원저접수번호 :09-029(2 차 -0710) 을지대학교을지대학병원신경과 김재국이상준조성래김진옥김효정윤동주고영채오건세이수주 Platelet Function Assay for Clopidogrel and Ticlopidine in Patients with Ischemic Stroke Jae Guk Kim, MD, Sang Jun Lee, MD, Sung Rae Jo, MD, Jin Ok Kim, MD, Hyo Jeong Kim, MD, Dong Joo Yun, MD, Yungchai Ko, MD, Gun-Sei Oh, MD, Soo Joo Lee, MD Department of Neurology, Eulji University Hospital, Eulji University, Daejeon, Korea Background: The rapid platelet function assay (RPFA) has recently been developed and used to monitor the antiplatelet effects on the P2Y12 ADP receptor. We describe the platelet response to clopidogrel and ticlopidine using the RPFA and identify the clinical factor related to laboratory resistance in patients with ischemic stroke. Methods: Of the 172 outpatients with ischemic stroke or transient ischemic attack (TIA) enrolled in this study, 86 were taking clopidogrel (75 mg/day) and 86 were taking ticlopidine (500 mg/day). Demographic data, vascular risk factors, stroke subtypes, and the results of blood tests were recorded. Inhibition is described as the percentage change from baseline aggregation, and is calculated from the P2Y12 reaction unit (PRU) and the base PRU on the RPFA. Those patients who displayed ineffective aggregation-inhibition (inhibition <20%) on the RPFA were defined as nonresponders. Results: The response of platelet aggregation-inhibition to clopidogrel and ticlopidine exhibited a variable distribution (PRU; coefficient of variability, 0.477). Ineffective platelet inhibition was detected in 25.6% of the clopidogrel group and 3.5% of the ticlopidine group (p<0.001). In addition to clopidogrel, TIA and diabetes exhibited significantly higher ineffective platelet inhibition in a univariate analysis. In the multivariate analysis, clopidogrel and TIA remained significant, and diabetes fell to borderline significance (p=0.061). Conclusions: The response to clopidogrel and ticlopidine can vary between patients. Platelet inhibition is lower for clopidogrel than for ticlopidine on the platelet function test in patients with ischemic stroke. The clinical impact of these results remains uncertain; further investigations are needed. J Korean Neurol Assoc 29(3):184-191, 2011 Key Words: Clopidogrel, Ticlopidine, Platelet function test, Stroke 서론 Received December 21, 2010 Revised March 2, 2011 Accepted March 2, 2011 *Soo Joo Lee, MD Department of