Cardiac glycosides in patients with heart failure and reduced ejection fraction: a systematic review and meta-analysis

Background The prognostic benefits of cardiac glycosides in patients with heart failure and reduced ejection fraction (HFrEF) remain controversial. Although digitoxin exhibits more favorable pharmacokinetic characteristics than digoxin, its potential to provide superior clinical efficacy has not yet been established. Methods A systematic review and meta-analysis were performed. The PubMed, EMBASE, Cochrane Library, and Web of Science databases were systematically searched for relevant studies published up to September 12, 2025. The study population was limited to patients with HFrEF. Randomized controlled trails that compare clinical outcomes between cardiac glycosides and placebo were included. The primary outcome was all-cause mortality, and the secondary outcome was hospitalization due to heart failure. Additionally, an indirect comparison was performed to compare the efficacy of digitoxin vs. digoxin. This study was registered with PROSPERO (No. CRD420251142262). Results A total of 6 RCTs encompassing 8,488 patients were included. Compared with placebo, cardiac glycoside therapy was associated with a significantly lower risk of hospitalization for heart failure [HR = 0.79, 95% CI (0.67–0.94)]. However, there was no significant difference in all-cause mortality [HR = 0.98, 95% CI (0.92–1.04)]. Furthermore, no significant differences were observed between digitoxin and digoxin in terms of mortality reduction [HR = 0.93, 95% CI (0.77–1.13)] or hospitalization risk for heart failure [HR = 1.35, 95% CI (0.70–2.60)]. Conclusion In patients with HFrEF, cardiac glycoside therapy may reduce the risk of hospitalization for heart failure. Compared with digoxin, digitoxin has not demonstrated any significant advantage with respect to all-cause mortality or hospitalization for heart failure. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251142262 , PROSPERO CRD420251142262.