Association of Sex With Severity of Coronary Artery Disease, Ischemia, and Symptom Burden in Patients With Moderate or Severe Ischemia: Secondary Analysis of the ISCHEMIA Randomized Clinical Trial | Cardiology | JAMA Cardiology | JAMA Network
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Figure.  Sex Differences in Ischemia Severity, Atherosclerosis, and Angina Among Randomized ISCHEMIA Trial Participants
Sex Differences in Ischemia Severity, Atherosclerosis, and Angina Among Randomized ISCHEMIA Trial Participants

Stress imaging includes stress nuclear, stress echocardiography, and stress cardiac magnetic resonance imaging. Number of vessels diseased is shown based on the threshold of 50% stenosis. Frequency of angina is determined based on the Seattle Angina Questionnaire angina frequency scale, where 100 indicates no angina; 61 to 99, monthly angina; 31 to 60, weekly angina; and 0 to 30, daily angina. ETT indicates exercise tolerance test.

Table 1.  CCTA Findings by Sex Among Enrolled Participants
CCTA Findings by Sex Among Enrolled Participants
Table 2.  Likelihood of Obstructive CAD by Sex and Stress Test Findings, by Modality, in Enrolled Participants
Likelihood of Obstructive CAD by Sex and Stress Test Findings, by Modality, in Enrolled Participants
Table 3.  Randomized Participant Baseline Characteristics by Sex
Randomized Participant Baseline Characteristics by Sex
Table 4.  Stress Test Results, Coronary Anatomy on CCTA, and Angina by Sex Among Randomized Participants
Stress Test Results, Coronary Anatomy on CCTA, and Angina by Sex Among Randomized Participants
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Original Investigation
March 30, 2020

Association of Sex With Severity of Coronary Artery Disease, Ischemia, and Symptom Burden in Patients With Moderate or Severe Ischemia: Secondary Analysis of the ISCHEMIA Randomized Clinical Trial

Author Affiliations
  • 1NYU Grossman School of Medicine, New York, New York
  • 2Weill Cornell Medicine, New York, New York
  • 3UMKC School of Medicine, Kansas City, Missouri
  • 4St Louis University School of Medicine, St Louis, Missouri
  • 5Cedars-Sinai Medical Center, Los Angeles, California
  • 6Massachusetts General Hospital and Harvard Medical School, Boston
  • 7Brigham and Women’s Hospital, Boston, Massachusetts
  • 8Cedars-Sinai Smidt Heart Institute, Los Angeles, California
  • 9Duke Clinical Research Institute, Durham, North Carolina
  • 10Hospital Universitario La Paz. Idipaz. UAM. CIBER-CV, Madrid, Spain
  • 11Uppsala University, Uppsala, Sweden
  • 12National Institute of Cardiology, Warsaw, Poland
  • 13Northwick Park Hospital-Royal Brompton Hospital, London, United Kingdom
  • 14Montreal Heart Institute, Montreal, Quebec, Canada
  • 15Government Medical College, Kerla, India
  • 16National Research Center for Cardiovascular Surgery, Moscow, Russia
  • 17Guangdong General Hospital, Guangzhou, China
  • 18E.Meshalkin National medical research center of the Ministry of Health of the Russian Federation (E.Meshalkin NMRC), Moscow, Russia
  • 19All India Institute of Medical Sciences, New Delhi, India
  • 20UHC Bezanijska kosa, Belgrade, Serbia
  • 21Wroclaw Medical University, T. Marciniak Hospital, Wroclaw, Poland
  • 22The University of Hull/Castle Hill Hospital, Cottingham, United Kingdom
  • 23VA New England Healthcare System/Boston, Boston, Massachusetts
  • 24Department of Medicine, Stanford University, Stanford, California
JAMA Cardiol. 2020;5(7):773-786. doi:10.1001/jamacardio.2020.0822
Key Points

Question  When considering patients who have obstructive coronary artery disease and ischemia on stress testing, are there sex differences in severity of coronary artery disease, ischemia, and/or symptoms?