Neurology, Eulji University Hospital, Eulji University, 1306 Dunsan-dong, Seo-gu, Daejeon 302-799, Korea Tel: +82-42-611-3430 Fax: +82-42-611-3858 E-mail: sjoolee@eulji.ac.kr * This work was supported by a grant (A060171) of the Korea Health 21 R&D project, Ministry of Health, Welfare, and Family Affairs, Republic of Korea and EMBRI Grants 2010 (EMBRI DJ- 2010-04) from the Eulji University. 클로피도그렐 (clopidogrel) 과티클로피딘 (ticlopidine) 은 thienopyridine 의화학적유도체로서혈소판의 P2Y12 ADP (adenosine diphosphate) 수용체를비가역적으로변화시켜혈소판응집에중요한피브리노겐 (fibrinogen) 과혈소판의결합을선택적으로억제하는항혈소판제이다. 1 현재까지알려진연구결과를근거로클로피도그렐과티클로피딘은허혈성뇌졸중의 2차예방을위해널리사용되고있다. 2-4 하지만혈소판기능검사에서나타나는혈소판억제효과가모든환자들에서일정하게나타나지않고, 예방목적으로항혈소 184 대한신경과학회지제 29 권제 3 호, 2011
판제를복용해도혈관질환이재발하는경우가있어이를항혈소판제저항성 (antiplatelet drug resistance) 이라고한다. 5 여기서저항성은임상적저항성 (clinical resistance) 과실험적저항성 (laboratory resistance) 으로구분한다. 임상적저항성은예방목적으로항혈소판제를복용해도심혈관질환들이발생할때사용하며실험적저항성은혈소판기능검사에서항혈소판제에의한혈소판응집억제효과가충분하지않을때사용한다. 혈소판기능검사를통해나타난클로피도그렐저항성을확인한연구는대부분관상동맥중재요법을시행한환자가대상이었으며그빈도는 5-44% 정도로다양했다. 6 관상동맥질환환자에대한연구에비해뇌졸중환자를대상으로 2차적인예방을위해복용하는항혈소판제의불충분한응집억제반응을평가한연구는드물며특히티클로피딘저항성에대한보고는거의없다. 7-10 본연구에서저자들은클로피도그렐또는티클로피딘을복용하는허혈성뇌졸중환자를대상으로혈소판기능검사를이용하여두항혈소판제에의한혈소판응집억제반응을평가하고불충분한응집억제반응과관련된임상인자들을알아보고자하였다. 대상과방법 1. 대상 본연구는 2006 년 3월부터 2010 년 2월까지허혈성뇌졸중으로진단받은뒤최소 1개월이상외래에서경과관찰하면서 2차예방목적으로클로피도그렐 (75 mg/day) 혹은티클로피딘 (500 mg/day) 단일요법을사용중인환자를대상으로하였다. 무증상뇌졸중환자를제외하기위해허혈성뇌졸중진단은 CT나 MRI 에서증상에합당한뇌경색병변을확인하였거나병력에서일과성허혈발작 (transient ischemic attack, TIA) 을확인한경우로하였다. 환자들은연속적으로등록하였으며아스피린등다른항혈소판제또는혈소판응집에영향을미칠수있는보조약제를복용한경우, 항응고제를사용한경우, 출혈성질환의가족력이나과거력이있는경우, 혈소판수치가 150,000/μL 이하또는 450 10 3 /μl 이상인경우, 헤모글로빈이 8.0 g/dl 이하인경우, 혈소판기능검사상오류가발생한경우등은대상에서제외하였다. 2. 방법 1) 임상자료의수집해당환자들에게연구에필요한정보를미리제공하고혈소 판기능검사전에키, 몸무게, 허리둘레등을측정하였다. 대상환자의나이, 성별, 고혈압, 당뇨, 고지혈증등의유무, 기본혈액검사결과, 항혈소판제복용기간, 병용투약기록등의자료를병력청취와의무기록을통해수집하였다. 고혈압은기존에고혈압을진단받고치료중이거나 2회이상혈압을측정하여수축기혈압이 140 mmhg, 이완기혈압이 90 mmhg 이상인경우로, 당뇨병은기존에당뇨병으로진단받았거나공복시혈당이 126 mg/dl 이상인경우로, 고지혈증은이전에고지혈증으로진단받아치료중인환자들과총콜레스테롤이 220 mg/dl 이상인경우로정의하였다. 비만유무는체질량지수 (BMI, body mass index) 25 kg/m 2 이상을기준으로하였으며, 대사증후군은수정된 National Cholesterol Education Program (NECP) 의 Adult Treatment Panel (ATP) III 정의에의해다음중 3개이상의기준을만족시키는경우에진단하였다. (1) 허리둘레 (Asian-Pacific region criteria) 남자 90 cm, 여자 80 cm, (2) 중성지방 (serum triglycerides) 150 mg/dl, (3) 고밀도지질단백콜레스테롤 (HDL cholesterol) 남자 <40 mg/dl, 여자 <50 mg/dl, (4) 공복혈당 (fasting blood glucose) 100 mg/dl 또는당뇨병치료중인경우, (5) 혈압 (systemic arterial blood pressure) 130/85 mmhg 또는항고혈압제복용중인경우. 