Pilot Study and Protocol of the CanadianTrial of Atrial Fibrillation (CTAF)

Denis Roy, MD, Mario Talajic, MD, Bernard Thibault, MD, Marc Dubuc, MD,Stanley Nattel, MD, Mark J. Eisenberg, MD, MPH, Antonio Ciampi, PhD,

and the CTAF Investigators*

Antiarrhythmic drug prophylaxis in patients with atrialfibrillation (AF) is associated with a high incidence ofarrhythmic recurrence. Uncontrolled studies have sug-gested that low-dose amiodarone may be superior interms of efficacy to other antiarrhythmic drugs whilehaving an acceptable side effect profile. The CanadianTrial of Atrial Fibrillation (CTAF) is a 25-center studysponsored by the Medical Research Council of Canadato determine the best treatment strategy to maintainsinus rhythm in patients with persistent or paroxysmalAF. Recruitment began in November 1996 and will con-tinue for 1.5 years. Patients are randomized to receiveeither low-dose amiodarone or conventional antiar-rhythmic drug therapy. Patients assigned to the amio-darone group will receive an oral loading regimen of 10mg/kg/day during a minimum 14-day period. Patientsassigned to conventional antiarrhythmic therapy willreceive 1 of 2 agents commonly used in AF prophylaxis:sotalol or propafenone. Drug selection and loading, and

electrical cardioversion, if necessary, will be performedwithin 21 days of randomization. The long-term main-tenance dose of amiodarone is 200 mg/day. We haveplanned a minimum follow-up period of 1 year. Theprimary end point is the time to the first relapse of AF.Data will be analyzed on an intention-to-treat basis.Secondary outcomes are medication toxicity, mortality,major clinical events, costs of each approach, and qual-ity of life. For the purpose of sample size calculations, itis anticipated that recurrence of AF at 1 year will occurin 50% of patients on conventional treatment comparedwith 35% in those receiving amiodarone. In order tohave an 80% power and a 2-tailed type I error of 0.05,assuming a 15% loss to follow-up rate, a total samplesize of 400 patients will be required. A pilot study doneat the Montreal Heart Institute has shown that the re-search protocol is feasible. Q1997 by Excerpta Med-ica, Inc.

(Am J Cardiol 1997;80:464–468)

Interest in the use of low doses of amiodarone foratrial fibrillation (AF) has recently grown.1,2 Effi-

cacy for the maintenance of sinus rhythm has beenreported to be from 53% to 79% for periods of 15 to27 months.3–11These results are even more impressivesince most patients receiving amiodarone are usuallyrefractory to a variety of other agents before amioda-rone is considered. There have been only 2 smallrandomized evaluations of amiodarone prophylaxispublished to date, with evidence suggesting superior-ity of amiodarone over quinidine and disopyramide.3,7

Reluctance to use amiodarone as an agent of firstchoice stems from the impressive list of side effectsthat can result from its use. However, the majority ofamiodarone side effects are dose related and are re-versible. Much of the fear of using this agent hasarisen from the initial experience of its use in patientswith ventricular arrhythmias at much higher dosesthan normally administered to patients with atrial ar-rhythmias.4–6 Ventricular proarrhythmic effects arerarely observed12–14 and contrary to what has been

observed with class I drugs, amiodarone may decreasemortality in patients after myocardial infarction and inpatients with congestive heart failure.15–18 There isuncontrolled evidence that low-dose amiodarone maybe a superior therapy for the treatment of AF19 andthat the mortality rate of amiodarone-treated patientsmay be lower.20

PILOT STUDYA pilot study was designed to determine the feasi-

bility of performing a large-scale trial to test thehypothesis that the initial use of low-dose amiodaronetherapy would reduce the incidence of recurrent AFwhen compared with conventional antiarrhythmicdrug therapy. The pilot study was performed at theMontreal Heart Institute.21 It started in January 1995and enrollment ended in August 1995.

Forty-five patients were recruited (29 men and 16women, mean age 606 9 years). Twenty-six patientshad paroxysmal AF and 19 had persistent AF. Twen-ty-five patients were randomized to amiodarone and20 were given conventional therapy (sotalol: 9 pa-tients, propafenone: 10, disopyramide: 1). There were3 early dropouts (7%) (2 in the conventional group).

