Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial

Document Type

Article

Publication Date

8-1-2016

Publication Title

European journal of heart failure : journal of the Working Group on Heart Failure of the European Society of Cardiology

Abstract

AIMS: Many patients with heart failure and reduced EF remain at high risk for hospitalization despite evidence-based therapy. Digoxin may decrease hospitalization; however, uncertainty persists concerning its proper administration and effect on mortality. This study investigated whether using dose response concepts to re-evaluate the relationship between serum digoxin concentration and key mortality outcomes in patients with reduced EF in the Digitalis Investigation Group trial would help clarify efficacy and safety.

METHODS AND RESULTS: Multivariable Cox proportional hazards modelling and propensity score adjustment assessed the relationship between serum digoxin concentration (≥0.5 ng/mL) as a continuous variable and mortality outcomes. In patients treated with digoxin, a significant linear association was found between serum concentration and all-cause mortality [adjusted hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.14-1.38, P < 0.001 per 0.5 ng/mL increase in serum concentration]. Based on this relationship, a bidirectional association was found between digoxin therapy and all-cause mortality when compared with placebo. The lowest serum concentrations (0.5-0.7 ng/mL) were associated with the lowest risk of all-cause mortality (adjusted HR 0.77, 95% CI 0.67-0.89, P < 0.001) while high serum concentrations (1.6-2.0 ng/mL) were associated with increased mortality (adjusted HR 1.33, 95% CI 1.12-1.58, P = 0.001). Consistent with this finding, lower serum concentrations (0.5-0.7 ng/mL) were associated with reduced death from worsening heart failure and a neutral effect on cardiovascular death not due to worsening heart failure.

CONCLUSION: These findings favour targeting serum concentrations from 0.5 to 0.7 ng/mL when dosing digoxin in patients with heart failure and reduced EF.

Medical Subject Headings

Aged; Cardiotonic Agents; Cause of Death; Digoxin; Dose-Response Relationship, Drug; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mortality; Multivariate Analysis; Propensity Score; Proportional Hazards Models; Stroke Volume; Treatment Outcome

PubMed ID

27492641

Volume

18

Issue

8

First Page

1072

Last Page

1081

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