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急性缺血性卒中溶栓治疗概述•静脉溶栓–组织纤溶酶原激活物(tPA)•NINDS•ECASSI&II,ATLANTIS–链激酶•MAST-I,MAST-E,ASK•动脉溶栓–前循环:大脑中动脉(PROACTII)–后循环:基底动脉•与安慰剂相比,3h内IVrtPA(0、9mg/kg

)能改善90天时的预后•出血发生率为6、4%,安慰剂为0、6%,但死亡率无差异•所有亚组预后均优于安慰剂组•益处可持续1年rt-PA:NINDS•随机,多中心,双盲,安慰剂对比•620例;排除CT早期梗塞灶(预后不良)•干预–rtPA(1、1mg/kg)vs

、placebo–起病6h内•主要终点–BarthelIndexandmodifiedRankinScaleat90days–rtPA与安慰剂组无明显差别rt-PA:ECASSIHackeetal、,JAMA、1995;274:1017-1025•随机,多中心,双盲,安慰剂对比

•800例;排除CT早期明显梗塞灶•干预–rtPA(0、9mg/kg)vs、placebo–起病6h内•主要终点–modifiedRankinScaleScoreof≤1at90days–rtPA与安慰剂组无明显差别rt-PA:ECASSIIHackeetal、,Lancet、1998;352

:1245-1251•随机,多中心,双盲,安慰剂对比•613例•干预–rtPA(0、9mg/kg)vs、placebo–起病3-5h内•主要终点–NIHSSof≤1at90days–rtPA与安慰剂组无明

显差别rt-PA:ATLANTISAlteplaseThrombolysisforAcuteNoninterventionalRxinIschStrokeClarketal、,JAMA、1999;282:2019-2

026rt-PA:小结•与安慰剂相比,3h内IVrtPA(0、9mg/kg)能改善90天时的预后、I类证据•目前证据显示,超过3h予IVtPA无效、I类证据链激酶(SK)研究药物剂量治疗窗结果MulticenterAcuteStr

okeTrial-Europe(MAST-E)NEJM1996;335:145-50SK1、5MU6hSK组出血和死亡率高提早终止试验MulticenterAcuteStrokeTrial-Italy(MAST-I)Lancet19

95;346:1509-14SKaspirin1、5MU300mg/d6hSK组,尤其是SK+aspirin组出血和死亡率高提早终止试验AustralianStreptokinaseTrial(ASK)Donna

netal、,Lancet1995;345:578-9SK1、5MU4h提早终止;治疗窗4h无明显益处,结果不良•与安慰剂相比,6h内予IVSK1、5MU预后不良(出血和死亡率高)、I类证据动脉溶栓•前循环–大脑中动脉阻塞•后循环–椎基底动脉阻塞•与安慰剂相比,6h内予IAProUK经造影证实M

CAM1或M2段阻塞的患者有效、I类证据•15%绝对有效(numberneededtotreat=7)•增加颅内出血,死亡率无差异PROACTII:小结急性椎基底动脉阻塞•数项病例报道(IV、V类证据)•非随机化

•无对比组Brandtetal、,CerebrovascDis,1995;5:182-7小结•3h内静脉用tPA能降低90天时的残障功能、I类证据•静脉用链激酶(1、5MU)增加出血和死亡率、I类证据•6h内动脉用尿激酶前体(Pro-UK,未被FDA通过)能降

低90天时的残障功能、I类证据•有证据支持在急性椎基底动脉阻塞中应用动脉溶栓、IV、V类证据急性缺血性卒中抗凝治疗概述•肝素•LMWheparin•LMWheparinoid-作用于抗凝血酶III(抑制凝血因子IIa,

IXa,andXa)•1effectonXa•reducedpltinteraction•longerhalf-life•simplertoadminister•lowerbleedingrisk•reducedeffectonIIaSummary:trialre

sultsNdrugresultsCanadian225HepIVnodifferenceIST19,435HepscnodifferenceTOAST1281heparinoidnodifferencelargeartbet

terat3mo?HK308LMWHdead/depat6moFISS767LMWHnodifferenceTAIST1486LMWHnodifferenceTOPAS404LMWHnodifferenceamongdoses各卒中亚型急性抗凝治疗•房颤和心源性栓塞•大动脉粥样硬化•椎基底

