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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%大脑中动脉
2、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
3、管内治疗（单纯/合并）,有效 快速 容易,复杂,血管内机械再通治疗,The Impact of Recanalization on Ischemic Stroke OutcomeA Meta-Analysis,spontaneous(24.1%),intravenous fibrinolytic(46.2%),intra-arterial fibrinolytic(63.2%),combined intravenousintra-arterial(67.5%),and mechanical(83.6%)recanalized versus nonrecanalized:odds ratio o
4、f 4.43(95%CI,3.32 to 5.91)mortality was reduced in recanalized patients(odds ratio,0.24;95%CI,0.16 to 0.35)SICH:did not differ between the 2 groups,Stroke.2007;38:967-973;,Anterior circulation:randomized thrombolysis trials in hemispheric stroke,NINDS:National Institute of Neurological Disorders and
5、 Stroke;ECASS:European Cooperative Acute Stroke StudyPROACT:Prolyse in Acute Cerebral Thromboembolism,Posterior circulation:Major treatment studies in acute vertebrobasilar occlusion,IVT:intravenous thrombolysis;LIT:local intraarterial thrombolysis;,Guidelines for the Early Management of Patients Wi
6、th Acute Ischemic Stroke,Intravenous 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rtPA（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 Guideline,Guidelines for the Early Management of Patients With Acute Ischemic Stroke,Endovascular Interventions时间窗内：静脉优先于动脉（I级推荐，A
7、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，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 Guideline,SWIFT Trial：Solitai
8、reMerci,Merci Retrieval Device,X6、X5；L5；Kmini、V,Penumbra System,Thrombus aspiration and proximal thrombectomy,FDA 2007,Penumbra System,支架回收机械取栓,支架回收机械取栓,Castano et al.Stroke 2010;41:1836-40,Endovascular treatment of acute ischemic strokethe end or the beginning?,IMS IIII:interventional Management of
9、 StrokeMR RESCUE:Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy SYNTHESIS Expansion:A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic Stroke,Neurosurg Focus 36(1):E5,2014,Bridging Therapy,Bridging Therapy in Acute Ischemic St
10、roke:A Systematic Review and Meta-Analysis,Systematic review of all studies using bridging therapy published between January 1966 and March 2011The literature search identified 15 studies.In this meta-analysis,pooled estimates associated with bridging therapy were 69.6%for recanalization rates,48.9%
11、for favorable outcome,17.9%for mortality,and 8.6%for sICH.,Stroke.2012;43:1302-1308,Pooled Rates of Recanalization and Clinical Outcomes,ConclusionsBridging therapy is associated with acceptable safety and efficacy in stroke patients.Time to intravenous treatment is critical to improve recanalizatio
12、n rates and favorable outcomes.,IMS III trial,Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Strokewithin 3 hoursStopped 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 Me
13、d.2013 March 7;368(10):893903.,IMS III trial,IMS III trial,CONCLUSIONSSimilar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA,as compared with intravenous t-PA alone,N Engl J Med.2013 March 7;368(10):893903.,Endovascular treat
14、ment of acute ischemic strokethe end or the beginning?,IMS IIII:interventional Management of StrokeMR RESCUE:Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy SYNTHESIS Expansion:A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic
15、 Stroke,Neurosurg Focus 36(1):E5,2014,MR RESCUE A Trial of Imaging Selection andEndovascular Treatment for Ischemic Stroke,A favorable penumbral pattern on neuroimaging did not identify patients who woulddifferentially benefit from endovascular therapy for acute ischemic stroke,nor wasembolectomy sh
16、own 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,Saver et al.ISC 2012 Feb,SWIFT Trial:Randomized,All P0.001,Endovascular treatment of acute ischemic strokethe end or the beginning?,IMS IIII:
17、interventional Management of StrokeMR RESCUE:Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy SYNTHESIS Expansion:A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic Stroke,Neurosurg Focus 36(1):E5,2014,SYNTHESIS ExpansionEndovas
18、cular Treatment for Acute IschemicStroke,within 4.5 hours after onsetendovascular therapy(intraarterial thrombolysis with t-PA,mechanical clot disruption or retrieval,or a combination of these approaches)VS intravenous t-PAAt 3 months,55 patients in the endovascular-therapy group(30.4%)and 63 in the
19、 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 differences between groups in the rates of other serious adverse events or the case fatality rate,C
