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1 대한내과학회지 : 제 93 권제 2 호 What s new? 2018 대한부정맥학회심방세동환자의심박수조절지침 1 서울대학교보라매병원순환기내과, 2 서울대학교서울대학교병원순환기내과, 3 연세대학교세브란스병원심장내과, 4 울산대학교서울아산병원심장내과 임우현 1 최의근 2 정보영 3 최기준 Korean Heart Rhythm Society Guidelines for The Rate Control of Atrial Fibrillation Woo-Hyun Lim 1, Eue-Keun Choi 2, Boyoung Joung 3, and Kee-Joon Choi 4 1 Division of Cardiology, Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul; 2 Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul; 3 Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul; 4 Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Atrial fibrillation (AF) is characterized by irregular and relatively rapid heart rate, which occasionally causes symptoms such as palpitations, dyspnea, or reduced exercise capacity. Controlling the ventricular rate is a mainstay for the symptom management of patients with AF. Rate control can be achieved with beta-blockers, non-dihydropyridine calcium channel blockers, digoxin, or combination therapy. Rhythm control is an option for patients in whom appropriate rate control cannot be achieved or who have persistent symptoms despite rate control. The choices of drug and target heart rate are usually specified by international guidelines for AF management. However, pivotal trials included in those guidelines enrolled only a small number of Asian subjects, which limit application of those guidelines to a Korean population. The Korean Heart Rhythm Society organized the Korean AF Management Guideline Committee and analyzed all available studies regarding management of AF including studies with Korean patients. Then, expert consensus or guidelines for optimal management in Korean patients with AF were achieved after systematic review with intensive discussion. This article provides general principles for rate control therapy in Korean patients with AF. (Korean J Med 2018;93: ) Keywords: Atrial fibrillation; Heart rate; Practice guideline Correspondence to Eue-Keun Choi, M.D., Ph.D. Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: , Fax: , choiek17@snu.ac.kr Copyright c 2018 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 - The Korean Journal of Medicine: Vol. 93, No. 2, 서론심방세동환자의치료에있어심실박동수를적절히조절하는것은중요한부분을차지한다. 동율동유지를위한다양한약물적또는비약물적치료방법의발전으로동율동조절전략은증상이있는심방세동환자의일부에서유용하게사용되고있다. 반면, 심박수조절치료는대다수의심방세동환자에서중요하고유용한치료법인데, 심박수조절이된후무증상이거나증상이거의없는환자들의경우특히그렇다. 심박수조절을위해다양한약제들을사용할수있으나그근거는심방세동환자의뇌졸중예방에대한근거와비교하여약한편이다 [1,2]. 약제에의한심박수조절은베타차단제, 칼슘통로차단제, 디곡신또는이들의조합을사용할수있다. 항부정맥제 ( 아미오다론, 드로네다론등 ) 와같은약제는심박수조절기능을가지고있으나이러한약제는동율동조절이필요한환자에서만제한적으로사용할것을추천한다. 표 1에심방세동환자의심박수조절지침이정리되어있다. 수는환자의특성, 증상, 좌심실박출률과혈역학적상태에따라결정되나초기에는느슨하게 (lenient) 심박수를조절하는것이무난하다. 박출률저하심부전의경우베타차단제와디곡신또는이들의병용사용을추천하며, 딜티아젬이나베라파밀은심실수축력을저하시킬수있어사용에주의해야한다 [10]. 중환자이거나심한좌심실기능저하가있는환자에서심박수상승이혈역학적불안정성을초래할수있을경우아미오다론주사제를사용할수있다 [11-13]. 혈역학적으로불안정할경우긴급심장율동전환을고려해야한다 (Fig. 1 and Table 1). 급성기심박수조절 새로발생한심방세동환자의경우증상조절을위해심박수조절이필요한경우가많다. 담당의사는심박수상승의원인이될수있는요인들, 예를들어, 감염, 내분비장애, 빈혈, 폐색전증등이있는지우선감별을해야한다. 급성기심박수조절을위해서는베타차단제와칼슘통로차단제가빠른작용과교감신경항진시효과적인심박수조절이가능하기때문에디곡신보다선호된다 [3-9]. 약제선택과목표심박 Figure 1. Acute heart rate control in patients with atrial fibrillation. See Table 2 for drug dosage. AF, atrial fibrillation; LVEF, left ventricular ejection fraction; bpm, beats per minute. Table 1. Summary of recommendations for rate control of atrial fibrillation 1. 좌심실박출률 40% 이상인환자의심박수조절을위해베타차단제, 디곡신, 베라파밀및딜티아젬이추천된다. (class I, level of evidence B) 2. 좌심실박출률 40% 미만인환자의심박수조절을위해베타차단제, 디곡신이추천된다. (class I, level of evidence B) 3. 한가지약제로심박수조절이되지않을경우다른약제와조합으로심박수조절을시도해볼수있다. (class IIa, level of evidence C) 4. 혈역학적으로불안정하거나심한좌심실기능저하를보일경우, 심박수조절을위해아미오다론을사용할수있다. (class IIb, level of evidence B) 5. 영구형심방세동환자에서항부정맥제를사용한심박수조절은추천되지않는다. (class III, level of evidence A) 6. 심방세동환자의목표심박수는안정시 110 회 / 분이하로유지할것을추천한다. (class IIa, level of evidence B) 7. 조기흥분증후군또는임신중발생한심방세동의경우심박수조절보다는리듬조절을우선시해야한다. (class IIa, level of evidence C) 8. 집중적인심박수및리듬조절치료에반응하지않거나약물치료를잘견디지못하는환자들에서향후박동조율기에의존해야함을받아들일경우방실결절절제술을고려할수있다. (class IIa, level of evidence B)

