溶栓相關(guān)試驗及進展.

1、急性缺血性腦卒中血管再通臨床證據(jù)與進展首都醫(yī)科大學宣武醫(yī)院神經(jīng)外科王亞冰缺血性腦卒中溶栓治療循證 靜脈溶栓（NINDS， ECASS III ） 動脈溶栓（PROACT） 動靜脈溶栓（IMS） 機械取栓（MERCI，SEIS） 指南 其他證據(jù)靜脈溶栓治療美國FDA批準臨床應用-1995年NINDS研究證明3h內(nèi)靜脈注射重組組織纖溶酶原激活劑（rtPA）溶栓治療的有效性AHA:-2008年歐洲急性卒中協(xié)作ECASS III研究表明靜脈rtPA溶栓治療的時間窗可延長至4.5h靜脈rtPA溶栓的不足受益患者少 - 僅1-3%的患者能夠在發(fā)病3h內(nèi)接受治療血管再通率較低 - 僅約6%的頸內(nèi)動脈、30%

2、大腦中動脈和30%椎基底動脈可獲得血管再通39歲女性，意識障礙2小時A：T2相正常B、C：DWI顯示右側(cè)MCA分布區(qū)細胞毒性水腫，以右側(cè)放射冠明顯動脈內(nèi)溶栓治療3天后復查D：病變范圍無增大，僅皮層及放射冠有小梗塞灶。Dismatch未行溶栓治療的病例缺血性腦卒中的早期治療 血管再通臨床有效發(fā)現(xiàn)新策略!缺血區(qū)的血流灌注缺血性腦卒中血管再通：早期治療關(guān)鍵-NINDS：1995年，靜脈溶栓，3h-ECASS-：2008年，靜脈溶栓，4.5h-大血管閉塞（ICA T-6%，TCD）發(fā)展：-大血管閉塞（ICA，MCA，VA，BA）-Real-time window 至 病理生理時間窗-多模式的血管內(nèi)治療

3、（單純/合并）有效有效 快速快速 容易容易復雜復雜血管內(nèi)機械再通治療PROACT II MERCIMulti MERCIPenumbraNINDSIV rtPAN121141164125182Age6467686468NIHSS1720191817Recanalization66%48%68%82%N/AsICH10%7.8%9.8%11.2%6.6%90 days mRS 240%27.7%36%25%39%90 days mortality25%43.5%34%32.8%21%The Impact of Recanalization on Ischemic Stroke OutcomeA

4、Meta-Analysispspontaneous (24.1%), intravenous fibrinolytic (46.2%), intra-arterial fibrinolytic (63.2%), combined intravenousintra-arterial (67.5%), and mechanical (83.6%)precanalized versus nonrecanalized: odds ratio of 4.43 (95% CI, 3.32 to 5.91)pmortality was reduced in recanalized patients (odd

5、s ratio, 0.24; 95% CI, 0.16 to 0.35)pSICH: did not differ between the 2 groupsStroke. 2007;38:967-973;Anterior circulation: randomized thrombolysis trials in hemispheric strokeNINDS: National Institute of Neurological Disorders and Stroke;ECASS: European Cooperative Acute Stroke StudyPROACT:Prolyse

6、in Acute Cerebral ThromboembolismPosterior circulation: Major treatment studies in acute vertebrobasilar occlusionIVT: intravenous thrombolysis; LIT: local intraarterial thrombolysis;Guidelines for the Early Management of Patients With Acute Ischemic StrokeIntravenous rtPA推薦對起病3小時內(nèi)符合標準的缺血性卒中患者靜脈輸注rt

7、PA（0.9mg/kg，最大劑量90mg），I級推薦，A級證據(jù)。 推薦有適應征、起病后3-4.5小時的卒中患者使用靜脈用rtPA（0.9mg/kg，最大劑量90mg），I級推薦，B級證據(jù)。AHA/ASA GuidelineGuidelines for the Early Management of Patients With Acute Ischemic StrokeEndovascular Interventions時間窗內(nèi)：靜脈優(yōu)先于動脈（I級推薦，A級證據(jù)）對于大腦中動脈大面積缺血性卒中患者，病程小于6小時的，動脈內(nèi)溶栓治療審慎選擇的患者（他們不適合使用rtPA治療）可以獲益。（I級推薦