20、onclusions: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 Expansion,SYNTHESIS ExpansionEndovascular Treatment for Acute IschemicStroke,At 3 months,55 patients in the endovascul
21、ar-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 differences between groups in the rates of other serious advers
22、e 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.,Thrombolysis(different doses,routes of administration andagents)for acute ischaemic stroke(Re
23、view),20 trialsfive trials:one agent versus another and five trials:different routes of administration13 trials:comparison of higher dose with lower dose,up-to-date:19 March 2013,There was no evidence of any benefit for intra-arterial over intravenous treatment.,At present,intravenous rt-PA at 0.9mg
24、/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 for Acute Ischemic Stroke:A Systematic Review and Meta-analysis,To February 12,20135 randomized trials enro
25、lling 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 was found to have better outcomes in patients with severe stroke(NIHSS,20),showing a dose-response gradient and im
26、proving 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 Clin Proc.,Endovascular Therapy for Acute Ischemic Stroke:A Systematic Review and Meta-analysis,Overall,ET is not superio
27、r 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 limited due to sample size.There is a need for further trials evaluating the role of ET in this high-risk group.,2013 Mayo Found
28、ation 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 stent retriever thrombectomy in acuteischemic stroke,In acute stroke treated with Solitaire stent retriever thrombectomy,highe
29、r thrombus HU values are predictive of successful recanalization.Such information can be used in decision making when estimating recanalization success rate with different endovascular 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3
30、h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研究证实了静脉和动脉内rtPA联合溶栓治疗的有效性,TIMI Flow,TIMI 2/TIMI 3：成功血管再通,出血性转化,ECASS标准，分为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
31、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,mRS 2：良好临床结局,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,IA rtPA治疗完全再通,PROACT II研究,溶栓治疗,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
32、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,Mechanical Thrombectomy,Thrombus aspiration and proximal thrombectomy-Penumbra system,FDA 2007Distal thrombectomy-Merci Retriever,FDA 2004-Stent Retriever FDA？Solitaire FR;TREVO;PULSE;Revive,Merci机械取
33、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,X6、X5；L5；Kmini、V,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50 mg/dL颈部血管严重异常情况导致介入治疗所需的导管和器械无法进入颅内病
34、变部位已知全身出血性疾病和凝血功能障碍疾病,禁忌证,正在进行口服抗凝药物治疗并且INR1.048h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,完全血管再通,DWI PWI NIHSS,治疗前 24治疗后 6,Merci治疗MCA卒中,DWI,PWI,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MR
35、I,Merci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 Merci,P=0.09,P0.001,Outcomes by revascularization and IV tPA overall and by occl
36、usion site,Mortality by revascularization and IV tPA overall and by occlusion site,MERCI：症状性出血性转化,141例，7.8%,Multi MERCI：症状性出血性转化,164例，9.8%,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PH,Merci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 rtPA溶栓治疗后出血转化的一个危险因素脑白质疏松是
37、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 3,Score 0,Score 1,Score 2,Score 3,0，无1，轻度2，中度3，重度,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 Characteristics,Revascularization and Clinical Outcome by L
38、eukoaraiosis,Severe deep LA vs Parenchymal Hematoma,Univariate Analysis of Predictors for Hemorrhage after Thrombectomy,Univariate Analysis of Predictors for Parenchymal Hematoma,Multivariate 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
39、的发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 System,Thrombus aspiration and proximal thrombectomy,FDA 2007,Penumbra System,Penumbra Pivotal Stroke Trial,125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%,Pe
40、numbra Pivotal vs Penumbra POST trial,*P0.05,Penumbra Trial,100%(21/21),82%(102/125),87%(137/157),2007,2008,2009,10%(2/20),11%(14/125),6.4%(10/157),2007,2008,2009,Penumbra Trial,45%(9/20),33%(41/125),20%*(31/157),2007,2008,2009,Penumbra Trial,35%(7/20),25%(31/125),41%*(50/122),2007,2008,2009,(30 day
41、 outcomes),Penumbra Trial,血管内机械再通治疗,支架回收机械取栓,支架回收机械取栓,Castano et al.Stroke 2010;41:1836-40,Stent Retriever Thrombectomy,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,Saver et al.ISC 2012 Feb,SWIFT Trial:Randomized,All P0.001,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,
