International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA)
Phase: NA
Conditions: Cardiovascular Diseases, Coronary Disease, Coronary Artery Disease, Heart Diseases, Myocardial Ischemia
Sponsor: NYU Langone Health

  
 
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ISCHEMIA Trial Protocol 
International Study of Comparative Health Effectiveness 
with Medical and Invasive Approaches 
Sponsor: 
National Heart, Lung, and Blood Institute (NHLBI) 
 
Study Chair 
 
Judith S. Hochman, MD 
 
 
Study Co-Chair 
 
 
David J. Maron, 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: 
 
       January 18, 2012 
 

  
 
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PROTOCOL VERSION AND AMENDMENT TRACKING 
 
Version Number/Amendment 
Approval Date 
 
 
 
 
 
 
 
 
 
 
 

  
 
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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:  January 18, 2012 
 
_________________________________ 
 
_________________________ 
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 
Study Objectives 
Primary objective is to determine whether an invasive (INV) strategy of 
routine early cardiac catheterization with intent for optimal 
revascularization in addition to optimal medical therapy in patients with 
stable ischemic heart disease (SIHD) and at least moderate ischemia on 
stress imaging reduces the incidence of the composite of cardiovascular 
death or nonfatal myocardial infarction compared with a conservative 
(CON) strategy of optimal medical therapy alone with cardiac 
catheterization and revascularization reserved for patients with refractory 
angina, acute coronary syndrome, acute ischemic heart failure or 
resuscitated cardiac arrest.  
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 is an international comparative effectiveness study. 
Participants will be recruited following clinically indicated stress testing but 
before catheterization and randomized in a 1:1 fashion to an INV or CON 
strategy. 
Number of 
Participants 
Approximately 8,000 participants randomized 
Trial Location 
Multinational: approximately 500 sites worldwide 
Inclusion Criteria 
• At least moderate ischemia on a stress imaging test with nuclear 
myocardial perfusion (≥10% myocardium), echo or cardiac magnetic 
resonance wall motion (≥3/16 segments with stress-induced severe 
hypokinesis or akinesis), or cardiac magnetic resonance perfusion 
(≥12% myocardium). 
• Participant is willing to comply with all aspects of the protocol, including 

  
 
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adherence to medical therapy and follow-up visits 
• 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 
• Prior known 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 or CABG within the previous 12 months 
• Stroke within the previous 6 months or intracranial hemorrhage at any 
time 
• History of ventricular tachycardia requiring therapy for termination, or 
symptomatic sustained ventricular tachycardia 
• 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 
• End stage renal disease on dialysis or estimated glomerular filtration 
rate (eGFR) <30mL/min 
• Severe valvular disease or valvular disease likely to require surgery 
within 5 years 
• 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   
• Life expectancy less than 5 years due to non-cardiovascular 
comorbidity 

  
 
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• Pregnancy (known to be pregnant; to be confirmed before CCTA 
and/or randomization, if applicable) 
• Patient with eGFR 30-59 ml/min who, in the judgment of the patient’s 
physician, is likely to have 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 CCTA or cardiac catheterization at 
the site 
Primary Endpoint 
Time to first occurrence of cardiovascular 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 
or heart failure. 
• Health resource utilization, costs, and cost-effectiveness 
Assessment 
Schedule 
Pre-eligibility screening, CCTA visit, randomization, 1.5 months, 3 months, 
6 months, 12 months, and every 6 months thereafter. 
Study Duration 
Enrollment will occur over approximately 4 years with an expected 
minimum of 18-24 months follow-up and an average of approximately 

  
 
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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, 
stroke, and transient ischemic attack. 
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 8,000 randomized participants is expected 
to provide over 90% power to detect a 15% 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. 
HYPOTHESIS ........................................................................................................................................ 18 
4. 
STUDY OBJECTIVES ............................................................................................................................. 19 
5. 
STUDY DESIGN .................................................................................................................................... 20 
5.1 
Study Flow ........................................................................................................................ 20 
5.2 
Study Population ............................................................................................................... 22 
5.3 
Inclusion/Exclusion Criteria ............................................................................................... 22 
5.3.1 
Criteria Prior to Informed Consent ....................................................................................................... 22 
5.3.2 
Criteria After Enrollment (Informed Consent) and Prior to Randomization ....................................... 23 
6. 
STUDY PROCEDURES .......................................................................................................................... 24 
6.1 
Qualifying Stress Imaging Study ......................................................................................... 24 
6.2 
Informed Consent Process ................................................................................................. 24 
6.3 
Interactive Voice Response System (IVRS) and Interactive Web Response System (IXRS) ..... 25 
6.4 
Core Lab Ischemia Verification ........................................................................................... 25 
6.5 
Coronary Computed Tomography Angiography (CCTA) ....................................................... 26 
7. 
MANAGEMENT STRATEGIES .............................................................................................................. 28 
7.1 
Conservative (CON) Strategy .............................................................................................. 28 
7.2 
Invasive (INV) Strategy ...................................................................................................... 28 
7.3 
Optimal Medical Therapy (OMT) ........................................................................................ 28 
7.3.1 
Management of Angina in CON Participants........................................................................................ 29 
7.3.2 
Management of Angina in INV Participants ......................................................................................... 29 
7.4 
Optimal Revascularization Therapy (ORT) .......................................................................... 29 
7.4.1 
Criteria to Select PCI vs. CABG .............................................................................................................. 30 
7.4.2 
Guidelines for Optimal Percutaneous Coronary Intervention ............................................................. 30 
7.4.3 
Guidelines for Optimal Surgical Revascularization .............................................................................. 30 
7.5 
Maximizing Adherence to CON Strategy ............................................................................. 30 
7.6 
Cath in Participants Randomized to CON Strategy .............................................................. 31 
8. 
AUXILLIARY SCREENING LOG AND SURVEY ....................................................................................... 33 
8.1 
Screening Log .................................................................................................................... 33 
8.2 
Screening Survey ............................................................................................................... 33 
9. 
Study Assessments ............................................................................................................................. 35 

  
 
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9.1 
Creatinine and Pregnancy Test ........................................................................................... 35 
9.2 
Standard Blood Tests ......................................................................................................... 35 
9.3 
Endpoint Assessments ....................................................................................................... 35 
9.4 
Blood Biomarkers and Genomics Biorepository .................................................................. 35 
9.5 
Medication Adherence ...................................................................................................... 36 
9.6 
Lifestyle Assessment ......................................................................................................... 36 
9.7 
Quality of Life Assessment ................................................................................................. 36 
9.8 
Economics Assessment ...................................................................................................... 36 
10. 
SCHEDULE OF ASSESSMENTS ......................................................................................................... 38 
11. 
ADJUDICATION OF CLINICAL EVENTS ............................................................................................ 48 
12. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ............................................................. 49 
12.1 
Sample Size Determination and Statistical Power ............................................................... 49 
12.1.1 
Considerations and Assumptions ..................................................................................................... 49 
12.1.2 
Summary of Power and Precision .................................................................................................... 49 
12.2 
Statistical Analysis Plan ..................................................................................................... 51 
12.2.1 
Analysis of the Primary Endpoint ..................................................................................................... 51 
12.2.2 
Analysis of the Secondary Endpoints ............................................................................................... 51 
12.2.3 
Contingency Plan For Insufficient Primary Endpoint Events ........................................................... 52 
12.2.4 
Quality of Life (QOL) Analysis ........................................................................................................... 52 
12.2.5 
Health Economics Analysis ............................................................................................................... 53 
12.2.6 
Interim Analysis ................................................................................................................................ 53 
13. 
DATA HANDLING AND RECORD KEEPING ...................................................................................... 56 
13.1 
Electronic Data Capture (EDC) System ................................................................................ 56 
13.2 
Data Management and Quality .......................................................................................... 56 
13.3 
Data Confidentiality and Security ....................................................................................... 56 
13.4 
Training ............................................................................................................................ 57 
13.5 
Records Retention ............................................................................................................. 57 
13.6 
Management of Economic and Quality of Life (EQOL) Data ................................................. 57 
14. 
SAFETY MONITORING PLAN ........................................................................................................... 58 
14.1 
Data and Safety Monitoring Board ..................................................................................... 58 
14.2 
Risks and Benefits ............................................................................................................. 58 
14.3 
Safety Monitoring Objectives and Rationale ...................................................................... 59 
14.4 
Adverse Events Reporting by Investigators ......................................................................... 60 
14.5 
Events to be Monitored ..................................................................................................... 60 

  
 
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15. 
ETHICAL CONSIDERATIONS ............................................................................................................ 62 
15.1 
Regulatory and Ethical Compliance .................................................................................... 62 
15.2 
Informed Consent Process ................................................................................................. 62 
15.3 
Responsibilities of the Investigator and IRB/IEC/REB .......................................................... 62 
15.4 
Protocol Amendments ....................................................................................................... 63 
15.5 
Early Termination of the Study .......................................................................................... 63 
16. 
STUDY ORGANIZATION .................................................................................................................. 64 
17. 
DATA ACCESS AND SHARING ......................................................................................................... 65 
18. 
PUBLICATIONS POLICY: OVERVIEW ............................................................................................... 66 
19. 
REFERENCE LIST .............................................................................................................................. 67 
 

  
 
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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  
CCTA 
coronary computed tomography angiography 
CEC 
clinical event adjudication committee 
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 
DNA 
deoxyribonucleic acid 

  
 
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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 
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 
ICC 
Ischemia Imaging Coordinating Center 
ICH 
International Conference on Harmonization 
IEC 
institutional ethics committee 
INV 
invasive management strategy (cath with intent to perform optimal 
revascularization plus optimal medical therapy) 
IRB 
Institutional Review Board 
ISCHEMIA 
International Study of Comparative Health Effectiveness with Medical and 
Invasive Approaches trial 

  
 
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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 
PIPEDA 
Personal Information Protection and Electronic Documents Act 
PSS 
Perceived Stress Scale 
REB 
Research Ethics Board 

  
 
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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  
Coronary artery disease (CAD) is the leading cause of death and disability worldwide and 
affects 17.6 million Americans, resulting in about 450,000 deaths in the United States annually.1 
Globally, 7.2 million deaths are caused by CAD each year.2 An invasive approach to the 
evaluation and treatment of CAD is common, yet evidence that this approach to management 
favorably influences long-term clinical outcomes in patients with stable ischemic heart disease 
(SIHD) is outdated. In randomized clinical trials conducted in the 1970s, surgical 
revascularization (coronary artery bypass graft [CABG]) improved survival compared to medical 
therapy in SIHD patients.3-6 The benefit was most apparent in subsets with high-risk anatomic 
features. The relevance of these studies to present-day patients with SIHD is unclear for many 
reasons. Most importantly, effective medical therapy proven in more recent trials to reduce 
clinical events was used minimally if at all. These therapies include aspirin, beta-blockers, 
statins, angiotensin-converting-enzyme (ACE) inhibitors, and lifestyle interventions.7-17 High-
dose statins, in particular, are disease and prognosis modifying agents. Moreover, in aggregate, 
these therapies could be expected to yield ~50% relative reduction in risk of clinical events.9, 18-
20 Thus, the continued relevance of findings from CABG vs. medicine trials conducted in an 
earlier era is, at best, speculative. 
In the contemporary era, revascularization in addition to medical therapy vs. medical therapy 
alone has been studied in several patient populations. The Surgical Treatment for Ischemic 
Heart Failure (STICH) trial assessed all-cause mortality for CABG vs. medical therapy alone in a 
heart failure cohort at high risk of death: those with severe HF, an ejection fraction ≤35%, and 
coronary artery disease. These patients are excluded from the ISCHEMIA trial. STICH reported 
no significant difference in all-cause mortality (the primary end point) between the two treatment 
strategies (P = 0.12); CABG reduced the composite of CV death and hospitalization.21 In a 
STICH substudy, myocardial viability did not identify patients with a differential treatment effect 
from CABG, as compared with medical therapy alone.22  
The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation 
(COURAGE)23 and the Bypass Angioplasty Revascularization Investigation 2 Diabetes 
(BARI 2D)24 trials demonstrated that in patients with SIHD, predominantly without severe LV 
dysfunction, a management strategy of revascularization plus optimal medical therapy (OMT) 
did not reduce the risk of death or MI as compared with OMT alone. Importantly, both of these 
trials randomized patients after cardiac catheterization (cath). Cath is an invasive diagnostic test 
that typically triggers a therapeutic cascade involving revascularization.25 This phenomenon is 
attributed, in part, to the common attitude among patients and physicians that visualized 
stenoses need to be “fixed” and that a revascularization procedure will prolong their lives and/or 
prevent MI, not just relieve angina.26-28 Consequently, the decision to proceed with 
revascularization often hinges more on anatomic feasibility than on evidence that 
revascularization is clinically beneficial.26, 28 The inherent assumption of this approach is that 
coronary revascularization of flow-limiting stenoses will prevent or reduce clinical events. This 
assumption is not warranted, based on the results of modern randomized trials.   