动脉阻塞•TIA•进展性卒中•动脉夹层•静脉血栓形成各卒中亚型急性抗凝治疗:小结CCTsubgrpNresults心源性栓塞123618nodiff大动脉硬化0413,2851+(?)/3-后循环032318nodiffTIA1055nodiff进展性卒中20204nodiff夹层00286no

diff静脉血栓20791+/1-小结急性期抗凝减少深静脉血栓和肺栓塞发生,不增加颅内出血几率、I类证据急性缺血性卒中阿司匹林治疗InternationalStrokeStrial(IST)ASA300mg/dx2wksbegunwithin

48hrs2wkendptsASAN=9720NoASAN=9715Recurrentischemic2、8%*3、9%Allrecurrentstroke3、7%4、6%Majorextracranialbleed1、1%*0、6%Death9、0%9

、4%*p<、01ChineseAcuteStrokeTrial(CAST)Lancet1997;349:1641ASA160mg/dx4wksbegunwithin48hrs4wkendptsASAN=10335Placebo

N=10320Recurrentischemic1、6%*2、1%Allrecurrentstroke3、2%3、4%Majorextracranbleed0、8%*0、6%Death3、3%*3、9%*p<、05小结基于IST和CAST,阿司匹林在急性缺血性卒中后2-

4周内,每1000例患者中有10人可减少死亡和复发。非心源性卒中二级预防:抗栓治疗概述•抗血小板药Antiplatelet、➢阿司匹林Aspirin➢抵克立得(噻氯匹啶)Ticlid®(Ticlopidine)➢波力维(氯吡格雷)Plavix®(Clopidogrel)➢艾诺思Agg

renox®(aspirin+extended-releasedipyridamole)•Warfarinfornon-cardioembolicarterialstroke:includinglargevesseldiseas

e、•抗磷脂抗体综合征(ASP)、•颈椎动脉夹层、高剂量阿司匹林随机对比试验、、、、、、、、、、、、*Riskofvascularevents(death,stroke,MI)inthecontrolgroup低剂

量阿司匹林随机对比试验、、、、、、、、、、、*Vascularevents(death,MI,stroke)inplacebo、**strokeinplacebo•100,000ptsfrom145trials、•Allantiplateletagentswereincluded、•Clumped

allvasculareventstogether、•Overalloddsreductionforvasculareventswas25%、•ForptswithminorstrokeorTIA(18trials)antiplateletagen

tsledtooddsreductionof22%forvasculareventsand23%fornonfatalstroke、•Didnotanswerquestionsaboutaspirindose、•Usedoddsratioinstead

ofrelativerisk、•Usedallantiplateletagents、、、、、、FDA、FederalRegister、1998;63:56802、†3-yearstudyendpoints,N=3,069、Endpoint†StrokeStroke,MI,orvasculard

eathRRR21%9%(P=0、024)Hassetal、NEnglJMed、1989;321:501、Easton、InHassandEaston(eds)、Ticlopidine,PlateletsandVascularDisease、NewYork:Springer-Verlag;1993

:141、*Ticlopidine(250mgbid)vsASA(650mgbid)、(NS)Ticlopidine(%)Aspirin(%)DiarrheaRashNauseaGastritis,ulcer,GIbleedingSeverene

utropenia(ANC<450/mm3)Cerebralhemorrhage20、4*11、9*11、12、10、9*0、69、85、210、26、0*0、00、7*P<0、05AdaptedfromHassetal、NEnglJMed、1989;321:501、、MonthsofFoll

ow-UpCumulativeEventRate(%)0481216ClopidogrelAspirin0369121518212427303336Aspirin5、83%5、32%ClopidogrelEventRateperYear*P=0、043CAPRIESteeringm

ittee、Lancet1996;348:1329-1339、ARR=0、51NNT=1/0、005=196Clopidogrel(%)ASA(%)GIplaintsAnybleedingdisorder

RashDiarrheaGIbleedingIntracranialhemorrhage1、901、200、90*0、420、520、212、41*1、370、410、270、*P<0、05CAPRIESteeringmittee、Lancet、1996;348:1329-1

339、ManagementofAtherothrombosiswithClopidogrelinHigh-riskpatients(MATCH)•氯吡格雷(75mg)+阿司匹林(75mg)与单用氯吡格雷(75mg)的疗效进行比较,结果是失败的•两组的主要终点指标,即缺血性卒中、心肌梗死

和血管源性死亡发生率与急性缺血事件(心绞痛、周围动脉症状恶化或TIA)无统计学差异•联合治疗同时增加了严重出血的概率•TestedefficacyofASA/ER-DPforsecondarystrokepreventio

n•Addressedclinicalquestions–Doeslow-doseASApreventstroke?–DoesER-DPpreventstroke?–IsASA/ER-DPsuperiortoASAalone?ToER-DPalone?

