Dofetilide for Atrial Arrhythmias in Congenital HeartDisease: A Multicenter StudyRONALD WELLS, M.D.,* PAUL KHAIRY, M.D., PH.D.,† LOUISE HARRIS, M.D.,‡C. CHRISTIAN ANDERSON, M.D.,§ and SESHADRI BALAJI, M.B.B.S., M.R.C.P. (U.K.), PH.D.*From the *Division of Pediatric Cardiology, Department of Pediatrics, Oregon Health & Science University, Portland,Oregon; †Adult Congenital Heart Center, Montreal Heart Institute, Montreal, PQ, Canada; ‡Toronto GeneralHospital, Toronto, Ontario, Canada; and §Northwest Center for Congenital Heart Disease, Spokane, Washington

Background: Very little is known about use of the class III antiarrhythmic dofetilide in patients withcongenital heart disease (CHD).

Methods: A multicenter retrospective review of experience with dofetilide in CHD patients wasundertaken.

Results: Twenty adults with CHD and refractory atrial arrhythmias were treated with dofetilide at fourinstitutions over a 7-year period. Three (15%) experienced adverse effects during in-hospital initiationof dofetilide (two with torsade de pointes, one with excessive QTc prolongation) and were not continuedon this therapy. The remaining 17 were discharged taking dofetilide, with either resolved or improvedarrhythmia. One was lost to follow-up. Five subsequently discontinued dofetilide due to waning effective-ness, manifest by recurrence of their arrhythmias. Eleven (55%) remained on dofetilide at most recentvisit, with a median follow-up of nearly 1 year. Seven of these 11, or 35% of the CHD patients originallystarted on dofetilide, experienced a complete resolution of their arrhythmia. The remaining four hadbreakthrough episodes of atrial arrhythmia, but remained on dofetilide. No patient experienced torsadede pointes after the in-hospital initiation period.

Conclusions: Used appropriately, dofetilide appears to be a viable adjunct to catheter-based ablationand alternative pharmacological approaches for the treatment of atrial arrhythmias in adult patients withcongenital heart disease. (PACE 2009; 32:1313–1318)

pediatrics, pharmacology

IntroductionAs modern medical and surgical management

of structural congenital heart disease (CHD) allowsmore patients to survive, long-term complications,including arrhythmias, become the major chal-lenge in their management.1 Atrial arrhythmiassuch as atrial fibrillation (AF), atrial flutter (AFL),and incisional atrial reentrant tachycardia (IART)are a major source of morbidity and even mortal-ity,1 particularly for patients following Fontan pal-liation.2 Current management strategies, includingcatheter-based ablation; surgical antiarrhythmiaprocedures; and medications such as flecainide,propafenone, amiodarone, and sotalol, are oftenunsatisfactory in their results. There is room foradditional therapeutic options.

The U.S. Food and Drug Administration(FDA) approved dofetilide for use in the United

Financial disclosures: None.

Address for reprints: Seshadri Balaji, M.B.B.S., M.R.C.P. (U.K.),Ph.D., 707 SW Gaines Street, CDRC-P; Portland, OR 97239. Fax:503-494-2824; e-mail: balajis@ohsu.edu

Received December 4, 2008; revised May 8, 2009; accepted May31, 2009.

doi: 10.1111/j.1540-8159.2009.02479.x

States on October 1, 1999, for the treatment ofpersistent atrial arrhythmia in adults3 and it isavailable in Canada through Health Canada’s spe-cial access program. The specific indications are:(1) conversion of AF/AFL to normal sinus rhythm(NSR) and (2) maintenance of NSR in patients withAF/AFL of greater than 1-week duration who havebeen converted to NSR.4 Dofetilide is a pure classIII antiarrhythmic agent, selectively blocking therapid component of the delayed rectifier current,IKr. It prolongs myocardial repolarization and theeffective refractory period.5 The QT interval is pro-longed, thus increasing risk of torsade de pointes(TdP). Information regarding dofetilide use in pa-tients with CHD is limited. Concerns about safetyand efficacy have limited its use in this popula-tion. We present the combined experience of fourcenters using dofetilide in patients with CHD.

Materials and MethodsStudy Design

This institutional review board-approvedstudy is a multicenter, retrospective study ofthe use of dofetilide to treat atrial arrhythmiasin patients with CHD from September 2000 toDecember 2007.

C©2009, The Authors. Journal compilation C©2009 Wiley Periodicals, Inc.

PACE, Vol. 32 October 2009 1313

WELLS, ET AL.

Subjects

All members of the Pediatric and CongenitalElectrophysiology Society (PACES) were con-tacted via email, and invited to submit data onpatients with CHD and atrial arrhythmia whohad been treated with dofetilide. Physicians atfour centers responded to our request and con-tributed data. One center from Europe respondedwith data on the use of intravenous dofetilidebut was rejected because this fell outside thepurview of the current study. We are unsurewhether dofetilide was used at other institutionson similar patients. Subjects at Oregon Health& Science University (OHSU) and the MontrealHeart Institute were identified by querying thepharmacy database for dofetilide dispensed, thenidentifying all instances in which the recipienthad CHD. Subjects at the other two institutionswere identified by treating physician’s personalknowledge of patients with CHD who had receiveddofetilide. Electronic and paper medical recordswere reviewed for demographic information,CHD diagnoses, prior cardiac surgeries, arrhyth-mia diagnoses, prior antiarrhythmic medication(AAM) use (including intravenous ibutilide),catheter-based ablation attempts, pacemaker use,echocardiography reports of ventricular function,and physiologic data related to initiation ofdofetilide (creatinine clearance, cardiac rhythm,QTc duration). Response to dofetilide, whetherdofetilide was continued and for how long, rea-sons for discontinuation, and adverse events weredetermined. The complete success of dofetilidetherapy was defined as conversion to or mainte-nance of NSR with minimal or no breakthrough,with no adverse effect. Partial success was definedas a reduction in the frequency and/or severityof episodes of arrhythmia, such that therapy wasdeemed worth continuing.

Analysis

Data were collected on a standardized work-sheet and tabulated. Continuous variables arepresented as mean ± standard deviation (SD)or median and range, depending on normalityof their distribution. Dichotomous variables aresummarized as frequencies and percentages. Com-parisons between baseline and peak QTc wereperformed using a nonparametric paired-signtest. A two-tailed P-value < 0.05 was consideredstatistically significant. Testing was performedwith SAS software Version 9.1 (SAS Institute,Cary, NC, USA).

ResultsTwenty patients with CHD who had received

dofetilide for atrial arrhythmia were identified and

reviewed. Table I summarizes their characteris-tics; the patients are listed in a chronological or-der by date of dofetilide initiation (earliest to mostrecent).

The median age at dofetilide initiation was30 years (range: 19–53 years). Specific CHD diag-noses are listed in Table I. All but one had under-gone prior cardiac surgery, with a mean of 2.4 ±1.2 cardiac operations per patient. Eleven of 20(55%) had completed staged palliation to Fontan.Arrhythmia diagnoses were as follows: AF (n =4), AF/IART (n = 3), and IART (n = 13). Patientshad been given an average of 3.3 ± 1.2 other AAMprior to dofetilide; see Table I for details. Three(patient numbers 3, 8, and 9) had previously re-ceived ibutilide (patient 8 did not convert to NSR;the other two did convert, but relapsed). Four-teen of 20 (70%) had undergone at least one priorcatheter-based ablation attempt (1.5 ± 0.9 per pa-tient). Ablation attempts were either unsuccess-ful, or initially successful with subsequent relapseand/or the onset of new arrhythmias. Three pa-tients had undergone prior Maze operations, allat the time of Fontan revision. Eight (40%) hadcardiac pacemakers, and three (15%) had an au-tomatic implantable cardiac defibrillator (AICD).The ventricular function of these patients as esti-mated by echocardiography was variable (Table I).Of the two patients with TdP, one had mild reduc-tion in function and the other, normal function.Neither of the two patients with severe reductionin function experienced TdP (see Table I).

The starting dose of dofetilide was at thediscretion of the treating physician. By standardcalculations, no patient had impaired creatinineclearance (average: 118 ± 29 mL/min), and no pa-tient required dosing adjustment for renal impair-ment. Ten patients were started on 500 mcg po bid,the recommended starting dose for adults withoutrenal impairment, six on 250 mcg po bid, one on125 mcg po tid, and three on 125 mcg po bid dos-ing regimens.

The response to dofetilide is summarized inFigure 1. Corrected QT interval (QTc) increased bya median of 7%, from 447 ms (range: 389–595 ms)at baseline to a peak of 482 ms (range: 425–600 ms),P = 0.004.

There were three (15%) immediate treatmentfailures. Two (10%) patients (#4 and #9) expe-rienced TdP. Both received a dofetilide dose of500 mcg po bid, and experienced TdP duringthe hospitalization in which dofetilide was ini-tiated. The potentially life-threatening ventriculararrhythmia was quickly recognized with success-ful resuscitation in both cases. One patient (#7)who also received 500 mcg po bid of dofetilidehad excessive QTc prolongation prompting drugdiscontinuation.

1314 October 2009 PACE, Vol. 32

DOFETILIDE IN CONGENITAL HEART DISEASE

Tab

leI.

Pat

ient

Cha

ract

eris

tics

Init

ial

Lo

ng

-P

atie

nt/

Ag

eC

HD

CH

DP

rio

rC

ath

eter

Ven

tric

ula

rD

ose

(mcg

Init

ial

Term

Use

Rea

son

Gen

der

(y)

Dia

gn

ose

sS

urg

erie

sA

rrh

yth

mia

AA

Ms

Ab

lati

on

sF

un

ctio

np

ob

id)

Eff

ect

Eff

ect

Du

rati

on

for

d/c

Effi

cacy

1/M

22D

ILV

;L-T

GA

LT-F

AF

/IAR

TS

T;P

R;

2N

500

MN

SR

WE

1.5

year

sW

EP

DG

;DI

2/M

47TO

FTO

FA

F/IA

RT

DG

;AM

2N

500

MN

SR

LTF

U?

?3/

M19

SV

AP

-FIA

RT

VR

;AM

;3

N50

0M

NS

RM

NS

R5+

year

sS

DG

;ST

4/F

35Tr

A;P

AP

VR

TrA

/PA

PV

RIA

RT

VR

;DG

;PC

0M

ild↓

500

TdP

–3

days

PrA

rF

5/F

20D

ILV

;TA

;PS

AP

-F;F

RIA

RT

AM

;DG

0N

500

MN

SR

AR

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6/M

40D

-TG

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rdIA

RT

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;DG

2M

ild↓

500

CN

SR

MN

SR

5+ye

ars

S7/

M53

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TOF

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RIA

RT

AT2

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↓50

0M

NS

R–

1do

sein

crea

sed

FQ

Tc

8/M

34B

AV

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VR

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IAR

TA

M;D

I;S

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Mod

↓50

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NS

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norm

alM

V9/

F20

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500

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–A

few

dose

sP

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FAT

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10/F

21TA

AP

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RA

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RT

FL;

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2N

500

MP

RD

A1+

year

P11

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PA-I

VS

AP

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RT

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;PR

0N

125

tidM

NS

RD

A3

wee

ksS

AP

12/M

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P-F

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AF

AM

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;DI

0M

od↓

125

CN

SR

MN

SR

*9+

mon

ths

P13

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D-T

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Mus

tard

AF

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Mod

↓25

0M

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RM

NS

R6+

mon

ths

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P;D

G14

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TA

M;S

T;

1M

od↓

250

MN

SR

MN

SR

5+m

onth

sS

BB

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15/M

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Font

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RT

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ev↓

125

DA

DA

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16/F

29TA

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RT

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;DG

2N

250

EA

EA

11+

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ths

S17

/M40

DO

RV

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AFo

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IAR

TA

M;P

R;D

G2

N25

0M

NS

RM

NS

R*

10+

mon

ths

P18

/F49

PA;V

SD

;AP

Cno

neIA

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0M

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125

MN

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MN

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6+m

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ricul

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chyc

ardi

a.

PACE, Vol. 32 October 2009 1315

WELLS, ET AL.

Figure 1. Response to dofetilide in CHD patients with atrial arrhythmias.

