溶栓相关试验及进展课件.pptx

1、急性缺血性脑卒中血管再通临床证据与进展首都医科大学宣武医院神经外科王亚冰缺血性脑卒中溶栓治疗循证 静脉溶栓（NINDS， ECASS III ） 动脉溶栓（PROACT） 动静脉溶栓（IMS） 机械取栓（MERCI，SEIS） 指南 其他证据静脉溶栓治疗美国FDA批准临床应用-1995年NINDS研究证明3h内静脉注射重组组织纤溶酶原激活剂（rtPA）溶栓治疗的有效性AHA:-2008年欧洲急性卒中协作ECASS III研究表明静脉rtPA溶栓治疗的时间窗可延长至4.5h静脉rtPA溶栓的不足受益患者少 - 仅1-3%的患者能够在发病3h内接受治疗血管再通率较低 - 仅约6%的颈内动脉、30%

2、大脑中动脉和30%椎基底动脉可获得血管再通39岁女性，意识障碍2小时A：T2相正常B、C：DWI显示右侧MCA分布区细胞毒性水肿，以右侧放射冠明显动脉内溶栓治疗3天后复查D：病变范围无增大，仅皮层及放射冠有小梗塞灶。Dismatch未行溶栓治疗的病例缺血性脑卒中的早期治疗 血管再通临床有效发现新策略!缺血区的血流灌注缺血性脑卒中血管再通：早期治疗关键-NINDS：1995年，静脉溶栓，3h-ECASS-：2008年，静脉溶栓，4.5h-大血管闭塞（ICA T-6%，TCD）发展：-大血管闭塞（ICA，MCA，VA，BA）-Real-time window 至 病理生理时间窗-多模式的血管内治疗

3、（单纯/合并）有效有效 快速快速 容易容易复杂复杂血管内机械再通治疗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推荐对起病3小时内符合标准的缺血性卒中患者静脉输注rt

7、PA（0.9mg/kg，最大剂量90mg），I级推荐，A级证据。 推荐有适应征、起病后3-4.5小时的卒中患者使用静脉用rtPA（0.9mg/kg，最大剂量90mg），I级推荐，B级证据。AHA/ASA GuidelineGuidelines for the Early Management of Patients With Acute Ischemic StrokeEndovascular Interventions时间窗内：静脉优先于动脉（I级推荐，A级证据）对于大脑中动脉大面积缺血性卒中患者，病程小于6小时的，动脉内溶栓治疗审慎选择的患者（他们不适合使用rtPA治疗）可以获益。（I级推荐

8、，B级证据）。机械取栓方面，支架取栓器（如Solitaire FR和Trevo）总体上优于弹簧圈取栓器（如Merci）。Penumbra系统相较支架取栓器的相对效果尚不明确。I级推荐，A级证据。联合溶栓：对于大动脉梗死静脉溶栓没有出现应答的患者进行补救性动脉内溶栓或机械取栓术是合理的。需要更多的随机试验结果（IIb级推荐，B级证据）。急诊颅内血管成形术和/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支架回收机械取栓支架回收机械取栓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美国多中心、随机对照研究血管内机械再通治疗颅内大血管闭塞Solitaire Retriever vs Merci Retriever主要疗效终点：成功血管

17、再通、无症状性出血次要疗效终点：良好临床结局、死亡率和严重并发症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. 问题 局限性：一种方法，解决所有的闭塞-不同的闭塞部位（远近，前后循环）-闭塞的原因-栓子的性质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 多模的血管内再通方式，再通率高 不同的方法-不同的闭塞部位（远近，前后循环）-闭塞的原因-栓子的性质 血管再通后的治疗静脉rtPA溶栓的不足受益患者少 - 仅1-3%的患者能够在发病3h内接受治疗血管再通率较低 - 仅约6%的颈内动脉、30%大脑中动脉和30%椎基底动脉可获得血管再通动脉溶栓治疗发病6h内，超选择性脑动脉内溶栓治疗药物经动脉途径可以迅速到达靶点发挥作用，直接接触血栓，降低全身应用溶栓药物引起的出血并发症采用rtPA或尿激酶动脉内溶栓是一种有效的治疗方法，但至今未获美国FDA批准卒中介入治疗的IMS I/II研究证实

32、了静脉和动脉内rtPA联合溶栓治疗的有效性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出血性转化ECASS标准，分为

33、出血性梗塞和脑实质血肿两类出血性梗塞1型（HI-1）：沿梗塞灶边缘有小瘀点、瘀斑出血性梗塞2型（HI-2）：在梗塞区内有融合的瘀点、瘀斑，但未形成占位效应出血性转化实质性血肿1型（PH-1）：脑实质血肿占小于30%的梗塞面积，伴一些轻微的占位效应实质性血肿2型（PH-2）：脑实质血肿占大于30%的梗塞面积，有大量占位效应出血性转化无症状性出血转化症状性出血性转化 - 术后24小时 - NIHSS4改良Rankin评分 完全无症状尽管有症状，但无明显功能障碍，能完成所有日常职责和活动轻度残疾，不能完成病前所有活动，但不需帮助能照顾自己的事务中度残疾，要求一些帮助，但行走不需帮助重度残疾，不能独立

