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The Korean Journal of Gastrointestinal Endoscopy Room B 항응고제및항혈소판제복용환자의내시경시술을위한관리 이옥재 경상대학교의학전문대학원내과학교실 Anticoagulation and Antiplatelet Therapy for Endoscopy Ok-Jae Lee, M.D. Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinu, Korea 서론 노령인구가증가함에따라심혈관및뇌혈관계혈전색전질환이나정맥혈전색전증과같이항응고제를필요로하는질환이점점늘고있으며, 항응고제및항혈소판제의종류가다양해졌을뿐만아니라새로운약제가계속개발출시되고있다. 내시경기기및기술이빠르게발전하면서진단및치료목적의내시경시술이많이시행되면서, 장기적인항혈전제를복용하는중에내시경시술을필요로하는환자도점점증가하고있다. 이러한상황에서항혈전제에대한적절한관리가임상적으로매우중요하다. 그러나내시경시술전후의적절한항혈전제의관리는결코간단한문제가아니며, 이에대한근거를제시할만한대규모의전향적무작위대조연구가현실적으로매우어렵기때문에근거가아직충분하지않다. 따라서이에대한가이드라인은현재까지의후향적인연구결과와전문가의의견을참고로하여수립하는실정이다. 1 결국항혈전치료를중단했을경우의혈전색전위험과내시경시술에따른출혈위험을비교ㆍ평가하여적절한결정을해야한다. 저자는 American Society for Gastrointestinal Endoscopy (ASGE) 및 British Society of Gastroenterology (BSG) 에서발표한가이드라인 1-4 과대한소화기내시경학회의진단 5 및치료 6 소화관내시경길잡이및이후의연구보고들을검토하여항혈전치료제를복용하는환자에서내시경시술을위한관리에대하여기술하고자한다. 본론 1. 항혈전제치료환자에서내시경시술전에고려할사항 우선내시경시술의긴급성과다음의위험성 ; (1) 항혈전제자체로인한출혈위험 (2) 항혈전치료중에시행할내시경시술자체의출혈위험 (3) 항혈전치료를중단한경우의혈전색전증의위험을고려해야한다. 내시경을대신할다른검사법 ( 예, 캡 슐내시경이나방사선조영술 ), 경구외항혈전치료제, 항혈전치료를모니터할검사등에대해서도숙지해야한다. 1 2. 항혈전제의종류및출혈위험 항혈전제는항응고제와항혈소판제로분류하며, 항응고제는와파린, heparin 및 LMWH (low molecular weight heparin) 이속하고, 항혈소판제에는아스피린, nonsteroidal anti-inflammatory drugs (NSAIDs), dipyridamole, thienopyridines (eg, clopidrogrel, ticlopidine) 및 glycoprotein IIb/IIIa receptor inhibitors 등이포함된다. 각항혈전제의종류와작용시간및항혈전작용에대한역전치료는 Table 1에요약하였다. 1 1) 항응고제 (1) 와파린 : 합성 coumarin유도체로비타민 K epoxide reductase를억제함으로써항응고작용을하며 cytochrome P450 에의해대사되는약제와약물상호작용을한다. 반감기는환자마다다르지만평균 40시간으로 4시간이면최고혈장농도에도달한다. 복용후 2일부터항응고효과가시작되어 5 7일에완전한항혈전치료효과에도달하고, 약제중단후 2 4일이면정상응고상태로회복된다. 8 항응고효과는 INR (international normalized ratio) 2 3이적절하고, 1.5 미만이면출혈위험이정상인과유사하다. INR이 4 이상인환자의약 81% 에서내시경검사로위장관출혈병변을확인할수있었으며 7 INR 6 이상은출혈위험성이더욱높다. 8 (2) 헤파린 (UFH, unfractionated heparin) 과 LMWH: 헤파린은가장흔히사용하는경구외항혈전제로 antithrombin III 의기능을활성화시키고 anti-xa 작용을증가시켜항응고효과를나타낸다. 즉각적인항응고효과가필요할때사용하며, 헤파린의효과는 APTT (activated partial thromboplastin time) ratio를측정하여모니터하는데 15 20 U/kg/day 용량으로시작하여 APTT가정상의 2배가량 (1.5 2.5) 연장되도록조절한다. 9 헤파린을사용하는환자에서 APTT ratio가 3 이상이면출혈위험이증가한다. 4 LMWH은헤파린과유사한항혈전효과를가지면서기존의헤파린에비해단백결합이적어용량에따른 152 The Korean Journal of Gastrointestinal Endoscopy

Table 1. Antithrombotic Drugs: Duration of Action and Routes for Reversal Drug class Specific agent (s) Duration of action Test to monitor Elective Routes for reversal Urgent Antiplatelet agents Anticoagulants Aspirin NSAIDs Dipyridamole Thienopyridines (clopidogrel, ticlopidine) GP IIb/IIIa inhibitors (tirofiban, abciximab, eptifibatide) Warfarin Unfractionated heparin LMWH 10 days Varies 2 3 days 3 7 days Varies 3 5 days 4 6 h 12 24 h BT INR APTT APTT NA NA Hold Hold NA Hold Hold Hold Transfuse platelets Transfuse platelets Transfuse platelets Transfuse platelets± desmopressin if overdose Transfuse platelets; in case of overdose, some agents can be removed with dialysis FFP±vitamin K, consider protamine sulfate* Hold or consider protamine sulfate* Hold or consider protamine sulfate* BT, bleeding rime; APTT, activated prothrombin time; NA, not applicable; NSAID, nonsteroidal anti-inflammatory drug; GP, glycoprotein; FFP, fresh frozen plasma; LMWH, low molecular weight heparin. *Caution: Can cause severe hypotension and anaphylaxis. Adapted from Gastrointest Endosc 2009;70:1060-1070. 