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1 한국임상약학회지제 26 권제 1 호 Korean J Clin Pharm, Vol. 26, No. 1, 2016 Clinical Information Korean Journal of Clinical Pharmacy Official Journal of Korean College of Clinical Pharmacy Available online at pissn: 심방세동치료를위한미국과유럽의심박수및율동조절약물요법가이드라인비교연구 정은주 손기호 백인환 * 경성대학교약학대학 (2016년 2월 24일접수 2016년 3월 13일수정 2016년 3월 15일승인 ) A Comparative Study of USA and Europe Guidelines of Rate and Rhythm Control Pharmacotherapy in Atrial Fibrillation Eun Joo Jung, KieHo Sohn, and In-Hwan Baek* College of Pharmacy, Kyungsung University, Busan 48434, Republic of Korea (Received February Revised March 13, 2016 Accepted March 15, 2016) ABSTRACT Objective: Atrial fibrillation (AF) guidelines have been published in the USA and Europe. Recently, the USA and Europe have updated their guidelines, respectively. These new AF guidelines help in addressing key management issues in clinical situations. This study, therefore, systematically compared guidelines for rate and rhythm control pharmacotherapy of patients with AF between the USA (American College of Cardiology and American Heart Association, ACC/AHA) and Europe (European Society of Cardiology, ESC). Methods: This study investigated and compared American guidelines (2014) and European guidelines (2010 and 2012). Results: Generally, there are four meaningful differences between ACC/AHA and ESC guidelines. Important differences are treatment classification system, level of recommendation, drug list, and dosage. In addition, ACC/AHA described pharmacokinetic drug interactions for antiarrhythmic drugs. ESC emphasized ECG and atrioventricular nodal slowing as feature of antiarrhythmic drugs. Conclusion: This research addresses important use of anti-arrhythmic drugs and movement to accept recent recommendations in Korea. For the successful application of the guidelines, a role of pharmacists is crucial in clinical situation. KEY WORDS: Atrial fibrillation, pharmacotherapy, ACC/AHA, ESC, guideline 부정맥 (arrhythmia) 이란심박동수가비정상적으로증감하거나불규칙하게되는것을뜻하며, 충동생성부위의변동, 전도장애및이에대한심근의반응장애로인해생성된다. 1) 여러종류의부정맥중에서심방세동 (atrial fibrillation) 은가장일반적이고복잡한형태이며심혈관계유병률및사망률과매우연관이높다. 이러한심방세동은전세계적으로각나라마다 2% 정도의인구에서나타나는데, 인구의고령화가더진행되면서이수치는급격히증가하고있다. 2) 심방세동은미국에서부정맥으로인한주요한입원원인이며, 유럽에서도부정맥으로인한입원율의 1/3을차지한다 3) 최근우리나라와같은고령화사회에서심방세동으로인한유병률과사망률증가는중요한보건사회학적문제로대두되고있다. 특히심방세동은뇌졸중 (stroke) 과심부전 (heart failure) 을비롯한전신색전증 (systemic embolization) 을일으키는중요한원인이되는복합적이며사회적부담이큰질환이다. 4-6) 심방세동은임상적으로발작성 (paroxysmal), 지속성 (persistent), 장기지속성 (longstanding persistent) 및영구형 (permanent) 심방세동으로구분된다. 7) 심방세동의치료는크게 4가지로나눌수있다. 심박수조절 (rate control), 동율동으로의전환 (sinus rhythm control), 항혈전치료 (anti-coagulant therapy), 그리고비약물적치료이다. 8,9) 심박수조절에는칼슘차단제 (calcium channel blocker), 베타차단제 (beta-blocker), 디기탈리스 (digitalis) 등효과적인약제를사용한다. 10) 동율동전환을위해서는항부정맥제와직류심율동전환 (direct-current cardioversion, DCC) 등을이용한다. 11) 항혈전치료는뇌졸증예방을위해항응고약물을사용 *Correspondence to: In-Hwan Baek, College of Pharmacy, Kyungsung University, 309, Suyeong-ro, Nam-gu, Busan 48434, Republic of Korea Tel: , Fax: baek@ks.ac.kr 84

2 심방세동치료를위한미국과유럽의심박수및율동조절약물요법가이드라인비교연구 / 85 하는것을말한다. 12) 마지막으로비약물적인치료로는박동기를이용한치료, 도관절제술등수술적인치료를의미한다. 13) 심방세동의치료에있어서 1차적으로는환자상태에따라심박수조절치료를할지율동조절을할것인지를적절히선택하여야한다. 14) 이중, 정상동율동으로의전환시키는방법에는약제를이용하는방법 (pharmacological cardioversion) 과전기충격 (direct-current cardioversion, DCC) 이있으며, 약제를이용하는방법에서는항부정맥제 (anti-arrhythmic drugs) 를표준약물요법으로권장하고있다. 15) 하지만최근심실성부정맥의특정환자에게일부항부정맥제의사용이오히려사망률은더증가시킨다는것이많은임상연구나임상현장에서보고되고있다. 16) 또한 Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) 이나 Cardiac Arrhythmia Suppression Trial (CAST) 등임상시험을통하여항부정맥제가심방세동으로인한심부전, 전신색전증, 그리고사망률등을크게호전시키지못한다는주장이제기되었으며, 최근에는전극도자절제술이부정맥치료에광범위하게사용되면서항부정맥제는임상에서의적용이많이위축되었다. 17) 동율동유지를위해널리사용하는기존의항부정맥제들은그효능이제한적이거나부작용으로인해장기적사용이어렵고, 약물로인한조직독성및또다른부정맥유발 (proarrhythmia) 가능성등의이유로사용에여러제약이따르는것이사실이다. 18) 그럼에도불구하고간편하고환자에게육체적이나심리적으로부담감이덜하다는장점이나재발방지목적등의여러이유로미국심장학회 / 협회 (ACC/ AHA) 나유럽심장학회 (ESC) 등에서는부정맥의초기치료로서혹은심박동기 / 제세동기삽입후보조적또는병행치료수단으로서항부정맥제의역할은여전히고려되어야한다고권고하고있다. 19) 또한, 여태까지심실빈맥이나심실세동만큼위험하지않고약물을이용하여어느정도조절이가능했기때문에심방세동에대한치료법의연구에소홀했던것이사실이다. 하지만심방세동에서선택해야할치료방법이나약물의사용이실제임상에서는더어려운경우가많다. 20,21) 대표적인부작용인항부정맥제사용으로인한또다른부정맥유발에대한위험성이나조직에대한독성등을감안하여최근에는단순히심방세동의증상치료가아니라임상적으로효과를보는것에초점을맞추고있는추세이다. 22) 이뿐만아니라, 최근이러한항부정맥제의부작용을최소화하거나더나은새로운특성을지닌신약개발이지속적으로행해지고있다. 23) 그대표적인예가 2009년개발되어유럽, 북미, 그리고국내에서사용이승인된 dronedarone이다. 24) Drondedarone은발작성또는지속성심방세동환자의심혈관성질환으로인한입원또는사망률을획기적으로감소시키는최초이자유일한항부정맥제라고주목을받고있다. 