Conversion to or maintenance of NSR withno adverse effect during the 72-hour in-hospitalobservation following initiation of dofetilide wasobserved in 17 (85%) patients. These 17 were alltaking dofetilide at the time of discharge from thehospitalization during which dofetilide was ini-tiated. One of them (#2) was lost to follow-upshortly after starting dofetilide, and long-term ef-fects or adverse events could not be determined.Five of the 17 patients who left the hospital tak-ing dofetilide subsequently discontinued it as aresult of waning benefit, with recurrent arrhyth-mias. One these five discontinued the drug foreconomic reasons, despite having some reductionin the frequency of arrhythmia. Two of those whodiscontinued for waning effect went on to success-ful catheter ablation.

Eleven of 20 patients (55%) started ondofetilide in this series were still taking it at mostrecent follow-up. Duration of therapy ranged fromabout 1 month to greater than 5 years, with a me-dian follow-up approaching 1 year. Seven of the20 (35%) have had total suppression of their ar-rhythmia, and are considered complete successes.Four of the 20 (20%) continue to have occasionalbreakthrough episodes of their underlying atrialarrhythmia, but find their episodes less frequentand subjectively less severe. Despite occasionalbreakthroughs, these patients wish to continuedofetilide therapy. No patient experienced TdPsince hospital discharge.

DiscussionDofetilide successfully converted and main-

tained NSR in a significant proportion of patients

with CHD and atrial arrhythmias in this study,with small (but not negligible) incidence of seriousadverse effect.

Efficacy

The patients reported in the current studywere refractory to previously attempted therapies.They were given a variety of alternative AAMswith unsatisfactory results or intolerable side ef-fects. Fifteen of 20 (75%) had undergone at leastone prior ablation attempt.

Initial success with dofetilide was impres-sive, with 85% of patients converting to or main-taining NSR during the in-hospital observationperiod immediately following dofetilide initia-tion. Mykytsey et al. reported initial success withdofetilide in 31 of 34 patients (91%) with paroxys-mal AF and normal left ventricular (LV) function(no CHD).6 The Symptomatic Atrial FibrillationInvestigative Research on Dofetilide (SAFIRE-D)study was a double-blinded, placebo-controlled,multicenter study to determine the efficacy andsafety of dofetilide in converting to and main-taining NSR in patients with AF or AFL (noCHD).7 The investigators reported an initial phar-macologic conversion rate of 6.1%, 9.8%, and29.9% in subjects given 125, 250, and 500 mcgof dofetilide twice daily respectively, versus 1.2%in the placebo group.7 A direct comparison can-not be made between these results and those ofthe group presently reported, as some of the CHDpatients were in NSR at the time of dofetilide ini-tiation. Nonetheless, the observed initial successof dofetilide in managing atrial arrhythmias in pa-tients with CHD is encouraging.

1316 October 2009 PACE, Vol. 32

DOFETILIDE IN CONGENITAL HEART DISEASE

Perhaps more clinically meaningful is the55% long-term success rate (patients still takingthe medication with diminished or suppressedarrhythmia at a median follow-up of nearly oneyear) in patients with CHD and previously refrac-tory atrial arrhythmias. Mykytsey et al. reportedsymptomatic improvement persisted at 12 monthsin 18 of 31 (58%) in their series.6 Seven of 20 pa-tients (35%) in the presently reported series expe-rienced complete suppression of their arrhythmia.This compares favorably with the long-term suc-cess rate of dofetilide reported in patients with-out CHD. A substudy of the Danish Investiga-tions of Arrhythmia and Mortality ON Dofetilidein congestive heart failure (DIAMOND-CHF) andacute myocardial infarction (DIAMOND-MI) stud-ies specifically evaluated the efficacy of dofetilidein treating AF/AFL in patients with reduced LVfunction.8 The investigators reported that 112 of249 (45%) patients randomized to dofetilide ex-perienced and maintained spontaneous or phar-macologically induced conversion to NSR duringthe study period (minimum follow-up period of12 months), versus 35 of 257 (14%) of placebo-treated controls (P < 0.001).8 In the SAFIRE-D study, the probability of maintaining NSR at360 days following conversion by any means(pharmacologic or electric) was 40%, 37%, and58% in the 125, 250, and 500 mcg twice dailygroups, respectively, versus 25% in the placebogroup (P = 0.001 for the 500 mcg twice daily groupversus placebo).7

