients approached for participation.  
     The enrolment and consent targets are informed by the planned recruitment of 2500 

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patients in 23 transplant centers over three years in the definitive trial. The definitive trial 
sample size of 2500 is based on the assumption that a no-regular screening strategy will be 
considered non-inferior to a regular screening strategy if there is  1% absolute increase in 
the combined outcome of non-fatal MI and cardiac death in the no-regular screening group. 
Rationale for focus on use of screening tests after wait-listing:  
     Although evidence for CAD screening prior to placement on the waiting list is lacking, the 
study will focus on the use of screening tests after activation to the waiting list because: 
1. Physicians are unwilling to forgo initial cardiac evaluation:  
     In preparation for this application, we surveyed all 15 adult Canadian Transplant 
Centers. All centers screen for CAD during the initial transplant evaluation. Most (13/15) 
did not support randomization of patients to use or non-use of cardiac investigations 
during the initial evaluation of patients for activation onto the waiting list. These tests are 
viewed as necessary to determine initial transplant eligibility.  
2. In contrast, there is clinical equipoise around the use of screening AFTER wait-listing:  
      In a survey conducted in support of this application, all Canadian centers reported 
screening for CAD after wait-listing. The majority of transplant centers (11/15) had a 
screening protocol, while in four centers transplant physicians individually selected 
patients for screening. The frequency of screening reported in hypothetical patient 
scenarios equaled or exceeded that recommended in the Transplant Guidelines. All 15 
centers were willing to randomize patients to regular or no-regular screening after wait-
listing.  
3. The largest health services impact is related to the use of multiple screening tests during 
the years of wait-listing (typically 2-8 years), rather than the one time testing prior to 
placement on the waiting-list.  
 
1.2 Need for the Trial 
     A recent joint Scientific Statement from the American Heart Association and the 
American College of Cardiology Foundation concluded “that there is no strong evidence for 
or against routine cardiac screening of asymptomatic transplant candidates” and that more 
evidence from randomized clinical trials was needed.(6) The following sections review the 
urgent need for a definitive trial. 
1.2.1 WAIT-LISTED PATIENTS ARE INCREASING IN NUMBER AND MEDICAL COMPLEXITY 
     There are 3500 patients active on the waiting list in Canada, with over 800 deceased 
donor transplants performed annually.(11)  In comparison, over 92,000 patients are 
currently wait listed in the United States with approximately 10,600 deceased donor 
transplants performed annually.(12) Wait-list candidates are increasingly complex. For 
example, the proportion of transplant candidates ≥ 50 years increased from 29% to 62% 
between 1991 and 2011,(12) while the percentage with type I or type II diabetes increased 
from 23% to 28% between 1998 and 2008.(13)  
1.2.2 LONGER WAITING TIMES AND CHANGING DONOR CHARACTERISTICS INCREASE CAD RISK  
     Despite efforts to increase organ donation, the demand for transplantation continues to 
exceed the supply of transplantable organs. The median waiting time for deceased donor 
transplantation increased from 2.8 to 4.6 years between 2004 to 2006, and in 2011 the 
median waiting times for Canadian transplant recipients ranged from 864 to 1954 days 
(2.3-5.3 years) (Figure 1, Appendix).(14) Exposure to dialysis is a major factor increasing 
the risk of cardiac events before and after transplantation.(15) As a result, the cardiac 

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fitness of wait-listed patients for transplant surgery must be maintained for longer time 
periods. Due to the organ shortage, patients are now transplanted with kidneys from older 
deceased donors, and donation after circulatory death donors that have more peri-
operative complications, and a higher risk of peri-operative cardiac events.(12) 
1.2.3 WAIT-LISTED PATIENTS ARE AT HIGH RISK FOR CAD BUT ARE COMMONLY ASYMPTOMATIC      
     ESRD patients are at increased risk for CAD.(16) The cumulative incidence of myocardial 
infarction ranges from 8.7% to 16.7% by 3 years after wait-listing, and from 4.7% to 11.1% 
after kidney transplantation.(6, 17) The risk of cardiac events is highest during the first 
post-transplant month but remains elevated during the first post-transplant year.(1, 18) 
Cardiovascular disease is the most common cause of death in both wait-listed patients (18) 
and patients with a functioning transplant, accounting for 30% of mortality overall.(12) 
However, because of physical limitations and neuropathies, ESRD patients may not develop 
symptoms of CAD. For example, among patients hospitalized with myocardial infarction in 
the third National Registry of Myocardial Infarction, chest pain at presentation was less 
common in dialysis (44%) compared to non-dialysis patients (68%).(19) 
1.2.4 THE STANDARD OF CARE IS NOT EVIDENCE BASED AND EXPENSIVE      
     The current standard of care involves serial non-invasive cardiac testing of asymptomatic 
wait-listed patients.(7) Patients with abnormal non-invasive tests undergo coronary 
angiography followed by revascularization of any hemodynamically critical stenosis by 
coronary angioplasty with or without coronary stenting, or coronary artery by-pass 
grafting.(7) During this period of investigation, patients are inactivated on the waiting list 
and unable to receive a transplant. In 1992, Manske reported the only randomized trial 
examining this strategy: In a single center, 26 insulin dependent diabetic transplant 
candidates with coronary artery stenoses greater than 75%, atypical or no chest pain, and a 
left ventricular ejection fraction greater than 35% were randomized to medical therapy 
(calcium channel blocker plus asprin) or revascularization with angioplasty or coronary 
artery bypass grafting (CABG). Among the 13 patients assigned to medical therapy, 10 had 
a cardiac end point (including 4 deaths) compared to 2/13 revascularized patients (p 
<0.01).(8) The study was prematurely terminated because of the imbalance of events 
between groups and slow recruitment. The applicability of this study is limited for several 
reasons: i) the medical therapy has changed substantially ii) the study focused on a specific 
high-risk population (insulin-dependent diabetics) representing < 20% of the wait-listed 
population(20); iii) the study evaluated one time screening in an era when transplant 
waiting times were dramatically shorter; iv) the trial had few events and the results have 
substantial fragility, and the trial was stopped early for a too good to be true treatment 
effect. 
     The rationale for screening is challenged by observations that not all of the excess 
cardiovascular disease burden of ESRD is related to CAD. ESRD patients frequently die of 
sudden cardiac death, that is arrhythmogenic in orgin and may be related to uremic 
cardiomyopathy.(21, 22) The rationale for screening for critical coronary stenoses also 
ignores evidence that the mechanism of myocardial infarction in the operative and non-
operative setting is atherosclerotic plaque rupture followed by thrombosis and occlusion of 
the affected coronary artery.(23) The risk of plaque rupture in the peri-operative period is 
related to tachycardia, increased sheer stress, and a hypercoagulable state.(24, 25) The 
most occlusive plaques are not necessarily prone to rupture and thrombosis.(26) One third 
of patients with peri-operative myocardial infarction sustain damage in areas distal to 

