What hematologists should know about VerifyNow ?· What hematologists should know about VerifyNow Hematology…

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  • WhathematologistsshouldknowaboutVerifyNow

    Hematologyfellowsconference12/13/2013Presenter:ChristinaFitzmaurice,MD,MPH

    Discussant:DanielSabath,MD,PhD

  • HMCconsultpatient

    54yo womanadmittedwithSAH2/2ICAaneurysm

    UnderwentstentplacementbyIR Preprocedurallyclopidogrel 150mgandaspirin325mgwerestarted

    Followupangiogramonday3showedalmostcompletethrombosisoftheaneurysm

  • Repeatangiogramonday7showedrecanalizationofaneurysm

    Concernthatpatienthastoomuchplateletinhibition

    VerifyNow wasordered Clopidogrel changedtoqod Hematologywasconsulted

    HMCconsultpatient

  • VerifyWHAT???

    1. Whatdoesitmeasure?2. Isitpredictiveofbleedingorthrombosis?

    3. Canitbeusedtoadjustplateletinhibitors?

  • 1.WhatdoesVerifyNowmeasure?

  • VerifyNow

    Measures plateletresponsetomajorantiplateletagents(P2Y12inhibitors,aspirin,GPIIb/IIIa inhibitors)

    Measuresplateletreactivitybytherateandextentoflightchangesinwholebloodasplateletsaggregate

  • VerifyNow P2Y12assayChamber1:TRAPtodeterminebaselineplateletfunction(agonistforplateletactivationindependentofaspirinandclopidogrel)

    Chamber2:ADPandProstaglandinE1(PGE1addedtosuppressADPactivationthroughP2Y1receptor)

  • P2Y12assay

    ResultsreportedasP2Y12reactionunits(PRU) PRU

  • HMCpatient

    PRU=5(repeatedtwice)

  • Clopidogrel metabolism

    Sangkuhl Katrin,KleinTeriE,AltmanRussB."Clopidogrelpathway"Pharmacogeneticsandgenomics (2010).

  • Influenceofgenotypeonclopidogrelmetabolism

    Differentisotypes ofCYP2C19havebeenassociatedwithresponse: CYP2C19*1wildtype CYP2C19*2lossoffunction CYP2C19*17gainoffunction

    2040%ofpatientsarenonrespondersorpoorresponderstoclopidogrel

    Brandtetal:CommonpolymorphismsofCYP2C19andCYP2C9affectthepharmacokineticandpharmacodynamic responsetoclopidogrel butnotprasugrel.JThromb Haemost.2007Dec;5(12):242936.Epub 2007Sep26.

  • CorrelationbetweenPRUandgenotype

    Harmsze etal:TheinfluenceofCYP2C19*2and*17onontreatmentplateletreactivityandbleedingeventsinpatientsundergoingelectivecoronarystenting.Pharmacogenetics andGenomics2012,22:169175

    Poormetabolizer

    Intermediatemetabolizer

    Extensivemetabolizer

    Ultrarapid metabolizer

    HMCpatientwithPRU=5:Mostlikelynotapoormetabolizer

  • UWtesting

  • MedicalProductSafetyInformation

  • Clinicalpharmacogenetics implementationconsortiumguidelines2013

    Scottetal:Clinicalpharmacogenetics implementationconsortiumguidelinesforCYP2C19genotypeandclopidogrel therapy:2013update.Clin Pharmacol Ther.2013Sep;94(3):31723.doi:10.1038/clpt.2013.105.Epub 2013May22.

    UM:Ultrarapid metabolizerEM:ExtensivemetabolizerIM:IntermediatemetabolizerPM:Poormetabolizer

  • Benefitofplateletfunctiontesting

    Plateletinhibitoreffect(e.g.Clopidogrel)

    Plateletinhibitoreffect(e.g.Clopidogrel)

    Concomitantdiseases(e.g.diabetes)

    Concomitantdiseases(e.g.diabetes)

    Genetics(e.g.CYP2C19)

    Genetics(e.g.CYP2C19)

    Noncompliance

    Noncompliance

    Concomitantmedications(e.g.PPIs,warfarin)

    Concomitantmedications(e.g.PPIs,warfarin)

    Plateletfunctiontestingmeasurespharmacodynamic effect

  • 2.AreVerifyNow resultspredictiveofbleedingorthrombosis?

