Efficacy of digitoxin according to LVEF in DIGIT-HF

Interest in the use of digitalis glycosides to treat heart failure has had a resurgence following the presentation of the DIGIT-HF trial at ESC Congress 2025 [1] and the DECISION trial plus meta-analysis at Heart Failure 2026 [2,3]. Today, Professor Udo Bavendiek (Hannover Medical School - Hannover, Germany) presents an analysis of the DIGIT-HF trial across the range of LVEF.

DIGIT-HF randomised patients with symptomatic heart failure with reduced ejection fraction (HFrEF; NYHA class ≥II and LVEF ≤30% or NYHA class ≥III and LVEF ≤40%) to digitoxin or placebo on top of standard of care [1]. In the overall trial, digitoxin significantly reduced the primary endpoint of all-cause mortality or hospitalisation for worsening heart failure compared with placebo (hazard ratio [HR] 0.82; 95% CI 0.69 to 0.98; p=0.03)

Of the 1,212 patients included in the intention-to-treat population, 34.7% of patients had LVEF <26%, 30.2% had LVEF 26–30% and 35.2% had LVEF 31–40% at baseline. One-fifth of patients were women and 27% had a history of atrial fibrillation at baseline with no significant difference between LVEF categories.

The reduction in primary outcome by digitoxin was consistent across LVEF tertiles (LVEF <26%: HR 0.80; 95% CI 0.59 to 1.09; LVEF 26–30%: HR 0.81; 95% CI 0.57 to 1.16; LVEF 31–40%: HR 0.80; 95% CI 0.58 to 1.11), with no statistically significant interaction between them (p=0.95). Similar results were observed when considering the individual components of the primary outcome.

Restricted cubic spline plot analysis across a continuous LVEF range indicated a greater reduction in the primary outcome by digitoxin among patients with LVEF <20% at trial entry. This was supported by a specific analysis in 98 patients with LVEF <20% (HR 0.45; 95% CI 0.23 to 0.89).

The authors conclude that digitoxin reduced the primary outcome consistently across the spectrum of reduced LVEF, while exploratory analyses suggested a potentially greater benefit in patients with severely impaired systolic function.

And what do the new 2026 ESC Guidelines on heart failure say about the use of digitalis? The full guidelines are published today in the European Heart Journal and are presented at ESC Congress 2026 this afternoon.