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noncritical stenoses.(26) Finally, the available screening tests do not necessarily identify 
plaques at risk of rupture and thrombosis.  
     Screening for CAD is expensive. In our study, of 604 wait-listed patients in British 
Columbia followed for 3.7 1.8 years, 530 non-invasive cardiac screening tests with an 
estimated cost of over $550,000 were required by current National Kidney Foundation 
guidelines.(20) When the additional costs of program administration, coronary 
angiography, consultations and revascularization procedures in patients with abnormal 
screening tests are considered, the current non-evidence based strategy conservatively 
costs $15 million per year in Canada.(27) The estimated cost of a single screening test for 
the over 90,000 wait-listed patients in the United States is $210 million.(28) No studies 
have examined the cost-effectiveness of screening for CAD. In order to ensure health care 
system sustainability and maximize patient outcomes given finite availability of health care 
resources, it is critical that the effectiveness and cost-effectiveness of screening strategies be 
determined. 
1.2.5 THE CURRENT STANDARD OF CARE MAY BE HARMFUL 
     The potential harms related to the current strategy of screening and revascularization of 
asymptomatic transplant candidates are summarized in Table 2 below.  
 
Table 2.Complications of revascularization are higher in End Stage Renal Disease (ESRD) 
Patients 
Population 
U.S. Dialysis patients 1978-95 
 
U.S. Transplant recipient 
1995-9 
Non-ESRD patients reported 
by Bari Investigators 
Event Type 
2 Yr mortality post PTCA 
2 Yr mortality post CABG 
2 Yr mortality post PTCA 
2 Yr mortality post CABG 
5 year mortality post 
PTCA 
5 year mortality post 
CABG 
Event Rate 
52% 
44%  
18% 
17-26% 
14% 
12%                              
Ref 
(29) 
(29) 
(30) 
(30) 
(31) 
(31) 
2. Asymptomatic ESRD patients may be considered too high risk for surgery and 
excluded from transplantation rather than revascularized  
(10) 
3. Screening prolongs waiting time prior to transplantation: 
Audit of 130 wait-list candidates in B.C.: 45 were put on hold for transplantation 
because of abnormal screening tests for a mean of 446 days (only 5/45 were ever 
revascularized). 
Audit 
for 
grant 
4. There is increased risk of bleeding with use of anti-coagulation after 
revascularization in ESRD patients and some surgeons will not transplant anti-
coagulated patients  
(32) 
(6) 
5. Angiography causes loss of residual kidney function. Preservation of residual 
kidney function is associated with increased dialysis survival 
(33) 
 
1.3 Systematic Literature review 
     The American College of Cardiology and American Heart Association Scientific Statement 
published in July, 2012 included a comprehensive systematic review of the literature 
between 1990-March, 2010.(6) We updated the literature review in August, 2013 and 

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found no further relevant trials. The publication is available 
(.http://content.onlinejacc.org/collection.aspx?ArticleTypeid=11552).  
Key issues most relevant to the proposed trial are reviewed in section 1.41-1.44 below:  
1.3.1 NON-INVASIVE SCREENING TESTS HAVE LIMITED PREDICTIVE ABILITY FOR CAD 
     Noninvasive testing for CAD has imperfect sensitivity and specificity in ESRD patients. In 
patients with GFR ≤ 15 mL/min/1.73 m2 or on dialysis, the sensitivity of Dobutamine Stress 
Echocardiography and Myocardial Perfusion Scintigraphy varies from 0.44 to 0.89 and 0.29 
to 0.92 while the specificity varies from 0.71 to 0.94 and 0.67 to 0.89, respectively, for 
identifying one or more coronary stenoses ≥ 70%.(6, 34-36) Noninvasive tests are most 
predictive of significant coronary stenoses in patients with a high pre-test probability for 
disease.(37) Assuming a sensitivity and specificity of 0.7, and a pre-test probability of 
disease of 50%, the positive predictive value of a non-invasive test would only be 70%. 
Furthermore, a recent meta-analyses evaluating non-invasive cardiac stress tests (e.g., 
stress echocardiography, nuclear scintigraphy imaging) demonstrated that more than a 
third of the patients who suffered a major perioperative cardiovascular event had a 
negative test result.  
1.3.2 RANDOMIZED STUDIES IN ASYMPTOMATIC NON-RENAL FAILURE SURGICAL CANDIDATES HAVE NOT 
DEMONSTRATED A BENEFIT OF REVASCULARIZATION PRIOR TO ELECTIVE SURGERY 
     The DIAD study(38) and COURAGE Trial(39) failed to demonstrate that a strategy of 
screening and revascularization of CAD in asymptomatic patients reduced cardiac events. 
These pivotal trials excluded ESRD patients and did not focus on the issue of CAD 
management in surgical candidates limiting the relevance of these trials for the wait-listed 
kidney transplant population. 
     The randomized CARP trial was the first study to address the strategy of prophylactic 
revascularization compared with optimal medical therapy in patients with clinically stable 
CAD scheduled for major vascular surgery.(40) Long-term mortality was similar in patients 
randomized to prophylactic coronary revascularization (23%) or medical treatment only 
(22%) (p=0.92). This trial demonstrated a statistically significant higher incidence of 
perioperative myocardial infarction at 30 days after noncardiac surgery in the patients who 
first underwent coronary revascularization prior to their noncardiac surgery (confidential 
unpublished data, personal communication: Dr. Edward McFalls).  If hemodynamically 
significant stenoses are the major cause of perioperative myocardial infarction, it is 
surprising that there was an increase in risk of a perioperative myocardial infarction 
despite coronary revascularization prior to noncardiac surgery. The trial excluded patients 
who had left main coronary lesions >50%, a cardiac ejection fraction < 20%, or severe 
aortic stenosis. Importantly, CARP excluded patients with renal failure. 
1.3.3 TRANSPLANT SPECIFIC GUIDELINES CONTRADICT GUIDELINES FOR THE GENERAL PUBLIC  
     Published transplant specific guidelines recommend longitudinal screening for 
asymptomatic wait-listed patients and contradict recommendations for the non-ESRD 
population (Table C, Appendix). The most recent American College of Cardiology / 
American Heart Association Guidelines on Peri-operative Cardiovascular Evaluation and 
Care for Noncardiac Surgery suggest evaluation of symptomatic patients, but do not 
encourage further testing for asymptomatic patients or those with a functional capacity of 
≥ 4 METS (i.e. ability to climb a flight of stairs) irrespective of diabetic status, history of 
CAD, or presence of cardiac risk factors.(9)  
 1.3.4 NO-REGULAR USE OF SCREENING TESTS MAY BE SAFE IN WAIT-LISTED PATIENTS 

