Interaction between digoxin and dronedarone in the PALLAS trial.
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.


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.


BACKGROUND
http://www.clinicaltrials.gov. Unique identifier: NCT01151137.
From the Division of Clinical Electrophysiology, J.W. Goethe University, Frankfurt, Germany (S.H.H.); Population Health Research Institute, McMaster University, Hamilton, ON, Canada (P.G., S.J.C.); Department of Clinical Sciences, St George's University of London, London, United Kingdom (A.J.C.); The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (J.L.H.); and Sanofi Recherche, Paris, France (D.R.). hohnloser@em.uni-frankfurt.de.
Stefan H
SH
Hohnloser
From the Division of Clinical Electrophysiology, J.W. Goethe University, Frankfurt, Germany (S.H.H.); Population Health Research Institute, McMaster University, Hamilton, ON, Canada (P.G., S.J.C.); Department of Clinical Sciences, St George's University of London, London, United Kingdom (A.J.C.); The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (J.L.H.); and Sanofi Recherche, Paris, France (D.R.).
Jonathan L
JL
Halperin
From the Division of Clinical Electrophysiology, J.W. Goethe University, Frankfurt, Germany (S.H.H.); Population Health Research Institute, McMaster University, Hamilton, ON, Canada (P.G., S.J.C.); Department of Clinical Sciences, St George's University of London, London, United Kingdom (A.J.C.); The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (J.L.H.); and Sanofi Recherche, Paris, France (D.R.).
A John
AJ
Camm
From the Division of Clinical Electrophysiology, J.W. Goethe University, Frankfurt, Germany (S.H.H.); Population Health Research Institute, McMaster University, Hamilton, ON, Canada (P.G., S.J.C.); Department of Clinical Sciences, St George's University of London, London, United Kingdom (A.J.C.); The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (J.L.H.); and Sanofi Recherche, Paris, France (D.R.).
Peggy
P
Gao
From the Division of Clinical Electrophysiology, J.W. Goethe University, Frankfurt, Germany (S.H.H.); Population Health Research Institute, McMaster University, Hamilton, ON, Canada (P.G., S.J.C.); Department of Clinical Sciences, St George's University of London, London, United Kingdom (A.J.C.); The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (J.L.H.); and Sanofi Recherche, Paris, France (D.R.).
David
D
Radzik
From the Division of Clinical Electrophysiology, J.W. Goethe University, Frankfurt, Germany (S.H.H.); Population Health Research Institute, McMaster University, Hamilton, ON, Canada (P.G., S.J.C.); Department of Clinical Sciences, St George's University of London, London, United Kingdom (A.J.C.); The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (J.L.H.); and Sanofi Recherche, Paris, France (D.R.).
Stuart J
SJ
Connolly
D000368:Aged; D000369:Aged, 80 and over; D000638:Amiodarone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D002423:Cause of Death; D004077:Digoxin / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D004311:Double-Blind Method; D000077764:Dronedarone; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D016016:Proportional Hazards Models; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D004077:Digoxin; D000077764:Dronedarone; D000638:Amiodarone
antiarrhythmic drug; atrial fibrillation; digoxin