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1 대한소화기내시경학회지 2007;35(Suppl. 1): Managing Anticoagulation and Antiplatelet Agents around Endoscopic Procedure 원광의과대학소화기내과학교실, 소화기질환연구소 최석채ㆍ김기훈 서 최근서구화된생활습관에따라관상동맥질환, 뇌졸중, 심부정맥혈전증등의치료및예방목적으로항응고제와항혈소판제의사용이늘어나면서색전및혈전증의예방과치료측면에서는장점이있지만부작용으로출혈및내시경시술과연관된출혈의위험성을증가시킨다. 출혈경향환자의확인은문진및이학적소견에서항응고제나항혈소판제의약제복용유무를확인하고객혈, 토혈, 흑색변, 혈변과, 간, 신질환등의출혈성경향이있는전신질환에대한평가가필요하다. 검사실소견으로는혈소판수, PT, PT INR, aptt, BT 등이있고, 이중항응고제를복용하는경우는 PT INR을측정하는것이임상적으로유용하다. 1,2 내시경에연관된출혈위험도는진단목적으로사용하는경우 0.03% 로낮지만, 3 치료내시경은진단내시경 론 에비하여출혈의위험성이증가하며시술위험도에따라저위험군과고위험군으로분류한다 (Table 1). 3,4 하지만시술자의숙련도, 시술의위험성, 기저질환, 항응고제등사용하는약제의용량과용법등의요인들에따라출혈의합병증발생빈도는다양할수있다. 예를들면항응고제사용시약제의치료적인측면을강조하면내시경과연관된출혈의합병증이증가하지만, 내시경에의한출혈합병증을줄이기위한약제의용량과용법을줄이면혈전과색전위험이증가하여치명적결과를가져올수있다. 즉두가지의관점에서균형적인노력이필요하며, 이에관련된논의는미국의경우가이드라인 5,6 이있고, 국내에서는대한소화기내시경학회세미나에서다루어졌다. 7-9 본고에서는특히내시경시술과연관된항응고제와항혈소판제를사용하는환자에서출혈의예방및치료에대한관점을기술하고자한다. Table 1. Risk of Bleeding during Endoscopic Procedures (greater than 1%) (less than 1%) Polypectomy Gastric (4%) Colonic (0.2 to 3%) Mucosectomy (2% to 5%) Endoscopic sphincterotomy (2% to 3%) Ampullectomy Treatment of varices PEG* Fine needle aspiration (by EUS)* Pneumatic dilation* EUS-guided therapy EGD (±biopsy) Sigmoidoscopy (±biopsy) Colonoscopy (±biopsy) ERCP without dilation or sphincterotomy Diagnostic EUS Enteroscopy Polypectomy with use of a detachable snare Esophageal stenting *These procedures may induce bleeding that cannot be controlled endoscopically. This is not proven but could reduce the risk of polypectomy when the polyp is pedunculated. 328

2 최석채ㆍ김기훈 :Managing Anticoagulation and Antiplatelet Agents around Endoscopic Procedure 329 본 1. 항응고제사용과위장관출혈및혈전색전증의위험도 항응고제의종류는 warfarin, coumadine, unfractionated heparin, LMWH (low molecular weight heparin) 이있고, 약물의사용에따라위장관출혈위험도및내시경시술과연관된합병증이증가되지만투약을중단하면혈전색전증의위험이증가한다. 따라서항응고제를사용시출혈을줄이고효과적인혈전색전증을예방하기위한전략을마련해야한다. 이를뒷받침하는연구로는 Gerson 등 10 의보고에의하면항응고제를꾸준히복용하고있는 104명에서 171회의내시경시술을분석한결과 111회의내시경시술은출혈위험성이낮은시술, 60회가용종절제술을포함한고위험시술이었다. 혈전색전증위험도는 86명이저위험군, 18명이고위험군이었다. 이환자에서미국의내시경가이드라인의근간을 5 이루고있는분류에따라치료한결과내시경관련또는혈전색전증의합병증은없었다. 항응고제의사용과출혈의연관성은잘밝혀진합병증으로가능한위험인자들로는항응고제의용량, 65세이상의고령, 위출혈의기왕력, 심근경색, 신장질환등다른질환과동반된경우, 아스피린또는비스테로이드성소염진통제를같이복용하는경우증가한다. 11,12 이외에도 PT INR이 2.0 이상, 최근 3개월내와파린치료를한경우, 3가지이상의동반된질환이있는경우에서출혈의위험성이높지만고령, 고혈압등은위험인자가아니라는연구도있다. 