낮음이입증되었다. 4 그러나비타민 K 비의존성경구용항응고제와연관된두개내출혈의임상양상및예후가어떠한지에대해서는아직까지그근거가부족한실정이다. 4 경구용항혈소판제도자발성두개내출혈의중요한위험인자중하나이다 그러나경구용항혈소판제가경구용항혈소판제와연관된두개내출혈의출혈량과사

Transcription

1 REVIEW J Neurocrit Care 2016;9(2): eissn 경구용항혈전제투여와연관된두개내출혈의관리 장윤경 김용재 송태진이화여자대학교의과대학의학전문대학원신경과학교실 Management of Oral Anti-Thrombotic Agents Associated Intracerebral Hemorrhage Yoonkyung Chang, MD, Yong-Jae Kim, MD, PhD, Tae-Jin Song, MD, PhD Department of Neurology, Ewha Womans University School of Medicine, Seoul, Korea Oral anti-thrombotic agents including anti-coagulants or anti-platelet agents are widely used to prevent cerebral infarction in patients with certain risk factors for ischemic stroke. Oral anti-coagulants, particularly warfarin, have long been used after Stroke Prevention in Atrial Fibrillation (SPAF) trials and European Atrial Fibrillation Trial proved its preventive effect. But along with the increased use of oral anti-thrombotic agents, the incidence of oral anti-thrombotic agent-associated intracranial hemorrhage has also increased. In many clinical trials, the recently approved oral anti-coagulants had a lower risk of hemorrhagic complication compared to warfarin, and real world evidence showed that non-vitamin K antagonist oral anti-coagulants have a relatively lower risk of hemorrhagic complication, especially intracerebral hemorrhage. However, the clinical outcome of non-vitamin K antagonist oral anti-coagulant-related intracerebral hemorrhage seems to be unfavorable. Moreover, management and prognosis of anti-platelet agent-associated intracerebral hemorrhage have been limited. The aim of this article is to review the currently suggested clinical evidences for 1. incidence and prognosis, 2. risk factors, 3. treatment, 4. resumption of anti-thrombotics in oral anti-thrombotic agent-associated intracerebral hemorrhage. J Neurocrit Care 2016;9(2): Key words: Atrial fibrillation; Cerebral hemorrhage; Warfarin; Anticoagulants; Platelet aggregation inhibitors Received September 26, 2016 Revised October 20, 2016 Accepted October 21, 2016 