Table 1.

Summary of Dronedarone clinical trials data

Trial	Drug studied	Population and end points	Results	Conclusion/dose finding study
DAFNE62 DB, R, PC Location: Europe and Israel N = 269 = completed Only 199 patients in whom NSR was restored were included in the analysis	Dronedarone (n = 54): 400 mg BID Dronedarone† (n = 54): 600 mg BID Dronedarone† (n = 43): 800 mg BID Placebo (n = 48): BID Duration: 6 months	Inclusion: Persistent AF (>72 hours and < 12 months duration of the present episode at the screening visit) for whom cardioversion and antiarrhythmic treatment was warranted; Exclusion: Atrial Flutter, unstable angina, or recent MI; NYHA class III or IV heart failure; $2 cardioversions in the last 6 months; End points: Primary: time to first documented AF recurrence Secondary: Heart rate in AF recurrence; rate of adverse events.	Primary end point: Time to first recurrence of AF 400 mg median was 60 days vs 5.3 days in placebo RRR 55% (95% CI, 28%–72%, P = 0.001) No significant effect seen at higher doses. Drug induced QTc prolongation only noticed in one patient with 1600 mg. Compliance with study drug 77% (1600 mg) vs 96% (800 mg) mainly due to GI side effects 4.4%. Withdrawal due to ADR 15% with dronedarone vs 10% with placebo; No evidence of thyroid, hepatic, neurological, ocular, or pulmonary complications	Only 400 mg BID dose was safe and effective as well as well tolerated Higher doses 600 mg and 800 mg BID were not effective.
DIONYSOS59 DB, R Location: multinational study 504: randomized 339: completed study period	Dronedarone: 400 mg bid (n = 249) Amiodarone: 600 mg daily for 28 days then 200 mg daily (n = 255) Duration: 6 months median follow-up 7 months	Inclusion: Persistent AF for more than 72 hours for whom cardioversion and antiarrhythmic treatment is indicated in the opinion of the investigator and under oral anticoagulation. Exclusion: Acute MI or hemodynamic instability; overt heart failure or NYHA class III or IV heart failure; continuous AF > 12 months. End points: Primary: Treatment failure defined as recurrence of AF documented by scheduled or unscheduled 12 lead-ECG or premature drug discontinuation. Secondary: AF recurrence.	Primary: Treatment failure defined as recurrence of AF documented by scheduled or unscheduled 12 lead-ECG or premature drug discontinuation. Treatment failure occurred with 184 (74%) patients in the dronedarone arm vs 141 (55%) in the Amiodarone arm, P < 0.001. Premature study drug discontinuation occurred in 26 (10.4%) dronedarone vs 34 (13.3%) amiodarone, all with exception of 1 patient due to safety. Safety endpoints: 83 (33%) dronedarone vs 107 (42%) amiodarone Hazard ratio 0.80, P = 0.12 Thyroid 2 vs 15, Neurologic 3 vs 17 favor dronedarone. Higher GI side effects with dronedarone 99 vs 61, P = 0.0021.	Dronedarone was better tolerated but not as effective as amiodarone for suppressing AF recurrance.
ATHENA52 DB, R, PC 4628: randomized 4604: treated	Dronedarone: 400 mg bid (n = 2301) Placebo BID (n = 2327) Duration: 12 months Median follow-up: 21 ± 5 months	Inclusion: Pt could be either in sinus rhythm, or in AF or AFL with following criteria: (1) one of the following risk factors: age ≥ 70 years, hypertension, diabetes, prior CV accident, LVEF ≤ 0.4 (2) ECG within last 6 months showing AF/AFL (3) ECG within last 6 months showing pt in sinus rhythm. On March 8; 2006 protocol was amended to include pts aged 75 or older with or without additional risk factors. Exclusion: Permanent AF, hemodynamic instability, decompensated heart failure or NYHA class IV heart failure, MI. Primary: Death from any cause or hospitalization for CV cause. Secondary: Death from CV cause Death from any cause Hospitalization for CV cause	Primary end point occurred in 734 (31.9%) dronedarone vs 917 (39.4%) Placebo HR 0.76 (0.69–0.84) P < 0.001. Pre-specified primary: Hospitalization due to a cardiovascular event 675 (29.3%) dronedarone vs 859 (36.9) Placebo HR 0.74 (0.67–0.82) P < 0.001. Pre-specified secondary: Death from any cause 116 (5.0%) dronedarone vs 139 (6.0) Placebo HR 0.84 (0.66–1.08) P = 0.18 Death from CV cause 2.7% dronedarone vs 3.9% Placebo HR 0.71 (0.51–0.98) P = 0.03 Hospitalization for CV cause 29.3 dronedarone vs 36.9% placebo HR 0.74 95% CI (0.67–0.82) P < 0.001. Tolerability: Premature discontinuation dronedarone 30.2 vs 30.8 placebo NS withdrawal due to ADR 12.7 vs 8.2 P < 0.001 respectively. Adverse events dronedarone vs placebo respectively: Bradycardia 3.5 vs 1.2 QT prolongation 1.7 vs 0.6 (P < 0.001), GI 26 vs 22 (P < 0.001), skin related 10.3 vs 7.6 (P < 0.001), increases in Scr 4.7 vs 1.3 (P < 0.001) Endocrine, pulmonary, and neurological toxicities did not differ between treatment groups.	Evaluation of dronedarone in a group of older patients with significant comorbidities including stable heart failure class II or III, with hospitalization and mortality rather than control of rate or rhythm as the endpoint. Basis of FDA approval.
ANDROMEDA63 DB, R, P Locations: Multinational European study (no involvement of North American Centers) 627: randomized	Dronedarone 400 mg BID (n = 310) Placebo BID (n = 317) Median follow-up: 2 months	Inclusion: Patients hospitalized with new or worsening heart failure and who had at least one episode of shortness of breath on exertion or at rest NYHA functional class III or IV) or PND within 1 month before admission and Wall motion index of <1.2 (ie, LVEF < 35%). Patients were assigned no later then 7 days after hospital admission. Exclusion: Acute MI, bradycardia, sinoatrial or atrioventricular block, acute pulmonary edema. End Points: Primary end point: death from any cause or hospitalization for worsening heart failure. Secondary end point: Death from any cause. Hospitalization for CV cause	No significant difference in primary end point 53 (17.1%) events in dronedarone vs 40 (12.6%) in placebo arm HR 1.38; P = 0.12 The study was prematurely halted due to an increase in mortality during a median follow-up of 2 months, 25 (8.1) patients in the dronedarone arm vs 12 (3.8) in the placebo arm 95% CI 1.07–4.25; P = 0.03; this was due to excess heart failure, 10 deaths in dronedarone vs 2 in placebo. Increased hospitalization for heart failure (35 patients vs 30 patients) and for cardiovascular causes (71 patients vs 50 patients P = 0.02) were observed in the dronedarone group.	Treatment of unstable patients admitted with heart failure exacerbation with severe heart failure and systolic dysfunction is associated with increased early mortality related to worsening heart failure.
ADONIS64 DB, R, P Locations: multinational (US, Canada, Australian-African, Australia, South Africa, Argentina) 629: randomized 625: completed EURIDIS64 DB, R, P Location: multinational European study 615: randomized 612: completed	Dronedarone 400 mg BID vs Placebo BID Duration: 12 months Vaughan–Williams–Singh Class I and III antiarrhythmic drugs (including sotalol) other than the study drug were not to be administered during the study and had to be withdrawn for at least 5 plasma half-lives prior to the first study drug administration	Inclusion: Patients, in sinus rhythm for at least 1 hour at the time of randomization and with at least 1 ECG-documented AF/AFL episode in the last 3 months. Exclusion: AF > 12 months, torsade de pointes, NYHA class III or IV heart failure, Scr > 1.7 mg/dl. End points: Primary: Time from randomization to first documented AF/AFL recurrence defined as an episode lasting 10 minutes or more, as indicated by 2 consecutive 12-lead ECG or TTEM tracings recorded approximately 10 minutes apart and both showing AF/AFL. Secondary end point: Mean ventricular rate during first recurrence.	Median Time to first recurrence for 59 days for dronedarone and 158 for placebo (P = 0.002) Mean ventricular rate 104.6 ± 27.1 BPM dronedarone vs 116.6 ± 31.9 BPM placebo (P < 0.001) Number of patients with first AF/AFL within 12 months of randomization 51.3% dronedarone and 62.6% placebo HR 0.74%, P = 0.02 Death/Hospitalization NS Median time to first recurrence for 41 days for dronedarone and 96 for placebo (P = 0.001) Mean ventricular rate 102.3 ± 24.7 BPM dronedarone vs 117 ± 29.1 BPM placebo (P < 0.001) Number of patients with first AF/AFL within 1 2 months of randomization 56.4% dronedarone and 69.5% placebo HR 0.71%, P = 0.006 Death/hospitalization NS	Dronedarone was better than placebo at maintaining sinus rhythm and reducing ventricular rate. Dornedarone lengthened QTc by 9 msec no association with torsade de pointes.
Trial name: ERATO51 DB, R, P Location: European trial 174: randomized	Dronedarone: 400 mg BID (n = 85) Placebo BID (n = 89) Duration: 4 months	Inclusion. Patients symptomatic, permanent symptomatic AF (duration of AF > 6 months) for which cardioversion was not considered. Resting ventricular rate ≥ 80 bpm at screening. Primary: The change in mean HR measured by 24-hour Holter at Day 14, as compared to baseline. Secondary: Mean 24-hour ventricular HR at 4 months	Primary outcome: Compared to placebo on day 14 dronedarone reduced ventriclar rate by 11.7 BPM, P < 0.0001, this reduction was sustained throughout the 4 month period (10.1 vs 1.3 BPM P < 0.0001). Mean reduction during exercise was 24.5 BPM P < 0.0001 without any reduction in exercise tolerance as measured by maximal exercise duration.	Dronedarone improves ventricular rate control in patients with AF, including patients on β-blocker, digoxin, or calcium channel blocker.

Abbreviations: DB, double blind; R, randomized; PC, placebo controlled; ns, not significant; HR, heart rate; BID, twice a day.