1 항응고효과를예측할수있으며헤파린보다반감기가길면서출혈위험이적다. LMWH는피하주사가가능하고, HITT (heparin induced thrombocytopenia with thrombosis) 증후군의발현빈도가낮으며, 응고시간의측정없이몸무게에따라일정량을주입하므로외래에서도사용할수있다. 9 헤파린은중단후작용시간이 4 6시간까지지속되며, LMWH은 8시간이경과하면항응고작용이사라진다. 10 2) 항혈소판제 (1) 아스피린및 NSAIDs: 아스피린은혈소판의 cyclooxygenase (COX) 를비가역적으로아세틸화하여혈소판의 thromboxane A2 합성을억제함으로써혈소판응집을방해한다. 따라서혈소판의수명기간인 7 10일동안작용한다. 7 건강인에서아스피린복용후 3일이경과되면출혈시간과혈소판응집검사가정상화된다. 11,12 아스피린에비해 NSAIDs 는가역적으로 COX-1을억제하며, 내시경시술시출혈의위험성을증가시키지않는다. 13 (2) Adenosine diphosphate (ADP) 수용체억제제 (clopidogrel, ticlopidine): Clopidogrel과 ticlopidine은 thienopyridine 유도체로 ADP가혈소판막에존재하는 ADP 수용체에결합하는것을비가역적으로차단하여혈소판응집을방해한다. 14 투여 3 5일후에항혈소판작용을나타내며, 투약을중단하면 7 10일후에혈소판기능이완전히회복된다. Cytochrome P450 체계의 CYP2C19을통해활성화되므로이효소를억제하는 PPI (proton pump inhibitor), 특히오메프라졸을병용하면 clopidogrel 의항혈소판효과가감소된다. 15,16 Clopidogrel 의위장관출혈위험은아스피린보다는낮으며 (2.0 vs. 2.7%), 17 아스피린과 clopidogrel 을병용할경우에출혈위험이증가한다. 7 (3) Adenosine 재흡수억제제 (dipyridamole): Adenosine 의재흡수를억제하여항혈소판작용을나타내며아직까지고위 험내시경시술중의안전성은알려지지않았지만, 3 출혈의위험성이아스피린보다낮으며아스피린과병용해도아스피린의출혈위험을증가시키지는않는것으로보이므로, 18 표준용량을사용한다면내시경시술을위해중단할필요가없다. 1 (4) Glycoprotein IIb/IIIa 수용체억제제 (abciximab, eptifibatide, tirofiban): 혈소판응집의최종단계인 GP IIb/ IIIa 수용체와피브리노겐이결합하는것을억제하는주사제로, 중단후약효지속시간은 abciximab은 24시간, eptifibatide와 tirofiban은 4시간이다. 이약제들은중증출혈의위험도가높아급성관상증후군등의특수한경우에만사용하고있으며아직까지소개할만한연구결과가없어정확한치료지침이없다. 3 약제투여중생명을위협할정도의출혈을보이면사용을중단하고혈소판혹은 desmopressin 를투여할것을권고한다. 7 3. 내시경시술의출혈위험 (procedure risks) 내시경시술은출혈유발위험도에따라고위험시술과저위험시술로분류할수있다 (Table 2). 7 위험도가낮은시술은일반적으로출혈위험이 1% 미만인시술을지칭하며, 상부위장관내시경 (0.01 0.13%), 19 소장내시경 (0.1%), 19,20 대장내시경 (0 0.02%), 21,22 등의점막생검을포함한모든진단내시경검사와, ERCP 및조임근절개술 (sphincterotomy) 을시행하지않는담 / 췌관스텐트삽입술 (0.26%), 23 세침흡인을시행하지않는내시경초음파와캡슐내시경을포함한다. 위험도가높은시술은입원치료, 수혈, 내시경적지혈술또는수술을필요로하는정도의출혈을일으킬위험이 1% 이상으로알려진시술을말하며, 폴립절제술 (0.7 10.3%), 21,24-27 내시경점막절제술 (22%), 28 조임근절개술 (2.0 3.2%), 29,30 풍선 / 부우지확장술 (1.7%), 31 식도스텐트삽입술 (0.5 5.3%), 32-34 PEG Vol. 41 (Suppl 2), 2010 (152-165) 153

Table 2. Procedure Risk for Bleeding Procedure Low risk of bleeding (<1%) Diagnostic endoscopy with or without biopsy EGD Double balloon enteroscopy Colonoscopy ERCP, Biliary/pancreatic stent without sphincterotomy Endosonography without FNA Wireless capsule endoscopy High risk of bleeding ( 1%) Polypectomy Gastric Duodenal/ampullary 1 3 cm >3 cm Colonic Endoscopic mucosal resection Biliary sphincterotomy Pneumatic/balloon dilation in achalasia Esophageal stenting PEG placement Endosonography with FNA Laser ablation and coagulation Variceal sclerotherapy Variceal band ligation Thermal ablation and coagulation 0.01 0.13% 19 0.1% 19,20 0 0.02% 21,22 0.26% 23 * * 7.2% 24 4.5% 25 10.3% 25 0.7 3.3% 21,26,27 22%,28 2.0 3.2% 29,30 1.7%,31 0.5 5.3% 32-34 2.5% 35 1.3 6%,36-38 1.1% 39 4 25.4 % 40,41 2.4 5.7% 41,42 5% 2 Risk of bleeding EGD, esophagogastroduodenoscopy; FNA, fine-needle aspiration; PEG, percutaneous endoscopic gastrostomy; *Limited data, presumed negligible; Majority of bleeding in lesions >2 cm; Minor bleeding is reported commonly with balloon and bougie dilators 43 ; Negligible for solid lesions; Less ulceration in band ligation. Adapted from Am J Gastroenterol 2009;104:3085-3097. 