New era for therapeutic strategy for heart failure: Destination therapy by left ventricular assist device

Availableonlineatwww.sciencedirect.com

j o ur n a l ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / j j c c

Review

New

era

for

therapeutic

strategy

for

heart

failure:

Destination

therapy

by

left

ventricular

assist

device

Shunei

Kyo

(MD,

FJCC)

,

Taishi

Minami

,

Takashi

Nishimura

(MD)

,

Satoshi

Gojo

(MD)

, Minoru

Ono

(MD,

FJCC)

a_{DepartmentofTherapeuticStrategyforHeartFailure,UniversityofTokyoHospital,Tokyo,Japan} b_{DepartmentofCardiothoracicSurgery,UniversityofTokyoHospital,Tokyo,Japan}

Received30October2011;accepted1December2011

Availableonline10February2012

KEYWORDS

Leftventricularassist device; Destinationtherapy; Heart transplantation; Bridgetotransplant; Heartfailure

Summary Until2010,JapanhadbeenusingtheToyobo(Nipro,Osaka,Japan)extracorporeal leftventricularassistdevice(VAD)developed30yearsagoasa2—3yearbridgeto transplan-tation(BTT).Incontrast,westernnationsstartedtouseimplantableVADsinthe1980sthat allowin-homecareasdestinationtherapy(DT)aswellasBTT.Designatedin2007as‘‘medical devicesinhighdemand,’’the5majorimplantablemechanicalheartsaresmoothlyundergoing clinicaltesting.TheHeartMateXVE(ThoratecCorp.,Pleasanton,CA,USA)gainedapprovalfrom theMinistryofHealthinNovemberof2009,theDuraHeart(TerumoHeart,AnnArbor,MI,USA) andEVAHEART(SunMedical,Nagano,Japan)inDecember2010,andobtainedformalinsurance reimbursementinApril2011.TheJarvik2000(JarvikHeartInc.,NewYork,NY,USA)and Heart-MateII(Thoratec)VADsarependingapproval.Ontheotherhand, theorgantransplantation lawallowingexplantationofdonororgansfrombrain-deadpatientsfinallypassedinJuly2009 andwasrealizedinJuly2010.Thislawpavedthewaytopediatrichearttransplantsaswell asadramaticincreaseinoverallorgantransplantationcases.Becausemanyjuvenilepatients awaitingdonororgansneedaVADasalong-termbridge,developmentandclinicalintroduction ofpediatricVADscapableofimplantationisanexigency.Althoughexpectationsfortransplants arehigh,thedonornumbersarelow.Therefore,thedemandforimplantableVADscapableof long-termhometreatmentisextremelyhighinJapan.

©2012PublishedbyElsevierLtdonbehalfofJapaneseCollegeofCardiology.

Contents

Introduction... 102 ArtificialhearttreatmentinJapan... 102 ImplantableVADuseindestinationtherapy... 102

∗_{Correspondingauthor.Tel.:+81358009082;fax:+81358009082.} E-mailaddress:kyo-stm@umin.ac.jp(S.Kyo).

0914-5087/$—seefrontmatter©2012PublishedbyElsevierLtdonbehalfofJapaneseCollegeofCardiology. doi:10.1016/j.jjcc.2012.01.001

ery(BTR),’’but asa temporarymeasureforself-recovery of the heart [4—6]. It was not intended for long-term care for chronic heart failure caused by cardiomyopathy. Recently,theconnotationofBTR hassignificantlychanged

[7—9], as it now refers to the recovery of the heart throughvariousmeansoftreatment,incorporatingsurgery

[10,11],medicine[12—14],cardiacresynchronization ther-apy [15—18], apheresis [19], and regenerative medicine

[20,17,21],andnotjusttheuseofVADs.

On the other end of the spectrum,the artificial heart projectthatstartedin theUSAduringthe1960saimedto makeareplaceableandimplantableventriculardevicethat wouldbetheultimatealternativetohearttransplantation

[22].Because of this prestigious objective,it took nearly 30yearsuntilthecompletionofAbioCorin2000(Abiomed, Danvers,MA, USA)(Fig.1) [23].However,in therealmof long-termversatility,itisstillfarfromperfection.Although theterm‘‘destination therapy(DT)’’insinuates an impec-cablealternative tohearttransplantation, becauseofthe limitstolong-termuseatthistime,itreferstothecareof elderlyorunfitpatientsthatarenotreasonablecandidates fortransplant[24].However,ifmechanicalhearttreatment can surpass the 10-year survival rate for heart transplan-tation,it isareasonablevisionthatVADswillbethemost commonformofcardiac failurecare, excludingtheyouth

[25,26].