Twenty-five patients (56%) had recurrence of AFduring a mean follow-up of 1966 67 days (range 5 to368). Excluding the 3 patients who never received thestudy drug (efficacy analysis), the recurrence rate was22 of 42 patients (52%). Using an intention-to-treatanalysis (Figure 1), 12 of the 25 patients (48%) in theamiodarone group had recurrence of AF compared

From the Department of Medicine, Montreal Heart Institute, Universityof Montreal, Montreal, Quebec, Canada. This study was supported inpart by the Fonds de recherche de l’Institut de Cardiologie de Mont-real, the Medical Research Council of Canada, and the Fonds de larecherche en sante du Quebec, Montreal, Quebec, Canada. Manu-script received January 21, 1997; revised manuscript received andaccepted April 24, 1997.

Address for reprints: Denis Roy, MD, Montreal Heart Institute,5000 Belanger Street East, Montreal, Quebec H1T 1C8, Canada.

*A list of the CTAF investigators and their affiliations appears in theAppendix.

464 ©1997 by Excerpta Medica, Inc. 0002-9149/97/$17.00All rights reserved. PII S0002-9149(97)00396-2

with 13 of the 20 patients (65%) in the conventionalgroup (p5 NS). The mean time of recurrence was23 6 39 days (range 1 to 171).

The study drug was discontinued because of sideeffects in 4 of the amiodarone patients and in 1 patientin the conventional group. There were no serious sideeffects and no deaths occurred. We concluded that themulticenter trial was feasible and that the assumptionsregarding AF recurrence were reasonable.

A grant application for a multicenter clinical trialwas submitted to the Medical Research Council ofCanada. Reviewers suggested that the study would bebetter served by a more rigidly controlled, randomizeddrug trial comparing a more limited number of drugs.We chose to use propafenone and sotalol as conven-tional therapy because a large number of patients havebeen exposed to both drugs, and there is substantialexperience to suggest that they are equally effectivebut are better tolerated than older type IA drugs. Also,more patients are likely to continue long-term therapyon sotalol or propafenone than with quinidine or di-sopyramide. Furthermore, sotalol and propafenone areboth widely prescribed by Canadian cardiologists forthe treatment of AF. The reapplication was approvedand funding was obtained for the multicenter trial inJuly 1996.

MULTICENTER TRIALFour hundred patients will be enrolled from 25

cardiology centers across Canada. The enrollment pe-riod will be 1.5 years. Patient entry into the trial beganon November 11, 1996.

Patient selection: All patients with recent (,6months), symptomatic AF for whom chronic antiarrhyth-mic drug therapy is planned will be screened. At least 1episode of AF must have lasted$10 minutes and elec-trocardiographic documentation must have been ob-tained in order to qualify. Patients will be assessed for the

following exclusion criteria: myocar-dial infarction during the previous 6months; heart surgery during the pre-vious 30 days; New York Heart Asso-ciation functional class III or IV; AFassociated with an acute reversiblecondition; renal failure (creatinine.250 mmol/L); elevated hepatic en-zymes (alanine transaminases.2.5times the upper limit of normal);chronic obstructive lung disease re-quiring bronchodilator therapy; Wolff-Parkinson-White syndrome; premeno-pausal women without prior tuballigation or hysterectomy; previouslong-term treatment ($4 weeks); fail-ure of, or intolerance to, either sotalol,propafenone or amiodarone; untreatedhypothyroidism; history of significantpulmonary interstitial disease; QTc.480 ms or absolute QT.500 ms inthe absence of bundle branch block;bradycardia ,50/min while awakeduring $1 minute of measurement;

second or third degree atrioventricular block without apermanent pacemaker implanted; sinus pause.2.0 sec-onds; history of Torsades de pointes; antiarrhythmictherapy required for other arrhythmias; geographic orsocial factors making follow-up difficult; age,18 yearsold; and medical conditions making 1-year survival un-likely.

PROTOCOLRandomization: If no exclusion criteria are present,

block randomization will take place. Patients will bestratified according to the study center (Figure 2).Before randomization, decisions regarding anticoagu-lation will be made by the local investigator accordingto previously published guidelines.22 Those patients inwhom anticoagulation with warfarin is planned beforecardioversion must achieve therapeutic levels (inter-national normalized ratio [INR]$2.0) for a minimumof 3 weeks before antiarrhythmic drug loading isstarted.

Drug loading: Patients assigned to the amiodaronegroup will receive an oral loading regimen (10 mg/kg/day) during a minimum of 14 days. Antiarrhythmicdrug therapy will be chosen randomly for each patientin the conventional group. The minimum treatmentperiod on sotalol and propafenone will be 4 days. Apatient who develops intolerable side effects with thefirst drug will stop the agent in question and will startthe other drug. Electrical direct-current cardioversionwill be performed in those patients who do not convertspontaneously and remain in AF after the minimumtreatment period of each drug. Incrementally dosedsynchronized shocks will be administered after induc-tion of general anesthesia (200, 300, 360 and 360 J).

