WCN 2019 Teaching Course ICH RELATED TO ORAL

ANTICOAGULANTS ProfSelmaKesraoui

DepartmentOfNeurology:ProfM.ArezkiBlidaHospitalUniversity(Algeria)

Kes_selma@yahoo.fr

Disclosures

IdeclarethatIhavenoconflictsofinterest

ObjecDves

Todetermineandunderstand1/ThemodeofacMonandpharmacocineMcofAnMcoagulanttherapyVitamineKAntagonistsDirectoralanMcoagulants2/Causesofcerebralhemorrhage3/AssociaMonICHandOACanditscomplicaMon4/ReversalofanMcoagulaMonrelatedtoICH

IntroducDon q Intracerebralhemorrhage(ICH)isanon-traumaMcbrainparenchymalhemorrhage,thatmayextendintotheventricularsystemorintothesubarachnoidspace(1).

q intracerebralhemorrhage(ICH)isresponsibleformostdeathscausedbybleedingcomplicaMonsduringlong-termanMcoagulaMon.(2)

q Thesebleedingsareduetohypertensionandcerebralamyloidangiopathy

q HoweveranMcoagulanttherapyconcernsalsoapartofthesecauses,generallyinpaMentstakingoralanMcoagulanttheannualrateofintracranialhemorrhageis0,3%to0,6%ofthese46%to86%areintracerebral(3,4)

1/ AnDcoagulant therapy

1)  VitaminKantgonists(VKAs)OralanMcoagulantsareamaincomponentofcardiovasculartherapy,andforover60yearsvitaminKantagonists(VKAs)weretheonlyavailableagentsforlong-termuse.

• Overalleffect:dose-dependentanMcoagulanteffect• Avantages:self-monitoringandself-managementprogrammes.•  Inconvenients:SlowonsetofacMonVariabledoserequirementMulMpledrug-druginteracMonsDietaryvitaminKintake

2)DirectoralanMcoagulants(DOACs)4(DOACs)-Dabigatran,-Rivaroxaban,-Apixaban,-andEdoxabanareasefficaciousandsafeaswarfarinforstrokeprevenMoninpaMentswithatrialfibrillaMon(AF).(5)•  ThesesmoleculeshavebeendeveloppedtolimitpharmacodynamicandpharmacocyneMcvariability

PharmacocyneDc parameMers

Mechanismofac-on

Tmax(h) Voied’élimina-on

T½(h) dialyse Pro-drug Foodeffect

Dosing

Dabigatran

DirectFIIainhibitor

2 Rénale80%Fécale20%

14-17 Yes Yes No 1x/day(DVT,prevenMon)2x/day(DVT,AF)

Rivaroxaban DirectFXainhibitor

2-4 Fécale65%Rénale33%

7-13 No No No 1x/day(DVT,AF,PE)

Apixaban DirectFXainhibitor

3-4 Fécale75%Rénale25%

8-15 No No No 2x/dayallindicaMons

Edoxaban DirectFXainhibitor

1-2 Renal40% 9-11 No No No 1x/day(DVT,AF,PE)

DOACs VS VKA

Advantages Inconvenients

VKA TheINRiswidelyavailablewithrapidturn-around,canbedeterminedatthebedside

FoodanddruginteracMons

DOACs NofoodinteracMonsdonotgenerallyrequireregularinternaMonalnormalisaMonraMobloodtestmonitoring.(6)TheyhavefasteronsetandoffsetofacMon

RouMnecoagulaMontestsarelessusefulformeasuringtheanMcoagulanteffectsanabsenceoforalimitedchoiceofanMdotes,someofwhicharealsoexpensive.(7,8)

2/Causes of ICH

q Intracerebralhemorrhageisprovokedbydiseasesoflarge(15%)orsmall(85%)cerebralvessels.•  Largevesseldiseasesincludes:arterialaneurysmAVMandlessfrequentlyduralfistulesandvenousmalformaMons•  Smallvesseldisease:deposiMonofextracellularlipid«lipohyalinose»andβamyloidin«amyloidangiopathy».(9)

• CurrentdatasuggeststhatintracerebralhemorrhageinpaMentstakingOACreflectsspontaneousbleedingexacerbatedbyanMcoagulaMon.•  SoOACsustainsintracerebralhematomeformaMonbutdoesnotcauseit.

3/ AssociaDon ICH and OAC

Case fatality

•  Fatality=hematomaexpansion• HematomaexpansionresultsofvesselMssuepressuregradientandshearforces.(10)•  Thispressureishighestintheearlystagesanervesselruptureandthengraduallydecreases.

Case fatality =Hematoma expansion •  InpaMentsnotonOAC,hematomaexpansionoccursin30%to40%ofpaMentswithin3to6hoursaneronset.•  InpaMentstakingVKAshematomaexpansionisapproxymately54%firsthoursbutonenitisdelayed.

H24H2

A64YOwomanHistoryofAFonVKAAdmissionINR=6

• DOACs+ICHü ThereislimiteddataonthefrequencyofhematomaexpansiononDOACs.

ü IthasbeenreportedthathematomaexpansioninICHisthesameevenforpaMentsonVKAsoronDOACs.

