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1 대한내과학회지 : 제 87 권제 1 호 종설 (Review) 새로운항응고제의임상적적용 : 비판막성심방세동환자에서뇌졸중의예방을위한새로운항응고제의사용을중심으로 단국대학교의과대학내과학교실 김동민 이명용 Application of New Oral Anticoagulants: Prevention of Stroke in Patients with Nonvalvular Atrial Fibrillation Dongmin Kim and Myung-Yong Lee Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea Only anticoagulation has been shown to reduce atrial fibrillation-related deaths. Vitamin K antagonists are difficult to use due to their narrow therapeutic range, unpredictable response, requirement for frequent coagulation monitoring, frequent dose adjustment, slow onset-offset, and numerous drug-drug and drug-food interactions. New oral anticoagulants (NOACs), such as dabigatran, rivaroxaban, and apixaban have been developed and are available in Korea, and edoxaban was shown to be effective and safe, also. NOACs showed better pharmacodynamics with predictable serum concentrations and effects, and no requirement for coagulation monitoring. These drugs have been shown to be more effective and safer than warfarin for prevention of stroke and systemic thromboembolism in patients with nonvalvular atrial fibrillation. Broad, appropriate, and aggressive use of NOACs would improve the results of treatment in patients with nonvalvular atrial fibrillation in Korea. (Korean J Med 2014;87:26-33) Keywords: Nonvalvular atrial fibrillation; Stroke prevention; New oral anticoagulant; Dabigatran; Rivaroxaban; Apixaban; Edoxaban 고령화의진행으로우리나라에서도비판막성심방세동 (nonvalvular atrial fibrillation) 환자가점차늘어나면서흔히임상에서접하는질환이되었다. 심방세동은지속성심장부정맥중에서는가장흔하여전인구의 1-2% 에이를것으로추정되고있으며 [1,2] 사망, 허혈성뇌경색, 입원, 삶의질저하, 좌심실기능의저하및인지장애등을흔히일으킨다 [3-6]. 심방세동으로인한허혈성뇌경색은일반인에비하여 발생위험성이약 5배증가하며다른원인에의한뇌경색에비하여여러부위에경색이동시에발생하거나더큰부위의경색을일으키는경우가많으므로예후가불량한경우가많다. 비판막성심방세동의장기치료심방세동은표준 12 유도심전도로비교적쉽게진단이될 Correspondence to Myung-Yong Lee, M.D., Ph.D. Department of Internal Medicine, Dankook University, College of Medicine, 119 Dandae-ro, Dongnam-gu, Cheonan , Korea Tel: , Fax: , mel_lee@dankook.ac.kr Copyright c 2014 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 - Dongmin Kim, et al. New oral anticoagulant - 수있다. 일단진단이되면항응고치료의필요성을결정한다. 그리고빠른맥박수를조절하고, 동율동으로전환할것인지를결정하는장기치료계획을수립하게된다. 다기관무작위연구에서항부정맥제를이용하여정상동율동을유지하려고노력하는율동조절군 (rhythm control group) 은박동수만조절하는군 (rate control group) 에비하여사망률을낮추지못하였으며, 오히려박동수만조절하는군에서항부정맥제의부작용이적은효과를보임으로써 [7-9] 모든비판막성심방세동환자에서율동조절을위하여적극적인항부정맥제의사용의당위성이퇴색되었다. 