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Background 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.
Methods 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.
Results 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).
Conclusions 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.
Although men and women differ with respect to the risk, causes, and prognosis of heart failure,5 the Digitalis Investigation Group trial did not prespecify or report sex-specific subgroup analyses, and current clinical guidelines do not differentiate between the use of digoxin in men and the use of this agent in women. The majority of deaths attributable to heart failure occur in women,6 even though women with heart failure have a lower risk of death than men.7,8,9,10 Women with heart failure have more symptoms than men with similar ejection fractions,11 are older,8 and are more likely to have hypertension,12 diabetes mellitus,13 and preserved systolic function.13 Sex-based or sex hormone–associated differences have also been documented in myocardial-cell function,14,15,16 signal transduction and ion-channel activity,15,17,18,19,20 autonomic nervous system function,14 muscle metabolism,21 and cardiac-cell growth.16,22,23 Because the Digitalis Investigation Group trial enrolled nearly four men for every woman,24 any differences in the effect of digoxin among women would have been subsumed by the effect of digoxin therapy among men. Accordingly, we assessed whether the effect of digoxin therapy varied according to the sex of the patients in the Digitalis Investigation Group trial.
Methods
Trial Data Base
We obtained a public-use copy of the data base of the Digitalis Investigation Group trial by submitting a written request to the National Heart, Lung, and Blood Institute. None of the authors were members of the Digitalis Investigation Group Investigators, and thus none were involved in the conduct or initial analysis of the trial.
Study Design
Details of the design and results of the Digitalis Investigation Group trial have been reported previously.1,24 Patients who had stable heart failure were enrolled between February 1991 and August 1993 at 302 clinical centers in the United States and Canada. Patients were eligible for randomization if they had clinically confirmed heart failure, had an ejection fraction of 45 percent or less, and were in normal sinus rhythm. The diagnosis of heart failure was based on current or past clinical symptoms or signs or radiographic evidence of pulmonary congestion. A simultaneously conducted ancillary study enrolled patients who had symptomatic heart failure and an ejection fraction of more than 45 percent.
Treatment
The 6800 patients in the main trial and the 988 patients in the ancillary trial were assigned to receive digoxin or placebo therapy within each center according to a block-randomization approach. The initial recommended dose of the study drug was based on a nomogram that accounted for the patient's age, sex, weight, and renal function.25 Modifications in dosage were permitted to account for the dose of digoxin a patient had been taking before enrollment and the use of concomitant drugs that might affect the pharmacokinetics of digoxin. To avoid the loss of blinding, investigators were discouraged from having patients' serum digoxin levels determined locally.
Outcomes
The primary study outcome was death from any cause within 37 months (range, 24 to 48) after randomization in the main trial. The five prespecified secondary outcomes in the Digitalis Investigation Group trial were death from cardiovascular causes, death from worsening heart failure, hospitalization for worsening heart failure, hospitalization for causes other than worsening heart failure, and the composite end point of death or hospitalization for worsening heart failure in the ancillary trial.24 Causes of deaths and hospitalizations were prospectively recorded by local investigators who were blinded to the patients' treatment assignments.
Statistical Analysis
Analyses were conducted according to the intention-to-treat principle. Base-line characteristics were compared between men and women overall and stratified according to treatment-group assignment with the use of chi-square and Wilcoxon rank-sum tests. Rates of hospitalization for suspected digoxin-related toxicity and median serum digoxin levels, assessed 1 month and 12 months after randomization in a randomly selected subgroup of patients from the main trial cohort, were also compared.
Our analysis focused solely on the possible interaction between sex and digoxin therapy; no other subgroup analyses were conducted. Kaplan–Meier curves for death from any cause were plotted for the four groups represented by the combination of sex and treatment assignment — men randomly assigned to receive digoxin, men randomly assigned to receive placebo, women randomly assigned to receive digoxin, and women randomly assigned to receive placebo — and compared with use of a log-rank test.
