Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial.
Pubmed ID: 27492641
Journal: European journal of heart failure
Publication Date: 08/01/2016
Affiliation: Division of Cardiology, Mercer University School of Medicine, Macon, GA, USA.
MeSH Terms: Humans, Male, Female, Aged, Middle Aged, Proportional Hazards Models, Heart Failure, Hospitalization, Propensity Score, Treatment Outcome, Multivariate Analysis, Cause of Death, Cardiotonic Agents, Stroke Volume, Mortality, Digoxin, Dose-Response Relationship, Drug
Authors: Butler J, Adams KF, Patterson JH, Schwartz TA, van Veldhuisen DJ, Gattis Stough W, Bauman JL, Sabbah H, Mackowiak JI, Ventura HO, Ghali JK
Cite As: Adams KF Jr, Butler J, Patterson JH, Gattis Stough W, Bauman JL, van Veldhuisen DJ, Schwartz TA, Sabbah H, Mackowiak JI, Ventura HO, Ghali JK. Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial. Eur J Heart Fail 2016 Aug;18(8):1072-81.
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.