Dronedarone on Trial: EURIDIS and ADONIS

Linda Brookes, MSc

Disclosures

September 24, 2004

Editorial Collaboration

Medscape &

Presenter: Stephan H Hohnloser, MD, PhD, JW Goethe University (Frankfurt am Main, Germany)

Two phase 3 trials of dronedarone, a novel class III antiarrhythmic agent currently in development worldwide, have demonstrated that the drug is safe and effective for the maintenance of normal sinus rhythm in patients with atrial fibrillation (AF) or atrial flutter (AFl). In the European Trial In Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS) and the American-Australian Trial With Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm (ADONIS), dronedarone administered at a dose of 400 mg twice daily was effective in preventing both symptomatic and asymptomatic recurrences of AF or AFl and had a safety profile similar to that of placebo.[1]

Dronedarone

Dronedarone (SR-33589) is one of a number of analogues that derives from the currently most successful class III antiarrhythmic drug, amiodarone. These analogues are being developed with the aim of avoiding the significant extracardiac side effects of amiodarone itself. Dronedarone is a noniodinated amiodarone derivative that inhibits transmembrane Na+, K+, Ca2+, and L-type calcium currents. Dronedarone is also an antagonist at alpha- and beta-adrenoceptors and, unlike amiodarone, has little effect at thyroid receptors.

In the phase 2b clinical trial, Dronedarone Atrial Fibrillation Study After Electrical Cardioversion (DAFNE), a dose of 800 mg/day of dronedarone was established as effective and safe for the prevention of AF relapses after cardioversion.[2] One trial in the phase 3 development program, the Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA), carried out in Europe and evaluating high-risk patients, was stopped in January 2003 after an interim safety analysis identified a potential increased risk of heart failure death in the dronedarone group.

Positive results from EURIDIS and ADONIS were first announced in February 2004 by the company developing dronedarone, Sanofi-Synthelabo (Paris, France).

Study Protocol

Patients enrolled in EURIDIS and ADONIS were men and women aged ≥ 21 years who had been in sinus rhythm for ≥ 1 hour at the time of randomization and had experienced at least 1 electrocardiogram (ECG)-documented episode of AF/AFl during the previous 3 months. After a screening period (pretrial Day 6 to Day 1), patients in both trials were randomized 2:1 (dronedarone:placebo) to receive either 400 mg twice daily of dronedarone or matching placebo twice daily for 12 months.

Of the total 1237 patients enrolled in both trials (828 randomized to dronedarone and 409 to placebo), the principal investigator for EURIDIS, Prof. Hohnloser, randomized 615 patients at 77 centers in Europe. The principal investigator for ADONIS, Bramah N Singh, MD, PhD, UCLA Medical School (Los Angeles, California), randomized 629 patients at 115 centers in Australia, North America, South Africa, and South America.

The primary endpoint of both trials, time from randomization to first documented AF/AFl occurrence, was defined as an episode lasting ≥ 10 minutes as indicated by 2 consecutive 12-lead ECGs or trans-telephonic electrocardiographic monitoring (TTEM) tracings recorded approximately 10 minutes apart, with both showing AF/AFl.

Results

Both trials showed a significant decrease in the risk of recurrence of AF/AFl (Table 1). In EURIDIS, the median time to first recurrence of AF/AFl was 2.3 times longer in the dronedarone group than in the placebo group, with a 22% lower risk of a recurrence during the study. In ADONIS, there was an almost 3-fold increase in the median time to recurrence with dronedarone and a 28% reduction in the risk of AF/AFl recurrence.

Table 1: Patients With Adjudicated First Recurrence of Atrial Fibrillation (AF)/Flutter (AFL)
Placebo Dronedarone RR 95% CI P Value*
EURIDIS
Patients with AF/AFl 155 272 0.78 0.64-0.95 .0318
Median time to relapse (days) 41 96
ADONIS
Patients with AF/AFl 146 246 0.72 0.59-0.89 .0017
Median time to relapse (days) 59 158
*Log-rank test.

There were 3 subgroups of the primary endpoint prespecified for analysis, according to whether patients had

  • Cardioversion within 5 days of randomization,

  • Prior amiodarone treatment, or

  • Structural heart disease.

