缺血性卒中抗栓循證治療演示文稿第一頁，共七十三頁。（優(yōu)選）缺血性卒中抗栓循證治療第二頁，共七十三頁。急性缺血性卒中溶栓治療第三頁，共七十三頁。概述靜脈溶栓組織纖溶酶原激活物（tPA）

NINDSECASSI&II,ATLANTIS鏈激酶MAST-I,MAST-E,ASK動脈溶栓前循環(huán):大腦中動脈(PROACTII)后循環(huán):基底動脈

第四頁，共七十三頁。與安慰劑相比，3h內IVrtPA(0.9mg/kg)能改善90天時的預后出血發(fā)生率為6.4%，安慰劑為0.6%，但死亡率無差異所有亞組預后均優(yōu)于安慰劑組益處可持續(xù)1年rt-PA:NINDS第五頁，共七十三頁。隨機,多中心,雙盲,安慰劑對照620例;排除CT早期梗塞灶(預后不良)干預rtPA(1.1mg/kg)vs.placebo起病6h內主要終點BarthelIndexandmodifiedRankinScaleat90daysrtPA與安慰劑組無明顯差別rt-PA:

ECASSIHackeetal.,JAMA.1995;274:1017-1025第六頁，共七十三頁。隨機,多中心,雙盲,安慰劑對照800例;排除CT早期明顯梗塞灶

干預rtPA(0.9mg/kg)vs.placebo起病6h內

主要終點modifiedRankinScaleScoreof≤1at90daysrtPA與安慰劑組無明顯差別rt-PA:

ECASSIIHackeetal.,Lancet.1998;352:1245-1251第七頁，共七十三頁。隨機,多中心,雙盲,安慰劑對照613例干預rtPA(0.9mg/kg)vs.placebo起病3-5h內主要終點NIHSSof≤1at90daysrtPA與安慰劑組無明顯差別rt-PA:ATLANTIS

AlteplaseThrombolysisforAcuteNoninterventionalRxinIschStrokeClarketal.,JAMA.1999;282:2019-2026第八頁，共七十三頁。rt-PA:

小結與安慰劑相比，3h內IVrtPA(0.9mg/kg)能改善90天時的預后.I類證據目前證據顯示，超過3h予IVtPA無效.I類證據第九頁，共七十三頁。鏈激酶（SK）

研究藥物劑量治療窗結果MulticenterAcuteStrokeTrial-Europe(MAST-E)NEJM1996;335:145-50SK1.5MU6hSK組出血和死亡率高提前終止試驗MulticenterAcuteStrokeTrial-Italy(MAST-I)Lancet1995;346:1509-14SKaspirin1.5MU300mg/d6hSK組，尤其是SK+aspirin組出血和死亡率高提前終止試驗AustralianStreptokinaseTrial(ASK)Donnanetal.,Lancet1995;345:578-9SK1.5MU4h提前終止;治療窗4h無明顯益處，結果不良與安慰劑相比，6h內予IVSK1.5MU預后不良(出血和死亡率高).I類證據第十頁，共七十三頁。動脈溶栓前循環(huán)大腦中動脈阻塞后循環(huán)椎基底動脈阻塞第十一頁，共七十三頁。與安慰劑相比,6h內予IAProUK經造影證實MCAM1

或M2

段阻塞的患者有效.I類證據15%絕對有效(numberneededtotreat=7)增加顱內出血，死亡率無差異PROACTII:

小結第十二頁，共七十三頁。急性椎基底動脈阻塞數項病例報道(IV、V類證據)非隨機化無對照組

Brandtetal.,CerebrovascDis,1995;5:182-7

第十三頁，共七十三頁。小結3h內靜脈用tPA能降低90天時的殘障功能.I類證據靜脈用鏈激酶(1.5MU)增加出血和死亡率.I類證據6h內動脈用尿激酶前體(Pro-UK,未被FDA通過)能降低90天時的殘障功能.I類證據有證據支持在急性椎基底動脈阻塞中應用動脈溶栓.IV、V類證據第十四頁，共七十三頁。急性缺血性卒中抗凝治療第十五頁，共七十三頁。概述肝素LMWheparinLMWheparinoid- 作用于抗凝血酶III (抑制凝血因子IIa,IXa,andXa)

