Dronedarone: New and Improved Amiodarone?
Dronedarone: New and Improved Amiodarone?
Abstract & Commentary
By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco is a consultant for Novartis and does research for Medtronic and Guidant. This article originally appeared in the April 2009 issue of Clinical Cardiology Alert. It was edited by Michael H. Crawford, MD, and peer reviewed by Ethan J. Weiss, MD.
Source: Hohnloser SH. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360: 668-678.
Dronedarone is a new antiarrhythmic drug with structural similarities to amiodarone. During development of the molecule, the steps included removal of the iodine atoms and making the compound more lipophilic; the latter produces a shorter elimination half-life and reduced tissue accumulation. The primary goal was to reduce the risk for organ toxicity, especially thyroid, pulmonary, and hepatic adverse events. The ATHENA trial was a placebo-controlled study designed to determine whether dronedarone would reduce cardiovascular hospitalizations and deaths in patients with atrial fibrillation.
Initially, patients were eligible for inclusion in the trial if they had a history of paroxysmal or persistent atrial fibrillation and were either at least 70 years old or younger but had a risk factor for stroke or death. Subsequently, however, the entry criteria were modified such that patients between 70 and 75 years of age had to have at least one additional risk factor. Patients older than 75 continued to be eligible even if they had no additional risks. Patients younger than age 70 were no longer eligible. Patients were excluded from the study if they had permanent atrial fibrillation, a recent episode of decompensated heart failure or current New York Heart Association class IV symptoms, acute myocarditis, or significant bradycardia. Patients could be either in sinus rhythm at the time of enrollment or have a cardioversion planned. The primary study outcome was a composite endpoint that included a first hospitalization due to a cardiovascular event or death from any cause. Unplanned hospitalizations were classified as cardiac or non-cardiac in a blinded fashion by an events committee. Secondary study outcomes were death from any cause, death from cardiovascular cause, and first hospitalization due to a cardiovascular event.
ATHENA enrolled 4,620 patients; 2,301 in the dronedarone group and 2,327 in the placebo group. The mean age was 71.6 years, and 47% of the patients were women. Hypertension was the predominant underlying cardiovascular disease seen in 87% of the patients. Although 21% of the patients had a history of New York Heart Association class II or III heart failure, only 11.9% and 3.9% of the patients had a left-ventricular ejection fraction below 45% or 35%, respectively.
The median duration of follow-up was 22 months. Dronedarone was superior to placebo in terms of the primary outcome event. Among patients who received dronedarone, 675 patients (29.3%) had their first cardiovascular hospitalization and 59 (2.6%) patients died without prior hospitalization. In the placebo group, there were 859 (36.9%) first cardiovascular hospitalizations and 58 deaths before hospitalization (2.5%). The hazard ratio (HR) for the composite primary outcome was 0.76 (95% confidence interval [CI] 0.69 to 0.84; p < 0.001). Subgroup analysis showed a consistent beneficial effect of dronedarone across several important subgroups. Analysis of the secondary endpoints also favored dronedarone. There was a trend toward reduced total mortality in the dronedarone group, with 116 (5%) deaths in that group compared to 139 (6.0%) in the placebo group (HR 0.84, p = 0.18). Cardiovascular deaths were significantly reduced.
In the dronedarone group, there were 63 cardiovascular deaths (2.7%), compared to 90 cardiovascular deaths in the placebo group (HR 0.71, 95% CI, 0.51 to 0.98; p = 0.03). There were no significant differences between the groups in deaths resulting from cardiac arrhythmia. Atrial fibrillation recurrence was not an endpoint, but the reduction in cardiovascular hospitalization was driven mainly by a reduction in the number of hospitalizations for atrial fibrillation. There were 510 hospitalizations for atrial fibrillation in the placebo group vs. 335 (14.6%) in the dronedarone group. (HR 0.63, p < 0.001). There were no significant differences between the groups in number of hospitalizations for heart failure, syncope, or ventricular arrhythmias. There was a small decrease in the number of hospitalizations for acute coronary syndrome, with 62 (2.7%) in the dronedarone group and 89 (3.8%) in the placebo group (HR = 0.70; p = 0.03). Premature discontinuation of the study drug was observed in 30.2% of the patient receiving dronedarone compared to 30.8% of those receiving placebo. Presumed adverse events leading to discontinuation were seen in 12.7% of the patients in the dronedarone group vs. 8.1% in the placebo group. The most common significant adverse events observed with increased frequency in the dronedarone group were bradycardia, QT interval prolongation, gastrointestinal events, rash, and serum creatinine increase. There was no difference in the frequency of respiratory events, abnormal liver function tests, or thyroid dysfunction between the two groups. One case of polymorphic ventricular tachycardia with a long QT interval was observed in a 66-year-old woman on dronedarone during recovery from a previous out-of-hospital cardiac arrest. No other cases of torsades de pointes were documented.
Hohnloser et al concluded that dronedarone is associated with a significant reduction in the rate of hospitalization due to cardiovascular events or death, with a favorable side effect profile.
The criteria used to evaluate the efficacy of antiarrhythmic drugs in patients with atrial fibrillation need to be specific for the patient population studied. Among patients with frequent and highly symptomatic paroxysmal atrial fibrillation, changes in symptoms scores, the frequency and duration of episodes, and the need for hospitalizations are the primary useful measures. Among older patients with less frequent or less symptomatic episodes of atrial fibrillation, cardiovascular hospitalization, stroke, and death are more meaningful outcomes to measure. The ATHENA trial was the first really large study to use these new standards. In contrast to most prior antiarrhythmic drug studies, which have typically involved only several hundred patients, ATHENA included more than 4,600 subjects. The study did not really attempt to document recurrent atrial fibrillation, but rather focused on hospitalizations, many, but not all, of which were due to recurrent arrhythmia and death. Since dronedarone has effects to both prevent recurrent atrial fibrillation and also improve heart rate control during recurrent atrial fibrillation, this trial design highlights the benefits of a drug with more than one potentially beneficial activity.
It's important to note that patients with severe systolic heart failure were not included in ATHENA. Only a small number of patients had depressed left ventricular ejection fractions, and patients with recent or current decompensated heart failure were excluded. Another study of dronedarone, the ANDROMEDA trial, enrolled patients soon after a hospitalization for decompensated heart failure. In ADROMEDA, dronedarone was associated with increased mortality in the early phases, and the study was stopped by its Data Safety Monitoring Board. It has been hypothesized that some of this effect may have been due to reductions or discontinuation of ACE inhibitors or angiotensin receptor blockers in response to an early rise in serum creatinine after dronedarone was started. Investigators in ATHENA were aware that dronedarone can increase serum creatinine values without affecting the glomerular filtration rate and were instructed not to change therapy for minor creatinine elevations. However, the safety of dronedarone in patients with advanced heart failure with left-ventricular systolic dysfunction remains uncertain, and further data are needed before dronedarone can be recommended for use in such patients.Dronedarone is a new antiarrhythmic drug with structural similarities to amiodarone. During development of the molecule, the steps included removal of the iodine atoms and making the compound more lipophilic; the latter produces a shorter elimination half-life and reduced tissue accumulation.
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