  • VerifyNow predictingbleedingorthrombosesaftercerebralaneurysmstenting

    Thromboemboliccomplications

    Hemorrhagiccomplications

    PRU240(n=3) 2 1

    DelgadoAlmandoz JE,CrandallBM,Scholz JM,etal.JNeuro Intervent Surg 2013;5:iii3iii10.

    Retrospectiveanalysisof48patientsaftercerebralaneurysmstenting

    PreoperativedualantiplatelettherapystartedandadjustedbasedonPRU

  • Protocoltoadjustantiplatelettherapyinneurointerventionalprocedures

    DelgadoAlmandoz etal:AJNRAmJNeuroradiol.2013Jul4

  • ADAPTDESstudy

    Prospective,multicenterregistryof8665patients

    PatientswithcoronaryDESonaspirinandclopidogrel

    PlateletreactivitymeasuredwithVerifyNow

    Stoneetal:Lancet2013;382:61423

    AssessmentofDualAntiplateletTherapywithDrugElutingStents

  • GRAVITASTRIALGaugingResponsivenesswithaVerifyNow assay

    ImpactonThrombosisAndSafety

    RCTof2214patientsafterPCIwithPRU>235

    Randomizedtoeitherstandarddoseclopidogrel orrepeatedloadingwith150mgmaintenancedose

    Compositeendpointofdeath,MI,stentthrombosis

    Priceetal:Standard vs highdoseclopidogrel basedonplateletfunctiontestingafterpercutaneouscoronaryintervention:theGRAVITASrandomizedtrial.JAMA.2011Mar16;305(11):1097105.

  • GRAVITASTRIAL

    Underpoweredstudy Evenpatientswithhighdoseclopidogrel didnotachievePRU

  • TRIGGERPCI

    RCTof423electivePCIpatientswithPRU>208

    Randomizedtoprasugrel orclopidogrel

    Trenk etal:JAmColl Cardiol.2012Jun12;59(24):215964.Epub 2012Apr18.

    TestingPlateletReactivityinPatientsUndergoingElectiveStentPlacementonClopidogrel toGuideAlternativeTherapyWithPrasugrel

  • TRIGGERPCICVdeath,MI,stroke,orrehospitalization forcardiac

    ischemicevent

  • TRIGGERPCIRisk ofbleeding

  • Terminatedprematurelyduetolowerrateofischemicevents

    Possibleselectionbias(30%ofpatientsdeclinedrandomization)

    TRIGGERPCI

  • ARMYDABLEEDS

    Prospectivestudyof310consecutiveclopidogreltreatedpatientswhounderwentPCI

    PRUvalue189predicts30daybleeding(sensitivity87%,specificity70%)

    Pattietal:AmJCardiol.2011Apr1;107(7):9951000

    AntiplateletTherapyforReductionofMyocardialDamageDuringAngioplastyBleedingStudy

  • 2013ACCF/AHASTEMIGuidelines

    JACCVol.61,No.4,2013January29,2013:e78140

  • 2012ACC/AHAFocusedUpdatefortheManagementofPatientswithUA/NSTEMI

    PlateletfunctiontestingtodetermineplateletinhibitoryresponseinpatientswithUA/NSTEMI(or,afterACSandPCI)onP2Y12receptorinhibitortherapymaybeconsideredifresultsoftestingmayaltermanagement.LevelofEvidence:B,ClassIIb

    JAmColl Cardiol.2012;60(7):645681

  • 2012UpdateontheSocietyofThoracicSurgeonsGuidelinesonUseofAntiplateletDrugsinPatients

    havingCardiacandNoncardiac Operations

    Ferrarisetal:AnnThorac Surg 2012;94:176181

  • Conclusion

    PlateletfunctiontestingmaybemostappropriateinhighriskclopidogreltreatedpatientswithcurrentorpriorACSorhistoryofstentthrombosis

    Newerantiplateletagentscanbeconsideredinpatientswithhighplateletreactivity

    EvidenceissparseforusingPRUtoadjustdosingofantiplateletagents

    Fewdatainpatientsundergoingneurointerventional procedures

  • Thankyou