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 University School of Medicine, Iksan, Korea Atrial fibrillation (AF) is the most commonly occurring arrhythmia. An antithrombotic agent is considered mandatory as part of the management in most patients with AF. It has been conclusively demonstrated that long-term anticoagulation therapy can significantly reduce the risk of stroke in patients with non-valvular AF. While vitamin K antagonists (VKAs) such as warfarin are highly effective, they possess numerous limitations that curtail their use, or make their use challenging for clinicians and patients. A new generation of anticoagulants are being investigated in clinical trials in patients with AF. One or more of these agents have the potential to either replace or act as alternatives to VKA therapy in AF. This review summarizes the recent accumulated evidence on anticoagulation to prevent the thromboembolism in patients with non-valvular AF. (Korean J Med 2011;81:434-443) Keywords: Atrial fibrillation; Thromboembolism; Warfarin 서론심방세동은전인구의약 2% 정도에서나타나는가장흔한부정맥중하나로연령이높아질수록증가하여 65세이상인경우에는약 5% 의유병률을보인다. 모든뇌경색환자의약 15-20% 는심방세동이그원인으로알려져있다. 미국의 Framingham Heart Study에의하면 55-59세의심방세동환자에서 1년간발생하는뇌졸중은 1.5% 이지만 80-89세의노인에서는 23.5% 로증가한다 [1]. 심방세동에의한뇌경색은다른원인에의한것보다뇌경색의범위가크며동반된심 질환으로인하여조기및만기사망률이높다. 그러나심방세동에의한뇌졸중은항응고제를사용함으로써예방이가능하며뇌졸중의여러원인들중에서가장예방효과가뚜렷한유형이다 [2]. 항응고제중와파린을가장많이사용하고있으나, 여러가지문제로그사용이제한되어있다. 하지만최근에는새로운항응고제가개발되거나개발중에있으며, 이러한약물들은와파린을보완할수있을것으로기대된다. 이논문에서는최근에개정된치료지침및새로운항응고제를중심으로심방세동에서의항응고요법에대하여기술하고자한다 [3-5]. Correspondence to Nam-Ho Kim, M.D. Department of Internal Medicine, Wonkwang University School of Medicine, 344-2 Sinyong-dong, Iksan 570-711, Korea Tel: +82-63-859-2523, Fax: +82-63-852-8480, E-mail: cardionh@wonkwang.ac.kr * This paper was supported by Wonkwang University in 2010. - 434 -
- Jum Suk Ko, et al. Anticoagulation in atrial fibrillation - 본론심방세동환자에서경구용항응고치료류마티스열에의한판막질환에서동반된심방세동의경우정상대조군에비해뇌졸중의위험이 17배가량증가하는것으로알려져있으며, 뇌졸중예방을위하여항응고제투여는전향적인비교연구결과는없지만지금까지일반적인관행으로받아들여졌다. 비판막성심방세동의경우에는정상대조군에비하여 5-6 배가량의뇌졸중위험성이증가하며, 이러한환자에서항응고제투여효과에대한전향적인비교연구는 The Cophenhagen AFASAK [6], SPAF [7], BAATAF [8], SPINAF [9], CAFA [10] 에서증명되었다. 한편으로심방세동이있으면서일과성허혈발작또는뇌졸중이있었던환자군에서항응고제를이용한뇌졸중의이차예방효과또한증명되어 [11], 심방세동환자에서항응고제를투여하여뇌졸중을예방하는것은중요한치료지침이되었다. 항혈전제비교항응고제와위약비교비판막성심방세동환자에서색혈전증일차예방을위한 5개의연구 (AFASAK I, SPAF, BAATAF, CAFA, SPINAF) 와이차예방을위한 1개의연구 (EAFT) 를포함하여분석을하여보면, 모든뇌졸중의연간발생빈도가항응고제를사용한군에서위약을사용한군과비교하였을때 64% (95% CI, 49-74%) 감소하였다. 이러한감소효과는일차및이차예방 모두비슷하게나왔다. 또한항응고제를사용한군이총사망율을 26% 감소시키는효과가있었다 (Fig. 1) [2]. 