Post on 05-Mar-2021
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.