  
 
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Moderate to severe ischemia is a marker of increased risk for cardiovascular events.29 It 
remains unclear whether the increased risk associated with a greater magnitude of ischemia is 
related to the adverse effects of ischemia, occlusion of severe stenoses that cause ischemia, or 
if more severe ischemia is simply a marker of more extensive atherosclerosis and more 
vulnerable plaques. Vulnerable plaques, which may not themselves be flow-limiting, are more 
commonly sites of plaque rupture and thrombosis and the cause of MI than severe stenoses.30-
33 However, individual plaques with severe stenoses are more likely to occlude than less 
severely stenotic plaques.34 The power of the diagnostic-therapeutic cascade poses challenges 
for broad translation of COURAGE and BARI 2D results into practice. In both trials, 
randomization of patients after coronary anatomy had been visualized raises concerns that 
many patients with the most severe and treatable lesions may not have been enrolled but were 
instead revascularized preemptively while on the cath table, thus excluding an important high 
risk group from rigorous, prospective study. Although the finding that prompt revascularization in 
stable patients did not prevent death or MI suggests that cath may not be necessary in this 
cohort of patients, this conclusion is not valid due to the protocol design of these two landmark 
trials. 
Observational data suggest that early revascularization is associated with a lower likelihood of 
death and MI in patients with at least moderate ischemia on myocardial perfusion imaging 
(MPI),35-37 but this concept has never been fully tested in a prospective, randomized clinical trial. 
Within a small (n=314) nuclear substudy of patients who had baseline and follow-up stress 
perfusion scans at 6-18 months in the COURAGE study, there were 105 patients with at least 
moderate ischemia at baseline, as measured by MPI in a core laboratory. Among these 105 
patients, there was a significantly greater reduction in ischemia associated with PCI and OMT 
than OMT alone on follow-up MPI.38 For PCI and OMT groups combined, the rate of death or MI 
over 3.6 years was 16% for those who experienced ischemia reduction compared with 34% for 
those without significant ischemia reduction on follow-up MPI. These results support the 
hypothesis that the benefit of an invasive strategy in SIHD patients is most likely to be observed 
in patients with at least moderate ischemia. In contrast, a newer, unpublished COURAGE 
analysis of outcomes by treatment in 189 patients with at least moderate ischemia on baseline 
core lab-measured MPI, without regard to the ascertainment of a follow-up study, showed no 
reduction in death/MI (PCI and OMT vs. OMT 24% vs. 21%, respectively, hazard ratio [HR] 
1.19, 95% confidence interval [CI] 0.65-2.18). The same lack of benefit for PCI was 
demonstrated for a larger cohort of 468 patients with site-determined moderate or severe 
ischemia at baseline. 
Data from 9 reports representing 5,833 patients suggest that only 35 to 65% of patients 
with moderate or severe ischemia on MPI are referred for cath, reflecting equipoise in the 
community.39-47 It is presently unknown whether use rates for cath and revascularization are 
appropriate for optimal patient management. The results of COURAGE and BARI 2D are 
extremely valuable to physicians caring for patients with SIHD. However, a clinical trial to 
determine optimal management for SIHD patients uniformly at higher risk could not have been 
performed before the COURAGE and BARI 2D results were available. Moderate or severe 
ischemia is a marker for increased risk for death, but no well-designed clinical trial of patients 
with this degree of ischemia has studied whether an invasive strategy improves clinical 

  
 
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outcomes and quality of life. Given the potential clinical benefit from revascularization on the 
one hand, and the significant expense of an invasive strategy on the other, this is a critically 
important issue to resolve.  The results of ISCHEMIA will have profound implications for 
guidelines, health policy, and clinical practice.  
 

  
 
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3. 
HYPOTHESIS  
An invasive (INV) approach of routine early cardiac catheterization with intent for optimal 
revascularization in addition to OMT will reduce the incidence of major adverse cardiovascular 
events over an average of approximately 4 years in participants with SIHD and at least 
moderate ischemia as compared with an initial conservative (CON) approach of OMT alone, 
with catheterization reserved for refractory angina symptoms, acute coronary syndrome, acute 
ischemic heart failure, or resuscitated cardiac arrest. 

  
 
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4. 
STUDY OBJECTIVES 
PRIMARY AIM 
The primary aim of the ISCHEMIA trial is to determine whether an invasive strategy of routine 
early catheterization followed by optimal revascularization, in addition to OMT, will reduce the 
primary composite endpoint of cardiovascular 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 refractory angina symptoms, acute coronary syndrome, acute 
ischemic heart failure, or resuscitated cardiac arrest. 
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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5. 
STUDY DESIGN 
The ISCHEMIA trial is an international, randomized, comparative effectiveness study. 
Approximately 8,000 participants at approximately 500 sites worldwide with SIHD and at least 
moderate ischemia on stress imaging will be randomized in a 1:1 fashion to the INV or CON 
strategies. 
5.1 
Study Flow 
See figure 1 for details. Patients will be screened following clinically-indicated stress testing, but 
before catheterization. Patients with at least moderate ischemia on stress imaging (see section 
6.1) will be identified and screened for clinical inclusion/exclusion criteria (see section 5.3). 
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 6.3). Stress testing images will be transferred to the imaging core lab 
electronically for all enrolled participants (see Figure 1).  All participants with eGFR >60 ml/min 
will undergo a blinded CCTA. CCTA images will also be transferred electronically to the CCTA 
core lab for interpretation.  CCTAs will only be interpreted by the CCTA core lab and NOT at the 
site. The participant, participant’s physician, and site will not have access to the results of the 
CCTA unless the core lab determines the results reveal: 1) unprotected left main coronary 
artery stenosis (defined as ≥50% and not previously bypassed); 2) no obstructive lesions 
(≥50%) in any major coronary artery; or 3) incidental findings of clinical importance, such as an 
aortic aneurysm or suspected neoplasm. In the event of any of these three findings, the 
participant will not be eligible to continue in the study, and these results will be communicated to 
the site. The images will then be made available to the site for clinical use. All participants 
meeting CCTA eligibility criteria (see section 6.5) will then be randomized to the INV or CON 
strategy via the IVRS/IXRS system.  
 Participants with eGFR 30-59 ml/min will not undergo a CCTA due to the increased risk of 
developing contrast-induced nephropathy.  Participants with eGFR 30-59 ml/min who, according 
to the participant’s physician, are unlikely to have significant unprotected left main stenosis, will 
proceed directly to randomization. (Patients with eGFR <30 ml/min are not eligible for the trial.) 
Patients with eGFR 30-59 ml/min will not be enrolled into the study if the patient’s physician 
suspects significant left main stenosis on the basis of stress hemodynamic, ECG, and imaging 
results.  
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 4 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 10.

  
 
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Figure 1 
Study Flow 
 
 

 
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5.2 
Study Population 
 
Patients with SIHD and at least moderate ischemia on stress imaging. 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).  
 