Twenty-one day visit: All patients will be evaluatedon day 21 after randomization. Patients who success-fully complete drug loading and are in sinus rhythmwill be followed for rhythm-control treatment. The

FIGURE 1. Kaplan-Meier curves plotting the probability of remaining in sinus rhythmas a function of follow-up time in the Canadian Trial of Atrial Fibrillation pilot study.

ARRHYTHMIAS AND CONDUCTION DISTURBANCES/ATRIAL FIBRILLATION MULTICENTER TRIAL 465

long-term maintenance dose of amiodarone is 200mg/day. Patients who cannot be cardioverted or main-tained in sinus rhythm within 21 days of randomiza-tion and patients who permanently discontinue thestudy medication during the loading period will re-ceive usual therapy, off-protocol. Usual care may in-clude either treatment with atrioventricular nodalblocking drugs to control heart rate or therapy with anantiarrhythmic medication to maintain sinus rhythm.In addition, nonpharmacologic treatment with pacingor ablation may be used.

Follow-up: Patients will be reevaluated at 3, 6, and12 months, and every 6 months thereafter for a max-imum follow-up of 2.5 years. They will be providedwith a transtelephonic monitoring device and willtransmit their electrocardiogram anytime they experi-ence cardiac symptoms. Laboratory investigationswill be obtained as described in Table I.

Patients randomized to amiodarone therapy andwho suffer relapse of AF will continue to receive thestudy drug at the second maintenance dose of 300

mg/day. Electrical cardioversion willbe carried out if necessary. Patientsrandomized to conventional antiar-rhythmic drug therapy and who suf-fer a recurrence of AF will eitherreceive a higher dose of the antiar-rhythmic drug, or will stop the agentand begin taking the other drug fromthe conventional arm. The choicewhether to increase the dose or tochange the drug will be left to theinvestigator, who may also decide tocontinue the same antiarrhythmicdrug at the same dose for those pa-tients who have recurrences but aregreatly improved compared with be-fore randomization. Any patient de-veloping intolerable side effects orhaving 2 relapses requiring electricalcardioversion will discontinue thestudy medication and will receive themore common therapy as prescribedby the patient’s attending physician.

Outcome events: The primary endpoint will be the time to the firstrecurrence of AF. Recurrence is de-fined as any electrocardiographicallydocumented episode of AF lasting.10 minutes. For the purpose of theprimary end point, day 21 after ran-domization will be considered astime 0. Patients who do not achievesinus rhythm within 21 days of ran-domization are classified as having arecurrence at day 1.

In addition to the primary out-come, data will be collected and an-alyzed from the time of randomiza-tion regarding the followingsecondary outcome events: side ef-fects for each medication; time to

achieve sinus rhythm for each treatment group; num-ber and characterization of recurrences of AF duringthe study period; number and characterization ofthromboembolic events; mortality; number of patientsin sinus rhythm in the conventional group versus theamiodarone group at the end of the study; cost benefitby comparing hospitalization costs of each approach,and quality of life by self-administered questionnairesat baseline, and at 3 and 12 months of follow-up.

Sample size: The sample size calculations are basedupon analysis of relevant follow-up studies of drugtherapy for AF,1–11 and a recent analysis of 20 con-trolled trials of efficacy of drug therapy in maintainingsinus rhythm after electrical cardioversion.20 We ex-pect that recurrence of AF will occur at 1 year in 50%of patients on conventional treatment compared with35% of those receiving amiodarone. With these as-sumptions, we estimate that in order to have an 80%power and a 2-tailed type I error of 0.05, using alog-rank test to compare the 2 survival curves, a totalsample size of 341 patients will be required. In order

FIGURE 2. Randomization schema and drug treatment strategy for the Canadian Trialof Atrial Fibrillation.

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to allow for a loss to follow-up rate of 15%, a totalsample size of about 400 patients would be needed.

Data analysis: To evaluate the main hypothesis, theprimary outcome will be the time to first relapse ofAF. The intention-to-treat approach will be the pri-mary method of analysis. Censoring will occur if thepatient is lost to follow-up, dies, or reaches the end ofthe follow-up period. Patients who crossover or dis-continue the study medication will be followed forevent recurrence as per the intention-to-treat principle.The survival curves for the 2 main arms will becompared by the Mantel-Cox (log-rank) test,23 theBreslow test,24 the Tarone-Ware test,25 or the GehanWilcoxon test,26 depending on whether the propor-tional hazard hypothesis is satisfied or not. In addition,the data will be scrutinized for possible biases due toimbalance of prognostic factors across the 2 treatmentarms using a multivariate Cox regression model and atree-structured survival analysis.27

