1、缺血性卒中抗栓循证治缺血性卒中抗栓循证治疗疗证据等级I类证据随机对照试验，假阳性和假阴性错误低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Cook et al.,Chest,1992;102:305S-311S缺血性卒中抗栓循证治疗2急性缺血性卒中溶栓治疗缺血性卒中抗栓循证治疗3概述 静脉溶栓 组织纤溶酶原激活物（tPA）NINDS ECASS I&II,ATLANTIS 链激酶 MAST-I,MAST-E,ASK 动脉溶栓 前循环:大脑中动脉(PROACT II)后循环:基底动脉 缺血性卒中抗栓循证治疗4 与安慰剂相
2、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rt-PA:NINDS 缺血性卒中抗栓循证治疗5 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.placebo 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rt-PA:ECASS IHacke et al.,JAMA.1995;274:1017-102
3、5缺血性卒中抗栓循证治疗6 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rt-PA:ECASS IIHacke et al.,Lancet.1998;352:1245-1251缺血性卒中抗栓循证治疗7 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3-5h内 主要终点 NIHSS of 1 at 90 days rtP
4、A 与安慰剂组无明显差别rt-PA:ATLANTISAlteplase Thrombolysis for Acute Noninterventional Rx in Isch StrokeClark et al.,JAMA.1999;282:2019-2026缺血性卒中抗栓循证治疗8rt-PA: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 类证据缺血性卒中抗栓循证治疗9链激酶（SK）研究药物剂量治疗窗结果Multicenter Acute Stroke Trial-Europe(MAST-E)N
5、EJM 1996;335:145-50SK1.5 MU6hSK组出血和死亡率高提前终止试验Multicenter 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
6、和死亡率高).I 类证据缺血性卒中抗栓循证治疗10动脉溶栓 前循环 大脑中动脉阻塞 后循环 椎基底动脉阻塞缺血性卒中抗栓循证治疗11 与安慰剂相比,6h内予IA 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:小结缺血性卒中抗栓循证治疗12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;5:182-7缺血性卒中抗栓循证治疗13小结 3h内静脉用 tPA 能降低90天
7、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(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类证据缺血性卒中抗栓循证治疗14急性缺血性卒中抗凝治疗缺血性卒中抗栓循证治疗15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 low
8、er bleeding risk reduced effect on IIa缺血性卒中抗栓循证治疗16Summary:trial resultsNdrugresultsCanadian225Hep IVno differenceIST19,435Hep scno differenceTOAST1281heparinoidno differencelarge art better at 3 mo?HK308LMWH dead/dep at 6 moFISS767LMWHno differenceTAIST1486LMWHno differenceTOPAS404LMWHno difference
9、 among doses缺血性卒中抗栓循证治疗17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 静脉血栓形成缺血性卒中抗栓循证治疗18各卒中亚型急性抗凝治疗:小结CCTsubgrpNresults心源性栓塞123618no 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-缺血性卒中抗栓循证治疗19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 缺血性卒中抗栓循证治
10、疗20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缺血性卒中抗栓循证治疗21International Stroke Strial(IST)ASA 300 mg/d x 2 wks begun within 48 hrs2 wk endptsASAN=9720No ASAN=9715Recurrent ischemic2.8%*3.9%All recurrent stroke3.7%4.6%Major extracranial bleed1.1%*0.6%Death9.0%9.4%*p.01缺血性卒中抗栓循证治疗22Chinese Acute Stroke Trial(CAST)Lan
11、cet 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.05缺血性卒中抗栓循证治疗23小结小结基于 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。缺血性卒中抗栓循证治疗24非心源性卒中二级预防：非心源性卒中二级预
12、防：抗栓治疗抗栓治疗缺血性卒中抗栓循证治疗25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+extended-release dipyridamole)Warfarin for non-cardioembolic arterial stroke:including large vessel disease.抗磷脂抗体综合征（ASP）.颈椎动脉夹层.缺血性卒中抗栓循证治疗26Aspirin缺血性卒中抗栓循证治疗27高剂量阿司匹
13、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?26mTIA,S,death-6 to 31%*P(7.6)4Reuther 1978
14、1500mgA 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,stroke,MI)in the control group缺血性卒中抗栓循证
15、治疗28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 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
16、 250A1649P164966.724S,death or both18%*P(15.8)*Vascular events(death,MI,stroke)in placebo.*stroke in placebo缺血性卒中抗栓循证治疗29Antiplatelet 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%.Fo
