(특별기고).hwp

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1 특별기고 홍근식고상배 a 유경호 b 정철규 c 박석규 d 김병문 e 장철훈 f 배희준 g 허지회 h 오창완 i 이병철 b 김범태 j 김범수 k 정진상 l 윤병우 a 나정호 m 인제대학교의과대학신경과학교실, 서울대학교의과대학신경과학교실 a, 한림대학교의과대학신경과학교실 b, 서울대학교의과대학분당병원영상의학교실 c, 순천향대학교의과대학신경외과학교실 d, 연세대학교의과대학영상의학교실 e, 영남대학교의과대학신경외과학교실 f, 서울대학교의과대학분당병원신경과학교실 g, 연세대학교의과대학신경과학교실 h, 서울대학교의과대학분당병원신경외과학교실 i, 순천향대학교의과대학부천병원신경외과학교실 j, 가톨릭대학교의과대학영상의학교실 k, 성균관대학교의과대학신경과학교실 l, 인하대학교의과대학신경과학교실 m Update of the Korean Clinical Practice Guidelines for Endovascular Recanalization Therapy in Patients with Acute Ischemic Stroke Keun-Sik Hong, MD, Sang-Bae Ko, MD a, Kyung-Ho Yu, MD b, Cheolkyu Jung, MD c, Sukh Que Park, MD d, Byung Moon Kim, MD e, Chul-Hoon Chang, MD f, Hee-Joon Bae, MD g, Ji Hoe Heo, MD h, Chang Wan Oh, MD i, Byung-Chul Lee, MD b, Bum-Tae Kim, MD j, Bum-soo Kim, MD k, Chin-Sang Chung, MD l, Byung-Woo Yoon, MD a, Joung-Ho Rha, MD m Department of Neurology, Inje University Ilsan Paik Hospital, Goyang, Korea Department of Neurology, Seoul National University College of Medicine, Seoul, Korea a Department of Neurology, Hallym University College of Medicine, Anyang, Korea b Department of Radiology, Seoul National University Bundang Hospital, Seongnam, Korea c Department of Neurosurgery, Soonchunhyang University Seoul Hospital, Soonchunhyang University, Seoul, Korea d Department of Radiology, Yonsei University College of Medicine, Seoul, Korea e Department of Neurosurgery, Yeungnam University School of Medicine, Daegu, Korea f Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Korea g Department of Neurology, Yonsei University College of Medicine, Seoul, Korea h Department of Neurosurgery, Seoul National University Bundang Hospital, Seongnam, Korea i Department of Neurosurgery, Soonchunhyang University, Bucheon Hospital, Bucheon, Korea j Department of Radiology, Seoul St.Mary s Hospital, The Catholic University of Korea, Seoul, Korea k Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea l Department of Neurology, Inha University College of Medicine, Incheon, Korea m Received June 16, 2016 Revised July 21, 2016 Accepted July 21, 2016 Address for correspondence: Joung-Ho Rha, MD Department of Neurology, Inha University Hospital, Inha University College of Medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Korea Tel: Fax: jhrha@inha.ac.kr 이진료지침은 Journal of Stroke (2016 년, 18 권 1 호, ) 에영문으로게재된진료지침의한글판으로연관분야에종사하는독자들에게진료지침의내용을한글로전달할목적으로 Journal of Stroke 와대한신경과학회지편집위원회승인을얻어영문판 2 차출판한것임. 독자의이해를돕기위해영문판진료지침을그대로번역하기보다는영문판진료지침과진료지침애플리케이션 ( 뇌졸중진료지침 app: android 와 IOS version 으로제공됨 ) 의내용을종합하여일부내용을추가하였고부분적으로내용의배열을변경하였으나, 권고사항이나주요내용의변경은없음을밝혀둔다. 본진료지침을인용할때는 1 차출판한영문판진료지침 (Update of the Korean Clinical Practice Guidelines for Endovascular Recanalization Therapy in Patients with Acute Ischemic Stroke. J Stroke Jan;18(1): ) 을인용하여야한다. J Korean Neurol Assoc Volume 34 No. 4,

2 홍근식고상배유경호정철규박석규김병문장철훈배희준허지회오창완이병철김범태김범수정진상윤병우나정호 Patients with severe stroke due to acute large cerebral artery occlusion are likely to be severely disabled or die if reperfusion is not achieved in a timely manner. Intravenous tissue plasminogen activator (IV-TPA) administered within 4.5 hours after stroke onset was previously the only proven therapy, but IV-TPA alone does not sufficiently improve the outcome of patients with acute large artery occlusion. With the introduction of the advanced endovascular therapy that enables faster and more successful recanalization, recent randomized trials consecutively and consistently demonstrated the benefit of adding endovascular recanalization therapy (ERT) to IV-TPA. Accordingly, to update the recommendations, we assembled members of a writing committee appointed by the Korean Stroke Society, the Korean Society of Interventional Neuroradiology, and the Society of Korean Endovascular Neurosurgeons. The writing committee revised recommendations based on a review of the accumulated evidence, and a formal consensus was achieved by convening a panel of 34 experts from the participating academic societies. The current guideline provides evidence-based recommendations for ERT in patients with acute large cerebral artery occlusion regarding patient selection, treatment modalities, neuroimaging evaluation, and system organization. J Korean Neurol Assoc 34(4): , 2016 Key Words: Guidelines, Acute ischemic stroke, Large cerebral artery occlusion, Thrombolysis, Reperfusion, Endovascular recanalization therapy 이전까지는급성허혈뇌졸중환자에서무작위배정임상시험으로효과가입증된유일한혈전용해술치료는 4.5시간이내정맥내조직플라스미노겐활성제 (intravenous recombinant tissue plasminogen activator, IV-TPA) 투여였다. 1-3 그러나큰뇌동맥폐색으로인한중증허혈뇌졸중환자는 IV-TPA투여만으로는혈관재개통률이낮아많은환자들이중증장애를가지거나사망하였다. 