A New Dawn for Digitalis? Re-evaluating the Efficacy and Safety of Cardiac Glycosides in Heart Failure Reduced Ejection Fraction: A Meta-Analysis of 8,346 Patients

Abstract

Background and Purpose: Recently, the DIGIT-HF trial has reinvigorated the use of digitalis in patients with heart failure with reduced ejection fraction (HFrEF). Although the trial yielded interesting findings, its interpretation requires consideration of previous trials that have assessed digitalis in patients with HFrEF. This meta-analysis comprehensively investigates the safety and efficacy of digitalis in patients with HFrEF.

Methods: A systematic search of four electronic databases was conducted until October 2025. Trials reporting data on mortality, hospitalization, or adverse events in heart failure patients with an ejection fraction below 45% on digitalis alongside guideline-directed medical therapy were included. Complications incidence data (events/total) were pooled using standard methods for dichotomous outcomes with Risk Ratios (RR). A random-effects model was used for all analyses.

Results: The analysis included 8,346 patients receiving either digitalis or placebo/no digitalis alongside guideline-directed medical therapy. Digitalis did not significantly decrease all-cause mortality or heart-failure-related mortality compared to placebo/no digitalis (RR: 0.99; 95% Confidence Interval [CI]: 0.93, 1.05; P= 0.62) and (RR: 0.89; 95% CI: 0.79, 1.00; P= 0.05), respectively. Besides, Digitalis didn’t significantly decrease all-cause hospitalization or heart-failure-exacerbation-related hospitalization compared to placebo/no digitalis. Notably, Digitalis revealed an increased risk for cardiac adverse events and specifically ventricular fibrillation (RR: 1.98; 95% CI: 1.55, 2.53; P< 0.00001) and (RR: 1.25; 95% CI: 1.06, 1.48; P= 0.009), respectively. Interestingly, Sensitivity analysis in 3899 patients with HFrEF (EF<40%) showed significant reductions in cardiovascular deaths or heart failure hospitalization in the digitalis group (RR: 0.90; 95% CI: 0.86, 0.95; P< 0.0001).

Conclusions: Digitalis failed to improve mortality and dangerously increased cardiac arrhythmias in HFrEF patients. Conversely, it significantly reduced cardiovascular death or HF hospitalization in the severe EF<40% subgroup. Further studies are needed to understand the risk-benefit paradox, especially with modern quadruple therapy, to identify the specific patient profile who may benefit.