Digoxin Discontinuation in Patients with HFrEF on Beta-Blockers: Implication for Future "Knock-Out Trials" in Heart Failure

Phillip H Lam; Kevin Liu; Amiya A Ahmed; Javed Butler; Paul A Heidenreich; Markus S Anker; Charles Faselis; Prakash Deedwania; Wilbert S Aronow; Ioannis Kanonidis; Ravi Masson; Gauravpal S Gill; Charity J Morgan; Cherinne Arundel; Richard M Allman; Wen-Chih Wu; Gregg C Fonarow; Ali Ahmed

doi:10.1016/j.amjmed.2024.10.015

Digoxin Discontinuation in Patients with HFrEF on Beta-Blockers: Implication for Future "Knock-Out Trials" in Heart Failure

Am J Med. 2024 Oct 16:S0002-9343(24)00638-7. doi: 10.1016/j.amjmed.2024.10.015. Online ahead of print.

Authors

Phillip H Lam¹, Kevin Liu², Amiya A Ahmed³, Javed Butler⁴, Paul A Heidenreich⁵, Markus S Anker⁶, Charles Faselis⁷, Prakash Deedwania⁸, Wilbert S Aronow⁹, Ioannis Kanonidis¹⁰, Ravi Masson¹¹, Gauravpal S Gill¹², Charity J Morgan¹³, Cherinne Arundel¹⁴, Richard M Allman¹⁵, Wen-Chih Wu¹⁶, Gregg C Fonarow¹⁷, Ali Ahmed¹⁸

Affiliations

¹ Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC; Medstar Washington Hospital Center, Washington, DC.
² Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC.
³ Yale University, New Haven, CT; Veterans Affairs Medical Center, West Haven, CT.
⁴ Baylor Scott and White Research Institute, Dallas, TX; University of Mississippi, Jackson, MS.
⁵ Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; Stanford University School of Medicine, Stanford, CA.
⁶ Charité - University Medicine Berlin, Berlin, Germany.
⁷ Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC.
⁸ University of California, San Francisco, CA.
⁹ Westchester Medical Center, Valhalla, NY; New York Medical College, Valhalla, NY.
¹⁰ Aristotelian University, Thessaloniki, Greece.
¹¹ Loma Linda University, Loma Linda, CA.
¹² James River Cardiology, Colonial Heights, VA.
¹³ University of Alabama at Birmingham, Birmingham, AL.
¹⁴ Veterans Affairs Medical Center, Washington, DC; University of Alabama at Birmingham, Birmingham, AL.
¹⁵ George Washington University, Washington, DC; University of Alabama at Birmingham, Birmingham, AL; Wake Forest University, Winston-Salem, NC.
¹⁶ Veterans Affairs Medical Center, Providence, RI; Brown University, Providence, RI.
¹⁷ University of California, Los Angeles, CA.
¹⁸ Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC; George Washington University, Washington, DC. Electronic address: ali.ahmed@va.gov.

PMID: 39424217
DOI: 10.1016/j.amjmed.2024.10.015

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 2,477 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 one-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.

Keywords: HFrEF; beta-blockers; digoxin; discontinuation; heart failure.