Conditions: Cardiovascular Diseases Coronary Artery Disease Heart Diseases Myocardial Ischemia Kidney Disease End Stage Renal Failure on Dialysis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 777
Healthy volunteers: no

Brief summary:
The purpose of the ISCHEMIA-CKD trial is to determine the best management strategy for patients with stable ischemic heart disease (SIHD), at least moderate inducible ischemia and advanced chronic kidney disease (CKD; estimated glomerular filtration rate \[eGFR\] \<30 ml/min/1.73 m² or on dialysis). This is a multicenter randomized controlled trial of 777 randomized participants with advanced CKD. Participants were assigned at random to a routine invasive strategy (INV) with cardiac catheterization (cath) followed by revascularization (if suitable) plus optimal medical therapy (OMT) or to a conservative strategy (CON) of OMT, with cath and revascularization reserved for those who fail OMT. The trial is designed to run seamlessly in parallel to the main ISCHEMIA trial as a companion trial.

SPECIFIC AIMS

A. Primary Aim. The primary aim of the ISCHEMIA-CKD trial is to determine whether an invasive strategy of cardiac cath followed by optimal revascularization, in addition to OMT, will reduce the primary composite endpoint of death or nonfatal myocardial infarction in participants with SIHD and advanced CKD over an average follow-up of approximately 2.8 years compared with an initial conservative strategy of OMT alone with catheterization reserved for those who fail OMT. The primary endpoint is time to centrally adjudicated death or nonfatal myocardial infarction (MI).

B. Secondary Aims. Major: To compare the incident of the composite of death, nonfatal MI, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure, and angina symptoms and quality of life, as assessed by the Seattle Angina Questionnaire, between the INV and CON strategies. Other secondary aims include: comparing the incidence of the composite of death, nonfatal MI, hospitalization for unstable angina, hospitalization for heart failure, resuscitated cardiac arrest, or stroke; composite of death, nonfatal MI, or stroke; composite endpoints incorporating cardiovascular death; composite endpoints incorporating other definitions of MI as defined in the clinical event charter; individual components of the primary and major secondary endpoints; stroke and health resource utilization, costs, and cost effectiveness.

A major secondary aim of ISCHEMIA-CKD trial is to compare the quality of life (QOL) outcomes-patients' symptoms, functioning and well-being-between those assigned to an invasive strategy as compared with a conservative strategy. In the protocol, angina frequency and disease-specific quality of life measured by the Seattle Angina Questionnaire (SAQ) Angina Frequency and Quality of Life scales, respectively, are described as the tools that will be used to make this comparative assessment. Recent work has indicated that it is possible to combine the information from the individual domain scores in the SAQ into a new Summary Score that captures the information from the SAQ Angina Frequency, Physical Limitation and Quality of Life scales into a single overall score. The advantages of using a summary score as the primary measure of QOL effects of a therapy are a single primary endpoint comparison rather than two or three (eliminating concerns some may have about multiple comparisons) and a more intuitive holistic (patient-centric) interpretation of the effectiveness results. With these advantages in mind, the ISCHEMIA leadership has agreed that the SAQ Summary Score will be designated as the primary way this secondary endpoint will be analyzed and interpreted, with the individual SAQ scores being used in a secondary, explanatory and descriptive role. A key subgroup analysis will be to stratify the results among those with daily/weekly angina (baseline SAQ Angina Frequency score ≤60), monthly angina (SAQ Angina Frequency score 61-99) and no angina (SAQ Angina Frequency score = 100).

Condition: Coronary Disease Procedure: Cardiac catheterization Phase: Phase III Condition: Cardiovascular Diseases Procedure: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions Phase: Phase III Condition: Heart Diseases Procedure: Coronary Artery Bypass Surgery Phase: Phase III

Detailed description:
BACKGROUND:

Among patients with advanced CKD, cardiovascular disease is the leading cause of death,15-30 times higher than the age-adjusted cardiovascular mortality rate in the general population. The projected 4-year mortality is \>50% in patients with advanced CKD and is worse than that for patients in the general population who have cancers, heart failure, stroke or MI. Participants with advanced CKD are 5-10 times more likely to die than to reach end stage renal disease (ESRD). Despite this, \~80% of contemporary coronary artery disease (CAD) trials exclude participants with advanced CKD. Most of the treatments aimed at reducing cardiovascular events in advanced CKD are therefore extrapolated from cohorts without advanced CKD. Participants with advanced CKD and cardiovascular disease are undertreated with less frequent use of statins and revascularization therapies, and the optimal management approach to these patients is unknown. Participants with advanced CKD are notably underrepresented in contemporary trials comparing revascularization with medical therapy in SIHD patients, such as the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial or the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial,making any assessment about the efficacy of revascularization plus medical therapy vs. initial medical therapy alone in this cohort problematic.

Participants with advanced CKD are at increased risk for complications of the assigned invasive procedure, specifically contrast-induced acute kidney injury (AKI), dialysis, major bleeding and short-term risk of death. However, there is controversy in the medical literature regarding the incidence (\<1% to \>30%), effective treatment (saline hydration, N-acetyl cysteine, or sodium bicarbonate), and prognosis of contrast induced AKI (\<0.5% to \>5% requiring dialysis). In addition, although contrast induced AKI have been associated with increase in short-term mortality, residual confounding in these studies makes interpretation difficulty. Moreover, it is unknown if these short-term increased risks are offset by long-term benefits. Limited observational studies in the CKD cohort suggest a long-term survival benefit of revascularization when compared with medical therapy alone, despite an increase in short-term risks. However, the medical therapy in these trials was not optimized, drug eluting stents were rarely used and there is undoubtedly inherent selection and ascertainment bias with observational studies. The above has resulted in clinical equipoise in the management of these patients, with the rates of revascularization only around 10-45%. The results of ISCHEMIA-CKD will have profound implications for guidelines, health policy, and clinical practice.

Arms:
arm 1: Routine invasive strategy with cardiac catheterization followed by revascularization (Percutaneous Coronary Intervention or Coronary Artery Bypass Graft Surgery) plus optimal medical therapy. arm 2: Optimal medical therapy with cardiac catheterization and revascularization reserved for patients with OMT failure.

Interventions: intervention 1: Cardiac Catheterization intervention 2: Coronary Artery Bypass Graft Surgery intervention 3: Percutaneous Coronary Intervention intervention 4: Lifestyle intervention 5: Medication
Intervention descriptions: intervention 1: Narrowed blood vessels can be opened without surgery using stents or can be bypassed with surgery. To determine which is the best approach for you the doctor needs to look at your blood vessels to see where the narrowings are and how much narrowing there is. This is done by a procedure known as a cardiac catheterization. intervention 2: Artery narrowing is bypassed during surgery with a healthy artery or vein from another part of the body. This is known as coronary artery bypass grafting, or CABG (said "cabbage"). The surgery creates new routes around narrowed and blocked heart arteries. This allows more blood flow to the heart. intervention 3: Percutaneous coronary intervention may be done as part of the cardiac catheterization procedure. With this procedure a small, hollow, mesh tube (stent) is inserted into the narrowed part of the artery. The stent pushes the plaque against the artery wall, and opens the vessel to allow better blood flow. intervention 4: Diet, physical activity, smoking cessation intervention 5: antiplatelet, statin, other lipid lowering, antihypertensive, and anti-ischemic medical therapies

Protocol document:
Prot_SAP_000.pdf: 
  
 
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ISCHEMIA-CKD Trial Protocol 
International Study of Comparative Health Effectiveness 
with Medical and Invasive Approaches- Chronic Kidney 
Disease 
Sponsor: 
National Heart, Lung, and Blood Institute (NHLBI) 
 
ISCHEMIA Study Chair 
 
Judith S. Hochman, MD 
 
 
ISCHEMIA Study Co-Chair 
 
ISCHEMIA CKD Trial Principal 
Investigator  
 
David J. Maron, MD 
 
Sripal Bangalore, MD 
 
 
Clinical Coordinating Center 
 
Cardiovascular Clinical Research Center 
New York University School of Medicine 
 
 
 
 
Statistical and Data Coordinating 
Center 
 
 
Duke Clinical Research Institute 
Protocol Version Date: 
 
       December 18, 2014 
 
 
 
 


  
 
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PROTOCOL VERSION AND AMENDMENT TRACKING 
 
Version Number/Amendment 
Approval Date 
1.0 
December 18, 2014 
 
 
 
 
 
 
 


  
 
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Protocol Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable regulations and ICH guidelines.  
Version Date:  December 18, 2014 
 
_________________________________ 
 
_________________________ 
Signature of Principal Investigator                            Date 
 
_________________________________ 
 
 
Printed Name of Principal Investigator                       
 
_________________________________ 
 
 
Name of Facility 
 
_________________________________ 
 
 
Location of Facility (City, Country) 
 
 


  
 
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CLINICAL TRIAL SUMMARY  
Title 
International Study of Comparative Health Effectiveness with Medical and 
Invasive Approaches- Chronic Kidney Disease 
Study Objectives 
Primary objective is to determine whether an initial invasive (INV) strategy 
of cardiac catheterization and optimal revascularization, if feasible, in 
addition to optimal medical therapy (OMT) in patients with stable ischemic 
heart disease (SIHD) and at least moderate ischemia on ischemia testing 
reduces the incidence of the composite of death or nonfatal myocardial 
infarction compared with a conservative (CON) strategy of optimal medical 
therapy alone with cardiac catheterization and revascularization reserved 
for failure of OMT, in participants with advanced CKD (defined as those 
with estimated glomerular filtration rate [eGFR] <30 or on dialysis). 
Secondary objective is to determine whether an INV strategy is more 
effective than CON strategy in improving angina control, as assessed by 
the Seattle Angina Questionnaire (SAQ) Angina Frequency scale, and 
disease-specific quality of life, as assessed by the SAQ Quality of Life 
scale.  
Other secondary objectives include comparing the incidence of the 
composite of cardiovascular death, nonfatal myocardial infarction, 
resuscitated cardiac arrest, or hospitalization for unstable angina or heart 
failure; individual components of this endpoint; all-cause death; stroke; as 
well as comparing health resource utilization, cost, and cost-effectiveness 
between the two randomized strategies. 
Study Design 
ISCHEMIA-CKD is an international comparative effectiveness study. 
Participants will be recruited following clinically indicated ischemia testing 
and randomized in a 1:1 fashion to an INV or CON strategy. 
Number of 
Participants 
Approximately 1,000 participants randomized  
Trial Location 
Multinational: approximately 500 sites worldwide 
Inclusion Criteria 
 At least moderate ischemia on an ischemia test (see definitions in 
protocol appendix A)  
 End stage renal disease on dialysis or estimated glomerular filtration 
rate (eGFR) <30mL/min  
 Participant is willing to comply with all aspects of the protocol, including 
adherence to the assigned strategy, medical therapy and follow-up 
visits 


  
 
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 Participant is willing to give written informed consent 
 Age ≥ 21 years 
Exclusion Criteria 
 LVEF < 35% 
 History of unprotected left main stenosis >50% on prior coronary 
computed tomography angiography (CCTA) or prior cardiac 
catheterization (if available) 
 Finding of “no obstructive CAD” (<50% stenosis in all major epicardial 
vessels) on prior CCTA or prior catheterization, performed within 12 
months  
 Coronary anatomy unsuitable for either PCI or CABG  
 Unacceptable level of angina despite maximal medical therapy 
 Very dissatisfied with medical management of angina 
 History of noncompliance with medical therapy  
 Acute coronary syndrome within the previous 2 months  
 PCI within the previous 12 months 
 Stroke within the previous 6 months or spontaneous intracranial 
hemorrhage at any time 
 History of ventricular tachycardia requiring therapy for termination, or 
symptomatic sustained ventricular tachycardia not due to a transient 
reversible cause 
 NYHA class III-IV heart failure at entry or hospitalization for 
exacerbation of chronic heart failure within the previous 6 months 
 Non-ischemic dilated or hypertrophic cardiomyopathy 
 Severe valvular disease or valvular disease likely to require surgery or 
percutaneous valve replacement during the trial  
 Allergy to radiographic contrast that cannot be adequately pre-
medicated, or any prior anaphylaxis to radiographic contrast 
 Planned major surgery necessitating interruption of dual antiplatelet 
therapy  (note that patients may be eligible after planned surgery) 
 Life expectancy less than the duration of the trial due to non-
cardiovascular comorbidity  
 Pregnancy (known to be pregnant; to be confirmed 
beforerandomization, if applicable) 
 Patient who, in the judgment of the patient’s physician, is likely to have 


  
 
