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1 대한내과학회지 : 제 92 권제 6 호 클로피도그렐또는티카그렐러로치료받는환자에서혈소판수와특성이혈소판반응성에미치는영향 원광대학교병원권역심뇌혈관센터순환기내과 윤경호ㆍ조재영 Effects of Platelet Number and Platelet Indices on Platelet Reactivity in Patients Treated with Clopidogrel or Ticagrelor Kyeong Ho Yun and Jae Young Cho Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University Hospital, Iksan, Korea Background/Aims: Platelet counts and characteristics can influence platelet reactivity during antiplatelet therapy. We compared the effects of both platelet count and indices on platelet reactivity between patients who were treated with either clopodogrel or ticagrelor. Methods: Patients with coronary artery disease who underwent percutaneous coronary intervention were randomly assigned to either the clopidogrel (n = 63) or ticagrelor (n = 65) groups. Platelet count, platelet indices (including mean platelet volume, platelet distribution width, platelet large cell ratio, and immature platelet fraction), and platelet reactivity were measured before intervention, and 48 hours and 30 days post-intervention. High on-treatment platelet reactivity (HPR) was defined as 47 unit as assessed by multiple electrode platelet aggregometry. Results: Baseline platelet reactivity was similar between the two groups; however, at 48 hours and 30 days, platelet reactivity was significantly lower in the ticagrelor group than in the clopidogrel group. Platelet count, mean platelet volume, platelet distribution width, platelet large cell ratio, and immature platelet fraction were significantly correlated with platelet reactivity in the clopidogrel group; however, these correlations were attenuated in the ticagrelor group. The use of clopodogrel (hazard ratio [HR] 4.1, 95% confidence interval [CI] ; p = 0.010) and platelet count (HR 9.7, 95% CI ; p = 0.001) were independent predictors for 30 day HPR. Platelet count was an independent predictor of HPR in the clopidogrel group but not in the ticagrelor group. Conclusions: Platelet count and indices are significantly correlated with platelet reactivity. However, antiplatelet treatment with ticagrelor could overcome these associations. (Korean J Med 2017;92: ) Keywords: Platelets; Platelet function tests; P2Y12 receptor antagonists Received: Revised: Accepted: Correspondence to Jae Young Cho, M.D. Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University Hospital, 895 Muwang-ro, Iksan 54538, Korea Tel: , Fax: , librato46@gmail.com Copyright c 2017 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Kyeong Ho Yun, et al. Platelet reactivity and platelet indices - 서론혈소판 P2Y12 수용체억제제에대한비반응성, 즉높은치료중혈소판활성도 (high on-treatment platelet reactivity, HPR) 가급성관상동맥증후군이나관상동맥중재시술을받은환자의불량한예후와관계가있다고알려지고있다 [1-4]. HPR에관련된요인으로는급성관상동맥증후군, 심부전증, 만성콩팥병과당뇨병등의임상적요인이알려져있다 [5,6]. 그러나혈소판자체의숫자나여러가지지표들, 즉평균혈소판용적 (mean platelet volume), 혈소판분포폭 (platelet distribution width), 미숙혈소판분획 (immpature platelet fraction) 등이혈소판반응성에영향을미칠수있다 [7,8]. 