JAMA Cardiology · Jun 10, 2026

Cost Offset With Quadruple Therapy for Heart Failure

By Keykhaei M, Rashedi S, Greene SJ et al.

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.

doi.org/10.1001/jamacardio.2026.1552PubMed 42268625Interventions