急性缺血性卒中溶栓治療-課件

1、急性缺血性卒中溶栓治療急性缺血性卒中溶栓治療概述靜脈溶栓組織纖溶酶原激活物(tPA) NINDSECASS I & II, ATLANTIS鏈激酶 MAST-I, MAST-E, ASK動脈溶栓前循環(huán): 大腦中動脈 (PROACT II)后循環(huán): 基底動脈 概述靜脈溶栓與安慰劑相比,3h內(nèi)IV rtPA (0、9 mg/kg) 能改善90天時的預(yù)后出血發(fā)生率為 6、4% ,安慰劑為 0、6% ,但死亡率無差異所有亞組預(yù)后均優(yōu)于安慰劑組益處可持續(xù)1年rt-PA :NINDS 與安慰劑相比,3h內(nèi)IV rtPA (0、9 mg/kg) 隨機(jī), 多中心, 雙盲, 安慰劑對比620例; 排除CT早期梗

2、塞灶 (預(yù)后不良)干預(yù)rtPA (1、1 mg/kg) vs、 placebo起病6h內(nèi) 主要終點Barthel Index and modified Rankin Scale at 90 daysrtPA 與安慰劑組無明顯差別rt-PA : ECASS IHacke et al、, JAMA、 1995;274:1017-1025隨機(jī), 多中心, 雙盲, 安慰劑對比rt-PA : ECAS隨機(jī), 多中心, 雙盲, 安慰劑對比800 例;排除CT早期明顯梗塞灶 干預(yù)rtPA (0、9 mg/kg) vs、 placebo起病6h內(nèi) 主要終點modified Rankin Scale Score

3、 of 1 at 90 daysrtPA 與安慰劑組無明顯差別rt-PA : ECASS IIHacke et al、, Lancet、 1998;352:1245-1251隨機(jī), 多中心, 雙盲, 安慰劑對比rt-PA : ECAS隨機(jī), 多中心, 雙盲, 安慰劑對比613例干預(yù)rtPA (0、9 mg/kg) vs、 placebo起病3-5h內(nèi) 主要終點NIHSS of 1 at 90 daysrtPA 與安慰劑組無明顯差別rt-PA : ATLANTISAlteplase Thrombolysis for Acute Noninterventional Rx in Isch Strok

4、eClark et al、, JAMA、 1999;282:2019-2026隨機(jī), 多中心, 雙盲, 安慰劑對比rt-PA : ATLArt-PA:小結(jié)與安慰劑相比,3h內(nèi)IV rtPA (0、9 mg/kg) 能改善90天時的預(yù)后、 I 類證據(jù)目前證據(jù)顯示,超過3h 予IV tPA 無效、 I 類證據(jù)rt-PA:小結(jié)與安慰劑相比,3h內(nèi)IV rtPA (0、鏈激酶(SK)研究藥物劑量治療窗結(jié)果Multicenter Acute Stroke Trial-Europe (MAST-E)NEJM 1996;335:145-50SK1、5 MU6hSK組出血和死亡率高提早終止試驗Multicen

5、ter Acute Stroke Trial-Italy (MAST-I)Lancet 1995;346:1509-14SK aspirin1、5 MU300 mg/d6hSK組,尤其是SK + aspirin組出血和死亡率高提早終止試驗Australian Streptokinase Trial (ASK)Donnan et al、, Lancet 1995;345:578-9SK1、5 MU4h提早終止; 治療窗4h無明顯益處,結(jié)果不良與安慰劑相比,6h內(nèi)予IV SK 1、5 MU 預(yù)后不良 (出血和死亡率高)、 I 類證據(jù)鏈激酶(SK)研究藥物劑量治療窗結(jié)果Multicenter動脈溶栓

6、前循環(huán)大腦中動脈阻塞后循環(huán)椎基底動脈阻塞動脈溶栓前循環(huán)與安慰劑相比, 6h內(nèi)予IA ProUK 經(jīng)造影證實MCA M1 或M2 段阻塞的患者有效、 I 類證據(jù)15% 絕對有效 (number needed to treat = 7)增加顱內(nèi)出血,死亡率無差異PROACT II:小結(jié)與安慰劑相比, 6h內(nèi)予IA ProUK 經(jīng)造影證實MCA 急性椎基底動脈阻塞數(shù)項病例報道 (IV、V 類證據(jù))非隨機(jī)化無對比組 Brandt et al、, Cerebrovasc Dis, 1995;5:182-7急性椎基底動脈阻塞數(shù)項病例報道 (IV、V 類證據(jù))小結(jié)3h內(nèi)靜脈用 tPA 能降低90天時的殘障功