17、r pts with minor stroke or TIA(18 trials)antiplatelet agents led to odds reduction of 22%for vascular events and 23%for nonfatal stroke.Did not answer questions about aspirin dose.Used odds ratio instead of relative risk.Used all antiplatelet agents.缺血性卒中抗栓循证治疗30Is there a consensus.The FDA reviewed
18、 trials of aspirin vs placebo(including ESPS-2,SALT,and UK-TIA trials)to reduce the risk of stroke and death in patients 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
19、mg daily),are sufficient reason to lower the dosage of aspirin for subjects with TIA and ischemic stroke.”For“ischemic stroke and TIA:50 to 325 mg aspirin once a day.Continue therapy indefinitely.”FDA.Federal Register.1998;63:56802.缺血性卒中抗栓循证治疗31Ticlopidine 缺血性卒中抗栓循证治疗32TASS Study:Efficacy*3-year stu
20、dy 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).Ticlopidine,Platelets and Vascular Disease.New York:Springer-Verlag;1993:141.*Ticlopidine(250 mg bid)vs ASA(650 mg bid).(NS)缺血性卒中抗栓循证治疗33Ticlopidine(%)Asp
21、irin(%)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 Study:Side EffectsAdapted from Hass et al.N Engl J Med.1989;321:501.缺血性卒中抗栓循证治疗34Clopidogril缺血性卒中抗栓循证治疗35CAPRIE StudyEfficacy of Clopidogre
22、l vs.Aspirin(n=19,185)Primary Outcome:MI,Ischemic Stroke,or Vascular DeathARR=0.51NNT=1/0.005=196缺血性卒中抗栓循证治疗36Clopidogrel(%)ASA(%)GI complaintsAny bleeding disorderRashDiarrheaGI bleedingIntracranial hemorrhage1.901.200.90*0.420.520.212.41*1.370.410.270.93*0.33*P 0.05Side Effects causing discontinua
23、tion of drugCAPRIE Study缺血性卒中抗栓循证治疗37Management of Atherothrombosis with Clopidogrel in High-risk 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TIA）无统计学差异 联合治疗同时增加了严重出血的概率 缺血性卒中抗栓循证治疗38The Second European Stroke Prevention Study:ES
24、PS-2 Tested efficacy of ASA/ER-DP for secondary stroke prevention Addressed clinical questions Does low-dose ASA prevent stroke?Does ER-DP prevent stroke?Is ASA/ER-DP superior to ASA alone?To ER-DP alone?Is ASA/ER-DP well tolerated?The ESPS-2 Group.J Neurol Sci.1997;151:S3.Diener et al.J Neurol Sci.
25、1996;143:1.缺血性卒中抗栓循证治疗39ESPS-2 Results:Stroke Rates at 24 MonthsPlaceboASAER-DP ASA/ER-DP048121615.2%12.5%12.8%9.5%Incidence(%)ARR=5.7 over PlaceboNNT=1/0.057=17.5缺血性卒中抗栓循证治疗40ESPS-2: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)
26、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缺血性卒中抗栓循证治疗55主动脉弓粥样硬化Tunick P et al Am J Cardiol 2002;90:1320-5Level III evidence:benefit of statins缺血性卒中抗栓循证治疗56主动脉弓粥样硬化:OACTunick P et al Am J Cardiol 2002;90
27、:1320-5Level III evidence:no benefit of OAC缺血性卒中抗栓循证治疗57主动脉弓粥样硬化:APATunick P et al Am J Cardiol 2002;90:1320-5Level III evidence:no benefit of APA缺血性卒中抗栓循证治疗58主动脉弓粥样硬化:他汀类Tunick P et al Am J Cardiol 2002;90:1320-5Level III evidence:benefit of statins缺血性卒中抗栓循证治疗59 1 stroke prevention Retrospective da
28、ta show no benefit of OAC for native valve endocarditis,benefit for prosthetic valve endocarditis1-5 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 3Yeh et al Circulation 1967;35:I77-814Delahaye et al Eur Heart J 1990;11:1074-85Wilson
29、et al Circulation 1978;57:1004-7Level V evidence缺血性卒中抗栓循证治疗60?Pathogenesis:fibrin thrombi deposits on valves assoc with coagulopathy(usually DIC)Reported incidence of embolism varies(14-91%)Rx:Retrospective data suggest benefit of heparin,but not OAC1-3 68%with recurrent emboli when heparin d/cd ICH
30、 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 syndrome(mainly with DIC)缺血性卒中抗栓循证治疗61European Atrial Fibrillation Tria
31、l：EAFT(Lancet 1993;342:1255-1262)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 OAC缺血性卒中抗栓循证治疗62Optimum INR for prevention of 2 stroke associated with atrial fibr
32、illation(EAFT NEJM 1995;333:5-10)“The target value for the INR should be set at 3.0”缺血性卒中抗栓循证治疗63心肌梗死后一级预防:短期抗凝 Pre-thrombolytic era Heparin decreases stroke incidence 1-3 Heparin decreases mural thrombus 41Med Research Council BMJ 1969;1:335-422Drapkin&Merskey JAMA 1972;222:541-83VA Coop Study JAMA
33、 1973;225:724-94Vaitkus&Barnathau JACC 1993;22:100-9缺血性卒中抗栓循证治疗65心肌梗死后一级预防:短期抗凝 Post-thrombolytic 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 furt
34、her 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缺血性卒中抗栓循证治疗66心肌梗死后一级预防:长期抗凝 Relative to control,coumarins in moderate or high dose(INR 2-4.8)Si
35、gnificantly decrease stroke incidence Significantly increase incidence of major bleedingAnand&Yusuf JAMA 1999;282:2058-67缺血性卒中抗栓循证治疗67Modified from Anand&Yusuf JAMA 1999;282:2058-67But no benefit relative to ASAIncidence of strokeand significant increase in major bleeding缺血性卒中抗栓循证治疗68 RR(95%CI)Antic
36、oagulation*.19(.13-.27)Aspirin#.44(.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%缺血性卒中抗栓循证治疗69Rate(Events/100 Pt-Yr)Anticoagulation 0 (0/40)No Anticoagulation
37、0.35 (1/288)Low Risk for Primary Occurrence慢性室壁瘤系统栓塞(Lapeyre AC et al JACC 1985;6:534-538)缺血性卒中抗栓循证治疗70Patent Foramen Ovale in Cryptogenic Stroke Study(PICSS)(Homma S et al Circulation 2002;105:2625-31)Design:Prospective,randomized,double-blind,multi-center clinical trial Eligibility:Enrolled in WAR
38、SS Agree to have additional TEE Treatment:Warfarin(target INR 1.4-2.8,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 PFO缺血性卒中抗栓循证治疗71PICSSLevel II Evidence:No difference from aspirinoverall o
39、r in any subgroupNo increased event rate in PFO+ASA vs.PFO onlyNo increased rate with larger PFO size缺血性卒中抗栓循证治疗72Rheumatic 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:
40、Native valve:Level V-No benefit Prosthetic valve:Level V-benefitNBTE:Level V-No benefit(?benefit of heparin)Atrial fibrillation:Level I-Benefit over ASA INR 2.9(2.5-4.0)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
41、.9(2.5-4.0)PFO:Level II-No benefit over ASA(INR 1.4 2.8)MVP:Level V Not completely effectiveNo data Aortic valve disease Prosthetic heart valves MI LV dysfunction口服抗凝剂（OAC）二级预防:小结缺血性卒中抗栓循证治疗73 Mechanical prosthetic valve:Level I-Benefit of OAC+low dose ASA over OAC alone Bioprosthetic valve:Level V-
42、Benefit over no OAC in 1st 6 weeks after valve replacement MI:Level I-No benefit over ASA LVEF 40%:Level III-Benefit?INR over ASA LV aneurysm:low risk for 1 occurrence口服抗凝剂（OAC）一级预防:小结缺血性卒中抗栓循证治疗74心源性卒中二级预防（研究中）NVAF:SPORTIF V(Stroke Prevention by Oral Thrombin Inhibition)Fixed dose ximelagatran(thro
43、mbin inhibitor)vs.warfarin(INR 2-3)LV dysfunction WARCEF(Warfarin vs.Aspirin in Reduced Cardiac EF)Warfarin(INR 2.5-3)vs.ASA 325mg in EF 30%WATCH(Warfarin&Antiplatelet Therapy in Chronic Heart Failure)Warfarin(INR 2.5-3)vs.ASA 162mg vs.Clopidogrel 75mg in EF 35%Aortic Atheroma:ARCH(Aortic Arch Relat
44、ed Cerebral Hazard)warfarin(INR 2-3)vs.ASA+clopidogrel in mobile or 4mm-thick atheromaPFO:RESPECT(Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard Care Treatment Trial)Percutaneous PFO closure vs.antithrombotic Rx(ASA,clopidogrel,Aggrenox,ASA+clopidogrel,warfarin
45、in cryptogenic stroke with PFO)缺血性卒中抗栓循证治疗75结语1 抗血栓治疗仅能作为卒中预防策略组成部分之一；没有任何药物能完全消除卒中的复发风险，多项大规模试验结果为正确、合理地选择抗血栓治疗提供了证据；缺血性卒中抗栓循证治疗76结语2 3h内IV rt-PA(0.9mg/kg)疗效得到公认；3h-6h内IA ProUK证实有效；急性期阿司匹林疗效得到公认；急性期抗凝仅能降低DVT和PE发生率，但对动脉血栓疗效无差异缺血性卒中抗栓循证治疗77结语3 若无禁忌，心源性栓塞通常宜选择抗凝治疗，西美加群是一种有前景的华法林替代物；目前无证据支持抗凝治疗用于PFO、抗磷脂抗体综合征、颅内动脉粥样硬化或腔隙性梗塞患者，而推荐使用阿司匹林；阿司匹林联合华法林治疗不能增强预防作用，反而会带来更大的出血风险；阿司匹林和氯吡格雷预防卒中复发的效果相近，阿司匹林联用氯吡格雷并不优于单用氯吡格雷，且出血风险更高；在抗血小板药联合治疗试验中，只有ESPS2试验能证实阿司匹林联用ER-DIP有协同作用，期待PRoFESS试验能得出同样结论。缺血性卒中抗栓循证治疗78
