Efficacy and Safety of Digitalis Glycosides in Heart Failure

Importance: Digitalis glycosides may be used as additional therapy in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HF with reduced EF (HFrEF). Objective: To assess the effect of digitalis glycosides on clinical outcomes in patients with HFmrEF or HFrEF. Data Sources and Study Selection: PubMed was searched from inception to March 1, 2026, using medical subject headings and keywords related to digitalis glycosides and HF. The review was restricted to placebo-controlled randomized clinical trials including more than 1000 patients and articles published in the English language. Data Extraction and Synthesis: Data were extracted by 2 reviewers who followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Risk of bias was assessed with the Cochrane Risk of Bias tool (version 2). A fixed-effects model was used to estimate the hazard ratios (HRs) with 95% CIs. Main Outcomes and Measures: The primary end point was the composite of time to cardiovascular death or first worsening HF event. Secondary outcomes included individual components of the composite outcome and time to all-cause death. Results: A total of 3 studies met the inclusion criteria and included 9013 patients with HFmrEF or HFrEF (weighted mean age, 64.5 [weighted SD, 11.2] years; 22% female and 78% male). The composite outcome of cardiovascular death or first worsening HF event occurred in 1852 of 4510 patients (41%) in the digitalis glycoside group vs 2037 of 4503 patients (45%) in the placebo group (HR, 0.85 [95% CI, 0.80-0.90]; P < .001). First worsening HF event occurred in 1183 (26%) patients in the digitalis glycoside group vs 1474 (33%) patients in the placebo group (HR, 0.75 [95% CI, 0.69-0.81]; P < .001). There were 1224 cardiovascular events in the digitalis glycoside group vs 1224 in the placebo group (27% of participants in each group; HR, 0.99 [95% CI, 0.92-1.07]; P = .81) and there were 1466 vs 1497, respectively, all-cause deaths (32% of participants vs 33%; HR, 0.97 [95% CI, 0.90-1.04]; P = .41). There was no statistically significant heterogeneity by trial, type of digitalis glycoside treatment, or extent of background HF therapy. Conclusions and Relevance: Treatment with digitalis glycosides was associated with a lower risk of the composite of cardiovascular death or first worsening HF event in patients with HFmrEF or HFrEF, mainly through a lower risk of worsening HF events. There was no statistically significant interaction with important study characteristics, including the extent of HF background therapy or type of digitalis glycosides treatment. These results suggest digitalis glycosides may be used as additional medical therapy to reduce worsening HF events in patients with HFmrEF or HFrEF.