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Published on: March 19, 2018
Association of serum digoxin concentration and outcomes in patients with heart failure
Saif S Rathore1, Jeptha P Curtis, Yongfei Wang
1The Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Conn 06520, USA.
Insights
Higher serum digoxin concentrations (SDC) in heart failure patients correlate with increased mortality. Optimal effectiveness for digoxin therapy may be achieved with SDCs between 0.5-0.8 ng/mL.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Digoxin showed no mortality benefit but reduced hospitalizations in heart failure patients with reduced ejection fraction.
- Previous analyses of the Digitalis Investigation Group (DIG) trial did not assess clinical outcomes related to specific serum digoxin concentrations (SDC).
Purpose of the Study:
- To investigate the association between varying serum digoxin concentrations (SDC) and mortality and hospitalization rates in heart failure patients.
- To determine if a specific SDC range optimizes digoxin therapy effectiveness.
Main Methods:
- Post hoc analysis of the randomized, placebo-controlled DIG trial (1991-1995).
- Analysis included 3782 men with left ventricular ejection fraction ≤45%, comparing digoxin groups (based on 1-month SDC: 0.5-0.8, 0.9-1.1, ≥1.2 ng/mL) to placebo.
- Primary endpoint was all-cause mortality over a mean 37-month follow-up.
Main Results:
- Increased SDCs correlated with higher crude all-cause mortality rates (0.5-0.8 ng/mL: 29.9%; 0.9-1.1 ng/mL: 38.8%; ≥1.2 ng/mL: 48.0%).
- SDCs of 0.5-0.8 ng/mL were associated with a 6.3% mortality reduction versus placebo.
- SDCs ≥1.2 ng/mL showed an 11.8% higher mortality rate compared to placebo, persisting after multivariable adjustment.
Conclusions:
- Higher serum digoxin concentrations are linked to increased mortality in heart failure patients.
- Digoxin therapy effectiveness in men with heart failure and reduced ejection fraction may be optimized within the SDC range of 0.5 to 0.8 ng/mL.
Context:
The Digitalis Investigation Group (DIG) trial reported that digoxin provided no overall mortality benefit and only a modest reduction in hospitalizations among patients with heart failure and depressed left ventricular systolic function. The clinical outcomes associated with digoxin therapy at different serum concentrations in the DIG trial have not been assessed.
Objective:
To assess variations in serum digoxin concentration (SDC) and their association with mortality and hospitalization in patients with heart failure.
Design, Setting, And Patients:
Post hoc analysis of the randomized, double-blinded, placebo-controlled DIG trial, conducted from August 1991 to December 1995, with the main analysis restricted to men with a left ventricular ejection fraction of 45% or less (n = 3782). Patients randomly assigned to receive digoxin were divided into 3 groups based on SDC at 1 month (0.5-0.8 ng/mL, n = 572; 0.9-1.1 ng/mL, n = 322; and > or =1.2 ng/mL, n = 277) and compared with patients randomly assigned to receive placebo (n = 2611).
Main Outcome Measure:
All-cause mortality at a mean follow-up of 37 months.
Results:
Higher SDCs were associated with increased crude all-cause mortality rates (0.5-0.8 ng/mL, 29.9%; 0.9-1.1 ng/mL, 38.8%; and > or =1.2 ng/mL, 48.0%; P =.006 for trend). Patients with SDCs of 0.5 to 0.8 ng/mL had a 6.3% (95% confidence interval [CI], 2.1%-10.5%) lower mortality rate compared with patients receiving placebo. Digoxin was not associated with a reduction in mortality among patients with SDCs of 0.9 to 1.1 ng/mL (2.6% increase; 95% CI, - 3.0% to 8.3%), whereas patients with SDCs of 1.2 ng/mL and higher had an 11.8% (95% CI, 5.7%-18.0%) higher absolute mortality rate than patients receiving placebo. The association between SDC and mortality persisted after multivariable adjustment (SDC 0.5-0.8 ng/mL hazard ratio [HR] 0.80, 95% CI, 0.68-0.94; SDC 0.9-1.1 ng/mL HR 0.89, 95% CI, 0.74-1.08; SDC > or =1.2 ng/mL HR 1.16, 95% CI, 0.96-1.39; and HR of 1.00 [referent] for placebo).
Conclusions:
Our findings demonstrate that higher SDCs were associated with increased mortality and suggest that the effectiveness of digoxin therapy in men with heart failure and a left ventricular ejection fraction of 45% or less may be optimized in the SDC range of 0.5 to 0.8 ng/mL.
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