Digoxin Discontinuation in Patients With HFrEF on Beta-Blockers: Implication for Future 'Knock-Out Trials' in Heart Failure - 11/02/25

Doi : 10.1016/j.amjmed.2024.10.015

Phillip H. Lam, MD ^a,^b,^c, Kevin Liu, MD ^a,^b,^{^{#
Equal contribution}}, Amiya A. Ahmed, MD ^d,^e,^{^{#
Equal contribution}}, Javed Butler, MD, MPH ^f,^g, Paul A. Heidenreich, MD, MS ^h,ⁱ, Markus S. Anker, MD ^j, Charles Faselis, MD ^a,^k, Prakash Deedwania, MD ^l, Wilbert S. Aronow, MD ^m,ⁿ, Ioannis Kanonidis, MD, PhD ^o, Ravi Masson, MD ^p, Gauravpal S. Gill, MD ^q, Charity J. Morgan, PhD ^r, Cherinne Arundel, MD ^a,^b,^k, Richard M. Allman, MD ^k,^r,^s, Wen-Chih Wu, MD, MPH ^t,^u, Gregg C. Fonarow, MD ^v, Ali Ahmed, MD, MPH ^a,^b,^k,^⁎
^a Veterans Affairs Medical Center, Washington, DC
^b Georgetown University, Washington, DC
^c Medstar Washington Hospital Center, Washington, DC
^d Yale University, New Haven, Conn
^e Veterans Affairs Medical Center, West Haven, Conn
^f Baylor Scott and White Research Institute, Dallas, Tex
^g University of Mississippi, Jackson, Ms
^h Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif
ⁱ Stanford University School of Medicine, Stanford, Calif
^j Charité - University Medicine Berlin, Berlin, Germany
^k George Washington University, Washington, DC
^l University of California, San Francisco
^m Westchester Medical Center, Valhalla, NY
ⁿ New York Medical College, Valhalla, NY
^o Aristotelian University, Thessaloniki, Greece
^p Loma Linda University, Loma Linda, Calif
^q James River Cardiology, Colonial Heights, Va
^r University of Alabama at Birmingham, Birmingham, Al
^s Wake Forest University, Winston-Salem, NC
^t Veterans Affairs Medical Center, Providence, RI
^u Brown University, Providence, RI
^v University of California, Los Angeles, Calif

^⁎Requests for reprints should be addressed to Ali Ahmed, MD, MPH, Washington DC VA Medical Center, 50 Irving St. NW, Washington, DC 20422.Washington DC VA Medical Center50 Irving St. NWWashingtonDC20422

Abstract

Background

National heart failure guidelines recommend quadruple therapy with renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors for patients with heart failure with reduced ejection fraction (HFrEF), most of whom also receive loop diuretics. However, the guidelines are less clear about the safe approaches to discontinuing older drugs whose decreasing or residual benefit is less well understood. The objective of this study was to examine whether digoxin can be safely discontinued in patients with HFrEF receiving beta-blockers.

Methods

In OPTIMIZE-HF, of 2477 patients with HFrEF (EF ≤45%) receiving beta-blockers and digoxin, digoxin was discontinued in 450 patients. We assembled a propensity score-matched cohort of 433 pairs of patients in which digoxin continuation vs. discontinuation groups were balanced on 51 baseline characteristics. Using the same approach, from 992 patients not on beta-blockers, we assembled a matched cohort of 198 pairs of patients also balanced on 51 baseline characteristics. Hazard ratios (HRs) and 95% CIs for 1-year outcomes were estimated.

Results

Among patients receiving beta-blockers, digoxin discontinuation had no association with the combined endpoint of heart failure readmission or death (HR, 1.01; 95% CI, 0.85-1.19), heart failure readmission (HR, 1.03; 95% CI, 0.85-1.25) or death (HR, 0.91; 95% CI, 0.72-1.14). Respective HRs (95% CIs) among patients not receiving beta-blockers were 1.60 (1.25-2.04), 1.62 (1.18-2.22) and 1.43 (1.08-1.89).

Conclusions

Digoxin can be discontinued without increasing the risk of adverse outcomes in patients with HFrEF receiving beta-blockers. Future studies need to examine the residual benefit of older heart failure drugs to ensure their safe discontinuation in patients with HFrEF receiving newer guideline-directed medical therapy.

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Keywords : Beta-blockers, Digoxin, Discontinuation, Heart failure, HFrEF

Plan

Introduction

Methods

Data Source and Study Population

Assembly of Balanced Cohorts

Outcomes Data

Statistical Analyses

Results

Baseline Characteristics

Digoxin Discontinuation and Outcomes in Patients on Beta-Blockers

Digoxin Discontinuation and Outcomes in Patients Not on Beta-Blockers

Discussion

Limitations

Conclusions

	Funding: Dr. Ali Ahmed was in part supported by the National Institutes of Health through grants (R01-HL085561 and R01-HL097047) from the National Heart, Lung, and Blood Institute (NHLBI). OPTIMIZE-HF was sponsored by GlaxoSmithKline, but played no role in the design, conduct, analyses or interpretation of the current study.
	Conflict of Interest: Dr. Fonarow reports consulting with Abbott, Amgen, Bayer, Janssen, Medtronic, Novartis, and was the Principal Investigator of OPTIMIZE-HF. Dr. Butler reports consulting for Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardior, CSL Bearing, CVRx, Cytokinetics, Edwards, Element Science, Faraday, Foundry, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Pfize, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. None of the other authors report any conflicts of interest related to this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Department of Veterans Affairs.
	Authorship: PHL: Writing—review and editing, Writing—original draft, Supervision, Conceptualization; KL: Writing—review and editing, Writing—original draft, AAA: Writing—review and editing, Writing—original draft, JB: Writing—review and editing, Conceptualization, PAH: Writing—review and editing, MSA: Writing—review and editing, CF: Writing—review and editing, PD: Writing—review and editing, WSA: Writing—review and editing, IK: Writing—review and editing, RM: Writing—review and editing, GSG: Writing—review and editing, CJM: Methodology, Formal analysis, CA: Writing—review and editing, RMA: Writing—review and editing, WCW: Writing—review and editing, GCF: Writing—review and editing, AA: Writing—review and editing, Writing—original draft, Supervision, Methodology, Formal analysis, Data curation, Conceptualization.

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Digoxin Discontinuation in Patients With HFrEF on Beta-Blockers: Implication for Future 'Knock-Out Trials' in Heart Failure - 11/02/25

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