ClinicalPolicy: ReferenceNumber:CP.MP.121 CodingImplications LastReviewDate:05/18 RevisionLog SeeImportantReminderattheendofthispolicyforimportantregulatoryandlegal information. Description Homocysteineisanonproteinogenicaminoacidthatisgeneratedduringtheconversionof methioninetocysteine. Mutationsoftheenzymeswithinthebiochemicalpathwaysthatregulate homeostatichomocysteinelevelsareasociatedwithriskfactorsforvariousdiseases,including venousthromboembolism.supplementationoffolicacid,vitaminb6,andvitaminb12are knowntomodulatehomocysteinelevels,giventheinterplaybetweenthefolatecycleand metabolism. Thispolicydescribesthemedicalnecesityrequirementsfortestinglevelsof homocysteine. Policy/Criteria I. ItisthepolicyofhealthplansafiliatedwithCenteneCorporation thathomocysteinetesting ismedicalynecesary forthefolowingindications: A. BorderlinevitaminB12deficiency; B. Homocystinuriacausedbycystathioninebeta-synthasedeficiency; C. Idiopathicvenousthromboembolism,recurentvenousthromboembolism,thrombosis occuringat<45yearsofage,orthrombosisatanunusualsite. I.ItisthepolicyofhealthplansafiliatedwithCenteneCorporation thathomocysteinetesting isconsideredinvestigationalforthefolowingindications: A. Cardiovascularrisktesting; B. Forthetestingofalotherconditions. Background Homocysteineisanaturalyoccuringintermediaryaminoacidthatisgeneratedduringthe conversionofmethioninetocysteine. Whilehomoeostaticplasmalevelsofhomocysteine typicalyrangeatlowmicromolarconcentrations,epistaticmutationsandotheraberant modificationsofthemetabolicpathwaysmodulatehomocysteinelevels. 1 Themetabolicpathway ofhomocysteineconsistsofupstreamremethylationpathwaysandadownstreamtransulfuration pathway. Notably,mutationsincystathionine-β-synthase,akeyenzymeofthetransulfuration pathway,areasociatedwithexceslevelsofhomocysteineandprematurethromboticevents. 1 Furthermore,acommonmutationatasinglenucleotide(677C T)inthegeneencoding5,10- methenetetrahydrolatereductase,anenzymeinthefolatecyclewhosebyproductsarenecesary cofactorsinthemetabolismofhomocysteine,afectshomoeostaticlevelsofhomocysteine. This mutationpredisposestheindividualtolowfolateplasmalevels,andconsequentlyastatusof hyperhomocysteine. 2 ChangesintheplasmahomocysteinelevelscanresultfromalterationsinfolateorvitaminB6or vitaminb12. 7 Ameta-analysisof25randomizedclinicaltrialsdemonstratedthatdaily supplementationof 0.8mgfolicacidissuficienttoachievethemaximalreductioninplasma homocysteinelevels. 8 Moreover,basallevelsofhomocysteinerangebetween5-15μmol/L, Page1of5
whilemoderatehyperhomocysteineconcentrationsare15-30μmol/l,intermediatelevelsare30-100μmol/landseverehyperhomocysteineconcentrationsare>100μmol/l. 7 Hyperhomocysteinewasidentifiedasanindependentriskfactorforischemicheartdiseaseand vasculardisease. 3,4 Initialreportshypothesizedthatheterozygosityofcystathionine-β-synthase contributedtotheaccumulationofhomocysteine,andthesereportswerecoroboratedbylater meta-analyses. 3,4 However,thisrationalehasnotbeencoroborated,astworandomized controledtrials,theheartoutcomespreventionevaluation2(hope-2)andthenorwegian Vitamin(NORVIT)trialssimultaneouslydemonstratednoefectfromloweringhomocysteine levels,bywayoffolicacidorvitaminb6supplementation,oncardiovascularoutcomes. 