Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG trial

Abstract

Background: In heart failure (HF), digoxin at low serum digoxin concentrations (SDC) reduces all-cause mortality and HF hospitalizations. However, the effects of digoxin on other cause-specific outcomes have not been studied in a propensity-matched cohort.

Methods: The Digitalis Investigation Group trial, conducted during 1991-1993, enrolled 7788 ambulatory chronic HF patients. This analysis focuses on 4843 patients: 982 receiving digoxin with low (0.5-0.9 ng/ml) SDC at one month, and 3861 receiving placebo and alive at one month. Propensity scores for low SDC, calculated using a non-parsimonious multivariable logistic regression model, were used to match 982 low-SDC patients with 982 placebo patients. Matched Cox regression analyses were used to determine the effect of digoxin at low SDC on outcomes.

Results: All-cause mortality occurred in 315 placebo (rate, 1071/10,000 person-years) and 288 low-SDC digoxin (rate, 871/10,000 person-years) patients, respectively, during 2940 and 3305 years of follow up (hazard ratio {HR}, 0.81, 95% confidence interval {CI}, 0.68-0.98; p=0.028). Cardiovascular hospitalizations occurred in 493 placebo (2359/10,000 person-year) and 471 low-SDC digoxin (1963/10,000 person-year) patients, respectively during 2090 and 2399 years of follow up (HR, 0.82, 95% CI, 0.70-0.95; P=0.010). Low-SDC digoxin to placebo HR (95%CI) for HF mortality and HF hospitalizations were respectively, 0.65 (0.45-0.92; P=0.015) and 0.63 (0.52-0.77; P<0.0001). Low-dose digoxin (< or = 0.125 mg/day) was the strongest independent predictor of low SDC (adjusted odd ratio, 2.07, 95% CI 1.54-2.80).

Conclusions: Digoxin at low SDC significantly reduced mortality and hospitalizations in ambulatory chronic systolic and diastolic HF patients.

Figure 1

Distribution of propensity score for the low serum digoxin concentrations, for patients receiving digoxin and placebo, before (a) and after (b) matching

Figure 2

Kaplan-Meier plots for (a) mortality due to all-causes, and hospitalizations due to (b) cardiovascular causes, and (c) worsening heart failure

Figure 3

Effects of digoxin at low serum digoxin concentrations (0.5–0.9 ng/ml) on all-cause mortality in subgroups of propensity score matched heart failure patients (ACE=angiotensin-converting enzyme; CI= confidence interval; HR=hazard ratio; = NYHA=New York Heart Association)

Figure 4

Predictors of low (0.5–0.9 ng/ml) serum digoxin concentrations (SDC). An odds ratio >1 indicates increased odds of developing low SDC. For example, when adjusted for other predictors of SDC, presence of chronic renal dysfunction was associated with significant 59% lower odds of developing low SDC. Similarly, independent of other covariates, use of digoxin at ≤0.125 mg/day was associated with significant 107% higher odds of developing low SDC (*Adjusted for other covariates shown in the Figure, namely age, sex, race, chronic renal dysfunction, diuretic use, pulmonary congestion, and digoxin at ≤0.125 mg/day). Chronic renal dysfunction was defined as estimated glomerular filtration rate <60 ml/m/1.73 sq. m. by Modification of Diet in Renal Disease methods; OR=odds ratio, CI=confidence interval