Conditions: Cardiovascular Diseases Coronary Disease Coronary Artery Disease Heart Diseases Myocardial Ischemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5179
Healthy volunteers: no

Brief summary:
The purpose of the ISCHEMIA trial is to determine the best management strategy for higher-risk patients with stable ischemic heart disease (SIHD). This is a multicenter randomized controlled trial with 5179 randomized participants with moderate or severe ischemia on stress testing. A blinded coronary computed tomography angiogram (CCTA) was performed in most participants with eGFR ≥60 mL/min/1.73m2 to identify and exclude participants with either significant unprotected left main disease (≥50% stenosis) or those without obstructive CAD (\<50% stenosis in all major coronary arteries). Of 8518 participants enrolled, those that had insufficient ischemia, ineligible anatomy demonstrated on CCTA or another exclusion criterion, did not go on to randomization. Eligible participants were then assigned at random to a routine invasive strategy (INV) with cardiac catheterization followed by revascularization, if feasible, plus optimal medical therapy (OMT) or to a conservative strategy (CON) of OMT, with cardiac catheterization and revascularization reserved for those who fail OMT.

SPECIFIC AIMS

A. Primary Aim The primary aim of the ISCHEMIA trial is to determine whether an initial invasive strategy of cardiac catheterization followed by optimal revascularization, if feasible, in addition to OMT, will reduce the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure in participants with SIHD and moderate or severe ischemia over an average follow-up of approximately 3.5 years compared with an initial conservative strategy of OMT alone with catheterization reserved for failure of OMT.

B. Secondary Aims Secondary aims are to determine whether an initial invasive strategy compared to a conservative strategy will improve: 1) the composite of CV death or MI; 2) angina symptoms and quality of life, as assessed by the Seattle Angina Questionnaire; 3) all-cause mortality; 4) net clinical benefit assessed by including stroke in the primary and secondary composite endpoints; and 5) individual components of the composite endpoints.

Condition: Coronary Disease Procedure: Coronary CT Angiogram Procedure: Cardiac catheterization Phase: Phase III per NIH

Condition: Cardiovascular Diseases Procedure: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions Phase: Phase III per NIH

Condition: Heart Diseases Procedure: Coronary Artery Bypass Surgery Phase: Phase III per NIH

Detailed description:
BACKGROUND:

Evidence supporting a routine invasive practice paradigm for patients with SIHD is outdated. In strategy trials conducted in the 1970s, coronary artery bypass grafting (CABG) improved survival as compared with no CABG in SIHD patients with high-risk anatomic features. The relevance of these studies today is speculative because contemporary secondary prevention-aspirin, beta-blockers, statins, ACE inhibitors, and lifestyle interventions-were used minimally if at all. Subsequent trials have compared percutaneous coronary intervention (PCI) with medical therapy, as PCI has replaced CABG as the dominant method of revascularization for SIHD. To date, PCI has not been shown to reduce death or myocardial infarction (MI) compared with medical therapy in SIHD patients.

COURAGE and BARI 2D, the two largest trials comparing coronary revascularization vs. medical therapy in SIHD patients, found that among patients selected on the basis of coronary anatomy after cardiac catheterization, an initial management strategy of coronary revascularization (PCI, PCI or CABG, respectively) did not reduce the primary endpoints of death or MI (COURAGE), or death (BARI 2D) compared with OMT alone. These data suggest, but do not prove, that routine cardiac catheterization--which often leads to ad hoc PCI through the diagnostic-therapeutic cascade--may not be required in SIHD patients. However, most patients enrolled in COURAGE and BARI 2D who had ischemia severity documented at baseline had only mild or moderate ischemia, leaving open the question of the appropriate role of cardiac catheterization and revascularization among higher-risk patients with more severe ischemia. Observational data suggest that revascularization of patients with moderate-to-severe ischemia is associated with a lower mortality than medical therapy alone, but such data cannot establish a cause and effect relationship. In clinical practice only about half such patients are referred for cardiac catheterization, indicating equipoise. Furthermore, analysis of outcomes for 468 COURAGE patients with moderate-to-severe ischemia at baseline did not reveal a benefit from PCI. This issue cannot be resolved using available data because all prior SIHD strategy trials enrolled patients after cardiac catheterization, introducing undefined selection biases (e.g., highest risk patients not enrolled) and making translation of study results problematic for clinicians managing patients who have not yet had cardiac catheterization.

A clinical trial in SIHD patients uniformly at higher risk (which could not have been performed before COURAGE and BARI 2D results were available) is needed to inform optimal management for such patients.

DESIGN NARRATIVE, INCLUDING MODIFICATIONS DURING THE TRIAL

Primary Endpoint

A composite of CV death, MI, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure was proposed as the primary endpoint in the application that was funded by NLHBI, with a secondary endpoint of CV death or MI. Study protocol version 1.0 was finalized on January 18, 2012 after review and approval by the protocol review committee (DSMB) with the primary endpoint specified as the composite of CV death or MI. Regarding the final status of the primary endpoint, the protocol stated:

"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." All 5 event types were adjudicated throughout the trial. Study protocol v2.0 (January 2014) allowed ischemia eligibility by non-imaging exercise stress test if more stringent (≥70% stenosis) CCTA criteria were met. The 2016 protocol addendum describes the NHLBI-approved reduction in sample size and extension of recruitment and follow-up due to slower than projected recruitment.

The pre-specified first analysis for monitoring and projecting the final aggregate number of primary endpoint events was conducted in 2015. In 2016, the projected need to increase the power by extending follow-up and elevating the 5-component secondary endpoint to become primary was discussed at Steering Committee and Investigator meetings and communicated by email.

An Independent Advisory Panel convened by NHLBI met in May 2017, and in June 2017 NHLBI approved the Independent Advisory Panel's recommendation to elevate the 5-component secondary endpoint to become primary and retain the 2-component composite as a key secondary endpoint. The panel also recommended extension of follow-up. This was communicated to the Steering Committee and Investigators at August and November 2017 meetings and by email. The last visit date was June 30, 2019.

A statistical plan developed for the Independent Advisory Panel process in 2012 specified that a decision about changing the primary endpoint would be targeted to occur before 75% of the final number of primary endpoint events had accrued. Although the final number of primary endpoint events was unknown during the course of the trial, estimates performed at the time of the Advisory Panel meeting suggested that the ratio of accrued endpoint events to final endpoint events was below 50%. See Maron DJ et al. Am Heart J. 2018 201:124-135. PMC6005768 for additional details about modifications to the trial while it was being conducted.

Analysis of Patients' Health Status as a Key Secondary Endpoint

A key secondary objective of the ISCHEMIA trial is to compare the quality of life outcomes-patients' symptoms, functioning and well-being-between those assigned to an invasive strategy as compared with a conservative strategy. In the protocol, angina frequency and disease-specific quality of life measured by the Seattle Angina Questionnaire (SAQ) Angina Frequency and Quality of Life scales, respectively, are described as the tools that will be used to make this comparative assessment. Recent work has indicated that it is possible to combine the information from the individual domain scores in the SAQ into a new Summary Score that captures the information from the SAQ Angina Frequency, Physical Limitation and Quality of Life scales into a single overall score. The advantages of using a summary score as the primary measure of QOL effects of a therapy are a single primary endpoint comparison rather than two or three (eliminating concerns some may have about multiple comparisons) and a more intuitive holistic (patient-centric) interpretation of the effectiveness results. With these advantages in mind, the ISCHEMIA leadership has agreed that the SAQ Summary Score will be designated as the primary way this outcome for this key secondary endpoint of the ISCHEMIA trial will be analyzed and interpreted, with the individual SAQ scores being used in a secondary, explanatory and descriptive role.

PARTICIPATING COUNTRIES:

North America:

Canada; Mexico; USA

South America:

Argentina; Brazil; Peru

Asia:

China; India; Japan; Malaysia; Singapore; Taiwan; Thailand; Russian Federation

Pacifica:

Australia; New Zealand

Europe:

Austria; Belgium; France; Germany; Hungary; Italy; Lithuania; Macedonia; Netherlands; Poland; Portugal; Romania; Serbia; Spain; Sweden; Switzerland; UK

Middle East:

Egypt; Israel; Saudi Arabia

Africa:

South Africa

Arms:
arm 1: Routine invasive strategy with cardiac catheterization followed by revascularization plus optimal medical therapy. arm 2: Optimal medical therapy with cardiac catheterization and revascularization reserved for patients with acute coronary syndrome, ischemic heart failure, resuscitated cardiac arrest or refractory symptoms.

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

Protocol document:
Prot_002.pdf: 
International Study of Comparative Health Effectiveness with Medical and Invasive 
Approaches (ISCHEMIA) 
 
Protocol Addendum 
September 22, 2016 
___________________________________________________________________________________________  
 
 
This document is the required IRB/EC notification about ISCHEMIA protocol modifications. 
 
Summary:  
This document is an addendum to the ISCHEMIA protocol describing changes to:  
1. Minimum and average duration of follow-up for randomized participants, and  
2. Number of randomized participants planned for ISCHEMIA and ISCHEMIA-CKD trials 
3. The timeframe for serum creatinine measurement at enrollment for participants on dialysis 
 
The ISCHEMIA Data Safety and Monitoring Board and NHLBI approved these changes. These changes will not have 
any effect on participant safety or the risk-to-benefit ratio of study participation.  
 
Site IRBs/ECs should determine whether the sample size and minimum follow-up duration in the informed 
consent, if referenced, need to be changed. Any changes to the ISCHEMIA informed consent forms will require 
IRB/EC submission, review and approval. Sites are required to send copies of the IRB/EC approval letter and 
informed consent to the ISCHEMIA Clinical Coordinating Center when received. 
 
 
 
1. Minimum and average duration of follow-up for randomized participants 
Based on the ISCHEMIA and ISCHEMIA-CKD trials’ current observed randomization trajectory, enrollment and 
last follow-up dates will be extended beyond the original projected dates. Therefore, to achieve objectives 
within timelines allotted by the Sponsor, the minimum follow-up duration for randomized participants will be 
approximately 12-18 months (reduced from 18-24 months), with the average follow-up estimated to be 
approximately 3 years (reduced from 4 years). 
 
2. Number of randomized participants projected for ISCHEMIA and ISCHEMIA-CKD trials, modified to achieve 
the trials’ objectives within timelines allotted by the Sponsor, NHLBI. 
 
2.1. For ISCHEMIA, approximately 5,000 to 6,000 participants are projected to be randomized; a reduction 
from the original planned 8,000 randomized participants.  
 
The original planned sample size of approximately 8,000 participants afforded robust power (over 90%) 
to detect a 15% reduction in the rate of the primary endpoint of cardiovascular (CV) death or 
myocardial infarction (MI). It was more than three times the size of all prior strategy trials of cardiac 
catheterization/prompt revascularization vs. medical therapy only in both stable ischemic heart disease 
and non-ST elevation acute coronary syndrome (ACS, different population from ISCHEMIA). 
ISCHEMIA Protocol Addendum, September 22, 2016  
 
Page 1 of 2 


 
With a sample size of 5,000 participants followed for an average of 3 years (minimum of approximately 
12 months), the trial will have ≥ 83% power to detect an 18% reduction (from 20% to 16.4%) in the 4-
year rate of the primary composite endpoint in participants randomized to an invasive strategy (INV) as 
compared with a conservative strategy (CON), assuming a 4-year rate of the primary endpoint of 20% in 
the CON group. The true hazard ratio can be estimated to within a multiplicative margin of error of 1.15 
with 0.95 confidence.  
 
Based on the trial’s current observed randomization trajectory, the sample size was reduced to achieve 
the enrollment objectives within timelines allotted by the Sponsor, while maintaining a high level of 
statistical precision and adequate power to achieve original objectives. The projections are estimates 
based on randomization rates. If these rates increase, the number of randomized participants may 
exceed 6000. As expected the number of enrolled patients exceeds the number randomized due to 
failure to confirm eligibility in all enrolled participants.  
 
 
2.2. ISCHEMIA-CKD ancillary trial, approximately 500 to 700 participants are projected to be randomized, a 
reduction from the original planned 1,000 participants.    
 
The original planned sample size of approximately 1,000 participants was designed to provide 80-95% 
power to compare the primary endpoint across the two randomized groups assuming the 4-year 
cumulative rate of the primary composite endpoint is 50%-70% in participants randomized to the CON 
strategy and is less by a factor of 15% to 19% (relative reduction) in participants randomized to the INV 
strategy.  
  
Since the initial design, several sources of evidence reinforced the primary event rate assumed for the 
trial. Although none of the studies report the exact information needed for this trial, we have assumed 
a conservative death or MI event rate of 60% to 75%. Given the high risk of the CKD trial cohort, it is 
reasonable to power for a larger relative risk reduction than our previous assumption.  
 
With a final sample size of 500 participants, followed for an average of 3 years (minimum of 
approximately 18 months), the trial will have power of >81% for detecting a 23%-27% reduction in the 
4-year rate of the primary endpoint, assuming a cumulative 4-year event rate of 60% to 75% in the 
CON group.  
 
Based on the trial’s current observed randomization trajectory, the sample size was reduced to achieve 
the enrollment objectives within timelines allotted by the Sponsor, while maintaining a high level of 
statistical precision and adequate power to achieve original objectives. The projections are estimates 
based on randomization rates. If these rates increase, the number of randomized participants may 
exceed 700. As expected the number of enrolled patients exceeds the number randomized due to 
failure to confirm eligibility in all enrolled participants.  
 
 
3. The timeframe for serum creatinine measurement at enrollment for participants on dialysis 
The protocol requires serum creatinine measurement within 90 days prior to enrollment. This is to ensure 
that the renal function of enrolled participants is current. However, this is not applicable to participants who 
are already on dialysis, as serum creatinine is not needed in these participants for trial purposes.  
ISCHEMIA Protocol Addendum, September 22, 2016  
 
Page 2 of 2 

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ISCHEMIA  
STATISTICAL ANALYSIS PLAN 
 
 
August 14, 2018 
 
Version 1.0 - Final 
 
 
 


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STATISICAL ANALYSIS PLAN VERSION AND AMMENDMENT TRACKING 
Version Number/Amendment 
Approval Date 
1.0 
August 14, 2018 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1. INTRODUCTION .................................................................................................................................. 4 
2. STUDY DESIGN ..................................................................................................................................... 4 
3. STUDY OBJECTIVES ........................................................................................................................... 4 
4. SAMPLE SIZE CONSIDERATIONS .................................................................................................. 5 
5. RANDOMIZATION METHODOLOGY ............................................................................................. 7 
6. PARTICIPANT POPULATIONS ......................................................................................................... 7 
6.1. Intention-to-treat population .............................................................................................................. 7 
6.2. Protocol Version 2.0 Trial-eligible population .................................................................................. 7 
6.3. Core-lab determined ischemia population ......................................................................................... 8 
6.4. Procedure-based populations ............................................................................................................. 8 
7. DATA HANDLING ................................................................................................................................ 8 
7.1. Sources of Data Used in Analyses ..................................................................................................... 8 
7.2. Methods for Handling Missing Data .................................................................................................. 8 
8. ENROLLMENT SUMMARY ............................................................................................................... 9 
9. BASELINE SUMMARIES .................................................................................................................... 9 
9.1. Definition and timing of baseline variables ....................................................................................... 9 
9.2. Demographics and clinical history ................................................................................................... 10 
9.3. Protocol-assigned catheterization in the INV group ........................................................................ 10 
10. ANALYSIS OF CLINICAL ENDPOINTS....................................................................................... 10 
10.1. CEC adjudication ........................................................................................................................... 10 
10.2. General ........................................................................................................................................... 11 
10.3. Primary and secondary clinical endpoints ..................................................................................... 11 
10.4. Analysis of the primary endpoint ................................................................................................... 12 
10.4.1. Cox model for primary endpoint analysis. .............................................................................. 13 
10.4.2. Modeling of continuous variables ........................................................................................... 14 
10.4.3. Missing data ............................................................................................................................ 14 
10.4.4. Additional supportive analyses for the primary endpoint ....................................................... 15 
10.5. Consideration for the analysis of the core-lab ischemia population .............................................. 15 
10.6. Analyses of heterogeneity of treatment effect (HTE) .................................................................... 16 
10.6.1. Covariates for HTE analyses ................................................................................................... 16 


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10.6.2. Assessment of covariate-by-treatment interactions................................................................. 17 
10.6.3. Multiplicity considerations for HTE analyses ......................................................................... 17 
10.7. Analysis of angina control and QOL ............................................................................................. 18 
10.8. Analysis of protocol-defined secondary clinical endpoints ........................................................... 18 
10.9. Clinical endpoint data presentation ................................................................................................ 18 
10.10. Supportive analyses to quantify the size of MI’s ......................................................................... 18 
10.11. Supportive analyses to adjust for treatment non-adherence ......................................................... 19 
10.12. Multiple comparisons ................................................................................................................... 19 
11. INTERIM ANALYSES ...................................................................................................................... 19 
11.1. Violations of inclusion/exclusion criteria ...................................................................................... 19 
11.2. Completion of follow-up visits ...................................................................................................... 19 
11.3. Adherence to assigned treatment strategy ...................................................................................... 20 
11.3.1. Use of catheterization and revascularization in INV .............................................................. 20 
11.3.2. Non-use of discretionary catheterization and revascularization in CON ................................ 20 
11.4. Interim endpoint comparisons by treatment group ........................................................................ 22 
11.5. Contingency plan for insufficient primary endpoint events ........................................................... 23 
12. REFERENCES .................................................................................................................................... 25 
 
1. INTRODUCTION 
The purpose of this Statistical Analysis Plan is to outline the types of analyses and data presentations that 
will be used to answer the study objectives outlined in the protocol, and to explain in detail how the data 
will be handled and analyzed. It describes the study's planned final analysis for presentation in the 
primary and selected secondary manuscripts, planned interim endpoint comparisons by treatment 
performed for the Data & Safety and Monitoring Board (DSMB), and various additional planned interim 
analyses performed for operational monitoring and quality assurance.  
 
2. STUDY DESIGN 
ISCHEMIA is an international comparative effectiveness study. Participants are recruited following 
clinically indicated stress testing and randomized in a 1:1 fashion to an invasive or conservative strategy.  
 
3. STUDY OBJECTIVES 
The primary aim of ISCHEMIA is to determine for participants with stable ischemic heart disease (SIHD) 
and at least moderate ischemia by non-invasive assessment whether an initial invasive (INV) strategy of 
cardiac catheterization and feasible optimal revascularization in addition to optimal medical therapy 


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(OMT) will reduce adverse cardiovascular events when compared with an initial conservative (CON) 
strategy of OMT alone with catheterization and revascularization reserved for failure of OMT.  
The primary endpoint is the composite of cardiovascular (CV) death, non-fatal myocardial infarction 
(MI), and hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. This 5-item 
composite endpoint was the primary endpoint in the NHLBI grant application in 2010 but then was listed 
as a secondary endpoint in the original protocol. The primary endpoint in the original protocol was the 2-
item composite of CV death or MI. The primary endpoint was changed back to the 5-item composite in 
June 2017 after following a protocol-defined process to re-estimate power based on blinded review of 
accumulating study data and finding that power for the original 2-item primary composite endpoint was 
lower than originally expected (see Section 11.5 and the SAP Appendix for Contingency Plan for 
Insufficient Primary Endpoint Events for details; this was done with approval of the Director of the 
NHLBI). 
The incidence of the 2-item composite of CV death or MI will be compared between the INV and CON 
strategies and will be the major secondary analysis of the ISCHEMIA trial. 
Other secondary objectives include comparing the incidence of the following between the INV and CON 
strategies: 
1.  Inclusion of stroke with other components of the primary and the major secondary endpoints to assess 
“Net Clinical Benefit” as follows: 
a.  Cardiovascular events including CV death, non-fatal MI, and hospitalization for unstable 
angina, hospitalization for heart failure, resuscitated cardiac arrest or stroke 
b.  CV death, non-fatal MI or stroke 
2.  Individual components of the primary composite endpoint 
3.  Stroke 
4.  All-cause death 
Another secondary objective is to determine whether an INV strategy is more effective than a 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.  
Finally, health resource utilization, cost, and cost-effectiveness will also be compared between the two 
randomized strategies.  Separate Statistical Analysis Plans for secondary manuscripts will be developed 
for the analysis of disease-specific quality of life data. 
 
4. SAMPLE SIZE CONSIDERATIONS 
In designing ISCHEMIA, it was originally estimated that a study with 8,000 participants followed for an 
average of 3.7 years would have 90% power to detect a 15% relative reduction in the 4-year rate of the 
primary endpoint in participants randomized to an invasive strategy as compared with a conservative 
strategy, assuming a 4-year rate of the primary endpoint of 20% in the conservative strategy group. A 


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modest relative reduction was used in power calculations in light of ISCHEMIA's strategy trial design 
which includes participants without prior known anatomy and the expectation that not all participants in 
the target population will be suitable for revascularization or benefit equally from an invasive strategy. 
The modest between-group difference was also intended to account for attenuation of the treatment effect 
by non-adherence to the randomized treatment strategy. The between-group difference would be larger if 
a high adherence rate was expected. Participants in the conservative group who undergo catheterization 
for unacceptable angina despite maximal OMT are not considered non-adherent (because the conservative 
strategy includes performance of catheterization after OMT failure) but such catheterizations may reduce 
power for the primary endpoint if they, or the revascularizations that the catheterizations lead to, prevent 
the occurrence of primary endpoint events. Such attenuation was incorporated in sample size calculations 
by specifying a between-group difference that is smaller than it would be hypothetically if catheterization 
and revascularization was never performed in the conservative strategy.   
Based on the trial's observed monthly randomization numbers, an analysis performed in August 2015 
revealed that approximately 4,400 participants were projected to be randomized by the end of the trial’s 
original planned enrollment period (October 2012 – June 2017). In response, the study's leadership 
proposed extending enrollment for 6 months beyond the original projected last enrollment date (from June 
2017 to December 2017) and extending the follow-up period for 6 months beyond the original projected 
last follow-up date (from June 2018 to December 2018). Study leadership requested a reduction in sample 
size on the grounds that the original target of 8,000 was unlikely to be met and that the study would still 
be adequately powered albeit for a larger effect size. In August 2016, study leadership received 
permission from NHLBI to continue the study with a reduced sample size target of 5,000 randomized 
participants.  
To ensure an adequate number of endpoint events for the primary analysis, the initial ISCHEMIA 
protocol (version 1.0 dated January 18, 2012) included a contingency plan to allow changing the primary 
endpoint from the 2-item to the 5-item endpoint after trial initiation by following a process with 
safeguards incorporated to protect against bias and inflation of the type-I error rate (see Section 11.5 and 
SAP Appendix for Contingency Plan for Insufficient Primary Endpoint Events for details). At various 
points in the trial, the primary endpoint event rate and statistical power were re-estimated using updated 
assumptions derived from blinded pooled analyses (not by treatment group) of the accumulating trial data. 
In May 2017, an independent panel was convened by NHLBI for the purpose of reviewing relevant 
blinded aggregate study data and power calculations and advising the NHLBI director and study 
leadership about possible design modifications. After reviewing updated power and precision estimates, 
the panel recommended reverting to the grant-funded 5-component primary endpoint and extending 
follow-up to the maximum duration feasible in order to increase power. The panel's recommendation was 
approved by NHLBI and study leadership in June 2017.  
In February 2018, power was re-estimated for the study's revised primary endpoint (5-item composite) 
using updated event rate assumptions and assuming that participants would be followed until June 2019. 
The final sample size of 5,179 participants was estimated to provide 80% power to detect an 18.5% 
relative reduction in the 4-year rate of the 5-item primary composite endpoint. This sample size would 
also allow estimation of the hazard ratio to within a multiplicative margin of error of 1.17 with 0.95 
confidence.  
 


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5. RANDOMIZATION METHODOLOGY 
Enrollment and randomization is accomplished by contact with the interactive web/voice randomization 
system (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 or log into the IXRS 
to receive a participant identification number. At this point the participant is registered as enrolled. In 
order to randomize the participant, the study coordinator or investigator must call or log into the IXRS a 
second time. Participants meeting all clinical and site inclusion criteria are then randomized to either the 
INV or CON strategy and registered as randomized. Ischemia severity is determined by sites and is 
reported according to independent core laboratory review. Randomization information, including the 
randomized treatment assignment, is transmitted to the participant’s electronic case book within the 
electronic data capture (EDC) system. 
The original randomization scheme for ISCHEMIA was a permuted block design with stratification by 
enrolling site to balance the distribution of treatment assignments within the sites. The block sizes for 
each site were chosen at random to reduce the likelihood of an investigator predicting the next treatment 
group assignment. Beginning in March 2014, ISCHEMIA’s randomization system was modified to 
facilitate enrollment of participants into the ISCHEMIA-CKD ancillary trial. The randomization lists that 
were originally generated for ISCHEMIA were subsequently used for randomizing both ISCHEMIA and 
ISCHEMIA-CKD participants together. Assigned participant identification numbers are different 
depending on whether the participant was enrolled in ISCHEMIA-CKD or the ISCHEMIA main trial.  
Details about distinguishing between ISCHEMIA-CKD and ISCHEMIA main trial participants can be 
found in the SAP Appendix for Definitions and Reporting Conventions.   
 
6. PARTICIPANT POPULATIONS 
All major treatment comparisons between the randomized groups in this trial will be performed according 
to the principle of "intention-to-treat"; that is, participants will be analyzed according to the treatment 
group to which participants were randomized, regardless of subsequent non-adherence to protocol. 
Participant populations of interest are described below. 
6.1. Intention-to-treat population 
The intention-to-treat (ITT) population will include all participants who receive a randomized treatment 
assignment, including those who are later determined not to meet trial eligibility criteria, unless the 
randomization was an unintentional administrative error, as determined by the Clinical Coordinating 
Center (CCC) in conjunction with the Statistical and Data Coordinating Center (SDCC) and National 
Heart, Lung, and Blood Institute (NHLBI) program officers. Of note, the ITT population will include 
participants who are randomized prior to or in absence of core-lab determination of ischemia regardless of 
subsequent core lab findings. Similarly, participants randomized prior to or in absence of a study CCTA 
will be included regardless of any subsequent determination of left main disease or no obstructive disease. 
6.2. Protocol Version 2.0 population 
The Protocol Version 2.0 population will include all randomized participants except for those with a 
documented violation of trial eligibility criteria and those with prior CABG enrolled under Protocol 


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Version 1.0. In general, determination of eligibility will be based on the version of the protocol under 
which the participant was randomized. Participants with prior CABG enrolled under Version 1.0 are 
excluded in order to better reflect the final Version 2.0 target population which excludes prior CABG 
participants unless their coronary anatomy is known to be suitable for PCI or repeat CABG. Unlike the 
ITT population, the Protocol Version 2.0 population will exclude participants accidentally randomized 
despite having left main disease or no obstructive disease on study CCTA. For determining eligibility, the 
presence of at least moderate ischemia will be based on the local site interpretation rather than the core 
lab interpretation. Presence of left main disease or no obstructive CAD and ejection fraction will be based 
on diagnostic procedures performed prior to randomization and will not include information obtained 
from protocol-assigned catheterization procedures or core lab reviews of left ventricular angiography.   
6.3. Core-lab determined ischemia population 
The core-lab determined ischemia population is a subset of the ITT population. It consists of participants 
determined by the core lab to have moderate or severe ischemia on a pre-randomization imaging stress 
test or severe ischemia on a pre-randomization non-imaging exercise tolerance test (ETT).  Hereafter in 
this document, “moderate or severe ischemia” refers collectively to moderate or severe ischemia by stress 
imaging or severe ischemia by non-imaging ETT. 
6.4. Procedure-based populations 
Safety analyses will be performed in subgroups of participants for whom the safety issue is relevant. 
Thus, complications of protocol-assigned CCTA, catheterization, PCI, and CABG procedures will be 
evaluated in the subset of participants undergoing these procedures. Only procedure-related complications 
are systematically collected.  Complications of adjunctive therapies such as dual anti-platelet therapy are 
not systematically collected. 
 
7. DATA HANDLING 
7.1. Sources of Data Used in Analyses 
The data used for analysis will come from 4 main sources: the Interactive Web/Voice Response System 
(IXRS), the e-CRF, the clinical events committee (CEC) database, and the Clinical Trial Management 
System (CTMS) database. Data from the IXRS will be used to determine trial assignment (ISCHEMIA or 
ISCHEMIA-CKD) and treatment group. The e-CRF will be the source for site-level geographic 
information, all baseline and follow-up data, and will also contain data entered by the central core labs 
(CCTA, ECG, angiography, imaging). The CEC will provide adjudicated endpoints for primary analyses 
and auxiliary data, such as highest marker values associated with MI events, for secondary analyses. The 
CTMS database will provide site-level dates of site activation and deactivation.  Primary analyses of 
outcomes by treatment will pool data from across all sites and will not stratify by site. 
7.2. Methods for Handling Missing Data 
Every effort will be made to obtain complete data. In the unlikely event that there is missing data, rules on 
how to handle the missing data will be used. These rules for how to handle the missing data will be 
discussed in appropriate places in the analysis plan below. Further details on how missing data will be 
handled can be found in the SAP Appendix for Definitions and Reporting Conventions.  


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In general, all available data will be included in data listings and tabulations. Population denominators 
will be displayed in column headers. Individual denominators will be displayed for each summary such 
that the amount of missing values will be evident. Participants who withdraw from the study or are lost to 
follow-up will still be included in the denominators for any proportions where data are available prior to 
study withdrawal or when the participant is lost to follow up. 
 
8. ENROLLMENT SUMMARY  
An enrollment summary will be provided by geographic region and country. Country information will be 
obtained from the clinical database. Countries will be grouped as follows: 
 
Regions 
Countries 
 
 
North 
America 
Canada, USA 
 
 
Europe 
Austria, Belgium, France, Germany, Hungary, Italy, Lithuania, Macedonia, Netherlands, 
Poland, Portugal, Romania, Serbia, Spain, Sweden, Switzerland, United Kingdom. 
 
 
Latin 
America 
Argentina, Brazil, Mexico, Peru 
 
 
Asia 
China, India, Japan, Korea, Malaysia, Russia, Singapore, Taiwan, Thailand  
 
 
Pacifica 
Australia, New Zealand 
 
 
Africa 
Egypt, South Africa 
 
 
Middle 
East 
Israel, Saudi Arabia, United Arab Emirates 
 
The total number of enrolled and randomized participants and enrolling sites will be tabulated by region, 
country and overall for review by the DSMB and study leadership.  
 
9. BASELINE SUMMARIES 
9.1. Definition and timing of baseline variables 
For most summaries, the baseline value is the value given closest to the date and time of randomization. 
Weight, heart rate, and blood pressure are measured per protocol at the time of randomization or up to 30 
days prior. Baseline laboratory assessments (lipids, HbA1c, liver enzymes, complete blood counts, 
chemistry panel) are based on the most recent lab results available within 6 months prior to the 
randomization or up to 2 weeks post randomization if pre-randomization laboratory results are 
unavailable. Age will be computed as the difference in years between the participant’s date of birth and 


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randomization date. Body Mass Index (BMI) will be computed as weight (kg) / ((height (cm)/100)2).  
Obesity will be defined as values of BMI 30 kg/m2 or higher. 
9.2. Demographics and clinical history 
Baseline demographic and clinical characteristics will be tabulated by region and treatment group for the 
ITT population. The occurrence of incidental findings of clinical significance on study-related CCTA will 
be summarized overall and by type (ascending aortic dissection, descending aortic dissection, aortic 
aneurysm, large pleural effusion, pulmonary embolism, pulmonary mass, non-calcified pulmonary 
nodules ≥ 4mm, pulmonary infiltrate, pneumothorax, and moderate or large pericardial effusion).  
9.3. Protocol-assigned catheterization in the INV group 
Core-lab angiographic findings from the first post-randomization diagnostic catheterization procedure in 
participants assigned to INV will be summarized by the frequency distribution of the number of native 
vessels with at least 50% stenosis and the percentage of participants with at least 50% stenosis in specific 
locations (left anterior descending [LAD] disease, proximal LAD disease, circumflex disease, right 
coronary artery disease, left main disease). Summaries of native vessel stenosis will be presented for all 
participants and for the subset with no prior CABG. For participants with prior CABG, summaries will 
include the number vein or arterial grafts with ≥70% stenosis and the number of arterial grafts with at 
least ≥70% stenosis.  Other scores summarizing the extent and/or severity of disease may be reported in 
supplemental analyses and reports. 
 
10. ANALYSIS OF CLINICAL ENDPOINTS 
10.1. CEC adjudication 
CEC-adjudicated endpoints include CV death, myocardial infarction, resuscitated cardiac arrest, 
hospitalization for unstable angina, hospitalization for heart failure, and stroke. Definitions of these 
endpoints are included in the CEC Charter.  
Two versions of MI will be adjudicated in ISCHEMIA: a Primary Definition and Secondary Definition. 
Each definition includes a hierarchy of markers and threshold values as well as a set of rules for 
diagnosing MI when one or more key elements of the medical record are missing. The Primary Definition 
is based upon the Universal Definition of MI (UMI) [1] for Types 1, 2, and 3 MIs, but relies upon site-
reported MI decision limits for troponin (which may or may not be the same as the manufacturer 99% 
upper reference limit (URL)). In contrast, for MI after PCI or CABG (Type 4a, 5), CK-MB is the 
preferred biomarker and takes precedence over troponin, and unlike the UMI, troponin is compared 
against the site-reported MI Decision Limit. The Secondary Definition is based closely on the UMI 
definition, but includes contingencies to allow diagnosing MI when various elements of the medical 
record are missing. Troponin is compared against the 99% URL from the assay manufacturer’s package 
insert if known and against the laboratory-specific MI Decision Limit if the manufacturer 99th percentile 
is unknown. Additional supporting criteria (e.g. angiographic and ECG) are identical to the UMI 
definition for Type 4a MI. Analysis plans below refer to the Primary Definition unless otherwise 
specified. 


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Confirmed MI events will also be classified by the CEC as “complicated” or “not complicated” using 
criteria outlined in the CEC charter. The intent of the “complicated” designation is to identify a subset of 
MIs with features highly associated with poor prognosis. A complicated MI includes MIs occurring with 
serious complications such as hemodynamic instability, cardiogenic shock, a drop in ejection fraction 
greater than 10%, life-threatening ventricular arrhythmias, or acute heart failure.  
For all confirmed MI events, the CEC will record highest marker values for Troponin I, Troponin T, CK, 
and CKMB when these markers are available. The laboratory-specific upper limit of normal (ULN) will 
be recorded for all types of markers and the manufacturer-specified upper reference limit (i.e. the 99th 
percentile; URL) will be recorded for Troponins only.  
Confirmed MIs will be classified by the CEC using MI types provided by the UMI as follows: 
 
Type 1:  Spontaneous MI  
 
Type 2:  Secondary MI 
 
Type 3:  Sudden Death MI  
 
Type 4a:  MI related to PCI 
 
Type 4b:  MI related to stent thrombosis 
 
Type 4c:  MI related to stent restenosis 
 
Type 5:  MI related to CABG 
There will be some secondary analyses that will group together several MI types.  There will be two 
resulting groups of MI types that will be analyzed.  One group will correspond to procedural MIs and 
include Type 4a and 5 MIs.  The other group will correspond to non-procedural MIs and include Type 1, 
2, 4b and 4c MIs. 
10.2. General 
Statistical comparisons will be performed using two-sided significance tests and two-sided confidence 
intervals. Statistical comparisons of the two randomized groups with respect to primary and secondary 
clinical endpoints will be based on time-to-event analyses. In the time-to-event analyses, all available 
follow up information will be used. Recurrent events will be ignored in the primary analysis but will be 
analyzed in planned secondary manuscripts. Follow up will begin at the time of randomization and will be 
considered to be censored at the time of each participant’s last study visit for those participants not having 
an event of interest. The occurrence and timing of clinical endpoint events in the primary analysis will be 
based solely on CEC adjudicated endpoint data.  Unless otherwise stated, references to the non-fatal 
myocardial infarction (MI) event will refer to the Primary MI Definition (see Section 10.1 for details). 
10.3. Primary and secondary clinical endpoints 
The primary endpoint of this study is the composite of CV death, non-fatal myocardial infarction (MI), 
hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest as 
evaluated in the ITT population. The study's original protocol defined the primary endpoint as the 
composite of CV death or MI. The primary endpoint was reverted from the 2-item composite to the 
original grant peer-reviewed and current 5-item composite in June 2017 after following a protocol-
defined process and receiving input from an NHLBI-convened independent Advisory Panel (see Section 


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11.5 and the SAP Appendix for Contingency Plan for Insufficient Primary Endpoint Events for details, 
with approval of the Director of the NHLBI). 
Protocol-defined secondary endpoints are:  
(a) Composite of cardiovascular death or non-fatal MI 
(b) Angina control as measured by the Seattle Angina Questionnaire 
(c) Disease-specific quality of life as measured by the Seattle Angina Questionnaire 
(d) Composite of cardiovascular death, non-fatal MI or stroke 
(e) All-cause death 
(f) Cardiovascular death 
(g) Myocardial infarction 
(h) Resuscitated cardiac arrest 
(i) Hospitalization for unstable angina 
(j) Hospitalization for heart failure 
(k) Stroke 
(l) Composite of cardiovascular death, non-fatal MI, stroke, hospitalization for unstable angina, heart 
failure or resuscitated cardiac arrest 
Additional pre-specified secondary endpoints are:  
(m) MI as determined by the CEC Charter’s secondary MI definition 
(n) Composite of cardiovascular death or complicated MI as defined in the CEC charter 
(o) Complicated MI as defined in the CEC charter  
Other endpoints for supportive analyses to aid interpretation of the trial’s primary and secondary analyses 
include:  
(p) Composite of all-cause death or nonfatal MI 
(q) Composite of all-cause death, nonfatal MI, or stroke 
(r) Composite of all-cause death, nonfatal MI, or hospitalization for resuscitated cardiac arrest, 
unstable angina or heart failure 
(s) Composite of all-cause death, nonfatal MI, stroke, hospitalization for unstable angina, heart 
failure or resuscitated cardiac arrest 
For the analysis of MI and for composite endpoints that include MI as a component endpoint, analysis 
will be based primarily on the CEC Charter's primary MI definition and secondarily on the CEC Charter's 
secondary MI definition. Additional definitions of MI using criteria to categorize large infarctions are 
expected to be developed and reported in secondary manuscripts but are not included in the current 
statistical analysis plan.  
10.4. Analysis of the primary endpoint 
Time from randomization to the first occurrence of the primary endpoint will be compared between 
treatment groups using the statistical framework of Cox regression [2]. As described below in this section, 
estimation of event rates with 95% confidence intervals not assuming proportional hazards will be 
performed as an important secondary analysis. To preserve power and generalizability in the face of 
outcome heterogeneity due to variation across participants in important baseline variables [3-5], the Cox 


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model for each endpoint will be adjusted for a set of prognostically important baseline covariates, to 
include age, sex, estimated glomerular filtration rate (eGFR), ejection fraction, and diabetes, as detailed in 
Section 10.4.1 below. Ties in event times will be handled using Efron's approximation. 
Multiple endpoint events in the same participant, such as a recurrent non-fatal event, will not be 
considered in the primary results analysis, but will be analyzed in planned secondary analyses. 
The hazard ratio from the covariate-adjusted Cox model will be reported along with its two-sided 95% 
Wald-type confidence interval, and the associated p-value will be the primary measure of statistical 
significance. The half width of this confidence interval is expected to be 1.17 under the null hypothesis of 
identical covariate-specific time-to-event distributions. The critical value required for declaring endpoint 
differences to be statistically significant at the 0.05 level will depend on the exact timing of interim 
analyses, as described in Section 11.4 below. 
In addition to Cox regression, cumulative endpoint event rates will be estimated as a function of follow-
up time in each treatment group using Kalbfleisch & Prentice's nonparametric estimator of the cumulative 
incidence function (CIF) [6]. The Kalbfleisch & Prentice CIF estimator is equivalent to the Kaplan-
Meier[7] estimator when applied to endpoints that are not subject to competing risks. It was selected for 
this study in order to account for the competing risk of non-cardiac deaths in the analysis of the primary 
endpoint and the occurrence of any type of death in the analysis of individual non-fatal endpoints. 
Cumulative endpoint event rates and differences in cumulative endpoint event rates for INV versus CON 
at yearly time points will be estimated and presented with 95% confidence intervals. These non-
parametric analyses are important for descriptive purposes, to assess overall clinical impact, and will be a 
focus of interpretation if the event rate curves cross [8, 9]. These non-parametric analyses may also be 
used to construct summary measures of treatment effect which are interpretable when the proportional 
hazards assumption is violated. [9, 10] 
In addition to comparing overall outcomes for the two randomized groups, we will perform additional 
analyses to assess whether the treatment effect varies according to pre-specified participant baseline 
characteristics, as described in Section 10.6 below.  
Finally, as a sensitivity analysis, the analyses described in this section will be repeated in the Protocol 
Version 2.0 population and the core-lab ischemia population, as defined in Section 6.2 and 6.3 above. 
10.4.1. Cox model for primary endpoint analysis. 
As noted above, analysis of the primary endpoint will be adjusted for covariates and will be performed 
using the framework of Cox regression. Pre-specified covariates will consist of the following: 
 
Age  
 
Sex 
 
Estimated glomerular filtration rate (eGFR)  
 
Ejection fraction 
 
Diabetes 


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Covariates were selected on the basis of their established prognostic importance in other SIHD cohorts, 
highly complete data capture, and a sufficient range of values for risk to vary among participants meeting 
trial eligibility criteria. The following definitions and data handling conventions will be adopted: 
 
Age will be computed as the difference in years between the participant’s date of birth and 
randomization date as collected in the IXRS. The date of birth is only entered in the e-CRF in the 
event that the date of birth information entered in the IXRS system at the time of enrollment is 
incorrect.  If the IXRS system information is correct, then the date of birth as entered into the 
IXRS system at the time of enrollment will be used. Otherwise, the e-CRF entered date of birth 
will be used.   
 
Sex will be based on data collected in the DEMOGRAPHICS section of the e-CRF. In the 
unexpected event of missing data, the participant's sex will instead be obtained from information 
entered in the IXRS system at the time of enrollment.  
 
Estimated glomerular filtration rate (eGFR) will be calculated according to the 1999 Modification 
of Diet in Renal Disease (MDRD) formula using data captured in the DEMOGRAPHICS and 
MEDICAL HISTORY sections of the e-CRF. The formula is:  
eGFR = 186.3 × SerumCr−1.154 × age−0.2013 × 1.212(if participant is black) ×
0.742 (if female)  
where SerumCr denotes serum creatinine in mg/dL, and age denotes the participant’s age in 
years. eGFR values will be obtained from information entered in the IXRS system at the time of 
enrollment or from data entered in baseline CRF's if the IXRS-entered value is unavailable.  
 
Ejection fraction will be based on the site-reported value if available and on the core-lab entered 
value if the site-reported value is unavailable. Because missing data was anticipated in the design 
phase, the e-CRF was structured to capture ejection fraction as a categorical variable in 
participants for whom the categorical value is known but the continuous value is unknown. 
Categorical ejection fraction data will be incorporated in a multiple imputation procedure in order 
to impute continuous ejection fraction values in participants with only categorical values entered. 
 
Diabetes will be modeled as a simple indicator (yes/no) and will be based on data collected in the 
DEMOGRAPHICS section of the e-CRF.  
10.4.2. Modeling of continuous variables 
To allow for non-linear covariate effects, the continuous variables of age, ejection fraction and eGFR will 
be modeled as restricted cubic splines with knots at the approximate 10th, 50th, and 90th percentiles of 
each variable’s empirical distribution.  
The proportionality assumption of the Cox model will be assessed by examining log-log survival plots 
and by adding a time-dependent covariate to the Cox model representing the interaction between 
treatment and time. If this interaction is large and statistically significant, then there is evidence of non-
proportionality. In that case, a cautious interpretation of the Cox model hazard ratio will be encouraged, 
and non-parametric event rate estimates will be emphasized. 
10.4.3. Missing data 
Prior to selecting model covariates, participant baseline characteristics captured in the e-CRF were 
individually discussed by study investigators from the standpoint of prognostic significance and data 


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quality. With the exception of diabetes, covariates appearing in the model are required to be assessed by 
study coordinators for the purpose of determining trial eligibility and are therefore expected to be 100% 
complete on all participants. For example, participants cannot be randomized by the IXRS until after 
entering the participant’s age and creatinine in the IXRS system. Missing, out-of-range, or illogical values 
will be identified by the SDCC and will result in queries to ensure complete high-quality data.  
For each covariate to be used in the primary analysis, the number of missing records projected by study 
leadership is 10 or fewer. To make full use of the available covariate data, missing baseline covariate data 
will be imputed using multiple imputation statistical techniques. These techniques will account for 
additional variation in the analyses due to the fact that some of the data are missing. The imputation will 
use chained equations and predictive mean matching. Further details on what multiple imputation 
techniques will be used to impute missing baseline covariate data are found in the SAP Appendix for 
Multiple Imputation of Primary Baseline Covariates. Any rules of how to handle missing data prior to 
imputation are found in the SAP Appendix for Definitions and Reporting Conventions. 
10.4.4. Additional supportive analyses for the primary endpoint 
To supplement the conventional significance testing and confidence interval approaches that will 
constitute the major analyses for the primary endpoint, we will provide additional perspective on the 
assessment of the treatment effect by re-estimating the primary covariate-adjusted Cox model in a 
Bayesian statistical framework [11, 12]. Using the Bayesian posterior distribution, we will calculate the 
posterior probability that the unknown covariate-adjusted hazard ratio exceeds thresholds of 1.0, 1.05, 
1.10, 1.15, and 1.20 and reciprocals of those numbers. Because Bayesian inferences may be sensitive to 
the choice of prior distribution, sensitivity analyses will be performed and reported for a range of possible 
prior distributions. Additional details of the proposed Bayesian model and prior distributions are provided 
in the SAP Appendix for Bayesian Analysis of Primary Endpoint. 
10.5. Consideration for the analysis of the core-lab ischemia population 
In October 2014, operating procedures for ISCHEMIA were modified to remove the requirement for pre-
randomization core-lab determination of ischemia severity for most sites. The intent of this change was to 
simplify the work flow, increase the number of eligible participants, and improve site morale. It was 
determined that the imaging coordinating center would continue to interpret baseline stress tests for 100% 
of randomized participants, but the core-lab review may occur after randomization and would not 
determine a participant’s eligibility. Under the new process, approximately 80% to 90% of randomized 
participants were projected to meet trial criteria by core lab interpretation.  
 
Primary analysis will be based on the ITT population which includes 100% of randomized 
participants.  
 
Analysis of the core-lab determined ischemia population will be a major secondary analysis.  
Analysis of each of these cohorts is of interest for different reasons. 
 
Analysis of the ITT population is of particular relevance because real-world treatment decisions 
are based on local rather than core-lab interpretations of a patient’s degree of ischemia. Except for 
possible administrative randomization errors, all participants in the ITT population will have 
moderate or severe ischemia by local site interpretation.  


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 
The core-lab determined ischemia population is of particular interest because the efficacy of an 
invasive strategy as compared with a conservative strategy has never been tested in a large cohort 
of SIHD participants with core-lab determined moderate or severe ischemia. Theoretically, if the 
hypothesized benefit of an invasive strategy is concentrated in participants with moderate or 
severe ischemia, then the ITT treatment effect may be attenuated by unintentional inclusion of 
participants with mild or no ischemia.  
Endpoint comparisons for the primary analysis will be repeated in the population of participants where 
the core-lab agreed that criteria for moderate or severe ischemia were met. As discussed in Section 10.6.3, 
results of the core-lab determined ischemia population will be stated in strict context by prioritizing the 
results of the ITT cohort and by noting the increased potential for a type-I error. 
10.6. Analyses of heterogeneity of treatment effect (HTE) 
Analyses of HTE will focus on estimating hazard ratios for INV versus CON as a function of participant 
baseline characteristics, as listed below. The list of primary baseline characteristics to use for the HTE 
analyses was intentionally limited to only a few variables in order to reduce the potential for spurious 
findings and to focus attention on variables that were most likely to interact with treatment based on prior 
literature and clinical experience.  
10.6.1. Covariates for HTE analyses 
Pre-specified baseline covariates (primary interest) 
 
Core-lab determination of moderate or severe ischemia on stress test  
 
Diabetes 
 
New onset or worsening angina within 3 months 
 
Participants who have a high level of medical therapy optimization at baseline, defined as 
participants with all of the following characteristics at baseline: 
o Systolic blood pressure < 140 mmHg (a secondary analysis will be completed 
incorporating a systolic blood pressure goal of < 130 mmHg) 
o LDL <70 mg/dL and on any statin  
o Not smoking  
o Taking aspirin  
Another pre-specified baseline covariate of primary interest is the severity and extent of CAD as 
determined by core lab review of pre-randomization CCTA for those who have had that procedure 
completed. 
Other pre-specified baseline covariates of interest 
 
Ejection fraction 
 
Estimated GFR 
Ejection fraction and estimated GFR were not included in the list of pre-specified baseline covariates of 
primary interest due to the fact that it was anticipated that these covariates would have insufficient 
variation to be able to detect an appreciable difference in the treatment hazard ratios across the range of 
the covariates. 


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The following other baseline covariates are expected to be analyzed for descriptive purposes and 
completeness: age, sex, imaging modality (nuclear, echo, CMR, non-imaging ETT), prior MI, prior PCI, 
prior CABG, prior catheterization (≤12 months, >12 months, none), severity of angina as assessed by the 
SAQ and Canadian Cardiovascular Society (CCS) Class.  
Another pre-specified baseline covariate of interest is the presence of anterior ischemia for those 
participants with adequate stress imaging from the baseline screening process. As discussed in Section 
10.5, analysis of participants with core-lab determination of moderate or severe ischemia is of 
particular scientific interest and will constitute a major pre-planned secondary analysis.  
10.6.2. Assessment of covariate-by-treatment interactions 
For each baseline covariate listed above, the Cox model described in Section 10.4.1 will be augmented to 
include the covariate (if it is not already in the model) and the interaction between the covariate and 
treatment group. A treatment-by-covariate interaction test will be used to assess whether variation in the 
estimated treatment effect across levels of the covariate is consistent with chance. Continuous covariates 
will be modeled as restricted cubic splines with three knots, requiring two parameters per variable with 
one of the parameters being for the non-linear effect. For categorical covariates, category-specific hazard 
ratios will be estimated and reported with 95% confidence intervals. For continuous covariates, covariate-
specific hazard ratios will be estimated across the range of the continuous covariate and plotted as a 
continuous function and/or tabulated for representative numerical values of the covariate along with 
pointwise 95% confidence intervals.  
10.6.3. Multiplicity considerations for HTE analyses 
Statistical reporting of HTE analyses will emphasize estimation over hypothesis testing and will make 
liberal use of confidence intervals and other measures of statistical uncertainty. To provide context for 
interpreting treatment group comparisons within subgroups, subgroup-specific estimates will be 
accompanied by formal interaction tests. Differences in statistical significance of treatment effect 
estimates across subgroups will not be interpreted as evidence of heterogeneity. Because interaction tests 
are expected to have low statistical power for detecting a difference, these tests will be reported mainly 
for the purpose of encouraging readers to take an appropriately cautious interpretation of observed 
differences across the subgroups.  
As noted above, the subset analysis of participants with core-lab determination of sufficient ischemia is 
regarded as a major pre-planned secondary analysis. To ensure an appropriately cautious interpretation of 
results for this cohort, the following reporting guidelines have been agreed upon by study leadership:  
 
If the 95% confidence interval for the hazard ratio excludes 1.0 (or, equivalently, the p-value is 
less than 0.05), the results section of the primary manuscript (as well as methods and discussion) 
should report that this confidence interval or p-value was not adjusted for multiple comparisons. 
The result should not be described as being "statistically significant" and the methods section 
should not state a p-value that was considered to be "statistically significant".  
If the primary analysis fails to detect a difference in outcomes between the two randomized groups, the 
main conclusion of the study’s primary manuscript will reflect the lack of significance for the primary 
analysis. In this setting, if the 95% CI for the hazard ratio comparing the primary endpoint for INV versus 


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CON excludes 1.0 in the subset of participants with core-lab determined moderate or severe ischemia, this 
result may be referenced in the conclusion of the study’s primary manuscript, but the wording will be 
strictly consistent with the hypothesis that the observed result may be attributable to sampling variation. 
An example of wording that was regarded as appropriate by study leadership was: “In a pre-planned 
secondary analysis of participants with core-lab determined moderate or severe ischemia, participants 
assigned to the invasive [or conservative] strategy had a lower rate of cardiovascular death or myocardial 
infarction.” 
10.7. Analysis of angina control and QOL 
Plans for these endpoints are addressed in a separate SAP developed by the Economics and Quality of 
Life (EQOL) Coordinating Center. 
10.8. Analysis of protocol-defined secondary clinical endpoints 
For these secondary clinical endpoints, including the major secondary endpoint of CV death or MI, 
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. Analysis of each secondary endpoint will be 
based on a covariate-adjusted Cox model with adjustment for variables specified in Section 10.4 above. 
For each secondary endpoint, non-parametric cumulative incidence estimates will be calculated by 
treatment group and reported with 95% confidence intervals. P-values for each secondary clinical 
endpoint will be individually calculated and reported without adjustment for multiple comparisons (see 
Section 10.12).  
Just as what will be done for the analysis of primary clinical endpoints, multiple endpoint events in the 
same participant, such as a recurrent non-fatal event, will not be considered in the primary results 
analysis, but will be analyzed in planned secondary analyses. 
10.9. Clinical endpoint data presentation 
As described above, cumulative incidence estimates of endpoint probabilities will be displayed 
graphically and tabulated at yearly intervals following randomization along with two-sided 95% 
pointwise confidence intervals. In addition to these cumulative incidence estimates, the number of clinical 
endpoints by treatment group will also be presented. For MI, the number of CEC-confirmed endpoints 
will be reported overall, by UMI type (1, 2, 3, 4a, 4b, 4c, 5), and by presence/absence of the designation 
of “complicated MI”, as defined in the CEC Charter, and “large MI”. For these descriptive summaries, 
only the first MI event per participant will be counted. Not all of these analyses of MI data will be 
included in the primary manuscript. 
10.10. Supportive analyses to quantify the size of MI’s  
To shed light on the size of MI’s occurring in each treatment group, the distribution of CEC-determined 
highest marker elevation ratios (highest value divided by ULN as well as by the 99th percentile) will be 
summarized for all CEC-confirmed MI events with non-missing CKMB or troponin values. Summaries 
will be stratified by treatment group, MI type, and whether or not there was a Q-wave infarction. Marker 
elevation will be summarized by marker type, assay type, and/or degree of assay sensitivity. The resulting 
summaries will be regarded as informal descriptive statistics and will not be considered a primary or 
secondary protocol analysis. 


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10.11. Supportive analyses to adjust for treatment non-adherence 
Although the proposed primary analysis will be a standard ITT analysis, additional secondary analyses 
may be performed using inverse-probability-of-treatment weighting estimators to assess the causal effect 
of treatment assignment had all participants adhered to their assigned treatment strategy.[13-16]  This 
type of inference will be of particular interest if the study fails to detect a difference between INV and 
CON, as the observed treatment effect may have been attenuated by frequent non-adherence to protocol. 
An assessment of the causal effect of treatment assignment will also be addressed through the analyses of 
the primary and secondary endpoints in the Protocol Version 2.0 population.  Detailed plans for these 
supportive analyses may be developed after completion of the primary analysis if this topic is prioritized 
by the publications committee. Simple methods of adjusting for non-adherence to the randomized 
treatment strategy, such as censoring at the time of crossover, will not be used in this study as they are 
susceptible to bias [17, 18] and do not estimate a well-defined parameter of interest. [16] 
10.12. Multiple comparisons 
With the various primary and secondary endpoints, and multiple subgroup analyses, we recognize that 
there is a multiplicity of analyses to be performed, which leads to an increased probability that at least one 
of the comparisons could be statistically "significant" by chance. Although the overall level of 
significance for the assessment of the primary composite endpoint will not be adjusted to account for the 
analysis of other important endpoints and subgroups, we will be appropriately conservative in the 
interpretation of these secondary analyses, taking into account the magnitude of observed differences, the 
robustness of statistical significance, and looking for consistency across endpoints and subgroups. It is 
important to emphasize that several of the secondary endpoints involve components of the primary 
endpoint, and therefore a major purpose in comparing the randomized groups with respect to these 
endpoints is to aid in the interpretation of any differences between groups observed in the primary 
endpoint. The actual p-value for each comparison will be reported to aid in the overall interpretation.  
 
11. INTERIM ANALYSES 
The primary objective of interim analyses is to ensure the safety of the participants enrolled in the trial 
and to evaluate the accumulating endpoint data by treatment group to test for possible differences 
favoring either of the two randomized management strategies. In addition, interim monitoring will 
involve a review of participant recruitment, compliance with the study protocol, status of data collection, 
an assessment of whether control group event rates are consistent with the rates hypothesized in the 
sample size calculations, and other factors which reflect the overall progress and integrity of the study 
including potential geographic differences. Details of the study's major planned interim analyses are 
documented below.  
11.1. Violations of inclusion/exclusion criteria 
The number of participants with violations of the inclusion/exclusion criteria will be presented. Eligibility 
criteria not met will be identified directly from the RANDIE (randomization inclusion/exclusion criteria) 
panel of the e-CRF or will be identified indirectly based on site- and core-lab entered data from the 
enrollment and randomization visits. 
11.2. Completion of follow-up visits 


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Visit pages will be monitored for late entry in the clinical trial data base by the SDCC data management 
process. Additional summaries of visit completion by treatment will include the ratio of completed visits 
to expected visits and the percentage of visits performed within the expected visit time window.  These 
visit completion summaries will also be completed for the final analysis. 
11.3. Adherence to assigned treatment strategy 
11.3.1. Use of catheterization and revascularization in INV 
The INV strategy mandates use of early catheterization within a target of 30 days after randomization and 
revascularization soon thereafter, if appropriate, based upon coronary anatomy and other clinical 
considerations. To assess adherence to these requirements, the distributions of time from randomization to 
catheterization and time from randomization to revascularization will be estimated using the cumulative 
incidence function method for competing risks data.[6] For this analysis, participant follow-up will be 
censored at the date of last study visit. Death prior to catheterization or revascularization will be regarded 
as a competing risk. The cumulative proportion of participants receiving catheterization and 
revascularization will be estimated at specific time intervals (e.g. 30 days post randomization) both 
overall and within subgroups (e.g. prior CABG). For participants not undergoing catheterization by the 
time of the six-week and 3 month visits, the site-reported reason for no catheterization will be tabulated 
based on CRF-defined categories (participant preference, physician preference, intercurrent illness, 
participant died, other, unknown). For participants with site-reported planned medical therapy following 
catheterization, the reason for planned medical therapy will be tabulated according to CRF-defined 
categories (no obstructive CAD, anatomy not suitable for any mode of revascularization, participant 
preference, other). 
11.3.2. Non-use of discretionary catheterization and revascularization in CON 
The CON strategy mandates non-use of catheterization or revascularization procedures except in the case 
of suspected acute events (acute coronary syndrome, resuscitated cardiac arrest, or acute ischemic heart 
failure) or unacceptable angina refractory to maximally tolerated medical therapy. Catheterization or 
revascularization performed for other reasons, such as physician or participant preference, is considered 
non-adherence. A pattern of frequent early discretionary catheterization or revascularization in CON 
participants, especially those without prior endpoint events, may attenuate the treatment effect and cloud 
the interpretation of the study’s primary ITT analysis.  
Two types of analyses will be performed for estimating the cumulative incidence of catheterization and 
revascularization in the CON group. The first type of analysis will ignore the occurrence and timing of 
clinical endpoint events. The second type of analysis will only consider catheterization and 
revascularization procedures performed before the participant’s first primary clinical endpoint event. The 
latter analysis is of particular interest because procedures performed after the occurrence of a clinical 
endpoint event will not impact power or interpretation for analyses of that type of endpoint. Quantities to 
be estimated will include all or a subset of the following: 
 
Cumulative incidence of catheterization for any reason 
o All 
o Occurring before participant’s first primary endpoint event 
 
Cumulative incidence of catheterization for a suspected acute event 


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o All 
o Occurring before participant’s first primary endpoint event 
 
Cumulative incidence of catheterization for site-reported OMT failure/refractory angina 
o All 
o Occurring before participant’s first primary endpoint event 
 
Cumulative incidence of catheterization for any other reason (non-adherence) 
o All 
o Occurring before participant’s first primary endpoint event 
 
Cumulative incidence of revascularization for any reason 
o All 
o Occurring before participant’s first primary endpoint event 
 
Cumulative incidence of revascularization for a suspected acute event 
o All 
o Occurring before participant’s first primary endpoint event 
 
Cumulative incidence of revascularization for site-reported OMT failure/refractory angina 
o All 
o Occurring before participant’s first primary endpoint event 
 
Cumulative incidence of revascularization for any other reason (non-adherence) 
o All 
o Occurring before participant’s first primary endpoint event 
Incidence rates for each quantity listed above will be estimated using the cumulative incidence function 
method for competing risks data.[6] Participant follow-up will be censored at the last contact date or 
terminated after the participant’s death date, whichever occurs first. For estimating rates of catheterization 
and revascularization prior to endpoint events, occurrence of an endpoint event will be regarded as a 
competing risk. Reasons for catheterization will be based on the site-reported indication for the 
catheterization procedure as captured on the SITECATH1 form of the e-CRF. If one of the site-reported 
indications for the catheterization procedure includes MI, resuscitated cardiac arrest, or worsening or new 
onset heart failure, then the catheterization will be classified as “catheterization for a suspected acute 
event”. Otherwise, if one of the site-reported indications is “Failure of OMT/Refractory angina” then the 
catheterization will be classified as “catheterization for OMT failure/refractory angina”. Otherwise, if 
neither of the above conditions is met, the catheterization will be considered to be non-adherent to the 
CON strategy. Primary endpoints include MI, hospitalization for heart failure, hospitalization for unstable 
angina, and resuscitated cardiac arrest and will be based on best available data (i.e. adjudicated endpoints, 
if available, otherwise unadjudicated data will be used) while event adjudication is in progress. Endpoints 
occurring on the same day as catheterization or revascularization will be considered to occur before the 
catheterization or revascularization unless the endpoint was a PCI-related or CABG-related MI.  
The main goal of the analyses described above is to monitor the frequency of transitions from the state of 
"no post-randomization catheterization" to "at least 1 post-randomization catheterization" in CON 
participants.  Transitions occurring before the participant's first primary endpoint event are of particular 
concern because these have the potential to dilute power for the primary endpoint. Transitions occurring 
after a confirmed primary endpoint event will not dilute power because the endpoint is already counted.  


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Transitions occurring because of a suspected acute event or OMT failure may dilute power (because they 
occurred prior to a confirmed endpoint event) but are not violations of the CON strategy (because the 
strategy includes catheterizations performed in the case of a suspected acute event or OMT failure). 
Although these may dilute power, they do not necessarily reflect negatively on the study's conduct 
(because they are part of the treatment being studied).  
An additional set of analyses will focus on estimating the underlying hazard rates of elective 
catheterization and elective revascularization in the CON group. The main goal is to shed light on the 
extent to which statistical power may be attenuated by catheterization or revascularization performed on a 
non-emergency basis in the CON group. Analysis will focus on estimating the underlying “intensity 
rates” of elective catheterization and revascularization (as opposed to the cumulative incidence function 
accounting for competing risks) because power calculations using multi-state models and accounting for 
treatment crossover typically require specification of such intensity rate parameters. Because the analysis 
focuses specifically on “elective catheterization” and “elective revascularization,” and to avoid counting 
catheterizations and revascularizations that may be true endpoint events, follow-up for these analyses will 
be censored 7 days prior to the participant’s first best-available composite endpoint event (death, 
myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, resuscitated 
cardiac arrest). The intensity rates of elective catheterization and elective revascularization will be 
estimated parametrically under an exponential and/or Weibull model and non-parametrically using a 
Nelson-Aalen type estimator. Because interpretable summary measures derived from the Nelson-Aalen 
estimator require the strong and arguably implausible assumption that elective catheterization and 
revascularization are independent of censoring and death, they will be regarded as informal and 
exploratory, and will be presented in the context of their inherent limitations. 
11.4. Interim endpoint comparisons by treatment group 
Interim analyses may occur when the adjudication of one or more events is in progress.  Interim 
comparisons by treatment group will be performed primarily with only CEC adjudicated endpoint data 
and then repeated with best available data.  Best available data will use the result of CEC adjudication if 
an event has been adjudicated.  If an event has not been adjudicated, the site reported information for that 
event will be used. 
Interim analyses by treatment group will be performed for three endpoints: all-cause mortality, the 2-item 
secondary composite endpoint consisting of cardiovascular death or MI, and the 5-item primary 
composite endpoint consisting of cardiovascular death, MI, or hospitalization for unstable angina, 
hospitalization for heart failure, or resuscitated cardiac arrest.  
Cox proportional hazard models with adjustment for baseline covariates (age, sex, ejection fraction, 
diabetes, eGFR) will be used for these interim analyses. Estimated 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 DeMets [19] will be used as a 
guide for interpreting these interim analyses. As specified in the protocol, 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. These 


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proposed monitoring boundaries are intended as a guide for interpreting the interim analyses and not as a 
rule for early termination.  
On a DSMB teleconference on April 4, 2013, the DSMB formally resolved not to consider recommending 
early termination for efficacy until at least 50% of the expected number of events have accrued. Thus, 
they recommended that no alpha penalty should be incurred by early monitoring for safety. The DSMB 
further recommended that monitoring boundaries for subsequent examinations of unblinded data be 
computed using the Lan-DeMets alpha-spending approach with an O’Brien-Fleming-type alpha spending 
function.  
In light of the April 4, 2013 DSMB recommendation, interim monitoring will be based on an alpha-
spending function of the form 
𝛼∗(𝑡̂𝑘) = {
0
if 𝑡̂𝑘< 1/2
𝛼(𝑡̂𝑘)
if  𝑡̂𝑘≥1/2 
where 𝑡̂𝑘 denotes the estimated proportion of statistical information at the time of the 𝑘-th interim 
analysis and 𝛼(𝑡) = min{2[1 −Φ(𝑍𝛼/2/√𝑡)], 𝛼} is the O’Brien-Fleming-type spending function with 
type-I error rate 𝛼, as defined in Lan and DeMets (1983).  Critical values will be obtained based on 
integration of the multivariate normal distribution as implemented in R software with the gsDesign 
package Version 2.8-8 or later. Calculations of monitoring boundaries require an estimate of the variance 
of the treatment group coefficient (log hazard ratio) at each interim analysis. This variance will be 
obtained from the inverse of the observed information matrix evaluated at the unrestricted maximum 
partial-likelihood estimate (not the constrained estimate under H0).  Monitoring boundaries will control 
the type-I error rate for each monitored endpoint separately (not overall) at an overall two-sided 
significance level of α = 0.05. 
11.5. Contingency plan for insufficient primary endpoint events 
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. 
As described in the ISCHEMIA protocol, an independent Advisory Panel, separate from the DSMB, will 
be convened for the purpose of reviewing aggregate event rate data and making a recommendation to the 
NHLBI Director. Members of the Advisory Panel will not have access to unblinded data by treatment 
group or other data that would bias their recommendation.[20, 21] Prior to convening the Advisory Panel, 
the final number of projected primary endpoint events will be estimated and unconditional power (i.e. 
based on aggregate event rate; not by treatment group) will be re-calculated.[22] The protocol states that a 
design modification (e.g. extend follow-up, change the primary endpoint, or follow an independent panel 
recommendation) will be considered if power is less than the originally targeted 90%. 
The first analysis for monitoring and projecting the final aggregate number of CEC-confirmed primary 
endpoint events will begin approximately 3 years after the first participant is enrolled.  Subsequent 
analyses will be timed to coincide with scheduled DSMB reports. DSMB members will be informed of 
these interim analysis results but will not participate in deliberations about changing the primary endpoint 
or extending follow-up. The analysis plan for this activity is as follows:  


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At each interim analysis, the final number of CEC-confirmed primary endpoint events will be projected 
under a range of possible study assumptions. Scenarios for projecting endpoint events will be based on 
combinations of the following factors:  
1. Accrual rate. Accrual rate scenarios will be constructed by combining the current observed 
accrual rate up to the time of analysis with a range of possible future assumptions, to be 
determined by the SDCC in consultation with the CCC and NHLBI project office. 
2. Primary endpoint event rate. Event rate scenarios will be based on statistical estimates derived 
from the current available endpoint data at the time of interim analysis. The time-to-event curve 
will be estimated non-parametrically over the range of available follow-up and parametrically 
(based on extrapolation) beyond the range of follow-up. For these analyses, the target of 
estimation will be the distribution of time to first occurrence of a CEC-confirmed primary 
endpoint event.  The method of Cook and Kosorok [23] will be used to adjust for incomplete 
CEC adjudication at the time of analysis.  
3. Date of termination of accrual. 
4. Date of termination of follow-up.  
Factors #3 and #4 will be varied for the purpose of exploring the potential impact of shortening or 
extending accrual and/or follow-up. The projected final number of CEC-confirmed primary endpoint 
events will be calculated using a Markov model strategy similar to Cook [22].  
Results will be shared with members of study leadership (e.g., study Chair and Co-Chair, SDCC and CCC 
faculty, NHLBI project officers) who will deliberate internally about the need for extending follow-up or 
changing the primary endpoint as pre-specified in the study protocol. Only individuals who are blinded to 
outcomes by treatment group will participate in these deliberations. If study leadership feels that it may be 
beneficial to extend follow-up or change the primary endpoint, an independent panel will be convened by 
NHLBI for the purpose of advising the NHLBI director.   
Changing the primary endpoint after trial initiation may be counterproductive if it diminishes the trial’s 
perceived integrity or credibility. To minimize controversy, a decision about changing the primary 
endpoint will be targeted to occur before 75% of the projected total primary endpoint events have 
accrued. If feasible, extending follow-up will be preferred over switching from a relatively harder to 
softer primary composite endpoint. 
 


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12. REFERENCES 
1. Thygesen, K., et al., Third universal definition of myocardial infarction. J Am Coll Cardiol, 2012. 
60(16): p. 1581-98. 
2. Cox, D., Regression models and life-tables (with discussion). Journal of the Royal Statistical 
Society: Series B, 1972. 34: p. 187-220. 
3. Akazawa, K., T. Nakamura, and Y. Palesch, Power of logrank test and Cox regression model in 
clinical trials with heterogeneous samples. Statistics in Medicine, 1997. 16(5): p. 583-97. 
4. Hauck, W.W., S. Anderson, and S.M. Marcus, Should we adjust for covariates in nonlinear 
regression analyses of randomized trials? Control Clin Trials, 1998. 19(3): p. 249-56. 
5. Henderson, R.A., et al., Seven-year outcome in the RITA-2 trial: coronary angioplasty versus 
medical therapy. J Am Coll Cardiol, 2003. 42(7): p. 1161-70. 
6. Kalbfleisch, J.D. and R.L. Prentice, The statistical analysis of failure time data, second edition.  
Vol. 360. 2011: John Wiley & Sons. 
7. Kaplan, E. and P. Meier, Nonparametric estimation from incomplete observations. Journal of the 
American Statistical Association, 1958. 53: p. 457-481. 
8. Hernan, M.A., The Hazards of Hazard Ratios. Epidemiology, 2010. 21(1): p. 13-15. 
9. Royston, P. and M.K. Parmar, The use of restricted mean survival time to estimate the treatment 
effect in randomized clinical trials when the proportional hazards assumption is in doubt. 
Statistics in Medicine, 2011. 30(19): p. 2409-2421. 
10. Péron J., P. Roy, B. Ozenne, L. Roche, M. Buyse. The net chance of a longer survival as a 
patient-oriented measure of treatment benefit in randomized clinical trials. JAMA oncology. 2016 
Jul 1;2(7):901-5. 
11. Spiegelhalter, D., L. Freedman, and M. Parmar, Bayesian approaches to randomized trials. 
Journal of the Royal Statistical Society, 1994. 157: p. 357-416. 
12. Spiegelhalter, D.J., K.R. Abrams, and J.P. Myles, Bayesian Approaches to Clinical Trials and 
Health-Care Evaluation. 2004: Wiley. 
13. Robins, J., W.M.F. Wolfson, and A. Tsiatis, Adjusting for Differential Rates of Pneumocystis-
Carinii Pneumonia Prophylaxis in High Vs Low-Dose Azt Treatment Arms in an Aids 
Randomized Trial. American Journal of Epidemiology, 1991. 134(7): p. 717-717. 
14. Robins, J.M. and D.M. Finkelstein, Correcting for noncompliance and dependent censoring in an 
AIDS Clinical Trial with inverse probability of censoring weighted (IPCW) log-rank tests. 
Biometrics, 2000. 56(3): p. 779-88. 
15. Robins, J.M. and A.A. Tsiatis, Correcting for Noncompliance in Randomized Trials Using Rank 
Preserving Structural Failure Time Models. Communications in Statistics-Theory and Methods, 
1991. 20(8): p. 2609-2631. 
16. Zhang, M., et al., Inference on treatment effects from a randomized clinical trial in the presence 
of premature treatment discontinuation: the SYNERGY trial. Biostatistics, 2010. 
17. Bang, H. and C.E. Davis, On estimating treatment effects under non-compliance in randomized 
clinical trials: are intent-to-treat or instrumental variables analyses perfect solutions? Statistics in 
Medicine, 2007. 26(5): p. 954-964. 
18. Peduzzi, P., et al., Analysis as-randomized and the problem of non-adherence: an example from 
the Veterans Affairs Randomized Trial of Coronary Artery Bypass Surgery. Statistics in 
Medicine, 1993. 12(13): p. 1185-95. 
19. Lan, K. and D. DeMets, Discrete sequential boundaries for clinical trials. Biometrika, 1983. 70: p. 
659-663. 
20. Wittes, J., On changing a long‐term clinical trial midstream. Statistics in Medicine, 2002. 21(19): 
p. 2789-2795. 
21. Evans, S., When and how can endpoints be changed after initiation of a randomized clinical trial. 
PLoS clinical trials, 2007. 2(4): p. e18. 


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22. Cook, T.D., Methods for mid-course corrections in clinical trials with survival outcomes. 
Statistics in Medicine, 2003. 22(22): p. 3431-47. 
23. Cook, T.D. and M.R. Kosorok, Analysis of time-to-event data with incomplete event 
adjudication. Journal of the American Statistical Association, 2004. 99(468): p. 1140-1152. 
 
 

Prot_001.pdf: 
Protocol Date: Jan.06.2014 
Version 2.0 
1 
 
 
 
 
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 
 
 
 
ISCHEMIA CKD Ancillary Trial 
Principal Investigator 
David J. Maron, MD 
 
 
 
Sripal Bangalore, MD 
 
 
 
 
Clinical Coordinating Center 
Cardiovascular Clinical Research Center 
New York University School of Medicine 
 
 
 
 
 
Statistical and Data Coordinating 
Center 
Duke Clinical Research Institute 
 
 
 
 
Protocol Version Date: 
January 6, 2014 
 
 
 
 
 
 
Note: This version includes an appendix with CIAO-ISCHEMIA, an optional ancillary study for 
~75 selected sites. 


Protocol Date: Jan.06.2014 
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PROTOCOL VERSION AND AMENDMENT TRACKING 
 
 
 
 
Version Number/Amendment 
Approval Date 
1.0 
January 18, 2012 
2.0 
January 6, 2014 


Protocol Date: Jan.06.2014 
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3 
 
 
 
 
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 6, 2014 
 
 
 
 
 
 
Signature of Principal Investigator 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 
 
Name of Facility 
 
 
 
 
 
 
Location of Facility (City, Country) 


Protocol Date: Jan.06.2014 
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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 initial invasive (INV) strategy 
of cardiac catheterization and optimal revascularization, if feasible, in 
addition to optimal medical therapy (OMT) in patients with stable ischemic 
heart disease (SIHD) and at least moderate ischemia on ischemia testing 
reduces the incidence of the composite of cardiovascular death or nonfatal 
myocardial infarction compared with a conservative (CON) strategy of 
optimal medical therapy alone with cardiac catheterization and 
revascularization reserved for failure of OMT. 
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 ischemia testing 
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 an ischemia test (see definitions in 
protocol appendix A) 
• Participant is willing to comply with all aspects of the protocol, including 
adherence to the assigned strategy, medical therapy and follow-up 
visits 
• Participant is willing to give written informed consent 
• Age ≥ 21 years 


Protocol Date: Jan.06.2014 
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Exclusion Criteria 
•  LVEF < 35% 
• History of unprotected left main stenosis >50% on prior coronary 
computed tomography angiography (CCTA) or prior cardiac 
catheterization (if available) 
• Finding of “no obstructive CAD” (<50% stenosis in all major epicardial 
vessels) on prior CCTA or prior catheterization, performed within 12 
months 
• Coronary anatomy unsuitable for either PCI or CABG 
• Unacceptable level of angina despite maximal medical therapy 
• Very dissatisfied with medical management of angina 
• History of noncompliance with medical therapy 
• Acute coronary syndrome within the previous 2 months 
• PCI within the previous 12 months 
• Stroke within the previous 6 months or spontaneous intracranial 
hemorrhage at any time 
• History of ventricular tachycardia requiring therapy for termination, or 
symptomatic sustained ventricular tachycardia not due to a transient 
reversible cause 
• NYHA class III-IV heart failure at entry or hospitalization for 
exacerbation of chronic heart failure within the previous 6 months 
• Non-ischemic dilated or hypertrophic cardiomyopathy 
• End stage renal disease on dialysis or estimated glomerular filtration 
rate (eGFR) <30mL/min (not an exclusion criterion for CKD ancillary 
trial, see CKD ancillary trial, Section 18) 
• Severe valvular disease or valvular disease likely to require surgery or 
percutaneous valve replacement during the trial 
• Allergy to radiographic contrast that cannot be adequately pre- 
medicated, or any prior anaphylaxis to radiographic contrast 
• Planned major surgery necessitating interruption of dual antiplatelet 
therapy (note that patients may be eligible after planned surgery) 
• Life expectancy less than the duration of the trial due to non- 
cardiovascular comorbidity 
• Pregnancy (known to be pregnant; to be confirmed before CCTA 
and/or randomization, if applicable) 
• Patient who, in the judgment of the patient’s physician, is likely to have 


Protocol Date: Jan.06.2014 
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significant unprotected left main stenosis (Those who are able to 
undergo CCTA will have visual assessment of the left main coronary 
artery by the CCTA core lab) 
• 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 
• Canadian Cardiovascular Society Class III angina of recent onset, OR 
angina of any class with a rapidly progressive or accelerating pattern 
• Canadian Cardiovascular Society Class IV angina, including 
unprovoked rest angina 
• High risk of bleeding which would contraindicate the use of dual 
antiplatelet therapy 
• Cardiac transplant recipient 
• Prior CABG, unless CABG was performed more than 12 months ago, 
and coronary anatomy has been demonstrated to be suitable for PCI 
or repeat CABG to accomplish complete revascularization of ischemic 
areas (CCC approval required) 
Primary Endpoint 
Time to first occurrence of 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 


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• 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 
4 years follow-up. 
Clinical Event 
Adjudication 
Committee 
The following events will be adjudicated by a blinded Clinical Event 
Adjudication Committee: death, myocardial infarction, resuscitated cardiac 
arrest, hospitalization for unstable angina, hospitalization for heart failure, 
and stroke. 
Data and Safety 
Monitoring Board 
An independent Data and Safety Monitoring Board will advise the NHLBI 
and study leadership on safety aspects and overall progress of the study. 
Statistical 
Considerations 
A sample size of approximately 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. 
Ancillary Studies 
(optional) 
1. ISCHEMIA-CKD ancillary trial 
Approximately 1000 additional patients with advanced CKD (estimated 
glomerular filtration rate [eGFR] <30 or on dialysis) with moderate to 
severe ischemia and who satisfy all other ISCHEMIA trial inclusion and 
exclusion criteria (other than the eGFR) will be included in the 
ISCHEMIA-CKD ancillary trial. The primary objective of the trial is to 
determine whether an invasive (INV) strategy reduces the incidence of 
the composite of death from any cause 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. The trial is designed to run seamlessly with the main 
trial but sites can opt out if they choose not to participate. See section  
18 for more details. 
2. CIAO-ISCHEMIA (Changes in Ischemia and Angina over One year 
among ISCHEMIA trial screen failures with no obstructive coronary 


Protocol Date: Jan.06.2014 
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artery disease on CT angiography). See appendix B 
 
300 participants recruited from main trial screen failures enrolled using 
stress echo or CMR and excluded from the main trial due to absence 
of obstructive CAD on CCTA. Participants undergo symptom 
assessment and repeat stress imaging at one year. 


Protocol Date: Jan.06.2014 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS ....................................................................................... 13 
2. 
BACKGROUND AND RATIONALE ........................................................................................................ 17 
3. 
STUDY OBJECTIVES ............................................................................................................................. 20 
4. 
STUDY DESIGN .................................................................................................................................... 21 
4.1 
Study Flow ........................................................................................................................ 21 
4.2 
Study Population ............................................................................................................... 24 
4.3 
Inclusion/Exclusion Criteria ................................................................................................ 24 
4.3.1 
Criteria Prior to Informed Consent ....................................................................................................... 24 
4.3.2 
Criteria After Enrollment (Informed Consent) and Prior to Randomization......................................... 25 
5. 
STUDY PROCEDURES ........................................................................................................................... 27 
5.1 
Qualifying Stress Test ......................................................................................................... 27 
5.2 
Informed Consent Process .................................................................................................. 27 
5.3 
Interactive Voice Response System (IVRS) and Interactive Web Response System (IXRS) ......... 27 
5.4 
Core Lab Ischemia Verification ........................................................................................... 28 
5.5 
Coronary Computed Tomography Angiography (CCTA) ........................................................ 28 
6. 
MANAGEMENT STRATEGIES ............................................................................................................... 30 
6.1 
Conservative (CON) Strategy .............................................................................................. 30 
6.2 
Invasive (INV) Strategy ....................................................................................................... 30 
6.3 
Optimal Medical Therapy (OMT) ........................................................................................ 30 
6.3.1 
Management of Angina in CON Participants ........................................................................................ 31 
6.3.2 
Management of Angina in INV Participants ......................................................................................... 31 
6.4 
Optimal Revascularization Therapy (ORT) ........................................................................... 31 
6.4.1 
Criteria to Select PCI vs. CABG .............................................................................................................. 32 
6.4.2 
Guidelines for Optimal Percutaneous Coronary Intervention .............................................................. 32 
6.4.3 
Guidelines for Optimal Surgical Revascularization ............................................................................... 32 
6.5 
Maximizing Adherence to CON Strategy ................................................................................. 32 
6.6 
Cath in Participants Randomized to CON Strategy ............................................................... 33 
7. 
AUXILLIARY SCREENING LOG AND SURVEY ........................................................................................ 35 
7.1 
Screening Log .................................................................................................................... 35 
7.2 
Screening Survey ............................................................................................................... 35 
8. 
Study Assessments ............................................................................................................................. 37 
8.1 
Creatinine and Pregnancy Test ........................................................................................... 37 
8.2 
Standard Blood Tests ......................................................................................................... 37 


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8.3 
Endpoint Assessments ....................................................................................................... 37 
8.4 
Blood Biomarkers and Genomics Biorepository ................................................................... 37 
8.5 
Medication Adherence....................................................................................................... 38 
8.6 
Lifestyle Assessment .......................................................................................................... 38 
8.7 
Quality of Life Assessment ................................................................................................. 38 
8.8 
Economics Assessment ...................................................................................................... 38 
9. 
SCHEDULE OF ASSESSMENTS .............................................................................................................. 40 
10. 
ADJUDICATION OF CLINICAL EVENTS ............................................................................................. 50 
11. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ................................................................... 51 
11.1 
Sample Size Determination and Statistical Power ................................................................ 51 
11.1.1 
Considerations and Assumptions ..................................................................................................... 51 
11.1.2 
Summary of Power and Precision ..................................................................................................... 51 
11.2 
Statistical Analysis Plan ...................................................................................................... 53 
11.2.1 
Analysis of the Primary Endpoint ..................................................................................................... 53 
11.2.2 
Analysis of the Secondary Endpoints................................................................................................ 53 
11.2.3 
Contingency Plan For Insufficient Primary Endpoint Events ............................................................ 54 
11.2.4 
Quality of Life (QOL) Analysis ........................................................................................................... 54 
11.2.5 
Health Economics Analysis ............................................................................................................... 55 
11.2.6 
Interim Analysis ................................................................................................................................ 55 
12. 
DATA HANDLING AND RECORD KEEPING ....................................................................................... 58 
12.1 
Electronic Data Capture (EDC) System .................................................................................... 58 
12.2 
Data Management and Quality .......................................................................................... 58 
12.3 
Data Confidentiality and Security ....................................................................................... 58 
12.4 
Training ............................................................................................................................. 59 
12.5 
Records Retention ............................................................................................................. 59 
12.6 
Management of Economic and Quality of Life (EQOL) Data .................................................. 59 
13. 
SAFETY MONITORING PLAN ................................................................................................................ 60 
13.1 
Data and Safety Monitoring Board ..................................................................................... 60 
13.2 
Risks and Benefits .............................................................................................................. 60 
13.3 
Safety Monitoring Objectives and Rationale ....................................................................... 61 
13.4 
Adverse Events Reporting by Investigators .......................................................................... 62 
13.5 
Events to be Monitored ..................................................................................................... 62 
14. 
ETHICAL CONSIDERATIONS ............................................................................................................. 64 
14.1 
Regulatory and Ethical Compliance ..................................................................................... 64 


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14.2 
Informed Consent Process .................................................................................................. 64 
14.3 
Responsibilities of the Investigator and IRB/IEC/REB ........................................................... 64 
14.4 
Protocol Amendments ....................................................................................................... 64 
14.5 
Early Termination of the Study ............................................................................................... 65 
15. 
STUDY ORGANIZATION ................................................................................................................... 66 
16. 
DATA ACCESS AND SHARING .......................................................................................................... 67 
17. 
PUBLICATIONS POLICY: OVERVIEW ................................................................................................ 68 
18. 
ISCHEMIA-CKD Ancillary Trial ......................................................................................................... 69 
18.1 
Background ....................................................................................................................... 69 
18.2 
Objectives ......................................................................................................................... 70 
18.3 
Study Design ..................................................................................................................... 70 
18.4 
Statistical Consideration and Power ................................................................................... 70 
18.5 
Safety Monitoring Plan ...................................................................................................... 71 
18.5.1 
Data and Safety Monitoring Board ................................................................................................... 71 
18.5.2 
Risks and Benefits ............................................................................................................................. 71 
18.5.3 
Adverse Events Reporting by Investigators ...................................................................................... 72 
18.5.4 
Events to be Monitored .................................................................................................................... 72 
18.6 
Adjudication of Clinical Events (See Section 10) ................................................................... 73 
18.7 
Data Handling and Record Keeping (See Section 12) ............................................................ 73 
18.8 
Ethical Consideration (See Section 14) ................................................................................ 73 
18.9 
Study Organization (See Section 15) ................................................................................... 73 
18.10 
Data Access and Sharing (See Section 16) ........................................................................ 73 
18.11 
Publication Policy (See Section 17) .................................................................................. 73 
19. 
REFERENCE LIST .............................................................................................................................. 74 
20. 
APPENDIX A .................................................................................................................................... 80 
21. 
APPENDIX B CIAO-ISCHEMIA Ancillary Study ................................................................................ 82 
21.1 
Background ....................................................................................................................... 82 
21.2 
Objectives ......................................................................................................................... 82 
21.2.1 
Primary Specific Aim ......................................................................................................................... 82 
21.2.2 
Other Specific Aims ........................................................................................................................... 82 
21.3 
Study Design and Procedures ............................................................................................. 83 
21.3.1 
Study Population and Eligibility Criteria ........................................................................................... 83 
21.3.2 
Informed Consent Process ................................................................................................................ 83 


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21.3.3 
Study Flow ......................................................................................................................................... 84 
21.3.4 
Schedule of Study Assessments ........................................................................................................ 84 
21.4 
Statistical Considerations ................................................................................................... 85 
21.4.1 
Analysis of the Primary Specific Aim ................................................................................................ 85 
21.4.2 
Analysis of Other Specific Aims......................................................................................................... 87 
21.4.3 
Analysis of Events.............................................................................................................................. 88 
21.4.4 
Descriptive Analysis .......................................................................................................................... 89 
21.5 
Data and Safety Monitoring Plan ........................................................................................... 89 
21.5.1 
Data and Safety Monitoring Board ................................................................................................... 89 
21.5.2 
Risks and Benefits ............................................................................................................................. 89 
21.6 
Data Handling and Record Keeping ..................................................................................... 90 
21.6.1 
Data Collection, Management and Security ..................................................................................... 90 
21.7 
Ethical Considerations........................................................................................................ 91 
21.8 
References ........................................................................................................................ 91 


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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 
CI 
confidence interval 
CKD 
Chronic kidney disease (defined as those with estimated glomerular filtration 
rate [eGFR] <30 or on dialysis) 
CK-MB 
creatinine kinase-MB 
CIAO-ISCHEMIA 
Ancillary study. Changes in Ischemia and Angina over One year among 
ISCHEMIA trial screen failures with no obstructive coronary artery disease 
on CT angiography. 
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) 


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COURAGE 
Clinical Outcomes Utilizing Revascularization and Aggressive Drug 
Evaluation trial 
CV 
Cardiovascular 
DASI 
Duke Activity Status Index 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
Echo 
echocardiography 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetraacetic acid 
ERES 
electronic signature 
eGFR 
estimated glomerular filtration rate 
EQ-5D 
self-reported generic preference-based measure of health, developed by the 
EuroQol Group 
EQOL 
economic and quality of life 
EQOLCC 
EQOL Coordinating Center 
ESC 
European Society of Cardiology 
ETT 
Exercise tolerance testing 
EU Directive 
European Union Directive on Data Privacy 
FFR 
fractional flow reserve 
HbA1c 
hemoglobin A1c 
HDL 
high density lipoprotein 
HF 
heart failure 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Hazard Ratio 


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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 
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 


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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 
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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FAME 2 was a trial of FFR-guided PCI with medical therapy vs. medical therapy alone in SIHD 
patients with at least 1 stenosis with FFR ≤0.80. Patients with recent ACS and stabilized class 
IV angina were included. FAME 2 was halted prematurely after only 54% of planned enrollment 
due to a statistically significant reduction in the primary endpoint (death, MI, urgent 
revascularization) in the PCI group at an average follow-up of only 7 months.29 The difference in 
the primary endpoint was driven by a reduction in urgent revascularization, with no difference in 
death or MI between groups.29 FAME 2 suffers from similar limitations of prior trials by 
randomizing all patients after cath, when physicians and patients knew anatomic and 
physiologic findings which could influence the decision to undergo urgent revascularization. If 
COURAGE and BARI 2D had included revascularization in the primary endpoint they would 
have had similar findings. 
 