5,6 A2017Cochranereviewofhomocysteine-loweringinterventionsforpreventingcardiovascular eventsconcludedthatb-vitaminsupplementsloweredhomocysteinebutdidnotreduceriskof myocardialinfarctionor reducedeathratesinpatientsatriskof,orlivingwithcardiovascular disease. 11 Comparedwithplacebo,loweredhomocysteineresultingfromB-vitamin supplementationcombinedwithantihypertensivemedicationsproduceduncertainbenefitin preventingstroke-approximately143peoplewouldneedtobetreatedfor5.4yearstoprevent1 stroke. 11 Hyperhomocysteineisalsoariskfactorforvenousthromboembolicdisease. Rayetal. performedameta-analysisof9casecontrolstudiesmeasuringfastingplasmahomocystine,as welas5studiesmeasuredaftermethionineloading. Al9studiesdemonstratedasimilartrend inthelevelsandtheasociatedriskforvenousthromboembolism;folowingmethionineloading, thetrendincreasedtowardtheriskofvenousthromboembolism. 9,10 Highlevelsofserumhomocysteinehavebeenproposedasariskfactorfordementia,andseveral studieshaveevaluatedtheroleofb-vitaminsupplementationinloweringhomocysteineandthus improvingcognitivefunction,orpreventingcognitivedecline.ameta-analysisbyclarkeetal. determinedthatb-vitaminsupplementationsignificantlyreducedhomocysteinelevels,butdid nothaveaclinicalysignificantefectonglobalcognitivefunctionoroncognitiveaging. 12 In contrast,a2018internationalconsensusstatementarguesforthepresenceofacausal relationshipbetweenhomocysteinelevelsandcognitivedecline,andforscreeningfor hyperhomocysteineandtreatmentwithbvitaminsinpatientspresentingtomemoryclinics. 13 However,theconsensusbodynotesthat76%oftheparticipantsinthetrialsinthelargestmetaanalysisonthetopicdidnotincludebaselinemeasuresofcognitivefunction,andthuscouldn t adequatelycomparetheinterventiongrouptotheplacebogroup.furthermore,theypointtothe lackofanestablishedhomocysteinethresholdforintervention,whichreducestheclinical relevanceofthemeasure. CodingImplications ThisclinicalpolicyreferencesCurentProceduralTerminology(CPT ).CPT isaregistered trademarkoftheamerican MedicalAsociation.AlCPTcodesanddescriptionsarecopyrighted 2018,American MedicalAsociation.Alrightsreserved.CPTcodesandCPTdescriptionsare fromthecurentmanualsandthoseincludedhereinarenotintendedtobeal-inclusiveandare includedforinformationalpurposesonly. Codesreferencedinthisclinicalpolicyarefor informationalpurposesonly.inclusionorexclusionofanycodesdoesnotguaranteecoverage. Page2of5
Providersshouldreferencethemostup-to-datesourcesofprofesionalcodingguidancepriorto thesubmisionofclaimsforreimbursementofcoveredservices. CPT Description Codes 83090 Homocysteine HCPCS Codes N/A Description ICD-10-CMDiagnosisCodesthatSupportCoverageCriteria ICD-10-CM Description Code D51.0-D51.9 VitaminB12deficiencyanemia E53.8 DeficiencyofotherunspecifiedBgroupvitamins E72.10 Disordersofsulfur-bearingamino-acidmetabolism,unspecified E72.11 Homocystinuria E72.19 Otherdisordersofsulphur-bearingamino-acidmetabolism I26.01-I26.99 Pulmonaryembolism I81 Portalveinthrombosis I82.0-I82.91 Othervenousembolismandthrombosis Z86.711 Personalhistoryofpulmonaryembolism Z86.718 Personalhistoryofothervenousthrombosisorembolism Reviews,Revisions,andApprovals Date Approval Date Policydeveloped 07/16 08/16 Referencesreviewedandupdated 07/17 08/17 Backgroundupdated.Referencesreviewedandupdated. 