Substantial Residual Risk and High Costs Persist in HFrEF Despite Optimal Quadruple Therapy at Discharge

Introduction

The management of heart failure with reduced ejection fraction (HFrEF) has undergone a paradigm shift over the last decade. The transition from a sequential titration of therapies to the simultaneous or rapid initiation of the four pillars of guideline-directed medical therapy (GDMT)—angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter 2 inhibitors (SGLT2i)—now represents the gold standard of care. Clinical trials have consistently demonstrated that this quadruple therapy significantly reduces mortality and hospitalization. However, the translation of these clinical trial results into real-world practice often faces hurdles, and the residual risk remaining for patients successfully initiated on all four classes remains under-characterized. A recent nationwide cohort study published in JAMA Cardiology by Greene et al. (2026) provides a sobering look at the clinical and economic trajectory of these patients following hospital discharge.

Study Highlights

The study offers several critical insights into the current state of HFrEF management in the United States:

Low Implementation Rates

Despite the clear benefits, only 7.2% of eligible patients were prescribed quadruple therapy at the time of discharge.

High Residual Risk

Among those receiving quadruple therapy, the one-year risk of death or heart failure (HF) hospitalization was 37.1%.

Economic Burden

The median 12-month healthcare expenditure for these patients was $27,956, driven largely by inpatient costs.

Hospital Variation

There was significant variation between hospitals in the likelihood of prescribing quadruple therapy, with a median odds ratio of 2.04.

Background and Disease Burden

Heart failure remains a leading cause of morbidity and mortality globally, particularly among the elderly. In the United States, HF is a primary driver of hospitalizations and carries a staggering economic burden. The ‘vulnerable period’—the first 30 to 90 days following a heart failure hospitalization—is a time of exceptionally high risk for readmission and death. While GDMT is designed to mitigate this risk, clinical inertia and concerns over polypharmacy, hypotension, or renal function often lead to sub-optimal prescribing at discharge. The 2022 AHA/ACC/HFSA guidelines strongly recommend the initiation of all four pillars of GDMT, yet the real-world outcomes for those who actually receive this ‘optimal’ regimen have not been well-defined until now.

Study Design and Methodology

This retrospective cohort study utilized the Get With The Guidelines-Heart Failure (GWTG-HF) registry, linked with Medicare administrative claims data. The researchers focused on Medicare beneficiaries (aged 65 and older) hospitalized for HFrEF (ejection fraction ≤40%) and discharged between July 2021 and December 2023. The exposure of interest was the prescription of quadruple medical therapy at discharge, defined as receiving an ARNI, a beta-blocker, an MRA, and an SGLT2i. The study primary endpoints were all-cause mortality, HF hospitalization, a composite of mortality or HF hospitalization, and total Medicare Part A and B expenditures over a 12-month follow-up period. This design allowed for a robust assessment of real-world outcomes in a population often excluded from or underrepresented in randomized controlled trials due to age and multimorbidity.

Key Findings: A Reality Check for HFrEF Management

The analysis included 20,651 eligible patients across 532 US hospitals. The results highlight a significant gap between guideline recommendations and clinical practice, as well as the limits of pharmacological intervention alone.

The Prescription Gap

Only 1,490 patients (7.2%) were discharged on quadruple therapy. While this number showed some increase over the study period, the overall uptake remains remarkably low. The study also noted that patients receiving quadruple therapy were generally younger (median age 74) compared to those not receiving it.

Clinical Outcomes

Despite being on the best available medical regimen, the outcomes at one year were concerning. The cumulative incidence of all-cause mortality was 19.3%. When looking at heart failure hospitalizations, 26.0% of patients were readmitted within a year. The composite endpoint of death or HF hospitalization reached 37.1%. These figures suggest that while quadruple therapy is life-saving, it does not eliminate the high-risk nature of the HFrEF syndrome, especially in an older population with significant comorbidities.

Healthcare Expenditures

The economic data showed a median per-patient cost of $27,956 over 12 months. The interquartile range was wide ($7,478–$61,126), reflecting a subset of ‘high-utilizer’ patients who experience multiple readmissions or prolonged hospital stays. This underscores that even when medications are optimized, the cost of managing heart failure remains a significant challenge for the healthcare system.

The Role of Hospital Culture

The significant between-hospital variance (MOR 2.04) suggests that the likelihood of receiving optimal therapy is heavily influenced by the specific hospital’s protocols and culture rather than just patient-level factors. Some institutions are clearly more aggressive in implementing new guidelines than others.

Expert Commentary and Clinical Interpretation

The findings from Greene et al. provoke several questions regarding the ‘residual risk’ in heart failure. Why is the risk still so high? Several factors may contribute:

The Severity of Post-Hospitalization HFrEF

Patients hospitalized for HF represent a higher-risk phenotype than those in stable outpatient trials. The hospitalization itself often signals a transition to a more advanced stage of the disease where the myocardium and peripheral organs (like the kidneys) are increasingly resistant to therapy.

Dosing and Adherence

The study measured prescriptions at discharge, but it did not account for whether patients were titrated to target doses or whether they remained adherent to the quadruple regimen throughout the year. Sub-target dosing is a known issue in GDMT implementation.

Multimorbidity

The median age of 74 suggests a high prevalence of non-cardiac comorbidities, such as chronic kidney disease, COPD, and frailty, which contribute to both mortality and the need for hospitalization, regardless of the quality of HF-specific care.

Biological Plausibility of Residual Risk

Even with quadruple therapy, pathways involving inflammation, fibrosis, and advanced secondary mitral regurgitation may remain unaddressed. This suggests that for many patients, pharmacological therapy is a foundation that must be supplemented with device therapies (e.g., ICD, CRT) or advanced heart failure interventions.

Conclusion and Implications for Practice

The study by Greene and colleagues serves as a critical reminder that while quadruple medical therapy is a cornerstone of HFrEF management, it is not a panacea. The high rates of residual mortality and hospitalization, coupled with significant healthcare costs, highlight that the ‘vulnerable period’ extends far beyond the immediate post-discharge window. For clinicians, the takeaway is twofold: first, the urgent need to increase the uptake of quadruple therapy, as 92.8% of eligible patients are still not receiving it; and second, the necessity of a multidisciplinary approach that includes close follow-up, symptom monitoring, and management of comorbidities to mitigate the persistent risks. Future research should focus on strategies to close the implementation gap and investigate novel therapies that target the pathways responsible for this significant residual risk.

References

1. Greene SJ, Xu H, Chiswell K, et al. One-Year Outcomes in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction Prescribed Quadruple Medical Therapy at Discharge. JAMA Cardiol. 2026. doi:10.1001/jamacardio.2025.5339. 2. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. 3. Vaduganathan M, Claggett BL, Jhund PS, et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet. 2020;396(10244):121-128. 4. Butler J, Anker SD, Packer M. Redefining Heart Failure With Reduced Ejection Fraction: Adopting the 4 Pillars of Therapy. Circulation. 2021;143(8):763-766.