Questions Raised During Public Consultation Phase

1192:

Final Decision Analytic Protocol (DAP) to guide the assessment of reduction of mitral regurgitation through tissue approximation using transvenous/transseptal techniques

May 2012

Table of Contents

Questions raised during public consultation phase

MSAC and PASC

Purpose of this document

Purpose of application

Intervention

Indication for intervention

Description of intervention

Administration and duration of treatment

Co-administered interventions

Background

Current arrangementsfor public reimbursement

Regulatory status

Patient population

Clinical place for proposed intervention

Proposed MBS listing

Comparator

Mitral valve repair or replacement surgery

Medical management

Clinical claim

Outcomesandhealthcareresourcesaffectedbyintroductionofproposed intervention

Outcomes

Health careresources

Proposed structure of economicevaluation (decision-analytic)

Clinical research questions for public funding

Decision analytic diagram

References

Questions raised during public consultation phase

ThefollowingquestionswerepresentedintheConsultationDAP,whenthedocumentwasavailable for public review and comment:

1. Ithasbeenproposedthatconsideration of thisdeviceforpublic fundingmaybepremature at thisstage;basedonthe adequacyor inadequacy ofavailableclinicalevidence(considering issuessuchasavailablelengthoffollow-up andpatientpopulationsexamined),shouldthis assessment proceed?

1. Ifnot,whatadditionalevidence(e.g.longerfollow-upofsafetyand/oreffectiveness outcomes, evaluation ofspecific patientpopulations)may be required?

1. Ifso,isitreasonabletorestrictthepopulationgrouptothosepatientsmeeting eligibility criteria for available clinical studies?

1. IsanydetailedinformationavailableregardingtheMitraCliptrainingprogram,oranyspecific accreditationrequired for practitioners to perform thisprocedure?

NocommentsonthesespecificquestionsorontheConsultationDAPingeneralwerereceivedduring the public consultation phase.

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MSAC and PASC

The Medical ServicesAdvisoryCommittee(MSAC)isanindependentexpertcommitteeappointedby theAustralianGovernmentHealth Minister to strengthentheroleof evidenceinhealth financing decisionsinAustralia.MSACadvisestheCommonwealthMinisterforHealthontheevidencerelating tothesafety,effectiveness,andcost-effectiveness ofnewandexistingmedicaltechnologiesand proceduresand under what circumstances public funding should be supported.

TheProtocolAdvisorySub-Committee(PASC)is astandingsub-committee ofMSAC.Itsprimary objectiveisthedeterminationofprotocolstoguideclinicaland economicassessmentsof medical interventionsproposed forpublic funding.

Purpose of this document

Thisdocumentisintendedtoprovideadraftdecision analyticprotocolthatwillbeusedtoguidethe assessmentofaninterventionforaparticularpopulationofpatients.Thedraftprotocolwillbe finalisedafter invitingrelevantstakeholderstoprovideinputtotheprotocol.Thefinalprotocolwill provide the basis for the assessmentofthe intervention.

Theprotocolguidingtheassessment ofthehealthinterventionhasbeendevelopedusingthewidely accepted “PICO” approach. The PICO approach involves a clear articulation of the followingaspectsof the researchquestion thatthe assessment is intendedto answer:

Patients–specificationofthecharacteristicsofthepatientsinwhomtheinterventionistobe considered for use;

Intervention– specification of the proposed intervention

Comparator–specificationofthetherapymostlikely tobereplacedbytheproposed intervention

Outcomes–specificationofthehealthoutcomesandthehealthcareresourceslikelytobe affected by the introductionof the proposed intervention

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Purpose of application

AproposalforanapplicationrequestingMedicare BenefitsSchedule(MBS)listingofpercutaneous reconstructionofaninsufficientmitral valvethroughtissueapproximationusing transvenous/transseptaltechniquesforpatientswithmitralregurgitationwasreceivedfromAbbott Vascular by the Department of Healthand Ageing in August 2011.

Intervention

Indication for intervention

Themitralvalveis one offourvalvesinthe heartwhichfunctiontoensurethatbloodflows unidirectionally.Properfunctioningofthemitralvalveisdependentonacomplexinteraction between thevalveleaflets,valveannulus,sub-valvularapparatus,comprisedofthechordaetendineaeand papillarymuscles,and theleft atrium andleftventricle. Mitral regurgitation(MR)occurs whenthe mitralvalveleafletsdonotcoaptorcloseproperly,allowingbackwardflowofbloodfrom theleft ventricleintotheleftatriumduringsystole.Asaconsequencethereisdecreasedforwardflowinto theaortaandsystemiccirculation,requiringthehearttoworkhardertomaintainanadequate forward strokevolume.MRisaprogressivecondition; over time, left ventricular (LV) dilatationoccurs inanattempttoaccommodatetheincreasedvolumeloadand maintaincardiacoutput.Often,the resultisapureleftventricularvolumeoverload which,ifprolonged,canleadtoleft ventricular remodelling and progressive left ventricular dysfunction (Olsonet al1987).

