缺血性卒中的抗栓治疗.ppt

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） 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,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,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 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 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 days rtPA 与安慰剂组无明显差别,rt-PA : ATLANTIS Alteplase Thrombolysis 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 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,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 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, 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 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 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 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: Efficacy*, 3-year study endpoints, N = 3,069.,Endpoint Stroke Stroke, MI, or vascular death,RRR 21% 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 (%),Diarrhea Rash Nausea Gastritis, ulcer, GI bleeding Severe neutropenia (ANC 450/mm3) Cerebral hemorrhage,20.4* 11.9* 11.1 2.1 0.9* 0.6,9.8 5.2 10.2 6.0* 0.0 0.7,*P 0.05,TASS Study: Side Effects,Adapted from Hass et al. N Engl J Med. 1989;321:501.,Clopidogril,CAPRIE Study Efficacy of Clopidogrel vs. Aspirin (n = 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,Aspirin 5.83%,5.32% Clopidogrel,Event Rate per Year,*P = 0.043,CAPRIE Steering Committee. Lancet 1996;348:1329-1339.,ARR= 0.51 NNT= 1/0.005= 196,Clopidogrel (%),ASA (%),GI complaints Any bleeding disorder Rash Diarrhea GI bleeding Intracranial hemorrhage,1.90 1.20 0.90* 0.42 0.52 0.21,2.41* 1.37 0.41 0.27 0.93* 0.33,*P 0.05,CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.,Side Effects causing discontinuation of drug,CAPRIE Study,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 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. 1996;143:1.,ESPS-2 Results: Stroke Rates at 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 Placebo NNT= 1/0.057= 17.5,ESPS-2 : Side Effect Profile,Placebo ASA ASA+ED GI 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% *=P0.05,Meta-Analysis: ASA/DP vs ASA,Adapted from Diener. Neurology. 1998;51(suppl 3):S17.,Trials Toulouse TIA (N = 284) AICLA (N = 400) ACCSG (N = 890) ESPS-2 (N = 3,299) Overall (N = 4,873) 15% RRR,Relative Risk (of stroke, MI, or vascular death),0.5,1,1.5,2,2.5,3,ASA/DP Better,ASA Better,Prevention Regimen for Effectively Avoiding Second Strokes（PRoFESS）,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，ER-DP200mg+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。,Warfarin-Aspirin Recurrent Stroke Study（WARSS）,2206 patients followed for 2 years IS or Death Mjr bleed /100 pt-yrs Warfarin 17.8% 2.22 Aspirin 16.0% 1.49,p=.25,No significant difference between warfarin and aspirin,The Warfarin-Aspirin Symptomatic Intracranial Disease study（WASID）,多中心前瞻性随机双盲试验 华法林INR为23，阿司匹林为1300mg 两组的卒中发生率和血管源性病死率无统计学差异 华法林组出血并发症的发生率较高促使试验提前终止,The Warfarin-Aspirin Symptomatic Intracranial Disease Study. Neurology. 1995 Aug;45(8):1488-93.,Effect of Treatment on Recurrent Ischemic Stroke and Death At Two Years in APASS/WARSS (Brey, RL: presented at the 27 International Stroke Conference, San Antonio, TX, February 9, 2002),Primary Endpoint (%),抗磷脂抗体阳性组与阴性组无差异，阿司匹林与华法林无差异,颈动脉和椎动脉夹层,Natural history of carotid dissection: (Hart et al Neurol Clin North Am 1:155, 1983) Cerebral infarction in 33% (23% minor, 10% major or fatal. TIA in 45; Head and neck pain in 16%; Pulsatile tinnitus 4%; and bruit in 2%. Proper management is controversial. Most pts do well, either because of or despite treatment.,心源性卒中预防： 抗血栓治疗,心源性卒中可能病因,Valvular heart disease心脏瓣膜病 Rheumatic mitral valve disease风湿性二尖瓣病 Prosthetic heart valves人工心脏瓣膜 Mitral valve prolapse二尖瓣脱垂 Aortic valve disease主动脉瓣病 Aortic arch atherosclerosis主动脉弓粥样硬化 Endocarditis (infective or nonbacterial thrombotic)心内膜炎（感染性或非细菌性血栓） Atrial fibrillation心房颤动 Myocardial infarction心肌梗死 Left ventricular dysfunction左心室功能不全 Patent foramen ovale卵圆孔未闭,Rheumatic mitral valve disease: 2 stroke prevention,No randomized trials Observational studies: OAC