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  • AnticoagulantsinRenal Impairment

    AgnesYYLee,MD,MSc,FRCPCDirector,ThrombosisProgramOctober2011

  • Disclosures

    Bayer

    Boehringer

    Ingelheim

    BristolMyersSquibb

    DaiichiSankyo

    Eisai

    LaboratoryInstruments

    LeoPharma

    Pfizer

    SanofiAventis

  • Objectives

    Reviewmechanismsofactionandroutesof clearanceofanticoagulants

    Compareandcontrasttraditionalandnovel oralanticoagulants

    Summarizeclinicaldataonnoveloral anticoagulants

    OutlineACCPguidelinesonanticoagulantuse inrenalimpairment

  • FibrinClot

    XII

    VIIVIIIIX

    XI

    II

    V

    X

    I

    Unfractionated Heparin

    WarfarinLow Molecular

    Weight Heparin

    AnticoagulantSitesofAction

    DirectThrombin

    (IIa)Inhibitors

    DirectFactorXa

    Inhibitors

    Courtesey

    ofDr.JAnsell.

  • HeparinandLMWHs

    Pentasaccharide

    sequencebindsto ATandaccelerates itsinhibitoryactivity

    UFHinhibitsboth

    factorXa

    andIIa

    (thrombin)

    LMWHs

    havelow

    activityagainst thrombinbecause

    longerchainlength isrequired

    WeitzNEngl

    JMed1997.

  • ClearanceofUFHandLMWHs

    HigherMWchainsareclearedbydosedependenthepatic

    mechanism

    LowerMWchainsareclearedbydoseindependentrenal

    route

    Agent AverageMW(daltons) AntiXa:IIa

    RatioUFH 15,000 1:1

    Tinzaparin 6,500 1.9:1

    Dalteparin 5,600 2.0 2.7:1

    Enoxaparin 4,500 2.7 4.1:1

    Nadroparin 4,300 3.2

    3.7:1

    Pharmacotherapy2001;21:21834;Pharmacotherapy2005;25:8815

  • VitaminKisrequiredto

    carboxylate

    andactivatecoagulationfactors

    VitaminKAntagonists

    VitaminKH2

    isrequiredfor

    carboxylation

    andfunctionof

    vitaminKdependentfactors

    Warfarininterfereswith

    interconversion

    ofvitamin

    KH2

    andvitaminKO

    DietaryvitaminK

    bypassesthewarfarin blockade

    Anticoagulanteffect

    dependentonhalflivesof circulatingcoagulationfactors

    Ansell, J. et al. Chest 2004.

  • DirectThrombinInhibitors

    DTIs

    havekeyadvantagesoverUFHbytheir

    inactivationofclotboundthrombinandfluidphasethrombin

    SubstrateSubstrateRecognitionRecognition

    sitesite

    HeparinHeparinBindingBindingsitesite

    CatalyticCatalyticSiteSite

    IIaIIa

    ArgatrobanArgatrobanXimelagatranXimelagatranDabigatranDabigatran

    IIaIIaHirudinLepirudin

    IIaIIa

    BivalirudinBivalirudin

    IIaIIa

  • FactorXa

    Inhibitors

    IndirectInhibitors Fondaparinux Idraparinux

    DirectInhibitors Rivaroxaban Apixaban Edoxaban Betrixaban

    FONDAPARINUX

  • WarfarinDabigatran

    etexilate Rivaroxaban ApixabanTarget Vit

    Kepoxide

    reductase Thrombin FactorXa FactorXa

    Oral

    bioavailability

    99% 67% 6080% 80%

    T(max) 7296h 2h 24h 3h

    Halflife 40h 1417h59hhealthy913helderly

    815h

    Monitoring INRadjusted Notneeded Notneeded Notneeded

    Administration QD QDorBID QDorBID BIDMetabolism/Elimination

    Cytochrome

    P450

    80%renal20%biliary

    66%renal33%biliary

    25%renal75%biliary

    Antidoteor

    treatmentof

    bleeding

    VitaminK+PCC Standardofcare(considerPCCorrVIIa)