7 (2.5%), 35 내시경초음파및세침흡인술 (1.3 6%) 36-38 및위장관출혈에대한지혈술 (1.1 25.4%) 2,39-42 등의치료목적의시술이속한다. 환자측의요인도시술후의출혈에영향을줄수있으며연령, 44,45 담관염, 혈액응고장애, 혈액투석등 29,46 이고위험내시경시술후출혈위험을높인다. 아직데이터는부족하지만신부전, 간경변증, 선천성 / 후천성혈액응고장애및혈소판감소증도고위험내시경시술중에출혈위험을높일수있다. 7 기타시술관련출혈위험도와관련하는요인으로내시경시술자의경험정도와병변의크기, 형태및폴립의위치와같은병변자체관련요인, 그리고폴립절제술에사용하는기술적인측면 (diathermy 열치료, endoloop 설치, 주입등 ) 을들수있다. 시술에따라서식도확장술이나스텐트삽입술과내시경초음파하세침흡인술에의해장기밖에혈종이생기는경우와같이내시경이도달하기어려운부위의출혈을일으켜수술을필요로함으로써이환율을증가시킬수도있다. 7 4. 혈전색전증의위험 (condition risks) 내시경시술을위해항혈전치료를중단할경우에혈전색전증 의발생가능성은환자가항혈전치료를필요로했던기저질환과관련하며, 혈전색전증의위험도에따라서저위험군과고위험군으로분류한다 (Table 3). 1,7 저위험군은심부정맥혈전증 (DVT), 판막질환과무관한만성또는발작성심방세동, 생체인공판막 (bioprosthetic valve), 인공대동맥판막치환술을한경우가속하고, 고위험군은심장판막질환환자, 인공판막치환술을받은환자, CHADS2 점수가 3 이상인환자에서동반된심방세동환자, 인공승모판막치환술을받은환자, 인공판막치환술의위치와무관하게이전에혈전색전증의병력이있는환자, 관상동맥스텐트 ( 특히 drug-eluting stent, DES) 삽입환자가포함되며특히최소권장기간이전에 dual antiplatelet therapy (DAT) 를중단한경우에는스텐트혈전의위험이높다. 1-4,7 American Heart Association (AHA) 의지침은 DES 삽입후 12개월간 DAT를지속할것을권장하고있다. 47 CHADS2 점수는 Congestive heart failure, Hypertension, Age>75, Diabetes mellitus, history of Stroke or transient ischemic attack (TIA) 의머리글자에서유래한용어로판막질환과무관한심방세동환자에서색전위험을정하는분류방법으로가장널리사용하는방법이다. 48 심부전증, 고혈압, 나이 75세 154 The Korean Journal of Gastrointestinal Endoscopy

Table 3. Condition Risk for Thromboembolic Event Atrial fibrillation Mechanical valve Coronary disease and stents DVT/PE Higher-risk condition Associated valvular heart disease, Prosthetic valves, Active congestive heart failure, Left ventricular ejection fraction<35%, A history of a thromboembolic event, Hypertension, Diabetes mellitus, Age 75 yr Discontinuing antiplatelet/anticoagulant in bioprosthetic valve <3 months Mechanical valve in mitral position Any position with previous thromboembolic event Recent acute coronary event <4 6 wks Recently (<1 yr) placed coronary stent Nonstented percutaneous coronary intervention after myocardial infarction Discontinuing dual antiplatelet therapy in: Drug-eluting stent <1 year Bare metal stent <1 month Discontinuing anticoagulation in event <3 months Recurrent DVT/PE Severe hypercoagulable states: active cancer, paroxysmal nocturnal hemoglobinuria, myeloproliferative syndromes Low-risk condition Uncomplicated or paroxysmal nonvalvular atrial fibrillation Bioprosthetic valve Mechanical valve in the aortic position Deep vein thrombosis DVT, deep venous thrombosis; PE, pulmonary embolism. Adapted from Gastrointest Endosc 2009;70:1060-1070 1 and Am J Gastroenterol 2009;104:3085-3097. 7 이상, 당뇨의점수를각각 1점으로산정하고, 혈전색전증의병력을 2점으로계산하여 0점에서 6점까지분류하여높을수록혈전색전증의발생위험이높다. 5. 항혈전치료제복용환자의계획된내시경시술 1) 항혈전치료중내시경시술에의한출혈위험 (1) 진단내시경 : 아스피린은복용후 48시간까지출혈시간 (bleeding time, BT) 을연장시키지만, 49 아스피린이나 clopidogrel 투여중에조직생검을포함한진단내시경검사로인해출혈빈도가증가하였다고입증한임상보고는없었다. 와파린도출혈위험이낮은시술을하는경우에는내시경시술전후에중단하지않고지속해도출혈위험도가낮았다. 50 대장내시경선별검사의경우에는저위험군이라도와파린을일시중단하고시행하여폴립절제술까지시행하는것이가장비용-효율적이다. 51 또는와파린을그대로사용하면서검사를시행하고폴립절제술이필요한크기의폴립이있는경우에나중에와파린을중단하고시술을다시시행해야한다. 고위험군도폴립절제술의가능성을염두에두어와파린을중단하고 bridge therapy를하면서검사를시행하며, 폴립크기가작고, INR이 <2.5이며내시경시술자가폴립절제술후출혈을충분히관리할수있으면절제술을시행한다. 7 (2) 대장폴립절제술 : 아스피린 /NSAIDs은복용하는중에폴립절제술을해도출혈의증가는없거나 1% 미만이었으며, 13,52 와파린은데이터가제한적이지만복용중에폴립절제술을시행 하거나폴립절제술후 1주이내에와파린이나헤파린의투여를재개한경우에출혈위험은증가하였다. 