reduce recurrent embolic events/fatal events by 2/3 or more1-3 Extrapolation from 1 large randomized study in NVAF (EAFT) provides additional data for patients with RHD + AF (but RHD excluded),1 Szekely P BMJ 1964;1:209-12 2Adams GF et al JNNP 1974;37:378-83 3Fleming 47:599-604,Level III-IV: Benefit of OAC,Prosthetic heart valves: mechanical valves 1 stroke prevention,Observational data: APA may be sufficient to prevent embolism in absence of AF, but OAC needed to prevent valve thrombosis1-2 RCT: addition of ASA 100 mg to warfarin (INR 3-4.5) cerebral embolism (4/186 vs. 12/184)3 NonRCT: addition of ASA 500 mg tripled risk of major hemorrhage (14% vs. 5%)4,Level I evidence: benefit of OAC + ASA over OAC alone,1 Hartz R et al J Thorac CV Surg 1986;92:684-90 2Ribeiro P et al J Thorac CV Surg 1986;91:92-8 3 Turpie A et al NEJM 1993;329:524-9 4Chesebro J et al Am J Card 1983;51:1537-41,Prosthetic heart valves: mechanical valves 2 stroke prevention,No direct data ACCP recommendations: OAC + baby ASA based on extrapolation of 1 prevention data,6th ACCP Consensus Conference on Antithrombotic Therapy 2001,Prosthetic heart valves: bioprosthetic valves,1Nunez et al Ann Thorac Surg 1982;33:354-8,But no difference in embolic rate with OAC (4.6%, 7/260) in comparison to ASA (3.7%, 5/135), and significantly higher rate of hemorrhagic complications (5.5% vs. 0.4%)1 (Interestingly, low rate of late embolism in pts with AF despite lack of chronic AC in both of these studies,1 prevention: Level IV evidence: benefit of early OAC over no OAC Level V evidence: no difference between OAC ASA 2 prevention: no evidence,Mitral Valve Prolapse : 2 stroke prevention,Level V evidence: neither ASA nor AC completely effective,Stroke recurrence in MVP: case series,MVP + AF: extrapolate data from EAFT,1Watson RT Neurol 1979;29:886-9 2Hanson M et al Stroke 1980;11:499-506,Atherosclerosis of the thoracic aorta: benefit of OAC,50 patients with atheroma 4mm Level III: benefit,34 patients with mobile atheroma Level 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: OAC Tunick 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: APA Tunick 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 endocarditis1-5 2 stroke prevention: No data,感染性心内膜炎,1Davenport et al Stroke 1990;21:993-9 2Paschalis et al Eur Neurol 1990;30:87-9 3Yeh et al Circulation 1967;35:I77-81 4Delahaye et al Eur Heart J 1990;11:1074-8 5Wilson et al Circulation 1978;57:1004-7,Level V evidence,? 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 risk lower than in infective endocarditis,1Rogers et al Am J Med 1987;83:746-56 2Lopez et al Am Heart J 1987;113:773-84 3Sack 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 Endpoint 0.60 (.41 - .87) All stroke 0.38 (.23 - .64) Bleeding 2.8 (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 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。,心肌梗死后一级预防: 短期抗凝,Pre-thrombolytic era Heparin decreases stroke incidence 1-3 Heparin decreases mural thrombus 4,1Med Research Council BMJ 1969;1:335-42 2Drapkin 22:100-9,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 further reducing stroke risk,1Collins et al BMJ 1996;313:652-9 2Collins et al NEJM 1997;336:847-60 3FRAMI Kontny et al JACC 1997;30:962-9 4SCATI Lancet 1989;2:182-6 5Gissi-2 Vecchio et al Circulation 1991;84:512-9,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 incidence Significantly 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 increase 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-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),Patent 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 WARSS 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,PICSS,Level II Evidence: No difference from aspirin overall or in any subgroup,No increased event rate in PFO + ASA vs. PFO only No increased rate with larger PFO size,Rheumatic MV dz: Level III - Benefit over no OAC Aortic 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 benefit Prosthetic valve: Level V - benefit NBTE: 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 effective 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 e