缺血性卒中抗栓循证治疗

缺血性卒中抗栓循证治疗(zhìliáo)共七十九页证据(zhèngjù)等级I类证据

随机对照试验，

假阳性和假阴性(yīnxìng)错误低II类证据

随机对照试验，

假阳性和假阴性错误高III类证据

非随机对列研究IV类证据

回顾性非随机对列研究，V类证据

经验性研究Cooketal.,Chest,1992;102:305S-311S共七十九页急性(jíxìng)缺血性卒中溶栓治疗共七十九页概述(ɡàishù)静脉(jìngmài)溶栓组织纤溶酶原激活物（tPA）

NINDSECASSI&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

共七十九页与安慰剂相比(xiānɡbǐ)，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共七十九页随机,多中心,双盲,安慰剂对照620例;排除CT早期梗塞灶

(预后(yùhòu)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rt-PA:

ECASSIHackeetal.,JAMA.1995;274:1017-1025共七十九页随机,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(qǐbìnɡ)6h内

主要终点modifiedRankinScaleScoreof≤1at90daysrtPA与安慰剂组无明显差别rt-PA:

ECASSIIHackeetal.,Lancet.1998;352:1245-1251共七十九页随机,多中心,双盲,安慰剂对照613例干预rtPA(0.9mg/kg)vs.placebo起病(qǐbìnɡ)3-5h内主要终点NIHSSof≤1at90daysrtPA与安慰剂组无明显差别rt-PA:ATLANTIS

AlteplaseThrombolysisforAcuteNoninterventionalRxinIschStrokeClarketal.,JAMA.1999;282:2019-2026共七十九页rt-PA:

小结(xiǎojié)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(chāoguò)3h予IVtPA无效.I类证据共七十九页链激酶（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(yùhòu)不良(出血和死亡率高).I类证据共七十九页动脉(dòngmài)溶栓前循环大脑(dànǎo)中动脉阻塞后循环椎基底动脉阻塞共七十九页与安慰剂相比,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(zēngjiā)颅内出血，死亡率无差异PROACTII:

小结(xiǎojié)共七十九页急性椎基底(jīdǐ)动脉阻塞数项病例报道(bàodào)(IV、V类证据)非随机化无对照组

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

共七十九页小结(xiǎojié)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(tōngguò))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类证据共七十九页急性(jíxìng)缺血性卒中抗凝治疗共七十九页概述(ɡàishù)肝素(ɡānsù)LMWheparinLMWheparinoid- 作用于抗凝血酶III (抑制凝血因子IIa,IXa,andXa)

1

effectonXareducedpltinteractionlongerhalf-life

simplertoadministerlowerbleedingriskreducedeffectonIIa共七十九页Summary:trialresultsNdrugresultsCanadian225HepIVnodifferenceIST19,435HepscnodifferenceTOAST1281heparinoidnodifferencelargeartbetterat3mo?HK308LMWH

dead/depat6moFISS767LMWHnodifferenceTAIST1486LMWHnodifferenceTOPAS404LMWHnodifferenceamongdoses共七十九页各卒中亚型急性(jíxìng)抗凝治疗

房颤

和心源性栓塞大动脉粥样硬化椎基底(jīdǐ)动脉阻塞

TIA进展性卒中动脉夹层静脉血栓形成共七十九页各卒中亚型急性抗凝治疗(zhìliáo):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-共七十九页小结(xiǎojié)

急性期抗凝减少深静脉(jìngmài)血栓和肺栓塞发生，不增加颅内出血几率.I类证据

共七十九页急性缺血性卒中阿司匹林(āsīpǐlín)治疗共七十九页

InternationalStrokeStrial(IST)ASA300mg/dx2wksbegunwithin48hrs2wkendptsASAN=9720NoASAN=9715Recurrentischemic2.8%*3.9%Allrecurrentstroke3.7%4.6%Majorextracranialbleed1.1%*0.6%Death9.0%9.4%*p<.01共七十九页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共七十九页小结(xiǎojié)

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(jiǎnshǎo)死亡和复发。共七十九页非心源性卒中二级预防(yùfáng)：

