Baseline Characteristics and Risk Profiles of Participants in the ISCHEMIA Randomized Clinical Trial

Key Points

Question  What were the characteristics of International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial participants, and did qualification by stress imaging or nonimaging exercise tolerance test influence risk profiles?

Findings  In this analysis of randomized clinical trial data from the ISCHEMIA trial, randomized participants (n = 5179) were a median age of 64 years, 41% had diabetes, 19% had prior myocardial infarction, and 90% had prior angina. Stress imaging was the qualifying test for 75% (86% with moderate or severe ischemia); of those with coronary computed tomography angiography, 79% had multivessel, 87% had left anterior descending coronary artery, and 47% had proximal left anterior descending coronary artery disease.

Meaning  The International Study of Comparative Health Effectiveness With Medical and Invasive Approaches trial randomized stable patients with moderate or severe ischemia and predominantly multivessel and/or left anterior descending coronary artery disease

Importance  It is unknown whether coronary revascularization, when added to optimal medical therapy, improves prognosis in patients with stable ischemic heart disease (SIHD) at increased risk of cardiovascular events owing to moderate or severe ischemia.

Objective  To describe baseline characteristics of participants enrolled and randomized in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial and to evaluate whether qualification by stress imaging or nonimaging exercise tolerance test (ETT) influenced risk profiles.

Design, Setting, and Participants  The ISCHEMIA trial recruited patients with SIHD with moderate or severe ischemia on stress testing. Blinded coronary computed tomography angiography was performed in most participants and reviewed by a core laboratory to exclude left main stenosis of at least 50% or no obstructive coronary artery disease (CAD) (<50% for imaging stress test and <70% for ETT). The study included 341 enrolling sites (320 randomizing) in 38 countries and patients with SIHD and moderate or severe ischemia on stress testing. Data presented were extracted on December 17, 2018.

Main Outcomes and Measures  Enrolled, excluded, and randomized participants’ baseline characteristics. No clinical outcomes are reported.

Results  A total of 8518 patients were enrolled, and 5179 were randomized. Common reasons for exclusion were core laboratory determination of insufficient ischemia, unprotected left main stenosis of at least 50%, or no stenosis that met study obstructive CAD criteria on study coronary computed tomography angiography. Randomized participants had a median age of 64 years, with 1168 women (22.6%), 1726 nonwhite participants (33.7%), 748 Hispanic participants (15.5%), 2122 with diabetes (41.0%), and 4643 with a history of angina (89.7%). Among the 3909 participants randomized after stress imaging, core laboratory assessment of ischemia severity (in 3901 participants) was severe in 1748 (44.8%), moderate in 1600 (41.0%), mild in 317 (8.1%) and none or uninterpretable in 236 (6.0%), Among the 1270 participants who were randomized after nonimaging ETT, core laboratory determination of ischemia severity (in 1266 participants) was severe (an eligibility criterion) in 1051 (83.0%), moderate in 101 (8.0%), mild in 34 (2.7%) and none or uninterpretable in 80 (6.3%). Among the 3912 of 5179 randomized participants who underwent coronary computed tomography angiography, 79.0% had multivessel CAD (n = 2679 of 3390) and 86.8% had left anterior descending (LAD) stenosis (n = 3190 of 3677) (proximal in 46.8% [n = 1749 of 3739]). Participants undergoing ETT had greater frequency of 3-vessel CAD, LAD, and proximal LAD stenosis than participants undergoing stress imaging.

Conclusions and Relevance  The ISCHEMIA trial randomized an SIHD population with moderate or severe ischemia on stress testing, of whom most had multivessel CAD.

Trial Registration  ClinicalTrials.gov Identifier: NCT01471522

Prior strategy trials in patients with stable ischemic heart disease (SIHD) that evaluated routine revascularization added to optimal medical therapy (OMT), as compared with an initial conservative strategy of OMT alone, did not show a reduction in death or myocardial infarction (MI) with early revascularization.^1-3 While these trials used more intensive medical therapy in contrast to trials conducted in the prior era, cardiac catheterization was performed prior to randomization such that the coronary anatomy was known to the physician, patient, and study team and may have introduced bias in patient selection and subsequent treatment. Moreover, patients were not selected based on a predefined threshold of baseline ischemia. It is possible that randomization prior to cardiac catheterization (to minimize selection bias) and inclusion of patients at higher cardiovascular risk (such as those with moderate or severe ischemia) may increase the likelihood of demonstrating that an initial invasive strategy improves prognosis in patients with SIHD, if any such benefit exists.

The primary aim of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial is to assess whether, in addition to OMT, an initial invasive strategy of cardiac catheterization and revascularization when feasible reduces clinical events as compared with an initial conservative strategy of OMT, with catheterization and revascularization reserved for failure of medical therapy, in patients with SIHD with moderate or severe ischemia on stress testing. The purpose of this report is to (1) outline reasons for exclusion of those who were enrolled but not randomized, (2) describe the baseline characteristics of the randomized population, and (3) describe the cohort randomized following stress imaging tests and nonimaging exercise tolerance tests (ETT).

Details of the study design have been published.⁴ The primary end point is the composite of cardiovascular death, MI, hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest, all strictly defined and blindly adjudicated. A major secondary end point is the composite of cardiovascular death or MI. The first enrollment was in July 2012, with sequential initiation of 341 sites in 38 countries that enrolled and 320 sites that randomized participants (see eTable 1 and eTable 2 in Supplement 1 for a list of site personnel, committees, and study center personnel); the last randomization was on January 31, 2018. The projected mean follow-up is approximately 3.5 years, with a range of 1.5 to 7 years. The data in this manuscript are from a data extract on December 17, 2018. The data will not be final until database lock and therefore are subject to change. The formal trial protocols are detailed in Supplement 2. The study was approved by the New York University School of Medicine institutional review board on March 29, 2012. In addition, each enrolling site obtained approval from its local or national institutional review board or ethics committee that holds an institutional review board organization number from the US Department of Health and Human Services Office for Human Research Protections and complies with the Code of Federal Regulations title 45, part 46. Every participant was required to provide written consent prior to enrollment and randomization.

Patients with SIHD and moderate or severe ischemia on clinically indicated stress imaging or severe ischemia on nonimaging ETT were eligible if they were clinically stable, including medically controlled angina or silent ischemia. Key exclusion criteria were estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m², MI or unstable angina within 2 months, left ventricular ejection fraction less than 35%, unprotected left main stenosis of at least 50%, New York Heart Association class III to IV heart failure or exacerbation of chronic heart failure within 6 months, or unacceptable angina despite maximally tolerated medical therapy. The latter were evaluated primarily prior to enrollment, with confirmation before randomization when participants were asked about the frequency of angina. At least daily angina without ability to further titrate medical or antianginal therapy excluded the participant from randomization. Alternatively, prior to randomization, individuals were asked “How bothersome is it for you to take your pills for chest pain, chest tightness, or angina as prescribed?” Of 6 potential responses, participants who chose “extremely bothersome” were excluded. Assessment of eligibility based on ischemia severity was made locally, but stress studies were also read by independent core laboratories for each modality (nuclear, echocardiography, cardiac magnetic resonance, and ETT) either before or after randomization. Core laboratories educated sites about the target level of ischemia during site training. As detailed in the protocol and in the trial design report,⁴ the Clinical Coordinating Center (CCC) designated sites that were permitted to randomize participants based on site interpretation of the stress test result (ie, before stress core laboratory review). These sites were advised to submit stress test results for core laboratory review before randomization whenever there was local uncertainty about ischemia severity. Remaining sites were advised to delay randomization until the stress core laboratory confirmed moderate or severe ischemia and to exclude any enrolled participants with insufficient ischemia based on the interpretation of the core laboratory (eTable 3 in Supplement 1).⁵ To reduce workflow complexity and therefore enhance enrollment, in October 2014, many more sites were given permission to randomize participants based on accruing data on concordance with core laboratory interpretation. Therefore, some enrolled participants were excluded from randomization owing to insufficient ischemia as determined by core laboratory review, and some randomized participants were determined to have less than moderate ischemia by core laboratories after randomization, which was consistent with the protocol. Sites were monitored for concordance of stress test interpretation with the core laboratories. Corrective actions were taken for sites with discordant reads, including an education session with the core laboratory and/or requirement to wait for confirmation of ischemia severity before randomizing future participants. This operational workflow was intended to assure that most participants were considered by independent experts to have moderate or severe ischemia and to preserve trial power.