MRisacomplexandheterogeneouscondition, andcanbeclassifiedasprimaryorsecondary dependingonthe underlyingpathophysiology. Thetwocategories havedifferingaetiology,natural history,treatmentoptionsandoutcomes.Primary MR,alsoreferredtoasDegenerative MR(DMR), referstoMRcausedbyastructuralabnormalityof thevalveapparatuswhichresultsinpoorleaflet coaptation. Common aetiologies of DMR include myxomatous degeneration and fibroelastic deficiency.In patientswithdegenerativeMR theleftventricleis usuallynormalinsize and function initially.Withtheonsetof MR,LVcontractilityincreasestocopewiththeincreasedvolumeload,but overtimeLV dilatation andsystolic impairment occur.Inthecaseofsevere degenerativeMRthere maybeaprolongedasymptomaticphase,followedbysubstantialmorbidityandmortalitydueto heartfailureandarrhythmia.InsecondaryMR,also referredtoasfunctionalMR(FMR),themitral valveisgenerallystructurallynormal.Poorleafletcoaptation occursdueto anabnormalityof theleft ventricleorpapillarymusclesassociated witheitherlocalised(e.g.ischaemiaor infarction)orglobal (e.g.cardiomyopathy)causes(Rosenetal1994).Ingeneral,patientswithFMRhave apoorerLV contractilereserveand as sucharelessabletoincreaseLVstrokevolumeinresponsetoMR.FMRis more common than DMR,and is associated with a poorer prognosis.

Whileasmallproportionofpatientspresentwith acutesevereMR,themajoritypresentwithchronic progressivediseasewhich mayormay notbesymptomatic.Prognosisforpatientswithmoderateor severeMRcanbepoorinbothsymptomaticandasymptomaticpatients.Ifleftuntreated,MRcan leadto pulmonary oedema,congestive heart failure,irreversible LV systolicdysfunction,thromboembolismresultingfromatrialfibrillation,andinsomecasessuddendeath(HansonandAlfonso 2011), and shouldbe considereda significant cardiovascular disease.

Description of intervention

TheMitraClipsystemisbasedontheprincipleofedge-to-edge repair(alsoknownasthe‘Alfieri technique)– anexistingsurgicaltechniqueformitral valverepairinwhichasutureisplaced through themiddlescallops ofthe mitralleafletstoform adoubleorifice valve. Thedoubleorifice structure reducesMRbutstillenablesadequatebloodflowthroughthevalveduringdiastole.TheMitraClip systemisa catheter-baseddevicewhichenablesphysiciansto performpercutaneousmitralvalve repairforthetreatment ofMR,providingan alternativetoongoingmedicalmanagementand conventionalopenchest,arrestedheartsurgery.Inplaceofasutureasusedinconventionaledge- to-edgesurgicalrepair,a mechanicalclipholdsthemiddleportionofthevalveleafletstogetherto form a double orifice valve for MR reduction.

TheMitraClipsystem consists of three major technological components:

•MitraClipdevice(implant):a4mm-widecobalt-chromiumimplantwithtwoarmsthatare openedandclosedbyamechanismonthehandleoftheclipdeliverysystem.Adjacentto eacharmis a‘gripper’tosecuretheleaflets astheyarecapturedduringclosure ofthe arms. Eachleafletisindependentlysecuredbetweenanarmandagripper.Theclip hasalocking mechanismtomaintainclosureandis covered withapolyester fabricto promotetissue ingrowth.

•Clip delivery system.

•Steerableguidecatheter:atri-axialcatheterthattogetherwiththeclipdeliverysystem enablesplacementofthecliponthemitralvalveleaflets.Dialsontheclipdeliverysystem and catheterhandle allowdeflection inmultiple planes.

Administration and duration of treatment

Apatientwillgenerallybereferredbyageneralpractitionertoacardiologistifthepresence ofMRis suspected,whointurnrefersthepatienttoeitheraninterventionalcardiologistor acardiothoracic surgeon.Itisproposedthata‘heartteam’will jointlyrecommend apatientreceive treatmentwith MitraClip.Whilefurtherdetails ontheexactprofessionalcompositionof thisheartteam are required, expertopinionsuggeststhisshouldincludecardiothoracicsurgeonsandboth aninterventionaland non-interventionalcardiologist. Having arecommendationfrombothcardiologistsandcardiothoracic surgeonshelpsfacilitate anappropriateandoptimal approach towardspatient selection andtherapy delivery.Furtherdetailisrequiredastowhether aheartteamwouldbereimbursedunder a"case- conferencing"item rather than individualconsultationitems.

