Observational cohort study of the safety of digoxin use in women with heart failure

Abstract

Objectives

This study aims to assess whether digoxin has a different effect on mortality risk for women than it does for men in patients with heart failure (HF).

Design

This study uses the UK-based The Health Information Network population database in a cohort study of the impact of digoxin exposure on mortality for men and women who carry the diagnosis of HF. Digoxin exposure was assessed based on prescribing data. Multivariable Cox proportional hazards models were used to assess whether there was an interaction between sex and digoxin affecting mortality hazard.

Setting

The setting was primary care outpatient practices.

Participants

The study cohort consisted of 17 707 men and 19 227 women with the diagnosis of HF who contributed only time without digoxin exposure and 9487 men and 10 808 women with the diagnosis of HF who contributed time with digoxin exposure.

Main outcome measures

The main outcome measure was all-cause mortality.

Results

The primary outcome of this study was the absence of a large interaction between digoxin use and sex affecting mortality. For men, digoxin use was associated with a HR for mortality of 1.00, while for women, the HR was also 1.00 (p value for interaction 0.65). The results of sensitivity analyses were consistent with those of the primary analysis.

Conclusion

Observational data do not support the concern that there is a substantial increased risk of mortality due to the use of digoxin in women. This finding is consistent with previous observational studies but discordant with results from a post hoc analysis of a randomised controlled trial of digoxin versus placebo.

Article summary

Article focus

• Digoxin is used in patients with HF and has been shown in one major randomised control trial, the Digitalis Investigation Group study, to reduce the rate of hospitalisations in that population.

• Post hoc analysis of Digitalis Investigation Group indicated that digoxin, when used in the treatment of HF, may increase mortality by approximately 20% in women but not in men. Further randomised trials evaluating the interaction between digoxin and sex have not emerged.

Key messages

• For men, digoxin use was associated with a HR for mortality of 1.00, while for women, the HR was also 1.00 (p value for interaction 0.65). There was no evidence of a different association between digoxin use and mortality in women compared with men. Sensitivity analyses did not affect this estimate materially.

• An interesting incidental finding of this study is that interventions known to reduce mortality in HF are used less in women than in men who have been diagnosed with HF.

Strengths and limitations of this study

• The major strength of this study was its large sample size, which allowed adjustment for many covariates and numerous sensitivity analyses, none of which affected the conclusions.

• The major limitation of this study is that it is non-randomised. Although there is no evidence of substantial confounding of the main study result, confounding could still bias these results.