–IsASA/ER-DPwelltolerated?TheESPS-2Group、JNeurolSci、1997;151:S3、Dieneretal、JNeurolSci、1996;14PlaceboASAER-DPASA/ER-DP048121615、2%12、5%12、8%

9、5%Incidence(%)ARR=5、7overPlaceboNNT=1/0、057=17、5、、、、、、、、、、、、、AdaptedfromDiener、Neurology、1998;51(supp

l3):S17、TrialsToulouseTIA(N=284)AICLA(N=400)ACCSG(N=890)ESPS-2(N=3,299)Overall(N=4,873)15%RRRRelativeRisk(of

stroke,MI,orvasculardeath)0、511、522、53ASA/DPBetterASABetterPreventionRegimenforEffectivelyAvoidingSecondStrokes(PRoFESS)•是由30个国家

参入,纳入18500例患者,为期4年的随机双盲多中心试验,直截了当比较艾诺思Aggrenox(双嘧达莫缓释剂200mg+阿司匹林25mg,ER-DP200mg+ASA25mg,2次/d)与氯吡格雷(75mg,1次/d)在卒中二级预防中的疗效,预

期结果将在2008年报道。Warfarin-AspirinRecurrentStrokeStudy(WARSS)2206patientsfollowedfor2yearsISorDeathMjrbleed/100pt-yrsWarfarin17、8%2、

22Aspirin16、0%1、49p=、25NosignificantdifferencebetweenwarfarinandaspirinTheWarfarin-AspirinSymptomaticIntra

cranialDiseasestudy(WASID)•多中心前瞻性随机双盲试验•华法林INR为2~3,阿司匹林为1300mg•两组的卒中发生率和血管源性病死率无统计学差异•华法林组出血并发症的发生率较高促使试验提早终止•TheWarfarin-AspirinSy

mptomaticIntracranialDiseaseStudy、Neurology、1995Aug;45(8):1488-93、EffectofTreatmentonRecurrentIschemicStrokeandDe

athAtTwoYearsinAPASS/WARSS(Brey,RL:presentedatthe27InternationalStrokeConference,SanAntonio,TX,Februar

y9,2002)051015202530aPL+aPL-AspirinWarfarinPrimaryEndpoint(%)抗磷脂抗体阳性组与阴性组无差异,阿司匹林与华法林无差异颈动脉和椎动脉夹层•Naturalhistoryofcarotiddissection:

(HartetalNeurolClinNorthAm1:155,1983)–Cerebralinfarctionin33%(23%minor,10%majororfatal、–TIAin45;Headandnec

kpainin16%;Pulsatiletinnitus4%;andbruitin2%、•Propermanagementiscontroversial、Mostptsdowell,eitherbecauseofordespitetreatment、心源性卒中预防:抗血

栓治疗心源性卒中估计病因•Valvularheartdisease心脏瓣膜病–Rheumaticmitralvalvedisease风湿性二尖瓣病–Prostheticheartvalves人工心脏瓣膜–Mitralvalveprol

apse二尖瓣脱垂–Aorticvalvedisease主动脉瓣病–Aorticarchatherosclerosis主动脉弓粥样硬化–Endocarditis(infectiveornonbacterialth

rombotic)心内膜炎(感染性或非细菌性血栓)•Atrialfibrillation心房颤动•Myocardialinfarction心肌梗死•Leftventriculardysfunction左心室功能不全•Patentforamenovale卵圆孔未闭Rheumatic

mitralvalvedisease:2°strokeprevention•Norandomizedtrials•Observationalstudies:OACreducerecurrentembolicevents/fatalevent

sby2/3ormore1-3•Extrapolationfrom1largerandomizedstudyinNVAF(EAFT)providesadditionaldataforpatientswithRHD+AF(butRHDexcluded)1S

zekelyPBMJ1964;1:209-122AdamsGFetalJNNP1974;37:378-833Fleming&BaileyPostgradMed1971;47:599-604LevelIII