TheMitraClipprocedure isperformed whiletheheart isbeating,whichbetter allowstheidentification oftheoriginofMR.Theguidecatheterandclip deliverysystemareintroducedthroughthefemoral veinandintotheleftatriumviatransseptalpuncture.Theclipis advancedintotheleftatriumand steereduntil positioned overthe originof theregurgitantjet. The cliparmsare opened,theclip advancedintotheleftventricleandthenretracteduntilbothleaflets aregrasped.Closureoftheclip drawsthemitralleafletstogether. TheMitraClipsystemisdesignedtoenablethephysiciantoassess leafletcoaptationandMRreductionpriortofinaldeployment oftheMitraClipdevicebyintraoperative transoesophagealechocardiography.IfthephysicianisnotsatisfiedwithMRreductionuponinitialplacement of the MitraClipdeviceafterthemitral valveleafletshavebeengraspedand approximated, theclipcanbereopened,leafletsreleased,andthecliprepositioned.When adequatereductionofMR has been achieved, the clip is deployed. If, during deployment of one MitraClip device, it is determinedthata second MitraClipdevicewouldresultinfurtherreductionofthepatient’sMR, the physicianmayplaceaseconddevice.Followingclipdeploymentthedeliverysystem andcatheter are withdrawn andthevenouspuncturesiteisclosed. Theaveragelengthof aMitraClipprocedure,as measuredfromthetimeoftransseptalpuncturetoremovalofthesteerableguidecatheter,isunder2 hours.

Anumberof scenariosexistwithrespecttotreatmentfailure.If MRisunabletobesatisfactorily reducedduringtheprocedure,thephysicianisabletoremovetheMitraClipdevicecompletely, leaving the patient with the same therapeutic options as prior to the procedure, including surgical intervention.However,itisimportanttonotethattheMitraClipdeviceand deploymentsystem is single-use, and cannot be reused in subsequent procedures. If MR recurs subsequent to an initially successful MitraClipprocedure,afurtherinterventionwithaseconddeviceisonepossibletreatment option ifasingledevice wasimplantedintheinitialprocedure.Surgicalrepair mayalsobean option afterMitraClipfailure;however,thelikelihoodof successfulsurgicalrepair maybereduceddueto changesinthemitralvalvetissueresultingfrom Mitraclipplacement.Expertopinionsuggeststhat valvetissueisoftenfoundtobesubstantiallytorn orfibroticafterMitraClipfailureanditssubsequent removal.Inthiscase,replacementofthemitralvalvewouldbetheonlysurgicaloptionavailableto the patient orthe patientmay return tomedical management if further surgeryis contraindicated.

Physiciansand hospital staff are required to complete a trainingprogram for MitraClip prior to use of thesystem. Themaintrainingprogramgenerallyincludesdidacticcoursework(e.g.lectures and presentations)and‘handson’useofademonstrationsystem whichincludesaheartmodel,andis delivered over five days. Further detail on the trainingprogram, such as whether it could be incorporatedintoalargerheartvalvetreatmenttrainingprogram,wouldbeinformative.Inorderto be eligible for the trainingprogram thephysician must meet the following requirements:

1. Be either an interventionalcardiologist or cardiac surgeon.
2. Have experience in transseptal technique and have an understanding or experience in structural heart disease (patent foramenovale, atrial septal defect,aortic valve,etc.).
3. Havea multidisciplinary team to supportthe procedure, including:
4. Adedicatedechocardiologistforpatientscreeningandtobepresentduringthe procedure.
5. Ifthephysicianisaninterventionalcardiologist,acardiacsurgeontoprovidesupportand assist with the process.
6. Identify five suitable patients prior to training.
7. Beabletocontinuetohaveareasonablevolumeofpatientssoastomaintainminimumskills levels and optimal patientoutcomes.

Theprocedureshouldbedeliveredonlyincentres andfacilitiesthatprovideinterventionalcardiac servicesviathecatheterisationorhybridlaboratory andalsoprovideacardiothoracicsurgicalservice. Boththecatheterisationandhybridlaboratoryaresuitableforthedeliveryoftherapy,anddonotrequiremajorstaffingchanges.Theprocedureshouldonlyberebated ifitisdeliveredbyan appropriately trained medical practitioner.

Co-administered interventions

Undernormal circumstances,apatient sufferingfrom suspected MRwillbereferredfor aconsultation withacardiologist.,During thisconsultationarange ofinvestigationalproceduresmaybeperformed to diagnoseor identify severity of MR.These may include:

•electrocardiography (ECG;MBS Item 11700, 11701 and 11702)

•chestx-ray (MBS Item 58503)

•transthoracicechocardiography (TTE; MBS Item 55113, 55114 and55115)

•transesophageal echocardiography (TEE; MBS Item 55118)

•cardiac catheterisation (MBS Item 38203 and 38206)

•CT coronaryangiography

•exercise tests (MBS item 11712)

IfthepatientisfoundtomeeteligibilityfortreatmentwithMitraClip,thepatientwouldbereferredto atreatingphysician–eitheraninterventionalcardiologist oracardiothoracicsurgeon–withwhom a pre-proceduralconsultationwouldberequired. AnotherTEEexaminationislikelytobeperformed shortly before the procedure to determine the patient’s final eligibility for treatment.

TheMitraClipprocedureitselfisperformedundergeneralanaesthesiawithintra-operative TEE(MBS Item 55130 and 55135) and fluoroscopic guidance of device delivery (MBS item 61109). Guidance, confirmationofclippositioning,andassessmentof leafletcoaptationandMRreductionpriortofinal MitraClip deploymentare all done primarily through use of intra-operative TEE.