    Standardofcare(considerPCCorrVIIa)

    Standardofcare(considerPCCorrVIIa)

    Coag

    Assay PT/INRTTisextremely

    sensitive

    Notavailable Notavailable

    DrugInteractionsCYP2C9,

    1A2,

    and3A4

    PotentPgp

    inhibitors/inducers;

    PPIs

    decreaseabsorp

    PotentPgp

    inhibitors/inducers;

    CYP3A4inhibitors

    PotentPgp

    inhibitors/inducers;

    CYP3A4inhibitors

    ComparativeFeaturesofWarfarinandNewOralAnticoagulants

  • AdvantagesandLimitationsofNOA

    Advantages

    Fixeddosing

    Monitoringofanticoagulanteffectnotrequired

    Fewerdruginteractionsthanwarfarin

    Limitations

    Measurementofanticoagulanteffectnotavailable

    Lackofspecificantidote

    Somedruginteractions

    Doseadjustmentsrequiredinrenal/hepaticdysfunction

  • DrugInteractionsofNewAnticoagulants

    DonotinhibitorinduceCYP450

    InteractionswithinhibitorsandinducersofPglycoprotein+/

    CYP3A4

    antifungals

    ritonavir

    amiodarone

    verapamil

    clarithromycin

    quinidine

    tamoxifen

    TKIs

    cyclosporin

    tacrolimus

    Inhibitors

    rifampicin

    phenytoin

    carbamazepine

    phenobarbitone

    dexamethasone

    doxorubicin

    vinblastine

    St. Johns wort

    Inducers

  • NovelOralAnticoagulants

    IndicationDabigatran

    DTI

    Rivaroxaban

    FXa

    inhibitor

    Apixaban

    FXa

    inhibitor

    Orthopedic

    Prophylaxis

    REMOBILIZE

    REMODEL

    RENOVATE

    RECORD1

    RECORD2

    RECORD3

    RECORD4

    ADVANCE1

    ADVANCE2

    ADVANCE3

    StrokePrevention RELY ROCKETAFAVERROES(ASA)

    ARISTOTLE(W)

    VTETreatmentRECOVER

    REMEDY

    EINSTEINPE

    EINSTEINDVT

    EINSTEINEXT

    AMPLIFY

    AMPLIFYEXT

    ACS REDEEM ATLASTIMI46 APPRAISE

    MedProphylaxis MAGELLAN ADOPT

  • OrthopedicProphylaxisSummary

    Noveloralanticoagulantsaresimilarorsuperiorto enoxaparininefficacyinTKR/THR

    Dabigatran

    220mgoncedaily

    Rivaroxaban

    10mgoncedaily

    Apixaban

    2.5mgtwicedaily

    Seriousbleedingsimilarormarginallyhigher

    Costbenefitanalysesnotavailable

    Manycentres

    haveswitchedtorivaroxaban

    in patientswithCrCl

    >30mL/min

    PharmaCare

    approvalTHR35daysTKR14days

  • 0

    1

    2

    3

    4Dabig110Dabig150Warfarin

    P

  • 0

    0.5

    1

    1.5

    2

    2.5

    3

    3.5

    4

    Stroke&SE MajorBleed ICH

    RivaroxabanWarfarin

    Even

    tRate,%

    2.1

    3.6

    0.5

    2.4

    3.5

    0.7

    Rivaroxaban

    inAtrialFibrillation ROCKETAF

    HR0.67p=0.019

    HR1.04p=0.576

    IntentiontoTreatHR0.88;p=0.117

    PateletalNewEngl

    JMed2011.