25) 그렇지 만이약제역시도다른항부정맥제가가지는위험을완전히일으키지않는다는확신은할수없으며약효나안정성을모두고려하여다른항부정맥과함께임상상황에서적절한때에사용되어야한다. 26) 이렇듯유병률과사망률이높고복잡한심방세동에서항부정맥제를포함하여심박수및율동조절을위한약물요법에대한보다나은이해와실제임상에서적절한사용을목표로미국과유럽을비롯한선진국에서개정된가이드라인을발표하였다. 27) 현재국내약 30만명의심방세동환자에더하여매년 1만명정도의증가추세를고려하면관련가이드라인작업에대한움직임이절실히필요하다. 이러한상황에서올바른치료방법의선택과그에따른적절한약물요법의신중한사용으로임상에서의효과적인적용을기대하기위해서약에대한전문가인임상약사의역할이더욱더중요하게여겨지고있다. 28,29) 따라서본연구에서는미국과유럽에서각각개정되어온심방세동가이드라인에대한흐름을조사하고나아가두나라간의최신표준약물지침가이드라인을비교하고자한다. 이를바탕으로심방세동에서심박수및율동조절을위한약물요법의중요성과임상에서부정맥치료약물사용에대한변화를파악하고자한다 ) 연구방법 심방세동에관한미국과유럽각각의가이드라인이개정되어온변화를알아보기위하여다음각기관의사이트를활용하였다. 미국심장학회 (the American College of Cardiology, ACC) / 미국심장협회 (the American Heart Association, AHA) Joint Guidelines ( UCM_321694_Article.jsp) 유럽심장학회 (European Society of Cardiology, ESC) Clinical Practice Guidelines ( lines-&-education/clinical-practice-guidelines/esc- Clinical-Practice-Guidelines-list/listing) 심혈관질환의하나인부정맥중에서도심방세동치료에초점을맞추어서위기관들으로부터발행된치료가이드라인에대하여조사하였다. 이러한가이드라인에대하여본연구에서는미국과유럽두나라에서새로이개정된최신약물요법가이드라인을비교연구수행하였다. 미국 ACC/AHA의경우는 2014년가이드라인을연구하였고, 유럽 ESC는 2010년가이드라인을기본토대로 2012년가이드라인에서부분적인업데이트사항들이추가되었으므로 2010년가이드라인과 2012년가이드라인모두연

3 86 / Korean J Clin Pharm, Vol. 26, No. 1, 2016 구하였다. 그리고이후, 2014년미국가이드라인과비교분석하였다 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation Guidelines for the Management of Atrial Fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) 2012 Focused Update of the ESC Guidelines for the Management of Atrial Fibrillation 연구결과 미국과유럽의심방세동치료에서약물요법가이드라인현황미국심장학회 (ACC), 미국심장협회 (AHA), 미국심장학회재단 (ACCF), 그리고미국심장박동학회 (HRS) 에서심방세동에대해 2003년에첫가이드라인을발행한이후로꾸준하게개정해오고있다. 2003년에유럽심장학회 (ESC) 와공동으로심방세동을상심실성부정맥으로명칭하여 Supraventricular Arrhythmias (ACC/AHA/ESC Guidelines for the Management of Patients with) 을처음발행하였다. 바로다음개정가이드라인도두나라에서공동작업하여 2006년에 ACC/ AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation 을발행하였다. 2008년에는미국의사협회와공동으로심방세동과심방조동을가진성인환자에있 어서의임상진료지침 ACC/AHA/Physician Consortium 2008 Clinical Performance Measures for Adults with Nonvalvular Atrial Fibrillation or Atrial Flutter 을독립적으로발표하였다. 이는거의대부분의임상상황을고려하여보다나은환자치료와진료및치료방법개선할목적을가진다. 33) 5년후인 2011년에신규항응고제인 dabigatran 추가한 2011 ACCF/ AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation (update on dabigatran) 와가이드라인의요약인 Pocket Guideline: Guidelines for the Management of Patients with Atrial Fibrillation: 2011 Update 을개정하여발표하였다. 같은년도에 2006년가이드라인을통합한 2011 ACCF/AHA/HRS Focused Updates Incorporated into the ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation 을업데이트하였다. 2006년과 2011년가이드라인을편집하고보완한 Management of Patients with Atrial Fibrillation (Compilation of 2006 ACCF/ AHA/ESC and 2011 ACCF/AHA HRS Recommendations) 가 2013년에나왔다. 그리고현재미국의심방세동치료를위한최신약물요법가이드라인은바로다음해인 2014년에발행된 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation 이다 (Table 1). 이에반해유럽의가이드라인발행과개정은단세차례밖에이루어지지않았다. 유럽심장학회 (ESC) 의경우에는미국심장학회 / 협회 (ACC/AHA) 와함께 Supraventricular Arrhythmias (ACC/AHA/ESC Guidelines for the Management of Table 1. Publication history of pharmacotherapy guidelines for atrial fibrillation of ACC/AHA (USA). ACC/AHA Guidelines Publication Year Supraventricular Arrhythmias (ACC/AHA/ESC Guidelines for the Management of Patients with) 2003 ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation 2006 ACC/AHA/Physician Consortium 2008 Clinical Performance Measures for Adults With Nonvalvular Atrial Fibrillation or Atrial Flutter ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Update on Dabigatran) ACCF/AHA/HRS Focused Updates Incorporated Into the ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation 2011 Pocket Guideline: Guidelines for the Management of Patients with Atrial Fibrillation: 2011 Update (PDF) 2011 Management of Patients With Atrial Fibrillation (Compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS Recommendations) AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation 2014 Table 2. Publication history of pharmacotherapy guidelines for atrial fibrillation of ESC (Europe). ESC Guidelines Publication Year Supraventricular Arrhythmias (ACC/AHA/ESC Guidelines for the Management of Patients with) 2003 Guidelines for the Management of Atrial Fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) Focused Update of the ESC Guidelines for the Management of Atrial Fibrillation 2012