TEEisusedtoconfirmapatient’ssuitabilitytobedischargedfollowingtheprocedure,aswellas duringpatientfollow-up.Post-treatment follow-up wouldalsoinvolveblood-thinningmedications,as well as laboratory testing and further clinical consultation.

Background

International estimatesrevealthatmitralvalvediseaseisthesecondmostcommonvalvularlesion, precededonlybyaorticstenosis,withMRaffectingapproximately5in10,000peoplewithinthe UnitedStates(Hanson and Alfonso2011).Theonly definitivetreatmentfor MRissurgery; however, duetopotentialmorbidityandmortality associatedwiththeprocedure,theactualnumber ofpatients whohave surgeryisonlyapproximately20to30percentof newlydiagnosedannualcases.Thus, therearemanyindividualswithsignificantMRwho donotundergosurgeryeachyear.Nonetheless, approximately50,000mitralvalveoperationsareperformedintheUnitedStateseachyear(Danget al2005). Concomitantwithanagingpopulation, MRhasalsobeenfoundtobeincreasingin prevalence inthe United States (Thom et al 2006).

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AnestimateoftheprevalenceofMRanddemandfortreatmentwithinAustraliaisnotreadily available.Accordingto AustralianInstitute of Health andWelfare(AIHW)data,there were3,066 hospital separations for the principal diagnosis of non-rheumatic mitral valve disorders (which includesmitralinsufficiency,mitralprolapse and mitralstenosis)in2009-10(AustralianInstituteof Health andWelfare2011).Giventherelativelylowproportionofpatientswhoreceivesurgical treatment,thisisaconservativeestimateofthe prevalenceofMRwithintheAustralianpopulation; basedontheavailableAIHWdataandtheprevalenceratereportedbyHansonandAlfonso(2011) this isestimated to be in the range of 10,000 to 15,000 people.

Current arrangementsfor public reimbursement

The MBSlistingandreimbursementfeesforproceduresrelatingtoMRarelistedinTable1 (Medicare Australia2011b).Fromusagedata,therewere 3,814MBSclaimsmadein 2010-11for surgical proceduresrelating toMR(MedicareAustralia2011a).Itisimportanttonote,however,that only a proportionoftheseprocedureswouldhavebeenperformedformitralvalvetreatment,asmany wouldhavebeenclaimedfortreatment oftheaorticortricuspidvalve. Thereisnowaytodetermine from these figures the frequency withwhich treatment of the mitral valve wasperformed.

Table 1:Current MBS Items relatedtothe surgicaltreatmentofmitralregurgitation

MBS Item
Number / MBS Listing / Benefit
(AU$) / Number of Claims
(Jul2010-Jun2011)
38480 / Valverepair, 1leaflet / 1,966.00 / 559
38481 / Valverepair, 2ormoreleaflets / 2,238.15 / 331
38485 / Mitral annulus, reconstruction of, after decalcification, when performed in association withvalvesurgery / 801.85 / 153
38488 / Valvereplacementwithbioprosthesis ormechanicalprosthesis / 1,874.00 / 2,469
38489 / Valvereplacementwithallograft(subcoronary orcylindricalimplant),orunstented xenograft / 2,228.70 / 57
38490 / Sub-valvularstructures,reconstructionandre-implantationof,associatedwith mitralandtricuspidvalvereplacement / 544.20 / 245
51303 / Assistanceatany operationidentifiedby theword"assist"forwhichthe fee exceeds $54794orataseries ofoperations identifiedby theword"assist"which the aggregate feeexceeds $547.90filesave / Derivedfee:*

MBS:MedicareBenefitsSchedule

*derivedfeeisbasedononefifthoftheestablishedfeefortheoperationorcombinationofoperations.

The MitraClip system was introduced into Australian practice at Sir Charles Gairdner Hospital, Perth, in early2011. Dueprimarily to thenoveltyof thetechnology,MitraClipdoesnotcurrentlyhave MBS listing for either permanent or interim funding, nor has it been previously considered by MSAC. Abbott Vascularisprovidingsupportto apost-approvalclinicaltrialtotracktheinitialclinicalexperienceof MitraClip in Australia and New Zealand (

Regulatory status

RegulatoryapprovalfortheMitraClipsystem was receivedfrom theTherapeuticGoodsAdministration (TGA)on18November 2010.DetailsregardingitslistingontheAustralianRegister ofTherapeutic Goods(ARTG) are providedin Table 2.

Table 2:ARTG listings forMitraClip system

ARTG
number / Sponsor name / ARTG label name / Functional description / Intended purpose
177709 / AbbottVascular DivisionofAbbott AustralasiaPty Ltd / MSK02STMitraClip System–Mitralvalve tissuerepair system / Thesteerableguidecatheterandclip delivery systemaretypically steered and actuated throughthe useofcontrolknobs,levers and torquetranslationtechniques andguidedby echocardiographic and fluoroscopic imaging. Theclipis positionedandthe mitralvalve leafletsarecoaptedtoreducemitral regurgitation.The system includesareusable non-sterilestabilizer(whichis sterilizedbefore use),supportplate and liftwhichprovidea workingplatform during theprocedure. / Asystem ofdevices intendedfor thepercutaneousreconstruction of aninsufficientmitralvalve throughtissueapproximation usingtransvenous/transseptal techniques.

