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Digoxin Might Increase Mortality Risk in Women with Heart Failure

Researchers revisited data from a 1997 trial and found a previously unappreciated sex difference.

Digitalis has been used to treat heart failure for more than 200 years. Not until 1997, however, did a large, randomized controlled trial (DIG) define digoxin's benefits in heart failure: Digoxin did not significantly reduce 3-year all-cause mortality risk, but it modestly reduced the risks for hospitalization for worsening heart failure and hospitalization for any cause. To tease out the all-cause mortality benefits of digoxin in men versus women, researchers conducted a post-hoc analysis of DIG (6800 patients).

Although male digoxin recipients and male placebo recipients had similar all-cause mortality rates (35.2% and 36.9%, P=0.22), the rate among female digoxin recipients was somewhat higher than among female placebo recipients (33.1% vs. 28.9%, P=0.078). A significant interaction between sex and digoxin use was found (P=0.034), such that digoxin's effect on all-cause mortality was an absolute 5.8% higher in women than in men. In a multivariable analysis, digoxin was associated with a nonsignificantly lower all-cause mortality risk among men and a significantly higher risk among women. Median serum digoxin levels 1 month after study entry were slightly, though significantly, higher in a subgroup of randomly selected women (0.9 ng/mL) than in a subgroup of randomly selected men (0.8 ng/mL).

Comment: Though based on post-hoc analysis, these data still raise concerns about using digoxin in women with heart failure. Using lower doses and, thereby, limiting plasma drug concentrations may achieve therapeutic benefits without increasing mortality risk in women. Given that digoxin's overall benefits in heart failure are modest, the potential risk in women should be considered in clinical risk-benefit assessment.

— William T. Abraham, MD

Published in Journal Watch Cardiology December 20, 2002

Citation(s):

Rathore SS et al. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002 Oct 31; 347:1403-11.

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Eichhorn EJ and Gheorghiade M. Digoxin -- New perspective on an old drug. N Engl J Med 2002 Oct 31; 347:1394-5.

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• Medline abstract (Free)