혈관내재개통치료 (endovascular recanalization therapy, ERT) 는혈관조영술을이용하여막힌혈관을뚫고혈류를재개통시켜환자의예후를호전시킬수있을것으로기대되었으며, PROlyse in Acute Cerebral Thromboembolism (PROACT) II 3상임상시험과메타분석에서혈전용해술을받지않는경우에비해 ERT를받은환자의예후가개선되었고, 비록증상성뇌출혈은증가하였지만사망률은증가하지않았다. 4,5 그러나초기 ERT 방법을사용한임상시험에서 ERT를 IV-TPA 에추가하거나또는단독으로시행한경우 IV-TPA 단독치료에비해환자의예후를개선시키지못하였다. 6-8 하지만, 실패한임상시험들은 1) 무작위배정전모든환자에서큰동맥폐색을확인하지않았거나, 2) 치료시작이늦었거나, 또는 3) 재개통률이낮고시간이오래걸리는 ERT 방법을사용한문제점이있었다. 스텐트를이용한혈전제거술 (stent-retriever thrombectomy) 과치료효과가좋을대상환자를선별하는뇌영상기법이발전하면서, 2014년후반처음으로 Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN) 임상시험이 ERT 효과를입증하였고, 이후 4개임상시험도연속적으로 ERT 효과를입증하여급성큰뇌동맥폐색으로인한중증허혈뇌졸중환자의치료에획기적변화를가져오게되었다 스텐트를이용하여혈전을제거한 5개임상시험은 1) 스텐트혈전제거술을이용하여혈관재개통성공률과속도를향상시켰고, 2) 발전된뇌영상기법및비침습적혈관조영술로적절한환자를선별하였으며, 3) 빨리 ERT를시행할수있는응급진료체계를정착하였기때문에 ERT 효과를성공적으로증명할수있었다. 2012년 12월혈전용해술에대한진료지침이개정된이후 14 급성큰뇌동맥폐색으로인한중증허혈뇌졸중환자의진료에중대한영향을미칠수있는주요근거들이발표되었기때문에, 대한뇌졸중학회, 대한뇌혈관내수술학회, 대한신경중재치료의학회 3개학회에서추천받은 34명의전문가들이근거를정리하고고찰한후권고안에대한합의를이루어진료지침을개정하게되었다. 15 기존의국내진료지침권고사항 년에발표되었던동맥내혈전용해술진료지침의권고사항은다음과같다. 1. 동맥내혈전용해술은 6시간이내에발생한중대뇌동맥이나내경동맥폐색환자중정맥내혈전용해술치료의적응증이되지않거나최근수술등으로금기인환자를대상으로고려할수있다. ( 근거수준 Ia, 권고수준 A)-근거수준및권고수준개정 2. 동맥내혈전용해술을시행하는기관은뇌혈관조영장비가즉각적으로사용가능해야하며훈련받은중재시술전문가가있어야한다. 각기관은동맥내혈전용해술을시행하는의사의기준을마련하도록노력해야한다. (GPP)-근거수준및권고수준개정 3. 뇌기저동맥 (basilar artery) 폐색과같은뒤순환계뇌졸중환자에서동맥내혈전용해술을기관내기준에따라치료방법으로사 298 대한신경과학회지제 34 권제 4 호, 2016

3 용할수있다. ( 근거수준 III, 권고수준 B)-근거수준및권고수준개정 4. 정맥내혈전용해술이가능하면우선시행하고, 반응이없는경우추가적으로동맥내혈전용해술을시도할수있다. ( 근거수준 III, 권고수준 B)-추가 5. 물리적혈전용해술은 8시간이내에발생한주요동맥폐색허혈뇌졸중환자에서시행할수있다. 기구선택은 stent retriever 계열을우선고려할수있으며, 환자의상태에따라시행자가결정할수있다. ( 근거수준 Ib, 권고수준 A)-추가진료지침집필진조직대한뇌졸중학회의임상진료지침위원회는대한뇌졸중학회, 대한신경중재치료의학회, 그리고대한뇌혈관내수술학회에서추천받은전문가들로진료지침집필진을구성하였다. 위배정임상시험, 2) 치료군에서 ERT 시행, 3) 대조군은 IV-TPA 를포함한당시대표준치료시행, 그리고 4) 90일또는연구기간종료시수정 Rankin 척도 (modified Rankin Scale, mrs) 가보고된경우였다. 문헌검색과검토를통해 15개논문을선정하였고, 총 2,899명환자 (ERT군 1,575명 ; 대조군 1,324명 ) 자료를분석하였다. 각논문의질은 Cochrane 그룹에서권고하는비뚤림위험 (risk of bias) 5개항목을평가하였다. 16 두명의집필진 ( 고상배, 홍근식 ) 이자료를추출하고결과를서로비교하였고, 이견이있는경우다른두명의집필진 ( 유경호, 나정호 ) 과상의후합의를이루었다. 추출된자료를바탕으로다양한임상결과에대한 ERT 효과의통합추정값 (pooled estimate) 을산출하여, 자세한방법론과결과를별도의메타분석논문으로발표하였다. 17 추가적으로해외주요학회에서발표한진료지침을검토하였고, 년 5월이후추가적으로발표된미국뇌졸중학회의진료지침도검토하여필요한내용을본진료지침에반영하였다. 21 근거논문검색및분석 근거수준과권고수준 진료지침개정을위한근거들을고찰하고정리하기위해 1998 년 1월부터 20015년 5월까지 Pubmed와 EMBASE에발표된문헌들을검색하여 ( 검색어 : [ischemic stroke] and [intra-arterial and thrombolysis or thrombectomy]with restriction to humans and clinical trials) 체계적문헌고찰을시행하였다. 그외에선정된논문들의참고문헌과집필진들의검토를통해제외된문헌들이있는지확인하였다. 두명의집필진 ( 고상배, 홍근식 ) 이초록과전문을검토하여기준에부합되는논문을선정하였다. 선정기준은 1) 무작 본진료지침에서사용한근거수준과권고수준결정방식은이전진료지침과통일성을유지하기위해 1993년에발표된 US Agency for Health Care Policy and Research ( 현재는 Agency for Healthcare Research and Quality [AHRQ]) 방식을따랐다 (Table 1). 22 권고한도출, 합의, 승인이전문헌의근거를종합하여집필진이 1차권고안과진료지침 Table 1. Level of evidence and grade of recommendation LOE Ia Ib IIa IIb III IV GOR A (LOE Ia, Ib) B (LOE IIa, IIb, III) C (LOE IV) Evidence obtained from meta-analysis of randomized controlled trials Evidence obtained from at least one randomized controlled trial Evidence obtained from at least one well-designed controlled study without randomization Evidence obtained from at least one other type of well-designed quasi-experimental study Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities Required-at least one randomized controlled trial as part of the body of literature of overall good quality and consistency addressing specific recommendation Required-availability of well conducted clinical studies but no randomized clinical trials on the topic of recommendation Required-evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. This grade indicates absence clinical of directly applicable studies of good quality Recommended best practice based on the clinical experience of the guideline development group GPP LOE; level of evidence, GOR; grade of recommendation, GPP; good practice points. J Korean Neurol Assoc Volume 34 No. 4,

4 홍근식고상배유경호정철규박석규김병문장철훈배희준허지회오창완이병철김범태김범수정진상윤병우나정호 을작성하였다. 집필진이제안한권고안에대한공식적합의를위해 3개학회 42명전문가 ( 대한뇌졸중학회 20명, 대한신경중재치료학회 11명, 대한혈관내수술학회 11명 ) 를초청하여패널을구성하였고, Delphi 방법을이용하여권고안에대한합의과정을진행하였다. 참여한전문가들은개별적으로집필진이제안한 20개권고안에대해 RAND Corporation 에서제안한 9점척도를이용하여평가를하였고동의하지않는경우에는그이유를제시하였다 : 동의 (7-9점), 불분명함 (4-6점), 동의하지않음 (1-3점). 23 참여한전문가들중 75% 이상이동의한권고안은합의가이루어진것으로정의하였다. 동의율이 75% 미만인권고안은전문가들의견을반영한수정권고안을작성하여 2차 Delphi round를실시하였다. 2차 Delphi round에서는다른전문가들의동의유무와의견을익명으로모든참여자에게제공하였다. 초청된 42명전문가중, 43명 (81%) 이 Delphi round에참여하였 다 (Supplementary Table 1). 1차 Delphi round에서 18개권고안에대한합의가이루어졌다. 합의에도달하지못한 2개권고안의동의율은각각 68% 와 71% 였고, 수정된권고안에대한 2차 Delphi round에서동의율은각각 100% 와 96% 였다 (Supplementary Table 2). 집필진은합의된권고안으로진료지침최종원고를작성하여, 참여한학회의승인을얻어 Journal of Stroke에출판하였다. 