Corresponding Author: Tae-Jin Song, MD, PhD Department of Neurology, Ewha Womans University School of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul 07985, Korea Tel: Fax: knstar@ewha.ac.kr Copyright 2016 The Korean Neurocritical Care Society 서론 혈관질환의치료및예방을위해현재사용되는경구용항혈전제 (anti-thrombotics) 는크게항응고제와항혈소판제로나눌수있다. 이중에서와파린은전세계적으로가장널리사용되는경구용항응고제이다. 와파린은비타민 K 의존응고인자 II, VII, IX, 그리고 X의 N-말단부위의글루탐산의번역 (translation) 후카르복시화 (carboxylation) 를억제하여항응고효과를낸다. 1 혈전색전증예방, 특히심방세동이나심근경색후의혈전색전 증예방에대한와파린의효과는이미여러연구에서입증된바있다. 2 그러나, 와파린은치료효과를보일수있는약물의혈중유지범위가좁고음식과병용약제에많은영향을받기때문에약물농도조절이어려우며출혈부작용, 특히두개내출혈의발생위험을유의하게높이는명백한단점이있다. 3 최근에개발된비타민 K 비의존성경구용항응고제의경우여러임상연구에서와파린대비전반적인출혈부작용의위험성이낮음이입증되었으며실제다수의인구집단을대상으로한연구에서도출혈부작용, 특히두개내출혈의발생위험이상대적으로 cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited

2 낮음이입증되었다. 4 그러나비타민 K 비의존성경구용항응고제와연관된두개내출혈의임상양상및예후가어떠한지에대해서는아직까지그근거가부족한실정이다. 4 경구용항혈소판제도자발성두개내출혈의중요한위험인자중하나이다 그러나경구용항혈소판제가경구용항혈소판제와연관된두개내출혈의출혈량과사망률을증가시키는지에대해서는여러연구결과들이일관적이지않다 본종설에서는경구용항응고제와항혈소판제투여와연관된두개내출혈의 1. 빈도및예후, 2. 위험인자, 3. 치료, 4. 항혈전제의재시작에대한현재까지제시된임상적인증거들에대해확인하고자한다. 본론 1. 빈도및예후여러보고를종합해보면와파린으로대표되는경구용항응고제와연관된두개내출혈의빈도는전체두개내출혈의약 5-12% 정도를차지하며 13 미국의경우 1년발생률은약 3,000 명정도로알려져있다 여러무작위임상시험결과를종합하면와파린과연관된두개내출혈은항응고요법을시행하는원인에따라출혈발생률이약간씩차이가있다 ( 기계판막 [1-8.3%], 심방세동 [0-6.6%], 관상동맥질환 [0-19.3%], 정맥혈전증 [0-16.7%], 뇌경색 [2-13%]). 17 또한, 여러임상시험에서와파린과연관된두개내출혈의 1년발생률은약 0.3% 였고, 10만명당 2-9명꼴로발생하였으며항응고요법을시행하지않는인구집단에비해 7-10 배의높은발생위험도를보였다. 18,19 이러한와파린과연관된두개내출혈의발생빈도는최근들어증가하고있는데, 이는뇌경색의 2차예방을위해와파린의사용빈도가많아지게되고특히항혈소판제와의병용치료를하는경우가많아진것때문으로판단되고있다. 16,20 비타민 K 비의존성경구용항응고제의경우와파린과비교한여러임상시험의결과를종합할때평균 2년동안의추적관찰기간동안최대 3% 미만의환자에서두개내출혈이발생하였으며와파린보다유의하게두개내출혈발생위험성이낮았다. 4 또한임상시험이아닌최근의실제임상상황에서결과도크게다르지않았다. 21,22 와파린과연관된두개내출혈은일반적으로항응고제투여중이아닌상태에서발생한두개내출혈과비교하였을때예후가나쁘다. 와파린투여중발생한두개내출혈의사망확률은 44-68% 에달하며대부분두개내출혈발생수일내에사망한다. 23,24 이렇게사망률이높은이유는와파린과연관된두개내출혈이출혈량이상대적으로많고두개내출혈직후출혈의확 장이단시간에발생하며출혈이확장되는양자체도많기때문 이다. 25,26 비타민 K 비의존성경구용항응고제의경우실제임 상상황에서두개내출혈의발생빈도자체는와파린대비상대 적으로적은것으로입증되긴하였지만, 27 최근의실제임상상 황을대표하는대규모코호트연구결과에의하면전체 61 명의 비타민 K 비의존성경구용항응고제투여중발생한두개내출 혈의환자에서 28% 의환자가 3 개월째사망하였으며, 출혈의 확장을뇌 CT 나 magnetic resonance imaging (MRI) 를시행하 여확인한하위분석에서 38% 의환자에서출혈의확장이관찰 된바있고프로트롬빈복합농축물을투여하여도 3 개월째의 수정랜킨척도가프로트롬빈복합농축물을투여하지않는군 과비교해서차이가없었다. 