Coronary anatomic entry criteria were incorporated into the trial as follows: blinded coronary computed tomographic angiography (CCTA) was performed in most participants with eGFR of at least 60 mL/min/1.73 m² who qualified based on stress imaging. Coronary CTA was not required in all participants, eg, those with eGFR less than 60 mL/min/1.73m², known coronary anatomy, or other reasons with a low index of suspicion of left main stenosis.⁴ Study staff, participants, and their physicians were advised whether the blinded CCTA core-laboratory interpretation demonstrated anatomic eligibility, but no further details regarding extent and severity of coronary artery disease (CAD) were provided unless they were excluded from randomization.

Anatomic eligibility criteria after imaging stress tests required at least 50% stenosis in at least 1 major coronary artery. To avoid false-positives among participants who underwent nonimaging ETT and to maximize enrollment of patients at increased risk, either CCTA or, in a small number of participants, cardiac catheterization within the prior year was required for these participants. In addition, eligibility criteria for participants enrolled based on ETT required all of the following: (1) history of stable or exercise test-induced typical angina; (2) an interpretable resting electrocardiogram (eg, no resting ST-segment depression ≥1 mm and no left ventricular hypertrophy with repolarization abnormalities); (3) at least 2 leads showing new exercise-induced ST-segment depression of at least 1.5 mm or a single lead of at least 2 mm, or exercise-induced ST-segment elevation of at least 1.5 mm in a noninfarct territory, as compared to the baseline tracing, occurring at an early stage (≤7 METS) or at heart rate less than 75% of age-predicted maximum; and (4) demonstration of at least 70% stenosis in a coronary artery serving a large myocardial region, defined as the proximal or mid left anterior descending (LAD), proximal or mid right coronary artery, or proximal left circumflex or equivalent.⁴

Anatomic eligibility was assessed at an independent CCTA core laboratory prior to randomization, defined as the absence of at least 50% unprotected left main stenosis and presence of obstructive CAD using the stress test modality–specific definitions listed previously, based on a consensus of 2 readers, with a third reader as needed to resolve discrepancies. To maximize data on coronary anatomy, we subsequently collected available CCTA images (nonstudy CCTA) that were performed less than 1 year prior to enrollment for CCTA core laboratory review (n = 148). For each arterial segment, percent stenosis was categorized as 0%, 1% to 24%, 25% to 49%, 50% to 69%, 70% to 100%, or uninterpretable for severity of stenosis by the core laboratory. The principles guiding core laboratory review were to maintain participant safety with regard to exclusion of significant left main CAD and to diagnose the presence or absence of obstructive CAD in other major coronary arteries. The CCTA core laboratory director reviewed all cases to confirm the absence of significant unprotected left main stenosis. The core laboratory readers made their best attempt to characterize stenosis in any scans of suboptimal quality in this trial population, which included patients with conditions that could limit scan quality (eg, difficulty with breath holding or extensive coronary calcification).

The number of vessels diseased was determined for CCTA studies in which at least all of the following segments were interpretable for percent stenosis: left main, proximal and mid LAD, first diagonal, proximal left circumflex, first obtuse marginal, proximal and mid right coronary artery, and the posterior descending artery. In addition, the CCTA was included in the assessment of number of vessels diseased if the right coronary artery was evaluable and the left main or both the LAD and left circumflex had at least 50% stenosis. Coronary CTA studies were categorized as showing multivessel disease if the left main coronary artery had at least 50% stenosis and/or at least 2 of the LAD, left circumflex, and right coronary artery had at least 50% stenosis, even if 1 of these 3 coronary arteries could not be assessed for percent stenosis.

Enrolled participants who met all eligibility criteria were randomized to an invasive or conservative strategy via an interactive web response system (IXRS; Almac Group). Details of the 2 strategies have been published.⁴

Baseline characteristics are presented as medians (25th, 75th percentiles) of continuous variables and as counts (percentages) of categorical variables. Characteristics of randomized participants vs those excluded after enrollment and between participants qualifying on the basis of stress imaging vs ETT are shown in the tables. Hypothesis testing of between-group differences was not performed because these groups were known to differ as a result of different selection criteria. All analyses were performed using SAS, version 9.4 (SAS Institute Inc).

Of 8518 participants enrolled, 3339 failed eligibility screening and 5179 were randomized (61%): 2588 to the invasive and 2591 to the conservative strategy groups. Baseline characteristics of participants who were enrolled, excluded after enrollment, and randomized are shown in Table 1, with reasons for screen failure depicted in the Figure. The most common reasons for ineligibility in excluded participants were unprotected left main stenosis of at least 50% (n = 434), no significant obstructive CAD on study CCTA (n = 1218) defined according to imaging vs nonimaging stress test modality, or insufficient ischemia (n = 1350), as determined by the designated core laboratories when stress test results were reviewed prior to randomization. Randomized participants had similar demographics compared with eligible, nonrandomized participants, except the proportion of women was higher among those who were excluded after enrollment than among those who were randomized (n = 1094 [33%] vs n = 1168 [23%]) (Table 1). These differences were largely owing to higher frequency of insufficient ischemia on stress testing and of no obstructive disease on CCTA among women. The remaining description pertains to the randomized cohort.

Clinical characteristics of the randomized population are shown in Table 2, stratified according to whether the patient qualified for the trial by stress imaging or ETT. Median age was 64 years, with a high prevalence of diabetes (n = 2122 of 5179 [41.0%]) and hypertension (n = 3789 of 5161 [73.4%]). Overall, 990 of 5161 (19.2%) had prior MI. Left ventricular ejection fraction was normal in most participants. Most participants had a history of angina prior to enrollment, with only 536 of 5179 (10.3%) reporting no history of angina, ie, silent ischemia, and 4138 of 5177 (79.9%) reporting angina within the last month (Table 3). The median Seattle Angina Questionnaire angina frequency score (range 0-100, higher more favorable) was 80. New or worsening angina was reported in the prior 3 months in 1358 of 4637 participants (29.3%), with new onset of angina within that time in 858 of 4918 (17.4%). Only 206 of 5179 (4.0%) had a history of heart failure. Study team assessment of heart failure symptoms, eg, dyspnea on exertion, in all randomized participants the month prior to enrollment revealed that 2015 of 5179 (38.9%) had New York Heart Association class I to II symptoms.