  • 0

    1

    2

    3

    4

    StrokeorSE MajorBleed CRNMB ICH

    ApixabanASA

    %

    1.6

    3.7

    1.41.2

    3.1

    2.7

    0.4 0.4

    P

  • 0

    1

    2

    3

    4

    5

    StrokeorSE MajorBleed Death ICH

    Apixabanwarfarin

    %

    1.31.6

    2.1

    3.1

    3.5

    3.9

    0.3

    0.8

    P=0.01

    P

  • Dabigatran

    isnoninferiortowarfarinforpreventionofrecurrentorfatalVTEwithcomparablemajorbleedingrisk(1.6%

    vs

    1.9%)

    Schulmanetal.NewEngl

    JMed2009.

    Dabigatran

    inVTETreatment RECOVER

    INRinrange60%aboverange19%belowrange21%

    P

  • Cumulativeeven

    trate(%

    )

    0 30 60 90 120 150 180 210 240 270 300 330 3600

    1.0

    2.0

    3.0

    Rivaroxaban

    (2.1%;36/1,731)

    Enoxaparin/VKA(3.0%;51/1,718)4.0

    Timetoevent(days)

    Rivaroxaban

    inDVTTreatment EINSTEIN

    Buller

    etal.NewEngl

    JMed2010.

    INRinrange58%aboverange16%belowrange24%

    Rivaroxaban

    isnoninferiortowarfarinforpreventionofrecurrentorfatalVTEwithcomparablemajorbleedingrisk(0.8%

    vs

    1.2%)

    P

  • noveloralanticoagulantsareefficaciousalternativesin:

    Bleedingriskofnewagentsissimilarorslightlybettercompared

    totraditionalregimens

    Inabilitytomeasureanticoagulanteffectandlackofspecific

    antidotearemajorlimitationsofallneworalanticoagulants

    NewOralAnticoagulantsClinicalTrials Summary

    Dabigatran Rivaroxaban Apixaban

    StrokepreventioninAF

    ProphylaxisinTJR

    TreatmentofDVT

    TreatmentofPE

    LevelIevidenceApprovalinUS+Canada

    CanadaonlyEurope

  • AnticoagulantOptions

    Drugswithnosignificantrenalclearance

    Unfractionated

    heparin(UFH)

    Warfarin

    DirectThrombinInhibitors:argatroban

    FactorXa

    inhibitors:apixaban

    Drugswithsignificantdependenceonrenalclearance

    Lowmolecularweightheparins(LMWHs)

    Pentasaccharide:fondaparinux

    Heparinoids:Danaparoid

    DirectThrombinInhibitors:lepirudin,bivalirudin,dabigatran

    FactorXa

    inhibitors:rivaroxaban

  • ThrombosisinChronicRenalDisease

    Higherincidenceofarterialandvenousthrombosiscompared

    togeneralpopulation

    6foldhigherriskforPEindialysispatients

    Renalveinthrombosisandvascularaccessthrombosisare

    particularlyproblematic

    DVTreportedinupto15%ofpatientswithnephrotic

    syndrome

    Multipleriskfactors:inflammation,infection,immobility,

    reducedlevelsofendogenousanticoagulants,endothelial dysfunction,rEPO

  • Pathophysiology

    ofBleedinginRenal Impairment

    Defect Mechanism

    Platelets

    Adhesion

    Secretion

    Aggregation

    Alteredarachidonicacidmetabolism

    AbnormalCa2+

    mobilization

    ADP,epinephrine,5HTproduction

    GPIb,GPIIbIIIa

    receptorfunction

    Fibrinogenbindingtoactivatedplatelets

    Inhibitorinuremicplasma(e.g.urea,guanidinesuccinate)

    Plateletvessel

    wall

    interaction

    Interaction

    vWF

    activity

    Inhibitorinuremicplasma

    Releaseofprostacyclin

    andnitricoxide

    RBC

    hematocrit

    Anemia

    Alteredbloodrheology

    RBCs

    impactonplatelets

    Reducedclearanceofnitricoxide

    Other

    Medications

    Comorbid

    diseases

    Invasiveprocedures

    Antiplatelet

    andanticoagulanttherapy

    Irondeficiency,ma

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