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significant unprotected left main stenosis 
 Enrolled in a competing trial that involves a non-approved cardiac drug 
or device 
 Inability to comply with the protocol  
 Exceeds the weight or size limit for cardiac catheterization at the site 
 Canadian Cardiovascular Society Class III angina of recent onset, OR 
angina of any class with a rapidly progressive or accelerating pattern 
 Canadian Cardiovascular Society Class IV angina, including 
unprovoked rest angina  
 High risk of bleeding which would contraindicate the use of dual 
antiplatelet therapy  
 Cardiac transplant recipient  
 Prior CABG, unless CABG was performed more than 12 months ago, 
and coronary anatomy has been demonstrated to be suitable for PCI 
or repeat CABG to accomplish complete revascularization of ischemic 
areas (CCC approval required) 
Primary Endpoint 
Time to first occurrence of death or nonfatal myocardial infarction. 
Secondary 
Endpoints 
 Angina control per SAQ Angina Frequency Scale 
 Disease-specific quality of life per SAQ Quality of Life Scale  
 Composite of cardiovascular death, nonfatal myocardial infarction, or 
stroke 
 Composite of cardiovascular death, nonfatal myocardial infarction, 
resuscitated cardiac arrest, or hospitalization for unstable angina or 
heart failure 
 All-cause death 
 Cardiovascular death 
 Nonfatal MI  
 Resuscitated cardiac arrest 
 Hospitalization for unstable angina 
 Hospitalization for heart failure 
 Stroke 
 Composite of cardiovascular death, nonfatal myocardial infarction, 
stroke, resuscitated cardiac arrest, hospitalization for unstable angina 


  
 
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or heart failure. 
 Health resource utilization, costs, and cost-effectiveness 
Assessment 
Schedule 
Pre-eligibility screening, randomization, 1.5 months, 3 months, 6 months, 
12 months, and every 6 months thereafter. 
Study Duration 
Enrollment will occur over approximately 3.5 years with an expected 
minimum of 18-24 months follow-up and an average of approximately 
4 years follow-up.  
Clinical Event 
Adjudication 
Committee 
The following events will be adjudicated by a blinded Clinical Event 
Adjudication Committee: death, myocardial infarction, resuscitated cardiac 
arrest, hospitalization for unstable angina, hospitalization for heart failure, 
and stroke. 
Data and Safety 
Monitoring Board 
An independent Data and Safety Monitoring Board will advise the NHLBI 
and study leadership on safety aspects and overall progress of the study. 
Statistical 
Considerations 
A sample size of approximately 1,000 randomized participants is expected 
to provide ≥80-95% power to detect a 15%-19% reduction in the primary 
composite event rate in participants randomized to INV as compared with 
CON strategy. 
 
 
 


  
 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS ...................................................................................... 11 
2. 
BACKGROUND AND RATIONALE ........................................................................................................ 15 
3. 
STUDY OBJECTIVES ............................................................................................................................. 16 
4. 
STUDY DESIGN .................................................................................................................................... 17 
4.1 
Study Flow ........................................................................................................................ 17 
4.2 
Study Population ............................................................................................................... 19 
4.3 
Inclusion/Exclusion Criteria ............................................................................................... 19 
4.3.1 
Criteria Prior to Informed Consent ....................................................................................................... 19 
4.3.2 
Criteria After Enrollment (Informed Consent) and Prior to Randomization ....................................... 20 
5. 
STUDY PROCEDURES .......................................................................................................................... 21 
5.1 
Qualifying Ischemia Test .................................................................................................... 21 
5.2 
Informed Consent Process ................................................................................................. 21 
5.3 
Interactive Voice Response System (IVRS) and Interactive Web Response System (IXRS) ..... 21 
5.4 
Core Lab Ischemia Verification ........................................................................................... 22 
6. 
MANAGEMENT STRATEGIES .............................................................................................................. 23 
6.1 
Conservative (CON) Strategy .............................................................................................. 23 
6.2 
Invasive (INV) Strategy ...................................................................................................... 23 
6.3 
Optimal Medical Therapy (OMT) ........................................................................................ 23 
6.3.1 
Management of Angina in CON Participants........................................................................................ 24 
6.3.2 
Management of Angina in INV Participants ......................................................................................... 24 
6.4 
Optimal Revascularization Therapy (ORT) .......................................................................... 24 
6.4.1 
Criteria to Select PCI vs. CABG .............................................................................................................. 25 
6.4.2 
Guidelines for Optimal Percutaneous Coronary Intervention ............................................................. 25 
6.4.3 
Guidelines for Optimal Surgical Revascularization .............................................................................. 25 
6.5 
Maximizing Adherence to CON Strategy ............................................................................. 25 
6.6 
Cath in Participants Randomized to CON Strategy .............................................................. 26 
7. 
AUXILLIARY SCREENING LOG  ............................................................................................................ 28 
7.1 
Screening Log .................................................................................................................... 28 
8. 
Study Assessments ............................................................................................................................. 29 
8.1 
Creatinine and Pregnancy Test ........................................................................................... 29 
8.2 
Standard Blood Tests ......................................................................................................... 29 
8.3 
Endpoint Assessments ....................................................................................................... 29 


  
 
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8.4 
Blood Biomarkers and Genomics Biorepository .................................................................. 29 
8.5 
Medication Adherence ...................................................................................................... 30 
8.6 
Lifestyle Assessment ......................................................................................................... 30 
8.7 
Quality of Life Assessment ................................................................................................. 30 
8.8 
Economics Assessment ...................................................................................................... 30 
9. 
SCHEDULE OF ASSESSMENTS ............................................................................................................. 31 
10. 
ADJUDICATION OF CLINICAL EVENTS ............................................................................................ 40 
11. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN .................................................................. 41 
11.1 
Sample Size Determination and Statistical Power ............................................................... 41 
11.1.1 
Summary of Power and Precision .................................................................................................... 41 
11.2 
Statistical Analysis Plan ..................................................................................................... 41 
11.2.1 
Analysis of the Primary Endpoint ..................................................................................................... 42 
11.2.2 
Analysis of the Secondary Endpoints ............................................................................................... 42 
11.2.3 
Contingency Plan For Insufficient Primary Endpoint Events ........................................................... 43 
11.2.4 
Quality of Life (QOL) Analysis ........................................................................................................... 43 
11.2.5 
Health Economics Analysis ............................................................................................................... 44 
11.2.6 
Interim Analysis ................................................................................................................................ 44 
12. 
DATA HANDLING AND RECORD KEEPING ...................................................................................... 46 
12.1 
Electronic Data Capture (EDC) System ................................................................................ 46 
12.2 
Data Management and Quality .......................................................................................... 46 
12.3 
Data Confidentiality and Security ....................................................................................... 46 
12.4 
Training ............................................................................................................................ 47 
12.5 
Records Retention ............................................................................................................. 47 
13. 
SAFETY MONITORING PLAN ........................................................................................................... 48 
13.1 
Data and Safety Monitoring Board ..................................................................................... 48 
13.2 
Risks and Benefits ............................................................................................................. 48 
13.3 
Safety Monitoring Objectives and Rationale ...................................................................... 49 
13.4 
Adverse Events Reporting by Investigators ......................................................................... 49 
13.5 
Events to be Monitored ..................................................................................................... 49 
14. 
ETHICAL CONSIDERATIONS ............................................................................................................ 51 
14.1 
Regulatory and Ethical Compliance .................................................................................... 51 
14.2 
Informed Consent Process ................................................................................................. 51 
14.3 
Responsibilities of the Investigator and IRB/IEC/REB .......................................................... 51 
14.4 
Protocol Amendments ....................................................................................................... 51 


  
 
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14.5 
Early Termination of the Study .......................................................................................... 52 
15. 
STUDY ORGANIZATION .................................................................................................................. 53 
16. 
DATA ACCESS AND SHARING ......................................................................................................... 54 
17. 
PUBLICATIONS POLICY: OVERVIEW ............................................................................................... 55 
18. 
REFERENCE LIST .............................................................................................................................. 56 
19. 
APPENDIX A .................................................................................................................................... 59 
 


  
 
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1. 
LIST OF ABBREVIATIONS AND DEFINITIONS  
ACC 
American College of Cardiology 
ACE-I 
angiotensin converting enzyme inhibitor 
ACS 
acute coronary syndrome 
AHA 
American Heart Association 
AST 
aspartate aminotransferase 
ALT 
alanine aminotransferase 
BARI 2D 
Bypass Angioplasty Revascularization Investigation 2 Diabetes trial 
CABG 
coronary artery bypass graft 
CAD 
coronary artery disease 
Cath 
cardiac catheterization 
CCC 
Clinical Coordinating Center 
CCS 
Canadian Cardiovascular Society  
CEC 
clinical event adjudication committee 
CI 
confidence interval 
CKD 
Chronic kidney disease (defined as those with estimated glomerular filtration 
rate [eGFR] <30 or on dialysis) 
CK-MB 
creatinine kinase-MB 
CL 
Core laboratory 
CMR 
cardiac magnetic resonance 
CON 
Conservative management strategy (initial management with OMT alone, 
with cath and revascularization reserved for refractory symptoms or acute 
ischemic events) 
COURAGE 
Clinical Outcomes Utilizing Revascularization and Aggressive Drug 
Evaluation trial 
CV 
Cardiovascular 
DASI 
Duke Activity Status Index 


  
 
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DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
Echo 
echocardiography  
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetraacetic acid 
ERES 
electronic signature 
eGFR 
estimated glomerular filtration rate 
EQ-5D 
self-reported generic preference-based measure of health, developed by the 
EuroQol Group 
EQOL 
economic and quality of life 
EQOLCC 
EQOL Coordinating Center 
ESC 
European Society of Cardiology 
ETT 
Exercise tolerance testing 
EU Directive 
European Union Directive on Data Privacy 
FFR 
fractional flow reserve 
HbA1c 
hemoglobin A1c 
HDL 
high density lipoprotein 
HF 
heart failure 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Hazard Ratio 
ICC 
Ischemia Imaging Coordinating Center 
ICH 
International Conference on Harmonization 
IEC 
institutional ethics committee 
INV 
invasive management strategy (cath with intent to perform optimal 


  
 
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revascularization plus optimal medical therapy) 
IRB 
Institutional Review Board 
ISCHEMIA 
International Study of Comparative Health Effectiveness with Medical and 
Invasive Approaches trial 
IVRS 
interactive voice response system 
IVUS 
intravascular ultrasound 
IXRS 
interactive web response system 
LM CAD 
left main coronary artery disease 
LOT-R 
Life Orientation Test – Revised 
LVEF 
left ventricular ejection fraction 
MI 
myocardial infarction 
MOE 
margin of error 
MOO 
Manual of Operations 
MPI 
myocardial perfusion imaging 
NHLBI 
National Heart, Lung, and Blood Institute 
NIH 
National Institutes of Health 
NINDS 
National Institute of Neurological Disorders and Stroke 
NYHA 
New York Heart Association 
OMT 
optimal medical therapy 
ORT 
optimal revascularization therapy 
PACE 
Patient-centered Assessment and Counseling for Exercise and nutrition 
PCI 
percutaneous coronary intervention 
PET 
positron emission tomography 
PHI 
protected health information 
PHQ-8 
Patient Health Questionnaire-8 
PI 
Principal Investigator 


  
 
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PIPEDA 
Personal Information Protection and Electronic Documents Act 
PSS 
Perceived Stress Scale 
REB 
Research Ethics Board 
RNA 
ribonucleic acid 
SAC 
statistical analysis center 
SAQ 
Seattle Angina Questionnaire 
SDCC 
Statistical and Data Coordinating Center 
SIHD 
stable ischemic heart disease 
SPECT 
single photon emission computed tomography 
WHF 
World Heart Federation 
 


  
 
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2. 
BACKGROUND AND RATIONALE  
Among patients with advanced CKD, cardiovascular disease is the leading cause of death,1, 2 
15-30 times higher than the age-adjusted cardiovascular mortality rate in the general 
population.3, 4 The projected 4-year mortality is >50% in patients with advanced CKD 5-9  and is 
worse than that for patients in the general population who have cancers, heart failure, stroke or 
MI.10 Participants with advanced CKD are 5-10 times more likely to die than to reach end stage 
renal disease (ESRD).11  Despite this, ~80% of contemporary coronary artery disease (CAD) 
trials exclude participants with advanced CKD. 12 Most of the treatments aimed at reducing 
cardiovascular events in advanced CKD are therefore extrapolated from cohorts without 
advanced CKD. Participants with advanced CKD and cardiovascular disease are undertreated 
with less frequent use of statins and revascularization therapies, and the optimal management 
approach to these patients is unknown. Participants with advanced CKD are notably 
underrepresented in contemporary trials comparing revascularization with medical therapy in 
SIHD patients, such as the Bypass Angioplasty Revascularization Investigation 2 Diabetes 
(BARI 2D) trial13 or the Clinical Outcomes Utilizing Revascularization and Aggressive Drug 
Evaluation (COURAGE) trial,14 making any assessment about the efficacy of revascularization 
plus medical therapy vs. initial medical therapy alone in this cohort problematic. 
Participants with advanced CKD are at increased risk for complications of the assigned invasive 
procedure, specifically contrast-induced acute kidney injury (AKI), 15, 16 dialysis, major bleeding 
and short-term risk of death. However, there is controversy in the medical literature regarding 
the incidence (<1% to >30%), effective treatment (saline hydration, N-acetyl cysteine, or sodium 
bicarbonate) and prognosis of contrast induced AKI (<0.5% to >5% requiring dialysis).17-20 In 
addition although contrast induced AKI have been associated with increase in short-term 
mortality residual confounding in these studies makes interpretation difficult. Moreover it is 
unknown if these short-term increased risks are offset by long-term benefits. Limited 
observational study in the CKD cohort suggests a survival benefit of revascularization when 
compared with medical therapy alone long-term, 21-24 despite increase in short-term risks. 
However, the medical therapy in these trials was not optimized, drug eluting stents were rarely 
used and there is undoubtedly inherent selection and ascertainment bias with observational 
studies. The above has resulted in substantial clinical equipoise in the management of 
these patients with the rates of revascularization of only around 10-45%.21, 23, 25 The results 
of ISCHEMIA-CKD will have profound implications for guidelines, health policy, and clinical 
practice. 
 