Of those randomized, the qualifying stress test modality was stress imaging in 3909 (75%); the remainder were nonimaging ETTs. Core laboratories judged that the trial-required level of ischemia was met (moderate or severe for imaging test results and severe for ETT) in 4399 of 5167 randomized participants (85%). Among the cohort randomized via stress imaging, 1748 of 3901 had severe ischemia (44.8%), 1600 of 3901 had moderate ischemia (41.0%), 317 of 3901 had mild ischemia (8.1%), and 236 of 3901 had no ischemia or were uninterpretable on core laboratory review (6.0%). Among the cohort randomized via ETT, 1051 of 1266 (83.0%) had severe ischemia, 101 of 1266 (8.0%) had moderate ischemia, 34 of 1266 (2.7%) had mild ischemia, and 80 of 1266 (6.3%) had no ischemia or were uninterpretable on core laboratory review. A higher proportion of participants who had ETT had severe ischemia because we defined the criteria to qualify by ETT as severe ischemia (Table 1 and Table 4).

Coronary CTA was not performed in some randomized participants owing to low eGFR (n = 568 of 5179 [11.0%]) known coronary anatomy (n = 570 of 5179 [11.0%]), or other reasons (n = 129 of 5179 [2.5%]). In the randomized cohort that had CCTA reviewed by the core laboratory (3912 of 5179 [76%], includes study and nonstudy CCTA), 99.9% (n = 3832 of 3836) had at least 50% stenosis of at least 1 vessel and 79.0% (n = 2679 of 3390) had multivessel CAD. Among the 2986 participants with CCTA evaluable for number of vessels diseased, 1-vessel, 2-vessel, and 3-vessel CAD was observed in 697 (23.3%), 938 (31.4%), and 1347 (45.1%) participants, respectively; 86.8% had LAD stenosis (n = 3190 of 3677), and 46.8% had proximal LAD stenosis (n = 1749 of 3739) (Table 4).

As compared with those who qualified based on stress imaging, those randomized based on ETT were younger, less often of white race and non-Hispanic ethnicity owing to more frequent use of ETT at Asian sites, and had fewer comorbidities including a lower prevalence of hypertension, prior MI, prior PCI, prior coronary artery bypass grafting, and prior stroke (Table 4). However, a higher proportion of participants randomized based on ETT had 3-vessel disease and disease in the LAD, including the proximal LAD, compared with those who qualified via stress imaging (Table 4).

Median baseline systolic blood pressure was 130 mm Hg (interquartile range [IQR], 120-142 mm Hg), and median low-density lipoprotein cholesterol level was 83 mg/dL (IQR, 63-111 mg/dL; to convert to micromoles per liter, multiply by 0.0259). Most participants had normal eGFR, with median 81 mL/min/1.73m² (IQR, 67-97 mL/min/1.73m²) (eTable 4 in Supplement 1). Medication use at baseline is shown in eTable 5 in Supplement 1. Almost all were receiving antiplatelet or anticoagulant therapy, statin therapy, and at least 1 antihypertensive/anti-ischemic/antianginal medication.

The ISCHEMIA trial randomized an SIHD population with median age of 64 years, 23% of whom were women (n = 1168 of 5179) and 41% of whom had diabetes (n = 2122 of 5179). Most participants (n = 3909 [75%]) had stress imaging tests, with confirmation of severe ischemia in 1748 of 3901 (44.8%) and moderate ischemia in 1600 of 3901 (41.0%) by independent imaging core laboratories. Eligibility for randomization by nonimaging ETT criteria required anginal symptoms, ischemia at an early workload, and at least 70% stenosis in a major non–left main coronary artery. Consequently, those randomized after ETT had more extensive anatomic CAD. The independent core laboratory confirmed that ETT trial entry criteria were met in 83%. Consistent with the design to recruit patients with at least moderate ischemia on stress imaging and severe ischemia with ETT, of all randomized participants who underwent CCTA, most had multivessel CAD and/or LAD stenosis, including proximal LAD in nearly half. Of note, those randomized following ETT had slightly higher rates of 3-vessel disease, LAD, and proximal LAD stenosis on CCTA than those randomized based on stress imaging, with a similar overall rate of multivessel CAD, thereby confirming that the eligibility criteria required for participants who underwent ETT achieved the objective of randomizing patients with at least as much CAD as those randomized based on imaging. Those randomized following ETT more often had angina compared with participants undergoing stress imaging because angina was required for enrollment following ETT. Finally, core laboratories judged that the trial-required level of ischemia was met in 85% of participants, despite frequent randomization before core laboratory review.

The most common reasons for exclusion in ISCHEMIA were associated with the key entry criteria for stress testing and CCTA. Consistent with the high degree of ischemia required for study entry, 8% of enrolled participants who had a study CCTA failed eligibility owing to significant unprotected left main coronary artery disease. Even with this degree of ischemia, a modest proportion had no stenosis of 50% or greater on CCTA, highlighting the differences between anatomic evidence of epicardial coronary artery disease and physiologic evidence of ischemia; false-positive test results may have also contributed to this finding. Women were more likely than men to be excluded from randomization after enrollment, particularly owing to nonobstructive CAD.

Most previous studies have demonstrated that the extent and severity of ischemia is associated with an increased risk for death and MI, and that revascularization is associated with better prognosis in these patients.^6-12 For example, Hachamovitch et al⁶ reported an observational study of 13 969 patients with a range of core laboratory quantitated inducible ischemia by single-photon emission computed tomography and mean 8.7-year follow-up. They reported improved survival for those selected for revascularization compared with those who did not undergo revascularization but only for those with at least 10% ischemia.⁶ Studies using other stress modalities reported similar findings of an association of more ischemia and higher risk of death or MI.^11,13-18 However, even in propensity-matched cohorts there is residual confounding, and a clinical trial was needed to verify this finding. Moreover, these patients did not receive OMT by contemporary standards, while in ISCHEMIA, the median baseline low-density lipoprotein cholesterol level was 83 mg/dL, with high rates of use of aspirin and potent statins, and this was prior to intensification of medical therapy when needed to achieve risk factor goals.

The principal objective of ISCHEMIA is to determine whether an initial invasive strategy of cardiac catheterization followed by routine revascularization, if feasible, plus OMT in participants with moderate or severe ischemia will reduce adverse ischemia-related events by a clinically meaningful amount compared with an initial conservative strategy of OMT alone, with catheterization and revascularization reserved for failure of medical therapy. In prior trials testing the incremental value of routine revascularization for SIHD, patients were enrolled without a specified level or quantitative threshold of ischemia required on a stress test.^1-3 In the ISCHEMIA trial, to maximize applicability of study results globally, participants could qualify based on stress nuclear, echocardiographic or cardiac magnetic resonance, or nonimaging ETT. These modalities detect ischemia in inherently different ways; for example, nuclear imaging and cardiac magnetic resonance definitions used in the trial assess perfusion, while echo assesses wall motion.

Numerous studies have also reported an association between the presence of more extensive anatomic CAD, including proximal LAD stenosis, and higher risk of death or MI.^19-21 However, prior randomized trials in patients with SIHD failed to demonstrate that routine revascularization reduced that risk. In these trials, patients were selected for enrollment after diagnostic catheterization. A possible explanation, in part, for the neutral findings of those trials is that they effectively (although not necessarily intentionally) limited inclusion of higher-risk patients or that knowledge of coronary anatomy prior to randomization introduced potential bias by excluding higher-risk patients who might have derived benefit from a strategy of routine revascularization. In contrast, ISCHEMIA was designed to assess whether an initial invasive strategy improves clinical outcomes in stable patients at higher risk of cardiovascular events based on more severe ischemia, without contemporaneous knowledge of their coronary anatomy.

