Clinical Efficacy of Dofetilide for the Treatment of AtrialTachyarrhythmias in Adults with Congenital Heart Disease

Javier E. Banchs, MD, Giselle A. Baquero, MD, Michelle J. Nickolaus, CRNP,Deborah L. Wolbrette, MD, John J. Kelleman, MD, Soraya Samii, MD, Jennifer Grando-Ting, MD,Erica Penny-Peterson, MD, William R. Davidson, Jr., MD, Sallie K. Young, PharmD,Gerald V. Naccarelli, MD, and Mario D. Gonzalez MD

Penn State Hershey Heart & Vascular Institute, Penn State University, Hershey, Pa, USA

A B S T R A C T

Background. Atrial tachyarrhythmias (AT) including atrial fibrillation (AF), atrial flutter (AFL), and atrial tachy-cardia represent a clinical challenge in the adult with congenital heart disease (CHD). Dofetilide (D) is a rapidlyactivating delayed rectifier potassium channel (IKr) blocker effective in pharmacological conversion and mainte-nance of normal sinus rhythm in patients with AF and AFL. There is limited knowledge regarding the role of D inadults with CHD.Methods. Safety and efficacy of D was evaluated in a consecutive group of thirteen adult patients (age 40 ± 11; sixwomen) with CHD and refractory AT.Results. Ten patients had persistent (four AFL, one AF, and five atrial tachycardia) and three paroxysmal (one AFand two atrial tachycardia) AT. All patients were symptomatic during tachycardia, 12 patients had previously failed2 ± 1 antiarrhythmic drugs. Mean systemic ventricular ejection fraction was 55 ± 9%; baseline QRS complexduration was 129 ± 45 ms (>120 ms in six patients). Patients were followed on D for 33 ± 39 months (median 16).Among 10 patients with persistent AT, seven patients (70%) pharmacologically converted to sinus rhythm on D andthree patients (30%) required direct current cardioversion. Two patients (15.4%) experienced complete arrhythmiasuppression, and seven (53.8%) experienced significant clinical improvement with sporadic recurrences; averagetime to recurrence was 5.5 ± 3.5 months. One patient developed torsade de pointes during loading, and the drug wasdiscontinued. D was discontinued in five (38.5%) other patients due to recurrence of AT (n = 4) and renal failure(n = 1). Corrected QT interval (QTc) increased from 452 ± 61 to 480 ± 49 ms (P = .04) and corrected JT interval( JTc) from 323 ± 39 to 341 ± 33 ms (P = .09).Conclusions. D should be considered a pharmacologic alternative when adult patients with CHD develop AT. Ddoes not depress conduction, sinus node, or ventricular function but needs close monitoring for potential ventricularpro-arrhythmia.

Key Words. Atrial Tachyarrhythmias; Congenital Heart Disease; Dofetilide

Introduction

Atrial tachyarrhythmias (AT) including atrialfibrillation (AF), atrial flutter (AFL), and atrial

tachycardia represent a frequent clinical challengeand major source of morbidity and mortality inadults with congenital heart disease (CHD).1,2

Dofetilide (D) is a class III antiarrhythmic, IKrselective blocker that prolongs atrial and ventricu-lar repolarization,3,4 shown to be effective in thepharmacological conversion and maintenance ofnormal sinus rhythm (NSR) in patients with AFand AFL.3–7 D was approved by the FDA for thetermination of persistent AF and AFL and main-tenance of sinus rhythm,8 based on the findings ofthe Symptomatic Atrial Fibrillation InvestigativeResearch on Dofetilide (SAFIRE-D) and Euro-pean and Australian Multicenter EvaluativeResearch on Atrial Fibrillation Dofetilide(EMERALD) studies.9,10 Furthermore, given the

No funding or grant support was used for this research.Part of the data was presented in abstract form at the5th Annual Congress of the European Cardiac Arrhyth-mia Society, April 20, 2009.

