CASE REPORT 외상으로인한진행성출혈이동반된와파린복용환자에서의새로운경구항응고제의적용 충북대학교병원 * 외상외과, 마취통증의학과 예진봉 * ㆍ설영훈 * ㆍ이진영 * ㆍ고승제 * ㆍ최정희 Adaptation of New Oral Anticoagulants for Warfarin Anticoagulated Patient with Traumatic Ongoing Hemorrhage Jin Bong Ye, M.D.*, Young Hoon Sul, M.D., Ph.D.*, Jin Young Lee, M.D.*, Seung Je Go, M.D.*, Jung Hee Choi, M.D. Departments of *Trauma Surgery and Anesthesiology and Pain Medicine, Chungbuk National University Hospital, Cheongju, Korea Correspondence to: Young Hoon Sul, M.D., Ph.D. Department of Trauma Surgery, Chungbuk National University Hospital, 776 1sunhwan-ro, Seowon-gu, Cheongju 28644, Korea Tel: +82-43-269-7847 Fax: +82-43-269-7810 E-mail: ssulyh@gmail.com ORCID: http://orcid.org/0000-0003-3184-3396 The traditional drug for anticoagulation in those with a high risk of thrombosis is a vitamin K antagonist, such as warfarin. On the other hand, this drug has several limitations and hemorrhagic complications. Recently, novel or non-vitamin K-dependent antagonist oral anticoagulants (NOACs) have been developed to solve these problems. This paper presents a case of adaptation of NOAC for a warfarin anticoagulated patient with traumatic ongoing hemorrhages with a discussion of the clinical implications of NOAC. (J Acute Care Surg 2018;8:33-37) Key Words: Anticoagulants, Warfarin, Trauma, Hemorrhage, Non-vitamin K-dependent antagonist oral anticoagulants Received May 31, 2017, Accepted January 12, 2018 Copyright 2018 by Korean Society of Acute Care Surgery cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. ISSN 2288-5862(Print), ISSN 2288-9582(Online) https://doi.org/10.17479/jacs.2018.8.1.33 서론 심방세동, 인공판막치환술등색전증을야기할수있는고위험군의환자에서는예방적항응고요법목적으로현재까지가장널리사용되던약제는비타민 K 길항제인와파린 (warfarin) 이다. 그러나약동학적인불안정성으로치료효과를나타내는범위가적은단점이있고, 그로인한부작용으로출혈성합병증이흔히 보고되고있는것이현실이며, 출혈성합병증이의심되는경우에는항응고제를중단하고심한경우신선냉동혈장이나비타민 K를투여하며응고이상을교정해야할필요성이있다. 최근에는이런항응고제를대체할수있는약제로새로운경구항응고제 (novel or non-vitamin K-dependent antagonist oral anticoagulant, NOAC) 가개발되었으며, 혈액검사를통한모니터링이없이색전증이발생할수있는고위험군의환자를대상으로혈전색전등의 J Acute Care Surg Vol. 8 No. 1, April 2018 33
