1、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）NINDS ECASS I&II,ATLANTIS 链激酶 MASTI,MASTE,ASK 动脉溶栓 前循环:大脑中动脉(PROACT II)后循环:基底动脉 与安慰剂相比，3h内IV rtPA(0.9 mg/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(1.1 mg/kg)vs.pla
2、cebo 起病6h内 主要终点 Barthel Index and modified Rankin Scale at 90 days rtPA 与安慰剂组无明显差别rtPA:ECASS IHacke et al.,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(0.9 mg/kg)vs.placebo 起病6h内 主要终点 modified Rankin Scale Score of 1 at 90 days rtPA 与安慰剂组无明显差别rtPA:ECASS IIHacke et al.,Lancet.199
3、8;352:1245-1251 随机,多中心,双盲,安慰剂对照 613例 干预 rtPA(0.9 mg/kg)vs.placebo 起病35h内 主要终点 NIHSS of 1 at 90 days rtPA 与安慰剂组无明显差别rtPA:ATLANTISAlteplase Thrombolysis for Acute Noninterventional Rx in Isch StrokeClark et al.,JAMA.1999;282:2019-2026Endocarditis(infective or nonbacterial thrombotic)心内膜炎（感染性或非细菌性血栓）An
4、tiplatelet TrialistsBleeding2.Fatal;nonfatal CI no TIA included波力维（氯吡格雷）Plavix(Clopidogrel)Same as medicalRheumatic MV dz:Level III Benefit over no OACRecurrent ischemic“The positive findings at lower dosages(eg,50,75,and 300 mg daily),along with the higher incidence of side effects expected at the
5、higher dosage(eg,1,300 mg daily),are sufficient reason to lower the dosage of aspirin for subjects with TIA and ischemic stroke.WarfarinAspirin Recurrent Stroke Study（WARSS）随机,多中心,双盲,安慰剂对照9 mg/kg)vs.Aspirin 16.2Collins et al NEJM 1997;336:847-60Ticlopidine(%)rtPA:ATLANTISAlteplase Thrombolysis for A
6、cute Noninterventional Rx in Isch StrokeProsthetic heart valves:bioprosthetic valvesSK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IV rtPA(0.9 mg/kg)能改善90天时的预后.I 类证据 目前证据显示，超过3h 予IV tPA 无效.I 类证据链激酶（SK）研究药物剂量治疗窗结果Multicenter Acute Stroke Trial-Europe(MAST-E)NEJM 1996;335:145-50SK1.5 MU6hSK组出血和死亡率高提前终止试验Multicente
7、r Acute Stroke Trial-Italy(MAST-I)Lancet 1995;346:1509-14SK aspirin1.5 MU300 mg/d6hSK组，尤其是SK+aspirin组出血和死亡率高提前终止试验Australian Streptokinase Trial(ASK)Donnan et al.,Lancet 1995;345:578-9SK1.5 MU4h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IV SK 1.5 MU 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IA
8、ProUK 经造影证实MCA M1 或M2 段阻塞的患者有效.I 类证据 15%绝对有效(number needed to treat=7)增加颅内出血，死亡率无差异PROACT II: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 Brandt et al.,Cerebrovasc Dis,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(1.5 MU)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.I
9、V、V类证据急性缺血性卒中抗凝治疗Aspirin#.Atrial fibrillation:Level I Benefit over ASA INR 2.3 Turpie A et al NEJM 1993;329:524-9Atrial fibrillation:Level I Benefit over ASA INR 2.3h内静脉用 tPA 能降低90天时的残障功能.1%30.Optimum INR for prevention of 2 stroke associated with atrial fibrillation(EAFT NEJM 1995;333:510)All strok
10、e0.Lightheadedness 30.Clopidogril所有亚组预后均优于安慰剂组Mitral Valve Prolapse:2 stroke prevention比较了口服直接凝血酶抑制剂西美加群（ximelagatran）与华法林（INR23）对心房颤动罹患卒中的影响；,Cerebrovasc Dis,1995;5:18271989;321:501.TIA,S,MI,vascular deathS,death or bothand significant increase in major bleedingand significant increase in major ble
11、eding慢性室壁瘤系统栓塞(Lapeyre AC et al JACC 1985;6:534-538)概述 肝素 LMW heparin LMW heparinoid作用于抗凝血酶 III(抑制凝血因子 IIa,IXa,and Xa)1 effect on Xa reduced plt interaction longer half-life simpler to administer lower bleeding risk reduced effect on IIaSummary:trial resultsNdrugresultsCanadian225Hep IVno difference
12、IST19,435Hep scno differenceTOAST1281heparinoidno differencelarge art better at 3 mo?HK308LMWH dead/dep at 6 moFISS767LMWHno differenceTAIST1486LMWHno differenceTOPAS404LMWHno difference among doses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123618n
