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1 한국임상약학회지제 25 권제 3 호 Korean J Clin Pharm, Vol. 25, No. 3, 2015 Original Article Korean Journal of Clinical Pharmacy Official Journal of Korean College of Clinical Pharmacy Available online at pissn: 급성관상동맥증후군치료를위한국내 외항혈소판제약물요법가이드라인비교연구 정은주 이채원 백인환 * 경성대학교약학대학 (2015년 5월 20일접수 2015년 8월 10일수정 2015년 8월 12일승인 ) A Comparative Study the USA, Europe and Korea Guidelines of Antiplatelet Therapy for Patients with Acute Coronary Syndrome Eun-Joo Jung, Chae-Won Lee, and In-Hwan Baek* College of Pharmacy, Kyungsung University, Busan 48434, South Korea (Received May 20, 2015 Revised August 10, 2015 Accepted August 12, 2015) ABSTRACT Objective: Patients with acute coronary syndrome (ACS) are typically managed with dual antiplatelet therapy of acetylsalicylic acid (aspirin) and P2Y 12 receptor inhibitor. In this study, we discussed current and previous antiplatelet therapy guidelines and compared with guidelines of the USA (ACC/AHA), Europe (ESC) and Korea (KSC). Method: This study investigated from ACC/AHA Joint Guidelines (the USA), ESC Clinical Practice Guidelines (Europe) and Korea Society of Interventional Cardiology (Korea) web site, respectively. Results: It is significant that difference between the current and the previous guidelines was integration of terminology from clopidogrel to P2Y 12 receptor inhibitors since prasugrel and ticagrelor, new antiplatelet drugs, has been added. The other difference was all three guidelines has differences in dose of aspirin. The most notable difference was class of recommendation (COR) in P2Y 12 receptor inhibitors. ACC/AHA and Korean guidelines recommend clopidogrel, prasugrel, and ticagrelor with COR IB; whereas, ESC recommend prasugrel and ticagrelor with IB which is higher than clopidogrel with IC. Conclusion: This research addresses important movement to revise the Korean existing guideline recommendations. New Korean antiplatelet therapy guideline should be avoiding obvious differences in ACC/AHA and ESC guidelines and harmonizing international guidelines. KEY WORDS: acute coronary syndrome, antiplatelet therapy, guideline, ACC/AHA, ESC, KSC 급성관상동맥증후군 (acute coronary syndrome; ACS) 이란, 관상동맥의혈관내에급성으로크고작은혈전이생겨이로인해순간적인혈관폐쇄또는혈전에서분비되는여러혈관수축성물질들이혈관을더심하게수축시켜심한관상동맥폐쇄로인하여심장으로의혈류공급이부족해져서생기는질환이다. 1) 심혈관질환은전세계적으로사망원인 1위의질환이며, 여러심혈관질환중에서도특히나급성관상동맥증후군은심혈관질환의주요위험요인이다. 