untitled

Anesth Pain Med 2014; 9: 31-35 임상연구 아스피린의중단시기와 PFA-100 을이용한혈소판부착및응집능검사 고려대학교의과대학구로병원마취통증의학과 김영성ㆍ이일옥ㆍ박혜윤ㆍ박지혜ㆍ임병건ㆍ김희주 Platelet function assay to determine the optimal preoperative cessation period of aspirin Young Sung Kim, Il-Ok Lee, Hye-yoon Park, Ji-hye Park, Byung Gun Lim, and Heezoo Kim Department of Anesthesiology and Pain Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea Background: This study was conducted to assess preoperative residual antiplatelet-induced platelet dysfunction using a platelet function assay to determine the optimal cessation period of aspirin during the preoperative period. Methods: Patients older than 20 years, who were scheduled for elective surgery under general anesthesia, were enrolled prospectively. The last ingestion of the aspirin had occurred within the previous 10 days before surgery (aspirin 100 mg per day). No history of antiplatelet intake was documented in the control group. Platelet function was assessed using a platelet function analyzer-100 (PFA-100). Receiver operating characteristic (ROC) curves were plotted to determine the ability of aspirin cessation time in order to predict platelet function as assessed by the PFA. Patients were assigned to groups according to the period of aspirin discontinuation. Results: Two hundred patients were enrolled in this study (100 control group and 100 aspirin group). The mean PFA value of the control group was significantly lower than that of the treated groups. The areas under the ROC curve (0.65, P = 0.03) of aspirin cessation period to discriminate PFA prolongation were significant. There were significant decreases in PFA values when aspirin medication was discontinued for 7 days, but not when the intake was discontinued for 5 days. Conclusions: Platelet function recovered if aspirin intake was discontinued > 7 days prior to surgery; therefore, in these patients, a preoperative platelet function test is not essential. However, the residual antiplatelet effect of aspirin should be assessed using the PFA in patients who discontinue aspirin less than 7 days prior to surgery. (Anesth Pain Med 2014; 9: 31-35) Key Words: Aspirin, Platelet function test, Preoperative period. 서 뇌졸중및관상동맥질환을가진환자의수가증가함에따라사회적비용이늘어나면서 [1] 고위험군환자에서뇌졸중과심근경색을방지하기위해아스피린및항혈소판제제가사용되고있다 [2,3]. 하지만항혈소판제제는수일간혈소판의기능저하를유도하며이는출혈경향을증가시킨다 [4]. 이전의연구에따르면혈소판의수명은대략 8 10일이며 [5] 아스피린은혈소판의 cyclooxygenase-1을비가역적으로억제하는작용을하며, 이러한아스피린의투여를중단한후 10일이경과되면아스피린의항혈소판작용의잔류효과가사라지는것으로여겨진다 [6]. American College of Chest Physicians의가이드라인에따르면수술전아스피린의중단이필요한경우에는 7일에서 10일이전에아스피린을끊도록권고하고있다 [7]. 하지만다른연구에서는아스피린의중단 5일부터는아스피린의잔류효과가거의없는것으로보인다고한다 [8]. 따라서본연구에서는평소아스피린을복용하는환자에서수술직전혈소판응집능검사를시행하여아스피린에의한혈소판기능장애의잔류정도를측정하였다. 수술전아스피린의중단시기가잔류항혈소판효과를예측할수있는지알아보고나아가서는수술전아스피린의적절한중단시기에대해고찰하고자한다. 론 Received: September 24, 2013. Revised: 1st, September 26, 2013; 2nd, October 4, 2013. Accepted: October 10, 2013. Corresponding author: Il-Ok Lee, M.D., Ph.D., Department of Anesthesiology and Pain Medicine, Korea University Guro Hospital, Korea University College of Medicine, 97, Gurodong-gil, Guro-gu, Seoul 152-703, Korea. Tel: 82-2-2626-3234, Fax: 82-2-851-9897, E-mail: iloklee@korea.ac.kr 대상및방법본연구는관찰연구로써 2012년 1월에서 2013년 5월까지본원에서전신마취가예정된계획수술을시행받는환자 200명을대상으로하였고윤리위원회의승인을받았다. 모든환자들은본연구의목적과방법에대해충분히설명을 31

32 Anesth Pain Med Vol. 9, No. 1, 2014 들었으며인지동의를시행하였다. 모든환자는 20세이상의미국마취과학회신체등급 1, 2인환자들이었으며심각한전신질환을갖고있거나저혈량증환자, 선천적혈소판장애를가진경우, 아스피린저항성의병력을가진환자, 아스피린외의다른항혈소판, 항응고제제, 한약제제를투약받은병력이있는환자들은제외하였다. 평소매일아침아스피린 100 mg을투약받으면서수술전 10일이내에수술을위해서아스피린복용을중단하거나계속투약중인환자 100명을아스피린군 (A군) 에포함하였고비교를위하여아스피린및다른항혈소판제복용병력이없는환자 100 명을대조군 (C군) 으로설정하였다. 측정변수는연령, 성별, 체중, prothrombin time (PT), activated partial thromboplastin time (aptt), 헤마토크리트 (hematocrit, Hct), 혈소판수 (platelet count, PLT), 혈소판부착및응집능검사값 (Collagen/Epinephrine Closure time of platelet adhesion and aggregation test of platelet function assay, PFA) 이었다. PFA는 collagen과 epinephrine이포함된일회용의카트리지 (COL-EPI cartridge) 를사용한 Platelet function analyzer-100 (PFA-100, Siemens, Eschborn, Germany) 를이용하여수술당일아침채혈하여검사하였다. 아스피린투약환자들은아스피린투약중단시기에따라투약중단 5일이하군 (A 5), 5일초과군 (A >5), 7일이하군 (A 7), 7일초과군 (A >7), 그리고 10일경과군 (A 10) 으로나누었다. 이전의연구에기초하여 PFA값의정상범위를 59 197 로설정하였고 PFA값이 197초를초과하는경우를연장되었다고간주하고이분형명목변수 (Dichotomous Categorical Variable) 로변환하였다 [9]. 통계분석은 SPSS 20.0 (SPSS Inc. Chicago, IL, USA) 을이용하였다. A 5 와 A >5, A 7 와 A >7, C와 A 10, A 5, A >5, A 7, A >7 의양군간연령, 성별, 체중, prothrombin time (PT), activated partial thromboplastin time (aptt), 헤마토크리트 (hematocrit, Hct), 혈소판수 (platelet count, PLT), PFA의차이 검정은 independent T test를사용하였고, 성별및명목변수로변환한 PFA의양군간차이검정은 chi-squared test 혹은기대빈도가 5보다작은값을가진측정치가 20% 이상존재시 Fisher s exact test을이용하였다. 그리고, 아스피린투약군에서아스피린투약중단시기가 PFA 연장여부를어느정도예측할수있을지를알아보기위해아스피린의중단시기를독립변수, 명목변수로변환한 PFA를종속변수로설정하고 binary logistic regression을통해수용자작용특징곡선 (receiver operating characteristic curve, ROC curve) 을그려서 area under the receiver operating characteristic curve (AUC) 값을구하였다 ( 대조군의경우아스피린의중단기간설정이불가능하여제외하였음 ). 또한아스피린중단시기에따른각각의민감도및특이도를계산하였다. P 값이 0.05 미만인경우를통계적으로유의한것으로판정하였다. 결과아스피린군 100명, 대조군 100명, 총 200명의환자가본연구에포함되었다. 아스피린군에서아스피린중단 5일이내인환자 30명, 5일초과인환자는 70명이었으며, 아스피린중단 7일이내인환자는 60명, 7일초과인환자는 40명이었다. 환자의연령, 성별, 체중, PT, aptt, 헤마토크리트, 혈소판수는각군의비교에서유의한차이를보이지않았다 (Table 1). 모든환자들중 PFA 값이정상범위의하한선인 59보다낮게측정된경우는없었다. C군에서 PFA값의 10th percentile 값은 79초, 90th percentile값은 136초로 PFA의정상범위인 59 197 사이에위치하였다. 전체 A군의 ROC 그래프에서 AUC값은 0.65로유의한결과를보였다 (P = 0.032). ROC 그래프에서민감도 = 1, 1-특이도 = 0에가장가까운변곡점은민감도 0.82, 1-특이도 0.46 인지점이었고, 두번째로가까운변곡점은민감도 Table 1. Demographic Data Group A 5 (n = 30) A >5 (n = 70) A 7 (n = 60) A >7 (n = 40) A 10 (n = 24) C (n =100) Sex (M/F) Age (yr) Wt (kg) PT INR aptt (sec) Hct (%) PLT ( 1,000/μl) 20/10 67.2 ± 11.3 62.5 ± 7.2 0.99 ± 0.07 35.3 ± 4.8 36.6 ± 4.5 241.1 ± 103.3 44/26 63.0 ± 8.9 65.8 ± 11.8 0.96 ± 0.06 34.8 ± 4.5 38.2 ± 5.1 241.3 ± 78.8 40/20 65.3 ± 9.6 63.6 ± 8.8 0.98 ± 0.07 34.6 ± 3.9 37.4 ± 5.4 245.5 ± 98.5 24/16 62.7 ± 9.9 66.5 ± 13.1 0.96 ± 0.05 35.5 ± 5.4 38.2 ± 4.2 235.0 ± 64.5 10/14 61.7 ± 9.8 69.6 ± 14.3 0.96 ± 0.06 36.8 ± 6.2 38.2 ± 4.3 221.2 ± 49.2 52/48 63.5 ± 8.1 62.4 ± 10.4 0.97 ± 0.05 34.7 ± 4.2 38.8 ± 3.8 229.0 ± 60.5 Values are numbers of patients or means ± SD. The A groups (aspirin group) were classified according to cut-day (period of aspirin discontinuation), group A 5: cut-day 5 in group A, group A >5: cut-day > 5 in group A, group A 7: cut-day 7 in group A, group A >7: cut-day > 7 in group A, group A 10: cut-day = 10 in group A, group C: control group. There were no significant differences in sex, age, Wt (weight), PT (prothrombin time), aptt (activated partial thromboplastin time), Hct (hematocrit), or PLT (platelet count) among groups.

김영성외 5 인 :Preoperative assessment of the effect of aspirin 33 0.45, 1-특이도 0.26인지점이었다 (Fig. 1). 아스피린투여를중단한지 5일이내에서 PFA 값은연장될것이라는가정하에서의민감도는 0.45 (0.24 to 0.68, 95% CI, confidence interval), 특이도는 0.74 (0.63 to 0.84, 95% CI) 였고아스피린투여를중단한지 7일이내에서 PFA 값이연장될것이다라는가정하에서의민감도는 0.82 (0.60 to 0.95, 95% CI), 특이도는 0.46 (0.35 to 0.58, 95% CI) 이었다 (Fig. 2). 아스피린투여를중단한지 5일이내인경우 33.3% (10/30) 에서 PFA 값이연장되었고 5일초과한경우는 17.9% (12/70) 에서 PFA 값이연장되었으나양군에서의 PFA 값이연장된환자들의관찰빈도는기대빈도와유의한차이가없었으며 (P = 0.073), 평균 PFA 값역시통계적유의성은없었다. 아스피린투여를중단한지 7일이내인경우는 30% (18/60) 에서 PFA 값이연장되었고 7일초과한경우는 10% (4/40) 에서 PFA 값이연장되어통계적으로유의한차이를보였으며 (P = 0.036) 평균 PFA 값역시유의하게차이를보 였다 (P = 0.007). 아스피린투여를중단한지 10일경과한경우에평균 PFA 값은대조군 C군의평균 PFA 값에비하여유의한차이를보이지않았으나그외의아스피린각군의 PFA 값과비교할때 C군의평균 PFA 값은유의하게낮았다 (Table 2). 고찰본연구결과, 수술전아스피린의투여를중단한지 7일이상이지난경우에는투약중단 7일이내의환자군과비교하여 PFA 연장의빈도및 PFA 값의유의한감소를보이지만아스피린의투여를중단한지 5일이상인경우에는투약중단 5일이내인환자군과비교하여 PFA 연장의빈도및 Fig. 1. Diagnostic value of the cut-day to discriminate between normal and prolonged platelet function assay, as determined by receiver operating characteristic (ROC) curves. Cut-day refers to the period of aspirin discontinuation. Area under curve = 0.650 (P = 0.032). Fig. 2. Dot histogram pairs for each group. The horizontal lines and the tables to the right of the graph represent the cut-off values for cut-day and the corresponding sensitivity/specificity. Cut-day refers to the period of aspirin discontinuation. Table 2. Platelet Function Assay (PFA) Results Group A 5 (n = 30) A >5 (n = 70) A 7 (n = 60) A >7 (n = 40) A 10 (n = 24) C (n =100) PFA value (sec) N/P (n) 145.4* ± 75.7 20/10* 137.8* ± 59.0 58/12* 152.5* ± 75.3 42/18* 121.4*, ± 36.0 112.1 ± 33.9 36/4*, 22/2 106.3 ± 24.0 100/0 Values are numbers of patients or means ± SD. N/P indicates the number of patients with normal PFA/prolonged PFA. The A groups (aspirin group) were classified according to cut-day (period of aspirin discontinuation), group A 5: cut-day 5 in group A, group A >5: cut-day > 5 in group A, group A 7: cut-day 7 in group A, group A >7: cut-day > 7 in group A, group A 10: cut-day = 10 in group A, group C: control group. There was no significant difference in PFA value between group A 5 and group A >5 or group A 10 and group C. The PFA value of group A >7 is significantly lower than that of group A 7. The PFA value of group C is significantly lower than that of group A 5, A >5, A 7 and A >7. The observed frequency of patients with prolonged PFA in group A >7 was significantly lower than the expected frequency when compared to group A 7. The observed frequency of patients with prolonged PFA in group A >5 was not significantly different from the expected frequency when compared to group A 5. *P < 0.05 compared with group C, P < 0.05 compared with group A 7.

34 Anesth Pain Med Vol. 9, No. 1, 2014 PFA 값에서유의한차이를보이지않았다. 이는 5일동안의아스피린의투여중단기간이혈소판기능이완전하게회복되기에충분하지않은기간이라는것을말해준다고할수있다. 가이드라인에의하면 AUC 값이 0.5인경우예측력에대한정보를제공할수없으며 0.5에서 0.7 이하인경우정확도가떨어지고, 0.7에서 0.9 이하인경우중등도의예측력을제공할수있으며, 1인경우완벽한예측을할수있다고한다 [10]. 본연구결과, ROC 곡선에의해계산된 AUC 값은아스피린의투여중단기간이 PFA 연장유무를예측하는데유의하다고볼수있으나 0.7에미치지않기때문에진단적도구로서의정확도는부족하다고볼수있다. 즉단순히아스피린의중단기간만으로 PFA 연장여부를예측하기는불충분하다고생각한다. 사실 PFA값이정상범위보다연장되었다는의미가임상적으로실제의혈소판기능이억제되었다고생각할수있는지에대한의의는제한적이라고한다. PFA-100을이용한 PFA 값은아스피린민감성 cyclooxygenase-1 경로에특이적이지않다고한다 [11]. 또한헤마토크리트, 혈소판의수, von Willebrand factor 등이 PFA-100을이용한 PFA 값에영향을미치기때문에 [9] 단순히아스피린의잔류영향을평가하는데에는부족함이있다고생각한다. 반면에 PFA는혈액응고장애를알아내거나감시하는데유용하다고하며수술전평가의측면에서출혈의위험성과수혈의필요성을예측하는데유용한진단적도구가된다고알려져있다 [12]. PT나 aptt는혈소판의기능을직접적으로평가할수없고, template bleeding time (BT) 은혈액응고장애의병력이없는환자에서수술중출혈의위험성의유용한예측지표가되지못한다고한다. 또한정상 BT수치가침습적시술에서과다한출혈의가능성을배제하지못한다고보고되었다 [13]. 따라서 BT는현재임상에서추천되지않는방법으로알려져있고, light transmission aggregometry, flow cytometry 등의다른혈소판기능검사는검사시간이오래걸리고어려운점이있어서선별검사의목적으로사용하는것은어렵다고생각한다 [14]. 본연구에서도아스피린군과대조군의환자들이 PT 와 aptt의값이유사함에도불구하고대조군의 PFA 값이유의하게낮았다. 따라서아스피린을투약중인환자들에서수술전평가로아스피린사용의병력을정확히청취하는것과동시에혈소판기능검사의시행이필요하다고생각한다. 본연구에서사용한 PFA는 platelet function analyzer를이용한 closure time을구한것으로빠른시간내에혈소판부착및응집능검사를시행할수있는선별검사법이다. 현재 PFA-100와함께임상적으로사용되는카트리지는두가지종류가있다 [15,16]. Collagen/ADP agonist (COL-ADP) 카트리지의경우에는혈소판장애를확인하는데유용하나이는아스피린에영향을받지않는것으로되어있다. 반면에 Collagen/epinephrine (COL-EPI) 카트리지는아스피린의항혈소판작용을감지하는데유용한것으로밝혀져있어 [16,17] 본연구에서는 COL-EPI를적용하였다. Cyclooxygenase 경로를억제하는아스피린이심근경색과뇌졸중을예방할수있다는효과는최근 50년간수백개의임상적검사를통해서널리알려져있다 [2,18]. 이러한이득에도불구하고아스피린은출혈의합병증을야기할수있다. 매일 100 mg 이상의아스피린을투약받을시출혈의빈도가 ADP-receptor blocker를사용하는환자만큼상대적으로증가하며 [4] 매일 75 150 mg의아스피린을투약받는환자에서두개외대출혈의위험성은 1.5배정도증가한다고보고되었다 [2]. American College of Chest Physicians의가이드라인은수술전아스피린의중단이필요한경우에는 7일에서 10일이전에아스피린을끊도록권고하고있으며 [7] 이는본연구의결과와일치한다. 본연구의제한점으로는 PFA가임상적으로얼마나수술중출혈사건을예측할수있는지에대해평가하지못하였던점이다. 즉, 본연구결과에서제시되는민감도와특이도는단순히중단시기가 PFA의연장유무를얼마나정확히예측가능한지정도만설명할수있으며술중출혈에직접적으로미치는영향에대해서는추가적연구가필요하리라생각한다. 혈소판기능검사를위해서 PFA-100를이용한검사법이외에도 bleeding time (BT), 다른혈소판응집검사, 혹은 thromboelastography (TEG) 등을동시에시행하여비교하지못하였던점도한계점으로들수있다. 또한본연구에서는진단되지않은아스피린저항성에대한사전적고려가없었다. Lee 등은 [19] 한국의아스피린저항성의발생빈도가 10.1% 정도이며낮은혈중헤모글로빈과높은혈소판수가아스피린저항성과연관이있는것으로보고하였다. 아스피린저항성을가진환자들은낮은혈중 11-dehydrothromboxane B2와함께 prostaglandin endoperoxide synthase 2 유전자 (G765C) 변이를보이는것으로알려져있으나 [20] 본연구에서이에대한추가적검사는이루어지지않았다. 이러한제한점들에도불구하고본연구는여러임상적의의를제공하고있다고생각한다. 만약 PFA 검사가불가능한상황일경우에본연구의결과를참고로생각해본다면, 아스피린의투여를 5일중단한것으로는혈소판기능의회복에유의한차이가없고, 7일이상아스피린의투여를중단하는것으로혈소판기능의유의한회복을기대하는것이적절함을시사하고있다. 또한대조군과비교하여아스피린군에서 PFA 값이아스피린의중단 10일이경과한환자를제외하고는연장되어있으므로이시기의 PFA 검사는의미가있을것으로생각된다. 관상동맥질환의위험성을가진환자에서아스피린의중단을최소화하기위해서는 PFA를시행하는것이도움이될수있으며이러한경우에 PFA 등의혈소판기능검사가수술전검사로써이루어져야

김영성외 5 인 :Preoperative assessment of the effect of aspirin 35 한다고생각한다. 결론적으로수술전아스피린의투여를중단한지 7일이내의환자에게서는아스피린의항혈소판잔류효과를측정하기위해서수술전혈소판기능검사를시행하는것이바람직할것으로여겨진다. 참고문헌 1. Johnston SC, Mendis S, Mathers CD. Global variation in stroke burden and mortality: estimates from monitoring, surveillance, and modelling. Lancet Neurol 2009; 8: 345-54. 2. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71-86. 3. Han JI. Perioperative risk of non-cardiac surgery in coronary artery disease patients. Anesth Pain Med 2007; 2: 55-60. 4. Serebruany VL, Malinin AI, Eisert RM, Sane DC. Risk of bleeding complications with antiplatelet agents: meta-analysis of 338,191 patients enrolled in 50 randomized controlled trials. Am J Hematol 2004; 75: 40-7. 5. Kamath S, Blann AD, Lip GY. Platelet activation: assessment and quantification. Eur Heart J 2001; 22: 1561-71. 6. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein. J Clin Invest 1975; 56: 624-32. 7. Douketis JD, Berger PB, Dunn AS, Jaffer AK, Spyropoulos AC, Becker RC, et al. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133(6 Suppl): S299-339. 8. Jámbor C, Weber CF, Gerhardt K, Dietrich W, Spannagl M, Heindl B, et al. Whole blood multiple electrode aggregometry is a reliable point-of-care test of aspirin-induced platelet dysfunction. Anesth Analg 2009; 109: 25-31. 9. Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008; 34: 709-33. 10. Greiner M, Pfeiffer D, Smith RD. Principles and practical application of the receiver-operating characteristic analysis for diagnostic tests. Prev Vet Med 2000; 45: 23-41. 11. Cammerer U, Dietrich W, Rampf T, Braun SL, Richter JA. The predictive value of modified computerized thromboelastography and platelet function analysis for postoperative blood loss in routine cardiac surgery. Anesth Analg 2003; 96: 51-7. 12. Sucker C, Litmathe J, Feindt P, Zotz R. Platelet function analyzer (PFA-100) as a useful tool for the prediction of transfusion requirements during aortic valve replacement. Thorac Cardiovasc Surg 2011; 59: 233-6. 13. Peterson P, Hayes TE, Arkin CF, Bovill EG, Fairweather RB, Rock WA Jr, et al. The preoperative bleeding time test lacks clinical benefit: College of American Pathologists' and American Society of Clinical Pathologists' position article. Arch Surg 1998; 133: 134-9. 14. Harrison P, Mackie I, Mumford A, Briggs C, Liesner R, Winter M, et al. Guidelines for the laboratory investigation of heritable disorders of platelet function. Br J Haematol 2011; 155: 30-44. 15. Gorog DA, Fuster V. Platelet function tests in clinical cardiology: unfulfilled expectations. J Am Coll Cardiol 2013; 61: 2115-29. 16. Kim NS, Yoo SH, Chung HU. Effects of oral aspirin on Platelet function analyzer-100 collagen-epinephrine closure time in patients undergoing elective surgery. Anesth Pain Med 2011; 6: 314-7. 17. Nazarian SM, Thompson JB, Gluckman TJ, Laws K, Jani JT, Kickler TS, et al. Clinical and laboratory factors associated with shear-dependent platelet hyper-reactivity in patients on chronic aspirin therapy. Thromb Res 2010; 126: 379-83. 18. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-60. 19. Lee YK, Kim HS, Park JY, Kang HJ. Incidence of aspirin resistance in the patient group of a university hospital in Korea. Korean J Lab Med 2008; 28: 251-7. 20. Xu ZH, Jiao JR, Yang R, Luo BY, Wang XF, Wu F. Aspirin resistance: clinical significance and genetic polymorphism. J Int Med Res 2012; 40: 282-92.