8、，B級證據(jù)）。機械取栓方面，支架取栓器（如Solitaire FR和Trevo）總體上優(yōu)于彈簧圈取栓器（如Merci）。Penumbra系統(tǒng)相較支架取栓器的相對效果尚不明確。I級推薦，A級證據(jù)。聯(lián)合溶栓：對于大動脈梗死靜脈溶栓沒有出現(xiàn)應答的患者進行補救性動脈內(nèi)溶栓或機械取栓術(shù)是合理的。需要更多的隨機試驗結(jié)果（IIb級推薦，B級證據(jù)）。急診顱內(nèi)血管成形術(shù)和/或支架置入的效果尚不肯定。AHA/ASA GuidelineSWIFT Trial：SolitaireMerciMerci Retrieval DevicePenumbra SystemThrombus aspiration and prox

9、imal thrombectomyPenumbra System支架回收機械取栓支架回收機械取栓Endovascular treatment of acute ischemic strokethe end or the beginning? IMS IIII: interventional Management of Stroke MR RESCUE: Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy SYNTHESIS Expansion: A Randomized Controlled Tri

10、al on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic StrokeNeurosurg Focus 36 (1):E5, 2014Bridging TherapyBridging Therapy in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis Systematic review of all studies using bridging therapy published between January 1966 and Marc

11、h 2011 The literature search identified 15 studies. In this meta-analysis, pooled estimates associated with bridging therapy were 69.6% for recanalization rates, 48.9% for favorable outcome, 17.9% for mortality, and 8.6% for sICH.Stroke. 2012;43:1302-1308Pooled Rates of Recanalization and Clinical O

12、utcomesConclusionsBridging therapy is associated with acceptable safety and efficacy in stroke patients. Time to intravenous treatment is critical to improve recanalization rates and favorable outcomes.IMS III trialEndovascular Therapy after Intravenous t-PA versus t-PA Alone for Strokewithin 3 hour

13、sStopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone)N Engl J Med. 2013 March 7; 368(10): 893903.IMS III trialIMS III trial CONCLUSIONSSimilar safety outcomes and no significant difference in fun

14、ctional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA aloneN Engl J Med. 2013 March 7; 368(10): 893903.Endovascular treatment of acute ischemic strokethe end or the beginning? IMS IIII: interventional Management of Stroke MR RESCUE: Mechanical Retri

15、eval and Recanalization of Stroke Clots Using Embolectomy SYNTHESIS Expansion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic StrokeNeurosurg Focus 36 (1):E5, 2014MR RESCUE A Trial of Imaging Selection andEndovascular Treatment for Ischemic StrokeA

16、favorable penumbral pattern on neuroimaging did not identify patients who woulddifferentially benefit from endovascular therapy for acute ischemic stroke, nor wasembolectomy shown to be superior to standard care.SWIFT Trial美國多中心、隨機對照研究血管內(nèi)機械再通治療顱內(nèi)大血管閉塞Solitaire Retriever vs Merci Retriever主要療效終點：成功血管

17、再通、無癥狀性出血次要療效終點：良好臨床結(jié)局、死亡率和嚴重并發(fā)癥SWIFT Trial: RandomizedEndpointSolitaire FR (n=58)Merci (n=55)Successful recanalization study device83.3%48.1%End of procedure successful recanalization88.9%67.3%Successful recanalization without sICH60.7%24.1%mRS 2 at 90 Days58.2%33.3%Mortality at 90 Days17.2%33.3%En

18、dovascular treatment of acute ischemic strokethe end or the beginning? IMS IIII: interventional Management of Stroke MR RESCUE: Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy SYNTHESIS Expansion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolys

19、is in Acute Ischemic StrokeNeurosurg Focus 36 (1):E5, 2014SYNTHESIS ExpansionEndovascular Treatment for Acute IschemicStrokewithin 4.5 hours after onsetendovascular therapy (intraarterial thrombolysis with t-PA, mechanical clot disruption or retrieval, or a combination of these approaches) VS intrav

20、enous t-PAAt 3 months, 55 patients in the endovascular-therapy group (30.4%) and 63 in the intravenous t-PA group (34.8%) were alive without disabilityFatal or nonfatal symptomatic intracranial hemorrhage within 7 days occurred in 6% of the patients in each group, and there were no significant diffe

21、rences between groups in the rates of other serious adverse events or the case fatality rateConclusions: The results of this trial in patients with acute ischemic stroke indicate that endovascular therapy is not superior to standard treatment with intravenous t-PA.SYNTHESIS ExpansionSYNTHESIS Expans

22、ionEndovascular Treatment for Acute IschemicStrokeAt 3 months, 55 patients in the endovascular-therapy group (30.4%) and 63 in the intravenous t-PA group (34.8%) were alive without disabilityFatal or nonfatal symptomatic intracranial hemorrhage within 7 days occurred in 6% of the patients in each gr

