急性缺血性卒中血管內(nèi)治療研究進(jìn)展

林育意 譚靜 路星辰

·綜述·

急性缺血性卒中血管內(nèi)治療研究進(jìn)展

林育意 譚靜 路星辰

急性缺血性卒中發(fā)病率、病殘率和病死率均較高，是目前對(duì)人類危害最嚴(yán)重的疾病之一。血管內(nèi)治療已獲得臨床充分肯定。血管內(nèi)治療適應(yīng)證的選擇、治療時(shí)間窗的確定、機(jī)械取栓裝置的選擇對(duì)預(yù)后至關(guān)重要。本文擬對(duì)急性缺血性卒中血管內(nèi)治療研究進(jìn)展進(jìn)行闡述。

卒中； 腦缺血； 血栓溶解療法； 血管成形術(shù)； 綜述

腦卒中是目前對(duì)人類危害最嚴(yán)重的疾病之一。全國(guó)第三次死因回顧抽樣調(diào)查和第二次全國(guó)殘疾人抽樣調(diào)查資料顯示，腦卒中已成為我國(guó)國(guó)民首位病殘和病死原因［1］。在美國(guó)，腦卒中是導(dǎo)致終身殘疾的首要原因，是第4位病死原因［2］。截至2010年，腦卒中位列全球病殘和病死原因的第3和2位［3?4］。雖然近年來(lái)腦卒中病死率有所下降，但病殘和病死的絕對(duì)病例數(shù)仍在增加［5］，據(jù)世界銀行預(yù)測(cè)，如果不采取有效措施，截至2030年，我國(guó)將有31.77×106例腦卒中患者［1］。勞動(dòng)力喪失和醫(yī)療負(fù)擔(dān)成為腦卒中生存者、家庭和社會(huì)的沉重負(fù)擔(dān)。有效的治療方法是臨床醫(yī)師不懈追求的目標(biāo)。

一、急性缺血性卒中靜脈溶栓治療

目前，缺血性卒中是我國(guó)腦卒中住院患者的主要類型，占全部腦卒中70%以上［1］。靜脈溶栓是經(jīng)典治療方法。研究證實(shí)，腦卒中靜脈溶栓治療有效，發(fā)病后3小時(shí)為治療時(shí)間窗［6?7］。1996年，重組組織型纖溶酶原激活物（rt?PA）經(jīng)美國(guó)食品與藥品管理局（FDA）批準(zhǔn)用于腦卒中靜脈溶栓治療［8］。2008年歐洲協(xié)作組急性腦卒中研究Ⅲ（ECASSⅢ）首次將腦卒中靜脈溶栓治療時(shí)間窗自3小時(shí)延長(zhǎng)至4.50小時(shí)［9］，并獲得臨床研究證據(jù)的支持［10?11］。

隨著臨床應(yīng)用的普及，靜脈溶栓治療的局限性也逐漸凸顯。（1）治療時(shí)間窗窄：盡管已將腦卒中靜脈溶栓治療時(shí)間窗延長(zhǎng)至發(fā)病后4.50小時(shí)，但在此時(shí)間窗內(nèi)仍有較多患者，特別是偏遠(yuǎn)地區(qū)、交通欠發(fā)達(dá)地區(qū)患者，難以到達(dá)有靜脈溶栓資質(zhì)的醫(yī)院，且此治療時(shí)間窗后不良結(jié)局發(fā)生率較高。（2）血管再通率低：頸內(nèi)動(dòng)脈（ICA）或基底動(dòng)脈閉塞后靜脈溶栓治療的血管再通率僅為4%～14%，大腦中動(dòng)脈（MCA）為55%，大腦中動(dòng)脈M1段閉塞為32%～37%，病殘率和病死率均較高［12?13］。（3）易導(dǎo)致腦出血：有文獻(xiàn)報(bào)道，靜脈溶栓治療后癥狀性腦出血發(fā)生率高達(dá)1.7% ～ 2.4%［9，14］。