28 따라서비타민 K 비의존성경구 용항응고제이비록두개내출혈의빈도는와파린에비해적지 만실제두개내출혈이발생하면그예후가나쁠수있음을주지 해야한다. 28 경구용항혈소판제와연관된두개내출혈은일차예방목적 으로투여시 1,000 인년당 0.2 건정도발생한다. 29 아스피린의 경우두개내출혈의위험이용량에비례하여증가하는것으로 Table 1. Risk factors for intracerebral hemorrhage in patients using anti-thrombotics 3,14,102 Proven risk factors Advancing age (especially > 75 years) Hypertension (especially systolic blood pressure > 160 mmhg) History of cerebrovascular disease Intensity of anti-coagulation (mainly if INR > 4.0) Possible risk factors Increased variation of INR Concomitant use of aspirin Cerebral amyloid angiopathy Tobacco smoking Heavy alcohol consumption Diabetes Serious heart disease Liver disease Malignancy Imaging and genetic markers Leukoaraiosis detected by brain CT/MRI Microbleeds by T2-Gradient recalled echo MRI APOE e2 or e4 genotype INR, international normalization ratio; CT, computed tomography; MRI, magnetic resonance imaging; APOE, Apolipoprotein E. 114

3 Yoonkyung Chang, et al. Anti-thrombotic associated intracerebral hemorrhage 보이며, 다른항혈소판제들도아스피린과비슷한결과를보였다. 7,30-38 한편, 이전연구에의하면, 혈소판의활성도를아스피린의경우 VerifyNow Aspirin, 클로피도그렐의경우 P2Y12 검사법으로측정하였을때, 혈소판의활성도감소는두개내출혈발생후 12시간뒤에측정한출혈량증가와관련되어있었으며뇌실내출혈량과 14일째사망률, 3개월째나쁜예후와도관련이있었다 두개내출혈환자를대상으로한아스피린과클로피도그렐을비교한후향적연구에서클로피도그렐사용군이아스피린투여군보다두개내출혈의크기가컸으며집으로의퇴원가능성이더낮았다. 또한사망률도증가하는경향을보였으나이는통계적으로유의하지는않았다. 42 따라서, 경구용항혈소판제와연관된두개내출혈도드물지않으며예후가좋지않을수있음을염두에두어야한다. 2. 경구용항혈전제와연관된두개내출혈의위험인자현재까지여러요인들이경구용항혈전제와연관된두개내출혈의위험인자로제시되고있다 (Table 1). 와파린의경우무엇보다 international normalized ratio (INR) 의상승이중요한출혈의위험인자이다. 일반적인치료범위인 INR 보다높은경우두개내출혈을포함한출혈가능성이높다. 뇌경색의 2 차예방을위해아스피린과와파린투여를비교한임상시험에서 INR을 로조절하였을때는, 두개내출혈을포함한주요출혈부작용이아스피린과차이가없었으나 43 INR을 로조절한연구에서는두개내출혈의발생이와파린군이아스피린에비해유의하게높아연구가조기중단된바있다. 44 또한, 여러연구들의결과를종합하여다수의환자를대상으로분석하였을때도 INR이 4.0가넘는경우유의하게와파린과연관된두개내출혈을포함한주요출혈의위험성이높았다. 45 이외에도항응고제와항혈소판제의병용투여, 고혈압, 흡연, 과도 한음주, 간기능이상, 암, 이전뇌출혈의병력, 그리고뇌아밀로이드혈관병의유전자검사소견 ( 아포지방단백 E ε2, ε4 alleles) 등이경구용항혈전제와연관된두개내출혈의위험인자로제시되었다. 