Sanofi-aventis reported the results of the Dionysos trial, evaluating the efficacy and safety of dronedarone versus amiodarone for the maintenance of sinus rhythm in 504 patients with persistent Atrial Fibrillation (AF) for a short treatment duration (mean follow up of seven months).
Unsurprisingly, dronedarone showed a decrease of safety events vs amiodarone but more occurrences of the composite primary endpoint (AF recurrence or premature drug discontinuation for intolerance or lack of efficacy).
There were 184 patients (73.9%) who reached the primary endpoint in the dronedarone arm as compared to 141 (55.3%) in the amiodarone arm (p<0.001). In the primary endpoint, atrial fibrillation after electrical cardioversion occurred in 36.5% of patients in the dronedarone arm vs. 24.3% of patients in the amiodarone arm. Patients on amiodarone tended to experience more premature drug discontinuation (34 vs. 26) than patients on dronedarone. The DIONYSOS trial also showed a decrease of 20% favouring dronedarone vs. amiodarone (83 vs. 107, p=0.1291) in the predefined main safety endpoint.
The predefined main safety endpoint included thyroid, hepatic, pulmonary, neurological, skin, ocular, and gastrointestinal adverse events as well as premature study drug discontinuation due to any adverse event. In the dronedarone arm less thyroid events (2 vs. 15), neurological events (3 vs. 17) and premature study drug discontinuation due to any adverse events (13 vs 28) was observed. In contrast, gastrointestinal events (diarrhea, vomiting, nausea) were more frequent in the dronedarone arm (32 vs 13), consistent with previously reported studies.
When excluding GI side effects from the main safety endpoint, as also predefined in the protocol, there was a statistically significant decrease of 39% favouring dronedarone (61 vs. 99 / p=0.0021). Less bradycardia (8 vs. 22) and less pronounced QTc prolongation (27 vs. 52) was seen in the dronedarone arm than the amiodarone arm and no torsades de pointes were reported in the study.
"These results are as expected. Amiodarone - more effective on ECG atrial fibrillation recurrence but at high cost of organ toxicity over the long term - should remain the antiarrhythmic treatment of last resort in all patients other than those with severe heart failure," said Pr John Camm, St George's University of London.
While the Dionysos study was not designed to assess cardiovascular morbidity or mortality which was evaluated with long term treatment with dronedarone in the landmark ATHENA trial, there were less deaths reported in the dronedarone arm than in the amiodarone arm during the treatment period.
The Dionysos study detailed results will be submitted to regulatory authorities, as planned. Detailed results will also be presented in a scientific congress in 2009.
Dronedarone (Multaq) is an investigational treatment and the only Anti-Arrhythmic Drug (AAD) to have shown a significant reduction in morbidity and mortality in AF/AFL patients with a favourable safety profile as evidenced by a low incidence of pro-arrhythmia (including torsades de pointes) and extra-cardiac organ toxicity.
The Dionysos trial is a short term, randomized double blind parallel group study comparing the efficacy and safety of dronedarone (400mg BID) versus amiodarone (600mg loading dose daily for 28 days, then 200mg daily thereafter) in 504 patients with documented atrial fibrillation for more than 72 hours for whom cardioversion and antiarrhythmic treatment were indicated in the opinion of the investigator and receiving anticoagulants.