심방세동의약물치료 원광대학교의과대학내과학교실김남호 Nam-Ho Kim, MD Department of Internal Medicine, Wonkwang University Medical School, Iksan, Korea ABSTRACT Management of AF patients is aimed at reducing symptoms and at preventing severe complications associated with AF. Prevention of AF-related complications relies on antithrombotic therapy, control of ventricular rate, and adequate therapy of concomitant cardiac diseases. These therapies may already alleviate symptoms, but symptom relief may require additional rhythm control therapy by cardioversion, antiarrhythmic drug therapy, or ablation therapy. In this paper, I would like to introduce the 2014 AHA ACC HRS guideline focuses on medical treatment of atrial fribrillation. Key Words: atrial fibrillation anti-arrhythmic agents guideline 서론 심박수조절치료 (Rate Control) 심방세동의약물치료는정상동율동을유지하는율동치료 (rhythm control) 및적절한심실박동수를유지하는심박수조절치료 (rate control) 가있다. 환자의상황에따라서이중한가지방법을선택하게되는데, 어떠한방법을선택하더라도혈전색전증 (thromboembolism) 을예방하기위한치료를병행해야한다. 본논문에서는 2014년미국심장학회 (AHA/ ACC/HRS) 에서발표한내용을기초로하여심방세동의약물치료를정리하였다. 1 심박수조절은심방세동의약물치료에서중요한치료전략으로삶의질향상, 이환율감소, 그리고빈맥-유발성심근증의발생을감소시키는역할을한다. 주로 beta-blockers, non-dihydropyridine calcium channel antagonists, digoxin, amiodarone, sotalol 같은약물을사용한다. 이중어떠한약물들을선택할것인가는환자의증상정도, 혈역학적상태, 심부전의유무, 심방세동의발생요인등을고려한다. 또한빠르게심박수를조절하기위해서는주사제를사용하거나전기적율동전환등을고려한다 (Table 1, Figure 1). Received: September 18, 2014 Revision Received: November 20, 2014 Accepted: December 15, 2014 Corresponding author: Nam-Ho Kim, MD, Division of Cardiology, Department of Internal Medicine, Wonkwang University Medical School, 344-2 Shinyong-dong, Iksan, Jeonbuk 570-711, Korea Tel: +82-63-859-2523, Fax: +82-63-855-2025 E-mail: cardionh@wku.ac.kr 14 The Official Journal of Korean Heart Rhythm Society
Table 1. Common medication dosage for rate control of atrial fibrillation 약물 정주 경구상용용량 s Metoprolol tartrate 2분에걸쳐 2.5-5.0 mg 투여, 3회까지 25-100 mg BID Metoprolol XL (succinate) 없음 50-400 mg QD MAIN TOPIC REVIEWS Atenolol 없음 25-100 mg QD Esmolol 1분에걸쳐 500 μg/kg, 이후에 50-300 μg/kg/min 없음 Propranolol 1분에걸쳐 1 mg, 2분간격으로 3회까지 10-40 mg TID 또는 QID Nadolol 없음 10-240 mg QD Carvedilol 없음 3.125-25 mg BID Bisoprolol 없음 2.5-10 mg QD Non-dihydropyridine calcium channel antagonists 2 분에걸쳐 0.075-0.15 mg/kg 투여, 반응이없으면 30 분후 10.0 mg 추가투여, 그리고 0.005 mg/kg/min 투여 서방형 : 180-480 mg QD Diltiazem 2분에걸쳐서 0.25 mg/kg 투여, 이후에 5-15 mg/h 서방형 : 120-360 mg QD Digitalis glycosides Digoxin 0.25 mg 투여, 반복하여 24시간에최대 1.5 mg까지투여 0.125-0.25 mg QD Others 1 시간에걸쳐서 300 mg, 이후에 24 시간에걸쳐서 10-50 mg/h 100-200 mg QD BID, twice daily; QD, once daily; QID, four times a day; TID, three times a day. 