내경동맥협착또는폐색은조영증강 (contrast-enhanced) MRI 에서 North American Symptomatic Carotid Endarterectomy Trial (NASCET) 방법으로계산한협착이 50% 이상이거나폐색된경우로정의하였으며, 11,12 뇌졸중의아형은 Trial of Org 10172 in Acute Ischemic Stroke Treatment (TOAST) 분류를기준으로 large artery disease (LAD), small vessel disease (SVD), cardioembolism (CE), other determined (OD), undetermined (UD) 로분류하였다. 13 2) 혈액검사연구대상으로선정된환자의정맥혈 3 ml 를 3.2% sodium citrate 가주입된진공튜브에채혈하였다. 튜브를부드럽게 4-5 회기울여 citrate 와혈액이잘섞이게한다음실온에서채혈후 30-240 분사이에 3 ml 의 citrated 혈액을피브리노겐이도포된구슬, 혈소판촉진제인트롬빈수용체활성화펩티드 (thrombin receptor activating peptide, TRAP) 와 ADP 가포함된카트리지 (cartridge) 에넣고신속혈소판기능검사 VerifyNow R -P2Y12 assay (Accumetrics Inc. San Diego, CA, USA) 를통해혈소판응집억제반응을측정하였다. VerifyNow R -P2Y12 assay 결과는 P2Y12 반응도 (P2Y12 Reaction Unit, PRU), 기저값 (base PRU, BASE), 혈소판응집 J Korean Neurol Assoc Volume 29 No. 3, 2011 185
김재국이상준조성래김진옥김효정윤동주고영채오건세이수주 저해백분율 [Inhibition, %=(1-PRU/BASE) 100] 로나타난다. PRU 는 ADP P2Y12 수용체에의한혈소판응집반응만을측정한결과값인반면에 BASE 는 ADP 가아닌 TRAP 에의해유도된혈소판응집반응을측정한값이다. 14 저자들은본연구에서 Inhibition 이 20% 미만이면불충분한혈소판응집억제반응으로판정하였다. 3) 통계분석환자들이복용한항혈소판제의종류에따라두군으로나누어비교하였다. 이때비연속성변수들은 Fisher's exact test 를, 연속성변수의비교는 Mann-Whitney U test 를이용해분석하였다. 모든통계는양측검정을하였으며유의수준은 p-value 가 0.05 미만인경우로하였다. 혈소판기능검사결과가환자들사이에다양하게나타나는지 (inter-patient variability) 확인하기위해 coefficient of variability (CV=standard deviation/ mean) 를이용했으며 CV 값이 0.25 보다클경우다양성 (variability) 이있는것으로판단했다. 15 통계분석은 Statistical Package for Social Science (SPSS Inc. Chicago, IL, USA) for window version 12.0 을사용하였다. 결과 본연구에등록된 176명의환자들중에서혈소판기능검사에서오류를보인 4명을제외한 172명 ( 클로피도그렐 86명, 티클로피딘 86명 ) 을최종분석했다. 환자들의평균연령은 63.6±10.8 세 ( 범위 : 36-84 세 ) 였으며남자는 89명 (51.7%) 이었다. 환자의헤모글로빈은 13.5±1.5 (g/dl), 혈소판수치는 273.7±64.6 ( 10 3 /μl) 이었다. 뇌졸중은 TOAST 분류기준으로 LAD 44명 (29.9%), SVD 42명 (28.6%), CE 3명 (2.0%), OD 2명 (1.4%), UD 56명 (38.1%) 이었다. 환자가복용한항혈소판제의종류에따라두군으로나누어비교한결과인구학적자료 ( 나이, 성별 ), 위험인자 ( 고혈압, 당뇨, 고지혈증, 비만, 대사증후군유무 ), 혈액검사자료 ( 헤모글로빈, 혈소판수치 ), 클로피도그렐복용기간, 병용하는 statin 종류, 뇌졸중의아형, 경부내경동맥협착이나폐색유무에따른차이는없었다 (Table 1). 티클로피딘을복용한환자군에서 Table 1. Comparison of clopidogrel and ticlopidine for baseline characteristics Clopidogrel Ticlopidine (n=86) (n=86) p-value Age, year, mean±sd 63.6±10.8 64.5±10.2 0.484 Sex, male, n (%) 41 (47.7) 48 (55.8) 0.285 Hypertension, n (%) 66 (76.7) 69 (80.2) 0.578 Diabetes, n (%) 26 (30.2) 19 (22.1) 0.225 Hyperlipidemia, n (%) 45 (52.3) 46 (53.5) 