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     In our observational study of n=604 wait-listed patients in British Columbia, clinicians 
utilized screening tests for CAD based on ongoing clinical evaluation during wait-listing. 
This strategy resulted in fewer screening tests than recommended by guidelines (n = 171 
versus 530 tests), and a trend toward a lower frequency of cardiovascular events 
(cardiovascular event rate in patients with and without the recommended frequency of 
investigation was 9.9 [95% CI, 7.1 to 13.7] and 6.7 [95% CI, 5.2 to 8.7] per 100 patient-
years).(20) Two other observational studies also suggest that no-regular screening may be 
safe: In a single centre study of 514 wait-listed candidates who were screened based on 
clinical criteria, the incidence of cardiac events at 5 years in the 224 patient who were not 
screened was 5.3% compared to 19.7% among the 290 patients who were screened. The 
use of screening tests in this study was based on clinical judgment of the treating physician, 
and some of the tests were likely performed in patients who had symptoms suggestive of 
CAD. (43) Similarly, in another study of 600 wait-listed patients, 174 patients were 
considered high risk based on clinical criteria and underwent screening for CAD and only 5 
(2.9%) were revascularized. Cardiac events were higher in screened patients 12/174 
(6.9%) versus unscreened patients 19/426 (4.5%).(44)    
1.3.5 SUMMARY WHY THE CARDIAC SCREENING TRIAL IS NEEDED 
     Medical advances have led to a paradigm shift away from revascularization of clinically 
silent coronary stenoses in non-ESRD patients. Current evidence based recommendations 
for CAD management in non-ESRD patients contradict the opinion-based recommendations 
for wait-listed kidney transplant candidates. However, non-ESRD guidelines emphasize the 
importance of symptoms and assume a short time course between evaluation and surgery, 
and may be less relevant for wait-listed ESRD transplant candidates in whom the timing of 
future transplant surgery cannot be precisely determined. Further, the goals of screening in 
transplant candidates extend beyond ensuring peri-operative safety and include 
maintenance of eligibility for transplantation, and ensuring that the potential long-term 
health benefits of transplantation are realized.    
    Canadian transplant physicians uniformly screen patients prior to accepting them onto 
the waiting list and are unwilling to randomize patients to use or non-use of screening at 
this stage. However, the main health services impact of screening occurs during the years 
of wait-listing for transplantation and there is clinical equipoise to conduct a definitive trial 
to determine the utility of screening for CAD after activation the waiting-list. Further if no-
regular screening is shown to be non-inferior, the clinical need for future studies 
comparing surgical versus medical management of coronary disease in asymptomatic 
transplant candidates will be significantly decreased.  
 
2.0 PLAN OF INVESTIGATION 
2.1 Trial Objectives 
This pilot trial will determine the feasibility of a multi-center, randomized, parallel group 
definitive trial.(45) Asymptomatic wait-listed patients will be randomized to routine 
screening for CAD (i.e. Myocardial Perfusion Scintigraphy (MPS) or Dobutamine Stress 
Echo (DSE)) as per the current standard of care (Table 1) versus no regular screening 
during wait-listing. Patients enrolled in the pilot will be included in the definitive trial 
analysis. The pilot trial will include six Canadian transplant centres. The definitive trial will 
be conducted in over 20 centers in Canada Australia and New Zealand.  

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2.1.1 PRIMARY OUTCOMES: In line with our primary objectives, the primary outcomes are 1) 
protocol adherence; 2) enrolment rates and 3) consent rates. A patient will be considered 
adherent if they were adherent to their allocated screening strategy (regular versus no-
regular screening) over the 24 month treatment period. Enrolment rates will be assessed 
monthly during the six month enrolment period.  Consent rates will be defined as the 
proportion of patients enrolled among eligible patients approached for enrolment and will 
be defined after completion of the six month enrolment period. 
2.1.2 SECONDARY OUTCOMES: In this pilot study the secondary clinical outcome is a composite 
outcome of cardiac death and non-fatal myocardial infarction (i.e. the proposed primary 
outcome in the definitive trial) and will be adjudicated by a blinded clinical endpoints 
committee using criteria from the POISE Trial.(46, 47). Total mortality, cardiovascular 
mortality, non-fatal cardiac arrest, stroke, life-threatening bleeding and major bleeding (ie. 
the proposed secondary outcomes in the definitive trial) will also be defined and 
adjudicated as in the POISE Trial.(46, 47).  
2.1.3 TERTIARY OUTCOMES: Transplant events, wait-list holds and wait-list removals including 
the indication will be measured.  We will also ascertain health care encounters related to 
the diagnosis and management of CAD. This information is required to: i) determine cost, 
and cost effectiveness of the two screening strategies in the proposed definitive trial; ii) 
document concurrent management practices that may impact the incidence of outcomes in 
the definitive trial. The information captured will include outpatient, day care, and 
emergency room use (including any diagnostic testing and all medical and surgical 
interventions (i.e. use of thrombolytics, revascularization procedures), inpatient 
encounters and resource utilization (hospitalizations, CAD-related procedural costs), 
physician consultations. Quality of life will also be measured using the EQ-5D. 
 
