(특별기고).hwp

특별기고 http://dx.doi.org/10.17340/jkna.2016.3.3 정근화유경호 a 김영대 b 박종무 c 홍근식 d 나정호 e 권순억 f 배희준 g 허지회 b 이병철 a 윤병우 서울대학교의과대학서울대학교병원신경과, 한림대학교의과대학한림대학교성심병원신경과 a, 연세대학교의과대학세브란스병원신경과 b, 을지대학교의과대학노원을지병원신경과 c, 인제대학교의과대학일산백병원신경과 d, 인하대학교의과대학인하대학교병원신경과 e, 울산대학교의과대학서울아산병원신경과 f, 서울대학교의과대학분당서울대병원신경과 g Focused Update of Guidelines for Antithrombotic Management of Patients with Atrial Fibrillation and Ischemic Stroke or Transient Ischemic Attack Keun-Hwa Jung, MD, Kyung-ho Yu, MD a, Young-Dae Kim, MD b, Jong-Moo Park, MD c, Keun-Sik Hong, MD d, Jeong-Ho Rha, MD e, Sun-Uk Kwon, MD f, Hee-Jun Bae, MD g, Ji-Hoe Heo, MD b, Byung-Chul Lee, MD a, Byung-Woo Yoon, MD Department of Neurology, Seoul National University Hospital, Seoul, Korea, Department of Neurology, Hallym Neurological Institute, Anyang, Korea a Department of Neurology, Yonsei University Hospital, Seoul, Korea b Department of Neurology, Eulji General Hospital, Eulji University, Seoul, Korea c Department of Neurology, Ilsan Paik Hospital, Inje University, Goyang, Korea d Department of Neurology, Inha University Hospital, Incheon, Korea e Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea f Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Korea g Cardioembolic stroke related to atrial fibrillation is problematic due to high recurrence, mortality, and morbidity rates. The optimal anticoagulant therapy therefore needs to be applied to prevent the occurrence of a second stroke in patients with nonvalvular atrial fibrillation. The oral anticoagulant warfarin has traditionally been used, but it is limited by its narrow efficacy window, complex pharmacokinetics, and multiple drug interactions, thus requiring frequent blood monitoring. New oral anticoagulants have recently been developed that target a specific coagulation component. Dabigatran (a direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (inhibitors of factor Xa) have advantages of rapid action time, short half-life, stable plasma concentration, and few drug interactions. Large randomized clinical trials and meta-analyses have recently been published on the efficacy and safety of these new oral anticoagulants. Based on the results obtained in recent clinical trials, we have revised the recommendations for selecting optimal anticoagulant therapy in patients with nonvalvular atrial fibrillation. J Korean Neurol Assoc 34(3):184-192, 2016 Key Words: Oral anticoagulant, Ischemic stroke, Secondary prevention, Atrial fibrillation, Dabigatran, Rivaroxaban, Apixaban Received January 28, 2015 Revised