4 심방세동치료를위한미국과유럽의심박수및율동조절약물요법가이드라인비교연구 / 87 Patients with) 로명명하여첫가이드라인을 2003년에발행하였다. 이후 2010년에 ESC 단독으로 Guidelines for the Management of Atrial Fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) 을발표하였다. 그리고현재사용되고있는최신약물요법가이드라인은 2012년에업데이트된 2012 Focused Update of the ESC Guidelines for the Management of Atrial Fibrillation 이다 (Table 2). 미국과유럽의심방세동치료에서항부정맥약물요법가이드라인비교 : 심박수조절미국 ACC/AHA 가이드라인과유럽 ESC 가이드라인은심박수조절치료방법에대한분류체계에서차이를나타내고있다. 유럽 ESC 가이드라인은이러한치료시기에따른세부분류를적용하여보다자세한권고안을보여주고있는반면, 34) 미국 ACC/AHA 가이드라인은이러한분류체계를적용하고있지않고하나의권고표로심박수조절치료가이드라인을제시하고있다. 미국과유럽가이드라인은심박수조절을위하여베타차단제 (beta-blocker), 비디하이드로피리딘계열칼슘채널차단제 (nondihydropyridine calcium channel blocker, non-ccb), 그리고디기탈리스글리코사이드 (digitalis glycoside) 를우선 적으로권고하고있다. 또한항부정맥제로 amiodarone과 dronedarone이심박수조절에권고된다. 혈액학적으로불안정한환자나, 운동중일때의심박수조절약제의사용이나적절한약물치료의실패시방실결절절제술을실시하는사항, 그리고좌심실수축기능이보존되어있고별다른증상이없는환자에게서 110 bmp 이하로심박수를조절하는사항은미국과유럽의가이드라인모두권고등급이나권고내용에서동일하였다. 하지만두나라의가이드라인에서권고내용은권고등급에서몇가지차이가있다. ACC/AHA에서는심박수조절의대표약물인베타차단제와 non-dihydropyridine CCB의사용을 class IB로권고하고있으나, ESC에서는 class IA로권고하고있다. 그리고증상이없는심방세동환자의목표심박수에관해서는 ACC/AHA는 class IIbB로권고하고있으며 ESC는 class IIaB로권고하고있다. 또한 ACC/AHA는증상이있는심방세동환자의휴식시목표심박수를 < 80 bpm 미만으로유지하기를권고하는반면, ESC는휴식시목표심박수뿐만아니라적정량의운동시의목표심박수를 < 110 bpm 미만으로추가권고하고있다. 더욱이 ESC는목표심박수에도달후 24시간 Holter monitor 사용도권고하고있다 (Table 3). 또한미국과유럽의가이드라인에서각약물군에나열한세부약물들의종류에는차이가있다. 베타차단제중하나인 Table 3. Comparison between ACC/AHA and ESC in recommendations for rate control. Classification ACC/AHA ESC Drug lists for paroxysmal, persistent, or permanent AF (without pre-excitation) During activity (exertion) Beta blocker (IV) or nondhp-ccb [IB] Use adequate pharmacological agents and therapy [IC] Acute: beta-blocker (IV)s or nondhp-ccb [IA] Long-term: Beta-blocker, nondhp CCB, digitalis, or a combination thereof [IA] Use adequate pharmacological agents and therapy [IC] Drug lists in pre-excitation (Acute) class I antiarrhythmic durgs or amiodarone (Long-term) propafenone or amiodarone Resting HR control for symptomatic pts Resting HR < 80 bpm [IIaB] Resting HR< 80 bpm and HR during moderate exercise < 110 bpm After achieving the strict HR target, a 24 h Holter monitor is recommended [IIaB] IV Amiodarone IV amiodarone for ill pts without pre-excitation [IIaB] Lenient rate-control strategy for asymptomatic pts Resting HR < 110 bpm [IIbB] Resting HR < 110 bpm [IIaB] Oral amiodarone Use when other measures are unsuccessful or contraindicated [IIbC] Use when other measures are unsuccessful or contraindicated [IIbC] Contraindication (without pre-excitation) NonDHP-CCB (in decompensated HF) [IIIC] Beta-blockers, nondhp-ccb, digoxin, and Digoxin, nondhp-ccb, or amiodarone [IIIB] adenosine [IIIC] Contraindication of dronedarone Pts with permanent AF [IIIB] Pts with permanent AF [IIIB] Contraindication of digitalis pts with paroxysmal AF [IIIB] nondhp-ccb = nondihydropyridine calcium cannerl blockers; IV = intra venous; N/A = not applicable; HR = heart rate; pt = patient; HF = heart failure; AF = atrial fibrillation.

5 88 / Korean J Clin Pharm, Vol. 26, No. 1, 2016 Table 4. Comparison drug lists for rate control of AF between ACC/AHA and ESC. Drugs Beta blockers Metoprolol Intravenous administration Usual oral maintenance dose ACC/AHA ESC ACC/AHA ESC mg IV bolus over 2min; up to 3 doses N/A mg BID N/A Metoprolo XL N/A mg IV bolus over 2min; Up to 3 doses (CR) mg QD mg QD (ER) Atenolol N/A N/A mg QD mg QD Esmolol 500 mcg/kg IV bolus over 1min, then mcg/kg/min IV mcg/kg/min IV N/A N/A Propranolol 1 mg IV over 1 min, up to 3 doses at 2-min intervals 0.15 mg/kg iv over 1min mg TID or QID mg TID Nadolol N/A N/A mg QD N/A Carvedilol N/A N/A mg BID mg BID Bisoprolol N/A N/A mg QD mg QD Nondihydropyridine calcium channel antagonists Verapamil mg/kg IV bolus over 2min; additional 10.0 mg after 30 min if no response, then mg/kg/min infusioin 0.25 mg/kg IV bolus over 2min, diltiazem then 5-15 mg/h Digitalis glycosides mg/kg IV over 2min mg QD (ER) 40 mg BID to 360 mg (ER) QD N/A mg QD (ER) 60 mg TID to 360 mg (ER) QD Digoxin 0.25 mg IV with to a maximum of 1.5 mg over 24 h mg mg QD mg-0.5 mg QD Digitoxin N/A mg N/A 0.05 mg-0.1 mg QD Others Amiodarone 300 mg IV over 1h, then mg/h over 24 h 5 mg/kg in 1h, then 50 mg/h mg QD 100 mg-200 mg QD Dronedarone N/A N/A N/A 400 mg BID N/A = not applicable; QD = once daily; BID = twice daily; TID = 3 times a day; QID = 4 times a day; XL/ER = extended release; CR = controlled release; IV = intra venous. nadolol은 ACC/AHA에서만언급하고있으며, 디기탈리스글리코사이드에속하는 digitoxin은 ESC에서만언급하고있는약물이다. 