Moderate to severe ischemia has been considered a marker of increased risk for cardiovascular 
events.30 It remains unclear whether a greater magnitude of ischemia may increase risk based 
on inherent 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.31- 
34 However, individual plaques with severe stenoses are more likely to occlude than less 
severely stenotic plaques.35 Notably, more recent studies call into question the association 
between presence and extent of ischemia and outcomes. The COURAGE baseline nuclear 
substudy found no relationship between the level of ischemia and risk.36 In the Surgical 
Treatment for Ischemic Heart Failure (STICH) trial there were no differences in death or 
cardiovascular hospitalization rate between patients with or without ischemia in a cohort with 
ejection fraction of 35% or less and coronary artery disease amenable to CABG.37 Moreover, 
ischemia was not a predictor of death among asymptomatic patients with previous 
revascularization and inducible ischemia on myocardial perfusion imaging (MPI).38 
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 all patients only 
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 MPI,39-41 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.42 
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 


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reduction on follow-up MPI. In contrast, a newer, COURAGE analysis of outcomes by treatment 
in 468 patients with site-determined moderate or severe ischemia at baseline showed no 
difference in death or MI between PCI+OMT vs. OMT alone (P = 0.53).36 The same lack of 
benefit for PCI was demonstrated in an unpublished analysis of 189 patients with at least 
moderate ischemia on baseline core lab-measured MPI among whom there was no reduction in 
death/MI (PCI and OMT vs. OMT 24% vs. 21%, respectivelyHR1.19, 95% CI0.65-2.18). 
Selection for repeat revascularization was not associated with lower mortality risk among 
patients with silent ischemia an average of 5 years after initial revascularization in an 
observational study.38 
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.43-51 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 with or without definition of the coronary anatomy before 
randomization has studied whether an invasive strategy of prompt revascularization improves 
clinical 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. 
STUDY OBJECTIVES 
 
PRIMARY AIM 
The primary aim of the ISCHEMIA trial is to determine whether an initial invasive strategy of 
cardiac catheterization and optimal revascularization, if feasible, in addition to OMT, will reduce 
the primary composite endpoint of 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 failure of OMT. 
 
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 
Please see section 18 for the primary and secondary aims of the ISCHEMIA-CKD ancillary trial. 


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4. 
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 ischemia testing will be randomized in a 1:1 fashion to the INV or CON 
strategies in the main trial. In addition, approximately 1,000 participants with advanced CKD 
(defined as eGFR <30 or on dialysis) and at least moderate ischemia on ischemia testing will be 
randomized in a 1:1 fashion to the INV or CON strategies in an optional CKD ancillary trial (see  
section 18).  Additionally, other optional ancillary studies will be conducted (see section 19). 
 
4.1 
Study Flow 
 
See figure 1 for details. Patients with at least moderate ischemia  (see section 1.1) will be 
identified and screened for clinical inclusion/exclusion criteria (see section 4.3). Patients who 
are suspected to be trial eligible may also be pre-screened , for example, prior to clinically 
indicated ischemia testing in clinical areas where SIHD patients are cared for. Patients who 
meet clinical and ischemia (site-interpreted) eligibility criteria and are interested in participating 
in the trial will be enrolled by signing an informed consent and receiving a study number via the 
interactive voice response system (IVRS) or interactive web response system (IXRS) (see 
section 5.3). Ischemia test data (e.g., images, ECG, report) will be transferred to the relevant 
core lab electronically for enrolled participants (see Figure 1). 
 
CCTA step: Participants with eGFR >60 ml/min will undergo a blinded CCTA unless they had 
visualization of the coronary arteries by CCTA or invasive angiography within 12 months with a 
stable subsequent clinical course, or unless CCTA is deemed clinically unnecessary by the site 
based on an exception as indicated in the MOO and approved by the CCC. Such examples 
might include variation in eGFR calculation based on local lab policies, or local rules for 
performance of CCTA which vary from the study protocol. CCTA images will also be transferred 
electronically to the CCTA core lab for interpretation.  Coronary CCTA images will not be 
interpreted at the sites unless: 1) the participant is excluded due to CCTA findings, including 
incidental findings.  In the event of any of these exclusionary findings, the participant will not be 
eligible to continue in the study, and these results will be communicated to the site; 2) the 
participant is excluded from randomization for any other reason; 3) the participant undergoes 
protocol-assigned or non-protocol assigned catheterization and review of CCTA findings is 
desirable for planning of revascularization. 
 
Sites may interpret non-coronary CT images locally to evaluate for any non-coronary incidental 
findings; this review will be encouraged if the core lab identifies an incidental finding on CCTA 
which does not disqualify the patient, e.g., smaller lung nodules.  A list of incidental findings for 
which the CCTA core lab routinely screens may be found in the MOO. 
 
All participants meeting CCTA eligibility criteria should then be randomized to the INV or CON 
strategy via the IVRS/IXRS system. 
 
Participants with known or a high likelihood of unprotected left main stenosis ≥50% will be 
excluded before randomization. The primary method to identify such patients is CCTA. 


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Participants with eGFR <60 ml/min will not undergo a CCTA due to the increased risk of 
developing contrast-induced nephropathy, unless the site investigator and participant’s personal 
physician believe the benefits outweigh the risks. Some participants with eGFR ≥ 60 may not 
undergo CCTA (see section 5.5 and MOO). Local practices vary regarding calculation of eGFR 
and cut points of eGFR used for performance of CCTA. Participants who do not undergo CCTA 
who, according to the participant’s physician, are unlikely to have significant unprotected left 
main stenosis, will proceed directly to randomization. 
 
Patients who qualify through exercise tolerance testing (ETT) alone without imaging (e.g. 
exercise treadmill and bicycle ergometer testing) will be required to be eligible for and to have a 
CCTA prior to randomization unless they meet a specified exception, e.g., patients who have 
had CCTA or invasive angiography within 12 months (see MOO for other exceptions). 
 
Timing of Randomization: Participants determined to be eligible for randomization should be 
randomized within a target of 15 days of consent, and participants randomized to INV strategy 
should undergo catheterization within a target of 30 days after randomization, with optimal 
revascularization therapy (ORT) soon thereafter as appropriate. Participants will be enrolled 
over approximately 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 9. 


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Target 30 Days 
 
Figure 1 
Study Flow 
 
Target 90 Days 
Target 15 Days Enrollment to Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
SIHD with 
at least 
moderate 
ischemia 
 
 
 
 
 
 
YES 
 
 
 
 
Meets all 
clinical and 
site 
determined 
ischemia 
criteria 
 
 
 
 
 
 
YES 
Consent 
and 
Enrollment 
(via IVRS) 
+ 
Transmit 
Qualifiying 
Ischemia 
Test to 
≥60 ml/min3 
 
 
 
 
2 
CCTA 
 
 
 
 
 
 
 
 
 
 
 
YES 
CCTA 
eligibility 
verified 
by core 
lab 
 
NO 
CCTA 
Screen 
Failure⁴ 
 
 
 
 
 
 
NO 
1 
Core Lab 
3 
< 60 ml/min 
 
 
 
Or coronary anatomy defined previously 
 
R A N D O M I Z 
E 
(via IVRS) 
 
 
 
 
 
Ineligible 
 
 
INV 
Strategy 
 
 
CON 
Strategy 
 
 
 
 
 
 
 
 
1 
See MOO for measures to ensure randomization of participants who meet ischemia eligibility 
2 
Cath and 
revascularization 
CCTA will not be performed in participants with eGFR <60 ml/min or in participants who have had 
invasive angiography or CCTA within the prior 12 months (the number of patients enrolled with 
recent invasive angiography or CCTA may be capped) 
3 
Participants with eGFR <60 ml/min with no clinical or ischemia testing characteristics suggestive of 
significant left main coronary artery stenosis are eligible to be randomized. Participants with 
eGFR<30 or on dialysis are included in the CKD ancillary trial. Some participants with eGFR>60 may 
not undergo CCTA (see 6.5 and MOO). Some participants with eGFR<60 may undergo CCTA based 
on physician preference. 
⁴CCTA screen failure due to no obstructive CAD will be enrolled in an ancillary study at participating 
sites 
 
 
 
 
 
 
 
Follow-up as per 
schedule of 
assessments 


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4.2 
Study Population 
 
 
Patients with SIHD and at least moderate ischemia. SIHD is synonymous with stable coronary 
artery disease, and refers to patients with coronary artery disease who are clinically stable (i.e., 
who are not in an unstable phase such as an acute coronary syndrome). 
 
Enrollment within any subgroup, including by trial site or region, may be capped in order to 
ensure the trial population’s representativeness. 
 
 
4.3 
Inclusion/Exclusion Criteria 
Screening for inclusion/exclusion criteria will include assessment for clinical and ischemia 
criteria at the local site, ability and willingness to provide informed consent and the need for 
CCTA. Core labs will work with sites to ensure randomization of participants with at least 
moderate ischemia. 
 
4.3.1  Criteria Prior to Informed Consent 
 
Patients will be screened for the following inclusion and exclusion criteria: 
 
Inclusion (pre informed consent) 
1. At least moderate ischemia on qualifying ischemia test (See protocol appendix A) 
2. 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. Coronary anatomy unsuitable for either PCI or CABG 
5. Unacceptable level of angina despite maximal medical therapy 
6. Very dissatisfied with medical management of angina 
7. History of noncompliance with medical therapy 
8. Acute coronary syndrome within the previous 2 months 
9. PCI within the previous 12 months 
10. Stroke within the previous 6 months or spontaneous intracranial hemorrhage at any time 


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11. History of ventricular tachycardia requiring therapy for termination, or symptomatic 
sustained ventricular tachycardia not due to a transient reversible cause 
12. NYHA class III-IV heart failure at entry or hospitalization for exacerbation of chronic 
heart failure within the previous 6 months 
13. Non-ischemic dilated or hypertrophic cardiomyopathy 
14. End stage renal disease on dialysis or estimated glomerular filtration rate (eGFR) <30 
ml/min (not an exclusion criterion for CKD ancillary trial, see CKD ancillary trial, section 
18) 
15. Severe valvular disease or valvular disease likely to require surgery or percutaneous 
valve replacement during the trial 
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 (note that 
patients may be eligible after planned surgery) 
18. Life expectancy less than the duration of the trial due to non-cardiovascular comorbidity 
19. Pregnancy (known to be pregnant; to be confirmed pre-CCTA and/or randomization, if 
applicable) 
20. Patient who, in the judgment of the patient’s physician, is likely to have significant 
unprotected left main stenosis (Those who are able to undergo CCTA will have visual 
assessment of the left main coronary artery by the CCTA core lab) 
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 
24. Canadian Cardiovascular Society Class III angina of recent onset, or angina of any class 
with a rapidly progressive or accelerating pattern 
25. Canadian Cardiovascular Society Class IV angina, including unprovoked rest angina 
26. High risk of bleeding which would contraindicate the use of dual antiplatelet therapy 
27. Cardiac transplant recipient 
28. Prior CABG, unless CABG was performed more than 12 months ago and coronary 
anatomy has been demonstrated to be suitable for PCI or CABG to accomplish complete 
revascularization of ischemic areas (CCC approval required) 
 
 
4.3.2  Criteria After Enrollment (Informed Consent) and Prior to Randomization 
 
Participants who provide informed consent and are clinically eligible will be registered via the 
IVRS/IXRS system. They are considered enrolled and will undergo assessment of ischemia by 


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the relevant core lab and may undergo a blinded CCTA (if eGFR >60 ml/min or as per the 
MOO). 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 (participants excluded from randomization for this reason 
will be considered for CIAO-ISCHEMIA ancillary study; see appendix B) 
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 event e.g., a primary or secondary endpoint event or 
interval development or discovery of an exclusion criterion 


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5. 
STUDY PROCEDURES 
 
5.1 
Qualifying Ischemia Test 
 
The criteria for at least moderate ischemia with each  test modality and the rationale for their 
selection are described in protocol appendix A. Ischemia tests documenting eligibility may be 
performed before or after medical therapy for SIHD has been initiated and adjusted. Similarly, 
participants already taking medical therapy for SIHD may have been on or off medications on the  
day of the ischemia test documenting eligibility, consistent with customary clinical practice.40, 41 A 24- 
hour, 7-day helpline will be available to sites for assistance with ascertainment of eligibility, 
enrollment, and adherence to protocol. Sites may send anonymized ischemia tests (images and/or 
ECG) for core lab verification of trial eligibility before trial enrollment, as permissible by local 
IRBs/ECs and privacy boards. 
 
5.2 
Informed Consent Process 
 
The study will be reviewed with the prospective study participant by the investigator or his/her 
designee. This discussion is a critical component of the consent process and the prospective study 
participant will be given adequate time for this discussion and to read the written consent form. Two 
standard clinical care strategies are being compared in this study and clinicians should enroll 
patients for whom there is clinical equipoise regarding their management. Prevailing practice 
patterns vary widely within and between regions; the discussion with prospective participants should 
note these local patterns. The investigator or his/her designee will be available to answer questions 
about the study including procedures, risks, and alternatives. The informed consent form will be 
signed and dated by the patient as per local regulation. 
 
In addition, prospective study participants will be requested to consent to a biorepository sample, 
and to allow use of the biorepository sample for biomarkers and/or genetic analysis (DNA) in this 
optional study component conducted at participating sites.  Prospective study participants will be 
informed that declining participation in the biomarker or genetic analysis portion of the study does 
not preclude their participation in the main study.  A copy of the signed consent form will be given to 
the participant and the original(s) will be kept securely with each participant’s research records. 
 
Specific consent will be obtained before any protocol-mandated procedure that requires consent 
(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. 
 
5.3 
Interactive Voice Response System (IVRS) and Interactive Web Response 
System (IXRS) 


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Enrollment and randomization will be accomplished by contact with the IVRS or IXRS. When a 
participant meeting site-determined clinical and ischemia test criteria has provided informed consent, 
the study coordinator or investigator at the site will call the IVRS or log on to the IXRS to receive a 
participant identification number.  At this point the participant is registered as enrolled. 
 
Several language options will be provided for international sites using IVRS/IXRS. To eliminate any 
manual transcription errors, IVRS/IXRS will be programmed to electronically transfer the participant 
data and study identification number to create the participant’s case book within the electronic data 
capture (EDC) system. 
 
In order to randomize the participant, the study coordinator or investigator will call IVRS or log in to 
IXRS a second time. Subjects meeting all clinical, 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. 
 
5.4 
Core Lab Ischemia Verification 
Ischemia test data (e.g., images, ECG, reports) will be transferred electronically to the appropriate 
core lab for enrolled participants. The core labs will review and interpret the degree of ischemia. 
Sites will wait for verification of ischemia before CCTA (or, for patients who will not undergo CCTA, 
before randomization) unless the CCC permits an exception. 
 
5.5 
Coronary Computed Tomography Angiography (CCTA) 
 
In general coronary computed tomography angiography (CCTA) will be performed in participants  
with eGFR ≥60ml/min to identify and exclude participants with significant left main stenosis (defined 
as ≥50% unprotected stenosis) and participants without obstructive coronary stenoses (with <50% 
stenosis in all epicardial coronary vessels). Participants with eGFR <60 ml/min will in general not 
undergo a CCTA due to the risk of developing contrast-induced nephropathy and trial eligibility will  
be based on physician determination of the likelihood of significant left main stenosis.  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, 
where applicable. However, if a significant left main stenosis is suspected, these participants will not 
be enrolled into the study.  There will be additional exceptions to eGFR-based determination of use 
of CCTA (see section 4.1 and the MOO). If local calculation of eGFR is different from the IXRS- 
generated eGFR, the site investigator must follow local practices regarding patient eligibility for 
CCTA (i.e., site may use local eGFR calculation to decide whether the participant is CCTA eligible or 
not). Participants qualifying via non-imaging exercise tolerance testing (ETT) will undergo CCTA  
prior to randomization unless they have a specified exception, e.g., patients who have had CCTA or 
invasive angiography within 12 months (see MOO for other exceptions). 
 
Radiation reduction techniques will be used. We will suggest 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 


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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.52-56 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, absence of 
obstructive stenosis or incidental findings. Further definition of the anatomy will not be disclosed to 
the participant, treating physicians, or the site except as in section 4.1. The interpretation of the CT, 
including coronary anatomy, will be made available to the treating physicians for participants 
excluded based on CCTA findings (see section 4.1 and MOO for details). In addition, there may be 
findings on CT of potential clinical significance that will not exclude patients from the study, such as 
lung nodules. The interpretation of these trial-specified incidental findings by the core lab will be 
made available to the treating physicians who are expected to request local clinical review and 
reporting of the incidental findings and to remain blinded to coronary findings (see MOO). 
 
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 who will not undergo CCTA) will be randomized to the INV or CON strategy via the 
IVRS/IXRS system. The targeted time to randomize a participant after consent is obtained is 15 
days (see Figure 1). 


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


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


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


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


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Figure 2 
Cath in Participants Randomized to CON Strategy 
 
 


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7. 
AUXILLIARY SCREENING LOG AND SURVEY 
 
7.1 
Screening Log 
 
During the study enrollment period, sites will maintain a de-identified, written screening log of 
patients with site-determined moderate or severe ischemia who have undergone testing at the site’s 
designated primary laboratory. Patient characteristics (age [recorded for patients <90 years of age, 
recorded as 90 if >90 years of age], sex, and, if excluded, reason(s) for exclusion will be recorded) 
and intended management strategy for patients who are eligible but not enrolled, if known. 
 
The screening log will be sent to the CCC on a regular basis, where it will help identify the major 
reasons why patients are not enrolled, thus allowing CCC staff to develop corrective action plans for 
sites that are not meeting target enrollment. Depending on the site’s enrollment rate over time, the 
CCC may decide that a given site no longer needs to submit its screening log, although the site 
should continue to maintain the log through the end of enrollment. In the event of poor enrollment, 
sites may be asked to provide comparable information about patients referred to cath without prior 
ischemia testing. 
 
7.2 
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 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 ischemia test (ischemia severity and location, where applicable) 
• 
Basic medical history from ischemia test 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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8. 
Study Assessments 
 
8.1 
Creatinine and Pregnancy Test 
At the screening visit a serum creatinine test must be drawn if one is not available within the 
previous 90 days. In addition, a pregnancy test is required if the participant is pre-menopausal. 
 
8.2 
Standard Blood Tests 
 
In this population with established coronary disease, as part of standard practice the following tests 
will typically be obtained by the participant’s treating physician: complete blood count, electrolytes, 
creatinine, glucose, liver transaminases, lipid profile, and HbA1c. If HbA1c results are available for 
nondiabetics they will be recorded. If these test results are not available within specified time 
windows around the randomization visit (see MOO), then the following should be obtained: complete 
blood count, lipid profile, and HbA1c (for diabetics only). Liver transaminases should only be 
obtained if not available before starting statin therapy. An attempt will be made to coordinate 
participant follow-up visits so that they occur close in time to routine follow-up visits with their 
physicians when routine blood tests are performed. At 6 month follow-up visits, if lipid tests (and 
HbA1c at annual visits for diabetics) are not available within specified time windows they will be 
obtained by the study coordinator or participants will be referred to their treating physicians for the 
tests. Creatinine values obtained clinically for participants with eGFR <60 at the three month follow- 
up visit and annually will also be recorded. 
 
8.3 
Endpoint Assessments 
 
At every visit after randomization, the study coordinator will ask participants if they have had any 
symptoms or a report from a healthcare provider consistent with an endpoint event since the last 
study visit. See MOO for detailed instructions on collection of source documents. 
 
8.4 
Blood Biomarkers and Genomics Biorepository 
 
Randomized participants will be invited to participate in the biorepository protocol, unless precluded 
by local regulations. Participants who give informed consent will be asked to allow storage of 
samples of their blood in two biorepository protocols, one for biomarkers and one for genetic 
analysis. Participants who decline participation in one or both of the biorepository protocols are still 
eligible to participate in the main trial. The biorepositories will serve as resources for future analyses. 
Although no specific scientific proposals are put forth in the present protocol, we anticipate a wealth 
of opportunities for ancillary studies and sharing of resources with other investigators. Participants 
will be asked to separately consent for use of their blood samples for the biomarker biorepository  
and the genetic (DNA) biorepository. If a site is unable to process blood samples they may still 
participate in the genetic biorepository; in this case saliva samples may be collected from 
participants. 
 
