S aand Tolerability of Long-termPropa#enometherapy for

Supraventricular TachyarrhythmiasPhilip J. Podrid, MD, and Jeffrey L Anderson, MD,

For the Propafenone Multicenter Study Group*

An importantissueregardingtheIong+ermuseof an-tiarrhythmicdrugsconcernsthesafetyof theseagenk,pa~.cularlywithregardtocardiactoxicity.Propafenoneisan #e&e dwg far preventingsupraveniriculartachy-arrhythmia,buttheincidenceofsideeffectsduringlong-termtherapyin patientswithsucharrhythmiashasnotbeenadequatelyrepo-. A takdof 480 patientsre-ceivedoral propafenoneas therapyfor symptomaticairialfibdatian,atrialflutter,or supraventiculartachy-cardia.Duringthefollow-up(mean14.4months),290patients(60%)discontinuedpropafenonetherapy,butinonly70 patients(150A)wasthereasonfordiscontin-uationan adversedrugreaction.Overall,284 patients(59%)experiencedat least1 adversereaction,andtheincidencewasrelatedtodoseandage >65 years.The

overallincidenceofsideeffectswasnotrelatedtostruc-turalheartdisease;however,cardiovasculartoxicityin-cludingarrhythmiaaggravation,congestiveheartfail-ure,andseriousconductiondisturbancesoccurredmoreoftenin‘hosewithheartdisease(20’%.vs 13%).sixteenpatientsdiedduringdrug therapy,but in only 1 casewasthedrugconsideredcontributory.Forpatientswitha supraventriculararrhfimia, propafenonewaswelltoleratedandwasinfrequentlydiscontinuedbecauseofsideeffects.Theincidenceof seriouscardiactaxici~whenpropafenonewasusedto treatsupraventriculararrhythmiawaslow,andhesesideeffectsweremorefrequentinpatientswithstructuralheartdisease.

(AmJCardiol1996;78:430-434)

supraventricular tachyarrhythmias, particularlyatrial fibrillation, are common and generally

require therapy, primarily for the elimination of as-sociated symptoms. Although many types of supra-ventricular tachycardia are treated with radio-frequency ablation,1,2the prevention of recurrent ep-isodes of atrial fibrillation or atrial flutter most oftenrequires pharmacologic therapy with antiarrhythmicdrugs.3Of growing concern, however, is the toxicityassociated with antiarrhythmic drug therapy, partic-ularly arrhythmia aggravation and other cardiac sideeffects.4 Although these complications have beenwell characterized in patients with serious ventricu-lar arrhythmia,5 their incidence in patients with su-praventricular arrhythmia is less well established.6Currently, there are only a few drugs approved in theUnited States for prevention of atrial arrhythmias,and there is a need for new drugs that are effectiveand well tolerated. One new agent is propafenone,which has been used for many years in patients withserious ventricular arrhythmias. While its side effectprofile is well established in these patients,7’8theincidence of side effects in patients with supraven-

From theDepartmentof Cardiology, Boston University School of Med-icine, Boston, Massachusetts, and Division of Cardiologyr latter DaySoint’s Hospital, Salt lake City, Utah. This studywas supportedin partby a grant from Knoll PharmaceuticalCompany, Whip any, New

CfJersey. Manuscript receivedOctober 24, 1995; revise manuscriptreceivedand acceptedMarch 7, 1996.

Address for reprints: Philip J. Podrid, MD, Departmentof Cardi-ology, Boston University School of Medicine, 88 East Newton Street,Boston, Massachusetts.

* See Appendix for a list of participants.

tricular arrhythmia is less well known. This studyreports the type and frequency of side effects in alarge group of patients receiving long-term propa-fenone for prevention of supraventricular arrhyth-mias.

METHODSPatients included in this trial were men and

women between the ages of 21 and 70 who had elec-trocardiogram (ECG) documented paroxysmal epi-sodes of atrioventricular (AV) nodal tachycardia,atrial tachycardia, atrial fibrillation, or atrial flutterand who, in the clinical judgment of the investigator,required antiarrhythmic therapy. Before therapy withpropafenone, all other antiarrhythmic drugs, includ-ing digoxin, type I and III antiamhythmicagents, cal-cium channel antagonists, and /3blockers, were dis-continued for at least 5 half-lives.

