Title of Trial
Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators

Date and Citation of Primary Publication(s) or References
Roy D. Talajic M. Dorian P. Connolly S. Eisenberg MJ. Green M. Kus T. Lambert J. Dubuc M. Gagne P. Nattel S. Thibault B. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. New England Journal of Medicine. 342(13):913-20, 2000 Mar 30

Purpose of the Trial
The purpose of this study was to compare the efficacy of low dose amiodarone compared to sotalol or propafenone in preventing recurrences of atrial fibrillation

Study Category
Atrial Fibrillation. Multicenter, randomized controlled trial.

Patient Population
Patient from 19 cardiology centers in Canada

Inclusion Criteria
To be eligible for enrollment in this study patients must have had an episode of symptomatic atrial fibrillation in the preceding six months. Long-term antiarrhythmic therapy must have been planned. ECG conformation of an episode was required, and at least one of the episodes had to have lasted at least 10 minutes, by history.

Exclusion Criteria
Patients were excluded from the trial if they fulfilled any of the following criteria: atrial fibrillation present for 6 continuous months, an MI in the past 6 months, cardiac surgery in the prior 30 days, NYHA class III or IV CHF, atrial fibrillation secondary to an acute or reversible cause, serum creatinine > 2.8, ALT>2.5 times normal, chronic lung disease, WPW syndrome, prior therapy or intolerance of amiodarone, sotalol or propafenone, untreated hypothyroidism, prolonged QTc, resting heart rate<50bpm, 2nd or 3rd degree AV block or sinus pauses without a pacemaker, age<18, need for antiarrhythmic therapy for a rhythm other than atrial fibrillation, expected survival<1 year, pre-menopausal state without hysterectomy or tubal ligation.

Study Design
All patients with atrial fibrillation duration of more than 48 hours were anticoagulated to achieve a goal INR of greater than 2 for 3 weeks prior to randomization. Patients were randomized in an open label fashion to two groups, the first received amiodarone and the second either propafenone or sotalol. Patients assigned to sotalol or propafenone were further randomized to determine which drug they would receive first. Electrical Cardioversion was performed 21 days after randomization in both groups if, after the loading period of all drugs (14 days in the amiodarone group, and 4 days in the propafenone/sotalol arm), atrial fibrillation persisted. If the cardioversion was unsuccessful, patients in the sotalol/propafenone arm were tried on the agent to which they were not randomized initially and cardioversion was reattempted. Amiodarone was given in a standard loading fashion with a maintenance dose of 200 mg a day. Sotalol was given based on creatinine clearance, with doses ranging between 160 mg and 80 mg twice a day. Propafenone was administered based on age and weight, in doses between 300 mg twice a day to 150 mg three times a day. Patients were seen in follow up at 21 days, 3 months and every six months thereafter. Patients transmitted ECG’s by phone initially on days 7 and 14 following randomization and whenever cardiac symptoms occurred. Chest x-rays, liver function tests and thyroid function was followed in those on amiodarone.

Primary Endpoints
The primary endpoint of the study was the length of time to the first ECG documented episode of atrial fibrillation that lasted for more than 10 minutes. Day 21 served as the beginning of follow up, and patients who required cardioversion at that point were classified as having a recurrence.

Secondary Endpoints
Secondary endpoints included adverse effects of the study medications, thromboembolic events, and death.

Baseline Characteristics

	Amiodarone (N=201)	Sotalol/Propafenone (N=202)	P value
Male (%)	55	56	0.81
Age (%)	65	65	0.68
CAD (%)	19	18	0.68
Valvular Disease (%)	14	13	0.76
HTN (%)	44	48	0.45
Paroxysmal Afib (%)	49	43	0.25
Persistent Afib (%)	51	57	0.25
LVH (%)	13	21	0.04
LVEF < 50%, (%)	12	12	0.85

Time to Follow-Up

403 patients were enrolled and 10 patients were lost to follow-up. The mean follow up period was 468+150 days.

Results
After follow-up,71 patients (35%) of the patients assigned to amiodarone had a recurrence of atrial fibrillation compared to 127 (63%) in the sotalol/propafenone group (p<0.001). The calculated probability of remaining in sinus rhythm after one year with amiodarone was 69% compared to 39% in the sotalol/propafenone group (p<0.001). There was no significant difference between sotalol and propafenone in prevention of atrial fibrillation. 8 percent of patients taking amiodarone discontinued the drug because of lack of efficacy compared to 28% of patients in the sotalol/propafenone group (p<0.001). 18 percent of patients assigned to amiodarone discontinued the drug because of adverse effects compared to 11 percent in the sotalol/propafenone group (p=0.06).

Sponsor
Medical Research Council of Canada

Trial Status: Completed

Review written by: Jonathan Weinstock, MD