Residual Clinical Risk and Economic Burden in HFrEF: Insights from the Quadruple Medical Therapy Era

Highlights

• Despite guideline recommendations, only 7.2% of eligible HFrEF patients were prescribed quadruple medical therapy at hospital discharge.
• The 12-month residual risk of all-cause mortality remains high at 19.3%, while heart failure hospitalization affects 26.0% of patients.
• The economic burden is substantial, with a median 12-month per-patient expenditure of $27,956.
• Significant between-hospital variance in prescribing patterns suggests missed opportunities for standardization in heart failure care.

Background

Heart failure with reduced ejection fraction (HFrEF) represents a progressive clinical syndrome characterized by significant morbidity, frequent hospitalizations, and a high mortality rate. Over the last decade, the pharmacological management of HFrEF has undergone a paradigm shift. The historical “triple therapy” approach (ACEi/ARB, beta-blocker, and MRA) has been superseded by a “quadruple therapy” regimen, comprising an Angiotensin Receptor-Neprilysin Inhibitor (ARNI), an evidence-based beta-blocker, a Mineralocorticoid Receptor Antagonist (MRA), and a Sodium-Glucose Cotransporter 2 inhibitor (SGLT2i).

While pivotal randomized controlled trials (RCTs)—such as PARADIGM-HF, DAPA-HF, and EMPEROR-Reduced—have demonstrated the additive benefits of these agents in reducing cardiovascular death and hospitalization, translating these findings into real-world clinical practice remains a challenge. Older Medicare beneficiaries often present with more complex comorbidities and higher frailty than trial participants. Understanding the residual clinical risk and the associated economic impact in this specific population is critical for health policy and clinical decision-making.

Key Content

Implementation and Prescription Patterns

In a comprehensive retrospective cohort study utilizing the Get With The Guidelines-Heart Failure (GWTG-HF) registry, researchers examined 20,651 patients eligible for quadruple therapy across 532 US hospitals. Surprisingly, only 1,490 patients (7.2%) were discharged with the full quadruple regimen. This low uptake highlights a significant gap between clinical guidelines and bedside implementation. Furthermore, the study revealed a high degree of between-hospital variance (median odds ratio, 2.04), indicating that a patient’s likelihood of receiving optimized therapy is heavily dependent on the specific institution where they receive care.

The Reality of Residual Clinical Risk

Even among the select group of patients who were successfully initiated on quadruple therapy at discharge, the one-year clinical outcomes remained sobering. The cumulative incidence of all-cause mortality was 19.3% (95% CI, 17.3%-21.4%), and the rate of heart failure hospitalization was 26.0% (95% CI, 23.6%-28.5%). When combined as a composite endpoint, 37.1% of patients experienced either death or re-hospitalization within 12 months.

These figures suggest that while quadruple therapy is a potent intervention, it is not a panacea for the advanced physiological decline seen in patients hospitalized for HFrEF. The median age of the cohort was 74 years, suggesting that age-related vulnerabilities and the “post-hospitalization syndrome” may attenuate the absolute benefit of these medications in a real-world setting compared to the relatively younger and more stable populations typically enrolled in phase III trials.

Economic Implications of Care

The study provides a detailed view of the economic burden associated with HFrEF management under modern GDMT. The median 12-month per-patient healthcare expenditure was $27,956, with a wide interquartile range ($7,478–$61,126). These costs reflect Medicare Part A and B expenditures, including inpatient stays, outpatient visits, and professional services. The high frequency of re-hospitalization (over 25% within a year) remains a primary driver of these costs, emphasizing that pharmacological optimization alone may not suffice to alleviate the economic strain on the healthcare system without concurrent improvements in transitional care and disease management programs.

Temporal Trends and Consistency

An important observation within the study was that outcomes (mortality and HF hospitalization) remained largely similar for patients prescribed quadruple therapy in the first half of the study period (mid-2021 to 2022) compared to the second half (2023). This suggests that the residual risk is a consistent feature of the disease state in older populations and has not yet been significantly mitigated by incremental improvements in health system delivery during the study window.

Expert Commentary

The findings by Greene et al. (2026) serve as a “reality check” for the heart failure community. There is a frequent assumption that once the “four pillars” are established, the clinical battle is largely won. However, these data indicate that the residual risk in older Medicare beneficiaries is remarkably high. Several factors may contribute to this:

• Dose Optimization: It is unclear if patients receiving quadruple therapy were titrated to target doses. Real-world evidence often shows that patients remain on sub-maximal doses due to hypotension, renal dysfunction, or therapeutic inertia.
• Comorbidity Burden: Older HFrEF patients often suffer from chronic kidney disease, atrial fibrillation, and frailty, which can drive non-cardiovascular mortality and complicate heart failure management.
• Timing of Initiation: The “vulnerable period” immediately following discharge is high-risk. While discharge is a critical moment for initiation, the physiological stabilization required to tolerate all four agents simultaneously can be difficult to achieve during a short acute stay.

From a policy perspective, the high between-hospital variance (MOR 2.04) suggests that national quality improvement initiatives must focus not just on individual medication use, but on institutional culture and standardized discharge protocols to ensure equitable access to GDMT.

Conclusion

In summary, while quadruple medical therapy is a cornerstone of HFrEF management, its implementation in US clinical practice is currently limited to a small fraction of eligible patients. Furthermore, for the older hospitalized population, even the most aggressive pharmacological regimen is associated with a 37% risk of death or re-hospitalization within one year and substantial healthcare costs. Future research and clinical efforts must move beyond simply initiating these drugs to optimizing their delivery, improving patient adherence, and addressing the holistic needs of the aging heart failure population to truly bend the curve of residual risk.

References

• 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 cardiology. 2026;11(3):293-297. PMID: 41604197.
• Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2022;79(17):e263-e421. PMID: 35379503.
• McMurray JJV, Solomon SD, Januzzi JL, et al. Management of Heart Failure With Reduced Ejection Fraction: The Breakthrough of Quadruple Therapy. Circulation. 2021;144:1363–1366.