2.2 Sample Size  
     Adherence to screening strategies is of utmost importance to demonstrate separation 
between the two strategies and fidelity of our interventions. In the pilot trial, a sample size 
of 144 will produce a 95% confidence interval equal to the sample adherence prevalence 
plus or minus 5% when the true prevalence of adherent patients is hypothesized to be 
90%. Thus, 72 patients will be allocated to each treatment group.   
     In the definitive trial,  randomization of 2500 patients is required to demonstrate that 
no-regular screening is non-inferior to regular screening,  with an absolute increase in the 
primary outcome of cardiac death and non-fatal MI ≤ 1% in the no-regular screening arm 
considered non-inferior.   
 
3.0 ELIGIBILITY CRITERIA 
Inclusion of incident wait-listed patients (i.e. patients activated to the waiting list after the 
start of the trial) and prevalent wait-list patients (i.e. patients already on the waiting list 
before the start of the trial) will enable successful enrolment, and ensure a high proportion 
of patients undergo transplantation during study follow-up. Only patients with an 
anticipated transplant date > 12 months from the date of enrolment will be included. The 
time to transplantation of wait-list candidates can be estimated in each center based on 
ABO blood type, and immunology testing for anti-HLA antibodies. Enrolment in the pilot 
trial will be enriched to include at least 66% prevalent wait-listed patients so that 

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approximately 50% of patients are expected to undergo transplantation during the 24 
month pilot trial follow up period. 
 
3.1 Inclusion criteria 
 
a) Adult patients ≥ 18 years of age, able to provide informed consent 
b) Patients with dialysis-dependent renal failure and active on the deceased donor 
transplant waiting list.  
c) Patients expected to require further screening for CAD prior to transplantation by the 
current standard of care.  Refer to Figure 1 below to determine screening frequency.  
It should be noted that some prevalent patients may already be past due for their cardiac 
screening test according to the current standard of care at the time of study enrolment. If 
randomized to the regular screening arm, these patients would be scheduled for a cardiac 
screening test within 1 month of enrolment. 
d) Investigator consented and signed off on patient eligibility.  
e) Patients anticipated to undergo transplantation more than 12 months from the date of 
enrolment. Although we cannot definitively predict the timing of transplantation, we will 
estimate this date based on ABO blood type, and immunology testing for anti-HLA 
antibodies indicated by panel reactive antibodies (PRA). The time to transplantation will 
vary between centers in each of these groups. Therefore the site investigator will complete 
Table 3 below to inform the time to transplantation in each center.  
 
3.2 Exclusion criteria:  
 
a) patients with signs or symptoms suggestive of active cardiac disease such as unstable 
coronary syndromes, decompensated heart failure, uncontrolled arrhythmia, new 
arrhythmia or conduction abnormality, valvular heart disease;  
b) patients who have been put “on hold” for  transplantation due to a medical problem (e.g. 
an infection);  
c) prior extra-renal transplant recipients;  
d) multi-organ transplant candidates (e.g. kidney pancreas transplant candidates);  
e) patients with a planned living donor transplant;  
f) patients receiving dialysis in a non-local unit 
g) patients with a non-approved requirement for surveillance echocardiography 
 
Table 3  Estimating time to transplantation from date of first wait-listing. To be 
completed by Site Investigator  in Each Center 
Blood Group 
PRA 0% 
PRA 1-29% 
PRA 30-79% 
PRA ≥ 80% 
A 
 
 
 
 
B 
 
 
 
 
AB 
 
 
 
 
O 
 
 
 
 
 
 
Figure 1.  

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Group 1 patients would be screen annually, group 2 patients would be screened every 24 
months, and group 3 patients would be screened every 36 months according to the 2005 
NKF Guidelines. Timing of screening tests would be determined according the date of the 
last screening test recorded on the transplant center chart. 
The Framingham CVD risk calculator can be found at 
https://www.cvdriskchecksecure.com/FraminghamRiskScore.aspx 
 
* Patients with known CAD include those with clinical, EKG or other evidence of CAD, but 
excludes patients with angiographically proven evidence of CAD.  Patients with 
angiographically proven CAD would be included in group 1.  
 
4.0 PATIENT RECRUITMENT AND INFORMED CONSENT 
     We will enroll approximately 24 patients per month during the six month enrolment 
period for a total sample size of 144 patients. With 6 enrolling centres – this is equal to four 
patients per month X 6 months.  The monthly enrolment rate is informed by the 
requirement to enroll approximately 70 patients per month in twenty-three centers for 36 
months to complete the definitive 2500 patient trial.  
     We plan to consent 40% of the eligible patients approached to participate in the pilot 
trial. This 40% target in the pilot trial exceeds the estimated consent rate of 34% required 
to complete the definitive trial. 
      We also aim to have 50% of participants undergo transplantation within 24 months of 
the date of enrolment. This is important to demonstrate the risk of no-regular screening. 

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This will achieved by enrolling both incident and prevalent wait-listed patients in the trial. 
To ensure this objective each site will enrol at least 66%  prevalent wait-list patients(i.e. 
16/24 patients at a given site should be prevalent patients). The data co-ordinating centre 
will not provide randomization if the site’s enrolment of prevalent patients falls below 66% 
during the pilot study. 
 
4.1 Incident patient identification and enrolment 
 
Although incident patients could be enrolled at the time of their initial transplant 
evaluation, patients usually require further evaluation and multi-disciplinary team 
discussion before they are officially activated to the list. Therefore the study co-ordinator 
should receive a listing of all newly activated wait-list patients on a weekly basis (i.e. on a 
Friday) from the Transplant Center to be approached the following week.  
 
Patients who reside locally should be identified for potential participation first. Note this 
could include patients on peritoneal or hemodialysis in the home or in- center setting.  An 
approach to contact and consent the patient for enrolment during a routine clinical 
encounter or dedicated study visit should then be defined (e.g. a telephone call followed by 
an in person enrolment visit during a dialysis treatment or outpatient clinic visit) using 
institution-specific policies and procedures. 
 