221

© 2013 Wiley Periodicals, Inc. Congenit Heart Dis. 2014;9:221–227

demonstrated neutral survival benefit in theDanish Investigations on Arrhythmia and Mortal-ity on Dofetilide (DIAMOND) trial,11 theAmerican College of Cardiology/American HeartAssociation/European Society of Cardiologyguidelines recommend D as first-line therapy forpatients with AF who have coronary artery diseaseor congestive heart failure.12

The use of D has been extrapolated in clinicalpractice to other populations, including patientswith ventricular arrhythmias13 and individualswith supraventricular tachycardias and otherforms of structural heart disease including CHD.However, current knowledge regarding the effi-cacy of this drug in adults with CHD is limited toour previously reported case series14 and a singleprevious retrospective multicenter study,15 both ofwhich demonstrated the potential role of D asan alternative pharmacological approach for thetreatment of AT in this population. The purposeof the present study is to report our institutionalexperience to date with D in adult patients withCHD and recurrent AT.

Methods

We evaluated all patients with CHD that wereadmitted to our institution for initiation of D forthe treatment of AT. Patients were classified ashaving persistent vs. paroxysmal AF, AFL, or atrialtachycardia according to electrocardiographic andclinical criteria.12,16 All ATs lasting more than 7days were classified as persistent, regardless of thesuspected mechanism. D starting dose was chosenand adjusted according the individual’s creatinineclearance and corrected QT interval (QTc), fol-lowing the guidelines established for theDIAMOND trial.17 All patients were kept on inpa-tient cardiac telemetry monitoring during the firstfive doses, and a 12-lead electrocardiogram wasrecorded 2 hours after each dose to monitorchanges in the QTc and JTc intervals (QTcinterval—QRS duration).18 The JTc interval wasrecorded as a surrogate of the QTc interval giventhe prevalence of conduction disease and wideQRS in this patient population. Patients with per-sistent AT who did not convert to sinus rhythmafter receiving D for 36–48 hours underwentexternal biphasic direct current cardioversion.

All patients were followed 1 month afterin-hospital initiation of D and then every 3–6months unless they had symptoms suggestive ofarrhythmia recurrence. Surface 12-lead electrocar-diogram, ambulatory Holter monitor, pacemaker/

defibrillator interrogation, and cardiac eventrecorder were obtained as appropriate during clinicvisits. The primary end point of the study was toevaluate the efficacy and safety of D in patients withCHD and recurrent AT. Response to D, treatmentduration, adverse effects, and reason for discon-tinuation were determined. Complete responsewas defined as maintenance of NSR with no symp-toms or documented arrhythmia recurrence. Wedefined partial response as significant clinicalimprovement, judged by the treating physician assatisfactory enough to continue drug therapy,despite occasional recurrences of symptoms orarrhythmia.

Statistical AnalysisContinuous variables are presented as mean ±standard deviation, unless otherwise specified.Comparison between baseline, loading, andfollow-up QTc/JTc was performed using thepaired Student’s t-test. A P value of <.05 was con-sidered statistically significant.

Results

The study population consisted of 13 adults (age40 ± 11; six women) with history of CHD andsymptomatic recurrent AT. Table 1 summarizesthe patient characteristics, underlying arrhyth-mias, and specific cardiac diagnoses. Cardiacabnormalities included tetralogy of Fallot,(TOF; n = 4) one with pulmonary atresia and rightsided aortic arch; atrial septal defect (n = 2),one secundum and one sinus venosus; transposi-tion of the great arteries (TGA; n = 3), onedextro-transposition (D-TGA) and two levo-transposition (L-TGA) with single ventricle physi-ology; tricuspid atresia (n = 2), one with atrial andventricular septal defects; ventricular septal defectwith pulmonary atresia (n = 1), and left ventricularnoncompaction (n = 1). Twelve patients hadundergone one or more corrective cardiac surger-ies. Surgeries included Blalock–Taussig shunt (n =5) for three patients with TOF and two patientswith tricuspid atresia; atrio pulmonary Fontan (n =4) in two patients with previous Blalock–Taussigshunt for tricuspid atresia and two patients withL-TGA. Two patients had previous pulmonicvalve replacement and one repair, all for TOF withprevious Blalock–Taussig shunt. One patient withTOF had two prior Rastelli procedures. Rakshidseptostomy and Senning procedure (n = 1) hadbeen performed in a patient with D-TGA and aBentall procedure (n = 1) for a different patient