- Woo-Hyun Lim, et al. Guidelines for rate control of atrial fibrillation - 심방세동의장기적심박수조절베타차단제베타아드레날린수용체차단제단일요법은심박수조절일차선택약제로서흔히사용된다. 이는베타차단제가디곡신보다급성기심박수조절을더잘한다는관찰연구를바탕으로한다.

14, p = 0.73), 동리듬환자들에서는확실히효과가있었다 (HR 0.73, 95% CI 0.67-0.80, p < 0.001) [14].

그이유는심박수조절에따른증상및기능개선효과가있고, 발표된연구들에따르면위해가없으며, 동리듬이든심방세동이든모든연령에서양호한내약성을보이기때문이다 [14,16]. 디지탈리스디곡신이나디지톡신과같은심장글리코시드는최근 15년간사용이줄어들고있긴하나 20여년간이상사용되어왔다.

관찰연구들에따르면심방세동환자들에서디곡신사용이사망률증가와관련되었다고하나 [23-25], 이러한관련성은디곡신자체의해로운효과라기보다는선택및처방치우침 (selection and prescription biases) 현상에의한것으로생각되는데 [26-28], 이는특히디곡신이보통더병든환자들에서더처방되기때문이다 [29].

3 - Woo-Hyun Lim, et al. Guidelines for rate control of atrial fibrillation - 심방세동의장기적심박수조절베타차단제베타아드레날린수용체차단제단일요법은심박수조절일차선택약제로서흔히사용된다. 이는베타차단제가디곡신보다급성기심박수조절을더잘한다는관찰연구를바탕으로한다. 흥미롭게도동리듬인박출률저하심부전환자들에서관찰되는베타차단제의예후개선효과는심방세동환자들에서는관찰되지않는다. 10개의무작위대조시험들을각환자- 수준에서메타분석한연구결과에따르면베타차단제는심방세동환자들에서는위약과비교하여총사망률을줄이지못하였으나 (hazard ratio [HR] 0.97, 95% confidence interval [CI] , p = 0.73), 동리듬환자들에서는확실히효과가있었다 (HR 0.73, 95% CI , p < 0.001) [14]. 반면, 우리나라건강보험공단표본코호트데이터베이스를분석한연구결과를보면, 심방세동이동반된심부전환자들의치료에있어서베타차단제는칼슘통로차단제나디곡신또는심박수조절약제를사용하지않는경우와비교하여사망률을유의하게감소시키는것으로나타났다 [15]. 이연구에서는좌심실박출룰에대한데이터가제시되지는않은제한점이있다. 본지침에서는베타차단제를모든심방세동환자들에서심박수조절일차선택약제로고려한다. 그이유는심박수조절에따른증상및기능개선효과가있고, 발표된연구들에따르면위해가없으며, 동리듬이든심방세동이든모든연령에서양호한내약성을보이기때문이다 [14,16]. 디지탈리스디곡신이나디지톡신과같은심장글리코시드는최근 15년간사용이줄어들고있긴하나 20여년간이상사용되어왔다. Digitalis Investigation Group 연구에서디곡신은동리듬의박출률저하심부전환자들에서위약과비교하여사망률에미치는효과는없었으나 (risk ratio [RR] 0.99, 95% CI ), 입원율을낮췄다 (RR 0.72, 95% CI ) [21,22]. 심방세동환자들에서디곡신을직접비교한무작위대조시험연구는없다. 관찰연구들에따르면심방세동환자들에서디곡신사용이사망률증가와관련되었다고하나 [23-25], 이러한관련성은디곡신자체의해로운효과라기보다는선택및처방치우침 (selection and prescription biases) 현상에의한것으로생각되는데 [26-28], 이는특히디곡신이보통더병든환자들에서더처방되기때문이다 [29]. 다른심박수조절약제들과의비교는대부분소규모의짧은기간진행된연구들을바탕으로하는데, 디곡신은운동능력, 삶의질, 또는좌심실박출률측면에서다른약제들과차이가없거나미미한차이정도만보였다 [30-33]. 혈청농도 ng/ml 에해당하는저용량의디곡신 ( 250 µg/day) 을사용할경우예후가더좋을가능성이있다 [29]. 아미오다론아미오다론은심박수조절의마지막수단으로유용하다. 아미오다론은다양한심장외부작용때문에, 병용요법 ( 예, 비-디히드로피리딘계칼슘통로차단제심방세동환자에서베라파밀또는딜티아젬을사용하여심박수조절을할수있다 [17]. 그러나이약제들은박출률저하심부전환자들에서는음성수축력작용이있기때문에사용을피해야한다 [10,18,19]. 베라파밀또는딜티아젬은부정맥관련증상을개선시킬수있다고보고되었다 [1]. 좌심실박출률이정상인만성심방세동환자를대상으로한소규모연구에따르면베라파밀또는딜티아젬은운동능력을증가시기고, 뇌나트륨이뇨펩티드수치를감소시키는반면, 베타차단제는운동능력을감소시키고뇌나트륨이뇨펩티드수치를증가시킨다고보고되었다 [20] Figure 2. Long-term heart rate control in patients with atrial fibrillation. See Table 2 for drug dosage. AF, atrial fibrillation; bpm, beats per minute; LVEF, left ventricular ejection fraction.

