Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002; 347:1403-11.
* PRACTICE RECOMMENDATIONS
Digoxin increases mortality in women with congestive heart failure, compared with men; however, the clinical significance of this is unknown since gender is a nonmodifiable risk factor. More importantly, there is a suggestion of harm when looking at women treated with digoxin versus placebo. Since there are other therapies with definite benefit in congestive heart failure (angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone), it is prudent to reconsider the use of digoxin in women with ejection fractions less than 45%.
* BACKGROUND
Is there a difference in the effect of digoxin for heart failure between women and men? This study is a subgroup analysis of the Digitalis Investigaton Group Trial (DIG), which, in 1997, showed that digoxin did not affect mortality in the treatment of heart failure. This subgroup analysis reexamined the data and looked for sex-based differences, which is important because women account for the majority of deaths from congestive heart failure.
* POPULATION STUDIED
The researchers from the original DIG trial enrolled 6800 patients who had stable heart failure with an ejection fraction of 45% or less and who were in normal sinus rhythm. Overall, the women in the study were older than the men, had a shorter duration of heart failure, had a higher median ejection fraction, and had greater disease severity as classified by the New York Heart Association system. The reported results, however, adjust for these differences.
* STUDY DESIGN AND VALIDITY
This is a post hoc analysis of the DIG trial, a randomized, double-blinded, placebo-controlled study of 5281 men and 1519 women randomized to receive either digoxin or placebo. This reanalysis of the DIG data looked at the outcomes separately for men and women.
This analysis (based on sex) was not planned when the trial was conceived. There is considerable risk with a post hoc analysis of this type. The authors statistically controlled for baseline differences between the sexes. Unfortunately, the study was not originally set up to evaluate differences by sex, and there was a disproportionate number of men. Another limitation is that it relies a great deal on statistical adjustments. There is also a risk that an association may occur by chance to multiple analyses.
* OUTCOMES MEASURED
The primary outcome was death from any cause within an average of 37 months (range 24 to 48 months). Other outcomes included death from cardiovascular disease, death from worsening heart failure, and hospitalization for heart failure.
* RESULTS
The investigators reported that women on digoxin had a significantly higher mortality compared with men (33.1% vs 35.2%, P=.034). Mortality was not significantly higher in women receiving digoxin compared with women receiving placebo (33.1% vs 28.9%, respectively; 95% confidence interval [CI], 20.5 to 8.8). However, after adjusting for other factors (eg, age, race, ejection fraction), digoxin use was associated with a significant increase in mortality in women compared with men (hazard ratio 1.23; 95% CI, 1.02-1.47; number needed to harm=22; 95% CI, 11-227).
There was no overall increase in mortality in men taking digoxin versus placebo. There was no significant difference between men and women regarding the secondary outcomes of death from cardiovascular disease or death from worsening heart failure. Higher rates of hospitalization in women with worsening heart failure approached statistical significance when compared with men (30.2% vs 25.8%, P=.053). There was no significant difference in rate of hospitalization for other causes.
Sharon See, PharmD and Patricio Bruno, DO, St. John's University, College of Pharmacy and Allied Health Professions, Jamaica, NY, and Department of Family Practice, Beth Israel Medical Center, New York, NY. E-mail: sees@stjohns.edu and patricbruno@cs.com.
COPYRIGHT 2003 Dowden Health Media, Inc.
COPYRIGHT 2003 Gale Group
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