Banchs et al.222

Congenit Heart Dis. 2014;9:221–227

with TOF after a previous Blalock–Taussig shunt.Prior atrial septal defect repair had been per-formed in two patients, one including a Wardenprocedure for surgical repair of a sinus venosusatrial septal defect with anomalous pulmonary veinconnection. One patient had a ventricular septaldefect closure with a right ventricular to pulmo-nary artery conduit for pulmonary atresia. Includ-ing all surgical repairs and revisions, the averagesurgical procedures was 1.7 ± 2 per patient.

Average systemic ventricular ejection fractionwas 55 ± 9% and left atrial systolic area was 23.2 ±6.2 (12.6–33.2) cm2. Two patients (15.4%) had apreviously implanted permanent pacemaker, onefor sinus node dysfunction and one for completeheart block. Three patients (23%) had implantablecardioverter defibrillators (ICDs), two for second-ary prevention due to coexisting ventriculararrhythmias, and one for primary prevention ofsudden cardiac death. Ten patients had persistentAT (four AFL, one AF, and five atrial tachycardia),and three patients had paroxysmal AT (one AF andtwo atrial tachycardia).

All patients were symptomatic during tachycar-dia and 12 had previously failed 2 ± 1 antiarrhyth-mic drugs, nine (69%) failed 2 ± 1 class I and/orclass III agent; three had been on beta blockers anddigoxin and one only on digoxin. Three patients(15.4%) had failed catheter ablation, one (7.7%)with AF had a prior successful ablation for AFL,and another patient (7.7%) had a previous surgicalablation (Maze procedure). Five patients had morethan one arrhythmia. AF and AFL coexisted in twopatients. Other two, had ventricular arrhythmiasin addition to AT.

Dofetilide Dosing and Repolarization IntervalsThe average QRS duration at baseline was 129 ±45 ms, (QRS > 120 ms in six patients due to rightbundle branch block). D was initiated as a twice-daily oral dose of 385 ± 125 μg (250 μg in sixpatients and 500 μg in seven patients). Fivepatients (38.5%) required reduction of the initialdose due to excessive QTc prolongation duringloading (n = 4) and headache (n = 1). Final loadingdose was 308 ± 135 μg (125 μg in two patients,250 μg in seven patients, and 500 μg in fourpatients) every 12 hours. After the loading phase,the QTc increased from 452 ± 61 to 480 ± 49 ms(P = .04), and the JTc increased from 323 ± 39 to341 ± 33 ms (P = .09) (Figure 1). Among the sevenpatients with baseline QRS of <120 ms, averageQTc after loading was 447 ± 14 ms. The baselineQTc among six patients with wide QRS (>120 ms)was 482 ± 55 ms, JTc was 326 ± 42 ms and afterloading increased to 500 ± 55 ms and 333 ± 41 ms,respectively. The QTc and JTc at 1 and 6 monthsof treatment remained stable (QTc = 459 ± 49 msand 458 ± 36 ms; JTc = 328 ± 35 ms and 321 ±30 ms) P = not significant (NS).