ü AnMcoagulantreversalshouldbeundertakenassoonaspossible

Par-cularcase:59YOmanHistoryofFA+diabetesTRT:Xarelto15mg

Hematoma+hemorrhagictransformaMonofacuteischemicstroke

3/Reversal of anDcoagulaDon related to ICH

1)  SelecMonoftheappropriatecoagulaMontestq VKAsaremonitoredbyusingtheinternaMonalnormalizedraMo(INR)wichisbasedonprothrombineMme(PT)

INR=paMentsPT/laboratoryreferencePTq DOACsü Dabigatran:thethrombineMmeisthemostsensiMveAnormaltestincaseofICHexcludesthepresenceofclinicallyrelevantdabigatran.ü Rivaroxaban,apixabanandedoxabanhaveagreatereffectonthePTAnMfactorXaisnotwidelyused.

2)ReversalofOACsq VKAs:VitKPCCFPPVitK:VitKIVwithin20to30mntoavoidanaphylactoidreacMonsPCC:ProthrombinComplexConcentratewhichcountains4or3factorformat(VII,IX,XandprothrombineorIX,Xandprothrombine)25-50UI/kgIVFFP• PCCissuperiorthanFPP:rapidnormalisaMonofINRReducMonofhematomaexpansionVIIa:avoided

q DOACs§ Dabigatran:Idarucizumab(praxbind)isafragmentofhumanizedanMbody(5gIVbolus)

§ Rivaroxaband,ApixabandandEdoxabanAndexanet(Andexxya):recombinantvariantofhumanfactorXaRecommendaMons• PlasmaconcentraMonofDabigatran≤30ng/mlNoreversalOrAPTTraMo≤1,2• PlasmaconcentraMonofRivaroxaban≤30ng/mlNoreversal• OrPTraMo≤1,2

In pracDce

1)InpaMentswithICH+OACVitK:5-10ngIVPCC:30-50UI/kgifINR>1,22)InpaMentswithICH+DOACsItisdifficulttodeterminethedruglevelsbecauseoftheirrelaMvelyshorthalflivesIdarucizumab(5g):PCC(50UI/kg):reversalofrivaroxaban,apixabanandedoxabanPendingavailabilityofandexanet.

Take home messages

•  IntracerebralhemorrhageisthemostseriouscomplicaMoninpaMentstakingoralanMcoagulaMon•  Theseverityisrelatedtohematomaexpansion• GenerallyhematomaexpansionoccursmorefrequentlyinpaMentstakingVKAsandcanbedelayedfromonsetbleeding• AttodaythereislimiteddataonthefrequencyofICHanditscomplicaMonsrelatedtotheuseofDOACs• AnMcoagulantreversalshouldbeundertakenassoonaspossibleforboth(VKAsandDOACs)

References

(1)A.I.Qureshi,A.D.Medelow,andD.F.Hanley,“Intracerebralhaemorrhage,”<eLancet,vol.373,no.9675,pp.1632–1644,2009.(2)FangMC,GoAS,ChangY,etal.Thirty-daymortalityanerischemicstrokeandintracranialhemorrhageinpaMentswithatrialfibrillaMononandoffanMcoagulants.Stroke.2012;43(7):1795-1799

(3)  HartRG,DienerHC,YangS,ConnollySJ,WallenMnL,ReillyPA,etal.IntracranialhemorrhageinatrialfibrillaMonpaMentsduringanMcoagulaMonwithwarfarinordabigatran:theRE-LYtrial.Stroke.2012;43:1511–1517.doi:10.1161/STROKEAHA.112.650614.

(4)  HankeyGJ,StevensSR,PicciniJP,LokhnyginaY,MahaffeyKW,HalperinJL,etal;ROCKETAFSteeringCommi{eeandInvesMgators.IntracranialhemorrhageamongpaMentswithatrialfibrillaMonanMcoagulatedwithwarfarinorrivaroxaban:therivaroxabanoncedaily,oral,directfactorXainhibiMoncomparedwithvitaminKantagonismforprevenMonofstrokeandembolismtrialinatrialfibrillaMon.Stroke.2014;45:1304–1312.doi:10.1161/STROKEAHA.113.004506.

(5)  ChanNC,PaikinJS,HirshJ,LauwMN,EikelboomJW,GinsbergJS.NeworalanMcoagulantsforstrokeprevenMoninatrialfibrillaMon:impactofstudydesign,doublecounMngandunexpectedfindingsoninterpretaMonofstudyresultsandconclusions.ThrombHaemost2014;111:798–807.

(6)LipGYH.AtrialfibrillaMonin2011:StrokeprevenMoninAF.NatRevCardiol2011;9:71-3.doi:10.1038/nrcardio.2011.203(7)HolsterIL,ValkhoffVE,KuipersEJ,TjwaET.NeworalanMcoagulantsincreaseriskforgastrointesMnalbleeding:asystemaMcreviewandmeta-analysis.Gastroenterology2013;145:105-12.e15.doi:10.1053/j.gastro.2013.02.041(8)  ZhengY,SorensenSV,GonschiorA-K,etal.Comparisonofthecost-effecMvenessofneworalanMcoagulantsfortheprevenMonofstroke

andsystemicembolisminatrialfibrillaMoninaUKse~ng.ClinTher2014;36:2015-28.e2.doi:10.1016/j.clinthera.2014.09.015.(9)  FisherCM.Hypertensivecerebralhemorrhage.DemonstraMonofthesourceofbleeding.JNeuropatholExpNeurol.2003;62:104–107.(10)  SchlunkF,GreenbergSM.ThepathophysiologyofintracerebralhemorrhageformaMonandexpansion.TranslStrokeRes.2015;6:257–263.

doi:10.1007/s12975-015-0410-1.