抗栓治疗共七十九页概述(ɡàishù)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+extended-releasedipyridamole)Warfarinfornon-cardioembolicarterialstroke:includinglargevesseldisease.抗磷脂抗体综合征（ASP）.颈椎动脉(dòngmài)夹层.共七十九页Aspirin共七十九页高剂量(jìliàng)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)inthecontrolgroup共七十九页低剂量阿司匹林(āsīpǐlín)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.**strokeinplacebo共七十九页AntiplateletTrialists’100,000ptsfrom145trials.Allantiplateletagentswereincluded.Clumpedallvasculareventstogether.Overalloddsreductionforvasculareventswas25%.ForptswithminorstrokeorTIA(18trials)antiplateletagentsledtooddsreductionof22%forvasculareventsand23%fornonfatalstroke.Didnotanswerquestionsaboutaspirindose.Usedoddsratioinsteadofrelativerisk.Usedallantiplateletagents.共七十九页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.共七十九页Ticlopidine

共七十九页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)共七十九页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.共七十九页Clopidogril共七十九页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共七十九页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共七十九页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(zhèngzhuàng)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共七十九页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.共七十九页ESPS-2Results:

StrokeRatesat24MonthsPlaceboASAER-DPASA/ER-DP048121615.2%12.5%12.8%9.5%Incidence(%)ARR=5.7overPlaceboNNT=1/0.057=17.5共七十九页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共七十九页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共七十九页PreventionRegimenforEffectivelyAvoidingSecondStrokes（PRoFESS）

是由30个国家参入，纳入18500例患者(huànzhě)，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，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。共七十九页Warfarin-AspirinRecurrentStrokeStudy（WARSS）2206patientsfollowedfor2years

ISorDeath Mjrbleed/100pt-yrsWarfarin 17.8%2.22Aspirin 16.0%1.49p=.25Nosignificantdifferencebetweenwarfarinandaspirin共七十九页TheWarfarin-AspirinSymptomaticIntracranialDiseasestudy（WASID）

多中心前瞻性随机(suíjī)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.共七十九页EffectofTreatmentonRecurrentIschemicStrokeandDeathAtTwoYearsinAPASS/WARSS

(Brey,RL:presentedatthe27InternationalStrokeConference,SanAntonio,TX,February9,2002)PrimaryEndpoint(%)抗磷脂(línzhī)抗体阳性组与阴性组无差异，阿司匹林与华法林无差异

共七十九页颈动脉和椎动脉夹层(jiācéng)Naturalhistoryofcarotiddissection:(HartetalNeurolClinNorthAm1:155,1983)Cerebralinfarctionin33%(23%minor,10%majororfatal.TIAin45;Headandneckpainin16%;Pulsatiletinnitus4%;andbruitin2%.Propermanagementiscontroversial.Mostptsdowell,eitherbecauseofordespitetreatment.共七十九页

心源性卒中预防(yùfáng)：

抗血栓治疗共七十九页心源性卒中可能(kěnéng)病因Valvularheartdisease心脏(xīnzàng)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卵圆孔未闭共七十九页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共七十九页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共七十九页Prostheticheartvalves:mechanicalvalves

2°strokepreventionNodirectdataACCPrecommendations:OAC+babyASAbasedonextrapolationof1°preventiondata6thACCPConsensusConferenceonAntithromboticTherapy2001共七十九页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共七十九页MitralValveProlapse:2°strokepreventionLevelVevidence:neitherASAnorACcompletelyeffectiveNwarfarinASANoRxWatson19791110/21/9Hanson19802221/40/120/6StrokerecurrenceinMVP:caseseriesMVP+AF:extrapolatedatafromEAFT1WatsonRTNeurol1979;29:886-92HansonMetalStroke1980;11:499-506共七十九页Atherosclerosisofthethoracicaorta:

benefitofOAC50patientswithatheroma>4mmLevelIII:benefit34patientswithmobileatheromaLevelIII:benefitFerrariEetalJACC1999;33:1317-22共七十九页主动脉弓(zhǔdòngmàigōng)粥样硬化

TunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:benefitofstatins共七十九页主动脉弓(zhǔdòngmàigōng)粥样硬化:OAC

TunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:nobenefitofOAC共七十九页主动脉弓(zhǔdòngmàigōng)粥样硬化:APA

TunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:nobenefitofAPA共七十九页主动脉弓(zhǔdòngmàigōng)粥样硬化:他汀类