To minimize concern about multiple testing, we based our statistical evaluation of the possible interaction between sex and digoxin therapy on the trial's primary outcome of death from any cause among patients enrolled in the main trial.1 The existence of an interaction between sex and digoxin therapy was formally evaluated with use of the Mantel–Haenszel test of the heterogeneity of the effects of digoxin therapy according to sex and a Cox proportional-hazards model incorporating terms for the main effect of sex, the main effect of digoxin therapy, and the interaction between sex and digoxin therapy. To quantify the magnitude of the interaction, we determined the difference in the effects of digoxin therapy between men and women.26,27
A multivariable Cox proportional-hazards analysis was conducted to determine whether the interaction between sex and digoxin therapy was independent of other clinical factors. Patients' characteristics assessed at base line, including demographic characteristics, medical history, history of digoxin use, and current medications, were entered in a backward, stepwise Cox proportional-hazards model to identify predictors of mortality. Variables with a P value of less than 0.50 were entered into the model, and those with a P value of less than 0.10 were retained. The characteristics incorporated into the final Cox proportional-hazards model for death from any cause were age, race, body-mass index, left ventricular ejection fraction, cardiothoracic ratio, New York Heart Association (NYHA) functional class, the number of signs and symptoms of heart failure, the serum creatinine level, systolic blood pressure, and the presence or absence of diabetes, prior digoxin use, and concomitant use of diuretics, nitrates, and other vasodilators. This model was also repeated separately for men and women to estimate the sex-specific effect of digoxin therapy. The trial's secondary outcomes were also analyzed in order to identify additional interactions between sex and digoxin therapy.
Results
Patients
In the main Digitalis Investigation Group trial, women as a whole were older than men and had a higher average left ventricular ejection fraction, heart rate, systolic blood pressure, and cardiothoracic ratio. A greater proportion of women had a history of diabetes, hypertension, angina, and prior use of digoxin than men or were in NYHA functional class III or IV, whereas fewer women presented with rales, a history of myocardial infarction, and ischemia as their primary cause of heart failure. Serum creatinine values and the initial dose of study medication prescribed were also lower in women (Table 1). There were no significant differences between the 2642 men who were randomly assigned to receive digoxin and the 2639 men who were randomly assigned to receive placebo or between the 755 women who were randomly assigned to receive digoxin and the 764 women who were randomly assigned to receive placebo.
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As reported in the original study,1 digoxin was not associated with a significant reduction in the rate of death from any cause (34.8 percent in the digoxin group, as compared with 35.1 percent in the placebo group; P=0.79; crude relative risk, 0.99; 95 percent confidence interval, 0.93 to 1.06). Women had a lower overall rate of death than men (31.0 percent vs. 36.1 percent, P<0.001). The rate of death was also lower among women in the placebo group than among men in this group (28.9 percent vs. 36.9 percent, P<0.001) and among women in the digoxin group than among men in the digoxin group (33.1 percent vs. 35.2 percent, P=0.034). Survival curves, however, differed significantly among the four subgroups (P=0.002) (Figure 1).
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Digoxin therapy was associated with a 4.7 percent (95 percent confidence interval, –0.6 to 10.0) smaller absolute reduction in the rate of hospitalization for worsening heart failure among women as compared with men (absolute difference between the digoxin and placebo groups, –4.2 percent [95 percent confidence interval, –8.9 to 0.5] for women and –8.9 percent [95 percent confidence interval, –11.4 to –6.5] for men; P=0.053 for the interaction between sex and digoxin). The effect of digoxin on the rate of death from cardiovascular causes differed by 4.3 percent (95 percent confidence interval, –0.8 to 9.4) between women and men (absolute difference between the digoxin and placebo groups, 3.7 percent [95 percent confidence interval, –0.7 to 8.1] for women and –0.6 percent [95 percent confidence interval, –3.1 to 1.9] for men; P=0.092 for the interaction between sex and digoxin). Digoxin was associated with a small, nonsignificant increase in the rate of death due to worsening heart failure among women but not among men (absolute difference between the digoxin and placebo groups, 0.5 percent [95 percent confidence interval, –2.8 to 3.8] for women and –2.2 percent [95 percent confidence interval, –4.0 to –0.4] for men; P=0.16 for the interaction between sex and digoxin). There was no interaction between sex and digoxin therapy with respect to the end point of hospitalization for causes other than worsening heart failure (P=0.78 for the interaction) or for the composite end point of death or hospitalization for worsening heart failure among patients enrolled in the ancillary trial (P=0.16 for the interaction) (Table 2).
