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Three new studies presented by University of Groningen researchers from the Netherlands during a "Late-Breaking Science" session at the Heart Failure 2026 conference have renewed interest in digitalis compounds — heart medications used for more than two centuries — as a potential treatment for heart failure (HF).

Digoxin and HF: Love-Hate Relationship

" Should digoxin still be used in heart failure?" Medscape's French edition asked this question in 2013. More than 20 years after the publication of the Digitalis Investigation Group (DIG) study— the trial that sparked the controversy — the question of digoxin'svalue in HF remains relevant, even though digitalis is likely the oldest medication in CV medicine.

Published in 1997, the DIG study showed a 30% reduction in hospitalizations for HF, but digoxin did not reduce mortality. This was followed in 2016 by a meta-analysis suggesting that digoxin was associated with an increased risk of mortality.

Faced with these conflicting results, doubts arose regarding the potential danger of the drug, and prescriptions for digoxin for hospitalized HF patients plummeted, particularly in the United States. In the absence of randomized trials, digoxin was ultimately relegated to the background, especially as new drugs such as beta-blockers, aldosterone antagonists, and angiotensin receptor-neprilysin inhibitors had since come onto the market.

Nevertheless, researchers who continue to believe in the potential of digitalis glycosides have relaunched studies in patients with HF and reduced or mildly reduced left ventricular ejection fraction (HF(m)rEF), and the results that have just been released seem to validate their persistence.

Randomized Double-Blind Trial

Among these new data, the DECISION trial was conducted "to determine whether low-dose digoxin improved cardiovascular (CV) outcomes in patients with HF(m)rEF receiving treatments recommended by current guidelines," explained the principal investigator, Dirk van Veldhuisen, of the University Medical Centre Groningen, Groningen, Netherlands.

Conducted at 43 sites in the Netherlands (NCT03783429), DECISION enrolled patients with mild to moderate symptomatic HF(m)rEF (left ventricular ejection fraction < 50%), who were randomized to receive low-dose digoxin or placebo, with a target serum digoxin concentration of 0.5 ng/ml to 0.9 ng/ml. Patients with sinus rhythm and those with atrial fibrillation were included. 

The primary endpoint was a composite of all worsening HF events (defined as the total number of hospitalizations or emergency department visits due to worsening heart failure) and CV mortality. A total of 1001 patients were randomized. The mean age of the participants was 73 years; 28% were women, and 29% had atrial fibrillation.

The results show that low-dose digoxin did not significantly reduce the primary endpoint. During a median follow-up of 36.5 months, 238 events corresponding to the primary endpoint occurred in 131 of the 500 patients in the digoxin group, while 291 events corresponding to the primary endpoint occurred in 152 of the 501 patients in the placebo group (rate ratio [RR] 0.81; 95% confidence interval [CI]: 0.61 to 1.07; P = 0.133).

However, the total number of worsening HF events was lower in the digoxin group than in the placebo group, although this difference was not statistically significant (RR 0.76; 95% CI: 0.54 - 1.05). CV mortality was similar between digoxin and placebo (hazard ratio [HR] 0.93; 95% CI: 0.69 - 1.26). Furthermore, low-dose digoxin was generally well tolerated and safe.

Digitoxin: 'The Mummy Returns'

These results echo those of the recently published DIGIT-HF trial, which examined another digitalis glycoside, digitoxin, in patients with advanced HF and reduced ejection fraction. Treatment with digitoxin led to a reduction in the risk of all-cause death or hospitalization for worsening heart failure. "This is a true renaissance for digitoxin, a drug that is primarily metabolized by the liver, whereas digoxin is primarily metabolized by the kidneys," commented Ahmed Bennis , MD, a cardiologist in Casablanca, Morocco, in a video interview for Medscape's French edition: "It's practically The Mummy Returns." (The video interview is in French, with an accompanying transcript available for browser translation.) 

Furthermore, during a second presentation at the HF 2026 conference, Kevin Damman , MD,a cardiologist at University Medical Centre Groningen, demonstrated the benefits of digoxin/digitoxin in a meta-analysisof the DECISION, DIGIT-HF, and DIG trials.

Among 9013 patients, treatment with digitalis glycosides reduced the risk of the primary endpoint — the time to CV death or first event of worsening heart failure — compared with placebo (HR 0.85; 95% CI: 0.80 to 0.90; P < 0.001).

This reduction was primarily attributable to the effect on the time to the first event of worsening HF (HR 0.75; 95% CI: 0.69 to 0.81; P < 0.001).

Furthermore, the effect was not attenuated in patients who were already receiving comprehensive HF treatment in accordance with guidelines.

Finally, a third presentation from Peter van der Meer , MD, a cardiologist at University Medical Centre Groningen, showed that discontinuation of digoxin was associated with clinical deterioration. This predefined blinded analysis followed patients who had stopped taking the study drug at the end of the DECISION trial and were then followed for an additional 6 weeks. Among the 587 patients, more CV deaths and heart failure-related events were observed after digoxin discontinuation than after placebo discontinuation (RR 7.37; 95% CI: 1.56 to 34.88; P = 0.012).

In summarizing the data, van Veldhuisen concluded: "In patients with HF(m)rEF, low-dose digitalis glycosides appear to be an effective, inexpensive, safe, and easy-to-use adjunctive pharmacological treatment option. Overall, the data support the role of low-dose digoxin in the current management of heart failure, although caution is advised when discontinuing it." 

The DECISION trial was funded by the Dutch Heart Foundation. The meta-analysis and the study on treatment discontinuation received no additional funding. 

Dirk van Veldhuisen has no conflicts of interest to report.

This story was translated from Medscape's French edition.