05/18 05/18 References 1. Wierzbicki,AnthonyS."Homocysteineandcardiovasculardisease:areviewofthe evidence."diabetesandvasculardiseaseresearch4.2(2007):143-149. 2. Födingeer, Manuela,etal."Recentinsightsintothemoleculargeneticsofthehomocysteine metabolism." Kidneyinternational 59(2001):S238-S242. 3. Clarke,Robert,etal."Hyperhomocysteinemia:anindependentriskfactorforvascular disease."nengljmed324.17(1991):1149-1155. 4. HomocysteineStudiesColaboration."Homocysteineandriskofischemicheartdiseaseand stroke:ameta-analysis."jama288.16(2002):2015-2022. 5. HeartOutcomesPreventionEvaluation(HOPE)2Investigators."Homocysteinelowering withfolicacidandbvitaminsinvasculardisease."nengljmed 2006.354(2006):1567-1577. 6. Boona,K.H.,I.Njolstad,andP. M.Ueland."Homocysteineloweringandcardiovascular eventsaftermyocardialinfarction."nengljmed 354(2006):1578-1588. Page3of5
7. RosensonRSandKangDS. Overviewofhomocysteine. In:UpToDate,Downey,BC (Ed),UpToDate, Waltham, MA.Accesedon May7,2018. 8. Graham,I. M.,E.DalyL,andH. M.Refsum."Dose-dependentefectsoffolicacidonblood concentrationsofhomocysteine:ameta-analysisoftherandomizedtrials."amjclinnutr 82.4(2005):806-812. 9. Ray,JoelG."Meta-analysisofhyperhomocysteinemiaasariskfactorforvenous thromboembolicdisease."archivesofinternalmedicine 158.19(1998):2101-2106. 10.DenHeijer, Martin,etal."Hyperhomocysteinemiaandvenousthrombosis:ametaanalysis."ThrombosisandHaemostasis-Stutgart-80(1998):874-877. 11.Martí-CarvajalAJ1,SolàI,LathyrisD,Dayer M. Homocysteine-loweringinterventionsfor preventingcardiovascularevents.cochranedatabasesystrev.2017aug17;8:cd006612. doi:10.1002/14651858.cd006612.pub5. 12.ClarkeR,BennetD,ParishS,etal.EfectsofhomocysteineloweringwithBvitaminson cognitiveaging:meta-analysisof11trialswithcognitivedataon22,000individuals.amj ClinNutr.2014Aug;100(2):657 666. 13.SmithAD,RefsumH,BotiglieriT,etal.Homocysteineanddementia:aninternational consensusstatement.jalzheimersdis.2018;62(2):561-570.doi:10.3233/jad-171042. 14.PresD, Alexander M.Preventionofdementia.UpToDate.DekoskyST,SchmaderKE (Eds.)Accesed May9,2018. ImportantReminder Thisclinicalpolicyhasbeendevelopedbyappropriatelyexperiencedandlicensedhealthcare profesionalsbasedonareviewandconsiderationofcurentlyavailablegeneralyaccepted standardsofmedicalpractice;peer-reviewedmedicalliterature;governmentagency/program approvalstatus;evidence-basedguidelinesandpositionsofleadingnationalhealthprofesional organizations;viewsofphysicianspracticinginrelevantclinicalareasafectedbythisclinical policy;andotheravailableclinicalinformation.thehealthplan makesnorepresentationsand acceptsnoliabilitywithrespecttothecontentofanyexternalinformationusedorrelieduponin developingthisclinicalpolicy.thisclinicalpolicyisconsistentwithstandardsofmedical practicecurentatthetimethatthisclinicalpolicywasapproved. HealthPlan meansahealth planthathasadoptedthisclinicalpolicyandthatisoperatedoradministered,inwholeorinpart, bycentene ManagementCompany,LLC,oranyofsuchhealthplan safiliates,asapplicable. Thepurposeofthisclinicalpolicyistoprovideaguidetomedicalnecesity,whichisa