缺血性卒中抗栓循证治疗复旦大学附属中山医院神经内科汪昕. 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,

缺血性卒中抗栓循证治疗复旦大学附属中山医院神经内科汪昕

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 ）研究药物剂量治疗窗结果 Multicenter Acute Stroke Trial-Europe (MAST-E) NEJM 1996;335:145-50 SK1.5 MU6h SK 组出血和死亡率高提前终止试验 Multicenter Acute Stroke Trial-Italy (MAST-I) Lancet 1995;346:1509-14 SK  aspirin 1.5 MU 300 mg/d 6h SK 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;345:578-9 SK1.5 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

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 M 1 或 M 2 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 Ndrugresults Canadian225Hep IVno difference IST19,435Hep scno difference TOAST1281heparinoid no difference large art better at 3 mo? HK308LMWH  dead/dep at 6 mo FISS767LMWHno difference TAIST1486LMWHno difference TOPAS404LMWHno 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 diff TIA1055no diff 进展性卒中 20204no diff 夹层 00286no diff 静脉血栓 20791+/1-

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 2 wk endpts ASA N=9720 No ASA N=9715 Recurrent ischemic2.8%*3.9% All recurrent stroke3.7%4.6% Major extracranial bleed1.1%*0.6% Death9.0%9.4% * p<.01

Chinese Acute Stroke Trial (CAST) Lancet 1997;349:1641 ASA 160 mg/d x4 wks begun within 48 hrs 4 wk endpts ASA N=10335 Placebo N=10320 Recurrent ischemic1.6%*2.1% All recurrent stroke3.2%3.4% Major extracran bleed0.8%*0.6% Death3.3%*3.9% * 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 # StudyASA dose# of ptsAgef/uPrim. Endpoint% of RR 1 AITIA 1977 Medical group 1300mgA 88; P 9060.237mTIA, CI, RI, death20 only with TIA. * P (15.7) 2 AITIA 1977 surgical group 650mgA 65; P 6060.3?TIA, CI, RI, deathSame as medical *P (15.7) 3 CCSG 1978 ASA+SP 1300mgA 144; P 139?26mTIA, S, death-6 to 31% *P (7.6) 4 Reuther 19781500mgA 29; P 295924mTIA, SNS *P (8.3) 5 AICLA 1983 ASA+DP 990mgA 198; P 20463.536mFatal; nonfatal CI no TIA included 41 *P(7.5) 6 Danish CS 19831000mgA 101; P 1025925mS or Death-77 *P (9.6) 7 Swedish CS 19871500mgA 253; P 2526824mS or Death0 *P(10.9) * Risk of vascular events (death, stroke, MI) in the control group

低剂量阿司匹林随机对照试验 #StudyASA dose in mg. #of ptsAgeF/uPrim. Endpoint % in RR 1Danish Low 1988 (post CEA) 50-100A150 P151 58.925TIA, S, MI, vascular death 11% (NS) *P(7.3) 2UK TIA 19911200 300 Placebo 815 806 814 59.848Major S, MI, Vasc. Death 15% vs P; NS between doses *P(5.7) 3SALT 199175A676 P684 66.932S or death16% *P(10.6) 4ESPS 250A1649 P1649 66.724S, death or both 18% **P(15.8) * 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/mm 3 ) 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 036 9 1215182124273033 36 Aspirin5.83% 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 PlaceboASAER-DPASA/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% *=P<0.05