미국과유럽의가이드라인은심박수조절에이용되는약물들의용량을정맥주사시용량 (intravenous administration) 과경구투여시유지용량 (usual oral maintenance dose) 으로나누어권고하고있다. 그중베타차단제인 metoprolol, propranolol, carvedilol, 그리고 bisoprolol의권고용량에서두가이드라인은차이를보이고있다. 먼저 ACC/AHA에서는 metoprolol을 metoprolol tartrate와 metoprolol XL로나누어설명하고있으나, metoprolol XL의정맥주사시용량에대하여언급하고있지않다 (not applicable, N/A). 반면 ESC에서는 metoprolol CR과 XL 모두 ACC/AHA에서 metoprolol tartrate 와같은용량인 mg 을정맥으로 2분간투여하는것을권고하고있다. Metoprolol의경구유지용량의경우 ACC/ AHA는하루한번 (QD) mg을투여하는것을권고하는데비하여 ESC는하루한번 (o.d) mg을투여하는것을권고하고있다. Propranolol의경우 ACC/AHA에서는 1분간 1mg 을정맥으로투여한뒤, 2분간격으로최대 3 번투여가가능하다고언급하는반면에, ESC에서는 1분간체중당 0.15 mg을투여하도록권고하고있다. 두가이드라인모두심박수조절을위하여 amiodarone의정맥투여와경구투여를권고하고있다. 하지만정맥투여시 ACC/AHA에서는 300 mg 을 1시간동안투여하는것을권고하고있는반면, ESC에서는체중당용량 (5 mg/kg) 으로제시하고있다. ACC/AHA에서심박수조절과동율동조절 (rhythm control) 을위하여 dronedarone을모두권고하고있으나, 심박수조절에서는용량에대한권고사항이없다. 반면에 ESC에서는심박수조절에대한 dronedarone의정맥주사투여는권고하고있지않으며경구투여로하루두번 (b.i.d) 400 mg 투

6 심방세동치료를위한미국과유럽의심박수및율동조절약물요법가이드라인비교연구 / 89 여하기를권고하고있다 (Table 4). 미국과유럽의심방세동치료에서항부정맥약물요법가이드라인비교 : 율동조절율동조절에는직류심율동전환 (direct-current cardioversion, DCC) 과약물심율동전환 (pharmacological cardioversion) 이있다. DCC에서 ACC/AHA에서는심방세동뿐만아니라심방조동 (atrial flutter) 까지언급하고있다는점이다. 이외에빠른심실반응이나약물치료에반응이없는경우에 DCC의사용, 혈역학적으로불안정한환자에서 DCC 사용, 그리고증상이심하고치료에반응하지않는환자에게서 DCC를반복하여사용하는권고내용은권고등급을포함하여미국과유럽두가이드라인에서유사하다. 약물을이용한심율동전환에서기본적으로사용되는약제는 flecainide, propafenone, ibutilide, amiodarone 등이있다. 하지만최근임상연구결과를반영함에따라두가이드라인에서권고하는약물종류와내용및권고등급에차이가있다. 권고하는약물에서 vernakalant은최신 2012년유럽의가이드라인에만있는약물이다. 또한 ESC는 DCC의성공을높이기위해서와심방세동재발을예방하기위해서전치료 (pre-treatment) 로항부정맥제를사용하는것을권고등급 IIaB로제시하고있다. Amiodarone은 ACC/AHA와 ESC 가이드라인에서율동조절을위해모두권고하고있으나, ESC에서는최근발병한 (recent-onset) 심방세동환자와구조적심질환을가진환자에한해서 class IA로더높은권고등급을두는등두가이드라인의권고등급에서차이가있다 (Table 5). 미국과유럽의심방세동치료에서항부정맥약물요법가이드라인비교 : 동율동유지를위한항부정맥제율동치료에중요한항부정맥제에대하여서는미국과유럽 Table 5. Comparison between ACC/AHA and ESC in recommendations for pharmacological cardioversion. Classification ACC/AHA ESC Flecainide [IA] [IA] Dofetilide [IA] [IA] Propafenone [IA] [IA] Ibutilide [IA] [IA] Vernakalant [IA] Amiodarone [IIaA] Only for pts with recent-onset AF and structural heart disease [IA] Contraindication of dofetilide Pts out of hospital [IIIB] Vernakalant Pts with AF 7 days and moderate structural heart disease Pts with NYHA class I-II heart failure (caution) [IIbB] Cardioversion of postoperactive AF 3 days in pts after cardiac surgery [IIbB] NYHA = New York Heart Association; pt = patient; AF = atrial fibrillation; N/A = not applicable. Table 6. Comparison between ACC/AHA and ESC in recommendations for maintenance of sinus rhythm. Classification ACC/AHA ESC Antiarrhythmic drugs Beta-blocker Risk of using the antiarrhythmic drugs Amiodarone, dofetilide, dronedarone, flecainide, propafenone, sotalol [IA] The risks of the antiarrhythmic drug, including proarrhythmia, should be considered before initiating therapy with each drug [IC] Amiodarone, dronedarone, flecainide, propafenone, d,l-sotalol [IA] Beta-blocker for prevention of adrenergic AF [IC] Use for rhythm (plus rate) control in pts with a first episode of AF [IIaC] Continuation of the antiarrhythmic drugs Use in the setting of infrequent, well-tolerated recurrences of AF when the drug has reduced the frequency or symptoms of AF [IIbC] Contraindication of dronedarone Short-term antiarrhythmic therapy (4 weeks) Pts with NYHA class III and IV HF Pts who have had an episode of decompensated HF in the past 4 weeks [IIIB] Pts with NYHA class III and IV, or with recently unstable (decompensation within the prior month) NYHA class II heart failure [IIIB] (After cardioversion) Use in selected pts (at risk for therapy-associated complications) [IIbB] NYHA = New York Heart Association; pt = patient; AF = atrial fibrillation; HF = heart failure.

