심방세동환자에서의항응고제치료 MAIN TOPIC REVIEWS 성균관대학교의과대학내과학교실온영근 Young Keun On, MD, PhD, FHRS Division of Cardiology, Department of Medicine Samsung Medical Cent

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심방세동환자에서의항응고제치료 성균관대학교의과대학내과학교실온영근 Young Keun On, MD, PhD, FHRS Division of Cardiology, Department of Medicine Samsung Medical Center, Sungkyunkwan University School of Medicine ABSTRACT Atrial

1 심방세동환자에서의항응고제치료 성균관대학교의과대학내과학교실온영근 Young Keun On, MD, PhD, FHRS Division of Cardiology, Department of Medicine Samsung Medical Center, Sungkyunkwan University School of Medicine 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 5 times and AF in the setting of mitral stenosis increases the risk of stroke 20 times over patients in sinus rhythm. Thromboembolism occurring with AF is associated with a greater risk of recurrent stroke, more severe disability, and mortality. The CHA2DS2-VASc score is recommended for thromboembolic risk evaluation in nonvalvular AF. HAS-BLED score is recommended for bleeding risk evaluation. Careful consideration is required to balance the benefits and the risks of bleeding of anticoagulation in each individual patient. Key Words: atrial fibrillation anticoagulation warfarin new oral anticoagulant 서론 심방세동은심장부정맥중에서가장흔한부정맥으로심방세동환자의경우혈전색전증에의한뇌졸중의빈도가약 5배증가하는것으로되어있고, 매년심방세동환자의약 5% 에서뇌졸중이발생하는것으로알려져있다. 혈전색전증에의한뇌졸중의원인을분석해보면약 20% 가심방세동에의한뇌졸중으로보고하고있다. 특히심방세동에의한 Received: August 28, 2014 Accepted: December 15, 2014 Correspondence: Young Keun On, MD, PhD, FHRS, Division of Cardiology, Department of Medicine Samsung Medical Center, Sungkyunkwan University School of Medicine #81 Irwon-ro Gangnamgu, Seoul, Korea, , Fax: yk.on@samsung.com, oykmd123@gmail.com 혈전색전뇌졸중이발생하는경우다른원인에의한경우보다뇌손상의범위가크고신경학적장애가심하여사망이나중증장애로이어질위험이높아항응고제치료를통한혈전색전증의예방이매우중요하다. 비판막성심방세동환자에서의항응고제치료는뇌졸중위험도와항응고제사용에따른출혈위험도를평가하여환자개개인별로적합한결정을해야한다. 이에 2012년 ESC (European Society of Cardiology) 심방세동치료권고안및 2014년 AHA/ ACC/HRS (American Heart Association/American College of Cardiology/Heart Rhythm Society) 심방세동치료권고안 1-3 을중점으로심방세동환자에서의항응고제치료에대해기술하고자한다. VOL.15 NO.4 21

2 Table 1. CHA2DS2-VASc score Letter Risk factor Score C Congestive heart failure/lv dysfunction 1 H Hypertension 1 A2 Age 75 2 D Diabetes mellitus 1 S2 Stroke/TIA/thromboembolism 2 V Vascular disease* 1 A Age S Sex category (i.e. female sex) 1 Maximum score 9 * Prior myocardial infarction, peripheral artery disease, aortic plaque LV, left ventricular; TIA, transient ischemic attack. 비판막성심방세동환자에서의뇌졸중위험도평가 비판막성심방세동환자의뇌졸중위험도평가에 있어기존에심부전 (Congestive heart failure), 고혈압 (Hypertension), 연령 (Age: 75 세이상 ), 당뇨병 (Diabetes mellitus), 뇌졸중 (Stroke) 등을고려한 CHADS2 점수 (CHADS2 score) 가주로사용되어왔다. 그러나나이를세분화하고 (75 세이상 2 점, 세 1 점 ), 성별 ( 여성 1 점 ) 및혈관질환 (Vascular disease) 등의변수를더추가한 CHA2DS2-VASc 점수 (Table 1) 를사용한경우예측력이좀더우수한것으로 알려짐에따라 2010 년 ESC 권고안부터는 CHA2DS2- VASc 점수를권고하기시작하였고, 2014 년 AHA/ ACC/HRS 권고안에서도 CHA2DS2-VASc 점수를 뇌졸중위험도평가를위해추천하고있다. 비판막성심방세동환자에서의항응고제치료에따른출혈위험도평가 항응고제사용에따른출혈위험도를임상에쉽게 평가하기위해 HAS-BLED 출혈위험점수 (HAS- BLED bleeding risk score) 의사용을추천하고있다 (Table 2). 이는고혈압 (Hypertension), 신장혹은간기능이상 (Abnormal renal/liver function), 뇌졸중 (Stroke), 출혈의병력이나성향 (Bleeding history or predisposition), 불안정한 INR (Labile INR [international normalized ratio]), 고령 (Elderly, 65세이상 ) 및출혈성향을증가시키는약제나과량의술 (Drug/alcohol) 등의복용을출혈위험인자로고려한점수로중증출혈의빈도가 0-1점이면약 1%, 5점이면 12.5% 정도로알려져있고, 3점이상이면중증출혈의빈도가 3.74% 정도나되어항응고제치료에따른손익을신중히고려해야한다. 그러므로항응고제치료시교정이가능한출혈위험인자는적극적으로교정해야한다. 항응고제사용 2012년 ESC 권고안에서는 CHA2DS2-VASc 점수에따라 2군으로나누어 1점및그이상인경우새로운경구항응고제의사용을 1차약제로권장하고, 대안으로 warfarin을사용할수있으며, 0점인경우항응고치료를하지않는다. 단, 여성환자로다른뇌졸중위험변수가없는경우에는 CHA2DS2-VASc 점수가 1점이라도항응고제치료를권장하지않는다. 22 The Official Journal of Korean Heart Rhythm Society

3 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. 한편 2014년 AHA/ACC/HRS 권고안에서는비판막성심방세동에서 CHA2DS2-VASc 점수 2점이상인경우항응고제의사용을권장하며, warfarin 또는 dabigatran, 4 rivaroxaban, 5 또는 apixaban 6 과같은새로운경구항응고제를사용할수있다. CHA2DS2- VASc 점수 2점이상이면서말기신부전 (CrCl <15 ml/ min) 환자에서는항응고제로 warfarin을사용한다. CHA2DS2-VASc 점수 1점인경우항응고제치료를하지않거나, 항응고제 ( 새로운경구항응고제또는 warfarin) 혹은 aspirin을고려할수있다. 0점인경우항응고치료를권장하지않는다. 인공기계판막이있는심방세동환자의경우에는 warfarin의사용을권고하고, 인공판막의종류와위치에따라 INR 범위 ( 또는 ) 를결정한다. Warfarin을사용하는경우치료시작시기에는매주 INR을검사하고, INR이안정된이후에는 1개월에한번 INR 검사를시행해야한다. 인공판막이있는심방세동환자에서 warfarin을중단해야하는시술또는수술을받는경우에는 heparin 또는저분자량 heparin (low molecular weight heparin, LMWH) 을 warfarin 중단기간에사용할것을권장하고, 인공판막이아닌심방세동환자에서의 heparin 또는 LMWH 사용여부는환자의뇌졸중위험도와출혈위험도및항응고중단기간을고려하여결정한다. 항혈소판제 심방세동환자의뇌졸중발생에서일차예방을위한 aspirin의효과에대한연구결과들을메타분석해보면약 19% 의상대적뇌졸중발생예방효과가있어매년절대값으로 0.8% 의뇌졸중을예방하는것으로알려져있다. 한편일과성허혈발작 (transient ischemic attack, TIA) 또는뇌졸중환자를대상으로한이차예방효과에서는 aspirin이절대값으로매년 2.5% 의뇌졸중을예방하는것으로보고되고있다. Aspirin과 clopidogrel 복합요법은 aspirin 단독요법에비해 28% 의상대적뇌졸중발생예방효과가있으나 warfarin에비해서는열등하여 warfarin이 aspirin과 clopidogrel 복합요법에비해 40% 의상대적뇌졸중발생예방효과가있는것으로알려져있다. VOL.15 NO.4 23

4 새로운항응고제 심방세동환자의뇌졸중발생에서 warfarin의효과에대한연구결과들을메타분석해보면약 64% 의상대적뇌졸중발생예방효과가있어매년절대값으로 2.7% 의뇌졸중을예방하는것으로알려져있다. Warfarin 사용시에는뇌졸중예방및출혈위험방지를위해 INR 을유지하는것이필수적이고, 따라서정기적인혈액검사가필요하다. 그렇지만실제임상상황에서는이러한 INR 을유지하는비율이절반이하인것으로알려져있고, warfarin의약물상호작용, 음식물과의상호작용, 정기적인혈액검사의불편함등이제시되어새로운항응고제의필요성이대두되었다. 새로개발된항응고제로는 dabigatran, rivaroxaban, apixaban, edoxaban이있으며, 대규모임상연구결과에의하면뇌졸중예방면에서 warfarin 과비슷한성적을보이고있고, 뇌출혈위험도면에서는오히려더우수한결과를보이고있다. Dabigatran Dabigatran은 direct thrombin 억제제로개발되어심방세동에서의뇌졸중예방효과를 warfarin과비교한 RE-LY (Randomized Evaluation of Long-term anticoagulant therapy) 연구가발표되어있다. 4 이연구에서 1개이상의뇌졸중위험인자를동반한심방세동환자를 dabigatran과 warfarin 사용군으로나누고, 평균 2년간추적관찰하여뇌졸중및혈전색전증을비교한결과 dabigatran 110 mg 또는 150 mg BID 투여군에서 warfarin 군에비해뇌졸중및혈전색전증발생예방효과가비열등하였다. Dabigatran 150 mg BID 투여군에서뇌졸중및혈전색전증이 1.11% 발생하여 warfarin 군의 1.69% 에비해예방효과면에서우월하였고 (RR=0.66), dabigatran 110 mg BID 투여군에서는중증의출혈이 2.71% 발생하여 warfarin 군의 3.36% 에비해중증출혈의발생이적었다. Rivaroxaban Rivaroxaban은 factor Xa 억제제로개발되어뇌졸중위험인자를동반한심방세동환자를대상으로 rivaroxaban 20 mg 복용군과 warfarin 군으로나누어평균 19개월동안의뇌졸중및혈전색전증의발생을비교한 ROCKET-AF (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) 연구가발표되었다. 5 뇌졸중및혈전색전증이 rivaroxaban 군에서 1.71 events/100 patient-year 발생하여 warfarin 군의 2.16 events/100 patient-year에비해우월하였다. 중증출혈의발생은 rivaroxaban 군에서 3.60 events/100 patient-year 발생하여 warfarin 군의 3.45 events/100 patient-year과비교하여차이가없었다. 출혈성합병증에서 rivaroxaban 군은 warfarin 군에비해출혈성뇌졸중 (0.26% versus 0.44%; HR, 0.59; p=0.024), 두개내출혈 (0.7% versus 0.5%; HR, 0.67; p=0.02) 및중증출혈은유의하게적었으나 (0.5% versus 0.2%; HR, 0.50; p=0.003), 위장관출혈은더많았다 (3.3% versus 2.2%; p<0.001). Apixaban Apixaban은 factor Xa 억제제로개발되어뇌졸중위험인자를동반한심방세동환자를대상으로 apixaban 5 mg BID 복용군과 warfarin 군으로나누어평균 1.8년동안의뇌졸중및혈전색전증의발생을비교한 ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) 연구가발표되었다. 6 CHADS2 점수 1점이상인비판막성심방세동환자에서 apixaban은 warfarin에비해우월한뇌졸중및전신색전증예방효과를보였으며, 중증출혈 (2.13% versus 3.09%; HR, 0.69; p<0.001), 출혈성뇌졸중 (0.24% versus 0.47%; HR, 0.51; p<0.001), 두개내출혈 (0.33% versus 0.80%; HR, 0.42; p<0.001) 등의발생은더낮았다. 24 The Official Journal of Korean Heart Rhythm Society

5 Edoxaban Edoxaban은 factor Xa 억제제로개발되어뇌졸중위험인자를동반한심방세동환자를대상으로 edoxaban 군과 warfarin 군으로나누어평균 2.8년동안의뇌졸중및혈전색전증의발생을비교한 ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation) 연구가발표되었다. 7 뇌졸중및혈전색전증의연간발생률은 warfarin 군 1.50%, 고용량 edoxaban 군 1.18% (HR, 0.79; p<0.001 for non-inferiority), 저용량 edoxaban 군 1.61% (HR, 1.07; p<0.005 for non-inferiority) 로비열등성이확인되었으며, 중증출혈의연간발생률은 warfarin 군 3.43% 에비하여고용량 edoxaban 군 2.75% (HR, 0.80; p<0.001) 및저용량 edoxaban 군 1.61% (HR, 0.47; p<0.001) 로 edoxaban 군각각이더적었다. 관상동맥중재술을시행하는심방세동환자 심방세동환자에게관상동맥중재술을시행하는경우에는시술중에항응고제투여를중단하여혈관천자부위의출혈위험성을줄이도록하고, BMS (bare metal stent) 를시술하여이중항혈소판제투여기간을최소화하도록권고한다. 관상동맥중재술또는수술이후에는 CHA2DS2-VASc 점수 2점이상인경우항응고제와 clopidogrel 병합요법을추천한다. 결론 심방세동의치료전략에는혈전색전에의한뇌졸중예방을위한항응고요법이매우중요하며, 뇌졸중위험도와항응고제사용에따른출혈위험도를평가하여환자개인별로맞춤치료를해야한다. 뇌졸중위험도평가를위해 CHA2DS2-VASc 점수를, 출혈위험도평가를위해 HAS-BLED 출혈위험점수를권고한다. CHA2DS2- VASc 점수 2점이상의뇌졸중고위험도인심방세동환자에서는항응고제의사용을권고하며, warfarin의투여 및 INR 2-3 유지또는새로운항응고제가추천되고있 다. 기존의 warfarin 을대체할수있는새로운항응고제 로는 dabigatran, rivaroxaban, apixaban, edoxaban 이 있으며, 대규모임상연구결과에의하면약제의종류, 용 량및제제에따라뇌졸중예방효과에있어 warfarin 치 료에비하여우수하거나동등하였고, 뇌출혈위험도면 에서오히려더안전한결과를보였다. References 1. January CT, Wann LS, Alpert JS, Calkins H, Cleveland JC, Jr., Cigarroa JE, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: A report of the American College of Cardiology/American Heart Association task force on practice guidelines and the Heart Rhythm Society. Circulation. 2014:129: Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33: Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31: Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2012;365: Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. VOL.15 NO.4 25

6 2011;365: Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369: The Official Journal of Korean Heart Rhythm Society

MAIN TOPIC REVIEWS Arrhythmia 2015;16(1):25-29 좌심방이폐색술의소개와적응증 Young Keun On, MD, PhD, FHRS Division of Cardiology, Department of Medicine, Samsung Med

MAIN TOPIC REVIEWS Arrhythmia 2015;16(1):25-29 좌심방이폐색술의소개와적응증 Young Keun On, MD, PhD, FHRS Division of Cardiology, Department of Medicine, Samsung Med 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: