Digoxin Benefits Heart Failure Patients, Study Shows
Analyses supporting the use of digitalis glycosides in patients with heart failure were presented in a Late-Breaking Science session today at Heart Failure 2026, [1–3] the annual congress of the Heart Failure Association of the European Society of Cardiology.
Investigations from researchers at University Medical Center Groningen, Netherlands, evaluated the effects of the digitalis glycosides, digoxin and digitoxin, in patients with heart failure (HF) and reduced or mildly reduced left ventricular ejection fraction (HF(m)rEF).
“Digoxin is the oldest drug in cardiovascular medicine, but there has been uncertainty about its value in HF(m)rEF management,” explained Principal Investigator, Professor Dirk van Veldhuisen. “In the DIG trial, published in 1997, digoxin had a neutral effect on the primary endpoint of mortality, but a 28% reduction in heart failure hospitalisations (a secondary endpoint) was observed. Later analyses from DIG showed that lower serum digoxin levels were associated with a favourable effect, while higher digoxin levels worsened prognosis. [4] We conducted the DECISION trial to investigate whether low-dose digoxin has positive effects on cardiovascular outcomes in patients with HF(m)rEF receiving contemporary guideline-recommended treatments.”[1]
The double-blind DECISION trial was conducted at 43 sites in the Netherlands (NCT03783429). Patients with symptomatic mild-to-moderate HF(m)rEF (left ventricular ejection fraction <50%). were randomised to low-dose digoxin or placebo, with a target serum digoxin concentration of 0.5–0.9 ng/ml. Both patients with sinus rhythm and atrial fibrillation were enrolled. The primary outcome was a composite of total worsening HF events (defined as total hospitalisations or total urgent hospital visits for worsening HF) and cardiovascular mortality. A total of 1,001 patients were randomised. The mean age of the participants was 73 years, 28% were women, and 29% had atrial fibrillation.
Low-dose digoxin did not significantly reduce the primary outcome. Over a median follow-up of 36.5 months, 238 primary-outcome events occurred in 131 of 500 patients in the digoxin group, while 291 primary-outcome events occurred in 152 of 501 patients in the placebo group (rate ratio [RR] 0.81; 95% confidence interval [CI] 0.61 to 1.07; p=0.133). Although not statistically significant, the total number of worsening HF events was lower in the digoxin group than in the placebo group (RR 0.76; 95% CI 0.54 to 1.05). Cardiovascular mortality was similar with digoxin and placebo (hazard ratio [HR] 0.93; 95% CI 0.69 to 1.26). Low-dose digoxin was generally well tolerated and safe.
Last year, results were published from the DIGIT-HF trial, which studied another digitalis glycoside, digitoxin, in patients with advanced HF and reduced ejection fraction. [5] Treatment with digitoxin led to a lower risk of death from any cause or hospital admission for worsening HF.
A second presentation at Heart Failure 2026, by Associate Professor Kevin Damman, demonstrated positive overall benefits with digoxin/digitoxin in a meta-analysis of the DECISION, DIGIT-HF and DIG trials. [2] Across 9,013 patients, digitalis glycoside treatment reduced the risk of the primary endpoint of time to cardiovascular death or first worsening HF event compared with placebo (HR 0.85; 95% CI 0.80 to 0.90; p<0.001). This reduction was mostly attributable to the effect on time to the first worsening HF event (HR 0.75; 95% CI 0.69 to 0.81; p<0.001). There was no statistically significant heterogeneity by trial, treatment period or type of digitalis glycoside. In addition, the effect was not attenuated in patients who were already receiving full guideline-directed HF treatment.
A third presentation, by Professor Peter van der Meer, found that digoxin withdrawal was associated with clinical deterioration. [3] This was a prespecified blinded analysis that followed patients who stopped taking study medication at the end of the DECISION trial, and were subsequently followed for another 6 weeks. Across 587 patients, there were more cardiovascular deaths and HF events in patients after withdrawal of digoxin than after placebo withdrawal (RR 7.37; 95% CI 1.56 to 34.88; p=0.012).
Summing up the evidence, Professor van Veldhuisen concluded, “In patients with HF(m)rEF, low-dose digitalis glycosides seem to be an effective additional medical treatment option, which are cheap, safe and easy to use. The totality of the evidence supports the role of low-dose digoxin in the contemporary management of HF, with caution warranted when it is stopped.”
References
[1] ‘Low-dose digoxin in heart failure’ presented during the Hottest trials (2) session on 10 May at 13:15 to 14:15 in Room 3, with simultaneous publication in Nature Medicine: https://doi.org/10.1038/s41591-026-04406-6.
[2] ‘DECISION/DIGIT-HF/DIG study level meta analysis’ presented during the Hottest trials (2) session on 10 May at 13:15 to 14:15 in Room 3.
[3] ‘Blinded withdrawal of digoxin or placebo’ presented during the Hottest trials (2) session on 10 May at 13:15 to 14:15 in Room 3.
[4] Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525−533.
[5] Bavendiek U, Großhennig A, Schwab J, et al. Digitoxin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2025;393:1155–1165.
Source: European Society of Cardiology