二、急性缺血性卒中血管內(nèi)治療

1.血管內(nèi)治療的有效性 2013年發(fā)表于N Engl J Med的3篇關(guān)于血管內(nèi)治療的隨機(jī)對(duì)照臨床試驗(yàn)并未顯示血管內(nèi)治療較rt?PA靜脈溶栓治療更有優(yōu)勢(shì)［15?17］。此后，Singh等［2］對(duì)上述3 項(xiàng)臨床研究進(jìn)行Meta分析，也得出相同結(jié)論。但是他們發(fā)現(xiàn)，對(duì)于重癥腦卒中，血管內(nèi)治療效果更佳［2，15?17］。究其原因，可能是血管內(nèi)治療尚缺乏大樣本多中心隨機(jī)雙盲對(duì)照臨床試驗(yàn)，也可能與機(jī)械取栓裝置Merci落后、患者征募緩慢、腦組織再灌注延遲、所納入病例均質(zhì)性不一致有關(guān)。隨著機(jī)械取栓裝置和取栓技術(shù)的進(jìn)步，血管內(nèi)治療的優(yōu)勢(shì)逐漸凸顯［2，18］，較單純靜脈溶栓治療效果更佳［19］。兩項(xiàng)采用機(jī)械取栓裝置Stentrievers治療腦卒中的隨機(jī)對(duì)照臨床試驗(yàn)結(jié)局均明顯改善［20?21］。截至2015年，5項(xiàng)里程碑式前瞻性隨機(jī)對(duì)照臨床試驗(yàn)均顯示，與靜脈溶栓相比，血管內(nèi)機(jī)械取栓治療近端動(dòng)脈閉塞性缺血性卒中的治療時(shí)間窗更長(zhǎng)、血管再通率更高、臨床預(yù)后更佳［22?26］。2013 和 2015 年的 8 項(xiàng)臨床研究雖然納入與排除標(biāo)準(zhǔn)不盡相同［15?17，22?26］，但 Badhiwala等［27］對(duì)其進(jìn)行Meta分析后發(fā)現(xiàn)，與內(nèi)科治療聯(lián)合rt?PA靜脈溶栓治療相比，急性缺血性卒中患者采用血管內(nèi)機(jī)械取栓治療能夠更好地改善神經(jīng)功能預(yù)后，腦血管造影顯示血管再通率更高，且不增加90天內(nèi)癥狀性腦出血發(fā)生率和各種原因?qū)е碌牟∷缆省?/p>