3,14 최근에는뇌 T2 gradient recalled echo image 나 susceptibility weighted imaging에서관찰되는미세출혈 (cerebral microbleeds) 이항혈전제, 특히항응고제투여시향후두개내출혈발생의주요위험인자및영상바이오마커의하나로대두되고있다. 46 특히미세출혈이뇌의엽 (lobar) 부위에다수분포하는경우에는뇌아밀로이드혈관병의가능성이매우높으며뇌아밀로이드혈관병은그자체가출혈가능성이높은질환이기때문에항혈전제투여로인한출혈부작용과향후뇌경색예방효과의득실을고려하여투여를시행하여야한다. 47 비타민 K 비의존성경구용항응고제의경우비록무작위임상시험의하위분석이기는하지만심방세동환자에서 apixaban과아스피린의효과를비교한연구에서연구시작시점및 1년뒤 T2 gradient recalled echo MRI 영상을시행하였을때, 양군에서새로생긴미세출혈의빈도에차이가없었다. 따라서비타민 K 비의존성경구용항응고제의경우미세출혈의발생또는악화가능성이아스피린과유사할것으로판단되지만이에대해서는추가연구가필요하다 경구용항혈전제와연관된두개내출혈의치료두개내출혈의악화및확장을방지하기위해절대안정, 머리의위치를 30도이상올리기, 수축기혈압을 140 mmhg보다낮게조절하는등의기본적인처치를시행함과동시에역전제를포함한적절한약제투여가필수적이다. 이러한위급한상황에서무작위대조군연구를시행하는것은사실상불가능하기때문에무작위대조군연구결과는거의없다. 와파린과연관된두개내출혈환자에서 INR을어느정도까지낮추어야할지에대 Table 2. Recommendations for use of specific reversal agents in OAC-ICH ,103 Treatment Dose Timing of OAC reversal Special considerations Discontinuing OAC therapy days Vitamin K mg IV over 30 min 2-24 h Anaphylactoid reaction Fresh frozen plasma 15 ml/kg Infusion 3-6 h Reversal h Prothrombin complex concentrate UI/kg Infusion 10 min to 1 h Reversal 15 min Recombinant factor VIIa μg/kg Bolus injection Reversal 15 min Volume overload Three-factor concentrates may not adequately correct INR, limited availability, cost, variable cofactor content based on the manufacturer, potentially prothrombotic Short half-life, cost, potentially prothrombotic, uncertain safety OAC-ICH, oral anti-coagulant related intracerebral hemorrhage; OAC, oral anti-coagulant; h, hours; INR, international normalization ratio. 115

4 해목표치가명확하게밝혀져있지않은상황이며실제여러연구들에서는 <1.3 에서 <1.5 사이의다양한목표를사용한바있다. 19 근본적으로와파린을비롯한비타민 K 길항제를복용중인환자에서두개내출혈이발생했다면우선비타민 K 길항제를중단하고이후 INR을빠르게교정해야한다 (class I; level of evidence C). 49 이를위해비타민 K 신선냉동혈장 (fresh frozen plasma, FFP), 프로트롬빈복합농축물의투여가추천된다 (class IIb; level of evidence B) (Table 2) 그러나외국의경우출혈로인한응급상황에서프로트롬빈복합농축물투여가가능하지만우리나라에서는제도적인한계로인해프로트롬빈복합농축물을항시병원에비치할수없기때문에두개내출혈환자에게신속하게사용하기에는현실적으로어려운상황이다. 따라서, 비타민 K의빠른작용을위해비타민 K의정맥주사와가능하다면 FFP를병용투여하는것이우리나라의현실에서는최선이라할수있다. 와파린과연관된두개내출혈에투여할수있는길항제들을살펴보면비타민 K 주사는투여직후효과를나타내지는못하지만가급적빠른약효를기대하기위해정맥내투여를원칙으로한다. 용량은일반적으로 5-10 mg을투여한다. 