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Published on: April 17, 2021
Characterization of ischemic etiology in heart failure with reduced ejection fraction randomized clinical trials: A
Marco Canepa1, Gianluca Anastasia2, Pietro Ameri1
1Cardiovascular Unit, Department of Internal Medicine, University of Genova, Italy; Cardiovascular Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Insights
Most heart failure with reduced ejection fraction (HFrEF) randomized controlled trials (RCTs) lack clear definitions for ischemic etiology. Assignment often relies on clinical judgment, with prior myocardial infarction (MI) being a key factor, though its reporting has declined.
Area of Science:
- Cardiology
- Clinical Trials
- Heart Failure Research
Background:
- Heart failure with reduced ejection fraction (HFrEF) is a significant cardiovascular condition.
- Accurate etiological classification, particularly ischemic versus non-ischemic, is crucial for guiding treatment.
- Randomized controlled trials (RCTs) are vital for advancing HFrEF therapies.
Purpose of the Study:
- To systematically review and analyze the methods used to assign ischemic etiology in HFrEF RCTs.
- To assess the prevalence and definitions of ischemic heart disease components within these trials.
- To identify trends in the reporting of ischemic etiology over time.
Main Methods:
- Systematic review and meta-analysis of 145 HFrEF RCTs.
- Extraction and analysis of data on definitions, rates of ischemic etiology, and specific components (coronary artery disease, myocardial infarction, revascularization, angina).
- Correlation analysis to determine the strength of association between components and assigned ischemic etiology.
Main Results:
- A majority of HFrEF RCTs (84.2%) lacked clear definitions for ischemic etiology.
- Ischemic etiology was assigned in 57.8% of patients across 122 RCTs.
- Prior myocardial infarction (MI) showed the strongest correlation with assigned ischemic etiology, but its reported rate decreased over time, while prior revascularization increased.
Conclusions:
- There is a significant lack of standardized definitions for ischemic etiology in HFrEF RCTs.
- Investigator clinical judgment frequently dictates the assignment of ischemic etiology.
- The declining rate of reported prior MI warrants attention, alongside the increasing rate of prior revascularization, in future trial design and 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.
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