Artificial

heart

treatment

in

Japan

In Japan, VAD treatment started in 1980 at the Mitsui Hospital[3] asa remedy for postcardiotomy heart failure (PCHF)andbyNovember2009,therehasbeen1128cases (Fig.2)[27].Themajorityofthosecasesareextracorporeal VADsmanufacturedbytheJapanesecompany,Nipro(Osaka, Japan)(Fig.3).ThefirstreportedcasethataVADwasused as a bridge to transplantation (BTT) occurred in 1992 at theSaitamaUniversity MedicalSchool andthe Osaka Uni-versityHospitalfor apatientwithdilatedcardiomyopathy [aNiproleft(L)VAD wasused]. The lattercase isthefirst successfulBTT,whena16-year-oldmalepatientwentfrom the University of Osaka to Texas in the USA and endured a 150-day bridge period.After the 1997 establishment of theOrgan Transplantation Law, hearttransplantation also started,withthefirstcaseoccurringin1999atthe Univer-sityofOsaka.ByJuly2010beforetherevisionoftheOrgan TransplantationLaw,therewereonly69hearttransplants.

receivedDT,eveniftheinitialpurposewasaBTT.Amajority of patients with extracorporeal VADs require hospitaliza-tion,whichstillconstitutesDT,butwithatremendouslylow qualityof life(QOL).Furthermore,manycardiologists are stilluneasyabout DTfor patientswhoarenoteligiblefor transplantation [28,29].Onthe brightside,thesuccessful implementationofimplantableLVADswillallowpatientsto returnhomeandwork,raisingtheQOL.Branchingfromthis, patients maybe abletoseekhigh qualityDT asan alter-native totransplantation inthenearfuture. Fourkindsof implantable LVAD which weresubmitted withthe request documentfromtherelevantacademic societiesabout the highestmedicalneeds,HeartMateXVE(1stgeneration), EVA-HEART (2nd generation),DuraHeart (3rdgeneration), and Jarvik2000(2ndgeneration)in2007andonemoreadded, HeartMateII(2ndgeneration),in2011.TheHeartMateXVE gainedapprovalfromtheMinistryofHealthinNovemberof 2009,theDuraHeartandEVAHEARTinDecember2010and obtainedformalinsurancereimbursementinApril2011.The Jarvik2000andHeartMateIIVADsarependingapproval.We havetreated20patientswithimplantablecontinuousflow LVADs(EVAHEART:8,DuraHeart:8,Jarvik2000:3,HeartMate II: 1) (Fig. 4)since2007 in theUniversity of Tokyo Hospi-tal andtheclinical outcomeofimplantable LVADsisquite differentfromthatofparacorporealNiproVAD(Fig.5).

Implantable

VAD

use

in

destination

therapy

Inrecentyears,manyJapaneseacademicconferences dis-putedthemeaningofDTwiththeuseofimplantableLVADs. In2008,thedefinition,‘‘long-termhometreatment,’’was proposed and it has been generally accepted ever since

[30]. In the past many total artificial hearts (TAH), such asthe1980Jarvik7[31]andthe2001AbioCor,underwent clinical trials [32] but none wereable to achievesuccess in DT.Rather inthepast 10years,theuseof implantable LVADs in DTfor patients not eligiblefor heart transplants dramaticallyincreased.Inthe2001HeartMateVEREMATCH study(RandomizedEvaluationofMechanicalAssistancefor theTreatmentofCongestiveHeartFailure)[33],theresults showed that HeartMate VE LVADtreatment excelled over internaltherapy.In2002,theUSFoodandDrug Administra-tion(FDA)approvedtheHeartMateVEforDT.Furthermore, in 2005, the HeartMate XVEstudy showedsimilar results, which certifiedincreasingDTrecords(Fig.6).Inthe USA, the HeartMate II underwent clinical trials for DT and

Figure1 Totallyimplantableartificialheart(AbioCor)producedbyAbioMed,Inc.(Danvers,MA,USA).

produced considerably enhanced records when compared to the HeartMate XVE. The American Heart Association (AHA)presentedtheserecordsin2009[34].Asaresult,the FDAapprovedtheHeartMateIIforDTinJanuary2010.