작용시작시간은 2시간이며, 간기능이정상인경우약 24시간째최대작용점에다다른다. 52 FFP를투여하기위해서는해동과혈장교차시험 (thawing and cross matching) 의과정이필요하며, 수혈에따른알러지, 감염등의위험이있고완전히 INR을되돌리기위해서는많은양을투여해야하며이로인한혈액수액과다공급의부작용을고려해야한다. 53 프로트롬빈복합농축물은응고인자 IX 결핍 (B형혈우병 ) 의치료를위해개발된혈장유도응고인자농축물이다. 3-factor 프로트롬빈복합농축물은 factors II, IX, X을포함하고있으며 4-factor 프로트롬빈복합농축물은에는 factor VII이추가로포함되어있다. 프로트롬빈복합농축물은혈장교차시험이필요하지않고적은양 (20-40 ml) 을신 Figure 1. Management of bleeding in patients taking non-vitamin K antagonist oral anticoagulants. Possible therapeutic measures in case of minor or severe bleeding in patients on non-vitamin K antagonist oral anticoagulant therapy. 68 NOACs, Nonvitamin K Antagonist Oral Anticoagulants. 116

5 Yoonkyung Chang, et al. Anti-thrombotic associated intracerebral hemorrhage 속하게투여할수있는장점이있으며와파린을복용중이었던환자에서 INR을수분이내로빠르게정상화시킨다 그러나몇몇연구에서 INR의교정은빠르지만임상적예후가호전되지는않았기때문에이에대해서는좀더증거가필요하며, 26,57,58 교정후심부정맥혈전증이나뇌경색이발생했다는보고도있어주의가필요하다. 54 와파린과연관된두개내출혈환자에서 FFP 단독투여와 FFP 에프로트롬빈복합농축물을병용투여를비교한무작위배정연구에서 FFP 단독사용군은상대적으로많은양의 FFP를사용하여수액과다공급에의한부작용이더높았다. 59 FFP와프로트롬빈복합농축물을비교하였을때, 24명의두개내출혈환자를포함한 2,002명의급성출혈환자를대상으로한무작위배정비교연구에서 4-factor 프로트롬빈복합농축물이 FFP 에비하여열등하지않음을입증된바있다. 60 이연구에서, 치료종료 30분이내에 INR이 1.3 미만에도달하는비율은프로트롬빈복합농축물군에서 62.2%, FFP에서 9.6% 였다. 또한혈전색전증발생비율은유의한차이가없었으며 ( 프로트롬빈복합농축물군에서 7.8%, FFP 군에서 6.4%), 수액과다공급에의한부작용은 FFP 군에서더욱많았다 (12.8% versus 4.9%) factor와 4-factor 프로트롬빈복합농축물를직접비교한임상연구는현재까지시행되지않았다. rfviia은선천성 factor VII 결핍으로인한혈우병환자에서승인되어사용하고있으며, 자발성혹은와파린과연관된두개내출혈을치료하기위한약제로서의사용가능성이제시되고있다. 그러나 rfviia는 VKA 연관두개내출혈에서 INR를빠른속도로정상화할수있으나 비타민 K 의존성응고인자를모두다보충하지는못하므로프로트롬빈복합농축물만큼의효과를내지못한다. 66 그리하여, 현재까지와파린과연관된두개내출혈에단독으로 rfviia를사용하는것은추천되지않는다 (class III; level of evidence C). 49,67 비타민 K 비의존성경구용항응고제과연관된두개내출혈에서비타민 K 또는프로트롬빈복합농축물등의약제와비타민 K 비의존성경구용항응고제자체의역전제에대한무작위배정연구는연구결과가많지않다. 현재사용되는비타민 K 비의존성경구용항응고제 (dabigatran, rivaroxaban, apixaban, edoxaban) 들은와파린에비해상대적으로반감기가짧아 (5-15 시간 ) 우선적으로약제를중단하는것이최우선이며빠른교정을위해프로트롬빈복합농축물또는 rfvii를사용하는것을고려할수있다. FFP는유용성이밝혀져있지않고, 비타민 K는효과가없다. 