1

effectonXareducedpltinteractionlongerhalf-life

simplertoadministerlowerbleedingriskreducedeffectonIIa第十六頁，共七十三頁。Summary:trialresultsNdrugresultsCanadian225HepIVnodifferenceIST19,435HepscnodifferenceTOAST1281heparinoidnodifferencelargeartbetterat3mo?HK308LMWH

dead/depat6moFISS767LMWHnodifferenceTAIST1486LMWHnodifferenceTOPAS404LMWHnodifferenceamongdoses第十七頁，共七十三頁。各卒中亞型急性抗凝治療

房顫

和心源性栓塞大動脈粥樣硬化椎基底動脈阻塞

TIA進展性卒中動脈夾層靜脈血栓形成第十八頁，共七十三頁。各卒中亞型急性抗凝治療:小結CCTsubgrpNresults心源性栓塞123618nodiff大動脈硬化0413,2851+(?)/3-后循環(huán)032318nodiffTIA1055nodiff進展性卒中20204nodiff夾層00286nodiff靜脈血栓20791+/1-第十九頁，共七十三頁。小結

急性期抗凝減少深靜脈血栓和肺栓塞發(fā)生，不增加顱內出血幾率.I類證據

第二十頁，共七十三頁。急性缺血性卒中阿司匹林治療第二十一頁，共七十三頁。

InternationalStrokeStrial(IST)ASA300mg/dx2wksbegunwithin48hrs2wkendptsASAN=9720NoASAN=9715Recurrentischemic2.8%*3.9%Allrecurrentstroke3.7%4.6%Majorextracranialbleed1.1%*0.6%Death9.0%9.4%*p<.01第二十二頁，共七十三頁。ChineseAcuteStrokeTrial(CAST)

Lancet1997;349:1641ASA160mg/dx4wksbegunwithin48hrs4wkendptsASAN=10335PlaceboN=10320Recurrentischemic1.6%*2.1%Allrecurrentstroke3.2%3.4%Majorextracranbleed0.8%*0.6%Death3.3%*3.9%*p<.05第二十三頁，共七十三頁。小結

基于IST和CAST,阿司匹林在急性缺血性卒中后2-4周內，每1000例患者中有10人可減少死亡和復發(fā)。第二十四頁，共七十三頁。非心源性卒中二級預防：

抗栓治療第二十五頁，共七十三頁。概述抗血小板藥Antiplatelet.阿司匹林Aspirin抵克立得（噻氯匹啶）Ticlid?(Ticlopidine)波力維（氯吡格雷）Plavix?(Clopidogrel)艾諾思Aggrenox?(aspirin+extended-releasedipyridamole)Warfarinfornon-cardioembolicarterialstroke:includinglargevesseldisease.抗磷脂抗體綜合征（ASP）.頸椎動脈夾層.第二十六頁，共七十三頁。Aspirin第二十七頁，共七十三頁。高劑量阿司匹林隨機對照試驗#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)inthecontrolgroup第二十八頁，共七十三頁。低劑量阿司匹林隨機對照試驗#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.**strokeinplacebo第二十九頁，共七十三頁。AntiplateletTrialists’100,000ptsfrom145trials.Allantiplateletagentswereincluded.Clumpedallvasculareventstogether.Overalloddsreductionforvasculareventswas25%.ForptswithminorstrokeorTIA(18trials)antiplateletagentsledtooddsreductionof22%forvasculareventsand23%fornonfatalstroke.Didnotanswerquestionsaboutaspirindose.Usedoddsratioinsteadofrelativerisk.Usedallantiplateletagents.第三十頁，共七十三頁。Isthereaconsensus.