The site PI should discuss eligible patients with the treating cardiologist (if applicable) to 
1) confirm the cardiologist’s agreement with participation in the trial 2) determine 
whether the patient meets any of the requirements for screening echocardiography (see 
Table 4 below). Patients declined for participation by their cardiologist will be considered 
ineligible.   
 
4.2 Prevalent patient identification and enrolment:  
At least 16/24 patients enrolled in each site will be prevalent patients.  
In addition to meeting study inclusion/exclusion criteria, prevalent patients should be 
under chronic dialysis treatment in a location that is accessible to study co-ordinators (i.e. 
local patients). 
The study co-ordinator should review all patients on the active transplant waiting list with 
the site PI, and identify eligible potential study participants who reside locally first.  
The site PI should discuss eligible patients with the treating cardiologist (if applicable) to 
1) confirm the cardiologist’s agreement with participation in the trial 2) determine 
whether the patient meets any of the requirements for screening echocardiography (see 
Table 4 ). Patients declined for participation by their cardiologist will be considered 
ineligible.   
 
4.3 Informed Consent: A study co-ordinator will approach eligible patients to obtain 
informed consent. 
 
4.4 Randomization 
A web-based randomization system will be used. A permuted blocked randomization 
method will be used to allocate patients. Patients will be stratified by centre and diabetic 

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status. A statistician, independent of the trial team, will generate the randomization 
scheme. The randomization process will consist of a computer-generated random listing of 
the treatment allocations stratified as above in variable permuted block sizes that will not 
be known to the investigators. The system will have backup in the form of a statistician and 
designated research assistant at the coordinating centre. Only the statistician and 
designated research assistant at the coordinating centre will have knowledge of the 
randomization codes.  After confirming eligibility and obtaining informed consent, the 
study nurse will access the trial website and provide the subject’s unique ID as well as a 
confirmation of consent and eligibility. The web site will provide the next available 
randomization number. The data co-ordinating centre will not provide randomization if the 
site’s enrolment of prevalent patients falls below 66% during the pilot study. 
 
5.0 TRIAL MANAGEMENT OF PATIENT RANDOMIZED TO REGULAR AND NO-REGULAR 
SCREENING  
 
5. 1 Screening test schedule: Patients randomized to regular screening will undergo non-
invasive testing for CAD according the 2005 National Kidney Foundation Guidelines (Table 
1 above).(7) Patients randomized to no-regular screening will not undergo regular non-
invasive testing for CAD in the absence of symptoms. Patients in both groups who develop 
symptoms of angina or an angina equivalent, will be investigated according to the local 
standard of care which may include the use of non-invasive or invasive cardiac testing.      
Patients will remain on the pilot trial protocol (i.e. regular or no-regular screening) until 
death, non-fatal MI, transplantation, permanent removal from the waiting list for any 
reason, or 24 months after enrolment in the pilot trial.  
 
 5.2 Type of non-invasive cardiac screening test:  The choice of non-invasive test(s) will 
be according to the existing practice of each transplant center. The National Kidney 
Foundation guidelines recommend that testing should be done with an exercise or 
pharmacological stress echocardiographic or nuclear imaging test.(7) The choice of 
exercise or pharmacological stress is determined by the presence of physical limitations 
(e.g. osteoarthritis) in transplant candidates. The high prevalence of left ventricular 
hypertrophy in ESRD patients may also decrease the utility of ECG treadmill testing.(6) The 
type of test used will be documented in all instances. 
 
5.3 Investigation and management of an abnormal screening test:  The management of 
an abnormal screening test including performance of coronary angiography as well as 
treatment of coronary stenoses will be carried out as per the usual standard of care in 
individual transplant centers and will not be influenced by the investigators or study 
personnel in any way.  CAD-related medical and surgical interventions will be recorded in 
both groups.  
 
5.4 Management of patients who develop clinical symptoms of CAD:  Any patient 
developing clinical symptoms of CAD (e.g. angina, congestive heart failure, or new 
arrhythmias) will be evaluated according to the standard of care in individual transplant 
centers and may include the use of non-invasive cardiac stress testing. Management of 
symptomatic CAD including revascularization will be according to the standard of care at 

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the local transplant center. Study personnel will document all surgical and medical 
interventions for CAD.   
 
5.5 Permitted investigations in randomized study patients:  
     The use of Myocardial Perfusion Scintigraphy or Dobutamine Stress Echo outside the 
study protocol will be strongly discouraged except for patients that develop signs or 
symptoms of active cardiac disease, and any use will be documented. Cardiac investigations 
(including coronary angiography) required prior to surgery for valvular heart disease are 
permitted. Although resting echocardiography is not indicated for detection of CAD, these 
tests are commonly performed in wait-listed patients and are discouraged outside the 
scenarios shown in Table 4 (below). 
 
Table 4. Accepted indications for resting echocardiography 
1. To follow progression of moderate or greater stenosis or regurgitant valvular 
disease  
2. To monitor patients with bioprosthetic/mechanical heart valves or valve repair 
3. To follow progression of pulmonary hypertension in patients with estimated 
pulmonary artery pressure (PAP) > 50 mmHg  or PAP > 40 mmHg with evidence of 
right heart failure 
4. To monitor left ventricular ejection fraction (LVEF) in patients with LVEF <40%  
 
5.6 Other study manoeuvres :  
Other than the use of cardiac screening tests, patient management will be as per the usual 
standard of care in participating transplant centers. Specific considerations include: (a) 
FREQUENCY OF CLINICAL EVALUATIONS DURING WAIT-LISTING: There may be variation in the 
follow-up of wait-listed patients by transplant centers. In both study groups, the frequency 
and content of clinical re-evaluations will be according to the existing practice of the 
participating study sites. Such evaluations may include cardiology consultations. Clinical 
evaluations by the study sites during wait-listing will be recorded in both groups. (b) USE 
OF MEDICAL OR BEHAVIOURAL TREATMENTS TO PREVENT CAD EVENTS:  Interventions to prevent 
cardiovascular disease events including the use of lipid lowering agents, aspirin, and beta-
blockers remain controversial due to the lack of definitive evidence regarding efficacy in 
ESRD patients.(6) Medical treatments will not be specified in the trial but will be 
documented by study personnel. Similarly behavioural therapies such as participation in 
weight loss, smoking cessation or healthy heart programs may used. 
 