5.3 
Inclusion/Exclusion Criteria  
 
Screening for inclusion/exclusion criteria will be conducted in two phases. First, clinical and 
ischemia criteria at the local site will be used to obtain informed consent; and second, after 
informed consent is obtained but before randomization, criteria for CCTA eligibility will be 
assessed. Stress imaging core labs will work with sites to ensure randomization of participants 
with at least moderate ischemia. 
5.3.1 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 stress imaging test (See Table 1) 
2. Participant is willing to give informed consent 
3. 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. Prior known 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 or CABG within the previous 12 months 
10. Stroke within the previous 6 months or intracranial hemorrhage at any time 
11. History of ventricular tachycardia requiring therapy for termination, or symptomatic 
sustained ventricular tachycardia 

 
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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. End stage renal disease on dialysis or estimated glomerular filtration rate (eGFR) <30 
ml/min 
15. Severe valvular disease or valvular disease likely to require surgery within 5 years 
16. Allergy to radiographic contrast that cannot be adequately pre-medicated, or any prior 
anaphylaxis to radiographic contrast 
17. Planned major surgery necessitating interruption of dual antiplatelet therapy 
18. Life expectancy less than 5 years due to non-cardiovascular comorbidity 
19. Pregnancy (known to be pregnant; to be confirmed pre-CCTA and/or randomization, if 
applicable) 
20. Patient with eGFR 30-59 ml/min who, in the judgment of the patient’s physician, is  likely 
to have significant unprotected left main stenosis 
21. Enrolled in a competing trial that involves a non-approved cardiac drug or device 
22. Inability to comply with the protocol 
23. Exceeds the weight or size limit for CCTA or cardiac catheterization at the site 
 
5.3.2 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 and will undergo measurement of ischemia by 
the stress imaging core lab and a blinded CCTA (if eGFR >60 ml/min). Participants meeting the 
following exclusion criteria will not be randomized. 
Exclusion (after informed consent and before randomization) 
1. Pregnant (negative pregnancy test before CCTA required for premenopausal females) 
2. Left main stenosis ≥50% (unprotected) on CCTA  
3. Finding of “no obstructive coronary artery disease” (<50% stenosis) in all major 
epicardial vessels on CCTA 
4. Incidental findings on CCTA of clinical importance (e.g., lung mass suspicious for 
malignancy; see MOO for details) 
5. Interval development of a clinical exclusion criterion or a primary or secondary endpoint 
event.

 
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6. 
STUDY PROCEDURES 
6.1 
Qualifying Stress Imaging Study  
The following imaging stress test modalities will be allowed for inclusion using exercise or 
pharmacologic stress:  
• 
Nuclear perfusion imaging (single photon emission computed tomography [SPECT] or 
positron emission tomography [PET]) 
• 
Echocardiography (Echo) 
• 
Cardiac magnetic resonance (CMR) 
Non-imaging stress tests (ECG only) will not be permitted to determine eligibility. The criteria for at 
least moderate ischemia with each imaging modality are listed in Table 1. Stress 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 stress imaging study documenting eligibility, consistent with 
customary clinical practice.36, 37 A 24-hour, 7-day helpline will be available to sites for assistance with 
ascertainment of eligibility, enrollment, and adherence to protocol. 
 
Table 1: Criteria for at least Moderate Ischemia by Stress Imaging Modality 
Imaging Modality 
Diagnostic criterion 
Nuclear perfusion via 
SPECT or PET 
≥10% myocardium ischemic 
Echo  
≥3/16 segments with stress-induced severe hypokinesis or 
akinesis 
CMR  
perfusion: ≥12% myocardium ischemic 
and/or wall motion: ≥3/16 segments with stress-induced 
severe hypokinesis or akinesis 
SPECT=single photon emission computed tomography, PET=positron emission tomography; Echo= echocardiography; 
CMR=cardiac magnetic resonance 
 
6.2 
Informed Consent Process 
The study will be reviewed with the prospective study participant by the investigator or his/her 
designee. The prospective study participant will be given adequate time to read the written consent 
form.  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. 

 
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In addition, prospective study participants will be requested to consent to a biorepository sample, 
and to allow use of the biorepository sample for genetic testing (DNA).  Prospective study 
participants will be informed that declining participation in the Biomarker or Genetic Testing 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 
(including CCTA) 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. 
6.3 
Interactive Voice Response System (IVRS) and Interactive Web Response 
System (IXRS) 
Enrollment and randomization will be accomplished by contact with the IVRS or IXRS. When a 
participant meeting site-determined clinical and stress imaging 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, site, and core lab inclusion/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. 
6.4 
Core Lab Ischemia Verification 
Stress imaging studies for all participants will be transferred electronically to the appropriate stress 
imaging core lab following enrollment of the participant into the study. The core lab will review and 
interpret the degree of ischemia. A purpose of core lab review is to ensure that participants enrolled 
in this study have at least moderate ischemia. Based on performance in the interpretation of tests 
meeting the definition of at least moderate ischemia, stress imaging core labs will certify that sites 

 
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can continue to advance participants to the next step, CCTA (or randomization, if the eGFR is 30-
59ml/min). (See MOO.) 
6.5 
Coronary Computed Tomography Angiography (CCTA) 
Coronary computed tomography angiography (CCTA) will be performed in all participants with eGFR 
≥60ml/min to identify and exclude participants with obstructive left main stenosis (defined as ≥50% 
unprotected stenosis) and participants without obstructive coronary stenoses (with <50% stenosis in 
all epicardial coronary vessels). Study staff will not view the CCTA; only the CCTA core laboratory 
will interpret results and sites will be blinded to the results of the scan. The scan and interpretation 
will not be stored in the local clinical imaging system. Participants with eGFR 30-59 ml/min will not 
undergo a CCTA due to the risk of developing contrast-induced nephropathy. In this subpopulation, 
participants can be randomized if the treating physician does not suspect significant unprotected left 
main stenosis based on the results of the stress test, including the imaging portion. However, if a 
significant left main stenosis is suspected, these participants will not be enrolled into the study.   
Radiation reduction techniques will be used. We will prescribe standardized patient-specific image 
acquisition protocols that permit high quality CCTA with low dose radiation. Radiation reduction 
methods will include ECG dose modulation, weight-based tube voltage, minimization of Z-axis 
coverage, limiting the field of view, and automatic exposure control. Importantly, all of these dose 
reduction techniques are additive, can be programmed into a single default protocol, and are 
available in all ≥64-detector row CT scanners. The investigative group has evaluated the efficacy of 
combined dose reduction techniques and found a >90% reduction in biological radiation dose 
(1-2 mSv) without compromise of image quality or diagnostic accuracy.48-52 Each site will be 
provided with a concise, easy-to-read manual and an instructional video, prepared for this trial, on 
how to obtain high quality CCTA images with low radiation dose. For newer scanners, we will 
employ further dose reduction algorithms including prospective ECG triggering, minimization of 
padding, and iterative reconstruction techniques.  
The CCTA core laboratory will interpret the images and sites will be notified if the participant is or is 
not eligible because of significant unprotected left main coronary artery stenosis or the absence of 
obstructive stenoses. Further definition of the anatomy will not be disclosed to the participant, 
treating physicians, or the site unless the participant is not eligible for randomization. Participants 
with incidental findings of clinical importance, such as aortic aneurysm or suspected neoplasm; see 
MOO for details), will not be randomized and the interpretation of the CT, including coronary 
anatomy, will be made available to the treating physicians. In addition, there may be findings on CT 
of potential clinical significance that will not exclude patients from the study, such as small lung 
nodules. In such cases, treating physicians will be given access to and will be encouraged to review 
the CT images locally. 
If a trial-consented participant is not randomized after CCTA, despite being confirmed eligible by the 
CCTA core laboratory, maintenance of investigator blinding will be investigated.  
Participants meeting the clinical, ischemia, and CCTA eligibility (or physician judgment for 
participants with eGFR 30-59 ml/min) will be randomized to the INV or CON strategy via the 

