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1 프로트롬빈시간모니터링을위한 CoaguChek XS 의유용성 순천향대학교병원 1 진단검사의학과, 순천향대학교부천병원 2 진단검사의학과, 3 흉부외과, 4 신경과, 5 내과박노진 1, 김용현 2, 권경옥 2, 나종성 2, 원용순 3, 성기범 4, 이내희 5, 최태윤 1, 신정원 1, 신희봉 2, 이용화 2, 이유경 2 Utility of CoaguChek XS for Monitoring the Prothrombin Time Rojin Park, M.D. 1, Yong-Hyun Kim, M.D. 2, Kyung Ock Kwon, M.T. 2, Jongsung Na, M.T. 2, Yong Soon Won, M.D. 3, Ki Bum Sung, M.D. 4, Nae-Hee Lee, M.D. 5, Tae Youn Choi, M.D. 1, Jeong Won Shin, M.D. 1, Hee Bong Shin, M.D. 2, Yong-Wha Lee, M.D. 2, You Kyeong Lee, M.D. 2 1 Department of Laboratory Medicine, Soonchunhyang University Hospital, Seoul, Departments of 2 Laboratory Medicine and Genetics, 3 Thoracic and Cardiovascular Surgery, 4 Neurology and 5 Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea Background: In order to achieve a maintenance level and to prevent hemorrhagic complications, regular monitoring of the INR is mandatory for patients on oral anticoagulation therapy (OAT). A point-of-care instrument for INR monitoring is convenient for users, but the accuracy of the results has been controversial, and so this calls for exact evaluation of the point-of-care instrument that is used for INR monitoring. Methods: From Aug 2007 through Feb 2008, 85 patients on OAT among the all the patients who were admitted to Soonchunhyang University Bucheon Hospital were involved in this study. Parallel measurements of the PT INR were performed using a CoaguChek-XS and, a CA-7000 laboratory reference instrument and the results were analyzed. In addition, the patients' clinical data, including the diagnosis and the frequency and interval of the INR measurements, were also analyzed. Results: Of the 85 patients, 25 were admitted more than once to undergo INR testing and the mean interval between testing was 8.6 weeks with 39% and 38% of the tests being less than INR 2 units with using the CoaguChek-XS and the reference method, respectively. The coefficients of variation of CoaguChek-XS were 4.50 and 2.45 for the high and low INR patients, respectively. An excellent correlation was found between the two methods with a R 2 of (p<0.001). Through Bland-Altman analysis, the mean INR difference between the two methods was 0.13 with the limit of agreement being with a 95% confidence interval. CoaguChek-XS was shown to overestimate the INR value for patients with an increasing INR, as compared to the reference method. Conclusion: CoaguChek-XS demonstrated great precision and accuracy for patients on OAT when compared to the laboratory INR results. Accordingly, the instrument should help to monitor the INR in the patients on OAT. (Tuberc Respir Dis 2008;65: ) Key Words: Prothrombin time, INR, CoaguChek-XS, Oral anticoagulant therapy 서 경구용항응고제인와파린은혈전성질환의치료및예방을위해서주로사용된다 1. 