티카그렐러 (Brilanta, AstraZeneca, Cambridge, UK) 는최근사용되는강력한항혈소판제로대규모임상시험을통해출혈의위험은높이지않으면서클로피도그렐 (Plavix, Sanofi, Paris, France) 에비해주요심혈관사건의발생을줄이는것으로나타난약물이다 [9]. 따라서저자들은강력한항혈소판제치료가혈소판특성에따른혈소판반응성의차이를극복할수있을것으로가정하였다. 본연구는관상동맥중재시술을받은환자들을대상으로클로피도그렐과티카그렐러를투여하고 30일째혈소판반응성과혈소판수, 혈소판지표들을비교하였다. 대상및방법대상본원에서관상동맥질환으로스텐트시술을받는환자를 1:1로무작위배정하여클로피도그렐과티카그렐러를투여하였다. 시술전각각의약물을부하용량으로투여하였고, 이후에는 1일유지용량을투여하였다 (clopidogrel 75 mg/day, ticagrelor 180 mg/day). 스텐트시술을하지않은환자, 기존에혈소판 P2Y12 수용체억제제를복용하고있는경우, 80세이상, 뇌출혈의기왕력이있는경우, 혈액질환으로치료받는환자, 혈색소가 10 g/dl 이하, 혈소판수치가 140,000/μL 이하또는 400,000/μL 이상인경우는제외하였다. 모든환자는기관생명윤리위원회의승인을얻은동의서에서명한이후치료에임하였고, 30일동안추적관찰되었다 ( HRE-031). 각군당 70명의환자가등록되었으나 30일이전에주요심장사건이발생한경우 2명, 동의철회 1명, 추적소실 4명, 30일째혈액검사거부 1명이있어최종적으로클로피도그 렐군 63명, 티카그렐러군 65명의환자에서연구를종료할수있었다. 혈소판지표와혈소판반응성측정혈액채혈은 ethylenediamine tetraacetic acid 용기를이용하여항혈소판제부하용량투여전, 시술후 48시간, 30일째시행하였다. 혈소판지표는자동화된혈구측정기 (XE2100, Sysmex, Kobe, Japan) 를이용하여혈소판수, 평균혈소판용적, 혈소판분포폭, 혈소판거대세포비율 (platelet large cell ratio) 그리고미숙혈소판분획을측정하였다. 혈소판반응성은자동혈소판응집측정장치 (multiple electrode platelet aggregometry [MEA], Multiplate analyzer, Roche Diagnostic GmbH, Mannheim, Germany) 를이용하여시행하였다. 항혈소판제투여전, 시술후 48시간, 30일째 adenosine diphosphate에의한혈소판응집정도를 unit (U) 로표시하였다. 기존보고에의해, 47 U 이상을 HPR로정의하였다 [10]. 통계분석기존연구에따라혈소판수, 평균혈소판용적그리고미숙혈소판분획의표준편차를 10% 로가정하였고, 1종오류 0.05, 2종오류 80% 로가정하였다 [8]. 따라서혈소판지표들의중앙값또는삼분위값에따른혈소판반응성의차이를알아보는데최소한군당 60명의환자가필요하였다. 측정값들은평균 ± 표준편차또는수 (%) 로표기하였다. 통계분석을위해 SPSS 소프트웨어 version 19.0 (SPSS Inc., Chicago, IL, USA) 를사용하였다. 각군간의비교는 t-test 및 chi-square test를통해비교하였고, 혈소판지표와혈소판반응성간의상관관계는 pearson correlation test를이용하여비교하였다. 30일째 HPR을예측하는독립적인위험인자를알아보기위해다변량분석을시행하였다. 단변량분석에서 p < 0.1 인변수를이용하여시행하였으며, 연속변수의경우상위삼분위수를이용하였다. p 값이 0.05 미만인경우통계적으로유의한값으로판단하였다. 결과대상자들의특성전체환자의기저혈소판반응성은 85.5 ± 35.7 U, 48시간째 32.4 ± 22.2 U, 30일째 34.0 ± 20.8 U였다. 치료군간의나이, 성별, 위험인자, 진단명은차이가없었다 (Table 1). 기저

3 - 대한내과학회지 : 제 92 권제 6 호통권제 679 호 Table 1. Baseline characteristics Characteristics Clopidogrel (n = 63) Ticagrelor (n = 65) p-value Age (years) 65.3 ± ± Male 41 (65.1) 48 (73.8) Diagnosis and risk factors at index PCI MI presentation 43 (68.3) 45 (69.2) ST-segment elevation MI 30 (47.6) 32 (49.2) Hypertension 33 (52.4) 37 (56.9) Diabetes mellitus 10 (15.9) 9 (13.8) Current smoker 22 (34.9) 21 (32.3) Previous PCI 4 (6.3) 1 (1.5) LDL-cholesterol (mg/dl) ± ± Baseline MEA ADP (unit) 84.2 ± ± Platelet count ( 10 3 /μl) ± ± MPV (fl) 10.2 ± ± PDW (fl) 11.6 ± ± Platelet large cell ratio 25.8 ± ± IPF 2.6 ± ± hours MEA ADP (unit) 43.6 ± ± 13.4 < day laboratory variables WBC count (/μl) ± ± Hemoglobin (g/dl) 13.5 ± ± Serum creatinine (mg/dl) 0.95 ± ± LDL-cholesterol (mg/dl) 62.5 ± ± MEA ADP (unit) 42.4 ± ± 16.8 < Platelet count ( 10 3 /μl) ± ± MPV (fl) 10.0 ± ± PDW (fl) 11.2 ± ± Platelet large cell ratio 24.3 ± ± IPF 3.3 ± ± HPR a 18 (28.6) 9 (13.8) Medications Aspirin 61 (96.8) 64 (98.5) Beta blocker 44 (69.8) 50 (76.9) ACEI 37 (58.7) 32 (49.2) ARB 15 (23.8) 21 (32.3) Statins 63 (100.0) 64 (98.5) Values are presented as mean ± standard deviation or number (%). PCI, percutaneous coronary intervention; MI, myocardial infarction; LDL, low density lipoprotein; MEA ADP, multiple electrode platelet aggregometry adenosine diphosphate test; MPV, mean platelet volume; PDW, platelet distribution width; IPF, immature platelet fraction; WBC, white blood cell; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker. a High on-treatment platelet reactivity defined as 47 unit in MEA ADP test. 혈소판반응성은두군간의차이가없었으나 48시간째, 30일째혈소판반응성은티카그렐러군에서유의하게낮았다. 따라서 30일째 HPR은티카그렐러군에서클로피도그렐군에비해낮았다 (28.6% vs. 13.8%, p = 0.052). 혈소판반응성과혈구지표들과의상관관계전체환자에서혈소판수는혈소판반응성과유의한상관 관계를보였다. 백혈구수, 평균혈소판용적, 혈소판분포폭, 혈소판거대세포비율그리고미숙혈소판분획은검사시점에따라혈소판반응성과상관관계를보이기도하고그렇지않기도하였다. 30일째혈소판반응성과의상관관계는클로피도그렐군에서백혈구수, 혈소판수, 평균혈소판용적, 혈소판분포폭, 혈소판거대세포비율그리고미숙혈소판분획모두에서유의

- 윤경호외 1 인. 혈소판반응성과혈소판지표 - Table 2. Correlation between platelet reactivity and platelet indices according to antiplatelet agent Baseline 30-day clopidogrel 30-day ticagrelor r p r p r p WBC count 0.

4 - 윤경호외 1 인. 혈소판반응성과혈소판지표 - Table 2. Correlation between platelet reactivity and platelet indices according to antiplatelet agent Baseline 30-day clopidogrel 30-day ticagrelor r p r p r p WBC count < Platelet count < MPV PDW Platelet large cell ratio IPF WBC, white blood cell; MPV, mean platelet volume; PDW, platelet size deviation width; IPF, immature platelet fraction. 30일째 HPR 에영향을미치는인자에대한다변량분석전체환자에서클로피도그렐의사용 (hazard ratio [HR] 4.1, 95% confidence interval [CI] , p = 0.010) 과혈소판수 (HR 9.7, 95% CI , p = 0.001) 가 30일째 HPR을예측하는독립적인위험요인이었다 (Table 3). 그러나각군간의분석에서클로피도그렐군에서는혈소판수가독립적인위험인자였으나티카그렐러군에서는위험인자가되지못하였다. 고 찰 Figure 1. Thirty-day platelet reactivity assessed by multiple electrode platelet aggregometry adenosine diphosphate test according to the tertile of platelet count and immature platelet fraction. 한상관관계를보였다 (Table 2). 그러나티카그렐러군에서는상관관계가없어지거나작아졌다. 30일째혈소판수와혈소판지수들을삼분위하여혈소판반응성과비교하였을때오직혈소판수만이클로피도그렐군에서유의한관계를보였다 (Fig. 1). 티카그렐러군에서는모든지표가삼분위에따라증가하여도혈소판반응성에영향이없었다. 본연구에서혈소판수와특성들이혈소판반응성과연관이있었다. 특히혈소판수가 30일째 HPR의독립적인위험인자였다. 그러나티카그렐러로치료받은환자에서는연관성이없었고, 혈소판수가독립적인위험인자도아니었다. 따라서강력한항혈소판치료가중재시술을받은환자에서는필요할것으로생각된다. 급성관상동맥증후군및스텐트시술후치료의필수적인요소는항혈판제치료이다. 과거아스피린과클로피도그렐의병합요법이표준으로사용되었고최근에는프라수그렐이나티카그렐러와같은새로운약제들이소개되고있다. 항혈소판제치료에도불구하고충분히혈소판억제가일어나지않는경우가보고되고있는데이를 HPR 현상이라한다 [1-4,11]. HPR 현상은클로피도그렐사용시약 20-30% 까지도보고되고있으며, 이는스텐트혈전증이나심장관련사건의발생과관련이있다. 최근의연구에의하면 HPR을보이는환자들은더심하고광범위한동맥경화성질환을가지고있으며병변의형태도취약한동맥경화반인섬유죽종의형태를보인다고하였다 [12-14]. 또한흡연자, 당뇨병, 만성콩팥병을가진환자들에서 HPR을보이고있어환자의기본특성이위험인자가많고불량한예후를갖는경우가많다

5 - The Korean Journal of Medicine: Vol. 92, No. 6, Table 3. Multivariate analysis for prediction of 30-day high on-treatment platelet reactivity OR 95% CI p-value All patients Use of clopidogrel Platelet count a Immature platelet fraction a White blood cell count a Platelet large cell ratio a Mean platelet volume a Clopidogrel group Platelet count a Immature platelet fraction a White blood cell count a Ticagrelor group Platelet count a Immature platelet fraction a White blood cell count a OR, odds ratio; CI, confidence interval. a For continuous variables, the upper tertile value was used as a cut-off point. Platelet count was /μl, immature platelet fraction 3.91%, white blood cell 7,660/μL, platelet large cell ratio 25.7%, and mean platelet volume 10.2 fl. [5,6]. 새로이개발된강력한항혈소판제를사용할경우 HPR 의빈도는감소하는것으로알려져있으나완전히위험이없어지는것은아니다. 따라서 HPR의위험인자를파악하고맞춤형치료를시행하는것이매우중요하다. 혈소판은그자체로혈전형성에관여할뿐만아니라동맥경화의발생과진행에중요한역할을한다 [15]. 병적인상황에서혈소판이매우증가하는환자들에서혈전성질환의위험이증가하는것은잘알려져있다. 그러나정상범위의혈소판수치를가지는환자에서혈소판숫자가혈전형성과관계가있는지는논란이있다. 최근의보고에의하면오히려혈소판의특성을나타내는지표들, 즉평균혈소판용적, 혈소판분포폭, 혈소판거대세포비율, 미숙혈소판분획등이혈전생성이나급성관상동맥증후군환자의주요심장사건의발생과연관이있다고한다 [16-19]. 혈소판지표들과혈소판반응성과의관계는아직논란이있다. Kim 등 [7] 은클로피도그렐치료를받는환자들을대상으로평균혈소판용적이혈소판반응성과관련이있다고보고하였다. Guthikonda 등 [8] 도클로피도그렐치료를받는환자들에서미숙혈소판비율과혈소판크기가혈소판반응성에영향을미친다고보고하였다. 그러나클로피도그렐치료를받는환자에서혈소판거대세포비율은혈소판반응성과무관하다는보고도있으며 [20], 티카그렐러로치료받는환자에서는미숙혈소판비율이나혈소판크기는혈소판반응성에 영향을미치지않는다는보고도있다 [21,22]. 본연구에서는혈소판숫자뿐만아니라평균혈소판용적, 혈소판분포폭, 혈소판거대세포비율, 미숙혈소판분획과같은혈소판지표들이모두혈소판반응성과연관성이있었다. 그러나치료약제에따라구분하였을때클로피도그렐군에서만연관성이나타났고, 티카그렐러군에서는연관성이없어지거나약해졌다. 일부연구에서프라수그렐로치료받은환자에서는미숙혈소판과혈소판반응성간의연관성이유지된다고보고하고있는바치료약제에따라연관성이다르게나타날수있다 [23]. 본연구의제한점은비록통계적방법을사용하였으나표본수가적다는것이다. 통계적방법은실제임상상황을모두반영할수없으며, 혈구숫자는임상상황에따라많은변이를보일수있기때문에충분히많은숫자의환자가필요할것이다. 또한, 환자의진단이통일되지않고안정형협심증부터심근경색증까지의모든환자가포함되었다는것이다. 그러나저자들은진단에따른변이를줄이고자 30일째혈소판반응성을연구종결점으로정하였다. 또한 30일째혈소판반응성이장기예후와어떤관련이있는지알지못한다. 혈소판수나지표들이혈소판반응성과연관되어예후에영향을미치는지, 항혈소판제치료가이를반영하여실제예후를개선하였는지는본연구로는알수없다. 결론적으로혈소판수와특성들은 30일째혈소판반응성

6 - Kyeong Ho Yun, et al. Platelet reactivity and platelet indices - 과연관성이있었으나티카그렐러치료는이연관성을약화시켰다. 티카그렐러치료가혈소판반응성을개선시켜장기예후를개선시키는지에대해더많은연구가필요할것이다. 요 목적 : 혈소판의수와특성은항혈소판제의혈소판반응성에영향을미칠수있다. 본연구는클로피도그렐과티카그렐러치료를받는관상동맥질환환자를대상으로혈소판지표들과혈소판반응성과의관계를비교하였다. 방법 : 관상동맥질환으로중재시술을받는환자들을대상으로클로피도그렐군 (63명), 티카그렐러군 (65명) 으로나누어약물을투여하였다. 약물투여전, 시술후 48시간째, 30일째혈액을채취하여혈소판수, 평균혈소판용적, 혈소판분포폭, 혈소판거대세포비율, 미숙혈소판분획그리고혈소판반응성을측정하였다. 높은치료중혈소판반응성 (HPR) 은자동혈소판응집측정장치에서측정값 47 U 이상인경우로정의하였다. 결과 : 기저혈소판반응성은두군간의차이가없었으나 48시간째, 30일째혈소판반응성은티카그렐러군에서유의하게낮았다. 30일째혈소판반응성과의상관관계는클로피도그렐군에서백혈구수, 혈소판수, 평균혈소판용적, 혈소판분포폭, 혈소판거대세포비율그리고미숙혈소판분획모두에서유의한상관관계를보였으나티카그렐러군에서는상관관계가없어지거나작아졌다. 전체환자에서클로피도그렐의사용 (HR 4.1, 95% CI , p = 0.010) 과혈소판수 (HR 9.7, 95% CI , p = 0.001) 가 30일째 HPR을예측하는독립적인위험요인이었다. 클로피도그렐군에서는혈소판수가독립적인위험인자였으나티카그렐러군에서는위험인자가되지못하였다. 결론 : 혈소판수와특성들은혈소판반응성과연관성이있으나, 티카그렐러로치료받는환자에서는영향을주지못한다. 중심단어 : 혈소판 ; 혈소판기능검사 ; P2Y12 수용체길항제 약 REFERENCES 1. Lee K, Lee SW, Lee JW, et al. The significance of clopidogrel low-responsiveness on stent thrombosis and cardiac death assessed by the Verifynow P2Y12 assay in patients with acute coronary syndrome within 6 months after drug-eluting stent implantation. Korean Circ J 2009;39: Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109: Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate? J Am Coll Cardiol 2007;49: Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007;49: Park KW, Park JJ, Jeon KH, et al. Clinical predictors of high posttreatment platelet reactivity to clopidogrel in Koreans. Cardiovasc Ther 2012;30: Kim YG, Suh JW, Yoon CH, et al. Platelet volume indices are associated with high residual platelet reactivity after antiplatelet therapy in patients undergoing percutaneous coronary intervention. J Atheroscler Thromb 2014;21: Guthikonda S, Alviar CL, Vaduganathan M, et al. Role of reticulated platelets and platelet size heterogeneity on platelet activity after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. J Am Coll Cardiol 2008;52: Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361: Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010;56: Lev EI, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006;47: Mangiacapra F, De Bruyne B, Muller O, et al. High residual platelet reactivity after clopidogrel: extent of coronary atherosclerosis and periprocedural myocardial infarction in patients with stable angina undergoing percutaneous coronary intervention. JACC Cardiovasc Interv 2010;3: Chirumamilla AP, Maehara A, Mintz GS, et al. High platelet reactivity on clopidogrel therapy correlates with increased coronary atherosclerosis and calcification: a volumetric in

7 - 대한내과학회지 : 제 92 권제 6 호통권제 679 호 travascular ultrasound study. JACC Cardiovasc Imaging 2012;5: Yun KH, Mintz GS, Witzenbichler B, et al. Relationship between platelet reactivity and culprit lesion morphology: an assessment from the ADAPT-DES intravascular ultrasound substudy. JACC Cardiovasc Imaging 2016;9: Linden MD, Jackson DE. Platelets: pleiotropic roles in atherogenesis and atherothrombosis. Int J Biochem Cell Biol 2010;42: Grove EL, Hvas AM, Kristensen SD. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009;101: Chu SG, Becker RC, Berger PB, et al. Mean platelet volume as a predictor of cardiovascular risk: a systematic review and meta-analysis. J Thromb Haemost 2010;8: Choi DH, Kang SH, Song H. Mean platelet volume: a potential biomarker of the risk and prognosis of heart disease. Korean J Intern Med 2016;31: Madjid M, Fatemi O. Components of the complete blood count as risk predictors for coronary heart disease: in-depth review and update. Tex Heart Inst J 2013;40: Verdoia M, Pergolini P, Rolla R, et al. Platelet larger cell ratio and high-on treatment platelet reactivity during dual antiplatelet therapy. Cardiovasc Drugs Ther 2015;29: Vaduganathan M, Zemer-Wassercug N, Rechavia E, et al. Relation between ticagrelor response and levels of circulating reticulated platelets in patients with non-st elevation acute coronary syndromes. J Thromb Thrombolysis 2015;40: Verdoia M, Sartori C, Pergolini P, et al. Immature platelet fraction and high-on treatment platelet reactivity with ticagrelor in patients with acute coronary syndromes. J Thromb Thrombolysis 2016;41: Perl L, Lerman-Shivek H, Rechavia E, et al. Response to prasugrel and levels of circulating reticulated platelets in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2014;63:

012임수진

012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar