Clinical Investigations

Clinical Investigations Effects of Dronedarone Started Rapidly After Amiodarone Discontinuation Address for correspondence: Laura Immordino, MD 100 E. Lancaster Avenue Wynnewood, PA 19096 laura.immordino@gmail.com Laura Immordino, MD; Stuart Connolly, MD; Harry Crijns, MD; Denis Roy, MD; Alessandro Capucci, MD; David Radzik, MD; Etienne Aliot, MD; Stefan Hohnloser, MD; Peter Kowey, MD Department of Cardiology (Immordino, Kowey), Lankenau Medical Center, Wynnewood, Pennsylvania; Department of Cardiology (Connolly), McMaster University, Hamilton, Ontario, Canada; Department of Cardiology (Crijns), Academic Hospital Maastricht, Maastricht, The Netherlands; Department of Cardiology (Roy), Montréal Heart Institute, Montréal, Québec, Canada; Department of Cardiology (Capucci), University of Ancona, Ancona, Italy; Research & Development, Cardiology, sanofi-aventis (Radzik), Bridgewater, New Jersey; Department of Cardiology (Aliot), Central Hospital, University of Nancy, Nancy, France; Department of Cardiology (Hohnloser), J.W. Goethe University, Frankfurt, Germany Background: Multiple studies have shown that amiodarone is effective in treating atrial fibrillation (AF), but is associated with a relatively high incidence of side effects; however, due to amiodarone s long elimination half-life (20 100 days), physicians may hesitate to start other drugs until it has fully cleared. Hypothesis: A rapid switch from amiodarone to dronedarone is feasible. Methods: EURIDIS and ADONIS were double-blind, multinational, parallel-group trials comparing the efficacy and safety of dronedarone with placebo over 12 months. This retrospective subanalysis of EURIDIS/ADONIS compared the effects of dronedarone in patients discontinuing amiodarone within 2 days before randomization ( rapid switch ) with results in patients who had received no amiodarone during the 2 months preceding randomization. Results: In total, 1237 patients were enrolled ( rapid switch, n = 154; no amiodarone, n = 1014). In both the rapid switch and the no amiodarone groups, dronedarone users had significantly lower AF recurrence than patients receiving placebo (HR = 0.64, 95% CI, 0.44 0.95; P = 0.0224 and HR = 0.79, 95% CI, 0.67 0.92; P = 0.0027, respectively). Dronedarone users had a higher incidence of bradyarrhythmic events than placebo-treated patients. A rapid switch from amiodarone to dronedarone was associated with a higher incidence of serious heart failure events and heart failure hospitalizations versus all other groups. Overall event rates were low and there was no significant difference in total adverse event rates or deaths between groups. Conclusion: In this patient population, a switch from amiodarone to dronedarone within a 2-day time frame might be feasible in certain patient categories, but further investigation is warranted. Introduction Multiple studies have shown that amiodarone is more effective than other antiarrhythmic drugs in maintaining sinus rhythm in patients with persistent or paroxysmal atrial fibrillation (AF). 1,2 However, due to the relatively high incidence of side effects, amiodarone has been recommended as second-line therapy, except in patients with significant left ventricular hypertrophy or heart failure Additional Supporting Information may be found in the online version of this article. The ADONIS/EURIDIS studies and this post hoc analysis were funded by sanofi-aventis. The authors have no other funding, financial relationships, or conflicts of interest to disclose. 88 (HF). 3,4 Additionally, amiodarone s large volume of distribution (often requiring weeks to reach maximal effectiveness) and its long elimination half-life (20 100 days) 5 may cause physicians to hesitate starting other antiarrhythmics until amiodarone has fully cleared. There is a paucity of information about switching from amiodarone to other agents. Dronedarone is a noniodinated benzofuran derivative, with a pharmacologic profile similar to amiodarone s but with different relative effects on individual ion channels. 6 Compared with amiodarone, dronedarone is less lipophilic, resulting in a smaller volume of distribution and a significantly attenuated elimination half-life. Dronedarone has been shown to prolong time to first AF recurrence vs placebo 7 9 and to reduce cardiovascular hospitalizations in patients with nonpermanent AF. 10 An increased risk of fatal cardiovascular events has been Received: June 28, 2012 Accepted with revision: November 21, 2012