SIGNIFICANCE OF STUDY RESULTSThe results of the current study will help guide

therapy for a difficult and often frustrating cardiacarrhythmia. The advent of catheter techniques for thetreatment of paroxysmal supraventricular tachycardiahas left AF as the last major supraventricular arrhyth-mia for which no adequate therapy exists. Given thehigh morbidity associated with AF and the enormouscosts to our healthcare system caused by this verycommon problem, new strategies are needed. Theresults of this study will offer definitive information ina large patient cohort concerning 2 separate ap-proaches to restoring and maintaining sinus rhythm.While not comparing this strategy directly to that ofrate control alone, it will, however, provide estimatesof the need for rate control when a strategy of main-tenance of sinus rhythm is chosen, and will monitorquality of life and economic indicators in patientsultimately receiving rate control. In addition, thisstudy will provide a basis on which a future formalcomparison can be planned.

APPENDIXCTAF Investigators: Rafael Castan, MD, Hoˆpital Jean-Talon, Montreal,

Quebec; Stuart Connolly, MD, Hamilton General Hospital, McMaster Clinic,

Hamilton, Ontario; Benoıˆt Coutu, MD, Claude Guimond, MD, Hoˆpital Notre-Dame, Montreal, Quebec; Paul Dorian, MD, David Newman, MD, St. Michael’sHospital, Toronto, Ontario; Eugene Downar, MD, Toronto General Hospital,Toronto, Ontario; Denis Gossard, MD, Hoˆpital Maisonneuve-Rosemont, Mont-real, Quebec; Gilbert Gosselin, MD, Hoˆpital LeGardeur, Repentigny, Quebec;Dominique Grandmont, MD, Centre Hospitalier Honore´-Mercier, Saint-Hya-cinthe, Quebec; Martin Green, MD, University of Ottawa Heart Institute, OttawaCivic Hospital, Ottawa, Ontario; Richard Harvey, MD, Centre Hospitalier Uni-versitaire de Sherbrooke, Sherbrooke, Quebec; Katherine Kavanagh, MD, Uni-versity of Alberta Hospital, Edmonton, Alberta; Simon Kouz, MD, Centre Hos-pitalier Regional de Lanaudie`re, Joliette, Quebec; Teresa Kus, MD, FranckMolin, MD, Hopital du Sacre´-Coeur de Montre´al, Montreal, Quebec; GillesO’Hara, MD, Institut de Cardiologie de Que´bec, Hopital Laval, Sainte-Foy,Quebec; Anne Ouellet, MD, Clinique des cardiologues associe´s de PierreBoucher, Longueuil, Quebec; Onorio Ruscito, MD, Hoˆpital Santa-Cabrini, Mon-treal, Quebec; Denis Roy, MD, Mario Talajic, MD, Marc Dubuc, MD, BernardThibault, MD, Pierre Gagne´, MD, Institut de Cardiologie de Montre´al, Montreal,Quebec; Zaev Wulffhart, MD, Cam Joyner, MD, Sunnybrook Health SciencesCenter, North York, Ontario.

Steering Committee: Antonio Ciampi, PhD, Stuart Connolly, MD, PaulDorian, MD, Mark J. Eisenberg, MD, MPH, Martin Green, MD, Teresa Kus, MD,Mary Morello, Denis Roy, MD (Chair), Mario Talajic, MD (co-chair).

External Safety and Efficacy Monitoring Committee: Gilles Dagenais,MD (Chair), Reginald Nadeau, MD, Robin Roberts, MD.

Validation and Events Committee: Jean Diodati, MD, Ihor Dyrda, MD(Chair), James Nasmith, MD, Normand Racine, MD.

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TABLE I Follow-Up Investigations

Baseline21 Days AfterRandomization

3 mo6 7 d

6 mo6 14 d

12 mo6 14 d

18 mo6 14 d

24 mo6 14 d

30 mo6 14 d

History X X X X X X X XClinical status X X X X X X X XChest x-ray* X X X XElectrocardiogram X X X X X X X XCreatinine, potassium XThyroid-stimulating hormone*‡ X X X X X XAlanine transaminases* XEchocardiogram† X X XQuality of life

*Repeat tests will be performed only for patients assigned to the amiodarone group.†If not performed within the last 12 months may be obtained within 1 month after randomization.‡If not performed within the last 6 months may be obtained within 1 month after randomization.Chest x-ray obtained #3 months before randomization and blood chemistry obtained #1 week before randomization will be acceptable for baseline evaluation.

ARRHYTHMIAS AND CONDUCTION DISTURBANCES/ATRIAL FIBRILLATION MULTICENTER TRIAL 467

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