Interaction between digoxin and dronedarone in the PALLAS trial

Area of Science:

• Cardiology
• Clinical Pharmacology
• Drug Safety

Background:

• Elevated serum digoxin concentrations can lead to toxicity and death.
• Dronedarone is known to increase digoxin levels through P-glycoprotein interactions.
• The PALLAS trial indicated increased cardiovascular death and heart failure with dronedarone in permanent atrial fibrillation.

Purpose of the Study:

• To investigate the impact of the dronedarone-digoxin interaction on adverse cardiovascular outcomes.
• To determine if concurrent digoxin use explains the increased mortality observed with dronedarone in the PALLAS trial.

Main Methods:

• Subgroup analysis of the PALLAS trial comparing patients on digoxin versus those not on digoxin.
• Assessment of cardiovascular death, arrhythmic death, and heart failure events in relation to dronedarone and digoxin use.
• Analysis of serum digoxin concentrations on day 7 of treatment.

Main Results:

• Dronedarone increased median serum digoxin concentration (1.1 vs. 0.7 ng/mL; P<0.001).
• Among digoxin users, cardiovascular deaths were significantly higher with dronedarone (8.6%/year) versus placebo (1.2%/year; aHR 7.31; P=0.009).
• A significant interaction (P=0.01) was observed for cardiovascular death, with no such interaction for heart failure events.

Conclusions:

• Concurrent digoxin use significantly potentiates the risk of cardiovascular death associated with dronedarone.
• The observed adverse effect of dronedarone on cardiovascular mortality in the PALLAS trial is strongly influenced by concomitant digoxin therapy.
• No interaction was found between digoxin use and the risk of heart failure events with dronedarone.