All 3 subanalyses showed the benefit of dronedarone over placebo in all groups. Furthermore, fewer patients had symptomatic recurrence of AF/AFl with dronedarone in EURIDIS (P = .055) and ADONIS (P = .021).

The other secondary endpoint of both trials, mean ventricular rate during AF/AFl at first recorded recurrence (12-lead ECG or TTEM), was significantly reduced in both trials (Table 2).

Table 2: Ventricular Rate (bpm) at First Recurrence of Atrial Fibrillation
Ventricular Rate (bpm) Placebo Dronedarone P Value
EURIDIS
Mean 117.5 102.3 .0001
SD 29.1 24.7
Min-max 70-204 53-173
ADONIS
Mean 116.6 104.6 .001
SD 31.9 27.1
Min-max 56-226 57-173
bpm = beats per minute; SD = standard deviation

The incidence of adverse events was similar in the dronedarone and placebo groups (Table 3). In addition, there was no evidence of proarrhythmia in the patients receiving dronedarone; in particular, no case of torsade de pointes was reported during the 12-month follow-up period. There was also no evidence of amiodarone-related toxicities (thyroid or pulmonary).

Table 3: EURIDIS and ADONIS Pooled Tolerability and Safety Data
Incidence of Treatment-Emergent
Adverse Events (TEAEs)
Placebo
(n = 409)
Dronedarone 800 mg
(n = 828)
Any adverse events (%) 65.8 69.8
Any serious adverse events (%) 24.4 19.8
Deaths (%) 0.7 1.0
Permanent drug discontinuations following TEAE (%) 7.1 9.7
Very Important Trial, but Maybe Not a Wonder Drug

The European Society of Cardiology-designated discussant Professor Martin Han Schalij, MD, PhD, University Hospital, Leiden (The Netherlands), called the 2 dronedarone studies "very important," because new antiarrhythmic drugs are needed. Dronedarone "may not be the wonder drug we are waiting for, but it seems as effective as the other drugs," he commented. It is difficult to compare antiarrhythmic drugs, he noted, because all studies in AF have involved different patient populations.

He cautioned that the results of EURIDIS and ADONIS could be called disappointing with respect to recurrence rates (around 75% for placebo and 65% for dronedarone in EURIDIS), and especially early recurrences, but it must be remembered that the trials enrolled patients with different types of symptoms, There might be differences according to duration of symptoms and also between patients with AF and AFl.

Prof. Schalij pointed to the need for studies of dronedarone with longer follow-up. Acknowledging that no problems with the drug were recorded over 12 months, he recalled that some studies have suggested that dronedarone is an antagonist of the thyroid hormone receptor alpha-1, and experimental data have indicated that it may be associated with more side effects on lung tissue than amiodarone. These may not be of clinical importance, but they should be investigated long term, along with any ophthalmologic and liver-related side effects, he believes. Another question that remains unanswered is how safe dronedarone is in patients with depressed left ventricular ejection fraction.

Dronedarone Development Worldwide

The results of another phase 3 trial with dronedarone, the Efficacy and Safety of Dronedarone for the Control of Ventricular Rate (ERATO), in patients with AF/AFl are expected to be reported in 2005. In addition, a phase 2 study in patients with AF is ongoing in Japan.

Results of a pilot study of dronedarone in patients with an implantable cardioverter defibrillator (ICD) and an indication for adjunctive antiarrhythmic therapy were reported at the 2004 annual meeting of the Heart Rhythm Society. Dronedarone at doses < 2000 mg/day was found to be safe, did not cause deterioration in ICD function, and reduced the need for ICD therapy.

A submission dossier for marketing approval of dronedarone is under discussion with regulatory authorities in Europe and in the United States.

References
  1. Hohnloser SH. EURIDIS and ADONIS: maintenance of sinus rhythm with dronedarone in patients with atrial fibrillation or flutter. Hot Line II: Acute coronary syndromes /medical treatment II. Program and abstracts from the European Society of Cardiology Congress 2004; August 28 - September 1, 2004; Munich, Germany.

  2. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J. 2003;24:1481-1487.

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