Characterization of ischemic etiology in heart failure with reduced ejection fraction randomized clinical trials: A systematic review and meta-analysis

Aims: We investigated how ischemic etiology has been assigned in heart failure with a reduced ejection fraction (HFrEF) randomized controlled trials (RCTs). Methods and results: We 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). Conclusions: An 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.