Effect of Oral Digoxin in High-risk Heart Failure Patient

A Pre-Specified Subgroup Analysis of the DIG Trial

Mihai Gheorghiade; Kanan Patel; Gerasimos Filippatos; Stefan D. Anker; Dirk J. van Veldhuisen; John G.F. Cleland; Marco Metra; Inmaculada B. Aban; Stephen J. Greene; Kirkwood F. Adams; John J.V. McMurray; Ali Ahmed


Eur J Heart Fail. 2013;15(5):551-559. 

In This Article

Abstract and Introduction


Aims In the Digitalis Investigation Group (DIG) trial, digoxin reduced mortality or hospitalization due to heart failure (HF) in several pre-specified high-risk subgroups of HF patients, but data on protocol-specified 2-year outcomes were not presented. In the current study, we examined the effect of digoxin on HF death or HF hospitalization and all-cause death or all-cause hospitalization in high-risk subgroups during the protocol-specified 2 years of post-randomization follow-up.

Methods and results In the DIG trial, 6800 ambulatory patients with chronic HF, normal sinus rhythm, and LVEF ≤45% (mean age 64 years, 26% women, 17% non-whites) were randomized to receive digoxin or placebo. The three high-risk groups were defined as NYHA class III–IV symptoms (n = 2223), LVEF <25% (n = 2256), and cardiothoracic ratio (CTR) >55% (n = 2345). In all three high-risk subgroups, compared with patients in the placebo group, those in the digoxin group had a significant reduction in the risk of the 2-year composite endpoint of HF mortality or HF hospitalization: NYHA III–IV [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.57–0.75; P < 0.001], LVEF <25% (HR 0.61; 95% CI 0.53–0.71; P < 0.001), and CTR >55% (HR 0.65; 95% CI 0.57–0.75; P < 0.001). Digoxin-associated HRs (95% CI) for 2-year all-cause mortality or all-cause hospitalization for subgroups with NYHA III–IV, LVEF <25%, and CTR >55% were 0.88 (0.80–0.97; P = 0.012), 0.84 (0.76–0.93; P = 0.001), and 0.85 (0.77–0.94; P = 0.002), respectively.

Conclusions Digoxin improves outcomes in chronic HF patients with NYHA class III–IV, LVEF <25%, or CTR >55%, and should be considered in these patients.


In the Digitalis Investigation Group (DIG) trial, the largest randomized clinical trial (RCT) of digoxin efficacy in heart failure (HF), digoxin reduced the combined endpoint of hospitalization due to worsening HF and death due to progressive HF, but had no association with all-cause mortality.[1] Taken together with the findings from the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE),[2,3] this cumulative evidence was used by the US Food and Drug Administration (FDA) to approve digoxin for use in HF in 1997 and, subsequently, all major national HF guidelines recommended the use of digoxin in HF.[4,5] The outcomes used by the FDA and presented in the package insert for Lanoxin® tablets were the combined endpoints of death or hospitalization due to HF and death or hospitalization due to all causes during the first 2 years of follow-up.[6] The DIG investigators hypothesized the effect of digoxin to be more pronounced during the first 2 years after randomization.[7] These analyses also included three high-risk subgroups.[6] The DIG report presented the effect of digoxin on HF death or HF hospitalization during the entire follow-up in these three subgroups.[1] However, baseline characteristics of these high-risk subgroups and the effect of digoxin on 2-year outcomes have not been previously published in the peer-reviewed medical literature. The objective of the current study was to examine the effect of digoxin on 2-year HF death or HF hospitalization and total death or total hospitalization in high-risk HF patients in the DIG trial.

The abstract of this paper was presented at The Late Breaking Clinical Trial Session at the Heart Failure Congress 2012 in Belgrade, Serbia, May 21, 2012.