Clinical Outcomes and Adverse EventsPatients who were discharged on D (n = 12) werefollowed on the drug for 33 ± 39 months (median16, range 1.5–105). Two patients (15.4%) werefree of arrhythmia during their follow-up periodof 58 ± 45 months (103 and 13 months) andtherefore experienced a complete response. Onepatient had no symptoms or documented recur-rence of arrhythmia after one and a half month ofD initiation but was later lost to follow-up. Long-

Table 1. Patient Characteristics

Pt Age G EF% CHD SVT OA ICD/PPM MRx ABL

1 53 F 60 TOF P AFL VT ICD A,BB,D,M,S —2 28 M 33 SV P AFL — PPM BB,D,S —3 43 M 55 TOF/PA P AFL AF — BB,D —4 44 F 45 LVNC P AF — PPM BB,D Y5 56 F 60 ASD Px AFL AFL — Pf —6 48 F 55 ASD Px AT — — A,Di,Dy,F,Q Y7 46 M 60 VSD/PA P AT VT ICD BB,D,Pf,Pr Y8 52 M 55 TOF P AT VT — D,Di,S —9 23 F 45 L-TGA/SV P AT — ICD A,D,S —

10 23 M 60 TA/VSD Px AT — — BB,D,Di,S —11 48 M 55 TOF P AT — — BB,D —12 27 M 70 D-TGA P AT — — D —13 33 F 60 TA P AFL — — A,BB,F —

A, amiodarone; ABL, previous catheter ablation; AF, atrial fibrillation; AFL, atrial flutter; ASD, atrial septal defect; BB, beta-blockers; CHD, congenital heart disease;D-TGA, dextro-transposition of great arteries; D, digoxin; Di, diltiazem; Dy, disopyramide; EF, ejection fraction; MRx, previous medical therapy; F, flecainide; G,gender; ICD, implantable cardioverter defibrillator; AT, atrial tachycardia; LVNC, left ventricular noncompaction; L-TGA, levo-transposition of great arteries; M,mexiletine; OA, other arrhythmias; Px, paroxysmal; Pt, patient; PPM, permanent pacemaker; P, persistent; PA, pulmonary atresia; Pr, procainamide; Pf,propefanone; Q, quinidine; SV, single ventricle; S, sotalol; SVT, supraventricular tachyarrhythmia; TOF, tetralogy of Fallot; TA, tricuspid atresia; VSD, ventricularseptal defect; VT, ventricular tachycardia; Y, yes.

Congenit Heart Dis. 2014;9:221–227

Dofetilide in Congenital Heart Disease 223

term response and adverse events were not evalu-ated in this patient. Seven patients (53.8%)experienced partial response represented by lessfrequency or duration of the arrhythmia episodes;the average time to arrhythmia recurrence was 5.5± 3.5 months. Overall, 10 patients (76.9%)reported subjective clinical improvement denotedby decrease or absence of symptoms or arrhythmia(Table 2). Among 10 patients presenting with per-sistent AT, seven patients (70%) pharmacologi-cally converted to NSR on D and 3 (30%)required direct current cardioversion.

There was one discontinuation of D duringloading secondary to torsade de pointes (TdP),leading to repeated ICD shocks that occurred afterthe second D dose. The patient had underlyingright bundle branch block with baseline QRS =144 ms, QTc = 493 ms, and the JTc to = 349 ms;after the second D dose QTc prolonged to = 550 ms

and the JTc = 400 ms (12 and 15% increase, respec-tively). D was later discontinued in other fivepatients (38.5%) after 9 ± 7 months of follow-up(median 4; range 2–19) due to recurrence ofarrhythmias (n = 4) or development of renal failure(n = 1). Two of the subjects with arrhythmia recur-rence underwent catheter-based ablation, one forthe first time and one as a repeat procedure.

There was one documented death after 63months of follow-up due to progressive heartfailure (Table 2). One patient experienced severeheadache during D loading that significantlyimproved after dose reduction. No other sideeffects or adverse events were documented.

Discussion

Patients with CHD have a high incidence of AT.Their underlying structural cardiac abnormalities

Figure 1. Graphic representation of the QTc and JTc before and after D loading. QTc increased from 452 ± 61 to 480 ±49 ms (P = .04) and the JTc from 323 ± 39 to 341 ± 33 ms (P = .09) after D loading.