5.7 Methods to protect against contamination: We will minimize the use of non-invasive 
CAD screening tests outside of the trial protocol by: 
1) Informing primary nephrologists and primary care physicians who oversee the care of 
wait-listed patients will about the trial and the need to avoid off-protocol non-invasive CAD 
screening tests. 
2) Informing cardiologists affiliated with a dialysis program about the study.  Eligible 
patients under active care of a cardiologist will be discussed to ensure agreement with 
participation.  
3) Placing a Study Alert on the patient’s dialysis chart. 

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4) Providing of a Wallet Card to patients containing a website with information about the 
trial.  
5) Educating patients to advise health care providers of their participation and to share the 
information in their Wallet Card. Annual communication in the form of a Thank You Card 
for participation will remind participants of trial responsibilities.  
 
6.0 FOLLOW-UP 
During wait-listing, follow-up telephone interviews and chart reviews will be performed 
every six months, with a final follow up interview at 27 months after enrolment performed 
in patients who do not undergo transplantation within 24 months of the date of study 
enrolment.  
 
Patients who undergo transplantation during the first 24 months after enrolment will be 
followed until three months after the date of transplantation. A chart review will occur at 
the time of discharge from hospital, and an in person or telephone interview and chart 
review will be performed 3 months after transplantation.  
 
For the small number of patients who undergo transplantation ≥ 24 months after 
enrolment, the last follow up will be 27 months after the date of enrolment even if the 3 
months of post transplant follow up are not possible. A chart review will occur at the time 
of discharge from hospital, and an in person or telephone interview and chart review will 
be performed 27 months after enrolment.  
 
7.0 TRIAL OUTCOME ASCERTAINMENT 
Standardized Case Report Forms will be used to assess all outcomes and study personnel 
will undergo formal orientation to these CRFs.  
 
Primary outcomes: 1) Protocol adherence: We will define adherence by completion of the 
expected number of screening tests during follow up. For example, the expected number of 
screening tests in a diabetic patient who did not develop symptoms would be zero in the 
no-regular screening group, while the same patient would be expected to completed two 
annual screening tests if randomized to regular screening. Tests performed for clinical 
symptoms of CAD will be excluded from the determination of adherence.     
     Screening tests in patients randomized to the regular screening arm will be arranged by 
study personnel under direction of the site investigator. The study personnel will advise 
participants of their screening test and follow up directly with the testing facility to 
determine completion of the test and obtain test results. Use of cardiac screening tests and 
the reasons for testing, in both treatment groups will be determined using the following 
procedure: Patients will be interviewed in person during regular dialysis treatments or via 
telephone every six months. If an unscheduled test was performed the patient will be asked 
about the reason for test (i.e. presence of symptoms) and the identity of the organizing 
physician. We believe telephone interviews are feasible in this relatively healthy cohort of 
wait-listed patients. Patient interviews will be supplemented by review of the transplant 
center and dialysis patient chart or with treating physicians as necessary every six months.  
2) Enrolment will be determined monthly from the Ottawa Hospital Research Institute 
(OHRI) which issues the randomization scheme.  

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3) Consent rate: Each transplant center maintains an up-to-date record of incident and 
prevalent active wait-listed patients. Eligibility criteria will be abstracted from the 
transplant center chart to a standardized case report form. The case report form will be 
completed by the study co-ordinator and will include the estimated time to transplantation 
as determined by the site investigator.   
     For incident wait-list patients a monthly listing of newly activated wait-list candidates 
will be obtained from the transplant center during the enrolment period. Eligible incident 
patients will be sequentially approached with a target enrolment of up to 8 incident 
patients in each site. Willingness to enroll in the study will be recorded on each patient’s 
case report form along with the reason for any refusal to consent. The number of incident 
patients approached to complete enrolment will be determined by review of the case 
report forms.  
 
     Prevalent Patients will be enrolled from the local dialysis population attached to each of 
pilot study transplant centers. The target number of prevalent patients at each site is 18 
but there is no maximum number of prevalent patients that can be enrolled. Consent will 
be documented as described for incident patients.  
 
Secondary Outcomes: 
     Ascertainment of secondary outcomes will be enabled by the fact that primary 
nephrologists and family doctors are required to inform the transplant center of any 
significant change in the health status of actively wait-listed patients that would impact 
transplant candidacy. Transplant center charts will be reviewed every six months. Events 
not reported to the transplant center, will be captured in the direct patient interviews 
(medical status, health history)and chart reviews (race, gender, medical history, 
hospitalizations, ER visits, results of Diagnostic Imagining, other test results)conducted 
every six months during wait-listing (see above).  Transplanted patients will have their 
charts reviewed at time of hospital discharge, and undergo an interview and chart review 
three months after transplantation. All cases will be recorded on a case report form that 
conceals treatment group assignment. Case report forms will be reviewed by the primary 
site investigator, and forwarded to the blinded CEC that will adjudicate outcomes according 
to the protocol used in the POISE Trial.(46, 47) 
Tertiary Outcomes:  
     Transplant events, and wait-list holds/removals will be assessed through direct monthly 
communication with the transplant centers. Ascertainment of health care resource 
encounters related to the diagnosis and management of CAD will be obtained by patient 
interview supplemented by chart reviews every six months and recorded on a 
standardized case report form. We will verify and supplement information regarding 
hospitalizations, emergency room visits, use of cardiac tests and revascularization 
procedures obtained in the telephone interview by review of clinical and electronic health 
records, as required. EQ-5D will be administered at time of enrolment and at time of the 
final study interview (27 months in non-transplanted patients and patients transplanted 
after 24 months of enrolment, OR 3 months post transplantation in patients transplanted 
≤24 months after enrolment). 
 
 

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8.0 OUTCOMES ADJUDICATION 
Outcome adjudicators (a committee of clinicians with expertise in cardiology) who are 
blinded to treatment allocation will adjudicated the following outcomes: death (cardiac or 
non-cardiac) and non-fatal myocardial infarction, non-fatal cardiac arrest, stroke,  life-
threatening bleeding, and major bleeding.  
 
