The association of digoxin with mortality in ischemic heart failure: a secondary analysis of the STICH trial

Abstract

Background: Digoxin, one of the first treatments for symptoms of congestive heart failure (CHF), is currently used in the management of persistent CHF symptoms as well as for ventricular rate control in atrial fibrillation. Current guidelines suggest digoxin as an adjunct to optimal medical therapy for symptomatic improvement in CHF. However, the data regarding the effect of digoxin use on mortality continue to be conflicting. Purpose: The aim of this retrospective study was to evaluate the association of digoxin therapy with mortality in patients with ischemic heart failure defined by severe left ventricular (LV) dysfunction and coronary artery disease (CAD) in the Surgical Treatment for Ischemic Heart Failure (STICH) trial. Methods: STICH randomized 1012 patients with CAD and LV ejection fraction<35% to coronary artery bypass graft (CABG) surgery and medical therapy vs. medical therapy alone. Factors predictive of digoxin use were identified with a binomial logistic regression model. Multivariable Cox proportional hazards modelling was performed with digoxin use modelled as a segmented time-dependent covariate. The model was adjusted for baseline clinical characteristics (including age, race, hypertension, hyperlipidemia, diabetes mellitus, peripheral vascular disease, NYHA heart failure class, previous myocardial infarction, atrial fibrillation, creatinine level, smoking status, and STICH treatment group) and stratified based on sex. All covariates were verified to meet the proportional hazards assumption. The primary outcome was all-cause mortality. Secondary outcomes included death and hospitalization due to cardiovascular causes. Relative risks were expressed as adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Results: Of the 1012 patients, 351 (35% [36% of male patients and 27% of female patients]) reported digoxin use for some duration during the study period. Significant predictors of digoxin use included minority status, NYHA class, previous myocardial infarction, and baseline diagnosis of hypertension, diabetes, or atrial fibrillation. At a mean follow-up of 9.8 years, 566 patients (55.7%) experienced all-cause mortality and 387 patients (38.1%) died due to cardiovascular causes. The adjusted Cox proportional hazards model demonstrated that digoxin use was independently associated with an increased risk of all-cause mortality (aHR 1.22, 95% CI: 1.00-1.49, P=0.049). Digoxin use was also associated with increased risk of cardiovascular death (aHR 1.29, 95% CI: 1.02-1.64, P=0.032). There was no impact of digoxin on hospitalization for cardiovascular causes. Conclusion: Use of digoxin in patients with ischemic heart failure was associated with an increased risk of both all-cause and cardiovascular death.