15 근거 1998년이후시행된 15개임상시험과메타분석을 Table 2에정리하였다 년 12월이전의근거 (Table 2) PROACT는첫 2상 ERT 임상시험으로, 중대뇌동맥 M1 또는 Table 2. Characteristics and results of 15 RCTs and 2 meta-analyses testing ERT in acute ischemic stroke Trial PROACT PROACT II Keris et al 25 Ducrocq et al 39 Macleod et al 26 MELT Publication year Participants (n) Age (year) Female (%) Baseline NIHSS (active/control) 17/19 17/17 25/26 23/18 14/14 Time window (hr) LAO confirmation (%) ICA/M1 occlusion (%) 2.5/52.5 / / /40.7 (active arm only) (active arm only) Onset to randomization/groin puncture/first reperfusion (min) BA or VA occlusion 0/71.0 /276/ //318 //229 //324 // //227 Active arm IA pro-uk IA pro-uk TPA (IA+IV) IA UK IA UK IA UK Control arm placebo placebo none IV UK none none IV-TPA (active/control), (%) 0/0 0/0 100/0 0/0 0/0 0/0 ERT performed in active arm (%) Stent-Retriever in active arm (%) mtici 2b-3 in active arm (%) Outcome assessment (days) mrs 0-2: active vs. control (%) mrs 0-1: active vs. control (%) 30.8 vs p= vs p= vs p= vs p= vs vs (0.70, 50.0), 1.54 (0.73, 3.23), p=0.28 p= vs vs. 22.8, 2.46 (1.09, 5.54), p=0.045 Shift analysis, Mortality: active vs. control (%) mrs 5-6: active vs. control (%) SICH: active vs. control (%) 26.9 vs p= vs p= vs p= vs vs. 1.9 p= vs vs vs p= vs. 0.0 p= vs vs vs vs. 3.5 p= vs vs. 1.8 p= 대한신경과학회지제 34 권제 4 호, 2016

5 M2 폐색 40명환자를대상으로 6시간이내에동맥으로 6 mg recombinant prourokinase (pro-uk) 투여군 (26명) 과위약투여군 (14명) 을비교하였다. Pro-UK 군에서부분적또는완전한혈관재개통률이높았으며 (57.7% vs. 14.3%; 2p=0.017), 증상성뇌출혈은유의하게증가하지않다 (15.4% vs. 7.1%, 2p=0.64). 24 PROACT에이어첫 3상임상시험인 PROACT II는 6시간이내치료를시작할수있는중대뇌동맥폐색 180명환자를대상으로 pro-uk 9 mg 치료군 (121명) 과위약군 (59명) 을비교하였다. PROACT와 PROACT II연구에서는카테터를이용한기계적혈전파괴를허용하지않았다. Pro-UK군에서치료 2시간후혈관재개통률이높았고 (66% vs. 18%, p<0.001), 일차결과변수인 90일 mrs 0-2점분율도높았으나 (40% vs. 25%, p=0.04), 이차결과변수인 mrs 0-1점분율은차이가없었다 (26% vs. 17%, p=0.16). 치료 24시간이내증상뇌출혈은 pro-uk군에서증가하는경향을보였지만 (10% vs. 2%, p=0.06), 90일사망률은비슷하였다 (25% vs. 27%, p=0.80). 그러나미국식약청이허가를위한추가적인임상시험을요구하여개발이중단되었다. 4 PROACT II 이후 2001년에서 2007년사이에 ERT군과혈전용해술비치료군을비교한소규모또는조기중단된임상시험이있었다 그중 Middle cerebral artery Embolism Local fibrinolytic Table 2. Characteristics and results of 15 RCTs and 2 meta-analyses testing ERT in acute ischemic stroke-continued Trial SYNTHESIS pilot SYNTHESIS- Expansion MR RESCUE IMS III MR CLEAN ESCAPE Publication year Participants (n) Age (year) Female (%) Baseline NIHSS (active/control) 17/16 13/ / /16 17/18 16/17 Time window (hr) LAO confirmation (%) ICA/M1 occlusion (%) / / 16.9/ / / /68.6 (active arm only) Onset to randomization/groin puncture/first reperfusion (min) 125// // /381/ 146/208/ /260/ 170/185/241 Active arm ERT only ERT only ERT with standard care ERT with IV-TPA ERT with standard care ERT with standard care Control arm IV-TPA IV-TPA standard care IV-TPA standard care standard care IV-TPA (active/control), (%) 0/96.6 0/ / / / /78.7 ERT performed in active arm, (%) Stent-Retriever in active arm, (%) mtici 2b-3 in active arm, (%) Outcome assessment (days) mrs 0-2: active vs. control (%) mrs 0-1: active vs. control (%) Shift analysis, Mortality: active vs. control (%) mrs 5-6: active vs. control (%) SICH: active vs. control (%) 56.0 vs vs (0.9, 11.4), p= vs vs (0.44, 1.14), p= vs vs vs Absolute difference, 1.5% ( 6.1 to 9.1) 29.4 vs vs (1.39, 3.38) 11.6 vs (1.07, 4.02) 53.0 vs (1.3, 2.2), p< vs p=0.99 p= (1.21, 2.30) 3.1 (2.0, 4.7), p< vs No difference, p value not provided 24.0 vs vs (0.1, 3.3), p= vs. 9.9 p= vs vs. 5.5 p= vs No difference, p value not provided 42.2 vs vs. 3.7 No difference, p value not provided 20.0 vs p= vs vs. 5.9 p= vs No difference, p value not provided 27.0 vs vs. 6.4 No difference, p value not provided 10.4 vs (0.3, 0.8), p= vs vs (0.3 to 4.6) p=non-significant J Korean Neurol Assoc Volume 34 No. 4,

6 홍근식고상배유경호정철규박석규김병문장철훈배희준허지회오창완이병철김범태김범수정진상윤병우나정호 intervention Trial (MELT) 는 6시간이내중대뇌동맥폐색 114명환자를대상으로 ERT군 ( 동맥내 urokinase 투여및카테터를이용한기계적혈전파괴 ) 과위약군을비교하였다. 일차결과변수인 mrs 0-2점분율은차이가없었으나 (49.1% vs. 38.6%, p=0.345), ERT군에서 mrs 0-1점분율 (42.1% vs. 22.8%, p=0.045) 과 NIH 뇌졸중척도 (National Institute of Health Stroke Scale, NIHSS) 0-1점분율이유의하게높았다 (35.1% vs. 14.0%, p=0.017) 년에서 2009년사이에발표된 ERT와비혈전용해술치료를비교한 5개임상시험 (395명환자) 메타분석에서, ERT는혈관재개통을증가시키고 (Thrombolysis in Myocardial Ischemia [TIMI] grade 2-3: odds ratio [OR] [95% CI], 6.42 [ ]; p< ), Table 2. Characteristics and results of 15 RCTs and 2 meta-analyses testing ERT in acute ischemic stroke-continued Trial EXTEND-IA SWIFT PRIME REVASCAT Meta-analysis Lee et al 5 Meta-analysis Hong et al 15 Publication year Participants (n) (5 RCTs) 2899 (15 RCTs) Age (year) Female (%) Baseline NIHSS (active/control) 17/13 17/17 17/17 Time window (hr) LAO confirmation (%) ICA/M1 occlusion (%) 31.4/ / /63.6 Onset to randomization/groin 