缺血性卒中抗栓循证治疗优秀案例课件

缺血性卒中抗栓循证治疗（优选）缺血性卒中抗栓循证治疗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）NINDSECASSI&II,ATLANTIS链激酶MASTI,MASTE,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rtPA:NINDS随机,多中心,双盲,安慰剂对照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BarthelIndexandmodifiedRankinScaleat90daysrtPA与安慰剂组无明显差别rtPA:ECASSIHackeetal.,JAMA.1995;274:1017-1025随机,多中心,双盲,安慰剂对照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≤1at90daysrtPA与安慰剂组无明显差别rtPA:ECASSIIHackeetal.,Lancet.1998;352:1245-1251随机,多中心,双盲,安慰剂对照613例干预rtPA(0.9mg/kg)vs.placebo起病35h内主要终点NIHSSof≤1at90daysrtPA与安慰剂组无明显差别rtPA:ATLANTIS

AlteplaseThrombolysisforAcuteNoninterventionalRxinIschStrokeClarketal.,JAMA.1999;282:2019-2026Endocarditis(infectiveornonbacterialthrombotic)心内膜炎（感染性或非细菌性血栓）AntiplateletTrialists’Bleeding 2.Fatal;nonfatalCInoTIAincluded波力维（氯吡格雷）Plavix®(Clopidogrel)SameasmedicalRheumaticMVdz:LevelIIIBenefitovernoOACRecurrentischemic“Thepositivefindingsatlowerdosages(eg,50,75,and300mgdaily),alongwiththehigherincidenceofsideeffectsexpectedatthehigherdosage(eg,1,300mgdaily),aresufficientreasontolowerthedosageofaspirinforsubjectswithTIAandischemicstroke.WarfarinAspirinRecurrentStrokeStudy（WARSS）随机,多中心,双盲,安慰剂对照9mg/kg)vs.Aspirin 16.2CollinsetalNEJM1997;336:847-60Ticlopidine(%)rtPA:ATLANTIS

AlteplaseThrombolysisforAcuteNoninterventionalRxinIschStrokeProstheticheartvalves:

bioprostheticvalvesSK组出血和死亡率高提前终止试验rtPA:

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MulticenterAcuteStrokeTrial-Europe(MAST-E)NEJM1996;335:145-50SK1.5MU6hSK组出血和死亡率高提前终止试验MulticenterAcuteStrokeTrial-Italy(MAST-I)Lancet1995;346:1509-14SKaspirin1.5MU300mg/d6hSK组，尤其是SK+aspirin组出血和死亡率高提前终止试验AustralianStreptokinaseTrial(ASK)Donnanetal.,Lancet1995;345:578-9SK1.5MU4h提前终止;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MCAM1

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)非随机化无对照组

Brandtetal.,CerebrovascDis,1995;5:1827

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(ProUK,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Aspirin# .Atrialfibrillation:LevelIBenefitoverASA[INR2.3TurpieAetalNEJM1993;329:524-9Atrialfibrillation:LevelIBenefitoverASA[INR2.3h内静脉用tPA能降低90天时的残障功能.1% 30.OptimumINRforpreventionof2°strokeassociatedwithatrialfibrillation

(EAFTNEJM1995;333:510)Allstroke 0.Lightheadedness 30.Clopidogril所有亚组预后均优于安慰剂组MitralValveProlapse:2°strokeprevention比较了口服直接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；,CerebrovascDis,1995;5:18271989;321:501.TIA,S,MI,vasculardeathS,deathorbothandsignificantincreaseinmajorbleedingandsignificantincreaseinmajorbleeding慢性室壁瘤系统栓塞

(LapeyreACetalJACC1985;6:534-538)概述肝素LMWheparinLMWheparinoid 作用于抗凝血酶III (抑制凝血因子IIa,IXa,andXa)