Findings  In this secondary analysis of the ISCHEMIA randomized clinical trial of 5179 patients, women had more frequent angina, less extensive coronary artery disease, and less severe ischemia than men. On multivariate analysis, female sex was independently associated with greater angina frequency.

Meaning  There may be inherent sex differences in the complex relationships between angina, ischemia, and atherosclerosis that may have implications for testing and treatment of patients with suspected coronary artery disease.

Abstract

Importance  While many features of stable ischemic heart disease vary by sex, differences in ischemia, coronary anatomy, and symptoms by sex have not been investigated among patients with moderate or severe ischemia. The enrolled ISCHEMIA trial cohort that underwent coronary computed tomographic angiography (CCTA) was required to have obstructive coronary artery disease (CAD) for randomization.

Objective  To describe sex differences in stress testing, CCTA findings, and symptoms in ISCHEMIA trial participants.

Design, Setting, and Participants  This secondary analysis of the multicenter ISCHEMIA randomized clinical trial analyzed baseline characteristics of patients with stable ischemic heart disease. Individuals were enrolled from July 2012 to January 2018 based on local reading of moderate or severe ischemia on a stress test, after which blinded CCTA was performed in most. Core laboratories reviewed stress tests and CCTAs. Participants with no obstructive CAD or with left main CAD of 50% or greater were excluded. Those who met eligibility criteria including CCTA (if performed) were randomized to a routine invasive or a conservative management strategy (N = 5179). Angina was assessed using the Seattle Angina Questionnaire. Analysis began October 1, 2018.

Interventions  CCTA and angina assessment.

Main Outcomes and Measures  Sex differences in stress test, CCTA findings, and symptom severity.

Results  Of 8518 patients enrolled, 6256 (77%) were men. Women were more likely to have no obstructive CAD (<50% stenosis in all vessels on CCTA) (352 of 1022 [34.4%] vs 378 of 3353 [11.3%]). Of individuals who were randomized, women had more angina at baseline than men (median [interquartile range] Seattle Angina Questionnaire Angina Frequency score: 80 [70-100] vs 90 [70-100]). Women had less severe ischemia on stress imaging (383 of 919 [41.7%] vs 1363 of 2972 [45.9%] with severe ischemia; 386 of 919 [42.0%] vs 1215 of 2972 [40.9%] with moderate ischemia; and 150 of 919 [16.3%] vs 394 of 2972 [13.3%] with mild or no ischemia). Ischemia was similar by sex on exercise tolerance testing. Women had less extensive CAD on CCTA (205 of 568 women [36%] vs 1142 of 2418 men [47%] with 3-vessel disease; 184 of 568 women [32%] vs 754 of 2418 men [31%] with 2-vessel disease; and 178 of 568 women [31%] vs 519 of 2418 men [22%] with 1-vessel disease). Female sex was independently associated with greater angina frequency (odds ratio, 1.41; 95% CI, 1.13-1.76).

Conclusions and Relevance  Women in the ISCHEMIA trial had more frequent angina, independent of less extensive CAD, and less severe ischemia than men. These findings reflect inherent sex differences in the complex relationships between angina, atherosclerosis, and ischemia that may have implications for testing and treatment of patients with suspected stable ischemic heart disease.

Trial Registration  ClinicalTrials.gov Identifier: NCT01471522

Introduction

Among patients with stable ischemic heart disease and acute coronary syndromes, women have a lesser extent of coronary atherosclerosis than men, despite a consistently higher risk profile including older age at presentation and a greater frequency of comorbidities.1-9 However, epicardial obstructive coronary artery disease (CAD) is more common among men, even when considering only patients with typical angina.10 In contrast, microvascular coronary dysfunction is more commonly seen among women as a cause of stable ischemic heart disease.11,12 Coronary artery spasm is a potential contributor to symptoms as well.13

Given the lower prevalence of obstructive CAD, previous studies have shown that diagnostic accuracy of stress testing is lower among women than men when considering the reference standard of obstructive CAD. In both sexes, specificity of stress testing for angiographically obstructive coronary stenoses is greater when a higher threshold for ischemia is used with various nonimaging stress testing modalities. Much of this evidence is from years past, used varied definitions for ischemia, and is fraught with selection bias. A contemporary evaluation of accuracy is not available. It remains unknown whether a more rigorous determination of the extent and severity of ischemia, using standardized approaches, increases the accuracy of testing to identify obstructive CAD in women.