2) 다시말해, 급성관상동맥증후군은심근의혈액공급저하에기인하는모든급성증상, 즉급성심근허혈 (myocardial ischemia) 에기인한모든임상증세를아우르는광범위한용어이다. 3) 이러한급성관상동맥증후군은불안정형협심증 (unstable angina, UA) 과급성심근경색증으로나뉠수있으며, 급성심근경색증은다시 ST분절상 승심근경색증 (ST-elevation myocardial infarction, STEMI) 과 ST분절비상승심근경색증 (Non-ST-elevation myocardial infarction, ) 로나뉘어진다 (Fig. 1). 3,4) 협심증이나심근경색증같은허혈성심질환은어느질환보다도높은사망률과장애유발등높은위험도를가지며그에따른직 간접적경제적비용역시증가시켜개인및사회에큰부담을주는질환이다. 5) 미국에서전체약 3억인구중 7백만이상의환자가심근경색증을앓고있으며, 우리나라에서도허혈성심장질환은심혈관질환사망의가장큰원인이며, 유병률은인구 1,000명당 6.4명으로전체환자수가 31만명에이른다. 그리고급성관상동맥증후군환자의발생이점차증가하고있는추세이다. 6) 사망률과위험률이큰질환인급성관상동맥증후군에해당하는환자의꾸준한증가추세와그에따른경 *Correspondence to: In-hwan Baek, College of Pharmacy, Kyungsung University, 309, Suyeong-ro, Nam-gu, Busan 48434, South Korea Tel: , Fax: baek@ks.ac.kr 200

2 급성관상동맥증후군치료를위한국내 외항혈소판제약물요법가이드라인비교연구 / 201 Fig. 1. The classification of Acute Coronary Syndrome. ECG (electrocardiogram); (non-st elevation myocardial infarction); STEMI (ST-elevation myocardial infarction). 제적인부담을고려하면이질환의이해와적절하고최신의약물요법치료를알고임상에서행하는것이중요하다. 7) 급성관상동맥증후군의치료는크게 4가지로나뉜다. 허혈증상과심근손상을줄이고예방하기위한항허혈치료, 병태생리에가장중요하게작용하는항혈전치료, 환자의위험도에따라관동맥협착이나폐색을해결하기위한혈관재관류요법, 그리고심혈관계발작을줄이기위한위험인자조절과약물치료가있다. 8) 이중에서급성관상동맥증후군의표준약물치료는항혈전치료에속하는항혈소판약물요법이다. 항혈소판약물요법은혈전생성을억제하여급성관상동맥증후군환자의치료에서매우중요한약제이다. 9) 이에속하는 1차치료제로써 aspirin과 clopidogrel이널리쓰여져왔으나, 최근에들어와내성의보고와약효면에문제점이제기되고있다. 10,11) 특히, clopidogrel의경우, 주요대사효소인 CYP2C19과관련한유전학적변이는저항성이있는환자에있어서심혈관사건의발생률이높고재발이나예방효과도감소가많이보고된다. 11,12) CYP2C19의변이가백인보다동양인에게더많고 ( 백인 30%, 동양인 55%) 이에따라같은용량의 clopidogrel을투여하여도치료효과가동일하지않고임상결과도다르게나타나게된다. 13) 낮은약물효과가발생하였다고해서단순히용량을증가시키는것으로임상적증상이개선되지않음을 GRAVITAS 연구등에서결론을내고있다. 14) 따라서새로운항혈소판제제에서새로운약제개발의필요성이대두되었고, 이런흐름에맞추어최근들어 clopidogrel을이은새로운 P2Y 12 수용체억제제로 prasugrel과 ticagrelor가개발되었다. 9,15) Clopidogrel의경우, 약효를내기위해서활성대사체로대사가이루어져야하고대사시에도제한적으로전 환이된다 ( 불활성화 85%, 활성화 15%). 반면에, prasugrel 은 100% 가중간체로되어간의효소에의해활성대사체로대사되므로대사에의한제한이없다. 그리고약효발현시간도 clopidogrel에비하여빠르고유전적변이의영향가능성도낮다고보여진다. 16) 또다른새로운약제인 ticagrelor의경우는앞의두약제와달리흡수가될때이미자체가활성약물의형태이며 P2Y 12 수용체에가역적으로작용한다. 17) 간에서대사과정을거치지않고바로작용하므로체내에서보다빠르게작용할수있는점과 CYP의유전적다형성과연관이없어서환자개인간항혈소판효과의차이의가능성도거의없다는점이큰장점이다. 18) 이렇듯기존표준치료약물의문제점에보고와이를개선시킨약물의등장으로항혈소판치료지침에변화가일어나는상황이다. 19,20) 이러한변화에맞추어미국과유럽을비롯한선진국에서는보다더효율적인급성관상동맥증후군관리를위해이를반영한개정된가이드라인을발표하였다. 21) 미국 ACC/AHA에서는 ST분절상승심근경색증에대해서 2004년나온이후로다양한주요연구결과들이더해지고꾸준히개정되어오면서최신약물지침으로 2013년도가이드라인이있다. 그리고불안정성협심증및 ST분절비상승심근경색증에서는 2007년도가이드라인을시작으로계속적으로개정이이루어지면서 2012 년도에발표된개정판이현재지침으로쓰이고있다. 22) 유럽 ESC에서도 2011년에불안정성협심증및 ST분절비상승심근경색증에대한권고안과 2012년에 ST분절상승심근경색증에대한권고안을발간하였다. 23) 국내에서도이러한새로운움직임에발맞추어, 선진국의치료지침개정판과주요연구결과들을반영한권고안의필요성이제기되고있다. 24)