March 9, 2015 Accepted March 9, 2015 Address for correspondence: Kyung-ho Yu, MD Department of Neurology, Hallym Neurological Institute, 22 Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang 14068, Korea Tel: +82-31-380-3743 Fax: +82-31-380-4659 E-mail : ykh1030@hallym.ac.kr This is a secondary publication of an essay of same title which was published in Journal of Stroke 2015; 17(2): 210-215 by permission of the Korean Stroke Society Editor. This article was copublished in Journal of Stroke as form of Executive Summary. 184 대한신경과학회지제 34 권제 3 호, 2016

서론 우리나라병원기반등록자료에의하면심장성색전뇌졸중은점차증가하여최근에는전체허혈뇌졸중의약 20% 를차지하고있으며, 1 허혈뇌졸중환자의 19% 에서심방세동이있다. 2 심방세동은심장성색전뇌졸중의가장흔한위험인자로나이가들수록유병률이높아지므로, 3 향후심방세동으로인한허혈뇌졸중의발생은증가할것이다. 심방세동으로인한허혈뇌졸중이나일과성허혈발작이발생한경우, 출혈부담이나특별한금기사항이없다면이차예방을위한항응고제치료는반드시고려해야한다. 항응고제는전통적으로와파린을사용해왔으나최근효과와안전성이입증된새로운경구항응고제 (New oral anticoagulant, NOAC) 가개발, 승인되면서심방세동환자의뇌졸중이차예방을위한주요치료법으로자리잡고있다. 2015년 1월현재직접트롬빈억제제인다비가트란 (dabigatran) 과직접 Xa억제제인리바록사반 (rivaroxaban), 아픽사반 (apixaban), 에독사반 (edoxaban) 이대표적인약물이며, 국내에서다비가트란, 리바록사반, 그리고아픽사반은승인을받아임상진료실에서처방이가능하고, 에독사반은심사중이다. 뇌졸중임상연구센터 (Clinical Research Center for Stroke) 진료지침집필위원회 ( 이하집필위원회 ) 는 2007년 6월 30일까지발표된근거를반영하여제1판한국뇌졸중임상진료지침을 2009년 5월에발간하였다. 2009년뇌졸중이차예방진료지침에는새로운항응고제에대한권고안이포함되지않았는데 (Table 1), 그동안발표된새로운항응고제의임상시험, 세부분석, 그리고메타분석연구의근거가뇌졸중이차예방을위한항혈전제치료에중요한영향을줄수있다고판단하여진료지침을개정하기로결정하였다. 근거검색과근거수준평가방법진료지침개정과정은국제표준방법인 Appraisal of Guidelines for Research & Evaluation (AGREE II) 에따라서진행하였 다. 지침개정에필요한모든증거를검색, 수집, 평가하여근거수준과권고수준을정하였다. 문헌수집은한국뇌졸중임상연구센터의표준방법에따라서검색기간, 발표형식, 중요단어, 검색방법, 데이터베이스종류를정하였다. 본지침개정을위하여 Pubmed, National Guideline Clearinghouse에서 2007년 7월부터 2014년 5 월까지심방세동 (atrial fibrillation) AND 뇌졸중 (stroke) OR 일과성허혈발작 (transient ischemic attack) AND 항응고제 (anticoagulant) AND 다비가트란 (Dabigatran) OR 리바록사반 (Rivaroxaban) OR 아픽사반 (Apixaban) OR 에독사반 (Edoxaban) AND 와파린 (Warfarin) AND 뇌졸중 (Stroke) 키워드를가진연구논문중메타분석 / 체계적분석논문, 무작위대조군비교연구논문으로제한하여자료를추출하였다. 일차검색으로심방세동환자에서항응고제사용에대한검색을진행하였고, 이차검색으로뇌졸중또는일과성허혈발작이있는환자로국한하여항응고제사용에대한검색을진행하였다. 이중카테터절제 (catheter ablation), 심장율동전환 (cardioversion), 판막치환술 (valve replacement surgery), 좌심방귀폐쇄술 (left atrial appendage closure) 을받은환자를대상으로한연구는배제하였다. 비판막성심방세동환자의이차예방진료지침개정을위해서앞에기술한검색방법에따라무작위대조군비교연구 8개, 메타분석 5개, 하위분석 4개, 국외진료지침 3개를추출하였다. 권고수준은근거수준에따라결정하였는데, 근거자료의수준을평가하기위해서는코크란 (Cochrane) 에서제공하는 GRADEpro를활용하였다. GRADEpro는 1) 디자인한계, 2) 이형성 (inconsistency), 3) 간접성 (indirectness), 4) 부정확성, 5) 출판비뚤림에대하여평가기준을제공하였고, 각항목당 0 ( 없음 ), 1 ( 중대함 ), 2 ( 매우중대함 ) 로구분하여, 근거의질을높음 (high), 중간 (moderate), 낮음 (low), 매우낮음 (very low) 으로평가한다. 