In 2022, the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA) formalized four foundational drug classes for heart failure with reduced ejection fraction (HFrEF): a renin-angiotensin system inhibitor, preferably an angiotensin receptor-neprilysin inhibitor (ARNI) when appropriate; an evidence-based beta-blocker; a mineralocorticoid receptor antagonist (MRA); and a sodium-glucose cotransporter-2 (SGLT2) inhibitor, regardless of diabetes status (Heidenreich et al., 2022). The major change since then is not a fifth HFrEF pillar. It is the move toward getting all four evidence-based mechanisms started earlier instead of maximizing one class before adding the next.
STRONG-HF helped establish the value of rapid optimization after an acute heart failure hospitalization. The trial validly randomized 1,078 patients to usual care or a high-intensity strategy that rapidly increased renin-angiotensin system inhibitors, beta-blockers, and MRAs with close follow-up. The 180-day primary-endpoint analysis included 1,008 participants enrolled at sites that followed patients through day 180. In that analysis, the composite of all-cause death or heart failure readmission was lower with high-intensity care than with usual care (15.2% versus 23.3%) (Mebazaa et al., 2022). STRONG-HF did not directly test rapid initiation of all four contemporary HFrEF pillars, because SGLT2 inhibitors were not one of the medication classes targeted in its titration protocol.
The 2024 ACC Expert Consensus Decision Pathway translates the broader evidence base into contemporary HFrEF sequencing. The goal is to establish all four foundational therapies early at tolerated doses, then titrate them toward evidence-based or maximally tolerated doses rather than waiting for one drug to reach target before starting the next. Sequencing still depends on the patient: beta-blockers should be initiated or advanced when the patient is hemodynamically compensated, while renal function, potassium, blood pressure, volume status, and medication access determine how quickly the remaining classes can be added and titrated (Maddox et al., 2024).
Heart failure with preserved ejection fraction (HFpEF) has changed as well. The 2026 ACC Expert Consensus Decision Pathway emphasizes phenotype-guided treatment and incorporates outcome data supporting SGLT2 inhibitors and finerenone, a nonsteroidal MRA, along with management of obesity, atrial fibrillation, hypertension, chronic kidney disease, and other drivers of the HFpEF syndrome (Kittleson et al., 2026). Finerenone is now part of that conversation after FINEARTS-HF enrolled 6,001 patients with left ventricular ejection fraction of at least 40% and found a lower rate of cardiovascular death or total worsening heart failure events with finerenone than with placebo, driven primarily by fewer worsening heart failure events (Solomon et al., 2024). For patients with HFpEF and a body mass index of at least 30 kg/m2, the 2026 pathway also incorporates semaglutide or tirzepatide to improve health status and exercise function and potentially reduce worsening heart failure events (Kittleson et al., 2026).
Management now diverges more clearly by phenotype. In HFrEF, establish the four foundational therapies early and build a follow-up schedule capable of supporting laboratory monitoring, volume assessment, adverse-effect surveillance, and dose optimization. In HFpEF and HFmrEF, pharmacotherapy extends well beyond diuresis, with SGLT2 inhibitors and finerenone playing larger roles in appropriate patients. In obesity-related HFpEF, incretin-based therapy adds another phenotype-specific option. Rapid treatment only works when follow-up is equally deliberate.
References
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Kittleson, M. M., Panjrath, G. S., Bates, K., Breathett, K. K., Dixon, D. L., Januzzi, J. L., Jr., & Mohammed, S. F. (2026). Management of heart failure with preserved ejection fraction: 2026 ACC expert consensus decision pathway. Journal of the American College of Cardiology. Advance online publication. https://doi.org/10.1016/j.jacc.2026.06.018
Maddox, T. M., Januzzi, J. L., Jr., Allen, L. A., Breathett, K., Brouse, S., Butler, J., Davis, L. L., Fonarow, G. C., Ibrahim, N. E., Lindenfeld, J., Masoudi, F. A., Motiwala, S. R., Oliveros, E., Walsh, M. N., Wasserman, A., Yancy, C. W., & Youmans, Q. R. (2024). 2024 ACC expert consensus decision pathway for treatment of heart failure with reduced ejection fraction: A report of the American College of Cardiology Solution Set Oversight Committee. Journal of the American College of Cardiology, 83(15), 1444–1488. https://doi.org/10.1016/j.jacc.2023.12.024
Mebazaa, A., Davison, B., Chioncel, O., Cohen-Solal, A., Diaz, R., Filippatos, G., Metra, M., Ponikowski, P., Sliwa, K., Voors, A. A., Edwards, C., Novosadova, M., Takagi, K., Damasceno, A., Saidu, H., Gayat, E., Pang, P. S., Celutkiene, J., & Cotter, G. (2022). Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): A multinational, open-label, randomised trial. The Lancet, 400(10367), 1938–1952. https://doi.org/10.1016/S0140-6736(22)02076-1
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