• Marco Canepa, Gianluca Anastasia, Pietro Ameri, Rocco Vergallo, Christopher M O'Connor, Gianfranco Sinagra, and Italo Porto.
• Cardiovascular Unit, Department of Internal Medicine, University of Genova, Italy; Cardiovascular Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy. Electronic address: marco.canepa@unige.it.
• Eur. J. Intern. Med. 2025 Feb 11.

AimsWe investigated how ischemic etiology has been assigned in heart failure with a reduced ejection fraction (HFrEF) randomized controlled trials (RCTs).Methods And ResultsWe performed a systematic review and meta-analysis of definitions, rates of ischemic etiology and of each ischemic definition component: i) coronary artery disease (CAD), ii) myocardial infarction (MI), iii) coronary revascularization, and iv) prior/current angina. A total of 145 HFrEF RCTs were selected, of which 133 (91.7 %) enrolling both ischemic and non-ischemic patients (629 patients/study on average, median age 64.8 years and ejection fraction 28.2 %). The majority of these RCTs (84.2 %) lacked of clear ischemic etiology definition. Rate of ischemic etiology was 57.8 % (122 RCTs, 169,855 patients), of CAD 53.8 % (25 RCTs, 18,756 patients), of prior MI 46.7 % (57 RCTs, 80,582 patients), of prior revascularization 39.9 % (32 RCTs, 30,730 patients), and of prior/current angina 25.5 % (22 RCTs, 25,572 patients). In studies presenting both variables, prior MI showed the strongest correlations with assigned ischemic etiology (β = 0.84, p < 0.0001, 49 RCTs), followed by prior/current angina (β = 0.84, p < 0.0001, 20 RCTs), prior revascularization (β = 0.30, p = 0.006, 28 RCTs), whereas CAD had no significant correlation (β = 0.29, p = 0.162, from 17 RCTs). Rate of prior MI decreased over time (1986-2007: 51.4 ± 11.6 %; 2008-2016: 48.2 ± 8.8 %; 2017-2023: 41.4 ± 16.6 %; p = 0.057), whereas the one of prior revascularization increased (28.3 ± 11.2 %; 40.7 ± 19.6 %; 49.3 ± 19.4 %; p = 0.048).ConclusionsAn accurate definition of ischemic etiology is mostly lacking in HFrEF RCTs, and primarily assigned based on investigators clinical judgment, sometimes in the presence of a prior MI, although the rate of this component showed a decline over time.Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.

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