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Updated: Sep 9, 2025

Lumped-Parameter and Finite Element Modeling of Heart Failure with Preserved Ejection Fraction
Published on: February 13, 2021
Global real-world data on heart failure with reduced ejection fraction: challenges in optimization and sex
Andrea Attanasio1,2, Gianluigi Guida1,2, Giandomenico Disabato1,2
1Cardiology University Department, IRCCS Policlinico San Donato, Via Morandi 30, San Donato Milanese 20097, Italy.
Insights
Prescribing guideline-directed medical therapies (GDMT) for heart failure with reduced ejection fraction (HFrEF) significantly reduces mortality. However, clinical inertia in treatment initiation persists, particularly for older patients, highlighting a need for improved adherence to GDMT.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Medicine
Background:
- Heart failure with reduced ejection fraction (HFrEF) treatment has advanced, yet clinical inertia in prescribing guideline-directed medical therapies (GDMT) is common.
- GDMT includes four main classes of medications crucial for managing HFrEF.
- Understanding adherence and timing of GDMT prescription is vital for improving patient outcomes.
Purpose of the Study:
- To assess the impact of adherence and timing of GDMT prescription on mortality in HFrEF patients.
- To evaluate potential sex-based differences in GDMT prescription and outcomes.
- To identify barriers to optimal GDMT utilization.
Main Methods:
- Retrospective analysis of a global cohort using the TriNetX database.
- Patients with HFrEF were categorized into four groups based on the number of GDMT classes prescribed.
- Primary endpoint was all-cause mortality; secondary analyses examined time to quadruple therapy and sex differences.
Main Results:
- Only 20% of HFrEF patients achieved quadruple therapy, with mineralocorticoid receptor antagonists (MRA) and SGLT2 inhibitors (SGLT2i) being least prescribed, especially in older/frail patients.
- Each additional GDMT class significantly reduced mortality (p < 0.001).
- Time to quadruple therapy within the first year did not significantly impact mortality; no significant sex differences in survival were observed.
Conclusions:
- Clinical inertia in prescribing GDMT for HFrEF remains a significant barrier to optimal care, particularly for vulnerable patient groups.
- Further research is needed to address sex-related differences in drug efficacy and patient characteristics for HFrEF.
- Strategies to overcome clinical inertia are essential for improving survival rates in HFrEF.
Aims:
Despite the advancements in the treatment of patients with heart failure with reduced ejection fraction (HFrEF), clinical inertia regarding the prescription of the four classes of guideline-directed medical therapies (GDMT) remains prevalent. This study aims to assess how adherence and time of prescription to GDMT in HFrEF impact mortality. Additionally, it seeks to evaluate sex differences in prescription and outcome.
Methods And Results:
The study retrospectively analysed data worldwide using the TriNetX database. Patients with HFrEF were divided into four groups (G1-G4) based on the number of classes of GDMT prescribed. The primary endpoint was all-cause mortality. Additional analysis was performed in the G4 group to examine the impact of the time to reach quadruple therapy on mortality. An age-matched subgroup analysis was conducted to assess whether sex influenced mortality. The total cohort included 17 668 patients (68% men, mean age 66.7 ± 14.6). Only 20% of patients received quadruple therapy; the least heart failure (HF) medications prescribed were mineralocorticoid receptor antagonists (39%) and sodium-glucose cotransporter-2 inhibitors (33%), especially among older and frail patients. Each additional HF therapy was associated with significant mortality reduction (P-value < 0.001 for each additional class prescribed). However, the timing of full treatment implementation within the first year did not significantly affect mortality in the G4 group. No significant sex-based differences in survival were found in the age-matched analysis.
Conclusion:
Clinical inertia remains a critical issue, especially in those who may most benefit from HF therapy. Further clinical trials should specifically assess sex-related differences in drug efficacy and patient characteristics.
Lay Summary:
Heart failure with reduced ejection fraction is a serious condition that affects many people worldwide. This study looked at how well heart failure medications are being used and their impact on survival. Out of all patients included, only a small percentage received all the recommended treatments, even though using more medications was linked to better survival. Differences between men and women were also noted, with women being older and having more health problems, but survival rates were similar when comparing men and women of the same age. These results highlight the need for better treatment approaches to improve outcomes for all patients.
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