본개정지침에서는국외진료지침 3개를제외한 17개의새로운근거자료에대해서 GRADEpro방법을적용하여근거의질을평가하였다. 집필위원회에서채택한개정권고안의근거수준과권고수준은 US Agency for Health Care Table 1. Previous Recommendations for Antithrombotic Management of Patients with Atrial Fibrillation and Ischemic Stroke or Transient Ischemic Attack (2009) 1 Warfarin treatment (INR 2.0-3.0) is recommended, unless contraindicated, in patients with ischemic stroke or TIA coexisting with sustained or paroxysmal AF (Evidence level: Ia, Recommendation grade: A). 2 If anticoagulants cannot be used, aspirin can be used instead (Evidence level: Ia, Recommendation grade: A) 3 A recommended daily dose of aspirin is 325mg. In Korea, a prescribable dose of 300mg may be considered (Evidence level: IV, Recommendation grade: GPP). 4 For the recurrence of ischemic stroke or TIA in the AF patients already receiving adequate anticoagulation therapy, increasing the therapeutic target to INR 2.5-3.5 or initiating a combination with antiplatelet agents may be considered (Evidence level: IV, Recommendation grade: C). INR; international normalized ratio, TIA; transient ischemic attack, AF; atrial fibrillation, GPP; good practice point. J Korean Neurol Assoc Volume 34 No. 3, 2016 185

정근화유경호김영대박종무홍근식나정호권순억배희준허지회이병철윤병우 Table 2. Statement method of the Korean Stroke Clinical Practice Guideline Level Ia Ib IIa IIb III IV Grade A (Evidence Levels Ia, Ib) B (Evidence Levels IIa, IIb, III) C (Evidence level IV) GPP (Good practice points) GPP; good practice point. Type of Evidence 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. Recommendation 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. Indicates absence of directly applicable clinical studies of good quality. Recommended best practice based on the clinical experience of the guideline development group. Policy and Research에서제안한방식에기반을두었다 (Table 2). 각권고사항은수정델파이 (Delphi) 방법을통해뇌졸중임상연구센터에서지명한전문가합의에의해도출되었고뇌졸중임상연구센터운영위원회의검토와의견을반영하여수정과정을거친후최종권고안을마련하였다. 심방세동환자의항혈전제치료에대한새로운연구자료 1. 대규모임상연구 1.1. Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE)-A 4 ACTIVE-A는항응고제치료가부적합한심방세동환자 7,554 명을대상으로아스피린단독요법과아스피린 / 클로피도그렐병합요법을비교한연구이다. 일차결과변수인뇌졸중, 심근경색, 비중추신경계전신색전증또는혈관성사망의복합사건연간발생률이병합요법군 6.8% 로단독요법군 7.6% 에비해유의하게낮았지만 (relative risk [RR], 0.89; 95% confidence interval [CI], 0.81-0.98; p=0.01), 주요출혈부작용의연간발생률은병합요법군에서유의하게높았다 (2.0% versus 1.3%; RR [95% CI], 1.57 [1.29-1.92]; p<0.001). 아스피린단독투여에비해아스피린 / 클로피도그렐병용요법을했을때주요혈관사건발생의상대위험도가 0.89이지만절대위험도감소는 0.8%/ 년인반면주요출혈에대해절대위험도증가가 0.7%/ 년이다. 주요출혈과주요혈관사건발생을 합쳐서결과변수로보면상대위험도는 0.97로유익하다고판단하기힘들다. 병합요법이단독요법에비하여뇌졸중과혈관질환발생에대한우월한예방효과를입증한대규모연구였지만, 출혈부작용이높았던점은고려해야할부분이다. 