The

use

of

destination

therapy

Today’sVAD treatment, likepost-operativecomplications, cangenerally bebroken downintotwocategories: usein acutecardiac failure,suchasacutemyocardial infarction orfulminantmyocarditis,anduseinchronicheartfailure, suchasdilatedorischemic cardiomyopathy.However,the lineofdistinctionisunclearandisbecomingmoreandmore perplexing. That is to say, if a patient is diagnosed with acutecardiacfailureandrequiresaVAD,heorshehasthree options:(1)Waitforahearttransplant(BTT);(2)Resortto

long-termVADuseasameanstoDT;and(3)Usewith medic-inaltreatment or cardiacresynchronizationtherapy (CRT) asmeans of BTR aiming at recovery of patients’ cardiac function. However, these same options exist for patients withchronic heart failure (Fig. 7). Certainly, in a donor-lackingcountrylikeJapan,patientsanticipatingaBTTmay endupreceivingDTinstead.Likewise,apatienthopingfor aBTTmayultimatelyachieveaBTRbyself-rehabilitation. Japanalsohasalongaveragewaitperiodfordonorhearts, rangingfrom2to3years.Therefore,BTTcasesrequireat least a 2-year VADtreatment. In other words, VAD treat-ment asa BTT in Japan requires as muchdurability asa DTdevice usedinthe USA.Also,becauseJapan’s current limit heart transplants tothe age of 59 years andunder, patientswhocanpotentiallyreceiveBTTtreatmentin west-erncountriescanonlyreceiveDTinJapan.Unfortunately,

Figure2 NumberofventricularassistdevicesinJapanreportedintheJapaneseregistryofartificialheartsbyT.Nakatani.The 15thAnnualMeetingoftheJapaneseAssociationforClinicalVentricularAssistSystem(TokiMesse:theNiigataconventioncenter, 2009).

Figure3 Niproleftventricularassistdevice(LVAD)system.Left:LVADmountedonanatomicalmodelofthehumanbody.Right: drivingconsoleVCT-50.

thelack of Japanese evidence showingLVAD DT predomi-nanceoverinternal therapymakesit difficultfor patients toreceive financial reimbursement. In Japan, circulatory internaltherapyhasmanywaysoftreatment,including CRT-defibrillator, intra-aortic balloon pump, or percutaneous cardiopulmonarysupport.Becauseof this,VADswereonly usedfor patientswithStageD cardiacfailure(Table1).It wasconsideredtobeafinalprocedureratherthanaroutine one.Therefore,therealityis thatthereis littledatathat accuratelyVADrecords.However,usingaVADforpatients with Stage D cardiac failure makes a bias point on the recordsbecausethechancesofrecoveryareslim.Recently

inwesternnations,abridgetodecision(placinga tempo-raryVADinapatientandwaitingforrecoveryuntilfurther action)hasbecomeincreasingly popular[35,36]duetoits financialaffordability.

LVAD

destination

therapy

and

future

prospects

In November 2009, the AHA presented the results of the HeartMateIIDestinationTherapyTrial.Thistrialconsistedof datacontrastingthefirst-generationpulsatilepump Heart-Mate XVE(PFVAD)andthesecond generation,continuous

Figure4 Four kindsofimplantableleftventricular assistdevicewhich weresubmitted withtherequestdocumentfromthe

relevantacademicsocietiesaboutthehighestmedicalneeds,HeartMateXVE(ThoratecCorp.),EVAHEART(SunMedical),DuraHeart

Figure 5 Clinical outcome ofleft ventricular assist device (VAD)therapyintheUniversityofTokyoHospitalsince2007.The

clinicaloutcomeofimplantablecontinuousflowVADsisquite

differentfromthatofparacorporealNiproVAD.

flowHeartMateII(CFVAD)[34].TheHeartMateIIpumpwas roughly 1/5 the size and 1/3.5 the weight of the Heart-MateXVE.Itallowedeasierimplantationforuseonsmaller patients.Mostimportantly,thistrialshowedtheHeartMate II’ssuperiorityoverthepredecessorintermsof2-year sur-vivalrate.TheHeartMateIImanageda46%(62/134)survival rateat24months,freefromdisablingstrokeorre-operation for device replacement (intention-to-treat) versus an 11% (7/66)ratefortheHeartMateXVE.Becausethe134patients withtheHeartMateIIwereallincriticalcondition,either duetotheirage,bodymass,diabetes,highbloodpressure, renalfailure,orrecentmigranttumors,the46%survivalrate freefrommajorcomplicationswasextraordinary.The aver-age age of these patients was 62—63 years old and over