이러한결과들은뇌졸중의위험을갖고있는환자들은특별한금기가없는한항응고제를사용해야하는임상적인배경이되었다. 항혈소판제와위약비교심방세동을갖는환자에서색혈전증예방을위하여아스피린을사용한연구 (AFASAK I, SPAF I, EAFT, ESPS II, LASAF, UK-TIA) 를분석하여보면, 모든뇌졸중의발생빈도가아스피린사용한군에서위약을사용한군과비교하여 19% (95% CI, 1-35%) 감소하였으며, 허혈성뇌졸중은 21% (95% CI, 1-38%) 감소하였다 (Fig. 2) [2]. 이연구들에서아스피린의하루용량은 50 mg에서 1,300 mg으로다양하였지만, 약리학적으로아스피린 75 mg이거의완전히혈소판억제를하며, 저용량의아스피린 (< 100 mg) 이고용량의아스피린 (> 300 mg) 보다출혈의위험성이적으므로, 만약아스피린을사용한다면저용량아스피린이권장된다. 항혈소판제 2제요법과단독요법의비교 ACTIVE-A 연구에서 1년간주요혈관질환사고율이아스피린과클로피도그렐병합사용군 6.8%, 아스피린단독사용군 7.8% 로아스피린과클로피도그렐병합사용군에서주요혈관질환사고율이 11% (RR 0.89; 95% CI, 0.81-0.98) 감소하였다 [12]. 이차이는주로뇌졸중의감소때문이었는데 1년간뇌졸중의발생률은아스피린과클로피도그렐병합사용군 2.4%, 아스피린단독군 3.3% 로병합사용군에서 28% Figure 1. Antithrombotic therapy for prevention of stroke (ischemic and hemorrhagic) in patients with non-valvular AF: adjusted-dose warfarin compared with placebo [2]. Figure 2. Antithrombotic therapy for prevention of stroke (ischemic and hemorrhagic) in patients with non-valvular AF: aspirin with placebo [2]. - 435 -
- 대한내과학회지 : 제 81 권제 4 호통권제 614 호 2011 - 감소하였다. 1년간중요한출혈은아스피린과클로피도그렐병합사용군 2.0%, 아스피린단독군 1.3% 로병합사용군에서 57% (RR 1.57; 95% CI, 1.29-1.92) 증가하였다. 그리고총출혈은아스피린과클로피도그렐병합사용군 9.7%, 아스피린단독군 5.7% 로 68% 증가하였다. 이러한결과는심방세동이있으면서항응고치료가필요하지만, 항응고제를사용할수없을때아스피린단독요법보다는아스피린과클로피도그렐을같이쓰면효과적이라는것을보여준다. 그러나클로피도그렐을같이사용시출혈이증가할수있으므로주의를요한다. 로, 항혈전치료가필요한경우에는특별한금기가없는한항응고제를사용하여야된다. 항혈소판제와항응고제병합치료항혈소판제와항응고제 (INR 2.0-3.0) 병합치료는허혈성뇌졸중예방및혈관사고예방에추가적인이익효과가없었으며, 출혈의위험성만증가하였다. 그래서심방세동환자에서항응고제를사용함에도불구하고허혈성뇌졸중의위험성이지속되는환자들은병합요법보다는항응고제 INR (3.0-3.5) 을올리는방안을고려해볼수있다. 항혈소판제와항응고제비교항응고제인와파린의장기적인투여는필연적으로출혈과관련된합병증을동반할수있으며이를피하기위하여정기적으로혈액검사를실시하여야한다. 이러한문제점의해결방안으로항응고제대신항혈소판제의사용을고려할수있다. 항응고제와아스피린의직접적인비교연구에서항응고제가중증뇌졸중 ( 뇌허혈성, 출혈성 ), 혈전증예방에 39-52% 더우수하였으며, 주된출혈에서는차이가없었다 (Fig. 3) [2]. ACTIVE-W 연구에서아스피린과클로피도그렐을동시에사용한군보다항응고제를단독으로사용한군에서뇌졸중위험도가 40% (95% CI, 18-56%) 감소하였고, 출혈합병증은차이가없었다 [13]. 이러한결과들은항혈소판제단독요법이든병합요법이든모두가항응고제보다는효과가약하므 Figure 3. Antithrombotic therapy for prevention of stroke (ischemic and hemorrhagic) in patients with non-valvular AF: warfarin compared with aspirin [2]. Table 1. Comparison of new oral antithrombotic agents Dabigatran Rivaroxaban Apixaban Mechanism of action Direct thrombin inhibitor Direct factor Xa inhibitor Direct factor Xa inhibitor Bioavailability 6-8% 80% 51-85% Administration route Oral Oral Oral Half-life 14-17 h 9-13 h 9-14 h Tmax 2 h 2-4 h 3 h Dosing frequency Twice daily Once daily Twice daily Renal excretion 80% 66% 25% Antidote No No No Monitoring No routine monitoring No routine monitoring No routine monitoring Recent studies RE-LY (III), RELY-ABLE (IIIb) ROCKET-AF (III) ARISTOLE (III), AVERROES (III) - 436 -