All patients underwent a complete history andphysical examination, a clinical laboratory evalua-tion (including a complete blood count, serum elec-trolytes, liver function tests, antinuclear antibodies,and urinalysis), chest x-ray, a 12-lead ECG andrhythm strip, and one 24-hour ambulatory electro-cardiographic recording. Upon completion of base-line studies, therapy with propafenone was begun atan initial dose of 150 mg every 8 hours. The dosecould be titrated upward at 2-day intervals to 300 mgevery 12 hours and then 300 mg every 8 hours. Ifthe initial dose of 150 mg caused undue side effects,it could be reduced. Once a satisfactory response wasachieved, the dose was not altered except for signsof drug toxicity or recurrent arrhythmia. Patient fol-

430 01996by Excerpta Medica, Inc.All rights reserved.

0002-9149/96/$15.00Pll S0002-9149(96)00332-3

TABLEI Clinical Features of Patients Enrolled in Study(n= 480)

No. Patients (%)

Arrhythmia history (%]Suprcrventricular tachycardia 274 (57)

Atrial fibrillation or flutter 195 (41)

Ventricular tachycardia 6 (1)

Atrial fibrillation and supraventricular 5 (1)

tachycardia

Coexisting cardiovascular disease (%) 320 (67)

Systemic hypertension 87(1 8)

Valvular heart disease 81 (17]

Coronary artery disease 59(1 2)

Congestive heart failure 53 [1 1)

Myocardial infarction 29 [6)

Cardiomyopathy 25 (5)

Duration of arrhythmia 7.8 A 9.3 yrS (0-68]

NYHA &lS5 (%)I 135 (29]

II 221 147]

Ill 111 [24)

Iv 4 (1]

Na. with symptoms (%] 471 (98)

Polpitotions 362 (71 )

Dizziness 171 (36)

Orthapnea 76 (16)

Angina 64 (13)

Syncope 50 (1 o)

NYHA = New Yark Heart Association.

low-up visits were at 2 weeks and at 1, 3, 6, 9, and12 months. At each visit, laboratory tests and ECGSwith rhythm strips were obtained, and a tablet countwas performed. An ambulatory ECG was repeatedat 6 months, and a chest x-ray was obtained at theend of the study (12 months).

Criteria for exclusion from the study includedovert congestive heart failure, acquired or congenitalvalvular disease resulting in hemodynamic impair-ment, therapy with an investigational drug, clinicallysignificant renal or hepatic dysfunction, terminal ill-ness, sick sinus syndrome, clinically significant AVblock, myocardial infarction within 1 month, a cer-ebrovascular accident within 3months, unstable an-gina, bleeding diathesis, hypotension (systolicbloodpressure <95 mm Hg), and unwillingness or inabil-ity to cooperate or to give written informed consent.

RESULTSPatientpopulation:A total of 480 patientswere

enrolled in the study. There were 271 men and 209women (average age 57 years). The presenting ar-rhythmias are displayed in Table I. Six patients whowere initially entered for a supraventricular tachy-cardia were later diagnosed as having ventriculartachycardia. Overall, structural heart disease waspresent in 259 patients (54%), whereas it was absentin 221. All but 9 patients had symptoms resultingfrom the arrhythmia. A total of 343 patients (72%)had previously been treated with digoxin or at least1 class I, III, or IV antiarrhythmic drug, and 147(31%) had received =2 agents. Prior therapy in-

cluded quinidine (28Yo), procainamide ( 199io),ve-rapamil ( 1690), and disopyramide ( 11%).

Outcomeof therapy:The mean duration of propa-fenone therapy was 14.4 months. During the courseof the study, side effects were assessed at daily dosesof drugs that were <450 mg in 109, 450 to 599 mgin 339, 600 to 899 mg in 335, and =900 mg in 270patients. At 12 months, 190 patients (40%) contin-ued to take propafenone, and 180 patients continuedfor over 12 months. The reasons for discontinuationamong the 290 patients (60%) are listed in Table II.Of note, only 70 patients ( 1570)discontinued due toan adverse reaction, whereas 140 patients (29%)withdrew because of drug inefficacy. Of the 70 pa-tients discontinuing the drug because of an adversereaction, most (44 patients, 63%) did so within 1month of therapy, whereas most of those discontin-uing because of lack of drug efficacy did so after 1month (26 patients, 59%).

Adversereactions:Overall, 284 patients (59% ) ex-perienced at least 1 adverse reaction while receivingpropafenone. In general, the incidence of adverse re-actions increased with higher doses of the drug. Atdoses of <450 mg/day, 10% of patients experiencedan adverse reaction; at 450 mg/day the incidencewas 32Y0,at 600 mg/day it was 3070,and at =900mg/day the incidence was 42Y0.The relation be-tween the dose and the incidence of adverse reactionswas most apparent for gastrointestinal and centralnervous system–related adverse reactions (TableIII). In 79 patients ( 17%), the side effect abatedwith a reduction in dose.

The most frequently reported adverse reactions,including unusual taste ( 1490),nausea or vomiting( 1l%), dizziness (9%), constipation (8%), fatigue(6% ), and headache (6%), were gastrointestinal andcentral nervous system related. Adverse reactionsoccurred most often during the firstmonth of therapy(36% of all patients), with only a small increase inincidence after 3 months (to 44$Z0). In general, therewas a minor association between the incidence ofadverse reactions and age. Among 166 patients >65years, 109 (66Yo)had an adverse reaction, whereas175 of 314 patients (56$10)<65 years had an adversereaction. The greater incidence inpatients >65 years

TABLE II Patient Outcame (n = 480)*

Withdrawn

Total <1 Month

Withdrawn (%) (%)

Reason far Discontinuing Drug

Adverse reactian 70 (15] 44 (9)

Unsatisfactory respanse 140 (29) 57(1 2)

Concurrent medical problem 8 (2) 1 (o)

Death 16 (3) o (o)

Therapy refused 12 (3] 3 (1)

Other 45 (9) 7 (2)

“ Number completing 12 m&ths of therapy: 190 (4070); numberdiscontinu-ing drug: 290 (60%).

ARRHYTHMIAS AND CONDUCTION DISTURBANCES/PROPAFENONE FOR SUPRAVENTRICULAR TACHYARRHWHMIAS 431

TABLE Ill Incidence of Adverse Reactions (%] by Body System

Propafenone dose (mg/day)Total no. af pts receiving treotmentPts with ony adverse drug reaction (%)

General body functionDermatologicMetabalic/endocrineCardiovascular

GenitourinaryHemapoieticGastrointestinalPulmonaryCentral nervous system

MusculoskeletalEmotional, mental & sexual statesEyes, ears, nose and throat

<450109

104012

.00702

00

450339

327

11810

1529122

600335

30

711

:o

1529113

=900

27042

7

;900

223

142

26

Any480

5914

32

17

1

420

236

wasprimarily related to general body function ( 19%vs 12Y0for those <65), especially fatigue and an-orexia, the cardiovascular system (21% vs 15% inthose <65) (particularly congestive heart failure),and the gastrointestinal system (34% vs 31%).

The overall incidence of adverse reactions wasequivalent in patients with and without underlyingstructural heart disease (62% vs 57%). There wereno differences in the incidence of adverse drug re-actions associated with any organ system, except fora higher incidence of cardiovascular toxicity amongpatients with structural heart disease (20% vs 13%in those without heart disease).

Overall, 70 patients ( 15%) required drug discon-tinuation because of an adverse reaction, and an ad-ditional 79 patients ( 1790) required a reduction in.drug dose. Approximately 44Y0of the adverse re-actions were considered to be mild by the investi-gator and patient, 42% were judged to be moderate,and 12Y0were considered to be severe.

Cardiovasculartaxiciiy:Although 1790of patientshad an adverse cardiovascular side effect, drug dis-continuation was necessary in only 490.Arrhythmiaaggravation occurred in 11 patients (29ZO),includingatrial flutter or atrial fibrillation with aberrancy in 4(1% ), new ventricular tachycardia in 2 (0.4% ), ven-tricular fibrillation in 2 (0.490), and cardiac arrest in3 (0.6%). However, in only 8 cases was the drugimplicated by the investigator. There was no asso-ciation between electrocardiographic changes andarrhythmia aggravation. Most cases of arrhythmiaaggravation occurred at a dose of 900 mg/day (6patients or 55% of episodes). Eight of the episodesoccurred inpatients with structural heart disease (3!Z0of this group), whereas 3 occurred in those withoutheart disease ( l%). Congestive heart failure oc-curred in 9 patients (270), and there was no apparentrelation to dose. Eight of the 9 episodes were ob-served in patients with heart disease (3Y0 of thisgroup), whereas 1 event occurred in a patient with-out heart disease and was related to a recurrenttachy-arrhythmia. Serious conduction abnormalities wereobserved in 19 patients (4$%0),and included AV dis-sociation (0.290), symptomatic bradycardia (290),

I

and sinoatrial block or sinus Dauses (290). These. ./abnormalities were not related to dose, but weremore common in patients with heart disease (590 vs3Y0in the absence of heart disease). Other minorchanges in conduction were observed, which in-cluded first-degree AV block (PR interval prolon-gation), asymptomatic sinus bradycardia, and intra-ventricular conduction delay. These changes areknown to be associated with the use of propafenone.Syncope or presyncope of unknown etiology was re-ported as an adverse reaction by 6 patients ( 1%).

Mortality:A totalof 16patientsdied during drugtherapy or within 1 month of study completion. Twoof the deaths occurred in patients who had ventric-ular tachycardia, and the drug was not considered tobe contributory in either case. The cause of deathincluded cardiac arrest in 4, complete heart block in1, acute myocardial infarction in 5, cerebrovascularaccident in 2, electromechanical dissociation in 1,and suicide, cancer, and accident in 1 each. In only1 case (patient with complete heart block) was thedeath believed to be related to the drug. A compar-ative evaluation of all-cause mortality in this trial hasrecently been published.9 In this comparison be-tween a patient sample with supraventiicular ar-rhythmia treated with propafenone and a sampletreated with other antiarrhythmics, there was no dif-ference in age-adjusted mortality.

DISCUSSIONMost patients with supraventricular tachyarrhyth-

mias requiring treatment, particularly those withsymptomatic atrial fibrillation or atrial flutter, re-ceive antiarrhythmic drugs.3 At present, there areonly a few such agents approved for supraventriculartachyarrhythmia therapy, although there are otheragents available that are effective. A major limitationto the use of pharmacologic therapy is the associatedtoxicity. Although most adverse reactions are mildand not serious (i.e., they are nuisance side effects),there are other potential side effects that are moreserious, particularly cardiovascular toxicity and es-pecially arrhythmia aggravation. This complicationis well established when antiarrhythmic drug therapy

432 THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL 78 AUGUST 15, 1996

is used in patients with underlying heart disease whohave serious ventricular arrhythmia.5The incidencein such patients is approximately 9%, ranging from5% to 19% for individual antiarrhythmic drugs.s Inthis population, the incidence of arrhythmia aggra-vation associated with propafenone is 8Y0.5It hasbeen reported that patients at greatest risk for thisside effect are those with a history of congestiveheart failure who are being treated for a sustainedventricular tachyarrhythmia.5 Arrhythmia aggrava-tion has also been observed in other groups of pa-tients, and the reported incidence associated withpropafenone therapy in those with any ventriculararrhythmia is 5.39i0.8

Arrhythmia aggravation has also been reported inpatients receiving therapy for a supraventricular ar-rhythmia, although the incidence is not well estab-lished. Coplen and coworkers10performed a meta-analysis of 6 controlled trials involving patients withatrial fibrillation receiving quinidine therapy or nodrug therapy. The authors reported that total mortal-ity was significantly higher in the quinidine groupthan in the control group (2.9% vs 0.8%, p < 0.05).However, sudden death, presumably due to quini-dine related torsades de pointes, occurred in only 3patients (0.7% ). Although there were no episodes oftorsades de pointes in the control groups, this wasnot a significant difference. The Stroke Preventionin Atrial Fibrillation study11also reported that pa-tients with atrial fibrillationand congestive heart fail-ure who were treated with antiarrhythmic drugs, pri-marily quinidine, had a higher mortality than thosenot receiving these agents. However, the reason forthis increased mortality was not reported. Neverthe-less, these data have caused much concern and haveraised questions about the safety of pharmacologictherapy in patients with symptomatic supraventric-ular tachyarrhythmias, particularly in those who alsohave underlying heart disease.

