Digoxin-associated mortality: a systematic review and meta-analysis of the literature

Vamos M, Erath JW, Hohnloser SH.
Eur Heart J. May 4 2015.DOI: http://dx.doi.org/10.1093/eurheartj/ehv143

Background

Digoxin has been used in clinical practice for over 200 years, mainly as treatment of symptomatic heart failure (HF) in patients with impaired left-ventricular function and of rate control in patients with atrial fibrillation (AF). Although evidence supporting its use for these indications is limited, the indications are endorsed by recent guideline recommendations [1-3].
Digoxin has a narrow therapeutic window, partly related to significant drug-drug interactions. Careful administration encompassing regular measurement of serum digoxin levels is needed to prevent harm. The benefit of digoxin in addition to contemporary HF treatment has recently been challenged [4-9], and some observations even suggest a possible negative effect on mortality.
Considering the conflicting data, a systematic review of published data was performed to estimate the safety of digoxin therapy in the patient populations. Data from 19 studies of original databases were included in the analysis, comprising data from 235047 AF patients and 91379 patients with HF, with follow-up time ranging from 0.83 to 4.7 years (average: 2.57+1.13 years). Only one randomised controlled clinical trial could be included, the rest of the studies were retrospective or prospective observational studies.

Main results

• In the analysis of all 19 trials, digoxin use was associated with a 21% higher relative risk of all-cause mortality as compared to patients not receiving digoxin (HR: 1.21, 95%CI: 1.07-1.38, P<0.01).
• In AF patients, digoxin was associated with a 29% higher mortality risk as compared to AF patients who did not receive digoxin (HR: 1.29, 95%CI: 1.21-1.39, P<0.01).
• HF patients receiving digoxin also showed a higher mortality risk than HF patients not on digoxin (HR: 1.14, 95%CI: 1.06-1.22, P<0.01).
• Three large studies reported all-cause mortality data for subgroups of patients with AF and HF. Pooling these studies showed a statistically significantly increased digoxin-related mortality risk for AF patients (HR: 1.28, 95%CI; 1.12-1.46, P<0.01), but not for patients with congestive HF (HR: 1.05, 95%CI: 0.91-1.20, P=0.52).  

Conclusion

This meta-analysis on the effects of digoxin on all-cause mortality indicates that digoxin is associated with increased mortality risk in patients with AF or congestive HF. The effect was strongest in AF patients. These observations call for randomised trials evaluating dose-adjusted digoxin therapy. Until those have been completed, digoxin should be used with great caution, especially when used for rate control in AF.

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