Don't Miss a Beat: Treatment Sequencing in New Era of Heart Failure Management

This episode of Don’t Miss a Beat, recorded at the American College of Cardiology (ACC) 2025 Annual Scientific Sessions, explores the evolving landscape of heart failure with preserved ejection fraction (HFpEF) treatment, focusing on the implementation of combination therapies. Hosts Steve Greene, MD, and Muthiah Vaduganathan, MD, MPH, discuss the transition from a previously limited treatment landscape to a new era with multiple proven therapeutic options.

To open the episode, Greene argues in favor of rapid-sequence implementation of HFpEF therapies, drawing parallels to the established 4-pillar guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF). He highlights 3 key classes of medications—SGLT2 inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and incretin-based therapies—as the foundation of HFpEF treatment. He emphasizes the importance of early and aggressive therapy initiation to maximize clinical benefits and reduce the risk of delayed or missed treatment opportunities among this population.

Vaduganathan acknowledges the strength of the data supporting combination therapy but suggests a more risk-based approach, considering the broad clinical variability among HFpEF patients. He advocates for prioritizing rapid implementation in high-risk patients, such as those recently hospitalized, while allowing a more measured approach for lower-risk individuals. The discussion also touches on the role of phenotyping in tailoring treatment decisions, with GLP-1 receptor agonists being particularly relevant for patients with obesity and ARNi potentially benefiting those with mildly reduced ejection fraction.

Looking ahead, the hosts preview upcoming trials, including CONFIDENCE and CONFIRMATION, which will evaluate combination therapy strategies in chronic kidney disease and HFpEF populations. They also discuss the potential of fixed-dose combination therapies to simplify implementation and improve adherence. The episode closes with both experts agreeing on the need for a structured, evidence-based approach to HFpEF treatment while emphasizing the importance of translating trial data into real-world practice.

Relevant disclosures for Vaduganathan include Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, Lexicon, and others. Relevant disclosures for Greene include Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, and others.

References:

1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(17):1757-1780. doi:10.1016/j.jacc.2021.12.011.

2. Patel R, Wadid M, Makwana B, et al. GLP-1 Receptor Agonists Among Patients With Overweight or Obesity, Diabetes, and HFpEF on SGLT2 Inhibitors. JACC Heart Fail. 2024;12(11):1814-1826. doi:10.1016/j.jchf.2024.07.006.