ARTG:AustralianRegisterofTherapeuticoods

ItshouldalsobenotedthatatpresentMitraCliphasyettoreceiveapprovalfromtheUnitedStatesFoodand Drug Administration.

Patient population

Aspartoftheclinicalassessment,allpatients shouldbeechocardiographicallyscreenedfor suitability bythephysician.Bothtransthoracic(TTE)andtransoesophageal(TOE)echocardiographyare usedto evaluatetheclinicalconsiderationsfor each patient.Inordertobeconsideredfortreatmentwith MitraClip,a patientshouldmeet allofthe following clinical requirements:

•Presentwithclinicallysignificantmitralvalveregurgitation,classifiedusingechocardiography andanumberofobjectiveandsubjectivemeasures.AnMRgradingof3+(regardedas

‘moderate’to‘severe’)or4+(regardedas‘severe’)isgenerallyconsideredtobeclinically significant (Bonowet al 2006).

•Presentwithsymptoms,orbeasymptomaticwithevidenceofleftventriculardysfunctionor dilatation.

•Theprimaryregurgitantjetoriginatesfrommalcoaptationofthemitralvalveinalocation accessiblewiththeMitraClipimplant.Ifasecondaryjetexists,itshouldbeconsidered clinically insignificant.

•Transseptal catheterisationis determined to be feasible by the treating physician.

Assessment of the mitral valve anatomy is an important consideration when determining the suitabilityofthepatientfor MitraCliptherapy.Patientswhoaremostlikelytobetreated successfully arethosein whomthejetofMRoriginatesfromtheA2/P2mitralvalveleafletsandisrelatively discrete.Ifaflailleafletispresent,thegapbetween thetwoleafletsshouldnotbetoogreat(i.e.flail segment widthgreater than15mm,or a flailgapgreater than10mm).MitraClipisless likelyto be successfulinpatientswithevidenceofcalcificationorcleftofthegraspingarea,severebileafletflail orprolapse,lackofboth primaryand secondary chordalsupport,or amitralvalve orificearea of≥4cm2.MitraClipshould notbeimplantedinpatients withactiveendocarditisor other clinically significant infection, or in patients in whomMR is resulting from rheumatic heart disease.

Asmentioned,surgicalmitralvalverepairorreplacementisdelayed ornot anoptioninmanypatients duetoitsinherentriskofmortalityandmorbidity,includingcardiac,neurological,respiratoryand renalcomplications,some ofwhich are related totheuse ofcardiopulmonarybypass. Risksrelatedto surgeryincreasewithspecificcomorbiditiessuchaspriorcardiothoracicsurgeryandadvancedage

(Sundt2011).Itisproposedthat MitraClipmaybe ofgreatestutilityfor thetreatment of particular patientgroupswhomay otherwisebeatahighrisk ofadverseoutcomesfromsurgicalmitralvalve treatment. Furtherdetailisrequiredastothe specificcomorbiditiesthatleadto apatientbeing classified as ‘high-risk’ forsurgery.However, these groups may potentially include:

•Patients with functionalMR

•Patients at high risk of compliations from cardiopulmonary bypass

•Elderly patients

•Youngerpatientsasabridgetocardiacsurgerylaterinlife(e.g.patientsforwhomlife-long anticoagulant usewould beanunacceptableconsequenceofmechanical mitralvalve replacement,such asyoungwomenpriortochildbearingthough anticoagulanttreatment is not requiredafter mitral valve repairor mitral valvebioprosthesis)

Anyreportedoutcomesrelatedtothetreatmentofthesepatientgroupswouldbeofparticular interest for this assessment.

Itshouldbenotedthatexpert opinionisthatthenumberofpatientsunsuitableforsurgicalmitral valverepairisdecreasing as advancementsinsurgicalvalve treatment, such asminimally-invasive approaches, aremade.Expertopinion alsosuggeststhatasMitraClipdoesnotutiliseanannuloplasty ring,itdoesnotsatisfactorilyaddressdilatationof themitralvalveannulus.Assuch,itmaybeof limitedbenefitinpatients withsubstantialannular dilatationdue toischaemic ornon-ischaemicheart damage, as is the case with many elderly patients.

Clinical place for proposed intervention

ManagementofMRcurrentlyvariesbasedonthe onsetand severity of symptoms,the severityofMR, andthedegreeofLVdysfunction.Themajorityof patientspresentwithchronicprogressiveMRand mayormay notbesymptomatic,whileasmallproportionofpatientspresentwithsevereacuteMR. The2006AmericanCollegeofCardiology/American HeartAssociationguidelinesforthemanagement ofpatientswithvalvularheartdisease(Bonowet al2006)recommendthatclinicalevaluationand echocardiographyshould beperformedatregularintervalstoassessthedegreeofMR,LVfunction, and clinical symptoms.