It is worth noting that DIAMOND-CHF,9DIAMOND-MI,10 the DIAMOND substudy ofdofetilide in patients with AF/AFL and reducedLV function,8 and SAFIRE-D7 had comparablemortality rates for patients treated with dofetilideversus placebo. Despite favorable effects on mor-bidity in many patients in the presently reportedgroup, it remains to be seen whether there is trulyany long-term mortality benefit.

Safety

Serious adverse effect, namely TdP, was ob-served in a small but significant minority of pa-tients in this series (two patients, 10% of CHDpatients given dofetilide in this series). There wasno observable correlation between occurrence ofTdP and ventricular function in these two patients.Both had been started on 500 mcg orally twicea day, which is the recommended starting dosein patients without renal impairment. In both in-stances the patient was still in the hospital, facil-itating rapid identification and resuscitation, andunderscoring the importance of adherence to cur-rent prescribing guidelines that mandate inpatientobservation with continuous monitoring for a min-imum 3 days when dofetilide is initiated. The re-

ported incidence of TdP in larger series of non-CHD patients is between 0.4% and 2.9% wheninitial dose is based on renal function as recom-mended.4 Patients with CHD may be more sus-ceptible to TdP when given dofetilide; the limitednumber of subjects in this series prevents conclu-sive evaluation of this possibility. There has beena trend to use a lower than recommended startingdose in the more recent patients reported in thisseries; the last nine patients have been initiatedon less than 500 mcg twice daily. Although thelimited sample size precludes inferential analyses,antiarrhythmic efficacy was noted at lower thanrecommended doses with no episodes of TdP de-spite ongoing therapy in all but one patient. There-fore, in patients with CHD it may be prudent toinitiate dofetilide therapy at lower than standarddoses with judicious and monitored titration asneeded.

Alternatives

The efficacy and safety of dofetilide needs tobe assessed in the context of other antiarrhyth-mic agents currently available. Alternatives in-clude class IA agents quinidine and procainamide,class IC agents flecainide11 and propafenone,12

and class III agents sotalol13 and amiodarone.14

All of these agents are associated with significantside effects, including proarrhythmia.

Limitations

Despite drawing on the experience of four in-stitutions, the present study is hampered by rel-atively limited number of subjects. It is however,to our knowledge, the only study currently avail-able evaluating the safety and efficacy of dofetilidein CHD. Inconsistency in the starting dose is oneof the inherent challenges of a retrospective eval-uation of clinical practice. Nonetheless, the po-tentially valuable observations that TdP occurredonly in two patients receiving the package-insertrecommended starting dose of 500 mcg orallytwice daily, and that as the trend in initial dosehas been toward lower doses no patient has experi-enced TdP, may be useful in clinical practice. Onemight consider a lower starting dose of dofetilidein subgroups of CHD patients even in the presenceof apparently unimpaired renal function.

ConclusionsThese findings suggest that, while dofetilide is

not the answer for every CHD patient with atrial ar-rhythmias, when used appropriately it can benefita significant proportion of these patients who areoften difficult to treat. Initial efficacy of dofetilidefor the treatment of refractory atrial arrhythmiasin CHD patients is high, with long-term efficacyhistorically comparable to patients without CHD.

PACE, Vol. 32 October 2009 1317

WELLS, ET AL.

Subtypes of patients with CHD, such as those withuniventricular physiology, may be at higher risk ofTdP when standard recommended starting dosesof dofetilide are utilized. Adherence to prescribingguidelines that mandate inpatient monitoring fora minimum 3-day observation following dofetilideinitiation is critical. Consideration should be givento using a lower than recommended starting dose,despite apparently normal renal function. In the

challenging population of CHD patients with re-fractory atrial arrhythmias, dofetilide appears tobe a viable adjunct to catheter-based ablation andalternative pharmacological approaches.

Acknowledgments: The authors wish to thank MaudeBergeron, RN (Montreal Heart Institute) for her expertassistance.

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