1.2. Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) 5 RE-LY 임상시험은한가지이상위험인자가있는비판막성심방세동환자 18,113명을대상으로두가지용량의트롬빈억제제인다비가트란과와파린을비교한 PROBE(prospective, randomized, open-label, blinded endpoint) 연구이다. 다비가트란-110 mg, 다비가트란-150 mg, 와파린군에서뇌졸중또는전신색전증의연간발생빈도는각각 1.53%, 1.11%, 1.69% 였고, 주요출혈부작용의연간발생빈도는 2.71%, 3.11%, 3.36% 였다. 다비가트란 - 110 mg 은와파린에비하여뇌졸중또는전신색전증의발생에대한예방효과는비슷하였고 (RR [95% CI], 0.91 [0.74-1.11]; p<0.001 for non-inferiority; p=0.34 for superiority), 주요출혈은유의하게감소하였다 (p=0.03). 다비가트란 - 150 mg은와파린에비하여효과면에서는우월하였고 (RR [95% CI], 0.61 [0.53-0.82]; p<0.001 for superiority), 안전성은비슷하였다 (p=0.31). 또한, 인종, 지역에따른차이를분석한 RE-LY의세부연구에서 6 와파린대비다비가트란의효과와안전성은인종에따라큰차이가없었다. 단, 와파린을복용했을때출혈뇌졸중이비아시아인에비해서아시아인에서더많이발생하였는데다비가트란을복용했을때는두인종모두유 186 대한신경과학회지제 34 권제 3 호, 2016

의하게감소하였다. 1.3. Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) 7 RELY-ABLE 은 RE-LY의평균 2년동안추적관찰하고추가로 2.25년더연장하여다비가트란 110 mg과 150 mg을비교한장기추적관찰연구로연간뇌졸중혹은전신색전증빈도는다비가트란 - 110 mg, 다비가트란 - 150 mg에서각각연간 1.60%, 1.46% 로이전결과와유사하였으나, 주요출혈부작용은연간 2.99%, 3.74% 로다비가트란 - 150 mg에서유의하게증가하는경향을보였다. 1.4. Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) 8 ROCKET-AF는중등도이상위험성이있는심방세동환자 14,264명에서 Xa억제제인리바록사반 (20 mg, 1일 1회 ; 사구체여과율 30-49 ml/min인경우 15 mg, 1일 1회 ) 과와파린을비교한무작위이중맹검임상시험이다. ROCKET-AF는다른임상시험에비해뇌졸중이차예방에해당되는뇌졸중또는일과성허혈발작의과거력이있는환자가 52.4% 로다른연구에비해서높았고, 와파린군에서 INR이목표범위에유지된기간 (time in INR therapeutic range, TTR) 이 55% 로다른연구에비하여낮았다. 치료의도집단 (Intention-to-treat) 분석에서연간뇌졸중과전신색전증발생률은리바록사반 2.1%, 와파린 2.4% 로비열등성은입증하였으나우월성은입증하지못했다 (hazard ratio [HR], 0.88; [95% CI], 0.74-1.03; p<0.001 for noninferiority; p=0.12 for superiority). 그러나계획서순응집단 (per-protocol) 분석에서는리바록사반 1.7%/ 년, 와파린 2.2%/ 년으로비열등성과우월성이함께입증되었다 (HR [95% CI], 0.79 [0.66-0.96]; p<0.001 for non-inferiority; p=0.01 for superiority). 주요출혈과임상적으로의미있는출혈부작용은 14.9%, 14.5% 로두군에서차이가없었으나 (HR [95% CI], 1.03 [0.96-1.11]; p=0.44), 두개내출혈 (0.5% vs. 0.7%, p=0.02) 과치명적출혈 (0.2% vs. 0.5%, p=0.003) 은리바록사반에서유의하게낮았다. 1.5. Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) 9 AVERROES는와파린사용이어려운심방세동환자 5,599명에서아스피린과 Xa억제제인아픽사반 (5 mg, 1일 2회 ; 80세이상, 체중 60kg 이하, 혈장크레아티닌 >1.5 mg/dl 중두가지이상에해당되는경우 2.5 mg, 1일 2회 ) 을비교한이중맹검연구이다. 아스피린, 아픽사반군에서연간뇌졸중또는전신색전증의발생빈도는각각 3.7%, 1.6% 로아픽사반군에서유의하게감소하여 (HR [95% CI], 0.45 [0.32-0.62]; p<0.001) 중간분석후종료되었다. 주요출혈부작용은아스피린, 아픽사반각각 1.2%, 1.4% 로비슷하였다 (HR [95% CI], 1.13 [0.74-1.75]; p=0.57). 1.6. Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) 10 ARISTOTLE은중등도이상의위험성이있는심방세동환자 18,201명에서와파린과 Xa억제제인아픽사반 (5 mg, 1일 2회 ; 80 세이상, 체중 60kg 이하, 혈장크레아티닌 >1.5 mg/dl 중두가지이상에해당되는경우 2.5 mg, 1일 2회 ) 을비교한이중맹검연구이다. 연간뇌졸중또는전신색전증의발생빈도는아픽사반, 와파린의경우각각 1.27%, 1.60% 로아픽사반군에서유의하게감소하였고 (HR [95% CI], 0.79 [0.66-0.95]; p<0.001 for noninferiority; p=0.01 for superiority), 주요출혈부작용또한 2.13%, 3.09% 로아픽사반군에서유의하게감소하였다 (HR [95% CI], 0.69 [0.60-0.80]; p<0.001). 아픽사반이와파린에비하여뇌졸중또는전신색전증의발생에대한예방효과와안전성에대해열등하지않을뿐만아니라우월함을입증한대규모연구이다. 1.7. Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) 11 ENGAGE AF-TIMI 48은중등도이상의위험성이있는심방세동환자 21,105명에서와파린과 Xa억제제인에독사반을비교한이중맹검연구이다. 연간뇌졸중또는전신색전증발생빈도는에독사반 - 30 mg, 에독사반 - 60 mg, 와파린의경우각각 1.61%, 1.18%, 1.50% 로비슷하였고 ( 에독사반 - 30 mg: HR [95% CI], 1.07 [0.87-1.31]; p=0.005 for noninferiority; 에독사반 - 60 mg: HR [95% CI], 0.79 [0.63-0.99]; p<0.001 for noninferiority), 주요출혈부작용은 1.61%, 2.75%, 3.43% 로에독사반군에서의미있게낮았다 ( 에독사반 - 30 mg: HR [95% CI], 0.47 [0.41-0.55]; p<0.001; 에독사반 - 60 mg: HR [95% CI], 0.80 [0.71-0.91]; p<0.001). 에독사반이와파린에비하여뇌졸중또는전신색전증의발생에대한예방효과와안전성이열등하지않음을입증한대규 J Korean Neurol Assoc Volume 34 No. 3, 2016 187

정근화유경호김영대박종무홍근식나정호권순억배희준허지회이병철윤병우 모연구이다. 2. 메타분석연구 RE-LY, ROCKET-AF, ARISTOTLE 세가지임상시험에대한메타분석연구에서 12 와파린과비교하여새로운항응고제는뇌졸중과전신색전증발생상대위험도가 0.78 (95% CI 0.67-0.92) 로유의하게감소하였다. 두개내출혈은새로운항응고제가와파린에비해 50% 이상의미있게감소하였으나 (RR 0.49, 95% CI 0.36-0.66), 주요출혈 (RR 0.88, 95% CI 0.71-1.09) 은감소경향만을, 위장관내출혈 (RR 1.25, 95% CI 0.91-1.72) 은증가경향을보였다. 2상과 3상임상시험 12개에대한메타분석연구에서도 13 와파린과비교하여새로운항응고제는뇌졸중과전신색전증의위험을유의하게감소시켰다 (RR [95% CI], 0.77 [0.70-0.86]). 두개내출혈은새로운항응고제에서유의한감소결과 (RR [95% CI], 0.46, [0.39-0.56]) 를보였으나, 주요출혈 (RR, [95% CI], 0.86 [0.72-1.02]) 은감소경향만을보였다. 뇌출혈위험도평가가주목적이었던 6개임상시험의메타분석연구에서 14 뇌출혈에대한새로운항응고제의안전성을확인하였다. 와파린과비교하여새로운항응고제의뇌출혈교차비는 0.49 (95%CI, 0.36-0.65) 로의미있는감소효과를보였고, 약물사이에의미있는차이는관찰되지않았다. RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF-TIMI 48 임상시험에대한메타분석에서 15 와파린과비교하여새로운항응고제의뇌졸중과전신색전증상대위험도는 0.81 (95% CI 0.73-0.91; p<0.0001) 로유의한감소효과를보였다. 두개내출혈은새로운항응고제에서의미있게감소하였으나 (RR 0.48, 95% CI 0.39-0.59), 위장관내출혈은증가하였다 (RR 1.25, 95% CI 1.01-1.55). 새로운저용량항응고제는뇌졸중또는전신색전증발생에대하여와파린과비슷한감소효과를보였고, 출혈부작용의감소와허혈뇌졸중의증가경향이동시에나타났다. 3. 새로운항응고제의뇌졸중이차예방효과에대한세부분석연구 150 mg, 와파린군에서 2.32%, 2.07%, 2.78% 로비슷하였고, 주요출혈부작용은와파린에비해다비가트란 - 110 mg 군에서유의하게감소하였고, 다비가트란 - 150 mg 군도비슷하였다. 이는와파린과비교하여다비가트란이이차예방효과와안전성에서열등하지않다고해석할수있다. ROCKET-AF 연구에서 17 뇌졸중또는일과성허혈발작의기왕력이있는환자군의연간뇌졸중또는전신색전증발생빈도는리바록사반, 와파린군에서각각 2.79%, 2.96% 였고, 주요출혈과임상적으로의미있는출혈부작용은 13.31%, 13.37% 로비슷하였다. 즉, 와파린과비교하여리바록사반이이차예방효과와안전성이열등하지않았다. AVERROES 연구에서는 18 뇌졸중또는일과성허혈발작의기왕력이있는환자군의연간뇌졸중또는전신색전증발생빈도가아픽사반, 아스피린군에서각각 2.39%, 9.16% 로아픽사반군에서더낮았고, 주요출혈부작용빈도는기왕력이있는군에서더높았으나각치료사이에는차이가없었다. 이는아스피린과비교하여아픽사반이이차예방효과가우월함을시사한다. 