One-Year Outcomes in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction Prescribed Quadruple Medical Therapy at Discharge

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.