documented in patients with severe congestive HF and in patients with permanent AF taking dronedarone. 11 In addition, a few cases of liver toxicity have been reported in postmarketing surveillance; however, no organ toxicity was observed during clinical development, and dronedarone had a low proarrhythmic potential. The large clinical program conducted for dronedarone in disparate populations has helped define the indications and contraindications of this agent. Dronedarone is approved in the United States for patients with a history of paroxysmal or persistent AF to reduce the risk of hospitalization for AF in patients in sinus rhythm. 12 In Europe, it is approved for the maintenance of sinus rhythm after successful cardioversion in patients with a history of paroxysmal or persistent AF or atrial flutter (AFL). 13 Dronedarone contraindications in the United States include permanent AF, symptomatic HF with recent decompensation requiring hospitalization, or New York Heart Association class IV symptoms. 12 In Europe, contraindications include any history of or current HF or left ventricular systolic dysfunction. 13 Dronedarone has a class 1, level A recommendation in the updated 2012 European Society of Cardiology guidelines for patients with recurrent AF as a moderately effective antiarrhythmic agent for the maintenance of sinus rhythm. 14 Because dronedarone has a better long-term safety profile than amiodarone, 15 many physicians have been interested in switching patients from long-term amiodarone to dronedarone. However, there has been concern over potential additive effects of dronedarone, such as QT prolongation and bradycardia, if initiated amiodarone has cleared. Trials investigating the optimal timing of therapy switch Optimal Timing of Dronedarone Initiation After Conversion in Patients With Persistent Atrial Fibrillation (ARTEMIS Load) and Pharmacokinetics and Optimal Timing of Dronedarone Initiation Following Long-term Amiodarone in Patients With Paroxysmal or Persistent Atrial Fibrillation (ARTEMIS AF LT) have recently completed and results are awaited. Currently, no published data are available to help physicians manage switching from amiodarone to dronedarone. Here we report a retrospective, post hoc, exploratory subanalysis of the European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS) and American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm (ADO- NIS) studies. 8 We aimed to document the effects of rapid switching from amiodarone to dronedarone (amiodarone discontinuation 2 days before randomization) in patients with AF to determine the safety of early dronedarone initiation after amiodarone discontinuation. Methods Study Design Both EURIDIS and ADONIS were multinational, placebocontrolled, double-blind, parallel-group trials. 8 The efficacy and safety of dronedarone 400 mg twice daily (bid) were compared with placebo in 828 and 409 patients with AF, respectively, with a 12-month follow-up. Inclusion and exclusion criteria for these studies have been published. 