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial (NCT01471522) enrolled and randomized participants based on the severity of ischemia and the presence of obstructive CAD. The main objective of this report was to analyze the possible sex differences in symptoms, ischemia severity, and anatomic severity of disease in the ISCHEMIA randomized clinical trial cohort because this trial cohort provides fewer confounding effects from the lower likelihood of finding any epicardial CAD in women.

Methods

The design of the ISCHEMIA trial has been published in detail.14,15 In brief, patients with known or suspected stable ischemic heart disease were selected for enrollment based on the finding of moderate or severe ischemia on a stress imaging test or severe ischemia on a nonimaging exercise tolerance test (ETT) and provided written informed consent. Ischemia severity was determined by sites before enrollment and assessed independently by experienced core laboratories. Thus, some randomized participants were deemed by core laboratories not to have moderate or severe ischemia, even though they were eligible for randomization by site determination of ischemia severity. Key exclusion criteria were acute coronary syndrome within the prior 2 months, left ventricular ejection fraction less than 35%, estimated glomerular filtration rate less than 30 mL/min, unacceptable angina severity despite maximal medical therapy, heart failure exacerbation within the last 6 months, or New York Heart Association class III or IV heart failure. Coronary computed tomography angiography (CCTA) was performed with the goal of excluding from randomization patients with 50% or greater left main coronary stenosis and participants with less than 50% stenosis of an epicardial coronary artery. Coronary computed tomography angiography was not required when estimated glomerular filtration rate was less than 60 mL/min or coronary anatomy was known to meet entry criteria based on prior testing, typically prior invasive angiography.14,16 Race/ethnicity were self-reported. Fully eligible participants were randomized to an invasive strategy or a conservative strategy.14 The study was approved by the NYU School of Medicine Institutional Review Board.

In this report, enrolled refers to patients who signed consent and were enrolled in the trial, and randomized refers to those who were randomized to the invasive vs conservative strategy. Screening logs were completed at sites intermittently as requested by the clinical coordinating center, recording only patients locally determined to meet ischemia entry criteria.

The predictive accuracy of stress testing for obstructive CAD was assessed by comparing the proportion of participants with obstructive disease who did and did not meet various trial defined stress test criteria. Values were computed comparing women vs men among patients whose stress test did vs did not meet trial defined criteria per the core laboratory.

Stress Imaging Definitions

On nuclear imaging, ischemia was quantified based on percent reversible ischemia of the left ventricle on a myocardial perfusion scan (severe, ≥15%; moderate, 10% to <15%; mild, 5% to <10%; none, <5%). On stress echocardiography, ischemia was quantified based on the number of segments with inducible hypokinesia or akinesia (severe, ≥4; moderate, 3; mild, 1 or 2; none, 0). On stress cardiac magnetic resonance imaging, ischemia was quantified based on percent reversible ischemia of the left ventricle (severe, ≥15%; moderate, 10% to <15%; mild, 5% to <10%; none, <5%). On nonimaging ETT, ischemia was categorized based on ST depression and workload (severe, ≥1.5 mm ST depression in 2 leads or ≥2 mm ST depression in 1 lead at a specified workload on exercise tolerance testing in the presence of exertional angina before or during the stress test; see Chiha et al4 for additional categories). Image interpretation used standard segmental models.17

CCTA Definitions

The Duke prognostic index is a validated ordinal categorical scale of severity of CAD based on CCTA.18 The segment stenosis score is defined as the sum across 16 coronary segments, with segmental score assigned as 0 if 0% stenosis, 1 if 1% to 24% stenosis, 2 if 25% to 49% stenosis, 3 if 50% to 69% stenosis, and 4 if 70% to 100% stenosis. The segment involvement score is defined similarly to the segment stenosis score, but the per-segment score is 0 for 0% stenosis and 1 for 1% to 100% stenosis.