TunickPetalAmJCardiol2002;90:1320-5LevelIIIevidence:benefitofstatins共七十九页1°strokepreventionRetrospectivedatashownobenefitofOACfornativevalveendocarditis,benefitforprostheticvalveendocarditis1-52°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共七十九页?Pathogenesis:fibrinthrombidepositsonvalvesassocwithcoagulopathy(usuallyDIC)Reportedincidenceofembolismvaries(14-91%)Rx:Retrospectivedatasuggestbenefitofheparin,butnotOAC1-368%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)共七十九页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共七十九页OptimumINRforpreventionof2°strokeassociatedwithatrialfibrillation

(EAFTNEJM1995;333:5-10)“ThetargetvaluefortheINRshouldbesetat3.0”共七十九页StrokePreventionwiththeORaldirectThrombinInhibitorinpatientswithnon-valvularatrialFibrillation(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(gàilǜ)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。共七十九页心肌梗死(xīnjīɡěnɡsǐ)后一级预防:短期抗凝Pre-thrombolyticeraHeparindecreasesstrokeincidence1-3Heparindecreasesmuralthrombus41MedResearchCouncilBMJ1969;1:335-422Drapkin&MerskeyJAMA1972;222:541-83VACoopStudyJAMA1973;225:724-94Vaitkus&BarnathauJACC1993;22:100-9共七十九页心肌梗死(xīnjīɡěnɡsǐ)后一级预防:短期抗凝Post-thrombolyticerabaselineratesofdeath,reinfarction,stroke,&PEmarkedlylowerwiththrombolytics&ASAadditionofheparin/LMWHmaydecreasemuralthrombusformation,butincreasesriskofmajorbleedingwithoutfurtherreducingstrokerisk1CollinsetalBMJ1996;313:652-92CollinsetalNEJM1997;336:847-603FRAMIKontnyetalJACC1997;30:962-94SCATILancet1989;2:182-65Gissi-2VecchioetalCirculation1991;84:512-9共七十九页心肌梗死(xīnjīɡěnɡsǐ)后一级预防:长期抗凝Relativetocontrol,coumarinsinmoderateorhighdose(INR2-4.8)SignificantlydecreasestrokeincidenceSignificantlyincreaseincidenceofmajorbleedingAnand&YusufJAMA1999;282:2058-67共七十九页ModifiedfromAnand&YusufJAMA1999;282:2058-67…ButnobenefitrelativetoASAIncidenceofstrokeandsignificantincreaseinmajorbleeding共七十九页

RR(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(biànliàng)分析

(LohEetalNEJM1997;336:251-257)*

similar

riskatalllevelsofEF<40%#similar

riskatalllevelsofEF<35%共七十九页

Rate(Events/100Pt-Yr)Anticoagulation 0(0/40)NoAnticoagulation 0.35(1/288)

LowRiskforPrimaryOccurrence慢性室壁瘤系统(xìtǒng)栓塞

(LapeyreACetalJACC1985;6:534-538)共七十九页PatentForamenOvaleinCryptogenicStrokeStudy(PICSS)

(HommaSetalCirculation2002;105:2625-31)Design:Prospective,randomized,double-blind,multi-centerclinicaltrialEligibility:EnrolledinWARSSAgreetohaveadditionalTEETreatment:Warfarin(targetINR1.4-2.8,mean2.1)vs.aspirin325mg1°endpoint:Recurrentischemicstrokeordeathwithin2years601patients42%withcryptogenicstrokeasqualifyingevent34%withPFO共七十九页PICSSLevelIIEvidence:NodifferencefromaspirinoverallorinanysubgroupNoincreasedeventrateinPFO+ASAvs.PFOonlyNoincreasedratewithlargerPFOsize共七十九页RheumaticMVdz:LevelIII

-BenefitovernoOACAorticarchatheroma:Level

III

-BenefitoverAPAin1study;NobenefitofOACorAPAinanother(butbenefitofstatins)Infectiveendocarditis:Nativevalve:LevelV-NobenefitProstheticvalve:LevelV-

benefitNBTE:LevelV-Nobenefit

(?benefitofheparin)Atrialfibrillation:

Level

I

-BenefitoverASA[INR2.9(2.5-4.0)]PFO:

LevelII

-NobenefitoverASA(INR1.4–2.8)MVP:

LevelV

–NotcompletelyeffectiveAtrialfibrillation:

LevelI

-BenefitoverASA[INR2.9(2.5-4.0)]

PFO:

Leve