3 202 / Korean J Clin Pharm, Vol. 25, No. 3, 2015 본연구에서는전체적인흐름을파악하기위하여미국과유럽각각의가이드라인이개정되어온것을조사하고, 그이후에최신가이드라인과이전가이드라인의비교를통하여선진국에서의 ST분절상승심근경색증과불안정협심증 /ST분절비상승심근경색증에서의항혈소판제의약물요법가이드라인에대한변화를파악하고자한다. 더나아가서는미국, 유럽, 그리고한국간의최신가이드라인을비교하고자한다. 연구방법 급성관상동맥증후군에관한미국, 유럽그리고한국각각의가이드라인이개정되어온변화를알아보기위하여다음의각기관의사이트를활용하였다. 22,23,25) 미국심장학회 (the American College of Cardiology, ACC) / 미국심장협회 (the American Heart Association, AHA) Joint Guidelines ( Guidelines/ByTopic/TopicsA-C/ACCAHA-Joint-Guidelines_UCM_321694_Article.jsp) 유럽심장학회 (European Society of Cardiology, ESC) Clinical Practice Guidelines ( Practice-Guidelines/ESC-Clinical-Practice-Guidelineslist/listing) 대한심혈관중재학회 (Korea Society of Interventional Cardiology, KSC) ( page/1/b_id/5) 위기관으로부터발행된급성관상동맥증후군치료가이드라인은 ST-분절상승심근경색증 과 불안정협심증 /ST-분절비상승심근경색증 으로구분되어있으며, 이두질환의치료가이드라인에대하여조사하였다. 이러한가이드라인에대하여본연구에서는새로이개정된최신약물요법가이드라인과이전에발행한가이드라인을비교연구수행하였고, 또한각나라별로가이드라인을비교연구수행하였다 (Fig. 2). 최신약물요법가이드라인과이전가이드라인을비교연구하기위하여미국의경우, ST-분절상승심근경색증에관해서 2013년도와 2009년도가이드라인을비교분석하였다. 26,27) 2013 ACCF/AHA Guideline for the Management of Patients With ST-Elevation Myocardial Infarction 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update Fig. 2. Diagram of guidelines comparison between the USA, Europe, and Korea. The numbers indicate publication years.

4 급성관상동맥증후군치료를위한국내 외항혈소판제약물요법가이드라인비교연구 / 203 불안정협심증 /ST- 분절비상승심근경색증은 2012 년도와 2011 년도가이드라인을비교분석하였다. 28,29) 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non-ST- Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update) 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction 각나라별최신약물요법가이드라인비교연구를위하여 ST-분절상승심근경색증의경우미국 ACC/AHA (2013년가이드라인 ), 유럽 ESC (2012년가이드라인 ), 그리고한국의 KSC (2012년가이드라인 ) 에서각각발행한아래의가이드라인을비교분석하였다. 25,26,30) 2013 ACCF/AHA Guideline for the Management of Patients With ST-Elevation Myocardial Infarction Acute Myocardial Infarction in Patients Presenting With ST-Segment Elevation (Management of ESC guideline) 2012 Guideline for pharmacotherapy of anti-platelet agent for acute coronary syndrome (KSC guideline) 또한 ST-분절비상승심근경색증에대하여역시미국 ACC/ AHA (2012년가이드라인 ), 유럽 ESC (2011년가이드라인 ), 그리고한국 KSC (2012년가이드라인 ) 에서발행한다음의최신약물요법가이드라인을비교분석하였다. 