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


Harmony R. Reynolds, NYU Grossman School of Medicine
Leslee J. Shaw, Weill Cornell Medicine
James K. Min, Weill Cornell Medicine
John A. Spertus, UMKC School of Medicine
Bernard R. Chaitman, St. Louis University School of Medicine
Daniel S. Berman, Cedars-Sinai Medical Center
Michael H. Picard, Harvard Medical School
Raymond Y. Kwong, Brigham and Women's Hospital
C. Noel Bairey-Merz, Cedars-Sinai Medical Center
Derek D. Cyr, Duke Clinical Research Institute
Renato D. Lopes, Duke Clinical Research Institute
Jose Luis Lopez-Sendon, Hospital Universitario La Paz
Claes Held, Uppsala Universitet
Hanna Szwed, Instytut Kardiologii im. Prymasa Tysiaclecia Stefana Kardynała Wyszynskiego
Roxy Senior, Royal Brompton Hospital
Gilbert Gosselin, Institut de Cardiologie de Montreal
Rajesh Gopalan Nair, Government Medical College
Ahmed Elghamaz, Royal Brompton Hospital
Olga Bockeria, Bakulev National Medical Research Center for Cardiovascular Surgery
Jiyan Chen, Guangdong General Hospital
Alexander M. Chernyavskiy, E.N. Meshalkin National Medical Research Center
Balram Bhargava, All India Institute of Medical Sciences, New Delhi
Jonathan D. Newman, NYU Grossman School of Medicine
Sasa B. Hinic, Medical Center Bezanijska Kosa
Joanna Jaroch, Wroclaw Medical University
Angela Hoye, Castle Hill Hospital
Jeffrey Berger, NYU Grossman School of Medicine
William E. Boden, VA Medical Center
Sean M. O'Brien, Duke Clinical Research Institute
David J. Maron, Stanford University School of Medicine
Judith S. Hochman, NYU Grossman School of Medicine

Document Type

Journal Article

Publication Date



JAMA Cardiology








© 2020 American Medical Association. All rights reserved. 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) (353 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 1361 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 [16.4%] 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: Identifier: NCT01471522.