ThereisnogenerallyacceptedeffectivepharmacologicregimenforpatientswithMR(Bonowetal

2006).Medicalmanagement is regarded as palliative at best, and no pharmacologic study has definitivelydemonstratedimprovedhaemodynamics,a delayin timeto surgery,orareductionin mortalitywithchronicMR.Medicalmanagementisgenerallyinstitutedforpatientspresentingwith mildtomoderate MR,primarilytomitigatepreload,afterload, andhypertension.Inthesmall proportionofpatients withacutesevereMR, medicalmanagementis employed to stabilize the patient haemodynamicallyinpreparationforemergencysurgery(Bonowetal2006). Medicalmanagement may also be an acceptable treatment option for patients who are unfit for surgery due to feasibility or safety concerns.

Wheneverpossible,patientswithsymptomaticsevereMRorasymptomaticsevereMRwithevidence ofLVdysfunctionordilatationaregenerallyconsideredforsurgery (Bonowetal2006).Theprimary treatmentforsignificantMRismitralvalverepairor replacementsurgery,whichisbeneficialformost patientswhoreceive treatment. Althoughminimallyinvasivemitralvalvesurgeryisevolving,both mitralvalverepairandreplacementgenerallyoccurthroughopenchest,arrestedheartsurgery,

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performedundergeneralanaestheticandrequiringcardiopulmonarybypass.Torepairthemitral valve, the surgeonmayinserta cloth-coveredringaroundthevalvetobring theleafletsintocontact witheach other(annuloplasty),reshapethe valve byremovingredundant orloose segments ofthe leaflets(quadrangularresection),orresuspendthe leafletswithartificialchordsor“switching”and reinsertionof thenativechordae(chordaltransposition).Incomparison,mitralvalvereplacement involvesthe surgicalremovalofthedamagedvalve,whichisreplacedwith a mechanical(metal or plastic)or biological (tissue) valve.

Thedecision betweenrepairingandreplacingthevalvedependsonthetypeandextentofdamageto themitralvalve.Repairismoresuccessfulifthereislimiteddamagetocertainareasofthemitral valveleafletsorchordaetendineae.Mitralvalverepairisconsideredtobethesurgical procedureof choiceformostpatients,sincethenativevalvetissueandsub-valvularapparatusarespared, resultinginsuperiorhemodynamicsand leftventricularfunction. Replacementisusuallypreferred for patientswhoarenotgood candidatesformitralvalverepair,suchasthosewhohaveahard,calcified mitral annulus or widespread damageto the valveand surroundingtissue.

Thecurrentclinicalmanagementalgorithmfordiagnosingand treatingpatientswithMRatis illustrated in Figure 1.

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Figure 1: Clinical management algorithm for diagnosisandtreatmentofmitral regurgitation at present

AF:atrialfibrillation;EF:ejectionfraction;ESD:end-systolicdimension;GP:generalpractitioner;HT:hypertension;LV:left ventricular;MR:mitral regurgitation;MV:mitralvalve

aMVrepairmaybe performedinasymptomaticpatientswithnormalLVfunctionifperformedbyanexperiencedsurgicalteamandifthelikelihoodof successfulMVrepairisgreaterthan90%.

bPotentialcontraindicationstoMVsurgerywithcardiopulmonarybypassinclude:existingdamagetotheheart;highriskofcomplicationfrom cardiopulmonarybypass;advancedage;unacceptableriskoflife-longanticoagulantrequirement

Adaptedfrom:Bonowetal(2006).

Figure2illustratestheclinicalmanagementalgorithm fordiagnosingandtreatingpatientswithMR, withthe availabilityoftheMitraClipsystemasproposed. The MitraClipsystem isdesigned tobea directsubstitute(i.e.providespatientswithanewtreatmentalternative)forthecurrently subsidised interventionofsurgicalmitralvalverepairorreplacement.Inthecaseofpatientswhowould otherwisebe deemedunfittoundergosurgicaltreatment,itmay actasadirectsubstituteformedical managementof MR.

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Figure 2: Proposed clinical managementalgorithmfor diagnosis and treatmentofmitral regurgitationwith availability of percutaneousmitral valve reconstruction(MitraClip)

Proposed MBS listing

Afterexpertinputand PASCconsideration,theterm‘tissueapproximation’asoriginallyproposedwas amendedto‘permanentcoaptation ofmitralvalve leaflets’tomorespecificallyreflecttheintended effect oftheMitraClipprocedure. Atthesuggestionof thesponsor andexpertinput,apotential explanatorynotewas addedrequiringtheprovision ofajointrecommendation froma‘heartteam’, comprisingatleasttwocardiologists(includingonenon-interventional cardiologist)andtwo cardiothoracicsurgeons,forapatienttobedeemed appropriatetoreceivetreatment.The potential descriptorhasbeenfurtheramendedtoreflecttherequirementsfortheprovisionoftheserviceand is provided inTable 3.

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Proposed MBSItemdescriptorfor MitraClip system

Category3 – Therapeutic Procedures

MBS 38xxx

Percutaneous reconstruction of an insufficient mitral valve using transvenous/transseptal techniques for :

•permanent placement of up to two tissue approximation devicesor

•subsequentremovalofuptotwotissueapproximationdevicesasaresultofpostpercutaneousreconstruction recurrent mitralregurgitation requiringfurther surgical or medicalmanagement.(Anaes.) (Assist.)