- 고점석외 1 인. 심방세동에서의항응고요법 - 새로운경구용항응고제현재널리사용되고있는항응고제인와파린은좁은치료범위, 긴반감기에의해효과가늦게나타나는점, 약물및음식물과의상호작용등에의해 INR을일정하게유지하기힘들며, 자주 INR 감시를해야하는단점이있다. 최근에부작용은최소화하면서, 효과는같거나더좋은작용을나타내며, 용량조절및감시가필요하지않는새로운항응고제들이개발되어임상연구가활발히진행되고있다 (Table 1). 이러한항응고제들은 Xa 차단제와트롬빈억제제로나누어이야기할수있다 (Fig. 4). Dabigatran Dabigatran 은경구용직접적인트롬빈억제제 (direct thrombin inhibitor) 로반감기는 14-17시간이고음식물과상호작용이없으며신장으로배설된다. 이러한약리효과는 INR 감시가필요없으며, 고정된용량을투여할수있는장점이있다. 심방세동환자에서와파린과의직접비교연구 [14] 에서 dabigatran 110 mg 하루 2번투여는와파린과비교하여뇌졸중의예방효과에서는비슷 (non-inferior) 하며, 출혈성부작용은적었다. 150 mg 하루 2번복용은뇌졸중예방효과에서는와파린보다우수하였으며 (RR 0.66; 95% CI, 0.53-0.82; p < 0.001 for superiority), 출혈의위험성은비슷하였다. 2011년미국심장학회에서는심방세동환자에서뇌졸중과전신성색전증의위험성을갖고있는경우에는이를예방하기위해와파린대신 dabigatran 를대체해서사용할수있음을제시하였다 [5]. 하지만, 판막질환자, 기계성판막치환자에서 dabigatran 효과에대한임상연구는아직없으므로이런환자에서의사용은주의를요한다. Rivaroxaban Rivaroxaban은하루에 1번복용하는 direct factor Xa inhibitor 로서반감기는 9-13시간이고, 음식물과상호작용이없는장점을갖고있다. 심방세동환자에서와파린과직접비교한연구 [15] 에서 rivaroxaban 20 mg은뇌졸중및전신색전증예방에있어서와파린과비슷 (non-inferior) 한결과를보였으며 (HR 0.79; 95% CI, 0.66-0.96; p < 0.001 for non-inferiority), 출혈의위험성은비슷하였다. Apixaban Apixaban은경구용 direct factor Xa inhibitor로서반감기는 9-14시간이고, 음식물과상호작용이없는약물로, 심부정맥혈전증의치료에사용된다. 심방세동의환자에있어서는아스피린과의직접비교한연구 [16] 에서와파린을사용할수없는환자들을대상으로 apixaban 5 mg 하루 2번사용한경우아스피린 81-324 mg을사용한경우보다뇌졸중을예방하는효과가뛰어나며, 출혈의위험성은비슷한결과를보였다. 와파린과의직접적인비교연구 [17] 에서는뇌졸중및전신성색전증예방에있어서더우수하였으며 (RR 0.79; 95% CI, 0.66-0.95; p < 0.001 for non-inferiority; p = 0.01 for superiority), 출혈 (RR 0.69; 95% CI, 0.60-0.80; p < 0.001) 및사망 (RR 0.89; 95% CI, 0.80-0.99; p = 0.047) 의위험성이더적었다. Table 2. Risk factors for ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation Figure 4. Illustration show the sites of action of new anticoagulation in the coagulation cascade. Risk factors Relative risk Previous stroke or TIA 2.5 Diabetes mellitus 1.7 History of hypertension 1.6 Heart failure 1.4 Advanced age (continuous, per decade) 1.4 Relative risk refers to comparison of patients with AF to patients without these risk factors. TIA, transient ischemic stroke. - 437 -
- The Korean Journal of Medicine: Vol. 81, No. 4, 2011 - 색혈전증위험인자의계층화및치료전략심방세동환자에서뇌졸중의위험인자는나이, 성별, 고혈압, 허혈성또는류마티스심장질환, 기계판막, 심부전, 뇌졸중또는일과성허혈성발작의병력, 색혈전증병력, 심장내혈전의증거, 당뇨병등이다 (Table 2). 2010년유럽치료지침에의하면고위험군 ( Major risk factors) 은뇌졸중이나일과성허혈성발작의병력, 색혈전증, 75세이상의고령, 승모판막협착증, 기계심장판막이며, 중등도위험군 ( clinically relevant non-major risk factors) 은심부전 ( 좌심실구혈률 40% 이하 ), 고혈압, 당뇨병, 여성, 65-74세고령, 혈관질환 ( 심근경색증, 복합성대동맥플라크, 사지혈관질환 ) 이다. 이러한중등도위험인자들이 2개이상존재할경우에는고위험군으로판단한다 (Table 3). 