One of the key design objectives of ISCHEMIA was to select a population that would include participants who, if randomized to the conservative strategy, would be less likely to undergo elective catheterization and revascularization after randomization (ie, crossover). Thus, ISCHEMIA seeks to study the prognostic benefits of catheterization and revascularization separated to the extent possible from the use of these procedures for symptom control. Hence, most ISCHEMIA participants had mild-to-moderate angina at baseline, 10% had no history of angina, and approximately 20% had silent ischemia at the time of randomization. The baseline median Seattle Angina Questionnaire angina frequency score of 80 is consistent with monthly angina.²²

The data in this article are from a data extract on December 17, 2018. The data will not be final until database lock and, therefore, are subject to change.

Based on the demographic and clinical profile of participants randomized in ISCHEMIA, the results will inform the care of a broad range of patients with SIHD with moderate or severe ischemia on stress testing, including those with multivessel CAD and angina who can be treated medically without revascularization for symptom control. For such patients, the trial will provide robust and contemporary scientific evidence regarding the risk of clinically important events with a routine early invasive vs initial conservative management strategy.

Corresponding Author: Judith S. Hochman, MD, New York University School of Medicine, 530 First Ave, Skirball 9R, New York, NY 10016 (judith.hochman@nyumc.org).

Accepted for Publication: December 21, 2018.

Correction: This article was corrected on April 10, 2019, to fix minor typographical errors in the Group Information section and to update the Additional Contributions section.

Published Online: February 27, 2019. doi:10.1001/jamacardio.2019.0014

Author Contributions: Drs O’Brien and Hochman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Reynolds, Bangalore, O'Brien, Alexander, Stone, Goodman, Lopez-Sendon, Shaw, Min, Picard, Berman, Mark, Ruzyllo, Rosenberg, Maron.

Study concept and design: Hochman.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Hochman, Shaw, Min, Picard, Berman, Cyr, Chernyavskiy.

Critical revision of the manuscript for important intellectual content: Hochman, Reynolds, Bangalore, O'Brien, Alexander, Senior, Boden, Stone, Goodman, Lopes, Lopez-Sendon, White, Maggioni, Shaw, Min, Picard, Berman, Chaitman, Mark, Spertus, Cyr, Bhargava, Ruzyllo, Wander, Rosenberg, Maron.

Statistical analysis: O'Brien, Alexander, Cyr.

Obtained funding: Hochman, Reynolds, O'Brien, Shaw, Min, Mark, Maron.

Administrative, technical, or material support: Hochman, Senior, Goodman, Shaw, Min, Picard, Chaitman, Bhargava, Ruzyllo, Rosenberg.

Study supervision: Hochman, O'Brien, Alexander, Stone, Goodman, Lopez-Sendon, Shaw, Min, Picard, Berman, Ruzyllo.

Quality of Life core lab and grant acquisition: Spertus.

Coordination of the Italian part of the study: Maggioni.

Generated the data for the stress echo interpretations: Picard.

Contributed in data collection: Wander.

Conflict of Interest Disclosures: Dr Hochman is Principal Investigator for the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial for which, in addition to support by a National Heart, Lung, and Blood Institute grant, devices and medications were provided by Abbott Vascular, Medtronic, Inc, St Jude Medical Inc, Volcano Corporation, Arbor Pharmaceuticals LLC, AstraZeneca, Merck Sharp and Dohme Corp, Omron Healthcare Inc, and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca. Dr Reynolds reports a National Institutes of Health (NIH) ISCHEMIA grant and CIAO-ISCHEMIA ancillary study grant and other support from Abbott Vascular (donation of optical coherence tomography catheters for an unrelated research study). Dr Bangalore receives research grants from the National Heart, Lung, and Blood Institute (for ISCHEMIA and ISCHEMIA-CKD) and Abbott Vascular and is a consultant or receives honoraria from Abbott Vascular, Biotronik, Pfizer, Amgen, Merck, AstraZeneca, and Menarini. Dr Alexander receives grants from Sanofi Aventis, NIH, and Gilead. Dr Goodman reports research grant, salary support, and speaker/consulting honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, Eli Lilly, Fenix Group International, Ferring Pharmaceuticals, Glaxo Smith Kline, Janssen/Johnson and Johnson, Luitpold Pharmaceuticals, Matrizyme, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, Tenax Therapeutics, Heart and Stroke Foundation of Ontario/University of Toronto, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Duke Clinical Research Institute, PERFUSE, and the NIH. Dr Lopes received funding from Bayer; Boehringer Ingleheim, Bristol Myers Squibb, Daiichi Sankyo, Glaxo Smith Kline, Medtronic, Merck, Pfizer, Portola, and Sanofi. Dr White reports grants from the NIH, grants and personal fees from Eli Lilly and Company, Omthera Pharmaceuticals, Pfizer New Zealand, Elsai Inc, DalCor Pharma UK Inc, CSL Behring LLC, Luitpold Pharmaceuticals Ltd, and Sanofi Aventis; personal fees from Sirtex and Acetelion; and personal fees and nonfinancial support from AstraZeneca outside the submitted work. Dr Min receives funding from the Dalio Foundation, NIH, and GE Healthcare; serves on the scientific advisory board of Arineta and GE Healthcare; and has an equity interest in Cleerly. Dr Berman receives software royalties from Cedars-Sinai Medical Center. Dr Spertus reports copyright to Seattle Angina Questionnaire. No other disclosures were reported.

Funding/Support: This article refers to work supported by National Heart, Lung, and Blood Institute grants U01HL105907, U01HL105907, U01HL105462, U01HL105561, and U01HL105565; devices and medications provided by Abbott Vascular, Medtronic Inc, St Jude Medical Inc, Volcano Corporation, Amgen Inc, Arbor Pharmaceuticals LLC, AstraZeneca Pharmaceuticals LP, Merck Sharp and Dohme Corp, Omron Healthcare Inc, and by financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP.

Role of the Funder/Sponsor: The National Heart, Lung, and Blood Institute program staff had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript. They did not have a role in the decision to submit the manuscript for publication.