169/210/ 185/224/ /269/355 puncture/first reperfusion (min) Active arm ERT with IV-TPA ERT with IV-TPA ERT with standard ERT ERT care Control arm IV-TPA IV-TPA standard care No thrombolysis IV-TPA or no IV-TPA IV-TPA (active/control) (%) 100/ / /77.0 ERT performed in active arm (%) Stent-retriever in active arm (%) mtici 2b-3 in active arm (%) Outcome assessment (days) , 180, or , 60, or 90 mrs 0-2: active vs. control (%) mrs 0-1: active vs. control (%) Shift analysis, OR (95% CI) or p value Mortality: active vs. control (%) mrs 5-6: active vs. control (%) SICH: active vs. control (%) 71.4 vs (1.4, 12), p= vs (0.87, 6.6), p= vs (1.23, 2.33), p< vs (1.2, 3.8), p= (1.57, 4.40), p< vs (0.1, 2.1), p= vs vs. 5.7 Absolute difference: 6% ( 13, 2), p= vs (0.33, 1.68), p= vs vs. 3.1 p= vs (1.1, 4.0) 24.3 vs vs (1.33, 3.14), p= vs (1.31, 3.51), p= vs (1.34, 2.40), p< vs (1.34, 2.44), p= (1.05, 2.8) 18.4 vs (0.6, 2.2), p= vs vs (0.1, 7.0), p= vs (0.48, 1.39), p= vs (1.21, 6.83), p= vs (0.71, 1.05), p= vs (0.61, 0.97), p= vs (0.83, 1.69), p= RCTs; randomized clinical trials, IMS; interventional management of stroke, MR RESCUE; mechanical retrieval and recanalization of stroke clots using embolectomy, SYNTHESIS-Expansion; in the synthesis, a randomized controlled trial on intra-arterial versus intravenous thrombolysis in acute ischemic stroke, MR CLEAN; multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands, ESCAPE; endovascular treatment for small core and anterior circulation proximal occlusion with emphasis on minimizing CT to recanalization times, EXTEND-IA; extending the time for thrombolysis in emergency neurological deficits-intra-arterial, SWIFT PRIME; solitaire with the intention for thrombectomy as primary endovascular treatment trial, REVASCAT; revascularization with the solitaire FR device versus best medical therapy in the treatment of acute stroke due to anterior circulation large vessel occlusion presenting within eight hours of symptom onset. 302 대한신경과학회지제 34 권제 4 호, 2016

7 mrs 0-2점분율 (2.05 [1.33 to 3.14]; p=0.001) 과 mrs 0-1점분율 (2.14 [1.31 to 3.51]; p=0.003) 을증가시키는효과가있었고, 미미한신경계장애 (NIHSS 0-1점 ) 만남는분율과바텔지수양호군 (90-100점또는 점 ) 분율을증가시키는효과도있었다. ERT는혈전용해술치료를하지않는경우에비해증상성두개내출혈위험을증가시켰지만 (2.87 [ ]; p=0.02) 사망률을증가시키지는않았다 (0.83 [ ]; p=0.46) 년기계적혈전제거술 (mechanical thrombectomy) 효과를향상시킬수있는 MERCI 기구가개발되어, 2004년처음으로급성허혈뇌졸중환자에서혈관재개통목적으로사용할수있는기구로미국식약청의승인을받았다. 첫전향적단일군다기관임상시험에서 IV-TPA 투여금기이며, 급성큰대뇌동맥폐색으로인한중증허혈뇌졸중 141명환자를대상으로 8시간이내 MERCI 기구로치료한결과, 혈관재개통률은 48% 였다. 그러나대상환자의중증도가높았다는점을감안하더라도 90일 mrs 0-2 점분율이 22.6% 로낮았고, 사망률은 43.5% 로매우높았다. 28 Multi-MERCI (Mechanical Embolus Removal in Cerebral Ischemia) 는 80% 환자를개선된 MERCI 기구로치료한추가적연구였으며, IV-TPA 금기이거나 IV-TPA 투여후에도큰뇌동맥폐색이있는 164명환자를 8시간이내에치료하였다. 개선된 MERCI 기구결과만보면혈관재개통률이 57.3%, 추가적으로동맥 TPA를투여한경우 69.5% 였다. 그러나전체적으로 90일 mrs 0-2점분율은 36%, 그리고사망률은 34% 로만족스러운결과가아니었다. 29 동맥류코일시술에사용하던스텐트를이용하여혈전을제거한증례가보고된이후 30 stent retriever 혈전제거술이본격적으로연구되기시작하였다. Solitaire with the Intention for Thrombectomy (SWIFT) 임상시험은 113명환자를대상으로 Solitaire 기구와 MERCI 기구를비교하였는데 Solitaire를사용한경우가증상성뇌출혈을동반하지않는 TIMI 2-3 혈관재개통률이높았고 (61% vs. 24%; OR 4.87 [ ], 비열등성 p<0.0001, 우월성 p=0.0001), 90일신경학적양호상태 (mrs 0-2점, 뇌졸중전 mrs로회복, 또는 NIHSS 10 점이상개선 ) 분율도높았으며 (58% vs. 33%; OR 2.78 [ ], 비열등성 p=0.0001, 우월성 p=0.02), 사망률도낮았다 (17% vs. 38%; OR 0.34 [ ], 비열등성 p=0.0001, 우월성 p=0.02). 31 TREVO2 임상시험은 SWIFT 연구대상과비슷한 178명환자를대상으로다른종류의 stent retriever인 Trevo 기구를이용하여 MERCI 기구와비교하였는데, 마찬가지로 Trevo를사용한경우가 TIMI 2-3 혈관재개통률이높았고 (86% vs. 24%; OR 4.22 [ ], 비열등성및우월성 p<0.0001), 90일 mrs 0-2점분율도높 았으며 (40% vs. 22%; OR 2.39 [ ], p=0.013), 사망률은차이가없었다 (33% vs. 24%; OR 1.61 [ ], p=0.1845). 32 그외에연구들로 8시간이내환자를 Penumbra aspiration 기구를이용하여 % 의높은혈관재개통률을보고하였으나대조군과비교한연구는없었다. 33,34 BASICS(Basilar Artery International Cooperation Study) 은급성기저동맥폐색환자중항혈전제치료군 183명, IV-TPA 치료군 121명, 그리고 ERT 치료군 288명에대한예후를비교한관찰연구였는데, 347명중증허혈뇌졸중환자에서는항혈전제에비하여 IV-TPA(adjusted RR 0 88, ) 와 ERT (adjusted RR 0.94, ) 가매우불량한예후인 mrs 4-6점분율을감소시키는경향을보였으나, IV-TPA와 ERT를비교하였을때에는차이가없었다 (adjusted RR 1.06, ) 년 12월이후의근거 (Table 2) ERT는혈관재개통률을증가시킬수있으나치료를시작하는데시간이걸린다. 따라서 IV-TPA 투여를시작한후 ERT를실시하는, 즉빨리치료를시작하면서혈관재개통률을높이기위한연구들이진행되었다. 2004년에서 2012년사이에 IV-TPA 치료를위주로하는표준치료와 ERT를비교한 3개의주요 3상임상시험인 Interventional Management of Stroke (IMS) III, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), 그리고 In the Synthesis: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic Stroke (SYNTHESIS-Expansion) 이진행되었으나모두 ERT 효과를증명하는데실패하였다. 6-8 대표적임상시험인 IMS III는 2001년과 2006년사이에수행되었던 IMS I/II 연구결과를바탕으로계획되었다. 36,37 IMS III는 3 시간이내내원한중등도이상신경계장애 (NIHSS 10점이상또는 CT 혈관조영술에서중대뇌동맥 M1, 내경동맥, 또는기저동맥폐색 ) 를가진 656명환자를대상으로 ERT군 (IV-TPA 와 ERT 병합치료 ) 과 IV-TPA 단독치료군을비교하였다. 일차결과변수인 90일 mrs 0-2점분율이 ERT군 40.8%, IV-TPA군 38.7% (absolute risk reduction, 1.5% [-6.1 to 9.1]) 로차이가없었다. NIHSS 중증도, 연령, 폐색부위, 그리고치료시작시간등사전에계획한아집단분석 (subgroup analysis) 에서도두치료는차이가없었다. 증상성뇌출혈 (6.2% vs. 5.9%, p=0.83) 과사망률 (19.1% vs. 21.6%, p=0.52) 도차이가없었다. 6 MR RESCUE 는 MRI로확산관류불일치 (perfusion-diffusion mismatch) 를평가하여뇌허혈반음영 (penumbra) 이있는환자를선 J Korean Neurol Assoc Volume 34 No. 4,

