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Beware High Serum Digoxin Concentrations

Laurie Barclay, MD

Feb. 18, 2003 — It's time to change the therapeutic window of digoxin to 0.5 to 0.8 ng/mL for men with heart failure, according to the results of a post-hoc analysis published in the Feb. 19 issue of The Journal of the American Medical Association.

"The Digitalis Investigation Group (DIG) 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," write Saif S. Rathore, MPH, from Yale University in New Haven, Connecticut, and colleagues. "The clinical outcomes associated with digoxin therapy at different serum concentrations in the DIG trial have not been assessed."

This post-hoc analysis evaluated data from 3,782 men enrolled in the DIG trial from August 1991 to December 1995 who had a left ventricular ejection fraction of 45% or less. At one month, serum digoxin concentration (SDC) in men randomized to digoxin therapy was 0.5 to 0.8 ng/mL in 572 men, 0.9 to 1.1 ng/mL in 322 men, and 1.2 ng/mL or greater in 277 men; 2,611 men were randomized to placebo.

All-cause mortality at a mean follow-up of 37 months was 29.9% for SDC 0.5 to 0.8 ng/mL, 38.8% for SDC 0.9 to 1.1 ng/mL, and 48.0% for SDC 1.2 ng/ml or greater (P = .006 for trend). Compared with men receiving placebo, men with SDC 0.5 to 0.8 ng/mL had a 6.3% lower mortality rate (95% confidence interval [CI], 2.1 - 10.5%), but men with SDC 1.2 ng/mL or higher had an 11.8% higher mortality rate (95% CI, 5.7% - 18.0%).

After multivariable adjustment, SDC was still linked to mortality risk. Hazard ratio was 0.80 for SDC 0.5 to 0.8 (95% CI, 0.68 - 0.94), 0.89 for SDC 0.9 to 1.1 ng/mL (95% CI, 0.74 - 1.08), and 1.16 for SDC 1.2 ng/mL or greater (95% CI, 0.96 - 1.39).

"Given that no study has demonstrated any substantive clinical benefit for higher SDCs, prudent practice would support an SDC of 0.5 to 0.8 ng/mL as a revised therapeutic range," the authors write. "Only a randomized controlled trial can confirm this recommendation; however, we believe our data provide sufficient grounds for consideration of lower target SDCs for men with stable heart failure and left ventricular dysfunction."

JAMA. 2003;289:871-878

Reviewed by Gary D. Vogin, MD