Digitoxin in Patients with Heart Failure and Reduced Ejection Fraction.

Summary

In a double-blind, placebo-controlled international RCT (n=1212), digitoxin added to guideline-directed therapy in HFrEF reduced the composite of all-cause death or first HF hospitalization (HR 0.82). All-cause mortality and first HF hospitalization individually trended favorable without statistical significance; serious adverse events were infrequent.

Key Findings

• Primary composite (all-cause death or first HF hospitalization) reduced with digitoxin vs placebo (HR 0.82; 95% CI 0.69–0.98; P=0.03).
• All-cause mortality (HR 0.86; 95% CI 0.69–1.07) and first HF hospitalization (HR 0.85; 95% CI 0.69–1.05) favored digitoxin but were not individually significant.
• Serious adverse events occurred in 4.7% with digitoxin vs 2.8% with placebo.

Clinical Implications

Digitoxin can be considered as an add-on in symptomatic HFrEF patients already on guideline-directed therapy to reduce the risk of death or worsening-HF hospitalization, with attention to dosing and monitoring for glycoside-related adverse effects.

Limitations

• Individual components did not reach statistical significance
• Slightly higher serious adverse events with digitoxin necessitate careful monitoring

Future Directions

Define target patient subgroups (e.g., rhythm status, renal function) most likely to benefit; explore dose–response and safety optimization; assess cost-effectiveness and real-world implementation.