缺血性卒中抗栓循证治疗培训课件

缺血性卒中抗栓循证治疗缺血性卒中抗栓循证治疗1（优选）缺血性卒中抗栓循证治疗（优选）缺血性卒中抗栓循证治疗2急性缺血性卒中溶栓治疗急性缺血性卒中溶栓治疗3概述静脉溶栓组织纤溶酶原激活物（tPA）NINDSECASS 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 概述静脉溶栓4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 与安慰剂相比，3h内IV rtPA(0.9 mg/kg)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 daysrtPA 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rtPA:ECASS6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 daysrtPA 与安慰剂组无明显差别rtPA:ECASS IIHacke et al.,Lancet.1998;352:1245-1251随机,多中心,双盲,安慰剂对照rtPA:ECASS7PROACT 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 differenceN 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 daysrtPA 与安慰剂组无明显差别rtPA:ATLANTISAlteplase Thrombolysis for Acute Noninterventional Rx in Isch StrokeClark et al.,JAMA.1999;282:2019-2026PROACT II:小结随机,多中心,双盲,安慰剂对8rtPA: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rtPA:小结与安慰剂相比，3h内IV rtPA(0.99The 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;nonfatal 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 all 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 bothMulticenter 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 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(出血和死亡率高).I 类证据The Second European Stroke Pre10动脉溶栓前循环大脑中动脉阻塞后循环椎基底动脉阻塞动脉溶栓前循环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:小结与安慰剂相比,6h内予IA ProUK 经造影证实MCA 129 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 1990;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。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（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;5:18279 mg/kg)vs.急性椎基底动脉阻塞数项病例报道(I13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类证据小结3h内静脉用 tPA 能降低90天时的残障功能.I类14急性缺血性卒中抗凝治疗急性缺血性卒中抗凝治疗15概述肝素LMW heparinLMW 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 IIa概述肝素作用于抗凝血酶 III 1 effect on16Summary:trial resultsNdrugresultsCanadian225Hep IVno differenceIST19,435Hep scno differenceTOAST1281heparinoidno differencelarge art better at 3 mo?HK308LMWH dead/dep at 6 moFISS767LMWHno differenceTAIST1486LMWHno differenceTOPAS404LMWHno difference among dosesSummary:trial resultsNdrugres17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 房颤 和心源性栓塞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-各卒中亚型急性抗凝治疗:小结CCTsubgrpNresult19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 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急性缺血性卒中阿司匹林治疗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.01International Stroke Strial(22Chinese 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 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 Trialists100,000 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 events and 23%for nonfatal stroke.Did not answer questions about aspirin dose.Used odds ratio instead of relative risk.Used all antiplatelet agents.MVP+AF:extrapolate data fro30Is 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 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.Is there a consensus.The FDA 31Ticlopidine Ticlopidine 32TASS 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).Ticlopidine,Platelets and Vascular Disease.New York:Springer-Verlag;1993:141.*Ticlopidine(250 mg bid)vs ASA(650 mg bid).(NS)TASS Study:Efficacy*3-year 33Ticlopidine(%)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 Study:Side EffectsAdapted from Hass et al.N Engl J Med.1989;321:501.Ticlopidine(%)Aspirin(%)Diar34ClopidogrilClopidogril35CAPRIE StudyEfficacy of Clopidogrel vs.Aspirin(n=19,185)Primary Outcome:MI,Ischemic Stroke,or Vascular DeathMonths of Follow-UpMonths of Follow-UpCumulative Cumulative Event Rate(%)Event Rate(%)0 04 48 812121616ClopidogrelClopidogrelAspirinAspirin0 03 36 69 91212 1515 1818 2121 2424 2727 3030 3333 3636AspirinAspirin5.83%5.83%5.32%5.32%ClopidogrelClopidogrelEvent Rate per YearEvent Rate per Year*P P=0.043=0.043CAPRIE Steering Committee.Lancet 1996;348:1329-1339.CAPRIE Steering Committee.Lancet 1996;348:1329-1339.ARR=0.51NNT=1/0.005=196CAPRIE StudyEfficacy of Clopi36Clopidogrel(%)ASA(%)GI complaintsAny bleeding disorderRashDiarrheaGI bleedingIntracranial hemorrhage1.901.200.90*0.420.520.212.41*1.370.410.270.93*0.33*P 0.05CAPRIE Steering Committee.CAPRIE Steering Committee.LancetLancet.1996;348:1329-1339.1996;348:1329-1339.Side Effects causing discontinuation of drugCAPRIE StudyClopidogrel(%)ASA(%)GI compl37Management 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TIA）无统计学差异 联合治疗同时增加了严重出血的概率 Management of Atherothrombosis38The Second European Stroke Prevention Study:ESPS2Tested efficacy of ASA/ERDP for secondary stroke preventionAddressed clinical questionsDoes 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.The Second European Stroke Pre39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 XaFatal;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=17.5所有亚组预后均优于安慰剂组ESPS2 Results:S40ESPS2:Side Effect ProfilePlacebo 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;33:1317-22Danish CS 1983Atherosclerosis 55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Tunick P et al Am J C56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:OACTunick P et al A572Hanson 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 anticoagulants(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 assoc 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 APA2Hanson M et al Stroke 1980;1158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 statins主动脉弓粥样硬化:他汀类Tunick P et al A59no difference among dosesSwedish CS 1987Left 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(usually 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%RR69Rate(Events/100 PtYr)Anticoagulation 0 (0/40)No Anticoagulation 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)Rate(Events/100 PtYr)Lo70Patent 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 WARSSAgree to have additional TEETreatment:Warfarin(target INR 1.42.8,mean 2.1)vs.aspirin 325 mg1 endpoint:Recurrent ischemic stroke or death within 2 years601 patients42%with cryptogenic stroke as qualifying event34%with PFOPatent Foramen Ovale in Crypto71PICSSLevel II Evidence:No difference from aspirinoverall or in any subgroupNo increased event rate in PFO+ASA vs.PFO onlyNo increased rate with larger PFO sizePICSSLevel II Evidence:No incr72GI 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 prevent 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=284)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 or 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(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:Native 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GI Event*28.Toulouse TIA(N=73