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1 대한내과학회지 : 제 76 권제 6 호 2009 원저 관상동맥스텐트삽입술후 Ultegra rapid platelet function Assay-ASA 을이용한 Aspirin 저항성의임상적의의 울산대학교의과대학서울아산병원내과 임지혜 박성욱 이승환 최형오 이필형 선병주박덕우 김영학 이철환 홍명기 김재중 박승정 Clinical impact of aspirin resistance measured using the Ultegra Rapid Platelet Function Assay-ASA in patients undergoing percutaneous coronary intervention Ji Hye Yim, M.D., Seong-Wook Park, M.D., Ph.D., Seung-Whan Lee, M.D., Hyung Oh Choi, M.D., Pil Hyung Lee, M.D., Byung Joo Sun, M.D., Duk-Woo Park, M.D., Ph.D., Young-Hak Kim, M.D., Cheol Whan Lee, M.D., Ph.D., Myeong-Ki Hong, M.D., Ph.D., Jae-Joong Kim, M.D., Ph,D. and Seung-Jung Park, M.D., Ph.D. Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea Background/Aims: Aspirin resistance is reported to be associated with myocardial infarction, stroke, and myonecrosis after percutaneous coronary intervention. However, aspirin resistance and its clinical implications in patients undergoing drug-eluting stent (DES) implantation have not been evaluated sufficiently. Methods: The study enrolled 419 consecutive patients who underwent DES implantation. All of the patients took aspirin 100 mg (228 patients, 54.4%) or 200 mg (191 patients, 45.6%). Aspirin resistance was measured using the Ultegra Rapid Platelet Function Assay-ASA (Accumetrics, San Diego, CA, USA). The results were expressed as aspirin reaction units (ARU). Aspirin resistance was defined as ARU 550. We followed all patients for 9 months. Results: Aspirin resistance was found in 33 patients (33/419, 7.9%). The aspirin dose (118.18±39.2 vs ±50.0 mg, p= 0.011) was lower in the aspirin-resistant (n=33) versus the aspirin-sensitive (n=386) group. There was no significant difference in the occurrence of myocardial necrosis (15.6% vs. 15.5%, p=0.988). On multivariate analysis, low-dose aspirin (odds ratio (OR) 4.714; 95% confidence interval (CI) ; p=0.001), age (OR 1.048; 95% CI , p=0.029), platelet count (OR 1.007; 95% CI , p=0.011), and hypercholesterolemia (OR 2.937; 95% CI , p=0.009) were independent predictors of aspirin resistance. Over the 9 months, no stent thrombosis or death occurred; one acute myocardial infarction occurred in the aspirin-sensitive group. Conclusions: Low-dose aspirin, old age, a higher platelet count, and hypercholesterolemia were associated with a high incidence of aspirin resistance in patients who underwent DES implantation. However, no significant differences in clinical outcome were found between the aspirin-resistant and -sensitive groups during a 9-month follow-up. (Korean J Med 76: , 2009) Key Words: Aspirin resistance; Stent; Coronary artery disease Received: Accepted: Correspondence to Seong-Wook Park, M.D., Ph.D., Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Poongnap-2-dong, Songpa-gu, Seoul , Korea swpark@amc.seoul.kr

