EfficacyofAtrial

Ibutilide for Termination ofFibrillation and Flutter

KennethA. Ellenbogen, MD, Henry F. Clemo, MD, PhD, Bruce S. Stambler, MD,Mark A. Wood, MD, and James T. VanderLugt, MD

Theclinicalutilifyal ibuiil”hbnarale (Gxwtl for theacutecanvmkmolairialtachyarrhythmias~mhtn:~sd@hm hasbeendemonstmlwl in stsvera

.

pkbmnhM clinicaltrials.Theekacy of intrave:nousibutitideformpidconversionofahialflutterisinthemngeOf50-7~o, whereasitsefficacyfarCanwrsh ofahialfibrktion is30-50%.Ap +tachyan+ythmiosthatterminfromtheinitiationof theintmvenaus infusion.Ibutitideismoreektive thaneitherintravenouspmcainamidaor in-tmvenaus5atcdalfar Canversianof atrialfibriltatianandahialher to sinusrhythm.Age,presenceof sfwlumlheartdisease,genderandCancamitantmedicationdanotappearto inkence theefficacyof ibutihde;however,shorterdurationofatrialfibrillationisa strongpmdictarafsuccessfultermination.Plasmacamentmlianof ibutitiiandQT. intend prolongationarenotdirectlycomebdwiththesuccessratefarcanversianofatrkdiachyanhyth-mias.Ibutdide’sgreaterefficacycomparedw’thotheran-

1butilide fumarate (Corvert, injection; Upjohn, Kal-amazoo, MI) is a novel intravenous antiarrhythmic

agent with class III antiarrhythmic properties. Ibu-tilide has been approved by the Food and Drug Ad-ministration for the rapid conversion of atrial fibril-lation or atrial flutter to sinus rhythm. l%is reviewsummarizes the pharmacology and the results ofclinical trials that document the efficacy of ibutilidefor the termination of atrial tachyarrhythmia.

CLINICALPHARMACOLOGYThe effects of ibutilide fumarate have been pri-

marily attributed to its class III activity and its phar-macodynamics. In healthy male volunteers, ibutilidefumarate has been given as a rapid infusion (0.03mg/kg/10 rein) or as a continuous infusion (0.1 mg/kg/8 hours) and resulted in prolongation of the QTCinterval by 38–43Y0.1The QT. interval prolongationcorrelated directly with the plasma concentration ofibutilide. Infusions of ibutilide did not result in clin-ically significant alterations of blood pressure, heartrate, or QRS intervals. In patients with reduced leftventricular function (left ventricular ejection fraction<3570), ibutilide had no significanteffect on cardiac

From the De artment of Medicine (Cordiolo y) (K.A, E., H. F.C.,$ YM. A.W.) an Physiology (H. F.C. ), Medical Co Iege of Virginia and

McGuire Veterans AHairs Medical Center; West Raxbury VeteransAffairs Medical Center and Harvard Medical School (B.S.S.], WestRoxbury, Massachusetts; and Pharmocia& Upjohn, Inc. (J.T.V.), Kal-amazoo{ Michigan.

Address for re rints: KennethA. Ellenbogen, MD, Clinical Elec-Etrophysialogy La oratory, Medical College of Virginia, Box

~ 980053{ Richmond, Virginia 23298-0053.

tia+hmic drugsmaybe relatedb itsabilitytocausegmaierpmbngatbnofairiolmonaphasicactionpotentialduraiian&live toatriolcyclelength.Twminatkmofatrialflutterwithibutilidewasprecededbyincreased*al cyclelengthvariability.Ibutilidam . Iyanddhscti+canverts

fahialfibrillationand atrial utterto sinusdylhm whenadministwwdasa l-mg totaldosefollowedby a secondl-mgdose.ItshauldbeJusedincan@tionwithcontinuouseMrocardiogm*icmonitoringforat least4 hoursofbrthetsmninatianal theinfusion,or untiltheQT. intervalreturnsto baseline.liypokalemiaand hypomagnesemiashouldbe comecbdbeforethestartof theinfusion.AnexternalcardiacdefiHatar, intmvenousmagnesium,andanexiemaltranscutaneauS cardiac pacemakerShOU~ k

readily availablefar immediateuseintheeventthatpol-ymorphicventriculartachycdythmiasoccur.Ibutilideisanewinlmvwawagentthatsafelyand mpidlyconvertsatrialfibrillationandatrialfluttertosinusrhythm.