Group Information: The ISCHEMIA Research Group members (site principal investigators) are Kreton Mavromatis, MD, Atlanta VA Medical Center; Todd Miller, MD, Mayo Clinic; Subhash Banerjee, MD, V.A. North Texas Health Care System; Harmony R. Reynolds, MD, NYU Langone Medical Center-Bellevue Hospital; Khaled Abdul-Nour, MD, Henry Ford Health System; Peter H. Stone, MD, Brigham & Women's Hospital, Harvard Medical School; James J. Jang, MD, Kaiser Permanente San Jose; Steven Weitz, MD, Cardiology Associates of Schenectady P.C.; Suzanne Arnold, MD, Saint Luke's Hospital; Michael D. Shapiro, DO, Oregon Health & Science University; Mohammad El-Hajjar, MD, Albany Medical Center Hospital; Edward O. McFalls, MD, PhD, Minneapolis VAMC; Michel Georges Khouri, MD, Duke University Medical Center; Jonathan L. Goldberg, MS, MD, Louis Stokes Cleveland Veterans Affairs Medical Center; Richard Goldweit, MD, Englewood Hospital and Medical Center; Ronny A. Cohen, MD, NYU-HHC Woodhull Hospital; David E. Winchester, MD, MS, Malcom Randall VAMC; Marvin Kronenberg, MD, Vanderbilt University Medical Center; John F. Heitner, MD, New York -Presbyterian/Brooklyn Methodist Hospital; Ira M. Dauber, MD, South Denver Cardiology Associates, P.C.; Charles Cannan, MD, Providence Heart and Vascular Institute; Sriram Sudarshan, MD, Wichita Falls Heart Clinic; Puja K. Mehta, MD, Emory University; Chester M. Hedgepeth, MD, PhD, Kent Hospital; Zakir Sahul, MD, Michigan Heart, PC; David Booth, MD, University of Kentucky; Sampoornima Setty, MD, Gundersen Lutheran Medical Center; Rajat S. Barua, MD, PhD, Kansas City VA Medical Center; Fadi Hage, MD, UAB Vascular Biology and Hypertension Program; Khaled Dajani, MD, Loyola University Medical Center; Mohammad El-Hajjar, MD, Samuel Stratton VA Medical Center of Albany NY; Imran Arif, MD, Cincinnati VA Medical Center; Jorge F. Trejo (Gutierrez), MD, Mayo Clinic Florida; Anthony Gemignani, MD, VAMC-White River Junction; Judith L. Meadows, MD, VA Connecticut Healthcare System; Jason T. Call, MD, Winchester Cardiology and Vascular Medicine, PC; Joseph Hannan, MD, Saint Vincent Hospital at Worcester Medical Center; Edward T. Martin, MS, MD, Oklahoma Heart Institute; Gabriel Vorobiof, MD, Ronald Reagan UCLA Medical Center; Alec Moorman, MD, University of Washington Medical Center; Scott Kinlay, MBBS, PhD, VA Boston Healthcare System; Glenn Rayos, MD, Daytona Heart Group; Ashraf Seedhom, MD, Capital Cardiology Associates; Gregory Kumkumian, MD, NIH Heart Center at Suburban Hospital; Steven P. Sedlis, MD, VA New York Harbor Health Care System (past member); Jacqueline E. Tamis-Holland, MD, Mount Sinai Saint Luke's Hospital; Souheil Saba, MD, Providence - Providence Park Hospital; Umesh Badami, MD, Covenant Medical Center, Inc.; Kevin Marzo, MD, NYU Winthrop; Inga H. Robbins, MD, AtlantiCare Regional Medical Center; Glenn S. Hamroff, MD, NYP Medical Medical Group Hudson Valley Cardiology; Raymond W. Little, MD, Houston Heart & Vascular Associates; Charles Y. Lui, MD, Salt Lake City VA Medical Center; David Booth, MD, Lexington VA Medical Center; Bob Hu, MD, Palo Alto Medical Foundation Research Institute; Arthur J. Labovitz, MD, University of South Florida; David J. Maron, MD, Stanford University School of Medicine; Fatima Rodriguez, MD, MPH, Stanford University School of Medicine; Prakash Deedwania, MD, UCSF - Fresno Community Regional Medical Center; Joseph Sweeny, MD, Icahn School of Medicine at Mount Sinai; Christopher Spizzieri, MD, Holy Spirit Hospital Cardiovascular Institute; Claudia P Hochberg, MD, Boston Medical Center; William D. Salerno, MD, Hackensack University Medical Center; Ray Wyman, MD, Torrance Memorial Medical Center; Amer Zarka, MD, Coastal Heart Medical Group; Thomas Haldis, DO, Sanford Health; Jeffrey A. Kohn, MD, NYU New York Medical Associates; Saket Girotra, MD, University of Iowa Hospitals and Clinics; Omar Almousalli, MD, Advanced Heart Care Group; Mayil S. Krishnam, MD, University of California Irvine Medical Center; Rita Coram, MD, University of Louisville; Sabu Thomas, MD, MSc, University of Rochester; Mahfouz El Shahawy, MD, Cardiovascular Center of Sarasota; James Stafford, MD, University of Maryland Medical Center; William B. Abernethy, MD, Asheville Cardiology Associates; Andrew Zurick, MD, Saint Thomas Hospital; Thomas M. Meyer, MD, Stroobants Cardiovascular Center; Bruce Rutkin, MD, Northwell Health – Manhasset; Sabahat Bokhari, MD, Columbia University Medical Center; Seth I. Sokol, MD, Jacobi Medical Center; Ihab Hamzeh, MD, Baylor College of Medicine; Michael C. Turner, MD, Cardiovascular Specialists of Southwest Louisiana; Arnold P. Good, MD, Ohio Health Grant Medical Center; Nicolas W. Shammas, MD, MS, Midwest Cardiovascular Research Foundation; Robert Chilton, MD, Audie Murphy V.A.; Patricia K. Nguyen, MD, VA Palo Alto Healthcare System; Matthew Jezior, MD, Walter Reed National Military Medical Center; Paul C. Gordon, MD, Miriam Hospital; Robert Stenberg, MD, Conemaugh Valley Memorial Hospital; Ronald P. Pedalino, MD, NYU-HHC Kings County Hospital Center; Joseph Wiesel, MD, New York University - Langone Cardiovascular Associates; George J. Juang, MD, Coney Island Hospital; Mohammed Al-Amoodi, MD, Yuma Regional Medical Center; David Wohns, MD, Spectrum Health; Ellis W. Lader, MD, Mid Valley Cardiology; Michael Mumma, MD, Sarasota Memorial Hospital; Lekshmi Dharmarajan, MD, NYU-HHC Lincoln Medical and Mental Health Center; Joseph F.X. McGarvey Jr, MD, Doylestown Health Cardiology; Thomas R. Downes, MD (till Dec. 2016), Medical Center of the Rockies; Benjamin Cheong, MD, Baylor St. Luke's Medical Center; Srinivasa Potluri, MD, Baylor Research Institute at Legacy Heart Center; Ronald A. Mastouri, MD, Indiana University/Krannert Institute of Cardiology; Dayuan Li, MD, HealthEast Saint Joseph's Hospital; Kenneth Giedd, MD, Beth Israel Medical Center; Wayne Old, MD, Cardiovascular Associates, Ltd.; Francis Burt, MD, Saint Luke's Hospital and Health Network; Kozhaya Sokhon, MD, Medicus Alliance Clinical Research Org., Inc.; Deepika Gopal, MD, The Heart Hospital Baylor; Uma S. Valeti, MD, University of Minnesota; Jon Kobashigawa, MD, Cedars Sinai Medical Center; Sajeev Chakanalil Govindan, MD, DNB, DM, PhD, Government Medical College; Cholenahally Nanjappa Manjunath, MD, DM, Sri Jayadeva Institute of Cardiovascular Sciences and Research; Neeraj Pandit, MD, DM, Dr Ram Manohar Lohia Hospital; S.K. Dwivedi, DM, King George's