53 항혈전제복용환자 31명에서 1 cm 미만의폴립을절제한후예방적헤모클립을시행했을때출혈률이 0 3.3% 로낮았다는보고 54-56 가있었으나, 아직무작위대조연구가없어서확실한임상데이터가부족하고비용으로인해현재로서는예방적헤모클립이나분리형올가미의일괄적인사용은권장하지않는다. 1 (3) Sphincterotomy 및 PEG: 아스피린이나 NSAID는조임근절개술을시행하기 7일전부터중단해도출혈위험을줄이지못한다. 57 그러나와파린이나시술후 3일이내헤파린정맥투여는조임근절개술후출혈위험을증가시켰다. 58 항혈전치료중인환자에서 PEG의출혈위험은알려진정보가없다. 2) 계획된내시경시술전항혈전제중단의위험 : DVT와같이항혈전치료가일시적인경우에는가능하면항응고치료가더이상필요하지않을때까지계획된내시경시술을연기한다. 특히최근에관상동맥스텐트삽입을받은환자에서는스텐트폐쇄로인하여급성관상동맥증후군및사망까지이어질수있으므로시술을연기해야한다. 59-61 만일항혈전치료중인환자에게내시경시술을하기로결정했다면항혈전제의중단이나역전치료여부를환자개개인에따라차별화해야한다. 시술을위해역전치료로써비타민 K를투여하는것은항응고제투여를재개했을때치료효과를지연시키기때문에피해야한다. 62 2006 AHA/American College of Cardiology (ACC) 가이드라인은혈전위험이낮은환자 (Table 3) 에서는시술전에와 Vol. 41 (Suppl 2), 2010 (152-165) 155

파린을그냥중단하고헤파린 bridge therapy는일반적으로필요하지않다고권고하고있다. 항응고제를 4 7일간중단한환자에서색전증의절대적인위험은약 1% 이다. 63,64 최근에 1,024 명을대상으로대장내시경, 안과수술, 구강수술등의계획된시술을위하여와파린을중단한 1,293건에대해조사한대규모의전향적다기관연구 63 가보고되었다. 와파린중단기간은다양했지만 80% 이상이응고제를 5일미만중단하였고 8.3% 에서만헤파린 /LMWH bridge therapy를받았다. 시술관련출혈을보인환자의 61% 가헤파린 bridge therapy를받았으며, 연구대상가운데 0.7% 인 7명만이시술후 30일이내에혈전색전증을경험했으며 7명모두 bridge therapy를받지않았다고보고하면서장기적인항응고요법을하고있는환자가가벼운외래시술을시행하는경우에 5일이하의와파린중단은혈전색전증의위험을높이지않는다고하였다. 따라서가벼운시술을할경우에는 bridge therapy를결정하기에앞서출혈위험과혈전색전의위험을비교평가하여환자에따라차별화할필요가있다. 3) 내시경시술을위한 bridge therapy 의역할 : 와파린을사용하는혈전색전증고위험환자는내시경시술을전후하여작용시간이짧은 UFH (unfractionated heparin) 나 LMWH으로 bridge therapy를할수있다. Bridge therapy에대한증거는제한적이지만, LMWH으로 bridge therapy를하면서내시경시술을받은 98명의환자에서혈전색전증은발생하지않았으며, 의미있는출혈도오직 2예에서만발생했는데내시경이나치료와는무관한출혈이었다. 65 심방세동 / 심장판막질환환자에서계획된침습적시술시의항응고제의관리에대한 AHA/ACC 가이드라인을 Table 4에요약하였다. 66-68 4) 계획된내시경시술후항혈전제의투여재개 : 내시경시술을마친후항혈전치료제투여를재개하는적절한시기에대한컨센서스는아직없다. 혈전색전증의예방을위해항혈전제투여를즉시재개함으로써얻는이점과이로인한출혈위험을비교ㆍ평가해야하고, 시술에자체에의한출혈위험을고려하여결정해야할것이다. 1 AHA/ACC 가이드라인은심장판막질환이있지만혈전색전증의위험이낮은환자에서는시술 24시간내에와파린투여를재개하고혈전색전증의위험이높은환자에서는출혈이안정되는대로최대한빨리 UFH나 LMWH 투여를재개하고 INR이적절한치료수준에도달할때까지지속해야한다고권고하였다. 치료목적의시술을마친후 UFH는 2 6시간후에재투여하며 Table 4. Periprocedural Management of Warfarin for Patients with Atrial Fibrillation or Valvular Heart Disease Undergoing Elective Endoscopy Condition Associated diagnosis Management Atrial fibrillation Valvular heart disease None Mechanical valve(s) and/or history of cerebrovascular accident, transient ischemic attack, or systemic embolism Mechanical bileaflet, aortic valve Mechanical mitral valve or mechanical aortic valve plus any of the following: atrial fibrillation, previous thromboembolic event, left ventricular dysfunction, hypercoagulable condition, mechanical tricuspid valve or >1 mechanical valve Hold warfarin 3 5 days before procedure. Restart warfarin within 24 h.* Hold warfarin and start UFH when INR 2.0. Stop UFH 4 6 h before procedure and restart after procedure. Resume warfarin on the evening of the procedure and continue both agents until INR is therapeutic.* Therapeutic doses of SQ UFH or LMWH may be considered in lieu of IV UFH. Hold warfarin 48 72 h before procedure for a target INR <1.5. Restart warfarin within 24 h.* Hold warfarin and start UFH when INR 2.0. Stop UFH 4 6 h before procedure and restart after procedure. Resume warfarin on the evening of the procedure and continue both agents until INR is therapeutic.