Digoxin in Patients With Symptomatic Rheumatic Heart Disease

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.

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Journal
JAMA
Published
2026-05-10
DOI
https://doi.org/10.1001/jama.2026.7335
Primary Topic
Streptococcal Infections and Treatments
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article
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article

Digoxin in Patients With Symptomatic Rheumatic Heart Disease

Rishi Sethi, G Karthikeyan, Nitya Wadhwa, Sanjeev Asotra et al.
JAMA
Streptococcal Infections and Treatments
article

Digoxin in Patients With Symptomatic Rheumatic Heart Disease

Rishi Sethi, G Karthikeyan, Nitya Wadhwa, Sanjeev Asotra, Dorairaj Prabhakaran, Arun Gopalakrishnan, Monika Bhandari, Shivakumar Kailasam, Pravesh Vishwakarma, Ravi S. Math, Niveditha Devasenapathy, Satyavir Yadav, Aarti Sharma, Chandra Bhan Meena, Shyamashree Biswas, Denis Xavier, Arpita Ghosh, Neeraj Parakh, Neha Bansal, Ankit Kumar Sahu, Sudhir Kumar Dwivedi, Suryaprakash Narayanappa, Anupam Singh -, Supriyanka Rana, Prayaag Kini, Ravindra Mohan Pandey, Vinod Abraham, Romika Jhajhria, Aman Rastogi, Charu Priya, N B Senguttuvan, Daniel Rolston, Mohit D. Gupta, DKS Subrahmanyam, Ritesh Kumar, Santhosh Satheesh, Aditya Kapoor, Sandeep Bansal, G. Bhuvneshwari, Archana Gupta, Girish M. Palleda, Ankit Gupta, Anand Krishnan, Vivekanandan M, Gaurav Purohit, Meenakshi Sharma, Soundarya Narasimhappa, Deepti Siddharthan, Nishi Tiwari, Dig-RHD Investigators, Jayaranganath M, Manasvi Shukla, Nandita Nataraj, J S Thakur, Pritish John, Shyam S Kothari, Akshaya Pradhan, Puneet Gupta, Nitish Naik, Rajesh Sharma, Anamika Singh, Vivekanand Jha, Raja J. Selvaraj, R Anil Kumar, Reeta Varyani, Mehak Munjal, Preeti Gupta, Saichandran B. V, Ashish Dass, A.B. Arya, Vineeth C. P, Manoj Soni, Erik Fung, Pragya Singh, Prakash Chand Negi, Satish Kumar, Birbal Kaushik, Sandeep Singh
article en

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.

JAMA
Sanjay Gandhi Post Graduate Institute of Medical Sciences (IN), SMS Medical College (IN), Manipal Academy of Higher Education (IN), Vardhman Mahavir Medical College & Safdarjung Hospital (IN), Sri Ramachandra Institute of Higher Education and Research (IN), Indira Gandhi Medical College (IN), Sree Chitra Thirunal Institute for Medical Sciences and Technology (IN), Translational Health Science and Technology Institute (IN), Dignity Health (US), Sri Jayadeva Institute of Cardiovascular Sciences and Research (IN), King George's Medical University (IN), UNSW Sydney (AU), Sri Sathya Sai Institute of Higher Medical Sciences (IN), George Institute for Global Health (IN), Govind Ballabh Pant Hospital (IN), Imperial College London (GB), Jawaharlal Institute of Post Graduate Medical Education and Research (IN), All India Institute of Medical Sciences (IN)
Good health and well-being
Openalex Percentile: Top 4%
Streptococcal Infections and Treatments
DOISourceOpenAlex
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