One-Year Outcomes in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction Prescribed Quadruple Medical Therapy at Discharge
Key result
Quadruple therapy at discharge leaves older HFrEF patients with a ~37% 1-year event rate.
- 95% CI 34.4-39.8
- n=20,651
Key Points
- Substantial residual risk of mortality and readmission persists among older patients prescribed quadruple medical therapy for heart failure with reduced ejection fraction.
- Over one year, cumulative mortality or rehospitalization reached 37.1% for patients receiving quadruple medical therapy, alongside a 19.3% all-cause mortality rate.
- Retrospective cohort study evaluated 20 651 registry admissions across 532 hospitals to assess heart failure with reduced ejection fraction discharge regimens.
- Highlights that discharge prescription of quadruple medical therapy leaves older adults with heart failure with reduced ejection fraction facing substantial residual risk.
Study Design
Type
Cohort (n=20,651)
Multicenter
Yes
Structured PICO
P
Population
20,651 Medicare beneficiaries hospitalized for HFrEF, of whom 1,490 were prescribed quadruple medical therapy at discharge and followed for 12 months.
E
Exposure
Quadruple medical therapy (angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor) at any dose prescribed at the time of hospital discharge.
O
Outcome
Mortality, heart failure hospitalization, composite of mortality or heart failure hospitalization, and per-patient health care expenditure (Medicare Part A and B inpatient and outpatient costs) over 12-month follow-up.composite
Even when prescribed guideline-directed quadruple medical therapy at discharge, older US patients hospitalized for HFrEF face a substantial 1-year residual risk of mortality or readmission (37.1%).
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“We're talking strikingly large benefits. Compared to almost anything else we do in cardiology, it's hard to find treatment effects this large affecting this number of individuals each year. The impact we could have with optimal implementation of these therapies is profound.”
“We need to turn our thinking on its head about heart failure in clinical practice.”
“For hospitalized patients with HFrEF, there is an imperative to overcome these timid algorithms and timid thinking. They should be on full quadruple therapy before discharge.”
Implication
Clinicians must revise expectations for outcomes with quadruple therapy in older HFrEF; leaves open need for novel therapies targeting residual events.
Abstract
Importance Among patients with heart failure with reduced ejection fraction (HFrEF) in US clinical practice, the residual risk of poor clinical outcomes despite quadruple medical therapy is not well characterized. Objective To evaluate clinical outcomes and health care costs among patients hospitalized for HFrEF prescribed quadruple medical therapy at discharge. Design, Setting, and Participants This retrospective cohort study examined Medicare beneficiaries hospitalized for HFrEF in the Get With The Guidelines–Heart Failure registry and discharged from US hospitals receiving any dose of quadruple medical therapy (angiotensin receptor–neprilysin inhibitor, β-blocker, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor) between July 1, 2021, and December 31, 2023. Data analysis was conducted from October 2024 through March 2025. Exposure Prescription of quadruple medical therapy (angiotensin receptor–neprilysin inhibitor, β-blocker, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor) at time of hospital discharge. Main Outcomes and Measures The primary outcomes were mortality, HF hospitalization, mortality or HF hospitalization, and per-patient health care expenditure (Medicare Part A and B inpatient and outpatient costs, in 2023 US dollars). Results Among 20 651 patients with HFrEF eligible for quadruple medical therapy across 532 US hospitals, 1490 (7.2%) were prescribed quadruple therapy at discharge, with high between-hospital variance (median odds ratio, 2.04; 95% CI, 1.89-2.24). Median (IQR) age of patients prescribed quadruple therapy was 74 (69-81) years, and 543 patients (36.4%) were women. Over 12-month follow-up, cumulative incidences of all-cause mortality, HF hospitalization, and all-cause mortality or HF hospitalization were 19.3% (95% CI, 17.3%-21.4%), 26.0% (95% CI, 23.6%-28.5%), and 37.1% (95% CI, 34.4%-39.8%), respectively. Median (IQR) 12-month per-patient health care expenditure was $27 956 ($7478-$61 126). Twelve-month mortality and HF hospitalization outcomes were similar for patients prescribed quadruple medical therapy at discharge in the first half vs the second half of the study period. Conclusions and Relevance In this nationwide cohort study, even when prescribed quadruple medical therapy, older patients hospitalized for HFrEF in US clinical practice face substantial residual risk of death and HF readmission and often accrue high health care costs.
Discussion
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Cite This Study
Greene et al. (2026) conducted a cohort in Heart failure with reduced ejection fraction (HFrEF) (n=20,651). Quadruple medical therapy (angiotensin receptor-neprilysin inhibitor, β-blocker, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor) was evaluated on Mortality, HF hospitalization, mortality or HF hospitalization, and per-patient health care expenditure (95% CI 34.4-39.8). Older patients hospitalized for HFrEF and prescribed quadruple medical therapy at discharge faced a 37.1% cumulative incidence of mortality or HF hospitalization at 12 months.