Interaction between digoxin and dronedarone in the PALLAS trial

Stefan H Hohnloser; Jonathan L Halperin; A John Camm; Peggy Gao; David Radzik; Stuart J Connolly; PALLAS investigators

doi:10.1161/CIRCEP.114.002046

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.

Authors

Stefan H Hohnloser¹, Jonathan L Halperin², A John Camm², Peggy Gao², David Radzik², Stuart J Connolly²; PALLAS investigators

Collaborators

PALLAS investigators:
A Caccavo, L R Cartasegna, C A Cuneo, M A Garrido, L A Guzman, M A Hominal, J R Llanos, I J Mackinnon, M L Vico, D R Vogel, C J Zaidman, D Colquhoun, J T Counsell, F J de Looze, V K Durbidge, P W Purnell, A L Soward, W J van Gaal, M William, D Burkart-Kuettner, K Huber, B Pieske, F X Roithinger, E M Catez, F J C Cools, L De Roy, P De Vusser, L De Wolf, O Deceuninck, D Dilling-Boer, M P Goethals, G H Mairesse, G Paparella, F Provenier, C Scavée, G Vervoort, R V Botelho, J S Braga, A A de Paola, W K S B de Souza, M E Hernandes, J Jaber, A M Lorga-Filho, E R Manenti, J C Moura Jorge, D B Précoma, G Reis, P R Rossi, A C S Sousa, S L Zimmermann, N I Gronkova, H S Tumbev, S Bose, P Jr Boucher, J Y Cha, C M Constance, P Costi, B Coutu, M Gupta, J S Healey, S Kouz, A S Lam, R Leather, A S Pandey, T Rebane, D Savard, R St-Hilaire, S Vizel, J L Cobos, R Corbalan, H Donoso, E Escobar, M E Medina, S H Potthoff, C A Raffo, J G Saavedra, M A Tijerino, L Ballek, P Boček, M Choura, V Dědek, A Egert, M Hudcovic, Z Klimsa, R Labrova, J Malecha, I Petrova, I Podpera, Z Poklopová, T Velimsky, A Brandes, U Dixen, K Egstrup, L Frost, G Gislason, S E Husted, T J Jakobsen, J Jeppesen, K Kaae Dodt, K K Klarlund, T M Melchior, H Nielsen, K Skagen, A Aro, H V Huikuri, V Kyto, K Nyman, S Utriainen, A Ylitalo, R Fouche, K Gacem, M Mansour, J L Pasquie, J E Poulard, K F Appel, C Axthelm, R F Bosch, P Bushoven, H Darius, G C Grönefeld, C Hanefeld, W Haverkamp, T Horacek, C W Israel, H Killat, T Klingenheben, J Kreuzer, M Leicht, M B Licka, M Niethammer, W A Rieker, P Salbach, I Schenkenberger, A Schmidt, S G Spitzer, N Toursarkissian, R Veltkamp, C Veltmann, M Weißbrodt, B R Winkelmann, J Wurziger, C Zemmrich, I A Vogiatzis, C W Siu, G Z Duray, G Ferencz, A Katona, K Keltai, Z Kovács, Z Laszlo, F Poor, I Szakal, E Toldy-Schedel, A Vertes, S Atar, M Eldar, M Elias, N A Freedberg, S Halabi, S Hamoud, A Katz, E E Klainman, A Marmor, A Medina, M Mosseri, M Motro, G Y Stein, T Weiss, D Zeltser, R Zimlichman, D Calabrese, F Cosmi, F de Tommasi, N Glorioso, M M Gulizia, M Mennuni, G Piovaccari, P Verdecchia, K H Chee, M A Alcocer Gamba, R Alvarado-Ruiz, J L Arenas, E Bayram Llamas, C G Calvo Vargas, J Carrillo, P Fernandez-Bonetti, J F Gomez, G Llamas-Esperón, E Lopez Rosas, N Matadamas Hernandez, J M Ramirez Isunza, E Salcido, R G Velasco-Sanchez, G L Bartels, D C G Basart, F Bracke, T A Bruning, L Cozijnsen, G J de Weerd, F R den Hartog, H Geertman, K Hamraoui, W F Heesen, I Hunze, H H D Idzerda, J Kragten, A H Liem, D J Lok, A Moens, J Plomp, L Pos, A R Ramdat Misier, J J Remmen, J H Ruiter, M F Scholten, H P Swart, J G M Tans, L Theunissen, R Tukkie, R van der Heijden, D J Van Doorn, Van Gelder, M W J van Hessen, P H M Westendorp, A R Willems, S K Zoet-Nugteren, S A Aitken, J M Elliott, J E Scales, B Scott, L F Ternouth, J Tisch, J Berg-Johansen, M A Husvik, H Istad, K Risberg, R Rød, P A Sirnes, G K Skjelvan, J Bednarski, M Bronisz, L Bryniarski, J R Gniot, T Kawka-Urbanek, J