DIGIT-HF Trial
DIGIT-HF Trial
Source: Medical News – ESC 2025. August 29,2025
1. Trial Design
• DIGIT-HF: Randomized, placebo-controlled trial (8+ years, 1240 patients, LVEF ≤ 40%, symptomatic HFrEF).
• Intervention: Digitoxin added to standard HF therapy vs placebo.
• Median follow-up: 3 years.
2. Primary Results
• Event (death or first HF hospitalization): 39.5% digitoxin vs 44.1% placebo.
• Absolute risk reduction: 4.6% (NNT = 22).
• Relative risk reduction: 18% (HR 0.82; 95% CI 0.69–0.98; P = 0.03).
• Subgroup benefit: stronger in patients with SBP <120 mmHg and HR ≥75 bpm.
3. Safety
• Serious adverse events: 4.7% digitoxin vs 2.8% placebo.
• No increase in sudden cardiac death.
• Safety signal reassures against past fears of harm from cardiac glycosides.
4. Key Messages (Mandrola’s Five Lessons)
• Safety confirmed: Past harm signals were likely due to observational bias.
• Benefit despite good background therapy: Effect added on top of beta-blockers, ARNI, MRA; only ~20% were on SGLT2i.
• Meaningful effect size: Nearly 5% absolute risk reduction, comparable to SGLT2 trials, at very low cost.
• AF subgroup: ~30% had AF; effect size similar → raises question if glycosides should be first for rate control in AF + HFrEF.
• Statistical fragility: Results are significant but borderline (upper CI 0.98; P = .03; modest event numbers).
5. Digitoxin vs Digoxin
• Both inhibit Na⁺/K⁺-ATPase → positive inotropy + neurohormonal modulation.
• Digitoxin: steadier blood levels, less affected by kidney function (extra enterohepatic clearance).
• Digoxin: available in US, but harder to monitor in routine care.
• Ongoing Dutch DECISION trial will test digoxin specifically in HFrEF.
6. Clinical Implications
• Digitoxin may re-enter discussion for HFrEF therapy, especially in cost-constrained settings.
• Raises question: should HFrEF patients now get five core drugs instead of four?
• Potentially useful in AF + HFrEF when beta-blockers are limited.
7. Limitations
• Borderline statistical robustness.
• Some loss to follow-up (17 digitoxin vs 8 placebo).
• Unclear if findings translate directly to digoxin use in the US.
Conclusion:
DIGIT-HF revives interest in cardiac glycosides. Digitoxin showed statistically significant, clinically relevant benefit in HFrEF on top of modern therapy, with no major safety concerns. But statistical fragility and differences from digoxin mean more evidence is needed before routine global adoption.