4 - 대한내과학회지 : 제 93 권제 2 호통권제 681 호 Table 2. Rate control therapy in atrial fibrillation Drug Acute rate control (IV) Long-term rate control (PO) Adverse effect Comments Beta-blockers Bisoprolol Carvedilol Metoprolol Nebivolol Esmolol mg QD or split mg BID 8-64 mg QD (ER) mg BID mg QD (ER) mg QD or split Bradycardia, atrioventricular block, and hypotension. Lethargy, headache, peripheral edema, upper respiratory tract symptoms, gastrointestinal upset, and dizziness. Calcium-chan nel blockers Diltiazem Verapamil Cardiac glycosides Digoxin 500 mcg/kg IV bolus over 1 minute, then mcg/kg/min 0.25 mg/kg IV bolus over 2 minutes, then 5-15 mg/hr mg TID mg QD (ER) mg/kg IV mg TID bolus over 2 minutes, mg QD (ER) then 5 mcg/kg/min Bradycardia, atrioventricular block, and hypotension (prolonged hypotension possible with verapamil. Dizziness, malaise, lethargy, headache, hot flushes, gastrointestinal upset, and edema mg IV with repeated dosing to a maximum of mg over 24 hours mg QD Gastrointestinal upset, dizziness, blurred vision, headache, and rash. In toxic states (serum levels > 2 ng/ml), digoxin is proarrhythmic and can aggravate heart failure, particularly with coexistent hypokalemia. Specific indications Amiodarone 300 mg IV over 1 hour, then mg/hr over 24 hours (preferably via central venous catheter) mg QD Hypotension, bradycardia, nausea, QT prolongation, pulmonary toxicity, skin discoloration, thyroid dysfunction, corneal deposits and cutaneous reaction with extravasation. Bronchospasm is rare. In cases of asthma, recommend beta-1 selective agents. Contra-indicated in acute heart failure and a history of severe bronchospasm. Use with caution in combination with beta-blockers. Reduce dose with hepatic impairment and start with smaller dose in renal impairment. Contra-indicated in LV failure with pulmonary congestion or LVEF < 40%. High plasma levels associated with increased risk of death. Check renal function before starting and adapt dose in patients with CKD. Contra-indicated in patients with accessory pathways, ventricular tachycardia and hypertrophic cardiomyopathy with outflow tract obstruction. Suggested as adjunctive therapy in patients where heart rate control cannot be achieved using combination therapy. IV, intravenous; PO, per os; QD, once daily; BID, twice daily; ER, extended release; TID, 3 times a day; LV, left ventricular; LVEF, left ventricular ejection fraction; CKD, chronic kidney disease. 베타차단제또는베라파밀 / 딜티아젬과디곡신의조합 ) 을통해서도심박수조절이되지않는환자들에게서예비약제로사용되어야한다. 정리하면, 심방세동에서다양한심박수조절약제들의사용에는균형이존재한다. 베타차단제, 딜티아젬 / 베라파밀, 디곡신, 또는병용요법을선택할지는환자의특성및선호를고려하여개별적으로결정되어야한다. 각치료약제들은각각의부작용가능성이있기때문에저용량부터시작하여증상이개선될때까지증량되어야한다. 임상적으로심박수 110회 / 분이하를달성하기위해서는병용요법이종종필요