25,28,31) 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non-ST- Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update) Acute Coronary Syndromes (ACS) In Patients Presenting Without Persistent ST-segment Elevation (Management of) (ESC guideline) 2012 Guideline for pharmacotherapy of anti-platelet agent for acute coronary syndrome (KSC guideline) 연구결과 미국과유럽의급성관상동맥증후군치료에서약물요법가이드라인현황미국심장학회 (ACC), 미국심장학회재단 (ACCF), 그리고미 Table 1. History of pharmacotherapy guidelines for ST-Elevation Myocardial Infarction and Unstable Angina /Non-ST-Elevation Myocardial Infarction in the USA. STEMI STEMI/ STEMI STEMI/ STEMI STEMI ACC/AHA Guidelines ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction ACC/AHA Clinical Performance Measures for Adults With ST-Elevation and Non-ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST- Elevation Myocardial Infarction 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction ACC/AHA 2008 Performance Measures for Adults With ST-Elevation and Non-ST-Elevation Myocardial Infarction 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/ SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update) 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline) 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update) 2013 ACCF/AHA Guideline for the Management of Patients With ST-Elevation Myocardial Infarction Year Published

5 204 / Korean J Clin Pharm, Vol. 25, No. 3, 2015 Table 2. History of pharmacotherapy guidelines for ST-Elevation Myocardial Infarction and Unstable Angina /Non-ST-Elevation Myocardial Infarction in Europe. ESC Guidelines Year Published STEMI/ Antiplatelet Agents (Expert Consensus Document on the Use of) 2004 Acute Coronary Syndromes (ACS) In Patients Presenting Without Persistent ST-segment Elevation (Management of) 2011 STEMI Acute Myocardial Infarction in Patients Presenting With ST-Segment Elevation (Management of) 2012 국심장협회 (AHA) 에서 ST-분절상승심근경색증 (STEMI) 과불안정협심증 /ST분절비상승심근경색증 (UA/) 에대해질환별로가이드라인을꾸준히개정해오고있다. 먼저 STEMI에관해서는 2004년 ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction 을시작으로 3년후인 2007년에개정이이루어졌고, 2004와 2007 가이드라인을업데이트한가이드라인이 2009년에나왔다. 그리고현재미국의 STEMI 치료를위한최신약물요법가이드라인은 2012년도에발행된 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction 이다 (Table 1). 에관련하여서는, 2007년에 ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction 으로첫가이드라인이나왔다. 