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Saif S. Rathore, MPH; Jeptha P. Curtis, MD; Yongfei Wang, MS; Michael R. Bristow, MD, PhD; Harlan M. Krumholz, MD, SM

JAMA. 2003;289:871-878.

Context  The Digitalis Investigation Group (DIG) trial reported that digoxin provided no overall mortality benefit and only a modest reduction in hospitalizations among patients with heart failure and depressed left ventricular systolic function. The clinical outcomes associated with digoxin therapy at different serum concentrations in the DIG trial have not been assessed.

Objective  To assess variations in serum digoxin concentration (SDC) and their association with mortality and hospitalization in patients with heart failure.

Design, Setting, and Patients  Post hoc analysis of the randomized, double-blinded, placebo-controlled DIG trial, conducted from August 1991 to December 1995, with the main analysis restricted to men with a left ventricular ejection fraction of 45% or less (n = 3782). Patients randomly assigned to receive digoxin were divided into 3 groups based on SDC at 1 month (0.5-0.8 ng/mL, n = 572; 0.9-1.1 ng/mL, n = 322; and 1.2 ng/mL, n = 277) and compared with patients randomly assigned to receive placebo (n = 2611).

Main Outcome Measure  All-cause mortality at a mean follow-up of 37 months.

Results  Higher SDCs were associated with increased crude all-cause mortality rates (0.5-0.8 ng/mL, 29.9%; 0.9-1.1 ng/mL, 38.8%; and 1.2 ng/mL, 48.0%; P = .006 for trend). Patients with SDCs of 0.5 to 0.8 ng/mL had a 6.3% (95% confidence interval [CI], 2.1%-10.5%) lower mortality rate compared with patients receiving placebo. Digoxin was not associated with a reduction in mortality among patients with SDCs of 0.9 to 1.1 ng/mL (2.6% increase; 95% CI, - 3.0% to 8.3%), whereas patients with SDCs of 1.2 ng/mL and higher had an 11.8% (95% CI, 5.7%-18.0%) higher absolute mortality rate than patients receiving placebo. The association between SDC and mortality persisted after multivariable adjustment (SDC 0.5-0.8 ng/mL hazard ratio [HR] 0.80, 95% CI, 0.68-0.94; SDC 0.9-1.1 ng/mL HR 0.89, 95% CI, 0.74-1.08; SDC 1.2 ng/mL HR 1.16, 95% CI, 0.96-1.39; and HR of 1.00 [referent] for placebo).

Conclusions  Our findings demonstrate that higher SDCs were associated with increased mortality and suggest that the effectiveness of digoxin therapy in men with heart failure and a left ventricular ejection fraction of 45% or less may be optimized in the SDC range of 0.5 to 0.8 ng/mL.

Author Affiliations: The Section of Cardiovascular Medicine (Messrs Rathore and Wang and Drs Curtis and Krumholz), Department of Internal Medicine and the Section of Health Policy and Administration (Dr Krumholz), Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Conn; Division of Cardiology, University of Colorado Health Sciences Center, Denver (Dr Bristow); and the Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn (Dr Krumholz).

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