Cardiac glycosides had been used for the treatment of heart failure (HF) long before the introduction of contemporary guideline-directed medical therapy (GDMT). The DIG (Digitalis Investigation Group) trial results, published in 1997, compared digoxin with placebo in patients with heart failure with reduced ejection fraction (HFrEF; i.e., left ventricular ejection fraction [LVEF] <45%).¹ Digoxin was not associated with a significant mortality benefit, but the trial did meet the secondary endpoint of reduced hospitalizations. One concern regarding digoxin has been the narrow therapeutic window, with post hoc analysis of the DIG trial demonstrating that higher serum concentration of digoxin was associated with increased mortality.² Medical therapy for HF at the time of the DIG trial included only diuretics and angiotensin-converting enzyme inhibitors. Given these findings, digoxin has a Class 2b recommendation to decrease HF hospitalizations in patients with HFrEF taking maximal GDMT.³

Digitoxin is another cardiac glycoside available in many countries, although not in the United States. The DIGIT-HF (Digitoxin to Improve Outcomes in Patients with Advanced Chronic Heart Failure) trial, published August 2025, was a European, double-blinded trial comparing digitoxin with placebo in patients with HFrEF (LVEF <40%) taking optimal GDMT.⁴ The primary outcome was death from any cause or HF exacerbation hospitalization, whichever occurred first. In this study, 1,212 patients were randomly assigned in a 1:1 fashion between digitoxin (n = 613) and placebo (n = 599). The digitoxin group was initiated on a dose of 0.07 mg, with dose adjustments made using a predefined algorithm with a goal digitoxin concentration of 8-18 ng/mL. The mean LVEF was 29%, with most patients classifying their symptoms as New York Heart Association (NYHA) class III or IV; approximately 30% had NYHA class II HF symptoms. Regarding contemporary GDMT, at the beginning of the trial, almost all patients were receiving concomitant treatment with a renin-angiotensin system blocker and a beta-blocker, approximately 75% were taking a mineralocorticoid receptor antagonist, and approximately 20% were taking a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

After a median follow-up of 36 months, the primary outcome event occurred in 39.5% of patients in the digitoxin group and in 44.1% in the placebo group, which was statistically significant (p < 0.03). Death from any cause occurred in 27.2% of the digitoxin group and 29.5% of the placebo group. Hospitalization for an acute HF exacerbation occurred in 28.1% of the digitoxin group and 30.4% of the placebo group. The number of patients needed to treat to prevent one primary outcome was 22. At least one serious adverse event occurred in 4.7% of the digitoxin group and 2.8% of the placebo group. Benefit was consistent across subgroups, even in patients taking all four pillars of GDMT (19.8% of the study population).

The benefits of digitoxin in patients with HFrEF appear to be similar to what was seen with digoxin in the DIG trial, despite the advances in GDMT that have occurred since 1997. There are several limitations that need to be mentioned. Most patients were male, with <20% of the study population being female. This percentage is of particular importance because a post hoc analysis of the DIG trial suggested higher all-cause mortality with digoxin in females.⁵ The final sample size fell below the initial projection due to recruitment challenges, limiting the robustness of the findings. The use of SGLT2 inhibitors in the DIGIT-HF trial was approximately 20% of the study population. Serum digitoxin concentrations were assessed following randomization to maintain a target range of 8-18 ng/mL. Whether such close monitoring and adherence can be maintained in clinical practice remains to be seen. Finally, this trial's findings cannot be generalized to digoxin, given different pharmacokinetics between the two agents.⁶ Investigators for the DIGIT-HF trial speculated that the enterohepatic excretion of digitoxin in patients with kidney disease may lead to more stable drug concentration and less cardiac toxicity in patients with HF.

A trial of digoxin in patients with HFrEF, the DECISION (Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands), was underway at the time of this writing.⁷ This trial aimed for serum digoxin level 0.5-0.9 ng/mL to mitigate the adverse events seen with serum digoxin level >1 ng/mL in the DIG trial. The beneficial effects on symptoms of HF from cardiac glycosides in the foxglove plant have been observed since the Middle Ages. However, the use of cardiac glycosides has steadily declined since publication of the DIG trial results because of a lack of mortality benefit and concerns regarding toxicity. It is remarkable that a medication used in the 18^th century to treat dropsy (i.e., swelling) could still hold value for patients with HF in today's era of advanced therapies. Will the number of digits that are used to treat HFrEF soon be five?

References

1. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525-533. doi:10.1056/NEJM199702203360801
2. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003;289(7):871-878. doi:10.1001/jama.289.7.871
3. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(17):e263-e421. doi:10.1016/j.jacc.2021.12.012
4. Bavendiek U, Großhennig A, Schwab J, et al. Digitoxin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2025;393(12):1155-1165. doi:10.1056/NEJMoa2415471
5. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med. 2002;347(18):1403-1411. doi:10.1056/NEJMoa021266
6. Smith TW. Pharmacokinetics, bioavailability and serum levels of cardiac glycosides. J Am Coll Cardiol. 1985;5(5 Suppl A):43A-50A. doi:10.1016/s0735-1097(85)80462-9
7. van Veldhuisen DJ, Rienstra M, Mosterd A, et al. Efficacy and safety of low-dose digoxin in patients with heart failure. Rationale and design of the DECISION trial. Eur J Heart Fail. 2024;26(10):2223-2230. doi:10.1002/ejhf.3428