Figure7 The targetoftreatmentby implantable left ven-tricularassistdevice(LVAD)istocontrolheartfailureathome

andregainsocial activitiesforapatientwhoisdependingon

cathecholamineinhospital.ThegoalofimplantableLVAD

ther-apycanbehearttransplant(BTT),recoveryofthefunctionof

nativeheart(BTR),orlife-prolongingtreatment(DT,destination therapy).InJapanthehearttransplantisrestrictedextremely,

and we should consider it to be second guessing whether

the goal is BTT, BTR, or DT. CRT, cardiac resynchronization

therapy.

2/3 had ischemic cardiomyopathy with 20% experiencing braincomplications.Thestudiesonpost-operative compli-cationsalsoshowedthatmanysufferedrenalfailure,pump exchanges, infections, cardiac arrhythmia, and breathing problems(Fig.8). Perhapsaboveall, thepump complica-tions1—2yearsafterimplantation,HeartMateXVE’slargest drawback,droppedsharply(0.06/year vs.0.51/year),and HeartMateII’spumpexchangeratedecreasedto6casesout ofevery 100VADs. In January2010, theHeartMate II was

Figure6 Survival curvereportedinREMATCHstudy(HeartMateXVEDestinationTherapyTrial)andHeartMateIIDestination TherapyTrial.HeartMateIIshowedsignificanthighersurvivalrateattwoyearsoverHeartMateXVE[35,36].

circulation IIIinhibitor,orintra-aorticballoonpump,extracorporealventricularassistdevice Age Under65yearsisdesirable(dependingonphysicalstrength,ittakesaged65andover

intoconsideration)

Bodysurfacearea Asystemprescribesindividually Hemodynamics StageD,pasthistoryofNYHAClassIV

Condition ThepatientinwhichhighQOLcanbeobtainedbyparticipatinginmedicaltreatment, canperformlong-termhometreatment,andcanexpectsocialrehabilitationbythe patienttowhomtheprolongationoflifecouldnotbeexpectedunderothermedical treatmentand,towhomtheobstacleoftheQOLwascarriedoutremarkably Patientunderstanding She/heunderstandsthelimitandcomplicationsofanassistedartificialheart,andan

understandingandsupportofafamilyareobtained Exclusioncriteria

Infection Seriousinfection

Respiratoryailment Seriouschronicobstructivepulmonarydisease Advancedpulmonaryhypertension

Pulmonaryarteryembolismwhosesymptomswereshownwithin30days Cardiovasculardisease Theearlystageafteropenheartsurgery(abouttwoweeks)

Theabdominalaneurysmandtheseriousperipheralvasculardiseasewhichcannotbe treated

Thoracicaorticaneurysm,leftventricularaneurysm,rupturedinterventricularseptum Aorticinsufficiencymorethanmoderatedegree

Calcificationcriticalinthethoracicaorta Neuropathy Seriousdamageinthecentralnervoussystem

Drugintoxicationorthepasthistoryofalcoholdependence

Apsychoneuroticdisorderoritisnotfollowedtoaprotocol,totheextentthatitis judgedthatanunderstandingisimpossible

Otherorgandisease Systemicdiseases,suchasserioushepaticdisease,seriousbleedingtendency,advanced chronicrenalfailure,hemodialysispatientduetochronicrenalfailure,andvirulent diseasewithpoorlifeprognosessuchascancer,collagendisease,andinsulindependent diabetes

Pregnancy Underpregnancy

Others Thecasejudgedunsuitablebytheinstitutionalreviewboard,suchasremarkable overweightandtransfusionrefusal.

LVAD,leftventricularassistdevice;NYHA,NewYorkHeartAssociation;QOL,qualityoflife.

approvedforDTuse,andduetothis,itisthoughtthatDT willimprovedrastically.