68 Direct thrombin inhibitor (dabigatran) 에는 factor eight inhibitor bypassing activity (FEIBA) 혹은 rfviia가, factor Xa inhibitors인 rivaroxaban과 apixaban에는다른프로 트롬빈복합농축물이더효과적일것으로제시되었으나, 이는 예비결과로대규모임상시험결과가필요하다 수시간이내 에 dabigatran, apixaban, rivaroxaban 을복용하였을때에는활 성화차콜을사용하여가장최근복용한약물의흡수를억제 할수있다. 73 Dabigatran 에대하여는투석을고려해볼수있으 나, rivaroxaban 과 apixaban 은단백결합률이높아효과적이지 않을수있다 (Fig. 1). 62 각각의약물에대한특이적해독제가현 재임상개발단계에있으며 74 최근에는 dabigatran 역전제가임 상시험을통해효과와안전성이입증된뒤국내에서도사용이 가능해진상태이다. 75 항혈소판제와연관된두개내출혈의치료및혈종의크기증 가를막기위해혈소판수혈을고려해볼수있다. 76,77 아스피린 과클로피도그렐을사용하는환자에서 단위의혈소 판수혈을하였을때혈소판기능이정상으로회복되었다는보 고가있다 명의자발성두개내출혈환자에서혈소판억제 정도를측정후입원 12 시간내혈소판수혈을시행하였을때 혈소판억제정도가큰환자중에서 12 시간내에혈소판수혈 을받은환자는 12 시간이후혈소판수혈을받은환자군에비 하여혈종크기가덜증가하였으며또한좋은예후를보였다. 79 반면항혈소판제와연관된두개내출혈환자에서혈소판수혈 로역전을시도한 35 명과그렇지않은 31 명의임상경과와예 후를비교한다른연구에서는두군간에혈종의크기증가나 예후에차이가없었다. 80 더구나최근에발표된항혈소판제와 연관된두개내출혈환자에서혈소판수혈을통해항혈소판제 의효과를역전시키는치료에대한무작위배정연구 (platelet transfusion in cerebral hemorrhage [PATCH] trial) 에서는혈소 판을수혈한군이수혈하지않은군보다사망또는 3 개월째의 의존도 (dependence) 가유의하게높았다. 따라서항혈소판제와 연관된두개내출혈환자에서혈소판수혈을통한항혈소판제 의역전은더이상추천하기힘들다 경구용항혈전제와연관된두개내출혈환자에서항혈전제의재시작 항응고요법을시행하고있던환자들은항응고요법을중단하 면필연적으로혈전색전증의위험성이높아진다. 따라서대부 분의경우항응고요법을재시작해야할필요가있다. 한편, 두 개내출혈병력이있는환자들은추후두개내출혈을포함한출 혈이발생할가능성이두개내출혈의병력이없는환자보다높 다. 82 특히두개내출혈의재발위험은두개내출혈이후 1 년이내 에가장높으며특히두개내출혈이뇌의엽 (lobar) 에위치한두 개내출혈일경우더욱높다. 83,84 또한, 조절되지않는고혈압, 고 117

6 령화등도두개내출혈의재발의중요한위험인자이다. 83,85 고혈압은심부와엽에위치한두개내출혈모두의재발위험을높이며 85 고령에서의두개내출혈의위험증가는뇌아밀로이드혈관병의유병률증가또는다른동반질환들과이로인한항혈전제사용증가에의한것으로판단된다. 86 특히뇌아밀로이드혈관병은그자체가두개내출혈의재발의위험인자이며, 특히엽에위치한두개내출혈이잘발생한다. 85 또한아포지방단백 E ε2, ε 4 대립유전자가있는경우나 87 미세출혈의수가많을수록 ( 특히뇌의엽에위치했을경우 ) 두개내출혈재발의위험이크다. 86,88 심방세동을동반한뇌경색환자를대상으로장기간 ( 중앙값 2.5년 ) 추적관찰한연구에서연구에포함된환자의사망여부및사망원인과미세출혈의연관성을분석하였을때미세출혈이다수 (5개이상 ) 이거나뇌의엽에분포하는경우는향후두개내출혈로인한사망과유의하게연관되어있었다. 89 따라서미세출혈이뇌의엽부위에다수 (5개이상 ) 분포하는환자에서는항응고요법의재시작여부는신중히판단하여시행해야한다. 재출혈의위험성이높거나기타여러이유로인해항응고제를재시작하기가어려운환자에서는항혈소판제 ( 아스피린, 아스피린및클로피도그렐병용 ) 를사용하거나 90 좌심방폐색술 (percutaneous left atrial appendage closure) 91 등을고려해볼수도있다. 항혈소판제제는두개내출혈상태에서혈종의크기를증가시킬위험성을크게높이지않았으며 11,92 127명의엽에위치한두개내출혈환자와 80명의심부두개내출혈환자를대상으로한연구에서두개내출혈의재발에항혈소판제투여가관련이없었다. 93 따라서엽에위치한두개내출혈이나뇌아밀로이드혈관병으로인한두개내출혈환자에서항응고요법이어렵다면항혈소판제가대안이될수있다. 비타민 K 비의존성경구 용항응고제의경우일관성있게심방세동환자에서와파린보다두개내출혈의위험이낮은것으로보고되었으나 두개내출혈이후와파린대용으로사용이가능할지와두개내출혈의재발의위험을감소시키는지는명확하지않아추가연구가필요하다. 최근의진료지침에따르면와파린과연관된두개내출혈이후항응고요법의재시작에대해서두개내출혈환자에서두개내출혈의재발의위험인자로 (1) 엽에위치한두개내출혈 ; (2) 고령 ; (3) 미세출혈의유무및개수 ; (4) 항응고치료여부 ; (5) 아포지방단백 E ε2 or ε4 alleles 유무 (class IIa; level of evidence B) 등을고려할것을언급하였다. 그리고와파린과연관된두개내출혈중엽에위치한두개내출혈의경우는재발의위험성이높기때문에, 비판막성심방세동의치료로와파린등의항응고제의장기간투여를피할것을언급하였다 (class IIa; level of evidence B). 또한, 비엽성 (nonlobar) 두개내출혈의경우는혈전색전증의재발위험성이높은환자라면항혈소판제, 항응고제모두투여를고려할수있음을명시한바있다 (class IIb; level of evidence B). 49 와파린또는비타민 K 비의존성경구용항응고제와연관된두개내출혈이후항응고요법재개시기는연구에따라의견이분분하며이에대한무작위배정연구결과도없어근거가매우부족하다. 본종설에서는항응고요법을 2주이내재시작한 ( 대부분 72시간내재시작 ) 연구와 2주이후재시작한연구로나누어정리하였다 (Table 3). 결론적으로이전의연구결과들을종합해보면특별한이유가없다면적어도 2주뒤에항응고요법을재시작하는것이혈전색전증과재출혈의예방에좀더나은것으로판단된다. 비교적최근의 234명의와파린과연관된두개내출혈환자를 34주간추적관찰한연구에서는항응고요법을 Table 3. Main results of early versus late anti-coagulation with full-dose heparin or warfarin in patients with OAC-ICH Author Number of study population Anti-coagulation Rebleeding Embolism Phan et al Late 0 3 Bertram et al Early 3 3 Butler and Tait Early 1 3 Leker and Abramsky Early 0 0 Nagakawa et al Early 0 0 Kawamata et al Early 0 0 Lieberman et al Early 1 0 Summary of findings 83 5 (6.0%) 9 (10.8%) Early anti-coagulation 49 5 (10.2%) 6 (12.2%) Late anti-coagulation (8.8%) Early anti-coagulation was restarted within 14 days (mainly within 72 hours), Late anti-coagulation was restarted after 14 days. OAC-ICH, oral anti-coagulant related intracerebral hemorrhage. 118

7 Yoonkyung Chang, et al. Anti-thrombotic associated intracerebral hemorrhage 약 10주이후에시작하는것이허혈성과출혈성뇌졸중의위험을최소화하는것으로나타났으며이연구의저자들은혈전색전위험성을고려할때와파린과연관된두개내출혈이후이후적어도 4주이후에항응고요법을재시작하는것을제시하였다. 97 최근의진료지침에서도와파린과연관된두개내출혈이후재시작시기는근거가부족하며인공심장판막이있어상대적으로조기에항응고요법의재시작이필요한환자가아니라면최소한 4주간은경구항응고요법을피하는것을고려하도록하고있다 (class IIb; level of evidence B). 49 또한만약필요하다면두개내출혈이후수일내에아스피린단독투여를고려할수는있으나역시그시작시기에대한근거는부족함을언급하였다 (class IIa; level of evidence B). 49 두개내출혈을비롯한치명적인재출혈위험성에도불구하고항혈소판제를중단하는것에는위험이따른다. 일반적으로뇌혈관및심장혈관스텐트삽입술을시행받은환자에서항혈소판제를어떠한이유든중단하였을경우스텐트내혈전발생및심근경색, 뇌경색의위험성이높아진다 두개내에스텐트삽입술을시행받은환자도마찬가지로항혈소판제를중단하면뇌경색과일과성뇌허혈증이발생할위험성이높다. 101 따라서, 항혈소판제를절대적으로투여할수없는경우가아니라면항혈소판제투여가필요한환자에서는재투여를고려해야한다. 