Evaluation of the Switch From Amiodarone to Dronedarone in Patients With Atrial Fibrillation: Results of the ARTEMIS AF Studies

Abstract

Background: Switching between antiarrhythmic drugs is timed to minimize arrhythmia recurrence and adverse reactions. Dronedarone and amiodarone have similar electrophysiological profiles; however, little is known about the optimal timing of switching, given the long half-life of amiodarone.

Methods: The ARTEMIS atrial fibrillation (AF) Loading and Long-term studies evaluated switching patients with paroxysmal/persistent AF from amiodarone to dronedarone. Patients were randomized based on the timing of the switch: immediate, after a 2-week, or after a 4-week washout of amiodarone. Patients who did not convert to sinus rhythm after amiodarone loading underwent electrical cardioversion. The primary objectives were, for the Loading study, to evaluate recurrence of AF ≤60 days; and for the Long-term study, to profile the pharmacokinetics of dronedarone and its metabolite according to different timings of dronedarone initiation.

Results: In ARTEMIS AF Loading, 176 were randomized (planned 768) after a 28 ± 2 days load of oral amiodarone. Atrial fibrillation recurrence trended less in the immediate switch versus 4-week washout group (hazard ratio [HR] = 0.65 [97.5% CI: 0.34-1.23]; P = .14) and in the 2-week washout versus the 4-week washout group (HR = 0.75 [97.5% CI: 0.41-1.37]; P = .32). In ARTEMIS AF Long-term, 108 patients were randomized (planned 105). Pharmacokinetic analyses (n = 97) showed no significant differences for dronedarone/SR35021 exposures in the 3 groups.

Conclusion: The trial was terminated early due to poor recruitment and so our findings are limited by low numbers. However, immediate switching from amiodarone to dronedarone appeared to be well tolerated and safe.

Trial registration: ClinicalTrials.gov NCT01199081 NCT01140581.

Keywords: amiodarone; antiarrhythmic drug therapy; atrial fibrillation; dronedarone.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. G.V.N. is a consultant for Janssen, Omeicos, Acesion, Milestone, and Sanofi; and has a research grant from Janssen unrelated to this project. D.L.B has participated in advisory boards for Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, PLx Pharma, and Regado Biosciences; is a member of the Board of Directors of Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; is Chair of the American Heart Association Quality Oversight Committee; is on the data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); has other relationships with Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); is a site co-investigator for Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte; is a trustee for American College of Cardiology; and has performed unfunded research for FlowCo, Merck, Novo Nordisk, and Takeda. J.-Y.L.H. has worked on advisory boards for Sanofi, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Meda, MSD, Pfizer, and Servier. A.J.C. has worked on advisory boards and/or speaker’s bureaus for Acesion, Actelion, AstraZeneca, Bayer, Biotronik, Boehringer Ingleheim, Boston Scientific, Bristol-Myers Squibb, ChanRX, Daiichi-Sankyo, Gilead, GSK, InfoBionic, Incarda, Johnson & Johnson, Medtronic, Menarini, Merck, Mitsubishi, Novartis, Omeicos, Otsuka, Pfizer, Sanofi, Servier, St. Jude Medical, Takeda, and Xention. F.L. is a consultant for Sanofi and has also worked on speaker’s bureaus for AstraZeneca, Daiichi-Sankyo, and Merck. J.T. is a consultant for and/or has worked on speaker’s bureaus for Menarini and MSD; and has received honoraria from Menarini, BMS, and Pfizer. J.-M.M. and L.N.-B. are both employees of Sanofi and own stock.

Figures

Figure 1.

Study design. aAmiodarone initiation in Loading study, day - 28 ± 2 days (at visit 2 of the screening period, patients were given a loading dose of amiodarone consisting of 600 mg daily [one 200 mg tablet 3 times daily] for 1 week, 400 mg daily [one 200 mg tablet twice daily] for 1 week, and 200 mg daily [one 200 mg tablet once daily] for 2 weeks). bElectrical cardioversion is allowed (after 7 days of amiodarone in loading study) up to day 1 inclusive. cWith at least the last 2 months at a regimen of 200 mg/d.

Figure 2.

A, First recurrence of AF ≤60 days after randomization in the Loading study (ITT population), and (B) First recurrence of AF ≤60 days after randomization in the Long-term study (ITT population). Cumulative incidence function with Kaplan–Meier estimates, based on adjudicated data. AF indicates atrial fibrillation; ITT, intent-to-treat.

Figure 3.

(A) Dronedarone and SR35021 Cmax calculated at the first dronedarone intake (Long-term study Bayesian data set), (B) dronedarone and SR35021 AUC24 hours at the first day of dronedarone administration (Long-term study Bayesian data set), (C) dronedarone and SR35021 AUC336 hours calculated over the first 2 weeks of dronedarone intake (Long-term study Bayesian data set), and (D) dronedarone and SR35021 AUC672 hours calculated over the first 4 weeks of dronedarone intake (Long-term study Bayesian data set). White dots represent individual values; black dots and error bars are mean values ± SD. The horizontal error bars quantify the variation in the timing of dronedarone initiation after amiodarone discontinuation in each group. The vertical error bars describe the variation in dronedarone concentrations. AUC indicates area under the curve; Cmax, maximum concentration.