Dronedarone: A New Antiarrhythmic Drug
Dronedarone: A New Antiarrhythmic Drug
Abstract & Commentary
By John P. DiMarco, MD, PhD
Source: Kober L, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358: 2678-2687.
Dronedarone is a new multichannel blocking agent with electrophysiologic properties similar to those of amiodarone that is under development for the treatment of atrial arrhythmias. In this multicenter study, Kober et al tested the hypothesis that treatment with dronedarone would reduce the combined endpoint of hospitalization due to heart failure and all-cause mortality in patients with a recent hospitalization for symptomatic heart failure. The trial was conducted at 72 hospitals in Europe. Kober et al screened patients hospitalized for new or worsening heart failure for inclusion into the trial. Left ventricular function was assessed using an echocardiogram, and patients with a wall motion index of less than 1.2 (equivalent to a LV ejection fraction of less than 35%) were eligible for inclusion. Patients were randomized to receive either placebo or oral dronedarone, 400 mg twice daily. The primary endpoints for the study were death from any cause or hospitalization for worsening heart failure. Secondary endpoints included death from all causes, hospitalization for cardiovascular causes, or worsening heart failure, occurrence of atrial fibrillation or flutter, death from arrhythmia, or sudden death. A treatment blinded critical events committee classified all deaths and hospitalizations.
The study originally was designed to include 1,000 patients who would be followed for a minimum of one year. However, the study was terminated prematurely seven months after initiation because of an excess of deaths in the treatment group.
At the time the study was terminated, 627 patients had been entered into the trial. Baseline characteristics in the dronedarone group and the placebo group were well matched. The median age was 71 years. Ischemic heart disease was the most common diagnosis. A history of atrial fibrillation or flutter was noted in 38% of the patients, and 25% had atrial fibrillation at randomization. At randomization, about 40% were New York Heart Association functional class II, 56% New York Heart Association functional class III, and 3% New York Heart Association functional class IV.
Seven months after the first patient was enrolled, the trial was discontinued for safety reasons on the recommendations of the Data and Safety Monitoring Board. During the double-blind, randomized study, there were 25 deaths in the dronedarone group as compared to only 12 deaths in the placebo group (hazard ratio, 2.13; 95% confidence interval, 1.07 to 4.25, p = 0.03). The excessive deaths were largely attributable to deaths due to worsening heart failure, with 10 such deaths in dronedarone group compared to only two in the placebo group. Subgroup analysis showed that the risk of death was increased among patients with lower wall motion indices and with poorer renal function. At the time the study was stopped, there was no significant difference in the primary endpoint of all-cause mortality or hospitalization for worsening heart failure. There were 53 events in the dronedarone group vs 40 events in the placebo group (hazard ratio 1.38; p = 0.12). However, there were more first hospitalizations for acute cardiovascular cause in the dronedarone group (71) than in the placebo group (50), (p = 0.02). There were no significant differences in other adverse events except for more frequent increases in serum creatinine in the dronedarone group.
Kober et al concluded that dronedarone should not be used in patients with heart failure and reduced left ventricular systolic function.
Dronedarone is a multichannel-blocking antiarrhythmic drug with structural similarities to amiodarone. It was developed for the treatment of atrial fibrillation, and there is relatively little experience in its use for treating ventricular arrhythmias. In this study, the ANDROMEDA trial, Kober et al tested the hypothesis that dronedarone therapy would decrease all-cause mortality and heart failure hospitalizations in patients with a recent hospitalization for heart failure and reduced left ventricular systolic function. The trial was stopped after only seven months when an excess of deaths were noted in the dronedarone group. The reasons for this are uncertain. The excess deaths were due mostly to deaths caused by worsening heart failure. The mechanism responsible for this has not been determined. Dronedarone has not previously been shown clinically, or in limited preclinical testing, to have adverse effects on left ventricular function. Dronedarone, however, does block renal secretion of creatinine and, therefore, can raise serum creatinine concentrations even though it does not lower glomerular filtration rates. This was not appreciated at the time ANDROMEDA was conducted, and some investigators have speculated that decreases in dosage or discontinuation of ACE inhibitors or angiotensin receptor blocker agents in reaction to the changes in creatinine may have contributed to the excess mortality seen in this trial.
Recently, preliminary data from another study with dronedarone, ATHENA, have been presented. In the latter trial, elderly patients with atrial fibrillation were treated either with dronedarone or placebo. Investigators were cautioned not to change necessary therapy with ACE inhibitors or angiotensin receptor blockers. In ATHENA, decreases in both mortality and cardiovascular hospitalizations were noted. Although the patients in ATHENA were elderly and would be considered moderately high-risk atrial fibrillation patients, only a minor fraction had advanced heart failure. However, ATHENA enrolled more than 4,000 patients and followed them for an average of almost two years, so the experience in patients with heart failure in that study was not small.
It is likely that dronedarone will be reviewed by regulatory agencies in the United States and Europe within the next year. I anticipate that labeling for use in patients with advanced heart failure will be restricted pending data from future trials focusing on patients with heart failure or ventricular arrhythmias.Dronedarone is a new multichannel blocking agent with electrophysiologic properties similar to those of amiodarone that is under development for the treatment of atrial arrhythmias.
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