Statistical Methods

Baseline characteristics are presented for enrolled participants by sex and randomized participants by sex. Data collection for enrolled participants who were not randomized was much less extensive than for those who were randomized. Imaging test results presented here represent core laboratory evaluation. Reasons for screen failure were tabulated by sex.

Differences between women and men were assessed using the χ2 test or Cochran-Armitage trend test to account for the ordered nature of categories. Continuous variables are presented as the number of nonmissing values and median (Q1, Q3); differences were assessed using the Wilcoxon rank sum test.

The accuracy of stress testing for obstructive CAD was assessed by comparing the proportion of participants with obstructive CAD (separately for ≥50% and ≥70% stenosis) for participants who did vs did not meet trial-defined stress test criteria. For women and men, the risk ratio (95% CI) and P value for the likelihood of obstructive CAD for participants whose stress test did vs did not meet the trial-defined criteria is reported in addition to the ratio (95% CI) and P value of the sex-specific risk ratios (women vs men). In a sensitivity analysis, we analyzed only participants without evidence of prior infarction on the stress test.

A multivariate proportional odds model was created to assess the association between the extent of angina and the extent of ischemia and CAD jointly within the subset of patients who have not had antianginal medications changed in the last 3 months. The Seattle Angina Questionnaire frequency scale was grouped into the following categories: absent (score of 100), monthly (61-99), weekly (31-60), and daily (0-30). The model was adjusted for the following baseline clinical characteristics: age, sex, race/ethnicity, hypertension, diabetes, smoking status, prior myocardial infarction, estimated glomerular filtration rate, left ventricular ejection fraction, and anti-anginal medical therapy. Age, estimated glomerular filtration rate, and left ventricular ejection fraction were included as restricted cubic splines with knots at the 10th, 50th, and 90th percentiles. P values were 2-sided, and the significance threshold was .05. Analysis began October 1, 2018.

Results

Among 2262 enrolled women and 6256 enrolled men, fewer women underwent CCTA (1524 of 2262 [67.4%] vs 4382 of 6256 [70.0%]; Table 1), but age was similar by sex. Women were more likely to have nonobstructive CAD (<50% stenosis in all vessels on CCTA) (352 of 1022 [34.4%] vs 378 of 3353 [11.3%]). The frequency of at least 50% stenosis was lower among women than men in every vessel (Table 1). Women were more likely than men to be excluded from randomization (odds ratio [95% CI] for randomization: 0.62 [0.55-0.69] after adjustment for age, race, estimated glomerular filtration rate, hypertension, diabetes, smoking status, prior myocardial infarction, qualifying stress test modality, and country of enrollment). The most common reasons for exclusion were insufficient ischemia in the opinion of the core laboratory and no obstructive CAD on study CCTA for both sexes (Table 1). Fewer enrolled women withdrew consent than enrolled men (66 of 1094 [6.0%] vs 195 of 2245 [8.7%]). However, among 5424 patients who were locally determined to be clinically eligible at sites completing screening logs, women were less likely to agree to participate (719 of 1552 women [46%] vs 2044 of 3872 men [53%]). A similar proportion of patients of both sexes were deemed by sites to be eligible for consent as recorded on the screening logs (1552 of 7277 women [21%] vs 3872 of 17 354 men [22%]. Clinical and stress test characteristics of enrolled participants by sex appear in eTable 1 in the Supplement.

We next evaluated the association between ischemia severity and CCTA findings by sex. The likelihood of obstructive CAD was higher when the core laboratory confirmed trial-eligible ischemia than when the core laboratory did not agree with the site that ischemia was moderate or severe. There was no difference in this association by sex (ratio of sex-specific rate ratios of 50% stenosis 1.03; 95% CI, 0.92-1.16; Table 2). There was no such sex difference for any individual stress test modality. In every subgroup defined by sex, stress test modality and stress test results, men had a higher likelihood of obstructive CAD than women. In a sensitivity analysis excluding participants with evidence of prior infarction on the stress test, results were unchanged (data not shown).

