MAIN TOPIC REVIEWS Young Keun On, MD, PhD, FHRS Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine Received: November 7, 2014 Revision Received: February 23, 2015 Accepted: March 26, 2015 Corresponding author: Young Keun On, MD, PhD, FHRS, Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, #81 Irwon-ro Gangnam-gu, Seoul, Korea, 135-710 Tel: +82-2-3410-3420, Fax: +82-2-3410-3849 E-mail: yk.on@samsung.com, oykmd123@gmail.com Copyright 2015 The Official Journal of Korean Heart Rhythm Society Editorial Board & MMK Co., Ltd. ABSTRACT Atrial fibrillation (AF), whether paroxysmal, persistent, or permanent, and whether symptomatic or silent, significantly increases the risk of thromboembolic ischemic stroke. Non-valvular AF increases the risk of stroke by 5 times. Thromboembolism occurring with AF is associated with a greater risk of recurrent stroke, more severe disability, and mortality. Most strokes in patients with AF result from thrombus formation in the left atrial appendage (LAA). Occlusion of the LAA by means of a device could be an alternative to oral anticoagulation, mainly in patients who cannot tolerate the latter because of a high bleeding risk. Key Words: atrial fibrillation, thromboembolism, anticoagulation, left atrial appendage 서론 심방세동은심장부정맥중에서가장흔한부정맥으로비판막성심방세동환자의경우혈전색전증에의한뇌졸중의빈도가약 5배증가하고, 매년약 5% 의뇌졸중이발생하는것으로알려져있다. 심방세동에의한혈전색전증으로뇌졸중이발생하는경우의 90% 가좌심방이에서유발된혈전색전증에의한것으로알려져있고, 다른원인에의한경우보다뇌손상의범위가크며, 신경학적장애가심하여사망이나중증장애로이어질위험이높다. 따라서심방세동환자에서항응고제치료를통한혈전색전증예방은매우중요한치료전략중하나이다. 그렇지만이러한항응고제치료는출혈위험도를증가시키는문제점이있다. 최근에새로운항응고제를이용한여러연구에서도추적관찰결과 20-30% 의환자에서항응고제를중단하는것으로보고되었고, 이렇게항응고제투여를중단한경우에혈전색전증의위험성이증가하였다. 하지만심방세동환자에서항응고제의사용에문제가있는경우좌심방이폐색술이항응고제를대체할수있을것으로생각된다. 현재경피적좌심방이폐색기구로서 Watchman 과 Amplatzer Cardiac Plug (ACP) 두가지기구가시술에사용되고있으며, 비교적좋은결과가발표되고있다. 이에비판막성심방세동환자에서좌심방이폐색술치료에대한소개및적응증에대해기술하고자한다. 비판막성심방세동환자에서뇌졸중위험도평가 2012년 ESC (European Society of Cardiology) 심방세동치료권고안및 2014년 AHA/ACC/HRS (American Heart Association/American College of Cardiology/Heart Rhythm Society) 심방세동치료권고안에서 CHA2DS2- VASc 점수 (Table 1) 를뇌졸중위험도평가를위해추천하고있다. 심부전 (Congestive heart failure), 고혈압 (Hypertension), 연령 (Age: 75세이상 2점, 65-74세 1점 ), 25
Table 1. CHA 2DS 2-VASc score Letter Risk factor Score C Congestive heart failure/lv dysfunction 1 H Hypertension 1 A 2 Age 75 2 D Diabetes mellitus 1 S 2 Stroke/TIA/thromboembolism 2 V Vascular disease* 1 A Age 65-74 1 S Sex category (i.e. female sex) 1 * Prior myocardial infarction, peripheral artery disease, aortic plaque LV, left ventricular; TIA, transient ischemic attack. Maximum score 9 당뇨병 (Diabetes mellitus), 뇌졸중 (Stroke), 혈관질환 (Vascular disease) 과성별 ( 여성 1 점 ) 의종합점수로비판막성 심방세동환자에서의뇌졸중위험도를평가한다. CHA2DS2- VASc 점수 2 점이상인뇌졸중고위험군환자에서는반드시 항응고제를사용하도록권고하고, CHA2DS2-VASc 점수 1 점에서도뇌졸중위험도와출혈위험도를비교하여 항응고제의사용을고려하도록권고하고있다. 비판막성심방세동환자에서항응고제치료에따른출혈위험도평가 항응고제사용에따른출혈위험도를임상에서쉽게 평가하기위해 HAS-BLED 출혈위험점수 (HAS-BLED bleeding risk score, Table 2) 의사용을추천하고있다. 이는 고혈압 (Hypertension), 신장혹은간기능이상 (Abnormal renal/liver function), 뇌졸중 (Stroke), 출혈의병력이나성향 (Bleeding history or predisposition), 불안정한 INR (Labile INR [international normalized ratio]), 고령 (Elderly, 65 세 이상 ) 및출혈성향을증가시키는약제나과량의술 (Drug/ alcohol) 등의복용을출혈위험인자로고려한점수이다. HAS-BLED 출혈위험점수가 0-1 점이면중증출혈의 빈도가약 1%, 5 점이면 12.5% 정도로알려져있고, 3 점 이상이면중증출혈의빈도가 3.74% 정도로고위험군에 해당된다. 그러나출혈고위험군환자라도항응고제의사용을 금기하는것은아니며, 항응고제치료시교정이가능한출혈 위험인자를적극적으로교정하도록권고하고있다. 좌심방이의해부학적이해 비판막성심방세동에의한혈전색전증으로발생하는뇌졸중의약 90% 는좌심방이에서유발된혈전색전증에의한것으로알려져있다. 좌심방이는방실구 (atrioventricular sulcus) 의앞쪽에위치하고있고, 주위에좌회선동맥 (left circumflex artery), 좌측횡격막신경 (left phrenic nerve), 좌측폐동맥 (left pulmonary artery), 좌측폐정맥 (left pulmonary vein) 등이분포하고있다. 좌심방이의모양은매우다양하고, 크게 4가지형태로분류한다. 선인장 (cactus) 형태, 닭날개 (chicken wing) 형태, 풍향계 (windsock) 형태, 양배추 (cauliflower) 형태로나뉘어진다. 혈전색전성뇌졸중을예방하기위해좌심방이폐색술및절제술이시행되고있고, 이러한치료법에는심장수술과동시에시행하는좌심방이절제술, 흉강경을통한좌심방이절제술, 심외접근을통한경피적좌심방이폐색술, 혈관을통한경피적심내접근좌심방이폐색술등이있다. 혈전색전성뇌졸중을예방하기위한좌심방이폐색술을시행하기위해서는좌심방이및주위구조물에대한정확한해부학적인이해가필요하다. 시술전및시술중좌심방이구조물에대한경식도심초음파, CT, X-선투시검사, 조영술등을포함한다양한영상검사의이해및적절한좌심방이폐색술기구의선택이필요하며, 시술후에도 26
Table 2. HAS-BLED bleeding risk score Letter Risk factor Score H Hypertension 1 A Abnormal renal and liver function (1 points each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INRs 1 E Elderly (e.g. age >65 years) 1 D Drugs or alcohol (1 point each) 1 or 2 Maximum score 9 * 'Hypertension' is defined as >systolic blood pressure 160 mmhg, Abnormal kidney function is defined as the presence of chronic dialysis or renal transplantation or serum creatinine 200 mmol/l. Abnormal liver function is defined as chronic hepatic disease (cirrhosis) or biochemical evidence of significant hepatic derangement (bilirubin >2 x upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.). Bleeding refers to previous bleeding history and/or predisposition to bleeding, e.g. bleeding diathesis, anemia, etc. Labile INRs refers to unstable/high INRs or poor time in therapeutic range (<60%). Drugs/alcohol use refers to concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse, etc. INR, international normalized ratio. 좌심방이구조물에대한경식도심초음파검사등의영상추적관찰이필요하다. 좌심방이폐색술의기존연구 심방세동환자에서항응고제의사용에문제가있는경우좌심방이폐색술이항응고제를대체하여사용될수있을것으로생각되고, 현재경피적좌심방이폐색기구로서 Watchman device (Boston Scientific, Maple Grove, MN, USA) 와 ACP (St. Jude Medical, Minneapolis, MN, USA) 두가지기구가국내에서시술되고있다. 현재까지좌심방이폐색술에대한대규모임상은부족한실정이며, Watchman device에대한소규모무작위배정연구및 Watchman device와 ACP device에대한몇몇관찰연구에서좋은결과가발표되고있다. PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With AF) 1 는좌심방이폐색술에대한최초의무작위배정연구로항응고제치료에비하여 Watchman device의비열등성을보고자한연구이다. 연구대상자의기준은 18세이상의비판막성심방세동환자로 CHADS2 점수 1점이상으로하였고, 제외기준은 warfarin 금기환자, 좌심방이내에혈전, 심방중격류 (septal aneurysm) 를동반한난원공개존증 (patent foramen ovale), 움직이는대동맥죽종, 증상이있는경동맥질환등이었다. 좌심방이폐색술이후 warfarin을 45일간사용하였고, 경식도심초음파검사후에 warfarin을중단하고 aspirin과 clopidogrel 병합요법을 6개월까지투여하였으며, 이후 aspirin 단독으로진행하였다. Warfarin 군은 6개월동안 2주간격으로 INR을 2-3으로유지하였고, 이후한달간격으로검사하였다. 1년추적관찰결과 warfarin 군 66% 에서 INR 2-3의범위를보였고, Watchman device 군과 warfarin 군에서혈전색전의차이는없었다. Watchman device 군에서주로시술과관련된합병증이약 10% 로보고되었다. 이러한시술과관련된합병증은시술자의경험이쌓임에따라감소하여이후발표된 CAP (continuous access protocol) registry 2 에서는약 3.7% 로보고되었다. ASAP (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology) 연구 3 는 warfarin 금기환자를대상으로 CHADS2 점수 1점이상 ( 평균 2.8) 으로하였고, 좌심방이폐색술이후 aspirin과 clopidogrel 병합요법을 6개월까지투여하였으며, 이후 aspirin 단독으로진행하였다. 95% 에서성공적으로 Watchman device 를시술하였고, 1년추적관찰결과허혈성뇌졸중이 1.7% 발생하여유사한 CHADS2 점수의심방세동환자군에비해 27
Non-valvular atrial fibrillation Thromboembolic risk (CHA 2DS 2-VASc 2) AND Bleeding risk (HAS-BLED 3) Thromboembolic risk (CHA 2DS 2-VASc 2) but no effective anticoagulation Recurrent bleeding on Contraindication to Intolerant to Prior stroke/tia while on Persistent noncompliance with Unwilling to take LAAC Figure 1. Evaluation scheme for considering left atrial appendage occlusion. LAAC, left atrial appendage closure, TIA, transient ischemic attack. 77% 의뇌졸중감소율, aspirin과 clopidogrel 병합요법군에비해 64% 의뇌졸중감소율을보였을것으로보고하였다. ACP device에대한유럽의관찰연구 4 에의하면 152명의환자에서시술되었으며, 15명 (9.8%) 에서시술관련부작용이관찰되었고, 10년간추적관찰하였을때 1.3% 의혈전색전증관련사건이발생하였다. ACP device에대한캐나다의관찰연구 5 에의하면비판막성심방세동환자로 warfarin 금기증인평균 CHADS2 점수 3점인환자를대상으로 98% 의환자에서시술에성공하였고, 1.9% 에서기구색전, 1.9% 에서심낭삼출의합병증이관찰되었다. 시술이후 3개월까지 aspirin과 clopidogrel 병합요법을시행하고, 이후단독항혈소판제요법을시행하였다. 평균 20개월추적관찰에서 3.4% 의뇌졸중및색전증을보여기대치 10% 에비해낮은 수치를보고하였고, 주된출혈도 3.4% 로기대치 8.7% 에비해낮은수치를보였다. 좌심방이폐색술의적응증 2012년 ESC 권고안에는비판막성심방세동환자에서뇌졸중발생위험이높고, 장기간의항응고제사용이금기인경우에좌심방이폐색술을고려할수있다고언급하였다 (Figure 1). 기존에발표된연구들을참고하여비판막성심방세동환자중에서 1) CHA2DS2-VASc 점수 2 이상이고 HAS-BLED 출혈위험점수 3 이상인고위험군에서항응고제사용후에반복적인출혈로항응고제를사용할수없는경우, 2) 항응고제의과민증등의금기증이있는경우, 3) 항응고제를 28
사용하기어려운경우에좌심방이폐색술을고려할수있고, 또한 4) CHA2DS2-VASc 점수 2 이상인고위험군에서항응고제사용후에도뇌졸중이발생하거나 5) 항응고제사용의순응도가낮은경우, 6) 항응고제의사용을거부하는경우에좌심방이폐색술을고려할수있다. 6 현재까지좌심방이폐색술의대규모임상은부족한실정으로좌심방이폐색술의효과에대한좀더장기적인연구결과및새로운항응고제에대한비교연구등이필요하므로무차별적인좌심방이폐색술에대한시도보다는가장효과적일수있는적응증에대한연구가필요하리라생각된다. 결론 심방세동의치료전략에는혈전색전증에의한뇌졸중예방을위한항응고요법이매우중요하며, 뇌졸중위험도와항응고제사용에따른출혈위험도를평가하여환자개인별로맞춤치료를해야한다. CHA2DS2-VASc 점수 2점이상에서는반드시항응고제를사용하도록권고하고있지만, 비판막성심방세동환자에서항응고제의사용에문제가있는경우는좌심방이폐색술이항응고제를대체하여사용될수있을것으로기대한다. 또한좌심방이폐색술이가장효과적인적응증에대한연구도필요할것이다. Left Atrial Appendage Closure Technology (ASAP Study). J Am Coll Cardiol. 2013;61:2551-2556. 4) Nietlispach F, Gloekler S, Krause R, Shakir S, Schmid M, Khattab AA, Wenaweser P, Windecker S, Meier B. Amplatzer left atrial appendage occlusion: single center 10-year experience. Catheter Cardiovasc Interv. 2013;82:283-289. 5) Urena M, Rodes-Cabau J, Freixa X, Saw J, Webb JG, Freeman M, Horlick E, Osten M, Chan A, Marquis JF, Champagne J, Ibrahim R. Percutaneous left atrial appendage closure with the AMPLATZER cardiac plug device in patients with nonvalvular atrial fibrillation and contraindications to anticoagulation. J Am Coll Cardiol. 2013;62:96-102. 6) John CA, Colombo A, Corbucci G, Palletized L. Left atrial appendage closure: a new technique for clinical practice. Heart Rhythm. 2014;11:514-521. References 1) Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M, Mullin CM, Sick P; PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet. 2009;374:534-542. 2) Reddy VY, Holmes D, Doshi SK, Neuzil P, Kar S. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation. 2011;123:417-424. 3) Reddy VY, Mobius-Winkler S, Sievert H, Miller MA, Neuzil P, Schuler G, Wiebe J, Sick P, Sievert H. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: ASA Plavix Feasibility Study with Watchman 29