J Acute Care Surg Vol. 8, No. 1, Apr. 2018 예방을위해많이사용되는등그효과가각광을받고있다. 저자들은와파린을복용하던환자에서외상후진행성출혈이관찰되어혈관조영술을통한색전술을시행하여지혈을유도한후혈전색전증의예방을위해 NOAC을적용한증례를보고하며 NOAC에관한최신문헌을고찰하고자한다. 증례 82세남자환자가내원 7일전실내에서넘어지면서우측옆구리를부딪힌후발생한우측옆구리의통증및종괴로타박상의증하에인근병원에서입원치료를시행하던중, 내원 2일전부터우측옆구리의통증이악화되고종괴의크기가증가되어혈액검사및복부단층촬영을시행하였으며, 혈색소수치 5 g/dl 및복부단층촬영상복벽및후복막강혈종이의심되어농축적혈구 (packed red cell) 5 units을수혈하며본원으로전원되었다. 환자는과거력상고혈압및심방세동으로약물복용을하던중 10년전뇌졸중이발생하였으며, 6년전부터심부정맥혈전증, 폐동맥 색전증이동반되어와파린 7.5 mg/day를복용하였다. 본원내원당시환자의 Glasgow coma scale은 15점이었으며, 활력징후는혈압 147/76 mmhg, 맥박 114회 / 분, 호흡수 20회 / 분, 체온 36.8 C였다. 이학적검사상우측옆구리에서 15 10 cm 크기의반상출혈을동반한종괴에서압통및열감이관찰되었으나, 그외복부에서복막자극증상은관찰되지않았다. 본원에내원하여시행한일반혈액검사상백혈구수치는 21,400/mm 3, 혈색소수치는 6.0 g/dl, 혈소판수치는 225,000/mm 3 였으며, 혈액응고검사상프로트롬빈시간 (prothrombin time, PT; %) 은 2.4%, 국제표준화비율 (international normalized ratio, INR) 이 13.09, activated partial thromboplastin time은 117.4초였다. 본원에서시행한복부단층촬영상우측복벽및요근, 장요근의혈종에서조영제의활동성유출을동반되어있었으며 (Fig. 1), 혈관조영술을통한색전술을시행하였다 (Fig. 2-4). 시술후기존항응고요법을중지하고, 신선동결혈장과비타민 K를보충하며 INR을교정하였다. 이후우측옆구리의통증은점차호전되는양상을보였으며, 내원 7일후부터 enoxaparin Fig. 1. Initial computed tomography (CT) findings showing extravasation (white arrows). (A) Abdominal wall hematoma, (B) intramuscular hematoma of psoas muscle, (C) intramuscular hematoma of ilio-psoas muscle. Fig. 2. Angiography for abdomial wall hematoma. (A) Pre-embolization showing extravasation (white arrow), (B) post-embolization showing no extravasation. 34 www.jacs.or.kr
Jin Bong Ye, et al: Adaptation of New Oral Anticoagulants Fig. 3. Angiography for intramuscular hematoma of psoas muscle. (A) Preembolization showing extravasation (white arrow), (B) post-embolization showing no extravasation Fig. 4. Angiography for intramuscular hematoma of ilio-psoas muscle. (A) Pre-embolization showing extravasation (white arrow), (B) post-embolization showing no extravasation. 40 mg/day로예방적항응고요법을시행하였고, 기존폐동맥심부정맥혈전증선별검사를목적으로흉부단층촬영을시행하였고. 검사결과양측심부정맥의혈전이관찰되었다. 내원 10일후 NOAC (edoxaban, 2.5 mg qd, [once daily]) 로항응고요법을교체하였으며, 내원 13일후퇴원하여현재는외래에서특별한혈전색전증의후유증없이추적관찰중이다. 고찰 혈관색전증의고위험군환자들에게있어서경구용항응고제는일상생활중장기적으로복용하여야하는약물이다. 기존의비타민 K 길항제는간에서합성된이후, vitamin K conversion cycle을통하여카르복실화 (carboxylation) 되어활성화되는혈액응고인자 II, VII, IX, X, protein C, protein S에서 vitamin K conversion cycle을경쟁적으로억제한다. 이들인자의불활성화를통하여혈액응고인자 II, VII, IX, X이관여하는혈액응고과정 (coagulation cascade) 의내인성및외인성경로 (intrinsic and extrinsic pathway) 를억제하는약제이다 [1]. 비타민 K 길항제는비타민 K 섭취, 간에서의약물대사, 유전적영향등다양한상호작용이존재하여, 임상에서여러가지제한점을가지게된다. 첫째, 약물의작용이나타날때까지걸리는시간이길어, 빠른시간내에항응고효과를보는것이필요한환자는헤파린 (heparin) 과같은약제를가교치료 (bridging therapy) 로사용해야하며. 반감기가길어수술또는시술전에수일간복용을중지하고 PT가낮아졌는지측정해야하는불편이있다. 둘째, 항응고요법이필요한환자의경우심혈관계질환을가지고있는경우가많이있는데와파린은 cytochrome P450 (CYP) 2C9에의해부분적으로대사되기때문에대표적인억제자인아미오다론 (amiodarone) 이와파린과같이처방되는경우에는와파린의용량조절에주의가필요하다. 셋째, 약물대사와관련된 CYP 2C9과비타민 K 대사에관련된 VKORC1 유전자의다형성으로개인별와파린용량의차이도발생하는경우도있다. 넷째, 치료효과가나타나는영역이좁아잦은모니터링이필요하며, 끝으로, 다양한식품들이대사나작용에영향을미치므로주의를요구한다. 이러한제한점은혈관색전증의합병증으로인해뇌졸중의과 www.jacs.or.kr 35