와파린의치료효과를유지하고부작용을방지하기위해서는수시로프로트롬빈시 Address for correspondence: You Kyeong Lee, M.D. Department of Laboratory Medicine and Genetics, Soonchunhyang University Bucheon Hospital, 1174, Jung 1- dong, Wonmi-gu, Bucheon , Korea Phone: , Fax: cecilia@schbc.ac.kr Received: Nov. 10, 2008 Accepted: Dec. 4, 2008 론 간 (prothrombin time, PT) 을모니터링할필요가있다 2. 일반적으로 PT 측정의표준은구연산첨가정맥혈로부터분리된혈장을사용하여검사실의혈액응고측정장비로검사하는것이다 3. 표준방법의 PT측정을위해서는환자가직접내원하여수시로정맥혈을채혈하여야하는어려움이있기때문에보다신속하고간편하게측정할수있는현장검사 (Point-of-care, POC test) 기기가출현하게되었다. 이러한기기들은손가락끝의모세혈을이용하여불과수초만에 INR (international normalized ratio) 값을산출해냄으로써검사후바로와파린용량을조절할수있게해준다. 구미각국에서이러한현장검사기기는휴대용으로서, 가정에서, 외래에서, 심지어입원환자에서도 471

2 R Park et al: Utility of CoaguChek XS 유용하게사용되고있다. 그러나모세혈을이용한 INR 산출의정확도과신빙도에대해서는아직까지도논쟁이되고있다. 따라서이러한기기의사용에앞서그정확도를평가하는것은매우중요하다고할수있다 3-5. 이연구에서는최근에개선되어나온 PT 모니터링을위한 POC장비인 CoaguChek-XS (Roche Diagnostics, Mannheim, Germany) 의유용성을평가하기위해서와파린투여중인외래환자를대상으로검사실의표준검사법과결과를비교하여그유용성을알아보고자하였다. 대상및방법 1. 대상 2007년 8월부터 2008년 2월까지순천향대학교부천병원에내원한환자중에서장기간와파린을복용하고있는 85명의환자들을대상으로하였다. 환자들은각각신경과, 흉부외과, 심장내과등에서심근경색, 뇌경색, 판막질환, 심부정맥혈전증, 폐색전증, 심방세동등의질환으로치료를받고있었다. 본연구는임상시험심사위원회 (IRB) 의승인을받았으며, 모든피험대상으로부터연구에대한서면동의를받았다. 2. 프로트롬빈시간측정와파린을복용하고있는환자 85명을대상으로하여정맥혈채혈과동시에모세혈을이용하여 CoaguChek-XS 로 PT를측정하였다. 모세혈은미세혈침자를이용하여채취하고, 검사스트립에적용하였다. 채혈된정맥혈은검사실로가져와 CA-7000 혈액응고분석기를이용하여 PT를측정하였다. 1) CoaguChek-XS: 일반적인 PT 검사가트롬보플라스틴을첨가한후응고가일어나기까지의시간을측정하는반면, CoaguChek-XS 는트롬보플라스틴 (15U) 에의해활성화된트롬빈이스트립의표면에묻혀져있는펩티드기질 (peptide substrate) 을분해할때발생하는전기적인신호에의해결과를산출한다. 정도관리는단일채널로스트립에내장되어있다. 환자를대상으로검사를수행하기에앞서각스트립내의 Resazurin 과그환원물인 Resorufin 을측정하여각검사스트립의 integrity 를평가해주는역할을한다. 칼리브레이션은국제보건기구의지침을따르고있다. 빌리루빈 30 mg/dl, 중성지방 1,000 mg/dl, 헤파린 1.0 U/mL 까지는간섭을받지않으며, 최소검체요구량이 10μL이며적혈구용적률은 25 55% 이어야한다. 평균정상 PT는 12초, ISI (international sensitivity index) 는 1로설정되어있다. 2) CA-7000: 3.2% (0.109M) 구연산나트륨항응고제가포함되어있는튜브 (Becton Dickinson, Rutherford, NJ, USA) 에혈액을채취하여 2,000 g (gravity) 에서 15분간원침하고혈소판결핍혈장을얻어서 37 o C에서 PT 검사를시행하였다. 모든검사는검체채취후 30분이내에시행되었다. 검사는 PT 시약 (Thromborel S; Dade Behring Marburg GmbH, Marburg, Germany) 을사용하여자동혈액응고분석기 (CA-7000; Sysmex Corporation, Kobe, Japan) 에서시행하였다. 405 nm의파장을이용하여혈액이응고되기까지의시간을측정하고, ISI값을적용하여계산된 INR값을산출해낸다. 3. 비교분석 CoaguChek-XS 의정밀도는와파린을복용하는환자를대상으로하여검사실의표준검사법 (CA-7000) 에서 INR 수치가치료범위에도달하지못한환자 1명과치료범위에도달한환자 1명을대상으로전혈을채취하여각각 5회씩측정하고, 변이계수를구하였다. 두기기에서의 INR 결과값을비교하기위하여범위를 <1.5, , 2 2.9, 3 4.5, >4.5로나누어비교하였다. 또한두기기간의 INR 측정치차이를 0 0.5, , >1.0의범위로나누고측정치의개수와퍼센트를계산하였다. 두기기간의전체적인상관성을비교하기위해서회귀분석을사용하였다. 기기들의 INR 결과값에대한일치도를평가하기위해서 Bland-Altman 분석을이용하였다. 결과환자군은남자 48명 (28 84세, 평균 56.7세 ), 여자 37 명 (34 84세, 평균 60.8세 ) 으로이루어졌으며, 항응고치료의적응증은심방세동 50명, 심장판막질환 25명, 심부정맥혈전증및폐색전증 7명, 심근경색 3명이었다. 이중 60명이 1회, 23명이 2회, 1명이 3회, 1명이 4회내원하였으며, 4회내원한환자는폐색전및심부정맥혈전증으로치료를받았다. 최소 2회이상내원한환자들의 INR 측정간격은평균 8.6주 (3 17 주 ) 로, 내과 8.4주, 신경과 7.4주, 흉부외과 11.2 주이었으며, 4주이하의간격으로 INR을측정한환자는모두 5명이었다. 와파린을복용하는환자에서 INR 수치가치료범위에도달하지못한환자 (INR 0.98) 와치료범위에도달한환자 (INR 3.50) 에서 5회반복측정 472

3 Tuberculosis and Respiratory Diseases Vol. 65. No. 6, Dec Table 1. Number of INR values in the respective INR ranges obtained using CoaguChek-XS and standard method INR value CoaguChek-XS (n/%) Reference method (n/%) <1.5 20/18% 17/15% /21% 26/23% /33% 47/42% /23% 19/17% >4.5 6/5% 4/4% INR: international normalized ratio; n: number of patients. Figure 1. INR (international normalized ratio) comparison between CoaguChek-XS and reference method (CA- 7000) by linear-regression analysis. Table 2. INR difference between CoaguChek-XS and standard method among 113 measurements of 85 patients with oral anticoagulation INR difference between CoaguChek-XS and reference method Number of patients /percentage /92% /6% 1.3 1/1% 1.5 1/1% INR: international normalized ratio. Figure 2. Bland-Altman bias plot for CoaguChek-XS and reference method INR (international normalized ratio) values. Mean INR difference between two methods was The limit of agreement was 한 INR의평균값은두기기간에유의한차이가없었다. 검사내변이계수는 CoaguChek-XS 이각각 4.50, 2.45, CA-7000은각각 1.67, 0.66으로 CA-7000에비해서 CoaguChek-XS 의변이계수가더높았다. CoaguChek-XS 와 CA-7000을사용하여검사한결과값은높은상관관계를보였다 (R 2 =0.966, p<0.001) (Figure 1). Bland-Altman 분석에의하면두검사법의 INR 측정치차이의평균 (mean bias) 은 0.13이었다. 두검사법의일치범위의한계 (limit of agreement) 는 95% 신뢰구간으로 이었고전체측정값의 96% 가이범위에포함되었다 (Figure 2). 항응고효과의정도는 CoaguChek-XS 와표준검사법에서각각측정값의 56%, 59% 가 INR 사 이에분포하였다. 각각의검사법에서 39%, 38% 가 INR 2.0 미만이었고, 5%, 4% 가 INR 4.5 이상이었다 (Table 1). 측정값의 92% 에서두검사법간의차이는 0.5 INR 이내에존재하였고, 98% 의측정치들이검사법간의 INR 차이가 1.0을넘지않았다. 단지두측정값들이 INR 차이가각각 1.3, 1.5로 1.0보다높았다 (Table 2). 고찰항응고제치료의중요한점은항혈전효과와함께, 치료와연관하여출혈이발생하지않도록지속적인모니터링을통해적절한 INR값을유지시키는것이다. 현재구미각국에서는항응고제를복용하는많은환자들을대상으로 POC 기기를사용해서 PT INR 수치를모니터링하고있지만현재까지우리나라에서는대부분의환자들이병원검사실내의표준검사법에의존하고있다. 미국흉부의사협회 (American College of Chest Physicians, ACCP) 에서는항응고제를장기간복용하는환자들은 INR 측정간격이 4주를초과하지않도록권고하고있다 6. 더욱이여러 473

4 R Park et al: Utility of CoaguChek XS 연구에서 INR의측정빈도와치료범위의유지기간은비례한다고보고하고있다 1,7. 검사실의표준검사법을통한 INR 측정이보다정확하고재현성있는결과를제공하지만장기간경구용항응고제를복용하는환자들에서빈번한 INR 모니터링과엄격한치료범위의유지를위해서는보다간편한방법의 POC 기기를사용한모니터링도이제는필요한시점이라고생각된다. POC 장비를통한 INR 측정은정확한분석능과함께항응고제복용환자를위한효과적인자기관리프로그램이뒷받침되면 INR의자가측정을통해항응고치료의효과를향상시킬수있다 7. 검사실의표준검사법과비교한결과, 로슈사의 Coagu- Chek-XS 기기는 R 2 이 0.97이고, 모든 INR 측정치의 92% 가표준검사법과의차이가 0.5 INR units 이하로국내외의여러연구와유사하게우수한상관관계를보였다 (Figure 1) 여러연구를통해 CoaguChek 기기의표준검사법과의상관성은기기작동에대한교육을받은의료종사자들에의해사용된경우에비해환자들이직접사용했을경우에상관성이떨어지므로 3,5,14,15, 향후환자들에의해서직접사용될경우, 교육이반드시필요함을알수있다. 와파린을복용하는환자를대상으로측정한검사내변이계수는표준장비인 CA-7000에비해서 CoaguChek-XS에서높은값을보였다. 재현성에있어서표준장비에는미치지못함을알수있었다. Bland-Altman 분석을통해 96% 의측정치가 95% 신뢰구간인 범위에포함됨을알수있었다. 그러나 INR 값이증가할수록 CoaguChek-XS 의측정값은표준검사법에비해서높게측정되는경향을보였다 (Figure 2). 비슷한결과가이전의연구에서도보였으나여러연구들은표준검사법에의한결과에비해낮은결과를보임을기술하였다 3,5,9,11,16. 이번연구는 7개월동안단일기관에서외래진료를통해항응고제를처방받는환자들을대상으로하였는데, 이기간동안 85명의와파린투여환자가외래진료를받았다. 이기간중에 60명이 1회, 23명이 2회, 1명이 3회, 1명이 4회내원하였다. 최소 2회이상내원한환자들의 INR 측정간격은평균 8.6주이었으며, INR 측정간격이평균 4주이하인환자는 5명으로 ACCP 의권고사항과는많은차이가있다. 아직까지우리나라에는항응고치료의지침이표준화되어있지않은것도원인일수있지만, 표준검사법을위한채혈과상대적으로긴검사시간이환자또는주치의로하여금활발하게 INR을추적검사하기어렵게만드는요인의하나가될수있다고생각한다. 또한환자들은이미경구용항응고제를장기간복용하던중이었음에도 불구하고 INR 2.0 미만의측정값들이 CoaguChek-XS 와표준검사법에서각각 39%, 38% 를차지하였다는사실은 INR 측정간격이너무길거나환자들의순응도가떨어진다는것을의미한다. 따라서장기간항응고제를복용하는환자들에서는빈번한 INR 모니터링이반드시필요함을알수있다. 결론적으로 CoaguChek-XS 는경구항응고제복용환자의 INR을효과적으로모니터링해서적시에항응고제의용량을조정하고출혈의합병증을예방해줌으로써치료에도움을줄것으로생각된다. 요약연구배경 : 와파린의치료효과를유지하고부작용을방지하기위해서는수시로프로트롬빈시간을모니터링할필요가있다. 이러한목적의현장검사기기는편리하지만그정확성에있어서문제가될수있으므로평가가필요하다. 방법 : 2007년 8월부터 2008년 2월까지순천향대학교부천병원에내원한환자중에서경구용항응고제 ( 와파린 ) 를복용하는 85명의환자들을대상으로하여검사실표준검사법과 CoaguChek-XS 를사용하여각각 INR값을측정하고비교분석하였다. 결과 : 전체 85명환자중 2번이상 INR 을측정한사람은모두 25명으로이들의 INR 측정간격은평균 8.6 주이었고, CoaguChek-XS 와표준검사법에서 INR 2.0 미만의측정값들이각각 39%, 38% 를차지하였다. 와파린을복용하는환자에서표준검사법으로측정한 INR값이높고, 낮은두명의환자에서각각 5번씩측정한결과 CoaguChek-XS 의변이계수는각각 4.50, 2.45, CA-7000은각각 1.67, 0.66이었다. 두검사기기간의상관성은 R 2 이 0.966으로서우수하였으며 Bland-Altman 분석을통해서두기기간차이의평균이 0.13이었고일치범위의한계 (95% 신뢰구간 ) 는 이었다. 또한 INR 값이증가할수록 CoaguChek-XS 의측정값은표준방법에비해서높게측정되는경향을보였다. 결론 : CoaguChek-XS 는정밀도가좋고기존의검사실표준검사법과의상관성이우수하였다. 따라서 CoguChek XS는경구항응고제치료환자의 INR을모니터링하는데도움이될것으로생각된다. 474

5 Tuberculosis and Respiratory Diseases Vol. 65. No. 6, Dec 참고문헌 1. Horstkotte D, Piper C, Wiemer M. Optimal frequency of patient monitoring and intensity of oral anticoagulation therapy in valvular heart disease. J Thromb Thrombolysis 1998;5 Suppl 1: Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D'Angelo A, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996; 348: Hentrich DP, Fritschi J, Muller PR, Wuillemin WA. INR comparison between the CoaguChek S and a standard laboratory method among patients with self-management of oral anticoagulation. Thromb Res 2007;119: Khoschnewis S, Hannes FM, Tschopp M, Wuillemin WA. INR comparison between the CoaguChek Pro PT(N) and a standard laboratory method. Thromb Res 2004;113: Jackson SL, Bereznicki LR, Peterson GM, Marsden KA, Jupe DM, Tegg E, et al. Accuracy, reproducibility and clinical utility of the CoaguChek S portable international normalized ratio monitor in an outpatient anticoagulation clinic. Clin Lab Haematol 2004;26: Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126: 204S-33S. 7. Sawicki PT. A structured teaching and self-management program for patients receiving oral anticoagulation: a randomized controlled trial. Working Group for the Study of Patient Self-Management of Oral Anticoagulation. JAMA 1999;281: Lee JH, Lee KS, Kim DS, Lee HS, Choi SI, Cho YG. Evaluation of CoaguChek-XS for measuring prothrombin time in patients receiving long-term oral anticoagulation therapy. Korean J Lab Med 2007;27: Kim JW, Kim MH, Kim KH, Han J, Paik JH, Yu LH, et al. Comparison between the portable prothrombin time self monitor CoaguChek XS and a standard laboratory method, Sysmex CA-1500 for monitoring anticoagulant therapy of outpatients. Korean Circ J 2007; 37: Nam MH, Roh KH, Pak HN, Lee CK, Kim YH, Lee KN, et al. Evaluation of the Roche CoaguChek XS handheld coagulation analyzer in a cardiac outpatient clinic. Ann Clin Lab Sci 2008;38: Bereznicki LR, Jackson SL, Peterson GM, Jeffrey EC, Marsden KA, Jupe DM. Accuracy and clinical utility of the CoaguChek XS portable international normalised ratio monitor in a pilot study of warfarin home-monitoring. J Clin Pathol 2007;60: Bauman ME, Black KL, Massicotte MP, Bauman ML, Kuhle S, Howlett-Clyne S, et al. Accuracy of the CoaguChek XS for point-of-care international normalized ratio (INR) measurement in children requiring warfarin. Thromb Haemost 2008;99: Braun S, Watzke H, Hasenkam JM, Schwab M, Wolf T, Dovifat C, et al. Performance evaluation of the new CoaguChek XS system compared with the established CoaguChek system by patients experienced in INR-self management. Thromb Haemost 2007;97: Loebstein R, Kurnik D, Lubetsky A, Ezra D, Halkin H. Potential dosing errors using portable prothrombin time monitoring devices. Blood Coagul Fibrinolysis 2003;14: Taborski U, Braun SL, Völler H. Analytical performance of the new coagulation monitoring system INRatio for the determination of INR compared with the coagulation monitor Coaguchek S and an established laboratory method. J Thromb Thrombolysis 2004;18: Gardiner C, Williams K, Mackie IJ, Machin SJ, Cohen H. Patient self-testing is a reliable and acceptable alternative to laboratory INR monitoring. Br J Haematol 2005;128:

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Microsoft Word doc Original ORIGINAL Article ARTICLE Korean Circulation J 2007;37:216-220 ISSN 1738-5520 c 2007, The Korean Society of Circulation 외래항응고치료환자에서자가프로트롬빈시간측정기 CoaguChek XS 와중앙검사실기기와의비교평가 동아대학교의과대학내과학교실, 1 진단검사의학교실