 
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IVRS/IXRS system. The targeted time to randomize a participant after consent is obtained is 15 
days (see Figure 1). 

 
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7. 
MANAGEMENT STRATEGIES 
Table 3.  Components of CON and INV management strategies 
 
CON (Section 7.1) 
 
INV (Section 7.2) 
• 
Optimal medical therapy (OMT; includes 
angina management) (Section 7.3) 
• 
Provisional cardiac catheterization (Section 
7.6) 
• 
Optimal medical therapy (OMT; includes 
angina management) (Section 7.3) 
• 
Cardiac catheterization  
• 
Optimal revascularization therapy (ORT) 
(Section 7.4) 
 
7.1 
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.  
7.2 
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. 
7.3 
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. 
7.3.1 Management of Angina in CON Participants 
Medical management of angina in CON participants will be intensified according to the ISCHEMIA 
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. 
7.3.2 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 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. 
7.4 
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. 
• 
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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7.4.1 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. 
7.4.2 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. 
7.4.3 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. 
 
7.5 
Maximizing Adherence to CON Strategy 
Adherence to the CON strategy means that all CON participants receive OMT and that none 
undergo cath or revascularization 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 management of refractory angina). Cath 

 
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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 must call the 24-hour helpline when elective cath is being considered, 
and they must complete a checklist. 
 
7.6 
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 (7.4) 
apply.  
 
 
 
 
 
 
 
 
 
 
 
 

 
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Figure 2 
 Cath in Participants Randomized to CON Strategy  
 

 
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8. 
AUXILLIARY SCREENING LOG AND SURVEY 
8.1 
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 stress imaging 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). 
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 
stress imaging. 
 
8.2 
Screening Survey 
For brief designated periods, sites will collect de-identified data on all patients with at least moderate 
ischemia who are screened but not enrolled by the study team. The goal of this effort will be to 
describe the characteristics of patients who are screened but not enrolled and to document the 
major reasons for exclusion. This screening survey will include the site’s primary stress imaging 
laboratory and any other screening and referral sources. Data will be entered via a web-based EDC 
system which will not include patient identifiers and will be separate from the main trial EDC system. 
For analysis, we will compare baseline characteristics and treatment plan of patients who were 
screened and met inclusion criteria but were not randomized with those who were randomized. This 
information will provide insight into any potential bias in trial enrollment. Examples of data elements 
to be collected, when available, include: 
• 
Age (excluding any age ≥90) 
• 
Sex 
• 
Race/ethnicity 
• 
LVEF 
• 
Results of the stress imaging test (ischemia severity and location) 
• 
Basic medical history from stress imaging report (if available) 
• 
Presence or absence of LM stenosis >50% on previous CCTA or cardiac catheterization 
• 
History of ACS within the last 2 months 
• 
History of PCI or CABG within the last 12 months 
• 
History of stroke within the last 6 months or intracranial hemorrhage at any time 
• 
End stage renal disease or  eGFR 15-29 mL/min 

 
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• 
History of NYHA III/IV heart failure or admission to hospital in the last 6 months 
• 
Planned non cardiac surgery within the next 12 months 
• 
Severity of angina symptoms 
• 
Current anti-angina medications 
• 
Willingness to take medications 
• 
Plan for treatment (e.g., cardiac catheterization, mode of revascularization if applicable)  
• 
Actual treatment received (e.g., cardiac catheterization, mode of revascularization if 
applicable) 
• 
Reason for not participating in the trial 
 
Only de-identified health information will be recorded. An informed consent waiver will be obtained 
where applicable. There will be no follow-up of these screening survey patients. 
 

 
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9. 
Study Assessments 
9.1 
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. 
 
9.2 
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 they will be obtained (HbA1c required for 
diabetics only but recommended for all participants). 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 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. 
9.3 
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. 
9.4 
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 testing. 
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, 
DNA. At the 3 month follow-up visit, up to 49 mL of blood may be drawn.   

 
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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. 
9.5 
Medication Adherence 
To assess medication adherence, a 4-item modified Morisky adherence survey (Likert scale 
responses to 4 questions)53-56 will be completed at the randomization visit, 6 month visit, and all 
subsequent visits. 
9.6 
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. 
 
9.7 
Quality of Life Assessment  
 
To quantify the full spectrum of patient-reported quality of life outcomes in ISCHEMIA, 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; physical function 
by the disease-specific Duke Activity Status Index (DASI) and angina-specific SAQ physical 
limitations sub-scale; a Rand general health rating; psychological well-being and depression 
screening symptoms by the Perceived Stress Scale (PSS) and Patient Health Questionnaire-8 
(PHQ-8); a measure of optimism about the future from the Life Orientation Test-Revised (LOT-R); 
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. 
 