8 Prior treatment with amiodarone was permitted, and patients could be enrolled immediately after amiodarone discontinuation, with no protocol restrictions for amiodarone washout; with other antiarrhythmics (Vaughan-Williams class I and III), withdrawal had to be 5 plasma half-lives prior to first study-drug administration. Eligible patients were randomized 2:1 to dronedarone 400 mg bid or placebo. Vital signs, symptoms, and electrocardiograms (ECG) were assessed/performed on days 7, 14, and 21, and at 2, 4, 6, 9, and 12 months. All patients were given transtelephonic ECG monitors; ECGs were transmitted on days 2, 3, and 5, at months 3, 5, 7, and 10, and whenever symptoms occurred. All ECGs (including transtelephonic) were centrally adjudicated. Subanalysis This retrospective, post hoc, exploratory subanalysis of the EURIDIS and ADONIS databases focused on 2 main groups: patients who discontinued amiodarone within 2 days before randomization to dronedarone 400 mg/placebo bid ( rapid switch ) and patients who had received no prior amiodarone during the 2 months preceding randomization ( no amiodarone ). Any potential amiodarone use occurring >2 months before randomization was considered as no amiodarone, as the remnant effect is likely minimal after 2 months of washout. The strongest contrast in terms of efficacy and safety parameters was expected between these 2 groups. Parameters compared were time to first recurrence of AF/AFL within 12 months from randomization, defined as an episode lasting 10 minutes as indicated by 2 consecutive 12-lead ECGs or transtelephonic ECG monitor tracings reviewed by a core laboratory, heart rate (HR) during the first recurrence of AF/AFL, and incidence and type of adverse events (AEs), which included bradycardia, QT prolongation, HF, overall cardiac events, gastrointestinal events, and changes in thyroid and creatinine levels. A small number of patients discontinued amiodarone >2 days but <2 months before randomization ( intermediate switch ). The small size of this group resulted in wide confidence intervals (CI) for the parameters analyzed. No meaningful comparisons with the other groups were therefore possible; thus, only descriptive analysis of the demographic characteristics is presented. Statistical Analysis Analyses were performed according to a modified intentionto-treat principle, with all randomized patients who received 11 doses of study drug included. As amiodarone treatment during the 2 months preceding randomization was a stratification variable, patients were classified as having received amiodarone or not before randomization according to their stratification factor. Time to first AF/AFL was estimated using the Kaplan-Meier method and compared via the log-rank test. Hazard ratios with 95% CIs were estimated using the Cox proportional hazard model. Relative risks (RR) and 95% CIs of AEs were calculated in the rapid-switch and no-amiodarone groups, and P values of interaction between amiodarone intake and treatment are based on logistic regression. All reported P values are 2-tailed, and statistical significance was assumed at P < 0.05. 89

Figure1. Schematic representation showing disposition of patients enrolled in the EURIDIS and ADONIS trials. Results Of the 1237 patients enrolled in the EURIDIS and ADONIS studies, 223 had previously received amiodarone and 1014 had not received amiodarone for 2 months preceding randomization (Figure 1). Patient demographics and baseline characteristics are summarized in Table 1. Slight differences between groups in hypertension, structural heart disease, coronary artery disease, valvular heart disease, or cardiovascular-medication use did not appear to be clinically meaningful. A higher percentage of patients in the no-amiodarone group had lone AF vs those in the rapid-switch group. Any differences are not unexpected in a retrospective analysis. Efficacy: Time to First Atrial Fibrillation/Atrial Flutter Recurrence Dronedarone users in both groups had a significantly lower incidence of AF/AFL recurrence at 12 months vs patients randomized to placebo (64.3% vs 80.4% in the rapid-switch group and 63.1% vs 72.2% in the no-amiodarone group (online Figures 1A and 1B). Heart Rate During First Recurrence of Atrial Fibrillation/Atrial Flutter Of patients receiving placebo, those with prior amiodarone use had a mean HR of 109 bpm vs 119 bpm in those without prior amiodarone use. In patients taking dronedarone, those with prior amiodarone use had a mean HR of 102 bpm vs 104 bpm