Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study

Abstract

Background: Despite endorsement of digoxin in clinical practice guidelines, there exist limited data on its safety in atrial fibrillation/flutter (AF).

Objectives: The goal of this study was to evaluate the association of digoxin with mortality in AF.

Methods: Using complete data of the TREAT-AF (The Retrospective Evaluation and Assessment of Therapies in AF) study from the U.S. Department of Veterans Affairs (VA) healthcare system, we identified patients with newly diagnosed, nonvalvular AF seen within 90 days in an outpatient setting between VA fiscal years 2004 and 2008. We used multivariate and propensity-matched Cox proportional hazards to evaluate the association of digoxin use with death. Residual confounding was assessed by sensitivity analysis.

Results: Of 122,465 patients with 353,168 person-years of follow-up (age 72.1 ± 10.3 years, 98.4% male), 28,679 (23.4%) patients received digoxin. Cumulative mortality rates were higher for digoxin-treated patients than for untreated patients (95 vs. 67 per 1,000 person-years; p < 0.001). Digoxin use was independently associated with mortality after multivariate adjustment (hazard ratio [HR]: 1.26, 95% confidence interval [CI]: 1.23 to 1.29, p < 0.001) and propensity matching (HR: 1.21, 95% CI: 1.17 to 1.25, p < 0.001), even after adjustment for drug adherence. The risk of death was not modified by age, sex, heart failure, kidney function, or concomitant use of beta-blockers, amiodarone, or warfarin.

Conclusions: Digoxin was associated with increased risk of death in patients with newly diagnosed AF, independent of drug adherence, kidney function, cardiovascular comorbidities, and concomitant therapies. These findings challenge current cardiovascular society recommendations on use of digoxin in AF.

Keywords: atrial fibrillation; digoxin; mortality; safety.

Figure 1. Consort Diagram

Shows detailed inclusion and exclusion criteria used to select the cohort of 122,465 patients studied in this analysis.

Figure 2. Cumulative Incidence of Death in Propensity-Matched Cohort

Shows cumulative incidence of death, comparing treated and untreated patients in the propensity matched cohort, with curves estimated using the Kaplan-Meier method. Differences in treated and untreated groups were assessed using the log-rank test.

Figure 3. Effect of Unmeasured Confounding Factors

This sensitivity analysis shows how powerful a single unmeasured confounder would have to be to explain the increased hazard of death associated with digoxin. The hypothetical prevalence of an unmeasured confounder in the treated group (x-axis) is graphed against the hypothetical prevalence in the untreated group (colored curves associated with 5%, 10%, 20%, 30%, and 40%). The y-axis represents the hypothetical hazard ratio of the unmeasured confounder required to fully explain the mortality difference observed between the treated and untreated groups for digoxin. For example, if a confounder affected 5% of untreated patients (lightest blue curved line) but 20% of the group treated with digoxin (x-axis), the confounder could explain the observed risk of death from digoxin only if the confounder independently increased the risk of death by a factor (HR) of 2.4.