8 홍근식고상배유경호정철규박석규김병문장철훈배희준허지회오창완이병철김범태김범수정진상윤병우나정호 별하여 MERCI 기구를이용한 ERT를표준치료에추가하여예후를향상시킬수있는지평가하기위한연구였다. 증상발생 8시간이내급성큰뇌동맥폐색이있고중등도이상신경계장애를보이는환자를뇌허혈반음영이있는환자와없는환자로나누어표준치료와 ERT를추가한치료를비교하였다. 전체 118명의환자중 44명 (37%) 환자는 IV-TPA 치료를받았다. 기대와달리뇌허혈반음영존재유무에상관없이 MERCI 기구를이용한 ERT는표준치료에비해환자의예후를개선시키지못했고, 증상성뇌출혈과사망률도차이가없었다. 8 SYNTHESIS-Expansion 은 SYNTHESIS-pilot 연구에서치료시작이늦어지더라도 ERT 단독치료가 IV-TPA에비해증상성뇌출혈을증가시키지않으면서예후를개선시키는경향을보여시행하였던 3상임상시험이다. 7,38 증상발생 4.5시간이내 362명환자를대상으로 ERT 단독치료와 IV-TPA 치료를비교하였으며 ERT군으로배정된경우에는 IV-TPA 치료를하지않았기때문에치료시작시간이약 1시간늦어졌다. 일차결과변수인 90일 mrs 0-1점분율, 7일이내증상성뇌출혈, 그리고사망률도두치료군에서차이가없었다. SYNTHESIS-pilot 연구결과와달리통계적으로유의하지는않았지만 mrs 0-1점분율은 ERT군에서 IV-TPA 군에비해오히려낮았다 (30.4% vs. 34.8%; OR [95% CI], 0.71 [ ]; p=0.16). 7 실패한 IMS III, MR RESCUE, 그리고 SYNTHESIS-Expansion 임상시험은대부분환자에서혈관재개통률이낮고, 시간도오래걸리는기구를사용하여 ERT를시행한공통점이있다. 또한 IMS III와 SYNTHESIS-Expansion에서는큰뇌동맥폐색을확인하지않고무작위배정을하였기때문에큰뇌동맥폐색이없는환자들이포함되어 IV-TPA에대한 ERT의상대적효과를희석시킨문제점이있었다. MR RESCUE 는뇌졸중발생 5.5시간이지난후무작위배정이이루어져치료시작이늦었으며, 확산자기공명영상에서큰병변이있어혈관재개통의효과가낮을환자도포함한단점이있다. 이전임상시험의실패요인을보완하여 2010년에서 2013년사이에급성앞순환큰뇌동맥폐색환자를대상으로 5개임상시험이진행되었고, ERT의효과를증명하여 2014년과 2015년에그결과를발표하였다 개임상시험의특징은 1) 대부분환자에서혈관재개통률효과가개선된 stent-retriever 기구를사용하였고, 2) 무작위배정전큰뇌동맥폐색을모든환자에서확인하였으며, 3) 대부분임상시험이경색중심부 (infarct core), 뇌허혈반음영, 또는곁순환 (collateral circulation) 을평가하여혈관재개통으로인한효과가기대되는환자를선별했다는점, 그리고 4) 빨리 ERT를시행할수있는시스템을도입하였다는것이다. MR CLEAN 은처음으로 IV-TPA와비교하여 ERT 효과를증명한임상시험이다. 9 6시간이내치료가가능한앞순환큰뇌동맥폐색환자중 NIHSS가 2점이상이면연구자가판단하여등록하였고, 다른 stent-retriever 임상시험과달리경색중심부, 뇌허혈반음영, 또는곁순환에대한제한기준을두지않은실용주의적임상시험 (pragmatic trial) 이었다. 최근시행된 5개임상시험중가장많은환자인 500명을등록하였는데, 환자들의 NIHSS 중앙값은 17.5점이었고, 약 90% 환자가 IV-TPA 치료를받았다. 일차결과변수인 90일 mrs 분포가 ERT군에서표준치료군에비해향상되었으며 (OR 1.67 [ ]), mrs 0-2점분율도 ERT군에서높았다 (32.6% vs. 19.1%; 2.16 [1.39, 3.38]). 증상성뇌출혈과 90일사망률은두군에차이가없었다. Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times (ESCAPE) 는 12시간이내치료가가능한 500명환자를모집할계획하였으나, MR CLEAN 결과가발표된후 315명환자에대한중간분석을실시하여 ERT 효과를확인하고조기종료하였다. 10 대상환자의 NIHSS 중앙값은 16.5점이었고, 6 시간이내치료한환자는 84.5%, 12시간이내에치료한환자는 15.5% 였다. 전체환자의약 75% 가 IV-TPA 치료를받았다. 일차결과변수인 90일 mrs 분포가 ERT군에서표준치료군에비해유의하게개선되었고 (adjusted OR 3.1 [ ]; p<0.001), mrs 0-2 점분율도 ERT군에서높았다 (53.0% vs. 29.3%; 1.7 [ ]; p<0.001) 증상성뇌출혈은두군에서차이가없었으며, 90일사망률이 ERT군에서유의하게낮았다 (10.4% vs. 19.0%; 0.5 [ ]; p=0.04). ESCAPE 은 ERT로사망률이감소한유일한연구이다. ESCAPE 특징은 Alberta Stroke Program Early CT Score (ASPECTS) 평가에서경색중심부크기가작고, 다중시기 (multiphase) CT에서곁순환이좋은환자를선별하였으며, 병원도착후치료시작까지걸리는시간을단축하기위한노력을통하여 CT 검사부터첫혈관재개통시도까지단 84분 ( 중앙값 ) 만이소요되었다. Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA) 는 6시간이내 ERT를시작할수있는환자중영상자료처리소프트웨어를이용하여경색중심부가작고뇌허혈반음영을가진환자를선별하였다 명환자를모집하였는데, NIHSS가 ERT군은 17점표준치료군은 13점이었고 100% 환자가 IV-TPA치료를받았다. 표준치료군에비해 ERT군에서일차결과변수인 24시간재관류율 (100% vs. 37%; 4.7 [ ]; p<0.001) 과 3일후 NIHSS 8점이상개선또는 0-1점분율 (80% vs. 37%; 6.0 [ ]: p=0.002) 이유의하게증가하였 304 대한신경과학회지제 34 권제 4 호, 2016

9 다. ERT군에서 90일 mrs 분포와 (2.0 [ ]; p=0.006) mrs 0-2점분율 (71% vs. 40%; 4.2 [1.4-12]; p=0.01) 도유의하게향상되었다. 증상성뇌출혈 (0% vs. 5.7%; p=0.49) 과사망률 (8.6% vs. 20.0%; 0.45 [ ]; p=0.31) 이 ERT군에서낮았으나환자수가적어서통계적인유의성은없었다. EXTEND-IA는다른연구에비해예후가가장좋았는데, 이는 ERT의효과가아주좋을환자를제한적으로선별하였기때문이고, 70명이라는적은수를모집하고도 ERT 효과를증명할수있었다. 그러나너무제한된기준으로환자를선정하였기때문에실제임상진료에서 EXTEND-IA 기준으로대상환자를선별하는경우치료효과가있을환자들이많이배제될수있는문제점도있다. Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment Trial (SWIFT PRIME) 는 6시간이내 ERT 치료가가능한환자중 ASPECTS 또는 CT 관류영상을이용하여경색중심부크기가적은환자들을선별하였다. MR CLEAN 과 ESCAPE결과가발표되어 196명에대한중간분석을실시하여 ERT 효과를확인하고조기종료하였다. 13 대상환자의 NIHSS는 17 점이었고 ERT군과표준치료군에배정된모든환자가 IV-TPA치료를받았다. ERT군에서일차결과변수인 90일 mrs 분포가유의하게개선되었고 (2.63 [ ]; p<0.001), mrs 0-2점분율도증가하였다 (60.2% vs. 35.5%; 1.70 [ ]; p<0.001). 증상성뇌출혈 (0% vs. 3.1%; p=0.12) 과 90일사망률 (9.2% vs. 12.4%; 0.74 [ ]; p=0.50) 은두군에서차이가없었다. SWIFT PRIME 도치료과정을단축시켜병원도착후혈관조영술시작까지걸린시간이평균 90분이었다. Revascularization With the Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset (REVASCAT) 은 690명을모집할예정이었는데다른연구에서 ERT 효과가뚜렷하여 206명만모집하고조기종료하였다. 8시간이내치료시작이가능하며, CT/MRI 에서 ASPECTS가 7/6 이하로경색중심부크기가작고, IV-TPA 치료시작후 30분이내호전이없는환자를무작위배정하였다. 대상환자의 NIHSS는 17점이었고 ERT군 68%, 표준치료군 77% 가 IV-TPA 치료를받았다. ERT군에서일차결과변수인 90일 mrs 분포가유의하게개선되었으며 (1.7 [ ]), mrs 0-2점분율도유의하게증가하였다 (43.7% vs. 28.2%; 2.1 [ ]). 증상성뇌출혈 (1.9% vs. 1.9%; p=1.00) 과 90일사망률 (18.4% vs. 15.5%; p=0.60) 은두군에서차이가없었다. 3. ERT 임상시험요약및메타분석 17 1) 1998년이후 ERT와표준치료를비교한임상시험 (Table 2) 1998년부터 15개임상시험 (ERT군 1,575명, 표준치료군 1,324 명 ) 이시행되었는데, 6개임상시험에서는비혈전용해술을, 4,24-27,39 그리고 9개임상시험은 IV-TPA( %) 를 6-13,38 표준치료로사용하였다. 