Table 1.

Clinical trials

Trial acronym/design	Objective	Treatment	Inclusion criteria	Exclusion criteria	Treatment duration	Primary endpoint	Secondary endpoint	Main outcome/adverse events
DAFNE Multinational, multicenter, double-blind, randomized, parallel arm, placebo-controlled, Phase II trial n = 270	Dose finding study	Placebo or dronedarone: 400 mg twice daily, 600 mg twice daily or 800 mg twice daily	Aged 21–85 y Persistent AF >72 h and <12 mo AF: alone or associated with ischemic, hypertensive heart disease or dilated cardiomyopathy Cardioversion and anti-arrhythmic treatment warranted	>2 cardioversions within prior 6 mo AFL as presenting arrhythmia Reversible condition (eg, alcohol intake, thyrotoxicosis, infection, recent cardiac surgery) CHF NYHA II or IV Concomitant use of antiarrhythmic drug or potent CYP3A4 inhibitor	6 mo	Time to first AF recurrence in patients converted to SR	Spontaneous conversion of AF following randomization Heart rate in case of AF recurrence Incidence of side effects	Dronedarone 400 mg twice daily significantly prolonged time to first AF/AFL by 55% vs placebo Adverse events: GI problems were most frequent side effects in dronedarone groups, and increased dependent on dose QT prolongation increased dependent on dose
EURIDIS/ADONIS Multinational, multicenter, double-blind, randomized, parallel arm, placebocontrolled, Phase II trials n = 1237	Effect of dronedarone in maintaining SR after electrical, pharmacological or spontaneous conversion of AF/AFL	Placebo or dronedarone 400 mg twice daily	Aged ≥21 y ≥1 AF episode in prior 3 mo SR for ≥1 h before randomization	Permanent AF Reversible condition (eg, alcohol intake, thyrotoxicosis, infection, recent cardiac surgery) CHF NYHA II or IV Concomitant use of antiarrhythmic drug or potent CYP3A4 inhibitor	12 mo	Time to first AF/AFL recurrence	Symptomatic AF/AFL among adjudicated first AF/AFL recurrence Time between steady state and adjudicated first AF/AFL recurrence Mean ventricular rate during first AF recurrence CV hospitalization	Dronedarone significantly increased time to first recurrence −25% RR (116 days vs 53 days) and significantly reduced the rate during AF recurrence (−16.7 bpm) Adverse events: Similar between drug and placebo Dronedarone induced slight increase in serum creatinine levels, reversible upon discontinuation of the drug
ERATO Multinational, multicenter, double-blind, randomized, parallel arm, placebocontrolled, Phase II trials n = 174	Efficacy of dronedarone for ventricular rate control in permanent AF	Placebo or dronedarone 400 mg twice daily	Aged ≥21 y Documented symptomatic permanent AF >6 mo Resting ventricular rate ≥ 80 bpm	CHF NYHA II or IV History of unstable angina History of TdP Concomitant use of antiarrhythmic drug or potent CYP3A4 inhibitor	6 mo	Mean ventricular rate at 2 weeks	Ventricular rate during submaximal and maximal exercise at 2 wk Change in maximal exercise duration at 2 wk Mean 24-h ventricular rate at 4 mo	Dronedarone significantly reduced 24-h average heart rate by 11.7 bpm and maximal exercise ventricular rate by 24.5 bpm at day 14 vs baseline Adverse events: Similar between drug and placebo Most frequent adverse events included infections (31% in dronedarone group vs 25% in placebo group) and GI side effects (20% in dronedarone group vs 14% in placebo group)
ANDROMEDA Multinational, multicenter, double-blind, parallel arm, placebocontrolled, Phase II trial n = 627	Assess the potential benefit of dronedarone on all cause death or hospitalization for worsening heart failure in high-risk patients with left ventricular dysfunction and recent hospitalization for a severe episode (NYHA II or IV)	Placebo or dronedarone 400 mg twice daily	Aged ≥18 y Hospitalized with new or worsening heart failure ≥1 episode of shortness of breath on minimal exertion or at rest or paroxysmal nocturnal dyspnea within the month prior to admission Wall-motion index at screening ≤1.2 (LVEF ≤35%)	Acute MI within 7 d prior to screening Heart rate <50 bpm PR interval >280 ms Sinoatrial block or second- or third-degree AV block not treated with pacemakers History of TdP QTc interval >500 ms Concomitant use of antiarrhythmic drug or potent CYP3A4 inhibitor	Median follow-up of 2 