1effectonXareducedpltinteractionlongerhalf-life

simplertoadministerlowerbleedingriskreducedeffectonIIaSummary:trialresultsNdrugresultsCanadian225HepIVnodifferenceIST19,435HepscnodifferenceTOAST1281heparinoidnodifferencelargeartbetterat3mo?HK308LMWHdead/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00286nodiff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/dx2wksbegunwithin48hrs2wkendptsASAN=9720NoASAN=9715Recurrentischemic2.8%*3.9%Allrecurrentstroke3.7%4.6%Majorextracranialbleed1.1%*0.6%Death9.0%9.4%*p<.01ChineseAcuteStrokeTrial(CAST)

Lancet1997;349:1641ASA160mg/dx4wksbegunwithin48hrs4wkendptsASAN=10335PlaceboN=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24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Aggrenox®(aspirin+extendedreleasedipyridamole)Warfarinfornoncardioembolicarterialstroke:includinglargevesseldisease.抗磷脂抗体综合征（ASP）.颈椎动脉夹层.Aspirin高剂量阿司匹林随机对照试验#StudyASAdose#ofptsAgef/uPrim.Endpoint%ofRR1AITIA1977Medicalgroup1300mgA88;P9060.237mTIA,CI,RI,death20onlywithTIA.*P(15.7)2AITIA1977surgicalgroup650mgA65;P6060.3?TIA,CI,RI,deathSameasmedical*P(15.7)3CCSG1978ASA+SP1300mgA144;P139?26mTIA,S,death-6to31%*P(7.6)4Reuther19781500mgA29;P295924mTIA,SNS*P(8.3)5AICLA1983ASA+DP990mgA198;P20463.536mFatal;nonfatalCInoTIAincluded41*P(7.5)6DanishCS19831000mgA101;P1025925mSorDeath-77*P(9.6)7SwedishCS19871500mgA253;P2526824mSorDeath0*P(10.9)*Riskofvascularevents(death,stroke,MI)inthecontrolgroupCAPRIESteeringCommittee.TIA,CI,RI,death1effectonXaRelativeRiskA253;P2523TurpieAetalNEJM1993;329:524-9低剂量阿司匹林随机对照试验Headache* 32.ClopidogrelTiclopidine,PlateletsandVascularDisease.PROACTII:

小结WarfarinAspirinRecurrentStrokeStudy（WARSS）#similarriskatalllevelsofEF<35%Neurology.MulticenterAcuteStrokeTrial-Europe(MAST-E)AnybleedingdisorderAICLA(N=400)Isthereaconsensus.JNeurolSci.Prostheticheartvalves主动脉弓粥样硬化

TunickPetalAmJCardiol2002;90:13205低剂量阿司匹林随机对照试验#StudyASAdoseinmg.#ofptsAgeF/uPrim.Endpoint%inRR1DanishLow1988(postCEA)50-100A150P15158.925TIA,S,MI,vasculardeath11%(NS)*P(7.3)2UKTIA19911200300Placebo81580681459.848MajorS,MI,Vasc.Death

15%vsP;NSbetweendoses*P(5.7)3SALT199175A676P68466.932Sordeath16%*P(10.6)4ESPS250A1649P164966.724S,deathorboth18%**P(15.8)*Vascularevents(death,MI,stroke)inplacebo.**strokeinplaceboAntiplateletTrialists’100,000ptsfrom145trials.Allantiplateletagentswereincluded.Clumpedallvasculareventstogether.Overalloddsreductionforvasculareventswas25%.ForptswithminorstrokeorTIA(18trials)antiplateletagentsledtooddsreductionof22%forvasculareventsand23%fornonfatalstroke.Didnotanswerquestionsaboutaspirindose.Usedoddsratioinsteadofrelativerisk.Usedallantiplateletagents.Isthereaconsensus.TheFDAreviewedtrialsofaspirinvsplacebo(includingESPS2,SALT,andUKTIAtrials)toreducetheriskofstrokeanddeathinpatientswithpriorTIAorstroke.“Thepositivefindingsatlowerdosages(eg,50,75,and300mgdaily),alongwiththehigherincidenceofsideeffectsexpectedatthehigherdosage(eg,1,300mgdaily),aresufficientreasontolowerthedosageofaspirinforsubjectswithTIAandischemicstroke.”For“ischemicstrokeandTIA:50to325mg[aspirin]onceaday.Continuetherapyindefinitely.”FDA.FederalRegister.1998;63:56802.Ticlopidine