2.血管內(nèi)治療患者的選擇 Chia等［28］在南澳大利亞的Adelaide西郊進(jìn)行一項(xiàng)以人群為基礎(chǔ)的隊(duì)列研究，結(jié)果顯示，在嚴(yán)格［改良Rankin量表（mRS）評(píng)分0～1分，發(fā)病至入院時(shí)間＜3.50小時(shí)，梗死灶核心與缺血半暗帶區(qū)不匹配］和寬松（mRS評(píng)分0～3分，發(fā)病至入院時(shí)間＜5小時(shí)）兩種標(biāo)準(zhǔn)下，符合血管內(nèi)血栓切除術(shù)（ET）治療的潛在腦卒中患者約占全部腦卒中患者的7%和13%，寬松標(biāo)準(zhǔn)預(yù)測(cè)每年符合血管內(nèi)血栓切除術(shù)治療的潛在患者≤22/10萬(wàn)。2015年，Urra等［29］對(duì)納入前循環(huán)大血管閉塞致急性腦卒中8小時(shí)內(nèi)Solitaire FR支架取栓與內(nèi)科治療隨機(jī)對(duì)照試驗(yàn)（REVASCAT）的西班牙前循環(huán)大血管閉塞性缺血性卒中患者和未納入該項(xiàng)試驗(yàn)的其他類型腦卒中患者的血管內(nèi)機(jī)械取栓治療效果進(jìn)行分析，結(jié)果顯示療效無(wú)明顯差異，表明血管內(nèi)血栓切除術(shù)不僅適用于前循環(huán)大血管閉塞性缺血性卒中，還具有更廣泛的適應(yīng)證。如何準(zhǔn)確、快速地篩選血管內(nèi)治療適應(yīng)證患者，是所有神經(jīng)科醫(yī)師面臨的挑戰(zhàn)。Alberta腦卒中計(jì)劃早期CT評(píng)分（ASPECTS）是一種采用頭部非增強(qiáng)CT掃描快速、簡(jiǎn)單、可靠、系統(tǒng)化評(píng)價(jià)腦組織早期缺血性改變的方法［30］。該評(píng)分系統(tǒng)中CT檢查操作簡(jiǎn)單、檢查時(shí)間短、設(shè)備普及率高，可以廣泛應(yīng)用于血管內(nèi)治療患者的篩查。研究顯示，ASPECTS評(píng)分＞7分的缺血性卒中患者，動(dòng)脈或靜脈溶栓治療后預(yù)后較好［31?32］。目前，ASPECTS評(píng)分廣泛應(yīng)用于選擇適合血管內(nèi)治療的患者。Goyal等［33］對(duì)2015年發(fā)表的5項(xiàng)關(guān)于血管內(nèi)治療的隨機(jī)對(duì)照臨床試驗(yàn)進(jìn)行Meta分析，結(jié)果顯示，ASPECTS評(píng)分優(yōu)良（7～10分）的患者經(jīng)血管內(nèi)治療后獲益明顯，而ASPECT評(píng)分差（0～6分）的患者經(jīng)血管內(nèi)治療后亦未發(fā)現(xiàn)有害證據(jù)。Yoo等［34］對(duì)荷蘭急性缺血性卒中血管內(nèi)治療多中心隨機(jī)對(duì)照臨床試驗(yàn)（MR CLEAN）進(jìn)行亞組分析，結(jié)果顯示，中等梗死灶（ASPECTS評(píng)分5～7分）患者經(jīng)血管內(nèi)治療后獲益最大，小梗死灶（ASPECTS評(píng)分8～10分）患者經(jīng)血管內(nèi)治療聯(lián)合常規(guī)治療后缺血性卒中復(fù)發(fā)率增加，大梗死灶（ASPECTS評(píng)分0～4分）患者經(jīng)血管內(nèi)治療后是否獲益仍不明確，尚待進(jìn)一步研究。上述研究結(jié)論的差異可能是由于CT平掃對(duì)急性梗死灶敏感性和精確性均較差［35］；ASPECTS評(píng)分應(yīng)用者之間的異質(zhì)性較大，約1/3研究者對(duì)15%缺血性卒中患者的ASPECTS評(píng)分意見(jiàn)不一致［36］，因此，ASPECTS評(píng)分用于血管內(nèi)治療適應(yīng)證的選擇尚存局限性。研究顯示，缺血半暗帶血栓檢測(cè)、CTA原始圖像（CTA?SI）有助于選擇適合血管內(nèi)治療的急性缺血性卒中患者［37］。然而，綜合比較CT平掃的簡(jiǎn)便快捷（可以爭(zhēng)取更多時(shí)間進(jìn)行血管內(nèi)治療以挽救缺血半暗帶）與MRI和CTA等檢查（準(zhǔn)確性高但檢測(cè)時(shí)間較長(zhǎng)）之間的關(guān)系，目前尚無(wú)除ASPECTS評(píng)分外的更好評(píng)價(jià)方法［38］。