(AmJCardial1996;78(suppl8A):42-45)

output, mean pulmonary arterial pressure, or pul-monary capillary wedge pressure.

The pharmacokineticsof ibutilide are unique andhave implicationsfor its dosing.Ibutilidefumaratehasa high plasma clearance rate that approximates liverblood flow and follows a triexponentialcourse.2It ismetabolized primarily by the liver to inactive metab-olizesby oxidation.Ibutilidemust be infused intrave-nously because the bioavailabilityof orally adminis-tered ibutilide fumarate is low due to the extensivehepatic metabolism. While many metabolizesof ibu-tilidehave been identified,none of them has significantantiarrhythmicproperties.Importantly,the metabolismof ibutilidedoes not appear to be affected by digoxin,$1blockers,or calcium antagonists.Approximately5-10?ZOof ibutilideis recovered intact in the urine.

The drug’s elimination half-life is approximately6 hours, with a range of 2–12 hours.3 In healthyvolunteers, the pharmacokinetics of ibutilide fuma-rate are linear with respect to the dose of ibutilideinfused over the range of 0.01–0.1 mg/kg during an8-hour infusion. Ibutilide consists of 2 enantiomerswhose pharrnacokinetic and electrophysiologicproperties are similar to each other. The pharmaco-kinetics of ibutilide in patients being treated for atrialflutter and atrial fibrillation are similar to those mea-sured in healthy volunteers. There is little informa-tion available about the clearance of ibutilide in pa-tients with severe congestive heart failure ormoderate to severe reduction in creatinine clearance.

CLINICALTRIALSTheclinicalutilityof ibutilidefumaratefor the con-

version of atrial tachyarrhythmia to normal sinus

42 01996 by Excerpta Medica, Inc.

All rights reserved.

0002-9149/96/$15.00

Pll S0002-9149(96)00565-6

rhythm was first demonstrated in a pilot study byDiMarco in 1991.4In this dose-rangingstudy, 17 pa-tients with atrial flutterand 19 patientswith atrial fib-rillation were treated with sequentialdoses of intrave-nous ibutilide(0.005,0.010, and 0.020 mg/kg) infisedover 10 minutes and separated by 5-minute intervals;10% of the patientsconvertedto normal sinus rhythmat the lowest dose, 50% converted with a cumulativedose of =0.015 mg/kg, and 90% convertedwith a cu-mulativedose of s0.035 mgkg. In all cases, ibutilidesignificantlyprolongedthe QTGinterval.

In subsequent trials, ibutilide has been administ-ered to an additional 1,000 patients.

Ibutilide’s efficacy was tested in a study involving100patients with sustainedatrial fibrillation(durations90 days) and 100 patients with stable atrial tlutter.sThis dose-ranging study involved the use of placeboor one of several intravenous doses of ibutilide,0.005-0.025 mg/kg, infused over 10 minutes. Theplacebo conversion rate was 3%. At a dose of 0.010mgkg, ibutilide fumarate restored sinus rhythm in30% of the patients with atrial flutter and 37% of thepatients with atrial fibrillation. A peak efficacy of58% for conversion of atrial flutter to normal sinusrhythm was observed with the 0.015 mg/kg dose. Inthe setting of atrial fibrillation,a peak efficacyof 40%was seen with the 0.025 mg/kg dose, Almost 80% ofthe atrial tachyarrhythmiaswere terminated within 30minutes from the start of the ibutilide infusion; <590of the atrial tachyarrhythmiasconverted with placebo.Six of the 200 patientsexperienced an episodeof non-sustained or sustainedpolymorphicventricular tachy-cardia.

