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1 대한내과학회지 : 제 85 권제 1 호 특집 (Special Review) - 항혈소판제제의최신지견 수술전후항혈소판제제의관리 원광대학교의과대학순환기내과학교실 오석규 Management of Perioperative Antiplatelet Therapy Seok Kyu Oh Department of Cardiovascular Medicine, Wonkwang University College of Medicine, Iksan, Korea Drug-eluting stent (DES) implatation was the major method of coronary revascularization and marked reduction in target-lesion revascularization. Stent thrombosis (ST) is a severe complication that is associated with a high incidence of acute myocardial infarction and death. To prevent ST, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is recommended for at least 12 months. The premature discontinuation of DAPT is the single most significant predictor of perioperative ST. The risk of surgical bleeding is increased approximately 20% by aspirin or clopidogrel alone, and 50% by DAPT. But the increased risk of perioperative bleeding is not necessarily associated with increased mortality or surgical outcome. Usually, the risk of a cardiovascular event when stopping antiplatelet agents preoperatively is higher than the risk of surgical bleeding when continuing these drugs, except during high risk surgery in a closed space. We remember that DES are never low risk situation for ST and aspirin must never be stopped in all patients with DES. (Korean J Med 2013;85:22-28) Keywords: Drug-eluting stents; Stent thrombosis; Antiplatelet therapy; Perioperative management 서론약물용출스텐트를이용한관상동맥중재시술은관상동맥질환의가장중요한치료법이되었다. 반면약물용출스텐트시술은일반금속스텐트에비해재협착률및표적병변재시술률을의미있게감소시켰지만후기스텐트혈전증이라는생명을위협하는치명적인합병증이중요한문제로대두되었다 [1,2]. 스텐트혈전증예방의가장중요한방법은아스피린 (aspirin) 과클로피도그렐 (clopidogrel) 을함께사용하 는이제항혈소판제 (dual antiplatelet therapy) 치료이며이는시술후최소 1년동안유지해야하는것으로권고되고있다 [3]. 스텐트시술을받은환자중약 5% 는 1년이내에비심장수술을요하며수술전후항혈소판제중단으로인한스텐트혈전증이약 40% 까지발생할수있다는보고가있다 [4]. 스텐트시술후스텐트혈전증예방을위해서는항혈소판제치료는필수적이나수술중항혈소판제치료가출혈의위험을증가시킬수있기때문에수술전에중단해야하는딜레마가있다. 이에본장에서는스텐트혈전증위험성과출혈 Correspondence to Seok Kyu Oh, M.D. Department of Cardiovascular Medicine, Regional Cardiocerebrovascular Center, Wonkwang University College of Medicine, Iksan-daero 460, Iksan , Korea Tel: , Fax: , oskcar@wonkwang.ac.kr Copyright c 2013 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 - Seok Kyu Oh. Management of perioperative antiplatelet therapy - 위험성을평가하고수술전후항혈소판제제사용에대해간략하게알아보고자한다. 