in those without prior amiodarone use. Safety and Tolerability: Overall Adverse Events In the rapid-switch group, switching from amiodarone to dronedarone within 48 hours was not associated with a higher incidence of treatment-emergent AEs vs switching to placebo (Table 2). Incidence rates of serious AEs and events leading to hospitalization or death were similar across all groups. There was a higher incidence of AEs leading to drug discontinuation in dronedarone vs placebo users in both groups; however, this was not statistically significant (9.1% vs 6.3% in the no-amiodarone group and 8.2% vs 3.6% in the rapid-switch group). Bradyarrhythmic Events: There was a higher incidence of bradyarrhythmic events in dronedarone-treated patients vs placebo-treated patients, regardless of prior amiodarone use (Table 2). Overall bradyarrhythmic-event rates were similar among all dronedarone users; however, the rate of these events leading to drug discontinuation was significantly higher in the rapid-switch group than in the noamiodarone group (3.1% vs 0.7%; RR: 4.16, 95% CI: 1.01 7.15) (Table 3). Overall, the proportion of patients with serious bradyarrhythmic events and those leading to hospitalization was low. Overall Cardiac Events: Overall cardiac event rates were similar among the rapid-switch and no-amiodarone groups. Patients in the rapid-switch/dronedarone group tended to have more serious cardiac events and cardiac events leading to drug discontinuation and hospitalization than all other groups; however, these were not statistically significant (Tables 2 and 3). Heart Failure Events: Overall HF-event rates did not significantly differ among patients in the rapid-switch and no-amiodarone groups (Table 2). There were more serious HF events and HF hospitalizations in the rapidswitch/dronedarone group compared with other groups (Tables 2 and 3; RR: 5.95, 95% CI: 2.04 17.33). However, no HF cases led to death or drug discontinuation in dronedarone-treated patients, and 1 fatal case of HF was reported in the no-amiodarone/placebo group (Table 2). Electrocardiographic Abnormalities: Overall, dronedarone users had a higher incidence of bradycardia documented on ECG, defined by a HR 50 bpm and a drop of 15 bpm from baseline (10.5% vs 5.7% with placebo). However, 90

Table 1. Demographics and Baseline Characteristics According to Previous Intake of Amiodarone Per Stratification Factor (All Randomized and Treated Patients) Rapid Switch Intermediate Switch No Amiodarone N = 56 N = 98 N = 17 N = 35 N = 334 N = 680 Demographics Mean age, y (SD) 61.8(9.8) 64.4(8.7) 64.8(9.3) 65.9(12.6) 62.1(11.4) 63.2(10.9) <65, % 62.5 52.0 52.9 37.1 50.9 50.7 65, % 37.5 48.0 47.1 62.9 49.1 49.3 Women, % 30.4 38.8 35.3 28.6 31.4 28.8 Cardiovascular history, % Hypertension 51.8 67.3 47.1 60.0 49.7 59.0 Structural heart disease 42.6 42.9 47.1 58.8 38.7 41.0 Lone AF 26.8 18.4 23.5 11.8 33.5 26.6 CAD 17.9 21.4 23.5 25.7 18.0 23.7 Valvular heart disease 14.3 17.3 11.8 28.6 15.0 15.6 Pacemaker 1.8 11.2 5.9 2.9 5.4 7.2 Dilated cardiomyopathy 10.7 8.2 0.0 8.6 7.2 5.1 Baseline medication, % Oral anticoagulant 80.4 77.6 88.2 62.9 63.2 60.1 β-blocker 30.4 27.6 41.2 40.0 46.4 49.6 ACEI or ARB 44.6 49.0 47.1 54.3 40.4 42.1 Chronic antiplatelet therapy 25.0 26.5 0.0 37.1 30.5 33.8 Diuretic 23.2 33.7 23.5 28.6 24.6 24.7 Statin 32.1 24.5 11.8 14.3 22.5 27.1 Digitalis 12.5 15.3 11.8 5.7 20.1 18.4 Moderate inhibitor of CYP3A4 5.4 13.3 5.9 2.9 14.4 13.4 NSAID 8.9 5.1 17.6 11.4 8.7 9.0 Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; CAD, coronary artery disease; CYP3A4, cytochrome P450 3A4; NSAID, nonsteroidal anti-inflammatory drug; SD, standard deviation. the incidence of bradycardia in all dronedarone users was similar, regardless of prior amiodarone use (10.5% in rapidswitch group vs 10.9% in the no-amiodarone group). Amiodarone users had a higher mean corrected QT interval (QTc) at baseline than nonusers (435 ms vs 400 ms). Those who switched to dronedarone had a relatively stable QTc interval over the