New Drug for Atrial Arrhythmias

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 November 2007 issue of Clinical Cardiology Alert. It was edited by Michael Crawford, MD, and peer reviewed by Rakesh Mishra, MD

Synopsis: Dronedarone was significantly more effective than placebo in maintaining sinus rhythm and in reducing the ventricular rate during recurrence of arrhythmia.

Source: Singh BN, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357:987-999.

This paper gives the results of 2 trials that evaluated the effects of dronedarone, a new antiarrhythmic agent, on the recurrence of atrial fibrillation or atrial flutter. The 2 studies reported were identical placebo-controlled, double-blind, parallel-group trials, with one conducted in Europe and the other in non-European countries. The data from the 2 studies were quite similar, and in this report, only the combined data will be discussed.

Patients qualified for the studies if they were at least 21-years-old and had had at least one episode of atrial fibrillation within the preceding 3 months. Patients could be cardioverted after screening, but had to be in sinus rhythm for at least one hour before randomization. Use of class I or class III antiarrhythmic agents was not permitted. Other criteria for exclusion included class III or class IV heart failure, significant sinus bradycardia, or a PR interval of greater than 0.28 seconds. Patients with a serum creatinine level of ≥ to 1.7 mg/dL were also excluded. Most patients had previously received treatment with one or more antiarrhythmic drugs, including amiodarone in 30%. Patients were randomly assigned in a 2:1 ratio to receive either 400 mg of oral dronedarone twice daily or matching placebo. Patients were followed with periodic transtelephonic electrocardiograms both on a regular schedule and whenever they had symptoms. They were also seen frequently for electrocardiograms and blood tests. The primary end point of the trial was time from randomization to the first documented recurrence of atrial fibrillation. For the purpose of the study, a recurrence was defined as an episode lasting for at least 10 minutes, confirmed by electrocardiography or transtelephonic monitoring.

The combined trials enrolled 820 patients who received dronedarone and 409 in the placebo group. The mean age was 63 years, and 69% were male. A history of hypertension was present in 50% of the placebo patients and in 60% of the dronedarone patients. Other structural heart disease was present in approximately 40% of the patients in both groups. The mean left ventricular ejection fraction was 58% in groups. Only a small percentage of patients had a history of congestive heart failure. Most patients had failed one or more antiarrhythmic drugs.

For the 2 trials combined, the median times to a documented recurrence of atrial fibrillation were 116 days in the dronedarone group and 53 days in the placebo group. The cumulative recurrence rate at 12 months was 64.1% in the dronedarone group and 75.2% in the placebo group (hazard ratio 0.75; P less than 0.001). If recurrences in the first 5 days of treatment were excluded, the hazard ratio decreased slightly to 0.72 (P less than 0.001). As anticipated from its pharmacologic profile, dronedarone decreased heart rate by 6.8%, prolonged the QT interval by 23.4 m/sec, and prolonged the QTc interval by 9.0 m/sec. There was no change in QRS duration. Among patients with documented recurrences, dronedarone slowed the ventricular rate from 117 ± 30 bpm in the placebo group to 103 ± 26 bpm. Hospitalization or death was seen in 30.9% of the placebo group vs 22.8% of the dronedarone group, with a hazard ratio 0.73 (P = 0.01). Dronedarone was well tolerated. There was no significant increase in the incidence of any of the following adverse reactions: cough, dyspnea, bradycardia, heart failure or shock, neurologic or gastrointestinal disorders, or hepatic enzyme elevations. More patients in the placebo group than the dronedarone group developed hyperthyroidism. There was no significant difference in the incidence of hypothyroidism. Serum creatinine became elevated in 2.4% of dronedarone group vs 0.2% in the placebo group (P = 0.004).

Singh and colleagues conclude that dronedarone is an effective antiarrhythmic drug that reduces the recurrence of atrial fibrillation with a favorable side-effect profile.

Commentary

Dronedarone is an antiarrhythmic drug that is structurally similar to amiodarone and has a similar electrophysiologic profile due to effects on multiple cardiac ion channels. However, the dronedarone molecule does not contain iodine, a factor which has been linked to the thyroid and pulmonary adverse reactions observed during amiodarone therapy. In this trial, dronedarone had a modest favorable effect on the recurrence of atrial fibrillation. However, most patients in the trial had previously failed one or more antiarrhythmic drugs, and the 25% to 30% reduction in atrial fibrillation recurrence is, therefore, likely to be clinically important. It is also significant that dronedarone was quite well-tolerated. The adverse events profiles between the placebo and dronedarone groups did not differ. The trial, however, did not include patients with advanced (class III or class IV) heart failure. Patients with advanced heart failure had been previously evaluated in an earlier trial (ANDROMEDA) during which there had been a suggestion of increased mortality. Subsequent reexamination of that trial's results suggested that heart failure management had been influenced by the effect of dronedarone to raise serum creatinine, and this perhaps explained the increase in mortality in the dronedarone group. However, the effects of dronedarone on serum creatinine are not due to changes in glomerular infiltration rate, but rather to tubular secretion of creatinine, and alterations in the dosage of angiotensin converting enzyme inhibitors was probably not appropriate. Additional studies with dronedarone in older and higher-risk patient groups are now underway. If they support the safety of the drug in these later groups, dronedarone should prove an important addition to our antiarrhythmic armamentarium.