DIGIT-HF: Digitoxin’s Evidence Remains Insufficient for a Digoxin-Level Recommendation

Heart failure with reduced ejection fraction (HFrEF), also called systolic heart failure, is a clinical syndrome of impaired ventricular systolic function defined by a left ventricular ejection fraction (LVEF) of 40% or less. HFrEF is associated with increased hospitalization, reduced quality of life, and increased mortality.¹

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The American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) guidelines for the management of heart failure recommend initiating guideline-directed medical therapy (GDMT) in patients with HFrEF. Each GDMT agent should be started promptly and uptitrated toward a target dose as tolerated by the patient.

GDMT includes the following 4 pillars¹:

• Angiotensin receptor-neprilysin inhibitor (ARNI) is preferred in New York Heart Association (NYHA) class II-III (Table 1). If ARNI is not feasible, an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) can be used.
• Evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol)
• Mineralocorticoid receptor antagonist (spironolactone or eplerenone)
• Evidence-based sodium-glucose cotransporter-2 inhibitor (SGLT2i; dapagliflozin or empagliflozin)

Table 1.¹ NYHA Functional Classification System

After optimizing GDMT, adjunct options for symptomatic HFrEF include ivabradine, vericiguat, and digoxin (a 2a recommendation).¹ The recommendation for digoxin is based on findings from the effect of digoxin on the quality of life in patients with heart failure trial. This trial demonstrated a reduction in heart failure-related hospitalizations without mortality benefit.²

Digoxin and digitoxin are cardiac glycosides that inhibit the Na⁺/K⁺-ATPase in cardiomyocytes, producing positive inotropy and increased vagal tone at the atrioventricular node, which can improve diastolic filling.³ Clinically, this translates to better exercise tolerance and fewer heart failure-related hospitalizations. Thus, digoxin use is typically reserved for patients who remain symptomatic despite optimization of GDMT.²

Digitoxin is not currently FDA-approved in the US and fell out of routine use as digoxin became the standard cardiac glycoside.⁴ Digitoxin is viewed by some clinicians as an appealing option in individuals with severe renal impairment because it is predominantly hepatically cleared.² However, its very long half-life (5-7 days), drug-interaction profile, and lack of an available antidote at the time limited its use (Table 2).^{4, 5} Digitoxin remains available in Canada and parts of Europe.⁴

The DIGIT-HF Trial

In the double-blind, international, randomized, placebo-controlled DIGIT-HF trial, 1240 patients were randomized across 55 sites. The modified intention-to-treat population included 613 patients assigned to receive digitoxin at a starting dose of 0.07 mg once daily (with dose titrations) and 599 patients assigned to receive a matching placebo. Eligible patients had symptomatic chronic HFrEF with an LVEF of 40% or less and NYHA III-IV, or an LVEF of 30% or less and NYHA II, and had received GDMT for at least 6 months.⁶

The primary outcome was a time-to-first-event composite of death from any cause or first hospitalization for worsening heart failure. The digitoxin treatment group had an 18% lower risk of the primary composite outcome compared to the placebo group over a median of 36 months, meeting superiority. However, the individual components of death from heart failure (95% CI = 0.57 to 1.31) and first hospitalization for heart failure (95% CI = 0.69 to 1.05) were not statistically significant.⁶

Although digitoxin may offer pharmacokinetic advantages in advanced chronic kidney disease or with fluctuating renal function, current evidence is insufficient to support a recommendation equivalent to digoxin in the AHA/ACC/HFSA guidelines for the management of HF.

REFERENCES

1. 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. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063

2. Lader E, Egan D, Hunsberger S, Garg R, Czajkowski S, McSherry F. The effect of digoxin on the quality of life in patients with heart failure. J Card Fail. 2003;9(1):4-12. doi:10.1054/jcaf.2003.7

3. Lanoxin [prescribing information]. Concordia Pharmaceuticals Inc; December 2016. Accessed September 16, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020405s013lbl.pdf

4. Zeitlin PL, Diener-West M, Callahan KA, et al. Digitoxin for airway inflammation in cystic fibrosis: preliminary assessment of safety, pharmacokinetics, and dose finding. Ann Am Thorac Soc. 2017;14(2):220-229. doi:10.1513/AnnalsATS.201608-649OC

5. AHFS Drug Information 2025. American Society of Health-System Pharmacists; 2025.

6. Bavendiek U, GroBhennig, Schwab J, et al. Digitoxin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2025. doi:10.1056/NEJMoa2415471