TheFDAreviewedtrialsofaspirinvsplacebo

(includingESPS-2,SALT,andUK-TIAtrials)toreducetheriskofstrokeanddeathinpatientswithpriorTIAorstroke.“Thepositivefindingsatlowerdosages

(eg,50,75,and300mgdaily),alongwiththehigherincidenceofsideeffectsexpectedatthehigherdosage(eg,1,300mgdaily),

aresufficientreasontolowerthedosageofaspirinforsubjectswithTIAandischemicstroke.”For

“ischemicstrokeandTIA:50to325mg

[aspirin]onceaday.Continuetherapyindefinitely.”FDA.FederalRegister.1998;63:56802.第三十一頁，共七十三頁。Ticlopidine

第三十二頁，共七十三頁。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)第三十三頁，共七十三頁。Ticlopidine(%)Aspirin(%)DiarrheaRashNauseaGastritis,ulcer,GIbleedingSevereneutropenia

(ANC<450/mm3)Cerebralhemorrhage20.4*11.9*11.12.10.9*0.69.85.210.26.0*0.00.7*P<0.05TASSStudy:SideEffectsAdaptedfromHassetal.NEnglJMed.1989;321:501.第三十四頁，共七十三頁。Clopidogril第三十五頁，共七十三頁。CAPRIEStudy

EfficacyofClopidogrelvs.Aspirin(n=19,185)PrimaryOutcome:MI,IschemicStroke,orVascularDeathMonthsofFollow-UpCumulative

EventRate(%)0481216ClopidogrelAspirin0369121518212427303336Aspirin5.83%5.32%ClopidogrelEventRateperYear*P=0.043CAPRIESteeringCommittee.Lancet1996;348:1329-1339.ARR=0.51NNT=1/0.005=196第三十六頁，共七十三頁。Clopidogrel(%)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.SideEffectscausingdiscontinuationofdrugCAPRIEStudy第三十七頁，共七十三頁。ManagementofAtherothrombosiswithClopidogrelinHigh-riskpatients（MATCH）

氯吡格雷（75mg）+阿司匹林（75mg）與單用氯吡格雷（75mg）的療效進行比較，結果是失敗的兩組的主要終點指標，即缺血性卒中、心肌梗死和血管源性死亡發(fā)生率與急性缺血事件（心絞痛、周圍動脈癥狀惡化或TIA）無統(tǒng)計學差異聯合治療同時增加了嚴重出血的概率第三十八頁，共七十三頁。TheSecondEuropeanStrokePreventionStudy:

ESPS-2TestedefficacyofASA/ER-DPforsecondarystrokepreventionAddressedclinicalquestionsDoeslow-doseASApreventstroke?DoesER-DPpreventstroke?IsASA/ER-DPsuperiortoASAalone?ToER-DPalone?IsASA/ER-DPwelltolerated?TheESPS-2Group.JNeurolSci.1997;151:S3.Dieneretal.JNeurolSci.1996;143:1.第三十九頁，共七十三頁。ESPS-2Results:

StrokeRatesat24MonthsPlaceboASAER-DPASA/ER-DP048121615.2%12.5%12.8%9.5%Incidence(%)ARR=5.7overPlaceboNNT=1/0.057=17.5第四十頁，共七十三頁。ESPS-2: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<0.05第四十一頁，共七十三頁。Meta-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/DPBetterASABetter第四十二頁，共七十三頁。PreventionRegimenforEffectivelyAvoidingSecondStrokes（PRoFESS）

是由30個國家參入，納入18500例患者，為期4年的隨機雙盲多中心試驗，直接比較艾諾思Aggrenox（雙嘧達莫緩釋劑200mg+阿司匹林25mg，ER-DP200mg+ASA25mg，2次/d）與氯吡格雷（75mg，1次/d）在卒中二級預防中的療效，預期結果將在2008年報道。第四十三頁，共七十三頁。Warfarin-AspirinRecurrentStrokeStudy（WARSS）2206patientsfollowedfor2years

ISorDeath Mjrbleed/100pt-yrsWarfarin 17.8%2.22Aspirin 16.0%1.49p=.25Nosignificantdifferencebetweenwarfarinandaspirin第四十四頁，共七十三頁。TheWarfarin-AspirinSymptomaticIntracranialDiseasestudy（WASID）

多中心前瞻性隨機雙盲試驗華法林INR為2~3，阿司匹林為1300mg兩組的卒中發(fā)生率和血管源性病死率無統(tǒng)計學差異華法林組出血并發(fā)癥的發(fā)生率較高促使試驗提前終止

TheWarfarin-AspirinSymptomaticIntracranialDiseaseStudy.