Explanatory notes

Itisrecommendedthata‘heartteam’,comprisingtwocardiologists(includingonenon-interventionalcardiologist)andtwo cardiothoracic surgeons, provide approval regarding the patient’ssuitability for treatment.

Thisitemmay notbeclaimedif thisdevicecannotbeplacedsatisfactorilyinthe patient;andabandonsurgeryitemmaybe claimed in this case.

Fee: $895.30Benefit: 75%= $671.5085%= $821.60

Thefeeproposedbythe applicantwas basedonthesurgicalrepairoftwoleaflets(MBSItem38481). However, afterPASCconsiderationit wasdeterminedthatrepairofan atrialseptaldefectvia transcatheterapproach(MBSItem38272)providesamorecomparablebasisfortheitemfeein termsof timeand complexity; the fee isshown inTable 3.

Giventhat thecostof eachsingle-use MitraClip deviceis approximately$35,000,thepotentialfortwo devicestobeusedinmanyprocedures,andthatthedevicecannotbereused evenwhenitisnot deployed,furtherdetail andjustificationregardingprocedural, equipment,andaftercarecostsis requiredforeconomicmodellingpurposesandtoverifytheappropriateness oftheproposedfee. Consideration shouldalsobegiventothedescriptor andtheeconomicmodeltoprovidefor instances wheretheMitraclipcannotbeplacedsuccessfullyat theprimaryintervention,asecondMitraclipis insertedatasecondinterventionandinstanceswhereoneortwoMitraClipsareremoveddueto failureorforrecurrentMRwherethepatientistobemedicallymanaged ortofacilitatefurther surgery.

Comparator

Mitral valve repair or replacement surgery

Ashighlightedinthe clinicalmanagementalgorithm(Figure1),themostappropriatecomparatorto MitraClipfor thetreatmentofMRisgenerallymitralvalverepairorreplacementsurgery.The anatomical considerationsfordeterminingthe suitabilityof apatientfor surgicaltreatment are similar to those forMitraClip.

Ingeneral,MitraClipisasystemforrepairof themitralvalve.Accordingly,thereferral pathway, clinicalalgorithmforpatientselection, andthehealthcareresources anddiagnostic tests usedto identifyappropriatepatientsfortreatmentandusedinpatientfollow-up arethesame forboth MitraClipand mitralvalve repairor replacement surgery. Theprimarydifferencesin theprocedures existin thedeliveryof thetherapy. WhileMitraCliptherapyisprovidedbyinterventionalcardiologists and/orcardiothoracic surgeonsinacatheterisation orhybridlab,mitralvalverepairorreplacement surgeryisdeliveredbycardiacsurgeonsinan operatingtheatreandrequiresthepresenceofa perfusionist tofacilitatecardiopulmonarybypass.Requirementsfor echocardiographyand anaesthesia arethesameforthetwotherapies. Howeveranaesthetictimeis significantlylessfortheinsertionof MitraClipthan for valve repair or replacement surgery and this shouldbe considered in the economic model.

Medical management

Aspreviously mentioned, surgicaltreatmentof MRmaynotbe appropriateforasmallproportion of patientsdue tofeasibilityorsafetyconcerns(e.g.existingdamagetotheheart,cardiopulmonary bypassrisk,advancedage,needfor avoidanceof anticoagulantuse).Insuchpatients,medical managementisan appropriatecomparatorto MitraClip.Notethatthereis nogenerallyaccepted effective pharmacologic regimen for patients with MR.

Clinical claim

AstheMitraClipdeviceisdeployedpercutaneously andisfittedinthebeating heart,chestincisions, cardiopulmonarybypass,andcardiac arrest arenotrequired,decreasingtherisk ofadverse outcomes inpatientswithcomorbidities and avoidingthelong recovery time associated withmitral valverepair or replacement surgery. As such, it is proposed thattreatment with MitraClip may:

•Lead to fewerprocedural and early adverse events than mitral valve repair surgery;

•Reducetheprocedurallengthofstay,withfewerdaysincoronarycareandintensivecare compared tomitral valve repair surgery;

•Significantly reduce hospitalisation rate in the12 months after the procedure compared to the previous 12months; and

•Leadtosignificantimprovementsinthesymptomaticstatus(e.g.NewYorkHeartAssociationFunctional Classification),and quality oflife(physicaland mental scores) of patients.

The overallclinicalclaim fortreatment withMitraClip is thatithas superior safetywith non-inferior effectiveness andcost-effectivenesswhencomparedtothecurrentlyMBS-fundedprocedureofmitral valverepair orreplacementsurgery.Assuch,theeconomicevaluationwillbebasedonacost- effectivenessor cost-utilityanalysis (seeTable 4for details).