메타분석결과, 표준치료에비해 ERT군에서 mrs 0-2 점분율 (pooled OR [95% CI], 1.79 [1.34, 2.40]; p<0.0001; number needed-to-treat [NNT]=9), mrs 0-1점분율 (1.81 [1.34, 2.44]; p=0.0001; NNT=11), 양호한신경학적회복분율 (3.11 [2.14, 4.53]; p<0.0001; NNT=6), 양호한일상생활수행능력 (activity of daily living, ADL) 분율 (2.24 [1.78, 2.82]; p<0.0001; NNT=5), 그리고혈관의부분또는완전개통률 (4.50 [1.97, 10.27]; p=0.0003; NNT=3) 이증가하였다. 증상성뇌출혈발생률 (1.19 [0.83, 1.69]; p=0.8695) 과 90일째사망률 (0.87 [0.71, 1.05]; p=0.1508; NNT=55) 은차이가없었다. 그러나중증장애가남거나사망하는 mrs 5-6점분율은 ERT군에서유의하게감소하였다 (0.77 [0.61, 0.97]; p=0.0246; NNT=21). 17 2) Stent-retriever ERT 와 IV-TPA 를비교한임상시험 (Table 2) 5개 stent-retriever 임상시험 (ERT군 633명, IV-TPA군 645명 ) 에서 90일 mrs 0-2점분율은 ERT군에서는 32.6% 에서 71.4% 였으며, IV-TPA군에서는 19.1% 에서 40% 였다 임상시험에따라 90일 mrs 0-2점에대한 NNT는 3-7명이었으며, mrs 분포를 1점이상개선시키기위한 NNT는 명이었다. 증상성뇌출혈발생률은 ERT군에서는 0-7.7%, IV-TPA군에서는 % 였으며, 모든임상시험에서 ERT군에서증상성뇌출혈발생이유의하게증가하지않았다. ESCAPE 에서는 ERT군의 90일사망률이유의하게낮았지만, 10 다른 4개임상시험에서는 ERT군의사망률이낮았지만통계적유의성은없었다. 9, 개 stent-retriever 임상시험을메타분석하면 17, IV-TPA군에비해 ERT군에서 mrs 0-2점분율 (pooled OR [95% CI]; 2.39 [1.88, 3.04]; p<0.0001; NNT=5), mrs 0-1점분율 (2.49 [1.85, 3.36]; p<0.0001; NNT=7), 양호한신경학적회복분율 (3.62 [2.26, 5.78]; p<0.0001; NNT=4), 양호한일상생활수행능력분율 (2.53 [1.83, 3.52]; p<0.0001; NNT=5), 그리고혈관의부분또는완전개통률 (5.68 [3.09, 10.45]; p<0.0001; NNT=3) 이증가하였다. 증상성뇌출혈은양군에서차이가없었다 (1.08 [0.61, 1.88]; p=0.7983). ERT군에서 90일사망률이유의하게감소하지는않았으나 (0.78 [0.54, 1.12]; p=0.1770; NNT=29), mrs 5-6점분율은유의하게 J Korean Neurol Assoc Volume 34 No. 4,

10 홍근식고상배유경호정철규박석규김병문장철훈배희준허지회오창완이병철김범태김범수정진상윤병우나정호 감소하였다 (0.57 [0.41, 0.78]; p=0.0006; NNT=9). 4. 기타근거 1) ERT 치료시간범위 1998년부터시행된 15개임상시험에서증상발생후 ERT 치료시작시간은최소 3시간에서 38 최대 24시간이었는데, 26 8개임상시험은 6시간이내, 4,9,11,12,24,25,27,39 특히 stent-retriever 임상시험중 MR CLEAN, EXTEND-IA, 그리고 SWIFT PRIME은증상발생 6시간이내환자를대상으로하였다. 9,11,12 REVASCAT과 ESCAPE 은각각 8시간과 12시간이기준이었으나 REVASCAT의 90.3%, ESCAPE의 84.5% 는 6시간이내환자들이었다. 10,13 Stent-retriever 임상시험에서증상발생부터평균 4.5시간만에혈관조영술을시작하였고, 첫재개통시도는 6시간이내에이루어졌다. 2) 경색중심부, 뇌관류, 곁순환평가비조영증강 CT는가장널리사용할수있는검사로출혈뇌졸중가능성과 ERT를하였을때반응이없거나증상성뇌출혈발생위험이높은조기허혈병변이광범위한환자를배제할수있다. ESCAPE, SWIFT PRIME, 그리고 REVASCAT에서는 CT검사에서 ASPECTS 6-10점을경색중심부가작은경우로정하였다. 10,12,13 MR CLEAN 은 ASPECTS로대상환자를선별하지는않았지만 ASPECTS 0-4점환자는 5.6% 에불과하였다. 9 EXTEND-IA는관류 CT를이용하여정상에비해 30% 미만으로혈류가떨어진영역이 70 ml 이하인환자를, 11 그리고 SWIFT PRIME은 81% 환자를관류 CT를이용하여경색중심부크기가 50 ml 이하인환자를선별하였다. 곁순환이좋은환자는회생가능한뇌허혈부위가더넓어서재관류가되는경우임상적으로도호전될가능성이더높고증상성뇌출혈위험이낮은것으로알려져있다. ESCAPE 은다중시기 CT 혈관조영술을이용하여곁순환을평가하였고, 곁순환으로중대뇌동맥영역 50% 이상에혈류가공급되는환자를선별하였다. 10 3) 비침습적혈관조영술로큰동맥폐색확인중증뇌졸중환자는큰동맥폐색이있을가능성이높지만, 3시간이내내원한 NIHSS 9점이상환자 19.3% 에서는큰뇌동맥폐색이없었다. 40 최근에는대부분병원에서응급상황에서 CT 또는 MR 혈관조영술이가능하므로, 중증급성뇌졸중환자는응급으로비침습적혈관조영술을시행하여큰뇌동맥폐색을확인하는것이바람직하다. IMS III에서는전체환자 656명중무작위배정전에 47% 인 306명환자에서만 CT 또는 MR 혈관조영술을시행하였고, 42% 인 282명환자에서만큰뇌동맥폐색을확인하였다. 결과적으로 ERT군환자중 18.4% 인 80명환자에서는 ERT 시술을들어갔을때큰뇌동맥폐색이관찰되지않았다. 6 IMS III 환자중무작위배정전 CT 혈관조영술로큰뇌동맥폐색을확인하였던 220명환자만분석해보면, IV-TPA군에비하여 ERT군에서 24시간후 CT 혈관조영술에서높은혈관재개통률을보였고, 90일 mrs 분포가개선되는경향을보였다. 41 반면에 5개 stent-retriever 임상시험모두에서는무작위배정전에 CT 또는 MR 혈관조영술로큰뇌동맥폐색을확인하였는데, % 환자가경동맥폐색, 그리고 % 환자는중대뇌동맥 M1 폐색이있었다. 따라서, 중증급성뇌졸중환자에서는치료방침을결정하기위하여큰뇌동맥폐색을확인하기위한비침습적혈관조영술이필요하다. 4) ERT 방법첫 3상임상시험이었던 PROACT II는 pro-uk 동맥내투여효과를확인하기위한연구로서카테터를이용하여기계적으로혈전을파괴하는것을허용하지않았다. 4 이후혈관재개통을향상시키기위한방법들이발전하여, 초기에는 micro-guide wire 를이용한혈전파괴를하다가 MERCI 기구가개발되었고, 이후 Penumbra aspiration 기구, 그리고 stent-retriever를이용한혈전제거술로발전하였다. 두 2상임상시험에서 MERCI 기구에비해 stent-retriever를사용하는경우혈관재개통률이더높았고, 환자의예후도더좋았다. 31,32 IV-TPA에비해 ERT 단독치료효과를입증하는데실패하였던 SYNTHESIS Expansion의경우, ERT 군의 66% 환자를동맥 TPA 투여와 micro-guide wire를이용한기계적혈전파괴로치료하였고, 13.9% 환자에서만 stent-retriever를사용하였다. 7 IMS III도 ERT 군환자의 1.5% 에서만 stent-retriever를사용하였고 47.9% 는동맥 TPA 투여및 micro-guide wire를이용한기계적혈전파괴, 28.4% 는 MERCI 기구, 그리고 16.2% 는 Penumbra aspiration 기구로치료하였다. IMS III에서는 ERT군의치료직후 mtici 2b-3 재개통률이 41% 정도로높지않았다. 6 반면에, stent-retriever 임상시험에서는 ERT군의치료직후 mtici 2b-3 재개통률이 58.7% 9 에서 88.0% 로향상되었다. 따라서, 현재로서는 ERT 방법으로 stent-retriever 가가장추천된다. 5) ERT 환자에서 IV-TPA 투여 4.5시간내 IV-TPA 투여는급성큰뇌동맥폐색환자에서효과가제한적이긴하지만, 입증된치료법이다. Stent-retriever 임상시험에서 ERT군 ( to 100% 11,12 ) 과대조군 ( to 100% 11,12 ) 대부분환자에서 IV-TPA가투여되었다. Stent-retriever 임상시험에 306 대한신경과학회지제 34 권제 4 호, 2016