34、行走，无他人帮助不能满足自身需求严重残疾，卧床、失禁，要求持续护理和关注死亡动脉溶栓治疗53岁，男性，突发左侧肢体偏瘫右侧顶叶区域低灌注，右侧MCA闭塞rtPA治疗PROACT II研究溶栓治疗tPA (n=182)tPA (n=418)(n=121)溶栓治疗的局限性治疗时间窗 - 3h， 4.5h - 6h静脉溶栓无效患者溶栓治疗（静脉或动脉）禁忌患者新治疗策略血管内机械再通治疗迅速恢复颅内闭塞血管的血流延长卒中治疗的时间窗至8h适用于静脉溶栓治疗无效或静脉溶栓禁忌的卒中患者治疗方法 - FDA批准：Merci取栓、Penumbra吸栓 - 支架植入、支架辅助性回收机械取栓 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机械取栓UCLA发明研制，2001年5月首例2004年8月获美国FDA批准临床应用Merci Retrieval Device适应证患者年龄1885岁具有急性颅内前或后循环卒中的症状体征NIHSS评分8

36、分头部CT扫描排除颅内出血适应证卒中发病3-8h的患者或者发病3h内静脉溶栓治疗禁忌或标准静脉溶栓治疗后无效的患者预计在卒中症状出现后8h内能够进行介入治疗全脑血管造影检查后，证实可治疗的血管闭塞部位，包括颈内动脉、大脑中动脉和椎基底动脉禁忌证NIHSS评分30分妊娠患者血糖1.048h内应用肝素治疗且PTT大于2倍正常值血小板185mmHg或舒张压110mmHg禁忌证CT检查发现显著的占位效应伴有中线结构移位或者1/3的MCA供血区域呈低密度影责任病灶的近端血管狭窄程度大于50%预计生存时间小于3个月Merci治疗ICA卒中血管造影左侧ICA闭塞Merci机械取栓Merci机械取栓完全血管再

37、通DWI PWI NIHSS治疗前 24治疗后 6Merci治疗MCA卒中血管造影右侧MCA M1闭塞Merci机械取栓机械再通治疗后复查CT和MRIMerci机械再通治疗效果北美多中心前瞻性研究：MERCI和Multi MERCI卒中8h内Merci机械取栓治疗ICA、MCA和椎基底动脉闭塞均有效305例患者，血管再通率64.6% 3个月良好结局32.4%血管再通：Merci vs 静脉溶栓 Merci治疗ICA卒中血管再通率 63%症状性出血率 10% 3个月良好临床结局 25%3个月死亡率 46%Merci治疗MCA 卒中：M1 vs M2静脉溶栓+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：症状性出血性转化Multi MERCI：症状性出血性转化血管内再通治疗：SAH血管内再通治疗：SAH临床预后差SAH Fisher III级SAH合并PHMerci治疗：出血转化的预测因素溶栓和血管内机械再通治疗缺血性卒中后均可发生出血性转化严重的颅内出血并发症可导致患者严重的预后不良研究表明脑白质疏松是IV和IA

39、 rtPA溶栓治疗后出血转化的一个危险因素脑白质疏松是否可以预测血管内机械取栓治疗后的出血并发症Fazekas and Schmidt scores of 0 to 3Score 0Score 1Score 2Score 3脑白质疏松预测Merci术后出血分析Merci治疗大脑前循环卒中患者资料治疗前MR FLAIR序列，判断患者脑白质疏松的部位（深部和脑室周围）和严重程度有无中重度深部脑白质疏松（2-3级）分为两组分析两组患者的临床特征、治疗后出血性转化和临床结局Baseline CharacteristicsRevascularization and Clinical Outcome by

40、 Leukoaraiosis Severe deep LA vs Parenchymal Hematoma Univariate Analysis of Predictors for Hemorrhage after ThrombectomyUnivariate Analysis of Predictors for Parenchymal HematomaMultivariate Analysis of Predictors for Parenchymal Hematoma脑白质疏松预测Merci术后出血中重度深部脑白质疏松组的患者治疗后出血转化和脑实质血肿发生较高，但是出血性梗塞和SAH的发

41、生率无差别中重度深部脑白质疏松分别是Merci术后出血转化和脑实质血肿的危险因素治疗后出现脑实质血肿的患者出院时临床结局较差，住院期间死亡率较高深部白质区域的中重度脑白质疏松可预测Merci取栓治疗后的脑实质血肿并发症Penumbra SystemThrombus aspiration and proximal thrombectomyPenumbra SystemPenumbra Pivotal Stroke Trial125例卒中8h内治疗ICA、MCA和椎基底动脉闭塞血管再通率 82%症状性出血率 11% 3个月良好临床预后 25%3个月死亡率 33%Penumbra Pivotal v

42、s Penumbra POST trialPenumbra Trial100%(21/21)82%(102/125)87%(137/157)20072007200820082009200910%(2/20)11%(14/125)6.4%(10/157)20072007200820082009200945%(9/20)33%(41/125)20%*(31/157)20072007200820082009200935%(7/20)25%(31/125)41%*(50/122)200720072008200820092009(30 day outcomes)(30 day outcomes)血管内机

43、械再通治疗tPAN支架回收机械取栓支架回收机械取栓Stent Retriever ThrombectomyDeviceSolitaire AB/FRSolitaire ABSolitaire AB/FRNSWIFT Trial美国多中心、随机对照研究血管内机械再通治疗颅内大血管闭塞Solitaire Retriever vs Merci Retriever主要疗效终点：成功血管再通、无症状性出血次要疗效终点：良好临床结局、死亡率和严重并发症SWIFT Trial: Randomized问题和展望术前MR选择最佳适应证何种介入技术更好降低再通治疗后出血性转化机械再通联合血管内注入神经保护药物术中MR评估