Table 4:Classificationof an intervention for determination of economic evaluation tobe presented

Comparative effectiveness versus comparator
Superior / Non-inferior / Inferior
Comparative safety versus comparator / Superior / CEA/CUA / CEA/CUA / Net clinicalbenefit / CEA/CUA
Neutral benefit / CEA/CUA*
Net harms / None^
Non-inferior / CEA/CUA / CEA/CUA* / None^
Inferior / Net clinicalbenefit / CEA/CUA / None^ / None^
Neutral benefit / CEA/CUA*
Net harms / None^

Abbreviations:CEA=cost-effectivenessanalysis;CUA=cost-utilityanalysis

*Maybereducedto cost-minimisationanalysis.Cost-minimisationanalysisshouldonlybepresentedwhentheproposedservicehasbeenindisputably demonstratedtobe noworsethanitsmaincomparator(s)intermsofbotheffectivenessandsafety,sothedifferencebetweentheserviceandthe appropriatecomparatorcanbereducedtoacomparisonofcosts.Inmostcases,therewillbesomeuncertaintyaroundsuchaconclusion(i.e.,the conclusionisoftennotindisputable).Therefore,whenanassessmentconcludesthataninterventionwasnoworsethanacomparator,anassessmentof theuncertaintyaroundthisconclusionshouldbeprovidedbypresentationofcost-effectivenessand/orcost-utilityanalyses.

^Noeconomicevaluationneedstobepresented;MSACisunlikelytorecommendgovernmentsubsidyofthisintervention

ItshouldbenotedthatthesponsorprovidednoclinicalclaimrelatingtotheuseofMitraClipin comparison to medical management.

Outcomesandhealthcareresourcesaffectedbyintroductionofproposed intervention

Outcomes

Potentialoutcomesofinterestforthe comparison oftherelativeclinicaleffectivenessandsafetyof MitraClipand mitralvalverepairorreplacementsurgeryareprovidedinTable5.Pleasenotethatthis is not necessarily a comprehensive listof potential outcomes.

Table 5:Potential effectiveness and safety outcomesof interest

Effectivenessoutcomes / Safety outcomes
Severity ofpost-treatmentmitral regurgitationa
Technical success(i.e. clip placement andsuccess oftheclip in permanently reducingMR)
Patientsurvival
Freedomfrom surgery forvalve dysfunctionb
Freedomfromfurthersurgery postMitraclip
Patientquality oflife
Post-procedural hospitalisationduration Post-procedural patientrecovery time Time taken toresumenormalactivities Procedure time / Patientmortality (e.g. procedure-related,30-daymortality) Myocardialinfarction
Reoperationforfailedsurgical treatment
Migrationof device
Non-electivecardiovascularsurgeryforadverseevents
Stroke
Renalfailure
Deepwoundinfection
Ventilation requiredfor48hours Gastrointestinalcomplicationrequiringsurgery Newonsetofpermanentatrialfibrillation Septicaemia
Transfusionoftwoormoreunits ofblood

aTobeconsideredequallyeffective,MitraClipshouldshowparitywithsurgicaltreatmentwithregardstopost-treatmentmitralregurgitation.

bProportionofpatientsrequiringvalvereplacementsurgeryduetodamagedvalvetissueafterMitraClipfailure/removalshouldalsobeevaluated.

Itisessential tonotethat instudies assessingsurgicalmitralvalverepairorreplacement,treatment successisgenerallydefinedas apost-treatment MRgradingof≤1+.Thisisconsiderablymore stringentthanthedefinitionusedin studiesassessingMitraClip,whichcommonlyregard apost- treatment MRof ≤2+tobe treatment success. Expert opinionsuggeststhat the condition of apatient withpost-treatment MR of 2+isalmost certainto worsen andrequirefollow-uptreatment. Assuch, comparisonofMitraClipto surgicaltreatmentmusttakethisdiscrepancyintoaccount,andassessthe clinicaloutcomesofboth treatmentsasuniformlyaspossible.However,instudiesthatexaminethe treatmentofpatientsdeemedunfitforsurgery(e.g.MitraClipcomparedtomedicalmanagement),it is accepted that a post-treatment MR grading of ≤2+may be considered an acceptable outcome.

Anyoutcomesrelatedspecificallytothetreatmentof patientsubgroupsdeemedtobeahighriskfor surgery(e.g.patientswithexistingdamagetothe heart,elderlypatients,patientsforwhomlife-long anticoagulant use wouldbeanunacceptableconsequence of surgery) are of particularinterest to this assessment,and should be reported indetail.

Asthedevelopment ofmitralregurgitationisoften adegenerativecondition,with thedisease and underlyingaetiologiesworseningovertime,long-term outcomesareofparticularimportancetothis assessment. Giventhenatureofthecondition,expertopinionrecommendsfiveyearstobethe minimum follow-up period necessary for an informed determination of the effectiveness of a treatmentsuchasMitraClip.However,therequired timehorizonmayvarybetweenpatientgroups (e.g. young patients,elderly patients, patients receiving MitraClip as a bridge to surgery).

Health careresources

DetailsonthehealthcareresourceswhoseutilisationislikelytobeimpactedshouldMitraClipbe made available as requested are listed below inTable6.

1

Table 6:Listof resources tobeconsidered in the economic analysis