TASSStudy:Efficacy*†3-yearstudyendpoints,N=3,069.Endpoint†StrokeStroke,MI,orvasculardeathRRR21%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,GIbleedingSevereneutropenia

(ANC<450/mm3)Cerebralhemorrhage20.4*11.9**10.26.0*0.00.7*P<0.05TASSStudy:SideEffectsAdaptedfromHassetal.NEnglJMed.1989;321:501.ClopidogrilCAPRIEStudy

EfficacyofClopidogrelvs.Aspirin(n=19,185)PrimaryOutcome:MI,IschemicStroke,orVascularDeathMonthsofFollow-UpCumulativeEventRate(%)0481216ClopidogrelAspirin0369121518212427303336Aspirin5.83%5.32%ClopidogrelEventRateperYear*P=0.043CAPRIESteeringCommittee.Lancet1996;348:1329-1339.ARR=0.51NNT=1/0.005=196Clopidogrel(%)ASA(%)GIcomplaintsAnybleedingdisorderRashDiarrheaGIbleedingIntracranialhemorrhage1.901.200.90*0.420.520.212.41*1.370.410.270.93*0.33*P<0.05CAPRIESteeringCommittee.Lancet.1996;348:1329-1339.SideEffectscausingdiscontinuationofdrugCAPRIEStudyManagementofAtherothrombosiswithClopidogrelinHighriskpatients（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

TheSecondEuropeanStrokePreventionStudy:

ESPS2TestedefficacyofASA/ERDPforsecondarystrokepreventionAddressedclinicalquestionsDoeslowdoseASApreventstroke?DoesERDPpreventstroke?IsASA/ERDPsuperiortoASAalone?ToERDPalone?IsASA/ERDPwelltolerated?TheESPS-2Group.JNeurolSci.1997;151:S3.Dieneretal.JNeurolSci.1996;143:1.4wkendptsPFO:LevelIINobenefitoverASA(INR1.Headache* 32.2°prevention:noevidenceClopidogrel(%)baselineratesofdeath,reinfarction,stroke,&PEmarkedlylowerwiththrombolytics&ASAClarketal.多中心前瞻性随机双盲试验5MU)增加出血和死亡率.4Vaitkus&BarnathauJACC1993;22:100-9JNeurolSci.Lightheadedness 30.MulticenterAcuteStrokeTrial-Europe(MAST-E)BarthelIndexandmodifiedRankinScaleat90daysUsedoddsratioinsteadofrelativerisk.Aspirin# .“Thepositivefindingsatlowerdosages(eg,50,75,and300mgdaily),alongwiththehigherincidenceofsideeffectsexpectedatthehigherdosage(eg,1,300mgdaily),aresufficientreasontolowerthedosageofaspirinforsubjectswithTIAandischemicstroke.NIHSSof≤1at90daysESPS2Results:

StrokeRatesat24MonthsPlaceboASAER-DPASA/ER-DP048121615.2%12.5%12.8%9.5%Incidence(%)ARR=5.7overPlaceboNNT=1/0.057=17.5ESPS2:SideEffectProfile

Placebo ASA ASA+EDGIEvent* 28.1% 30.4% 32.8%Headache* 32.3% 33.1% 38.1%Bleeding* 4.5% 8.2% 8.7%(anysite)Lightheadedness