13、o diff大动脉硬化0413,2851+(?)/3-后循环032318no diffTIA1055no diff进展性卒中20204no diff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急性缺血性卒中阿司匹林治疗International Stroke Strial(IST)ASA 300 mg/d x 2 wks begun within 48 hrs2 wk endptsASAN=9720No ASAN=9715Recurrent ischemic2.8%*3.9%All re
14、current stroke3.7%4.6%Major extracranial bleed1.1%*0.6%Death9.0%9.4%*p.01Chinese Acute Stroke Trial(CAST)Lancet 1997;349:1641ASA 160 mg/d x4 wks begun within 48 hrs4 wk endptsASAN=10335PlaceboN=10320Recurrent ischemic1.6%*2.1%All recurrent stroke3.2%3.4%Major extracran bleed0.8%*0.6%Death3.3%*3.9%*p
15、.05小结小结基于 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非心源性卒中二级预防抗栓治疗抗栓治疗概述 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+extendedrelease dipyridamole)Warfarin for noncardioembolic arterial stroke:including large vessel dis
16、ease.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#StudyASA dose#of ptsAgef/u Prim.Endpoint%of RR1AITIA 1977Medical group1300mgA 88;P 9060.237mTIA,CI,RI,death20 only with TIA.*P(15.7)2AITIA 1977 surgical group650mgA 65;P 6060.3?TIA,CI,RI,deathSame as medical*P(15.7)3CCSG 1978ASA+SP1300mgA 144;P 139?26mT
17、IA,S,death-6 to 31%*P(7.6)4Reuther 19781500mgA 29;P 295924mTIA,SNS*P(8.3)5AICLA 1983ASA+DP990mgA 198;P 20463.536mFatal;nonfatal CI no TIA included41*P(7.5)6Danish CS 19831000mgA 101;P 1025925mS or Death-77*P(9.6)7Swedish CS 19871500mgA 253;P 2526824mS or Death0*P(10.9)*Risk of vascular events(death,
18、stroke,MI)in the control groupCAPRIE Steering Committee.TIA,CI,RI,death1 effect on XaRelative RiskA 253;P 2523 Turpie A et al NEJM 1993;329:524-9低剂量阿司匹林随机对照试验Headache*32.ClopidogrelTiclopidine,Platelets and Vascular Disease.PROACT II:小结WarfarinAspirin Recurrent Stroke Study（WARSS）#similar risk at al
19、l levels of EF35%Neurology.Multicenter Acute Stroke Trial-Europe(MAST-E)Any bleeding disorderAICLA(N=400)Is there a consensus.J Neurol Sci.Prosthetic heart valves主动脉弓粥样硬化Tunick P et al Am J Cardiol 2002;90:13205低剂量阿司匹林随机对照试验#Study ASA dose in mg.#of ptsAgeF/uPrim.Endpoint%in RR1Danish Low 1988(post
20、CEA)50-100A150P15158.925TIA,S,MI,vascular death11%(NS)*P(7.3)2UK TIA 19911200300Placebo81580681459.848Major S,MI,Vasc.Death 15%vs P;NS between doses*P(5.7)3SALT 199175A676P68466.932S or death16%*P(10.6)4ESPS 250A1649P164966.724S,death or both18%*P(15.8)*Vascular events(death,MI,stroke)in placebo.*st
21、roke in placeboAntiplatelet Trialists 100,000 pts from 145 trials.All antiplatelet agents were included.Clumped all vascular events together.Overall odds reduction for vascular events was 25%.For pts with minor stroke or TIA(18 trials)antiplatelet agents led to odds reduction of 22%for vascular even
22、ts and 23%for nonfatal stroke.Did not answer questions about aspirin dose.Used odds ratio instead of relative risk.Used all antiplatelet agents.Is there a consensus.The FDA reviewed trials of aspirin vs placebo(including ESPS2,SALT,and UKTIA trials)to reduce the risk of stroke and death in patients
23、with prior TIA or stroke.“The positive findings at lower dosages(eg,50,75,and 300 mg daily),along with the higher incidence of side effects expected at the higher dosage(eg,1,300 mg daily),are sufficient reason to lower the dosage of aspirin for subjects with TIA and ischemic stroke.”For“ischemic st
24、roke and TIA:50 to 325 mg aspirin once a day.Continue therapy indefinitely.”FDA.Federal Register.1998;63:56802.Ticlopidine TASS Study:Efficacy*3-year study endpoints,N=3,069.EndpointStrokeStroke,MI,orvascular deathRRR21%9%(P=0.024)Hass et al.N Engl J Med.1989;321:501.Easton.In Hass and Easton(eds).T