심방세동환자에서항혈전치료는뇌졸중및색혈전증에대한위험인자의유무에따라결정된다. CHADS 2 (congestive heart failure, hypertension, age > 75 years, diabetes mellitus, previous TIA or stroke) 점수를이용한방법은간단하게적용할수있는장점이있으므로, 환자의첫치료적접근방법으로사용할수있고, 이는부정맥을전공하지않은일차진료기관에서도쉽게사용할수있다. 최근에는이를세분화한 CHA 2DS 2-VASc 점수를이용한치료적접근방법도사용되어진다 (Table 4). CHADS 2 점수및 CHA 2DS 2-VASc 점수가높을수록뇌졸중의위험도는증가한다 (Fig. 5). 항혈전치료는미국, 캐나다및유럽모두 CHADS 2 점수 2 이상인경우에는금기증이없는한항응고제 (INR 2.0-3.0) 사용을권장하고있다 (Table 5). CHADS 2 점수 0-1인경우에는좀더상세히위험도를평가하여적절한치료방법을선 Table 3. Risk factors for stroke and thrombo-embolism: 2010 ESC guidelines Major risk factors (previously referred to as high risk factors) 1. Non-valvular AF - previous stroke, TIA, or systemic embolism - age 75 years 2. Valvular AF - mitral stenosis - prosthetic heart valve Clinically relevant non-major risk factors (previously referred to as moderate risk factors) - heart failure or moderate to severe LV systolic dysfunction (e.g., 40%) - hypertension - diabetes mellitus - female sex - age 65-74 years - vascular disease Vascular disease; prior myocardial infarction, peripheral artery disease, aortic plaque. Actual rates of stroke in contemporary cohorts may vary from these estimates. Table 4. CHADS 2 score and CHA 2DS 2-VASc score: 2010 ESC guidelines CHADS 2 score CHA 2DS 2-VASc score Risk factor Score Risk factor Score Congestive heart failure 1 Congestive heart failure/lv dysfunction 1 Hypertension 1 Hypertension 1 Age > 75 years 1 Age 75 years 2 Diabetes mellitus 1 Diabetes mellitus 1 Stroke/TIA 2 Stroke/TIA/thrombo-embolism 2 Vascular disease 1 Age 65-74 years 1 Sex category (1.e., female) 1 Maximum score 6 Maximum score 9 TIA, transient ischemic stroke. - 438 -
- Jum Suk Ko, et al. Anticoagulation in atrial fibrillation - Table 5. Approach to thromboprophylaxis in patients with AF: 2010 ESC guidelines Risk category CHA 2DS 2-VASc score Recommend antithrombotic therapy One major risk factor or 2 clinically relevant non-major risk factors 2 OAC One clinically relevant non-major risk factors 1 Either OAC or aspirin 75-325 mg daily. Preferred: OAC rather than aspirin No risk factors 0 Either aspirin 75-325 mg daily or no antithrombotic therapy. Preferred: no antithrombotic therapy rather than aspirin OAC, oral anticoagulants. years, drugs or alcohol concomitantly) 점수로출혈의위험성을점수화하여 3점이상인경우에는고위험군으로분류하여항응고제를사용시규칙적인관찰과면밀한주의를권하였다 (Table 6, Fig. 6) [18]. 적절한 INR 유지 Figure 5. Adjusted stoke rate according to CHADS2 score and CHA2DS2-VASc score [3]. 택해야한다. CHA2DS2-VASc 점수를이용하면 CHADS2 점수가 2점미만인환자들을좀더상세히구별해낼수있겠지만, 아직까지 CHA2DS2-VASc 점수를이용한치료가 CHADS2 점수를이용한치료보다우월하다는증거는없다. 출혈의위험성 항응고제사용시심각한출혈이 0.1-6.0% 정도로발생하므로, 약물을사용하기전출혈의위험성에대한평가가필요하다. 