Table 2. Dofetilide Efficacy

Pt SPDConversionNSR

Initialeffect

AR Time to AR(months)

DDRx(months) SxI

Long-termeffect D/C Reason

Adverseevents Death

Cause ofDeath Response

1 Y NO DCV N — 0.067 — — Y PQTc/TdP TdP — — F2 Y YES NSR N — 103 Y NSR N — — — — CR3 Y NO DCV Y 3 4 N AR Y AR (AF) — — — F4 Y YES NSR Y 8 17 Y NSR/OR Y AR — — — PR5 Y — NSR Y 9 105 Y NSR/OR N — HA — — PR6 Y — NSR Y 12 54 Y NSR/OR N — — — — PR7 Y YES NSR Y 5 63 Y NSR/OR N — — Y HF PR8 Y NO DCV Y 3 3 N AR Y AR — — — F9 Y YES NSR N 3 14 Y NSR/OR N — — — — PR

10 Y — NSR Y 1 19 Y NSR/OR Y AR — — — PR11 Y YES NSR N — 2 Y NSR Y ARF — — — PR12 Y YES NSR N — 13 Y NSR N — — — — CR13 Y YES NSR N — 1.5 Y LFU N — — — — PR

AF, atrial fibrillation; AR, arrhythmia recurrence; ARF, acute renal failure; CR, complete response; D/C, discontinued; DCV, direct cardioversion was required;DDRx, dofetilide duration of treatment; F, failure; Initial effect, during loading; HA, headache; HF, heart failure; LFU, lost of follow-up; N, no; NSR, normal sinusrhythm; Pt, patient; OR, occasional arrhythmia recurrence; PR, partial response; PQTc, prolonged QTc; SPD, symptoms prior to dofetilide; TdP, torsade de pointes;SxI, symptom improvement; Y, yes.

Banchs et al.224

Congenit Heart Dis. 2014;9:221–227

modified by complex surgical procedures fre-quently result in a substrate leading to reentryand abnormal automaticity.1,2 Surgery initiallyimproves the hemodynamic abnormalities butcreates areas of scar, slow conduction, and conduc-tion block. These electrophysiological abnormali-ties can lead to reentry, abnormal automaticity, andtriggered activity. Abnormal cardiac hemodynam-ics predisposes the patient to poor tolerance ofAT, leading to early development and moreseverity of symptoms and heart failure, with subse-quent recurrent hospital admissions. Suppressionof the AT in these patients is required to improvesurvival and quality of life. Current managementstrategies include catheter-based ablation, antiar-rhythmic agents, and surgical procedures. Amongpatients with CHD and postoperative AT, class IIIantiarrhythmic drugs such as amiodarone andsotalol have proven to be effective in reducing thefrequency of AT.19–21 Nevertheless, arrhythmiarecurrence is still common, and long-term therapywith amiodarone represents a significant risk forserious side effects in a relatively young patientpopulation. Quite often, as described here and inprevious reports,15 patients still have symptomaticrecurrences of arrhythmia despite previous abla-tion and require trials of therapy with differentdrugs. We report the largest single center experi-ence with D among adults with CHD and AT. Ourpatient cohort had previously failed an average of 2± 1 antiarrhythmic drugs, three patients (15.4%)failed a previous ablation procedure, and onepatient (7.7%) failed a surgical maze. The search ofalternative antiarrhythmic therapies has become aclinical necessity in the management of patientswith CHD. Many clinically classified AT in thisstudy, likely correspond to large intra-atrial reentrymechanistically similar to AFL. Previous reportshave shown D to be more effective in the suppres-sion of AFL than AF,5,7,9 hence likely to adequatelysuppress reentrant AT in this population.