9.8 
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 throughout the trial at each ISCHEMIA study visit or contact and entered into the main 
study EDC database. These data, in conjunction with billing data (collected for the US study 
participants only by the EQOLCC economic team and entered into a database separate from the 
main EDC study database), 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 

 
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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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10. SCHEDULE OF ASSESSMENTS 
Overview of Visits 
All participants will undergo eligibility screening, informed consent, CCTA (for all participants with 
eGFR >60 ml/min) 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 4 for complete assessment schedule). The schedule of 
assessments (Table 4) 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 4). 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. 
Dependent on additional funding, telephone, in-person and/or email follow up may occur for 
participants who are enrolled and subsequently excluded from randomization due to CCTA findings 
of nonobstructive or LM CAD. It may include up to 5 visits over the first 18 months and up to 2 visits 
per year thereafter until the study ends. Participants who are excluded based on CCTA or stress test 
findings will be asked to provide consent for future contact for research purposes. 
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 
Collection of Economic and QOL data, including the follow-up Full QOL Questionnaire validated 
scales will be repeated at 3, 12, 24 and 36 months from randomization and at the final ISCHEMIA 
visit by trained telephone interviewer staff from the EQOL Coordinating Center (EQOLCC) for 
participants enrolled in North America and by the site coordinator in sites outside North America.  A 
Proxy QOL questionnaire obtained from a relative, caretaker, or medical record will be used when a 
participant has died in the follow-up interval, is too ill, otherwise incapacitated, or unable to 
participate. Lastly, 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 visit.  All symptom and QOL data will be data processed and analyzed by the EQOLCC 
quality of life team.  A Hospitalization assessment as part of the main study EDC database will be 
collected on all randomized ISCHEMIA participants at each follow-up study interval throughout the 
trial to provide a measure of resource utilization.  Additionally, as part of the economic data in 
ISCHEMIA, medical bills for participants enrolled at US sites only will be collected throughout the 
trial by the EQOLCC economic team from this Hospitalization assessment. The medical billing data 
will be obtained, extracted, data processed and analyzed by the EQOLCC.  

 
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Table 4 
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 Image 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 
Coronary CT Angiography (CCTA)  
 
XF 
 
 
 
 
 
 
 
 
 
 
 
Safety assessment G 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Vital signs, weight, heightH 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q12m 
Standard lab resultsI  
 
 
XJ 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q12m 
Biorepository blood draw  
 
 
X 
 
 
XK 
 
 
 
 
 
 
 
Cardiac biomarkersL  
 
 
 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) M 
 
 
X 
XN 
 
 
 
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 
Full Quality of Life (QOL) assessment O 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
@ closeout 
Brief symptoms/QOL assessmentP  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Initiate Optimal Medical Therapy (OMT) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical Therapy Evaluation and OptimizationQ 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Schedule catheterization for INV participantsR 
 
 
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).  

 
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*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 stress test images (immediately following enrollment and before randomization), technical worksheets, and site interpretations/local reports from qualifying stress tests 
to core labs. 
F CCTA not performed if estimated glomerular filtration rate < 60ml/min; Blinded CCTA images and technical worksheets will be transferred to CCTA core lab for interpretation. 
G Safety Assessment (refer to section 14.4). 
H Height is only needed at randomization, assessments only required if visit is completed in clinic. 
I Required labs include: lipids (preferably fasting), and liver transaminases (if indicated), 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. 
J Standard lab results needed at randomization include: complete blood count, electrolytes, creatinine, glucose, liver transaminases, lipid profile, HbA1c for diabetic participants.  
Request from participant’s physician, since it is expected that routine blood work will have been done within the last 6 months; if not it will need to be done at this time. 
K May be requested. 
L For participants undergoing PCI: CK-MB at 8-16 ± 2 hours or at hospital discharge, whichever comes earlier (troponin to be measured if CK-MB not available). For participants 
undergoing CABG: CK-MB at 18 ± 6 hours (troponin to be measured if CK-MB not available). All biomarker measurements should be recorded on eCRF.  It is recommended to 
obtain a biomarker measurement before all PCI and CABG procedures. 
M Send to ECG core lab; ECG required for all cardiac admissions and revascularizations; year 1 ECG optional (filed on site).  
N ECG done following procedure (60±30 mins post-PCI, 3 days post-CABG). 
O Seattle Angina Questionnaire/Duke Activity Status Index/Rand general health status item/Perceived Stress Scale/Patient Health Questionnaire/Life Orientation Test – 
Revised/EQ-5D/Demographic characteristics. 
P Selected Seattle Angina Questionnaire/Rose dyspnea scale/EQ-5D. 
Q At every follow-up visit the research 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. 
R Planned cath and revascularization only in the INV group.  See MOO for time windows for performing cath and revascularization after randomization.  Catheterization and 
optimal revascularization treatment should be targeted within 30 days after randomization in the Invasive strategy group. In the Conservative group, catheterization and optimal 
revascularization is reserved for participants with refractory angina symptoms or acute ischemic events. 
  

 
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 Screening visit 
• 
Patients with at least moderate ischemia by stress imaging test (see Table 1) 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 5.3 
• 
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 with an eGFR ≥30ml/min 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 stress testing images will be transferred electronically to the 
appropriate core laboratory. (see section 6.4) 
CCTA visit 
• 
For participants with eGFR ≥60ml/min, blinded CCTA will be performed 
• 
Blinded CCTA images will be transferred to CCTA core lab for interpretation 
• 
Participants with eGFR 30-59 ml/min do not require CCTA before randomization 
• 
Assessment for safety (e.g., complications of CCTA) 
Randomization visit (Baseline Visit) (targeted within 15 days of participant’s consent)  
• 
Confirm ischemia and CCTA eligibility 
• 
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) 
• 
Full QOL assessment will be collected (prior to actual randomization) 

 
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• 
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 
• 
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 CK-MB at 8-16 ± 2 hours post-PCI or at hospital discharge, 
whichever comes earlier (troponin to be measured if CK-MB not available) 
- 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 
- Blood draw for CK-MB at 18 ± 6 hours post-CABG (troponin to be measured if 
CK-MB not available) 

 
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- 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 
• 
Hospitalization assessment will be collected 
• 
Endpoints will be assessed 
• 
Obtain lab results from participant’s treating physician for lipids (preferably fasting) and 
liver transaminases (when indicated). If not available these tests should be obtained by 
the patient’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 
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 
• 
Full QOL assessment will be collected 
• 
Hospitalization assessment will be collected 
• 
Biorepository blood draw will be performed 
• 
Endpoints will be assessed 

 
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• 
Obtain lab results from participant’s treating physician for lipids (preferably fasting) and 
liver transaminases (when indicated). If not available these 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 
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  
• 
Hospitalization assessment will be collected 
• 
Endpoints will be assessed 
• 
Obtain lab results from participant’s treating physician for lipids (preferably fasting) and 
liver transaminases (when indicated). If not available these 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  

 
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• 
Brief symptoms/QOL assessment will be collected  
• 
Full QOL assessment will be collected  (until 36 months) 
• 
Hospitalization assessment will be collected 
• 
Endpoints will be assessed 
• 
Obtain lab results from participant’s treating physician for lipids (preferably fasting), liver 
transaminases (when indicated), and HbA1c for diabetic participants. If not available 
these 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 
Continuing Follow-Up Visits (every 6 months following the 36 month visit until close out) 
• 
Medical status assessment 
• 
NYHA and CCS class (see MOO) 
• 
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), liver 
transaminases (when indicated). HbA1c (only in participants with diabetes at every 12 
month visit). If not available these 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 

