New anticoagulants: Monitoring and not Monitoring? Not ... anticoagulants: Monitoring or not Monitoring? Not Monitoring Anna Falanga, MD ... • No available antidote

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  • Newanticoagulants:MonitoringornotMonitoring?

    NotMonitoring

    AnnaFalanga,MD

    ImmunohematologyandTransfusionMedicine

    &CenterofHemostasisandThrombosis,

    OspedaliRiuniti

    Bergamo,Italy

    The2nd

    WorldCongressonCONTROVERSIESINHEMATOLOGY(COHEM)Barcelona,Spain

    September68,2012

  • OLD ORAL ANTICOAGULANT DRUGS: Warfarin

    - slow onset (and offset) of action: requires bridging therapy with heparins.

    - unpredictable pharmacokinetics and pharmacodynamics- interacts with many other drugs- variability in relation to diet and comorbidities- variability in relation to genetic factors (CYP2C9 and VKORC1

    polymorphisms)

    - narrow therapeutic range- need for laboratory monitoring

  • Whatarethecharacteristicsoftheidealanticoagulants?

  • Prothrombinase

    Xa, Valipid

    ThrombinProthrombin

    FONDAPARINUX

    (XIMELAGATRAN)BIVALIRUDINARGATROBANDESIRUDIN

    Fibrinformation

    Plateletactivation

    Fibrinolysisinhibition

    Cellulareffects

    NewAnticoagulants(NOACs)

    APIXABANRIVAROXABAN

    DABIGATRAN

    EDOXABAN

  • Mainpharmacologicalcharacteristicsof selectedneworalanticoagulants

    Dabigatran Rivaroxaban Apixaban Edoxaban

    Target IIa Xa Xa Xa

    HourstoCmax 2 24 13 12

    Prodrug Yes No No No

    CYPmetabolism NoYes(CYP3A4/A5,

    CYP2J2)

    YES(CYP3A4,CYP1A2,CYP2J2)

    YES(CYP3A4)

    EffluxtransporterPgp Yes Yes Yes Yes

    Bioavilability 7% 80% 66% >45%

    Proteinbinding 35% >90% 87% 55%

    Halflife(Hours) 1214 913 815 810

    Renalelimination 80% 66% 25% 35%

    Dosing Twiceaday Onceaday Twiceaday Onceaday

    Bid=twicedaily;od=oncedaily;Tmax=timetopeakplasmaconcentration

  • ComparativefeaturesofVKAsandNOACs

    VKAs NOACs Needforregularanticoagulationmonitoring:foodanddruginteractions narrowtherapeuticwindow

    inter

    andintraindividualvariabilityindose

    response

    Fixeddoseregimenwithoutneedforroutine

    monitoring:lowpotentialforfoodanddruginteraction widertherapeuticwindow predictableanticoagulanteffect

    Delayedonsetofaction Rapidonsetofaction

    Longhalflife Shorthalflife

    Mainlyhepaticmetabolism Mainlyrenalclearence

    Availableantidote Noavailableantidote

    AnticoagulantmonitoringthroughINR Nostandardizedmonitoringtest

    INR:internationalnormalizedratio,NOACs:noveloralanticoagulants,VKAs:vitaminKantagonist

  • Whymonitoringdrugs?

    Drugmonitoringaimstooptimizedosageregimens inordertoincreaseefficacyand/orsafety

    If

    the

    plasma

    concentration

    of

    a

    drug

    can

    be accurately

    anticipated

    from

    the

    dose

    applied

    and

    the

    patients

    body

    weight,

    it

    does

    not

    usually requiremonitoring,evenifitstherapeuticwindow isnarrow.

  • Notmonitoring

    WhynotmonitoringNOACs?

  • Dabigatran:PredictablePharmacokinetics

    Doseproportional increaseinCmax

    andAUC indicatelinear

    pharmacokineticsovera widerangeofdoses

    AfteraSingleDose

    AtSteadyState

    StangierJ.:ClinPharmacokinet2008:47:285295

  • ReproduciblePKProfileofDabigatran

    PKprofileisreproducible

    acrossawiderangeofdoses1,2

    1Stangieretal.BrJClinPharmacol2007:64:2923032StangierClinPharmacokinet2008;47:285295

  • Theoraldirectthrombininhibitor Dabigatranhas:

    Apredictable,linearPK/PDprofile

    Quickonsetandoffsetofaction

  • PharmacokineticsofRivaroxaban

    KubitzaD.,etal.ClinPharmacolTher2005

    DoseproportionalandlinearPKwithnoaccumulationaftermultipledosing

  • Efficacyandsafety

    NomonitoringhasbeenusedinphaseIIIclinicaltrials thatestablishedtheefficacyandsafetyoftheNOACs

  • SchulmanSetal.NEJM2009;361:23422352

    Event rateEvent rateDABIGATRANDABIGATRAN 2.42.4

    % %

    WARFARINWARFARIN 2.12.1

    % %

    Efficacy outcomeEfficacy outcomeRecurrent venous thromboembolismRecurrent venous thromboembolism

    p< 0.001p< 0.001 for non inferiorityfor non inferiority

  • EINSTEINinvestigatorsNEJM2010;363:24992510

    Efficacy outcomeEfficacy outcome

    Safety outcomeSafety outcome

    Major bleeding or clinically Major bleeding or clinically relevant nonmajor bleedingrelevant nonmajor bleeding

