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Multicenter Study
. 2025 Aug 5;86(5):338-350.
doi: 10.1016/j.jacc.2025.05.040.

Guideline-Directed Medical Therapy and Outcomes Among Patients With Heart Failure With Improved Ejection Fraction

Kyung H Min  1 , Alan S Go  2 , Keane Lee  3 , Rishi V Parikh  4 , Kate M Horiuchi  2 , Andrew P Ambrosy  5 , Thida C Tan  2 , Kishan Srikanth  1 , Steven A Hamilton  6 , Jana Svetlichnaya  6 , Scott D Solomon  7 , Riccardo M Inciardi  8 , Orly Vardeny  9 , Elena Vasti  10 , Alexander T Sandhu  10 , Ivy A Ku  6 , Sirtaz Adatya  3 , Ankeet S Bhatt  11
Affiliations
Multicenter Study

Guideline-Directed Medical Therapy and Outcomes Among Patients With Heart Failure With Improved Ejection Fraction

Kyung H Min et al. J Am Coll Cardiol. .

Abstract

Background: The prevalence of heart failure with improved ejection fraction (HFimpEF) is anticipated to increase with the availability and implementation of novel pharmacotherapy for heart failure with reduced ejection fraction (HFrEF). However, there are limited data on contemporary epidemiology, management, and outcomes for this clinical entity.

Objectives: The aim of this study was to describe epidemiology, guideline-directed medical therapy (GDMT), and outcomes among patients with HFimpEF across a large, diverse, multisite integrated health care delivery system.

Methods: Patients who were diagnosed with incident HFrEF between January 2013 and December 2022 across the Kaiser Permanente Northern California integrated health care delivery system were identified. Rates of incident HFimpEF, defined as HFrEF with a follow-up ejection fraction >40% and with >10% absolute left ventricular ejection fraction improvement within 12 months of incident HFrEF diagnosis, were identified. GDMT was examined at the time of incident HFrEF and HFimpEF and in the year following HFimpEF. Rates of worsening heart failure events and death were examined and compared among those with HFimpEF vs persistent HFrEF.

Results: In total, 28,292 patients with newly diagnosed HFrEF (mean left ventricular ejection fraction 31.1% ± 7.4%) were identified, of whom 8,656 (30.6%) experienced HFimpEF within 12 months. Use of GDMT marginally decreased in most medication categories after incident HFimpEF during the study period. Rates of worsening heart failure were 17.4 per 100 person-years (95% CI: 16.9-18.0 per 100 person-years) among patients with HFimpEF vs 34.1 per 100 person-years (95% CI: 33.5-34.6 per 100 person-years) among patients with persistent HFrEF (HR: 0.58; 95% CI: 0.55-0.61 per 100 person-years). Rates of death were 5.7 per 100 person-years (95% CI: 5.4-6.0 per 100 person-years) and 11.0 per 100 person-years (95% CI: 10.7-11.3 per 100 person-years) among patients with HFimpEF and those with persistent HFrEF, respectively (HR: 0.52; 95% CI: 0.49-0.56). Withdrawal of GDMT was modestly associated with greater clinical risk.

Conclusions: A significant percentage of patients with HFrEF experience improvement in ejection fraction, transitioning to HFimpEF, yet remain at significant clinical risk. Further research is needed to evaluate the impact of sustained GDMT adherence and therapeutic optimization on outcomes in patients with HFimpEF.

Keywords: guideline-directed medical therapy; heart failure; heart failure with improved ejection fraction; outcomes.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Ambrosy has received relevant research support through grants to his institution from the National Heart, Lung, and Blood Institute (K23HL150159 and R01AG091005), the AHA (2nd Century Early Faculty Independence Award), the Permanente Medical Group, Northern California Community Benefits Programs, the Garfield Memorial Fund, Abbott Laboratories, Amarin Pharma, Bayer, Cordio Medical, Edwards Lifesciences, Esperion Therapeutics, Merck, and Novartis. Dr Go has received relevant research support through grants to his institution from the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, Amarin Pharma, Novartis, Janssen Research & Development, and CSL Behring. Dr Sandhu is supported by a grant from the National Heart, Lung, and Blood Institute (1K23HL151672-01). Dr Bhatt has received research grant support to his institution from the National Heart, Lung, and Blood Institute, the National Institute on Aging, the ACC Foundation, and the Centers for Disease Control and Prevention; and has received consulting fees from Heart Health Leaders and Novo Nordisk. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, the National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Eli Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Akros. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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