Therapeutic Impact of Cardiac Glycosides (Digoxin and Digitoxin) in Heart Failure With Reduced Ejection Fraction: A...

Heart failure (HF) is a major cause of hospitalization and mortality worldwide. Cardiac glycosides, particularly digoxin and digitoxin, are used in patients with HF with reduced ejection fraction (HFrEF) who are symptomatic despite guideline-directed therapy. However, their comparative effectiveness and safety remain unclear. This systematic review aims to compare the therapeutic effect of digoxin and digitoxin in patients with HFrEF. PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov were searched using predefined keywords related to cardiac glycosides and HFrEF to identify randomized controlled trials (RCTs). Eligible studies enrolled adults with HFrEF (left ventricular ejection fraction ≤ 40%) receiving digoxin or digitoxin versus placebo and reported mortality or hospitalization outcomes. Due to heterogeneity and the identification of only 2 eligible RCTs, a qualitative synthesis was performed. From 646 screened records, 2 RCTs involving 8012 patients were included. Neither digoxin nor digitoxin reduced all-cause mortality [Digitalis Investigation Group: 34.8% vs 35.1%, risk ratio (RR) 0.99; Digitoxin to Improve Outcomes in Patients with Advanced Chronic Heart Failure: 27.2% vs 29.5%, hazard ratio (HR) 0.86] or cardiovascular mortality (Digitalis Investigation Group: 29.9% vs 29.5%, RR 1.01; Digitoxin to Improve Outcomes in Patients with Advanced Chronic Heart Failure: 20.4% vs 22.4%, HR 0.87). HF-specific mortality showed no significant difference. Digoxin significantly reduced cardiovascular hospitalizations (49.9% vs 54.4%, RR 0.87) and HF hospitalizations (26.8% vs 34.7%, RR 0.72), while digitoxin similarly lowered HF hospitalization risk (28.1% vs 30.4%, HR 0.85). Both agents reduced the composite of HF death or hospitalization (digoxin: RR 0.85, P < 0.001; digitoxin: HR 0.82, P = 0.03). Cardiac glycosides do not reduce all-cause mortality in patients with HFrEF; however, digoxin significantly lowered hospitalizations for worsening HF. Both digoxin and digitoxin reduced the composite of mortality and HF hospitalization.