Multivariable modeling confirmed the interaction between sex and digoxin therapy that was observed in unadjusted analyses. Digoxin was associated with an increased risk of death from cardiovascular causes among women (hazard ratio, 1.24; 95 percent confidence interval, 1.02 to 1.52) but not among men (hazard ratio, 0.96; 95 percent confidence interval, 0.87 to 1.06; P=0.035 for the interaction between sex and digoxin). Digoxin was associated with a decreased risk of death from worsening heart failure among men (hazard ratio, 0.79; 95 percent confidence interval, 0.68 to 0.92) but not among women (hazard ratio, 1.17; 95 percent confidence interval, 0.87 to 1.56; P=0.026 for the interaction between sex and digoxin). Although men who were randomly assigned to receive digoxin had a lower risk of hospitalization for worsening heart failure than men who were assigned to receive placebo (hazard ratio, 0.66; 95 percent confidence interval, 0.60 to 0.73), the benefit was smaller for women (hazard ratio, 0.87; 95 percent confidence interval, 0.72 to 1.04; P=0.011 for the interaction between sex and digoxin). Digoxin had a similar effect in men and women with respect to the end point of hospitalization for causes other than worsening heart failure (hazard ratio for men, 1.17 [95 percent confidence interval, 1.07 to 1.28]; hazard ratio for women, 1.15 [95 percent confidence interval, 0.97 to 1.37]; P=0.91 for the interaction between sex and digoxin) and the end point of death or hospitalization due to worsening heart failure among patients enrolled in the ancillary trial (hazard ratio for men, 0.72 [95 percent confidence interval, 0.48 to 1.07]; hazard ratio for women, 0.92 [95 percent confidence interval, 0.64 to 1.31]; P=0.32 for the interaction between sex and digoxin) (Table 3).
Medication Doses, Serum Digoxin Levels, and Suspected Digoxin Toxicity
The mean daily dose of medication prescribed at randomization was 0.25 mg in men and 0.22 mg in women (P=0.28). When the dose was standardized according to the body-mass index, men received a higher dose of digoxin than women (0.0093 mg per unit of body-mass index vs. 0.0084 mg per unit of body-mass index, P<0.001). However, the median serum digoxin level was slightly higher in a group of 475 randomly selected women than in a group of 1653 randomly selected men one month after study entry (0.9 ng per milliliter vs. 0.8 ng per milliliter, P=0.007). The median serum digoxin level was the same 12 months after randomization among 581 randomly selected women and 2063 randomly selected men (0.6 ng per milliliter and 0.6 ng per milliliter, P=0.46). The proportion of patients who had serum digoxin levels of more than 2.0 ng per milliliter was similar among men and women 1 month after randomization (2.3 percent and 3.4 percent, respectively; P=0.20) and 12 months after randomization (2.1 percent and 1.4 percent, P=0.30). Although random assignment to digoxin therapy was associated with higher rates of hospitalization for suspected digoxin-related toxic effects in the main trial (2.0 percent, as compared with 0.9 percent in the placebo group; P<0.001), the magnitude of this effect was similar among men (1.8 percent and 0.8 percent, respectively; P=0.002) and women (2.5 percent and 1.2 percent, respectively; P=0.053; P=0.97 for the interaction between sex and digoxin).
Discussion
Our post hoc subgroup analysis of data from the Digitalis Investigation Group trial indicates that the effect of digoxin in the treatment of outpatients with stable heart failure differs between men and women. There was an absolute difference of 5.8 percent in the effect of digoxin on the rate of death from any cause between men and women. Digoxin was associated with an increased risk of death among women but not among men. Among women, digoxin therapy was also associated with an increased risk of the secondary outcomes of death from cardiovascular causes and death from worsening heart failure. Furthermore, women had a smaller digoxin-associated reduction in the rate of hospitalization for worsening heart failure than men. In the absence of other data concerning sex-based differences in the efficacy of digoxin, our findings raise strong concern about the appropriate role of digoxin therapy in women.
Subgroup analyses are generally not considered to provide definitive evidence for several reasons, including the manner in which post hoc analyses are planned and reported, the statistical methods used to identify interactions, and the spurious associations that may arise as a result of multiple testing.28,29,30,31,32,33,34 Our analysis addressed each of these issues. There are sufficient clinical data concerning sex-based differences in the pathophysiology and outcomes of heart failure to justify a post hoc investigation of the effect of these differences on the efficacy of digoxin therapy. We identified the interaction between sex and digoxin therapy using formal tests of treatment interaction rather than comparing the results of significance tests within the separate strata of men and women.30,35 We addressed concern about multiple testing31,36 by basing our evaluation of the interaction between sex and digoxin therapy principally on the trial's prespecified primary outcome of death from any cause. The magnitude of the interaction between sex and digoxin therapy and the precision in its estimation afforded by the size of the Digitalis Investigation Group trial lead us to believe that the interaction we identified is clinically significant and probably not a statistical artifact.