또한안정시심박동수를 80회 / 분미만으로, 운동시박동수를 110회 / 분미만으로엄격하게박동수를조절하는군 (strict rate-control strategy) 이나안정시맥박수를 110회 / 분미만으로적당히조절하는군 (lenient rate-control strategy) 간에사망률이나증상, 부작용, 삶의질등에서차이가없다는결과가나오게되면서심부전이나증상이없는환자에서적극적인박동수조절의의미도퇴색하게되었다 [10]. 결국심방세동환자에서사망률을낮출수있는치료는항혈전치료 (antithrombotic treatment) 가유일하다 [11]. 비판막성심방세동환자의항혈전치료항혈전치료는항혈소판치료 (antiplatelet therapy) 와항응고치료 (anticoagulation) 로나눌수있다. 아스피린과위약대조군을비교한메타분석을보면아스피린은위약에비하여 19% 의뇌졸중감소효과를보였으며통계적으로유의한우수성을증명하지못하였다 [12]. 동양의연구로는일본에서시행된무작위연구인 Japanese atrial fibrillation stroke trial이있으며아스피린을복용한군이위약대조군에비하여심혈관사망, 증상이있는뇌졸중, 일과성뇌허혈등이오히려유의하게더많이발생 ( 매년 3.1% 와 2.4%) 하였으며출혈성부작용도더많이 (1.6% 와 0.4%) 발생하였다 [13]. 특히아스피린은고령의환자에서사용하는경우뇌졸중의예방효과는적어지고출혈의합병증은늘어나므로오히려비타민 K 길항제인와파린에비하여유의하게출혈이많아지나 [14] 와파린의효과나합병증은나이와무관하게일정하게유지되므로고령일수록와파린의종합적인치료효과가아스피린보다유리하다. 위약대조군과비교한뇌졸중의감소효과에대한메타분 석에의하면와파린은통계적으로유의하게 64% 의뇌졸중위험성을감소시킨다 [12]. 아스피린과와파린의뇌졸중감소효과를직접비교한무작위연구의메타분석에따르면와파린은아스피린에비하여 39% 의뇌졸중감소효과가있으며이는통계적으로유의하였다 [12,15]. Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE) 연구에서는와파린군과아스피린 -클로피도그렐의두가지항혈전제복합치료군의뇌졸중감소효과를비교하는 ACTIVE-W 연구를시행하였으며, 와파린군이아스피린-클로피도그렐복합치료군에비하여 40% 의뇌졸중감소효과를추가로보이면서도 (95% confidence interval [CI], 18-56%) 출혈합병증은두군사이에차이를보이지않았다 [16]. 이상의연구결과로보아서비판막성심방세동환자의장기치료에서는아스피린단독혹은이스피린- 클로피도그렐복합의항혈전치료는크게도움이되지않으며, 오히려고령의환자에서출혈합병증을높이므로반드시항응고치료가필요하다. 관상동맥질환과같이높은압력과대량의혈류를보이는동맥질환의치료에있어서는항혈전치료가필수적이지만, 낮은압력과넓은부피를보이는좌심방에서의혈전예방에는항응고치료가필요한것으로생각된다. 비판막성심방세동환자에서의항혈전치료의선택항혈전치료는뇌졸중의고위험군환자에서시행하여야한다. 유럽, 미국및캐나다등나라마다실정에맞는진료지침을정하여치료에이용하고있으며약간의차이는있으나기본적인개념에서는큰차이를보이지않고있다 [17-19]. 비판막성심방세동환자에서뇌졸중의고위험군을판별하기위하여과거부터 CHADS 2 점수를많이사용하였다. 이점수체계는울혈성심부전 (congestive heart failure), 고혈압 (hypertension), 75세이상의나이 (age), 당뇨병 (diabetes mellitus) 에각각 1점을부여하고뇌졸중이나일과성뇌허혈의과거력 (previous stroke or transient ischemic attack) 에는 2점을부여하여 0점에서 6점의점수로표기한다. CHADS 2 점수 2점이상인뇌졸중의고위험군에서는반드시항응고치료가필요하다는점에서는세계모든나라에서이견이없다. 그러나이점수체계는 0-1점의환자군에서위험도를잘분리하지못하는문제가있으므로위험도가낮은환자군에서실제위험도를더잘반영하는 CHA 2DS 2-VASc

3 - 대한내과학회지 : 제 87 권제 1 호통권제 647 호 점수체계를개발하여사용하는것이보편화되고있다 (Table 1). 이점수체계는주요위험인자로이전의뇌졸중과 75세이상의나이로각각 2점의점수를부여하고다른위험인자들은 1점을부여하여최대총점 9점으로뇌졸중의위험도를평가한다. CHADS 2 점수로 0-1점인환자들의경우에는약한위험인자인혈관질환, 나이 65-74세, 여자등을점수화하여 CHA 2- DS 2-VASc 점수도 0점이라면심방세동이없는정상인과뇌졸중의위험이같다고보고아스피린등의항혈전제도투여하지않는, 그야말로아무런치료도하지않는것을권고한다. CHA 2DS 2-VASc 점수 1점에서는유럽은항응고치료를, Table 1. Risk factor-based approach expressed as a point based scoring system, with the acronym of CHA2DS2-VASc Risk factors Score Congestive heart failure/lv dysfunction a 1 HT b 1 Age 75 2 Diabetes mellitus 1 Stroke/TIA/systemic embolism 2 Vascular disease c 1 Age Sex category (i.e. Female sex) 1 Maximum score 9 LV, left ventricle; HT, hypertension; TIA, transient ischemic attack. a LV dysfunction was defined arbitrarily as LV ejection fraction 40%. b Untreated hypertension > 160/95 or use of anti-hypertensive drugs. c Prior myocardial infarction, peripheral arterial disease or aortic plaque. 