mo – all patients were followed for 6 mo (double-blind) following cessation of treatment	Death from any cause or hospitalization for worsening heart failure	Death from all causes Hospitalization for cardiovascular causes Hospitalization for worsening heart failure Occurrence of AF/AFL Death from arrhythmia Sudden death	Trial stopped because of an imbalance in the number of deaths between the dronedarone arm and the placebo arm (25 vs 12, respectively). The excess mortality in the dronedarone arm was predominantly related to worsening heart failure. As consequence dronedarone is contraindicated in NYHA II or IV and worsening CHF. Adverse events: More cases of increased creatinine concentration in the dronedarone group. No significant difference for arrhythmic events and sudden death
ATHENA Multinational, multicenter, double-blind, randomized, parallel arm, placebocontrolled, Phase II trial n = 4628	Efficacy of dronedarone for the prevention of cardiovascular hospitalization or death from any cause in patients with paroxysmal or persistent AF/AFL	Placebo or dronedarone 400 mg twice daily	AF/AFL and SR within the last 6 mo preceding inclusion (both ECG documented) Aged ≥75 y with or without additional risk factors or ≥70 y with one or more of the following risk factors: – hypertension – diabetes – prior cerebrovascular accident or systemic embolism – left atrial diameter ≥50 mm – LVEF ≤40%	Permanent AF CHF NYHA II or IV within the last 4 weeks Concomitant use of anti-arrhythmic drug or potent CYP3A4 inhibitor	Mean follow-up of 21 ± 5 mo, maximum 2.5 years	Combined all-cause mortality and hospitalizations for cardiac causes over a minimum treatment and follow-up duration of 12 mo	Death from any cause Cardiovascular death First hospitalization for cardiovascular reasons	Significant 24% RR reduction in the combined primary endpoint favoring dronedarone (P < 0.001) that was mainly driven by a lower hospitalization rate in the dronedarone (29.3%) than in the placebo group (36.9%), whereas deaths from any cause showed no significant differences Adverse events: More frequent in the dronedarone group (12.7%) than in the placebo group (8.1%), predominantly of GI cause (26% vs 22%). In addition bradycardia, QT prolongation, diarrhea, nausea, rash, and increase in the serum creatinine level
DIONYSOS Multinational, multicenter, double-blind, randomized, parallel arm, placebocontrolled, Phase II trial n = 504	Efficacy and safety of dronedarone vs amiodarone in AF	Dronedarone 400 mg twice daily or an amiodarone 600 mg loading dose daily for 28 days, and a maintenance dose of 200 mg/d thereafter	AF >72 h indicated for cardioversion and anti-arrhythmic therapy Receiving anticoagulants	Documented AF episode after an acute condition known to cause AF Chronic AF >12 mo QTc interval ≥500 ms AFL Paroxysmal AF CHF NYHA II or IV Severe bradycardia High degree AV block Contraindications to amiodarone Concomitant use of anti-arrhythmic drug or potent CYP3A4 inhibitor Previous chronic treatment with amiodarone	7 mo	Composite: Recurrence of AF (ECG documented) AF recurrence post-electrical cardioversion, unsuccessful electrical cardioversion, no spontaneous electrical cardioversion and no electrical cardioversion or Premature study discontinuation for intolerance or lack of efficacy	MSE: occurrence of thyroid, hepatic, pulmonary, neurological, skin, eye or GI specific events or premature study drug discontinuation following any adverse event Individual components of MSE MSE excluding GI adverse events	In total 184 patients (73.9%) reached the primary endpoint in the dronedarone arm, compared with 141 (55.3%) in the amiodarone arm (P < 0.001). Results were mainly driven by the AF recurrence component. Adverse events: Premature drug discontinuation component was less frequent in the dronedarone group than in the amiodarone group (10.4% vs 13.3%, respectively)

Abbreviations: AF, atrial fibrillation; AFL, atrial flutter; AV, atrioventricular; CHF, congestive heart failure; GI, gastrointestinal; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MSE, main safety endpoint; NYHA, New York Heart Association; RR, relative risk; SR, sinus rhythm; TdP, torsade de pointes; d, day; h, hour; mo, month; wk, week.