Blood will be drawn for the biorepository at the time of randomization, and may be drawn after 
3 months of follow-up. At the time of randomization, up to a maximum of 49 mL of whole blood will 
be collected, which will be processed and stored as serum, plasma, RNA and, where allowable, 


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DNA. At the 3 month follow-up visit, up to 49 mL of blood may be drawn. (If needed, specimen 
collection for genetic analysis may be collected at any point during the trial.) 
 
Measures will be taken to protect the identity of the blood sample donor by de-identifying the 
biospecimen samples at the enrollment site. The link between the participant's name and the 
numeric code will not be available to staff managing samples at the biorepository, or any 
investigative personnel requesting samples. Strict confidentiality and maintenance of the chain of 
custody will be observed in the collection and storage of biospecimens. Complete details of the 
biorepository protocol are provided in the MOO. 
 
8.5 
Medication Adherence 
To assess medication adherence, a 4-item modified Morisky adherence survey (Likert scale 
responses to 4 questions)57-60 will be completed at the randomization visit, 6 month visit, and all 
subsequent visits. 
 
8.6 
Lifestyle Assessment 
To assess each participant’s readiness to change health-related behaviors, study coordinators will 
use questionnaires developed by the Patient-centered Assessment and Counseling for Exercise and 
nutrition (PACE) program. Responses to these brief surveys will be used to tailor counseling for 
lifestyle change. These assessments will occur at randomization, 3 months, 12 months, annually, 
and at the closeout visit. 
 
8.7 
Quality of Life Assessment 
To quantify 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. 
 
8.8 
Economics Assessment 
 
As a measure of medical utilization, resource utilization data, including hospitalizations, emergency 
department visits, and selected cardiac procedures and tests will be collected by the Site 
Coordinators at each ISCHEMIA 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 


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clinical endpoints and quality of life data, to calculate the net incremental cost and quality-adjusted 
life expectancy associated with the invasive strategy and the resulting within-trial incremental cost- 
effectiveness ratio. Details are provided in the MOO. 


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9. 
SCHEDULE OF ASSESSMENTS 
 
Overview of Visits 
 
All participants will undergo eligibility screening, informed consent and randomization procedures. 
Participants will undergo CCTA according to criteria in section 5.5 and the MOO. 
Follow-up in randomized participants will occur at 1.5, 3, 6, and 12 months following randomization 
during the first year and every 6 months thereafter, with clinic visits, phone follow-up, and other 
testing as described below (See Table 2 for complete assessment schedule). The schedule of 
assessments (Table 2) specifies the preferred method of contact for each visit. Six-month visits may 
be via telephone or email, depending on participant stability, risk factor control, and the participant’s 
distance from the clinic (“geography”) (see Table 2). In the event that a scheduled clinic visit is not 
possible, to ensure participant follow-up other forms of contact should be used, such as telephone, 
email, communication from a personal physician, other allied health professional, or family member, 
or review of electronic health record or public records. After the first year, participants will be 
followed every 6 months until the end of the trial, at which time sites will be notified to perform a 
closeout visit. 
 
Dependent on additional funding, telephone or email follow-up every 6 months or ascertainment of 
database information on vital status may continue after all clinic visits have been completed, unless 
prohibited by local regulations. At these long-term follow-up contacts, information on current health 
and medications, and interval hospitalizations will be collected. 
 
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 no obstructive 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. All participants, including those excluded based on CCTA or 
ischemia 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.  For the ISCHEMIA-CKD ancillary trial, only the Brief/Symptom/QOL questionnaire 
is required, the Full QOL questionnaire will not be collected. 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 (not applicable to the ISCHEMIA-CKD ancillary trial). 
 
Collection of economic and QOL data may be capped within any subgroup or overall if needed 
based on achieved power and operational needs. 


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Table 2 
Schedule of Study Assessments and Procedures (see Manual of Operations for visit windows) 
 
Screening visit 
CCTA visit 
Randomization visit 
(Baseline Visit) 
Catheterization & 
PCI or CABG 
Follow up 
1.5mA 
Visit 1 
3mA 
Visit 2 
6mB 
Visit 3 
12mA 
Visit 4 
18mB 
Visit 5 
24m 
Visit 6 
B 
30m 
Visit 7 
36mC 
Visit 8 
Frequency 
beyond 36 
months 
Eligibility screen 
X 
Informed consent (including biorepository 
consent if applicable) 
X 
Creatinine and pregnancy testD 
X 
Medical History/Medical Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Cardiovascular medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Transmit Stress Test to Core LabE 
X 
NYHA* and CCS class** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q6m 
Release for medical records signed 
X 
X 
X 
X 
Q12m 
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 
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 ischemia test images (immediately following enrollment and before randomization), technical worksheets, and site interpretations/local reports from qualifying ischemia 
tests to core labs. 
F CCTA not performed if estimated glomerular filtration rate < 60ml/min (unless requested by the treating physician) and not performed in other selected participants (see 
sections 4.1 and 5.5 and MOO); Blinded CCTA images and technical worksheets will be transferred to CCTA core lab for interpretation. 
G Safety Assessment (refer to section 13.4). 
H Height is only needed at randomization, assessments only required if visit is completed in clinic. 
I Required labs include: lipids (preferably fasting) at 3 month visit then semiannually only, and HbA1c (at visit 4, 6, 8 and annually thereafter for diabetic participants. These lab 
results will be requested from the participant’s physician. If these results are not available they should be obtained by either the participant’s treating physician or study staff. 
Creatinine values obtained clinically for participants with eGFR <60 at the three month follow-up visit and annually will also be recorded. 
J Additional lab required at randomization includes complete blood count Request from participant’s physician, since it is expected that routine blood work will have been done 
within the last 6 months 
K May be requested. 
L For participants undergoing PCI: troponin and CK-MB pre-procedure and at 8-16 ± 2 hours post-PCI or at hospital discharge, whichever comes earlier. For participants 
undergoing CABG: troponin and CK-MB pre-procedure and at 18 ± 6 hours post-CABG. All biomarker measurements should be recorded on eCRF. A biomarker measurement 
should be obtained before and after all PCI and CABG procedures, whenever possible. 
M Send to ECG core lab; ECG required for all cardiac admissions and revascularizations; year 1 ECG optional (filed on site) and closeout. 
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. Not required for the ISCHEMIA CKD ancillary trial. 
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 (see protocol appendix A) will be assessed as 
potential study candidates 
 
• 
General medical and cardiac history will be reviewed for eligibility according to the 
inclusion/exclusion criteria in section 4.3 
 
• 
Willingness of both the prospective participant and their physician for participation 
throughout the study will be confirmed 
 
• 
All screened prospective participants will be recorded in the paper screening log 
 
• 
Prospective participants meeting clinical and site-based ischemia inclusion and 
exclusion criteria and interested in participating in the study will be consented for the 
study 
 
• 
Consented participants will receive a study ID number via IVRS/IXRS. These 
participants are considered “enrolled” (not randomized). 
 
• 
Creatinine testing if it has not been done within the last 90 days 
 
• 
Pregnancy test if premenopausal 
 
• 
For enrolled participants ischemia tests will be transferred electronically to the 
appropriate core laboratory. (see section 5.4) 
 
 
CCTA visit 
• 
For participants with eGFR ≥60ml/min and selected participants with lower eGFR, 
blinded CCTA will be performed (exceptions apply, see sections 4.1 and 5.5 and MOO) 
 
• 
Blinded CCTA images will be transferred to CCTA core lab for interpretation 
 
• 
Participants with eGFR <60 ml/min do not require CCTA before randomization 
(exceptions apply, see sections 4.1 and 5.5 and MOO) 
 
• 
Assessment for safety (e.g., complications of CCTA) 
 
• 
Participants excluded due to no obstructive CAD on CCTA will be considered for CIAO- 
ISCHEMIA ancillary study at participating sites (see appendix B) 
 
 
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 


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• 
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)(not applicable to 
the ISCHEMIA-CKD ancillary trial) 
 
• 
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 both CK-MB and troponin before PCI, and at 8-16 ± 2 hours post- 
PCI or at hospital discharge, whichever comes earlier, whenever possible 
- All pre- and post-procedure biomarker measurements that are obtained should 
be recorded on eCRF 


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• 
For participants undergoing CABG 
- 12 lead ECG to be performed on day 3 post-CABG or at hospital discharge 
whichever comes earlier, and as needed for chest pain 
- All pre- and post-procedure operative biomarker measurements that are obtained 
should be recorded on eCRF 
 
 
1.5 month (6 week) visit (Visit 1) 
• 
Medical status assessment 
 
• 
NYHA and CCS class (see MOO) 
 
• 
Vital signs and weight will be measured 
 
• 
Lifestyle counseling as per PACE will be performed 
 
• 
Brief symptoms/QOL assessment will be collected 
 
• 
Hospitalization assessment will be collected 
 
• 
Endpoints will be assessed 
 
• 
The study team, in collaboration with the treating physician(s), will evaluate effectiveness 
of medical therapy and optimize as needed according to guideline recommendations and 
study algorithms 
 
 
3 month visit (Visit 2) 
 
• 
Medical status assessment 
• 
NYHA and CCS class (see MOO) 
 
• 
Vital signs and weight will be measured 
 
• 
Lifestyle assessment and counseling as per PACE will be performed 
 
• 
Brief symptoms/QOL assessment will be collected 
• 
Full QOL assessment will be collected (not applicable to the ISCHEMIA-CKD ancillary 
trial) 
 
• 
Hospitalization assessment will be collected 
 
• 
Biorepository blood draw may be performed if additional funding is obtained 
 
• 
Endpoints will be assessed 


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• 
Obtain lab results from participant’s treating physician for lipids (preferably fasting). If not 
available these tests should be obtained by the participant’s treating physician or the 
study staff. Creatinine values obtained clinically for participants with eGFR <60 will be 
recorded. 
 
• 
The study team, in collaboration with the treating physician(s), will evaluate effectiveness 
of medical therapy and optimize as needed according to guideline recommendations and 
study algorithms 
 
 
6/18/30 month visits (Visits 3, 5, 7 respectively) 
 
• 
Medical status assessment 
• 
NYHA and CCS class (see MOO) 
 
• 
Vital signs and weight will be measured (only if clinic visit) 
• 
Modified Morisky medication adherence survey (see MOO) 
 
• 
Lifestyle counseling as per PACE will be performed 
 
• 
Brief symptoms/QOL assessment will be collected 
 
• 
Hospitalization assessment will be collected 
• 
Endpoints will be assessed 
 
• 
Obtain lab results from participant’s treating physician for lipids (preferably fasting). If not 
available lipid tests should be obtained by the participant’s treating physician or the  
study staff. 
 
• 
The study team, in collaboration with the treating physician(s), will evaluate effectiveness 
of medical therapy and optimize as needed according to guideline recommendations and 
study algorithms 
 
 
12/24/36 month visits (Visits 4, 6, 8 respectively) 
 
• 
Medical status assessment 
• 
NYHA and CCS class (see MOO) 
 
• 
Vital signs and weight will be measured 
 
• 
12 lead ECG will be performed and submitted to core lab only at 24 month visit. Optional 
ECG to be retained at site at 12 months 
• 
Modified Morisky medication adherence survey (see MOO) 


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• 
Lifestyle assessment and counseling as per PACE will be performed 
 
• 
Brief symptoms/QOL assessment will be collected 
• 
Full QOL assessment will be collected (until 36 months) (not applicable to the 
ISCHEMIA-CKD ancillary trial) 
 
• 
Hospitalization assessment will be collected 
 
• 
Endpoints will be assessed 
• 
Obtain lab results from participant’s treating physician for lipids (preferably fasting) and 
HbA1c for diabetic participants. If not available lipid tests should be obtained by the 
participant’s treating physician or the study staff. Creatinine values obtained clinically for 
participants with eGFR <60 will also be recorded. 
 
• 
The study team, in collaboration with the treating physician(s), will evaluate effectiveness 
of medical therapy and optimize as needed according to guideline recommendations and 
study algorithms 
 
 
Continuing Follow-Up Visits (every 6 months following the 36 month visit until close out) 
 
 
• 
Medical status assessment 
 
• 
NYHA and CCS class (see MOO) 
 
• 
Vital signs, and weight (only at every 12 month clinic visit) 
 
• 
Modified Morisky medication adherence survey 
 
• 
Lifestyle assessment as per PACE (only at every 12 month visit) 
 
• 
Lifestyle counseling as per PACE 
 
• 
Brief symptoms/QOL assessment will be collected 
 
• 
Hospitalization assessment will be collected 
 
• 
Endpoint will be assessed 
 
• 
Obtain lab results from participant’s treating physician for lipids (preferably fasting). If not 
available lipid tests should be obtained by the participant’s treating physician or the  
study staff. 
 
• 
The study team, in collaboration with the treating physician(s), will evaluate effectiveness 
of medical therapy and optimize as needed according to guideline recommendations and 
study algorithms 


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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 (not applicable to the ISCHEMIA CKD ancillary 
trial) 
 
• 
Obtain lab results from participant’s treating physician for lipids (preferably fasting) and 
HbA1c for diabetic participants. If not available from the participant’s treating physician 
these tests should be obtained by the participant’s treating physician or the study staff. 


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


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11. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
 
11.1 Sample Size Determination and Statistical Power 
 
11.1.1 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 3 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. 
 
11.1.2 Summary of Power and Precision 
 
As shown in Tables 3 and 4 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 
3 and Table 4 below. 
 
 
Table 3.   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 4.   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 3 for additional assumptions. 


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11.2 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. 
 
11.2.1 Analysis of the Primary Endpoint 
The statistical comparison of the two randomized groups with respect to the primary composite 
endpoint will be a “time-to-event” analysis, and will therefore be based on the time from 
randomization to the first occurrence of any of the components of the primary composite 
endpoint (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. 
 
11.2.2 Analysis of the Secondary Endpoints 
 
Secondary endpoints that will be evaluated include: (1) quality of life as measured by the SAQ 
Angina Frequency Scale and SAQ Quality of Life Scale; (2) composite of cardiovascular death, 
nonfatal myocardial infarction, or stroke; (3) composite of cardiovascular death, nonfatal MI, 
resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure; (4) all-cause 
death; (5) CV death (6) MI; (7) resuscitated cardiac arrest; (8) hospitalization for unstable 
angina; (9) hospitalization for heart failure; (10) stroke; (11) composite of cardiovascular death, 
nonfatal MI, stroke, resuscitated cardiac arrest, or hospitalization for unstable angina or heart 
failure; and (12) health resource utilization, cost, and cost effectiveness. Plans for the analysis  
of the quality of life and economic endpoints are addressed below in Sections 11.2.4 and 11.2.5. 
For other secondary endpoints, analysis will be similar to the primary endpoint, using time from 
randomization until the first occurrence of the specific secondary endpoint as the response 
variable. 
 
Unambiguous operational definitions of each study endpoint will be documented in the Clinical 
Event Committee Charter and statistical analysis plan before performing unblinded analysis. For 
MI we will specify a primary definition (adapted from the universal definition of MI61; 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. 
 
11.2.3 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.62, 63  Additional details will be finalized in cooperation with 
the DSMB and recorded in the statistical analysis plan before the first unblinded interim 
analysis. 
 
11.2.4 Quality of Life (QOL) Analysis 
All QOL comparisons will adhere to the intention-to-treat principle. For each QOL measure 
examined in this study, data analysis will proceed in several stages. First, we will provide simple 
descriptive and comparative analyses by intention-to-treat. Statistical power estimates for this 
part of our analysis, based on data collected in the COURAGE trial, show that we should have  
in excess of 99% power to detect ¼ SD differences in our 3 principal QOL measures.  Second, 
we will examine changes over time from baseline and identify the major determinants of those 
changes using regression analysis. Since there is currently no consensus in the statistical 
literature about the best way to deal with the multiple comparisons problem arising from testing 
each individual scale separately, we propose two complementary approaches. First, we will pre- 


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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. 
 
11.2.5 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. 
 
11.2.6 Interim Analysis 
 
For ethical reasons, interim examination of clinical endpoints and key safety events will be 
performed at regular intervals during the course of the trial. An independent Data and Safety 
Monitoring Board (DSMB) appointed by the NHLBI will monitor participant safety and to review 
performance of the trial (see 13.1). The primary objective of these interim analyses is to ensure 
the safety of the participants enrolled in the trial and evaluate the accumulating endpoint data by 
treatment group to test for possible differences favoring either of the two randomized 
management strategies. In addition, interim monitoring will involve a review of participant 
recruitment, compliance with the study protocol, status of data collection, an assessment of 
whether control group event rates are consistent with the rates hypothesized in the sample size 
calculations, and other factors which reflect the overall progress and integrity of the study. 


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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 
DeMets64 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.65 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.66 For this latter analysis participant follow-up will be censored at the 
last contact date or terminated after the participant’s first primary endpoint event, whichever 
occurs first. 
 
Judgment concerning the continuation of the study will involve not only the magnitude of 
observed differences between randomized strategies and degree of statistical significance, but 
also careful consideration of many other important factors including the need for precise 
parameter estimation, the overall progress and integrity of the trial (including the frequency of 
catheterization in the CON group, as discussed above), and information available from other 
studies at the time of DSMB deliberations. If a stopping boundary is crossed early in the trial, 
this result should be tempered by the knowledge that revascularization may result in early 
hazard, but long-term benefit. Although we hypothesize that outcomes will be improved by the 
INV strategy, it should be emphasized that a small treatment effect for the primary endpoint is 
not necessarily a negative result for the study. Indeed, evidence suggesting absence of a large 


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benefit from the invasive strategy would be highly important to future guidelines and clinical 
practice. However, a large sample size is required in order to derive such evidence. If the study 
were to be stopped early with less than the full sample size, the lack of statistically significant 
difference may be accompanied by wide confidence intervals and no clear conclusion might be 
possible. The DSMB will incorporate this perspective along with other considerations when 
making recommendations about continuation. 


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


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12.4 Training 
All investigational site and core lab staff authorized to enter ISCHEMIA study data will receive 
training on the EDC system. Training records will be retained by the EDC Helpdesk at the 
SDCC. 
 
12.5 Records Retention 
Study records will be maintained by the site investigators for a period of three (3) years following 
the expiration of the grant or length of time as required by local regulations, whichever is longer. 
 
12.6 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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13. 
SAFETY MONITORING PLAN 
 
13.1 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be appointed by the NHLBI to monitor 
participant safety and to review performance of the trial. A DSMB charter that outlines the 
operating guidelines for the committee and the procedures for the interim evaluations of study 
data will be developed by the NHLBI and agreed upon by the DSMB. Reports will be prepared 
regularly by the SDCC in accordance with the plan outlined in the charter and as requested by 
the DSMB chair, and will include interim analyses of primary and secondary endpoints; 
additional safety events; and other information as requested by the committee. After each 
meeting, the DSMB will make recommendations to the NHLBI and the trial leadership about the 
continuation of the study. After approval by the NHLBI director, a summary of the DSMB report 
and recommendations will be forwarded by the CCC to investigators for submission to their 
local, regional and national IRB/Ethics Committees, as applicable. DSMB reports will be the 
primary mechanism for reporting safety concerns to NIH and IRBs. 
 
13.2 Risks and Benefits 
All procedures and tests performed in this study are commonly performed in clinical practice 
and have well defined safety profiles. Furthermore, all procedures performed in this study, 
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 <60 ml/min will not undergo CCTA to minimize 
risk from this procedure in the trial, except as noted in sections 4.1, 5.5 and the MOO. Beta 
blockade, which is routinely used during CCTA, may cause bradycardia, hypotension or 
bronchospasm, and nitroglycerin can lower blood pressure and may cause headache. 


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Participants will be monitored throughout the procedure for these effects and treated if 
necessary. 
 
It is recognized that CCTA, as a 3-dimensional imaging modality, does not correlate perfectly 
with and may be more accurate for localization of a stenosis to a particular arterial segment than 
2-dimensional invasive angiography. Therefore CCTA may rarely be interpreted as showing no 
significant left main stenosis when invasive angiography shows left main stenosis >50%. 
 
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 13.1) 
 
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. 
 
13.3 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 


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Common Rule (45 CFR Part 46, Subpart A), as well as ICH Guidelines, IRBs and local 
regulations. 
 
13.4 Adverse Events Reporting by Investigators 
 
Data for monitoring participants’ safety will be captured within the EDC database as part of the 
required study data. There are no additional study-specific reporting requirements. Site 
investigators should follow usual clinical practices at their institutions for reporting serious, 
unexpected events related to standard of care medications and devices to regulatory agencies. 
 
13.5 Events to be Monitored 
Safety monitoring in ISCHEMIA 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/dialysis 
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 will be reported to the site according to the list specified in the MOO. The 
participant may be excluded from the study based on certain incidental findings (e.g., large 
aortic aneurysm or neoplasm). 
 
Cardiac catheterization and PCI: 
 
1. Severe contrast reaction such as anaphylaxis 
2. Periprocedural stroke 


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3. Emergency CABG 
4. Contrast-induced nephropathy/dialysis 
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  
11.2.6). 


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14. 
ETHICAL CONSIDERATIONS 
 
14.1 Regulatory and Ethical Compliance 
This clinical study was designed and shall be implemented and reported in accordance with the 
international conference on harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC, 
US Code of Federal Regulations Title 45 and Japanese Ministry of Health, Labor, and Welfare), 
and with the ethical principles laid down in the Declaration of Helsinki. 
 
14.2 Informed Consent Process 
 
Investigators must ensure that participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. Freely given written informed consent must be obtained from every participant or, in 
those situations where consent cannot be given by participants, their legally acceptable 
representative, prior to clinical study participation, including informed consent for study 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. 
 
14.3 Responsibilities of the Investigator and IRB/IEC/REB 
 
The protocol and the proposed informed consent forms (main consent form and genetics testing 
consent form) will be reviewed and approved by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB) at each site. A 
signed and dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB is required before site initiation. 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. 
 
14.4 Protocol Amendments 
 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by CCC, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for participant safety may be implemented prior to IRB/IEC/REB 


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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. 
 
14.5 Early Termination of the Study 
 
The CCC and NHLBI retain the right to terminate the study, a study site or an investigator at any 
time. The CCC will monitor the progress of the study. If warranted, the study may be suspended 
or discontinued early if there is an observation of safety concerns posing an unreasonable risk  
to the study population. If the study is terminated early, the CCC will provide a written statement 
to the site Principal Investigators to enable notification to site IRBs/IECs/REBs and study 
participants. The CCC will also inform the appropriate Competent Authorities. The CCC may 
terminate enrollment activity at a site, or participation in the study by the investigator and site if 
there is evidence of an investigator’s failure to maintain adequate clinical standards or failure to 
comply with the protocol. Notification of enrollment suspension or termination of the study or 
study site/investigator will be sent to the investigator and the IRBs/IECs/REBs. 