Neurology.1995Aug;45(8):1488-93.第四十五頁，共七十三頁。EffectofTreatmentonRecurrentIschemicStrokeandDeathAtTwoYearsinAPASS/WARSS

(Brey,RL:presentedatthe27InternationalStrokeConference,SanAntonio,TX,February9,2002)PrimaryEndpoint(%)抗磷脂抗體陽性組與陰性組無差異，阿司匹林與華法林無差異

第四十六頁，共七十三頁。頸動脈和椎動脈夾層Naturalhistoryofcarotiddissection:(HartetalNeurolClinNorthAm1:155,1983)Cerebralinfarctionin33%(23%minor,10%majororfatal.TIAin45;Headandneckpainin16%;Pulsatiletinnitus4%;andbruitin2%.Propermanagementiscontroversial.Mostptsdowell,eitherbecauseofordespitetreatment.第四十七頁，共七十三頁。

心源性卒中預防：

抗血栓治療第四十八頁，共七十三頁。心源性卒中可能病因Valvularheartdisease心臟瓣膜病Rheumaticmitralvalvedisease風濕性二尖瓣病Prostheticheartvalves人工心臟瓣膜Mitralvalveprolapse二尖瓣脫垂Aorticvalvedisease主動脈瓣病Aorticarchatherosclerosis主動脈弓粥樣硬化Endocarditis(infectiveornonbacterialthrombotic)心內膜炎（感染性或非細菌性血栓）Atrialfibrillation心房顫動Myocardialinfarction心肌梗死Leftventriculardysfunction左心室功能不全Patentforamenovale卵圓孔未閉第四十九頁，共七十三頁。Rheumaticmitralvalvedisease:

2°strokepreventionNorandomizedtrialsObservationalstudies:OACreducerecurrentembolicevents/fataleventsby2/3ormore1-3Extrapolationfrom1largerandomizedstudyinNVAF(EAFT)providesadditionaldataforpatientswithRHD+AF(butRHDexcluded)1SzekelyPBMJ1964;1:209-12

2AdamsGFetalJNNP1974;37:378-833Fleming&BaileyPostgradMed1971;47:599-604LevelIII-IV:BenefitofOAC第五十頁，共七十三頁。Prostheticheartvalves:mechanicalvalves

1°strokepreventionObservationaldata:APAmaybesufficienttopreventembolisminabsenceofAF,butOACneededtopreventvalvethrombosis1-2RCT:additionofASA100mgtowarfarin(INR3-4.5)

cerebralembolism(4/186vs.12/184)3NonRCT:additionofASA500mgtripledriskofmajorhemorrhage(14%vs.5%)4

LevelIevidence:benefitofOAC+ASAoverOACalone1HartzRetalJThoracCVSurg1986;92:684-902RibeiroPetalJThoracCVSurg1986;91:92-83TurpieAetalNEJM1993;329:524-94ChesebroJetalAmJCard1983;51:1537-41第五十一頁，共七十三頁。Prostheticheartvalves:mechanicalvalves

2°strokepreventionNodirectdataACCPrecommendations:OAC+babyASAbasedonextrapolationof1°preventiondata6thACCPConsensusConferenceonAntithromboticTherapy2001第五十二頁，共七十三頁。Prostheticheartvalves:

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:noevidence第五十三頁，共七十三頁。MitralValveProlapse:2°strokepreventionLevelVevidence:neitherASAnorACcompletelyeffectiveNwarfarinASANoRxWatson19791110/21/9Hanson19802221/40/120/6StrokerecurrenceinMVP:caseseriesMVP+AF:extrapolatedatafromEAFT1WatsonRTNeurol1979;29:886-92HansonMetalStroke1980;11:499-506第五十四頁，共七十三頁。Atherosclerosisofthethoracicaorta:

benefitofOAC50patientswithatheroma>4mmLevelIII:benefit34patientswithmobileatheromaLevelIII:benefitFerrariEetalJACC1999;33:1317-22第五十五頁，共七十三頁。主動脈弓粥樣硬化

TunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:benefitofstatins第五十六頁，共七十三頁。主動脈弓粥樣硬化:OAC

TunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:nobenefitofOAC第五十七頁，共七十三頁。主動脈弓粥樣硬化:APA

TunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:nobenefitofAPA第五十八頁，共七十三頁。主動脈弓粥樣硬化:他汀類

TunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:benefitofstatins第五十九頁，共七十三頁。1°strokepreventionRetrospectivedatashownobenefitofOACfornativevalveendocarditis,benefitforprostheticvalveendocarditis1-52°strokeprevention:Nodata感染性心內膜炎1DavenportetalStroke1990;21:993-92PaschalisetalEurNeurol1990;30:87-93YehetalCirculation1967;35:I77-814DelahayeetalEurHeartJ1990;11:1074-85WilsonetalCirculation1978;57:1004-7LevelVevidence第六十頁，共七十三頁。?Pathogenesis:fibrinthrombidepositsonvalvesassocwithcoagulopathy(usuallyDIC)Reportedincidenceofembolismvaries(14-91%)Rx:Retrospectivedatasuggestbenefitofheparin,butnotOAC1-368%withrecurrentemboliwhenheparind/c’dICHrisklowerthanininfectiveendocarditis1RogersetalAmJMed1987;83:746-562LopezetalAmHeartJ1987;113:773-843SacketalMedicine1977;56:1-37非細菌性血栓性心內膜炎LevelVevidence:nobenefitofOAC;benefitofheparininTrousseausyndrome(mainlywithDIC)第六十一頁，共七十三頁。EuropeanAtrialFibrillationTrial：EAFT

(Lancet1993;342:1255-1262)Oralanticoagulants(225)vs.Aspirin(230)

HR(95%CI)1°Endpoint 0.60(.41-.87)Allstroke 0.38(.23-.64)Bleeding 2.8(1.7-4.8)MajorbleedingOAC2.8%/yrvs.ASA0.9%/yr

LevelIEvidence:benefitofOAC第六十二頁，共七十三頁。OptimumINRforpreventionof2°strokeassociatedwithatrialfibrillation

(EAFTNEJM1995;333:5-10)“ThetargetvaluefortheINRshouldbesetat3.0”第六十三頁，共七十三頁。StrokePreventionwiththeORaldirectThrombinInhibitorinpatientswithnon-valvularatrialFibrillation(SPORTIF)

SPORTIFIII是一項開放試驗,SPORTIFV期是隨機雙盲多中心試驗；比較了口服直接凝血酶抑制劑西美加群（ximelagatran）與華法林（INR2~3）對心房顫動罹患卒中的影響；兩組預防缺血性卒中的療效無統(tǒng)計學差異，華法林組并發(fā)出血的概率較高，西美加群組肝酶升高發(fā)生率為6%，比華法林組（0.8%）高很多，這也是尚未獲得美國FDA批準的原因。第六十四頁，共七十三頁。心肌梗死后一級預防:短期抗凝Pre-thrombolyticeraHeparindecreasesstrokeincidence1-3Heparindecreasesmuralthrombus41MedResearchCouncilBMJ1969;1:335-422Drapkin&MerskeyJAMA1972;222:541-83VACoopStudyJAMA1973;225:724-94Vaitkus&BarnathauJACC1993;22:100-9第六十五頁，共七十三頁。心肌梗死后一級預防:短期抗凝Post-thrombolyticerabaselineratesofdeath,reinfarction,stroke,&PEmarkedlylowerwiththrombolytics&ASAadditionofheparin/LMWHmaydecreasemuralthrombusformation,butincreasesriskofmajorbleedingwithoutfurtherreducingstrokerisk1CollinsetalBMJ1996;313:652-92Collinse