LOS ANGELES -- Dronedarone, an investigational drug, proved significantly more effective than placebo in maintaining sinus rhythm and in reducing the ventricular rate during recurrent atrial fibrillation.
LOS ANGELES, Sept. 6 -- Dronedarone, an investigational drug, proved significantly more effective than placebo in maintaining sinus rhythm and in reducing the ventricular rate during recurrent atrial fibrillation.
Furthermore, patients on the drug saw no significant increase in rates of toxic effects in the lungs or of thyroid and liver dysfunction, Bramah N. Singh, M.D., D.Sc., of UCLA, and colleagues, reported in the Sept. 6 issue of the New England Journal of Medicine.
The safety assessment was an important finding, the researchers said, because dronedarone, pharmacologically related to amiodarone (Cordarone), was developed to reduce amiodarone's adverse effects on pulmonary, kidney, liver, and thyroid function.
The pooled findings came from two identical multicenter, double-blind, randomized trials, one conducted in Europe and one in the U.S., Canada, Australia, South Africa, and Argentina.
Among the 1,237 patients enrolled in the study, 828 received 400 mg of dronedarone twice daily and 409 received placebo.
Patients had had at least one episode of atrial fibrillation within the preceding three months and were in sinus rhythm when they first started taking the drug.
Rhythm was monitored trans-telephonically on days two, three, and five and at three, five, seven, and 10 months, during recurrence of arrhythmia, and at nine scheduled visits during a 12-month period.
The primary end point was the time to the first recurrence of atrial fibrillation or flutter.
With pooled data from the two trials, the median time to the recurrence of atrial fibrillation was 116 days in the dronedarone group and 53 days in the placebo group, the researchers reported.
In the European trial, the median times to recurrence were 41 days in the placebo group and 96 days in the dronedarone group (P=0.01). The corresponding durations in the non-European trial were 59 and 158 days (P=0.002).
At the recurrence of arrhythmia in the European trial, the mean ventricular rate was 117.5 beats per minute in the placebo group and 102.3 beats per minute in the dronedarone group (P<0.001). The corresponding rates in the non-European trial were 116.6 and 104.6 beats per minute (P<0.001).
Rates of pulmonary toxic effects and of thyroid and liver dysfunction were not significantly increased in the dronedarone group in either study, the researchers reported.
However, they noted, the rate of elevated serum creatinine levels was higher in the dronedarone patients than in the placebo patients (2.4% versus 0.2%, P=0.004).
In both trials, dronedarone prolonged the time to recurrence of atrial fibrillation by a factor of more than two, compared with placebo.
This finding, the researchers said, is consistent with the drug's propensity for markedly prolonging the atrial effective refractory period by inducing multiple ion-channel blockade.
However, they said, the effectiveness of dronedarone in maintaining sinus rhythm cannot be reliably compared with that of amiodarone on the basis of these data. These were placebo-controlled trials and in neither of the trials were dronedarone and amiodarone compared.
Therefore, they wrote, they could not be certain that the efficacy of dronedarone is similar to that of amiodarone, nor could they state with certainty that the rate of adverse events is significantly lower.
In addition, the low rate of adverse events, especially pulmonary toxic effects, may be explained in part by the short duration of the trials and by the fact that chest radiography and assessment of pulmonary function were not done unless symptoms were present.
A previous antiarrhythmic dronedarone study, the Andromeda trial, was discontinued early because an interim safety analysis suggested a potential increase in the risk of death with the drug.
The discontinued trial involved patients with moderate-to-severe congestive heart failure, a different and high-risk group excluded from these trials. Nonetheless, the researchers said, dronedarone should not be used in such patients until appropriate data are gathered.
In conclusion, the researchers said, despite the effectiveness of dronedarone in reducing the first recurrence of atrial fibrillation and the first symptomatic recurrence at one year, the available data are not directive with respect to the rates of adverse effects, as compared with amiodarone.
In an accompanying editorial, Michael Ezekowitz, M.B., Ch.B., of Lankenau Institute for Medical Research in Wynnewood, Pa., noted the limitation imposed by the comparison with placebo rather than with amiodarone. However, he said, the studies were consistent with FDA practice, since amiodarone is not approved for the management of atrial fibrillation.
He also pointed out that "the shorter half-life of dronedarone, as compared with that of amiodarone, may have beneficial consequences in terms of late toxic effects."
However, he noted, such a benefit would have to be proven in other studies and with longer follow-up.
The management of atrial fibrillation includes a multimechanism approach, which targets electrophysiological mechanisms simultaneously, and has proved to be effective for both amiodarone and dronedarone.
An alternative strategy is the single-mechanism method, using various types of channel blockers.
"My bet," Dr. Ezekowitz wrote, "is on the multimechanism approach. Singh and his colleagues may have signaled that the best is yet to come."
Dr. Singh reported receiving consulting and lecture fees from CV Therapeutics, Sanofi-Aventis, GlaxoSmithKline, Astellas, and Procter & Gamble Pharmaceuticals. Other authors reported various fees and support from Sanofi-Aventis, St. Jude Medical, Boehringer Ingelheim, Procter & Gamble Pharmaceuticals, and Solvay Pharmaceuticals, AstraZeneca, Cardiome, and Meda Pharma, Astellas, the Canadian Institutes of Health Research, Reliant, Pfizer, and Sorin-Ela. David Radzik, M.D., reported being employed by Sanofi-Aventis and having equity interest in the company No other potential conflict of interest relevant to this article was reported.
Dr. Ezekowitz, the editorial writer, reported receiving consulting fees from Sanofi-Aventis, Pfizer, Wyeth, Johnson & Johnson, Boehringer Ingelheim, Schering-Plough, and Aryx Therapeutics, lecture fees from Pfizer, Boehringer Ingelheim, and Astellas Pharma, and grant support from Boehringer Ingelheim and Aryx Therapeutics. No other potential conflict of interest relevant to this article was reported.