What is the clinical evidence from this study?

Study design: RCT. Population: Heart failure with reduced ejection fraction (HFrEF) (n=1212). Intervention: Digitoxin vs. Placebo. Primary outcome: Composite of death from any cause or first hospitalization for worsening heart failure (HR 0.82, 95% CI 0.69-0.98, p=0.03).

What question did this study set out to answer?

To determine whether adding digitoxin to guideline-directed medical therapy reduces adverse clinical outcomes in patients with advanced chronic heart failure with reduced ejection fraction.

April 3, 2026Cleveland Clinic Journal of MedicineOpen Access

Interpreting the DIGIT-HF trial: Time for a new look at digitalis?

Q: What are the key findings of this study?

Digitoxin reduced the composite endpoint of death from any cause or first hospitalization for worsening heart failure by 18% compared to placebo in patients with HFrEF.

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Key result

Digitoxin cuts death or HF hospitalization ~18% vs. placebo in HFrEF.

HR 0.82
95% CI 0.69-0.98
P=0.03
n=1,212

Why the study?

Does digitoxin reduce the composite of death or first hospitalization for worsening heart failure in patients with advanced HFrEF on guideline-directed medical therapy?

Key Points

To determine whether adding digitoxin to guideline-directed medical therapy reduces adverse clinical outcomes in patients with advanced chronic heart failure with reduced ejection fraction.
International, phase 4, multicenter, randomized, double-blind, placebo-controlled trial conducted at 65 centers in Austria, Germany, and Serbia.
Clinically stable adult patients with heart failure with reduced ejection fraction (LVEF ≤40% in NYHA class III/IV, or LVEF ≤30% in NYHA class II) receiving guideline-directed therapy were randomized 1:1 to digitoxin (started at 0.07 mg/day with a 6-week serum level check targeting 8–18 ng/mL) or placebo.
The primary endpoint was a composite of death from any cause or first hospitalization for worsening heart failure assessed over a median follow-up of 36 months by intention-to-treat analysis.
Digitoxin significantly reduced the primary composite outcome of all-cause death or first hospitalization for worsening heart failure compared with placebo by 18% (hazard ratio 0.82, 95% confidence interval 0.69–0.98).
Digitoxin met the prespecified noninferiority threshold (1.303) for all-cause mortality versus placebo with a hazard ratio of 0.86 (P < .001 for noninferiority), while showing no statistically significant differences in all-cause mortality or first hospitalizations alone.
Serious adverse events occurred in 4.7% of the digitoxin group compared with 2.8% of the placebo group, a difference that was not statistically significant.

Study Design

Type

RCT (n=1,212)

Blinding

Double-blind

Randomization

1:1

Multicenter

Yes

Structured PICO

Does digitoxin reduce the composite of death or first hospitalization for worsening heart failure in patients with advanced HFrEF on guideline-directed medical therapy?

Population

1,212 adults with advanced heart failure with reduced ejection fraction (HFrEF), defined as LVEF ≤40% and NYHA class III or IV, or LVEF ≤30% and NYHA class II. Patients were clinically stable for at least 6 months on guideline-directed medical therapy. Mean age 66 years, 20.4% female, multinational (Austria, Germany, Serbia).

Intervention

Digitoxin started at 0.07 mg/day orally, with a single serum level check at 6 weeks to adjust the dose and maintain serum concentration between 8 to 18 ng/mL, added to guideline-directed medical therapy.

Comparator

Matching placebo added to guideline-directed medical therapy.

Outcome

Composite of death from any cause or first hospitalization for worsening heart failure, whichever occurred first, over a median follow-up of 36 months.composite

Main Result

Effect estimate: HR 0.82 (95% CI 0.69-0.98)

Absolute Event Rate: 39.5% vs 44.1%

p-value: p=0.03

In patients with advanced HFrEF receiving optimal guideline-directed medical therapy, the addition of digitoxin provides a modest but clinically relevant reduction in the combined risk of death or heart failure hospitalization.

Limitations

Exclusively European population with underrepresentation of women and patients with atrial fibrillation
Did not meet the planned sample size or event rate, reducing statistical power
High treatment discontinuation rate (58.9% in the digitoxin group and 55.1% in the placebo group)
Absence of functional parameters and quality of life assessments
Unblinding occurred in a limited number of cases
Exclusively European population with fewer women (20%) and fewer patients with atrial fibrillation than comparable trials
Unblinding occurred in a limited number of cases (54 in digitoxin group, 28 in placebo group)
Lower recruitment and event rate than expected, reducing statistical power
High discontinuation rate for reasons other than death (58.9% digitoxin vs 55.1% placebo)

Implication

Supports selective digitoxin add-on in advanced HFrEF on GDMT; extends digitalis evidence but modest effects and endpoint fragility warrant caution.

Abstract

The DIGIT-HF (Digitoxin to Improve Outcomes in Patients With Advanced Chronic Heart Failure; N Engl J Med 2025; 393(12):1155–1165) trial compared digitoxin with placebo, added to guideline-directed medical therapy in patients with heart failure with reduced ejection fraction (HFrEF). Compared with placebo, digitoxin reduced the incidence of the composite endpoint of death from any cause or first hospitalization for worsening heart failure by 18% over a median follow-up of 36 months (hazard ratio 0.82, 95% confidence interval 0.69–0.98). There were no statistically significant differences in the rates of all-cause mortality, first hospitalization, or serious adverse events.

Discussion

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Cite This Study

Leiva-Murillo et al. (2026) conducted an RCT in Heart failure with reduced ejection fraction (HFrEF) (n=1,212). Digitoxin vs. Placebo was evaluated on Composite of death from any cause or first hospitalization for worsening heart failure (HR 0.82, 95% CI 0.69-0.98, p=0.03). Digitoxin reduced the composite endpoint of death from any cause or first hospitalization for worsening heart failure by 18% compared to placebo in patients with HFrEF.

synapsesocial.com/papers/69cf5d055a333a821460a9a4 https://doi.org/10.3949/ccjm.93a.25098

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Implication

Supports selective digitoxin add-on in advanced HFrEF on GDMT; extends digitalis evidence but modest effects and endpoint fragility warrant caution.

Interpreting the DIGIT-HF trial: Time for a new look at digitalis?

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Interpreting the DIGIT-HF trial: Time for a new look at digitalis?

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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