그러나항혈소판제와연관된두개내출혈환자에서항혈소판제를언제재시작해야하는지에대해서는근거가부족하다. 우선항응고제의재투여시의지침을참조할때두개내출혈 4주뒤재투여를시도해볼수있으며, 허혈성뇌경색을포함한혈전색전증의발생위험성이높은환자에게는두개내출혈이후수일내에투여도가능할수는있다. 이에대한해답을얻기위해서는향후신뢰도높은임상연구가필수적이다. 결론 와파린또는비타민 K 비의존성경구용항응고제와연관된두개내출혈은예후가좋지않을가능성이높기때문에신속한진단및치료가필수적이며와파린과연관된두개내출혈의경우는우리나라의현실에서는비타민 K와 FFP투여가권장된다. 와파린과연관된두개내출혈이후항응고요법을다시고려해야한다면위험인자및두개내출혈의위치등을고려하여재시작여부를결정하고적절한약제를선택하여야한다. 또한재시작시점은적어도 4주이후가적절하다고판단된다. 항혈소판제와연관된두개내출혈에서혈소판수혈은추천하기어려우 며두개내출혈이후항혈소판제재시작여부와시점에대해서는아직근거가부족하기때문에좀더연구가필요하다. Acknowledgements This research was supported by grants of Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A ). REFERENCES 1. Whitlon DS, Sadowski JA, Suttie JW. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry 1978;17: Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P; American College of Chest Physicians. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):630S-69S. 3. Schulman S, Beyth RJ, Kearon C, Levine MN; American College of Chest Physicians. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:257S-98S. 4. Kuznetsov S, Barcelona R, Josephson RA, Mohan SK. The Role of Nonvitamin K Antagonist Oral Anticoagulants (NOACs) in stroke prevention in patients with atrial fibrillation. Curr Neurol Neurosci Rep 2016;16: Campbell PG, Sen A, Yadla S, Jabbour P, Jallo J. Emergency reversal of antiplatelet agents in patients presenting with an intracranial hemorrhage: a clinical review. World Neurosurg 2010;74: Cantalapiedra A, Gutierrez O, Tortosa JI, Yañez M, Dueñas M, Fernandez Fontecha E, et al. Oral anticoagulant treatment: risk factors involved in 500 intracranial hemorrhages. J Thromb Thrombolysis 2006;22: Caso V, Paciaroni M, Venti M, Alberti A, Palmerini F, Milia P, et al. Effect of on-admission antiplatelet treatment on patients with cerebral hemorrhage. Cerebrovasc Dis 2007;24: Foerch C, Sitzer M, Steinmetz H, Neumann-Haefelin T. Pretreatment with antiplatelet agents is not independently associated with unfavorable outcome in intracerebral hemorrhage. Stroke 2006;37:

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