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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. Published online March 30, 2020. 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.


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  ClinicalTrials.gov Identifier: NCT01471522