2 - The Korean Journal of Medicine: Vol. 76, No. 6, 서론관상동맥중재술후발생할수있는혈전성합병증발생의가장중요한과정은혈소판응집이다 1-3). 경피적관상동맥중재술후, aspirin 과 clopidogrel을이용한항혈소판제는금속스텐트의경우최소 4주, 약물용출성스텐트의경우 1 년까지투약된다. 이러한항혈소판제의사용으로아급성스텐트폐색등스텐트관련혈전성합병증의발생이감소되었다 4-6). 하지만항혈소판제의적절한사용에도불구하고스텐트혈전은여전히 1% 내외로발생한다 6,7). 경피적관상동맥스텐트삽입술후사용되는기본적인항혈소판제인 aspirin 은 cyclooxygenase (COX) 을억제하여 thromboxane A2 (TXA2), prostacyclin 등의생산을효과적으로억제하고, 저용량에서도 COX-1을완전히억제한다 8-10). 하지만일정수준의항혈소판효과를거두기위해일부환자에서과량의 aspirin 이요구되는등약제의효과면에서개인차가존재한다. 또한 aspirin 저항성이있는환자에서는뇌혈관계질환, 말초혈관질환, 심혈관계질환의발생이높고, 관상동맥중재술후심근괴사가더큰것으로보고된다 11-14). 아직까지약물용출성스텐트삽입술후 aspirin 저항성과그임상적경과에관한연구는없는실정이다. 본연구는약물용출성스텐트삽입술을받은환자를대상으로치료시점 (point-of-care: POC) 검사인 Ultegra Rapid Platelet Function Assay-ASA (VerifiyNow - ASA, Accumetrics, San Diego, Calif, USA) 을이용하여 aspirin 저항성의빈도및임상양상을알아보고자하였다. 대상및방법 1. 대상 2006년 3월부터 2006년 9월까지서울아산병원심장내과에서안정형협심증, 불안정형협심증, 비ST분절상승심근경색 (NSTEMI) 에대해경피적관상동맥스텐트삽입술을시행받고항혈소판제를복용한 419명을대상으로전향적자료분석을하였다. 대상환자는경피적관상동맥스텐트삽입술시행최소 3일전부터 100 mg 또는 200 mg aspirin을복용중이었고, 시술 24시간전에 clopidogrel 300 mg 복용하고, 스텐트삽입후이제요법 (aspirin+clopidogrel 75 mg) 으로최소 6개월간처방받았으며임상의의판단에따라이제요법에 cilostazol 200 mg/day을최소한달간사용하는삼제요법 (aspirin+ clopidogrel+cilostazol) 으로동일기간처방받았다. ST분절상 승심근경색 (STEMI), glycoprotein IIb/IIIa inhibitor의사용, 30 일이내 aspirin 과 clopidogrel, cilostazol을제외한다른항혈소판제의복용, 출혈성경향의과거력, 심인성쇼크, 심한간기능장애 (AST 와 ALT가정상의 3배이상상승 ) 가동반된환자및시술직전심근효소의상승이관찰된환자는제외하였다. 2. 스텐트삽입시술스텐트삽입은일반적인방법으로시행되었으며, 시술직전 heparin 70 IU/kg을일시주입하고, 시술중응고시간 (ACT) 이 250초이상유지되도록하였다. 시술후혈관조영검사에서성공적인시술은 20% 미만의잔여협착과 TIMI 3 flow로정의하였다. 3. 혈소판기능분석 Aspirin 저항성은 VerifiyNow -ASA 을사용해측정하였다. 혈액채취는시술후 48시간에먼저첫번째주사기로 5 ml 의혈액을채취한후, 두번째주사기로채취한혈액을 3.2% sodium citrate tube (Vacutainer, Becton-Dickison, Inc., San Jose, CA) 에담았다. Citrate 처리된혈액을 fibrinogen으로덮힌염주알 (fibrinogen coated beads) 과 arachidonic acid, 보존제및완충제등을동결건조시킨 RPFA-ASA cartridge에첨가하였다. RPFA-ASA는 COX-1 pathway에서혈소판이 arachidonic acid에활성화되어응집하고, fibrinogen에부착하는성질을이용하여혈소판의기능을평가하는데, 결과는광학신호인 aspirin 반응단위 (aspirin reaction unit, ARU) 로측정되는탁도계측-광학시스템 (turbidimetric-based optical detection system) 으로표현되었다 15). Aspirin 저항성은 ARU 550을기준으로하였다. 4. 임상경과의관찰시술후 6시간, 12시간, 18시간에 CK-MB 를측정하였으며, 시술직전과시술후가장높은수치의차이를구한 CK-MB 상승정도를스텐트삽입술후심근괴사의지표로삼았다. 스텐트삽입술후 9개월간 1개월, 3개월, 9개월에주기적으로외래경과관찰하였고, 사망, 심근경색, 아급성스텐트혈전성폐색, 뇌혈관계및소화기계출혈성합병증의발생을관찰하였다. 심근경색은 30분이상지속되는전형적인전흉부통증또는심전도상의변화 ( 허혈성 ST 분절하강, ST 분절