 
 


  
 
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3. 
STUDY OBJECTIVES 
PRIMARY AIM 
The primary aim of the ISCHEMIA-CKD trial is to determine whether an initial invasive strategy 
of cardiac catheterization and optimal revascularization, if feasible, in addition to OMT, will 
reduce the primary composite endpoint of death or nonfatal myocardial infarction in participants 
with SIHD and at least moderate ischemia over an average follow-up of approximately 4 years 
compared with an initial conservative strategy of OMT alone with catheterization reserved for 
failure of OMT, in participants with advanced CKD. 
SECONDARY AIMS 
The secondary aims are to compare the following clinical and economic outcomes in 
participants randomized to INV or CON strategies: 
 
Angina control, as assessed by the Seattle Angina Questionnaire (SAQ) Angina 
Frequency scale 
 
Disease-specific quality of life, as assessed by the SAQ Quality of Life   
 
Composite of cardiovascular death, nonfatal myocardial infarction, or stroke 
 
Composite of cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac 
arrest, or hospitalization for unstable angina or heart failure 
 
All-cause death 
 
Cardiovascular death 
 
Nonfatal MI  
 
Resuscitated cardiac arrest 
 
Hospitalization for unstable angina 
 
Hospitalization for heart failure 
 
Stroke 
 
Composite of cardiovascular death, nonfatal myocardial infarction, stroke, resuscitated 
cardiac arrest, or hospitalization for unstable angina or heart failure. 
 
Health resource utilization, costs, and cost-effectiveness 
 
 


  
 
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4. 
STUDY DESIGN 
The ISCHEMIA-CKD trial is an international, randomized, comparative effectiveness study. 
Approximately 1,000 participants at approximately 500 sites worldwide with advanced CKD 
(defined as eGFR<30 or on dialysis) and at least moderate  ischemia on ischemia testing will be 
randomized in a 1:1 fashion to the INV or CON strategies. 
The design of the trial to randomize patients upstream of cath is advantageous as it will expose 
only 50% of participants (enrolled to INV) to contrast agent and will be the largest treatment 
strategy trial in advanced CKD patients with SIHD.  
ISCHEMIA-CKD is designed to run in parallel with it’s parent study, ISCHEMIA, which 
randomizes patients with eGFR >30, SIHD, and at least moderate ischemia in 1:1 fashion to the 
INV or CON strategies.  
4.1 
Study Flow 
See figure 1 for details. Patients with advanced CKD and at least moderate ischemia  (see 
section 5.1) will be identified and screened for clinical inclusion/exclusion criteria (see section 
4.3). Patients who are suspected to be trial eligible may also be pre-screened, for example, prior 
to clinically indicated ischemia testing in clinical areas where SIHD patients are cared for. 
Patients who meet clinical and ischemia (site-interpreted) eligibility criteria and are interested in 
participating in the trial will be enrolled by signing an informed consent and receiving a study 
number via the interactive voice response system (IVRS) or interactive web response system 
(IXRS) (see section 5.3). Ischemia test data (e.g., images, ECG, report) will be transferred to 
the relevant core lab electronically for enrolled participants (see Figure 1).   
Participants with known or a high likelihood of unprotected left main stenosis ≥50% will be 
excluded before randomization. Timing of Randomization: Participants determined to be eligible 
for randomization should be randomized within a target of 15 days of consent, and participants 
randomized to INV strategy should undergo catheterization within a target of 30 days after 
randomization, with optimal revascularization therapy (ORT) soon thereafter as appropriate. 
Participants will be enrolled over approximately 3.5 years. Randomized participants will be 
followed for an average of approximately 4 years.  The minimum follow-up period for 
randomized participants will be approximately 18-24 months following randomization of the final 
participant. A schedule of assessments is provided in section 9.


  
 
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18 
 
Figure 1 
Study Flow 
1
 Core lab interpretations will be used for post-hoc data analysissites   
R A N D O M I Z E  
(via IVRS) 
Follow-up as per 
schedule of 
assessments  
SIHD with 
at least 
moderate 
ischemia 
AND 
eGFR <30 
or on 
dialysis 
Meets all 
clinical and 
site 
determined 
ischemia 
criteria 
Consent and 
Enrollment 
(via IVRS)  
+  
Transmit 
Qualifying 
Ischemia Test 
to Core Lab
1
 
INV 
Strategy 
CON 
Strategy 
Ineligible 
Target 90 Days 
Target 15 Days Enrollment to Randomization 
YES 
YES 
NO 
      Target 30 Days 
Cath and 
revascularization 


 
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4.2 
Study Population 
 
Patients with advanced CKD, SIHD and at least moderate ischemia. SIHD is synonymous with 
stable coronary artery disease, and refers to patients with coronary artery disease who are 
clinically stable (i.e., who are not in an unstable phase such as an acute coronary syndrome).  
Enrollment within any subgroup, including by trial site or region, may be capped in order to 
ensure the trial population’s representativeness.  
 
4.3 
Inclusion/Exclusion Criteria  
Screening for inclusion/exclusion criteria will include assessment for clinical and ischemia 
criteria at the local site and ability and willingness to provide informed consent.  
4.3.1 Criteria Prior to Informed Consent 
Patients will be screened for the following inclusion and exclusion criteria: 
Inclusion (pre informed consent) 
1. At least moderate ischemia on qualifying ischemia test (See protocol appendix A) 
2. End stage renal disease on dialysis or estimated glomerular filtration rate (eGFR) <30 
ml/min 
3. Participant is willing to give informed consent 
4. Age ≥ 21 years 
Exclusion (pre informed consent) 
1. LVEF <35%  
2. History of unprotected left main stenosis ≥50% on prior coronary computed tomography 
angiography (CCTA) or prior cardiac catheterization (if available)  
3. Finding of “no obstructive CAD” (<50% stenosis in all major epicardial vessels) on prior 
CCTA or prior catheterization, performed within 12 months 
4. Coronary anatomy unsuitable for either PCI or CABG 
5. Unacceptable level of angina despite maximal medical therapy 
6. Very dissatisfied with medical management of angina  
7. History of noncompliance with medical therapy  
8. Acute coronary syndrome within the previous 2 months 
9. PCI within the previous 12 months 
10. Stroke within the previous 6 months or spontaneous intracranial hemorrhage at any time 


 
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11. History of ventricular tachycardia requiring therapy for termination, or symptomatic 
sustained ventricular tachycardia not due to a transient reversible cause 
12. NYHA class III-IV heart failure at entry or hospitalization for exacerbation of chronic 
heart failure within the previous 6 months 
13. Non-ischemic dilated or hypertrophic cardiomyopathy 
14. Severe valvular disease or valvular disease likely to require surgery or percutaneous 
valve replacement during the trial  
15. Allergy to radiographic contrast that cannot be adequately pre-medicated, or any prior 
anaphylaxis to radiographic contrast 
16. Planned major surgery necessitating interruption of dual antiplatelet therapy (note that 
patients may be eligible after planned surgery) 
17. Life expectancy less than the duration of the trial due to non-cardiovascular comorbidity 
18. Pregnancy (known to be pregnant; to be confirmed pre- randomization, if applicable) 
19. Patient who, in the judgment of the patient’s physician, is likely to have significant 
unprotected left main stenosis  
20. Enrolled in a competing trial that involves a non-approved cardiac drug or device 
21. Inability to comply with the protocol 
22. Exceeds the weight or size limit for cardiac catheterization at the site 
23. Canadian Cardiovascular Society Class III angina of recent onset, or angina of any class 
with a rapidly progressive or accelerating pattern 
24. Canadian Cardiovascular Society Class IV angina, including unprovoked rest angina 
25. High risk of bleeding which would contraindicate the use of dual antiplatelet therapy 
26. Cardiac transplant recipient 
27. Prior CABG, unless CABG was performed more than 12 months ago and coronary 
anatomy has been demonstrated to be suitable for PCI or CABG to accomplish complete 
revascularization of ischemic areas (CCC approval required) 
 
4.3.2 Criteria After Enrollment (Informed Consent) and Prior to Randomization  
Participants who provide informed consent and are clinically eligible will be registered via the 
IVRS/IXRS system. They are considered enrolled. Participants meeting the following exclusion 
criteria will not be randomized. 
Exclusion (after informed consent and before randomization) 
1. Pregnant (negative pregnancy test required for premenopausal females) 
2. Interval development of a clinical event e.g., a primary or secondary endpoint event or 
interval development or discovery of an exclusion criterion


 
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5. 
STUDY PROCEDURES 
5.1 
Qualifying Ischemia Test  
The criteria for at least moderate ischemia with each test modality and the rationale for their 
selection are described in protocol appendix A. Ischemia tests documenting eligibility may be 
performed before or after medical therapy for SIHD has been initiated and adjusted. Similarly, 
participants already taking medical therapy for SIHD may have been on or off medications on the 
day of the ischemia test documenting eligibility, consistent with customary clinical practice.26, 27 A 24-
hour, 7-day helpline will be available to sites for assistance with ascertainment of eligibility, 
enrollment, and adherence to protocol.  
5.2 
Informed Consent Process 
The study will be reviewed with the prospective study participant by the investigator or his/her 
designee. This discussion is a critical component of the consent process and the prospective study 
participant will be given adequate time for this discussion and to read the written consent form.  Two 
standard clinical care strategies are being compared in this study and clinicians should enroll 
patients for whom there is clinical equipoise regarding their management. Prevailing practice 
patterns vary widely within and between regions; the discussion with prospective participants should 
note these local patterns. The investigator or his/her designee will be available to answer questions 
about the study including procedures, risks, and alternatives. The informed consent form will be 
signed and dated by the patient as per local regulation. 
In addition, prospective study participants will be requested to consent to a biorepository sample, 
and to allow use of the biorepository sample for biomarkers and/or genetic analysis (DNA) in this 
optional study component conducted at participating sites.  Prospective study participants will be 
informed that declining participation in the biomarker or genetic analysis portion of the study does 
not preclude their participation in the main study.  A copy of the signed consent form will be given to 
the participant and the original(s) will be kept securely with each participant’s research records.   
Specific consent will be obtained before any protocol-mandated procedure that requires consent is 
performed. The consent will allow for protected health information (PHI) to be transferred to the 
Clinical Coordinating Center (CCC) and/or the Regional Research Organization that serves as the 
Coordinating Center in the country/region unless prohibited by regulations. This will make it possible 
for another site within that country or the CCC to follow participants if a site closes down or cannot 
continue follow-up for any reason, and to look up vital status. Privacy regulations in all countries will 
be followed, (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the US; Personal 
Information Protection and Electronic Documents Act [PIPEDA] in Canada; European Union 
Directive on Data Privacy [EU Directive]). For North American participants only, PHI will also be sent 
to the EQOLCC. 
5.3 
Interactive Voice Response System (IVRS) and Interactive Web Response 
System (IXRS) 


 
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Enrollment and randomization will be accomplished by contact with the IVRS or IXRS. When a 
participant meeting site-determined clinical and ischemia test criteria has provided informed consent, 
the study coordinator or investigator at the site will call the IVRS or log on to the IXRS to receive a 
participant identification number.  At this point the participant is registered as enrolled.   
Several language options will be provided for international sites using IVRS/IXRS. To eliminate any 
manual transcription errors, IVRS/IXRS will be programmed to electronically transfer the participant 
data and study identification number to create the participant’s case book within the electronic data 
capture (EDC) system.  
In order to randomize the participant, the study coordinator or investigator will call IVRS or log in to 
IXRS a second time. Subjects meeting all clinical, and siteinclusion/exclusion criteria will then be 
randomized to either the INV or CON strategy and will be registered as randomized. This information 
will be transmitted to the participant’s electronic case book within the EDC system.  
Detailed information on enrollment and randomization will be provided in the MOO and in specific 
IVRS/IXRS materials. 
5.4 
Core Lab Ischemia Verification 
Ischemia test data (e.g., images, ECG, reports) will be transferred electronically to the appropriate 
core lab for enrolled participants. The core labs will review and interpret the degree of ischemia; this 
data will be used for post-hoc analysis.    


 
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6. 
MANAGEMENT STRATEGIES 
Table 1.  Components of CON and INV management strategies 
 
CON (Section 6.1) 
 
INV (Section 6.2) 
 
Optimal medical therapy (OMT; includes 
angina management) (Section 6.3) 
 
Provisional cardiac catheterization (Section 
6.6) 
 
Optimal medical therapy (OMT; includes 
angina management) (Section 6.3) 
 
Cardiac catheterization  
 
Optimal revascularization therapy (ORT) 
(Section 6.4) 
 
6.1 
Conservative (CON) Strategy 
In participants randomized to the CON strategy, initial management with OMT alone will be 
employed (described below). A fundamental principle of the CON strategy is to restrict cath to 
participants who fail OMT, i.e., those who experience an acute coronary syndrome, acute ischemic 
heart failure or resuscitated cardiac arrest or who have angina that is refractory to maximal medical 
therapy. In such participants who require cath during follow-up, revascularization should be 
performed using the principles of optimal revascularization therapy as outlined below.  
6.2 
Invasive (INV) Strategy  
In participants randomized to INV strategy, initial management with cath will be performed, with 
subsequent revascularization, as appropriate, based upon coronary anatomy and other clinical 
considerations. The principles of optimal revascularization therapy will be followed (described 
below). In addition, all INV participants will receive OMT as outlined below. 
6.3 
Optimal Medical Therapy (OMT)  
OMT will consist of intensive, comprehensive secondary prevention with lifestyle and pharmacologic 
intervention applied equally to both treatment groups using individualized treatment regimens based 
on treat-to-target algorithms under supervision by the site PI and in conjunction with the participant’s 
primary care physician and/or cardiologist. The research team in collaboration with the participant’s 
treating physicians will implement changes in medical therapy in keeping with guideline 
recommendations. The research team will obtain results of routine laboratory tests that reflect 
secondary prevention targets performed by the participant’s physician and provide the results of any 
tests obtained by the study to the participant’s physician. Behavioral interventions will focus on 
smoking cessation, nutrition, physical activity, weight control, and medication adherence. 
Pharmacologic interventions will include anti-atherothrombotic and anti-ischemic medications. The 


 
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minimum goals of OMT will be those recommended for SIHD patients by national/international 
organizations (e.g., the National Cholesterol Education Program, American College of Cardiology, 
American Heart Association, European Society of Cardiology, and World Health Organization). 
Details of this strategy are provided in the MOO and will be updated, as needed, over the course of 
the trial. 
6.3.1 Management of Angina in CON Participants 
Medical management of angina in CON participants will be intensified according to the ISCHEMIA-
CKD angina treatment algorithm (see MOO). The goal for all CON participants is to control angina 
such that participants report a good angina-related quality of life. If the level of angina is 
unacceptable to the participant despite maximal medical therapy, then cath and possible 
revascularization is recommended, consistent with good medical care. 
6.3.2 Management of Angina in INV Participants 
Participants randomized to the INV strategy who experience angina following revascularization may 
be treated medically, as per the ISCHEMIA-CKD angina treatment algorithm (see MOO). The goal 
for all INV participants is to control angina such that participants report a good angina-related quality 
of life. Unlike the approach to CON participants with angina, repeat cath and revascularization may 
be performed without first maximizing medical therapy in INV participants. 
6.4 
Optimal Revascularization Therapy (ORT) 
Optimal revascularization therapy will be performed based on findings from the diagnostic 
catheterization and relevant clinical information. While the selection of PCI vs. CABG (or medical 
therapy only in cases of normal coronary arteries, diffuse small vessel disease, etc.) will be left to 
the discretion of the treating team per local standards and expertise, several general principles 
should be followed: 
 
The revascularization modality selected should have the highest likelihood to safely and 
effectively relieve significant ischemia in all viable myocardial territories of at least moderate 
size.  
 
Decisions regarding viability testing and revascularization decisions based on such testing 
should be based on routine clinical practice. 
 
Revascularization should be performed with a goal of relieving all areas of significant 
ischemia, i.e., ischemia that would be detected by non-invasive imaging or FFR. 
 
Prior to selection of the revascularization modality, ischemic territories should be identified 
based on the results of noninvasive tests, angiography and, in selected cases, FFR (as 
outlined in the MOO).  
Details of ORT are provided in the MOO and will be updated, as needed, over the course of the trial. 
 
 


 
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6.4.1 Criteria to Select PCI vs. CABG 
In general, the decision between PCI and CABG will be determined according to local hospital 
standards and practices. Guidelines from professional societies and appropriateness criteria should 
be incorporated into the decision process. It is desirable for the study Heart Team (interventional 
cardiologist and cardiac surgeon) to discuss each case after diagnostic angiogram to reach a 
consensus as to the best revascularization technique.  
It is recognized, however, that in some cases of non-complex coronary artery disease the 
performance of “ad hoc” PCI after diagnostic angiography may be preferred by participants and 
physicians. Whenever possible, the Heart Team should record an opinion on each participant 
regarding the best mode of revascularization, reaching consensus where possible and recording 
disagreement if not possible.   
Details are provided in the MOO. 
6.4.2 Guidelines for Optimal Percutaneous Coronary Intervention 
PCI should be performed in a manner considered optimal by contemporary standards and 
guidelines. Procedural strategy, device selection, adjunctive medical therapy, pre-procedural 
preparation, post-procedural care and supportive services, and clinical site and operator experience 
are each areas where optimal performance is required. Details of this are provided in the MOO and 
will be updated as needed over the course of the trial.  
6.4.3 Guidelines for Optimal Surgical Revascularization  
The term optimal CABG is reserved for a comprehensive approach towards surgical 
revascularization that minimizes periprocedural risk and optimizes short- and long-term outcomes 
with regard to the progressive nature of atherosclerotic heart disease. This goes well beyond the 
intraoperative technical aspects of surgical revascularization. 
 
The principles for optimal CABG include: 
 
Accurate assessment and evaluation of potential CABG participants 
 
Complete revascularization (anatomic and physiologic criteria)  
 
Optimize intraoperative management, including myocardial protection 
 
Minimize associated organ and system injury 
 
Maximize opportunity for long-term graft patency 
 
Optimize secondary prevention of atherosclerotic heart disease following CABG 
 
Details of this are provided in the MOO. 
 
6.5 
Maximizing Adherence to CON Strategy 
Adherence to the CON strategy means that all CON participants receive OMT and that none 
undergo cath or revascularization after randomization unless they 1) have an acute coronary 
syndrome, resuscitated cardiac arrest, or acute ischemic heart failure or 2) have unacceptable 
angina refractory to maximal medical therapy (see MOO for definition and recommended 


 
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management of refractory angina). Cath performed for any other reason, including changing 
physician or participant preferences, is not adherent to the CON strategy and is considered a 
protocol violation. All protocol violations will be reported according to the guidelines provided in the 
MOO and may require notification of the local IRB as required by local regulations. 
Investigators are discouraged from performing stress tests for the purpose of monitoring participants 
who are clinically stable. Guidelines for avoidance of crossover in participants with worsening 
symptoms in the absence of ACS may be found in the MOO. In brief, if angina worsens, medical 
therapy will be intensified. If symptoms are refractory to maximum medical therapy, or become 
unstable, participants should undergo cath. Site investigators must provide documentation, including 
current intensity of medical therapy, heart rate, blood pressure, and a repeat SAQ to document the 
appropriateness of cath. Sites are instructed to call the 24-hour helpline when elective cath is being 
considered, and they must complete a checklist. 
6.6 
Cath in Participants Randomized to CON Strategy 
Cath and/or revascularization for an acute coronary syndrome, resuscitated cardiac arrest, or acute 
ischemic heart failure is consistent with the CON strategy. Similarly, cath for refractory symptoms 
(according to the trial definition) is also consistent with CON strategy. Figure 2 describes cath in 
participants randomized to CON and the definitions of protocol adherence and non-adherence as it 
relates to this. Once the decision has been made that the performance of cath in a CON participant 
is consistent with the CON strategy, the same principles described for optimal revascularization (6.4) 
apply.  
 
 
 
 
 
 
 
 
 
 
 
 


 
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Figure 2 
 Cath in Participants Randomized to CON Strategy  
 


 
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7. 
AUXILLIARY SCREENING LOG  
7.1 
Screening Log 
During the study enrollment period, sites will maintain a de-identified, written screening log of 
patients with site-determined moderate or severe ischemia who have undergone testing at the site’s 
designated primary laboratory. Patient characteristics (age [recorded for patients <90 years of age, 
recorded as 90 if >90 years of age], sex, and, if excluded, reason(s) for exclusion will be recorded) 
and intended management strategy for patients who are eligible but not enrolled, if known. 
The screening log will be sent to the CCC on a regular basis, where it will help identify the major 
reasons why patients are not enrolled, thus allowing CCC staff to develop corrective action plans for 
sites that are not meeting target enrollment. Depending on the site’s enrollment rate over time, the 
CCC may decide that a given site no longer needs to submit its screening log, although the site 
should continue to maintain the log through the end of enrollment. In the event of poor enrollment, 
sites may be asked to provide comparable information about patients referred to cath without prior 
ischemia testing. 
  
 


 
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8. 
Study Assessments 
8.1 
Creatinine and Pregnancy Test 
At the screening visit a serum creatinine test must be drawn if one is not available within the 
previous 90 days. In addition, a pregnancy test is required if the participant is pre-menopausal. 
8.2 
Standard Blood Tests 
In this population with established coronary disease, as part of standard practice the following tests 
will typically be obtained by the participant’s treating physician: complete blood count, electrolytes, 
creatinine, glucose, liver transaminases, lipid profile, and HbA1c. If HbA1c results are available for 
nondiabetics they will be recorded. If these test results are not available within specified time 
windows around the randomization visit (see MOO), then the following should be obtained: complete 
blood count, lipid profile, and HbA1c (for diabetics only). Liver transaminases should only be 
obtained if not available before starting statin therapy. An attempt will be made to coordinate 
participant follow-up visits so that they occur close in time to routine follow-up visits with their 
physicians when routine blood tests are performed. At 6 month follow-up visits, if lipid tests (and 
HbA1c at annual visits for diabetics) are not available within specified time windows they will be 
obtained by the study coordinator or participants will be referred to their treating physicians for the 
tests. Creatinine values obtained clinically for participants at the three month follow-up visit and 
annually will also be recorded. 
8.3 
Endpoint Assessments 
At every visit after randomization, the study coordinator will ask participants if they have had any 
symptoms or a report from a healthcare provider consistent with an endpoint event since the last 
study visit. See MOO for detailed instructions on collection of source documents. 
8.4 
Blood Biomarkers and Genomics Biorepository 
Randomized participants will be invited to participate in the biorepository protocol, unless precluded 
by local regulations. Participants who give informed consent will be asked to allow storage of 
samples of their blood in two biorepository protocols, one for biomarkers and one for genetic 
analysis. Participants who decline participation in one or both of the biorepository protocols are still 
eligible to participate in the main trial. The biorepositories will serve as resources for future analyses. 
Although no specific scientific proposals are put forth in the present protocol, we anticipate a wealth 
of opportunities for ancillary studies and sharing of resources with other investigators. Participants 
will be asked to separately consent for use of their blood samples for the biomarker biorepository 
and the genetic (DNA) biorepository. If a site is unable to process blood samples they may still 
participate in the genetic biorepository; in this case saliva samples may be collected from 
participants.  
Blood will be drawn for the biorepository at the time of randomization, and may be drawn after 
3 months of follow-up. At the time of randomization, up to a maximum of 49 mL of whole blood will 
be collected, which will be processed and stored as serum, plasma, RNA and, where allowable, 


 
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DNA. At the 3 month follow-up visit, up to 49 mL of blood may be drawn. (If needed, specimen 
collection for genetic analysis may be collected at any point during the trial.)  
Measures will be taken to protect the identity of the blood sample donor by de-identifying the 
biospecimen samples at the enrollment site. The link between the participant's name and the 
numeric code will not be available to staff managing samples at the biorepository, or any 
investigative personnel requesting samples. Strict confidentiality and maintenance of the chain of 
custody will be observed in the collection and storage of biospecimens. Complete details of the 
biorepository protocol are provided in the MOO. 
8.5 
Medication Adherence 
To assess medication adherence, a 4-item modified Morisky adherence survey (Likert scale 
responses to 4 questions)28-31 will be completed at the randomization visit, 6 month visit, and all 
subsequent visits. 
8.6 
Lifestyle Assessment  
To assess each participant’s readiness to change health-related behaviors, study coordinators will 
use questionnaires developed by the Patient-centered Assessment and Counseling for Exercise and 
nutrition (PACE) program. Responses to these brief surveys will be used to tailor counseling for 
lifestyle change. These assessments will occur at randomization, 3 months, 12 months, annually, 
and at the closeout visit. 
8.7 
Quality of Life Assessment  
To quantify patient-reported quality of life outcomes in ISCHEMIA-CKD, a battery of validated 
instruments will be used. Angina-related quality of life will be measured by the Seattle Angina 
Questionnaire (SAQ); dyspnea symptoms from the Rose Dyspnea scale; the EQ-5D as a measure 
of overall, generic health status; and demographic items (e.g., marital status, education, perceived 
income).  We will use these data to analyze the health status of participants in both groups over time 
to quantify both the magnitude and trajectory of health status recovery as a function of randomized 
management strategy. 
8.8 
Economics Assessment 
As a measure of medical utilization, resource utilization data, including hospitalizations, emergency 
department visits, and selected cardiac procedures and tests will be collected by the Site 
Coordinators at each ISCHEMIA-CKD study visit or contact and entered into the main study EDC 
database. These data will be used to estimate and compare medical care costs from the perspective 
of the US healthcare system for both management strategy groups. They will also be used, along 
with the clinical endpoints and quality of life data, to calculate the net incremental cost and quality-
adjusted life expectancy associated with the invasive strategy and the resulting within-trial 
incremental cost-effectiveness ratio. Details are provided in the MOO. 