5 - 임우현외 3 인. 심방세동심박수조절지침 - 하다 (Fig. 2 and Table 2). 다양한심박수조절전략들이증상, 삶의질그리고다른목표를개선시킬지에대한연구들이진행중에있다. 심방세동에서목표심박수심방세동환자에게최상의목표심박수는아직명확하지않다. 영구형심방세동환자 614명을대상으로엄격한심박수조절군 ( 휴식시목표심박수 80회 / 분미만, 중등도운동시 110 회 / 분미만 ) 과느슨한심박수조절군 ( 안정시심박수 110회 / 분미만 ) 으로무작위배정하여두군간의임상적사건을관찰한 Rate Control Efficacy in Permanent Atrial Fibrillation (RACE) II 연구결과에따르면두군에서임상사건의복합지표 ( 엄격한심박수조절군에서 14.9%, 관대한심박수조절군에서 12.9%), New York Heart Association functional class 또는입원치료여부에차이가없었다 [34,35]. 즉엄격한심박수조절이느슨한심박수조절과비교하여임상적인이득이없었다. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) 연구와 RACE 연구를종합분석한결과도이와유사하였다 [36]. 그러나 AFFIRM 연구에서초기약물치료로목표심박수를달성한환자의비율이 58% 에불과하였다 [37]. RACE 연구의연구대상자들은대부분좌심실부전이없는환자들이며느슨한심박수조절군의 78% 가안정시맥박수가 100회 / 분으로양군간의심박수차이가 10회분에불과하였다 [34]. 이와함께심박수가적절히조절되고 ( 안정시심박수 회 / 분 ) 있더라도상당수의심방세동환자들은심한증상을호소하여추가적인치료가필요하다는점은주목할필요가있다 [38]. 결국, 느슨한심박수조절은증상조절을위해엄격한심박수조절이필요하지않는이상수용가능한초기접근이다. 동리듬인박출률저하심부전환자들의경우베타차단제를투약하여심박수를감소시키면사망률감소등예후개선효과가관찰되나심방세동환자들에서는관찰되지않는다 [14]. 반면, 스웨덴심부전등록 (Swedish Heart Failure Registry) 연구결과를보면박출률저하심부전이동반된심방세동환자들에서심박수가 100회 / 분이상으로조절될경우사망률이증가하는것으로나타났고베타차단제를사용할경우사망률을낮출수있는것으로보고되었다 [39]. 방실결절절제및심장조율약물치료를통해심박수및증상조절에실패하였을경우방실결절및히스속을절제하고 VVI형박동조율기를삽입하여심박수를조절할수있다. 특히박동조율기를방실결절절제수주전에삽입하고절제술후초기심박조율을 회 / 분으로설정할때합병증발생률이낮고장기사망률도낮다 [40-43]. 이시술은좌심실기능을저하시키지않고일부환자들에서는좌심실기능을호전시키기도한다 [44-47]. 일부의박출률저하심부전환자들에서양심실조율 ( 심장재동기화치료 ) 을통해심방세동이종료되기도한다 [48]. 물론심장재동기화치료의 리듬조절 효과는작을것으로생각되고검증이필요하다 [49]. 방실결절절제술은환자들에게남은여생을박동조율기에의존하게만들기때문에심박수조절약물또는적절한리듬조절중재술을통해서도증상이조절되지않는환자들에게만시행하도록한다. 박동조율기의선택 ( 우심실또는양심실조율및삽입형제세동기유무 ) 은좌심실박출률을포함한각환자의특성을고려하여결정한다 [50]. 결론동율동유지를위한다양한약물적또는비약물적치료법의발전에도불구하고심박수조절은심방세동환자의치료에있어여전히중요하다. 특히심박수조절후무증상이거나증상이거의없는환자들그리고영구형심방세동환자의증상조절을위해유용한치료법이다. 심박수조절을위해가능하면심장초음파를실시하여좌심실수축기능에대한평가를하고이를바탕으로적절한약물을선택한다. 방실결절차단약제인베타차단제, 비-디히드로피리딘계칼슘통로차단제 ( 딜티아젬및베라파밀 ), 디곡신또는이들의병용요법을사용할수있고초기심박수조절목표는안정시 110회 / 분미만이다. 증상조절이충분하지않을경우심박수를추가로낮춰볼수있겠다. 약제투여로심박수조절이잘되지않을경우드물게는발실결절절제및박동조율기삽입을고려할수도있다. 중심단어 : 심방세동 ; 심박수 ; 진료지침

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R