7 90 / Korean J Clin Pharm, Vol. 26, No. 1, 2016 두가이드라인모두권고등급 IA 로동일하게항부정맥제 (amiodarone, dronedarone, flecainide, propagenone, sotalol) 를권고하고있다. 특히항부정맥제에서최근이슈가되고있는 dronedarone의경우에도 class IA로다른약제들과같은수준으로두가이드라인에서권고하고있다. 다만, Class III에속하는 dofetilide는 ACC/AHA에만있는약물이다. 전부정맥 (proarrhythmia) 을비롯한항부정맥제의위험을고려하여각약물를사용하는점, 환자의증상빈도가감소하고내약성이좋을시약제사용의연장에관한점은 ACC/AHA에서만권고하고있다. 반면에, 심율동전환후단기간항부정맥제치료 (short-term antiarrhythmic therapy) 는 2012 ESC 가이드라인에추가된새권고안이며, beta-blocker나 disopyramide 의사용에관한내용, 그리고하나의항부정맥제실패시에다른항부정맥제사용관한내용역시 ESC에만있는권고안이다 (Table 6). 권고하는문서양식측면에서 ACC/AHA는항부정맥제를 Vaughan Williams classification에따라분류하여놓았다. 반면에, ESC의경우에는별도의분류체계없이약물명만나열하여권고표로만들어놓았다. ACC/AHA에서분류체계로하고있는 Vaughan Williams classification에따라, 먼저 class IA 약제인 disopyramide의경우즉시방출형 (immediate release, IR) 과서방형 (extended release, ER) 제제의용량을 ACC/AHA 에서는모두권고하고있고, 이와대조적으로, ESC 에서는 disopyramide의서방형제제에대한용량권고내용은없다. Quinidine에대한용량은 ACC/AHA에서만매 8시간마다 mg 으로권고하고있다. Class IC 에해당하는 flecainide 는 ACC/AHA는 mg 매 12시간마다투여를권고하고있는반면, ESC에서는즉시방출형과 flecainide XL로나누어각각 mg 하루두번과 200 mg 하루한번으로나누어권고하고있다. Amiodarone의경우, ESC에서는경구용량만제시하고있는반면에, ACC/AHA에서는경구투여시와정맥투여시로나누어상세하게용량을권고하고있다. 미국과유럽두가이드라인에서모두 sotalol의권고되는용량범위의최대용량 (maximum dose) 이 160 mg으로동일하다. 다만, 최소용량 (minimum dose) 이 ACC/AHA는 40 mg, ESC는그 2배인 80 mg으로제시하고있다 (Table 7). ESC는약물별주의사항 (precaution) 과금기사항 (contraindication) 을각각분리하여기술하고있다. 또한크레아티닌청소율 (creatinine clearance) 의구체적수치까지나타낸표현이나감소된좌심실박출률 (reduced LV ejection fraction) 에관한언급등은 ESC에만사용하고있다. 반면에간기능 (liver function) 에관한사항은 ACC/AHA에서만있으며, class IC에속하는 flecainide와 propafenone의사용시브루가다증후군 (brugada syndrome) 에서주의할것을권고하고있다. Class III 에속하는 amiodarone은미국과유럽의가이드라인에서 QT 간격연장 (prolonged QT interval) 에관한부분이동일하게권고되고있다. 가장최신항부정맥약물인 dronedarone은권고사항이혈청크레아티닌 (serum creatinine) 의수치나다른약과의병용투여시용량에대한표현등으로 ESC에서더상세하게기술되어있다 (Table 8). 동율동유지에있어서항부정맥제사용에관하여 ACC/ AHA에서만다루고있는약물의특성과 ESC에서만다루고 Table 7. Comparison usual dosage for maintenance of sinus rhythm in AF between ACC/AHA and ESC. Drug ACC/AHA ESC Vaughan Williams class IA Disopyramide IR: mg QID ER: mg BID mg t.i.d Quinidine mg TID Vaughan Williams class IC Flecainide mg BID IR: mg TID Propafenone ER: mg BID Vaughan Williams class III Flecainide: mg BID Flecainide XL: 200 mg QD Propafenone: mg TID Propafenone SR: mg BID Amiodarone Oral: mg for 2-4 weeks, then mg QD IV: 150 mg over 10 min; then 1 mg/min for 6 h; then 0.5 mg/ min for 18 h or change to oral dosing; after 24 h, consider decreasing dose to 0.25 mg/min Oral: 600 mg QD for 4 weeks, 400 mg QD for 4 weeks, then 200 mg QD Dofetilide mcg BID Dronedarone 400 mg BID 400 mg BID Sotalol (d,l- Sotalol) mg BID mg BID N/A = not applicable; QD = once daily; BID = twice daily; TID = 3 times a day; QID = 4 times a day; XL = extended release; SR = sustained release.

8 심방세동치료를위한미국과유럽의심박수및율동조절약물요법가이드라인비교연구 / 91 Table 8. Contraindication and precaution for maintenance of sinus rhythm in ACC/AHA and ESC. Drug ACC/AHA ESC Vaughan Williams class IA Disopyramide HF Prolonged QT interval Prostatism, glaucoma Avoid other QT interval-prolonging drugs Systolic heart failure (Contraindication). QT-prolonging drugs (Caution) Prolonged QT interval Quinidine Diarrhea Vaughan Williams class IC Flecainide Sinus or AV node dysfunction HF CAD Atrial flutter Infranodal conduction disease Brugada syndrome Renal or liver disease Creatinine clearance < 50 mg/ml (Contraindication) Coronary artery disease (Contraindication) LV ejection fraction reduction (Contraindication) Propafenone Vaughan Williams class III Sinus or AV node dysfunction HF CAD Atrial flutter Infranodal conduction disease Brugada syndrome Liver disease Asthma Coronary artery disease (Contraindication) LV ejection fraction reduction (Contraindication) Renal impairment (Caution) Amiodarone Dofetilide Dronedarone Sotalol (d,l-sotalol) Sinus or AV node dysfunction Infranodal conduction disease Lung disease Prolonged QT interval Prolonged QT interval Renal disease Hypokalemia Hypomagnesemia Diuretic therapy Avoid other QT interval-prolonging drugs Bradycardia HF Long-standing persistent AF/flutter Liver disease Prolonged QT interval Prolonged QT interval Renal disease Hypokalemina Hypomagnesemia Diuretic therapy Avoid other QT interval-prolonging drugs Sinus or AV nodal dysfunction HF Asthma QT-prolonging drugs (Caution) Heart failure (Caution) NYHA class III-IV (Contraindication) Unstable heart failure (Contraindication) QT-prolonging drugs (Contraindication) Powerful CYP3A4 inhibitors (Contraindication) Creatinine clearance < 30 mg/ml (Contraindication) LV hypertrophy (Contraindication) Systolic heart failure (Contraindication) Pre-existing QT prolongation (Contraindication) Hypokalaemia (Contraindication) Creatinine clearance < 50 mg/ml (Contraindication) 있는약물의특성이있다. ACC/AHA에서는약동학적인측면에서주요한약물상호작용 (major pharmacokinetic drug interactions) 에관한내용을기술하여각약물별로주요대사효소와그에따라혈중농도증가또는감소를화살표로보기 쉽게표현하고있다. 한편, ESC에서는용량감소나약물중단에영향을미치는심전도 (electrocardiography, ECG) 특징과방실결정을낮추는정도를각약물별로명시하고있다.