13 병원에입원한환자의경우에서는고용량의항응고제사용은뇌출혈등의중대한합병증을유발하여사망률을증가시킬수있어세심한주위가요구된다. 14 특히 INR이 6.0 이상인경우에는위장관출혈과뇌출혈의합병증이높다는 론 전향적연구결과가뒷받침하여주고있다. 15 하지만오랜기간항응고제를복용한경우는급성위장관출혈의유발및사망률에서약제를복용하지않는경우와차이가없다는보고도있다. 16 출혈및혈전색전증의합병증은예방및조기진단이중요하다. 가능한예방법으로는잘알려진위험관련인자를줄이는노력을하여야하고, 조기진단법으로는위장관출혈을유발하므로대변잠혈검사및 Hct을측정하자는보고 17 와 1.6 age+1.3 sex+2.2 malignancy의계산법을이용한예측모델을제시한연구도있다. 18 항응고제사용에의한위장관출혈의치료는조기에내시경을이용한조기지혈술이효과적이다. 16,19 혈전색전증위험군은만성심부정맥혈전증, 판막질환과관련없는만성혹은발작성심방세동, 생체인공판막 (bioprosthetic valves), 대동맥기계판막등의저위험군과기계판막을포함하여판막질환과연관된심방세동, 기계승모판막, 혈전색전증의기왕력이있는기계판막환자등의고위험군으로분류할수있다. 4,5 저위험군에서는 4 7일간항응고제를중단하여도거의혈전증이발생하지않지만, 5 급성심부정맥혈전증의경우발생후빨리항응고제를사용하지않으면재발률이높다. 20 만일재발이반복되면치명적인경과를보일수있어 최소한 1 6 개월간의투약이필요하다. 특히 1 3개월내발생된급성혈전색전증의경우는재발위험이매우높기에 24 지속적인투약이필요하다. 심인성동맥색전증의경우에는정맥보다재발위험이높고치명적인경과 25 를보이므로항응고제치료가필요하고약제를중단하여야하는경우세심한주의가필요하다. 하지만장기간항응고제를복용하는경우에는약제를중단하여도위험도는급성기에비해낮다. 26 고위험군인기계판막환자의경우는혈전색전증발생률은 8% 로높지만, warfarin을투여하여 INR을 3 Table 2. Recommendations for the Management of Anticoagulation, Aspirin and NSAID Use Inpatients Undergoing Endoscopic Procedures Based on the Relative Risks of the Procedure and Underlying Condition 5 Procedure risk Condition risk for thromboembolism Discontinue warfarin 3 5 days before procedure. Consider heparin while INR is beow therapeutic level Discontinue warfarin 3 5 days before procedure. Reinstitute warfarin after procedure No change in anticoagulation. Elective procedures should be delayed while INR is in supratherapeutic range.

3 330 대한소화기내시경학회지 2007;35(Suppl. 1): 로유지하는경우 75% 까지위험을감소시킬수있으므로 27,28 항응고제의지속적투여가중요하다. 저위험시술의경우는혈전색전증의발생위험도에관계없이항응고제를조절할필요가없는 4,5 경우가많다. 고위험시술의경우와파린은시술 3 5일전에중단하고, 저위험군의경우는주의깊게 PT INR을관찰하면서 INR 1.5미만에서시술을시행한다. 그러나고위험군의경우는투약중인항응고제를중단하면혈전색전증의발생이증가하기에 INR이치료수준이하로떨어지면반드시 heparin이나 unfractionated heparin을정맥으로투여하다가시술 4 6시간전에중단하며, 시술 2 6시간후에다시사용한다 (Table 2). 5 최근에는 LMWH이혈전색전증예방에는효과적이며출혈이나혈소판감소등의합병증이적어 heparin 을대체하고있어, 6 ACCP (American colledge of chest physicians) 에서도 bridge therapy로권고 29 하고있지만전향적인장기추적연구가부족하다. 사용용량은급성심부정맥혈전증등의경우처럼 antifactor Xa activity가 12시간지속되는것을고려하여 12시간마다 enoxaparin 1 mg/kg을피하로주입하며, 고위험시술 8시간전에중단하여야한다 (Table 3). 6 단기계판막을가진임산부에서는판막의혈전발생을증가시켰다는보고들이있어 30 금기이며, 임산부가아닌기계판막의경우는단기간사용한다. 31 치료가성공적으로이루어진후항응고제의재사용은환자의시술종류, 출혈위험도에따라결정되어진다. 일반적으로고위험시술의경우에도시술후출혈위험도가낮다면당일저녁에 warfarin을다시투여 5 하면서 heparin과 4 5일간또는 INR이 2 3을유지할때까지병용을한다. 32 이유는 warfarin의효과가늦기때문이다. 하지만유두괄약근절개술의경우는 3일안에항응고제를사용하면출혈위험이 10 15% 로높아지므로약제를재투여할경우주의가요구된다. 