30.9% 29.1% 29.5% *=P<0.05Meta-Analysis:ASA/DPvsASAAdaptedfromDiener.Neurology.1998;51(suppl3):S17.TrialsToulouseTIA(N=284)AICLA(N=400)ACCSG(N=890)ESPS-2(N=3,299)Overall(N=4,873)15%RRRRelativeRisk(ofstroke,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，直接比较艾诺思Aggrenox（双嘧达莫缓释剂200mg+阿司匹林25mg，ERDP200mg+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。WarfarinAspirinRecurrentStrokeStudy（WARSS）2206patientsfollowedfor2years ISorDeath Mjrbleed/100ptyrsWarfarin 17.8%2.22Aspirin 16.0%1.49p=.25NosignificantdifferencebetweenwarfarinandaspirinTheWarfarinAspirinSymptomaticIntracranialDiseasestudy（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前终止

TheWarfarin-AspirinSymptomaticIntracranialDiseaseStudy.

Neurology.1995Aug;45(8):1488-93.EffectofTreatmentonRecurrentIschemicStrokeandDeathAtTwoYearsinAPASS/WARSS

(Brey,RL:presentedatthe27InternationalStrokeConference,SanAntonio,TX,February9,2002)PrimaryEndpoint(%)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;Headandneckpainin16%;Pulsatiletinnitus4%;andbruitin2%.Propermanagementiscontroversial.Mostptsdowell,eitherbecauseofordespitetreatment.

心源性卒中预防

抗血栓治疗心源性卒中可能病因Valvularheartdisease心脏瓣膜病Rheumaticmitralvalvedisease风湿性二尖瓣病Prostheticheartvalves人工心脏瓣膜Mitralvalveprolapse二尖瓣脱垂Aorticvalvedisease主动脉瓣病Aorticarchatherosclerosis主动脉弓粥样硬化Endocarditis(infectiveornonbacterialthrombotic)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Rheumaticmitralvalvedisease:

2°strokepreventionNorandomizedtrialsObservationalstudies:OACreducerecurrentembolicevents/fataleventsby2/3ormore13Extrapolationfrom1largerandomizedstudyinNVAF(EAFT)providesadditionaldataforpatientswithRHD+AF(butRHDexcluded)1SzekelyPBMJ1964;1:209-12

2AdamsGFetalJNNP1974;37:378-833Fleming&BaileyPostgradMed1971;47:599-604LevelIII-IV:BenefitofOACProstheticheartvalves:mechanicalvalves

1°strokepreventionObservationaldata:APAmaybesufficienttopreventembolisminabsenceofAF,butOACneededtopreventvalvethrombosis12RCT:additionofASA100mgtowarfarin(INR34.5)cerebralembolism(4/186vs.12/184)3NonRCT:additionofASA500mgtripledriskofmajorhemorrhage(14%vs.5%)4LevelIevidence:benefitofOAC+ASAoverOACalone1HartzRetalJThoracCVSurg1986;92:684-902RibeiroPetalJThoracCVSurg1986;91:92-83TurpieAetalNEJM1993;329:524-94ChesebroJetalAmJCard1983;51:1537-41Prostheticheartvalves:mechanicalvalves

2°strokepreventionNodirectdataACCPrecommendations:OAC+babyASAbasedonextrapolationof1°preventiondata6thACCPConsensusConferenceonAntithromboticTherapy2001Prostheticheartvalves:

bioprostheticvalves1NunezetalAnnThoracSurg1982;33:354-8ButnodifferenceinembolicratewithOAC(4.6%,7/260)incomparisontoASA(3.7%,5/135),andsignificantlyhigherrateofhemorrhagiccomplications(5.5%vs.0.4%)1

