1、缺血性卒中抗栓循证治疗,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,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,与安慰剂相比，3h内IV rtPA (0.9 mg/kg) 能改善90天时的
2、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,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,rt-PA : ECASS I,Hacke 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
3、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,rt-PA : ECASS II,Hacke et al., Lancet. 1998;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
4、 for Acute Noninterventional Rx in Isch Stroke,Clark et al., JAMA. 1999;282:2019-2026,rt-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,链激酶（SK）,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 ProUK 经造影证实MCA M1 或M2 段阻塞的患者有效. I
5、 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;5:182-7,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(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,急性缺血性卒中抗凝治疗,
6、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,Summary: trial results,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,小结,急性期抗凝减少深静脉血栓和肺
7、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,International Stroke Strial (IST),ASA 300 mg/d x 2 wks begun within 48 hrs,* p.01,Chinese Acute Stroke Trial (CAST)Lancet 1997;349:1641,ASA 160 mg/d x4 wks begun within 48 hrs,* p.05,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。,非心源性卒中二级预防：抗栓治疗,概述,抗血小板
8、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.,Aspirin,高剂量阿司匹林随机对照试验,* Risk of vascular events (death, stroke
9、, MI) in the control group,低剂量阿司匹林随机对照试验,* Vascular events (death, MI, stroke) in placebo. * stroke in placebo,Antiplatelet 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
10、 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.,Is there a consensus.,The FDA reviewed trials of aspiri
11、n 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 mg dai
12、ly), 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: Efficacy*, 3-year study endpoints, N = 3,0
13、69.,EndpointStrokeStroke, MI, orvascular death,RRR21%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 (%),Aspirin
14、 (%),DiarrheaRashNauseaGastritis, ulcer, GI bleedingSevere neutropenia (ANC 450/mm3)Cerebral hemorrhage,20.4*11.9*11.1 2.10.9*0.6,9.85.210.2 6.0*0.00.7,*P 0.05,TASS Study: Side Effects,Adapted from Hass et al. N Engl J Med. 1989;321:501.,Clopidogril,CAPRIE StudyEfficacy of Clopidogrel vs. Aspirin (n
15、 = 19,185)Primary Outcome: MI, Ischemic Stroke, or Vascular Death,Months of Follow-Up,Cumulative Event Rate (%),0,4,8,12,16,Clopidogrel,Aspirin,0,3,6,9,12,15,18,21,24,27,30,33,36,Aspirin5.83%,5.32%Clopidogrel,Event Rate per Year,*P = 0.043,CAPRIE Steering Committee. Lancet 1996;348:1329-1339.,ARR= 0
16、.51NNT= 1/0.005= 196,Clopidogrel (%),ASA (%),GI complaintsAny bleeding disorderRashDiarrheaGI bleedingIntracranial hemorrhage,1.901.200.90*0.420.520.21,2.41*1.370.410.270.93*0.33,*P 0.05,CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.,Side Effects causing discontinuation of drug,CAPRIE Study,
17、Management 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,The Second European Stroke Prevention Study:ESPS-2,Tested efficacy of ASA/ER-DP for secondary
18、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 et al. J Neurol Sci. 1996;143:1.,ESPS-2 Results: Stroke Rates at
19、 24 Months,Placebo,ASA,ER-DP,ASA/ER-DP,0,4,8,12,16,15.2%,12.5%,12.8%,9.5%,Incidence (%),ARR= 5.7 over PlaceboNNT= 1/0.057= 17.5,ESPS-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)Lightheadedness 30.9%29.1%29.5%*=P 4mmLevel
20、III: benefit,34 patients with mobile atheromaLevel III: benefit,Ferrari E et al JACC 1999;33:1317-22,主动脉弓粥样硬化Tunick P et al Am J Cardiol 2002;90:1320-5,Level III evidence: benefit of statins,主动脉弓粥样硬化: OACTunick P et al Am J Cardiol 2002;90:1320-5,Level III evidence: no benefit of OAC,主动脉弓粥样硬化: APATu
21、nick P et al Am J Cardiol 2002;90:1320-5,Level 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;90:1320-5,Level III evidence: benefit of statins,1 stroke prevention Retrospective data show no benefit of OAC for native valve endocarditis, benefit for prosthetic valve endo
22、carditis1-52 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 et al Circulation 1978;57:1004-7,Level V evidence,? Pathogenesis: fibrin thrombi deposi
23、ts on valves assoc with coagulopathy (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 endocarditis,1Rogers et al Am J Med 1987;83:746-562Lopez et al
24、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),European Atrial Fibrillation Trial：EAFT (Lancet 1993;342:1255-1262),Oral anticoagulants (225) vs. Aspirin (230) HR (95%CI)1 Endpoint0
25、.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,Optimum INR for prevention of 2 stroke associated with atrial fibrillation(EAFT NEJM 1995;333:5-10),“The target value for the INR should be set at 3.0”,Stroke
26、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 ；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
27、防: 短期抗凝,Pre-thrombolytic eraHeparin decreases stroke incidence 1-3Heparin decreases mural thrombus 4,1Med Research Council BMJ 1969;1:335-422Drapkin 22:100-9,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 he
28、parin/LMWH may decrease mural thrombus formation, but increases risk of major bleeding without further reducing stroke risk,1Collins 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:
29、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 2-4.8)Significantly decrease stroke incidenceSignificantly increase incidence of major bleeding,Anand 282:2058-67,Modified from Anand 282:2058-67,But no benefit relative to ASA,Incidence of stroke,and significant incr
30、ease in major bleeding,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%,Rate (Events/ 100 Pt-Y
31、r)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),Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS)(Homma S et al Circulation 2002;105:2625-31),Design: Prospective, randomized, double- blind, multi-center
32、clinical trial Eligibility: Enrolled in WARSSAgree to have additional TEETreatment: Warfarin (target INR 1.4-2.8, mean 2.1) vs. aspirin 325 mg1 endpoint : Recurrent ischemic stroke or death within 2 years601 patients42% with cryptogenic stroke as qualifying event34% with PFO,PICSS,Level II Evidence:
33、 No difference from aspirinoverall or in any subgroup,No increased event rate in PFO + ASA vs. PFO onlyNo increased rate with larger PFO size,Rheumatic 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 benefi
34、t 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 (2.5-4.0) 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 2.9 (2.5-4.0) PFO: Level II - No benefit over ASA (INR 1.4 2.8)MVP: Level V Not completely effectiveNo dataAortic valve diseaseProsthetic heart valvesMILV dysfunction,