0.360 Hemoglobin, g/dl, mean±sd 13.6±1.5 13.4±1.4 0.294 Platelet, 10 3 /μl, mean±sd 267.1±50.3 280.2±76.4 0.292 Duration of treatment, n (%) 0.077 <6 months 30 (34.9) 41 (47.7) 6-12 months 23 (26.7) 21 (24.4) >12 months 33 (38.4) 24 (27.9) Obesity (BMI 25.0 kg/m 2 ), n (%) 29/61 (47.5) 28/68 (41.2) 0.467 Metabolic syndrome, n (%) 32/64 (50.0) 30/70 (42.9) 0.407 Coadministration of statins, n (%) 0.589 Lipophilic statins a 16 (18.6) 17 (19.8) Hydrophilic statins b 18 (20.9) 13 (15.1) Transient ischemic attack, n (%) 10 (11.6) 15 (17.4) 0.279 TOAST classification, stroke subtypes, n (%) 0.061 Large artery disease 25/76 (32.9) 19/71 (26.8) Small vessel disease 26/76 (34.2) 16/71 (22.5) Cardioembolism 0 (0) 3/71 (4.2) Other determined 2/76 (2.6) 0 (0) Undetermined 23/76 (30.3) 33/71 (46.5) Cervical ICA steno-occlusion, n (%) 17/80 (21.3) 14/70 (20.0) 0.850 p-values by Fisher's exact test or Mann-Whitney U test as appropriate. BMI; body mass index, ICA; internal carotid artery, n; number of patients, numbers in parentheses are percentages, SD; standard deviation, TOAST; Trail of Org 10172 in Acute Stroke Treatment. a Lipophilic statins include simvastatin and atorvastatin. b Hydrophilic statins contain pravastatin and rosuvastatin. 186 대한신경과학회지제 29 권제 3 호, 2011
응집억제반응이상관관계가있는것으로나타났고 (Table 2), 다변량분석결과클로피도그렐과 TIA 가불충분한응집억제반응과독립적인상관관계가있었다 ( 클로피도그렐 vs. 티클로피딘, p<0.001; TIA vs. Stroke, p=0.018). 고찰 Figure. Distribution of BASE (base P2Y12 reaction unit) and PRU (P2Y12 reaction unit). These graphs show the range of BASE using TRAP (thrombin receptor activating peptide) and PRU using ADP (adenosine diphosphate) on the rapid platelet function assay in the clopidogrel and ticlopidine groups. There are inter-individual variabilities in BASE and PRU. 복용기간이 6개월미만인환자수가상대적으로많고 1년이넘은환자수가적었으나통계적유의성은없었다 (p=0.077). VerifyNow R P2Y12 assay 결과 BASE 의중앙값 [ 사분위범위 ] 은클로피도그렐을복용한환자군이 293 [259-322], 티클로피딘을복용한환자군이 290 [234-334] 이었으며, 환자가복용한항혈소판제의종류에따른차이는없었다. PRU 의중앙값 [ 사분위범위 ] 은클로피도그렐을복용한환자군이 198 [149-261], 티클로피딘을복용한환자군이 120 [77-210] 이었다 (Fig.). Inhibition(%) 의중앙값 [ 사분위범위 ] 은클로피도그렐을복용한환자군이 30 [19-46], 티클로피딘을복용한환자군이 61 [40-75] 이었다. 위의 PRU 값과 Inhibition (%) 은환자들이복용한클로피도그렐과티클로피딘간에통계적으로유의한차이가있었다 (p<0.001). 또한혈소판응집저해백분율 (inhibition) 20% 미만의불충분한응집억제반응은클로피도그렐을복용한환자군이 22명 (25.6%), 티클로피딘을복용한환자군이 3명 (3.5%) 이었다 (p<0.001). 동일한용량의클로피도그렐또는티클로피딘을복용하였음에도혈소판기능검사에서환자마다다양한범위의 BASE, PRU, Inhibition (%) 을보였다 (CV; BASE 0.272, PRU 0.477, Inhibition 0.538). 