Sex-Based Differences in the Effect of Digoxin for the Treatment of Heart Failure

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Abstract
The Digitalis Investigation Group trial reported that treatment with digoxin did not decrease overall mortality among patients with heart failure and depressed left ventricular systolic function, although it did reduce hospitalizations slightly. Even though the epidemiologic features, causes, and prognosis of heart failure vary between men and women, sex-based differences in the effect of digoxin were not evaluated. We conducted a post hoc subgroup analysis to assess whether there were sex-based differences in the effect of digoxin therapy among the 6800 patients in the Digitalis Investigation Group study. The presence of an interaction between sex and digoxin therapy with respect to the primary end point of death from any cause was evaluated with the use of Mantel–Haenszel tests of heterogeneity and a multivariable Cox proportional-hazards model, adjusted for demographic and clinical variables. There was an absolute difference of 5.8 percent (95 percent confidence interval, 0.5 to 11.1) between men and women in the effect of digoxin on the rate of death from any cause (P=0.034 for the interaction). Specifically, women who were randomly assigned to digoxin had a higher rate of death than women who were randomly assigned to placebo (33.1 percent vs. 28.9 percent; absolute difference, 4.2 percent, 95 percent confidence interval, –0.5 to 8.8). In contrast, the rate of death was similar among men randomly assigned to digoxin and men randomly assigned to placebo (35.2 percent vs. 36.9 percent; absolute difference, –1.6 percent; 95 percent confidence interval, –4.2 to 1.0). In the multivariable analysis, digoxin was associated with a significantly higher risk of death among women (adjusted hazard ratio for the comparison with placebo, 1.23; 95 percent confidence interval, 1.02 to 1.47), but it had no significant effect among men (adjusted hazard ratio, 0.93; 95 percent confidence interval, 0.85 to 1.02; P=0.014 for the interaction). The effect of digoxin therapy differs between men and women. Digoxin therapy is associated with an increased risk of death from any cause among women, but not men, with heart failure and depressed left ventricular systolic function.