9 92 / Korean J Clin Pharm, Vol. 26, No. 1, 2016 Table 9. Comparison between ACC/AHA and ESC in recommendations for upstream therapy. Classification ACC/AHA ESC Drug lists (pts with HF and reduced left ventricular EF) ACEIs and ARBs [IIbB] ACEIs and ARBs [IIaA] Drug lists (pts with hypertension) ACEIs and ARBs [IIbB] ACEIs and ARBs [IIaB] Statins (patients with coronary artery surgery) Reasonable after coronary artery surgery [IIbA] Considered after coronary artery bypass grafting, isolated or in combination with valvular interventions [IIaB] Statins (pts with HF) [IIbB] Contraindication (pts without CAD) ACEIs, ARB, or statin is not beneficial for primary prevention of AF [IIIB] ACEIs, ARB, or statin is not beneficial for primary prevention of AF [IIIC] EF = ejection fraction; HF = heart failure; CAD; Coronary Artery Disease; ACEI = Angiotensin Converting Enzyme Inhibitor; ARB = Angiotensin Receptor Blocker; pts = patients; AF = atrial fibrillation. 미국과유럽의심방세동치료에서항부정맥약물요법가이드라인비교 : 조기치료일차예방 (primary prevention) 으로새로운심방세동의발생이나심근육의구조적재형성등을예방혹은지연시키거나, 이차예방 (secondary prevention) 으로재발률이나영구적심방세동을지연시키는치료로조기치료 (upstream therapy) 를미국과유럽두가이드라인에서모두권고하여왔다 (Table 9) ACC/AHA에서는여전히조기치료에사용되는관련약제에대해권고하고있지만, 이와대조적으로, 2012 ESC에서여태까지와는상반되는최근의여러임상연구결과를바탕으로조기치료에대한확실성에의문을제기하고있다. 특히조기치료에쓰이는약물인안지오텐신 -수용체차단제 (angiotensinreceptor blockers, ARBs) 나불포화지방산 (polyunsaturated fatty acids, PUFAs) 를가지고실험한최근임상연구결과들이기존의조기치료에쓰이는약제들의효과를증명하는데실패했다고말하며효과가거의없는것으로보고있다. 고찰 본연구는선진국에서의심방세동가이드라인의현황을알아보기위하여미국 ACC/AHA 와유럽 ESC 각각의기관사이트를통하여개정되어온가이드라인흐름을조사 분석하였다. 미국의경우 2003년에첫가이드라인발표를시작으로총 7번의개정을거치면서하나의임상지침안과두번의포켓가이드라인 (pocket guideline) 을포함하여 2014년에발행한최신임상치료가이드라인을현재사용하고있다 (Table 1). 유럽의경우는 2003년을시작으로 2010년과 2012년까지가이드라인이꾸준히발행되고있다 (Table 2). 이를토대로본연구에서는궁극적으로는미국과유럽의심방세동에관한최신가이드라인을비교및고찰하였다. 미국과유럽각나라별심방세동가이드라인의개정현황에대한조사에서는미국이유럽보다개정되어온횟수가더많았으며임상치료지침등도발표하여왔다. 35) 미국과유럽이 같이발표한 2003년가이드라인이후유럽은 2번의개정이있었던것과비교하면미국에서더활발하고세부적인것들도개정해왔음을알수있다. 36) 미국의경우는최신약물치료가이드라인이 2014년하나인것에비해, 유럽의경우는 2010년가이드라인을기본토대로추가적사항들만 2012에서권고하고있어서두가이드라인을모두분석하여서미국의가이드라인과최종비교 연구하였다. 37) 큰치료목표는 ACC/AHA와 ESC에서비슷하였으나세부적으로항목을나눈것이나특히권고하는약제의종류나용량의차이가다소있어일대일의완전한비교에는제약이따른다. 이러한이유로주요치료방향과약물들에초점을맞추어두나라의가이드라인을분석하였다. 심박수조절 (rate control) 에있어서큰차이로는내용적인면보다는권고하는치료목표의분류 (classification) 이다. ESC 의경우에는심박수조절을급성 (acute) 과장기 (long-term) 으로나누고방실결절절제 (atrioventricular node ablation) 까지모두나누어권고사항을기재하고있다. 38) 이와는대조적으로, ACC/AHA의경우는 ESC에서세가지로나눈분류를하나로모아서하나의권고표로제시하고있다. 39) 따라서유럽가이드라인이미국의가이드라인에비해각세부분류마다의추가되는권고사항들이더많다. 그리고약제를쓸때의조건들도더상세하게나와있다. 즉, 유럽의가이드라인에서심박수조절에있어서조금더세부적으로다루고있다. 40) 다음으로심박수를조절하는약제의용량권고에서는특이한점은 dronedarone에대한언급은 ESC에만있다는것이다. 41) 그리고 amiodarone의정맥투여경우에 ACC/AHA는고정된용량범위를권고하고있는데, ESC에서는체중당으로용량을권고하고있어서보다더환자상태에맞춘용량으로구체적으로권고하고있다. ESC에서만유일하게 vernakalant 약제를권고하고있는점은율동조절 (rhythm control) 에서가장두드러지는중요한사항이다. 42) Vernakalant는 ACC/AHA를비롯한 CCS (Canadian cardiovascular society) 등다른나라에서는전혀언급되고있

10 심방세동치료를위한미국과유럽의심박수및율동조절약물요법가이드라인비교연구 / 93 지않는약제이다. 43) Vernakalant는 class III에속하는항부정맥제로심방에존재하는칼륨채널 (potassium channel) 을막는작용을한다. 44) 이약이다른 class III 약제와다른점은심장에서칼륨을밖으로퍼내는 (cardiac transient outward potassium current) 특정채널을막아특히심박수가높은상태에서더효과적으로작용할수있다는것이다. 45) AVRO 등의임상시험에서는 vernakalant가안전성 (safety) 도좋으며, amiodarone보다도효과가더우수하다는결과를내었다. 46) 미국은 vernakalant에대하여 2008년승인을거부하였고, 이약의경구제형개발연구에관해서는약물승인및개발시간등의문제로 2012년에중단하였다. 47) 하지만이후에정맥주사제형개발및판매를위해노력하고경구형제제의개발도다시추진할것이라고카디옴파마 (Cardiom Pharma) 사에서발표한바있다. 이러한상황으로볼때, 아직승인이되지않은미국과캐나다등다른선진국에서도향후 vernakalant를승인할것이라예상된다 ) 동율동유지를위한항부정맥제 (antiarrhythmic drugs to maintain sinus rhythm) 에관한권고안비교연구에서는부정맥치료제에서큰주목을받고있는 dronedarone을미국과유럽가이드라인에서모두 ATHENA, EURIDIS 등관련임상시험들을근거로들면서언급하고있는점이특징이다 ) 중증도의환자를제외하고 1차치료제로두가이드라인모두 dronedarone을권고하고있다. 54) Amiodarone보다효과는작으나, 기관독성이적고안전성이우수하다는큰장점으로이약제를두가이드라인에서 1차치료제로권고하고있는점이심방세동표준치료지침에서가장최근업데이트된중요한사항이다. 55,56) 항부정맥약제간의비교 분석에서형식적인면에서눈에띄는점은 ACC/AHA에서는 Vaughan Williams classification 에따라좀더보기쉽게약들을분류하였고 ESC에서는별도의분류가없이약물을제시하고있다는것이다. 이분류체계에따라약물의작용기전이다르기때문에 ACC/AHA 가이드라인이약제들간의차이점파악에더용이하다. 이와는반대로, 각약제마다의사용시주의사항과금기에있어서는 ESC 가이드라인이두항목을더명확하게분류하여권고하고있다 (Table 7). 항부정맥제에관한두가이드라인에서또두드러지는차이점은약물동태학적측면 (pharmacokinetic) 에관한부분이다. ESC와는달리, ACC/AHA에서는각항부정맥제별로약물동태학적인부분과이에관련한약물간상호작용 (drug-drug interaction) 에대한언급을하고있다. 57) 이는전부정맥 (proarrhythmia) 의위험이있고다른약과의병용시주의할점이많은항부정맥제에있어서중요하게생각되는부분으로 ACC/AHA 가이드라인의큰장점이며중요하게참고하여야할사항으로보인다. 58) 마지막으로조기치료 (upstream) 에관한미국과유럽의가이드라인에서주목할만한점은 조기치료가효과가과연있는가 에관한사항이다. 59) 2012 ESC 가이드라인이전까지는조기치료를심방세동예방차원과재발방지의차원에서권고해왔고미국은가장최신가이드라인에서도여전히권고하고있다. 60) 하지만 2012년도유럽의가이드라인에서는최근여러임상시험들을근거로그효과가확실치않고오히려조기치료의효과증명에실패하였다고언급하고있다. 61) 하지만여전히실제임상에서는표준약물치료와함께조기치료에사용되는약제들이같이처방되고있다고마무리함으로써실질적으로조기치료약제들에대한사용을임상전문가들의경험과판단에맡기고있다고본다. 62) 항부정맥제를이용한부정맥치료는그효과가만족스럽지않고부작용발생의위험으로인해비록현재심방세동치료의주류를이루지만사용에주의를요한다. 63) 따라서당분간부정맥치료에있어서항부정맥제의역할은제한적일수밖에없고신중하게다루어져야한다. 이러한이유로적절한항부정맥제를적절한시기에사용하는것에대한판단과실제적용에있어서임상약사를포함한임상전문가들의역할이매우중요하다. 64) 또한여러연구기법들이바탕이되어이들약제의부작용을줄이거나새로운특성을지닌신약개발이지속적으로진행되고있으므로항부정맥제치료는앞으로도계속부정맥치료의중요한역할을담당하리라예상된다. 65) 더욱이국내의경우대한심장학회등관련기관에서공식적으로발행한치료지침또는약물요법지침이없는실정이다. 이에따라, 여러선진국들의심방세동가이드라인을비교 연구하여항부정맥제사용에대한정확한이해와, 나아가궁극적으로는국제적동향과국내실정에맞추어적극적으로심방세동에서의항부정맥제권고안의정립및보완이필요하다. 66) 결론 본연구에서는부정맥중에서도심방세동에대한미국 ACC/AHA와유럽 ESC 가이드라인의현황조사와두나라의최신가이드라인을비교 연구를실시하였다. 이를통해심방세동가이드라인에대한국제적동향을파악하고심방세동의치료방법으로심박수및율동조절약물요법의중요성에대해알아보고자하였다. 이러한가이드라인비교연구는최근가이드라인에업데이트된중요치료학적내용들을보다빠르고정확하게국내임상상황에반영할자료를구축하게한다. 또한, 임상에서심방세동의약물요법에있어서임상약사의역할의필요성과중요성을인식하게한다는의의를가진다. 이를위하여앞으로가이드라인에관한더많은비교분석이필요하며, 이러한연구를토대로하여임상약사를비롯한임상전문가들은국내심방세동환자와임상상황에맞추어적절하게새