미국과캐나다는아스피린만투여하는것을권고하고있다. 현재이들나라에서의진료지침은항응고치료를할때와파린보다는부작용이훨씬적고효과가뛰어난새로운경구용항응고제 (new oral anticoagulant, NOAC) 를먼저고려할것을권고하고있다. 임상에서는발작성심방세동 (paroxysmal atrial fibrillation) 이정상동율동으로전환되면항응고치료를중단하는경우를간혹볼수있다. 그러나발작성심방세동환자와영구적심방세동 (permanent atrial fibrillation) 환자의뇌졸중위험도는같으므로 [20], 발작성심방세동이라도일단심방세동으로진단이되면 CHADS 2 점수나 CHA 2DS 2-VASc 점수를계산하여뇌졸중의고위험군으로판단된다면평생에걸쳐서항응고치료를해야한다. 또한심방조동 (atrial flutter) 역시심방세동과같은뇌졸중위험도를갖는다. 항응고치료에서 NOAC 의필요성비타민 K 길항제는간에서합성되는혈액응고인자 II, VII, IX, X을모두억제하여혈액응고과정 (coagulation cascade) 의내인성및외인성경로 (intrinsic and extrinsic pathway) 를비특이적으로억제하는기전을가진약제로, 혈청단백과의결합이나대사과정때문에약물농도의예측이어렵고안전역이좁아서자주혈액검사를하여약물농도를조절해주어야한다. 또한약의효과가느리게발현되므로빠른약의작용을원할때사용이어렵고약을끊어도효과가느리게소실되므로출혈합병증이나응급수술등의상황에서어려운점이많다. 특히환자들은수많은약물과의혹은음식과의상 Table 2. Pharmacodynamics and pharmacokinetics of new oral anticoagulants Dabigatran [21] Rivaroxaban [22] Apixaban [23] Edoxaban [24] Mechanism (target) Thrombin Factor Xa Factor Xa Factor Xa Dosage Fixed, BID Fixed QD Fixed, BID Fixed, QD Oral bioavailability, % Time to peak level, hr Half-life, hr Renal clearance, % Metabolism (Cytochrome P450) No Yes Yes Yes Substrate of P-glycoprotein Yes Yes Yes Yes Monitoring of anticoagulation No No No No Antidote No No No No Factor Xa, activated factor X; BID, twice daily; QD, once daily

4 - 김동민외 1 인. 새로운경구용항응고제 - 호작용으로인하여고통받는다. 혈액응고과정의외인성및내인성경로후에는최종공통경로로응고인자 X이활성화 (activated factor X, factor Xa) 되어응고인자 II인프로트롬빈을트롬빈으로활성화시키는과정을밟으므로응고인자 X의활성화와트롬빈의활성화가혈액응고의마지막공통단계로볼수있다. 최근직접적인트롬빈억제제인 dabigatran과직접적인응고인자 Xa 억제제인 rivaroxaban, apixaban, edoxaban 등이개발되었으며이들약제들은표 2에서볼수있듯이예측가능한약역동학을보이므로혈액검사를통하여혈중농도를확인할필요가없으며투여후빠른작용을보이며약을끊으면비교적빠른시간내에약물효과가사라지고다른약물이나음식과의상호작용이거의없어서비타민 K 길항제에비하여사용하기훨씬쉽고안전하다 [21-24]. NOAC의효과모든 NOAC은임상시험을할때뇌졸중 ( 허혈성및출혈 성을모두포함 ) 과전신색전증을예방하는효과에대하여와파린에비하여열등하지않다 (non-inferiority) 는가설을주요종말점 (primary endpoint) 으로정하였다 [25-29]. 표 3에서확인할수있듯이약 14,000-21,000명의환자를 년간추적관찰하였다. 주요종말점에대하여 dabigatran 150 mg 하루두번복용하는용량 (BID), dabigatran 110 mg BID, rivaroxaban 20 mg 하루한번복용용량 (QD), apixaban 5 mg BID, edoxaban 60 mg QD는모두와파린에비하여열등하지않았으며, 특히 dabigatran 150 mg BID, apixaban 5 mg BID는와파린에비하여통계적으로의미있는우수한결과를나타내었다 (Fig. 1-A). Edoxaban 30 mg QD는주요종말점에있어서와파린에비하여통계적으로의미있게열등한결과를보였다. NOAC의효과는와파린에비하여허혈성뇌졸중을줄이는효과보다는와파린의부작용인출혈성뇌졸중을현저하게줄임으로써나타난다 (Fig. 1B). 