7、能、 I類證據(jù)靜脈用鏈激酶 (1、5 MU) 增加出血和死亡率、 I類證據(jù)6h內(nèi)動脈用尿激酶前體(Pro-UK,未被FDA通過)能降低90天時的殘障功能、 I類證據(jù)有證據(jù)支持在急性椎基底動脈阻塞中應(yīng)用動脈溶栓、 IV、V類證據(jù)小結(jié)3h內(nèi)靜脈用 tPA 能降低90天時的殘障功能、 I類急性缺血性卒中抗凝治療急性缺血性卒中抗凝治療概述肝素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各卒中亞型急性抗凝治療 房顫 和心源性栓塞大動脈粥樣硬化椎基底動脈阻塞 TIA進(jìn)展性卒中動脈夾層靜脈血栓形成各卒中亞型急性抗凝治療 房顫 和心源性栓塞各卒中亞型急性抗凝治療:小結(jié)CCTsubgrpNresults心源性栓塞123618no diff大動脈硬化0413,2851+(?)/3-后循環(huán)032318no diffTIA1055no diff進(jìn)展性卒中20204no diff夾層00286no diff靜脈血栓20791+/1-各卒中亞型急性抗凝治療

10、:小結(jié)CCTsubgrpNresult小結(jié)急性期抗凝減少深靜脈血栓和肺栓塞發(fā)生,不增加顱內(nèi)出血幾率、I類證據(jù) 小結(jié)急性期抗凝減少深靜脈血栓和肺栓塞發(fā)生,不增加顱內(nèi)出血幾急性缺血性卒中阿司匹林治療急性缺血性卒中阿司匹林治療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小結(jié)基于 IST 和 CAST, 阿司匹林在急性缺血性卒中后2-4周內(nèi),每1000例患者中有10人可減少死亡和復(fù)發(fā)。小結(jié)基于 IST 和 CAST, 阿司匹林在急性缺血性卒中非心源性卒中二級預(yù)防:抗栓治療非心源性卒中二級預(yù)防:抗栓治療概述抗血小板藥Antiplatelet、阿司匹林Aspirin抵克立得(噻氯匹啶)Ticlid (Ticlopidine)波力維(氯吡格雷)Plavix (Clopidogrel)艾諾思Aggrenox (aspirin + extended-release dipyridamole)Warfarin for non-cardioembo

13、lic arterial stroke: including large vessel disease、抗磷脂抗體綜合征(ASP)、頸椎動脈夾層、概述抗血小板藥Antiplatelet、AspirinAspirin高劑量阿司匹林隨機(jī)對比試驗#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高劑量阿司匹林隨機(jī)對比試驗#StudyASA dose# o低劑量阿司匹林隨機(jī)對比試驗#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低劑量阿司匹林隨機(jī)對比

17、試驗#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)與單用氯吡格雷(75mg)的療效進(jìn)行比較 ,結(jié)果是失敗的兩組的主要終點指標(biāo),即缺血性卒中、心肌梗死和血管源性死亡發(fā)生率與急性缺血事件(心絞痛、周圍動脈癥狀惡化或TIA)無統(tǒng)計學(xué)差異 聯(lián)合治療同時增加了嚴(yán)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主動脈弓粥樣硬化Tunick P et al Am J Cardiol 2002;90:1320-5Level III evide

29、nce: benefit of statins主動脈弓粥樣硬化Tunick P et al Am J C主動脈弓粥樣硬化: OACTunick P et al Am J Cardiol 2002;90:1320-5Level III evidence: no benefit of OAC主動脈弓粥樣硬化: OACTunick P et al A主動脈弓粥樣硬化: APATunick P et al Am J Cardiol 2002;90:1320-5Level III evidence: no benefit of APA主動脈弓粥樣硬化: APATunick P et al A主動脈弓粥樣

30、硬化: 他汀類Tunick P et al Am J Cardiol 2002;90:1320-5Level III evidence: benefit of statins主動脈弓粥樣硬化: 他汀類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感染性心內(nèi)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 感染性心內(nèi)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非細(xì)菌性血栓性心內(nèi)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”O(jiān)ptimum INR for prevention of Stroke Prevention with the ORal direct Thrombin Inhibitor in patients with non-valvular atrial Fibrillation(SPORTIF) SPORTIF III是一項開放試驗 , SPORTIF V期是隨機(jī)雙盲多中心試驗 ;比較了口服直截了當(dāng)凝血酶抑制劑西美加群(ximelagatran)與華法林(INR23)對心房顫動罹患卒中的影響 ;兩組預(yù)防缺血性卒中的療效無統(tǒng)計學(xué)差異,華法林組并發(fā)出血的概率較高,西美加群組肝酶升

36、高發(fā)生率為6%,比華法林組(0、8%)高特別多,這也是尚未獲得美國FDA批準(zhǔn)的原因。Stroke Prevention with the ORa心肌梗死后一級預(yù)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心肌梗死后一級預(yù)防: 短期抗凝Pre-thrombolyti心肌梗死后一級預(yù)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心肌梗死后一級預(yù)防: 短期抗凝Post-thrombolyt心肌梗死后一級預(yù)防: 長期抗凝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心肌梗死后一級預(yù)防: 長期抗凝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 :卒中危險因子多變量分析(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慢性室壁瘤系統(tǒng)栓塞(Lapeyre AC et al JACC 1985;6:534-538)Rate (Events/ 100 Pt-Yr)LPatent Foramen Ovale in Cryptogenic Stro