Medical University, Department of Cardiology; Gurpreet S. Wander, DM, Hero DMC Heart Institute, Dayanand Medical College and Hospital; Balram Bhargava, DM, All India Institute Of Medical Sciences; Anoop Mathew, MD, MOSC Medical College Hospital; Milind Avdhoot Gadkari, MD, KEM Hospital Pune; Santhosh Satheesh, MBBS, MD, DM, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER); Atul Mathur, MD, Fortis Escort Heart Institute; Johann Christopher, MD, DNB, Gurunanak CARE Hospital; Abraham Oomman, MD,DM,DNB, Apollo Research and Innovation; Sudhir Naik, MD, DM, Apollo Research & Innovations; Johann Christopher, MD, CARE Nampally; Purvez Grant, MD, Ruby Hall Clinic, Grant Medical Foundation; Ranjan Kachru, MD, Fortis Healthcare Fl.t Lt. Rajan Dhall Hospital; Ajit Kumar VK, MD, DM, Sree Chitra Tirunal Institute for Medical Sciences and Technology; Johann Christopher, MD, CARE Hospital; Upendra Kaul, MD, Batra Hospital and Medical Research Centre (BHMRC); Roxy Senior, MBBS, MD, DM, Northwick Park Hospital Harrow/ Royal Brompton Hospital London; Reto Andreas Gamma, MBBS, Broomfield Hospital; Mark A de Belder, MD, The James Cook University Hospital, Middlesbrough; Thuraia Nageh, BSc(Hons) MBBS MD MRCP, Southend University Hospital; Steven J. Lindsay, MD, Bradford Royal Infirmary; Angela Hoye, MD, The University of Hull/Castle Hill Hospital; Patrick Donnelly, MD, South Eastern Health and Social Care; Anoop Chauhan, MD, Blackpool Teaching Hospitals; Craig Barr, MD, Russells Hall Hospital; Khaled Alfakih, MBBS, MD, King's College NHS Foundation Hospital; Peter Henriksen, PhD, MB ChB, BSc(Hons), Royal Infirmary of Edinburgh; Peter OKane, MD, Royal Bournemouth Hospital; Ramesh de Silva, MB ChB, MD, Bedford Hospital NHS Trust; Dwayne S. G. Conway, MD, Pinderfields Hospital; Alexander A Sirker, MB BChir, PhD, University College London Hospitals NHS Foundation Trust, BartsHealth NHS Trust; Stephen P Hoole, MD, Papworth Hospital; Fraser N. Witherow, MD, Dorset County Hospital; Nicola Johnston, MB, Bch BAO, MRCP, MD, Belfast Trust; Matthew Luckie, MD, Central Manchester University Hospital; Jolanta Sobolewska, MD, The Pennine Acute Hospitals NHS Trust; Paramjit Jeetley, MD, Royal Free London NHS Foundation Trust; Christopher Travill, MBBS, MD, Luton and Dunstable University Hospital NHS FT; Denise Braganza, MD, Peterborough City Hospital; Robert Henderson, MD, Nottingham University Hospitals; Colin Berry, BSc MB ChB, PhD, University of Glasgow; Andrew J Moriarty, BSc MB PhD, Cardiovascular Research Unit, Craigavon Area Hospital; Jason D. Glover, MBBS, Hampshire Hospitals NHS Foundation Trust; Ghada Mikhail, MD, Imperial College Healthcare NHS Trust; Gilbert Gosselin, MD, Montreal Heart Institute; Ariel Diaz, MD, Centre Hospitalier de Regional Trois-Rivieres; Denis Carl Phaneuf, MD, CISSSL - Hopital Pierre-Le Gardeur; Pallav Garg, MBBS, MSc, London Health Sciences Centre; Benjamin J.W. Chow, MD, University of Ottawa Heart Institute; Kevin R. Bainey, MD, MSc, University of Alberta; Asim N. Cheema, MD, PhD, St. Michael's Hospital; Asim Nazir Cheema, MD, Dixie Medical Group; James Cha, MD, Dr. James Cha; Andrew G Howarth, MD, PhD, University of Calgary; Graham Wong, MD, Vancouver General Hospital;, Amar Uxa, MD, University Health Network; Paul Galiwango, MD, Scarborough Cardiology Research; Andy Lam, MD, West Lincoln Memorial Hospital; Shamir Mehta, MD, Hamilton General Hospital; Jacob Udell, MD, Women's College Hospital; Philippe Généreux, MD, Centre Intégré Universitaire de Santé et de Services Sociaux du Montréal; Adnan Hameed, MD, Saint Catharines General Hospital; Ledjalem Daba, MD, Northwest GTA Cardiovascular and Heart Rhythm Program; Whady Hueb, MD, Heart Institute (InCor) University of São Paulo; Paola Emanuela Poggio Smanio, MD, PhD, Instituto Dante Pazzanese de Cardiologia; Alexandre Schaan de Quadros, MD, Instituto de Cardiologia de Porto Alegre; João V Vitola, MD, PhD, Quanta Diagnostico & Terapia; José Antonio Marin-Neto, MD, PhD, Hospital das Clinicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo; Carísi A. Polanczyk, MD, Hospital de Clínicas de Porto Alegre; Antonio Carlos Carvalho, MD, PhD, Unifesp - Hospital Sao Paulo; Alvaro Rabelo Alves Junior, MD, Fundacao Bahiana de Cardilogia; Marianna D. A. Dracoulakis, MD, PhD, Hospital da Bahia; Estevao Figueiredo, MD, Hospital Lifecenter; Paulo Ricardo Caramori, MD, Hospital Sao Lucas da Pontificia Universidade Catolica do Rio Grande do Sol; Rogerio Tumelero, MD, Hospital Sao Vicente de Paulo; Frederico Dall’Orto, MD, Hospital Maternidade e Pronto Socorro Santa Lucia; Claudio T. Mesquita, MD, Hospital Pró-Cardíaco; Expedito Eustáquio Ribeiro da Silva, MD, PhD, Hospital TotalCor; Jose Francisco Saraiva, MD, Hospital Celso Pierro; Costantino Costantini, MD, PhD, Hospital Cardiologico Costantini; Marcin Demkow, MD, PhD, Coronary and Structural Heart Diseases Department, Institute of Cardiology; Tomasz Mazurek, MD, PhD, Medical University of Warsaw; Jaroslaw Drozdz, PhD, Cardiology Clinic, Medical University in Lodz; Hanna Szwed, MD, PhD, Institute of Cardiology, Warsaw; Adam Witkowski, MD, PhD, Department of Interventional Cardiology & Angiology, Institute of Cardiology; Grzegorz Gajos, MD, PhD, Department of Coronary Disease, John Paul II Hospital, Jagiellonian University Medical College; Piotr Pruszczyk, MD, PhD, Department of Internal Medicine and Cardiology, Infant Jesus Teaching Hospital, Medical University of Warsaw; Krystyna Łoboz-Grudzień, MD, PhD, T.Marciniak Hospital; Maciej Lesiak, Professor, MD, Szpital Kliniczny Przemienienia Pańskiego; Krzysztof W. Reczuch, MD, Military Hospital / Medical University; Zbigniew Kalarus, MD, Medical University of Silesia, School of Medicine with the Division of Dentistry, Department of Cardiology, Congenital Heart Diseases and Electrotherapy, Silesian Center for Heart Diseases; Wlodzimierz J. Musial, MD, University Hospital in Bialystok; Leo Bockeria, MD, PhD, National Medical Research Center for Cardiovascular Surgery; Alexander M. Chernyavskiy, MD, PhD, E. Meshalkin National Medical Research Center of the Ministry of Health of the Russian Federation; Leonid L. Bershtein, MD, PhD, North-Western State Medical University; Elena A. Demchenko, MD, PhD, Federal Almazov North-West Medical Research Centre; Jose Luis Lopez-Sendon, MD, PhD, Hospital La Paz, IdiPaz; Jesús Peteiro, MD, PhD, Complexo Hospitalario Universitario A Coruña (CHUAC) Sergas, Department of