 
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9. 
SCHEDULE OF ASSESSMENTS 
Overview of Visits 
All participants will undergo eligibility screening, informed consent and randomization procedures.  
Follow-up in randomized participants will occur at 1.5, 3, 6, and 12 months following randomization 
during the first year and every 6 months thereafter, with clinic visits, phone follow-up, and other 
testing as described below (See Table 2 for complete assessment schedule). The schedule of 
assessments (Table 2) specifies the preferred method of contact for each visit. Six-month visits may 
be via telephone or email, depending on participant stability, risk factor control, and the participant’s 
distance from the clinic (“geography”) (see Table 2). In the event that a scheduled clinic visit is not 
possible, to ensure participant follow-up other forms of contact should be used, such as telephone, 
email, communication from a personal physician, other allied health professional, or family member, 
or review of electronic health record or public records. After the first year, participants will be 
followed every 6 months until the end of the trial, at which time sites will be notified to perform a 
closeout visit. 
Dependent on additional funding, telephone or email follow-up every 6 months or ascertainment of 
database information on vital status may continue after all clinic visits have been completed, unless 
prohibited by local regulations. At these long-term follow-up contacts, information on current health 
and medications, and interval hospitalizations will be collected. 
Withdrawal from the Study:  Complete and accurate follow-up is extremely important for the 
duration of the study. The participant, however, may decline to continue with their assigned 
management strategy at any time. This does not constitute withdrawal from the study. Participants 
will continue to be followed per the assessment schedule. If at any time the subject refuses to 
continue with study visits, every attempt will be made to continue contact by telephone, written 
communication, email, by proxy contact with family, friends, or allied health care providers, or record 
review to determine if outcome events have occurred, unless the subject specifically refuses such 
follow-up. National databases that record deaths will be used to ascertain vital status, unless 
prohibited by local regulations. The reason for (and the level of) withdrawal will be documented for 
all subjects withdrawn from the study or for those having limited follow-up. The subject must specify 
in writing what follow-up (s)he will allow, if any, at the time of withdrawal discussion.  


 
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Quality of Life (QOL) and Economics Overview 
A brief set of items capturing selected interval angina and dyspnea symptoms QOL (Brief/Symptom/QOL) will be collected by the site 
coordinator and entered into the EDC study database at every study visit through 36 months and then each 6 months until the final 
closeout ISCHEMIA-CKD visit.   A Hospitalization assessment as part of the main study EDC database will be collected on all 
randomized ISCHEMIA-CKD participants at each follow-up study interval throughout the trial to provide a measure of resource utilization.  
   
Table 2 
Schedule of Study Assessments and Procedures (see Manual of Operations for visit windows) 
 
Screening visit 
CCTA visit 
Randomization visit 
(Baseline Visit) 
Catheterization & 
PCI or CABG  
Follow up 
 
 
 
 
 
1.5mA 
Visit 1 
3mA 
Visit 2 
6mB 
Visit 3 
12mA 
Visit 4 
18mB 
Visit 5 
24m 
Visit 6 
30mB 
Visit 7 
36mC 
Visit 8 
Frequency 
beyond 36 
months 
Eligibility screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent (including biorepository 
consent if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine and pregnancy testD  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Medical Status  
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Cardiovascular medications 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Transmit Stress Test to Core LabE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NYHA* and CCS class** 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Release for medical records signed 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Q12m 
Safety assessment F 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Vital signs, weight, heightG 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q12m 
Standard lab resultsH  
 
 
XI 
 
 
X 
X 
X 
X 
X 
X 
X 
Q12m 
Biorepository blood draw  
 
 
X 
 
 
XJ 
 
 
 
 
 
 
 
Cardiac biomarkersK  
 
 
 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) L 
 
 
X 
XM 
 
 
 
X 
 
X 
 
 
@ closeout 
Lifestyle Assessment (PACE)*** 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Q12m 
Lifestyle Counseling (PACE)***  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Modified Morisky Medication Adherence Survey 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Q6m 


 
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Brief symptoms/QOL assessmentN  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Initiate Optimal Medical Therapy (OMT) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical Therapy Evaluation and OptimizationO 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Schedule catheterization for INV participantsP 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Hospitalization assessment 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Endpoint assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Follow-up visits will be scheduled based on time since the date of randomization (baseline).  
*NYHA- New York Heart Association   **CCS- Canadian Cardiovascular Society    ***PACE- Patient-centered Assessment and Counseling for Exercise and nutrition (PACE) 
assessment and counseling    
                                                          
 
A 1.5, 3, and 12 month visits should be in clinic visits, depending on participant stability, risk factor control, and geography. 
B 6, 18, and 30 month visits may be via telephone, email, or in clinic depending on participant stability, risk factor control, and geography. 
C Following the 36 month visit, follow-up visits should be in clinic visits at least every 12 months. Clinic visits can be replaced by email or phone depending on participant 
stability, risk factor control, and geography. 
D Creatinine if not done within 90 days and pregnancy test if premenopausal. 
E Send ischemia test images (immediately following enrollment and before randomization), technical worksheets, and site interpretations/local reports from qualifying ischemia 
tests to core labs.  
F Safety Assessment (refer to section 13.4). 
G Height is only needed at randomization, assessments only required if visit is completed in clinic. 
H Required labs include: lipids (preferably fasting) at 3 month visit then semiannually only, and HbA1c (at visit 4, 6, 8 and annually thereafter for diabetic participants. These lab 
results will be requested from the participant’s physician. If these results are not available they should be obtained by either the participant’s treating physician or study staff. 
Creatinine values obtained clinically for participants with eGFR <60 at the three month follow-up visit and annually will also be recorded. 
I Additional lab required at randomization includes complete blood count  Request from participant’s physician, since it is expected that routine blood work will have been done 
within the last 6 months 
J May be requested. 
K For participants undergoing PCI: troponin and CK-MB pre-procedure and at 8-16 ± 2 hours post-PCI or at hospital discharge, whichever comes earlier. For participants 
undergoing CABG: troponin and CK-MB pre-procedure and at 18 ± 6 hours post-CABG. All biomarker measurements should be recorded on eCRF. A biomarker measurement 
should be obtained before and after all PCI and CABG procedures, whenever possible. 
L Send to ECG core lab; ECG required for all cardiac admissions and revascularizations; year 1 ECG optional (filed on site) and closeout.  
M ECG done following procedure (60±30 mins post-PCI, 3 days post-CABG). 
N Selected Seattle Angina Questionnaire/Rose dyspnea scale/EQ-5D. 
 
 


 
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O At every follow-up visit the research team, in collaboration with the treating physician(s), will evaluate effectiveness of medical therapy and optim
guideline recommendations and study algorithms. 
P Planned cath and revascularization only in the INV group.  See MOO for time windows for performing cath and revascularization after randomizatio
optimal revascularization treatment should be targeted within 30 days after randomization in the Invasive strategy group. In the Conservative group
revascularization is reserved for participants with refractory angina symptoms or acute ischemic events. 


 
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 Screening visit 
 
Patients with advanced CKD and at least moderate ischemia (see protocol appendix A) 
will be assessed as potential study candidates 
 
General medical and cardiac history will be reviewed for eligibility according to the 
inclusion/exclusion criteria in section 4.3 
 
Willingness of both the prospective participant and their physician for participation 
throughout the study will be confirmed  
 
All screened prospective participants will be recorded in the paper screening log 
 
Prospective participants meeting clinical and site-based ischemia inclusion and 
exclusion criteria and interested in participating in the study will be consented for the 
study 
 
Consented participants will receive a study ID number via IVRS/IXRS. These 
participants are considered “enrolled” (not randomized). 
 
Creatinine testing if it has not been done within the last 90 days 
 
Pregnancy test if premenopausal 
 
For enrolled participants ischemia tests will be transferred electronically to the 
appropriate core laboratory. (see section 5.4) 
Randomization visit (Baseline Visit) (targeted within 15 days of participant’s consent)  
 
Medical history including CV medications will be documented 
 
NYHA and CCS class (see MOO) 
 
Brief symptoms/QOL assessment will be collected (prior to actual randomization) 
 
Modified Morisky medication adherence survey (see MOO) 
 
Vital signs, height and weight will be measured 
 
12 lead ECG will be performed and sent to ECG core lab; stress ECG, and symptom, 
and hemodynamic results will be sent to ECG core lab 
 
Results of routine laboratory tests performed within 6 months of visit will be recorded, 
including HbA1c for diabetic participants. If these test results are not available a blood 
draw for routine laboratory tests will be done at this visit (see MOO) 
 
Baseline blood draw for biomarker/genetics biorepositories 


 
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 
Eligible participants will be randomized to INV or CON strategies via the IVRS/IXRS 
system. (These participants are considered randomized) 
 
Participants randomized to INV strategy should target to undergo catheterization, with 
optimal revascularization to be completed within a target of 30 days from randomization 
 
PACE will be implemented for all participants 
 
Initiate OMT in all randomized participants according to guideline recommendations and 
study algorithms 
Cath and Revascularization for participants randomized to INV strategy (protocol 
assigned); also applies to all revascularization procedures for participants in both 
management strategies 
 
For protocol assigned cardiac cath and revascularization (INV strategy participants), 
target completion within 30 days of randomization 
 
 
Revascularization to be performed as per Optimal Revascularization Therapy (ORT) 
(refer to MOO) 
 
 
For participants undergoing PCI 
- 12 lead ECG to be performed post-PCI at 60 ± 30 minutes, and as needed for 
chest pain 
- Blood draw for both CK-MB and troponin before PCI, and at 8-16 ± 2 hours post-
PCI or at hospital discharge, whichever comes earlier, whenever possible  
- All pre- and post-procedure biomarker measurements that are obtained should 
be recorded on eCRF 
 
 
For participants undergoing CABG 
- 12 lead ECG to be performed on day 3 post-CABG or at hospital discharge 
whichever comes earlier, and as needed for chest pain 
- All pre- and post-procedure operative biomarker measurements that are obtained 
should be recorded on eCRF 
1.5 month (6 week) visit (Visit 1) 
 
Medical status assessment  
 
NYHA and CCS class (see MOO) 
 
Vital signs and weight will be measured 
 
Lifestyle counseling as per PACE will be performed 
 
Brief symptoms/QOL assessment will be collected 


 
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 
Hospitalization assessment will be collected 
 
Endpoints will be assessed 
 
The study team, in collaboration with the treating physician(s), will evaluate effectiveness 
of medical therapy and optimize as needed according to guideline recommendations and 
study algorithms 
3 month visit (Visit 2) 
 
Medical status assessment 
 
NYHA and CCS class (see MOO) 
 
Vital signs and weight will be measured 
 
Lifestyle assessment and counseling as per PACE will be performed 
 
Brief symptoms/QOL assessment will be collected 
 
Hospitalization assessment will be collected 
 
Biorepository blood draw may be performed if additional funding is obtained 
 
Endpoints will be assessed 
 
Obtain lab results from participant’s treating physician for lipids (preferably fasting). If not 
available these tests should be obtained by the participant’s treating physician or the 
study staff. Creatinine values obtained clinically  will be recorded. 
 
The study team, in collaboration with the treating physician(s), will evaluate effectiveness 
of medical therapy and optimize as needed according to guideline recommendations and 
study algorithms 
6/18/30 month visits (Visits 3, 5, 7 respectively) 
 
Medical status assessment  
 
NYHA and CCS class (see MOO) 
 
Vital signs and weight will be measured (only if clinic visit)  
 
Modified Morisky medication adherence survey (see MOO) 
 
Lifestyle counseling as per PACE will be performed 
 
Brief symptoms/QOL assessment will be collected  


 
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 
Hospitalization assessment will be collected 
 
Endpoints will be assessed 
 
Obtain lab results from participant’s treating physician for lipids (preferably fasting). If not 
available lipid tests should be obtained by the participant’s treating physician or the 
study staff.  
 
The study team, in collaboration with the treating physician(s), will evaluate effectiveness 
of medical therapy and optimize as needed according to guideline recommendations and 
study algorithms 
12/24/36 month visits (Visits 4, 6, 8 respectively) 
 
Medical status assessment  
 
NYHA and CCS class (see MOO) 
 
Vital signs and weight will be measured 
 
12 lead ECG will be performed and submitted to core lab only at 24 month visit. Optional 
ECG to be retained at site at 12 months 
 
Modified Morisky medication adherence survey (see MOO) 
 
Lifestyle assessment and counseling as per PACE will be performed  
 
Brief symptoms/QOL assessment will be collected  
 
Hospitalization assessment will be collected 
 
Endpoints will be assessed 
 
Obtain lab results from participant’s treating physician for lipids (preferably fasting) and 
HbA1c for diabetic participants. If not available lipid tests should be obtained by the 
participant’s treating physician or the study staff. Creatinine values obtained clinically for 
will also be recorded. 
 
