Key result
Cardiac glycosides show no benefit over placebo for all-cause mortality in HFrEF.
Why the study?
Prognostic benefits of cardiac glycosides in HFrEF remain controversial, and whether digitoxin offers superior clinical efficacy over digoxin has not been established.
Does cardiac glycoside therapy reduce all-cause mortality or heart failure hospitalization in patients with HFrEF?
Systematic Review (n=8,488)
Does cardiac glycoside therapy reduce all-cause mortality or heart failure hospitalization in patients with HFrEF?
Hazard Ratio: 0.98 (95% CI 0.92–1.04)
In patients with HFrEF, cardiac glycosides reduce the risk of heart failure hospitalization but do not improve all-cause mortality, with no significant difference in efficacy between digitoxin and digoxin.
Cardiac glycosides may reduce HF hospitalization without mortality benefit in HFrEF; extends RCT evidence but leaves digitoxin superiority unproven.
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.
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Wang et al. (2026) conducted a systematic review in Heart failure and reduced ejection fraction (HFrEF) (n=8,488). Cardiac glycosides (digoxin or digitoxin) vs. Placebo was evaluated on All-cause mortality (HR 0.98, 95% CI 0.92-1.04). Cardiac glycoside therapy did not significantly reduce all-cause mortality (HR 0.98) compared to placebo in patients with heart failure and reduced ejection fraction.
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