 
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Close out visit (in addition to all assessments for the regularly scheduled visit) 
• 
12 lead ECG will be performed and submitted to core lab 
• 
Full QOL assessment will be collected 
• 
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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11. 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, 
stroke, and transient ischemic attack. 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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12. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
12.1 Sample Size Determination and Statistical Power 
12.1.1 Considerations and Assumptions 
The sample size of approximately 8,000 randomized participants was selected to yield high 
power for testing the primary superiority hypothesis under reasonable assumptions about the 
frequency of the primary composite endpoint, the magnitude of the difference in event rates for 
INV vs. CON strategies, and the pattern of accrual and dropout. Based on the distribution of 
coronary disease expected in this population (core-lab documentation of at least moderate 
ischemia; CCTA documentation of obstructive CAD) and based on unpublished data from the 
COURAGE trial and several observational stress imaging registries, the percent of participants 
experiencing the primary composite endpoint within 4 years of randomization in the CON group 
was projected to be 20% (range 15%-25%). In addition to the CON event rate, an additional key 
driver of the required sample size is the magnitude of benefit that can reasonably be expected 
to be achieved with the INV strategy. This determination was based on multiple factors including 
(i) effect size estimates from related studies; (ii) anticipated increase in effect size by using 
CCTA to exclude non-obstructive CAD, (iii) potential for CON participants to receive 
catheterization in violation of the protocol; and (iv) the investigators’ assessment of the minimum 
effect size needed to be impactful and clinically relevant. After careful consideration of these 
and other factors, the sample size was formulated to provide high power to detect a 15% 
relative reduction (i.e., from 20% to 17% at 4 years) in the 4-year rate of the primary composite 
endpoint for participants randomized to INV versus CON (See Table 5 footnote for other 
assumptions.) Recognizing that event rates and outcome differences in ISCHEMIA may differ 
somewhat from these assumptions, the required sample size was also calculated for several 
different plausible combinations of parameter values. The final sample size was chosen to 
provide adequate power, even if our current assumptions prove to be optimistic. Loss of power 
due to protocol non-adherence was reflected in the sample size analysis by computing power 
with a relatively modest assumed treatment effect (20% vs.17%). Ideally, with perfect protocol 
adherence, a larger treatment effect would be plausible. Although the study objectives are 
worded in terms of testing a hypothesis (i.e. that the INV strategy is superior), another important 
objective is to estimate the magnitude of difference in outcomes (to within an acceptable level of 
statistical precision), regardless of which strategy (if either) is proven superior. Thus, the study 
is powered for precise parameter estimation (i.e. narrow confidence intervals) as well as 
hypothesis testing power. 
12.1.2 Summary of Power and Precision 
As shown in Tables 5 and 6 below, the planned sample size of approximately 8,000 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 1.11 with probability 95% and will yield power ≥90% for comparing the 
primary composite endpoint across the two randomized groups assuming the 4-year cumulative 
rate of the primary composite endpoint is 20% in participants randomized to CON strategy and 
is less by a factor of 15% (i.e. is reduced from 20% to 17%) in participants randomized to INV 

 
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strategy. Power will be ≥80% if the 4-year event rate of the primary composite endpoint is 
reduced by 13% instead of 15%, still assuming the 4-year rate is 20% in the CON strategy. 
Thus we have excellent power even with a more conservative effect size projection. Finally, 
power will be ≥80% if the 4-year cumulative rate of the primary composite endpoint is 15% 
instead of 20% in the CON strategy group, and is reduced by a factor of 15% in the INV strategy 
group. Thus, we have excellent power even with a more conservative estimate of the incidence 
of the primary endpoint. Power and precision under other assumptions are summarized in Table 
5 and Table 6 below. 
 
Table 5. 
Estimated Power as a Function of the Anticipated 4-Year Cumulative Event 
Rate in CON and the 4-Year Cumulative Risk Reduction in INV (∆) 
CON anticipated 
4-year event rate 
Estimated Power 
Event % 
∆ = 0.13 
∆ = 0.15 
∆ = 0.17 
10% 
48% 
60% 
72% 
15% 
67% 
80% 
89% 
20% 
82% 
92% 
97% 
25% 
92% 
97% 
99% 
30% 
97% 
99% 
≥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; 4000 participants per group; average follow-up 3.7 
years; loss-to-follow-up 0.85% per year; survival times follow exponential distribution. 
 
Table 6. 
Range of Estimated Precision (Margin of Error) as a Function of the 
Anticipated 4-Year Cumulative Event Rate in CON and the 4-Year Cumulative Risk 
Reduction in INV (∆) 
CON anticipated 
4-year event rate 
Margin of Error (MOE) 
Event % 
∆ = 0.13 
∆ = 0.15 
∆ = 0.17 
10% 
1.16 
1.16 
1.16 
15% 
1.13 
1.13 
1.13 
20% 
1.11 
1.11 
1.11 
25% 
1.10 
1.10 
1.10 
30% 
1.09 
1.09 
1.09 
NOTE: MOE 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. See Table 5 for additional assumptions. 
 

 
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12.2 Statistical Analysis Plan 
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. 
12.2.1 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 (CV 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. 
 
12.2.2 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 12.2.4 and 12.2.5. 
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 MI57; 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 

 
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infarctions.  Data collection instruments and the adjudication process will allow construction of 
alternative endpoint MI definitions. 
 
12.2.3 Contingency Plan For Insufficient Primary Endpoint Events 
The projected event rate of 20% at 4 years for the primary composite endpoint in CON 
participants was based on multiple data sources including the COURAGE nuclear substudy and 
several stress imaging registries. 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 CV 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.58, 59  Additional details will be finalized in cooperation with 
the DSMB and recorded in the statistical analysis plan before the first unblinded interim 
analysis. 
12.2.4 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 

 
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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 
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. 
 
12.2.5 Health Economics Analysis  
The health economic analyses for ISCHEMIA will consist of two major parts, an empirical 
intention-to-treat cost comparison and a cost-effectiveness analysis. Primary statistical 
comparisons between the two treatment groups of empirical costs will be performed by 
intention-to-treat.  The participants enrolled outside the United States will be excluded from the 
primary cost intention-to-treat analyses. Confidence limits around the observed cost differences 
will be constructed using bootstrap methods. 
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. 
12.2.6 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 14.1). 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 

 
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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 (cardiovascular death and MI). Cox-proportional hazard models with 
treatment as the 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 
DeMets60 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.61 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.62 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 

 
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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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13. DATA HANDLING AND RECORD KEEPING 
13.1 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 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. 
 
13.2 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. 
 
13.3 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. 
Images will be stripped of identifiers present within the DICOM header during the image upload 
process, by a vendor which will be responsible for image transfer and storage for this trial. 