와파린사용시출혈의위험성은 INR 값과밀접한관련이있는데, 3.0 이상인경우에출혈의위험성이현저하게증가한다. 뇌출혈예측인자로는고령, 뇌졸중병력, 고혈압등이다. 이중고령과뇌졸중병력은변형시킬수없는인자이므로, 혈압의조절과 INR의적극적감시가뇌출혈을최소화할수있다. 특히제산제, 항부정맥제, 항우울제, 아스피린, NSAID, 스타틴과같은새로운약을추가시에는약물상호작용에대한주의가필요하다. 유럽심장학회에서는 HAS-BLED (hypertension, abnormal renal and liver function, stroke, bleeding history, elderly > 65 AFFIRM [19] 과 RACE [20] 연구에서뇌졸중이발생하였던환자군을분석하여보면항응고제사용이중단되었거나항응고수치가낮았던경우가대부분이었다. RACE 연구에서색혈전증을경험하였던환자 35명중 23명 (66%) 은 INR < 2.0 이었다. AFFIRM 연구에서도허혈성뇌졸중이발생하였던 175명중 113명 (72%) 은항응고제사용이중단되었거나 INR < 2.0이었으며, 율동조절 (rhythm control) 군에서색혈전증이발생한환자의 75% 는정상동율동으로유지되고있는중에발생하였다. 이러한결과는심실반응수를조절하든지또는동율동으로전환하여유지하든지경구용항응고제를사용하여 INR 2.0-3.0 사이로조절하는것이필요함을보여준다. 비판막성심방세동환자에서와파린을사용할때일반적으로 INR을 2-3으로유지하면출혈의위험성을높이지않으면서뇌졸중및전신적인혈전증을예방할수있다. 하지만, 와파린에대한반응은개인차가심하고, 약물및음식물과의상호작용이심하기때문에적절한수준의 INR을유지하는것이매우힘들다. 발표된임상연구들을보더라도 60-65% 정도에서만 INR이 2.0-3.0 정도로유지되므로, 실제임상에서는 50% 미만일것으로추정된다. 출혈의위험성때문에고령에서 INR을 1.8-2.5 정도로낮게유지하는것이제시되기도하는데, 이는임상증거가없으며, 코호트연구에서 INR 1.5-2.0은뇌졸중이 2배정도증가하므로, INR을 2 이하로유지하는것은권장되지않는다. - 439 -
- 대한내과학회지 : 제 81 권제 4 호통권제 614 호 2011 - Table 6. Clinical characteristics comprising the HAS-BLED bleeding risk score: 2010 ESC guidelines Letter Clinical characteristics Points awarded H Hypertension 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INRs 1 E Elderly (e.g., > 65 years) 1 D Drugs or alcohol (1 point each) 1 or 2 Maximum 9 points 기계판막으로치환받은환자나색혈전증에대한고위험군환자는와파린을끓는동안에헤파린 (LMWH 또는 UFH) 를사용하는 bridging 치료를고려해봐야한다. Figure 6. Adjusted major bleeding risk rate according to HAS-BLED score [18]. 특수상항에서항혈전치료 발작성심방세동에서항혈전치료발작성심방세동에서뇌졸중및색혈전증에대한위험및예방에대한것은정립이덜되어있기는하지만뇌졸중에대한위험도는지속성및영구형심방세동과큰차이가없다. 그래서발작성심방세동에서항혈전치료는지속성및영구형심방세동과동일하게뇌졸중의위험도에따른치료를원칙으로한다. 수술전후항응고치료항응고제를복용하고있는환자중수술또는침습적인시술전에약물을일시적으로중지해야할경우가있다. 많은수술의사들은수술전에 INR이 1.5 이하또는정상수치로유지하기를원한다. 와파린은반감기가 36-42시간이므로 INR이적절한정도까지떨어지려면수술 5일전부터중지해야한다. 적절한지혈이되었다면수술후그날저녁또는다음날아침부터는평상시사용하던용량의와파린을투여하기시작한다. 만성혈관질환이동반된환자에서항혈전치료항응고제를복용하고있는많은심방세동환자들이관상동맥, 경동맥또는사지동맥의혈관질환들을동반하고있다. 이러한환자들중상당수가항응고제에항혈소판제 ( 일반적으로아스피린 ) 를복합하여사용하고있다. 하지만이러한복합치료가뇌졸중및혈관사고 ( 심근경색증포함 ) 에대한위험성을감소시키지못하며, 오히려출혈을유의하게증가시킨다. 급성관상동맥증후군또는관동맥중재술후항혈전치료스텐트를시술받은관동맥질환환자에서아스피린과클로피도그렐을이용한이제요법은스텐트혈전증을예방하기위한항혈소판치료의표준이다. Bare-metal 스텐트경우에는시술후 4주, 약물용출성스텐트경우에는시술후 6-12개월, 급성관동맥증후군은스텐트종류에관계없이 9-12개월동안이제요법을일반적으로사용하고있다. 스텐트를시술받는환자의 5-7% 는중등도이상의혈전색전증위험이동반된심방세동환자들인데이들에게는스텐트혈전증예방을위한항혈소판제뿐만아니라뇌졸중예방을위한항응고제치료가필요하다. 심방세동이동반된관동맥질환환자들은일반환자들에비해주요심장사고발생률이높다. 삼제요법 ( 와파린, 아스피린, 클로피도그렐 ) 을한경우에 30일출혈유병률은 2.6-4.6% 로크게증가하지않으나, 12개월출혈유병률은 7.4-10.3% 로증가하게된다. 그래 - 440 -