Cardiology, INIBIC A Coruña, CIBER-CV, Universidad de A Coruña, Spain; Jose Ramon Gonzalez Juanatey, MD, PhD, Hospital Clinico Universitario de Santiago; Alessandro Sionis, MD, Hospital de la Santa Creu i Sant Pau, Vicente Miro, MD, Hospital Universitario y Politecnico La Fe; F. Marin Ortuño, MD, PhD, HUVA, Hospital Clínico Universitario Virgen De La Arrixaca; Montserrat Gracida Blancas, MD, Hospital De Bellvitge; Jose Enrique Castillo Luena, MD, Hospital Universitario Miguel Servet; Francisco Fernandez-Aviles, MD, Hospital General Universitario Gregorio Maranon; Jiyan Chen, MD, Guangdong General Hospital; Yongjian Wu, MD, PhD, Chinese Academy of Medical Sciences, Fuwai Hospital; Yitong Ma, MD, First Affiliated Hospital of Xinjiang Medical University; Zheng Ji, MD, Tangshan Gongren Hospital; Xinchun Yang, MD, Beijing Chao-yang Hospital, Capital Medical University; Wenhua Lin, MD, TEDA International Cardiovascular Hospital; Hesong Zeng, MD, Tongji Medical College; Xin Fu, MD, The First Affiliated Hospital of Zhengzhou University; Bin Yang, MD, Shanxi Cardiovascular Hospital; Songtao Wang, MD, Qingdao Fuwai Hospital; Gong Cheng, MD, Shanxi Provincial People’s Hospital; Yulan Zhao, MD, The Second Affiliated Hospital of Zhengzhou University; Xuehua Fang, MD, Liangxiang Hospital, Beijing Fangshan District; Qiutang Zeng, MD, Wuhan Union Hospital, Tongji Medical College, Huazhong Science and Tech University; Xi Su, MD, Wuhan Asia Heart Hospital; Qingxian Li, MD, Affiliated Hospital of Jining Medical University; Shao-ping Nie, MD, PhD, Beijing Anzhen Hospital; Qin Yu, MD, Affiliated Zhongshan Hospital of Dalian University; Jian'an Wang, MD, The Second Affiliated Hospital Zhejiang University School of Medicine; Shuyang Zhang, MD, PhD, Peking Union Medical College Hospital; Gian Piero Perna, MD, Cardiology and CCU - Ospedali Riuniti Ancona; Stefano Provasoli, MD, Ospedale di Circolo e Fondazione Macchi; Lorenzo Monti, MD, Humanitas Research Hospital, Rozzano (MI); Antonio Di Chiara, MD, Azienda Servizi Sanitaria n.3 Alto Friuli-Collinare-Medio Friuli; Andrea Mortara, MD, Policlinico di Monza, Monza MB; Marcello Galvani, MD, Ospedale “G.B. Morgagni – L. Pierantoni” Forli (AUSL della Romagna); Marco Sicuro, MD, Ospedale Regionale Umberto Parini; Paolo Calabro, MD, AORN Dei Colli "V. Monaldi" UOC Cardiologia Università della Campania "L.Vanvitelli"; Giuseppe Tarantini, MD, University of Padua- Cardiology Clinic; Emanuela Racca, MD, Azienda Ospedaliera S. Croce e Carle; Carlo Briguori, MD, Clinica Mediterranea; Roberto Amati, MD, UO Cardiologia Ospedale SS Cosma e Damiano; Aldo Russo, MD, IRCCS "Casa Sollievo della Sofferenza"; Kian-Keong Poh, MD, National University Heart Center Singapore; David Foo, MBBS, Tan Tock Seng Hospital; Terrance Chua, MD, National Heart Centre Singapore; Rolf Doerr, MD, Praxisklinik Herz und Gefaesse; Udo Sechtem, MD, Robert-Bosch-Krankenhaus; P. Christian Schulze, MD, PhD, University Hospital Jena; Georg Nickenig, MD, Universitatsklinikum Bonn; Herwig Schuchlenz, MD, LKH Graz West Austria; Irene Marthe Lang, MD, Medical University of Vienna, Department of Cardiology; Kurt Huber, MD, Wilhelminen Hospital Vienna, Andras Vertes, MD, Eszszk- Szent Istvan Hospital; Albert Varga, MD, PhD, University of Szeged; Geza Fontos, MD, George Gottsegen National Institute of Cardiology; Bela Merkely, MD, PhD, DSc, Heart and Vascular Center, Semmelweis University; Gabor Kerecsen, MD, Military Hospital, Budapest; Sasa Hinic, MD, BSc, University Hospital Center Bezanijska Kosa; Branko D. Beleslin, MD, PhD, Faculty of Medicine, University of Belgrade; Cardiology Clinic, Clinical Center of Serbia; Nada Cemerlic-Adjic, MD, Institute of Cardiovascular Diseases Vojvodina, Sremska Kamenica, Serbia and Faculty of Medicine, University of Novi Sad; Goran Davidović, MD, PhD, Clinical Center Kragujevac; Milica Nikola Dekleva, MD PhD, University Clinical Hospital Zvezdara; Goran Stankovic, MD, Clinical Center of Serbia; Svetlana Apostolovic, MD, Clinic for Cardiovascular Diseases, Clinical Center Nis; Jorge Escobedo, MD, (Instituto Mexicano del Seguro Social); Erick Alexánderson Rosas, MD (Instituto Nacional de Cardiología "Ignacio Chávez"); Joseph B. Selvanayagam, MBBS(Hons), DPhil Flinders Medical Centre; Suku T. Thambar, MBBS, John Hunter Hospital; John F. Beltrame, MD, The Queen Elizabeth Hospital; Graham S. Hillis, PhD, Royal Perth Hospital; Christophe Thuaire, MD, C.H. Louis Pasteur; Philippe-Gabriel Steg, MD, Bichat Hospital; Michel S. Slama, MD, Antoine-Beclere Hospital; Rami El Mahmoud, MD, Ambroise Pare Hospital; Eric Nicollet, MD, Centre Hospitalier Sud Francilien; Gilles Barone-Rochette, MD, Grenoble University Hospital; Alain Furber, MD, Centre Hospitalier Universitaire d'Angers; Aleksandras Laucevicius, MD, Vilnius University Hospital Santariskes Clinic; Elvin Kedhi MD, PhD, Isala Klinieken; Robert K. Riezebos, MD, PhD, Cardio Research Hartcentrum OLVG; Harry Suryapranata, MD, Radboudumc; Ruben Ramos, MD, Hospital de Santa Marta; Fausto J. Pinto, PhD, Santa Maria University Hospital, Cardiology Department, CHLN; Nuno Ferreira, MD, Centro Hospitalar de Vila Nova de Gaia/Espinho, EPE; Luis Guzman, MD, Instituto Medico DAMIC; Julio César Figal, MD, Fundación Favaloro; Carlos Alvarez, MD, Hospital Italiano Regional del Sur Bahia Blanca; Javier Courtis, MD, Clinica Romagosa and Clinica De La Familia; Lilia Schiavi, MD, Clinica Del Prado; Mariano Rubio, MD, Clínica Privada Vélez Sarsfield; Gerard Patrick Devlin, MD, Waikato Hospital; Ralph Alan Huston Stewart, MCChB, MD, Auckland City Hospital; Sasko Kedev, MD, PhD, University Clinic of Cardiology; Claes Held, MD, PhD (Uppsala University); Johannes Aspberg, MD, Karolinska Institutet at Danderyd Hospital; Tali Sharir, MD, Assuta Medical Centers; Arthur Kerner, MD, Rambam Medical Center; Keiichi Fukuda, MD, PhD, Keio University; Satoshi Yasuda, MD, PhD, National Cerebral and Cardiovascular Center; Shigeyuki Nishimura, MD, Saitama Medical University; Kaatje Goetschalckx, MD, University Hospital Leuven; Chung-Lieh Hung, MD, Mackay Memorial Hospital; Mpiko Ntsekhe, MD, Groote Schuur Hospital / University of Cape Town; Tiziano Moccetti, MD, Cardiocentro; Magdy Abdelhamid, MD, Cairo University; Calin Pop, MD, PhD, Emergency County Hospital Baia Mare; Bogdan A. Popescu, MD, PhD, Emergency Institute of Cardiovascular Diseases ''Prof. Dr. C. C. Iliescu''; Mouaz H. Al-Mallah, MD MSc, King AbdulAziz Cardiac Center; Walter