9.0 DATA ANALYSES 
For the pilot trial, descriptive analyses are planned. Feasibility will be summarized with 
proportions, rates, means, and medians as appropriate. Comparison of the definitive trial 
outcomes between treatment groups, will not be done at the end of the internal pilot as 
these patients will be included in the definitive trial. In the definitive trial primary and 
secondary outcomes will be analyzed according to the intention to treat principle.  
     Analyses of enrolment rates and consent rates will be done after the enrolment phase of 
the pilot trial in February, 2015 in support of application for the definitive trial. With a 
projected trial start date of Oct 1, 2014 this will allow for 5/6 months of enrolment phase 
data to be included in the definitive trial application.  
 
10.0 DATA SAFETY MONITORING COMMITTEE 
A data safety monitoring committee (DSMC) led by Dr. Braden Manns will oversee the pilot 
trial.  
The Data Safety Monitoring Committee (DSMC) will have responsibility for monitoring of 
adverse events and will ensure the safety of patients is protected. The DSMC will receive a 
report of all adjudicated outcomes and any other outcomes agreed to in the DSMC charter 
every 6 months after randomization of the first patient. The DSMC will immediately notify 
the Study Chair of any safety issue. The DSMC will work independently from the trial and 
serve in an advisory role to the Executive Committee and Study Chair. The DSMC will 
consist of 3 individuals, expert in clinical trials, biostatistics, transplant cardiology, and 
transplant nephrology. The secondary purpose of the DSMC in the pilot study is to ensure 
efficient and accurate reporting of serious adverse events (SAEs) in the definitive trial. Dr. 
Manns will establish a DSMC Charter in conjunction with the Study Chair. Dr. Manns will 
identify two additional members of the DSMC and nominate a Vice Chair.  
 
11.0 TRIAL MANAGEMENT 
11.1 What are the arrangements for the Day to Day Management of the Trial? 
The trial management will be through St. Paul’s Hospital in Vancouver. 
The Data Coordinating Centre will be located at the Clinical Epidemiology Program (CEP) of 
the OHRI and will be under the guidance of the Study Chair, Study Operations Director, 
central coordinator, senior trial methodologists and trial statistician. The CEP is currently 
overseeing over 40 trials and will be responsible for receiving, processing, editing, storing 
and analyzing all data from the sites. The Data Management will be transferred to St. Paul’s 
hospital starting from July 2016. A detailed overview of study procedures and work plan is 
provided in Table 5, below. 
 
 
Table 5. Overview of Study Procedures and Work Plan 
 
0 m 
6 m 
12 m 
18 m 
24 m 
27 m  CRF 

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Screening, Randomization 
Consent  
X 
 
 
 
 
 
CRF1 
Randomization 
X 
 
 
 
 
 
CRF1 
Screening tests for CAD  
Planned MIBI, DSE, 
Exercise stress 
 
 
 
 
 
 
Frequency of screening 
varies (12,24, 36 months) 
depending on patient risk 
Unplanned screening tests 
 
x 
x 
x 
x 
 
 
Patient Health Status  
Baseline Health Status 
X 
 
 
 
 
 
CRF2 
Quality of Life 
X 
 
 
 
 
X 
EQ-5D 
Is patient alive? 
 
X 
X 
X 
X 
X 
CRF2,12 
Did patient have 
Myocardial infarction, 
nonfatal cardiac arrest, 
stroke, bleeding? 
 
X 
X 
X 
X 
X 
CRF2,13, 14,15,16 
Did patient have coronary 
angiography? 
 
X 
X 
X 
X 
X 
CRF2,10 
Did patient have coronary 
revascularization 
 
X 
X 
X 
X 
X 
CRF2,11 
Is patient on hold on 
WL? 
 
X 
X 
X 
X 
X 
CRF2,17 
Is patient removed 
from WL? 
 
X 
X 
X 
X 
X 
CRF2,18 
Is patient 
transplanted? 
 
X 
X 
X 
X 
X 
CRF2,5 
Was patient unable to 
proceed with an offer 
for transplantation? 
 
X 
X 
X 
X 
X 
CRF2,5 
 
B. Clinical Encounters 
Hospitalizations, ER 
visits, Cardiac Day 
Procedures 
 
X 
X 
X 
X 
 
CRF2, 4 
Outpatient cardiology 
consults  
 
X 
X 
X 
X 
 
CRF2 
Transplant center 
evaluations 
 
X 
X 
X 
X 
 
CRF2 
 
D. Medications 
Medication Review 
X 
X 
X 
X 
X 
X 
CRF1, CRF2 
 
 
 
 
 
 
 
 
 
 
11.2 Methods for protecting against sources of bias:   
     Blinding of patients and health care providers is not possible because the results of non-
invasive cardiac tests are required for patient management as per the existing standard of 
care in participating transplant centers. The likelihood that co-interventions that may 
impact cardiovascular events will be differentially utilized in the two trial groups is 

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minimized by the fact that study patients are not under the direct care of a transplant 
physician while they are wait-listed on dialysis. We will mask allocation to ensure 
concealment of randomization. A web-based randomization system will prevent study 
personnel from tampering with allocation (e.g. will not be able to read allocation 
assignment through an envelope). In addition, random variation of block sizes will prevent 
sites from “gaming” the allocation by guessing the next treatment assignment. The reasons 
for use of CAD screening tests will be documented in all cases. The following additional 
methods will be used to protect against bias: 
 - ASSESSMENT OF OUTCOMES BY AN EXPERT CLINICAL OUTCOMES EVALUATION COMMITTEE (CEC) 
BLINDED TO THE  TREATMENT GROUP ASSIGNMENT: All the proposed primary and secondary  
outcomes for the definitive trial (death, non-fatal MI, non-fatal cardiac arrest, stroke, 
bleeding) will be reviewed by the independent CEC blinded to group assignment as well as 
patient and transplant centre identity.  
- METHODS TO PROTECT AGAINST CONTAMINATION: We will minimize the use of non-invasive 
CAD screening tests outside of the trial protocol by: 
1) Informing primary nephrologists and primary care physicians who oversee the care of 
wait-listed patients will about the trial and the need to avoid off-protocol non-invasive CAD 
screening tests. 
2) Informing cardiologists affiliated with a dialysis program about the study.  Eligible 
patients under active care of a cardiologist will be discussed to ensure agreement with 
participation.  
3) Placing a Study Alert on the patient’s dialysis chart. 
4) Providing of a Wallet Card to patients containing a website with information about the 
trial.  
5) Educating patients to advise health care providers of their participation and to share the 
information in their Wallet Card. Annual communication in the form of a Thank You Card 
for participation will remind participants of trial responsibilities.  
- RIGOROUS DOCUMENTATION OF ALL MEDICAL CO-INTERVENTIONS: The use of cardio-                                                                   
-protective medications (aspirin, beta-blockers, medications that block activation of  
the renin angiotensin system, lipid lowering agents) will be documented every six months 
in all trial participants.  The use of these medications in dialysis patients varies between 
centers and between physicians at the same center. Given that we are stratifying by site, it 
is expected that use of such interventions will be balanced between the treatment arms.    
 
