Cost Offset With Quadruple Therapy for Heart Failure

Importance Contemporary guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF), which includes angiotensin receptor–neprilysin inhibitors (ARNI), β-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium–glucose cotransporter 2 inhibitors (SGLT2i), reduces hospitalizations in randomized clinical trials (RCTs), but the combined economic impact of implementing full quadruple therapy after hospitalization is not well quantified. Objective To estimate the 1-year health care cost offset and net cost associated with implementation of quadruple GDMT after hospitalization for HFrEF. Design, Setting, and Participants This economic evaluation used Medicare-linked data from the American Heart Association’s Get With The Guidelines–Heart Failure (GWTG-HF) registry to identify adults 65 years or older hospitalized with HFrEF from 2016 to 2020 with up to 1-year postdischarge follow-up. Data were analyzed from November 2025 to February 2026. Exposures Receipt of quadruple GDMT, defined as concurrent use of an ARNI, β-blocker, MRA, and SGLT2i, at hospital discharge and modeled according to class-specific eligibility and treatment effect estimates from pivotal RCTs. Main Outcomes and Measures Mean per-patient total health care costs through 1 year after discharge were calculated using Medicare Parts A and B payments. Treatment effect estimates for ARNI, β-blockers, MRAs, and SGLT2i were derived from pivotal RCTs and combined multiplicatively on the log scale, incorporating class-specific eligibility, to estimate projected reductions in hospitalization-associated expenditures. Net annual cost was calculated by integrating drug acquisition costs across multiple pricing sources with predicted hospitalization cost reductions. Results The cohort included 50 598 older adults hospitalized with HFrEF (median IQR age, 78 72-85 years; 31 268 men 61. 8% and 19 330 women 38. 2%). Mean 1-year total health care costs were 41 802 per patient, with 25 172 attributable to all-cause hospitalizations. Modeled quadruple GDMT was associated with an 87% (95% CI, 81%-91%) relative reduction in HF hospitalizations and a 61% (95% CI, 51%-68%) reduction in all-cause hospitalizations. Full quadruple therapy implementation vs partial GDMT was projected to reduce hospitalization-associated expenditures by 9780 (95% CI, 7900-11 660) per patient annually. With annual drug costs ranging from 1223 to 16 136, the resulting net annual cost ranged from 8556 in savings to 6347 in net cost, with most regimens yielding net savings. Conclusions and Relevance Among US adults hospitalized with HFrEF, 1-year health care costs are substantial and driven predominantly by hospitalizations. Using combined trial effects and real-world Medicare data, this study found that implementation of quadruple GDMT would meaningfully reduce hospitalization-associated costs and often yield net savings after accounting for medication expenses.