Interaction between digoxin and dronedarone in the PALLAS trial

Circ Arrhythm Electrophysiol. 2014 Dec;7(6):1019-25. doi: 10.1161/CIRCEP.114.002046. Epub 2014 Nov 6.


Background: Elevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation. The present analysis examines whether the dronedarone-digoxin interaction might explain these adverse outcomes.

Methods and results: Subgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not. In PALLAS, 1619 patients were randomized to dronedarone and 1617 to placebo, of whom 544 (33.6%) and 526 (32.5%) were receiving digoxin, respectively. Median (Q1,Q3) digoxin serum concentration on day 7 was 1.1 (0.7,1.5) ng/mL on dronedarone and 0.7 (0.5,1.1) ng/mL on placebo (P<0.001). Among patients on digoxin, there were 15 (8.6%/year) cardiovascular deaths on dronedarone and 2 (1.2%/year) on placebo (adjusted hazard ratio, 7.31; 95% confidence interval, 1.66-32.20; P=0.009). Among patients not on digoxin, there were 6 cardiovascular deaths on dronedarone (1.7%/year) and 8 on placebo (2.2%/year; adjusted hazard ratio, 0.67; 95% confidence interval, 0.23-1.95; P=0.46; interaction P value 0.01). In patients on digoxin, there were 11 arrhythmic deaths on dronedarone and none on placebo; and in patients not on digoxin, there were 2 arrhythmic deaths on dronedarone and 4 on placebo (P value for interaction 0.002). There was no interaction between baseline digoxin use and the adverse effect of dronedarone on heart failure events.

Conclusions: In PALLAS, there was a strong effect of concurrent digoxin use on the adverse effect of dronedarone on cardiovascular death, but not on occurrence of heart failure.

Clinical trial registration: Unique identifier: NCT01151137.

Keywords: antiarrhythmic drug; atrial fibrillation; digoxin.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amiodarone / adverse effects
  • Amiodarone / analogs & derivatives*
  • Amiodarone / therapeutic use
  • Anti-Arrhythmia Agents / adverse effects
  • Anti-Arrhythmia Agents / blood
  • Anti-Arrhythmia Agents / therapeutic use*
  • Atrial Fibrillation / diagnosis
  • Atrial Fibrillation / drug therapy*
  • Atrial Fibrillation / mortality
  • Cardiotonic Agents / adverse effects
  • Cardiotonic Agents / blood
  • Cardiotonic Agents / therapeutic use*
  • Cause of Death
  • Digoxin / adverse effects
  • Digoxin / blood
  • Digoxin / therapeutic use*
  • Double-Blind Method
  • Dronedarone
  • Drug Interactions
  • Drug Monitoring
  • Drug Therapy, Combination
  • Electrocardiography
  • Female
  • Heart Failure / diagnosis
  • Heart Failure / drug therapy*
  • Heart Failure / mortality
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Proportional Hazards Models
  • Risk Factors
  • Time Factors
  • Treatment Outcome


  • Anti-Arrhythmia Agents
  • Cardiotonic Agents
  • Digoxin
  • Dronedarone
  • Amiodarone

Associated data