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

Adams, Kirkwood F., Jr., Butler, Javed, Patterson, J. Herbert, Stough, Wendy Gattis, Bauman, Jerry L., van Veldhuisen, Dirk J., Schwartz, Todd A., Sabbah, Hani, Mackowiak, John I., Ventura, Hector O. and Ghali, Jalal K. (2016) Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial. European Journal of Heart Failure, 18 8: 1072-1081. doi:10.1002/ejhf.584


Author Adams, Kirkwood F., Jr.
Butler, Javed
Patterson, J. Herbert
Stough, Wendy Gattis
Bauman, Jerry L.
van Veldhuisen, Dirk J.
Schwartz, Todd A.
Sabbah, Hani
Mackowiak, John I.
Ventura, Hector O.
Ghali, Jalal K.
Title Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial
Journal name European Journal of Heart Failure   Check publisher's open access policy
ISSN 1879-0844
1388-9842
Publication date 2016-08-01
Year available 2016
Sub-type Article (original research)
DOI 10.1002/ejhf.584
Open Access Status Not yet assessed
Volume 18
Issue 8
Start page 1072
End page 1081
Total pages 10
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Language eng
Abstract 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.

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.

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.
Formatted 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.
Keyword Digoxin
Drugs
Heart failure
Morbidity
Mortality
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Admin Only - School of Medicine
School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 2 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 4 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sat, 24 Sep 2016, 05:16:27 EST by System User on behalf of Learning and Research Services (UQ Library)