Original Investigation 

Digoxin in Patients With Symptomatic Rheumatic Heart Disease: A Randomized Clinical Trial

Ganesan Karthikeyan, Niveditha Devasenapathy, Arpita Ghosh, et al

JAMA Published Online: May 10, 2026

doi: 10.1001/jama.2026.7335

Key Points

Question  Does digoxin, compared with placebo, reduce the composite of all-cause death or new-onset or worsening heart failure in symptomatic rheumatic heart disease?

Findings  In this randomized clinical trial that included 1769 participants, digoxin, 0.125 to 0.25 mg/d added to usual care, compared with placebo, significantly reduced the risk of a composite of all-cause death or new-onset or worsening heart failure (31.4% vs 35.5%, respectively; hazard ratio, 0.82).

Meaning  The results of this trial, taken together with evidence from previous trials of digoxin, suggest that digoxin may be safely used in young patients with rheumatic heart disease to prevent heart failure worsening.

Abstract

Importance  Heart failure is the most common cause of death in patients with rheumatic heart disease. The efficacy and safety of digoxin in this population are not known.

Objective  To determine if digoxin, compared with placebo, improves the composite of death or new-onset or worsening heart failure in patients with symptomatic rheumatic heart disease.

Design, Setting, and Participants  Multicenter, randomized, placebo-controlled trial enrolling patients with rheumatic heart disease who additionally had heart failure or atrial fibrillation or were already taking digoxin at 12 tertiary care hospitals in India between February 25, 2022, and August 31, 2024; median follow-up was 2.1 years (until December 15, 2025).

Interventions  Patients were randomized in a 1:1 ratio, stratified by baseline rhythm, to receive oral digoxin, 0.125 to 0.25 mg once daily (n = 885), or matching placebo (n = 884).

Main Outcomes and Measures  The primary outcome was a composite of all-cause death or new-onset or worsening heart failure within 36 months of follow-up or until study end, whichever occurred first. Key secondary outcomes were all-cause death, new-onset or worsening heart failure, and a composite of heart failure–related death or new-onset or worsening heart failure.

Results  Of 1769 enrolled patients, 1759 took at least 1 dose of the study medication and were included in the primary analysis. The mean age was 46 years and 72% were female. Most patients (81.5%) had mixed lesions involving multiple valves, with 85% having moderate to severe mitral stenosis. Atrial fibrillation was present in 70%, and 90% were in New York Heart Association class II to IV. The primary composite outcome occurred in 276 patients (31.4%) receiving digoxin and 312 (35.5%) receiving placebo (hazard ratio, 0.82; 95% CI, 0.70-0.97; P = .02). New-onset or worsening heart failure occurred in 227 patients (25.8%) receiving digoxin and in 257 (29.2%) receiving placebo (hazard ratio, 0.82; 95% CI, 0.69-0.98). Most episodes of worsening heart failure were treated with augmentation of oral or intravenous diuretics without hospitalization. Death from any cause occurred in 88 patients (10%) receiving digoxin and 91 (10.4%) receiving placebo (hazard ratio, 0.94; 95% CI, 0.70-1.26). Ten patients receiving digoxin (1.1%) and 1 receiving placebo permanently discontinued study medication due to suspected digoxin toxicity.

Conclusions and Relevance  In patients with symptomatic rheumatic heart disease, digoxin reduced the risk of a composite of all-cause death or new-onset or worsening heart failure, with little risk of toxicity.

Trial Registration  CTRI Identifier: CTRI/2021/04/032858