Encouraging results from the Phase III ATHENA trial of dronedarone for the treatment of atrial fibrillation have been published in the New England Journal of Medicine (N. Engl. J. Med. 360, 668–678; 2009). This study follows trials that demonstrated the efficacy of dronedarone — a derivative of the older atrial fibrillation drug amiodarone — in maintaining sinus rhythm and controlling ventricular rate during recurrences of atrial fibrillation. Based on these results, Sanofi–Aventis has submitted a new drug application to the US FDA, which was due to consider the drug at an advisory committee meeting in mid-March.

Atrial fibrillation is the most common type of cardiac arrhythmia, and is a common cause of stroke and heart failure. Currently, there is a major unmet need for drugs that are capable of successfully controlling the arrhythmia, and the prevalence of disease-associated hospitalizations and death continues to increase.

Safety concerns are the major limitation of the current therapy for sinus rhythm maintenance in patients with atrial fibrillation. These concerns relate to both limited tolerability and, less frequently but more disturbingly, potentially lethal proarrhythmia, explains Stanley Nattel, Paul–David Chair in Cardiovascular Electrophysiology, University of Montreal, Canada (Nature Rev. Drug Discov. 5, 1034–1049; 2006). Indeed, the “...risk of such fatal complications poses a significant challenge to the development of novel agents,” says Richard Page, Head of Cardiology, University of Washington School of Medicine, USA (Nature Rev. Drug Discov. 4, 899–910; 2005), who was one of the investigators involved in the trial. “With this in mind, the safety of any new drug must be demonstrated in a large trial in typical atrial fibrillation patients, as is the case with ATHENA,” he adds.

ATHENA was therefore designed to evaluate the efficacy and safety of dronedarone in patients with atrial fibrillation who had additional cardiovascular risk factors for death, including old age, hypertension, diabetes or the previous occurrence of an ischaemic cerebrovascular event. The primary end point of the trial, which involved ∼4,600 patients, was a reduction in the rate of hospitalization due to cardiovascular events or a reduction in death from any cause. Compared with placebo, dronedarone reduced the risk of first cardiovascular hospitalization and/or death by 24%. Several secondary end points were also met; for example, there was a 29% reduction in cardiovascular death.

“This is the first trial of an antiarrhythmic drug of which I am aware that showed a statistically significant difference in a hard primary end point. The drug was also associated with interesting reductions in hospital admissions due to acute coronary syndromes and in deaths due to cardiac arrhythmias — again firsts to my knowledge for an anti-atrial fibrillation drug,” notes Nattel. “Although dronedarone did cause a significantly larger number of minor side effects than placebo, such as diarrhoea and rash, the most worrisome side effects of its parent compound, amiodarone, including thyroid dysfunction and pulmonary complication, were not seen,” he adds.

“The major message is that dronedarone is a safe antiarrhythmic medication for atrial fibrillation in most patients. In this way, the drug is unique, and will likely become first-line therapy for most patients if approved,” concludes Page. However, as Nattel notes, “...definition of the precise place of dronedarone in the atrial fibrillation armamentarium awaits controlled comparison trials against other antiarrhythmic agents.”