D was approved by the FDA for the terminationof persistent AF and AFL, as well as maintenanceof sinus rhythm in adults. The DIAMOND studydemonstrated that D can be safely administered topatients with coronary artery disease and left ven-tricular systolic dysfunction.11 Based on the safetyof D in other patient populations with structuralheart disease, we have speculated that D could beused safely in adults with CHD. As mentionedbefore, there is little information regarding theefficacy and/or safety of D in the control of ATsin the adult patient with CHD. In a retrospectivemulticenter report with few patients studied at

each center,15 D successfully converted and main-tained NSR in a significant proportion of CHDpatients with ATs. In the present single-centerstudy, an initial success was demonstrated with70% of patients with persistent AT pharmacologi-cally converting to NSR and all but one dis-charged in normal rhythm on the drug. Partialefficacy in rhythm control was maintained in76.9% of patients during the 33 ± 39 months offollow-up and complete suppression of supraven-tricular tachyarrhythmia occurred in two patients(15.4%). These results are encouraging andcompare favorably with the multicenter studyreported by Wells et al.15 and other series ofpatients without CHD.7,9,11,17 In a study byMyazaki et al.21 including 44 adult patients withATs and a variety of CHD including TOF, singleventricle, tricuspid stenosis or atresia, and TGAamong others, 41% of patients had complete sup-pression of their arrhythmia with sotalol and 34%partial suppression in a follow-up period of 13 ±12 months. In a previous publication, Villain19

reported 27 patients with either baffle or Fontanprocedures who received amiodarone for thetreatment of late postoperative AT. Completearrhythmia suppression was achieved in 71.5%with either amiodarone alone or in combinationwith beta blockers but at 4.5 years of follow-up,only 30% of patients were still on amiodarone andremaining arrhythmia free. All but one of ourpatients had previously failed at least one antiar-rhythmic drug and 69% one or more class I or IIIagents, 38% sotalol, and 31% amiodarone. Like inmany other clinical scenarios, amiodarone offershigher efficacy but at the expense of higher riskof multiple organ toxicity. Some of our patientswere considered poor candidates for amiodaronebecause of their relative young age or sinus nodedysfunction, or sotalol due to heart failure orpotential for worsening bradycardia. Similarly,class I antiarrhythmic drugs are not recommendedfor patients with structural heart disease due to therisk of pro-arrythmia, hence we do not commonlyconsider them an alternative for patients with ven-tricular scar or dilatation in absence of an ICD.

The higher prevalence of intraventricular con-duction disease among patients with CHD resultsin a prolonged QT even before the administrationof D. We routinely monitor both QTc and JTc18

with the latter, showing promising value in theassessment of repolarization changes during Dloading in patients with wide QRS. We speculatethat the JTc may be a more accurate assessment ofdispersion of repolarization across the myocar-

Congenit Heart Dis. 2014;9:221–227

Dofetilide in Congenital Heart Disease 225

dium than the QTc among patients with slow ven-tricular conduction or intraventricular conductionblock.

Serious adverse events occurred in one patientwith underlying right bundle branch block whoexperienced multiple defibrillator shocks due toTdP during the in-hospital loading periodprompting D discontinuation. The QTc did notprolong beyond what is considered safe while thepatient was adequately monitored, but the JTc didreach 15% prolongation from baseline. TdP is aknown complication of D and usually occursduring the loading phase while the patient ismonitored in the hospital as in the present case.7,15

As it can still occur during long-term administra-tion even in those patients who did not developTdP during the loading phase,22 close outpatientfollow-up is required. Based on two cases of TdPand one patient with excessive QTc prolongationin their series, Wells et al.15 concluded that it maybe prudent to consider initiating at lower thanstandard D doses in patients with CHD. In con-trast, the one patient who developed pro-arryhythmia in our cohort was started on 250 mcgand did not exhibit more than 15% QTc prolon-gation during monitoring. Interestingly, the JTcprolonged by 15%, and a JTc of 400 was onlyreached by this patient.

Overall, D was well tolerated; the only addi-tional side effect was severe headache in onepatient during D loading, which subsided afterdose reduction. The drug was eventually discon-tinued in five (38.5%) patients after 9 ± 7 monthsof treatment due to recurrence of AT in fourpatients and for safety considerations in onepatient who developed renal failure.

Given the particular efficacy of D for the treat-ment of arrhythmias with reentrant mechanism,the drug should be considered for the adult patientwith CHD and AT. In-hospital monitoring duringloading is mandatory. The high prevalence of con-duction disease in this population may pose a par-ticular challenge when monitoring drug effect.Monitoring the JTc interval may be useful in thisclinical scenario.