Sex Differences Among Randomized Participants

In the randomized cohort including 1168 women and 4011 men, hypertension and diabetes were more common among women, and women were slightly older (Table 3). Randomized women were less likely to have a smoking history or have a history of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting) but more likely to have prior history of heart failure.

Women were more likely to undergo stress imaging (924 of 1168 women [79.1%] vs 2985 of men 4011 [74.4%]). Among participants who had stress imaging, women were less likely than men to undergo nuclear imaging and more likely to have echocardiography or cardiac magnetic resonance imaging (Table 3). Women randomized after stress imaging had lesser severity of ischemia than men, driven by differences in the subset of participants enrolled after nuclear stress testing (Table 4 and Figure). On nuclear imaging, women had lower summed difference scores than men (median [interquartile range], 8 [7-11] vs 9 [7-12]). Women were less likely to exhibit severe ischemia (166 of 555 [30%] vs 802 of 2000 [40%]), more likely to have moderate ischemia (283 of 555 [51.0%] vs 920 of 2000 [46.0%]) and more likely to have mild or no ischemia (106 of 555 [19%] vs 278 of 2000 [14%]). Ischemia severity as determined by stress echo was nearly the same for women and men (median [interquartile range], 4 [3-5] segments with stress-induced wall motion abnormalities; Table 4). Ischemia severity by stress cardiac magnetic resonance imaging was also similar between women and men, although numbers were lower. There were no sex differences in severity of ischemia on ETT in the randomized cohort (189 of 226 women [84%] vs 862 of 988 men [87%] with severe ischemia).

Women were less likely to undergo exercise stress testing and more likely to have pharmacologic stress testing. Women who exercised achieved a lower peak metabolic equivalent level than men but attained a higher percentage of the maximal predicted heart rate (eTable 2 in the Supplement).

On CCTA, women had a lesser extent of CAD compared with men, with more single-vessel disease and less multivessel disease, particularly 3-vessel CAD, among women (Table 4 and Figure). The prevalence of left anterior descending disease was similar between randomized women and men, but right CAD and circumflex CAD were less frequent among women (Table 4). Sex differences in CCTA findings among only those participants with core laboratory-confirmed moderate or severe ischemia are presented in eTable 3 in the Supplement.

In contrast with less extensive CAD among randomized women in the ISCHEMIA trial and less severe ischemia on stress imaging among women, randomized women had lower scores on the Seattle Angina Questionnaire angina frequency scale, indicating a greater burden of angina (Table 4). Fewer women reported that they were free of angina in the last month (309 of 1156 [27%] vs 1447 of 3954 [37%]). The higher severity of symptoms among women was also reflected in provider assessment via the New York Heart Association classification and in self-reported dyspnea (Table 4). On multivariate analysis including demographics, clinical characteristics, ischemia severity and CCTA findings, female sex was independently associated with greater angina frequency (odds ratio, 1.41; 95% CI, 1.13-1.76; P < .001).

Sex differences in medications at the time of randomization are presented in eTable 4 in the Supplement. Laboratory values and vital signs are shown in eTable 5 in the Supplement. Women had higher low-density lipoprotein cholesterol at baseline and were less likely to be taking any statin, including high intensity statin.

Discussion

In this analysis of ISCHEMIA randomized clinical trial participants, women had a greater burden of angina symptoms than men, despite having less extensive CAD. This extends prior observations to a cohort selected based on the combination of high-risk stress testing results and obstructive CAD on CCTA. Overall, randomized women had less core laboratory-confirmed severe ischemia on stress imaging compared with randomized men, with no difference by sex in the likelihood of having core laboratory-confirmed trial-eligible ischemia on ETT.