The study team, in collaboration with the treating physician(s), will evaluate effectiveness 
of medical therapy and optimize as needed according to guideline recommendations and 
study algorithms 
Continuing Follow-Up Visits (every 6 months following the 36 month visit until close out) 
 
Medical status assessment 
 
NYHA and CCS class (see MOO) 


 
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 
Vital signs, and weight (only at every 12 month clinic visit) 
 
Modified Morisky medication adherence survey 
 
Lifestyle assessment as per PACE (only at every 12 month visit) 
 
Lifestyle counseling as per PACE  
 
Brief symptoms/QOL assessment will be collected 
 
Hospitalization assessment will be collected 
 
Endpoint will be assessed 
 
Obtain lab results from participant’s treating physician for lipids (preferably fasting). If not 
available lipid tests should be obtained by the participant’s treating physician or the 
study staff.  
 
 
The study team, in collaboration with the treating physician(s), will evaluate effectiveness 
of medical therapy and optimize as needed according to guideline recommendations and 
study algorithms 
Close out visit (in addition to all assessments for the regularly scheduled visit) 
 
12 lead ECG will be performed and submitted to core lab 
 
Obtain lab results from participant’s treating physician for lipids (preferably fasting) and 
HbA1c for diabetic participants. If not available from the participant’s treating physician 
these tests should be obtained by the participant’s treating physician or the study staff.  
 
 
 


 
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10. 
ADJUDICATION OF CLINICAL EVENTS 
An independent clinical event adjudication committee (CEC) will review and adjudicate all 
primary endpoint events and selected secondary endpoints in a blinded fashion based on study 
definitions. Endpoints to be adjudicated include death (including cause), myocardial infarction, 
resuscitated cardiac arrest, hospitalization for unstable angina, hospitalization for heart failure, 
and stroke. Because the trial is not blinded, to mitigate bias in the ascertainment of events, 
several strategies will be used to identify (“trigger”) all suspected endpoints in all participants 
including carefully constructed data collection tools that focus sites on key endpoint events, 
screening of ECG core lab data, site investigator and coordinator education about CEC 
procedures, and processing of events found by physicians during review of source documents 
pertaining to already identified endpoints. Care will be taken to blind reviewers to any 
information that could identify the participant or could reveal the randomized management 
strategy assignment. CEC members do not have access to management strategy assignment in 
order to avoid bias, which is an important process issue in this unblinded trial. 
 


 
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11. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
11.1 Sample Size Determination and Statistical Power 
11.1.1 Summary of Power and Precision 
As shown in Tables 3 and 4 below, the planned sample size of approximately 1,000 randomized 
participants will result in an estimate of the hazard ratio that differs from the true hazard ratio by 
no more than a factor of 1.19 with 95% probability and will yield power ≥80-95% for comparing 
the primary composite endpoint across the two randomized groups assuming the 4-year 
cumulative rate of the primary composite endpoint is 60% in participants randomized to CON 
strategy and is less by a factor of 15% to 19% (relative reduction) in participants randomized to 
INV strategy. Power and precision under other assumptions are summarized in Table 5 and 
Table 6 below. 
Table 3. Estimated Power as a Function of the Anticipated Cumulative Event Rate in 
CON and the Cumulative Risk Reduction in INV (∆) 
CON anticipated 4-year 
event rate 
Power 
Event % 
∆ = 0.15 
∆ = 0.17 
∆ = 0.19 
45% 
56 
67 
76 
50% 
64 
75 
84 
55% 
73 
83 
90 
60% 
81 
90 
95 
65% 
88 
95 
98 
70% 
94 
98 
99 
NOTE: ∆ denotes relative reduction in 4-year event rate in INV vs. CON groups. Assumptions: Two-
sided log-rank test with alpha = 0.05; 500 participants per group; average follow-up 3.7 years; loss-to-
follow-up 1% per year; survival times follow exponential distribution. 
 
 
Table 4. Range of Estimated Precision (Margin of Error) as a Function of the 
Anticipated Cumulative Event Rate in CON and the Cumulative Risk Reduction in INV 
(∆) 
CON anticipated 4-year 
event rate 
Margin of Error (MOE) 
Event % 
∆ = 0.15 
∆ = 0.17 
∆ = 0.19 
45% 
1.22 
1.22 
1.23 
50% 
1.21 
1.21 
1.21 
55% 
1.20 
1.20 
1.20 
60% 
1.19 
1.19 
1.19 
65% 
1.18 
1.18 
1.18 
70% 
1.17 
1.18 
1.18 
NOTE: Margin of Error is the anti-log of the expected half-width of the 95% confidence interval for the log-
hazard ratio. Assumptions: Based on a univariable Cox model with a binary treatment indicator and Wald-
type 95% confidence intervals. 
11.2 Statistical Analysis Plan 


 
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All major treatment comparisons between the randomized groups will be performed according to 
the principle of "intent-to-treat;" that is, participants will be analyzed (and endpoints attributed) 
according to the randomized strategy, regardless of subsequent invasive testing or treatment. 
Statistical comparisons will be performed using two-sided significance tests. A statistical 
analysis plan will be finalized before trial completion and data analysis.  
11.2.1 Analysis of the Primary Endpoint 
The statistical comparison of the two randomized groups with respect to the primary composite 
endpoint will be a “time-to-event” analysis, and will therefore be based on the time from 
randomization to the first occurrence of any of the components of the primary composite 
endpoint (death or nonfatal MI). The Cox proportional hazards will be the primary analytic tool 
for assessing outcome differences between the two randomized groups. To preserve power in 
the face of participant heterogeneity, the overall comparison may be adjusted for a selected set 
of prognostically important baseline covariates that will be carefully defined and pre-specified in 
the statistical analysis plan. The level of significance for the assessment of the primary endpoint 
will be α=0.05. In addition to Cox regression, event-free survival probabilities will be estimated 
as a function of follow-up time in each treatment group using the Kaplan-Meier method and 
presented with point wise 95% confidence intervals. If the data provide evidence of an overall 
difference in outcome between management strategy groups, we will further examine whether 
the therapeutic effect is similar for all participants, or whether it varies according to specific 
participant characteristics, which will be pre-specified in the statistical analysis plan. 
11.2.2 Analysis of the Secondary Endpoints 
Secondary endpoints that will be evaluated include: (1) quality of life as measured by the SAQ 
Angina Frequency Scale and SAQ Quality of Life Scale; (2) composite of cardiovascular death, 
nonfatal myocardial infarction, or stroke; (3) composite of cardiovascular death, nonfatal MI, 
resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure; (4) all-cause 
death; (5) CV death  (6) MI; (7) resuscitated cardiac arrest; (8) hospitalization for unstable 
angina; (9) hospitalization for heart failure; (10) stroke; (11) composite of cardiovascular death, 
nonfatal MI, stroke, resuscitated cardiac arrest, or hospitalization for unstable angina or heart 
failure; and (12) health resource utilization, cost, and cost effectiveness. Plans for the analysis 
of the quality of life and economic endpoints are addressed below in Sections 11.2.4 and 11.2.5. 
For other secondary endpoints, analysis will be similar to the primary endpoint, using time from 
randomization until the first occurrence of the specific secondary endpoint as the response 
variable. 
Unambiguous operational definitions of each study endpoint will be documented in the Clinical 
Event Committee Charter and statistical analysis plan before performing unblinded analysis. For 
MI we will specify a primary definition (adapted from the universal definition of MI32; to be used 
in the primary analysis of the primary and secondary endpoints). Other definitions (to be used in 
secondary analyses) will include the universal definition of MI and criteria to categorize large 
infarctions.  Data collection instruments and the adjudication process will allow construction of 
alternative endpoint MI definitions. 


 
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11.2.3 Contingency Plan For Insufficient Primary Endpoint Events 
The projected event rate of 60% at 4 years for the primary composite endpoint in CON 
participants was based on multiple data sources. Although we believe the projected rate is 
reasonably conservative, an acceptably precise estimate of the true event rate of the primary 
endpoint will not be known until substantial participant recruitment and follow-up have been 
accrued. To ensure that the primary analysis is well-powered and useful, a prospective plan to 
allow extending follow-up and/or changing the primary endpoint based on aggregate event rate 
data will be established prior to the first review of unblinded trial data. At a designated time 
during the trial, an analysis will be conducted to estimate the overall aggregate primary endpoint 
event rate and project the final number of observed events. If the estimated unconditional power 
(i.e. based on aggregate event rate data; not by treatment group) is less than the originally 
targeted 90%, then one or more of the following options will be considered: 
1. Extend follow-up to allow more events to accrue.  
2. Change the primary endpoint to one that occurs more frequently. 
 
The current primary endpoint would become a secondary endpoint 
 
The proposed new primary endpoint would be the composite of death, MI, 
resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure. 
3. Follow the recommendation of an independent advisory panel.  
An independent advisory panel, separate from the DSMB, will be convened for the purpose of 
reviewing unconditional power estimates and making a recommendation to the NHLBI Director.  
Members of this panel will not have access to unblinded data by treatment group or other data 
that may bias their recommendation.33, 34  Additional details will be finalized in cooperation with 
the DSMB and recorded in the statistical analysis plan before the first unblinded interim 
analysis. 
11.2.4 Quality of Life (QOL) Analysis 
All QOL comparisons will adhere to the intention-to-treat principle. For each QOL measure 
examined in this study, data analysis will proceed in several stages. First, we will provide simple 
descriptive and comparative analyses by intention-to-treat. Statistical power estimates for this 
part of our analysis, based on data collected in the COURAGE trial, show that we should have 
in excess of 99% power to detect ¼ SD differences in our 3 principal QOL measures.  Second, 
we will examine changes over time from baseline and identify the major determinants of those 
changes using regression analysis. Since there is currently no consensus in the statistical 
literature about the best way to deal with the multiple comparisons problem arising from testing 
each individual scale separately, we propose two complementary approaches. First, we will pre-
specify the angina frequency and QOL scales from the SAQ as the CAD-specific measures of 
primary interest and assign all other comparisons to a secondary (descriptive) status. Second, 
we will employ a mixed model methodology that makes use of all available QOL data at each 
study assessment point to model the time profile (fixed effect). Using the fitted model, we can 


 
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estimate the overall difference in the QOL measures as well as test the global hypothesis of no 
difference over time. We can also estimate the difference in the areas under the two QOL 
treatment curves (and test the hypothesis of no difference, on average). In addition, we can 
estimate differences in QOL at the end of the study or at intermediate points.  Lastly, to address 
the possibility that international differences in QOL exist despite our use of extensively culturally 
validated instruments, we will examine interactions between key QOL outcomes, treatment, and 
geographic region. 
11.2.5 Health Economics Analysis  
The health economic analyses for ISCHEMIA-CKD will consist of a cost-effectiveness analysis.  
The cost-effectiveness analyses will estimate the incremental cost required to add an extra life 
year with the INV strategy group relative to CON strategy group. In secondary analyses, we will 
incorporate utility weights to estimate the incremental cost per quality adjusted life year gained 
with the INV strategy relative to CON strategy. These analyses will be conducted from a societal 
perspective and will use a lifetime horizon so that the estimated incremental cost-effectiveness 
and cost-utility ratios can be compared with societal benchmarks. We will also calculate within-
trial cost-effectiveness/cost-utility ratios, although these ratios are limited in their value due to 
their failure to account for long-term benefits and costs and the absence of comparative 
benchmarks. Cost will be adjusted for inflation, and both costs and life expectancy will be 
discounted to present value at a 3% annual discount rate. Plots of cost-effectiveness 
acceptability curves indicating the probability that the intervention is cost-effective for a range of 
willingness-to-pay thresholds will be done. Extensive sensitivity analyses will be performed. 
11.2.6 Interim Analysis 
For ethical reasons, interim examination of clinical endpoints and key safety events will be 
performed at regular intervals during the course of the trial. An independent Data and Safety 
Monitoring Board (DSMB) appointed by the NHLBI will monitor participant safety and to review 
performance of the trial (see 13.1). The primary objective of these interim analyses is to ensure 
the safety of the participants enrolled in the trial and evaluate the accumulating endpoint data by 
treatment group to test for possible differences favoring either of the two randomized 
management strategies. In addition, interim monitoring will involve a review of participant 
recruitment, compliance with the study protocol, status of data collection, an assessment of 
whether control group event rates are consistent with the rates hypothesized in the sample size 
calculations, and other factors which reflect the overall progress and integrity of the study. 
Because interim analyses may occur when adjudication of an event is in progress, the interim 
analyses will be based primarily on adjudicated events and secondarily on all best available 
events, i.e., as adjudicated by CEC if present or as eCRF/Investigator defined if the event has 
not yet been adjudicated by CEC. The results of the interim analyses and status reports will be 
carefully and confidentially reviewed by the DSMB. Detailed plans for interim monitoring will be 
documented in a separate DSMB analysis plan.  
Interim comparisons by management strategy will focus on all-cause mortality and the primary 
composite endpoint (death and MI). Cox-proportional hazard models with treatment as the 