Limitations

A significant limitation is the small number ofpatients included in this report, with a variety ofdifferent anatomical defects, which is a commonproblem with studies involving adults with CHD.As it is the case with most low-prevalence condi-tions, it was not possible to establish a control

group. Each patient, having failed previous inter-ventions for the same arrhythmia was consideredtheir own control. Another significant limitation isthe documentation of arrhythmia recurrences trig-gered by symptoms or episodes of care, rather thansystematic use of continuous or extended ambula-tory heart rhythm monitoring devices.

Conclusions

Our clinical experience suggests that D is welltolerated and should be considered an alternativein the treatment of adults with CHD and AT.Recurrence of AT is still frequent despite 76.9% ofpatients reporting significant clinical improve-ment. The JTc appears to be of value for monitor-ing D effect among patients with a baselineprolonged QRS interval. Collaborative and pro-spective data from centers with specialized care foradults with CHD are needed to identify subgroupof patients in whom AT may be more responsive toD therapy.

Authors’ Contribution

Javier E. Banchs, MD: concept/design, IRB application,data collection, data analysis/interpretation, and draftingarticle.

Giselle A. Baquero, MD: data analysis/interpretation, IRBapplication, data collection, drafting article, and statistics.

Michelle J. Nickolaus, CRNP: data collection and criticalrevision of article.

Deborah L. Wolbrette, MD: data collection and criticalrevision of article.

John J. Kelleman, MD: data analysis/interpretation andcritical revision of article.

Soraya Samii, MD: concept/design and critical revision ofarticle.

Jennifer Grando-Ting, MD: drafting article and criticalrevision of article.

Erica Penny-Peterson, MD: data analysis/interpretationand data collection.

William R. Davidson, Jr., MD: concept/design and criticalrevision of article.

Sallie K. Young, PharmD: data collection and data analysis/interpretation.

Gerald V. Naccarelli, MD: concept/design, critical revisionof article, and approval of article.

Mario D. Gonzalez, MD: concept/design, draftingarticle, critical revision of article, and approval ofarticle.

Banchs et al.226

Congenit Heart Dis. 2014;9:221–227

Corresponding Author: Javier E. Banchs, MD, PennState Hershey Heart & Vascular Institute, Milton S.Hershey Medical Center, 500 University Drive, P.O.Box 850, Hershey, PA 17033-0850, USA. Tel: (717)531-3907; Fax: (717) 531-4077; E-mail: jbanchs@psu.edu

Conflict of interest: Dr. Naccarelli has been a consultantto Pfizer.

Accepted in final form: July 9, 2013.

References

1 Walsh EP, Cecchin F. Arrhythmias in adult patientswith congenital heart disease. Circulation. 2007;115:534–545.

2 Walsh EP. Interventional electrophysiology inpatients with congenital heart disease. Circulation.2007;115:3224–3234.

3 Roukoz H, Saliba W. Dofetilide: a new class IIIantiarrhythmic agent. Expert Rev Cardiovasc Ther.2007;5:9–19.

4 Maunsey JP, DiMarco JP. Cardiovascular drugs.Dofetilide. Circulation. 2000;102:2665–2670.

5 Falk RH, Pollak A, Singh SN, Friedrich T. Intrave-nous dofetilide a class III antiarrhythmic agent, forthe termination of sustained atrial fibrillation orflutter. Intravenous Dofetilide Investigators. J AmColl Cardiol. 1997;29:385–390.

6 Tai CT, Chen SA. Mechanisms of antiarrhythmicdrug action on termination of atrial flutter. PacingClin Electrophysiol. 2001;24:824–834.

7 Banchs JE, Wolbrette DL, Samii SM, et al. Efficacyand safety of dofetilide in patients with atrial fibril-lation and atrial flutter. J Interv Card Electrophysiol.2008;23:111–115.

