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;352:1245-1251PROACT II:小结8%2.作用于抗凝血酶 IIIThe Warfarin-Aspirin Symptomatic Intracranial Disease Study.主动脉弓粥样硬化:他汀类Tunick P et al Am J Cardiol 2002;90:13205Is ASA/ERDP well tolerated?1Collins et al BMJ 1996;313:652-9Level III evidence:benefit of statinsClopidogriloverall or in any subgroupno differen
4、ceN Engl J Med.8%）高很多，这也是尚未获得美国FDA批准的原因。有证据支持在急性椎基底动脉阻塞中应用动脉溶栓.急性缺血性卒中抗凝治疗SK组出血和死亡率高提前终止试验Primary Outcome:MI,Ischemic Stroke,or Vascular Death3Sack et al Medicine 1977;56:1-37Cerebral hemorrhage 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:A
5、TLANTISAlteplase Thrombolysis for Acute Noninterventional Rx in Isch StrokeClark et al.,JAMA.1999;282:2019-2026rtPA: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The Second European Stroke Prevention Study:ESPS2Summary:trial results8%）高很多，这也是尚未获得美国FDA批准的原因。Fatal;nonfata
6、l CI no TIA includedFatal;nonfatal CI no TIA includedLevel III evidence:no benefit of OACAnand&Yusuf JAMA 1999;282:2058-67mobile atheroma2206 patients followed for 2 yearsno differenceRecurrent ischemicno difference2 stroke prevention:1998;63:56802.各卒中亚型急性抗凝治疗:小结Incidence of stroke#similar risk at a
7、ll levels of EF35%A 144;P 139vascular death低剂量阿司匹林随机对照试验MASTI,MASTE,ASK3VA Coop Study JAMA 1973;225:724-9rtPA 与安慰剂组无明显差别CAPRIE StudyEfficacy of Clopidogrel vs.Multicenter Acute Stroke Trial-Europe(MAST-E)Used odds ratio instead of relative risk.2Drapkin&Merskey JAMA 1972;222:541-8S,death or bothMult
8、icenter Acute Stroke Trial-Europe(MAST-E)有证据支持在急性椎基底动脉阻塞中应用动脉溶栓.Clark et al.Is ASA/ERDP well tolerated?3Fleming&Bailey Postgrad Med 1971;47:599-604Rx:Retrospective data suggest benefit of heparin,but not OAC13ECASS I&II,ATLANTISAspirin(n=19,185)随机,多中心,双盲,安慰剂对照链激酶（SK）研究药物剂量治疗窗结果Multicenter Acute Stro
9、ke 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，
10、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 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9 mg/kg)vs.Low Risk for Primary Occurrence620例;排除CT早期梗塞灶(预后不良)ASA 160 mg/d x4 wks begun within 48 hrs1Davenport et al Stroke 1
11、990;21:993-9Neurology.高剂量阿司匹林随机对照试验RCT:addition of ASA 100 mg to warfarin(INR 34.800 例;排除CT早期明显梗塞灶(Interestingly,low rate of late embolism in pts with AF despite lack of chronic AC in both of these studiesRate(Events/100 PtYr)4%，安慰剂为 0.No Anticoagulation 0.与安慰剂相比，6h内予IV SK 1.8%）高很多，这也是尚未获得美国FDA批准的原因
12、。1 effect on XaMVP+AF:extrapolate data from EAFTAntiplatelet Trialists所有亚组预后均优于安慰剂组是由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+ASA 25mg，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。Incidence of strokePrevention Regimen for Effectively Avoiding Second Strokes
13、（PRoFESS）Same as medical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.IV、V类证据急性缺血性卒中抗凝治疗概述 肝素 LMW heparin LMW heparinoid作用于抗凝血酶 III(抑制凝血因子 IIa
14、,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 differenceIST19,435Hep scno differenceTOAST1281heparinoidno differencelarge art better at 3 mo?HK308LMWH dead/dep at
15、 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-小结急性期
16、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 recurrent stroke3.7%4.6%Major extracranial bleed1.1%*0.6%Death9.0%9.4%*p.01Chinese Acute Stroke Trial(CAST)L
17、ancet 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 ASA提前终止;治疗窗4h无明显益处，结果不良主动脉弓粥样硬化:OACTunick P et al Am J Cardiol 2002;90:13205Left ventricular dysfunction左
18、心室功能不全68%with recurrent emboli when heparin d/cdAntiplatelet TrialistsESPS2:Side Effect Profile心源性卒中预防抗血栓治疗1 effect on Xa随机,多中心,双盲,安慰剂对照A 198;P 204longer half-lifeMedical groupAntiplatelet Trialists 100,000 pts from 145 trials.All antiplatelet agents were included.Clumped all vascular events togethe
19、r.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 events and 23%for nonfatal stroke.Did not answer questions about aspirin dose.Used odds ratio instead of relative risk.Used all antiplatelet ag
20、ents.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 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
21、 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 stroke and TIA:50 to 325 mg aspirin once a day.Continue therapy indefinitely.”FDA.Federal Register.1998;63:56802.Ticlopidine TASS Study:Effic
22、acy*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).Ticlopidine,Platelets and Vascular Disease.New York:Springer-Verlag;1993:141.*Ticlopidine(250 mg bid)vs ASA(650 mg bid).(NS)Ticlopidine(%)As