In a subsequent double blind, randomized, pla-cebo-controlled, parallel group study, ibutilide fu-marate was administered as a “mg total dose,” in-stead of as a mglkg doseG;133 patients with atrialfibrillation and 133 patients with atrial flutter (dura-tion ranging from 3 hours to 45 days) were enrolled.The patients were equally stratifiedbased on arrhyth-mia type and dose. Each patient received a 10-minuteinfusion of either ibutilide or placebo. If the patientfailed to convert to normal sinus rhythm, a second10-minuteinfusion of placebo or ibutilide was given.Randomization groups included placebo/placebo, 1mg/O.5 mg ibutilide, and 1 mg/1 mg ibutilide. Theoverall 4770 conversion rate for the ibutilide groupswas significantlygreater than the conversion rate forthe placebo group (270).There was no significantdif-ference in conversion rates between the 2 regimensof ibutilide. The ibutilide regimens restored sinusrhythm in 6390of patients with atrial flutter and 31~oof patients with atrial fibrillation. In patients whofailed to convert to normal sinus rhythm with a firstdose of ibutilide fumarate, a second dose converted279?0(0.5 mg) and 36Y0(1 mg) of patients with eitheratrial fibrillation or atrial flutter to normal sinusrhythm. Of the patients who converted to sinusrhythm, ejection fraction, valvular heart disease, con-comitant medications, plasma ibutilideconcentration,and QT. interval prolongationdid not predict arrhyth-mia termination. In atrial fibrillation, but not atrialflutter, conversion rates were higher in patients with

a shorter arrhythmia duration or with a normal leftatrial size.

No clinicallysignificanteffects of ibutilideon sys-tolicor diastolicbloodpressurewere noted in the dose-ranging trials.s,sHeart failure was not significantlyworsenedby the ibutilideinfusion.There were no com-plicationsinpatientswho failedto convertafteributilidehfusion, directcurrentcardioversion,oratrial overdrivepace termination.Ibutilideenhancesthe abilityof over-drive pacing to terminate atrial flutter.TThere was noevidence in either trial to suggest that ibutilideraisedthe atrialdefibrillationthreshold.

A European study comparing ibutilide with intra-venous sotalol in 319 patients (260 with atrial fibri-Iation, 59 with atrial flutter)has been completed.sPa-tients received a single infusion of 1 mg ibutilide, 2mg ibutilide, or 1.5 mg/kg of intravenous sotalol. Ei-ther dose of ibutilide was significantlymore effectivethan intravenous sotalol in converting atrial fibrilla-tion or atial flutter to sinus rhythm. The 2-mg ibutil-ide dose converted >60fZ0of patients with atrial flut-ter and >409i0 of patients with atrial fibrillation.Intravenous sotalol terminated atrial flutter in 20% ofpatients and atrial fibrillationin 15% of patients. Theefficacy of ibutilide for termination of atrial fibrilla-tion and atrial flutter in these 3 large, randomized tri-alsj,b,aare summarized in Figure 1.

Prelim&y results of a double blind placebo-con-trolled trial comparing intravenous ibutilide to intra-venous procainamide in 127 patients with atrial fib-rillation and atria] flutter of 3 hours to 90 daysduration showed a 2- to 3-fold greater chance of con-version to sinus rhythm with ibutilide.g

A prospective,nonrandornizedcomparison of theabilityof intravenousibutilideand intravenousprocain-amide to convert patients with either atrial flutter oratrial fibrillationto normal sinus rhythm has been re-ported by Stambler et al.lo Sixty-sevenpatients withatrial fibrillationor atrialflutter,with durationsrangingfrom 3 hours to 90 days, receivedplacebo,or ibutilidefumarate (dosesof 0.005 to 0.025 mglkg), or procain-amide(12– 15mglkg)as an intravenousinfusion.In thesetting of atrial flutter, sinus rhythm was restored in37%of thepatientsreceivingibutilideandin no patientsreceivingprocainamide.In the settingof atrial fibrilla-tion, sinus rhythm was restored in 429oof patients re-ceiving ibutilideand in 95Z0of patients receiving pro-cainamide.The increasedefficacyof ibutilidefurnaratemay be related to its ability to cause a greater prolon-gation of right atrialmonophasicaction potentialdura-tion relative to atrial cycle length prolongation.]]Al-thoughprocainarnide prolongedatrial cycle length to amoderate degree, it had a lesser effect on prolongingrightatrialmonophasicactionpotentialdurationor atrialrepolarization.

