急性缺血性卒中溶栓治疗-课件

1、急性缺血性卒中溶栓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) NINDSECASS 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 概述静脉溶栓与安慰剂相比,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rt-PA :NINDS 与安慰剂相比,3h内IV rtPA (0、9 mg/kg) 随机, 多中心, 双盲, 安慰剂对比620例; 排除CT早期梗

2、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rt-PA : ECASS IHacke et al、, JAMA、 1995;274:1017-1025随机, 多中心, 双盲, 安慰剂对比rt-PA : ECAS随机, 多中心, 双盲, 安慰剂对比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

3、 of 1 at 90 daysrtPA 与安慰剂组无明显差别rt-PA : ECASS IIHacke et al、, Lancet、 1998;352:1245-1251随机, 多中心, 双盲, 安慰剂对比rt-PA : ECAS随机, 多中心, 双盲, 安慰剂对比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 daysrtPA 与安慰剂组无明显差别rt-PA : ATLANTISAlteplase Thrombolysis for Acute Noninterventional Rx in Isch Strok

4、eClark et al、, JAMA、 1999;282:2019-2026随机, 多中心, 双盲, 安慰剂对比rt-PA : ATLArt-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rt-PA:小结与安慰剂相比,3h内IV rtPA (0、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早终止试验Multicen

5、ter 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早终止试验Australian Streptokinase Trial (ASK)Donnan et al、, Lancet 1995;345:578-9SK1、5 MU4h提早终止; 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 类证据链激酶(SK)研究药物剂量治疗窗结果Multicenter动脉溶栓

6、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 急性椎基底动脉阻塞数项病例报道 (IV、V 类证据)非随机化无对比组 Brandt et al、, Cerebrovasc Dis, 1995;5:182-7急性椎基底动脉阻塞数项病例报道 (IV、V 类证据)小结3h内静脉用 tPA 能降低90天时的残障功

7、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类证据小结3h内静脉用 tPA 能降低90天时的残障功能、 I类急性缺血性卒中抗凝治疗急性缺血性卒中抗凝治疗概述肝素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 a

8、dminister lower bleeding risk reduced effect on IIa概述肝素-作用于抗凝血酶 III 1 effect oSummary: trial resultsNdrugresultsCanadian225Hep IVno differenceIST19,435Hep scno differenceTOAST1281heparinoidno differencelarge art better at 3 mo?HK308LMWH dead/dep at 6 moFISS767LMWHno differenceTAIST1486LMWHno differe

9、nceTOPAS404LMWHno difference among dosesSummary: trial resultsNdrugres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

10、:小结CCTsubgrpNresult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

11、、6%Death9、0%9、4%* p、01International Stroke Strial (Chinese 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、05Chinese Acute Str

12、oke Trial (CA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。小结基于 IST 和 CAST, 阿司匹林在急性缺血性卒中非心源性卒中二级预防:抗栓治疗非心源性卒中二级预防: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 + extended-release dipyridamole)Warfarin for non-cardioembo

13、lic arterial stroke: including large vessel disease、抗磷脂抗体综合征(ASP)、颈椎动脉夹层、概述抗血小板药Antiplatelet、AspirinAspirin高剂量阿司匹林随机对比试验#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

14、 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 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

15、-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高剂量阿司匹林随机对比试验#StudyASA dose# o低剂量阿司匹林随机对比试验#Study ASA dose in mg、#of ptsAgeF/uPrim、 Endpoint% in RR1Danish Low 1988 (post CEA)50-100A150P15158、925TIA, S, MI, vascula

16、r 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、 * stroke in placebo低剂量阿司匹林随机对比

17、试验#Study ASA dose iAntiplatelet 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 vascula

18、r events and 23% for nonfatal stroke、Did not answer questions about aspirin dose、Used odds ratio instead of relative risk、Used all antiplatelet agents、Antiplatelet Trialists100,000Is there a consensus、 The FDA reviewed trials of aspirin vs placebo (including ESPS-2, SALT, and UK-TIA trials) to reduc

19、e 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 sub

20、jects 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 Ticlopidine Ticlopidine TASS Study: Efficacy* 3-year study endpoints, N = 3,069、EndpointStrokeStroke, M

21、I, 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 Ticlopidine (%)Aspirin (%)D

22、iarrheaRashNauseaGastritis, 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 (%)DiarClopidogrilClopidogrilCAPRIE StudyEfficacy o

23、f Clopidogrel vs、 Aspirin (n = 19,185)Primary Oute: MI, Ischemic Stroke, or Vascular DeathMonths of Follow-UpCumulative Event Rate (%)0481216ClopidogrelAspirin0369121518212427303336Aspirin5、83%5、32%ClopidogrelEvent Rate per Year*P = 0、043CAPRIE Steering mittee、 Lancet 1996;348:1329-1339、ARR= 0、51NNT