first month, with modest decreases at the 4-, 9-, and 12-month follow-ups (Figure 2A). Those who switched to placebo had a relatively stable QTc interval over the first month, followed by a more profound decrease in QTc interval at the 4-month follow-up and subsequent stability in the QTc interval over the remainder of follow-up. Patients in the no-amiodarone/dronedarone group had an increased QTc interval at the 7-day follow-up, then relative stability of the QTc interval over the next 12 months (Figure 2A). Overall, dronedarone users had similar QTc intervals at 12 months, regardless of prior amiodarone use. The incidence of prolonged QTc (ie, QTc 500 ms) was higher in dronedarone users with recent amiodarone use vs those without (7.9% vs 4.4%). There were no episodes of torsades de pointes. Creatinine Levels: The rapid-switch/placebo patients had decreases in serum creatinine over the 12 months following randomization. rapid-switch/dronedarone patients had slight increases in serum creatinine, but to a lesser extent than no-amiodarone/dronedarone patients (Figure 2B). Thyroid Profile: Placebo-treated patients in the rapidswitch group had the highest rate of abnormal thyroidfunction tests, with 24.1% experiencing a change in thyroid-stimulating hormone levels outside normal range and 14.8% with a change in free-t3 levels (online 91

Table 2. AEs According to Amiodarone Intake Per Stratification Factor (All Randomized and Treated Patients From Rapid-Switch and No-Amiodarone Groups) Rapid Switch No Amiodarone n = 56 n = 98 RR (95% CI) n = 334 n = 680 RR (95% CI) TEAE, n (%) a 42 (75.0) 63 (64.3) 0.86 (0.69 1.06) 201 (60.2) 459 (67.5) 1.12 (1.01 1.24) Serious TEAE 8 (14.3) 15 (15.3) 1.07 (0.48 2.37) 54 (16.2) 93 (13.7) 0.85 (0.62 1.15) TEAE leading to hospitalization 8 (14.3) 15 (15.3) 1.07 (0.48 2.37) 51 (15.3) 85 (12.5) 0.82 (0.59 1.13) TEAE leading to death 1 (1.8) 1 (1.0) 0.57 (0.04 8.96) 2 (0.6) 5 (0.7) 1.23 (0.24 6.30) AE leading to premature study drug 2(3.6) 8 (8.2) 2.29 (0.50 10.39) 21 (6.3) 62 (9.1) 1.45 (0.90 2.34) discontinuation a,b,c Incidence of bradyarrhythmic events, n (%) d All events 0 4 (4.1) NC 9 (2.7) 35 (5.1) 1.91 (0.93 3.93) Serious events 0 1 (1.0) NC 3 (0.9) 9 (1.3) 1.47 (0.40 5.41) Events leading to drug discontinuation 0 3 (3.1) NC 0 5 (0.7) NC Events leading to hospitalization 0 1 (1.0) NC 3 (0.9) 9 (1.3) 1.47 (0.40 5.41) Events leading to death 0 1 (1.0) NC 0 0 NC Incidence of cardiac events, n (%) e All events 10 (17.9) 18 (18.4) 1.03 (0.51 2.07) 52 (15.6) 122 (17.9) 1.15 (0.86 1.55) Serious events 3 (5.4) 9 (9.2) 1.71 (0.48 6.07) 19 (5.7) 39 (5.7) 1.01 (0.59 1.72) Events leading to drug discontinuation 1 (1.8) 3 (3.1) 1.71 (0.18 16.09) 6 (1.8) 10 (1.5) 0.82 (0.30 2.23) Events leading to hospitalization 2 (3.6) 9 (9.2) 2.57 (0.58 11.49) 19 (5.7) 39 (5.7) 1.01 (0.59 1.72) Events leading to death 1 (1.8) 1 (1.0) 0.57 (0.04 8.96) 1 (0.3) 1 (0.1) 0.49 (0.03 7.83) Incidence of HF events, n (%) f All events 7 (12.5) 11 (11.2) 0.90 (0.37 2.18) 28 (8.4) 54 (7.9) 0.95 (0.61 1.47) Serious events 1 (1.8) 6 (6.1) 3.43 (0.42 27.76) 5 (1.5) 7 (1.0) 0.69 (0.22 2.15) Events leading to drug discontinuation 0 0 NC 3 (0.9) 0 NC Events leading to hospitalization 1 (1.8) 6 (6.1) 3.43 (0.42 27.76) 5 (1.5) 7 (1.0) 0.69 (0.22 2.15) Events leading to death 0 0 NC 1 (0.3) 0 NC Incidence of GI events, n (%) g All events 8 (14.3) 15 (15.3) 1.07 (0.48 2.37) 63 (18.9) 144 (21.2) 1.12 (0.86 1.46) Serious events 1 (1.8) 2 (2.0) 1.14 (0.11 12.32) 1 (0.3) 11 (1.6) 5.40 (0.70 41.67) Events leading to drug discontinuation 0 1 (1.0) NC 7 (2.1) 9 (1.3) 0.63 (0.24 1.68) Events leading to hospitalization 1 (1.8) 2 (2.0) 1.14 (0.11 12.32) 1 (0.3) 11 (1.6) 5.40 (0.70 41.67) Events leading to death 0 0 NC 0 0 NC Abbreviations: AE, adverse events; AF, atrial fibrillation; AFL, atrial flutter; CI, confidence interval; GI, gastrointestinal; HF, heart failure; MedDRA, Medical Dictionary for Regulatory Activities; NC, not calculated; RR, relative risk; SOC, system organ class; TEAE, treatment-emergent adverse event. AEs classified based on MedDRA selections. a Including serious AEs. b AEs leading to premature study drug discontinuation are all AEs (excluding AF/AFL) described on the End of Study form (onset date 10 d after final study drug administration). c Events beginning before first study drug intake were accounted for. d Bradyarrhythmic events selected using standardized MedDRA query bradyarrhythmia including conduct deficiencies sinus node disorders with broad selection, or preferred term, bradycardia. e Cardiac events selected using SOC cardiac disorders or vascular disorders. f HF events (narrow selection) selected using standardized MedDRA query cardiac failure. g GI events (narrow selection) selected using SOC gastrointestinal disorders. Table 1). Patients in the rapid-switch/dronedarone group had rates of abnormal thyroid function tests similar to the no-amiodarone/dronedarone and no-amiodarone/placebo groups (6% 10% had changes in thyroid-stimulating hormone levels, and 6% 9% had changes in free-t3 levels). 92

Table 3. AEs Among Patients Taking Dronedarone According to Prior Amiodarone Use (All Dronedarone-Treated Patients From Rapid Switch and No Amiodarone Groups) Incidence of bradyarrhythmic events, n (%) a Dronedarone-Treated Patients Rapid Switch, N = 98 No Amiodarone, N = 680 Relative Risk (95% CI) All events 4 (4.1) 35 (5.1) 0.79 (0.29 2.81) Serious events 1 (1.0) 9 (1.3) 0.77 (0.10 6.02) Events leading to drug discontinuation 3 (3.1) 5 (0.7) 4.16 (1.01 17.15) Events leading to hospitalization 1 (1.0) 9 (1.3) 0.77 (0.10 6.02) Events leading to death 1 (1.0) 0 NC Incidence of cardiac events, n (%) b All events 18 (18.4) 122 (17.9) 1.02 (0.65 1.60) Serious events 9 (9.2) 39 (5.7) 1.60 (0.80 3.20) Events leading to drug discontinuation 3 (3.1) 10 (1.5) 2.08 (0.58 7.43) Events leading to hospitalization 9 (9.2) 39 (5.7) 1.60 (0.80 3.20) Events leading to death 1 (1.0) 1 (0.1) 6.94 (0.44 110.04) Incidence of HF events, n (%) c All events 11 (11.2) 54 (7.9) 1.41 (0.77 2.61) Serious events 6 (6.1) 7 (1.0) 5.95 (2.04 17.33) Events leading to drug discontinuation 0 0 NC Events leading to hospitalization 6 (6.1) 7 (1.0) 5.95 (2.04 17.33) Events leading to death 0 0 NC Incidence of GI events, n (%) d All events 15 (15.3) 144 (21.2) 0.72 (0.44 1.18) Serious events 2 (2.0) 11 (1.6) 1.26 (0.28 5.61) Events leading to drug discontinuation 1 (1.0) 9 (1.3) 0.77 (1.10 6.02) Events leading to hospitalization 2 (2.0) 11 (1.6) 1.26 (0.28 5.61) Events leading to death 0 0 NC Abbreviations: AE, adverse event; CI, confidence interval; GI, gastrointestinal; HF, heart failure; MedDRA, Medical Dictionary for Regulatory Activities; NC, not calculated; SOC, system organ class. AEs classified based on MedDRA selections. a Bradyarrhythmic events selected using standardized MedDRA queries Bradyarrhythmia including conduct deficiencies sinus node disorders with broad selection, or preferred term, bradycardia. b Cardiac events selected using SOC cardiac disorders or vascular disorders. c HF events (narrow selection) selected using standardized MedDRA query cardiac failure. d GI events (narrow selection) selected using SOC gastrointestinal disorders. Discussion The EURIDIS and ADONIS studies demonstrated the efficacy of dronedarone in prolonging time to first AF recurrence vs placebo. 8 Retrospective analysis of these data confirms the effectiveness of dronedarone in a subset of patients who had discontinued amiodarone <2 days prior to starting dronedarone. Compared with the overall population, similar rates of AF recurrence were observed in patients in the rapid-switch group. Heart rate was slightly lower during the first recurrence of AF/AFL in the rapid-switch group vs the no-amiodarone group. Of those randomized to placebo, patients in the rapid-switch group had a lower mean HR than those in the no-amiodarone group, probably because these patients were still affected by the HR-lowering properties of amiodarone, due to its long elimination half-life. Interestingly, the rapidswitch/dronedarone patients had a mean HR only slightly lower than the rapid-switch/placebo patients, indicating a limited additive effect of dronedarone on HR in patients already treated with amiodarone. Dronedarone-treated patients had a higher incidence of bradyarrhythmic events than did placebo-treated patients. More bradyarrhythmic events causing drug discontinuation were seen in dronedarone users who had recently received 93