Kopaczewski, P Miekus, T J Pasierski, M Piepiorka, F Prochaczek, G Raczak, J Rekosz, J Stepinska, R Szelemej, M Szpajer, B Zaborska, M A Cinteza, A O Ciobanu, A R Dan, D Dimulescu, C G Fierbinteanu-Braticevici, O Istratoaie, D F Lighezan, B Minescu, M M Vintila, N M Akhmedzhanov, B A Alikhanov, A V Barabashkina, O Barbarash, V B Barbarich, B Y Bart, M V Boyarkin, N N Burova, L Bychkova, S B Fitilev, T P Gizatulina, L A Khaisheva, V O Konstantinov, N Koziolova, V Lesnov, Y Lukyanov, N P Lyamina, T A Malkina, O N Miller, V Moiseev, N V Novikova, O V Orlikova, V A Orlov, M F Osipenko, E Panchenko, D Y Platonov, S V Popov, V V Rafalakiy, M Y Ruda, S A Seliverstova, S V Shalaev, V V Shchekotov, Y Shubik, Y Shvarts, V A Sulimov, T V Tretyakova, S Vaniev, A Vishnevsky, V V Yakusevich, S S Yakushin, K N Zrazhevskiy, W S Teo, V Bugan, G Kaliská, M Masarovičová, J Nociar, D Pella, R Uhliar, M Bushidi, J M Engelbrecht, A M Okreglicki, T Pillay, F A Snyders, H D Theron, T P Venter, J G Cho, D Kim, Y H Kim, M H Lee, S Oh, Y K On, T H Rho, D H Shin, J Alzueta, J Bruguera, S Castrejon, E Díaz-Infante, L Grigorian Shamagian, A Martínez-Rubio, L Mont, M Vida, X Viñolas, S T Berglund, C Blomstrom-Lundqvist, P Cherfan, F Jacobsson, S Jakobsson, L Johansson, T Juhlin, P Kozak, F Rönn, M Rosenqvist, L Sprock, A F Gallino, P A Lyrer, T Moccetti, M C Chen, Y F Hu, J L Lin, M S Wen, O I Karpenko, S Kozhukhov, I Kraiz, S S Pavlyk, P I Potapenko, O V Prokhorov, I V Prudkyi, V Y Prykhodko, L V Rudenko, O S Sychov, V I Tseluyko, V A Vizir, O J Zharinov, R Aggarwal, A J Copley, P P Davey, H H Kadr, G Y H Lip, S Lord, A J Moriarty, S W Muir, M P Pye, A D Ryding, I Savelieva, R Abadier, S Ahmad, Z M Ahmad, K P Alexander, A D Alfieri, S Baker, E M Ball, L Baruch, R P Bellam, S A Benjamin, D A Brill, K F Browne, J T Call, K W Carr, H Chandna, C Chen, Y C J Chen, V S Chilakapati, D Colan, S F Cossu, J Dean, S P DeFehr, S J Dempsey Jr, V S Desai, M L Dohrmann, H S Ellison, G Emlein, N Farris, R H Fields, G J Fishbein, E A Flores, I R Friedlander, M D Gelernt, H C Genovely, E L Gillespie, B M Go, D W Gottlieb, P G Grena, T Guarnieri, D K Gupta, A A Haidar, G S Hamroff, J L Hargrove, E J Haskel, S E Hearne, D A Henderson, J M Herre, W R Herzog Jr, B L Hoppe, D Hotchkiss, D J Humiston, P G Igic, B K Jackson, A K Jacobson, N A Jaffrani, D Jarzabkowski, M R Jazayeri, A J Kaplan, R N Khant, A C Kim, K A Klancke, E J Kosinski, M Kovach, J H Kramer, E W Lader, J A LeLevier, N E Lepor, R M Levy, R H Littlefield, R N Marple, F A McGrew III, M J McWilliams, A Meholick, M J Mirro, J F Murphy, A V Murray, V K Nadar, M Nanna, A J Navarrete-Casas, D J O'Dea, P G O'Neill, S R Oza, R J Patel, N S Perlmutter, D L Pierce, S D Promisloff, J G Pulido, J Rahman, D V Rhodes, A M Rubin, J H Sandberg, C M Sandesara, R Schreiman, A Shah, K H Sheikh, N Singh, S B Sloan, C W Sofley Jr, C S Staniloae, J M Teixeira, W M Tuan, B R Vaid, R M Vicari, N K Vijay, K N Vora, R J Weiss, H S Wenocur, A Yunus

Affiliations

¹ 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.
² 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.).

PMID: 25378467
DOI: 10.1161/CIRCEP.114.002046

Abstract

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: http://www.clinicaltrials.gov. 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

Substances

Anti-Arrhythmia Agents
Cardiotonic Agents
Digoxin
Dronedarone
Amiodarone

Associated data

ClinicalTrials.gov/NCT01151137