불충분한응집억제반응유무에따라두군으로나누어비교한단변량분석에서는당뇨병, TIA, 클로피도그렐과불충분한 신속혈소판기능검사 VerifyNow R -P2Y12 assay 는혈소판기능검사가운데가장널리쓰이는고전적응집측정기법 (conventional aggregometry-born's method) 처럼혼탁도측정 (turbidometry) 이원리이다. 하지만검사에필요한혈액량이적고채혈된혈액 ( 전혈 ) 을그대로사용할수있으며검사방법이간단하고검사시간이짧아비전문가도현장검사 (point of care) 가가능하다는장점이있으며, 16 VerifyNow R -P2Y12 assay를이용하여측정한혈소판응집억제효과가고전적인응집측정기법을이용한것과일치도가높다고알려져있다. 17-19 혈소판응집억제반응은사람마다다양하게나타난다고알려져있다. 15,20,21 같은용량의항혈소판제를복용해도환자마다넓은범위의 BASE, PRU, Inhibition (%) 을보인이연구를통해혈소판응집억제반응의다양성을확인할수있었다. 본연구에서만성기허혈성뇌졸중환자를대상으로 VerifyNow R -P2Y12 assay 를시행한결과클로피도그렐 (75 mg/day) 을복용하는경우에 25.6%, 티클로피딘 (500 mg/day) 을복용하는경우에는 3.5% 에서불충분한혈소판응집억제반응이나타났다. 고전적인응집측정기법을이용한국내연구에서급성기뇌경색환자의 18.6%, 만성기뇌경색환자의 27.9% 에서클로피도글렐저항성이나타났으며, 7,10 이는우리연구결과와비슷하다. 외국의한연구에서는클로피도그렐을복용한환자의 18%, 티클로피딘을복용한환자의 4% 에서불충분한응집억제를보였다. 9 이런빈도의차이는불충분한응집억제반응에대한검사방법, 판단기준, 채혈시점등의차이때문으로추정한다. 하지만불충분한응집억제반응의빈도가티클로피딘에비해클로피도그렐을복용하는환자군에서더높았던점은이번연구의결과와일치한다. 이전연구에서사용하였던광투과도를이용한응집측정기법은 ADP 만을작용제로사용하여혈소판응집정도를측정하므로 P2Y12 ADP 수용체가아닌 P2Y1 ADP 수용체에의한혈소판응집효과를배제하지못한다. 따라서 VerifyNow R -P2Y12 assay 를이용한연구와비교할때혈소판기능검사로고전적인응집측정기법을이용한연구는혈소판응집억제효과를정확하게평가할수없다. 이런이유때문에검사방법에따라저항성을보이는비율에차이가날수있다. 또한측정시기에따라혈 J Korean Neurol Assoc Volume 29 No. 3, 2011 187
김재국이상준조성래김진옥김효정윤동주고영채오건세이수주 Table 2. Comparison of responders and non-responders Responders Non-responders a (n=147) (n=25) p-value Age, year, mean±sd 63.6±11.0 63.8±10.0 0.991 Sex, male, n (%) 74 (50.3) 15 (60.0) 0.372 Hypertension, n (%) 117 (79.6) 18 (72.8) 0.393 Diabetes, n (%) 34 (23.1) 11 (44.0) 0.028 Hyperlipidemia, n (%) 77 (52.4) 9 (36.0) 0.130 Hemoglobin, g/dl, mean±sd 13.5±1.5 13.8±1.3 0.361 Platelet, 10 3 /μl, mean±sd 277.4±66.7 252.7±50.0 0.076 Duration of treatment, n (%) 0.446 <6 months 63 (42.9) 8 (32.0) 6-12 months 36 (24.5) 8 (32.0) >12 months 48 (32.7) 9 (36.0) Obesity (BMI 25.0 kg/m 2 ), n (%) 50/111 (45.0) 7/18 (38.9) 0.626 Metabolic syndrome, n (%) 51/113 (45.1) 11/21 (52.4) 0.541 Coadministration of statins, n (%) 0.433 Lipophilic statins 30 (20.4) 5 (20.0) Hydrophilic statins 29 (19.7) 2 (8.0) Transient ischemic attack, n (%) 18 (12.2) 7 (28.0) 0.039 TOAST classification, stroke subtypes, n (%) 0.191 Large artery disease 39/129 (30.2) 5/18 (27.8) Small vessel disease 33/129 (25.6) 9/18 (50.0) Cardioembolism 3/129 (2.3) 0 (0) Other determined 2/129 (1.6) 0 (0) Undetermined 52/129 (40.3) 4/18 (22.2) Cervical ICA steno-occlusion, n (%) 27/127 (21.3) 4/23 (17.4) 0.786 Drug, n (%) <0.001 Clopidogrel 64 (43.5) 22 (88.0) Ticlopidine 83 (56.5) 3 (12.0) p-values by Fisher's exact test or Mann-Whitney U test as appropriate. BMI; body mass index, ICA; internal carotid artery, n; number of patients, numbers in parentheses are percentages, SD; standard deviation, TOAST; Trail of Org 10172 in Acute Stroke Treatment. a Non-responders are the patients displaying an inhibition of less than 20% with the rapid platelet function assay. 소판기능검사결과에약간의차이가난다는점을고려하면급성기뇌경색환자와만성기뇌경색환자의불충분한혈소판응집억제반응의빈도가다를수있음을설명할수있다. 본연구에서저자들은불충분한혈소판응집억제반응의판단기준으로 inhibition 20% 미만을사용했다. 최근발표된심혈관중재시술을받은환자를대상으로시행된외국연구에서는 VerifyNow R -P2Y12 assay 를이용하여측정한 PRU >235 를클로피도그렐저항성의적정기준으로사용하고임상결과를예측하는데유용하다고한반면국내연구에서는 20% 미만을저항성의기준으로사용했다. 22-24 이번연구의대상환자에게불충분한혈소판응집억제반응의기준으로 PRU >235 를적용하면클로피도그렐저항성은 32.6%, 티클로피딘저항성은 14.0% 의비율이다 (p=0.004). 이결과또한티클로피딘에비해클로피도그렐을복용한환자군의불충분한응집억제반응빈도가높았다. 클로피도그렐과티클로피딘은혈소판의 P2Y12 ADP 수용체 를억제함으로써항혈소판작용을나타내는 thienopyridine 의화학적유도체이지만이번연구에서불충분한응집억제반응은티클로피딘에비해클로피도그렐을복용한환자군에서더빈도가높았다. 이런차이는두항혈소판제의대사과정, 유전자다형태 (polymorphism) 등으로설명할수있다. 클로피도그렐과티클로피딘이항혈소판작용을나타내기위해서는경구섭취후장에서흡수된다음, 간의 cytochrome P 450 system (CYP) 에의한대사활성화과정이필요하다. 그런데장에서흡수된양의 15% 만이활성화형태로바뀌는클로피도그렐에비해티클로피딘은흡수된양의 80% 이상이활성화형태로변해서항혈소판작용을나타낸다. 25 또한클로피도그렐은간대사활성화과정에 CYP 3A4, 2C19 가주영향을주는데비해티클로피딘은특정 CYP 효소의산화과정에의존하지않는다. 25 따라서클로피도그렐의장흡수를결정하는 ABCB1 유전자나활성화를위한간대사에영향을주는 CYP 3A4, 2C19 유전자에다형태가있으면불충분한혈소판응집억제반응 188 대한신경과학회지제 29 권제 3 호, 2011
이더많이발생하게된다. 최근클로피도그렐저항성과관련된 CYP 2C19 유전자다형태가 55% 이상의동아시아인에게나타날정도로흔하며, 유전자다형태가있으면심근경색, 뇌졸중, 혈관질환에의한사망이증가하고스텐트삽입후혈전이발생할가능성이높다는연구결과가있었다. 26 비록대상환자들의유전자형을확인하지는못했지만동아시아인의 55% 이상이 CYP2C19 유전자다형태를보인다는점을고려했을때이번연구에클로피도그렐저항성에영향을주는 CYP2C19 유전자다형태를가진사람이많이포함되어티클로피딘에비해클로피도그렐저항성이높게나타났을가능성이있다. 임상결과를기준으로클로피도그렐과티클로피딘을비교한연구는심혈관중재술을시행받은급성심근경색환자를대상으로한연구와일본에서뇌졸중환자를대상으로한연구가있다. 27-29 급성심근경색환자를대상으로한연구는클로피도그렐사용이허혈의재발및중등도이상의출혈과관계가있으며, 27 일본의뇌졸중환자를대상으로한연구에서는안정성면에서는클로피도그렐이우수하였으나효능면에서는두항혈소판제사이에차이가없었다. 28,29 이상의연구들은혈소판기능검사결과가아닌임상결과를기준으로했으며, 급성심근경색환자의경우아스피린을병용했다는점, 일본의뇌졸중환자를대상으로한연구에서는 500 mg/day 가아닌 200 mg/day 의티클로피딘을사용했다는점때문에본연구의결과와직접비교하기는어렵다. 항혈소판제의종류 ( 클로피도그렐 ) 외에도 TIA 가불충분한혈소판응집억제반응과관련이있다. 저자들이체계적으로문헌을검색해보았으나, TIA 와혈소판응집억제반응의연관성에대한선행보고는없었다. 본연구에서 TIA 환자군은총 25명 (14.5%) 으로독립된환자군으로분류하여분석하기에는무리가있다. 그러나 TIA 환자에게투여하는항혈소판제의저항성여부는중요한연구주제이며임상적으로도꼭고려해야할사항이라고생각한다. 심혈관환자를대상으로한연구에서당뇨병환자는혈소판활성화와작용제에대한반응이높아서클로피도그렐저항성의빈도가높았다. 30 본연구에서당뇨병은단변량분석결과불충분한응집억제반응과상관관계가있었다 (p=0.028). 하지만다변량분석에서는경계수준의차이를보였다 (p=0.061). 이는당뇨병의경우에도위에서언급한것처럼합병증때문에심한장애가있는환자는연구대상에포함시키지않은선택오차때문으로추정할수있다. 혈액검사를통해나타난저항성과임상에서보이는치료실패즉혈관질환의재발이항상일치하는것은아니다. 5,6 하지만혈액검사를통해나타난저항성과임상적인혈관질환의재 발이연관이있다는연구도있다. 아스피린의경우혈소판기능검사에서저항성을보인환자가저항성이없는환자들에비해추후혈관질환재발에대한상대위험도가 4배정도높다는보고가있었다. 31 또한 VerifyNow P2Y12 assay 를이용하여측정한클로피도그렐저항성이심혈관계및뇌혈관중재치료과정에서생기는합병증과연관이있다는연구가최근발표되었다. 32-34 따라서혈액검사를통해확인한클로피도그렐저항성이스텐트삽입술후합병증발생을예측하는데도움이될수있다. 하지만허혈성뇌졸중과관련된연구는아직까지는드물다. 또한심혈관계질환이있거나뇌혈관중재치료를받는환자들은아스피린과클로피도그렐의복합항혈소판제요법으로치료하는데최근발표된허혈성뇌졸중진료지침에는복합요법보다는단일항혈소판제요법이우선이다. 따라서단일항혈소판제요법을사용하는허혈성뇌졸중환자를대상으로한연구가필요하다. 본연구는다음과같은한계가있다. 우선대상환자의수가비교적적어통계적인차이점을분석할때생길수있는제2종오류 (type 2 error) 의가능성이있다. 또한단일병원에방문한허혈성뇌졸중환자만을대상으로해서대표성이떨어지는약점이있다. 연구디자인면에서한환자에서일정기간클로피도그렐을사용한다음혈액검사를하고항혈소판제를티클로피딘으로바꾸어사용하다가다시혈액검사를하는환자- 교차연구 (case-crossover study) 방식이이상적이지만외래환자를대상으로하였기때문에그럴수없었다. 따라서두항혈소판제에대한혈소판기능검사결과를비교하는데있어통계적으로유의한차이는아니었지만환자의특성에의한영향을배제할수없었다. 마지막으로같은환자도항혈소판제복용기간에따라혈소판응집억제반응이다를수있으므로혈소판기능검사를한번시행하여판정하기보다는반복검사를통해결과를해석하는것이좋을것이다. 결론적으로허혈성뇌졸중환자에서클로피도그렐과티클로피딘에의한혈소판응집억제반응은다양하였으며, 티클로피딘에비해클로피도그렐을복용한환자군에서불충분한혈소판응집억제반응의빈도가더높았다. 따라서클로피도그렐을복용하는환자는유전적다형태와함께혈소판기능검사를이용하여응집억제반응을확인하는것이허혈성뇌졸중환자의치료에있어개별적인맞춤치료및재발, 예후판정에도움이되는지에대한추가연구가필요할것이다. 감사의글 We thank Yuyu Inc. for providing the RPFA system J Korean Neurol Assoc Volume 29 No. 3, 2011 189
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with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005;54:2430-2435. 31. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Huisman MV. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systemic review and meta-analysis. Arch Intern Med 2007;167:1593-1599. 32. Cuisset T, Hamilos M, Sarma J, Sarno G, Wyffels E, Vanderheyden M, et al. Relation of low response to clopidogrel assessed with point-of-care assay to periprocedural myonecrosis in patients undergoing elective coronary stenting for stable angina pectoris. Am J Cardiol 2008;101:1700-1703. 33. Lee DH, Arat A, Morsi H, Shaltoni H, Harris JR, Mawad ME. Dual antiplatelet therapy monitoring for neurointerventional procedures using a point-of-care platelet function test: a single-center experience. AJNR Am J Neuroradiol 2008;29:1389-1394. 34. Kang HS, Kwon BJ, Kim JE, Han MH. Preinterventional clopidogrel response variability for coil embolization of intracranial aneurysms: clinical implications. AJNR Am J Neuroradiol 2010;31: 1206-1210. J Korean Neurol Assoc Volume 29 No. 3, 2011 191