National Impact of Optimal Implementation of Guideline-Directed Medical Therapy in Heart Failure With Reduced Ejection Fraction.
BACKGROUND Despite robust evidence that quadruple guideline-directed medical therapy (GDMT), comprising angiotensin receptor-neprilysin inhibitors (ARNIs), evidence-based beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors, reduces mortality and hospitalizations in heart failure with reduced ejection fraction (HFrEF), implementation in clinical practice remains markedly incomplete. OBJECTIVES This study aimed to provide updated national estimates of the eligible untreated HFrEF population and to quantify deaths and hospitalizations preventable with optimal implementation of quadruple GDMT in the United States. METHODS The authors performed a population-level decision analytic modeling study using contemporary U.S. epidemiologic data. National HFrEF prevalence estimates were derived from the American Heart Association Heart Disease and Stroke Statistics 2026 report, and annual HFrEF hospitalization counts were derived from the National Inpatient Sample 2022-2023. Eligible untreated populations were estimated after sequential exclusions and therapy-specific contraindication adjustments using primary treatment rates from Epic Cosmos 2023-2025, with sensitivity analyses using alternative treatment-rate sources. Trial-derived numbers needed to treat and relative risk reductions were applied to estimate deaths preventable over 12 months and annual heart failure (HF) hospitalizations prevented. RESULTS An estimated 2.76 million U.S. adults with chronic symptomatic HFrEF were eligible for quadruple GDMT, yet only 18.2% received it. Eligible untreated populations included 733,891 for beta-blockers, 1,856,531 for ARNIs, 1,543,967 for MRAs, and 1,717,444 for SGLT2 inhibitors. Class-specific projected deaths preventable over 12 months were 26,210 for beta-blockers, 34,495 for ARNIs, 26,620 for MRAs, and 26,422 for SGLT2 inhibitors; the aggregate estimate across treatment gaps was 113,747 (95% uncertainty interval [UI]: 90,173-149,875). Optimal implementation was also projected to prevent 357,332 HF hospitalizations annually (95% UI: 297,493-425,674). CONCLUSIONS Incomplete implementation of quadruple GDMT in HFrEF remains a major modifiable opportunity to reduce preventable deaths and HF hospitalizations in the United States.