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CLINICAL STUDY: HEART FAILURE

Clinical benefits of low serum digoxin concentrations in heart failure

Kirkwood F. Adams, Jr, MD, FACC^*,*, Mihai Gheorghiade, MD, FACC, Barry F. Uretsky, MD, FACC^||, J. Herbert Patterson, PharmD, Todd A. Schwartz, MS and James B. Young, MD, FACC^¶

^* Departments of Medicine and Radiology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
Departments of Medicine and Radiology, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
Department of Biostatistics, School of Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
Department of Medicine, Northwestern University Medical School, Chicago, Illinois, USA
^|| Department of Medicine, University of Texas Medical Branch, Galveston, Texas, USA
^¶ Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA

Manuscript received September 15, 2000; revised manuscript received December 12, 2001, accepted December 21, 2001.

^* Reprint requests and correspondence: Dr. Kirkwood F. Adams, Jr., Division of Cardiology, University of North Carolina at Chapel Hill, CB #7075, Burnett-Womack Building, Chapel Hill, North Carolina 27599-7075, USA.
kfa{at}med.unc.edu

OBJECTIVES: We sought to determine whether there was a relationship between serum digoxin concentration (SDC), including SDCs typically regarded as low, and clinical efficacy related to digoxin in patients with symptomatic left ventricular dysfunction.

BACKGROUND: Digitalis glycosides have been used for 200 years in the treatment of heart failure (HF), but the SDC required for optimal clinical efficacy and acceptable toxicity remains controversial.

METHODS: This relationship was investigated by utilizing data from two randomized, double-blinded, placebo-controlled, digoxin-withdrawal trials: the Prospective Randomized study Of Ventricular failure and Efficacy of Digoxin (PROVED) and the Randomized Assessment of Digoxin on Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Major end points were worsening HF, change in left ventricular ejection fraction and treadmill time after randomization. The primary analysis investigated the relationship between SDC at randomization and these end points. A secondary categorical analysis compared these end points in patients who discontinued digoxin versus patients who continued digoxin and had low (0.5 to 0.9 ng/ml), moderate (0.9 to 1.2 ng/ml) or high (>1.2 ng/ml) SDCs at randomization.

RESULTS: Multiple regression analysis failed to find a relationship between randomization SDC, considered as a continuous variable, and any study end point (all p > 0.236). Multivariable Cox analysis found that the risk of worsening HF was significantly less (all p < 0.02) for patients in any category of SDC who continued digoxin, as compared with patients withdrawn from digoxin. Specifically, patients in the low SDC category were significantly less likely than placebo patients to experience worsening HF during follow-up (p = 0.018).

CONCLUSIONS: The beneficial effects of digoxin on common clinical end points in patients with HF were similar, regardless of SDC.

Abbreviations and Acronyms   RADIANCE   HF   heart failure   LV   left ventricular   LVEF   left ventricular ejection fraction   PROVED   Prospective Randomized study Of Ventricular failure and Efficacy of Digoxin   RADIANCE   Randomized Assessment of Digoxin on Inhibitors of the Angiotensin-Converting Enzyme   SDC   serum digoxin concentration

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