33 결론적으로항응고제의사용시효과적인출혈및 Table 3. Management of LMWH in Patients Undergoing Endoscopic Procedures 6 Procedure risk Recommendation Consider discontinuation at least 8 h before procedure No change in therapy Reinstitution of LMWH should be individualized. 혈전색전증예방을위하여가이드라인의제정과이를토대로한내시경세미나같은교육이필수적이다. 하지만최근영국의연구에서항응고제를복용하는경우내시경시행시합리적인가이드라인또는근거를토대로치료를하는가? 에대한설문연구에서부정적인결과를보인것은우리의현실을대변할수있다 항혈소판제 아스피린, NSAID 외에도 thienopyridine (clopidogrel R, ticlopidine R ), dipyridamole, PLT GP IIb/IIIa 수용체억제제등의항혈소판제가혈소판의활성화와접착, 응집을억제하여관상동맥질환, 뇌졸중, 말초혈관질환등에서혈전색전의예방에좋은효과를기대하고많이사용되어지고있다. 하지만항응고제와같이내시경시술과관련된출혈의합병증문제가대두되고있다. 아스피린은주로급성심근경색과같은순환기질환의일차또는이차합병증예방목적으로사용되어지고주로 mg의저용량이사용되어진다. 이약제에의한위점막의변화에대한내시경연구에서 mg의저용량은 mg의고용량을투여한것보다위점막손상을많이유발하고, 특히서방형제재가적게일으킨다. 35,36 이는저용량의 81mg 서방형아스피린을비교한내시경연구에서위약군에비하여위궤양의발생차이가없어이를입증해주었고, rofecoxib 25 mg과 aspirin 81 mg/day, 또는 ibuprofen 800 mg 을 3회투여한군에서는많은위궤양이발생하였다. 37 Clopidogrel과아스피린의비교에서는위장관출혈은아스피린에서위험도가높고, 타장기에서의출혈은차이가없다. 38 메타분석에의한보고는저용량아스피린의위장관출혈에대한상대적위험도는 2.07이고, 39 위험인자로는과거위출혈의기왕력이있거나, 스테로이드사용, 항응고제와같이복용하는경우등에서출혈경향이증가하는것으로알려져있다. 39,40 이러한아스피린과 clopidogrel에의한위궤양및점막손상의예방은 PPI의사용에의하여줄일수있다. 41,42 내시경시술시진단내시경및조직검사만을시행하는경우, 즉저위험도의시술의경우에는항혈소판제의사용을중단할필요는없을것이다. 하지만고위험도시술의경우는출혈의위험성이있기에약제의조절이필요하다. 용종절제술과관련된연구는 Yousfi 등 43 의연구에서 2개의기관에서 20,636번의용종절제술중 101명에서출혈이발생하였고이중 81명이용종절제술전아스피린을복용하고있었다. 이환자들과약제를복용하지

4 최석채ㆍ김기훈 :Managing Anticoagulation and Antiplatelet Agents around Endoscopic Procedure 331 않은경우와비교한연구를보면약제복용군에서 40%, 대조군에서 33% 의출혈이발생하였고, 두군사이에서유의한차이는없었다. Hui 등 44 의연구에서도항혈소판제의사용은용종절제술후출혈에영향을미치지않는다고비슷한결론을내렸다. Shiffman 등 45 의연구에서도위및장내시경후조직검사, 용종절제술전아스피린과 NSAID의복용은경한지연성출혈은증가 (6.3%) 시키지만다량의중한정도의출혈은약제를복용하지않은경우와차이가없었다. 하지만저용량 aspirin 투여중에도작은대장용종의 hot biopsy 시출혈위험이증가할수있다는 46 상반된보고도있기에주의를필요로한다. 만약에출혈의위험성이있다면얼마만큼의기간동안항혈소판제의사용을중단할수있는지에대한연구는거의없다. 하지만한건강한지원자를대상으로한연구를보면아스피린은 3일, ticlopidine은 5일, 두약제를같이복용하는경우는 7일정도중단이좋다. 47 이연구는실제로환자를대상으로한연구가아니며대상자수가적어서추후이를입증하는연구가필요하다. 내시경을이용한유두괄약근절개술은췌담도의폐쇄원인및치료를위하여많이이용되어진다. 기저출혈질환이없는경우에도 90% 의의사들은용종절제및유두괄약근절개술시표준용량의아스피린또는 NSAID의사용을중단한다. 48 Hui 등 49 은시술전아스피린의복용은출혈을증가시키고, 1주일이상약제를중단하면이를줄일수있다는긍정보고를하고있다. 하지만이연구는후향적연구이고대상자의수가적은등제한점이많은연구이다. 