componentoftheguidelinesusedtoasistinmakingcoveragedecisionsandadministering benefits.itdoesnotconstituteacontractorguaranteeregardingpaymentorresults.coverage decisionsandtheadministrationofbenefitsaresubjecttoalterms,conditions,exclusionsand limitationsofthecoveragedocuments(e.g.,evidenceofcoverage,certificateofcoverage,policy, contractofinsurance,etc.),aswelastostateandfederalrequirementsandapplicablehealth Plan-leveladministrativepoliciesandprocedures. ThisclinicalpolicyisefectiveasofthedatedeterminedbytheHealthPlan.Thedateofposting maynotbetheefectivedateofthisclinicalpolicy.thisclinicalpolicymaybesubjectto applicablelegalandregulatoryrequirementsrelatingtoprovidernotification.ifthereisa discrepancybetweentheefectivedateofthisclinicalpolicyandanyapplicablelegalor regulatoryrequirement,therequirementsoflawandregulationshalgovern.thehealthplan Page4of5
retainstherighttochange,amendorwithdrawthisclinicalpolicy,andadditionalclinical policiesmaybedevelopedandadoptedasneeded,atanytime. Thisclinicalpolicydoesnotconstitutemedicaladvice,medicaltreatmentormedicalcare.Itis notintendedtodictatetoprovidershowtopracticemedicine.providersareexpectedtoexercise profesionalmedicaljudgmentinprovidingthemostappropriatecare,andaresolelyresponsible forthemedicaladviceandtreatmentofmembers. Thisclinicalpolicyisnotintendedto recommendtreatmentformembers. Membersshouldconsultwiththeirtreatingphysicianin connectionwithdiagnosisandtreatmentdecisions. Providersreferedtointhisclinicalpolicyareindependentcontractorswhoexerciseindependent judgmentandoverwhomthehealthplanhasnocontrolorrightofcontrol.providersarenot agentsoremployeesofthehealthplan. ThisclinicalpolicyisthepropertyoftheHealthPlan.Unauthorizedcopying,use,and distributionofthisclinicalpolicyoranyinformationcontainedhereinarestrictlyprohibited. Providers,membersandtheirrepresentativesareboundtothetermsandconditionsexpresed hereinthroughthetermsoftheircontracts. Wherenosuchcontractexists,providers,members andtheirrepresentativesagreetobeboundbysuchtermsandconditionsbyprovidingservicesto membersand/orsubmitingclaimsforpaymentforsuchservices. Note:For Medicaidmembers,whenstate Medicaidcoverageprovisionsconflictwiththe coverageprovisionsinthisclinicalpolicy,state Medicaidcoverageprovisionstakeprecedence. Pleaserefertothestate Medicaidmanualforanycoverageprovisionspertainingtothisclinical policy. Note:For Medicaremembers,toensureconsistencywiththe MedicareNationalCoverage Determinations(NCD)andLocalCoverageDeterminations(LCD),alapplicableNCDs,LCDs, and MedicareCoverageArticlesshouldbereviewedpriortoapplyingthecriteriasetforthinthis clinicalpolicy.refertothecmswebsiteathtp:/www.cms.govforadditionalinformation. 2016CenteneCorporation.Alrightsreserved. Almaterialsareexclusivelyownedby CenteneCorporationandareprotectedbyUnitedStatescopyrightlawandinternational copyrightlaw. Nopartofthispublicationmaybereproduced,copied,modified,distributed, displayed,storedinaretrievalsystem,transmitedinanyformorbyanymeans,orotherwise publishedwithoutthepriorwritenpermisionofcentenecorporation.youmaynotalteror removeanytrademark,copyrightorothernoticecontainedherein.centene andcentene Corporation areregisteredtrademarksexclusivelyownedbycentenecorporation. Page5of5