23、oup, and there were no significant differences between groups in the rates of other serious adverse events or the case fatality rateConclusions: The results of this trial in patients with acute ischemic stroke indicate that endovascular therapy is not superior to standard treatment with intravenous

24、t-PA.Thrombolysis (different doses, routes of administration andagents) for acute ischaemic stroke (Review) 20 trials five trials: one agent versus another and five trials: different routes of administration 13 trials: comparison of higher dose with lower doseup-to-date: 19 March 2013There was no ev

25、idence of any benefit for intra-arterial over intravenous treatment.At present, intravenous rt-PA at 0.9mg/kg as licensed in many countries appears to represent best practice and other drugs, doses or routes of administration should only be used in randomised controlled trials.Endovascular Therapy f

26、or Acute Ischemic Stroke:A Systematic Review and Meta-analysisTo February 12, 20135 randomized trials enrolling 1197 patients; ET, 711; IV, 486;-Overall, no significant improvement in any of the outcomes in patients receiving ET compared with those receiving IV thrombolysis.-Subgroup analysis, ET wa

27、s found to have better outcomes in patients with severe stroke (NIHSS, 20), showing a dose-response gradient and improving excellent, good, and fair outcomes by an additional 4%, 7%, and 13%, respectively, compared with IV thrombolysis.2013 Mayo Foundation for Medical Education and Research n Mayo C

28、lin Proc. Endovascular Therapy for Acute Ischemic Stroke:A Systematic Review and Meta-analysisOverall, ET is not superior to IV thrombolysis for acute ischemic strokes (level B recommendation).However, ET showed promise and improved outcomes in patients with severe strokes, but the evidence is limit

29、ed due to sample size. There is a need for further trials evaluating the role of ET in this high-risk group.2013 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 問題 局限性：一種方法，解決所有的閉塞-不同的閉塞部位（遠近，前后循環(huán)）-閉塞的原因-栓子的性質(zhì)Thrombus density predicts successful recanalizationwith Solitaire sten

30、t retriever thrombectomy in acuteischemic strokeIn acute stroke treated with Solitaire stent retriever thrombectomy, higher thrombus HU values are predictive of successful recanalization. Such information can be used in decision making when estimating recanalization success rate with different endov

31、ascular treatment approaches.希望 多模的血管內(nèi)再通方式，再通率高 不同的方法-不同的閉塞部位（遠近，前后循環(huán)）-閉塞的原因-栓子的性質(zhì) 血管再通后的治療靜脈rtPA溶栓的不足受益患者少 - 僅1-3%的患者能夠在發(fā)病3h內(nèi)接受治療血管再通率較低 - 僅約6%的頸內(nèi)動脈、30%大腦中動脈和30%椎基底動脈可獲得血管再通動脈溶栓治療發(fā)病6h內(nèi)，超選擇性腦動脈內(nèi)溶栓治療藥物經(jīng)動脈途徑可以迅速到達靶點發(fā)揮作用，直接接觸血栓，降低全身應用溶栓藥物引起的出血并發(fā)癥采用rtPA或尿激酶動脈內(nèi)溶栓是一種有效的治療方法，但至今未獲美國FDA批準卒中介入治療的IMS I/II研究證實

32、了靜脈和動脈內(nèi)rtPA聯(lián)合溶栓治療的有效性TIMI Flow No perfusion Penetration without perfusion.perfusion past the initial occlusion, but no distal branch fillingPartial perfusion of the artery with incomplete or slow distal branch fillingComplete perfusion of the artery with filling of all distal branches出血性轉(zhuǎn)化ECASS標準，分為

33、出血性梗塞和腦實質(zhì)血腫兩類出血性梗塞1型（HI-1）：沿梗塞灶邊緣有小瘀點、瘀斑出血性梗塞2型（HI-2）：在梗塞區(qū)內(nèi)有融合的瘀點、瘀斑，但未形成占位效應出血性轉(zhuǎn)化實質(zhì)性血腫1型（PH-1）：腦實質(zhì)血腫占小于30%的梗塞面積，伴一些輕微的占位效應實質(zhì)性血腫2型（PH-2）：腦實質(zhì)血腫占大于30%的梗塞面積，有大量占位效應出血性轉(zhuǎn)化無癥狀性出血轉(zhuǎn)化癥狀性出血性轉(zhuǎn)化 - 術(shù)后24小時 - NIHSS4改良Rankin評分 完全無癥狀盡管有癥狀，但無明顯功能障礙，能完成所有日常職責和活動輕度殘疾，不能完成病前所有活動，但不需幫助能照顧自己的事務中度殘疾，要求一些幫助，但行走不需幫助重度殘疾，不能獨立