The conversionof atrial flutter to sinus rhythm byibutilide was analyzed by measuring beat-to-beatchanges in atrial cycle length.ll Twenty-five patientswith stable atrial flutterwere treated with ibutilidefu-marate doses of 0.005-0.025 mg/kg. Atrial cyclelength variability and atrial cycle length were mea-sured at baseline, immediatelybefore conversion,and5 minutes after infusion in those who did not convert.

A SYMPOSIUM: TREATMENT OF ATRIA1 FIBRIIIATION AND FLUTTER 43

Protocol 0014

Successrate (%)

60

40

20

Protocol 0015 Protocol 001960

1

40

.1

In20

oO.&s0.;10O.rilsO.&s 1 mg/O.5mg 1mgll mg 1 mg 2mg

mg/kg(logscale)

FIGURE1. Conversionmfesfor afrial fibrillaiianand atrial flutterfrom 3 doubte-blind,pkl-cebo-controlledfrialsof ibufilide.sA’8

150

1

■ Succsss

❑ Fsilure

100

AQTCfrombaaeline(msec) TT — T

-.

0.005 0.010 0.015Ibutilide (mglkg)

0.025

FIGURE2. Thsincreaeein QT. inferwddid not prsdicfwhichpafienteconvertto sinusrhythmwhile taking ibutilide.5

Ibutilidesignificantlyincreasedatrialcycle lengthvari-abilityonly in converters,whileit increasedatrialcyclelength in both convertersand nonconverters.This find-ing is consistent with the hypothesis that conversionof atrialllutter by ibutilideis associatedwith increasedvariability in atrial cycle length as noted in patientswith other supraventricularand ventricular tachycar-dias.12

Measurement of the QT interval in the setting ofatrial fibrillationand atrial flutteris difficult.Rate cor-rectionof the QT intervalis problematicdue to thewiderange of beat-to-beatheart rate changes seen in atrialfibrillation.Ibutilideinfusionis typicallyassociatedwithdose-dependentQT prolongation,sometimesto quite astriking degree. Termination of atrial fibrillationandatrial flutterdoes not appearto be predictedwell by thedegree of QT prolongation(Figure2). Analysisof vari-ance in severalstudiesdid not show a differencein QTintervalprolongationbetween patientsreceivingibutil-ide who converted and patients who did not convert.This findingimpliesthat dosing ibutilideinfusionsto apredefine QT intervalor degreeof QT prolongationtoachievereversionto sinusrhythmis unlikelyto be clin-ically useful. Variablessuch as age, presenceof struc-turalheartdisease,gender,and concomitantmedication

(e.g., atrioventricular[AV]nodalblockingdrugs)failedto predict successfulterminationof atrial fibrillationoratrial flutterby ibutilide.Only shorterdurationof atrialfibrillationpredicteda higherchanceof successfulcon-versionto sinusrhythm with ibutilide.

Experience with ibutilidefor the treatment of ven-tricular tachycardia is limited at the present time. Inthe firstclinicalexperiencewith ibutilidefor sustainedmonomorphic ventricular tachycardia, it suppressedreinduction of sustained ventricular tachycardia in44% of patients undergoing electrophysiologictest-ing.lq Studies examining the efficacy of ibutilide inpost–cardiac bypass or post–valve replacement pa-tients have been completed recently.

COMPARISONWITH OTHERAGENTSPrevious studies have examined the acute efficacy

of intravenousprocainamidefor the acute terminationof atrial fibrillationand atrial flutter.14-lcRestorationofsinus rhythm in 43–64% of patients with atrial fibril-lation receivingintravenousprocainarnidehas been re-ported in these trials. The mean duration of atrial fib-rillationin patientswas only 6 days in 2 trialsand <72hoursin a thirdtrial.Thesetrialsdifferfromthe ibutilidestudiesin that the durationof atrial fibrillationwas sig-