Figure2. Mean (standarddeviation)value over time for (a)qtc Fridericia (ms),and (b)creatinine levels (μmol/l) during on-treatment period (all randomized and treated patients in the rapid switch and no amiodarone groups). B, baseline; D, day; EOT, last value under treatment; M, month. amiodarone vs those with no prior amiodarone. Although the overall number of bradyarrhythmic events was low, this may be one potential drawback to a rapid switch and may indicate a subset of patients (those with borderline-low HR on amiodarone) that would benefit from a more gradual switch to dronedarone. Patients in the rapid-switch/dronedarone group also had more serious HF events and HF hospitalizations vs all other groups. Patients in the no-amiodarone/dronedarone group had HF-event rates similar to the no-amiodarone/placebo group, indicating a potential additive effect or interaction between recent amiodarone use and dronedarone. In dronedarone-treated patients, serum creatinine levels increased. A smaller increase was seen in the rapid-switch group vs the no-amiodarone group. A small rise in creatinine levels upon initiation is anticipated, as dronedarone reduces renal creatinine clearance, although without affecting the glomerular filtration rate. 15 Amiodarone produces similar changes, possibly via a similar mechanism, 16 explaining why serum creatinine decreased slightly in patients stopping amiodarone and receiving placebo but increased slightly in those receiving dronedarone. Changes in thyroid hormones in the rapid-switch group are related to the residual effects of amiodarone on 94

thyroid function. 17,18 The abnormalities were corrected after amiodarone discontinuation. Importantly, no changes in thyroid hormone levels were observed in patients randomized to dronedarone vs those receiving placebo. Limitations of this study include its retrospective, exploratory nature, and the small number of patients involved, limiting the statistical power. In addition, recent treatment with amiodarone prior to inclusion was not a randomized variable; it was present by definition in all rapidswitch patients and in no patients in the no-amiodarone group. Therefore, one cannot exclude the possibility that patients in the rapid-switch group had more severe heart disease to start with, as amiodarone is often prescribed in this setting. This hypothesis is supported by a slightly lower incidence of lone AF in rapid-switch patients compared with no prior amiodarone patients for both the placebo and the dronedarone subgroups. Similarly, the timing of amiodarone discontinuation prior to dronedarone initiation was at the discretion of the study physician, and a subset of patients had a delayed switch from amiodarone to dronedarone for reasons that cannot be ascertained. For these reasons, some degree of self-selection bias cannot be excluded in the rapid-switch group. Conclusion This retrospective analysis of a small subset of patients from the EURIDIS and ADONIS studies suggests that rapid switching (<48 hours) from amiodarone to dronedarone might be feasible in certain patients. Further clinical investigation will be required to determine the optimal time frame for switching drugs, and this decision will likely be on a case-by-case basis, taking individual patient characteristics into account. Acknowledgments Editorial assistance was provided by Sally Mitchell, PhD, and Sola Neunie of PPSI, and was funded by sanofi-aventis. References 1. Olshansky B, Rosenfeld LE, Warner AL, et al. 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