11 서 ERT군과대조군에서증상성뇌출혈발생에차이가없어, IV-TPA가증상성뇌출혈발생의주원인일가능성이있다. 그러나큰뇌동맥폐색환자의일부에서는 IV-TPA만으로도혈관재개통이이루어지기도하며, IV-TPA가 ERT의혈관재개통효과를상승시킬수있으며, 폐색원위부혈류를개선시킬수있다. 더구나 ERT 효과를증명하지못했던 SYNTHESIS-Expansion은 ERT군에서 IV-TPA를사용하지않았다. 7 따라서 ERT 대상환자에서적응증이되는경우 IV-TPA를사용하지않을근거가없다. Stent-retriever 임상시험중 REVASCAT은 IV-TPA 투여 30분후에도지속적으로혈관이막혀있는환자를선정하였지만, ESCAPE, EXTEND-IA, 그리고 SWIFT PRIME은 IV-TPA의효과를기다리지않고 IV-TPA 투여하는중에 ERT 시술을진행하였다 MR CLEAN의경우는 IV-TPA 반응을기다린후 ERT를실시하였는지분명하게보고하지않았다. 9 ERT 치료를빨리시작하기위해서는대부분환자에서 IV-TPA에대한반응여부를기다리지않고 ERT를시행하는것이더바람직할것으로판단된다. ERT와 IV-TPA 모두증상성뇌출혈위험을증가시킬수있으므로, 일부에서는 ERT를시행하는경우저용량 IV-TPA를사용하기도한다. IMS III도처음에는 ERT군에서 IV-TPA를용량을줄인 0.6 mg/kg을사용하였지만, 중간에프로토콜을개정하여표준용량인 0.9 mg/kg 투여로변경하였다. 6 모든 stent-retriever 임상시험에서는 ERT군과대조군모두 IV-TPA를표준용량인 0.9 mg/kg를투여하였다 따라서, 현재까지의근거는 ERT를시행하는환자에서도 IV-TPA를표준용량인 0.9 mg/kg 을사용하는것이바람직할것이다. 6) 의식하진정 (conscious sedation) 과전신마취 (general anesthesia) ERT 대상이되는중증허혈뇌졸중환자는협조가안되고심하게동요하는경우가흔하며, 이로인하여 ERT 시술중합병증이발생할위험이증가할수있다. 이런이유로병원에따라서는의식하진정보다전신마취를선호하기도한다. 그러나전신마취는 ERT 치료시작을지연시킬수있으며, 저혈압이발생하여허혈반음영부위의뇌관류압이떨어질수있고, 신경학적상태를평가할수없는단점이있다. 9개연구메타분석에서전신마취를하는경우사망률 (pooled OR [95% CI], 2.59 [1.87, 3.58]) 과호흡기합병증 (2.09 [1.36, 3.23]) 이증가하였고, 좋은예후로회복되는분율도감소하였다 (0.43 [0.35, 0.53]). 중증도가심한환자일수록전신마취를더많이사용하였을가능성도있으나, 42 뇌졸중중증도를보정한다른후향적연구에서도전신마취를한환자에서예후가나빴다 Stent-retriever 임상시험에서는 ERT군의 6.7% 13 에서 37.8% 9 의환 자들이전신마취를받았다. ERT군의 37.8% 환자들이전신마취를받은 MR CLEAN 연구의사후분석에서, 전신마취를한경우치료시작시간이지연되었고, ERT 효과가사라지는결과를보였다. 46 따라서가능하면의식하진정을시행하는것이권장된다. 7) 뒤순환큰뇌동맥폐색환자에서 ERT 뒤순환큰뇌동맥폐색으로인한중증허혈뇌졸중환자의경우도적절한시간내에혈관재개통이이루어지지않으면중증장애가남거나사망할위험이매우높다. 5개 stent-retriever 임상시험은앞순환큰뇌동맥폐색환자만을대상으로하였고, 뒤순환큰뇌동맥폐색환자만을대상으로한대규모임상시험은시행된적이없고, 앞으로도시행하기어려울것으로예상된다. 16명만모집하였던소규모임상시험에서예후양호군분율이 ERT군은 50% 였으며혈전용해술치료를하지않은군에서는 12.5% 였다 (p=0.28). 26 3개임상시험에서 % 환자가뒤순환허혈뇌졸중이었는데, 아집단분석에서 ERT 효과는유의하지않았다. 6,7,38 그러나급성기저동맥폐색환자에대한 45개관찰연구의메타분석에서 ERT를받은환자들의사망또는불량예후군 (0.67 [0.61, 0.72]) 그리고사망률 (0.48 [0.42, 0.55]) 이낮았다. 47 8) 조직체계및질향상 ERT는급성허혈뇌졸중치료중가장복잡하고많은자원이필요하여, 모든병원에서시행이가능한치료방법이아니다. 따라서지역별로 ERT를항상시행할수있는포괄적뇌졸중센터 (comprehensive stroke centers) 를설치하여, 주변의병원과연계시스템을이루는것이바람직할것이다. ERT를시행하는병원은다학제팀을구성하여 ERT 대상환자의평가, 치료방침결정, 그리고 ERT 시술모든과정이체계적이고유기적으로이루어질수있도록임상진료경로 (critical pathway) 를확립하는것이필요하다. IV-TPA 와마찬가지로 ERT에서도시간이중요하다. IMS III 자료의분석에의하면혈관재개통이빨리이루어질수록예후가좋을가능성이증가하였는데, 90일 mrs 0-2점분율이 5시간이내혈관재개통이이루어진경우 51.8% 였지만, 5-6시간이내이루어진경우는 45.4%, 그리고 6시간이후이루어진경우에는 26.5% 로감소하였다. 따라서혈관재개통이 30분늦어질때마다 mrs 0-2점이될확률은 12% 감소하였다. 48 Solitaire를이용하여 ERT 치료를받은환자자료분석에서도혈관재개통을 15분당길때마다 100명중 31명환자에서 mrs가 1점이상개선될것으로분석되었다. 49 미국에서발표된다학회질향상합의지침에서는 ERT 환자에서병원내원후 25분내신경영상검사를하고 45분이내결과를확인하 J Korean Neurol Assoc Volume 34 No. 4,

12 홍근식고상배유경호정철규박석규김병문장철훈배희준허지회오창완이병철김범태김범수정진상윤병우나정호 Table 3. Summary of updated recommendations Recommendations 혈관내재개통치료 (endovascular recanalization therapy, ERT) 1. 급성앞순환큰동맥 ( 내경동맥, 중대뇌동맥 M1 및큰 M2) 폐색으로인한중증허혈뇌졸중환자에서예후를개선시키기위해 6시간이내혈관내재개통치료 (endovascular recanalization therapy: ERT) 를권고한다 ( 근거수준 Ia, 권고수준 A). In patients with major ischemic stroke due to an acute large artery occlusion in the anterior circulation (internal carotid artery, M1, and possibly large M2 branch) within 6 hours, endovascular recanalization therapy (ERT) is recommended to improve clinical outcomes (LOE Ia, GOR A). 2. 정맥내조직플라스미노겐활성제 (IV-TPA) 치료대상환자는 ERT 시행전 IV-TPA 투여를권고한다 ( 근거수준 Ia, 권고수준 A). IV-TPA 가 ERT 를지연시키지말아야하므로, IV-TPA 에대한반응을기다리지말고투여하면서동시에 ER 를진행할것을권고한다. In patients eligible for intravenous tissue plasminogen activator (IV-TPA), administration of IV-TPA is recommended before the initiation of ERT (LOE Ia, GOR A). Since IV-TPA should not significantly delay ERT, it is recommended to simultaneously proceed ERT during IV-TPA treatment without waiting for clinical response to IV-TPA. 3. 급성앞순환큰동맥폐색으로인한중증허혈뇌졸중환자중 IV-TPA 치료가금기인경우, 6 시간이내 ERT 를우선적인치료로권고한다 ( 근거수준 IIa, 권고수준 B). In patients who are contraindicated for IV-TPA, ERT is recommended as a first-line therapy in patients with major ischemic stroke due to an acute large artery occlusion in the anterior circulation within 6 hours (LOE IIa, GOR B). 4. 뒤순환큰동맥 ( 바닥동맥, 후대뇌동맥 P1, 척추동맥 ) 폐색으로인한중증허혈뇌졸중환자에서 6시간이내 ERT를고려할수있다 ( 근거수준III, 권고수준 B). In patients with major ischemic stroke due to acute large artery occlusion in the poster circulation (basilar artery, P1, and vertebral artery) within 6 hours, ERT can be considered (LOE III, GOR B). 5. 앞순환이나뒤순환큰동맥폐색후 6시간이지난환자에서는다중기법영상을이용하여예상되는이득과안정성을평가한후좋은예후를기대할수있는환자에서는 ERT를고려할수있다. 이용가능한장비와검사법을고려하여각병원마다선정기준을규정하는것이권장된다 ( 근거수준 IV, 권고수준 C). For patients with acute large artery occlusion in the anterior or posterior circulation presenting after 6 hours, ERT can be considered for patients having favorable multimodal imaging profiles regarding expected benefit and safety. Each center is encouraged to define own selection criteria (LOE IV, GOR C). 6. 일단 ERT 적응증이되면, 가능한빨리시행하여야한다 ( 근거수준 IIa, 권고수준 B). If indicated, ERT should be initiated as fast as possible (LOE IIa, GOR B). 7. ERT 방법으로스텐트혈전제거술을우선적으로권고한다 ( 근거수준 Ia, 권고수준 A). Stent-retriever thrombectomy is recommended as a first-line ERT (LOE Ia, GOR A). 8. 스텐트혈전제거술로재개통이이루어지지않는경우, 예상효과와안전을고려하여다른 ERT 방법을추가하는것을고려할수있다 ( 근거수준 IV, 권고수준 C). If recanalization is not achieved with stent-retriever thrombectomy, the addition of other ERT modalities can be considered after taking into account the expected efficacy and safety (LOE IV, GOR C). 9. 