<303220C6AFC1FD3220C0CCB0E6BCAE2E687770>

Size: px

Start display at page:

Download "<303220C6AFC1FD3220C0CCB0E6BCAE2E687770>"

세정 안
5 years ago
Views:

1 대한내과학회지 : 제 90 권제 3 호 특집 (Special Review) - 빈맥질환의최신지견 심방세동에서항부정맥제의역할 전북대학교의과대학심장내과학교실심혈관연구소 이경석 The Role of Antiarrhythmics in Atrial Fibrillation Kyoung-Suk Rhee Institute of Cardiovascular Research, Divison of Cardiology, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea Atrial fibrillation (Afib) is the most common arrhythmia with clinical significance, and its incidence increases with advanced age. Afib is associated with a 3- to 5-fold increased risk of stroke, a 3-fold increase in the risk of heart failure, and higher mortality than without Afib. The treatment of Afib is multifold but revolves around one essential issue: whether to attempt to restore sinus rhythm or to simply control the ventricular rate. This decision depends on symptom severity, the age of the patient, underlying heart disease, and other comorbidities that may limit therapeutic options. The management of Afib with antiarrhythmic medications was reviewed. (Korean J Med 2016;90: ) Keywords: Atrial fibrillation; Anti-arrhythmic gents; Heart rate control; Cardioversion 서론심방세동은심방전체가무질서한전기적인활성화로인해효과적인수축을할수없는심실상성빈맥 (supraventricular tachyarrhythmia) 으로써치료를요하는부정맥중가장흔하다. 전체환자의약 1% 가 60세미만이며, 75-84세가약 12%, 1/3 이상의환자가 80세이상인것을보면, 심방세동은고령에서매우높은유병률을보이는질환임을알수있다 [1-3]. 심방세동은그지속기간에따라발생 1주일이내에종료되는경우를발작성심방세동 (paroxysmal atrial fibrillation), 1주이상지속되는경우는지속성 (persistent) 심방세동, 1년이상 지속되는경우장기지속성 (long standing persistent) 심방세동으로분류하고, 영구적인 (permanent) 심방세동이란기간의개념보다는동율동전환시도를완전히중단한경우로그의미가변하였다. 비판막성심방세동 이란새로운항응고제 (new oral anticoagulants) 와관련된연구에포함된환자군에의해부각된용어이며, 류마티스성승모판협착증, 인공심장판막, 승모판성형수술의기왕력등이없는심방세동을지칭한다 [4]. 심방세동은빠르거나느린조절되지않은심박수, 심방수축기능상실에의한불규칙한심실내혈액유입, 혈역학적불안정등으로인해피로, 심계항진, 호흡곤란등심부전증상과현기증또는실신을일으킬수있다. 심방세동의불규칙하고 Correspondence to Kyoung-Suk Rhee, M.D., Ph.D. Institute of Cardiovascular Research, Divison of Cardiology, Department of Internal Medicine, Chonbuk National University Medical School, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Korea Tel: , Fax: , ksee@jbnu.ac.kr Copyright c 2016 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 - Kyoung-Suk Rhee. Antiarrhythmics for atrial fibrillation - 빠른심실수축에의해빈맥유발성심근병증 (tachycardia induced cardiomyopathy) 이유발될수있으며, 섬유화및확장을동반한좌심방의변성이진행된다. 