(Interestingly,lowrateoflateembolisminptswithAFdespitelackofchronicACinbothofthesestudies1°prevention:LevelIVevidence:benefitofearlyOACovernoOACLevelVevidence:nodifferencebetweenOAC&ASA2°prevention:noevidenceMitralValveProlapse:2°strokepreventionLevelVevidence:neitherASAnorACcompletelyeffectiveNwarfarinASANoRxWatson19791110/21/9Hanson19802221/40/120/6StrokerecurrenceinMVP:caseseriesMVP+AF:extrapolatedatafromEAFT1WatsonRTNeurol1979;29:886-92HansonMetalStroke1980;11:499-506Atherosclerosisofthethoracicaorta:

benefitofOAC50patientswithatheroma>4mmLevelIII:benefit34patientswithmobileatheromaLevelIII:benefitFerrariEetalJACC1999;33:1317-22主动脉弓粥样硬化

TunickPetalAmJCardiol2002;90:13205LevelIIIevidence:benefitofstatins主动脉弓粥样硬化:OAC

TunickPetalAmJCardiol2002;90:13205LevelIIIevidence:nobenefitofOAC主动脉弓粥样硬化:APA

TunickPetalAmJCardiol2002;90:13205LevelIIIevidence:nobenefitofAPA主动脉弓粥样硬化:他汀类

TunickPetalAmJCardiol2002;90:13205LevelIIIevidence:benefitofstatins1°strokepreventionRetrospectivedatashownobenefitofOACfornativevalveendocarditis,benefitforprostheticvalveendocarditis152°strokeprevention:Nodata感染性心内膜炎1DavenportetalStroke1990;21:993-92PaschalisetalEurNeurol1990;30:87-93YehetalCirculation1967;35:I77-814DelahayeetalEurHeartJ1990;11:1074-85WilsonetalCirculation1978;57:1004-7LevelVevidence?Pathogenesis:fibrinthrombidepositsonvalvesassocwithcoagulopathy(usuallyDIC)Reportedincidenceofembolismvaries(1491%)Rx:Retrospectivedatasuggestbenefitofheparin,butnotOAC1368%withrecurrentemboliwhenheparind/c’dICHrisklowerthanininfectiveendocarditis1RogersetalAmJMed1987;83:746-562LopezetalAmHeartJ1987;113:773-843SacketalMedicine1977;56:1-37非细菌性血栓性心内膜炎LevelVevidence:nobenefitofOAC;benefitofheparininTrousseausyndrome(mainlywithDIC)EuropeanAtrialFibrillationTrialEAFT

(Lancet1993;342:12551262)Oralanticoagulants(225)vs.Aspirin(230)

HR(95%CI)1°Endpoint 0.60(.41.87)Allstroke 0.38(.23.64)Bleeding 2.8(1.74.8)MajorbleedingOAC2.8%/yrvs.ASA0.9%/yr

LevelIEvidence:benefitofOACOptimumINRforpreventionof2°strokeassociatedwithatrialfibrillation

(EAFTNEJM1995;333:510)“ThetargetvaluefortheINRshouldbesetat3.0”StrokePreventionwiththeORaldirectThrombinInhibitorinpatientswithnonvalvularatrialFibrillation(SPORTIF)SPORTIFIII是一项开放试验,SPORTIFV期是随机双盲多中心试验；比较了口服直接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%）高很多，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PrethrombolyticeraHeparindecreasesstrokeincidence13Heparindecreasesmuralthrombus41MedResearchCouncilBMJ1969;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Postthrombolyticerabaselineratesofdeath,reinfarction,stroke,&PEmarkedlylowerwiththrombolytics&ASAadditionofheparin/LMWHmaydecreasemuralthrombusformation,butincreasesriskofmajorbleedingwithoutfurtherreducingstrokerisk1CollinsetalBMJ1996;313:652-92CollinsetalNEJM1997;336:847-603FRAMIKontnyetalJACC1997;30:962-94SCATILancet1989;2:182-65Gissi-2VecchioetalCirculation1991;84:512-9心肌梗死后一级预防:长期抗凝Relativetocontrol,coumarinsinmoderateorhighdose(INR24.8)SignificantlydecreasestrokeincidenceSignificantlyincreaseincidenceofmajorbleedingAnand&YusufJAMA1999;282:2058-67Mo