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15. 
STUDY ORGANIZATION 
 
ISCHEMIA 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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16. 
DATA ACCESS AND SHARING 
 
The Publication Committee will authorize access to study data and biospecimens (in conjunction 
with the Biorepository Committee).  Investigators must submit a proposal requesting approval   
to access ISCHEMIA 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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17. 
PUBLICATIONS POLICY: OVERVIEW 
 
Primary and secondary reports of study findings will be published in peer-reviewed journals. 
Proposals for presentations and publications incorporating data obtained from participants 
involved in the ISCHEMIA 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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18. 
ISCHEMIA-CKD Ancillary Trial 
 
The ISCHEMIA-CKD ancillary trial will enroll 1000 additional patients with advanced CKD 
(defined as those with estimated glomerular filtration rate [eGFR] <30 or on dialysis) with 
moderate to severe ischemia randomized to invasive (INV) strategy versus a conservative 
(CON) strategy. The design of the trial to randomize patients upstream of cath is advantageous 
as it will expose only 50% of participants (enrolled to INV) to contrast agent and will be the 
largest treatment strategy trial in advanced CKD patients with SIHD. 
 
The trial is designed to run seamlessly with that of the main trial but sites can opt out if they 
choose not to participate. 
 
18.1 Background 
Among patients with advanced CKD, cardiovascular disease is the leading cause of death,67, 68 
15-30 times higher than the age-adjusted cardiovascular mortality rate in the general 
population.69, 70 The projected 4-year mortality is >50% in patients with advanced CKD 71-75  and 
is worse than that for patients in the general population who have cancers, heart failure, stroke 
or MI.76 Participants with advanced CKD are 5-10 times more likely to die than to reach end 
stage renal disease (ESRD).77   Despite this, ~80% of contemporary coronary artery disease 
(CAD) trials exclude participants with advanced CKD. 78 Most of the treatments aimed at 
reducing cardiovascular events in advanced CKD are therefore extrapolated from cohorts 
without advanced CKD. Participants with advanced CKD and cardiovascular disease are 
undertreated with less frequent use of statins and revascularization therapies, and the optimal 
management approach to these patients is unknown. Participants with advanced CKD are 
notably underrepresented in contemporary trials comparing revascularization with medical 
therapy in SIHD patients, such as the Bypass Angioplasty Revascularization Investigation 2 
Diabetes (BARI 2D) trial24 or the Clinical Outcomes Utilizing Revascularization and Aggressive 
Drug Evaluation (COURAGE) trial,79 making any assessment about the efficacy of 
revascularization plus medical therapy vs. initial medical therapy alone in this cohort 
problematic. 
 
Participants with advanced CKD are at increased risk for complications of the assigned invasive 
procedure, specifically contrast-induced acute kidney injury (AKI), 80, 81 dialysis, major bleeding 
and short-term risk of death. However, there is controversy in the medical literature regarding 
the incidence (<1% to >30%), effective treatment (saline hydration, N-acetyl cysteine, or sodium 
bicarbonate) and prognosis of contrast induced AKI (<0.5% to >5% requiring dialysis).82-85 In 
addition although contrast induced AKI have been associated with increase in short-term 
mortality residual confounding in these studies makes interpretation difficult. Moreover it is 
unknown if these short-term increased risks are offset by long-term benefits. Limited 
observational study in the CKD cohort suggests a survival benefit of revascularization when 
compared with medical therapy alone long-term, 86-89 despite increase in short-term risks. 
However, the medical therapy in these trials was not optimized, drug eluting stents were rarely 
used and there is undoubtedly inherent selection and ascertainment bias with observational 
studies. The above has resulted in substantial clinical equipoise in the management of 


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these patients with the rates of revascularization of only around 10-45%.86, 88, 90 The results 
of ISCHEMIA-CKD will have profound implications for guidelines, health policy, and clinical 
practice. 
 
18.2 Objectives 
 
The primary objective for the chronic kidney disease (CKD) ancillary trial is to determine 
whether the INV strategy reduces the incidence of death or nonfatal myocardial infarction 
compared with CON in participants with advanced CKD. 
 
The 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; composite of cardiovascular death or nonfatal myocardial infarction; 
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. 
 
18.3 Study Design 
 
The study design for the CKD ancillary trial is similar to that of the main trial participants with 
eGFR 30-59, with requirement of at least moderate ischemia on ischemia testing and no 
requirement for CCTA. Participants who otherwise meet ISCHEMIA trial eligibility but with 
advanced CKD will be randomized after a qualifying ischemia test to INV vs. CON. The study 
procedure (Section 5) and management strategies (Section 6) will be similar to that of the main 
trial. Strategies to minimize the volume of contrast used and reduce the risk of contrast induced 
AKI are outlined in the MOO. The follow-up and study assessments (Section 9) are similar to 
that of the main trial. The similarities and differences in processes between the main trial and 
the CKD ancillary trial are outlined in the MOO. 
 
18.4 Statistical Consideration and Power 
 
As shown in Tables 5 and 6 below, for participants in the CKD ancillary trial, the planned sample 
size of approximately 1,000 randomized participants will result in an estimate of the hazard ratio 
that differs from the true hazard ratio by no more than a factor of 1.19 with 95% probability and 
will yield power ≥80-95% for comparing the primary composite endpoint across the two 
randomized groups assuming the 4-year cumulative rate of the primary composite endpoint is 
60% in participants randomized to CON strategy and is less by a factor of 15% to 19% (relative 
reduction) in participants randomized to INV strategy. Power and precision under other 
assumptions are summarized in Table 5 and Table 6 below. 


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Table 5. Estimated Power as a Function of the Anticipated Cumulative Event Rate in 
CON and the Cumulative Risk Reduction in INV (∆) 
CON anticipated 4-year 
event rate 
Power 
Event % 
∆ = 0.15 
∆ = 0.17 
∆ = 0.19 
45% 
56 
67 
76 
50% 
64 
75 
84 
55% 
73 
83 
90 
60% 
81 
90 
95 
65% 
88 
95 
98 
70% 
94 
98 
99 
NOTE: ∆ denotes relative reduction in 4-year event rate in INV vs. CON groups. Assumptions: Two- 
sided log-rank test with alpha = 0.05; 500 participants per group; average follow-up 3.7 years; loss-to- 
follow-up 1% per year; survival times follow exponential distribution. 
 
 
Table 6. Range of Estimated Precision (Margin of Error) as a Function of the 
Anticipated Cumulative Event Rate in CON and the Cumulative Risk Reduction in INV 
(∆) 
CON anticipated 4-year 
event rate 
Margin of Error (MOE) 
Event % 
∆ = 0.15 
∆ = 0.17 
∆ = 0.19 
45% 
1.22 
1.22 
1.23 
50% 
1.21 
1.21 
1.21 
55% 
1.20 
1.20 
1.20 
60% 
1.19 
1.19 
1.19 
65% 
1.18 
1.18 
1.18 
70% 
1.17 
1.18 
1.18 
NOTE: Margin of Error is the anti-log of the expected half-width of the 95% confidence interval for the log- 
hazard ratio. Assumptions: Based on a univariable Cox model with a binary treatment indicator and Wald- 
type 95% confidence intervals. 
 
Other aspects of the statistical consideration including contingency plan for insufficient primary 
endpoint events, QOL analysis and health economic analysis are detailed in Section 11.2 
 
18.5 Safety Monitoring Plan 
 
18.5.1 Data and Safety Monitoring Board 
 
As reported in section 13, a Data and Safety Monitoring Board (DSMB) will be appointed by the 
NHLBI to monitor participant safety and to review performance of the trial. The main trial DSMB 
with a nephrologist added to the roster will serve as the DSMB for the CKD ancillary 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. After each meeting, the DSMB will make recommendations to the NHLBI and the trial 
leadership about the continuation of the study. DSMB reports will be the primary mechanism for 
reporting safety concerns to NIH and IRBs. 
 
18.5.2 Risks and Benefits 


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All procedures and tests performed in this study are commonly performed in clinical practice 
and have well defined safety profiles. The risks and benefits are described in more detail in  
section 13.2. The risks and benefits pertaining to the CKD cohort are described below. 
 
Risks: 
Cath/PCI/CABG Risks: Each of these procedures is performed in clinical practice for patients 
who meet eligibility criteria for the CKD trial. The major risks of these procedures include death, 
myocardial infarction and stroke. Other risks of catheterization and PCI include severe contrast 
reaction such as anaphylaxis, emergency CABG, bleeding, need for blood transfusion, contrast- 
induced AKI, AKI requiring dialysis and vascular access site complications including 
pseudoaneurysm, AV fistula, retroperitoneal bleed or infection. Other risks of CABG include 
return to operating room for bleeding, need for blood transfusion, infection, prolonged intubation, 
mediastinitis, AKI, AKI requiring dialysis and atrial fibrillation. Risks of these procedures vary in 
likelihood based on the patient’s risk profile and are generally higher in the CKD cohort than in 
participants without CKD. 
 
Risk Lowering Measures: 
 
The risk of cath and revascularization will be minimized by the selection of experienced 
operators who meet study certification criteria. Strategies to minimize the volume of contrast 
used and reduce the risk of contrast-induced AKI are outlined in the MOO. These risks are 
justified by the potential benefit (long-term reduction in events resulting from revascularization, 
as discussed in the background section). Moreover, a nephrologist will be involved in the care of 
the participants. 
 
Study procedures are designed to manage and minimize risks through careful selection of the 
patients who participate in the trial. Participants will be monitored closely through the trial at 
many time points to check on their health. In addition, an independent DSMB will monitor safety 
of the participants throughout the study (see section 13.1) 
Benefits: 
 
The ISCHEMIA-CKD trial results should provide evidence based data to support management 
of participants with CKD and SIHD. It is hoped the knowledge gained will be of benefit to others 
with a similar medical condition in the future. 
 
18.5.3 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. 
 
18.5.4 Events to be Monitored 
 
Safety monitoring for the CKD ancillary trial will be similar to ISCHEMIA and will be concerned 
with estimating event rates for the following types of clinical events: 


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1. Complications of cardiovascular tests (e.g. cardiac catheterization) and therapeutic 
procedures (e.g. PCI, CABG) 
2. Events occurring in the time period between consenting to participate in the trial and 
being randomized. 
3. Study endpoints. 
Details of the events to be monitored are outlined in section 13.5. The events to be monitored 
which are of special interest for the CKD ancillary trial are described below. 
 
Complications of cardiovascular therapeutic procedures 
All therapeutic procedures to be used in this trial have been extensively evaluated previously, 
have established safety profiles with known risks and benefits and are used in clinical practice. 
Events listed below occurring within 72 hours of the procedure will be considered as a 
complication of the procedure.  Some safety events related to specific tests and procedures 
captured within EDC, in addition to death and MI, include: 
 
Cardiac catheterization and PCI: 
 
1. Severe contrast reaction such as anaphylaxis 
2. Periprocedural stroke 
3. Emergency CABG 
4. AKI 
5. AKI requiring dialysis 
6. Vascular access site complications including pseudoaneurysm, AV fistula, 
retroperitoneal bleed 
 
CABG: 
1. Return to operating room for bleeding 
2. Prolonged intubation 
3. Mediastinitis 
4. Atrial fibrillation 
5. AKI requiring dialysis 
In addition the incidence of finding significant LM stenosis (>50%) on cardiac catheterization will 
be monitored and reported to the DSMB. 
 
18.6 Adjudication of Clinical Events (See Section 10) 
18.7 Data Handling and Record Keeping (See Section 12) 
18.8 Ethical Consideration (See Section 14) 
18.9 Study Organization (See Section 15) 
18.10 Data Access and Sharing (See Section 16) 
18.11 Publication Policy (See Section 17) 


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Chertow GM, Normand SL, McNeil BJ. "Renalism": inappropriately low rates of coronary 
angiography in elderly individuals with renal insufficiency. Journal of the American Society of Nephrology 
: JASN 2004; 15(9): 2462-8. 
84. 
James MT, Ghali WA, Knudtson ML, et al. Associations between acute kidney injury and 
cardiovascular and renal outcomes after coronary angiography. Circulation 2011; 123(4): 409-16. 
85. 
Rudnick MR, Goldfarb S, Wexler L, et al. Nephrotoxicity of ionic and nonionic contrast media in 
1196 patients: a randomized trial. The Iohexol Cooperative Study. Kidney international 1995; 47(1): 254- 
61. 


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86. 
Keeley EC, Kadakia R, Soman S, Borzak S, McCullough PA. Analysis of long-term survival after 
revascularization in patients with chronic kidney disease presenting with acute coronary syndromes. Am 
J Cardiol. 2003; 92(5): 509-14. 
87. 
Hemmelgarn BR, Southern D, Culleton BF, Mitchell LB, Knudtson ML, Ghali WA. Survival after 
coronary revascularization among patients with kidney disease. Circulation. 2004; 110(14): 1890-5. 
88. 
Reddan DN, Szczech LA, Tuttle RH, Shaw LK, Jones RH, Schwab SJ, et al. Chronic kidney disease, 
mortality, and treatment strategies among patients with clinically significant coronary artery disease. J 
Am Soc Nephrol. 2003; 14(9): 2373-80. 
89. 
Hannan EL, Samadashvili Z, Cozzens K, Walford G, Jacobs AK, Holmes DR, Jr., et al. Comparative 
outcomes for patients who do and do not undergo percutaneous coronary intervention for stable 
coronary artery disease in New York. Circulation. 2012; 125(15): 1870-9. 
90. 
Szummer K, Lundman P, Jacobson SH, Schon S, Lindback J, Stenestrand U, et al. Influence of 
renal function on the effects of early revascularization in non-ST-elevation myocardial infarction: data 
from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart 
Disease Evaluated According to Recommended Therapies (SWEDEHEART). Circulation. 2009; 120(10): 
851-8. 


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20. 
APPENDIX A 
 
Ischemia Test Eligibility Criteria 
 
Specific criteria for each modality were developed and refined based on data indicating that the 
risk of cardiovascular events based on inducible ischemia is consistent with that targeted in this 
trial. Criteria were harmonized across modalities in order to yield a similar risk of cardiovascular 
death or MI regardless of the type of stress test performed.1 
Table: Criteria for at least Moderate Ischemia by Stress Test Modality2 
 
Test Modality 
Diagnostic criterion 
Nuclear perfusion via 
SPECT or PET3 
≥10% myocardium ischemic 
Echo3 
≥3/16 segments with stress-induced severe hypokinesis 
or akinesis 
CMR3 
Perfusion: ≥12% myocardium ischemic 
and/or 
Wall motion: 
• 
≥3/16 segments with stress-induced severe 
hypokinesis or akinesis 
Exercise Test without 
Imaging 
(Criteria 1-4 must all be 
met) 
1. Clinical history of typical angina or typical angina 
during the exercise test 
2. Absence of resting ST segment depression ≥1.0 mm 
or confounders that render exercise ECG non- 
interpretable (LBBB, LVH with repolarization, 
pacemaker, etc.) 
3. As compared to the baseline tracing, additional 
exercise-induced horizontal or downsloping ST 
segment depression ≥1.5 mm in 2 leads or ≥2.0 mm 
in any lead; ST segment elevation ≥1mm in a non- 
infarct territory. Both the J-point and the ST segment 
at 80 msec. need to meet criteria. When the HR is 
>130/min, the ST segment at 60 msec. may be used 
if the segment at 80 msec. cannot be determined. 
4. Either of the following: 
a. Peak workload not to exceed completion of 
stage 2 of a standard Bruce protocol or <7 
METS if a non-Bruce protocol is used or 
b. ST segment criteria are met at <75% of the 
maximum predicted HR 
SPECT=single photon emission computed tomography, PET=positron emission tomography; Echo= 
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1 Shaw L, Berman D, Stone G, Picard M, Friedrich M, Kwong R, et al. Comparative definitions 
for moderate-severe ischemia in stress nuclear, echocardiography, and magnetic resonance 
imaging. JACC Cardiovasc Imaging (in press). 
 
 
2Additional criteria may be required for confirmation of obstructive coronary artery disease, 
depending on eGFR and type of ischemia test. See Section 5.5. 
 
3Ancillary findings may also be included in the core lab determination of severity of ischemia by 
imaging (see MOO). 
 
Note the exclusion criterion: Patient who, in the judgment of the patient’s physician, is likely to 
have significant unprotected left main stenosis will be excluded (see Section 4.3.1). 


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21. 
APPENDIX B  CIAO-ISCHEMIA Ancillary Study 
 
 
 
21.1 Background 
 
The relationship between ischemia, symptoms and atherosclerosis in patients without 
angiographically obstructive CAD remains to be fully elucidated. It is not known whether 
persistent chest pain represents ongoing ischemia, nor to what extent subgroups of patients 
with persistent chest pain, ischemia on imaging and greater atherosclerotic burden overlap. 
 
Angina and ischemia may not be correlated. Angina frequency and duration are similar among 
patients with and without ischemia on noninvasive testing.1 Small treatment trials have been 
undertaken showing improvement of angina that was not reflected in objective measurement of 
ischemia, though these studies were markedly underpowered for that comparison.2,3 Treatment 
for patients with symptoms and/or ischemia without obstructive CAD is highly variable in clinical 
practice.4 Guidelines focus on symptom management. 
 
 
21.2 Objectives 
 
This ancillary study will investigate the association between changes in ischemia over one year 
and changes in angina over one year in participants excluded from the main ISCHEMIA study 
based on the absence of obstructive CAD on the study CCTA. If the study finds that angina and 
ischemia vary together over time, symptoms in these patients are likely due to ischemia and not, 
for example, altered pain sensitivity. Alternatively, the study may find the trajectories of angina 
and ischemia are not associated and in this case, therapy might be better targeted to relief of 
ischemia than symptoms in these patients. Further, in this case it would be concluded that 
symptoms were not due to ischemia in some or all patients and ischemia was either silent or 
represented a false positive finding. 
 
21.2.1 Primary Specific Aim 
 
The primary aim of the CIAO-ISCHEMIA ancillary study is to investigate the association 
between change in angina severity and change in ischemia severity on stress wall motion 
imaging over one year in female and male patients with an initial finding of moderate-severe 
ischemia and with no obstructive CAD on CCTA. Severity of angina will be characterized by the 
Seattle Angina Questionnaire and severity of ischemia by the number of ischemic segments on 
stress wall  motion imaging. Changes in angina severity and stability of the finding of moderate- 
severe ischemia over one year will be described. Correlates of change in angina over time will 
be identified. Selection of core-lab confirmed moderate-severe ischemia is expected to reduce 
the likelihood of including patients with false positive tests 
 
21.2.2 Other Specific Aims 
 
• 
To determine the effect of medication classes selected by treating physicians on angina 
and change in ischemia over one year in this cohort 
• 
To  assess  the  relationship  between  change  in  ischemia  and  change  in  angina  in 
selected subgroups (by sex, age, presence/severity of atherosclerosis) 
• 
To  assess  the  relationship  between  severity  of  non-obstructive  atherosclerosis  and 
ischemia at baseline 


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• 
To  assess  the  relationship  between  severity  of  non-obstructive  atherosclerosis  and 
angina at baseline 
• 
To assess the relationship between severity of ischemia and angina at baseline. 
 
In addition the association of severity of ischemia with cardiovascular events over one year 
(death, MI, stroke, CV hospitalization/ER visits) will be assessed. 
 
21.3 Study Design and Procedures 
 
21.3.1 Study Population and Eligibility Criteria 
 
Refer to section 4.3 of the main ISCHEMIA protocol for all inclusion and exclusion criteria for the 
main study. Participants to be considered for this ancillary study will already have met ischemia 
(stress echo*) and coronary anatomic (CCTA) entry criteria for the main ISCHEMIA study and 
will be interested in participating in research as demonstrated by consent to the main study. 
This approach will maximize enrollment in the ancillary study. 
 
Only participants enrolled after stress echocardiography in the main ISCHEMIA study at 
participating sites, and who are not randomized due to the absence of obstructive CAD on 
CCTA will be considered for this ancillary study (see Figure 3)*. Participants enrolled in the 
CIAO-ISCHEMIA ancillary study are also required to have ischemic symptoms (chest pain or 
other potential ischemic equivalent). 
 
A total of 300 participants will be enrolled. 
 
Figure 3. Flow of participants into the CIAO-ISCHEMIA ancillary study 
 
 
* The study may be expanded to include stress CMR wall motion imaging based on enrollment; 
see MOO for details. 
21.3.2 Informed Consent Process 
 
ISCHEMIA anatomic screen failure patients due to non obstructive CAD will be approached for 
inclusion in this ancillary study.  These patients will be presented with an informed consent form 
which describes in detail the CIAO-ISCHEMIA ancillary study and what participating in the study 
means. The informed consent form will be signed by those patients who agree to participate in 
this ancillary study. 


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21.3.3 Study Flow 
 
Repeat stress wall motion imaging will be performed at one year. Symptoms will be assessed 
using the SAQ at 6 months and one year. Participants will be routinely treated for their condition 
according to standard of care guidelines and in accordance with local practice. Medical therapy 
will not be specified by this ancillary study. Events will be collected and monitored, including 
hospitalization for angina, hospitalization for heart failure, death, MI, stroke/TIA. 
 
21.3.4 Schedule of Study Assessments 
 
Data collected during screening for the main ISCHEMIA study will be used by the CIAO- 
ISCHEMIA ancillary study. This data includes general medical and cardiac history which was 
collected to determine eligibility for the main ISCHEMIA study. The stress imaging study that 
was used to determine eligibility for the main ISCHEMIA study, and transmitted to the Stress 
Core Laboratory, will also be used for the CIAO-ISCHEMIA ancillary study. 
 