- 고점석외 1 인. 심방세동에서의항응고요법 - 서삼제요법을하는경우에는위험성과이익을따져서그기간과방법을결정해야한다. 혈전색전증의위험이낮다면 (CHADS 2 score < 2) 짧은기간 ( 예, 1개월 ) 동안에이제항혈소판요법이항응고제를대치할수도있다. 하지만혈전색전증의위험도가중등도이상 (CHADS 2 score 2) 이라면항혈소판제에항응고제를추가하는것이좋다. 삼제요법은스텐트혈전증과전신혈전색전증을예방할수있는가장좋은방법이다. 따라서스텐트시술후스텐트내내막이다시생성되는초기에는삼제요법을쓰는것이좋다. 다만, 삼제요법은장기간사용시출혈의위험성이증가하므로스텐트삽입시개개인마다출혈의위험성을평가하여스텐트종류및약물사용시기등을결정하여야한다. 삼제요법을사용할경우출혈의위험성을줄이기위해 INR은되도록낮게유지한다 (INR 2.0-2.5). 출혈의위험성이높으면 bare-metal 스텐트를시술하여야하고, 이후삼제요법을 2주정도로줄여쓸수도있다. 또한스텐트시술없이풍선도자를이용한혈관성혈술만실시한후아스피린과항응고제만쓸수도있다. 삼제요법후에는항응고제에 항혈소판제 1개를이용한이제요법이사용되는데, 아스피린과클로피도그렐중어느것이더나은지에대한자료는없다 (Table 7). 심방세동동율동전환시항혈전치료심방세동이발생한지 48시간이내이면항응고제사용없이동율동전환을즉시시행할수있다. 그러나심방세동발생시점이병력상명확하지않거나 48시간이상지속되었을경우에는동율전전환전최소한 3주이상의항응고제를사용 (INR 2-3) 하여야하며, 전기적또는약물적동율동으로의전환후최소한 4주간항응고제를사용하여야한다. 동율동전환하기위하여 3주간항응고치료를하는대신경식도초음파를시행하여혈전의증거가없으면율동전환전에헤파린 (UFH 또는 LMWH) 을투여한후동율동전환을시도하고, 경구용항응고제는동율동전환후 4주간사용한다. 경식도심초음파에의해혈전이발견된경우에는경구용항응고제로최소한 3주간치료 (INR 2-3) 를실시한후혈전을확인후동율동전환을시도한다. Table 7. Antithrombotic strategies following coronary artery stenting in patients with AF at moderate to high thrombo-embolic risk: 2010 ESC guidelines Hemorrhagic risk Clinical setting Stent implanted Anticoagulation regimen Low or intermediate (HAS-BLED score 0-2) High (HAS-BLED score 3) Elective Bare-metal 1 month: triple therapy of VKA (INR 2.0-2.5) + aspirin 100 mg/day + clopidogrel 75 mg/day Lifelong: VKA (INR 2.0-3.0) alone Elective Drug-eluting 3 (-olimus group) to 6 (paclitaxel) months: triple therapy of VKA (INR 2.0-2.5) + aspirin 100 mg/day + clopidogrel 75 mg/day Up to 12th month: combination of VKA (INR 2.0-2.5) + clopidogrel 75 mg/day (or aspirin 100 mg/day) Lifelong: VKA (INR 2.0-3.0) alone ACS Bare-metal/drug-eluting 6 months: triple therapy of VKA (INR 2.0-2.5) + aspirin 100 mg/day + clopidogrel 75 mg/day Up to 12th month: combination of VKA (INR 2.0-2.5) + clopidogrel 75 mg/day (or aspirin 100 mg/day) Lifelong: VKA (INR 2.0-3.0) alone Elective Bare-metal 2-4 week: triple therapy of VKA (INR 2.0-2.5) + aspirin 100 mg/day + clopidogrel 75 mg/day Lifelong: VKA (INR 2.0-3.0) alone ACS Bare-metal 4 week: triple therapy of VAK (INR 2.0-2.5) + aspirin 100 mg/day + clopidogrel 75 mg/day Up to 12th month: combination of VKA (INR 2.0-2.5) + clopidogrel 75 mg/day (or aspirin 100 mg/day) Lifelong: VKA (INR 2.0-3.0) alone - 441 -