3 - Ji Hye Yim, et al. Aspirin resistance in percutaneous coronary intervention - Table 1. Baseline clinical characteristics according to the aspirin sensitivity status ASA-sensitive ASA-resistant (n=386) (n=33) p-value Age, years 61.44± ± Women, n (%) 115 (29.8%) 13 (39.4%) Aspirin dose, mg ± ± Diabetes, n (%) 126 (32.6%) 10 (7.4%) Hypertension, n (%) 201 (52.1%) 22 (66.7%) Chronic renal failure, n (%) 43 (11.4%) 5 (11.5%) Hypercholesterolemia, n (%) 81 (21.0%) 12 (36.4%) Smoker, n (%) 140 (36.3%) 10 (30.3%) Prior myocardial infarction, n (%) 20 (5.2%) 4 (12.5%) Hemoglobin g/dl 13.53± ± White blood cell count, 10 9 /L 6.80± ± Platelet count, 10 9 /L 204.1± ± Multi-vessel disease, n (%) 164 (42.5%) 19 (57.6%) Added cilostazol use, n (%) 102 (26.4%) 12 (36.4%) Prior in-stent restenosis lesion, n (%) 37 (9.6%) 3 (9.1%) Stents per patient 1.9± ± Left ventricular ejection fraction 60.49± ± Peak CK-MB elevation, ng/ml 6.68± ± Massive gastrointestinal bleeding, n (%) 0 (0%) 7 (1.8%) ASA-sensitive, aspirin-sensitive group; ASA-resistant, aspirin-resistant group. 상승또는병적인 Q파 ) 를동반한심근효소의상승 ( 정상치의 3배이상 ) 으로정의하였다. 5. 통계및자료분석통계분석은 SPSS 12 소프트웨어프로그램을사용하였고, 연속변수는평균 ± 표준편차로표기하고 Student t-검정을통해비교하였으며, 범주형변수는빈도 (%) 로표기하고 Chisquare 또는 Fisher s extract test로비교하였다. p 값이 0.05 미만인경우를통계적으로유의하다고인정하였다. Aspirin 저항성에기여하는독립인자를밝히기위해다변량로지스틱회귀분석을시행하였다. 결과 2006년 3월부터 2006년 9월까지약물용출성스텐트삽입술후 aspirin을복용한대상환자는 419명 ( 남자 : 291명 69.5%, 평균연령 61.7±9.87) 이었다. 대상환자중 aspirin 100 mg 복용군은 228명 (69.5%), 200 mg 복용군은 191명 (45.6%) 이고, 각각의 ARU 평균값은 445±66.4 ARU, 430±61.2 ARU 로 aspirin 100 mg군에서더높았다 (p=0.021). Aspirin저항성에따른임상특징은표 1과같다. ARU 550 이상인 aspirin 저항성환자는 33명 (7.9%) 이었고, 이제병합요법 (aspirin+clopidogrel, 305명 72.8%) 과삼제병합요법 (aspirin+clopidogrel+cilostazol, 114명 27.2%) 에따른 aspirin 저항성의빈도는차이가없었다 (6.9% vs. 10.5%, p=0.152). Aspirin 저항성여부에따른임상적특징은 aspirin 용량이 aspirin 저항성군에서감수성군에비해더적었으며 (118.18±39.2 mg vs ±50.0 mg, p= 0.001), 평균연령은더높았고 (61.44±10.0 vs ±8.2, p= 0.034), 고지혈증환자의비율도유의하게많았으나 (21.0% vs. 36.4%, p=0.041), 혈소판수의평균은 aspirin 저항성군에서더많은것으로나타났다 (229.6± /L vs ± /L, p=0.016). Aspirin 용량과저항성의관계를알아보기위하여 aspirin 100 mg과 200 mg군에서각각 aspirin 저항성군의비율을분석해보았다 ( 그림 1). Aspirin 100 mg을복용한 228명중 aspirin 감수성군이 88.2% 인반면에 200 mg 복용한 191명중

- 대한내과학회지 : 제 76 권제 6 호통권제 586 호 2009 - Figure 1. Effect of aspirin dose on the percentage of aspirin-sensitive patients (ARU<550). ASA, aspirin; ASA-S, aspirin sensitive; ASA-R, aspirin resistant.

4 - 대한내과학회지 : 제 76 권제 6 호통권제 586 호 Figure 1. Effect of aspirin dose on the percentage of aspirin-sensitive patients (ARU<550). ASA, aspirin; ASA-S, aspirin sensitive; ASA-R, aspirin resistant. 감수성군은 96.9% 로고용량 aspirin 군에서의미있게 aspirin 감수성군의비율이높았다 (p=0.001). 다변량로지스틱회귀분석을시행하여저용량 aspirin (odds ratio 4.714; 95% CI 1.865~11.914, p=0.001), 연령 (odds ratio 1.048; 95% CI 1.005~0.092, p=0.029), 혈소판수 (odds ratio % CI 1.001~1.014, p=0.011), 고지혈증 (odds ratio 2.937; 95% CI 1.310~6.583, p=0.009) 이 aspirin 저항성에기여함을알수있었다. 추적관찰기간동안스텐트삽입후급성또는아급성스텐트폐색, 사망환자는없었으며, 9개월경과관찰중 aspirin 감수성군에서급성심근경색이 1명발생하였다. 시술후최고농도의 CK-MB 상승을통한관상동맥스텐트삽입술후심근괴사의비교에있어서 aspirin 저항성군과감수성군에서 CK-MB 상승의빈도 (15.6% vs. 15.5%, p= 0.988) 및평균의차이는없었으며 (p=0.938), aspirin 용량에대해서도통계학적으로유의한차이는없었다 (p=0.376). 9개월간의외래경과관찰기간중뇌출혈을포함한중풍이발생한환자는없었으며, 혈변또는흑색변으로내원하여수혈이필요한정도의출혈성부작용이발생한환자는전체 419 명중 7명 (1.7%) 이고, aspirin 감수성군에서는없었으나통계적유의성은없었다. 고 본연구에서저자들은약물용출성스텐트삽입술을시행받고 aspirin 을복용중인환자를대상으로 RPFA-ASA를사 찰 용해혈소판기능분석을시행하여다음의결과를얻었다. 1) aspirin 용량이적을수록, 연령이높을수록, 혈소판수가많을수록그리고고지혈증이동반된경우에서 aspirin 저항성이더높았다. 2) aspirin 저항성군과감수성군간의시술후심근괴사의빈도, 9개월동안의사망및심근경색증등의임상사건은차이가없었다. 3) 입원이필요할정도의출혈성합병증은소화기계출혈로 1.7% 에서발생하였고, aspirin 저항성여부와출혈성합병증에있어서통계적으로유의한차이는없었다. Aspirin 복용중인관상동맥환자에서혈소판잔여반응 (residual platelet reactivity) 을측정할수있는방법에는여러가지가있고, 그중가장표준적인방법은 light transmittance aggregometry (LTA) 이지만특수한검사장비와수작업, 장시간이요구되어치료시점에이용하기어려운문제가있었다. 최근에는치료시점에이용할수있는새로운검사인 platelet function analyzer-100 (PFA-100; Dade-Behring, Marburg, Germany) 와 RPFA-ASA이도입되었다 15). Paniccia 등과 Gurbel 등은 LTA와 PFA-100, RPFA-ASA 을비교하여서로다른결과를보고하였다. Paniccia 등은 LTA와 PFA-100, RPFA-ASA 을시행하여혈소판잔여반응이일치함을보고하였으나 16), Gurbel 등은세가지검사를비교하여 aspirin 저항성이검사종류에따라달라진다고보고하여논란의여지가있다 17). 또한 aspirin 저항성의빈도에있어서도 LTA를이용한연구에서 5.2~29.3%, PFA-100을이용한연구에서 9.5~32.4%, 본연구에서는 7.2% 로저항성의빈도또한다양하게보고되고있다 16-20). 이는 LTA의경우 arachidonic acid의농도등이연구자마다차이를보이고, 또한환자의임상적특징도각기달라결과에영향을미친것으로생각된다 19). Aspirin 저항성을가진환자의예후에대한연구에서 TXA2 생성의안정적인지표인소변 11-dehydro TXB2 의농도가높은환자에서심근경색또는심혈관계질환, 뇌혈관계질환으로인한사망의위험이증가함을보고하였다 12). 또한 aspirin 저항성환자에대해장기간관찰하여사망, 심근경색, 뇌혈관질환의발생이증가함을보고하였다 4,20-22). Aspirin 저항성과관동맥스텐트삽입술이후에발생하는심근괴사의관계에대한연구가있었으나그결과는상이하였다. Chen 등은 RPFA-ASA을사용하여 aspirin 저항성군이감수성군에비해관상동맥스텐트삽입술시행후심근괴사가더많았다고보고했지만 13,23), Buch 등은시술후두군사이에유의한차이가발생하지않았다고보고하였다 24). 또한 Lee 등과 Gurbel 등은안정형협심증으로외래치료