11 94 / Korean J Clin Pharm, Vol. 26, No. 1, 2016 로운권고안들을적용하여야할것이다. 감사의말씀 이논문은 2015년도미래창조과학부의재원으로한국연구재단의지원을받아수행된기초연구사업임 (NRF-2015R1C- 1A1A ). 참고문헌 1. Gupta S, Tiruvoipati R, Green C. Atrial fibrillation and mortality in critically ill patients: a retrospective study. Am J Crit Care 2015;24(4): Lee G, Campbell-Cole C. Recognising and managing atrial fibrillation in the community. Br J Community Nurs 2014;19(9): Rahman F, Kwan GF, Benjamin EJ. Global epidemiology of atrial fibrillation. Nat Rev Cardiol 2014;11(11): De Backer O, Arnous S, Ihlemann N, et al. Percutaneous left atrial appendage occlusion for stroke prevention in atrial fibrillation: an update. Open Heart 2014;1(1):e Aryana A, Singh SK, Singh SM, et al. Association between incomplete surgical ligation of left atrial appendage and stroke and systemic embolization. Heart Rhythm 2015;12(7): Zhirov IV, Romanova NV, Tereshchenko SN, et al. Epidemiology and management of heart failure patients with atrial fibrillation. Kardiologiia 2015;55(3): Cutugno CL. Atrial fibrillation: updated management guidelines and nursing implications. Am J Nurs 2015;115(5): Berry E, Padgett H. Management of patients with atrial fibrillation: diagnosis and treatment. Nurs Stand 2012;26(22): Moukabary T, Gonzalez MD. Management of atrial fibrillation. Med Clin North Am 2015;99(4): Greenberg H. Evidenced-based pharmacotherapy for rate control in atrial fibrillation. Crit Care Nurs Q 2013;36(2): Stead LG, Vaidyanathan L. Evidence-based emergency medicine/systematic review abstract. Rhythm control with electrocardioversion for atrial fibrillation and flutter. Ann Emerg Med 2009;54(5): Hargroves D, Ward L. Anticoagulants for stroke prevention in patients with atrial fibrillation. Br J Neurosci Nurs 2015:Supplement Stroke Clinical Updates: Saltman AE, Gillinov AM. Surgical approaches for atrial fibrillation. Cardiol Clin 2009;27(1): Chatterjee S, Sardar P, Lichstein E, et al. Pharmacologic rate versus rhythm-control strategies in atrial fibrillation: an updated comprehensive review and meta-analysis. Pacing Clin Electrophysiol 2013;36(1): Lafuente-Lafuente C, Longas-Tejero MA, Bergmann J, et al. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2015(3):N.PAG. 16. Podrid PJ. Aggravation of arrhythmia: a complication of antiarrhythmic drugs. J Cardiovasc Electrophysiol 1993;4(3): Chung R, Houghtaling PL, Tchou M, et al. Left ventricular hypertrophy and antiarrhythmic drugs in atrial fibrillation: impact on mortality. Pacing Clin Electrophysiol 2014;37(10): Frommeyer G, Eckardt L. Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms. Nat Rev Cardiol, in press. 19. Estrada JC, Darbar D. Clinical use of and future perspectives on antiarrhythmic drugs. Eur J Clin Pharmacol 2008;64(12): Torres-Degayón, V, Torres-Murillo JM, Baena-Parejo MI, et al. Negative outcomes associated with medication in patients with chronic atrial fibrillation who present at the emergency department. J Clin Pharm Ther 2015;40(4): Freeman JV, Simon DN, Go A, et al. Association between atrial fibrillation symptoms, quality of life, and patient outcomes: results from the outcomes registry for better informed treatment of atrial fibrillation (ORBIT-AF). Circ Cardiovasc Qual Outcomes 2015;8(4): , 22. Taylor CJ, Hodgkinson J, Hobbs FDR. Rhythm control agents and adverse events in patients with atrial fibrillation. Int J Clin Pract 2010;64(8): Camm AJ, Yap YG. What should we expect from the next generation of antiarrhythmic drugs? J Cardiovasc Electrophysiol 1999;10(2): Lee EJ, Kim J. Evaluation of dronedarone as a therapeutic option for patients with atrial fibrillation. J Clin Pharm Ther 2014;39(2): Duray GZ, Torp-Pedersen C, Connolly SJ, et al. Effects of dronedarone on clinical outcomes in patients with lone atrial fibrillation: pooled post hoc analysis from the ATHENA/EURIDIS/ADONIS studies. J Cardiovasc Electrophysiol 2011;22(7): Rosman J, Hoffmeister P, Reynolds M, et al. Possible proarrhythmia with dronedarone. J Cardiovasc Electrophysiol 2013;24(1): Allen Lapointe NM, Lokhnygina Y, Sanders GD, et al. Adherence to guideline recommendations for antiarrhythmic drugs in atrial fibrillation. Am Heart J 2013;166(5): Musco S, Conway EL, Kowey PR. Drug therapy for atrial fibrillation. Med Clin North Am 2008;92(1): Capucci A, Aschieri D, Villani G. Clinical pharmacology of antiarrhythmic drugs. Drugs Aging. 1998;13(1): Craig T, January L. Samuel W, et al AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol 2014;64: Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation. Eur Heart J 2010;31: Camm AJ, Lip GY, De Caterina R, et al focused update of the ESC guidelines for the management of atrial fibrillation. Eur Heart J 2012;33: Estes NA III, Halperin JL, Calkins H, et al. ACC/AHA/Physician consortium 2008 clinical performance measures for adults with nonvalvular atrial fibrillation or atrial flutter. Circulation 2008;117: Nieuwlaat, R, Connolly, SJ. Lenient rate control is as effective as strict rate control for preventing cardiovascular events in AF. ACP J Club 2010;153(2):JC Kowey PR, Breithardt G, Camm J, et al. Physician stated atrial fibrillation management in light of treatment guidelines: data from an international, observational prospective survey. Clin Cardiol 2010;33(3): Curtis AB. Update on the clinical management of atrial fibrillation: guidelines and beyond. Postgrad Med 2011;123(6): Rajagopalan B, Curtis AB. Management of atrial fibrillation: what is new in the 2014 ACC/AHA/HRS guideline? Postgrad Med 2015; 127(4): Phillips SE. Guideline-specific management of atrial fibrillation. Formulary 2010;45(5): Ariansen I, Abdelnoor M, Tveit A, et al. Guidelines' criteria for rate control in atrial fibrillation: are they useful? Scand Cardiovasc J 2010; 44(3):