Enrique Mogrovejo Ramos, MD, Instituto Neuro Cardiovascular De Las Americas; Srun Kuanprasert, MD, Maharaj Nakorn Chiang Mai Hospital; Sukit Yamwong, MD, Ramathibodi Hospital; Ahmad Khairuddin, MD, Institut Jantung Negara. Other Members: Sean M. O'Brien, PhD (Duke Clinical Research Institute, Duke University Medical Center); William E. Boden, MD, (VA New England Healthcare System Boston); Bruce Ferguson, MD (Eisenhower Medical Center); Robert Harrington, MD (Stanford University); Gregg W. Stone, MD (Cardiovascular Research Foundation); David Williams, MD (Brigham & Women's Hospital, Harvard Medical School); Sripal Bangalore, MD, MHA (Cardiovascular Clinical Research Center, New York University School of Medicine); Jeffrey Berger, MD (Cardiovascular Clinical Research Center, New York University School of Medicine); Jonathan Newman, MD, MPH (Cardiovascular Clinical Research Center, New York University School of Medicine); Harmony R. Reynolds, MD (Cardiovascular Clinical Research Center, New York University School of Medicine); Mandeep Sidhu, MD (Albany Medical); Karen P. Alexander, MD (Duke Clinical Research Institute, Duke University Medical Center); Daniel B, Mark, MD, MPH (Duke University Medical Center); Leslee J. Shaw, PhD (Weill Cornell Medicine); John A. Spertus, MD, MPH (University of Missouri-Kansas City School of Medicine); Daniel S. Berman, MD (Cedars-Sinai Medical Center); Bernard R. Chaitman, MD (St Louis University School of Medicine); Rolf Doerr, MD (Praxisklinik Herz und Gefaesse); Vladimir Dzavik, MD (University of Toronto General hospital); Shaun G. Goodman, MD, MSc (St. Michael’s Hospital, University of Toronto); Gilbert Gosselin, MD (Montreal Heart Institute); Claes Held, MD, PhD (Uppsala University); Lixin Jiang, MD, PhD (Fuwai Hospital); Matyas Keltai, MD, PhD, DSc (Semmelweis University); Shun Kohsaka, MD (Keio University); Renato D. Lopes, MD, PhD (Duke Clinical Research Institute, Duke University Medical Center); Jose Luis Lopez-Sendon, MD, PhD (La Paz University Hospital); Aldo Maggioni, MD (Associazione Nazionale Medici Cardiologi Ospedalieri - ANMCO); GB John Mancini, MD (Vancouver General Hospital); C. Noel Bairey Merz, MD (Cedars-Sinai); James K. Min, MD (Weill Cornell Medicine); Michael H. Picard, MD (Massachusetts General Hospital, Harvard Medical School); Witold Ruzyllo, MD, PhD (The Cardinal Stefan Wyszynski Instititue of Cardiology); Joseph B. Selvanayagam, MBBS(Hons), DPhil (past member, South Australian Health and Medical Research Institute Ltd); Roxy Senior, MD, DM (Royal Brompton Hospital; Northwick Park Hospital); Philippe-Gabriel Steg, MD (French Alliance for Cardiovascular Trials and Hopital Bichat); Hanna Szwed, MD, PhD (Institute of Cardiology, Warsaw); William Weintraub, MD (Christiana Care Hospital); Harvey D. White, MB ChB, DSc (Green Lane Cardiovascular Services); Christie Ballantyne, MD (Baylor St. Lukes Medical Center); Karen J. Calfas, PhD (San Diego State University); Michael Davidson, MD (New Chicago Medicine); Peter H. Stone, MD (Brigham & Women's Hospital, Harvard Medical School); Matthias Friedrich, MD (McGill University Health Centre); Rory Hachamovitch, MD (Cleveland Clinic); Raymond Kwong, MD (Brigham & Women’s Hospital); Frank Harrell, PhD (Vanderbilt University); Iftikhar Kullo, MD (Mayo Clinic); Bruce McManus, MD, PhD (University of British Columbia); David J. Cohen, MD (Mid America Heart Institute); Raffaele Bugiardini, MD (University of Bologna); Jelena Celutkiene, MD, PhD (Vilnius University Hospital Santariskes Clinic); Jorge Escobedo, MD (Instituto Mexicano del Seguro Social); Angela Hoye, MD (The University of Hull/Castle Hill Hospital); Radmila Lyubarova, MD (Albany Medical Center Hospital); Deirdre Mattina, MD (Henry Ford Health System); Jesus Peteiro, MD (Complexo Hospitalario Universitario A Coruña (CHUAC) Sergas, Department of Cardiology, INIBIC A Coruña, CIBER-CV, Universidad de A Coruña); Samuel Nwosu, MS (Vanderbilt University Medical Center); Samuel Broderick, MS (Duke Clinical Research Institute, Duke University Medical Center); Derek Cyr, PhD (Duke Clinical Research Institute, Duke University Medical Center); Frank Rockhold, PhD (Duke Clinical Research Institute, Duke University Medical Center); Kevin Anstrom PhD (Duke Clinical Research Institute, Duke University Medical Center); Philip Jones, MS (Mid America Heart Institute), Lawrence Phillips, MD (New York University Langone Health); Sean W. Hayes, MD (Cedars-Sinai); John D. Friedman, MD (Cedar-Sinai); R. James Gerlach, MD (Cedars-Sinai); Raymond Y. Kwong, MD (Brigham & Women’s Hospital); Francois Pierre Mongeon, MD (Montreal Heart Institute); Judy Hung, MD (Massachusetts General Hospital); Marielle Scherrer-Crosbie, MD, PhD (Perelman School of Medicine); Xin Zeng, MD (Massachusetts General Hospital, Harvard Medical School); Ziad Ali, MD (Cardiovascular Research Foundation); Philippe Genereux, MD (Cardiovascular Research Foundation); Reza Arsanjani, MD (Weill Cornell Medicine); Matthew Budoff, MD (David Geffen School of Medicine at UCLA); Jonathan Leipsic, MD (St Paul’s Hospital); Rine Nakanishi, MD (Toho University); Tricia Youn, MD (Weill Cornell Medicine); Francesco Orso, MD (Associazione Nazionale Medici Cardiologi Ospedalieri); Antonio Carlos Carvalho, MD, PhD (Unifesp - Hospital Sao Paulo); Haibo Zhang, MD (China Oxford Centre for International Health Research); Lihua Zhang, MD, PhD (China Oxford Centre for International Health Research); Rafael Diaz, MD (past member, Estudios Clínicos Latino America); Frans Van de Werf, MD, PhD (KU Leuven Research & Development); Kaatje Goetschalckx, MD (KU Leuven Research & Development),Yves D. Rosenberg, MD, MPH (National Heart, Lung, and Blood Institute), Jerome Fleg, MD (National Heart, Lung, and Blood Institute); Ruth Kirby (National Heart, Lung, and Blood Institute); and Neal Jeffries, PhD (National Heart, Lung, and Blood Institute).

Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily reflect the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the US Department of Health and Human Services.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank study participants and enrolling site study teams for their contributions that made this trial possible. Thanks to Anna Naumova, MA, New York University School of Medicine for manuscript preparation. Compensation was received from a funding source for the contributions. ISCHEMIA group member Dr Carvalho is deceased.