 
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covariate will be used for the analysis. Estimates of hazard ratios and 95% confidence intervals 
comparing the INV and CON strategies will be reported. To account for repeated significance 
testing of the accumulating data, the group sequential method of Lan and DeMets35 will be used 
as a guide for interpreting these interim analyses. Monitoring boundaries for each endpoint will 
be based on a two-sided symmetric O’Brien-Fleming type spending function with an overall two-
sided significance level of α = 0.05. The O’Brien-Fleming approach requires large critical values 
early in the study but relaxes (i.e., decreases) the critical value as the trial progresses.36 These 
proposed monitoring boundaries are intended as a guide for interpreting the interim analyses 
and not as a rule for early termination.  
An additional key parameter for interim monitoring will be the frequency of early catheterization 
among participants randomized to the CON strategy. Such catheterizations will be classified 
according to (1) whether the catheterization was allowed by the protocol (e.g. for documented 
refractory symptoms) and (2) whether the catheterization was preceded by a nonfatal primary 
endpoint event (i.e., MI). A pattern of frequent early catheterization in CON participants without 
prior endpoint events would suggest that the study may have difficulty achieving high statistical 
power. Moreover, if this was due to frequent protocol violations, then a finding of no treatment 
effect may be challenging to interpret. To address these concerns, rates of early catheterization 
in the CON group will be analyzed and reported, with a focus on estimating the probability that a 
CON participant will undergo catheterization within a specified time interval and before an 
endpoint event. To obtain this probability, the distribution of “time from randomization to 
catheterization” for CON participants will be estimated using the cumulative incidence function 
method for competing risks.37 For this latter analysis participant follow-up will be censored at the 
last contact date or terminated after the participant’s first primary endpoint event, whichever 
occurs first. 
Judgment concerning the continuation of the study will involve not only the magnitude of 
observed differences between randomized strategies and degree of statistical significance, but 
also careful consideration of many other important factors including the need for precise 
parameter estimation, the overall progress and integrity of the trial (including the frequency of 
catheterization in the CON group, as discussed above), and information available from other 
studies at the time of DSMB deliberations. If a stopping boundary is crossed early in the trial, 
this result should be tempered by the knowledge that revascularization may result in early 
hazard, but long-term benefit. Although we hypothesize that outcomes will be improved by the 
INV strategy, it should be emphasized that a small treatment effect for the primary endpoint is 
not necessarily a negative result for the study. Indeed, evidence suggesting absence of a large 
benefit from the invasive strategy would be highly important to future guidelines and clinical 
practice. However, a large sample size is required in order to derive such evidence. If the study 
were to be stopped early with less than the full sample size, the lack of statistically significant 
difference may be accompanied by wide confidence intervals and no clear conclusion might be 
possible. The DSMB will incorporate this perspective along with other considerations when 
making recommendations about continuation. 
 


 
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12. 
DATA HANDLING AND RECORD KEEPING 
12.1 Electronic Data Capture (EDC) System  
The full study dataset will be collected for participants who enter the randomized phase of the 
study. The primary data collection system for ISCHEMIA-CKD will use a web-based electronic 
data capture (EDC) system, a validated Electronic Record, Electronic Signatures (ERES) 
compliant platform (21 CFR Part 11). All these data collected at any point in the trial except the 
economic and quality of life information, are entered into this EDC system. 
12.2 Data Management and Quality 
Any out-of-range values and missing or inconsistent key variables will be flagged and 
addressed at the site in real time during the data entry process. When a query is generated on a 
particular variable, a flag will be set in a field in the database enabling the system to track the 
queries and produce reports of outstanding queries.  Queries can also be generated from 
manual review of the data forms.  These queries will be entered into the database and tracked 
in the same manner as the computer-generated queries.  At regular intervals, all data will be 
transferred from the EDC database to SAS for statistical summarization, data description, and 
data analysis.  Further cross-checking of the data will be performed in SAS, and discrepant 
observations flagged and appropriately resolved through a data query system. The Statistical 
and Data Coordinating Center (SDCC) will perform internal database quality-control checks, and 
data audits throughout the course of the trial. 
12.3 Data Confidentiality and Security 
Computerized data will be accessible only by password, and a centralized monitoring system 
will record and report all access to data. The DCRI computer network is protected by a firewall.  
Electronic CRFs (eCRFs) will be identified by study number only, to ensure participant 
anonymity. No participant identifiers will be used in the presentation of data. Study records that 
might identify participants will be kept confidential as required by law. Except when required by 
law, participants will not be identified by name, personal identification number (e.g. social 
security number, social insurance number), address, telephone number, or any other direct 
personal identifier in study records. This information will be retained by each individual center 
and will not be disclosed to the Coordinating Center except as needed for centralized clinical, 
quality of life and economic follow-up of the participants. Participants will be informed that the 
study physician and his/her study team will report the results of study-related tests to the 
Coordinating Center and to the NIH. Participants will be informed that their records may be 
reviewed in order to meet federal, state or regional/local regulations. Reviewers may include the 
CCC/SDCC monitors, IRBs/ECs, the NIH, other government regulators as dictated by local law, 
or their delegates. 
Ischemia tests will be stripped of identifiers during the upload process, with the exception of 
date of study in DICOM headers, by a vendor which will be responsible for ischemia test 
transfer and storage for this trial.  


 
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12.4 Training 
All investigational site and core lab staff authorized to enter ISCHEMIA-CKD study data will 
receive training on the EDC system. Training records will be retained by the EDC Helpdesk at 
the SDCC. 
12.5 Records Retention  
Study records will be maintained by the site investigators for a period of three (3) years following 
the expiration of the grant or length of time as required by local regulations, whichever is longer. 


 
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13. 
SAFETY MONITORING PLAN 
13.1 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be appointed by the NHLBI to monitor 
participant safety and to review performance of the trial. The DSMB will include on its roster a 
nephrologist.  A DSMB charter that outlines the operating guidelines for the committee and the 
procedures for the interim evaluations of study data will be developed by the NHLBI and agreed 
upon by the DSMB. Reports will be prepared regularly by the SDCC in accordance with the plan 
outlined in the charter and as requested by the DSMB chair, and will include interim analyses of 
primary and secondary endpoints; additional safety events; and other information as requested 
by the committee. After each meeting, the DSMB will make recommendations to the NHLBI and 
the trial leadership about the continuation of the study. After approval by the NHLBI director, a 
summary of the DSMB report and recommendations will be forwarded by the CCC to 
investigators for submission to their local, regional and national IRB/Ethics Committees, as 
applicable. DSMB reports will be the primary mechanism for reporting safety concerns to NIH 
and IRBs. 
13.2 Risks and Benefits 
All procedures and tests performed in this study are commonly performed in clinical practice 
and have well defined safety profiles. Furthermore, all procedures performed in this study, are 
commonly performed for the patient population enrolled in the study, i.e., those with advanced 
CKD, SIHD and at least moderate ischemia. The risk of cath and revascularization will be 
minimized by the selection of experienced operators who meet study certification criteria. These 
risks are justified by the potential benefit (long-term reduction in events resulting from 
revascularization, as discussed in the background section). 
Risks: 
Cath/PCI/CABG Risks: Each of these procedures is performed in clinical practice for patients 
who meet eligibility criteria for the CKD trial. The major risks of these procedures include death, 
myocardial infarction and stroke. Other risks of catheterization and PCI include severe contrast 
reaction such as anaphylaxis, emergency CABG, bleeding, need for blood transfusion, contrast-
induced AKI, AKI requiring dialysis and vascular access site complications including 
pseudoaneurysm, AV fistula, retroperitoneal bleed or infection. Other risks of CABG include 
return to operating room for bleeding, need for blood transfusion, infection, prolonged intubation, 
mediastinitis, AKI, AKI requiring dialysis and atrial fibrillation. Risks of these procedures vary in 
likelihood based on the patient’s risk profile and are generally higher in the CKD cohort than in 
participants without CKD. 
 
Risk Lowering Measures: 
The risk of cath and revascularization will be minimized by the selection of experienced 
operators who meet study certification criteria. Strategies to minimize the volume of contrast 
used and reduce the risk of contrast-induced AKI are outlined in the MOO. These risks are 


 
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justified by the potential benefit (long-term reduction in events resulting from revascularization, 
as discussed in the background section). Study procedures are designed to manage and 
minimize risks through careful selection of the patients who participate in the trial. Participants 
will be monitored closely through the trial at many time points to check on their health. In 
addition, an independent DSMB will monitor safety of the participants throughout the study (see 
section 13.1) 
Benefits: 
The ISCHEMIA-CKD trial results should provide evidence based data to support management 
of participants with CKD and SIHD. It is hoped the knowledge gained will be of benefit to others 
with a similar medical condition in the future. 
There may be benefit from participation in this study by receiving the medications and lifestyle 
counseling that are proven to improve outcomes in patients as well as involvement of an 
additional team following the participants’ health status. Participants may receive some 
medications and stents free of cost, as available.  
13.3 Safety Monitoring Objectives and Rationale 
The main safety objectives in ISCHEMIA-CKD are to characterize the risk profiles of the two 
randomized management strategies and to monitor for unanticipated risks to study participants. 
All medications and procedures to be used/performed in this study are commonly 
used/performed for clinical indications as part of standard of care and have well-defined safety 
profiles. Because no investigational device, drug, diagnostic test or therapeutic intervention is 
being tested in this comparative effectiveness trial, reporting is primarily governed by the 
Common Rule (45 CFR Part 46, Subpart A), as well as ICH Guidelines, IRBs and local 
regulations.  
13.4 Adverse Events Reporting by Investigators 
Data for monitoring participants’ safety will be captured within the EDC database as part of the 
required study data. There are no additional study-specific reporting requirements. Site 
investigators should follow usual clinical practices at their institutions for reporting serious, 
unexpected events related to standard of care medications and devices to regulatory agencies.  
13.5 Events to be Monitored 
Safety monitoring in ISCHEMIA-CKD will be concerned with estimating event rates for the 
following types of clinical events: 
1. Complications of cardiovascular tests (e.g. cardiac catheterization) and therapeutic 
procedures (e.g. PCI, CABG) 
2. Events occurring in the time period between consenting to participate in the trial and 
being randomized.  
3. Study endpoints. 


 
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1. Complications of cardiovascular tests and therapeutic procedures 
All drugs, diagnostic tests and therapeutic procedures to be used in this trial have been 
extensively evaluated previously, have established safety profiles with known risks and benefits 
and are routinely used in clinical practice.  Events listed below occurring within 72 hours of the 
procedure will be considered as a complication of the procedure.  Some safety events related to 
specific tests and procedures captured within EDC, in addition to death and MI, include: 
Cardiac catheterization and PCI: 
1. Severe contrast reaction such as anaphylaxis 
2. Periprocedural stroke  
3. Emergency CABG 
4. AKI 
5. AKI requiring dialysis 
6. Vascular access site complications including pseudoaneurysm, AV fistula, 
retroperitoneal bleed 
CABG: 
1. Return to operating room for bleeding 
2. Prolonged intubation  
3. Mediastinitis 
4. Atrial fibrillation 
5. AKI requiring dialysis 
 
In addition the incidence of finding significant LM stenosis (>50%) on cardiac catheterization will 
be monitored and reported to the DSMB.  
 
2. Events occurring in the time period between consent and randomization 
In general, eligibility for randomization will not be known at the time of enrollment but will need 
to be confirmed after performing additional screening procedures (e.g. pregnancy test). As a 
result, several days may elapse before the participant is randomized. Frequency of clinical 
events (e.g. death, MI) occurring during this time period, prior to randomization, will be 
monitored and reported to the DSMB. 
3. Events that are trial endpoints 
Selected trial endpoints (e.g. all-cause mortality) will be monitored at regular intervals during the 
course of the trial for the purpose of protecting participants’ safety. Event rates in each 
treatment group will be confidentially reviewed by the DSMB. These analyses will inform the 
DSMB’s recommendation to stop or continue the study or modify the protocol (see section 
11.2.6). 


 
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14. 
ETHICAL CONSIDERATIONS 
14.1 Regulatory and Ethical Compliance 
This clinical study was designed and shall be implemented and reported in accordance with the 
international conference on harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC, 
US Code of Federal Regulations Title 45 and Japanese Ministry of Health, Labor, and Welfare), 
and with the ethical principles laid down in the Declaration of Helsinki. 
14.2 Informed Consent Process 
Investigators must ensure that participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. Freely given written informed consent must be obtained from every participant or, in 
those situations where consent cannot be given by participants, their legally acceptable 
representative, prior to clinical study participation. The rights, safety, and well-being of the study 
participants are the most important considerations and should prevail over interests of science 
and society. Women of child bearing potential will be informed that there may be unknown risks 
to the fetus if pregnancy were to occur during the study and they were exposed to radiation (e.g. 
cardiac catheterization and revascularization if randomized to the INV strategy group) and agree 
that in order to participate in the study they must adhere to the contraception requirement during 
this period of the study. If there is any question that the prospective participant will not reliably 
comply with study procedures and/or follow-up, they should not be entered in the study. 
14.3 Responsibilities of the Investigator and IRB/IEC/REB 
The protocol and the proposed informed consent forms (main consent form and genetics testing 
consent form) will be reviewed and approved by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB) at each site. A 
signed and dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB is required before site initiation. Prior to study start, the site principal investigator 
is required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to monitors, auditors, Clinical 
Quality Assurance representatives, designated agents of CCC, IRBs/IECs/REBs, and regulatory 
authorities as required. Investigators must agree to apply due diligence to avoid protocol 
deviations.  
14.4 Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by CCC, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for participant safety may be implemented prior to IRB/IEC/REB 
approval. As soon as possible, the implemented deviation or change, the reasons for it and, if 
appropriate, the proposed protocol amendment(s) will be submitted: (a) to the IRB/IEC/REB for 


 
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review and approval/favorable opinion; (b) to the sponsor, NIH/NHLBI for agreement; and, if 
required, (c) to the regulatory authority(ies). Notwithstanding the need for approval of formal 
protocol amendments, the investigator is expected to take any immediate action required for the 
safety of any participant included in this study, even if this action represents a deviation from the 
protocol. In such cases, CCC should be notified of this action and the IRB/IEC/REB at the study 
site should be informed. 
14.5 Early Termination of the Study 
The CCC and NHLBI retain the right to terminate the study, a study site or an investigator at any 
time. The CCC will monitor the progress of the study. If warranted, the study may be suspended 
or discontinued early if there is an observation of safety concerns posing an unreasonable risk 
to the study population. If the study is terminated early, the CCC will provide a written statement 
to the site Principal Investigators to enable notification to site IRBs/IECs/REBs and study 
participants. The CCC will also inform the appropriate Competent Authorities. The CCC may 
terminate enrollment activity at a site, or participation in the study by the investigator and site if 
there is evidence of an investigator’s failure to maintain adequate clinical standards or failure to 
comply with the protocol. Notification of enrollment suspension or termination of the study or 
study site/investigator will be sent to the investigator and the IRBs/IECs/REBs.  
 