5 - 임지혜외 11 인. Aspirin 저항성의임상적의의 - 중인환자를대상으로 Aspirin 용량에따른저항성의차이를보고하였다. 이연구에서 RPFA-ASA을시행하였고, aspirin 저항성군은감수성군에비해 aspirin 용량이더적었다 18). 후자도 LTA 및 PFA-100, RPFA-ASA 세가지검사를비교하여, 역시 aspirin 용량의차이에따른저항성의차이를보였다 17). 본연구에서는관상동맥스텐트삽입술을받은환자를대상으로 aspirin 저항성과 aspirin 용량에대해조사하여, aspirin 용량이적은경우 aspirin 저항성이더많음을알수있었다. 스텐트삽입후경과를관찰하였으나급성및아급성스텐트폐색은발생하지않았고, 사망은없었으며, 심근경색은 9개월경과관찰동안 1명이발생하여 aspirin 저항성군과감수성군사이에임상적차이를밝힐수없었다. 스텐트삽입술후심근괴사의정도에대해서는 aspirin 저항성군과감수성군사이에의미있는차이가없었다. 또한 aspirin 의용량과시술후심근괴사의정도를비교하였을때통계학적으로유의한차이가없어, 관상동맥스텐트삽입술시행환자에서 aspirin 저항성및 aspirin 용량은시술과관련된합병증의빈도증가와관련이없는것으로나타났다. 본연구에서 aspirin 감수성군과 aspirin 저항성군간에시술후심근괴사나임상경과에차이가없는것은 aspirin 과동시에투여된강력한항혈소판제인 clopidogrel이나 cilostazol의효과에기인한것으로사료되지만추후많은환자를대상으로장기간의연구가필요할것으로생각된다. 본연구에서는연령과혈소판수, 고지혈증여부가 aspirin 감수성과연관이있는것으로나타났다. Lee 등에따르면 aspirin 저항성군은감수성군에비해평균연령은더높지만, 혈소판수및고지혈증여부는차이가없었던반면, Chen 등의연구에서는연령, 혈소판수, 고지혈증여부가두군간에유의한차이가없어, 연구자간서로다른결과를보였다 18,25). 따라서 aspirin 저항성과임상특징과의연관성에대해서향후추가적인연구가필요할것으로생각된다. Aspirin 복용에있어서발생할수있는대표적인부작용은출혈이다. 대부분의연구에서 aspirin 용량의증가는출혈성합병증의발생을증가시킨다고보고하고있으나 26-28) 본연구에서는용량의증가에따른합병증의증가는관찰되지않았다. 본연구는단일센터에서시행된전향적관찰코호트연구이나, 대상환자수가적고추적관찰기간이짧다는한계가있다. 따라서더많은환자를대상으로장기간경과관찰하여, aspirin 저항성과용량에따른만성스텐트폐색 (late stent thrombosis), 급성심근경색, 사망등에대해비교하는것이의미있을것으로생각된다. 결론본연구에서약물용출성스텐트삽입술을시행한환자에서저용량의 aspirin 복용은 RPFA-ASA을통해더높은빈도의 aspirin 저항성과연관된다는것을알수있었지만, 9개월의관찰기간동안고용량의 aspirin 복용과비교하여스텐트폐색, 급성심근경색, 사망등임상적인결과에의미있는차이가없었다. 요약목적 : 이전연구에서 aspirin 저항성은심근경색, 뇌경색, 경피적관상동맥스텐트삽입술후심근괴사등과관련있다고보고된바있다. 그러나경피적관상동맥스텐트삽입술이시행된환자에서 aspirin 저항성과그임상적경과에대해서는잘알려져있지않다. 방법 : 경피적관상동맥중재술을시행받고항혈소판제재를복용한 419명을대상으로하였다. 100 mg 또는 200 mg aspirin 을복용중이었으며스텐트삽입술후 48시간에 aspirin 저항성을 RPFA-ASA를사용해측정하여 ARU 550을기준으로 aspirin 저항성을판단하였다. 스텐트삽입후 9개월간의임상경과를관찰하였다. 결과 : 전체 aspirin 저항성은 33명 (7.9%) 이었으며, aspirin 저항성군 (n=33) 에서 aspirin 감수성군 (n=386) 에비해 aspirin 용량은더적었다 (118.18±39.2 mg vs ±50.0 mg, p= 0.001). 양군간에스텐트삽입술후심근괴사의발생빈도역시통계학적으로유의한차이는없었다 (p=0.938). 다변량분석에서 aspirin 용량 (odds ratio 4.714; 95% CI 1.865~11.914, p=0.001), 연령 (odds ratio 1.048; 95% CI 1.005~0.092, p= 0.029), 혈소판수 (odds ratio 1.007; 95% CI 1.001~1.014, p= 0.011), 고지혈증 (odds ratio 2.937; 95% CI 1.310~6.583, p= 0.009) 이 aspirin 저항성에기여함을알수있었다. 스텐트삽입술후 9개월간의외래경과관찰기간중스텐트혈전증과사망은발생하지않았으며심근경색증은 aspirin 감수성군에서 1명발생하였다. 결론 : 관동맥스텐트삽입술후 aspirin 저항성은사용하는 aspirin 용량, 나이, 혈소판수, 고지혈증과관계있으며, 시술후 9개월경과관찰중 aspirin 저항성에따른임상경과에차이는없었다

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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