12 심방세동치료를위한미국과유럽의심박수및율동조절약물요법가이드라인비교연구 / Dixon BJ, Bracha Y, Loecke SW, et al. Principal atrial fibrillation discharges by the new ACC/AHA/ESC classification. Arch Intern Med 2005;165(16): Kirchhof P, Ammentorp B, Darius H, et al. Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC guidelines on atrial fibrillation: primary results of the PREvention of thromboemolic events--european Registry in Atrial Fibrillation (PREFER in AF). Europace 2014;16(1): Savelieva I, Graydon R, Camm AJ. Pharmacological cardioversion of atrial fibrillation with vernakalant: evidence in support of the ESC guidelines. Europace 2014;16(2): Kirchhof P, Curtis AB, Skanes AC, et al. Atrial fibrillation guidelines across the Atlantic: a comparison of the current recommendations of the European Society of Cardiology/European Heart Rhythm Association/European Association of Cardiothoracic Surgeons, the American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society, and the Canadian Cardiovascular Society. Eur Heart J 2013;34: Chen S, Liu S, Purerfellner H. Vernakalant as a novel anti-arrhythmic agent for converting of atrial fibrillation, molecular mechanism, updated clinical efficacy, and future development. Curr Pharm Des. in press. 45. Conde D, Baranchuk A. Vernakalant for the conversion of atrial fibrillation: the new kid on the block? Ann Noninvasive Electrocardiol 2014;19(4): Rudiger A, Breitenstein A, Arrigo M, et al. Suitability, efficacy, and safety of vernakalant for new onset atrial fibrillation in critically ill patients. Crit Care Res Pract. in press. 47. Camm AJ. The vernakalant story: how did it come to approval in Europe and what is the delay in the U.S.A? Curr Cardiol Rev 2014; 10(4): Duggan ST, Scott LJ. Intravenous vernakalant: a review of its use in the management of recent-onset atrial ribrillation. Drugs 2011;71(2): Ehrlich JR, Nattel S. Novel approaches for pharmacological management of atrial fibrillation. Drugs, 2009;69(7): Mao ZL, Townsend RW, Gao Y, et al. Population Pharmacokinetics of Vernakalant Hydrochloride Injection (RSD1235) in Patients With Atrial Fibrillation or Atrial Flutter. J Clin Pharmacol 2012;52(7): Torp-Pedersen C, Crijns HJ, Gaudin C, et al. Impact of dronedarone on hospitalization burden in patients with atrial fibrillation: results from the ATHENA study. Europace 2011;13(8): Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357(10): Rosa GM, Bianco D, Parodi A, et al. Pharmacokinetic and pharmacodynamic profile of dronedarone, a new antiarrhythmic agent for the treatment of atrial fibrillation. Expert Opin Drug Metab Toxicol 2014; 10(12): Iannone P, Haupt E, Flego G, et al. Dronedarone for atrial fibrillation: the limited reliability of clinical practice guidelines. JAMA Intern Med 2014;174(4): Le Heuzey J, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study: Randomized, Double-Blind TrIal to Evaluate the Efficacy and Safety of DrOnedarone [400 mg bid] Versus AmiodaroNe [600 mg qd for 28 days, then 200 mg qd Thereafter] for at Least 6 months for the Maintenance of Sinus Rhythm in Patients with AF. J Cardiovasc Electrophysiol 2010;21 (6): Lee EJ, Kim J. Evaluation of dronedarone as a therapeutic option for patients with atrial fibrillation. J Clin Pharm Ther 2014;39(2): Turgeon J, Murray KT, Roden DM. Effects of drug metabolism, metabolites, and stereoselectivity on antiarrhythmic drug action. J Cardiovasc Electrophysiol 1990;1(3): Lin CY, Lin YJ, Lo LW, et al. Factors predisposing to ventricular proarrhythmia during antiarrhythmic drug therapy for atrial fibrillation in patients with structurally normal heart. Heart Rhythm 2015;12(7): CalÒ L, Martino A, Ciccaglioni A, et al. Upstream effect for atrial fibrillation: still a dilemma? Pacing Clin Electrophysiol 2011;34(1): Kumagai K. Upstream therapy for atrial fibrillation. Nihon Rinsho 2013;71(1): Goette A, Hammwöhner M, Bukowska A. Upstream therapy for atrial fibrillation. Herzschrittmacherther Elektrophysiol 2014;25(1): Danelich IM, Reed BN, Hollis IB, et al. Clinical update on the management of atrial fibrillation. Pharmacotherapy 2013;33(4): Pandya B, Lambiase PD. An avoidable antiarrhythmic side effect. Br J Hosp Med (Lond), 2006;67(1):M Shu J, Zhou J, Patel C, et al. Pharmacotherapy of cardiac arrhythmiasbasic science for clinicians. Pacing Clin Electrophysiol 2009;32(11): Heijman J, Voigt N, Dobrev D. New directions in antiarrhythmic drug therapy for atrial fibrillation. Future Cardiol 2013;9(1): Darbar D, Roden DM. Future of antiarrhythmic drugs. Curr Opin Cardiol 2006;21(4):