TY - JOUR

T1 - Interaction between digoxin and dronedarone in the PALLAS trial

AU - Pallas Investigators

AU - Hohnloser, Stefan H.

AU - Halperin, Jonathan L.

AU - Camm, A. John

AU - Gao, Peggy

AU - Radzik, David

AU - Connolly, Stuart J.

AU - Caccavo, A.

AU - Cartasegna, L. R.

AU - Cuneo, C. A.

AU - Garrido, M. A.

AU - Guzman, L. A.

AU - Hominal, M. A.

AU - Llanos, J. R.

AU - Mackinnon, I. J.

AU - Vico, M. L.

AU - Vogel, D. R.

AU - Zaidman, C. J.

AU - Colquhoun, D.

AU - Counsell, J. T.

AU - de Looze, F. J.

AU - Durbidge, V. K.

AU - Purnell, P. W.

AU - Soward, A. L.

AU - van Gaal, W. J.

AU - William, M.

AU - Burkart-Kuettner, D.

AU - Huber, K.

AU - Pieske, B.

AU - Roithinger, F. X.

AU - Catez, E. M.

AU - Cools, F. J.

AU - De Roy, L.

AU - De Vusser, P.

AU - De Wolf, L.

AU - Deceuninck, O.

AU - Dilling-Boer, D.

AU - Goethals, M. P.

AU - Mairesse, G. H.

AU - Paparella, G.

AU - Provenier, F.

AU - Scavée, C.

AU - Vervoort, G.

AU - Botelho, R. V.

AU - Braga, J. S.

AU - de Paola, A. A.

AU - Petrova, I.

AU - Moiseev, V.

AU - Panchenko, E.

AU - Popov, S. V.

AU - Shubik, Y.

N1 - Publisher Copyright: © 2014 American Heart Association, Inc.

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

KW - Antiarrhythmic drug

KW - Atrial fibrillation

KW - Digoxin

UR - http://www.scopus.com/inward/record.url?scp=84925546808&partnerID=8YFLogxK

U2 - 10.1161/CIRCEP.114.002046

DO - 10.1161/CIRCEP.114.002046

M3 - Article

C2 - 25378467

AN - SCOPUS:84925546808

VL - 7

SP - 1019

EP - 1025

JO - Circulation: Arrhythmia and Electrophysiology

JF - Circulation: Arrhythmia and Electrophysiology

SN - 1941-3149

IS - 6

ER -