25、iclopidine,Platelets and Vascular Disease.New York:Springer-Verlag;1993:141.*Ticlopidine(250 mg bid)vs ASA(650 mg bid).(NS)Ticlopidine(%)Aspirin(%)DiarrheaRashNauseaGastritis,ulcer,GI bleedingSevere neutropenia (ANC 450/mm3)Cerebral hemorrhage20.4*11.9*11.1 2.10.9*0.69.85.210.2 6.0*0.00.7*P 0.05TASS
26、 Study:Side EffectsAdapted from Hass et al.N Engl J Med.1989;321:501.ClopidogrilCAPRIE StudyEfficacy of Clopidogrel vs.Aspirin(n=19,185)Primary Outcome:MI,Ischemic Stroke,or Vascular DeathARR=0.51NNT=1/0.005=196Clopidogrel(%)ASA(%)GI complaintsAny bleeding disorderRashDiarrheaGI bleedingIntracranial
27、 hemorrhage1.901.200.90*0.420.520.212.41*1.370.410.270.93*0.33*P 0.05Side Effects causing discontinuation of drugCAPRIE StudyManagement of Atherothrombosis with Clopidogrel in Highrisk patients（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
28、TIA）无统计学差异 联合治疗同时增加了严重出血的概率 The Second European Stroke Prevention Study:ESPS2 Tested efficacy of ASA/ERDP for secondary stroke prevention Addressed clinical questions Does lowdose ASA prevent stroke?Does ERDP prevent stroke?Is ASA/ERDP superior to ASA alone?To ERDP alone?Is ASA/ERDP well tolerated?T
29、he ESPS-2 Group.J Neurol Sci.1997;151:S3.Diener et al.J Neurol Sci.1996;143:1.4 wk endptsPFO:Level II No benefit over ASA(INR 1.Headache*32.2 prevention:no evidenceClopidogrel(%)baseline rates of death,reinfarction,stroke,&PE markedly lower with thrombolytics&ASAClark et al.多中心前瞻性随机双盲试验5 MU)增加出血和死亡率
30、.4Vaitkus&Barnathau JACC 1993;22:100-9J Neurol Sci.Lightheadedness 30.Multicenter Acute Stroke Trial-Europe(MAST-E)Barthel Index and modified Rankin Scale at 90 daysUsed odds ratio instead of relative risk.Aspirin#.“The positive findings at lower dosages(eg,50,75,and 300 mg daily),along with the hig
31、her incidence of side effects expected at the higher dosage(eg,1,300 mg daily),are sufficient reason to lower the dosage of aspirin for subjects with TIA and ischemic stroke.NIHSS of 1 at 90 daysESPS2 Results:Stroke Rates at 24 MonthsPlaceboASAER-DP ASA/ER-DP048121615.2%12.5%12.8%9.5%Incidence(%)ARR
32、=5.7 over PlaceboNNT=1/0.057=17.5ESPS2:Side Effect Profile Placebo ASA ASA+EDGI Event*28.1%30.4%32.8%Headache*32.3%33.1%38.1%Bleeding*4.5%8.2%8.7%(any site)Lightheadedness 30.9%29.1%29.5%*=P 4mmLevel III:benefit34 patients with mobile atheromaLevel III:benefitFerrari E et al JACC 1999;33:1317-22主动脉弓
33、粥样硬化Tunick P et al Am J Cardiol 2002;90:13205Level III evidence:benefit of statins主动脉弓粥样硬化:OACTunick P et al Am J Cardiol 2002;90:13205Level III evidence:no benefit of OAC主动脉弓粥样硬化:APATunick P et al Am J Cardiol 2002;90:13205Level III evidence:no benefit of APA主动脉弓粥样硬化:他汀类Tunick P et al Am J Cardiol
34、2002;90:13205Level III evidence:benefit of statins 1 stroke prevention Retrospective data show no benefit of OAC for native valve endocarditis,benefit for prosthetic valve endocarditis15 2 stroke prevention:No data感染性心内膜炎1Davenport et al Stroke 1990;21:993-92Paschalis et al Eur Neurol 1990;30:87-9 3
35、Yeh et al Circulation 1967;35:I77-814Delahaye et al Eur Heart J 1990;11:1074-85Wilson et al Circulation 1978;57:1004-7Level V evidence?Pathogenesis:fibrin thrombi deposits on valves assoc with coagulopathy(usually DIC)Reported incidence of embolism varies(1491%)Rx:Retrospective data suggest benefit
36、of heparin,but not OAC13 68%with recurrent emboli when heparin d/cd ICH risk lower than in infective endocarditis1Rogers et al Am J Med 1987;83:746-562Lopez et al Am Heart J 1987;113:773-843Sack et al Medicine 1977;56:1-37非细菌性血栓性心内膜炎Level V evidence:no benefit of OAC;benefit of heparin in Trousseau