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 1.522.53 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 2~3 ，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 more 1-3 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 2 Adams GF et al JNNP 1974;37:378-83 3 Fleming & Bailey Postgrad Med 1971;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 thrombosis 1-2 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 2 Ribeiro P et al J Thorac CV Surg 1986;91:92-8 3 Turpie A et al NEJM 1993;329:524-9 4 Chesebro 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 1 Nunez 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 NwarfarinASANo Rx Watson 1979 1 110/21/9 Hanson 1980 2 221/40/120/6 Stroke recurrence in MVP: case series MVP + AF: extrapolate data from EAFT 1 Watson RT Neurol 1979;29:886-9 2 Hanson 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 endocarditis 1-5 2° stroke prevention: –No data 感染性心内膜炎 1 Davenport et al Stroke 1990;21:993-9 2 Paschalis et al Eur Neurol 1990;30:87-9 3 Yeh et al Circulation 1967;35:I77-81 4 Delahaye et al Eur Heart J 1990;11:1074-8 5 Wilson 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 OAC 1-3 –68% with recurrent emboli when heparin d/c ’ d –ICH risk lower than in infective endocarditis 1 Rogers et al Am J Med 1987;83:746-56 2 Lopez et al Am Heart J 1987;113:773-84 3 Sack 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° Endpoint0.60 (.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 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（ INR2~3 ）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 1 Med Research Council BMJ 1969;1:335-42 2 Drapkin & Merskey JAMA 1972;222:541-8 3 VA Coop Study JAMA 1973;225:724-9 4 Vaitkus & Barnathau JACC 1993;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 1 Collins et al BMJ 1996;313:652-9 2 Collins et al NEJM 1997;336:847-60 3 FRAMI Kontny et al JACC 1997;30:962-9 4 SCATI Lancet 1989;2:182-6 5 Gissi-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 & Yusuf JAMA 1999;282:2058-67

Modified from Anand & Yusuf JAMA 1999;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 EF<40% # similar  risk at all levels of EF<35%

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, multicenter 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 effective No data –Aortic valve disease –Prosthetic heart valves –MI –LV dysfunction 口服抗凝剂（ OAC ）二级预防 : 小结

Mechanical prosthetic valve: Level I - Benefit of OAC + low dose ASA over OAC alone Bioprosthetic valve: Level V - Benefit over no OAC in 1 st 6 weeks after valve replacement MI: Level I - No benefit over ASA LVEF ≤ 40%: Level III - Benefit [? INR] over ASA LV aneurysm: low risk for 1° occurrence 口服抗凝剂（ OAC ）一级预防 : 小结

心源性卒中二级预防（研究中） NVAF: –SPORTIF V (Stroke Prevention by Oral Thrombin Inhibition) Fixed dose ximelagatran (thrombin inhibitor) vs. warfarin (INR 2-3) LV dysfunction –WARCEF (Warfarin vs. Aspirin in Reduced Cardiac EF) Warfarin (INR 2.5-3) vs. ASA 325mg in EF  30% –WATCH (Warfarin & Antiplatelet Therapy in Chronic Heart Failure) Warfarin (INR 2.5-3) vs. ASA 162mg vs. Clopidogrel 75mg in EF  35% Aortic Atheroma: –ARCH (Aortic Arch Related Cerebral Hazard) warfarin (INR 2-3) vs. ASA + clopidogrel in mobile or  4mm-thick atheroma PFO: –RESPECT (Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard Care Treatment Trial) Percutaneous PFO closure vs. antithrombotic Rx (ASA, clopidogrel, Aggrenox, ASA + clopidogrel, warfarin in cryptogenic stroke with PFO)

结语 1 抗血栓治疗仅能作为卒中预防策略组成部分之一；没有任何药物能完全消除卒中的复发风险，多项大规模试验结果为正确、合理地选择抗血栓治疗提供了证据；

结语 2 3h 内 IV rt-PA(0.9mg/kg) 疗效得到公认； 3h-6h 内 IA ProUK 证实有效；急性期阿司匹林疗效得到公认；急性期抗凝仅能降低 DVT 和 PE 发生率，但对动脉血栓疗效无差异

结语 3 若无禁忌，心源性栓塞通常宜选择抗凝治疗，西美加群是一种有前景的华法林替代物；目前无证据支持抗凝治疗用于 PFO 、抗磷脂抗体综合征、颅内动脉粥样硬化或腔隙性梗塞患者，而推荐使用阿司匹林；阿司匹林联合华法林治疗不能增强预防作用，反而会带来更大的出血风险；阿司匹林和氯吡格雷预防卒中复发的效果相近，阿司匹林联用氯吡格雷并不优于单用氯吡格雷，且出血风险更高；在抗血小板药联合治疗试验中，只有 ESPS2 试验能证实阿司匹林联用 ER-DIP 有协同作用，期待 PRoFESS 试验能得出同样结论。

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