실제로와파린에비해서허혈성뇌졸중을통계적으로유의하게줄이는 NOAC은 dabigatran 150 mg BID가유일하다 (Fig. 1C). Table 3. Phase 3 clinical trials for stroke prevention in atrial fibrillation Dabigatran [25] Rivaroxaban [26] Apixaban [27] Edoxaban [28] Study design PROBE Double blind Double blind Double blind Primary endpoint All (ischemic and hemorrhagic) stroke and systemic embolism All (ischemic and hemorrhagic) stroke and systemic embolism All (ischemic and hemorrhagic) stroke and systemic embolism All (ischemic and hemorrhagic) stroke and systemic embolism Number of patients 18,111 14,264 18,201 21,105 Median follow-up, yr Randomized groups Dose-adjusted warfarin Dabigatran 110 mg BID Dabigatran 150 mg BID Dose-adjusted warfarin Rivaroxaban 20 mg QD Dose-adjusted warfarin Apixaban 5 mg BID Dose-adjusted warfarin Edoxaban 60 mg QD Edoxaban 30 mg QD Analysis Intention to treat As treated Intention to treat Intention to treat Dose reductions No Ccr ml/min 2 of following criteria Age 80 yr Weight 60 kg Serum Cr 1.5 mg/dl Any of the following criteria Ccr mg/min Weight 60 kg Use of G-glycoprotein inhibitor TTR (INR ), % Age, yr 71.5 ± 8.7 (mean ± SD) 73 (65-78) 70 (63-76) 72 (64-78) Median (interquartile range) Median (interquartile range) Median (interquartile range) Male, % CHADS2 score (mean) PROBE, prospective randomized open-label and blind endpoints; BID, twice daily; QD, once daily; Ccr, Creatinine clearance; Cr, creatinine; SD, standard deviation; TTR, time in therapeutic range; INR, international normalized ratio.

5 - The Korean Journal of Medicine: Vol. 87, No. 1, A B C Figure 1. Efficacy of NOAC. This is not a head-to-head comparison. No clinical conclusion should be drawn from this graph. All the data were depicted from references as they were reported. (A) Efficacy of NOAC on prevention of all stroke and systemic embolism, (B) Efficacy of NOAC on prevention of hemorrhagic stroke, and (C) Efficacy of NOAC on prevention of ischemic stroke. NOAC, new oral anticoagulant; BID, twice daily; QD, once daily; HR, hazard ratio; CI, confidence interval. 이러한결과를해석하기위해서는표 3에나타난각임상시험의차이점에주의하여야한다. 모든임상시험이결과를분석할때 intention-to-treat에근거한통계분석을하는것이바람직하지만연구에따라서는 as treated 분석을사용하고있으므로결과를비교할때차이가있을수있으며, 임상시험계획에서치료약물의용량을줄여서줄수있게허용한연구들은와파린을복용하는환자군보다 NOAC을복용하는환자군에서부작용이적은것처럼보일수있다는점, 와파린투여군의치료효과가낮은 (time in therapeutic range 가낮은 ) 연구는연구약물의효능이과장되어나타나보일수있다는것을염두에두어야하며, 연구에등록된환자들의 CHADS 2 점수가높은연구는와파린군이나 NOAC군에서모두뇌졸중이발생할가능성이다른연구에비해서높을수있음을고려해서결과를해석해야할것으로사료된다. 따라서메타분석이아닌그림 1의결과를분석할때는주의가필요하다. NOAC 의안전성모든종류, 모든용량의 NOAC (rivaroxaban 의경우에는 as treated analysis) 은와파린과비교하여심각한주요출혈합병증에서열등하지않은결과를보였다 (Fig. 2A). 특히 apixaban 5 mg BID, dabigatran 110 mg BID, 그리고 edoxaban 60 mg QD의경우에는 warfarin 에비하여통계적으로유의하게적은주요출혈합병증을보였다. 심각한및심각하지않은출혈합병증을모두포함하는전체의출혈합병증에있어서는 rivaroxaban 20 mg QD를제외하고는모든약제와용법에있어서 warfarin에비하여통계적으로유의하게적은출혈합병증을보였다 (Fig. 2B). 위장관계출혈합병증을살펴볼때 dabigatran 150 mg BID, rivaroxaban 20 mg QD, 그리고 edoxaban 60 mg QD의경우에는 warfarin에비하여통계적으로유의하게출혈합병증을더많이유발하므로출혈을일으킬수있는위장관계기저질환을가진환자에서는이러한약제를사용할때는주의를요할것으로사료된다 (Fig. 2C). 또한 Dabigatran 150 mg BID 를사용하는경우에는 warfarin에비하여통계적으로유의하게심근경색증이더많이발생하는것으로나타났으며, dabigatran 110 mg BID의경우에도통계적으로유의하지는않으나심근경색증이많이발병하는경향을보이고있으므로허혈성심질환이있는환자에서 dabigatran 을사용할때는주의가필요할것으로사료된다 (Fig. 2D)

6 - Dongmin Kim, et al. New oral anticoagulant - A B C D Figure 2. Safety outcomes of NOAC. This is not a head-to-head comparison. No clinical conclusion should be drawn from this graph. All the data were depicted from references as they were reported. (A) Major bleeding of NOAC compared to warfarin, (B) Total (major and minor) bleeding of NOAC, (C) Gastrointestinal bleeding of NOAC, and (D) myocardial infarction of NOAC. NOAC, new oral anticoagulant; BID, twice daily; QD, once daily; HR, hazard ratio; CI, confidence interval. NOAC 사용의실제약제마다조금씩다르지만대부분의약제는금기증으로현재혹은최근의출혈, 혈액응고이상환자, 혈액응고의이상을보일정도의만성간질환자, 약제나유당에대한과민증이있는환자혹은다른항응고제를사용중인환자가포함된다. 이외에는강력한 P-glycoprotein 억제제인 HIV프로테아제억제제 ( 리토나비르 ), 경구용케토코나졸을포함한아졸계항진균제 ( 이트라코나졸, 보리코나졸, 포사코나졸 ) 그리고드로네다론등이포함된다. 경구용항진균제의치료가필요한경우중등도의 P-glycoprotein억제제인플루코나졸을이용할수있다. 약간의차이는있지만크레아티닌청소율 (creatinine clearance, Ccr) 30 ml/min 혹은혈청크레아티닌농도 (serum creatinine, Cr) 1.5 mg/dl (133 µmol/l) 미만으로신기능이저하된경우가금기증에속한다. NOAC을복용하는모든환자는적어도 1년에 1회는신기능을확인하는것이좋다. 그외의중등도의 P-glycoprotein억제제인아미오다론, 베라파밀, 퀴니딘, 에리드로마이신, 클래리트로마이신등과사용을할때, 아스피린이나클로피도그렐과같은항혈소판제 를같이사용하는경우, 75-80세이상의고령, 60 kg 이하의저체중, Ccr ml/min의중등도신기능저하환자에서는용량을감량하는것이좋다. 경구용항응고제인 warfarin 을복용하다가 NOAC으로변경하는경우에는프로트롬빈시간을측정하여국제표준화비율 (international normalized ratio, INR) 이 2.0 미만이되면 NOAC 을투여하기시작한다. 투여 2일이내에프로트롬빈시간을측정하면거짓으로 INR이상승되므로검사를하지않는것이좋다. 저분자량헤파린을투여받던환자는다음번투여예정시간 0-2시간전에 NOAC을투여하고저분자량헤파린을끊는다. 비분획헤파린을투여받던환자는비분획헤파린을끊으면서동시에 NOAC을투여한다. 약복용을잊은경우에는즉시약을복용하고다음번부터는원래의계획대로투여한다. 출혈의위험성이큰수술이나주요장기의수술의경우에는 48시간전에 NOAC을중단하고중등도의출혈위험성이있는수술의경우에는 24시간전에중단한다. 긴급 (urgent) 수술의경우라도마지막 NOAC 복용후최소 12시간후에수술을하는것이좋다. 또한노인이거나신기능이저하된

7 - 대한내과학회지 : 제 87 권제 1 호통권제 647 호 환자에서는약물의배설이느리므로조금더일찍 NOAC을중단하는것이좋다. NOAC의효과를판정하기위한검사는아직상업적으로이용이가능하지않으며길항제 (antidote) 도아직은없다. 출혈합병증이발생한경우에는가능한경우수술혹은비수술적으로지혈을하며필요한경우신선동결혈장 (fresh frozen plasma), 혈소판농축액 (platelet concentrate), 농축적혈구 (packed red blood cell) 등을투여한다. 길항제가없지만약물의반감기가짧아서오래기다리지않아도지혈이되는경우가많다. 심각한부위의출혈이거나지혈이장시간되지않는경우에는프로트롬빈복합농축액 (prothrombin complex concentrate), 활성프로트롬빈복합농축액 (activated prothrombin complex concentrate), 재조합인자 VIIa (recombinant factor VIIa) 등을사용해볼수있지만프로트롬빈복합농축액과활성프로트롬빈복합농축액은아직국내에서사용할수없고재조합인자 VIIa도구하기가쉽지않으며아직효과를연구한보고도없으므로효과를보장할수없다. 다른 NOAC과는달리 dabigatran 의과도한혈중활성화가의심이되는경우에는에카린응고시간 (Ecarin clotting time) 과트롬빈시간 (thrombin time) 이지연되는것을어느정도이용할수있다. 에카린응고시간이나트롬빈시간을검사할수없는상황이라면활성화부분트롬보플라스틴시간 (activated partial thromboplastin time) 을이용할수있다. 또한 dabigatran 은혈액투석으로제거할수있다. 현재까지의연구결과를종합하여볼때와파린이나 NOAC 을사용하던중허혈성뇌졸중이발생한다면와파린에비하여허혈성뇌졸중을예방하는효과가의미있게우수한 dabigatran 이추천이된다. 소화성궤양등위장관출혈의위험성이있는환자에서는 apixaban이추천이되고허혈성심질환이있는경우에는 dabigatran의사용이추천되지않지만 rivaroxaban 은심근효소의상승을동반한급성관동맥증후군에서의사용이허가된약제이므로허혈성심질환에서의사용이고려될수있겠다. 그러나출혈위험성이높은환자에서 rivaroxaban의사용은다시고려해보는것도필요할것으로사료된다. 또한신기능이저하된환자에서는약물의신장배설이가장적은 apixaban의이용이더안전할수있을것으로예측된다. 요 비판막성심방세동의장기치료에서사망률을낮출수있는치료는현재까지항응고치료가유일하다. 현재까지사용하고있는와파린은좁은안전역, 잦은검사의필요성, 예측되지않는약물반응, 약물상호작용, 음식상호작용, 느린효과의발현및소실등의문제로인하여사용이어려운약물이다. 최근개발된새로운기전의항응고제를 new oral anticoagulant (NOAC) 이라고하며 dabigatran, rivaroxaban, apixaban 등이국내에서이미사용이가능하며 edoxaban이최근좋은임상결과를발표하였다. NOAC은빠른효과를보이고약을끊었을때효과가빠르게소실이되며정해진용량을복용하였을때혈중약물농도를잘예측할수있으므로혈액검사로효과를확인할필요가없으며약물및음식과의상호작용이매우적은장점이있으면서뇌졸중의예방효과는와파린과비교하여비슷하거나더욱효과적이며합병증에있어서도와파린과비슷하거나오히려우수하다. 적극적인 NOAC의사용으로비판막성심방세동환자의치료결과가호전될것으로기대된다. 중심단어 : 비판막성심방세동 ; 뇌졸중의예방 ; 새로운경구용항응고제 ; 다비가트란 ; 리바록사반 ; 아픽사반 ; 에독사반 약 REFERENCES 1. Stewart S, Hart CL, Hole DJ, McMurray JJ. Population prevalence, incidence, and predictors of atrial fibrillation in the Renfrew/Paisley study. Heart 2001;86: Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285: Kirchhof P, Auricchio A, Bax J, et al. Outcome parameters for trials in atrial fibrillation: executive summary. Eur Heart J 2007;28: Stewart S, Hart CL, Hole DJ, McMurray JJ. A populationbased study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley Study. Am J Med 2002;113: Knecht S, Oelschläger C, Duning T, et al. Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy. Eur Heart J 2008;29:

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<3034C6AFC1FD20B1E8B3B2C8A32E687770> 대한내과학회지 : 제 81 권제 4 호 2011 특집 (Special Review) - 심방세동의이해와치료 심방세동에서의항응고요법 원광대학교의과대학내과학교실 고점석 김남호 Anticoagulation in Atrial Fibrillation Jum Suk Ko and Nam-Ho Kim Department of Internal Medicine, Wonkwang