Using DIG Trial to Examine The Association Between Digoxin Therapy and Clinical Outcomes in Heart Failure: A Subgroup and 1-Year Analysis

Q: What are the key findings of this study?

Digoxin reduced the 1-year risk of death or heart failure hospitalization across subgroups without significant subgroup interactions.

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Heart failure with reduced ejection fraction (HFrEF) (n=6800). Intervention: Digoxin vs. Placebo. Primary outcome: Composite of all-cause mortality or hospitalization due to worsening heart failure (in LVEF <= 25% subgroup at 1 year) (HR 0.652, 95% CI 0.567, 0.750, p=<.0001).

Q: What does this research mean for the field?

Digoxin therapy significantly reduces the risk of all-cause mortality or heart failure hospitalization in HFrEF patients across LVEF and NYHA subgroups, with particularly pronounced benefits observed in the first year without significant subgroup interactions. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To assess the association between digoxin therapy and the composite outcome of all-cause mortality or hospitalization for worsening heart failure across clinical subgroups and follow-up timeframes.

Aoran Cao

doi:10.62051/ijphmr.v6n9.04

November 3, 2026International Journal of Public Health and Medical ResearchOpen Access

Using DIG Trial to Examine The Association Between Digoxin Therapy and Clinical Outcomes in Heart Failure: A Subgroup and 1-Year Analysis

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Key result

Digoxin cuts 1-year death or heart failure hospitalization by ~35% across LVEF subgroups.

HR 0.652
95% CI 0.567, 0.750
P<.0001
n=6,800

Why the study?

This study evaluated the association between digoxin therapy and the composite of all-cause mortality or heart failure hospitalization across clinical subgroups and follow-up periods.

Does digoxin therapy reduce the composite outcome of all-cause mortality or hospitalization due to worsening heart failure across LVEF and NYHA subgroups in patients with HFrEF and normal sinus rhythm?

Key Points

To assess the association between digoxin therapy and the composite outcome of all-cause mortality or hospitalization for worsening heart failure across clinical subgroups and follow-up timeframes.
Evaluated patients with heart failure with reduced ejection fraction from the Digitalis Investigation Group trials (LVEF ≤ 25%: 1342 digoxin, 1343 placebo; LVEF > 25%: 2055 digoxin, 2060 placebo).
Applied Cox proportional hazards models to examine 1-year treatment-by-subgroup interaction terms and estimate subgroup-specific hazard ratios over full follow-up and the first year.
Within 1 year, digoxin use was associated with lower risk of the composite outcome in patients with LVEF ≤ 25% (HR 0.652, 95% CI 0.567 to 0.750, P<.0001) and LVEF > 25% (HR 0.748, 95% CI 0.650 to 0.860, P<.0001).
Digoxin was also associated with reduced hazards over full follow-up for LVEF ≤ 25% (HR 0.773, 95% CI 0.701 to 0.853) and LVEF > 25% (HR 0.864, 95% CI 0.787 to 0.948), with consistent 1-year reductions across NYHA classes I-II (HR 0.727, 95% CI 0.635 to 0.832, P<.0001) and III-IV (HR 0.657, 95% CI 0.568 to 0.760, P<.0001).
One-year interaction tests demonstrated no statistically significant effect modification across LVEF groups (P=0.1644), NYHA classes (P=0.2896), cardiothoracic ratio categories (P=0.8810), or prior digoxin use (P=0.6211).

Study Design

Type

RCT (n=6,800)

Blinding

Double-blind

Randomization

Randomized

Multicenter

Yes

Structured PICO

Does digoxin therapy reduce the composite outcome of all-cause mortality or hospitalization due to worsening heart failure across LVEF and NYHA subgroups in patients with HFrEF and normal sinus rhythm?

P

Population

6,800 patients (mean age ~63.5 years, 22.3% female) with chronic heart failure, normal sinus rhythm, and LVEF <= 0.45 from the DIG trial in the United States and Canada.

I

Intervention

Digoxin therapy (randomly assigned, analyzed by intention-to-treat)

C

Comparator

Placebo (with >92% of patients in both groups receiving ACE inhibitors)

O

Outcome

Composite of all-cause mortality or hospitalization due to worsening heart failure (evaluated at 1-year follow-up and full follow-up)composite

Main Result

Hazard Ratio: 0.652 (95% CI 0.567–0.75)

p-value: p=<.0001

In patients with HFrEF and normal sinus rhythm from the DIG trial, digoxin consistently reduced the composite risk of all-cause mortality or heart failure hospitalization across LVEF and NYHA subgroups, with numerically stronger associations during the first year of therapy.

Limitations

Subgroup analyses are exploratory and may lack sufficient statistical power to detect significant interactions.
Composite outcome does not distinguish between all-cause mortality and hospitalization.
Unmeasured or residual confounding and changes in treatment over time may affect the observed associations.
Subgroup analyses are exploratory and may lack sufficient statistical power to detect statistically significant interactions
Restricting interaction analyses to the first year reduces follow-up time
The composite outcome does not distinguish between all-cause mortality and hospitalization
Potential residual or unmeasured confounding and changes in treatment over time may affect the association between treatment and clinical outcomes

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

Supports consistent digoxin association across LVEF subgroups in HFrEF; hypothesis-generating and requires contemporary trials before practice change.

Abstract

This study evaluated the association between digoxin therapy and the composite outcome of all-cause mortality or hospitalization due to worsening heart failure. Patients with reduced election fractions (HFrEF) were obtained from the Digitails Investigation Group trials. Baseline characteristics were summarized by left ventricular ejection fraction (LVEF) subgroup and treatment group. This study used Cox proportional hazards models to examine treatment-by-subgroup interactions within the first year and to estimate subgroup-specific hazard ratios during both full and 1-year follow-up. Results showed that there is an association between digoxin therapy and a lower hazard composite outcome across LVEF and NYHA subgroups, with stronger numerical associations during the first-year follow-up period. However, there were no statistically significant interactions for LVEF, NYHA class, cardiothoracic ratio, and prior digoxin use. These findings indicate a consistent protective association across these examined subgroups, and a stronger early association could be interpreted cautiously because there is no formal evidence of significant effect modification found.

Discussion

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Cite This Study

Aoran Cao (2026) conducted an RCT in Heart failure with reduced ejection fraction (HFrEF) (n=6,800). Digoxin vs. Placebo was evaluated on Composite of all-cause mortality or hospitalization due to worsening heart failure (in LVEF <= 25% subgroup at 1 year) (HR 0.652, 95% CI 0.567, 0.750, p=<.0001). Digoxin reduced the 1-year risk of death or heart failure hospitalization across subgroups without significant subgroup interactions.

synapsesocial.com/papers/6aed6ef73dd5ffb8e184e691 https://doi.org/10.62051/ijphmr.v6n9.04

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Using DIG Trial to Examine The Association Between Digoxin Therapy and Clinical Outcomes in Heart Failure: A Subgroup and 1-Year Analysis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Using DIG Trial to Examine The Association Between Digoxin Therapy and Clinical Outcomes in Heart Failure: A Subgroup and 1-Year Analysis

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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