24、= 1/0、005= 196CAPRIE StudyEfficacy of ClopiClopidogrel (%)ASA (%)GI plaintsAny bleeding disorderRashDiarrheaGI bleedingIntracranial hemorrhage1、901、200、90*0、420、520、212、41*1、370、410、270、93*0、33*P 0、05CAPRIE Steering mittee、 Lancet、 1996;348:1329-1339、Side Effects causing discontinuation of drugCAPRI

25、E StudyClopidogrel (%)ASA (%)GI plainManagement 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 Management of AtherothrombosisThe Second European Stroke

26、Prevention Study:ESPS-2Tested efficacy of ASA/ER-DP for secondary stroke preventionAddressed clinical questionsDoes 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

27、 et al、 J Neurol Sci、 1996;143:1、The Second European Stroke PreESPS-2 Results: Stroke Rates at 24 MonthsPlaceboASAER-DPASA/ER-DP048121615、2%12、5%12、8%9、5%Incidence (%)ARR= 5、7 over PlaceboNNT= 1/0、057= 17、5ESPS-2 Results: Stroke Rates ESPS-2 : Side Effect Profile Placebo ASA ASA+EDGI Event*28、1% 30、

28、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;33:1317-22Atherosclerosis of the thoraci主动脉弓粥样硬化Tunick P et al Am J Cardiol 2002;90:1320-5Level III evide

29、nce: benefit of statins主动脉弓粥样硬化Tunick P et al Am J C主动脉弓粥样硬化: OACTunick P et al Am J Cardiol 2002;90:1320-5Level III evidence: no benefit of OAC主动脉弓粥样硬化: OACTunick P et al A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主动脉弓粥样硬化: APATunick P et al A主动脉弓粥样

30、硬化: 他汀类Tunick P et al Am J Cardiol 2002;90:1320-5Level III evidence: benefit of statins主动脉弓粥样硬化: 他汀类Tunick P et al A1 stroke prevention Retrospective data show no benefit of OAC for native valve endocarditis, benefit for prosthetic valve endocarditis1-52 stroke prevention: No data感染性心内膜炎1Davenport e

31、t 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 et al Circulation 1978;57:1004-7Level V evidence1 stroke prevention 感染性心内膜炎1D? Pathogenesis: fibrin thrombi deposits on valves assoc with coagulopa

32、thy (usually DIC)Reported incidence of embolism varies (14-91%)Rx: Retrospective data suggest benefit of heparin, but not OAC1-368% with recurrent emboli when heparin d/cdICH 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

33、 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)? Pathogenesis: fibrin thrombEuropean Atrial Fibrillation Trial:EAFT (Lancet 1993;342:1255-1262)Oral anticoagulants (225) vs、 Aspirin (230) HR (95%CI)1 Endpoint0、60 (、41

34、- 、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 OACEuropean Atrial Fibrillation TOptimum INR for prevention of 2 stroke associated with atrial fibrillation(EAFT NEJM 1995;333:5-10)“The target value for the INR should be

35、set at 3、0”Optimum INR for prevention of Stroke Prevention with the ORal direct Thrombin Inhibitor in patients with non-valvular 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 ;比较了口服直截了当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 ;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

36、高发生率为6%,比华法林组(0、8%)高特别多,这也是尚未获得美国FDA批准的原因。Stroke Prevention with the ORa心肌梗死后一级预防: 短期抗凝Pre-thrombolytic eraHeparin decreases stroke incidence 1-3Heparin decreases mural thrombus 41Med Research Council BMJ 1969;1:335-422Drapkin & Merskey JAMA 1972;222:541-83VA Coop Study JAMA 1973;225:724-94Vaitkus &

37、 Barnathau JACC 1993;22:100-9心肌梗死后一级预防: 短期抗凝Pre-thrombolyti心肌梗死后一级预防: 短期抗凝Post-thrombolytic erabaseline rates of death, reinfarction, stroke, & PE markedly lower with thrombolytics & ASAaddition of heparin/LMWH may decrease mural thrombus formation, but increases risk of major bleeding without furth

38、er 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: 短期抗凝Post-thrombolyt心肌梗死后一级预防: 长期抗凝Relative to control, coumarins in moderate or high

39、dose (INR 2-4、8)Significantly decrease stroke incidenceSignificantly increase incidence of major bleedingAnand & Yusuf JAMA 1999;282:2058-67心肌梗死后一级预防: 长期抗凝Relative to conModified from Anand & Yusuf JAMA 1999;282:2058-67But no benefit relative to ASAIncidence of strokeand significant increase in majo

40、r bleedingModified from Anand & Yusuf JA RR (95%CI)Anticoagulation * 、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% RRRate (Events/ 100 Pt-Yr)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 Pt-Yr)LPatent Foramen Ovale in Cryptogenic Stro