3.血管內(nèi)治療時(shí)間窗 腦卒中后應(yīng)盡可能縮短再灌注時(shí)間［19］，普遍認(rèn)為，再灌注時(shí)間延長(zhǎng)使臨床預(yù)后惡化，增加并發(fā)癥發(fā)生率［39］。晚近研究顯示，血管內(nèi)治療對(duì)發(fā)病6 小時(shí)內(nèi)患者安全、有效［22，24?25］。美國(guó)心臟協(xié)會(huì)（AHA）/美國(guó)卒中協(xié)會(huì)（ASA）制定的急性缺血性卒中血管內(nèi)治療指南［40］建議，應(yīng)于發(fā)病6小時(shí)內(nèi)行血管內(nèi)治療。《急性缺血性卒中血管內(nèi)治療中國(guó)指南2015》［41］推薦，血管內(nèi)機(jī)械取栓治療發(fā)病6小時(shí)內(nèi)的急性前循環(huán)大動(dòng)脈狹窄性缺血性卒中，如果發(fā)病4.50小時(shí)內(nèi)，可在足量靜脈溶栓基礎(chǔ)上實(shí)施血管內(nèi)機(jī)械取栓治療。但是發(fā)病6小時(shí)后行血管內(nèi)治療是否獲益尚存爭(zhēng)議。理論上講，如果側(cè)支循環(huán)良好、可挽救的缺血半暗帶體積足夠大，即使延長(zhǎng)治療時(shí)間窗也可以獲益。Jovin等［26］進(jìn)行的REVASCAT試驗(yàn)納入發(fā)病8小時(shí)內(nèi)的前循環(huán)大血管閉塞性缺血性卒中患者，血管內(nèi)機(jī)械取栓可顯著降低腦卒中后殘疾程度，增加生活自理［mRS評(píng)分0～2分］比例，且與單純內(nèi)科治療相比，癥狀性腦出血發(fā)生率和病死率差異無(wú)統(tǒng)計(jì)學(xué)意義。Saver等［42］的Meta分析顯示，腦卒中發(fā)病2小時(shí)內(nèi)行血管內(nèi)治療聯(lián)合內(nèi)科治療獲益最大，發(fā)病后7.30小時(shí)已無(wú)明顯獲益。Goyal等［23］的小梗死灶和前循環(huán)近端閉塞性缺血性卒中血管內(nèi)治療并強(qiáng)調(diào)最短化CT掃描至再通時(shí)間（ESCAPE）試驗(yàn)將納入時(shí)限延長(zhǎng)至發(fā)病12小時(shí)內(nèi)，同樣發(fā)現(xiàn)血管內(nèi)治療可以明顯改善患者功能預(yù)后并降低病死率。Lansberg等［43］的前瞻性多中心隊(duì)列研究——擴(kuò)散和灌注成像評(píng)價(jià)腦卒中進(jìn)展2（DEFUSE2）研究顯示，對(duì)于發(fā)病12小時(shí)內(nèi)灌注成像（PWI）?擴(kuò)散加權(quán)成像（DWI）不匹配的缺血性卒中患者，血管內(nèi)再灌注成功與功能和影像學(xué)預(yù)后改善（發(fā)病至接受再灌注治療時(shí)間）無(wú)時(shí)間依賴性。應(yīng)注意的是，加拿大腦卒中治療指南［44］建議，發(fā)病6小時(shí)內(nèi)血管內(nèi)治療效果最佳，最多可延長(zhǎng)至發(fā)病12小時(shí)內(nèi)。從個(gè)體水平看，發(fā)病超過(guò)6小時(shí)的缺血性卒中患者仍有可挽救的缺血半暗帶，可采用多模式影像學(xué)檢查，如CT灌注成像（CTP）、CTA、DWI和PWI篩選適合血管內(nèi)治療的患者，但是此類患者能否從急性缺血?再灌注中獲益，尚待進(jìn)一步隨機(jī)對(duì)照臨床試驗(yàn)的驗(yàn)證［40］。

