DIG-RHD: Digoxin Effective in Rheumatic Heart Disease

NEW ORLEANS, LA—Treating patients with symptomatic rheumatic heart disease (RHD) with digoxin appears to modestly reduce the risk of all-cause mortality or new-onset or worsening heart failure (HF), results of the DIG-RHD trial show.

The study, which was presented last week at the American College of Cardiology 2026 Scientific Session, suggests digoxin might be an inexpensive treatment option for a disease that largely affects people in developing countries.

“Rheumatic heart disease is a disease of poverty,” said lead investigator Ganesan Karthikeyan, MBBS, MD (All India Institute of Medical Sciences, New Delhi), during a press conference. “It’s seen mainly in low- and middle-income countries, and in pockets of disadvantaged individuals in high-income countries, such as the northern territory of Australia and the Māori of New Zealand. There are over 55 million living with rheumatic heart disease in the world and it contributes to 360,000 deaths every year. The people who die are relatively young.”  

Most of the deaths associated with RHD are due to HF and there are no medical therapies yet proven to improve clinical outcomes in this understudied population, said Karthikeyan.

Digoxin is used in roughly one-third of RHD cases, but there is a reluctance to use the drug out of concerns that it might cause harm. That concern, said Karthikeyan, stems from observational studies that have linked digoxin to a higher risk of mortality, but the signal of harm might have resulted from prescription bias in that the drug is often prescribed to the sickest patients. None of the randomized trials in patients with HF with reduced ejection fraction (HFrEF), including DIG with digoxin and DIGIT-HF with digitoxin, a similar cardiac glycoside, have shown an adverse effect on mortality.

Benefit on HF Outcomes

The DIG-RHD trial was conducted in India at 12 academic medical centers from 2022 to 2025, randomizing 880 patients with RHD confirmed on echocardiography to digoxin 0.25/0.125 mg once daily and 879 to placebo. The patients included in the trial were young—average age 46 years—and 71% were female. In all, 90% of randomized patients had NYHA class II-IV symptoms and 85% had moderate-to-severe mitral stenosis. About one third had a prior percutaneous mitral valvuloplasty and approximately 7% had a prior valve surgery. In all, 34% of patients were taking digoxin prior to randomization.

After 2.1 years, there was a 4.1% absolute reduction in the primary endpoint of all-cause mortality or new or worsening HF (41.4% vs 35.5%; HR 0.82; 95% CI 0.70-0.97), a difference driven by the HF component (26.2% vs 29.4%; HR 0.82; 95% CI 0.69-0.98). There was no significant difference in all-cause mortality. There was a reduction in a key secondary endpoint—HF mortality or new-onset/worsening HF—that favored digoxin, although there was no reduction in deaths due to HF alone.

These results are widely generalizable to all patients with symptomatic rheumatic heart disease. Ganesan Karthikeyan

The neutral effect on all-cause mortality is consistent with findings testing digoxin in patients with HFrEF, said Karthikeyan. There did appear to be a treatment effect in patients with atrial fibrillation (AF) at baseline versus none in those without AF (P = 0.052 for interaction).   

Over the course of the study, 10.3% of patients stopped digoxin permanently compared with 12.1% who stopped placebo. Digoxin toxicity was suspected in 10 patients who stopped treatment, which represented 1.1% of those randomized to treatment, and did not lead to hospitalizations or death.  

“Given the pragmatic nature of the trial, and given that digoxin is inexpensive and widely available, these results are widely generalizable to all patients with symptomatic rheumatic heart disease,” said Karthikeyan. Also of note, the trial cost less than $600,000 to complete, he said.

Cesar Herrera, MD (Albert Einstein College of Medicine, New York, NY), one of the discussants who wasn’t involved in the study, said these new data are very relevant to physicians who practice outside the United States and Europe.

Nicole Bhave, MD (University of Michigan Medical School, Ann Arbor), who spoke during the morning press conference, said RHD remains a critical global health problem. She also noted that digoxin is listed as an essential medicine by the World Health Organization and the results of DIG-RHD can be put into immediate practice.

“As we’ve seen with many other situations with digoxin, such as in those with heart failure with reduced ejection fraction, it may improve symptoms and hospitalizations, but it doesn’t improve mortality,” she said. “Really, the only definitive treatment for rheumatic mitral valve stenosis is an intervention, either with balloon valvuloplasty or surgery, but I think these results are encouraging in that digoxin can be an important adjunctive therapy in rheumatic heart disease.”