아픽사반을이용한또다른주요임상시험인 ARISTOTLE 연구에서 19 뇌졸중또는일과성허혈발작기왕력이있는환자의뇌졸중또는전신색전증발생빈도는아픽사반, 와파린군에서각각 2.46, 3.24/100 patient-year로절대감소율이 0.77 (95% CI -0.08-1.63) 였고, 주요출혈부작용은아픽사반이와파린에비해 1.07/100 patient-year (95% CI 0.09-2.04) 의절대위험도감소를보였다. 이는아픽사반의이차예방효과와안전성이우월하다고해석할수있겠다. RE-LY, ROCKET-AF, ARISTOTLE 연구를모두합쳐뇌졸중또는일과성허혈발작기왕력이있는환자에대한메타분석연구에서는 20 와파린과비교하여새로운항응고제의뇌졸중과전신색전증의교차비가 0.85 (95% CI, 0.74-0.99) 로 14% 상대위험도감소, 0.7% 의절대위험도감소, 치료에필요한환자수 (NNT) 는 134명으로유의한효과를보였다. 또한주요출혈도새로운항응고제군에서교차비는 0.86 (95% CI, 0.75-0.99) 로 13% 상대위험도감소, 0.8% 의절대위험도감소, NNT는 125명으로의미있게감소하였다. 전반적으로일과성허혈발작또는뇌졸중환자에서이차예방효과에대한연구에서는전체환자분석결과와비슷한양상을보였다. RE-LY 연구에서뇌졸중또는일과성허혈발작의기왕력이있는환자와없는환자를비교한세부분석연구가 16 발표되었다. 뇌졸중또는일과성허혈발작의기왕력이있는환자군에서연간뇌졸중또는전신색전증의발생빈도는다비가트란 - 110 mg, 다비가트란 - 4. 심방세동환자에서새로운항응고제치료에대한국내외진료지침개정현황 지금까지대규모임상시험과세부분석, 메타분석에서평가한네 188 대한신경과학회지제 34 권제 3 호, 2016

가지약물은모두와파린에비해서효과와안전성이비슷하거나우월하였고, 특히, 출혈뇌졸중이감소하였다. 이러한결과에기반하여 2012년유럽가이드라인에서는 21 와파린사용이필요하지만와파린을사용할수없을때 ( 예 : 치료농도유지가어려울때, 부작용이있을때, 혈액검사가어려울때 ) 새로운항응고제중하나를고려할수있다는권고안을포함하였다. 단, 심한신기능저하가있는경우에는고려대상이되지않고, 처방전후로정기적으로신기능에대한평가를시행하도록권고하였다. 2014년 American Heart Association/ American College of Cardiology/Heart Rhythm Society, American Heart Association/American Stroke Association에서는각각심방세동환자치료가이드라인과 22 심장성색전증환자의이차예방가이드라인을 23 새롭게개정하였다. 고위험환자에서는경구항응고제사용을권유하고선택약물로는와파린뿐만아니라다비가트란, 리바록사반, 아픽사반을함께권고하였다. 특히, INR 유지가어려운경우에는새로운항응고제사용을고려하고신기능검사에대한가이드라인, 만성신질환환자와투석환자에서새로운항응고제사용제한에대한권고안도유럽과비슷하게제시하였다. 우리나라뇌졸중임상연구센터에서도 2013년에뇌졸중일차예방에대한진료지침을수정하여발표하였다. 24 새로운항응고제에관한연구결과를기반으로심방세동환자일차예방에서항혈전치료의선택약물로다비가트란, 리바록사반, 아픽사반을권고하였다. 특히와파린대체제로이들을고려할수있다는권고안을권고수준 A, 근거수준 Ib로제시하였다. 한편, 신장기능에따른용량선택과사용제한에대한권고사항도추가하였다. 비판막성심방세동을동반한뇌졸중또는일과성허혈발작환자의뇌졸중이차예방분야수정권고안최근다비가트란, 리바록사반, 아픽사반, 에독사반에대한대규모무작위시험결과가발표되면서비판막성심방세동환자에서뇌졸중이차예방약물로와파린을대체할수있는새로운경구항응고제가각광을받기시작하였다. 2015년 1월현재, 네가지약물중에서에독사반을제외한세가지약물은승인을받아사용중이고, 에독사반은 FDA 승인대기중이다. 2009년심방세동환자에서한국뇌졸중이차예방권고안에는새로운항응고제대한내용이전혀반영되지않았다. 따라서본제안은일차예방개정방향을기반으로하여최근추가된이차예방관련세부분석과메타분석연구자료를참고하여표3과같이제시한다 (Table 3). 새로운근거와권고수준결정배경 1. 지속또는발작비판막성심방세동을동반한허혈뇌졸중또는일과성허혈발작환자에서특별한금기가없는한뇌졸중의이차예방목적으로와파린또는새로운경구항응고제인다비가트란, 리바록사반, 아픽사반을사용할수있다.( 근거수준 Ia, 권고수준 A) 약물의선택은환자의임상특성또는약물상호작용에따라판단한다.(GPP) ( 신규권고안 ) 뇌졸중이나일과성허혈발작환자만을대상으로하였던 European Atrial Fibrillation Trial (EAFT) 에서 25 와파린효과가입 Table 3. Revised Recommendations for Antithrombotic Management of Patients with Atrial Fibrillation and Ischemic Stroke or Transient Ischemic Attack 1 For patients who had ischemic stroke or transient ischemic attack with persistent or paroxysmal nonvalvular atrial fibrillation, oral anticoagulant therapy with warfarin, dabigatran, rivaroxaban, or apixaban is recommended for the prevention of recurrent stroke if not contraindicated (Evidence level: Ia, Recommendation grade: A). The selection of an anticoagulation therapy should be individualized based on clinical characteristics, patient preference, and potential for drug interactions (Recommendation grade: GPP). (New recommendation) 2 For patients treated with warfarin, adjusted-dose warfarin therapy targeting INR 2.0-3.0 is recommended (Evidence level: Ia, Recommendation grade: A). (Modified recommendation) 3 For patients treated with new oral anticoagulants, renal function should be evaluated prior to initiation of new oral anticoagulant. For patients with severe renal impairment, dabigatran, rivaroxaban, and apixaban are not recommended (Evidence level: III, Recommendation grade: B). (New recommendation) 4 For patients who had a cardioembolic ischemic stroke or transient ischemic attack despite adequate anticoagulation with warfarin, warfarin therapy targeting a higher INR, addition of an antiplatelet agent, or switch to one of dabigatran, rivaroxaban, and apixaban can be considered. (Evidence level: IV, Recommendation grade: C). (Revised recommendation) 5 Dabigatran, rivaroxaban, or apixaban can be considered in patients with nonvalvular atrial fibrillation who have a history of intracranial hemorrhage, or are at high risk of intracranial hemorrhage (Evidence level: III, Recommendation grade: B). (New recommendation) 6 For patients with ischemic stroke or TIA and atrial fibrillation who are not able to use oral anticoagulants, antiplatelet agent should be considered (Evidence level: I, Recommendation level A). Aspirin monotherapy or aspirin plus clopidogrel combination therapy can be considered, and the selection of antiplatelet therapy should be based on balancing the risks of ischemic events and major bleedings (Evidence level: Ib, Recommendation grade: A). (Modified recommendation) J Korean Neurol Assoc Volume 34 No. 3, 2016 189

정근화유경호김영대박종무홍근식나정호권순억배희준허지회이병철윤병우 증되었고, 뇌졸중이차예방에대한와파린의추가적인대규모임상시험은없었으나, 뇌졸중일차예방 ( 일부환자는이차예방에해당 ) 에대한와파린임상시험을합하여메타분석한결과에서 26 효과가입증되었으므로지속또는발작비판막성심방세동을동반한허혈뇌졸중또는일과성허혈발작환자에서특별한금기가없다면뇌졸중이차예방목적으로와파린을사용하는것에대해근거수준 Ia, 그리고권고수준 A를부여하며기존권고안을유지하였다. 새로운항응고제는, 대규모임상시험에서 5,8,10,11 와파린과비교하여효과와안전성이동등하거나우월함이입증되었고, 임상연구마다차이는있지만 4개의메타분석에서도 12-15 와파린과비교하여효과와안전성이동등하거나우월하였다. 뇌졸중이차예방에해당되는환자만을분석한하위그룹분석에서도 16-19 와파린대비효과와안전성이전체환자의결과와차이가없었고, 이차예방에대한메타분석에서와파린에비해뇌졸중또는전신색전증, 출혈뇌졸중, 그리고주요출혈부작용을유의하게감소시켰으므로, 20 지속또는발작비판막성심방세동을동반한허혈뇌졸중또는일과성허혈발작환자에서특별한금기가없다면뇌졸중이차예방목적으로와파린또는새로운경구항응고제인다비가트란, 리바록사반, 아픽사반을사용할수있다는권고안에근거수준 Ia를부여하고, 권고수준 A 를부여하였다. 약물제시순서는대규모임상연구발표와사용승인순서를고려하여표기하였다. 단, 대체약물선택은직접비교연구가없으므로 GPP 수준으로권고하였다. 