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.
AimsMany 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 resultsMultivariable Cox proportional hazards modelling and propensity score adjustment assessed the relationship between serum digoxin concentration (0.5ng/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 0.5ng/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 (0.5-0.7ng/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 (1.6-2.0ng/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 (0.5-0.7ng/mL) were associated with reduced death from worsening heart failure and a neutral effect on cardiovascular death not due to worsening heart failure.; ConclusionThese findings favour targeting serum concentrations from 0.5 to 0.7ng/mL when dosing digoxin in patients with heart failure and reduced EF.