37、syndrome(mainly with DIC)European Atrial Fibrillation TrialEAFT(Lancet 1993;342:12551262)Oral anticoagulants(225)vs.Aspirin(230)HR(95%CI)1 Endpoint0.60(.41 .87)All stroke0.38(.23 .64)Bleeding2.8 (1.7 4.8)Major bleeding OAC 2.8%/yr vs.ASA 0.9%/yr Level I Evidence:benefit of OACOptimum INR for prevent
38、ion of 2 stroke associated with atrial fibrillation(EAFT NEJM 1995;333:510)“The target value for the INR should be set at 3.0”Stroke Prevention with the ORal direct Thrombin Inhibitor in patients with nonvalvular atrial Fibrillation(SPORTIF)SPORTIF III是一项开放试验,SPORTIF V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（x
39、imelagatran）与华法林（INR23）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 Prethrombolytic era Heparin decreases stroke incidence 13 Heparin decreases mural thrombus 41Med Research Council BMJ 1969;1:335-422Drapkin&Merskey JAMA 1972;222:541-8
40、3VA Coop Study JAMA 1973;225:724-94Vaitkus&Barnathau JACC 1993;22:100-9心肌梗死后一级预防:短期抗凝 Postthrombolytic era baseline rates of death,reinfarction,stroke,&PE markedly lower with thrombolytics&ASA addition of heparin/LMWH may decrease mural thrombus formation,but increases risk of major bleeding without
41、 further reducing stroke risk1Collins et al BMJ 1996;313:652-9 2Collins et al NEJM 1997;336:847-603FRAMI Kontny et al JACC 1997;30:962-94SCATI Lancet 1989;2:182-65Gissi-2 Vecchio et al Circulation 1991;84:512-9心肌梗死后一级预防:长期抗凝 Relative to control,coumarins in moderate or high dose(INR 24.8)Significant
42、ly decrease stroke incidence Significantly increase incidence of major bleedingAnand&Yusuf JAMA 1999;282:2058-67Modified from Anand&Yusuf JAMA 1999;282:2058-67But no benefit relative to ASAIncidence of strokeand significant increase in major bleeding RR(95%CI)Anticoagulation*.19(.13 .27)Aspirin#.44(
43、.29 .65)Level III evidence:benefit of AC ASA for 1 prevention左心室功能不全:卒中危险因子多变量分析(Loh E et al NEJM 1997;336:251-257)*similar risk at all levels of EF40%#similar risk at all levels of EF35%Rate(Events/100 PtYr)Anticoagulation 0 (0/40)No Anticoagulation 0.35 (1/288)Low Risk for Primary Occurrence慢性室壁瘤系
44、统栓塞(Lapeyre AC et al JACC 1985;6:534-538)Patent Foramen Ovale in Cryptogenic Stroke Study(PICSS)(Homma S et al Circulation 2002;105:262531)Design:Prospective,randomized,double blind,multicenter clinical trial Eligibility:Enrolled in WARSS Agree to have additional TEE Treatment:Warfarin(target INR 1.
45、42.8,mean 2.1)vs.aspirin 325 mg 1 endpoint:Recurrent ischemic stroke or death within 2 years 601 patients 42%with cryptogenic stroke as qualifying event 34%with PFOPICSSLevel II Evidence:No difference from aspirinoverall or in any subgroupNo increased event rate in PFO+ASA vs.PFO onlyNo increased ra
46、te with larger PFO sizeRheumatic MV dz:Level III Benefit over no OACAortic arch atheroma:Level III Benefit over APA in 1 study;No benefit of OAC or APA in another(but benefit of statins)Infective endocarditis:Native valve:Level V No benefitProsthetic valve:Level V benefitNBTE:Level V No benefit(?ben
47、efit of heparin)Atrial fibrillation:Level I Benefit over ASA INR 2.9(2.54.0)PFO:Level II No benefit over ASA(INR 1.4 2.8)MVP:Level V Not completely effectiveAtrial fibrillation:Level I Benefit over ASA INR 2.9(2.54.0)PFO:Level II No benefit over ASA(INR 1.4 2.8)MVP:Level V Not completely effectiveNo dataAortic valve diseaseProsthetic heart valvesMILV dysfunction口服抗凝剂（OAC）二级预防:小结