Our analysis is novel in that we report sex-specific results of stress testing, CCTA, and anginal symptoms in a large ischemic heart disease trial cohort. Although numerous studies have evaluated sex differences in the extent of CAD, fewer have considered sex differences after excluding patients with nonobstructive CAD, which is more common among women.19,20 The ISCHEMIA randomized cohort offers an ideal resource to address this question because patients with no obstructive CAD were excluded from randomization and because patients were selected for enrollment based on stress testing alone rather than coronary angiographic results. Our findings of less extensive CAD and more angina among randomized female ISCHEMIA participants are similar to findings from the COURAGE21 and BARI 2D2 trials and from those of a Mayo Clinic cohort study, all of which selected patients based on conventional invasive angiography alone.1 Our data provide important confirmation with a different perspective because in these prior studies, participants were selected clinically for angiography, while in ISCHEMIA, CCTA was performed as a routine to determine anatomic eligibility among participants with moderate or severe ischemia, with detailed results blinded to patients and physicians2,14,21 reducing referral and survival biases.

The association between angina symptoms, epicardial stenosis severity, and ischemia is complex and appears to differ by sex. Across the spectrum of ischemic heart disease severity, women who have angina report more severe symptoms than men, even when the extent of disease is the same.2,8,21,22 It has been hypothesized that women may have more diffuse disease leading to ischemia in the setting of less extensive CAD, but we found that women had fewer segments affected by plaque. Our findings may relate to a greater contribution of mental stress–induced ischemia and to greater sensing or reporting of ischemic symptoms among women. In the ACIP trial,23 women had a similar number and duration of ischemic episodes to men as detected by ambulatory electrocardiography despite less extensive CAD on angiography. Mental stress is more likely to elicit ischemia among women than men, and mental stress–induced ischemia is not related to CAD severity among women,24 while it is in men. Women rated pain as more intense than men during objectively assessed ischemia and had more nonpain symptoms.25 Lower endorphin levels among women with CAD correlate with more chest pain in daily life.26 A greater severity of coexisting microvascular coronary disease and/or endothelial dysfunction among women may theoretically have contributed to our findings. The greater burden of angina in women is important, not only because symptoms are important to patients but because registry data show that angina is a predictor of cardiovascular death and myocardial infarction, independent of ischemia severity.27 The results of quality of life and outcomes in the ISCHEMIA trial by sex will be reported in the future.

Previous studies have shown that diagnostic accuracy of stress testing is lower among women than men when considering the reference standard of obstructive CAD. We confirm this in a cohort with moderate or severe ischemia but found no sex difference in the relative likelihood of obstructive CAD associated with more severe ischemia on stress testing.

The proportion of nonobstructive CAD based on CCTA findings, 34% among women and 11% among men, may be surprising given the requirement for a higher degree of ischemia on stress testing. However, this proportion is lower than in studies of invasive angiography to evaluate ischemia symptoms,28,29 and numerous studies have shown that true ischemia does occur in the setting of nonobstructive CAD.30 Unfortunately, we do not have data on angina symptoms in excluded participants. We believe that the requirement for moderate or severe ischemia is more likely to select for patients who have true ischemia, perhaps due to microvascular disease, but we cannot confirm this. Additional testing to confirm ischemia, such as coronary flow reserve testing, assessment of the index of microcirculatory resistance or nuclear mass spectroscopy, was not performed. The Changes in Ischemia and Angina (CIAO)–ISCHEMIA ancillary study (NCT02347215) enrolled patients with nonobstructive CAD on CCTA, evaluating changes in ischemia severity over time and how these changes relate to angina severity and the extent of nonobstructive atherosclerosis; CIAO enrolled a cohort that is nearly two-thirds female.

The proportion of randomized participants who are female (23%) is lower than the 35% we initially projected. This may be associated with the ischemia and CAD entry criteria. Our projection was likely too optimistic because the CLARIFY registry of stable ischemic heart disease patients included 23% women, and an analysis of appropriateness of revascularization included 25% women.22,31 These figures are very different from the 53% female cohort with potentially ischemic symptoms in the PROMISE trial32 of diagnostic testing because women are more likely to have negative tests than men. We worked closely with sites to maximize enrollment of eligible women in the trial. Women screened at sites were just as likely as men to be considered eligible for consent based on screening log data. Yet, a slightly lower proportion of women approached for consent agreed to participation. Once enrolled, women were slightly less likely to withdraw consent.

Limitations

Our analysis examined CAD severity as determined by CCTA, which was available in most participants. We recognize that CCTA results and invasive angiography findings may not be identical. Invasive angiography has been considered the reference standard for CAD severity, has the ability to assess collateral flow, and is the standard to which stress testing was originally compared. However, invasive angiography was not performed a priori for the trial in participants assigned to the conservative strategy. Fractional flow reserve can be derived from CCTA findings using proprietary software, but this was not available in the ISCHEMIA trial. Our analysis of the association between core laboratory confirmation of ischemia severity and atherosclerosis severity is limited by restriction to moderate or severe ischemia, so we were unable to report sensitivity or specificity of stress testing for obstructive CAD. We included 4 different stress testing modalities, which increases generalizability of trial results but limits our ability to detect sex differences for each of them. The steeper pressure-volume association in women and higher incidence of left ventricular hypertrophy have been implicated in increased symptoms in women with CAD, but we do not have access to measures of diastolic function parameters.

Conclusions

In conclusion, in the ISCHEMIA randomized trial population, identified on the basis of moderate or severe myocardial ischemia, women had more frequent angina, independent of their lesser extent and severity of coronary atherosclerosis than men and less severe ischemia as assessed by independent core laboratories. These results suggest that factors other than epicardial obstructive CAD underlie the severity of symptoms in women.

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Article Information

Corresponding Author: Harmony R. Reynolds, MD, Sarah Ross Soter Center for Women’s Cardiovascular Research, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 530 First Ave, SKI-9R, New York, NY 10016 (harmony.reynolds@nyulangone.org).

Accepted for Publication: February 28, 2020.

Published Online: March 30, 2020. doi:10.1001/jamacardio.2020.0822

Correction: This article was corrected on May 19, 2021, to fix data errors in the Abstract Results, Results, and tables.

Author Contributions: Dr Reynolds had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Reynolds, Shaw, Picard, Kwong, Lopes, Nair, Chernyavskiy, Hinic, Hochman.

Acquisition, analysis, or interpretation of data: Reynolds, Min, Spertus, Chaitman, Berman, Picard, Kwong, Bairey-Merz, Cyr, Lopez-Sendon, Held, Szwed, Senior, Gosselin, Nair, Elghamaz, Bockeria, Chen, Chernyavskiy, Bhargava, Newman, Hinic, Jaroch, Hoye, Berger, Boden, O’Brien, Maron, Hochman.

Drafting of the manuscript: Reynolds, Shaw, Picard, Kwong, Cyr, Chernyavskiy, Hinic, Hochman.

Critical revision of the manuscript for important intellectual content: Reynolds, Shaw, Min, Spertus, Chaitman, Berman, Picard, Kwong, Bairey-Merz, Cyr, Lopes, Lopez-Sendon, Held, Szwed, Senior, Gosselin, Nair, Elghamaz, Bockeria, Chen, Chernyavskiy, Bhargava, Newman, Jaroch, Hoye, Berger, Boden, O’Brien, Maron, Hochman.

Statistical analysis: Kwong, Cyr, Chernyavskiy, O’Brien.

Obtained funding: Reynolds, Gosselin, Hinic, Hochman.

Administrative, technical, or material support: Reynolds, Shaw, Min, Picard, Bairey-Merz, Senior, Gosselin, Nair, Elghamaz, Chen, Newman, Hinic, Hochman.

Supervision: Reynolds, Shaw, Picard, Bairey-Merz, Nair, Hinic, Hochman.