2011년에 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline) 와 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST- Elevation Myocardial Infarction 2개의가이드라인이발표되었다. 바로다음해인 2012년에는 2007과 2011 가이드라인을업데이트하여발행되었다 (Table 1). 이뿐만아니라, 임상에서지침으로쓰이도록 2006 년과 2008 년에 STEMI와 를가진성인환자를대상으로임상성과측정 (Clinical Performance Measures) 을실시하여 ACC와 AHA 에서발표한임상진료지침 (Clinical practice guidelines) 도있다. 신뢰할만한증거들을기반으로한이임상진료지침은실제임상에서환자의진료나치료적측면에서더나은결과를내고, 의료진들에게더발전되고개선된의료를환자에게제공하고검증할목적을가진다. 32,33) 한편, 유럽의심장학회인 European Society of Cardiology (ESC) 에서는 2004년에 Antiplatelet Agents (Expert Consensus Document on the Use of) 로항혈소판제공통의가이드라인으로시작하였다. STEMI에대하여서는 2012년에 Acute Myocardial Infarction in patients presenting with ST-segment elevation (Management of) 로, 는 2011년에 Acute Coronary Syndromes (ACS) In patients presenting without persistent ST-segment elevation (Management of) 로각각가이드라인이현재발행되어있다 (Table 2). 미국 ACC/AHA 가이드라인 2009년도와 2013년도비교 : ST분절상승심근경색증 STEMI 최신가이드라인과이전가이드라인에서가장두드러진점으로는 ticagrelor가새로이추가됨으로써기존에사용하던 clopidogrel나 prasugrel을각각사용하던용어가 P2Y 12 receptor inhibitor로통칭하여쓰고있다는것이다. 증거수준 (level of evidence; LOE) B로새로이추가된 ticagrelor의부하용량 (loading dose) 은 180 mg, 유지용량 (Maintenance dose) 은 90 mg 하루두번이다. 또다른차이점은 aspirin의유지용량이다. 81 mg으로이는직전의가이드라인과도달라진점이면서다른나라의가이드라인과비교시도더낮은유지용량으로특이한사항이다. 21) 항응고요법 (Anticoagulatn therapy) 에서 ClassIII에 fondaparinux에대한사항이새로이추가되었다. 혈전용해치료 (fibrinolytic therapy) 에서는증거수준이높아졌고 clopidogrel 투여지속기간도 1년으로변경되었다. 그외에도 GP IIb/IIIa 수용체길항제 (GP IIb/IIIa receptor antagonist) 에서는해당약물투여경로와방법그리고환자조건등을더상세히기술하고있다. 미국 ACC/AHA 가이드라인 2011년도와 2012년도비교 : 불안정협심증 /ST분절비상승심근경색증 에서도 STEMI와유사하게, 전반적으로 ticagrelor와 prasugrel이추가된것이가장큰특징이며, clopidogrel 단독이었거나, thienopyridine 등으로되어있던부분들이 prasugrel이나 ticagrelor의추가로인하여 P2Y 12 receptor inhibitor로더큰범위의용어로바뀌었다. 새로추가된두약물의용량은 ticagrelor의경우, 부하용량은 180 mg, 유지용량은 90 mg 하루두번이고, prasugrel은초기용량은 60 mg, 유지용량은 10 mg 으로권고하고있다. 또한, 항혈소판요법 (antiplatelet therapy) 의기간도 12개월까지로바뀌었다. 그리고 aspirin의유지용량도 STEMI와마찬가지로 81 mg으로변경하여가이드라인에제시하고있다. 마지막으로 warfarin 요법에서 aspirin과 P2Y 12 억제제 (P2Y 12 inhibitor) 약물요법을