34、行走，無他人幫助不能滿足自身需求嚴重殘疾，臥床、失禁，要求持續(xù)護理和關(guān)注死亡動脈溶栓治療53歲，男性，突發(fā)左側(cè)肢體偏癱右側(cè)頂葉區(qū)域低灌注，右側(cè)MCA閉塞rtPA治療PROACT II研究溶栓治療tPA (n=182)tPA (n=418)(n=121)溶栓治療的局限性治療時間窗 - 3h， 4.5h - 6h靜脈溶栓無效患者溶栓治療（靜脈或動脈）禁忌患者新治療策略血管內(nèi)機械再通治療迅速恢復顱內(nèi)閉塞血管的血流延長卒中治療的時間窗至8h適用于靜脈溶栓治療無效或靜脈溶栓禁忌的卒中患者治療方法 - FDA批準：Merci取栓、Penumbra吸栓 - 支架植入、支架輔助性回收機械取栓 Mechanic

35、al ThrombectomyThrombus aspiration and proximal thrombectomy - Penumbra system, FDA 2007Distal thrombectomy - Merci Retriever, FDA 2004 - Stent Retriever FDA ？ Solitaire FR; TREVO; PULSE; ReviveMerci機械取栓UCLA發(fā)明研制，2001年5月首例2004年8月獲美國FDA批準臨床應用Merci Retrieval Device適應證患者年齡1885歲具有急性顱內(nèi)前或后循環(huán)卒中的癥狀體征NIHSS評分8

36、分頭部CT掃描排除顱內(nèi)出血適應證卒中發(fā)病3-8h的患者或者發(fā)病3h內(nèi)靜脈溶栓治療禁忌或標準靜脈溶栓治療后無效的患者預計在卒中癥狀出現(xiàn)后8h內(nèi)能夠進行介入治療全腦血管造影檢查后，證實可治療的血管閉塞部位，包括頸內(nèi)動脈、大腦中動脈和椎基底動脈禁忌證NIHSS評分30分妊娠患者血糖1.048h內(nèi)應用肝素治療且PTT大于2倍正常值血小板185mmHg或舒張壓110mmHg禁忌證CT檢查發(fā)現(xiàn)顯著的占位效應伴有中線結(jié)構(gòu)移位或者1/3的MCA供血區(qū)域呈低密度影責任病灶的近端血管狹窄程度大于50%預計生存時間小于3個月Merci治療ICA卒中血管造影左側(cè)ICA閉塞Merci機械取栓Merci機械取栓完全血管再

37、通DWI PWI NIHSS治療前 24治療后 6Merci治療MCA卒中血管造影右側(cè)MCA M1閉塞Merci機械取栓機械再通治療后復查CT和MRIMerci機械再通治療效果北美多中心前瞻性研究：MERCI和Multi MERCI卒中8h內(nèi)Merci機械取栓治療ICA、MCA和椎基底動脈閉塞均有效305例患者，血管再通率64.6% 3個月良好結(jié)局32.4%血管再通：Merci vs 靜脈溶栓 Merci治療ICA卒中血管再通率 63%癥狀性出血率 10% 3個月良好臨床結(jié)局 25%3個月死亡率 46%Merci治療MCA 卒中：M1 vs M2靜脈溶栓+Merci vs MerciOutco

38、mes by revascularization and IV tPA overall and by occlusion siteMortality by revascularization and IV tPA overall and by occlusion siteMERCI：癥狀性出血性轉(zhuǎn)化Multi MERCI：癥狀性出血性轉(zhuǎn)化血管內(nèi)再通治療：SAH血管內(nèi)再通治療：SAH臨床預后差SAH Fisher III級SAH合并PHMerci治療：出血轉(zhuǎn)化的預測因素溶栓和血管內(nèi)機械再通治療缺血性卒中后均可發(fā)生出血性轉(zhuǎn)化嚴重的顱內(nèi)出血并發(fā)癥可導致患者嚴重的預后不良研究表明腦白質(zhì)疏松是IV和IA rtPA溶栓治療后出血轉(zhuǎn)化的一個危險因素腦白質(zhì)疏松是否可以預測血管內(nèi)機械取栓治療后的出血并發(fā)癥Fazekas and Schmidt scores of 0 to 3Score 0Score 1Score 2Score 3腦白質(zhì)疏松預測Merci術(shù)后出血分析Merci治療大腦前循環(huán)卒中患者資料治療前MR FLAIR序列，判斷患者腦白質(zhì)疏松的部位（深部和腦室周圍）和嚴重程度有無中重度深部腦白質(zhì)疏松（2-3級）分為兩組分析兩組