J Acute Care Surg Vol. 8, No. 1, Apr. 2018 거력이있거나, 대부분의환자군이고령임을감안하였을때, 치료의순응도를떨어뜨리는원인이라할수있으며, 그로인해출혈이라는심각한합병증을유발하기도한다. 항응고요법을시행받은환자는항응고요법을받지않는환자에비해출혈성합병증이발생한위험도가 5배더높은것으로보고되고있으며, 출혈성합병증이발생하는부위도두경부내출혈, 소화기계통의출혈, 후복막강출혈등으로다양하게보고되고있다 [2,3]. 본증례에서는발작성심방세동및폐동맥색전증의과거력이있는자가고용량의와파린을복용하고있었으나, 치료순응도가떨어지는상기원인들로인하여경미한외상에도활동성출혈이동반된다발성혈종이발생하였다. 이에최근에는비타민 K 길항제에비하여고위험뇌졸증환자에게서사용하기훨씬쉽고안전한약물로 NOAC을권고하고있다. 북미와유럽의심장학회가이드라인의하면비판막상심장질환자에서심방세동이있을경우항응고요법의대상이되는환자들은와파린과 NOAC을사용할수있다고권고하고있고, 유럽학회는 NOAC을임상적판단하에와파린보다우선해서사용하는것에대한경우를권고강도 IIa, 증거수준 A로권하고있다 [4-6]. NOAC 작용기전은혈액응고과정의최종공통경로인응고인자 X이활성화 (activated factor X, factor Xa) 되어응고인자 II인프로트롬빈을트롬빈 (thrombin) 으로활성화시키는과정를직접억제하는것으로 (Fig. 5), 최근직접적트롬빈억제제인 dabigatran 과직접적인응고인자 Xa 억제제인 rivaroxaban, apixaban, edoxaban 등이개발되었다 [1,7,8] 이들약물은예측가능한약역동학을보이므로혈액검사를통하여혈중농도를확인할필요가없으며투여후빠른작용을보이며약을끊으면비교적빠른시간내에약물효과가사라지고. 다른약물이나음식과의상호작용이거의없어서기존의비타민 K 길항제의제한점을많이보안하였다고볼수있겠다. NOAC의경우비교적약동학적으로안정적이지만신장으로 Fig. 5. Coagulation cascades of new oral anticoagulants. 주로배설되기때문에, 중등도의 P glycoprotein 억제제인아미오다론, 베라파밀 (verapamil), 퀴니딘 (quinidine), 에리트로마이신 (erythromycin), 클래리트로마이신 (clarithromycin) 등과동시처방을할경우, 75 80세이상의고령, 60 kg 이하의저체중, 크레아티닌청소율 (creatinine clearance, Ccr) 30 50 ml/min의중등도신기능저하환자에서는용량을감량하여야하며, 아직까지아스피린 (aspirin) 이나클로피도그렐 (clopidogrel) 과같은항혈소판제를같이사용하는경우에연구데이터가부족하여마찬가지로용량을감량하여야한다. 또한강력한 P glycoprotein 억제제인 human immunodeficiency virus protease 억제제 ( 리토나비르, ritonavir), 경구용케토코나졸 (ketoconazole) 을포함한아졸계항진균제 ( 이트라코나졸 [itraconazole], 보리코나졸 [voriconazole], 포사코나졸 [posaconazole]) 를사용중인환자이거나 Ccr 30 ml/min 혹은혈청크레아티닌농도 (serum creatinine, Cr) 1.5 mg/dl 미만인신기능저하환자의경우금기증에속한다 [9]. 또한주의를요하지않는환자에게있어서약물의조절은대개필요하지않지만 NOAC 을복용하는모든환자는매년혈액검사를통한신기능의추적관찰이필요하며 Ccr 30 49 ml/min의신기능저하자에게사용시는일년에 2 3회정도신기능의추적관찰을하는것을권고하고있다 [6]. 임상에서기존의경구용항응고제인와파린을복용하다가 NOAC으로변경하는경우에는 PT를측정하여 INR이 2.0 미만이되면 NOAC을복용하기시작하며, 복용이후 2일이내에는 PT가거짓으로상승되는경우가있어검사결과를해석하는데주의를요하겠다. 저분자량헤파린을투여받던환자는다음번투여예정시간 0 2시간전에 NOAC을투여하고저분자량헤파린을끊는다. 출혈의위험성이큰수술이나주요장기의수술의경우에는 3일전에 NOAC을중단하고중등도의출혈위험성이있는수술의경우에는 48시간전에중단한다. 신기능이저하된환자에서는약물의배설이느리므로조금더일찍 NOAC을중단하는것이좋다수술이후에는출혈가능성이높은큰수술이나주요장기의수술의경우 48시간이후복용을시작하며출혈위험성이적은수술의경우에는 24시간이후복용을시작한다 [10]. NOAC을사용하는환자에게서출혈이발생하였을경우 dabigatran의경우 idarucizumab (Boehringer Ingelheim Pharma GmbH & Go. KG, Biberach an der Riss, Germany) 이라는길항제가개발되었으나국내에서는아직까지사용할수없으며 NOAC의반감기가짧아특별한중재술없이단시간내지혈되는경우가많다. NOAC은약물및음식과의상호작용은기존의와파린에비해 36 www.jacs.or.kr