To our knowledge, there are no published data concerning interactions between sex and digoxin therapy with which to compare our results, and previous randomized, controlled trials of digoxin therapy in patients with heart failure did not report sex-stratified results.5,11,37 Although we cannot identify the mechanism of the interaction between sex and digoxin therapy, our data suggest that some hypotheses can be discounted. Instances of suspected digoxin toxicity and hospitalization for complications of digoxin therapy were infrequent, and there were no sex-based differences in digoxin-associated complications. The interaction between sex and digoxin therapy is not attributable to age, because age does not modify the efficacy of digoxin.38 The interaction does not reflect a dosing effect, since men received higher drug doses (standardized according to the body-mass index) than women. The slightly higher serum digoxin levels in women than in men one month after randomization raises the possibility of sex-associated differences in the pharmacokinetics of digoxin. Because serum digoxin levels were measured in less than one third of patients at one month, the trial had insufficient statistical power to test whether the interaction between sex and digoxin therapy was independent of sex-based differences in serum digoxin levels.
A possible mechanism for the increased risk of death among women may involve an interaction between hormone-replacement therapy and digoxin. Progestin may increase serum digoxin levels by inhibiting P-glycoprotein and thereby reducing the excretion of digoxin through the renal tubules.39 Furthermore, the Heart and Estrogen/Progestin Replacement Study reported an interaction between digoxin and hormone-replacement therapy that was associated with a higher rate of cardiovascular events.40 This hypothesis could not be tested because the Digitalis Investigation Group trial did not collect information about the use of hormone-replacement therapy. Other endogenous factors, which are either due to or associated with sex, may also be possible, although sex-based differences in pharmacodynamics are rare.
Although based on a post hoc analysis of the Digitalis Investigation Group trial, our study provides robust evidence of an interaction between sex and digoxin therapy and suggests an increased risk of death among women with heart failure treated with digoxin. This finding is particularly important for practice, given that the sole benefit of digoxin therapy is a small reduction in the secondary end point of hospitalization. There is no accepted method by which to balance a possible therapy-associated increased risk of death with a demonstrated therapy-associated benefit of a decreased risk of complications. However, women may not consider the potential increased risk of death associated with digoxin therapy worth the small reduction in the risk of hospitalization.
Our study underscores the importance of investigations of sex-based variations in treatment efficacy.5,41 However, few randomized, controlled trials are designed to test for sex-specific effects, and relatively few women have been enrolled in trials of heart-failure therapies.5,11,42 The interaction between sex and digoxin therapy can be confirmed only by a sex-stratified, randomized, controlled trial of digoxin therapy. However, such a study may not be considered ethical, since it would be designed to confirm risk and not benefit. In the absence of definitive evidence from trials and despite the lack of clear knowledge of the mechanism of the interaction of sex with digoxin, we believe that our data provide sufficient grounds for a reexamination of the use of digoxin therapy for women with heart failure.
The Digitalis Investigation Group study was conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the Digitalis Investigation Group Investigators. This manuscript was not prepared in collaboration with investigators of the Digitalis Investigation Group and does not necessarily reflect the opinions or the views of the Digitalis Investigation Group or the NHLBI.
We are indebted to Maria Johnson, B.A., for her editorial assistance; to Kevin Weinfurt, Ph.D., and Kerry Lee, Ph.D., for their statistical advice; and to Jared Selter, M.D., for his support of the project.
Source Information
From the Section of Cardiovascular Medicine, Department of Internal Medicine (S.S.R., Y.W., H.M.K.), and the Section of Health Policy and Administration, Department of Epidemiology and Public Health (H.M.K.), Yale University School of Medicine; and the Center for Outcomes Research and Evaluation, Yale–New Haven Hospital (H.M.K.) — both in New Haven, Conn.
References
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Related Letters:
Digoxin for the Treatment of Heart Failure
Moulias S., Tigoulet F., Meaume S., Hudson M., Pilote L., Hallberg P., Michaëlsson K., Melhus H., Rathore S. S., Krumholz H. M.
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N Engl J Med 2003;
348:661-663, Feb 13, 2003.
Correspondence
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