Digoxin Revisited: An Updated Review in the Light of Recent Trials

Department

Cardiology

Document Type

Article

Publication Title

Cardiology Research

Abstract

Isolated from Digitalis species following William Withering's 1785 work on foxglove, digoxin inhibits myocardial Na+/K+-ATPase, raising intracellular calcium and vagal tone to produce inotropic, rate-controlling, and neurohormonal-deactivating effects. The foundational DIG trial (1997) showed no mortality benefit but reduced heart failure hospitalizations, prompting a progressive guideline downgrade. Three decades later, DIGIT-HF (2025, digitoxin) and DECISION (2026, low dose digoxin) retested cardiac glycosides atop modern four pillar guideline-directed medical therapy (GDMT). DIGIT-HF significantly reduced the composite of death or worsening heart failure (hazard ratio (HR), 0.82), while DECISION showed a numerical but nonsignificant benefit. A pooled meta-analysis of DIG, DIGIT-HF, and DECISION (9,013 patients) confirmed a consistent 15% reduction in worsening heart failure events across three decades of changing background therapy, without a significant mortality effect. The Dig-RHD trial addressed an unstudied population: symptomatic rheumatic heart disease (RHD), a chronic valvular heart disease that results from permanent damage to cardiac valves due to group A streptococcal infection. RHD affects roughly 40 million people and causes approximately 300,000 deaths annually, disproportionately in low- and middle-income countries. In 1,769 patients randomized across 12 Indian centers, digoxin significantly reduced the composite of death or new-onset/worsening heart failure (31.4% vs. 35.5%; HR, 0.82; 95% confidence interval (CI), 0.70 to 0.97; P = 0.02), with greater benefit in atrial fibrillation, women, and patients with low body mass index (BMI), and a number needed to treat of approximately 14 over 2 years. Digoxin is not a mortality-reducing drug, but pooled contemporary evidence establishes it as a reproducible, low-cost tool for reducing heart failure events, now supported for the first time by high-quality randomized data in RHD, a population with substantial global burden and no prior evidence-based medical therapy. These findings warrant reconsideration of digoxin's guideline status and development of RHD-specific recommendations.

First Page

553

Last Page

560

DOI

10.14740/cr2287

Volume

17

Issue

6

Publication Date

12-1-2026

PubMed ID

42964409

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