 
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13.4 Training 
 
All investigational site and core lab staff authorized to enter ISCHEMIA Study data will receive 
training on the EDC system. Training records will be retained by the EDC Helpdesk at the 
SDCC. 
 
13.5 Records Retention  
 
Study records will be maintained by the site investigators for a period of six (6) years following 
the expiration of the grant or length of time as required by local regulations, whichever is longer. 
 
13.6 Management of Economic and Quality of Life (EQOL) Data 
The economic and quality of life studies will be fully integrated into the clinical trial and will be 
covered by the main trial Informed Consent Form. Interviewers will be blinded to the study 
group. Data processing, quality control, and analysis of EQOL data will be performed by the 
EQOLCCs. Although the EQOL computer network is not a regulated environment as are the 
clinical databases, EQOL follows the same network security protocols including password 
protection, expiring logons, and restricted access. Participant information records will be kept 
confidential in a separate, secured SQL Server database, and the participant’s name will never 
be released. Even though the interviewers must be unblinded to participant identity in order to 
collect the EQOL data, unblinded information is locked with restricted access, and none of the 
electronic databases or analysis files include direct participant identifiers. The electronic 
databases have (coded) study identifiers. In addition to participant identifiers never being linked 
to the clinical database, they are never passed on to the sponsor or third party. The interviewers 
obtain an approved Duke University IRB required consent from the participant on the telephone 
before a questionnaire may be administered. All of the EQOL data are analyzed in aggregate 
with only coded study identifiers (no direct participant identifiers), and no individual 
data/participant identifier will ever be presented in any oral or written form. No name or other 
identifiable information ever appears on the data or reports about the study. 

 
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14. SAFETY MONITORING PLAN 
14.1 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. 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. 
 
14.2 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, 
except CCTA, are commonly performed for the patient population enrolled in the study, i.e., 
those with SIHD and at least moderate ischemia. The only procedure being done for study 
purposes is CCTA. Although CCTA has increasingly been used to evaluate the presence and 
extent of coronary artery disease, it is not considered standard of care when used in the testing 
sequence in the trial. 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: 
 
CCTA Risks: The primary risk is an increased exposure to radiation from the CCTA scan.  On 
average, the estimated total radiation dose from this study (one CCTA scan) will range from 4-8 
mSv. In comparison, other estimated doses of medical radiation include: chest X-ray (0.05 
mSv); invasive cardiac catheterization (5-7 mSv); PCI (10-16 mSv); nuclear stress test (12-30 
mSv). In 1 year a person living at sea level is exposed to natural radiation of about 3 mSv, so 
the expected radiation dose from CCTA is around 1-3 times that amount. 
 
Other known risks of CCTA include allergy. Participants with known contrast allergy will be 
premedicated and participants with prior anaphylaxis to contrast will not be included in the 
study. As noted above participants with eGFR 30-59 ml/min will not undergo CCTA to minimize 
risk from this procedure in the trial. Patients with eGFR<30 ml/min will be excluded. Beta 
blockade, which is routinely used during CCTA, may cause bradycardia, hypotension or 

 
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bronchospasm, and nitroglycerin can lower blood pressure and may cause headache. 
Participants will be monitored throughout the procedure for these effects and treated if 
necessary. 
 
All females who are premenopausal must have a negative pregnancy test documented before 
undergoing the CCTA or being placed into either of the two study groups. 
 
Cath/PCI/CABG Risks: Each of these procedures is commonly performed in clinical practice for 
patients who meet eligibility criteria for the study. 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 nephropathy 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 and atrial fibrillation. Risks of these procedures vary in likelihood based on the 
patient’s risk profile. 
 
Risk Lowering Measures: 
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 14.1) 
Benefits: 
The ISCHEMIA trial results should provide evidence based data to support management of 
patients with SIHD.  
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. It is hoped the knowledge gained will be of 
benefit to others with a similar medical condition in the future. 
 
14.3 Safety Monitoring Objectives and Rationale 
The main safety objectives in ISCHEMIA 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.  

 
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14.4 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.  
14.5 Events to be Monitored 
 
Safety monitoring in ISCHEMIA will be concerned with estimating event rates for the following 
types of clinical events: 
1. Complications of cardiovascular tests (e.g. CT coronary angiogram, 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. 
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: 
CT coronary angiography: 
1. Severe contrast reaction such as anaphylaxis 
2. Hemodynamic instability, including symptomatic bradycardia or hypotension, due to the 
beta blockade or nitrates given for the CCTA scan acquisition  
3. Acute bronchospasm due to the beta blockade given for the CCTA scan 
4. Contrast induced nephropathy  
5. Radiation dose exposure 
 
In addition the incidence of finding significant LM stenosis (>50%) on cardiac catheterization not 
reported on CT coronary angiogram will be monitored and reported to the DSMB. Incidental 
findings on CCTA that are of clinical importance (e.g., aortic aneurysm or suspected neoplasm) 
will be reported to the site and the participant may be excluded from the study. 
Cardiac catheterization and PCI: 
1. Severe contrast reaction such as anaphylaxis 
2. Periprocedural stroke  
3. Emergency CABG 
4. Contrast-induced nephropathy 

 
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5. 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 
 
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 and 
blinded CCTA). 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 
12.2.6). 

 
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15. ETHICAL CONSIDERATIONS 
15.1 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. 
 
15.2 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, including informed consent for any screening 
procedures conducted to establish participant eligibility for the study (e.g. CCTA). 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. CCTA and 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. 
15.3 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. A separate IRB/IEC/REB waiver of consent may 
also be required for the screening survey, according to local regulations. 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.  
 
 
 

 
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15.4 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 
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. 
 
15.5 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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16. STUDY ORGANIZATION 
ISCHEMIA is sponsored by the US National Heart, Lung, and Blood Institute (NHLBI). The 
Clinical Coordinating Center (CCC), 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 Ischemia Imaging Coordinating Center 
(ICC) will organize and oversee the stress imaging core laboratories, coordinate and implement 
educational systems for sites and monitor site stress imaging performance. The Economics and 
Quality of Life Coordinating Center (EQOLCC) is responsible for the conduct of the quality of life 
and the economics and cost effectiveness portions of this study. The Computed Tomography 
Coronary Angiography Core Laboratory (CCTA CL) will interpret all CCTA scans and will 
provide technical support. 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. 
Details of the Committees, their charge and membership may be found in the MOO. These 
Committees include Leadership, Executive and Steering Committees, optimal medical therapy 
and optimal revascularization committees, committee on recruitment of women and minorities, 
biorepository, statistics, ancillary studies and publications committees. 

 
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17. DATA ACCESS AND SHARING 
The Publication Committee will authorize access to study data and biospecimens.  Investigators 
must submit a proposal requesting approval to access ISCHEMIA trial data/specimens. The 
ISCHEMIA 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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18. 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 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-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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