Cardiac Electrophysiology Review 2000;4:137–138©C 2000 Kluwer Academic Publishers. Manufactured in The Netherlands.

Clinical Implications of the Canadian Trial of AtrialFibrillation (CTAF)

Denis RoyMontreal Heart Institute, Montreal, Quebec, Canada

Introduction and Background

Atrial fibrillation is the most common sustainedarrhythmia requiring therapy. It is present inmore than 5% of the population older than 65 yearsand is associated with a 5% annual risk of strokeand a doubling of all-cause mortality [1]. Mainte-nance of sinus rhythm is a desirable goal in thetreatment of atrial fibrillation because it can im-prove cardiac function, relieve symptoms and maylessen the risk of thromboembolic events. How-ever, antiarrhythmic drug therapy is often inef-fective. Uncontrolled studies have suggested thatlow-dose amiodarone may be more effective andsafer than conventional drug therapy [2]. TheCanadian Trial of Atrial Fibrillation (CTAF) wasdesigned to test the hypothesis that low-dose amio-darone would reduce the incidence of recurrentatrial fibrillation when compared to the two com-monly used drugs [3]. The preliminary results werepresented at the 48th Annual Session of the Amer-ican College of Cardiology in March 1999.

Patients, Methods and Design

CTAF was a multicenter, randomized trial conduc-ted in 19 Cardiology centers throughout Canada.To be eligible, patients had to have a recent(<6 months) episode of symptomatic atrial fibril-lation for which chronic antiarrhythmic drug ther-apy was planned. Atrial fibrillation had to be docu-mented at least once by EKG and have a durationof 10 minutes. Of the 403 patients enrolled, 201were assigned to amiodarone (10 mg/kg/day for 14days, 300 mg/day for 4 weeks, maintenance dose of200 mg/day) and 202 to conventional therapy (101to sotalol and 101 to propafenone). Twenty-onedays were given to load the patient with the cho-sen therapy, adjust the dosage, and proceed to car-dioversion if necessary. All patients had a follow-up of 1 year and were given a transtelephonic ECGevent recorder. The primary endpoint was time tofirst ECG-documented recurrence of atrial fibril-lation. Analysis was by intention to treat.

Results

After a mean follow-up of 16 months, 35% of pa-tients randomized to amiodarone had recurrence

of atrial fibrillation compared to 63% of those ran-domized to either sotalol or propafenone. TheKaplan-Meier rates for maintaining sinus rhythmat 1 year were 69% for amiodarone and 39% for theconventional group (p < 0.0001). The Cox hazardsratio was 0.43 (95% conventional interval, 0.32 to0.57) reflecting a 57% risk reduction with amio-darone. Major clinical events noted during follow-up were 17 deaths, 9 in the amiodarone group and8 in the conventional group. Adverse events re-quiring study medication discontinuation occurredin 37 (18%) of amiodarone patients and in 23 (11%)of patients in the conventional group (p = 0.06).

Clinical Implications

This trial clearly shows that low-dose amiodaroneis more effective than other antiarrhythmic drugsat maintaining sinus in patients with paroxys-mal or persistent atrial fibrillation. The CTAF re-sults suggest that amiodarone should be consid-ered early on for the pharmacological treatmentof patients with recurrent and symptomatic atrialfibrillation. Because of its recognized cardiovas-cular safety [4], amiodarone should probably bea drug of first choice in patients with atrial fib-rillation and structural heart disease. In CTAF,most patients assigned to amiodarone were stillreceiving the drug at 1 year (72% as comparedto 58% in the conventional group). However, thelong-term effectiveness, side effects and compli-ance were not assessed. The potential for serious,late adverse effects with low-dose amiodarone re-mains uncertain.

Recommendations for AntiarrhythmicDrug Therapy in Atrial Fibrillation

Antiarrhythmic drug therapy remains the primarytreatment to prevent recurrences of atrial fibrilla-tion. The decision to maintain sinus rhythm andinitiate drug therapy should be individualized,taking into account symptoms, frequency, andseverity of recurrences. Occasional recurrence of

Address correspondence to: Denis Roy, M.D., Montreal HeartInstitute, 5000 Belanger Street, Montreal, Quebec, Canada,H1T 1C8. E-mail: roy@icm.umontreal.ca

137

138 Roy CEPR 2000; Vol. 4, No. 2

100

80

60

40

20

0

Time (days)

Amiodarone (n=201)

Sotalol/Propafenone (n=202)

p < 0.001

6005004003002001000

Hazard ratio (Cox)0.43 (0.32-0.57)

Pat

ient

s w

ithou

t re

curr

ence

of a

tria

l fib

rilla

tion

(%)

Fig. 1. Kaplan-Meier estimates of the percentage of patients free of recurrence of atrial fibrillation (Reprinted fromDenis Roy, MD, New Engl J Med 2000;342: 913–920).

well-tolerated atrial fibrillation should not be nec-essarily considered failure of drug therapy. It isimportant to emphasize that currently there isno proof that maintaining sinus rhythm with an-tiarrhythmic drugs improves survival or decreasesthromboembolic risk. The ongoing Atrial Fibril-lation Follow-up Investigation of Rhythm Man-agement (AFFIRM) study of the National Heart,Lung, and Blood Institute is addressing thisissue.

Class I: NoneClass IIa: Amiodarone therapy is probably

the drug of choice post-cardioversionand for maintaining sinus rhythmin patients with ischemic heartdisease, left ventricular dysfunctionand symptomatic atrial fibrillation.

Class IIb: Amiodarone in low doses (200 mg/dayor less) may be indicated either asfirst-line antiarrhythmic therapy orif other drugs are ineffective, insymptomatic patients with mild orno underlying heart disease. Itshould probably be considered beforeatrioventricular node ablation andpacemaker implantation.

Conclusion

CTAF is the first large scale randomized trial toshow that amiodarone is more effective than otherdrugs for atrial fibrillation. The results challengethe notion that amiodarone should be reservedonly for drug-resistant patients.

References

1. Feinberg WM, Blackshear JL, Laupacis A, KronmalR, Hart RG. Prevalence, age, distribution, and gen-der of patients with atrial fibrillation. Analysis andimplications. Arch Intern Med 1995;155:469–473.

2. Nattel S, Hadjis T, Talajic M. The treatment ofatrial fibrillation. An evaluation of drug therapy,electrical modalities and therapeutic considera-tions. Drugs 1994;4:345–371.

3. Roy D, Talajic M, Thibault B, Dubuc M, Nattel S,Eisenberg MJ, Ciampi A and the CTAF investi-gators: Pilot study and protocol of the CanadianTrial of Atrial Fibrillation (CTAF). Am J Cardiol1997;80:464–468.

4. Amiodarone Trial Meta-Analysis Investigators: Ef-fect of prophylactic amiodarone on mortality af-ter acute myocardial infarction and in conges-tive heart failure: Meta-analysis of individual datafrom 6500 patients in randomized trials. Lancet1997;350:1417–1424.