As with other agents, there is concern about thesafe use of propafenone,7”2a drug used for therapyof ventricular arrhythmia, in patients with supraven-tricular arrhythmia. This study involves a large num-ber of patients treated for a mean duration of 14months. Importantly, arrhythmia aggravation oc-curred in only 11 patients (290), and in only 8 pa-tients was the drug judged by the investigator to beresponsible. As with previous studies, the incidencewas higher in patients with structural heart diseasethan in those without heart disease (3% vs l%).Other cardiovascular adverse reactions were also in-frequently observed. Overall, congestive heart fail-ure occurred in 2?ioof patients; all but 1 of thesepatients had structural heart disease. Importantly, thedrug was discontinued in only 4% of patients be-cause of untoward cardiovascular events, whereasthe dose was only reduced in 4% of patients. Al-though the overall incidence of any side effect was59%, it is important to note that in only 70 patients( 15%) was the drug discontinued because of a side

effect, whereas in 79 patients ( 179i0) a reduction indose eliminated the side effect.

Comparisonto patientswithventriculararrhfimia:There are a number of studies reporting side effectson propafenone when administered to patients withventricular arrhythmias. The largest experiencewas reported by Ravid and coworkers8 in a studyinvolving 774 patients. In contrast to our study,90% of these patients had underlying structuralheart disease. Interestingly, the incidence of allside effects was 58Y0,identical to what was ob-served in our study. The percentage of patients re-quiring drug discontinuation because of side ef-fects was also similar. Not unexpectedly, theincidence of cardiac toxicity was higher in patientsreceiving propafenone for ventricular arrhythmia(27%) than in those with supraventricular arrhyth-mia ( 1790), most likely due to the fact that heartdisease was more common in the former group.Not surprisingly, in patients with ventricular ar-rhythmia, the incidence of arrhythmia aggravation(5% ) and congestive heart failure (3% ) was higherthan in patients with supraventricular arrhythmia,whereas the incidence of a serious conduction ab-normality was equivalent (490). Gastrointestinalside effects from propafenone were more com-mon in patients with supraventricular arrhythmia(32%) than in those with ventricular arrhythmia(21%), but the reason for this is unclear.

In conclusion, propafenone is an effective an-tiarrhythmic drug for the treatment of supraven-tricular arrhythmia. As with other agents, mild sideeffects during propafenone therapy are frequent,although discontinuation of the drug because ofadverse reactions is only infrequently necessary.Serious cardiac adverse reactions do occur, but theincidence is low, and such reactions are most oftenassociated with the presence of structural heart dis-ease.

APPENDIXThe PropraferroneMrdticenter Study Group included: Michael Brodsky,MD, University of California, Irvine Medical Center, Orange, California;Stuart Connolly, MD, McMasters University, Hamilton General Hospital,Hamilton, Onturio, Canada; Peter Friedman, MD, Peter Bent BrighamHospital, Boston, Massachusetts; Lawrence German, MD, Eric Prys-towsky, MD, Duke University Medical Center, Durham, North Carolina;Johrr Haas, MD, Mayo Clinic, Jacksonville, Fforida; Kenneth Haisty,MD, The Bowmarr Gray School of Medicine, Wake Forest University,Winston-Salem, North Cmolina; Stephen C. Hammill, MD, Mayo Clinic,Rochester, Minnesota; Charles Kerr, MD, University of British Columbia,Vancouver General Hospital, Vancouver General Hospital, Vancouver,British Columbia, Canada; George Klein, MD, University Hospital, Lon-don, Ontario, Carrada; Edwwd Pritchett, MD, Duke University MedicalCenter, Durharrr, North Carolina; Michael Rosengarten, MD, MontrealUniversity Hospital, Montreal, Quebec, Canada; Mohammad Shenasa,MD, Hospital de Sacre Coeur, Montreal, Quebec, Canada; Ruey Sung,MD, San Francisco General Hospital, San Francisco, California.

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