 


 
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15. 
STUDY ORGANIZATION 
ISCHEMIA-CKD is sponsored by the US National Heart, Lung, and Blood Institute (NHLBI). The 
Clinical Coordinating Center (CCC), Principal investigator, Study Chair, and Study Co-Chair 
maintain responsibility for the overall conduct of the study, including site management and site 
monitoring in participating countries, analysis and reporting.  The Statistical and Data 
Coordinating Center (SDCC) is responsible for the treatment allocations of eligible participants, 
receipt and processing of data collected by the clinical sites, core laboratories and coordinating 
centers, quality control programs, and statistical analysis and reporting. The angiographic core 
laboratories (ACL) will characterize coronary anatomy for participants undergoing coronary 
angiography and procedural outcomes for those undergoing PCI. Members of the NHLBI will 
participate in the study leadership. Details regarding the Cores and Coordinating Centers may 
be found in the MOO. 


 
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16. 
DATA ACCESS AND SHARING 
The Publication Committee will authorize access to study data and biospecimens (in conjunction 
with the Biorepository Committee).   Investigators must submit a proposal requesting approval 
to access ISCHEMIA-CKD trial data/specimens. The ISCHEMIA-CKD  trial will participate in the 
NHLBI Central Repository for study data and specimens. 
All data access will follow guidelines described in the NHLBI Limited Access Data Policy 
(www.nhlbi.nih.gov/resources/deca/policy_new.htm), the NIH Data Sharing Policy 
(http://grants.nih.gov/grants/gwas/index.htm), and the Policy for Sharing of Data Obtained in 
NIH Supported or Conducted Genome-Wide Association Studies (GWAS) 
http://grants.nih.gov/grants/gwas/index.htm) with regard to documentation, content, storage and 
timing. 


 
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17. 
PUBLICATIONS POLICY: OVERVIEW 
Primary and secondary reports of study findings will be published in peer-reviewed journals. 
Proposals for presentations and publications incorporating data obtained from participants 
involved in the ISCHEMIA-CKD trial must be submitted for review by the publications 
committee. The primary publication will be authored by the trial’s writing committee. No site is 
permitted to present or publish data obtained during the conduct of this trial without prior 
approval from the publications committee. Authorship for ISCHEMIA-CKD-related publications 
will be determined by the publications committee taking into account contribution to the trial and 
the relevant analyses. The full publications policy may be found in the MOO. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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18. 
REFERENCE LIST 
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of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. 
Annals of internal medicine 2002; 137(7): 555-62. 
2. 
Tonelli M, Wiebe N, Culleton B, et al. Chronic kidney disease and mortality risk: a systematic 
review. J Am Soc Nephrol 2006; 17(7): 2034-47. 
3. 
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, 
cardiovascular events, and hospitalization. The New England journal of medicine 2004; 351(13): 1296-
305. 
4. 
Hachamovitch R, Berman DS, Kiat H, et al. Exercise myocardial perfusion SPECT in patients 
without known coronary artery disease: incremental prognostic value and use in risk stratification. 
Circulation 1996; 93(5): 905-14. 
5. 
Al-Mallah MH, Hachamovitch R, Dorbala S, Di Carli MF. Incremental prognostic value of 
myocardial perfusion imaging in patients referred to stress single-photon emission computed 
tomography with renal dysfunction. Circulation Cardiovascular imaging 2009; 2(6): 429-36. 
6. 
Karagiannis SE, Feringa HH, Elhendy A, et al. Prognostic significance of renal function in patients 
undergoing dobutamine stress echocardiography. Nephrology, dialysis, transplantation : official 
publication of the European Dialysis and Transplant Association - European Renal Association 2008; 
23(2): 601-7. 
7. 
Bergeron S, Hillis GS, Haugen EN, Oh JK, Bailey KR, Pellikka PA. Prognostic value of dobutamine 
stress echocardiography in patients with chronic kidney disease. American heart journal 2007; 153(3): 
385-91. 
8. 
Hakeem A, Bhatti S, Dillie KS, et al. Predictive value of myocardial perfusion single-photon 
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Bangalore S, Kamalakkannan G, Aziz E, et al. Prognostic impact of renal function in 
patients undergoing stress echocardiography (Abstr). J Am Soc Echocardiogr 2006; 19(5): 647. 
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U.S. Renal Data System. USRDS 2011 Annual Data Report: Atlas of Chronic Kidney 
Disease and End-Stage Renal Disease in the United States. Bethesda, MD, 2011. 
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US Renal Data System. USRDS 2002 Annual Data Report: Atlas of End-Stage Renal 
Disease in the United States 2002. Bethesda, MD: National Institute of Health, National 
Institutes of Diabetes and Digestive and Kidney Diseases. 
12. 
Charytan D, Kuntz RE. The exclusion of patients with chronic kidney disease from clinical trials in 
coronary artery disease. Kidney international 2006; 70(11): 2021-30. 
13. 
Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and 
coronary artery disease. The New England journal of medicine 2009; 360(24): 2503-15. 
14. 
Sedlis SP, Jurkovitz CT, Hartigan PM, et al. Optimal medical therapy with or without 
percutaneous coronary intervention for patients with stable coronary artery disease and chronic kidney 
disease. The American journal of cardiology 2009; 104(12): 1647-53. 
15. 
McCullough PA. Contrast-induced acute kidney injury. J Am Coll Cardiol 2008; 51(15): 1419-28. 
16. 
Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced 
nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll 
Cardiol 2004; 44(7): 1393-9. 
17. 
Josephson SA, Dillon WP, Smith WS. Incidence of contrast nephropathy from cerebral CT 
angiography and CT perfusion imaging. Neurology 2005; 64(10): 1805-6. 


 
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18. 
Chertow GM, Normand SL, McNeil BJ. "Renalism": inappropriately low rates of coronary 
angiography in elderly individuals with renal insufficiency. J Am Soc Nephrol 2004; 15(9): 2462-8. 
19. 
James MT, Ghali WA, Knudtson ML, et al. Associations between acute kidney injury and 
cardiovascular and renal outcomes after coronary angiography. Circulation 2011; 123(4): 409-16. 
20. 
Rudnick MR, Goldfarb S, Wexler L, et al. Nephrotoxicity of ionic and nonionic contrast media in 
1196 patients: a randomized trial. The Iohexol Cooperative Study. Kidney international 1995; 47(1): 254-
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Keeley EC, Kadakia R, Soman S, Borzak S, McCullough PA. Analysis of long-term survival after 
revascularization in patients with chronic kidney disease presenting with acute coronary syndromes. The 
American journal of cardiology 2003; 92(5): 509-14. 
22. 
Hemmelgarn BR, Southern D, Culleton BF, Mitchell LB, Knudtson ML, Ghali WA. Survival after 
coronary revascularization among patients with kidney disease. Circulation 2004; 110(14): 1890-5. 
23. 
Reddan DN, Szczech LA, Tuttle RH, et al. Chronic kidney disease, mortality, and treatment 
strategies among patients with clinically significant coronary artery disease. J Am Soc Nephrol 2003; 
14(9): 2373-80. 
24. 
Hannan EL, Samadashvili Z, Cozzens K, et al. Comparative outcomes for patients who do and do 
not undergo percutaneous coronary intervention for stable coronary artery disease in New York. 
Circulation 2012; 125(15): 1870-9. 
25. 
Szummer K, Lundman P, Jacobson SH, et al. Influence of renal function on the effects of early 
revascularization in non-ST-elevation myocardial infarction: data from the Swedish Web-System for 
Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to 
Recommended Therapies (SWEDEHEART). Circulation 2009; 120(10): 851-8. 
26. 
Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term 
survival benefit associated with revascularization compared with medical therapy in patients with no 
prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed 
tomography. Circulation 2003; 107(23): 2900-7. 
27. 
Hachamovitch R, Rozanski A, Hayes SW, et al. Predicting therapeutic benefit from myocardial 
revascularization procedures: are measurements of both resting left ventricular ejection fraction and 
stress-induced myocardial ischemia necessary? J Nucl Cardiol 2006; 13(6): 768-78. 
28. 
Trivedi RB, Ayotte BJ, Thorpe CT, Edelman D, Bosworth HB. Is there a nonadherent subtype of 
hypertensive patient? A latent class analysis approach. Patient preference and adherence 2010; 4: 255-
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Bosworth HB, Olsen MK, Grubber JM, et al. Two self-management interventions to improve 
hypertension control: a randomized trial. Annals of internal medicine 2009; 151(10): 687-95. 
30. 
Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure 
of medication adherence. Medical care 1986; 24(1): 67-74. 
31. 
Lowry KP, Dudley TK, Oddone EZ, Bosworth HB. Intentional and unintentional nonadherence to 
antihypertensive medication. The Annals of pharmacotherapy 2005; 39(7-8): 1198-203. 
32. 
Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 
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33. 
Wittes J. On changing a long-term clinical trial midstream. Statistics in medicine 2002; 21(19): 
2789-95. 
34. 
S. E. When and how can endpoints be changed after initiation of a randomized clinical trial? 
PLoS Clin Trials 2007; 2: e18. 
35. 
Lan KKG DD. Discrete sequential boundaries for clinical trials. Biometrika 1983; 70: 659-63. 
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O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 35(3): 
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37. 
Kalbfleisch JD PR. The statistical analysis of failure time data. 2002; 2nd Edition(Hoboken, N.J): J. 
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19. 
APPENDIX A 
Ischemia Test Eligibility Criteria 
Specific criteria for each modality were developed and refined based on data indicating that the 
risk of cardiovascular events based on inducible ischemia is consistent with that targeted in this 
trial. Criteria were harmonized across modalities in order to yield a similar risk of cardiovascular 
death or MI regardless of the type of stress test performed.1  
Table: Criteria for at least Moderate Ischemia by Stress Test Modality2 
Test Modality 
Diagnostic criterion 
Nuclear perfusion via 
SPECT or PET3 
≥10% myocardium ischemic 
Echo3  
≥3/16 segments with stress-induced severe hypokinesis 
or akinesis 
CMR3  
Perfusion: ≥12% myocardium ischemic 
and/or 
Wall motion:  
 
≥3/16 segments with stress-induced severe 
hypokinesis or akinesis 
Exercise Test without 
Imaging 
(Criteria 1-3 must all be 
met) 
1. Absence of resting ST segment depression ≥1.0 mm 
or confounders that render exercise ECG non-
interpretable (LBBB, LVH with repolarization, 
pacemaker, etc.) 
2. As compared to the baseline tracing, additional 
exercise-induced horizontal or downsloping ST 
segment depression ≥1.5 mm in 2 leads or ≥2.0 mm 
in any lead; ST segment elevation ≥1mm in a non-
infarct territory. Both the J-point and the ST segment 
at 80 msec. need to meet criteria. When the HR is 
>130/min, the ST segment at 60 msec. may be used 
if the segment at 80 msec. cannot be determined.  
3. Either of the following: 
a. Peak workload not to exceed completion of 
stage 2 of a standard Bruce protocol or <7 
METS if a non-Bruce protocol is used or  
             b. ST segment criteria are met at <75% of the        
                 maximum predicted HR  
SPECT=single photon emission computed tomography, PET=positron emission tomography; Echo= 
echocardiography; CMR=cardiac magnetic resonance 
 


 
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1 Shaw L, Berman D, Stone G, Picard M, Friedrich M, Kwong R, et al. Comparative definitions 
for moderate-severe ischemia in stress nuclear, echocardiography, and magnetic resonance 
imaging. JACC Cardiovasc Imaging (in press).  
 
2Additional criteria may be required for confirmation of obstructive coronary artery disease, 
depending on eGFR and type of ischemia test. See Section 5.5.  
 
3Ancillary findings may also be included in the determination of severity of ischemia by imaging 
(see MOO). 
 
Note the exclusion criterion: Patient who, in the judgment of the patient’s physician, is likely to 
have significant unprotected left main stenosis will be excluded (see Section 4.3.1).