6 급성관상동맥증후군치료를위한국내 외항혈소판제약물요법가이드라인비교연구 / 205 받고있는 UA/ 환자에게 INR 수치를낮추는것에있어서경구항응고요법이적합하다고새권고를 2012 가이드라인에근거수준 C로추가하였다. 미국, 유럽그리고한국의급성관상동맥증후군치료에서항혈소판약물요법가이드라인비교 : ST분절상승심근경색증 1차적으로두가이드라인모두 aspirin을가능한빨리조기사용과한번사용후에는평생복용을권고하고있다. 초기용량에는 ACC/AHA에서는 mg/ 일그리고 ESC에서는경구투여시는 mg, 정맥주사시는 mg을제시하고있다. 국내의경우에는초기용량 mg으로두나라와다른용량범위를권고하고있다. 평생치료 (life-long therapy) 에는 ACC/AHA는초기용량과같은 mg, ESC 에서는 mg을하루권장량으로언급하고있다. 특이사항으로는 ACC/AHA에서는 P2Y 12 수용체억제제로 ticagrelor를선택할시잠재적인높은용량의 aspirin을복용하게되면, ticagrelor의작용에영향을더미칠수있다고보아 81 mg으로낮은유지용량을조심스레권고하고있다. 국내에서는 mg을하루에투여하고지속적으로평생투여하기를권하고있다. ACC/AHA와 ESC 가이드라인모두 aspirin에 P2Y 12 수용체억제제를가능한추가하고이중항혈소판요법 (dual of dual antiplatelet therapy, DAPT) 으로 12개월을권고하고있다. 두가이드라인의가장큰차이점은 P2Y 12 수용체억제제에해당하는약물들간의권고등급 (class of recommendation, COR) 이다. ACC/AHA에서는 clopidogrel, prasugrel 그리고 ticagrelor 를권고등급 IB로세약물모두동일하게두고있으나, ESC에서는새로추가된 prasugrel과 ticagrelor를 IB로 clopidogrel를 IC 로, clopidogrel을 prasugrel이나 ticagrelor 사용이불가능한경우에사용하라는전제를붙이면서권고수준을더높게두고있다. 국내의경우에는 P2Y 12 수용체억제제인세약물의권고등급이미국과같은 IB 로두고있다. GP IIb/IIIa 수용체길항제를 PCI동안사용하는것의중요도가두가이드라인모두이전과비교시감소하였고, abciximab 이권고등급 IA로 IB의 eptifibatide 또는 tirofiban보다여전히더높은권고약제로유지하였다. 상류루틴치료 (upstream routine therapy) 로 GP IIb/IIIa 수용체길항제를사용하는것은두가이드라인모두 IIbB로낮은권고등급을가지며, 특히나, ESC에서는거대혈전이있고 (massive thrombus load), 재혈류 (reflow) 흐름이낮거나없는경우에 GP IIb/IIIa 수용체길항제를구제치료 (bailout therapy) 로사용하기를권고하고있다. 국내에서도 Class I에해당하는 GP IIb/IIIa 수용체길항제관련권고안은없고 Class IIa로일차적관동맥중재술시작시스텐트삽입여부와관계없이 GP IIb/IIIa 수용체길항제를 투여할수있다고언급한다. 해당약제간의권고등급은미국과같다. 미국, 유럽그리고한국의급성관상동맥증후군치료에서항혈소판약물요법가이드라인비교 : 불안정협심증 /ST분절비상승심근경색증두가이드라인모두 aspirin을가능한빨리조기사용과한번사용후에는평생복용을권고하고있다. 초기용량에는 ACC/ AHA에서는 mg/ 일그리고 ESC에서는경구투여시는 mg, 정맥주사시는 mg을제시하고있다. 평생치료 (life-long therapy) 에는 ACC/AHA는초기용량과같은 mg, 출혈경향성이증가된환자의경우는 mg, ESC에서는 mg을하루권장량으로언급하고있다. 국내권고안에서는용량에대한언급은없으며평생지속적으로복용하라고제시하고있다. STEMI에서와같이 에서도 ACC/AHA와 ESC 가이드라인모두 aspirin에 P2Y 12 수용체억제제를가능한추가하며 12개월을이중항혈소판요법의기간으로권고하고있다. P2Y 12 수용체억제제약제들의권고등급은 에서도 STEMI에서와동일하며, 다른점은 ACC/AHA에서 PCI 시에 prasugrel 유지용량이 10 mg인데, 75세이상노인환자이거나 60 kg 이하의저체중환자의경우에는 5mg으로절반의용량을권고하고있다는것이다. 국내에서는 에서추가된다른점은 clopidogrel에서의높아진유지용량이다. 권고등급은 ACC/AHA가 IIbB이고 ESC가 IIaB로다르지만, 유지용량을투여하는첫 1주일가량은 150 mg을사용하고이후 75 mg 으로감량하여투여하는점은두가이드라인모두동일하게권고하고있다. 국내의경우에는 STEMI와마찬가지로해당약제들의권고등급이동일하게 IB로두고있다. 차이가나는부분은 PCI전초기침습적치료에있어서미국과는달리국내에서는 ticagrelor가빠져있다는점이다. 그외의다른점은 clopidogrel 초기용량이 mg으로범위가국내의경우넓다는것이다. 그리고가장두드러지는점은삼제요법에관한것이다. Clopidogrel의유전적다형성에기인한내성을극복하기위한방법으로국내에서는 aspirin, clopidogrel, 그리고 cilostazol 세약제를같이투여하는삼제요법을국내에서만제기하고있다. GP IIb/IIIa 수용체길항제에서두가이드라인모두 eptifibatide 또는 tirofiban을더선호하며권고등급은 ACC/AHA 가 IB이고 ESC가 IIaB로다르다. 또다른점은 ACC/AHA에서는 GP IIb/IIIa 수용체길항제를높은출혈위험성이나허혈성문제에관한낮은위험성을가진환자에서상류치료로사용하기를권고하지않고있으며, ESC에는루틴상류치료에사용되는그자체를권고하지않고있다. 국내권고안에서는 GP IIb/IIIa 수용체길항제에관한언급이되어있지않다.