본론이제항혈소판제치료혈전증발생의시작은혈소판유착, 혈소판활성화및혈소판응집에서부터시작한다. 따라서혈전증예방의가장기본적인치료는혈소판활성화및응집을억제하는항혈소판제치료이다. 관상동맥스텐트삽입술후아스피린과클로피도그렐을함께사용하는이제항혈소판제치료는스텐트혈전증예방을위한가장필수적인치료이다. 아스피린은혈소판의 cyclo-oxygenase를비가역적으로억제하여 thromboxan A 2 의형성을차단함으로써혈소판활성화를억제하고 thienopyridine 계열의클로피도그렐은혈소판 P2Y12 수용체를비가역적으로억제하여혈소판활성화및응집을억제하는약제이다. 최근에는클로피도그렐보다더강력한효과를갖지만출혈위험이약간더높은프라수그렐 (prasugrel) 과티카그렐러 (ticagrelor) 가새롭게개발되어사용되고있다 [3]. 스텐트혈전증발생은아스피린단독사용 (3.5%) 에비해이제항혈소판제사용 (0.5%) 시의미있게감소되어이제항혈소판제사용은스텐트시술후표준치료가되었다 [3]. 일반적인이제항혈소파제치료원칙은아스피린은평생동안사용하고클로피도그렐은일반금속스텐트를시술받은경우에는최소 1개월이상사용하고가능하면 1년동안유지하며약물용출스텐트를시술받은환자는최소 1년동안반드시사용할것을권장하고있다 [3]. 약물용출스텐트시술 1 년이후에이제항혈소판제유지하는것이사망률이나심근경색증발생을줄인다는보고도있는반면 1년이후에아스피린만유지해도그효과는지속된다는보고도있어 1년이후에이제항혈소판제사용에대한논란은아직남아있다 [5,6]. 그러나일반적으로좌주간동맥병변, 근위부병변, 분지혈관병변, 만성폐쇄병변, 석회화병변, 작은혈관병변, 다혈관질환, 여러개스텐트시술, 중복스텐트시술및당뇨병, 만성신부전환자등고위험환자군에서는 1년이후에도더오랫동안사용할것을권장하고있다 [3]. 스텐트혈전증발생스텐트혈전증은대부분급성심근경색증 (22-90%) 으로발 현되며 10-45% 의높은사망률을보이는치명적인합병증이다 [7]. 스텐트혈전증은이제항혈소판제를사용하여도장기적으로는약 2% 에서발생할수있으며특히 1세대약물용출스텐트를삽입한환자의경우에는매년 % 씩발생하는것으로보고되고있다 [2]. 최근에개발되어널리이용되고있는 2세대약물용출스텐트는 1세대에비해스텐트혈전증을의미있게감소시켰지만아직까지스텐트혈전증으로부터자유롭지는못한상태이다 [8]. 스텐트혈전증은발생시기에따라급성 (acute, 24시간이내 ), 아급성 (subacute, 1-30일 ), 후기 (late, 1-12 개월 ) 및아주후기 (very late, 1년이후 ) 로구분하며스텐트시술후 30일이내에발생하는초기스텐트혈전증이전체발생의 60-75% 를차지하는것으로알려져있다. 스텐트혈전증발생기전은시기에따라차이가있다. 초기스텐트혈전증은시술과관련된원인이가장많고 1개월이후에발생하는후기스텐트혈전증은스텐트시술부위의불완전한재내피화로대표되는지연된치유가주된원인이며 1년이후에발생하는아주후기스텐트혈전증은스텐트나폴리머에대한과민반응, 섬유소의과다축적및신생죽상경화증등의비정상적인혈관반응이주된원인이되는것으로알려져있다 [9]. 후기스텐트혈전증의발생은시술부위의지연된치유및비정상혈관반응이주된원인이기때문에항혈소판제의조기중단은가장강력한스텐트혈전증의유발인자이며 [10] 이제항혈소판제의조기중단시스텐트혈전증발생이 90배이상증가하는것으로알려져있다 [7]. 스텐트혈전증은생명을위협하는치명적인합병증이기때문에반드시예방해야할합병증이며항혈소판제치료를적극고려해야한다. 수술과관련된스텐트혈전증발생 (Fig. 1) 수술과관련되어발생할수있는스텐트혈전증발생은항혈소판제의갑작스런중단, 수술자체및수술시기가중요하게관여한다. 장기적으로사용했던환자에서항혈소판제의갑작스런중단은혈소판반응및반동효과증가로혈전증발생을증가시킬수있다 [11,12]. 수술자체는수술스트레스에대한내분비적반응으로혈관경련같은혈관반응도증가, 혈소판활성화, 혈장내응고인자증가, 생리적인혈전용해감소등수술자체가혈전생성상황을초래할수있으며수술에대한이런반응은이제항혈소판제치료로도예방할수없는강력한위험인자이다 [12,13]. 스텐트삽입술

3 - 대한내과학회지 : 제 85 권제 1 호통권제 635 호 Figure 1. The pathophysiololgy of acute perioperative stent thrombosis [16]. 후초기에는협착병변이불안정하기때문에스텐트삽입후초기에비심장수술을시행하는것은환자의사망률과이환율을 5-10배정도증가시킬수있으며 [14], 6주이내비심장수술은사망률을증가시킬수있음이보고되었다 [15]. 또한일반금속스텐트삽입환자의경우 30일이내수술시주요심혈관사건발생률이 30일이후에수술한환자보다 10배이상높고약물용출스텐트삽입환자의경우 1년이내수술이 1년이후수술에비해역시 2배이상높다는보고가있다 [16]. 수술에의한스텐트혈전증의발생의가장중요한기전은항혈소판제의갑작스런중단과수술자체에의한강력한혈전증성향및염증반응증가가상승적으로작용하여불완전하게재내피화된스텐트에혈전이발생하는것으로설명할수있다 (Fig. 1) [12]. 