심방세동의약물치료 심혈관질환없음 고혈압또는좌심실기능이보존된심부전 좌심실기능부전또는심부전 만성폐쇄성호흡기질환 Diltiazem Diltiazem Digoxin Diltiazem Figure 1. Approach to selecting drug therapy for ventricular rate control Beta blockers should be instituted following stabilization of patients with decompensated HF. The choice of beta blocker (cardioselective, etc.) depends on the patient s clinical condition. Digoxin is not usually first-line therapy. It may be combined with a beta blocker and/or a non-dihydropyridine calcium channel blocker when ventricular rate control is insufficient and may be useful in patients with HF. In part because of concern over its side-effect profile, use of amiodarone for chronic control of ventricular rate should be reserved for patients who do not respond to or are intolerant of beta blockers or non-dihydropyridine calcium antagonists. VOL.15 NO.4 15
Table 2. Recommended drug doses for pharmacological cardioversion of atrial fibrillation 약물투여경로용량부작용 경구 정주 하루에 600-800 mg 을나누어서총 10 g 까지투여, 이후에 200 mg QD 유지 150 mg을 10분에걸쳐, 이후에 1 mg/min을 6시간, 0.5 mg/min을 18시간또는경구용량 정맥염, 저혈압, 서맥, QT 간격연장, torsades de pointes ( 드뭄 ), 위장장애, 변비, INR 증가 Dofetilide 경구 CrCl (ml/min) >60 40-60 20-40 <20 용량 (μg BID) 500 250 125 권장되지않음 QT 간격연장, torsades de pointes; 신장기능, 체격, 연령에따라용량조절 Flecainide 경구 200-300 mg 1* 저혈압, 1:1 전도되는심방조동, proarrhythmia; 관상동맥질환과중요한구조적심장질환이있는환자에서금기 Ibutilide 정주 1 mg 을 10 분에걸쳐투여, 충분한반응이나올때까지 1 mg 반복 (60 kg 미만 -0.01 mg/kg) QT 간격연장, torsades de pointes, 저혈압 Propafenone 경구 450-600 mg 1* 저혈압, 1:1 전도되는심방조동, proarrhythmia; 관상동맥질환과중요한구조적심장질환이있는환자에서금기 * Recommended given in conjunction with a beta blocker or non-dihydropyridine calcium channel antagonist administered 30 minutes before administering the Vaughan Williams Class IC agent. BID, twice daily; QD, once daily 심박수조절에대한권장사항 Class I 1. 발작성, 지속성, 영구형심방세동환자에서심박수조절을위해 beta-blocker 또는 nondihydropyridine calcium channel antagonist 사용을권장한다 (level of evidence: B). 2. 조기흥분이없는심방세동환자에서급히심박수조절을위해서는 beta-blocker 또는 non-dihydropyridine calcium channel blocker 의주사제사용을권장한다. 혈역학적으로불안정한환자에서는전기적율동전환을시도한다 (level of evidence: B). 3. 활동시심방세동과관련된증상이있는환자에서는생리적인범위내의심박수를유지하도록필요한약물치료를통하여적절한심박수조절을평가해야한다 (level of evidence: C). 16 The Official Journal of Korean Heart Rhythm Society
Table 3. Dosage and safety considerations for maintenance of sinus rhythm in atrial fibrillation 약물용량금기및사용시주의약물상호작용 Vaughan Williams class IA Disopyramide 속효성 : 100-200 mg 을 6 시간간격 서방형 : 200-400 mg 을 12 시간간격 심부전 증가된 QT 간격 칼륨, 녹내장 QT 간격을연장시키는약물 CYP3A4 에의해대사 : 억제제 (verapamil, diltiazem, ketoconazole, macrolide antibiotics, protease inhibitors, 포도주스 ) 와유도제 (rifampin, phenobarbital, phenytoin) 사용주의 MAIN TOPIC REVIEWS Quinidine 324-648 mg을 8시간간격 증가된 QT 간격 설사 CYP2D6 억제 : tricyclic antidepressants, metoprolol, antipsychotics 농도증가 P-glycoprotein 억제 : digoxin 농도증가 Vaughan Williams class IC Flecainide 50-200 mg을 12시간간격 동결절또는방실결절장애 심부전 관상동맥질환 심방조동 방실결절하방전도장애 브루가다증후군 신장또는간질환 CYP2D6 에의해대사 : 억제제 (quinidine, fluoxetine, tricyclics); 유전적으로 7-10% 인구에서는없다. 신장배설 Propafenone 속효성 : 150-300 mg 을 8 시간간격 서방형 : 225-425 mg 을 12 시간간격 동결절또는방실결절장애 심부전 관상동맥질환 심방조동 방실결절하방전도장애 브루가다증후군 간질환 천식 CYP2D6 에의해대사 : 억제제 (quinidine, fluoxetine, tricyclics); 유전적으로 7-10% 인구에서는없다. Poor metabolizer 는베타차단작용을증가시킨다. P-glycoprotein 억제 : digoxin 농도증가 CYP2C9 억제 : warfarin 농도증가 (INR 25% 상승 ) Vaughan Williams class III 경구 : 2-4 주간하루 400-600 mg 을분복 ; 이후하루에 1 번 100-200 mg 유지 주사 : 150 mg 을 10 분이상투여 ; 그리고 6 시간동안 1 mg/min; 이후 18 시간은 0.5 mg/min 투여하거나경구제제로변경 ; 24 시간이후 0.25 mg/min 감량고려 동결절또는방실결절장애 방실결절하방전도장애 간질환 증가된 QT 간격 대부분의 CYP 억제 : warfarin (INR 0-200% 상승 ), statin, 그리고많은다른약물들의농도증가 P-glycoprotein 억제 : digoxin 농도증가 Dofetilide 125-500 μg 을 12시간간격 증가된 QT 간격 신장질환 저칼륨혈증 이뇨제사용 QT 간격을연장시키는약물 CYP3A 에의해대사 : 금기 (verapamil, hydrochlorothiazide, cimetidine, ketoconazole, trimethoprim, prochlorperazine, megestrol); amiodarone 은약물투여최소 3 개월전중지 Dronedarone 400 mg을 12시간간격 서맥 심부전 long-standing AF/flutter 간질환 증가된 QT 간격 CYP3A 에의해대사 : 억제제 (verapamil, diltiazem, ketoconazole, macrolide antibiotics, protease inhibitors, 포도주스 ) 와유도제 (rifampin, phenobarbital, phenytoin) 사용주의 CYP3A, CYP2D6, P-glycoprotein 억제 : 일부 statins, sirolimus, tacrolimus, beta-blockers, digoxin 농도증가 Sotalol 40-160 mg을 12시간간격 증가된 QT 간격 신장질환 저칼륨혈증 이뇨제사용 QT 간격을연장시키는약물 동결절또는방실결절장애 심부전 천식 없음 ( 신장배설 ) VOL.15 NO.4 17
구조적심장질환없음 구조적심장질환 관상동맥질환 심부전 Dofetilide Dronedarone Flecainide Propafenone Sotalol 전극도자절제술 Dofeilide Dronedarone Sotalol 전극도자절제술 Dofetilide Figure 2. Strategies for rhythm control in patients with paroxysmal and persistent AF Catheter ablation is only recommended as first-line therapy (dotted line) for patients with paroxysmal AF (Class IIa recommendation). Depending on patient preference when performed in experienced centers. Dofetilide, flecainide, propafenone, sotalol are not recommended with severe LVH (wall thickness >1.5 cm). Defetilide, sotalol should be used with caution in patients at risk for torsades de pointes ventricular tachycardia. Flecainide, propafenone should be combined with AV nodal blocking agents. Class IIa 1. 심박수조절 ( 안정시심박수 <80회 / 분 ) 은심방세동의증상관리를위해타당하다 (level of evidence: B). 2. 정주용 amiodarone은조기흥분이없는중환자의심박수조절에유용할수있다 (level of evidence: B). 3. 방실결절절제술및영구적인방실조율은약물치료가불충분하고율동치료가안되는경우에심박수조절을위해사용할수있다 (level of evidence: B). Class IIb 1. 증상이없으면서좌심실수축기기능이보존되어있는경우에는심박수조절 ( 안정시심박수 <110 회 / 분 ) 을느슨하게하는것도타당성이있을것 같다 (level of evidence: B). 2. 경구용 amiodarone은다른방법들이실패하거나금기일때심박수조절을위해사용할수있을것같다 (level of evidence: C). Class III 1. 방실결절절제술및영구적인방실조율은약물치료에의해심박수조절을시도하지않은상태에서는시행하지않는다 (level of evidence: C). 2. Non-dihydropyridine calcium channel antagonist는혈류역학적손상을초래할수있으므로비대상성심부전 (decompensated heart failure) 환자에서는사용해서는안된다 (level of evidence: C). 3. 조기흥분이있는심방세동환자에서는 digoxin, 18 The Official Journal of Korean Heart Rhythm Society
non-dihydropyridine calcium channel antagonist, 정주용 amiodarone을사용해서는안된다. 이약제들은심박수를증가시켜심실세동을유발할수있다 (level of evidence: B). 4. Dronedarone은영구형심방세동환자에서심박수조절을위해사용해서는안된다. 뇌졸중, 심근경색증, 전신성혈전증, 심혈관사망의위험성을증가시킨다 (level of evidence: B). 율동치료 (Rhythm Control) 많은환자에서심박수조절치료가선행되나증상이조절되지않는경우, 적절한심박수조절이어려운경우, 젊은환자, 빈맥-유발성심근증, 첫번째인경우, 환자가원하는경우등에는율동치료를고려한다. 율동치료는전기적율동전환, 항부정맥제, 그리고전극도자절제술을고려할수있다. 여기서는약물에의한동율동전환및유지에대해서만언급하기로한다 (Table 2, 3, Figure 2). 약물에의한동율동전환시권장사항 Class I 1. Flecainide, dofetilide, propafenone, 정주용 ibutilide가선택된약물에대한금기사항이없다면심방세동및심방조동의약물적인동율동전환에유용하다 (level of evidence: A). Class IIa 1. 경구용 amiodarone 투여가심방세동의약물학적동율동전환에합리적인선택이다 (level of evidence: A). 2. 또는 non-dihydropyridine calcium channel antagonist에추가한 propafenone 또는 flecainide ( pill-in-thepocket ) 는선택한환자의모니터링환경에서안전하게사용했던적이있다면병원밖에서심방세동을종료하기위한방법으로사용할수 있다 (level of evidence: B). Class III 1. Dofetilide는과도한 QT 간격의연장을유도하여 torsades de pointes를일으킬위험성이있기때문에병원밖에서치료를시작해서는안된다 (level of evidence: B). 동율동유지를위한항부정맥제에대한권장사항 Class I 1. 항부정맥치료를시작하기전에심방세동의가역적인원인및유발요인에대한치료가이루어져야한다 (level of evidence: A). 2. 심방세동환자에서다음과같은항부정맥제를기저심장질환및동반된질환에따라동율동을유지하기위해사용한다 (level of evidence: A). a. b. Dofetilide c. Dronedarone d. Flecainide e. Propafenone f. Sotalol 3. 항부정맥제를사용하기전에각각항부정맥제의부작용 ( 특히 proarrhythmia) 을고려해야한다 (level of evidence: C). 4. 을사용할때에는 amiodarone의독성에의한위험성을고려해야하고, 다른약물로치료에실패하거나다른약물이금기일때사용해야한다 (level of evidence: C). Class IIa 1. 심방세동환자에서빈맥-유발성심근증의치료에항부정맥제를이용한율동치료는유용하다 (level of evidence: C). Class IIb 1. 항부정맥제에의해심방세동의빈도수또는 MAIN TOPIC REVIEWS VOL.15 NO.4 19
증상이감소했을때, 심방세동의재발이빈번하지않고증상이심하지않더라도현상태의항부정맥제를지속하는것은타당할것같다 (level of evidence: C). Class III 1. 심방세동이영구형으로진행되면율동치료를위한항부정맥제 ( 특히 dronedarone) 사용은중지해야한다 (level of evidence: B). 2. Dronedarone 은심부전 (NYHA [New York Heart Association] class III, IV) 이있거나지난 4주이내에비대상성심부전이있었던경우심방세동의치료를위해사용해서는안된다 (level of evidence: B). 결론 이번 2014년미국심장학회의심방세동치료에대한권장사항중혈전색전증예방을위한위험도평가및약물사용에있어서는큰변화가관찰되나, 약물을사용한심박수조절및율동조절에대해서는크게바뀐것은없는것같다. 하지만항부정맥제사용시그효과와부작용에대한심도있는고려가필요함을강조하고있다. 그래서환자의임상상태및심방세동발생요인등을종합적으로평가하여적절한치료전략을수립하고환자에게접근하는것이좋겠다. Reference 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. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/ American Heart Association task force on practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014 [Epub ahead of print] 20 The Official Journal of Korean Heart Rhythm Society