7 206 / Korean J Clin Pharm, Vol. 25, No. 3, 2015 고찰 본연구에서미국과유럽각각의가이드라인현황과미국 ACC/AHA의경우, 최신가이드라인과이전가이드라인비교분석을하고궁극적으로는미국, 유럽그리고한국의가이드라인을비교및고찰하였다. 미국과유럽각각가이드라인현황비교는미국의경우는개정되어온횟수는 STEMI나 UA/ 둘다같았고중간에두번임상지침안도두질환묶어서나왔다. 22) 다만 UA/가 STEMI에비해서비교적더최근에개정이자주이루어졌고, 가이드라인현황비교표에서는빠졌으나최근에 UA/에관한개정된 2014 가이드라인이발표되었다. 22,34) 이와같이가이드라인이자주업데이트되므로이런변화를이해하고빨리받아들이기위해서라도본연구와같은가이드라인비교및연구가더빈번하게필요하다. 유럽의경우는 STEMI와 단독가이드라인은아직하나씩나와서그간의현황이나최신과직전가이드라인비교를할수없어서미국 ACC/AHA에서와같은연구진행을동일하게하지못하였다. 미국과유럽을비교하여보았을때, 미국 ACC/AHA에서더많은개정을하여왔고, 거기에더하여임상진료지침도같이개정해왔던사실을기반으로미국 ACC/AHA 가이드라인을유럽 ESC 가이드라인보다좀더면밀하게분석하였다. 이러한이유와더불어유럽의가이드라인이 STEMI와 UA/ 각각하나씩만존재하기때문에미국 ACC/AHA 최신과직전가이드라인을직접비교분석하였다. 23) 결론적으로가장큰특징으로 P2Y 12 수용체억제제로용어의통합과이차예방으로써의 aspirin의유지용량이다. 21) Aspirin의유지용량은유럽 ESC 가이드라인과비교시도미국 ACC/AHA 가이드라인의특징적인차이점이다. 최근에개발된신약인 ticagrelor와병용시 ticagrelor의작용을강화시켜부작용을유발할수도있다는보고를미국에서는받아들여새롭게가이드라인에추가한것으로사료된다 ) 이러한부분이미국과유럽이각각가이드라인에서 P2Y 12 수용체억제제약제들간의권고등급의차이에도기여하였을것이라고본다. 미국 ACC/AHA와유럽 ESC 가이드라인을비교하였을시, STEMI에서위에서언급한 aspirin의유지용량이 ACC/AHA 의경우가 ESC보다더낮은용량을권고하고있다는것이첫번째로주목할만한부분이다. 38) 그리고다음으로주의깊게볼사항은 P2Y 12 수용체억제제약제들간의권고등급의차이이다. 39) 사실상이러한두가이드라인의차이와신약인 prasugrel과 ticagrelor의등장과임상연구결과들을바탕으로본연구가시작되고진행되었다. 연구배경에서도언급하였듯이, clopidogrel의유전적대립인자존재시의기대한항혈소판효과의저해와내성의문제로 prasugrel과 ticagrelor의개발이되었다. 11,40,41) 새로운두약물모두이러한유전적다형성에 영향을거의받지않는다고보고되고있고특히 ticagrelor의경우그자체가활성형이라약효발현시간이빠른장점이있어시간이중요한급성관상동맥증후군치료에서큰관심을받고있다. 42) 이러한최신임상연구결과를더반영하여 ESC 가이드라인에서새로운두약제의권고등급이기존의 P2Y 12 수용체억제제의표준치료제로여겨졌던 clopidogrel보다더높게된것이라고본다. 반면에미국의경우는앞서말한대로급성관상동맥증후군에서가장일차적으로쓰이는 aspirin과 ticagrelor와의병용투여시의의도치않은효과에대한고려로인해 ticagrelor를더조심스럽게권고하고있는것으로보인다. 43) Clopidogrel의단점이었던약물반응의변동성이 ticagrelor에서는보다개선되어약물반응이일정해졌다고는하나약물반응에는하나의원인인자만이영향을미치는것이아니기때문에여러변동에기인하는인자들이여전히존재하므로신규약제들이완전히기존약제를대체하기는힘들다고본다. 