    Recurrent venous Recurrent venous thromboembolismthromboembolism

    p< 0.001p< 0.001 for non inferiorityfor non inferiority

    P= 0.77P= 0.77

    Event rateEvent rateRIVAROXABANRIVAROXABAN 2.12.1

    % %

    EnoxEnox--

    WARFARINWARFARIN 3.03.0

    % %

    Event rateEvent rateRIVAROXABANRIVAROXABAN 8.18.1

    % %

    EnoxEnox--

    WARFARINWARFARIN 8.18.1

    % %

  • EffectsofNOACsonCoagulationAssays

  • NOACscauseasignificantprolongationofcoagulation reactionsproducingmisleadingresultsinroutine

    clottingassays

    DirectThrombinInhibitors DirectFXaInhibitors

    PTinsecandINR APTT ThrombinTime(TT) NoFibrinogen(Clauss) No/ NoDdimers No No

    These

    alterations

    do

    not

    correlate

    with

    the

    drug

    concentration,

    therefore thesetestsarenottobeperformedtodeterminethedrugactivity.

  • EffectofDabigatran

    onAPTT

  • EffectsofDabigatran

    onCoagulationAssays

    VanRynJetal,ThrombsandHaemost2010

    ThetimecurvesforaPTT,PT(expressedasinternationalnormalisedratio

    [INR]),TTandECTvalues

    paralleltheplasmaconcentrationtimecurveofdabigatran.

    Themaximumeffectofdabigatranonclottingparametersoccursatthesametimeasmaximalplasma

    concentrations,indicatingthatthrombininhibitionbydabigatranisadirecteffectlinkedtothecentral

    plasmacompartment.

  • EffectsofRivaroxaban

    onCoagulationAssays

    HarenbergJetal,ExpertRev.Hematol.2012

  • Monitoring

    vsmeasuring theanticoagulanteffectsoftheNOACs

  • Measurementoftheanticoagulantactivityaftera therapeuticdoseofrivaroxabanordabigatranetexilate

    maybeinformativeincasesof:

    Patientswithlowbodyweightsorobesepatients PediatricPatients Renalorhepaticimpairment Accidentalordeliberateoverdose Tomeasureadherence Toevaluatepatientswithhemorrhagicorthromboticcomplication Beforesurgery

    However,

    in

    the

    absence

    of

    specific

    antidotes,

    a

    measured

    high

    activity

    merely allowsustoapproximateafterwhichtimethedrugactivitywill

    vanish,according

    toitspharmacokineticproperties,whichcouldhave

    been

    calculated

    if

    the

    timing ofadministrationandtheexactdoseareknown.

  • Currentproblemswithmeasuringthesedrugs

    Novalidatedassays

    Eachdrughasuniqueeffect

    Drugeffectonclottingfactorsistransient

    Therapeuticrangesareuncertain

  • WHICH TEST?

    APTT

    Thrombin Time (TT)

    PT-INR

    Ecarin clotting time (ECT)

    Anti-Xa

    Thrombin Generation

  • DABIGATRAN

    Features Test

    APTT PT ECT TT

    Responsiveness + - ++ ++++Linearity - + + +Standardization - - + -

    Availability -+ + +

  • RIVAROXABAN/APIXABAN

    Characteristics Test

    PT APTT HepTest DRVVT aXa

    Responsiveness + + ++ ++ ++

    Linearity + + - - +

    Standardization +/- - ? ? +/-

    Availability -+ + - -

  • ECT might be the choice for Dabigatran

    PT and/or aXa might be the choice for Rivaroxaban/Apixaban

    Forthetimebeing,andonlyincaseitisneeded:

  • Whattheusersoftheneworalanticoagulants needtoknow

    ThenewdirectFactorXa

    andIIainhibitorsaffect conventionalclottingtests

    Theseeffectsarereagentdependent

    DonotroutinelymeasureaPTTorprothrombintimeto detectover

    orunderdose

    Usespecifictestsrecommended(ifavailable)todetect over

    orunderdose,inparticularinspecialpatient

    populations

    Howeverthereisnoneedforroutine

    monitoring.

  • NOACsdonotneedmonitoringonaroutinebasis

    New anticoagulants: Monitoring or not Monitoring? Not Monitoring OLD ORAL ANTICOAGULANT DRUGS: WarfarinWhat are the characteristics of the ideal anticoagulants?New Anticoagulants (NOACs)Main pharmacological characteristics of selected new oral anticoagulantsComparative features of VKAs and NOACsWhy monitoring drugs?Why not monitoring NOACs?Dabigatran: Predictable PharmacokineticsReproducible PK Profile of DabigatranThe oral direct thrombin inhibitor Dabigatran has:Pharmacokinetics of Rivaroxaban Efficacy and safetySlide Number 14Slide Number 15Slide Number 16NOACs cause a significant prolongation of coagulation reactions producing misleading results in routine clotting assaysEffect of Dabigatran on APTTEffects of Dabigatran on Coagulation AssaysEffects of Rivaroxaban on Coagulation AssaysMonitoring vs measuring the anticoagulant effects of the NOACs Slide Number 22Current problems with measuring these drugsWHICH TEST? DABIGATRANRIVAROXABAN/APIXABANFor the time being, and only in case it is needed:Slide Number 28NOACs do not need monitoring on a routine basis