- The Korean Journal of Medicine: Vol. 81, No. 4, 2011 - 뇌졸중예방을위한비약물적방법 좌심방 appendage가심방혈전증의주된장소이다. 그래서좌심방 appendage의입구를막으면심방의혈전증이감소하고, 이는뇌졸중의발생을감소시킬수있을것으로예측된다. 특히, 항응고제의장기간사용이힘든환자에서좋은적응증이되리라생각된다. PROTECT AF연구 [21] 에서 WAT- CHMAN 기구를이용하여좌심방 appendage의입구를막은환자와와파린을사용한환자에서뇌졸중, 심혈관계사망, 전신적인색전증을비교하였는데, 두군간에비슷한결과를얻었다. 하지만, 시술과관련된안전성등아직해결해야할부분들이남아있다. 결 현재경구용항응고치료는색혈전증의고위험군인심방세동환자에서뇌졸중을예방하는가장효과적인방법이다. 최근에는와파린과비교하여효과는비슷하면서 INR검사가필요없으며, 약물간상호작용이없는새로운항응고제들이개발되어임상연구가한창이다. 특히 dabigatran 을포함한몇몇약물들은와파린을대체할수있을것으로기대된다. 아스피린단독요법및아스피린과클로피도그렐복합요법은모두와파린보다뇌졸중예방효과가떨어지므로경도및중등도의위험군에제한적으로사용할수있다. 현재많은의사들이와파린의사용상제한점때문에이의적절한사용을간과하는경우가많은데항상주의를기울어야하겠다. 론 중심단어 : 심방세동 ; 색혈전증 ; 와파린 REFERENCES 1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-988. 2. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131:492-501. 3. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010;12:1360-1420. Erratum in: Europace 2011;32:1172. 4. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 123:104-123. 5. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/ HRS focused update on the management of patients with atrial fibrillation (updateon dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 2011; 57:1330-1337. 6. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK Study. Lancet 1989;1: 175-179. 7. Stroke Prevention in Atrial Fibrillation Study: final results. Circulation 1991;84:527-539. 8. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation: the Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med 1990;323:1505-1511. 9. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation: Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 1992;327: 1406-1412. 10. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991;18:349-355. 11. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke: EAFT (European Atrial Fibrillation Trial) Study Group. Lancet 1993;342: 1255-1262. 12. Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066-2078. 13. Connolly S, Pogue J, Hart R, et al.clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for prevention of vascular events (ACTIVE W): a randomised controlled trial. Lancet 2006;367: 1903-1912. 14. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-1151. 15. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883-891. 16. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients - 442 -
- Jum Suk Ko, et al. Anticoagulation in atrial fibrillation - with atrial fibrillation. N Engl J Med 2011;364:806-817. 17. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992. 18. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138:1093-1100. 19. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825-1833. 20. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm controlin patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834-1840. 21. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised noninferiority trial. Lancet 2009;374:534-542. - 443 -