* Therapeutic doses of SQ UFH or LMWH may be considered in lieu of IV UFH. UFH, unfractionated heparin; INR, international normalized ratio; SQ, subcutaneous; LMWH, low molecular weight heparin; *Continuation or reinitiation of anticoagulation should be adjusted according to the stability of the patient and estimated risks surrounding the specific intervention/procedure performed. This table was adapted from the following guidelines: 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines 66 and American College of Cardiology/American Heart Association 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 67 156 The Korean Journal of Gastrointestinal Endoscopy

LMWH 의적절한투여재개시기는알려져있지않다. 1 6. 항혈전제치료중에급성출혈이발생한환자에서의응급내시경시술 1) 항혈전치료환자의급성위장관출혈 : 장기간의항응고제복용의부작용으로발생하는출혈가운데위장관출혈이가장흔해서 69 와파린을복용하는환자의약 5% 에서급성위장관출혈이발생한다. 70 이와같은경우에는항응고제의중단에의한혈전색전증의위험과항응고제유지로인한심각한출혈위험이공존하고, 한편으로항응고치료에대한적극적인역전치료 (reversal) 의여부와중단후투여재개의시기를결정해야하는문제로치료는매우복잡하고어려워진다. 2) 급성위장관출혈환자에서항응고치료중단의위험성 : 급성위장관출혈상황에서항응고제중단의위험에대해알려진것이많지않으며, 급성위장관출혈로인하여와파린을 4 15 일중단했을때혈전색전증은없거나매우낮았다. 71,72 3) 급성출혈환자에서항혈전제를어떻게할것인가?(Stopping or reversing antithrombotic agents in the acutely bleeding patient): 항혈전제의중단, 감량, 역전치료여부의결정은이로인한혈전색전증발생위험과항혈전제를유지함으로써계속될출혈위험을비교ㆍ평가해서환자별로차별화하여판단해야한다. 생명을위협할정도의심각한출혈의경우라면항응고치료의위험이혈전색전증의위험을능가하므로약제의중단과함께즉시적극적인역전치료를해야하고 (Table 1), 7 출혈이적절하게조절된것을확인할때까지투여를재개하지말아야한다. 그러나대부분의경우위험도를명확하게판단하기가어려우므로항응고제를처방한심장전문의나혈액전문의와의긴밀한협진을통해환자개개인의상황에맞는처치를해야한다. American College of Chest Physicians의지침에따르면, 생명을위협할정도의심각한출혈환자에서는와파린은중단하고비타민 K 10 mg을천천히정주하고 FFP, 프로트롬빈복합농축제제, 재조합응고인자 VIIa를투여를고려하도록권고하였다. 73 그러나 AHA/ACC 지침에서인공판막을가진환자에서는루틴으로고용량비타민 K (10 mg) 을투여할경우과다응고상태를초래할위험이있으므로피해야한다고하였다. 74 고용량비타민 K보다는 FFP가더적절하며저용량의비타민 K (1 2 mg) 을단독으로또는 FFP와함께투여하는것이적절하다. 항혈소판제의경우는사용중인환자가심각한생명을위협하는출혈을할경우약제를중단하거나약제중단과함께혈소판을수혈할수있다. 1 그러나 clopidogrel 을복용하는고위험환자에서는중단하기전에심장전문의와협의하여야한다. 만일 clopidogrel을중단할필요가있는상황이라면중단기간을최대한 5일로제한해야한다. 항혈전제를지속하거나최소기간만중단하면서조기에내시경시술을시행하여지혈하는것 을최우선목표로해야한다. 4 4) 급성위장관출혈을동반한항혈전제복용환자에서내시경치료의유효성 (Efficacy of endoscopic therapy in patients actively taking antithrombotic agents): INR이치료범위를벗어나는 ( 4) 환자를대상으로위장관출혈을조사하였을때약 81% 에서내시경검사상병변을확인할수있으므로 75 위장관출혈증상을보이는모든환자에서내시경검사를시행해야한다. 다행히도항응고치료환자에서가장흔한출혈부위는내시경치료가가능한범위내에있으며상부위장관에서는소화성궤양이이러한환자들의약절반정도를차지하고, 69,70,76,77 하부위장관에서는게실출혈이다. 78,79 따라서항혈전제복용중에위장관출혈이발생한환자에서내시경검사와치료는타당할뿐만아니라안전하다. 70 이와같은상황에서안전하고성공적인내시경치료를위해어느정도의 INR 값이필요한가는아직전향적연구데이터가없지만, INR을 1.5 2.5 또는 1.3 2.7로교정하면항응고제치료를받지않는일반환자와마찬가지로내시경진단과여러가지지혈술을성공적으로시행할수있다. 69,80 내시경지혈술후즉각적인항응고제투여가필요한고위험환자에서는연구보고는없지만헤모클립과같은기계적인지혈술이더유용할수있다. 1 5) 내시경지혈술후항혈전제투여의재개 : 대부분의환자에서지혈후에항혈전제의투여재개가필요하지만, 투여재개의시기에대한데이터는부족하다. 항혈전제투여재개의여부도심장전문의나혈액전문의와의긴밀한협진을통해환자개인별로차별화해야한다. 일반적으로혈전색전위험이재출혈위험을능가하는경우에투여재개를고려해야하며출혈부위의적절한지혈이이루어진경우에고려하게된다. 항응고제의시급한투여재개가요구되는고위험환자에서는와파린투여재개전에비교적작용시간이짧은 UFH 정주로 bridge therapy를하면재출혈시에즉시중단하거나역전치료가가능하기때문에 LMWH보다장점이있다. LMWHs는 UFH보다반감기가길고 protamine sulfate에의한역전치료효과가적다. 1,7 아스피린과관련된궤양출혈환자에서는재출혈을막기위해 clopidogrel으로전환하는것보다는아스피린과 PPI를병용하는것이더유용하다. 81,82 급성위장관출혈환자에서지혈술후아스피린을 30일간중단한경우와 3 5일에투여를재개한경우를비교하였을때, 재출혈률은 11% vs. 19% 로낮았으나 2 개월후사망률은 14.5% vs. 1.7% 로더높았다. 83 다른항혈소판제는투여재개의시기에대한데이터는아직없다. 7. DAT 중인혈관스텐트 / 급성관상동맥증후군환자의내시경시술 1) Elective endoscopy ( 계획된내시경시술 ): 혈관스텐트, 급성관상동맥증후군, 뇌혈관질환환자에서아스피린과 clo- Vol. 41 (Suppl 2), 2010 (152-165) 157