Complications

with

LVAD

destination

therapy

and

the

trend

in

the

USA

Duetotheexpensiveprice,VADsin theUSAcancostover $150,000 including the surgery fee, the use of LVADs for

DT has been strictly controlled. In the early periods of LVADs, the hospital and insurancecompany had contracts that were in favor of the insurance company. Therefore, hospitalshadtobepreparedforafairlylargefinancialloss whentheyinstalledLVADs[37,38].InJapan,Novacor (Rueil-Malmaison,France)wasapprovedbyinsuranceagenciesas BTTappropriatein2004.However,duetothefactthatthe oldmodelwasapprovedandcostalargesumtoexchange batteries,themanufacturercouldnotmaintainuseofthe

Figure8 Comparisonoftwo-yearevent-freesurvivalrate(freefromdeath,disablingstroke,orre-operationfordevice replace-ment)betweenCFLVADandPFLVAD.SignificantsuperiorityofCFLVADintwo-yearevent-freesurvivalrate(46%vs.11%)[36].CF, continuousflow;LVAD,leftventricularassistdevice;PF,pulsatileflow.

product and dropped out of the competitive market in 2 years.Japanese academicsocietieshaverepeatedly asked forinsurancereimbursementsfordevicemaintenancepast 91daysforimplantableLVADs.Thistime,inregardstothe EVAHEART and DuraHeart VADs’ manufacturers’ approval

and insurance reimbursements, the academic society’s main concern is that those newregulations do notshape theJapanesemarketforimplantableLVADs[39].Withouta structuredmarket,implantableLVADswilldisappear,much like the Novacor VAD. Furthermore, patients waiting for

Figure9 Changesofinsurance reimbursementoftheHeartMate left ventricularassistdevice(LVAD) implantationsurgeryby

MedicareintheUSA.Althoughitwasalittlelessthan40,000-dollarreimbursedin2002whendestinationtherapybyHeartmate

VEwasrecognized,insurancereimbursementwasincreasedtoalmost200,000dollarsin2010whenHeartMateIIwasrecognized.

(Fig.9).Especially, the HeartMateII implantationsurgery at teaching hospitals received $290,000, which indicates ‘‘high qualitymedical care’’ for that medicalinstitution. Clinical effectiveness and medical costs should correlate withoneanotherinacapitalisticeconomythroughmarket theory.Byinitiatingthatcorrelation, thecompetitiverace tomanufacturehighqualitymedicaldevicesfinallybegins

[41—43]. Also, this motivation for higher achievement is vitaltoJapan’smedicaldeviceindustry.

Conclusion

In Japan, the fact that an extracorporeal VAD developed 30 years ago that gained approval 30-day use and medi-cal reimbursement for acute heart failure in 1994 which wasnot permitted for BTT use until 2006, being used as a2—3yearBTTiscompletenonsense.Notonlydoesforcing long-term hospitalization during the bridge period signifi-cantlyreduce patientQOL,butitalsolimitsthehospital’s profitduetothelack ofopenbedsfornewpatients. Sup-portinghospitalizationforover20patientswithVADsisan extremeburdenonthehospitalandtwo-thirdsofthemare notabletoreceiveadonororgan.Insummary,thelackin qualityandquantityofVADshasbeensolelycausedby gov-ernmentadministrations.Indevelopednationssuchasthe USA,patientsareallowedtorecoverat homeasaBTT or DT.Incontrast,thecurrentregulationinJapanseverely lim-itsthenumberofVADpatients.Isthissomethingthatcan beoverlooked?AsJapanattemptstoprovideeveryonewith fairmedicalcare,inreality,theadministrationis restrain-ing patients with 30-year-old VADs in hospitals until they either receive a donor heart or pass away. There is defi-nitely aneed toclearly saythat somethingis wrong. The clinicaltrialsforthe5majorimplantableLVADsdesignated in2007aregoingsmoothly.Thefirstendpointobservation (6monthsafterimplantation)hasbeencompletedandthe HeartMateXVEwasapprovedinNovember2009,the Dura-HeartandEVAHEARTinDecember2010;Jarvik2000andthe HeartMateIIarependingapproval.Incontrast,the regula-tionsforhearttransplantsaremorethan10yearsbehind. The neworgantransplant lawpassed in July 2009. There ismuchanticipation thatthisnewlaw willcarvethe way for pediatric organ transplants. Since minors have a high demand for long-term LVADs due to the extended bridge period, new, improved VADs are needed more than they everwere.

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