44 THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL 78 (8A] OCTOBER 17, 1996

nificantlyshorterin the patientsreceivingprocainarnide.Direct comparisonof differentpatient populationsre-ceiving intravenousprocainarnideto patientsreceivingibutilidein othertrialsis difficult,as thedurationof atrialfibrillationmay be themostimportantvariableppxlictingarrhythmiatermination.Few dataare availableregardingthe efficacyof intravenousamiodaronefor terminationof atrialtachyarrhythmias.A preliminaryreportcompar-ing intravenous dofetilide to intravenous amiodaronefound a conversionrate of 35% for patientswith atrialfibrillationwho receiveddofetilideand 4% for patientswho receivedintravenousamibdarone.17

There are no prospectivestudiescomparing ibutil-ide or other antiarrhythmicagentsto directcurrentcar-dioversion alone. In one study,18 Resnekov andMcDonald reported an immediate successrate of 88%in 220 patients, but 13$Z0reverted to atrial fibrillationwithin 24 hours; approximately 40% were receivingquinidine. Ibutilideinfusion would not be expected topreventrecurrencesof atrialfibrillation.In the ibutilidestudies cited above, chronic antiarrhythmicdrug ther-apy was initiated within 24 hours in many patients.Patients shouldbe anticoagulatedwith heparin,or cou-madin, before and after chemical or electricalconver-sion of atrial fibrillation.

MODE OF USEIbutilide’fumarate is administered intravenously

for the acute treatment of atrial tachyarrhythmias.Ibutilide’isgenerally effective within 1 hour of intra-venous administration. It is strongly recommendedthat patients receiving ibutilide undergo continuouselectrocardiographic monitoring for at least 4 hoursfollowing termination of the infusion or until the QTCinterval has returned to baseline. Longer monitoringmay be necessary if the patient developspolymorphicventricular tachycardia. Hypokalemia and hypomag-nesemia should be corrected before infusion of ibu-tilide. A cardiac defibrillator, a transcutaneous (ex-ternal) cardiac pacing device, and intravenousmagnesium should be readily available for immediateuse if necessary.

Current recommendations for dosing are an initiall-mg infusion over 10 minutes for patients weighing>60 kg (132 pounds), followed 10 minutes later bya second 10-minute infusion of equal dosage. In pa-tients weighing <60 kg, the initial and subsequentinfhsion dose is 0.01 mg/kg.

Ibutilide is potentially useful in several groupsof patients requiring conversion of atrial fibrillationor flutter. It would be especially useful in the man-agement of patients with a first episode of atrialfibrillation or in patients in whom chronic antiar-rhythmic drug therapy is not contemplated. In theintensive care unit setting where patients cannottake oral medication, ibutilide would be useful fortermination of atrial fibrillation, especially in thosewith compromised left ventricular function or thoseunable to tolerate the hypotension frequentlycaused by intravenous atrioventricular nodal block-ing drugs. Ibutilide has potential utility as therapyfor patients with atrial fibrillation in the operatingroom or in the cardiac’ catheterization laboratory

where rapid restoration of sinus rhythm is desirable.The safety and efficacy of ibutilide in patients pre-senting with recurrent atrial fibrillation while takingclass 1A or IC antiarrhythmic drugs is unknown;its use in this situation may be an area of futureclinical investigation.

CONCLUSIONSIbutilide is a new and effective agent for the con-

version of atrial fibrillationand flutterto noqnal sinusrhythm. It has minimal hemodynamic effects and israpidly effective in the termination of atrial arrhyth-mia. The appropriate use of ibutilide requires moni-toring of a patient’s electrocardiogram,awareness ofthe potentialfor proarrhythmia,and the abilityto man-age proarrhythmia if it occurs. Future studies areneeded to evaluatethe role of ibutilidein patientswithrecurrent atrial fibrillation already taking antiar-rhythmicagents,as well as the assessmentof the short-and long-termbenefitsof ibutilidein patientsfollowingopen heart surgery.