44,45) 이렇게생각하는다른이유로는 clopidogrel의특허만료기간이끝남으로써고가의신약과는달리약물가격이낮아져서경제적측면의이점을가질수가있다는것과, 여기에더하여최근약물스텐트기술이 1세대에서 2세대로발전하면서기존의항혈소판약물과신규항혈소판약물간의혈소판억제작용에대한임상적결과를비교하여검증하기도힘들다는것이다 ) 이러한점들을전반적으로고려하여보았을때, 그래도유전자검사나혈소판활성도검사등을통해 clopidogrel 의효과가덜하다고판단되는경우등에는 prasugrel 이나 ticagrelor를우선적으로사용하여도임상적효과측면에서더좋다고생각한다 ) 미국ACC/AHA에서도 clopidogrel 과 prasugrel 또는 ticagrelor간의권고등급차이가그리크게나는것이아니며다만유럽 ESC의가이드라인보다조금더조심스럽게신규약제들을권고하고있을뿐이다. 국제적흐름이 prasugrel과 ticagrelor 이두신규약제들쪽으로기울고있다고볼수있다. 54) 국내권고안을보면 P2Y 12 수용체억제제약제들의권고등급도미국과동일하게 ClassIB인것을보아유럽보다는미국의가이드라인과더가깝다고보여진다. UA/에서는초기침습적치료에서는 PCI전에는 ticagrelor가언급되어있지않고삼제요법으로도 clopidogrel을쓰고있으며, 보존적치료에서도 ticagrelor에대해서는권고하는내용이없다. 55) 이로보아국내의경우는 P2Y 12 수용체억제제약제들로 prasugrel 과 ticagrelor를미국과같은등급으로권고는있으나, 실제임상적사용에서의권고는없는것으로판단된다. Clopidogrel 내성에기인하는대사효소 CYP2C19의변이가백인보다동양인에게더많다는사실을생각한다면신규약제들에대하여국내권고안의개정이중요함을알수있다. 56) 이러한좀더한국에특이적상황과국제적동향에맞추어보다적극적인신규약제들에관한권고사항의보완이필요하다. 57)

8 급성관상동맥증후군치료를위한국내 외항혈소판제약물요법가이드라인비교연구 / 207 결론 본연구에서는급성관성동맥증후군인 ST-분절상승심근경색증과불안정협심증 /ST-분절비상승심근경색증으로나누어미국 ACC/AHA와유럽 ESC 가이드라인의현황조사하였고이를바탕으로최신가이드라인과직전의가이드라인의비교연구를하였다. 더나아가미국, 유럽그리고한국의가이드라인을비교함으로써국제적흐름과동향을파악하고국내권고안의보완이필요하다는결론에도달하였다. 이러한가이드라인비교연구와국제적흐름파악은선진국과국내가이드라인사이의차이점을줄이고좀더나은임상적치료효과를내기위해약물요법발전의필요성을인식하게하고따라서국내권고안의개정의움직임에힘을실어준다는의의를가진다. 앞으로이를위하여보다빠른권고안의개정에대한노력과나아가미국과유럽과는다른국내임상현장을고려하고각환자의상황에맞추어임상전문가들의판단하에새로운권고사항들을적용하여야할것이다. 참고문헌 1. Overbaugh, Kristen J. Acute coronary syndrome. AJN 2009;109(5): Yun DD, Alpert JS. Acute coronary syndromes. Cardiology 1997;88: Park SJ. Acute coronary syndrome. Korean Circulation J 1998;28(12): Molife C, Frech-Tamas F, DeKoven M, et al. Comparison of healthcare resource utilization and costs in patients hospitalized for acute coronary syndrome managed with percutaneous coronary intervention and receiving prasugrel or ticagrelor. J Med Econ, in press. 5. Fanari Z, Weiss S, Weintraub WS. 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