Kirkwood F Adams1, Javed Butler2, J Herbert Patterson3, Wendy Gattis Stough4, Jerry L Bauman5, Dirk J van Veldhuisen6, Todd A Schwartz7, Hani Sabbah8, John I Mackowiak9, Hector O Ventura10, Jalal K Ghali11. 1. Departments of Medicine and Radiology, School of Medicine, Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 2. Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA, USA. 3. Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill Eshelman School of Pharmacy, Chapel Hill, NC, USA. 4. Departments of Clinical Research and Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC, USA. 5. Departments of Pharmacy Practice and Medicine, Section of Cardiology, Colleges of Pharmacy and Medicine, University of Illinois at Chicago, Chicago, IL, USA. 6. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 7. Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 8. Division of Cardiology, Wayne State University, Henry Ford Health System, Detroit, MI, USA. 9. Center for Outcomes Research, Nashville, TN, USA. 10. John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, USA. 11. Division of Cardiology, Mercer University School of Medicine, Macon, GA, USA.
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.
RCT Entities:
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.