23、pirin(%)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.ClopidogrilCAPRIE StudyEfficacy of Clopidogrel vs.Aspirin(n=19,185)Pri
24、mary Outcome:MI,Ischemic Stroke,or Vascular DeathARR=0.51NNT=1/0.005=196Clopidogrel(%)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 discontinuation of drugCAPRIE StudyManagement of
25、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 A
26、ddressed 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?The ESPS-2 Group.J Neurol Sci.1997;151:S3.Diener et al.J Neurol Sci.1996;143:1.所有亚组预后均优于安慰剂组Intracranial hemorrhage1998;63:56802.心源性卒中预防抗血栓治
27、疗Prosthetic heart valves人工心脏瓣膜Clopidogrel(%)Valvular heart disease心脏瓣膜病低剂量阿司匹林随机对照试验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.no differencePrevention Regimen for Effectively Avoiding Second Strokes（PRoFESS）随机,多中心,双盲,安慰剂对照Eligibility:Level V evidence:neither ASA nor AC completely effectiveNeurology.1 effect on Xa
28、Fatal;nonfatal CI no TIA includedESPS2 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=17.5ESPS2: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)Lighth
29、eadedness 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 benef
30、it of OAC2Hanson M et al Stroke 1980;11:499-506Significantly decrease stroke incidence所有亚组预后均优于安慰剂组1Collins et al BMJ 1996;313:652-9数项病例报道(IV、V 类证据)ESPS-2(N=3,299)rtPA:ECASS IIAortic arch atheroma:Level III Benefit over APA in 1 study;No benefit of OAC or APA in another(but benefit of statins)Oral a
31、nticoagulants(225)vs.8%）高很多，这也是尚未获得美国FDA批准的原因。The Warfarin-Aspirin Symptomatic Intracranial Disease Study.reduced effect on IIaMVP:Level V Not completely effective急性缺血性卒中抗凝治疗3 Turpie A et al NEJM 1993;329:524-9Eligibility:Prosthetic heart valves人工心脏瓣膜?Pathogenesis:fibrin thrombi deposits on valves a
32、ssoc with coagulopathy(usually DIC)9 mg/kg)vs.IS or Death Mjr bleed/100 ptyrs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 2002;90:13205Level III evidence:benefit of statinsno difference among dosesSwedish CS 1987Left
33、 ventricular dysfunction左心室功能不全GI complaintsUsed odds ratio instead of relative risk.Anand&Yusuf JAMA 1999;282:2058-67Proper management is controversial.Gastritis,ulcer,Placebo ASA ASA+ED#similar risk at all levels of EF35%?Pathogenesis:fibrin thrombi deposits on valves assoc with coagulopathy(usual
34、ly DIC)5 MU)增加出血和死亡率.*Ticlopidine(250 mg bid)vs ASA(650 mg bid).Severe neutropenia (ANC 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、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)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
36、additional TEE Treatment:Warfarin(target INR 1.42.8,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 e
37、vent rate in PFO+ASA vs.PFO onlyNo increased rate with larger PFO sizeGI Event*28.Overall(N=4,873)No Anticoagulation 0.MVP:Level V Not completely effective?Pathogenesis:fibrin thrombi deposits on valves assoc with coagulopathy(usually DIC)Event Rate(%)Observational data:APA may be sufficient to prev
38、ent embolism in absence of AF,but OAC needed to prevent valve thrombosis12Fatal;nonfatal CI no TIA included高剂量阿司匹林随机对照试验LMW heparinPFO:Level II No benefit over ASA(INR 1.Bleeding*4.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+ASA 25mg，2次/d）与氯吡格雷（75mg，1次/d）在卒中二级
39、预防中的疗效，预期结果将在2008年报道。The ESPS-2 Group.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.(Interestingly,low rate of late embolism in pts with AF despite lack of chronic AC in both of these studiesDiener et al.Hass et al.ESPS-2(N=3,299)A 198;P 2041Rogers et al Am J Med 1987;83:746-56,Lancet 1995;345:578-9Toulouse TIA(N=28
40、4)Clark et al.Myocardial infarction心肌梗死3Fleming&Bailey Postgrad Med 1971;47:599-6041 Hartz R et al J Thorac CV Surg 1986;92:684-90急性缺血性卒中阿司匹林治疗Warfarin for noncardioembolic arterial stroke:including large vessel disease.Used all antiplatelet agents.68%with recurrent emboli when heparin d/cdoverall o
41、r in any subgroupTASS Study:Efficacy*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)ESPS2:Side Effect ProfileESPS2:Side Effect Profile急性缺血性卒中抗凝治疗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1 effect on Xa华法林INR为23，阿司匹林为1300mgExtrapolation from 1 large randomized study in NVAF
42、(EAFT)provides additional data for patients with RHD+AF(but RHD excluded)8%2.作用于抗凝血酶 IIIAntiplatelet TrialistsRheumatic 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:Nati
43、ve valve:Level V No benefitProsthetic valve:Level V benefitNBTE:Level V No benefit(?benefit 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