11.3 Trial Oversight 
Dr. Gill (nominated principal applicant) will serve as Study Chair, and Dr. Kim (principal 
applicant) will serve as Study Vice-Chair; Dr. Devereaux  (principal applicant) will serve as 
a senior trial methodologist and oversee all issues regarding cardiac testing and 
adjudication; Dr Knoll (principal applicant) will serve as study Operations Director 
overseeing data management and central data coordination at OHRI; From July 2016 Dr. 
Gill will take over the position of study Operations Director overseeing data management 
and central data coordination at St. Paul’s Hospital; Dr. Fergusson (co-applicant) and will 
serve as a senior trial methodologist; Dr Ramsay (co-applicant) will serve as the trial 
statistician; Dr. Tonelli (co-applicant) and Chair of the Canadian Task Force on Preventative 
Healthcare, will provide dialysis content expertise. Drs. Gill, Kim, Knoll, Devereaux, 
Fergusson, Ramsay, Cantarovich (co-applicant) and Tonelli will sit on the study Executive 

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Committee. Dr Ramanathan a cardiologist (co-applicant), Dr. Ribic a transplant 
nephrologist (co-applicant), and Dr Tonelli will assist Dr Devereaux with event 
adjudication. Dr. Klarenbach (co-applicant) will oversee the data collection required for the 
health economic analyses in the definitive trial.   
 
11.4 Trial Steering Committee  
The Steering Committee will consist of members of the Executive Committee as well as 
central and site-specific research staff. The committee will have two organizational 
teleconferences before study initiation and teleconferences quarterly during study 
recruitment and follow-up. The committee will review and implement all aspects of this 
trial. Clinical events will be adjudicated at six month intervals during the pilot trial. 
 
11.5 Monitoring 
11.5.1 SITE MONITORING 
The trial data, compliance, adverse events will be rigorously monitored using remote 
methods of surveillance. This ensures that trial-related data are accurate, complete and 
verifiable from source documents and that participant rights and safety are protected. This 
process will ensure compliance with the regulatory requirements, protocol, GCP, study-
specific procedures and participant eligibility. In addition to evaluating the reported data 
for accuracy and completeness, trends indicative of insufficient documentation or protocol 
deviations will be identified.  
 
Discrepancies noted in the data will be recorded and the site will be informed of all 
observations in subsequent monitoring reports. 
 
A representative of the steering committee or delegate will review deficiencies with the 
appropriate study team member in order to implement corrective actions or to recommend 
follow-up procedures. Documentation of all deficiencies will be recorded and appear in the 
site monitoring report.  
 
11.5.2 TIMING AND FREQUENCY OF MONITORING VISITS 
Interim Monitoring Visit: 
Remote monitoring will be performed for this pilot study. To ensure patient safety and data 
integrity, on-site monitoring may be required at the discretion of the Steering Committee if 
remote monitoring shows discrepancies in data, lack of compliance with regulations or if 
requested by the DSMC or the site Investigator.  
 
If an onsite monitoring visit is required, the study monitor will assess: 
 CRF source data verification 
 Patient eligibility and consent 
 Study specific SOPs 
 Delegation logs 
 SAEs for recording and reporting completeness 
 Regulatory documentation (for site and/or sponsor) 
 Training documents 

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 Protocol defined endpoints 
 Essential document maintenance 
 Deviation/violation recording and reporting 
 Privacy considerations 
 Any protocol-specific procedures 
 
After completion of the enrolment phase, the data co-ordinating center will contact each 
site to resolve any queries regarding missing or inaccurate data. De-identified data from 
each site may be requested and will be sent via secured courier. Documentation to be sent 
to the monitor for remote Source Data Verification will be specified by the data co-
ordinating center and may include: 
 Copies of signed and dated de-identified patient assessment forms (CRFs) with 
corresponding de-identified source documents 
 Copies of de-identified source documentation that supports subjects eligibility to 
be enrolled into the study 
 Copies of de-identified Investigator progress notes regarding patient-related 
decisions  
 Signed and dated training logs as well as copies of materials used to train study 
staff (slide presentations, hand-outs) 
 
All data to be couriered will be checked by the site coordinator prior to sending in order to 
ensure patient privacy and confidentiality is maintained. No identifying materials will be 
sent off-site.  
 
 11.5.3 MONITORING PROCEDURES 
Study monitoring is a Sponsor responsibility as outlined in ICH-GCP.  
 
11.6 Ensuring Data Quality: 
1. all research personnel will undergo a training session prior to trial start 
2. all centres will have a detailed trail manual outlining all steps in the protocol 
3. all investigators have direct access to the study PI via cell phone contact 
4. the data co-ordinating center will evaluate all data as soon as it is received and 
quality control checks will identify any errors or omissions; 
5. The programmer will create internal validity and range checks for all data 
6. data management assistants will undertake multi-level regular quality control 
report 
7. the data-co-ordinating office will contact the site to rectify any errors or omissions 
and this will be done by secure internet correspondence. Issues not rectified in a 
suitable time frame will be advanced to the attention of the Steering Committee. 
8. detailed monthly reports on patient follow-up, data transmission, consistency, 
thoroughness, and completeness of data collection, and event rates will be compiled 
by the data co-ordinating center and submitted to the trial Steering Committee on a 
monthly basis