책임중재시술자의판단에따라기술적측면을고려하여다른방법의기계적혈전제거술이나혈전흡입술을우선적으로고려할수있다 ( 근거수준 IV, 권고수준 C). Other mechanical thrombectomy or thrombus aspiration devices may be considered as a first-line modality at the discretion of responsible interventionists after taking into account technical aspects (LOE IV, GOR C). 10. ERT 중전신마취보다는의식하진정 (conscious sedation) 이일반적으로선호된다. 그러나환자상태와병원의경험을고려하여결정하는것을권고한다 ( 근거수준 III, 권고수준 B). During ERT, conscious sedation is generally preferred to general anesthesia. However, the decision should be made after consideration of patient s condition and center s experience (LOE III, GOR B). 신경영상검사 (neuroimaging evaluation) 1. 출혈뇌졸중이나다른뇌졸중이외의원인을배제하기위해비조영증강 CT나 MRI를시행하여야한다 (GPP). Noncontrast CT or MRI should be conducted to exclude hemorrhagic stroke or other non-stroke etiologies (GPP). 2. 중증허혈뇌졸중환자에서급성큰동맥폐색을확인하기위해비침습적혈관조영술 (CT 및 MR 혈관조영술 ) 을권고한다 (GPP). Non-invasive vascular imaging (CT angiography or MR angiography) is recommended to confirm acute large artery occlusion for patients with major ischemic stroke (GPP). 3. 비침습적혈관영상이불가능한환자에서는, 뇌졸중중증도또는비조영증강 CT의혈전신호등이 ERT 결정에도움이될수있다 (GPP). For patients who are not able to perform non-invasive vascular imaging, stroke severity or clot sign on noncontrast CT can guide decision for ERT (GPP). 4. 광범위한조기허혈손상변화를평가하는신경영상법을이용하여 ERT 대상환자를선별할수있다 (GPP) For selecting patients, neuroimaging evaluation for extensive early ischemic injury can guide decision for ERT (GPP). 5. ERT 효과가있을환자를선별하기위해, 최신다중기법영상으로곁순환, 허혈중심 (ischemic core) 크기, 또는관류 - 확산불일치정도에대한평가를고려할수있다 (GPP). 그러나다중기법영상으로인해 ERT 가지연되어서는안된다. Advanced multimodal imaging to assess collaterals, extent of ischemic core, or perfusion-diffusion mismatch can be considered to identify patients who are likely to benefit from ERT (GPP). However, the multimodal imaging should not significantly delay ERT. 참고문헌 9 13, , , 13 48, , 17, 31, 32 9, 10, 17 9, 10, , 14 18, 6 13, , 28, 대한신경과학회지제 34 권제 4 호, 2016

13 Table 3. Summary of updated recommendations-continued 조직체계 (system organization) 1. ERT 시행이가능한병원은 ERT가빨리이루어지도록주임상경로및문서화된프로토콜을조직하고정착할것을권고한다 (GPP). For centers capable of providing ERT, the organization and implementation of critical pathway and formal protocol is recommended to accelerate the delivery of ERT (GPP). 2. ERT 시행에필요한충분한전문인력이부족한병원은대상환자를 ERT 가가능한병원으로이송할수있는계획안을마련할것을권고한다. IV-TPA 대상환자의경우, 이송전에 IV-TPA 투여를시작하는것이권장된다 (CPP). For centers which are not adequately staffed for ERT, it is encouraged to have a referral plan to a center capable of ERT for patients eligible for ERT. If indicated, initiating IV-TPA before referral is encouraged (GPP). 3. 각병원은초기평가, ERT 시행유무결정과시술을담당할다학제 (multidisciplinary) ERT 팀의기준을자체적으로규정할것을권장한다 (GPP). Each center is encouraged to define own criteria for the multidisciplinary ERT team that is responsible for initial evaluation, decision making, and ERT procedure (GPP). 4. ERT 질평가및개선을위해, 각병원은방문 - 신경영상 (door-to neuroimaging) 또는방문 - 혈관조영술개시 (door-to-groin puncture) 같은핵심시간지표를추적관찰하고평가할것을권장한다 (GPP). To assess and improve the quality of ERT, each center is encouraged to monitor key time metrics of door-to-neuroimaging and door-to-groin puncture (GPP). 5. ERT 후에기능적예후, 재개통율, 합병증율등을평가하는것을권장한다 (GPP). It is encouraged to assess functional outcome, recanalization rate, and complication rate after ERT (GPP). 10, 12, , 18 20, 는분율은 80% 이상, 120분이내혈관조영술시작하는분율은 75% 이상, 그리고혈관조영술시작에서첫혈관재개통시도까지 45분이내시행하는분율을 50% 이상유지할것을권고하고있다. 19 따라서각병원들은핵심시간지표를평가하고개선하기위한노력을하는것이권장된다. 임상시험에서증명된 ERT 효과는선정및제외기준에합당한환자들을선별하여경험이많은병원에서치료한결과이다. 따라서일반적진료환경에서도임상시험에서보고한 ERT 효과가그대로나타날지는확실하지않다. 따라서실제임상진료에서도 ERT 의안전성과효과가있는지확인하기위해서는각병원별로, 더바람직하게는다기관등록연구를통하여 ERT 치료를받은환자들의예후와합병증을평가하는것이필요하다. 과를가진치료이며, 효과적으로 ERT를시행하기위해서는대상환자선별과치료과정이신속하고체계적으로이루어져야한다. 시설뿐아니라많은인력자원과인력자원의유기적협력이필요한신경계질환뿐아니라혈관계질환중가장복잡한과정을요하는치료로서적절한지원과보상이동반되어야치료시스템을정착시키고유지할수있을것이다. 개정된권고사항개정된권고사항과근거가되는참고문헌을 Table 3에정리하였다. REFERENCES 5. ERT 대상환자예측우리나라에서는매년 75,000명의허혈뇌졸중환자가새로발생할것으로예측된다. 50 국내다기관대규모연구에의하면 년사이에전체허혈뇌졸중환자의 4.6% 가 ERT 치료를받았다. 51 미국의경우 2012년에허혈뇌졸중환자의 2% 가 ERT 치료를받았다. 52 보수적으로예측하여우리나라에서도 2-3% 환자가 ERT 치료를받는다고가정하면 1년에 1,500-2,250명의환자가 ERT 치료를받고있는것으로예측된다. 그러나국내대규모연구결과를보면급성큰뇌동맥폐색에의할가능성이높은 NIHSS 10점이상인중증허혈뇌졸중환자비율이약 20% 정도이므로, 51 병원도착시간이빨라지면 ERT 대상환자는훨씬많을것으로예상된다. ERT는중증허혈뇌졸중환자에게큰도움을줄수있는강력한효 1. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group. N Engl J Med 1995;333: Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359: Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384: Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999;282: Lee M, Hong KS, Saver JL. Efficacy of intra-arterial fibrinolysis for acute ischemic stroke: meta-analysis of randomized controlled trials. Stroke 2010;41: J Korean Neurol Assoc Volume 34 No. 4,

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