-IV:BenefitofOACProstheticheartvalves:mechanicalvalves1°strokeprevention•Observationaldata:APAmaybesuff

icienttopreventembolisminabsenceofAF,butOACneededtopreventvalvethrombosis1-2•RCT:additionofASA100mgtowarfarin(INR3-4、5)cerebralembolism(4/186vs、12/

184)3•NonRCT:additionofASA500mgtripledriskofmajorhemorrhage(14%vs、5%)4LevelIevidence:benefitofOAC+ASAover

OACalone1HartzRetalJThoracCVSurg1986;92:684-902RibeiroPetalJThoracCVSurg1986;91:92-83TurpieAetalNEJM1993;329:524-94ChesebroJetalAmJ

Card1983;51:1537-41Prostheticheartvalves:mechanicalvalves2°strokeprevention•Nodirectdata•ACCPremendations:OAC+babyASAbasedonextrapolationof

1°preventiondata6thACCPConsensusConferenceonAntithromboticTherapy2001Prostheticheartvalves:bioprostheticvalves1NunezetalAnnThoracSurg1982;33:354-8•B

utnodifferenceinembolicratewithOAC(4、6%,7/260)inparisontoASA(3、7%,5/135),andsignificantlyhigherrateofhemorrhagicplications(5、5%vs、0、4%)1

•(Interestingly,lowrateoflateembolisminptswithAFdespitelackofchronicACinbothofthesestudies1°prevention:LevelIVevidence:benefitofe

arlyOACovernoOACLevelVevidence:nodifferencebetweenOAC&ASA2°prevention:noevidenceMitralValveProlapse:2°strokepreventionLevelVevidence:neither

ASAnorACpletelyeffectiveNwarfarinASANoRxWatson19791110/21/9Hanson19802221/40/120/6•StrokerecurrenceinMV

P:caseseries•MVP+AF:extrapolatedatafromEAFT1WatsonRTNeurol1979;29:886-92HansonMetalStroke1980;11:499-506Atherosclerosisofthe

thoracicaorta:benefitofOAC50patientswithatheroma>4mmLevelIII:benefit34patientswithmobileatheromaLevelIII:benefitFerrar

iEetalJACC1999;33:1317-22主动脉弓粥样硬化TunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:benefitofstatins主动脉

弓粥样硬化:OACTunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:nobenefitofOAC主动脉弓粥样硬化:APATunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:nobe

nefitofAPA主动脉弓粥样硬化:他汀类TunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:benefitofstatins•1°strokeprevention–Retrospectivedat

ashownobenefitofOACfornativevalveendocarditis,benefitforprostheticvalveendocarditis1-5•2°strokeprevention:–Nodata感染性心内膜炎1Davenpo

rtetalStroke1990;21:993-92PaschalisetalEurNeurol1990;30:87-93YehetalCirculation1967;35:I77-814DelahayeetalEurHeartJ1990;11:1074-85WilsonetalCi

rculation1978;57:1004-7LevelVevidence•?Pathogenesis:fibrinthrombidepositsonvalvesassocwithcoagulopathy(

usuallyDIC)•Reportedincidenceofembolismvaries(14-91%)•Rx:Retrospectivedatasuggestbenefitofheparin,butnotOAC1-3–68%withrecurrentemboliwhenheparin

d/c’d–ICHrisklowerthanininfectiveendocarditis1RogersetalAmJMed1987;83:746-562LopezetalAmHeartJ1987;113:773-843SacketalMedi

cine1977;56:1-37非细菌性血栓性心内膜炎LevelVevidence:nobenefitofOAC;benefitofheparininTrousseausyndrome(mainlywithDIC)EuropeanAtrialFib

rillationTrial:EAFT(Lancet1993;342:1255-1262)Oralanticoagulants(225)vs、Aspirin(230)HR(95%CI)1°Endpoint0、60(、41-、87)Allstroke0、38(、23

-、64)Bleeding2、8(1、7-4、8)LevelIEvidence:benefitofOACOptimumINRforpreventionof2°strokeassociatedwithatrialfibrillation(EAFTNEJM1995;333:

5-10)“ThetargetvaluefortheINRshouldbesetat3、0”StrokePreventionwiththeORaldirectThrombinInhibitorinpatientswithnon-val

vularatrialFibrillation(SPORTIF)•SPORTIFIII是一项开放试验,SPORTIFV期是随机双盲多中心试验;•比较了口服直截了当凝血酶抑制剂西美加群(ximelagatran)与华法林(INR2~3)对心房颤动罹患卒

中的影响;•两组预防缺血性卒中的疗效无统计学差异,华法林组并发出血的概率较高,西美加群组肝酶升高发生率为6%,比华法林组(0、8%)高特别多,这也是尚未获得美国FDA批准的原因。心肌梗死后一级预防:短期抗凝•Pre-thrombolyticera–Heparindecrease

sstrokeincidence1-3–Heparindecreasesmuralthrombus41MedResearchCouncilBMJ1969;1:335-422Drapkin&MerskeyJAMA1972;222:

541-83VACoopStudyJAMA1973;225:724-94Vaitkus&BarnathauJACC1993;22:100-9心肌梗死后一级预防:短期抗凝•Post-thrombolyticera–baselineratesofde

ath,reinfarction,stroke,&PEmarkedlylowerwiththrombolytics&ASA–additionofheparin/LMWHmaydecreasemuralthrombusformation,butincreasesriskof

majorbleedingwithoutfurtherreducingstrokerisk1CollinsetalBMJ1996;313:652-92CollinsetalNEJM1997;336:847-603FRAMIKontnyetalJACC1997;30:962-94SCATI

Lancet1989;2:182-65Gissi-2VecchioetalCirculation1991;84:512-9心肌梗死后一级预防:长期抗凝•Relativetocontrol,coumarinsinmoderateorhighdose(INR2-4、

8)–Significantlydecreasestrokeincidence–SignificantlyincreaseincidenceofmajorbleedingAnand&YusufJAMA1999;282:20

58-67ModifiedfromAnand&YusufJAMA1999;282:2058-67…ButnobenefitrelativetoASAIncidenceofstrokeandsignificantincreaseinmajorbleed

ingRR(95%CI)Anticoagulation*、19(、13-、27)Aspirin#、44(、29-、65)LevelIIIevidence:benefitofAC>ASAfor1°prevention左心室功能不全:卒中危险因子多变量分析(LohEetalNEJM1

997;336:251-257)*similarriskatalllevelsofEF<40%#similarriskatalllevelsofEF<35%Rate(Events/100Pt-Yr)A

nticoagulation0(0/40)NoAnticoagulation0、35(1/288)LowRiskforPrimaryOccurrence慢性室壁瘤系统栓塞(LapeyreACetalJACC1985;6:534-538

)PatentForamenOvaleinCryptogenicStrokeStudy(PICSS)(HommaSetalCirculation2002;105:2625-31)•Design:Prospective,randomized,double-blind,mul

ti-centerclinicaltrial•Eligibility:–EnrolledinWARSS–AgreetohaveadditionalTEE•Treatment:Warfarin(targetINR1、4-2、8,mean2、1)v

s、aspirin325mg•1°endpoint:Recurrentischemicstrokeordeathwithin2years•601patients–42%withcryptogenicstrokeasqua

lifyingevent–34%withPFOPICSSLevelIIEvidence:NodifferencefromaspirinoverallorinanysubgroupNoincreasedev

entrateinPFO+ASAvs、PFOonlyNoincreasedratewithlargerPFOsize•RheumaticMVdz:LevelIII-BenefitovernoOAC•Aort

icarchatheroma:LevelIII-BenefitoverAPAin1study;NobenefitofOACorAPAinanother(butbenefitofstatins)•Infectiveendocarditis:–Nativev

alve:LevelV-Nobenefit–Prostheticvalve:LevelV-benefit•NBTE:LevelV-Nobenefit(?benefitofheparin)•Atrialfibrillation:LevelI-BenefitoverAS

A[INR2、9(2、5-4、0)]•PFO:LevelII-NobenefitoverASA(INR1、4–2、8)•MVP:LevelV–Notpletelyeffective•Atrialfibril

lation:LevelI-BenefitoverASA[INR2、9(2、5-4、0)]•PFO:LevelII-NobenefitoverASA(INR1、4–2、8)•MVP:LevelV–Notpletelyeffective•Nodata–Aorticvalved

isease–Prostheticheartvalves–MI–LVdysfunction口服抗凝剂(OAC)二级预防:小结感谢您的聆听！