Digoxin Improves Outcomes in Patients With Rheumatic Heart Disease

Patients with rheumatic heart disease who took the heart failure drug digoxin were 18% less likely to die or experience new-onset or worsening heart failure during a two-year follow-up compared with those who received a placebo, according to a study presented at the American College of Cardiology’s Annual Scientific Session (ACC.26).

Rheumatic heart disease, which results from heart valve damage caused by rheumatic fever, affects an estimated 55 million people worldwide, and about 360,000 people die from it each year, most in low- and middle-income countries, according to the World Health Organization. Rheumatic fever is triggered by an abnormal immune response to strep throat, usually in childhood, and the resulting heart disease often appears in early adulthood, where it can lead to heart failure and early death.

While valve damage caused by rheumatic heart disease can be surgically repaired, such procedures are unavailable or inaccessible in many poorer countries where the disease is most common, leaving millions of patients with limited options. This study is the first randomized trial to show that digoxin, which is often given to slow the heart rate of patients with severe rheumatic heart disease symptoms, can benefit patients with the disease.

“Our findings suggest that these patients have a reduction in new-onset or worsening heart failure and relatively few events of digoxin toxicity,” said Ganesan Karthikeyan, MD, professor of cardiology at All India Institute of Medical Sciences in New Delhi and the study’s senior author. “It shows that digoxin is probably safe to use in young patients with rheumatic heart disease and provides some benefit in terms of improvement in heart failure symptoms.”

The trial included 1,769 patients treated for symptomatic rheumatic heart disease at 12 sites in India between 2022-2025. The trial’s all-comer enrollment excluded only patients in whom digoxin would not normally be given; 34% were already taking digoxin before enrolling in the study. Participants were young adults—with an average age of 46 years—and 72% were women, consistent with the typical patient population affected by this disease.

Half of the participants were prescribed digoxin, and half were given a placebo, with the dosing and administration strategy left to the discretion of the treating clinician. At a median of 2.1 years of follow-up, those taking digoxin showed an 18% lower rate of the trial’s combined primary endpoint of death from any cause or new-onset or worsening heart failure, a significant benefit in favor of digoxin. Analyzing the components of the primary endpoint separately, researchers found that the difference in outcomes was driven by a reduction in new-onset or worsening heart failure, with no significant difference in mortality between groups. The study also showed an 18% reduction in the composite secondary endpoint of death related to heart failure and new-onset or worsening heart failure.

Digoxin can cause side effects including gastrointestinal problems, vision changes and irregular heartbeat, including some severe reactions that can be life-threatening. Overall, the trial reported a low rate of such effects with 1% of participants experiencing toxicities. Most side effects were minor, and there were no toxicity-related hospitalizations or deaths.

The study findings offer reassurance that digoxin is a generally safe and effective treatment for rheumatic heart disease, researchers said. The results showed no differences in outcomes by sex or body mass index. Patients with atrial fibrillation appeared to benefit from digoxin to a greater degree than those without atrial fibrillation, although the study was not powered to definitively assess this association.

“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,” Karthikeyan said. “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.”

Although the trial was conducted only in India, researchers said that it should be generalizable to patients in many developing low- and middle-income countries since its pragmatic design and all-comer population reflects the patients who typically come to the hospital for rheumatic heart disease in such regions. Karthikeyan said the metric used in the trial to assess worsening heart failure, which included adding or increasing diuretic treatment or the administration of intravenous diuretics with or without hospitalization, is different from the metric that is conventionally used in developed countries, heart failure hospitalization, since it is rare for patients in developing countries to be admitted to the hospital for heart failure symptoms.