결국수술과관련된스텐트혈전증발생을줄이기위해서는수술자체가혈전형성에중요하게관여하기때문에항혈소판제중단은반드시피해야하며약물용출스텐트를삽입한환자에서수술시기는응급수술이아닌경우 1년이후로연기할것을권장하고있다. 수술중항혈소판제치료에따른출혈위험성수술중출혈의원인은항혈소판제사용과수술자체에의한출혈이다. 아스피린단독사용에비해이제항혈소판제 사용시출혈위험이증가하는것은당연한사실이다. 이제항혈소판제사용은아스피린단독사용에비해출혈시간을 3-4배증가시키고출혈을 30-50% 까지증가시키는것으로알려져있다 [17,18]. 이에비해아스피린단독사용은출혈의위험을 % 까지약간증가시키지만환자의사망률이나이환율은증가시키지않는것으로알려져있다 [11,18]. 결국비심장수술시출혈은경한합병증이며심각한사건은스텐트혈전증으로인해심장으로부터발생하기때문에아스피린단독요법은모든수술환자에서실시해야한다고권장하고있다. 출혈에따른수술위험도계층화 (Table 1) 여러연구결과를토대로출혈에따른수술위험도를계층화하였다 [12,18-20]. 고위험수술은폐쇄된공간에서소량의출혈만있어도심각한결과를초래할수있는두개내수술, 척주관수술및후안방수술등이포함된다. 중등도위험수술은수혈을가끔필요로하는수술로내장수술, 심혈관수술, 중요한정형외과, 이비인후과, 성형외과수술, 그리고내시경적비뇨기과수술이해당된다. 저위험도수술은정상적으로수혈이필요치않는수술로내시경, 발치및치과수술, 말초수술, 성형수술, 간단한정형외과및이비인후과수술, 조직검사, 전안방수술등이해당된다. 최근항혈소판제

4 - 오석규. 수술전후항혈소판제제의관리 - Table 1. Risk stratification of the surgical hemorrhage and the stent thrombosis [18-20] Surgical hemorrhage Stent thrombosis High risk Intracranial neurosurgery Spinal canal surgery Eye posterior chamber surgery < 12 months after DES < 6 weeks after BMS < 6 weeks after PTCA < 6 weeks after MI < 6 weeks after CABG Intermediate risk Low risk Visceral surgery Cardiovascular surgery Major orthopedic, ENT, reconstructive surgery Endoscopic urology surgery Endocopy Dental extraction and surgery Peripheral, plastic, and general surgery Biopsy Minor orthopedic, ENT, and general surgery Eye anterior chamber surgery > 12 months after DES High-risk stents (long, proximal, multiple, overlapping, small vessel, bifurcation) 6-24 weeks after BMS 6-24 weeks after PTCA 6-24 weeks after MI 6-24 weeks after CABG Lower EF Diabetes > 6 months after BMS > 6 months after PTCA > 6 months after MI > 6 months after CABG DES, drug-eluting stent; BMS, bare metal stent; PTCA, percutaneous transluminal coronary angioplasty; MI, myocardial infarction; CABG, coronary artery bypassl graft; EF, ejection fraction. 중단여부에대해가장많이의뢰되고있는내시경과발치및치과수술은저위험수술에해당하기때문에약물용출스텐트를시술받은환자는아스피린과클로피도그렐을지속적으로투여해야한다. 스텐트혈전증의위험도계층화 (Table 1) 많은연구결과를토대로스텐트혈전증발생의위험도를계층화하였다 [12,18-20]. 스텐트혈전증발생의고위험환자는 12개월이내에약물용출스텐트시술을받은환자, 6주이내에심근경색증, 일반금속스텐트시술, 풍선확장성형술및관상동맥우회로술을받은환자등이포함된다. 중등도위험환자는약물용출스텐트시술받고 12개월이지난환자, 6-24주사이에심근경색증, 일반금속스텐트시술, 풍선확장성형술및관상동맥우회로술등을받은환자, 좌주간동맥병변, 근위부병변, 분지혈관병변, 만성폐쇄병변, 석회화병변, 작은혈관병변, 다혈관질환병변, 여러개스텐트시술, 중복스텐트시술등고위험병변에스텐트시술을받은환자, 좌심실구혈률이낮은환자, 당뇨병혹은만성신부전환자등이포함된다. 저위험환자는심근경색증, 일반 금속스텐트시술, 풍선확장성형술및관상동맥우회로술등을받고 6개월이지난환자들이포함된다. 결국약물용출스텐트를시술받은환자중 1년이지나지않은환자는모두스텐트혈전증발생의고위험환자이며 1년이지난환자는중등도위험환자로약물용출스텐트를시술받은모든환자는절대저위험환자가아님을반드시기억하고항혈소판제치료를지속해야한다. 출혈위험도와스텐트혈전증위험도에따른항혈소판제치료방법 (Table 2) [12,18-20] 아스피린은약물용출스텐트를시술받은모든환자에수술과상관없이반드시투여해야한다. 약물용출스텐트를시술받고 1년이지난환자가두개내, 척주관및후안방수술같은고위험수술을받는경우에는아스피린을유지하거나필요시아스피린을 ibuprofen으로대체하여사용할수있다. Ibuprofen은 cyclo-oxygenase-1 을선택적으로차단하는비스테로이드성항염증약물로아스피린과는달리가역적으로차단하기때문에중단후 24시간이내에혈소판기능이완전히회복되는점을이용하여고위험수술환자에서아스피린

5 - The Korean Journal of Medicine: Vol. 85, No. 1, Table 2. Perioperative management of patients taking antiplatelet therapy and requiring surgery after DES implantation [18-20] Surgical hemorrhagic risk High risk Intermediate risk Low risk DES, drug-eluting stent. Stent thrombosis and cardiovascular risk High risk: < 12 months after DES Intermediate risk: > 12 months after DES Low risk Clopidogrel: stop Bridging therapy with tirofiban or heparin Clopidogrel: maintain Clopidogrel: maintain or replace by ibuprofen Clopidogrel: stop Clopidogrel: maintain (if prescribed) Clopidogrel: maintain (if prescribed) Aspirin: stop 을대신하여사용할수있다 [21]. 수술전아스피린 200 mg 을투여받고있는환자는아스피린 100 mg으로감량하고항혈소판제단독요법으로클로피도그렐을사용하고있는환자는아스피린으로바꾸어투여할수있다. 결국아스피린은약물용출스텐트를시술받은모든환자에서수술및출혈위험도와상관없이지속적으로투여해야한다. 클로피도그렐은출혈에대한고위험수술을받는환자에서는반드시중단해야한다. 그리고클로피도그렐은약물용출스텐트를시술받고 1년이지나지않은환자는반드시투여하고 1년이지난환자에서는투여하고있다면지속적으로유지할수있으며필요시일시적으로중단할수있다. 수술과스텐트혈전증모두에서고위험환자인경우는아스피린은유지하면서클로피도그렐은중단하고대신헤파린 (heparin) 이나티로피반 (tirofiban) 을연결치료 (bridging therapy) 로유지하면서수술할것을권장하고있다 [18-20]. 헤파린이나티로피반의연결치료는클로피도그렐중단후 2-4일이내에시작하여수술전 4-8시간전에중단하고수술하는치료법이나 [22,23], 현재까지연결치료를안전하게권장할만큼충분한증거는없는상태이다. 헤파린은혈액응고체계에서트롬빈 (thrombin) 의기능을차단하여혈액응고를억제하는항트롬빈제로항혈소판제가아니기때문에기본적으로혈소판활성화및응집에의해발생하는스텐트혈전증예방에이상적인약제는아니며오히려사망률을증가시킬수있다는보고도있다 [24]. 티로피반은혈소판의당단백 IIb/IIIa 수용체를차단하여혈소판응집을신속하고강력하게억제하는주사제로반감기가짧아중단후 2-4시간후에혈소판기능이회복되기때문에고위험수술환자에서연결치료로이용될수있으나출혈증가가능성은항시고려해야한다 [23]. 당단백 IIb/IIIa 수용체차단제중 abciximab은반감기가길기때문에연결치료로절대사용해서는안된다. 아스피린이나클로피도그렐의중단시간은가능한최소화해야한다. 아스피린은수술 2-5일전, 클로피도그렐은 5일전, 티카그렐러는 5일전, 프라수그렐은 7일전에중단하는것을권장하고있다 [20]. 또한수술후다시투여시작은가능한 12-24시간이내에빠르게해야하며부하용량 (loading dose) 으로아스피린은 250 mg, 클로피도그렐은 mg, 프라수그렐은 60 mg, 티카그렐러는 180 mg을투여후에치료를시작할것을권장하고있다 [24]. 수술전후항혈소판제치료시기억해야할사항 약물용출스텐트를시술받은환자에서스텐트혈전증은대부분심근경색증으로발현되며, 사망률이 10-45% 에달하는치명적인합병증이다. 수술자체는혈전증발생을촉진하며수술을이유로항혈소판제중단시서로의상승작용으로스텐트혈전증발생이 20-40% 까지급증할수있다. 수술중항혈소판제사용은출혈을증가시킬수있으나출혈이수술의결과나사망률을증가시키지않는다. 약물용출스텐트를시술받고 1년이지나지않은환자는모두스텐트혈전증발생의고위험환자이며 1년이지난환자는중등도위험환자로약물용출스텐트를시술받은모든환자는스텐트혈전증발생에서절대저위험환자가아니다. 약물용출스텐트를시술받은모든환자는수술종류에상관없이반드시아스피린을유지해야한다. 약물용출스텐트를시술받고 1년이지나지않은환자

6 - Seok Kyu Oh. Management of perioperative antiplatelet therapy - 는두개내, 척주관및후안방수술처럼폐쇄된공간에소량의출혈로도중대한영향을미치는고위험수술을제외한모든수술시클로피도그렐을투여해야한다. 약물용출스텐트를시술받고 1년이지난환자는클로피도그렐투여를일시중단할수있다. 응급을요하지않는대기수술은약물용출스텐트시술 1년이후로연기하는것이안전할수있다. 약물용출스텐트를시술받은환자에서비심장수술시출혈은경한합병증이며심각한사건은스텐트혈전증으로인해심장에서발생하기때문에가능한항혈소판제를지속적으로치료해야한다. 결 약물용출스텐트를시술받은환자가수술을해야하는경우항혈소판제치료지속여부에대해많은논란이있다. 약물용출스텐트를시술받은환자는스텐트혈전증발생시대부분급성심근경색증으로발현하고사망률이높기때문에스텐트혈전증예방을위해반드시이제항혈소판제를사용한다. 또한항혈소판제를유지하면서수술하는경우출혈의위험이증가하는것역시사실이다. 그러나수술중출혈증가는수술결과및사망률과직접관련이없기때문에수술중지속적인항혈소판제치료를권장하고있다. 약물용출스텐트를시술받은환자는두개내, 척주관및후안방수술등고위험수술을제외한모든수술시가능한이제항혈소판제를유지해야한다. 특히항혈소판제중단의가장많은원인이되고있는내시경이나발치를위해항혈소판제를중단하는경우는절대없어야하겠다. 중심단어 : 약물용출스텐트 ; 스텐트혈전증 ; 항혈소판제 ; 수술 론 REFERENCES 1. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med 2007;356: Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxeleluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369: Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting: Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339: Artang R, Dieter R. Analysis of 36 reported cases of late thrombosis in drug-eluting stents placed in coronary arteries. Am J Cardiol 2007;99: Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2007;297: Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010;362: Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293: Park KW, Lee JM, Kang SH, et al. Safety and efficacy of second-generation everolimus-eluting Xience V stents versus zotarolimus-eluting resolute stents in real-world practice: patient-related and stent-related outcomes from the multicenter prospective EXCELLENT and RESOLUTE- Korea registries. J Am Coll Cardiol 2013;61: Nakazawa G, Otsuka F, Nakano M, et al. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol 2011;57: Baran KW, Lasala JM, Cox DA, et al. A clinical risk score for prediction of stent thrombosis. Am J Cardiol 2008;102: Burger W, Chemnitius JM, Kneissl GD, Rücker G. Low-dose aspirin for secondary cardiovascular preventioncardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation- review and meta-analysis. J Intern Med 2005;257: Newsome LT, Weller RS, Gerancher JC, Kutcher MA, Royster RL. Coronary artery stents: II. Perioperative considerations and management. Anesth Analg 2008;107: Samama CM, Thiry D, Elalamy I, et al. Perioperative activation of hemostasis in vascular surgery patients. Anesthesiology 2001;94: Sharma AK, Ajani AE, Hamwi SM, et al. Major noncardiac surgery following coronary stenting: when is it safe to operate? Catheter Cardiovasc Interv 2004;63: Schouten O, Bax JJ, Damen J, Poldermans D. Coronary artery stent placement immediately before noncardiac surgery: a potential risk? Anesthesiology 2007;106: Van Kuijk JP, Flu WJ, Schouten O, et al. Timing of noncardiac surgery after coronary artery stenting with bare

7 - 대한내과학회지 : 제 85 권제 1 호통권제 635 호 metal or drug-eluting stents. Am J Cardiol 2009;104: Payne DA, Hayes PD, Jones CI, Belham P, Naylor AR, Goodall AH. Combined therapy with clopidogrel and aspirin significantly increases the bleeding time through a synergistic antiplatelet action. J Vasc Surg 2002;35: Chassot PG, Delabays A, Spahn DR. Perioperative antiplatelet therapy: the case for continuing therapy in patients at risk of myocardial infarction. Br J Anaesth 2007; 99: Abualsaud AO, Eisenberg MJ. Perioperative management of patients with drug-eluting stents. JACC Cardiovasc Interv 2010;3: Llau JV, Ferrandis R, Sierra P, Gómez-Luque A. Prevention of the renarrowing of coronary arteries using drug-eluting stents in the perioperative period: an update. Vasc Health Risk Manag 2010;6: Samama CM. Preoperative nonsteroidal antiinflammatory agents as substitutes for aspirin: already too late? Anesthesiology 2007;106: Broad L, Lee T, Conroy M, et al. Successful management of patients with a drug-eluting coronary stent presenting for elective, non-cardiac surgery. Br J Anaesth 2007;98: Bigalke B, Seizer P, Geisler T, Lindemann S, Gawaz M, May AE. Perioperative antiplatelet therapy in patients at risk for coronary stent thrombosis undergoing noncardiac surgery. Clin Res Cardiol 2009;98: Vicenzi MN, Meislitzer T, Heitzinger B, Halaj M, Fleisher LA, Metzler H. Coronary artery stenting and non-cardiac surgery: a prospective outcome study. Br J Anaesth 2006; 96:

노영남

노영남 Purpose: Delayed massive hemorrhages from pseudoaneurysm rupture of the peripancreatic large arteries, after pancreaticoduodenectomy, are fatal. We reviewed the clinical course and outcome of bleeding