Jin Bong Ye, et al: Adaptation of New Oral Anticoagulants 매우적으나와파린과비교하여뇌졸중의예방효과는비슷하거나더욱효과적인것으로보고되고있어, 기존의불편한약물복용으로고통받는의료진과환자들에게 NOAC 는간편한복용법을장점으로널리사용될것으로기대된다. 국내에서는보험기준은 dabigatran의경우, 1) 비판막성심방세동환자중에서뇌졸증, 일과성허혈발작, 혈전색전증의과거력이있거나 75세이상환자또는 2) 6가지위험인자 ( 심부전, 고혈압, 당뇨, 혈관성질환, 65 74세, 여성 ) 중 2가지이상의조건을가지고있는고위험군환자에서와파린을사용할수없는경우 ( 와파린에과민반응, 금기, INR 조절실패등 ) 에소견서를첨부한경우로인정하고있으며, rivaroxaban, apixaban, edoxaban의경우는심재성정맥혈전증, 폐색전증의치료및재발위험의감소를위한경우까지보험급여기준이확대되어인정되고있다. 비록국내에서보험기준이제시되어사용되고있지만아직까지아시아인을대상으로한데이터가많이부족한상태로향후임상의들은이들약물의사용시에발생할수있는부작용혹은치료효과등에관련한세심한관찰이필요하겠다. 본증례에서는심방세동환자에서뇌줄증위험도를평가하기위한 CHADS 2 점수에서 4점으로지속적인항응고요법이필요한환자로, 보험기준중비판막성심방세동환자에서뇌졸중의과거력이동반되고, 75세이상으로와파린사용중 INR 조절실패로인한출혈성경향을보인상태에서폐색전증의재발위험을감소를위하여 edoxaban 을사용하기로결정하였다. Conflicts of Interest No potential conflict of interest relevant to this article was reported. References 1. Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1998;114(5 Suppl):445S-69S. 2. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993;95:315-28. 3. Zago G, Appel-da-Silva MC, Danzmann LC. Iliopsoas muscle hematoma during treatment with warfarin. Arq Bras Cardiol 2010;94:e1-3. 4. Skanes AC, Healey JS, Cairns JA, Dorian P, Gillis AM, McMurtry MS, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012;28:125 36. 5. Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 2013; 61:1935-44. 6. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33:2719-47. 7. Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundam Clin Pharmacol 2012;26:27-32. 8. Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis 2011;31:478-92. 9. Mendell J, Zahir H, Matsushima N, Noveck R, Lee F, Chen S, et al. Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. Am J Cardiovasc Drugs 2013;13:331-42. 10. Sié P, Samama CM, Godier A, Rosencher N, Steib A, Llau JV, et al. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-xa inhibitors. Recommendations of the working group on perioperative Haemostasis and the French study group on thrombosis and Haemostasis. Arch Cardiovasc Dis 2011;104:669-76. www.jacs.or.kr 37