Rethinking the reasons to treat atrial fibrillation? The role of dronedarone in reducing cardiovascular hospitalizations.

The management of patients with atrial fibrillation has changed considerably over the past decade, largely because of data derived from clinical trials. Although studies comparing strategies of rate control vs. rhythm control consistently failed to demonstrate the benefit of a rhythm control strategy, to argue that rhythm control is of no value to argue with imprecision. AFFIRM, the largest of the rate vs. rhythm trials, showed, in multivariate analysis, that those patients who stayed in sinus rhythm had a reduced mortality, although this was offset by the use of antiarrhythmic drugs. In contrast, although no benefit of a rhythm control strategy was found in the AF-CHF study (in which all patients had left ventricular dysfunction and the predominant antiarrhythmic drug used was amiodarone), there was also no trend towards increased mortality with the use of antiarrhythmic therapy. Despite negative outcomes in terms of mortality, rhythm control does have some benefits. Analyses of patients who were able to maintain sinus rhythm (as opposed to being randomized to a rhythm control strategy regardless of outcome) does appear to show a benefit of rhythm control, at least in terms of quality of life. In addition, there are many patients with atrial fibrillation in whom the arrhythmia is clearly associated with unpleasant or intolerable symptoms and these patients benefit symptomatically from restoration of sinus rhythm. Antiarrhythmic drugs remain problematic, however, given their side effects and propensity for significant proarrhythmia. Until recently, clinical trials of antiarrhythmic drugs in patients with atrial fibrillation concentrated on suppression of the arrhythmia as determined by freedom from atrial fibrillation at a predetermined endpoint (usually 1 year or less) or by measuring time to first symptomatic recurrence. Data from antiarrhythmic trials that utilize daily transtelephonic monitoring and from interrogation of permanent pacemakers reveal a high prevalence of asymptomatic atrial fibrillation and demonstrate the weakness of using symptomatic arrhythmia recurrences as an endpoint. Not only does a primary endpoint of symptomatic arrhythmia recurrence fail to capture asymptomatic episodes, but the design of such trials often includes withdrawal of study drug once recurrence has been documented. If antiarrhythmic drugs are stopped at this point, it becomes difficult to address the long-term safety of these agents and precludes the use of additional potential endpoints. Mortality is a difficult sole primary endpoint in trials of atrial fibrillation, as annual mortality is relatively low and highly dependent on the cause of the arrhythmia. Nevertheless, it is a vital measurement to address. Professional societies on both sides of the Atlantic have recently considered the problems of trials of drugs in atrial fibrillation and have suggested that additional endpoints may be valuable in the assessment of these agents. These include the reduction in outcomes of atrial fibrillation such as mortality, hospitalization, and stroke, as well as economic factors such as the cost of treatment. The ATHENA trial, which compared the atrial antiarrhythmic agent dronedarone to placebo in the treatment of atrial fibrillation, was designed with these aspects in mind. Based in large part on the ATHENA results, dronedarone was approved this summer by regulatory agencies in North America and it has subsequently been released in the USA with the unique indication of reducing the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial flutter or fibrillation. The trial is named after a Greek goddess, born, fully formed, and clothed in armour, from Zeus’s head. Does this trial, the largest published antiarrhythmic study, provide new and definitive data specific to dronedarone, or are there chinks in Athena’s armour which leave the results vulnerable to interpretation? In the ATHENA trial, patients were kept on the assigned therapy (dronedarone or placebo) for at least 1 year of follow-up, regardless of whether or not atrial fibrillation recurred, and the combined endpoint consisted of a first hospitalization for a cardiovascular