Digitalis glycosides may still have a role in selected patients with heart failure despite longstanding uncertainty regarding their use in modern therapy. At Heart Failure 2026, new analyses revisited whether low-dose digoxin and digitoxin provide additional benefit in patients already receiving guideline-directed heart failure treatment.
“Digoxin is the oldest drug in cardiovascular medicine, but there has been uncertainty about its value in HF(m)rEF management,” said Principal Investigator Dirk van Veldhuisen of University Medical Center Groningen, Netherlands. He noted that the historic DIG trial showed neutral effects on mortality. However, later analyses suggested that lower serum digoxin concentrations may be associated with more favorable outcomes.
The double-blind DECISION trial enrolled 1,001 patients with symptomatic heart failure with reduced or mildly reduced ejection fraction (HFrEF/HFmrEF) across 43 centers in the Netherlands. Patients were randomized to low-dose digoxin or placebo in addition to contemporary guideline-directed therapy. The target serum digoxin concentration was 0.5-0.9 ng/mL. Over a median follow-up of 36.5 months, the primary composite endpoint of worsening heart failure events and cardiovascular mortality was not significantly reduced with digoxin versus placebo (rate ratio [RR] 0.81; 95% confidence interval [CI] 0.61-1.07; p=0.133).
Although the primary endpoint was neutral, worsening HF events numerically favored digoxin (RR 0.76; 95% CI 0.54-1.05). Cardiovascular mortality remained similar between groups (hazard ratio [HR] 0.93; 95% CI 0.69-1.26). Low-dose digoxin was generally well tolerated and safe.
Additional findings presented during the Late-Breaking Science session strengthened the signal toward fewer worsening HF events with digitalis therapy. A pooled meta-analysis of the DECISION, DIGIT-HF, and DIG trials included 9,013 patients. Digoxin/digitoxin treatment was associated with a lower risk of cardiovascular death or first worsening HF event versus placebo (HR 0.85; 95% CI 0.80–0.90; p<0.001). The reduction was largely driven by worsening HF events. The effect was not attenuated in patients already receiving full guideline-directed HF therapy.
A separate withdrawal analysis presented by Peter van der Meer followed patients who stopped study medication after DECISION completion. More cardiovascular deaths and worsening HF events occurred after digoxin withdrawal than after placebo withdrawal (RR 7.37; 95% CI 1.56-34.88; p=0.012).
“In patients with HF(m)rEF, low-dose digitalis glycosides seem to be an effective additional medical treatment option,” van Veldhuisen said. He also cautioned that discontinuation may be associated with clinical deterioration.
The findings suggest that digitalis glycosides may retain adjunctive value in selected patients with HFrEF/HFmrEF, particularly for worsening HF events. However, the neutral primary endpoint in DECISION warrants cautious interpretation.