pidogrel 병용과같은 DAT가임상에서점점늘고있다. ACC/ AHA 지침에따르면금속스텐트삽입후최소한 1개월의 DAT 가, DES 삽입후나경피관상동맥중재술을받은환자에서는출혈위험이높지않으면 12개월의 DAT가이상적이다. 60,84 한종류의항혈전제복용에비해 DAT는상부위장관출혈위험을 3배증가시킨다. 85 이와같은출혈위험에도불구하고, 특히 DES 환자에서 DAT의조기중단은스텐트혈전의발생률을높이므로가능하면이약제들을중단하지말아야한다. 86 따라서지금까지의증거로볼때, DAT 치료환자에서는모든계획된고위험시술은환자가 ACC/AHA 지침에서권고하는최소의치료기간을완료할때까지연기해야한다. 84 일단최소치료기간이경과하면환자및관련된자문의사와논의하여위험도와얻을수있는이점을비교평가한후에시술의진행여부를결정해야한다. 2가지항혈전제중어느약제를중단했을때내시경시술로인한출혈위험이낮은지비교한연구는없다. 다만, clopidogrel 과아스피린의혈전색전증위험의감소효과를비교한무작위전향적연구에서 clopidogrel이아스피린보다허혈성 stroke, 심근경색및혈관질환으로인한사망의위험을줄이는데유효했다. 17 그러나현재까지 clopidogrel 을복용중인경우보다는아스피린을복용하는중에폴립절제술의안전성을보고한데이터가훨씬많다. 13,52,53 따라서, 일반적으로항혈전제 2가지중 clopidogrel을중단하고 aspirin을유지하면서내시경을시행한다. 1-4,7 2) 급성관상동맥증후군 (ACS) 또는최근에혈관스텐트를삽입한환자에서의응급내시경 : 많은 ACS 및최근혈관스텐트삽입환자가혈소판 glycoprotein IIb/IIIa 수용체길항제를포함하여여러가지약제를동시에사용하고있으며, ACS 환자의 1 3% 에서첫입원중에위장관출혈이발생한다. 86-89 ACS 상황중에위장관출혈이발생한환자는위장관출혈이없는 ACS환자에비해입원중사망률이 4 7배증가한다. 87,88 이러한상황에서임상의는시술로인한합병증의위험이높은환자에게내시경검사를진행해야하는가하는딜레마에빠지게된다. 90,91 급성심장발작이일어난당일에내시경을받은환자에서시술합병증은 12% 로높지만, 91 심근경색후상부위장관내시경의전체합병증빈도는약 1 2% 이며 90 대장내시경의합병증빈도는 1% 이다. 91 급성심근경색증발작후 30일이내에내시경검사를받은 200명에대한후향적조사에서위염, 위궤양, 십이지장궤양, Mallory-Weiss 열상등의다양한병변이발견되었다. 90 이와같이급성위장관출혈자체가급성심근경색증을유발할수도있으므로, 이러한환자에서내시경검사는유용하다. 또한위장관출혈후에급성심근경색이발생한환자가급성심근경색증치료후에위장관출혈을보인환자보다내시경치료를더필요로하였다고한다. 89 ACS 환자나최근에혈관스텐트를삽입환자에서 DAT 및 glycoprotein IIb/IIIa 억제제를포함한항혈전제의복용중에도 내시경검사는안전하지만, 이에대한정보는새로운경험과지식이축적됨에따라지속적으로발전하고변화하고있어서, 약제중단여부에대한강력한지침을정하기는매우어렵다. 따라서약제를중단하기전에심장전문의, 신경과전문의등과의협의가필요하다. 요약 1. Recommendations 다음의권고안은 the strength of the supporting evidence (Table 5) 92 를기초로작성한 2009년 ASGE 지침의권장사항 1 과 2008년 BSG의가이드라인 4 을요약한것이다. 약한권고사항은 suggest 로표기하였고, 강력하게권고할내용은 recommend 로표기하였다. 1) Elective procedures (Fig. 1, Table 6) (1) 일시적인항응고제치료를받는환자 ( 예, DVT로와파린을복용하는환자 ): 계획된내시경시술은항혈전치료를완료할때까지연기한다 (suggest). (2) 아스피린및 / 또는 NSAIDs: 모든내시경시술에도지속한다 (recommend). 고위험시술예정인경우에는환자의항혈소판제적응증인기저질환에따라서시술전 5 7일간아스피린 &/or NSAIDs의중지를고려할수있다. (3) 최근혈관스텐트삽입했거나 ACS환자 (DAT) 1 계획된내시경시술을적절한전문기관의현재지침에서권장하는항혈전제의최소투여기간 ( 금속스텐트삽입후최소한 1개월, DES 삽입후나경피관상동맥중재술후 12개월 ) 을완료할때까지연기한다 (recommend). 2 최소투여기간을경과하면 clopidogrel 이나 ticlopidine 을시술전약 7 10일간중지하고아스피린은지속한다 (suggest). 3 아스피린을복용하지않는환자는내시경시술전후에 clopidogrel을중단하는동안아스피린을복용하면혈전색전증의위험을감소시킬수있다. 4 Clopidogrel이나 ticlopidine은환자의상태와내시경시술을고려하여시술후곧투여를재개할수있다. 환자의심장전문의나다른적절한전문가와협의하여적절한치료를결정한다. (4) Clopidogrel 과 ticlopidine을 3의적응증외에사용한경우 1 저위험내시경시술 : 중단하지않고유지한다 (suggest). 2 고위험내시경시술 : 시술하기약 7 10일전에중단한다 (suggest). ᄀ환자가아스피린을복용하면아스피린은지속한다. ᄂ아스피린을사용하지않는환자는내시경시술전후에 clopidogrel을중단하는동안아스피린을복용하면혈 158 The Korean Journal of Gastrointestinal Endoscopy

Figure 1. Management of antithrombotic agents in the elective endoscopic setting. Adapted from Gastrointest Endosc 2009; 70:1060-1070. 1 Figure 2. Management of antithrombotic agents in the urgent endoscopic setting. Adapted from Gastrointest Endosc 2009; 70:1060-1070. 1 Table 5. GRADE System for Rating the Quality of Evidence for Guidelines Quality of evidence Definition Symbol High quality Moderate quality Low quality Very low quality Further research is very unlikely to change our confidence in the estimate of effect Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Any estimate of effect is very uncertain Weaker recommendations are indicated by phrases such as "we suggest", whereas stronger recommendations are typically stated as "we recommend". Adapted from BMJ 2008;336:924-926. 92 Vol. 41 (Suppl 2), 2010 (152-165) 159