하지만잘계획된환자대조군연구에서는유두괄약근절개술에의한출혈의 Table 4. Management of Antiplatelet Medication (Clopidogrel or Ticlopidine) for Endoscopic Procedures 6 Procedure risk Recommendation Consider discontinuation 7 10 day before procedure No change in therapy Patients on combination therapy (e.g., clopidogrel and aspirin) may be at an additional increased risk of bleeding For acute GI hemorrhage in the patient on clopidogrel or ticlopidine, the decision to transfuse platelets should be individualized, usually weighing the risk of an acute cardiovascular event against continued bleeding 위험성을증가시키지않는다는상반된보고를하고있다. 50 대표적으로많이연구되어진용종절제술과내시경을이용한유두괄약근절개술시항혈소판제의중단여부, 기간, 용량등에대한과학적입증이적은상황이다. 특히혈소판표면의 ADP P2 수용체결합을억제하는새로운개념의항혈소판제인 clopidogrel과 ticlopidine의경우는거의연구가없지만저위험시술은약제를중단할필요가없고, 고위험시술의경우시술 7 10일전에중단을고려해야한다는미국내시경학회의가이드라인이제정되었다 (Table 4). 결 출혈위험이높은내시경적시술의증가에따라안전한내시경을시행하기위해서세심한주의가필요하다. 특히항응고제및항혈소판제의사용이늘어나면서진단및치료목적의내시경시행시약제지속여부를결정해야한다. 출혈경향환자의임상상은다양하기에안전한내시경을시행하기위한단일기준을만드는것은어렵다. 이에미국가이드라인및대한소화기내시경학회세미나를기준으로시행되어져야한다. 또한순환기내과, 혈액내과, 신경과등과의긴밀한협조관계를통해시술에따른합병증과투여약제의조절에따른혈전색전증위험성을예방하는전략이요구된다 론 참고문헌 1. Van Os EC, Kamath PS, Gostout CJ, Heit JA. Gastroenterological procedures among patients with disorders of hemostasis: evaluation and management recommendations. Gastrointest Endosc 1999;50: Zachee P, Vermylen J, Boogaerts MA. Hematologic aspects of end-stage renal failure. Ann Hematol 1994;69: Newcomer MK, Brazer SR. Complications of upper gastrointestinal endoscopy and their management. Gastrointest Endosc Clin N Am 1994;4: Hittelet A, Deviere J. Management of anticoagulants before and after endoscopy. Can J Gastroenterol 2003;17: Eisen GM, Baron TH, Dominitz JA, et al. American Society for Gastrointestinal Endoscopy. Guideline on the management of anticoagulation and antiplatelet therapy for endoscopic procedures. Gastrointest Endosc 2002;55: Zuckerman MJ, Hirota WK, Adler DG, et al. ASGE guideline: The management of low-molecular-weight heparin and nonaspirin antiplatelet agents for endoscopic procedures. Gastro-

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76세여성환자가속쓰림으로시행한위내시경검사에서위각부전벽에약 1.0 cm 크기의조기위암이발견되었다. ( 그림4) 환자는평소고혈압과, 1 년전뇌졸증의병력이있어서 clopidogrel 75 mg을복용중이었다. 시술전신경과와심장내과협진을하였고, 왼쪽소뇌에뇌경색흔적과, 오른쪽폐동

76세여성환자가속쓰림으로시행한위내시경검사에서위각부전벽에약 1.0 cm 크기의조기위암이발견되었다. ( 그림4) 환자는평소고혈압과, 1 년전뇌졸증의병력이있어서 clopidogrel 75 mg을복용중이었다. 시술전신경과와심장내과협진을하였고, 왼쪽소뇌에뇌경색흔적과, 오른쪽폐동 5 월대한소화기내시경학회교육자료 - 항혈소판, 항응고제사용환자에서의안전한내시경시술 - 인구의고령화와생활및식습관의변화에따라서고혈압과당뇨병등의유병률이증가하고있다. 심혈관계질환을치료하거나, 1차또는 2차예방목적으로아스피린이나다른항혈소판제를복용하는환자가늘고있다. 항혈소판제나항응고제를복용하는경우시술여부와관계없이위장관출혈의위험성이증가되는것으로알려져있다. 내시경검사전에이러한약제를사용하고있다면약제를중단할것인지,