4.血管內(nèi)治療裝置的選擇 目前，血管內(nèi)取栓裝置根據(jù)取栓方法可以分為兩種類型，一種以Merci（美國(guó)Concentric Medical公司）取栓系統(tǒng)和Penumbra（美國(guó)Penumbra公司）吸栓系統(tǒng)為代表，一種以Solitaire（美國(guó)EV3公司）和Trevo（美國(guó)Stryker公司）可回收支架取栓系統(tǒng)為代表。支架種類、型號(hào)、形狀和物理性質(zhì)對(duì)臨床實(shí)踐和預(yù)后結(jié)局的影響尚不明確，因此，機(jī)械取栓裝置的選擇也尚無(wú)定論。有5項(xiàng)隨機(jī)對(duì)照臨床試驗(yàn)證實(shí)可回收支架取栓系統(tǒng)的優(yōu)良效果［22?26，33］。Dippel等［45］對(duì) MR CLEAN試驗(yàn)中不同取栓裝置的臨床結(jié)局進(jìn)行分析，發(fā)現(xiàn)Solitaire和Trevo支架取栓裝置的效果最佳，Catch（美國(guó)Guidant公司）、Lazarus（美國(guó)Lazarus Effect公司）、Merci、Penumbra、Revive（美 國(guó) Johnsonamp;Johnson公司）等裝置取栓后7天和3個(gè)月病死率和蛛網(wǎng)膜下隙出血發(fā)生率均明顯高于Solitaire和Trevo支架取栓裝置，而二者的臨床結(jié)局、神經(jīng)修復(fù)、血管再通率、最終梗死灶面積和病死率差異則無(wú)統(tǒng)計(jì)學(xué)意義。Mendon?a等［46］的前瞻性臨床研究對(duì)前循環(huán)閉塞后Solitaire和Trevo支架取栓裝置的療效進(jìn)行比較，結(jié)果顯示，兩種裝置取栓后血管再通率均較高（60%對(duì)77%，P=0.456），且臨床、影像學(xué)和功能結(jié)局差異均無(wú)統(tǒng)計(jì)學(xué)意義；然而由于樣本量較?。▋H33例），該項(xiàng)研究結(jié)論尚待進(jìn)一步證實(shí)。Grech等［47］對(duì)2010-2013年發(fā)表的20篇關(guān)于血管內(nèi)機(jī)械取栓裝置的臨床研究（包括Solitaire支架17篇、Trevo支架3篇）進(jìn)行Meta分析，結(jié)果顯示，Solitaire和Trevo支架取栓后血管再通率均＞80%，二者功能結(jié)局、病死率和癥狀性腦出血發(fā)生率差異均無(wú)統(tǒng)計(jì)學(xué)意義。因此認(rèn)為，第一種類型的吸栓系統(tǒng)療效未能達(dá)到預(yù)期，而第二類型的可回收支架取栓系統(tǒng)療效達(dá)到預(yù)期，表現(xiàn)卓越。

綜上所述，血管內(nèi)治療已獲得臨床充分肯定，中國(guó)神經(jīng)外科醫(yī)師、相關(guān)學(xué)者和科研機(jī)構(gòu)也緊隨時(shí)代步伐在該領(lǐng)域作出大量工作［48?49］。隨著相關(guān)設(shè)備和技術(shù)的迅速發(fā)展，相信在不久的將來(lái)，血管內(nèi)治療必將得到進(jìn)一步的完善和普及。

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Research progress of endovascular therapy for acute ischemic stroke

LIN Yu?yi1,TAN Jing2,LU Xing?chen3

1Department of Neurosurgery,Southeast Hospital of Chongqing,Chongqing 401336,China

2Department of Neurology,Chongqing Armed Corps Police Hospital,Chongqing 400061,China

3Medical Team,Unit 78526 of Chinese PLA,Leshan 614100,Sichuan,China
Corresponding author:LU Xing?chen(Email:410484527@qq.com)

Acute ischemic stroke which has the high mobidity,disability rate and mortality is one of the most serious diseases threatening mankind.Endovascular therapy is difinite.Slection of patient,therapeutic time window and device is closely associated with the prognosis.This paper reviews the issues mentioned above.

Stroke;Brain ischemia;Thrombolytic therapy;Angioplasty;Review

10.3969/j.issn.1672?6731.2017.09.013

401336重慶市東南醫(yī)院神經(jīng)外科（林育意）；400061武警重慶總隊(duì)醫(yī)院神經(jīng)內(nèi)科（譚靜）；614100樂(lè)山，解放軍78526部隊(duì)衛(wèi)生隊(duì)（路星辰）

路星辰（Email：410484527@qq.com）

2017?08?21）