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Azimilide—CardiOversion MaintenancE Trial–I - A-COMET-I
Description:
The goal of the trial was to evaluate treatment with azimilide compared with placebo on arrhythmia recurrence in patients with structural heart disease who had atrial fibrillation (AF) converted to sinus rhythm.
Study Design
Study Design:
Patients Enrolled: 446
Mean Follow Up: 6 months
Mean Patient Age: Mean age 65 years
Female: 33
Patient Populations:
Age ≥18 years, history of documented symptomatic AF present for >48 hours and <6 months="" months="">
Exclusions:
Systolic blood pressure of >180 mm Hg or diastolic blood pressure of >100 mm Hg; ventricular rate of <70 bpm;="" corrected="" qt="" interval="" of="">440; AF due to electrolyte imbalance, hyperthyroidism, pericarditis, or other reversible illness; unstable angina; class IV heart failure; Wolff-Parkinson-White syndrome unless treated with successful ablation; moderate or severe hypertrophic, restrictive, or infiltrative heart disease; severe valvular heart disease; single-chamber or DVI pacemaker; implanted defibrillator; a history of syncope or angina precipitated by an arrhythmia; a history of torsades de pointes, any polymorphic ventricular tachycardia, sustained monomorphic ventricular tachycardia, or cardiac arrest; a history of failed electric cardioversion; a history of second- or third-degree atrioventricular block unless a pacemaker had since been implanted; a history of myocardial infarction, cardiac surgery, thoracic surgery, stroke, or reversible ischemic neurologic deficit within the prior 1 month; a history of treatment with ticlopidine or clopidogrel within the prior 1 month; history or family history of prolonged QT syndrome; failed efficacy of any class III antiarrhythmic drug
Primary Endpoints:
Recurrence of AF, restricted to the population with structural heart disease (n = 314)
Drug/Procedures Used:
Patients were randomized to azimilide (125 mg twice daily for 1-3 days, then once daily for 6 months; n = 227) or placebo (n = 219). Patients not in sinus rhythm by days 4-6 underwent electric cardioversion. If sinus was not restored, patients were withdrawn from the study.
Principal Findings:
At baseline, the majority of patients had been in AF for >27 days (72%). Structural heart disease was present in 70% of patients, 41% had a history of prior electric conversion, and 20% had cardiomyopathy. Sinus was not restored with electric conversion in 25 patients in each group.
The primary endpoint of arrhythmia recurrence in patients with structural heart disease did not differ between treatment groups (hazard ratio [HR], 1.104; p = 0.46), with a median time to recurrence of 13 days in each group. Likewise, there was no difference in arrhythmia recurrence in the entire intent-to-treat cohort (HR, 1.092; p = 0.43) or in patients with structural heart disease who were in sinus rhythm on day 4 (HR, 1.133; p = 0.43).
There were 3 deaths due to cardiac arrhythmia in the azimilide group and 1 death due to noncardiovascular causes in the placebo group. Serious adverse events occurred in 16.3% of the azimilide group and 7.3% of the placebo group. Torsades de pointes occurred in 2.6% (n = 6) of patients in the azimilide group.
Interpretation:
Among patients with structural heart disease who had AF converted to sinus rhythm, treatment with azimilide was not associated with a difference in the primary endpoint of arrhythmia recurrence through 6 months compared with placebo.
In addition to showing no effect on arrhythmia recurrence, azimilide was associated with a small but substantial number of cases of torsades de pointes. Prior studies have shown mixed results with azimilide in AF, but the most promising subgroup was in patients with structural heart disease, which is why this cohort was selected as the primary efficacy population for the current trial. No efficacy signal was observed in those with structural heart disease, those who had converted to sinus rhythm spontaneously by day 4, or in the entire intent-to-treat population.
References:
Pritchett EL, Kowey P, Connolly S, Page RL, Kerr C, Wilkinson WE. Antiarrhythmic efficacy of azimilide in patients with atrial fibrillation. Maintenance of sinus rhythm after conversion to sinus rhythm. Am Heart J 2006;151:1043-9.
Keywords: Imidazolidines, Cardiomyopathies, Electric Countershock, Piperazines, Torsades de Pointes
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