JAMA
Old drug, new context: Digitalis lowers HF events but not mortality
Clinical Takeaway: In patients with heart failure with mildly reduced or reduced ejection fraction who remain symptomatic despite guideline-directed therapy, low-dose digoxin or digitoxin may be considered to reduce worsening HF events. Mortality is unchanged, and caution is warranted if therapy is withdrawn.
Digitalis glycosides—among the oldest drugs in cardiovascular medicine—have long occupied an uncertain place in heart failure (HF) care. The landmark DIG trial in the 1990s showed that digoxin reduced hospitalizations for worsening HF but did not improve survival, contributing to declining use as therapies with proven mortality benefit emerged. More recently, contemporary trials have revisited low-dose digitalis in patients receiving modern HF therapy, prompting renewed debate over its clinical value.
At Heart Failure 2026, new data from the DECISION trial and a prespecified meta-analysis were presented, reexamining the role of digoxin and digitoxin in current practice. This study randomized 1,001 patients with symptomatic mild-to-moderate heart failure with mildly reduced or reduced ejection fraction (LVEF <50%), meeting additional natriuretic peptide criteria, to low-dose digoxin or placebo, targeting serum digoxin concentrations of 0.5–0.9 ng/mL. Both patients in sinus rhythm and those with atrial fibrillation were included.
Over a median follow-up of 36.5 months, low-dose digoxin did not significantly reduce the primary composite outcome of cardiovascular death and total (recurrent) worsening HF events (rate ratio, 0.81; 95% CI ,0.61–1.07). Worsening HF events were numerically fewer with digoxin, while cardiovascular mortality was similar between groups. Treatment was generally well tolerated and safe.
To place these findings in broader context, investigators pooled DECISION with two prior large placebo-controlled trials—DIG and DIGIT-HF—in a study-level meta-analysis enrolling 9,013 patients with heart failure with mildly reduced ejection fraction (HFmrEF; LVEF 40%–49%) or reduced ejection fraction (HFrEF; LVEF <40%). The weighted mean age was 64.5 years, and 22% of participants were women.
Across a median follow-up of approximately 3 years, digitalis glycosides reduced the composite of cardiovascular death or first worsening HF event (41% vs. 45%). This effect was driven largely by fewer first worsening HF events (26% vs. 33%), while cardiovascular death (27% in both groups) and all-cause mortality (32% vs. 33%) were unchanged. Benefits were similar with digoxin and digitoxin, across older and modern treatment eras, and even in patients already receiving guideline‑directed HF therapy.
Additional late-breaking data raised caution about discontinuation. In a prespecified blinded withdrawal analysis following DECISION, patients who stopped digoxin after trial completion experienced more cardiovascular deaths and HF events over the subsequent six weeks compared with those who stopped placebo. Although event numbers were small and confidence intervals wide, the findings suggest potential clinical deterioration with abrupt withdrawal in stabilized patients.
“In patients with HFmrEF, 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,” said Dirk van Veldhuisen, MD, PhD, senior investigator of the DECISION trial and co-author of the meta-analysis, of University Medical Center Groningen (Netherlands).
Sources:
Damman, K, et al. (2026, May 10). JAMA. Efficacy and Safety of Digitalis Glycosides in Heart Failure: A Meta-Analysis
van Veldhuisen, DJ, et al. (2026, May 10). Nat Med. Low-dose digoxin in patients with heart failure with reduced or mildly reduced ejection fraction: a randomized controlled trial
Van Der Meer, P, Low-dose digoxin in heart failure; Damman, K, DECISION/DIGIT-HF/DIG study level meta analysis; van Veldhuisen, DJ, Blinded withdrawal of digoxin or placebo. Presented at Heart Failure 2026, Hottest trials sessions; May 10, 2026; Barcelona, Spain.