Baseline Visit 
• 
Patients who have not been randomized to the main ISCHEMIA study will be assessed 
as potential CIAO-ISCHEMIA ancillary study candidates 
• 
General medical and cardiac history will be reviewed for eligibility according to the 
eligibility criteria described above 
• 
Informed consent will be obtained from patients who are willing to participate in this 
ancillary study. 
• 
If Stress Core Lab interpretation has not already been done (by the time of exclusion 
from the main ISCHEMIA study) it will be done at this time. 
• 
Coronary non-obstructive plaque scoring will be performed based on the CCTA 
interpretation provided by the CCTA Core Lab for the main ISCHEMIA study 
• 
Physical exam 
• 
Concomitant medications will be reviewed and recorded including use of beta-blockers, 
calcium channel blockers, long-acting nitrates, ranolazine, ivabrandine/other anti- 
anginals, statins, other lipid-lowering agents, aspirin, other anti-platelets 
• 
Symptom assessment including the SAQ and CCS Class 
• 
Event assessment and ascertainment including: death, myocardial infarction, unstable 
angina, stroke, cardiovascular hospitalizations, cardiac catheterization, and coronary 
revascularization procedures (PCI or CABG) 
 
Visit 2 (6 month follow-up) 
• 
Concomitant medications will be reviewed and recorded including use of beta-blockers, 
calcium channel blockers, long-acting nitrates, ranolazine, ivabrandine/other anti- 
anginals, statins, other lipid-lowering agents, aspirin, other anti-platelets 
• 
Symptom assessment including the SAQ and CCS Class 
• 
Event assessment and ascertainment including: death, myocardial infarction, unstable 
angina, stroke, cardiovascular hospitalizations, cardiac catheterization, and coronary 
revascularization procedures (PCI or CABG) 
 
End of Study (1 year follow-up) 
• 
Repeat stress echocardiogram (or CMR if the study is expanded to include CMR; see 
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• 
Transmittal to and interpretation by the Stress Core Lab of the repeat stress imaging test 
• 
General medical and cardiac history 
• 
Physical exam 
• 
Concomitant medications will be reviewed and recorded including use of beta-blockers, 
calcium channel blockers, long-acting nitrates, ranolazine, ivabrandine/other anti- 
anginals, statins, other lipid-lowering agents, aspirin, other anti-platelets 
• 
Symptom assessment including the SAQ and CCS Class 
• 
Event assessment and ascertainment including: death, myocardial infarction, unstable 
angina, stroke, cardiovascular hospitalizations, cardiac catheterization, and coronary 
revascularization procedures (PCI or CABG) 
 
 
Figure 4: Schedule of Assessments for CIAO-ISCHEMIA ancillary study 
 
Main 
Trial 
Ancillary 
Study 
Baseline Visit 
6 month 
follow 
up3 
1 year 
follow 
up 
Main Trial Consent 
X 
Ancillary Study Consent 
X 
X¹ 
Inclusion/exclusion Criteria assessment 
X 
X 
Stress Echocardiogram2 
Acquisition 
X 
X 
Transmittal to core lab 
X 
X 
Core lab interpretation 
X 
X 
X 
Coronary CTA showing no obstructive CAD (core lab interpretation) 
X 
Coronary non-obstructive plaque scoring based on core lab interpretation 
X 
History and physical 
X 
X 
Concomitant medications 
X 
X 
X 
Symptom assessment (including SAQ and CCS class) 
X 
X 
X 
Event ascertainment 
X 
X 
X 
 
1If not done with main study consent. 2Or stress CMR, if permitted per the MOO.3May be conducted in 
person or by telephone per participant preference. 
 
See MOO for acquisition of 1-year stress imaging test. Data will be collected in InForm, using 
the same participant number which was assigned at the time of enrollment in the main study. 
 
 
21.4 Statistical Considerations 
 
21.4.1 Analysis of the Primary Specific Aim 
 
Primary Analysis 
 
The primary goal of this study is to examine the association between change in angina severity 
as measured by the SAQ (continuous scale) and change in severity of ischemia as estimated by 
stress wall motion imaging and quantified by the number of ischemic segments (nIS; ordinal 
categorical scale) from baseline to one year. It is hypothesized that changes in ischemia and 
angina over time will be associated, because angina is hypothesized to be due to ischemia in 
these patients. Alternatively, if ischemia resolves as symptoms continue (including symptoms 


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which may be considered refractory to medical therapy), we will conclude that symptoms are not 
due to ischemia. If symptoms resolve but ischemia continues, then either a partial response 
occurred or symptoms were not due to ischemia. All participants will have nIS ≥3 at baseline 
due to selection criteria. For primary analysis, ischemia at one year will be categorized as 
improved (nIS at baseline minus nIS at 1 year is >1) or not improved (nIS at baseline minus nIS 
at 1 year is ≤1) for all participants with paired data available. This cutpoint of 2 segments with 
resolution of inducible severe hypokinesis or akinesis was selected to minimize the potential 
effects of intra/interobserver variability. 
 
Secondary Analyses 
 
Secondary analyses will be performed using change in ischemia (nIS at one year minus nIS at 
baseline) as an ordinal categorical variable. The association between change in ischemia and 
change in angina will be examined based on a one-way analysis-of-variance (ANOVA) 7 model, 
a regression model (e.g., the proportional odds model) and/or logistic regression to estimate the 
probability of at least moderate angina improvement across categories of ischemia 
improvement. Sensitivity analysis will be used to assess the validity of study results. Best-case 
and worst-case scenarios will be considered for imputing the missing values for both nIS and 
SAQ, resulting in a range of estimates for the association. Given a consistent range of the 
estimates, the study results will be considered reliable and unaffected by the missing data. The 
CCC will work with sites to minimize loss to follow up. The 1-year mortality rate is expected to  
be very low (e.g., 0-2 participants). Predictors of death and loss to follow up will be analyzed. 
 
Sample Size and Power 
 
Sample size calculations are based on the primary analysis, taking into account the likelihood 
that severity of ischemia at baseline will not be normally distributed based on selection criteria 
(at least 3 segments with ischemia) and early trial data showing that ~40% of patients are likely 
to have moderate (as opposed to severe) ischemia on the baseline stress imaging test. 
Participants will be categorized based on 1-year improvement in ischemia or no improvement, 
as discussed. Taking into consideration 10% estimated dropout or death rate, use of the two- 
sided Mann-Whitney test, equal groups and a projected standard deviation of the change in 
SAQ score of 21 based on prior literature, the sample size of 300 participants will provide 80% 
power to detect a difference of 7.3 in SAQ score between those with and without improvement 
in ischemia over one year, at the 0.05 significance level. This difference size is less than the 
previously described clinically meaningful effect size of 8-10 for the SAQ physical limitation 
score and 10-20 for the angina frequency score. In the same setting, the study has 90% power 
to detect an 8.4 difference in SAQ score between those with and without improvement in 
ischemia at one year with a sample size of 300 and 80% power to detect a difference of 8.5 with 
a sample size of 220. 
 
Additional Analysis 
 
To determine the stability of ischemia over one year, we will calculate the proportion of patients 
whose ischemia has resolved (nIS at one year is zero), improved (nIS at baseline minus nIS at 
1 year is >1), or did not improve (nIS at baseline minus nIS at 1 year is ≤1). Results will be 
expressed as percentages and reported with 95% binomial confidence intervals. 
 
To assess angina severity at baseline and over one year, descriptive statistics at baseline and 
at  1 year  will be  presented using  appropriate measures  of  center  (mean or  median)  and 


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variability (standard deviation or interquartile range) overall and with stratification by sex. 
Changes in angina will be examined using paired t-test or a non-parametric alternative 
(Wilcoxon signed rank test10) depending on whether angina severity measures have normal 
distribution. Changes of angina severity on categorical scale will be examined using chi-square 
tests and exact tests of proportions (such as Binomial or Fisher’s exact test). 11 
 
21.4.2 Analysis of Other Specific Aims 
 
Effect of medication classes on angina and change in ischemia 
Summary statistics will be used to present frequency of medication use by type of medication 
and/or by change in angina and change in ischemia. Medications will be classified as anti- 
anginal (beta blockers, calcium channel blockers, long-acting nitrates, ranolazine, ivabradine, 
other anti-anginals) or anti-atherosclerotic (aspirin or statin). To explore the impact of 
medication, we will first examine association between change in angina and change in ischemia 
in subgroups of patients defined based on whether or not any medication in the grouping (anti- 
anginal or anti-atherosclerotic) was reported by the patient during follow up. Follow up 
medications will be used rather than baseline medications based on prior research showing that 
physicians frequently stop medications after learning of the absence of obstructive CAD.4,12 It is 
hypothesized that anti-anginal, but not anti-atherosclerotic, medications will lead to less angina 
and less ischemia. Next, we will examine whether medication groups modify the relationship 
between change in angina and change in ischemia based on ANOVA10. In this analysis, change 
in angina is a response variable. Additional analyses will be performed to examine the main, 
additive, and interactive effects of medication and change in ischemia. In investigating these 
effects, our analysis may focus on the one most frequently used medication, to improve power. 
Multivariate adjustments for clinically important variables (e.g., age, sex, characteristics of initial 
test) will be considered. 
 
Relationship between change in angina and change in ischemia in subgroups 
This association will be examined in subgroups of participants categorized by sex, age, 
presence or absence of atherosclerosis on CCTA performed for the main study, and 
characteristics of the initial stress  test (e.g., use of exercise or dobutamine during  stress 
testing). This may provide insight into the reasons for an association between change in angina 
and change in ischemia if it is present, or may identify a subgroup in whom the two are 
associated if the primary analysis does not identify a significant association between these two 
change variables. 
 
Baseline relationship between severity of non-obstructive atherosclerosis and 
severity of ischemia 
Non-obstructive atherosclerosis severity in each vessel is defined on a categorical scale with 
three levels based on CCTA core lab interpretation according to guidelines (i.e., 0 stenosis, 1- 
24% stenosis, 25-49% stenosis). From this information, a composite score representing severity 
of non-obstructive atherosclerosis throughout the coronary tree will be calculated according to 
the methods of Lin et al.13: each of 16 coronary segments will be assigned a score of 0 for no 
atherosclerosis or 1 for 1-49% stenosis in the segment. The sum of the segment scores will be 
the global atherosclerosis score, which varies from 0-16. Although the sensitivity of CCTA for 
“significant” plaque vs. no significant plaque is lower in distal segments, the ability of CCTA to 
distinguish between the absence of plaque and the presence of non-obstructive plaque is 
excellent, ~97%.14 
 
Descriptive analysis will be used to present location of ischemia and severity of non-obstructive 
atherosclerosis  at  baseline.  For  this  descriptive  analysis,  atherosclerosis  severity  will  be 


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presented by vessel (using categories as above) and based on the global atherosclerosis score. 
The relationship between atherosclerosis severity and ischemia severity will be examined using 
tests of proportions, such as chi-square tests and exact tests.11 In addition, the relationship 
between the global atherosclerosis score and severity of ischemia will be examined using 
ANOVA and multinomial logistic model, proportional odds model or cumulative logits model. 
Alternatively, multinomial logistic model may elucidate an effect of the global atherosclerosis 
score on ischemia severity. Similarly, tests of proportions will be used to examine whether the 
ischemic segments on the stress imaging study correspond to the artery with the worst stenosis 
(e.g. test if the proportion of correspondences is significantly different from zero). 
 
For this analysis, we will not attempt to match location of ischemia to location of non-obstructive 
atherosclerosis. Although this analysis would be of interest, it is quite complicated. In the simple 
case of anterior wall ischemia and atherosclerosis in the LAD alone, it would be clear that 
location of atherosclerosis and ischemia matched. However, ischemia may be identified in 
multiple coronary territories, and atherosclerosis is frequently present in multiple vessels. We 
considered matching location based on the most severe non-obstructive stenosis, but it is likely 
that multiple vessels will be categorized as having 25-49% stenosis in some patients in whom 
only one coronary territory is ischemic, and in that case it would be unclear whether location of 
ischemia matched the vessel with the greatest degree of atherosclerosis. Based on these and 
other permutations, we elected not to examine this association in this proposal. 
 
Relationship between severity of non-obstructive atherosclerosis and severity of angina 
at baseline 
The relationship between severity of non-obstructive atherosclerosis on a continuous scale 
(global score) and severity of angina at baseline (SAQ score) will be explored using linear 
regression models. Nonparametric alternatives and appropriate transformations will be 
considered. Next, multivariate linear regression model will be used to examine the relationship 
between location & severity of non-obstructive atherosclerosis and severity of angina (response 
variable). Multivariate adjustments for clinically important variables will also be considered. 
 
Relationship between severity of ischemia and severity of angina at baseline 
This analysis will follow schemes described above. 
 
 
21.4.3 Analysis of Events 
 
We will explore the association of severity of angina, ischemia and atherosclerosis with 
cardiovascular events over 1 year. This analysis will be based on a composite outcome: death, 
MI, stroke, CV hospitalizations/ER visits. The projected composite event rate is projected to be 
10% over one year. Events will be ascertained by sites according to definitions specified in the 
manual of operations. CV hospitalization and ER visits are expected to be the most common 
events. Regardless of any independent confirmation, if patients present to hospitals with chest 
pain/ischemic symptoms, this is an important outcome to the health care system. Summary of 
mortality predictors: Depending on the number of events, we will consider examining the 
association with other components of this composite outcome (e.g., death). Descriptive analysis 
will be used to present baseline severity of angina, ischemia and atherosclerosis in subgroups 
defined based on the occurrence of cardiovascular events over one year. Appropriate tests of 
means (two independent samples t-test or Wilcoxon test) and proportions (Chi-square or 
Fisher’s exact) will be used to examine differences. Univariate logistic regression models will be 
used to study main effects of severity of angina, ischemia and atherosclerosis on the  
occurrence of the composite cardiovascular event. Additive and interactive effects of these 


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factors will be studied based on multivariate logistic regression model. Some covariates, such 
as chest pain, will be included in the model as time-dependent covariates. Adjustments for 
clinically important variables will also be considered. 
 
Power for analysis of events 
 
Considering two groups of patients (based on severity of ischemia) and estimating that the 
event rate in one group is 10%, with 150 participants in each group, the two-sided two sample 
Fisher’s exact test will have 62% power to detect an absolute increase in the composite event 
rate of 10% in patients with more severe ischemia, at the 0.05 significance level.15 Due to low 
power, these analyses are considered exploratory and hypothesis-generating. Precision for the 
event rate is estimated as follows: the projected 95% CI for a projected event rate of 10% with 
300 patients would be 0.068, 0.140. 
 
 
21.4.4 Descriptive Analysis 
 
Characteristics of study participants will be summarized overall and within important subgroups 
(e.g. by sex). Differences across subgroups will be assessed using T-tests/F-tests for 
continuous variables (e.g. age) and chi-square tests for categorical variables.11 The frequency 
of missing data will be summarized for  baseline and follow-up data. Missing data will be 
investigated by inferring a relationship between baseline characteristics and a 0-1 indicator that 
defines whether a measurement is observed. The analysis may help identify factors likely to 
cause measurements to be missing. These analyses will be based on logistic regression model. 
Baseline characteristics will be summarized as percentages for categorical variables and 
appropriate measures of center (mean or median) and variability (standard deviation, 25th and 
75th percentiles (interquartile range) for continuous variables. In all of the proposed analyses, 
assumptions will be checked, and non-parametric approaches will be used if assumptions are 
violated. Multiple comparisons will be addressed by pre-specifying a single primary endpoint for 
each aim, and other comparisons will be given a secondary status. 
 
 
21.5 Data and Safety Monitoring Plan 
 
21.5.1 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 study. Any serious, study related, and 
unexpected events will be reported to the NIH and the DSMB in an expedited fashion. 
 
 
21.5.2 Risks and Benefits 
 
Risks 
 
All procedures and tests performed in this ancillary study are commonly performed in clinical 
practice and have well defined safety profiles. Furthermore, all procedures performed in this 
study are commonly performed for the patient population enrolled in the study. 
The main potential risk in this study is risk of stress imaging. Each participant will already have 
undergone stress wall motion testing safely at baseline before main study inclusion. Local 
investigators will assess participants for safety to undergo stress imaging before scheduling the 
procedure. A very rare but major risk is myocardial infarction and death which happens in less 


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than 1 in 10,000 procedures. Other side effects during the procedure are chest pain, irregular 
heartbeat, dizziness and nausea. Per clinical routine, a physician and/or cardiac nurse will 
supervise the stress test at sites, including monitoring of hemodynamics and symptoms during 
the test. 
 
Risk Lowering Measures: 
 
Study procedures are designed to manage and minimize risks through careful selection of the 
patients who participate in the study. Participants will be monitored closely through the study to 
check on their health. In addition, an independent DSMB will monitor safety of the participants 
throughout the study (see section 13.1 of the main ISCHEMIA protocol). There is no radiation 
exposure based on this protocol. 
 
Benefits 
 
The CIAO-ISCHEMIA ancillary study results should provide evidence based data to support 
management of patients with symptoms and/or ischemia without obstructive CAD. 
 
The one year stress imaging test will be made available for clinical care and may prove useful 
for risk stratification for future events.16 
Adverse Event Monitoring 
 
Study-related serious adverse events (SAEs) will be collected on an eCRF which will be part of 
the overall study’s InForm™ database and will ultimately be reviewed by the DSMB. The DSMB 
will report on all serious and unexpected adverse events or other unanticipated problems that 
involve risk to study participants or others at any site, and whether these appear to be related to 
the study-based interventions or research assessment protocols. 
 
 
21.6 Data Handling and Record Keeping 
 
21.6.1 Data Collection, Management and Security 
 
The same data handling principles apply to the CIAO-ISCHEMIA ancillary study as were 
described in the main ISCHEMIA protocol (see section 12 of the main ISCHEMIA protocol for 
complete details). The same web-based EDC system as in the main ISCHEMIA study, InForm, 
will be used for this ancillary study 
 
Also, the same unique patient identification number assigned by the interactive voice-response 
system (see section 5.3 of the main ISCHEMIA protocol) at the time of main ISCHEMIA study 
enrollment will be used for the CIAO-ISCHEMIA ancillary study database to reduce the potential 
for error and facilitate use of data from the main ISCHEMIA study database to reduce workload. 
 
The CIAO-ISCHEMIA eCRF will record relevant history, symptoms, physical exam, stress 
imaging studies, vital signs, and clinically ordered laboratory results. Instructions regarding 
collection of these data elements will mirror those in the main ISCHEMIA study; all of the data 
elements to be collected are also collected in the main ISCHEMIA study. 
 
Imaging studies will be uploaded by the site using a commercially available internet-based 
secure server with a software package that de-identifies the DICOM header for the study and 


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assigns the unique study identifier. Images will be distributed from this server to the stress 
imaging core lab for interpretation, as is done in the main ISCHEMIA study. 
Follow-up visits will be made in person or by telephone to determine symptom status, any re- 
hospitalizations or ER visits. Attempts to collect follow-up data will be made for all except those 
who specifically withdraw consent for release of such information. 
Hospitalization records will be obtained, and extracted, by site staff for completion of 
subsequent hospitalization report form (eCRF). 
 
21.7 Ethical Considerations 
 
The CIAO-ISCHEMIA ancillary study will uphold the same ethical and regulatory conditions as 
the main ISCHEMIA study (see section 14 of the main ISCHEMIA protocol). 
 
 
21.8 References 
 
1. 
Olson MB, Kelsey SF, Matthews K, et al. Symptoms, myocardial ischaemia and quality 
of life in women. European Heart Journal. August 1, 2003 2003;24(16):1506-1514. 
 
2. 
Merz CNB, Olson MB, McClure C, et al. A randomized controlled trial of low-dose 
hormone therapy on myocardial ischemia in postmenopausal women with no obstructive 
coronary artery disease: Results from the National Institutes of Health/National Heart, Lung, and 
Blood Institute–sponsored Women's Ischemia Syndrome Evaluation (WISE). American Heart 
Journal. 2010;159(6):987.e981-987.e987. 
 
3. 
Mehta PK, Goykhman P, Thomson LEJ, et al. Ranolazine Improves Angina in Women 
With Evidence of Myocardial Ischemia But No Obstructive Coronary Artery Disease. JACC: 
Cardiovascular Imaging. 2011;4(5):514-522. 
 
4. 
Johnston N, Schenck-Gustafsson K, Lagerqvist B. Are we using cardiovascular 
medications and coronary angiography appropriately in men and women with chest pain? 
European Heart Journal. February 10, 2011 2011. 
 
5. 
Members C, Braunwald E, Antman EM, et al. ACC/AHA Guidelines for the Management 
of Patients With Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction: 
Executive Summary and Recommendations. Circulation. September 5, 2000 
2000;102(10):1193-1209. 
 
6. 
Fox K, Garcia MAA, Ardissino D, et al. Guidelines on the management of stable angina 
pectoris: executive summary. European Heart Journal. June 1, 2006 2006;27(11):1341-1381. 
 
7. 
Freedman DA. Statistical Models: Theory and Practice. 1st ed: Cambridge University 
Press; 2005. 
 
8. 
Weintraub W, Spertus J, Kolm P, et al. Effect of PCI on quality of life in patients with 
stable coronary disease. N Engl J Med. 2008;359(7):677-687. 


Protocol Date: Jan.06.2014 
Version 2.0 
92 
 
9. 
Spertus J, Winder J, Dewhurst T, et al. Development and evaluation of the Seattle 
Angina Questionnaire: a new functional status measure for coronary artery disease. J Am Coll 
Cardiol. . 1995;25(2):333-341. 
 
10. 
Higgins JJ. Introduction to Modern Nonparametric statistics. Cengage Learning 2003. 
 
11. 
Agresti A. An introduction to categorical data analysis. 2nd ed: Wiley-Interscience; 2007. 
 
12. 
Bairey Merz CN. 2012. 
 
13. 
Lin FY, Shaw LJ, Dunning AM, et al. Mortality Risk in Symptomatic Patients With 
Nonobstructive Coronary Artery Disease: A Prospective 2-Center Study of 2,583 Patients 
Undergoing 64-Detector Row Coronary Computed Tomographic Angiography. Journal of the 
American College of Cardiology. 2011;58(5):510-519. 
 
14. 
Leber AW, Knez A, von Ziegler F, et al. Quantification of Obstructive and Nonobstructive 
Coronary Lesions by 64-Slice Computed TomographyA Comparative Study With Quantitative 
Coronary Angiography and Intravascular Ultrasound. Journal of the American College of 
Cardiology. 2005;46(1):147-154. 
 
15. 
Hintze J. PASS. 11 ed: NCSS. 
 
16. 
Sicari R, Palinkas A, Pasanisi EG, Venneri L, Picano E. Long-term survival of patients 
with chest pain syndrome and angiographically normal or near-normal coronary arteries: the 
additional prognostic value of dipyridamole echocardiography test (DET). European Heart 
Journal. October 2005 2005;26(20):2136-2141. 

Prot_000.pdf: 
  
 
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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 
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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 
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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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19. REFERENCE LIST 
1. 
Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, 
Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard 
V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, 
Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, 
Roger VL, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J. Heart disease and 
stroke statistics--2010 update: A report from the american heart association. Circulation. 
2010;121:e46-e215 
2. 
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