8 Pfizer. Tikosyn (Dofetilide). Drug Approvalpackage. 1999.

9 Singh S, Zoble RG, Yellen L, et al. Efficacy andsafety of oral dofetilide in converting to and main-taining sinus rhythm in patients with chronic atrialfibrillation or atrial flutter: the symptomatic atrialfibrillation investigative research on defetilide(SAFIRE-D) study. Circulation. 2000;102:2385–2390.

10 Greenbaum RA, Campbell TJ, Channer KS, et al.Conversion of atrial fibrillation and maintenanceof sinus rhythm by dofetilide. The EMERALD(European and Australian Multicenter EvaluativeResearch on Atrial Fibrillation and Dofetilide) study(abstract). Circulation. 1998;17(suppl):I–633.

11 Køber L, Bloch Thomsen PE, Møller M, et al.;Danish Investigations of Arrhythmia and Mortalityon Dofetilide (DIAMOND) Study Group. Effect ofdofetilide in patients with recent myocardial infarc-

tion and left-ventricular dysfunction: a randomizedtrial. Lancet. 2000;356:2052–2058.

12 Fuster V, Rydén LE, Cannom DS, et al.; AmericanCollege of Cardiology Foundation/American HeartAssociation Task Force. 2011 ACCF/AHA/HRSfocused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management ofpatients with atrial fibrillation: a report of theAmerican College of Cardiology Foundation/American Heart Association Task Force on practiceguidelines. Circulation. 2011;123:e269–e367.

13 Baquero GA, Banchs JE, Depalma S, et al.Dofetilide reduces the frequency of ventriculararrhythmias and implantable cardioverter defibrilla-tor therapies. J Cardiovasc Electrophysiol. 2012;23:296–301.

14 Banchs JE, Nickolaus M, Gonzalez M, et al. Clinicalefficacy of dofetilide for the treatment of supraven-tricular tachyarrhythmias in adults with congenitalheart disease. J Interv Card Electrophysiol. 2009;24:267–268.

15 Wells R, Khairy P, Harris L, Anderson CC, Balaji S.Dofetilide for atrial arrhythmias in congenital heartdisease: a multicenter study. Pacing Clin Electro-physiol. 2009;32:1313–1318.

16 Aiba T, Shimizu W, Noda T, et al. Noninvasivecharacterization of intra-atrial reentrant tachyar-rhythmias after surgical repair of congenital heartdiseases. Circ J. 2009;73:451–460.

17 Pedersen OD, Bagger H, Keller N, Marchant B,Køber L, Torp-Pedersen C. Efficacy of dofetilide inthe treatment of atrial fibrillation-flutter in patientswith reduced left ventricular function: a Danishinvestigations of arrhythmia and mortality ondofetilide (diamond) substudy. Circulation. 2001;104:292–296.

18 Spodick DH. Reduction of QT-interval imprecisionand variance by measuring the JT interval. Am JCardiol. 1992;70:103.

19 Villain E. Amiodarone as treatment for atrial tachy-cardias after surgery. Pacing Clin Electrophysiol.1997;20(8 pt 2):2130–2132.

20 Beaufort-Krol GC, Bink-Boelkens MT. Sotalolfor atrial tachycardias after surgery for congenitalheart disease. Pacing Clin Electrophysiol. 1997;20(8 pt2):2125–2129.

21 Miyazaki A, Ohuchi H, Kurosaki K, Kamakura S,Yagihara T, Yamada O. Efficacy and safety of sotalolfor refractory tachyarrhythmias in congenital heartdisease. Circ J. 2008;72:1998–2003.

22 Mazur A, Anderson ME, Bonney S, Roden DM.Pause-dependent polymorphic ventricular tachycar-dia during long-term treatment with dofetilide: aplacebo controlled, implantable cardioverter-defibrillator-based evaluation. J Am Coll Cardiol.2001;37:1100–1105.

Congenit Heart Dis. 2014;9:221–227

Dofetilide in Congenital Heart Disease 227