Key Points:
- The Dig-RHD trial, a multicenter, double-blind, placebo-controlled trial conducted in India, randomized 1,769 patients with symptomatic RHD to oral digoxin or matching placebo. The primary outcome was a composite of all-cause death or new-onset or worsening heart failure.
- At a median follow-up of 2.1 years, digoxin was associated with a significant 18% reduction in the primary composite endpoint, driven by a reduction in new-onset or worsening heart failure, with no significant effect on mortality. Suspected digoxin toxicity was infrequent, occurring in approximately 1% of participants.
Rheumatic heart disease (RHD) results from heart valve damage caused by rheumatic fever due to streptococcal pharyngitis that typically occurs in childhood. The resulting valvular disease often manifests in early adulthood and can lead to heart failure and premature death. RHD affects an estimated 55 million people worldwide, with approximately 360,000 deaths annually, the vast majority in low- and middle-income countries where access to surgical valve repair is limited. Heart failure is the leading cause of death in patients with RHD, yet there are no randomized trials demonstrating that any medical therapy improves clinical outcomes in this population. Digoxin is used in up to 40% of patients with RHD based on clinical experience, and has been shown to reduce heart failure events in patients with heart failure with reduced ejection fraction (HFrEF), but its efficacy and safety in RHD have never been evaluated in a randomized trial.
On March 30th 2026, the results of “Digoxin in Rheumatic Heart Disease: A Multi-center, Randomized, Double Blind, Placebo-controlled Trial (Dig-RHD)” were presented at ACC Scientific Sessions 2026 in New Orleans, LA. The purpose of this trial was to evaluate whether digoxin reduces the incidence of death or new-onset or worsening heart failure in patients with symptomatic RHD. The trial design manuscript was published in American Heart Journal in November 2025.
Dig-RHD was an investigator-initiated, multicenter, pragmatic, double-blind, placebo-controlled trial conducted at 12 academic medical centers in India. Patients were eligible if they were symptomatic, had echocardiographically confirmed RHD, and did not have contraindications to digoxin use. Randomization was web-based and stratified by the presence of atrial fibrillation (AF). Patients were assigned in a 1:1 ratio to oral digoxin (0.25 mg or 0.125 mg once daily) or matching placebo on a background of usual care, with dosing left to clinician discretion. The primary outcome was a composite of all-cause death or new-onset or worsening heart failure. Secondary outcomes included all-cause death, new-onset or worsening heart failure, heart failure–related death, hospitalization for heart failure, sudden death, and self-reported quality of life. The primary outcome was changed from all-cause mortality within three months of trial commencement, prior to enrollment of 180 patients.
Between February 2022 and August 2024, 1,769 patients were enrolled (880 digoxin, 879 placebo). The population was young (mean age 46 years) and predominantly female (71%). Approximately 70% had AF or atrial flutter, 90% were in NYHA class II or III, and 85% had moderate-to-severe mitral stenosis, with a mean mitral valve area of 1.2 cm². The mean left ventricular ejection fraction was 58%. At baseline, one third of participants were already receiving digoxin prior to randomization. Background therapies included diuretics (93%), beta blockers (70%), and oral anticoagulation (96% among those with AF).
At a median follow-up of 2.1 years, the primary composite outcome occurred in 276 patients (31.4%) in the digoxin group and 312 patients (35.5%) in the placebo group (HR 0.82 [95% CI: 0.70, 0.97]; p=0.02). This benefit was driven by a reduction in new-onset or worsening heart failure, which occurred in 227 patients (26.2%) in the digoxin group versus 257 patients (29.4%) in the placebo group (HR 0.82 [95% CI: 0.69, 0.98]). There was no significant difference in all-cause mortality between groups (10.0% vs. 10.4%; HR 0.94 [95% CI: 0.70, 1.26]), consistent with prior data on digoxin in HFrEF. There was also an 18% reduction in the composite secondary endpoint of heart failure-related death or new-onset or worsening heart failure. In subgroup analyses, the effect of digoxin appeared greater among those with AF at baseline (HR 0.75 [95% CI: 0.62, 0.90]) compared to those without AF (HR 1.08 [95% CI: 0.79, 1.48]; p-interaction=0.05), and among those already taking digoxin at enrollment (HR 0.61 [95% CI: 0.46, 0.81]) compared to those not on digoxin (HR 0.95 [95% CI: 0.78, 1.17]; p-interaction=0.01). Suspected digoxin toxicity led to permanent drug discontinuation in 10 patients (1.1%), most of which were minor; there were no toxicity-related hospitalizations or deaths.
Dig-RHD is the first randomized trial to demonstrate that any medical therapy improves clinical outcomes in patients with RHD, providing evidence for digoxin as a safe and inexpensive treatment option for this underserved population.
Limitations include that the trial was conducted exclusively in India, although the pragmatic design and all-comer population ay reflect the typical patient profile seen in low- and middle-income countries. Medication adherence declined over time in both groups, and the primary outcome was changed early in the trial. Finally, the trial was not powered to assess whether the differential effect observed in patients with AF represents a true treatment interaction; further research is needed.
Ganesan Karthikeyan, MD, DM, FRCP, Professor of Cardiology at the All India Institute of Medical Sciences in New Delhi, India, concluded: “Digoxin is used in about 30%-40% of rheumatic heart disease cases currently, but it’s based on the physician’s gut feeling and there’s always a concern that it will worsen things. With the publication of this trial, I think people will be a little more confident about using digoxin. We have few other drugs to benefit these patients – and this is the first drug which has evidence of benefit from a randomized trial – so I think its use will increase.”