The Pharmaceutical Journal
Vol 269 No 7223 p667
9 November 2002

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Digoxin is safer in men than in women, study claims

Digoxin may increase the risk of death among women who have heart failure and depressed left ventricular systolic function, but not among men, according to American researchers.

Their post hoc analysis of a trial involving 6,800 heart failure patients, half of whom were taking digoxin, revealed a difference of almost 6 per cent between the rates of all-cause mortality among men and women taking digoxin (P=0.034) (New England Journal of Medicine 2002:347:1403).

Women who were randomly assigned to receive a mean daily dose of 0.22mg digoxin had a higher death rate than those given placebo (33.1 versus 28.9 per cent, P=0.034). In contrast, death rates among men taking a mean daily dose of 0.25mg digoxin or placebo were comparable. After adjustment, digoxin was found to increase the risk of all-cause mortality among women by almost a quarter compared with placebo (hazard ratio 1.23, confidence interval 1.02–1.47, P=0.014), but no such association was found among men (hazard ratio 0.93, confidence interval 0.85–1.02).

Despite men taking a higher mean daily dose of digoxin, analysis of blood samples from a subset of patients taken a month into the trial showed that serum digoxin was higher in women — 0.9nanogram/ml compared with 0.8ng/ml in men (P=0.007).

Although these levels had fallen to the same level of 0.6nanogram/ml after 12 months, the researchers suggest that sex-based differences in the pharmacokinetics of the drug could exist. They say the results raise concerns about the use of digoxin in women and conclude that their data "provide sufficient grounds for a re-examination of the use of digoxin therapy for women with heart failure".

However, in an accompanying editorial (ibid, p1394), Dr Eric Eichhorn, from Medical City Dallas Hospital in Texas, and Dr Mihai Gheorghiade, from Northwestern University Medical School in Chicago, argue that the digoxin dose used in the trial may have been too high. "Unfortunately the investigators did not adjust for serum digoxin levels. What [they] may have demonstrated is that digoxin use in women should be undertaken with greater attention to the appropriate dose. We should not abandon a therapy that may help women with heart failure. Rather, we should use a dose that will result in a serum concentration lower than 1.0nanogram/ml," they conclude.