Conflict of Interest Disclosures: Dr Reynolds reports grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study and nonfinancial support from Abbott Vascular and BioTelemetry outside the submitted work. Dr Shaw reports grants from the NHLBI during the conduct of the study. Dr Min reports grants from the NHLBI during the conduct of the study; and other from Cleerly Inc, Arineta, and GE Healthcare outside the submitted work. Dr Spertus reports grants from the NHLBI during the conduct of the study; grants from the American College of Cardiology outside the submitted work; personal fees from AstraZeneca, Bayer, Novartis, Amgen, Merck, UnitedHealthcare, and Janssen Pharmaceuticals outside the submitted work; has a patent to copyright to the Seattle Angina Questionnaire; and is a member of the board of directors of Blue Cross and Blue Shield of Kansas City and Equity in Health Outcomes Sciences. Dr Chaitman reports grants from National Heart, Lung, and Blood Institute; consultant fees from Novo Nordisk, Merck, Daiichi Sankyo, XyloCor, Cirius Therapeutics, DisperSol Technologies, NGM Biopharmaceuticals, and Sun Pharma; and serves as a data and safety monitoring board member for Relypsaand Tricida. Dr Berman reports grants from National Heart, Lung, and Blood Institute during the conduct of the study and software royalties from Cedars-Sinai Medical Center. Drs Picard, Kwong, Cyr, Held, Szwed, Gosselin, Nair, Elghamaz, Bockeria, Chen, Chernyavskiy, Bhargava, Hinic, Jaroch, O’Brien, and Maron report grants from National Heart, Lung, and Blood Institute during the conduct of the study. Dr Bairey-Merz reports grants from National Heart, Lung, and Blood Institute; personal fees from iRhythm; grant support from Sanofi-Vascular; consultant for Medscape, Sanofi-Vascular, iRhythm, and Caladrius Biosciences; and reports honorarium for Abbott Diagnostics during the conduct of the study. Dr Lopes reports grants from National Heart, Lung, and Blood Institute; consulting for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola Pharmaceuticals, and Sanofi; and grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi outside the submitted work. Dr Lopez-Sendon reports grants from National Heart, Lung, and Blood Institute during the conduct of the study. Dr Senior reports grants from National Heart, Lung, and Blood Institute during the conduct of the study and speaker fees from Bracco, Lantheus Medical Imaging Boston USA, and Philips Healthcare outside the submitted work. Dr Newman reports grants from National Heart, Lung, and Blood Institute during the conduct of the study and grant K23HL125991 from National Institutes of Health. Dr Hoye reports grants from National Heart, Lung, and Blood Institute during the conduct of the study. Dr Berger reports grants from National Heart, Lung, and Blood Institute during the conduct of the study. Dr Hochman reports being principal investigator for the 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; St Jude Medical; Volcano Corporation; Arbor Pharmaceuticals; AstraZeneca; Merck Sharp & Dohme Corp; Omron Healthcare; and financial donations from Arbor Pharmaceuticals and AstraZeneca. No other disclosures were reported.

Funding/Support: This article was supported by National Heart, Lung, and Blood Institute (grants U01HL105907, U01HL105462, U01HL105561, U01HL105565). Abbott Vascular, Medtronic, St Jude Medical, Volcano Corporation, and Omron Healthcare donated devices for this study. Medications were provided by Amgen, Arbor Pharmaceuticals, AstraZeneca, and Merck Sharp & Dohme. Financial donations came from Arbor Pharmaceuticals and AstraZeneca.

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; VA 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 PC: 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, PC: 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; 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 (deceased); VA New York Harbor Health Care System: 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 L. Murphy Memorial VA Hospital: 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 (until December 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 Flt 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 O’Kane, 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; 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 Jr, 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, 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 Cardiovascuar 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: G. B. 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 (deceased); *(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 Bochat: 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; 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: Neal Jeffries, PhD; National Heart, Lung and Blood Institute. Past members/past organizations: Rafael Diaz, MD; Deceased: Antonio Carlos Carvalho, MD, PhD. eTable 6 in the Supplement lists study personnel, and eTable 7 in the Supplement lists the ISCHEMIA Committee, clinical coordinating center, and trial-related personnel.

Disclaimer: The content of this manuscript 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.

Meeting Presentation: This paper was presented at ACC 2020: American College of Cardiology 69th Scientific Session and Expo; March 28, 2020; virtual meeting.

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