Table 6. Management of Anticoagulant and Antiplatelet Agents for Endoscopic Procedures Low-risk condition High-risk condition Elective endoscopy Postpone endoscopy for patients on temporary anticoagulation therapy (eg, warfarin for DVT) Low-risk procedure Aspirin/NSAIDs Continue aspirin/nsaids Warfarin Continue warfarin Check INR 1 week before endoscopy If INR within therapeutic range, continue usual daily dose If INR above therapeutic range but <5, reduce daily warfarin dose until INR returns to therapeutic range. If INR 5, postpone endoscopy & contact reasonable consultant Clopidogrel Continue clopidogrel High-risk procedure Aspirin/NSAIDs Continue or stop for 5 7 days Continue aspirin/nsaids Warfarin Stop warfarin 5 days before endoscopy Check INR prior to procedure to ensure <1.5 Restart warfarin evening of procedure with usual daily dose Check INR 1 week later to ensure adequate anticoagulation Stop warfarin 5 days before procedure & Bridge therapy Start LMWH 2 days after stopping warfarin Omit LMWH on day of the procedure Restart warfarin evening of procedure with usual daily dose Restart LMWH 1 day after procedure Continue LMWH until INR adequate Clopidogrel Urgent endoscopy; Acute GI bleeding Warfarin Clopidogrel/ticlopidine Stop clopidogrel 7 days before endoscopy Continue aspirin if already prescribed If not on aspirin, then consider aspirin therapy while clopidogrel discontinued Stop warfarin until hemostasis is achieved FFP, prothrombin complex concentrate, and/or vitamin K should be individualized Protamine reserved for life-threatening bleeding on heparin because of anaphylaxis and severe hypotension risk Stop antiplatelet until hemostasis is achieved Transfuse platelets for life-threatening or serious bleeding Discuss with cardiologist Stop clopidogrel 7 days before endoscopy if; >12 months after insertion of DES >1 month after insertion of bare metal coronary stent Continue or prescribe aspirin Restart clopidogrel on day following the procedure Consult cardiologist if; recently (<1 year) placed vascular stent &/or ACS before stopping warfarin Stop warfarin for life-threatening bleeding Correct anticoagulation if supratherapeutic INR After hemostasis, timing for resumption of anticoagulation individualized If high-risk stigmata for rebleeding (eg, visible vessel) then use IV UFH Consult cardiologist if; recently (<1 year) placed vascular stent &/or ACS before stopping antiplatelet agent NSAIDs, nonsteroidal antiinflammatory durgs; INR, international normalized ratio; LMWH, low molecular weight heparin; DES, drug eluting stent; ACS, acute coronary syndrome; UFH, unfractionated heparin. Adapted from Gastrointest Endosc 2009;70:1060-1070 1 and Gut 2008;57:1322-1329. 4 전색전증의위험을줄일수있다. ᄃ Clopidogrel 이나 ticlopidine 은환자의상태와내시경시에시행하는치료를고려하여시술후곧투여를재개할수있다. ᄅ Clopidogrel 을중단기간에계획된내시경시술을시행하지못하고기간을넘기게되면 clopidogrel 을다시투여하고시술날짜를다시잡을것을고려해야한다. ᄆ Clopidogrel: 환자의주치심장전문의와협의한후에만 160 The Korean Journal of Gastrointestinal Endoscopy

clopidogrel 의중단을고려해야한다. 또한내시경시술담당의는내시경수술이필수적인가를확인해야한다. (5) 항응고제복용환자 1 저위험내시경시술 : 항응고제를중단하지않고지속한다 (suggest). ᄀ와파린을사용하는환자는 INR을검사하여치료범위를초과하지않도록한다. ᄂ환자가와파린을유지하도록하고내시경시술 1주일전에 INR을검사한다. ᄃ NR이치료범위이내라면현재사용용량을유지한다. ᄅ INR이치료범위를넘고 <5이면치료범위이내로회복하도록와파린일일복용량을감량한다. ᄆ INR 5 이상이면내시경시술을연기하고담당심장전문의나항응고제처방의와협의해야한다. 2 고위험내시경시술, 저위험환자 ; 와파린등의항응고제는일시중단한다 (suggest). ᄀ내시경시술 5일전에와파린을중단한다. ᄂ내시경시술전에 INR을검사하여 <1.5를확인한다. ᄃ내시경시술당일밤에와파린평소용량의투여를재개한다 (bridge therapy필요가없다 ) ᄅ시술 1주후에 INR을검사하여적절한항응고효과를유지한다. 3 고위험내시경시술, 고위험환자 : 와파린은일시중단하고, brdige therapy의적응이되면 LMWH이나 UFH으로 bridge therapy로전환한다 (suggest). ᄀ와파린을시술 5일전에중단해야한다. ᄂ와파린중단 2일후 LMWH 치료용량을시작한다. ᄃ시술당일에는 LMWH를생략한다. ᄅ시술시행한당일밤에와파린투여재개가권장된다. ᄆ시술 1일후에 LMWH 치료용량을재개한다. ᄇ INR이치료범위에도달할때까지 LMWH를지속한다. 항응고제를복용하지않는환자와비슷한정도로시술후출혈위험이있음을환자에게고지하여야한다. 6 항응고제복용환자에서폴립절제술후기계적클립의예방적사용에대한근거는아직충분하지않다. 7 내시경중재술후에적절한항응고제치료의재개시기 : 아직콘센서스가없으며, 시술에따른상황과환자의항응고제투여적응기저질환에따라결정한다. 혈전색전증의예방에있어서의즉각적인항응고제치료재개의이점과출혈위험을비교평가하여환자개인별 (case-by-case basis) 로결정한다 (suggest). 고위험환자는 UFH나 LMWH bridging therapy를가능한즉시시행하고, 와파린은출혈이없으면시술당일투여를재개한다 (suggest). UFH는내시경치료시술후 2 6시간부터재개할수있다. 내시경시술후 LMWH을재개하는적절한시기는아직결정된바가없다. 저위험환자 (Table 3) 는시술후출혈 이없다면와파린을시술당일저녁부터재개하고, bridge therapy는필요가없다 (suggest). 8 인공심장판막을가진임산부의내시경시술 : 계획된내시경시술은가능하면출산할때까지연기하고, 연기가불가능하면 LMWH나 UFH bridge therapy를고려한다 (recommend). 환자의심장전문의및산과의와협진을해야한다. 2) Urgent and emergent procedures (Fig. 2, Table 6) (1) 항혈소판제를복용하는급성위장관출혈환자 ; 지혈될때까지약제를중단한다 (suggest). 생명이위독한출혈이나심각한출혈환자는혈소판투여가도움이될수있다. 최근 1년이내에혈관스텐트를삽입한환자나 ASC환자에서의미있는출혈이발생했다면, 항혈소판제를중단하기전에심장전문의와의협의가요구된다 (suggest). (2) 항응고제를복용하는급성위장관출혈환자 ; 지혈될때까지약제를중단한다 (recommend). FFP, 프로트롬빈복합농축제제, 비타민 K 등의투여는환자개인에따라결정해야한다. 프로타민은아나필락시스및심각한저혈압의위험이있으므로, 생명위급한출혈환자에게만제한해야한다 (suggest). 최근 1년이내에혈관스텐트를삽입한환자나 ACS 환자가의미있는출혈을보일경우항응고제를중단하기전에약제를처방한전문가와협의를해야한다 (recommend). (3) 효과적인내시경치료에필요한적정수준의 INR이결정된바는없지만, 와파린복용중에치료범위의 INR을벗어난급성위장관출혈환자는항응고상태를교정해야한다 (recommend). (4) 항응고치료를재개해야만하는환자에서내시경지혈술후에재출혈의절대적인위험도는알려지지않았으며, 항응고제의재개시기는환자개인에따라정해야한다. 혈관노출과같은재출혈의위험이높은징표를보이는환자에서는초기에작용시간이짧은 UFH bridge therapy를한다 (suggest). 결론항응고제나항혈소판제를복용하는환자에게내시경시술이필요한경우, 복용중인약제를어떻게관리해야하는가는내시경시술에의한출혈위험성과약제를중단했을때의환자의혈전색전증위험성, 내시경시술의긴박성, 약제의종류를고려하여결정해야한다. 일반적으로출혈위험이낮은내시경시술을할때에는모든항응고제나항혈소판제의조정이나중단이필요하지않다. 출혈위험이높은내시경시술의경우계획된시술을할때에는아스피린과 NSAIDs는중단할필요가없으며, 환자의혈전색전증의위험도에따라서저위험환자에서는환자의상태에따라지속하거나시술전에중단할수있고, 고위험 Vol. 41 (Suppl 2), 2010 (152-165) 161

환자에서는와파린은 3 5일전에 clopidogrel은 7 10일전에중단하고 LMWH나 UFH로 bridge therapy를시행한다. 응급내시경이필요한급성출혈환자에서는지혈이될때까지항응고제나항혈소판제를중단하고생명이위독한심각한출혈의경우혈소판이나항응고제의역전치료를할수있고, 만일환자가최근 1년이내에혈관스텐트를삽입했거나급성관상동맥증후군환자라면약제를중단하기전에환자의심장전문의와협의를하여야한다. 이러한지침은현재까지알려진정보와과학적근거를기초로하여내시경을시행하는임상의가환자를적절하게진료하는데도움을주고자하는권장사항으로절대적인규칙이라할수는없다. 여러국가의관련기관에서지속적으로최신가이드라인을새로이발표해온것처럼, 향후의여러연구에서얻는새로운정보와경험이더욱축적되면현재의지침은계속변경될것이다. 따라서이러한새로운지침을잘숙지하고환자의여러가지상황을고려해서적용해야한다. 참고문헌 1. ASGE Standards of Practice Committee, Anderson MA, Ben- Menachem T, Gan SI, et al. Management of antithrombotic agents for endoscopic procedures. Gastrointest Endosc 2009; 70:1060-1070. 2. Eisen GM, Baron TH, Dominitz JA, et al. Guideline on the management of anticoagulation and antiplatelet therapy for endoscopic procedures. Gastrointest Endosc 2002;55:775-779. 3. Zuckerman MJ, Hirota WK, Adler DG, et al. Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy. 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