2. 와파린사용시에는 INR 2.0-3.0 목표로약물농도조절이권장된다.( 근거수준Ia, 권고수준A) ( 수정권고안 ) 와파린의효과가입증된 EAFT 25 와메타분석에서 26 INR 2.0-3.0을목표로용량을조절하였으므로기존근거수준 Ia, 그리고권고수준 A를유지하였다. 3. 새로운경구항응고제사용을고려할때신기능을평가해야한다. 항응고제치료가필요한비판막성심방세동환자에서중증의신기능저하가있는경우다비가트란, 리바록사반및아픽사반사용은권장되지않는다.( 근거수준 III, 권고수준 B) ( 신규권고안 ) 새로운항응고제무작위대조군비교연구는신기능에따른용량조절을시도하거나중증의신기능저하의경우제외하는기준을두었다. 국내식약처허가기준은약물마다다른기준을제시하고있는데다비가트란에서는크레아티닌청소율 30 ml/min 이하의경우금기, 리바록사반과아픽사반에서는중증신기능저하에서약물감량을통한신중한투여를권장하고있다. 하지만, 기존근거가신기능에따른무작위연구가아니었고, 크레아티닌청소율 15 ml/min 이하환자에대한리바록사반, 아픽사반사용의임상근거는없는상황으로약물마다서로다른근거를제시하기보다는중증신기능저하에서는새로운항응고제사용을권장하지않는다는권고안으로근거수준 III, 권고수준 B를제시하였다. 4. 와파린치료를받던심방세동환자에서심장성허혈뇌졸중또는일과성허혈발작이재발한경우, INR 치료목표를높이거나, 항혈소판제를추가, 혹은새로운경구항응고제사용을고려할수있다.( 근거수준 IV, 권고수준C) ( 수정권고안 ) 와파린사용중뇌졸중이재발한환자에대한항혈전제치료에대한임상시험은없으나임상현장에서자주발생하는문제이므로전문가합의에기반을둔권고안을제시할필요가있다고판단하였다. 기존지침에서 INR 상향조정을근거수준 IV, 권고수준 C로제시하였고, 다른진료지침에서 21-23 전문가의견으로새로운경구항응고제를고려할수있다고제시하였다. 뇌졸중임상연구센터에서의뢰한전문가합의에서도같은의견을제시하여근거수준 IV, 권고수준 C로결정하였다. 5. 비판막성심방세동을동반한환자에서두개내출혈을경험했거나두개내출혈의위험이높은경우이차예방으로새로운경구항응고제를고려할수있다.( 근거수준 III, 권고수준 B) ( 신규권고안 ) 뇌내출혈을경험한환자나위험이높은환자만을대상으로한임상시험은없었다. 그러나, 임상시험, 5-11 메타분석, 12-15 그리고이차예방환자만을분석한하위그룹분석에서도 16-19 새로운항응고제는와파린과비교하여출혈뇌졸중을뚜렷하게감소시켰다. 따라서비판막성심방세동을동반한허혈뇌졸중또는일과성허혈발작환자에서출혈뇌졸중을경험했거나출혈뇌졸중의위험이높지만항응고제치료가필요한경우새로운경구항응고제를고려할수있다는내용을근거수준 III, 권고수준 B로제안하였다. 6. 비판막성심방세동을동반한허혈뇌졸중또는일과성허혈발작환자에서항응고제를투여할수없다면, 항혈소판제치료가고려되어야한다.( 근거수준 Ia, 권고수준 A) 항혈소판제는아스피린단독투여또는아스피린과클로피도그렐병용요법을사용할수있으며, 출혈위험성과허혈성혈관질환의감소효과간의균형을고려하여개별적으로결정되어야할것이다.( 근거수준 Ib, 권고수준 A) ( 수정권고안 ) 개정전진료지침은항응고제를사용할수없는심방세동환자에서아스피린사용을근거수준 Ia, 권고수준 A로권고하였는데메타연구에서 27 위약과비교하여항혈소판제의예방효과가입증되 190 대한신경과학회지제 34 권제 3 호, 2016

었으므로아스피린을항혈소판제로변경하였다. ACITIV-A에서 4 아스피린단독투여에비해아스피린과클로피도그렐병용요법을했을때주요혈관사건발생의상대위험도가 0.89이지만절대위험도감소는 0.8%/ 년인반면주요출혈에대해절대위험도증가가 0.7%/ 년이다. 주요출혈과주요혈관사건발생을합쳐서결과변수로보면상대위험도는 0.97로효과가있다고판단하기힘들다. 따라서항혈소판제는아스피린단독투여또는아스피린과클로피도그렐병용요법을사용할수있으며, 출혈위험성과허혈혈관질환의감소효과사이의균형을고려하여개별적으로결정해야한다는내용을근거수준 Ib, 권고수준 A로제안하였다. 7. 적절한아스피린용량으로는하루 325 mg가권장되나, 우리나라에서는실제처방가능한용량인하루 300 mg을고려할수있다. ( 근거수준IV, 권고수준GPP) ( 기존권고안에서삭제 ) 비판막성심방세동환자의이차예방을위해서기존권고안에있던아스피린용량선택관련권고사항은근거수준이낮고진료현장에서활용가치가낮아서삭제하였다. Acknowledgements This study was supported by a grant of the Korean Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065). This is a secondary publication of an essay of same title which was published in Journal of Stroke 2015; 17(2): 210-215 by permission of the Korean Stroke Society Editor. This article was copublished in Journal of Stroke as form of Executive Summary. REFERENCES 1. Jung KH, Lee SH, Kim BJ, Yu KH, Hong KS, Lee BC, et al. 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