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CLINICAL RESEARCH: HEART FAILURE

Relationship of Serum Digoxin Concentration to Mortality and Morbidity in Women in the Digitalis Investigation Group Trial

A Retrospective Analysis

Kirkwood F. Adams, Jr, MD, FACC^_*,_*, J. Herbert Patterson, PharmD, Wendy A. Gattis, PharmD, Christopher M. O’Connor, MD, FACC, Craig R. Lee, PharmD, Todd A. Schwartz, DrPH and Mihai Gheorghiade, MD, FACC^||

^_* Department of Medicine and Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Department of Biostatistics, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Department of Medicine, Duke Clinical Research Institute, Duke University, Durham, North Carolina
^|| Department of Medicine, Northwestern University Medical School, Chicago, Illinois.

Manuscript received November 12, 2004; revised manuscript received February 8, 2005, accepted February 14, 2005.

^_* Reprint requests and correspondence: Dr. Kirkwood F. Adams, Jr., UNC Heart Failure Program, 6110 Falconbridge Road, Suite 101, Chapel Hill, North Carolina 27517. (Email: kfa{at}med.unc.edu).

OBJECTIVES: The purpose of this study was to investigate the relationship of serum digoxin concentration (SDC) and outcomes in women with heart failure (HF).

BACKGROUND: Controversy continues concerning the clinical utility of digoxin in women with HF.

METHODS: Our analysis was retrospective with data from the Digitalis Investigation Group (DIG) trial. The principal study analysis reviewed 4,944 patients with HF due to systolic dysfunction who survived for at least 4 weeks (all 3,366 patients randomized to placebo and the 1,578 of 3,372 patients randomized to digoxin who had serum concentration measured 6 to 30 h [inclusive] after the last dose of study drug at 4 weeks).

RESULTS: Continuous multivariable analysis demonstrated a significant linear relationship between SDC and mortality in women (p = 0.008) and men (p = 0.002, p = 0.766 for gender interaction). Averaging hazard ratios (HRs) across serum concentrations from 0.5 to 0.9 ng/ml in women produced a HR for death of 0.8 (95% confidence interval [CI] 0.62 to 1.13, p = 0.245) and for death or hospital stay for worsening HF of 0.73 (95% CI 0.58 to 0.93, p = 0.011). In contrast, SDCs from 1.2 to 2.0 ng/ml were associated with a HR for death for women of 1.33 (95% CI 1.001 to 1.76, p = 0.049).

CONCLUSIONS: Retrospective analysis of data from the DIG trial indicates a beneficial effect of digoxin on morbidity and no excess mortality in women at serum concentrations from 0.5 to 0.9 ng/ml, whereas serum concentrations 1.2 ng/ml seem harmful.

Abbreviations and Acronyms   CI = confidence interval   DIG = Digitalis Investigation Group   HF = heart failure   HR = hazard ratio   SDC = serum digoxin concentration

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