1. VauderLugt JT, Gaylor SK, Wakefeld LK, et al. Effects of ibutilide fumarate,a new class III arrtiarrhythrric agent. Cbr PharrrracolTher 1991;49:188.2. Jungbluth GL, VanderLugt JT, Kabell GG, Walters RR. The pharrnacoti-netics and pharmacodynamics of ibutilide fumwate after intravenous infusionsin healthy volunteers. PharrnRes 1990;7:S211.3. Jungbluth GL, Della-Coletta AA, VanderLugt JT. Evaluation of the phar-macokinetics arrdpharrriacadynarnics of ibutilide fumarate and its errantiomersin healthy male volunteers, PharrrrRes 1991;8:S249.4. DiMarco JP. Cardioversion of atrial flutter by intravenous ibutilide, a newclass III antiarrhythrnic agent, (Abstr.) JAm Coil Cardirrl 1991;17:324A.5. EllenbogenKA, StarnblerBS, Wood MA, Sager PT, Wesley RC, Meissner MD,Zoble RG, Waketield w Perry XT, VunderLugtJT, fur the Ib+rdlideInvestigatorsEfticucyof irrtravenousibutilidefor acute teminadon of atrial fibrillationarrdatrialflutter:a dose response study.JAm COUCardiol 1996;28:130-136.6. Mumbler BS, Pnrtnow AS, Wood MA, et al. Proven efficacy of repeated doseintravenous ibutilide, a class III rmtiarrhytbmic drug for rapid termination ofchronic atriaf flutter or fibrillation: results of a multicenter placeo controlledstudy. (Abstr.) JAm COUCardiol 1995;25:230A.7. Starnbler BS, Wood MA, Ellenbngen KA. Comparative efficacy of intrave-nous ibutilide versus procainarnide for enhancing termination of atrial flutter byatrial overdrive pining. Am J Cardiol 1996;77:960-966.8. Harry JD, Perry KT, Grauwels D, Wakefield LK, VanderLugt JT. A multi-national study comparing the safety and efficacy of intravenous ibutilide fu-rnaratc with the safety and efficacy of intravenous dl-sotalol in termination ofatrial flutter arrd atrird fibrillation. Technical Report on file with FDA.9. Volgman AS, Stumbler BS, Kappagoda C, et al. Comparison of intravenousibutilide versus procainamide for the rapid termination of atrial fibrillation orflutter. PACE Pacing Clin Electrophysiol 1996;19:608.10. Stambler BS, WmM MA, Belz MR. et rd. Electmphysiologicdeterminants ofpharrmicologiccmrvemionof human amid fibrillationand flutter:enhancedefficacyof ibutlide, a new class ff3rmtkdrythrnic drug. Cimdatirm 1993:88:1-445.11.Guo GB-F, Ellenbogen KA, Wood MA, et al. Conversion of atrial flutterbyibutilide is a.ssrrciatcdwith increased atrial cycle length variability. JAm COUCardiol 1996;27:1083-1089.12. Duff HJ, Mitchell B, Gillis AM, et al. Electrocardiographic correlates ofspontaneous termination of sustained ventricular tachycmdia associated withcoronary disease. Circukrtimr 1993;88:10541062.13. Wood M, Stambler B, Gilligan D, et al. Suppressionof inducible ventriculartachycardia by intravenous ibutilide in patients with coronary artery disease.PACE Pacing CZin.E3ecfrophysiol1996;19:618.14. Fenster PE, Comess KA, Marsh R, et al. Conversion of atrial fibrillation tosinus rhythm by acute intravenous procainmnide infusion. Am Heart J1983;106:501-504..15. Halpem SW, Ellmdt G, Singb BN, MarrdelWJ. Efficacy of intravenous pm-cainamide infusion on convertirw atrial fibrillation to sinus rbvtbrn. Br Heart J1980;44:589.16. Madrid ~, Mum C, Marin-Hnerta E, et al. Comparison of flezainide arrdpm aimmrideirrcaediovemionofatrial tibrillatinn.Eur HearlJ 1993;14:1127-1130.17. Biarrconi L, Dinelli M, Pappahudo A, et ULComparison of intravenouslyadministered dofetilide versus arniodarone in the acute termination of atrialfibrillation and flutter. A multicenter, randomized, double-blind, placebo-con-trolled study. Circulation 1995;92:1-774.18. Resnekov L, McDonald L. Appraisal of electroconversion irr treatment ofcardiac dysrhythrnias. Br Heart J 1968;30:786-811.

A SYMPOSIUM: TREATMENT OF ATRIAL FIBRIL4TION AND FLJ~ER 45