Digitalis Glycosides Reduce Worsening Heart Failure Events in HFmrEF, HFrEF

Digitalis glycosides were associated with a reduced risk of worsening heart failure (HF) events among patients with HF with mildly reduced ejection fraction (HFmrEF) or HF with reduced ejection fraction (HFrEF), according to a new meta-analysis published in JAMA.¹

The findings suggest the longstanding therapy could still play a role as an adjunctive treatment option despite the expansion of modern guideline-directed medical therapies.

“HF is a syndrome characterized by signs and symptoms of fluid overload and may include impaired cardiac output resulting from structural or functional cardiac abnormalities,” the researchers wrote. “HF is associated with reduced quality of life and a high risk of morbidity and mortality.”

Meta-Analysis Evaluates Digitalis Glycosides in HF

Investigators conducted a meta-analysis of placebo-controlled randomized clinical trials to evaluate whether digitalis glycosides improved cardiovascular outcomes in patients with HFmrEF or HFrEF. They searched PubMed through March 1, 2026, and included English-language trials with more than 1000 participants.

The analysis included 9013 patients from 3 major randomized trials comparing digitalis glycosides with placebo. Participants had a weighted mean age of 64.5 (weighted SD, 11.2) years, and 22% were women. Overall, treatment with digitalis glycosides was associated with a statistically significant reduction in the primary composite end point of cardiovascular death or first worsening HF event.

Specifically, the composite outcome occurred in 41% of patients receiving digitalis glycosides compared with 45% of patients receiving placebo (HR, 0.85; 95% CI, 0.80-0.90; P < .001). Investigators noted that the benefit was largely driven by reductions in worsening HF events rather than improvements in mortality outcomes.

Reduction in Worsening HF Events Observed

Worsening HF events occurred in 26% of patients treated with digitalis glycosides compared with 33% of patients in the placebo arm (HR, 0.75; 95% CI, 0.69-0.81; P < .001). However, cardiovascular death rates were identical between groups, with 1224 events reported in both the treatment and placebo arms (HR, 0.99; 95% CI, 0.92-1.07; P = .81).

Similarly, no significant difference was observed in all-cause mortality, which occurred in 32% of patients receiving digitalis glycosides and 33% receiving placebo (HR, 0.97; 95% CI, 0.90-1.04; P = .41).

Importantly, the researchers found no statistically significant heterogeneity based on trial characteristics, type of digitalis glycoside used, or extent of background HF therapy. This consistency suggests that the observed reduction in worsening HF events may persist even in the setting of evolving HF treatment regimens.

However, they noted several limitations. Because the study relied on trial-level rather than individual patient-level data, researchers were unable to fully evaluate how specific patient subgroups may have responded to digitalis glycosides. Additionally, variations in study design and differing definitions of worsening HF events across trials may also have introduced heterogeneity, although sensitivity analyses using random-effects models produced similar results, supporting the overall robustness of the findings.

Digitalis Glycosides May Still Have a Role in Modern HF Care

The findings arrive as clinicians continue to seek strategies for reducing hospitalizations and symptom burden in patients with chronic HF. Although newer therapies, including sodium-glucose cotransporter 2 inhibitors, angiotensin receptor-neprilysin inhibitors, and mineralocorticoid receptor antagonists, have transformed HF care, residual risk for worsening HF remains high.

HF affects more than 6 million adults in the US and remains a leading cause of hospitalization among older adults, according to the American Heart Association.²

Historically, digoxin has been used to improve symptoms and reduce hospitalizations in HFrEF, but its use has declined amid concerns over toxicity and the availability of newer agents.¹ Still, the current analysis suggests digitalis glycosides may continue to provide value as adjunctive therapy, particularly for patients who remain symptomatic despite optimized treatment.

The authors emphasized that while digitalis glycosides did not reduce mortality in this analysis, the observed decrease in worsening HF events could still provide clinically meaningful benefits by reducing hospitalizations and disease progression.

“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,” the researchers wrote. “There was no statistically significant interaction with important study characteristics, including the extent of HF background therapy or type of digitalis glycoside treatment. These results suggest digitalis glycosides may be used as additional medical therapy to reduce worsening HF events in patients with HFmrEF or HFrEF.”

References

1. Damman K, van Veldhuisen DJ, Bauersachs J, et al. Efficacy and safety of digitalis glycosides in heart failure: a meta-analysis. JAMA. Published online May 10, 2026. doi:10.1001/jama.2026.7886

2. Martin SS, Aday AW, Almarzooq ZI, et al. 2024 heart disease and stroke statistics: a report of US and global data from the American Heart Association. Circulation. 2024;149:e347–e913. doi:10.1161/CIR.0000000000001209