심방내혈류정체로인해주로좌심방이 (left atrial appendage) 에서생성되는혈전에의한뇌졸중및전신색전증은가장피하고싶은심방세동의합병증이라할수있다. 심방세동의치료는다양한면을고려해야하겠지만, 우선적으로는증상의중증도, 환자의나이, 기저심질환유무및동반질환상태등에따라동율동 (sinus rhythm) 을회복시키고자하는율동조절방침 (rhythm control strategy) 과심방세동은그대로두고심실박동수만을일정범위내로조절하는심박수조절방침 (rate control strategy) 중하나를선택하게된다. 심방세동상태라하더라도신체활동능력에지장이없는경우에는심박수조절만으로도적절한치료가될수있다. 하지만심한좌심실비후등, 심실이완기장애와같이심방수축이심실내혈액유입에지대한역할을하는경우는단순히심박수조절만으로심부전증상이나신체활동능력을충분히개선시키기어렵기때문에심방수축의회복을기대할수있는율동조절방침이도움이될수있다. 또한, 심박수의조절여부와관계없이심방세동자체가심방의변성을초래함으로써영구적으로동율동회복을기대할수없는상황까지진행하기때문에젊은환자의경우적극적인율동조절을시도하게된다. 동율동을유지하는것은심박수만조절된심방세동에비해당연히좋을것으로기대된다. 하지만, 동율동을유지하기위해서는상당한노력이필요하고, 항부정맥제와연관된어느정도의위험까지도감수해야하기때문에, 단순한심박수조절만으로도일상생활에지장이없는상당수의심방세동환자들에게과연율동조절이의미있는도움이될것인가에대해서오랜논란이있어왔다. 이에관한 atrial fibrillation follow-up investigation of rhythm management (AFFIRM) [5] 와 rate control versus electrical cardioversion for persistent atrial fibrillation (RACE) 연구 [6] 를보면의외로심박수조절에비해율동조절의장점이입증되지않았다. 이는동율동이유지될때기대되었던장점이항부정맥제자체의부작용에의해상쇄되었을가능성이있으며, 율동조절환자군에서많았던항응고요법중단에의한뇌졸중위험의증가도부분적으로연관이있었을가능성이제시되었다. 이결과가발표된후지속성심방세동환자에서율동조절을위한노력을덜하게된것이사실이지만, AFFIRM 의하위연구에서동율동의존재와사망률의감소사이에분명한상관관계가있었다는것은주의깊게봐야할점이다. 심박수조절방침 (rate control strategy) 심방세동환자의심박수조절목표를어떻게정하는것이가장바람직할것인지에관해서는논란이있다. AFFIRM 연구에서의평균심박수목표치는안정시 80회 / 분, 활동중 110 회 / 분이었다 [5]. RACE-II 연구 [6] 에서는심박수의엄격한조절군 ( 안정시 < 80회 / 분 ) 과관대한조절군 ( 안정시 < 110회 / 분 ) 을 3년간비교관찰한결과심혈관계사망, 심부전에의한입원, 뇌졸중, 전신색전증, 출혈, 치명적인부정맥등의복합종점 (composite endpoint) 에서양군간의미있는차이가없었다. 하지만이결과를주의깊게살펴보면, RACE-II 연구에참여한대다수환자의심실수축력은이상이없었고, 결과적으로보면, 조절되었던안정시평균심박수차이는양군간에단지 10회 / 분이었으며, 관대한조절군의 78% 에서안정시심박수가 100회 / 분미만이었다. 따라서, 이러한관대한목표심박수를전체심방세동환자에게적용하고자한다면조심스러운접근이필요하다. 환자의증상과심부전, 판막질환등동반질환의정도에따라최적의심박수가다를수있으며, 앞으로이에대한추가연구들이필요하다. 심박수조절에대한지침은표 1에정리하였다. 심박수조절에사용되는주요약제베타차단제 (beta blockers) 교감신경활성화를차단함으로써심박수를조절하게되며, 심부전을동반한심방세동에서금기사항이없는한가장도움이되는약제이다. 심박수조절이급히필요한경우에는에스몰롤 (esmolol), 프로프라놀롤 (propranolol) 등정맥주사가유용하다. 급성대상부전 (acute decompensation) 상태의심부전에서베타차단제가금기사항이라는것은잘알려져있다. 하지만급성심부전상태의주요원인이심한빈맥인경우베타차단제정맥투여는큰도움이되며, 심박수가조절됨에따라심부전상태및증상의급격한호전을기대할수있다. 특히, 작용시간이매우짧은에스몰롤은타약제에비해안전하게시도해볼수있다. 경구용베타차단제로는비소프롤롤 (bisoprolol), 카베딜롤 (carvedilol), 아테놀롤 (atenolol), 네비볼롤 (nebivolol), 프로프라놀롤 (propranolol) 등이흔히사용된다. 경구용약제를이용하여심박수조절을시도할때, 경우에따라서는과도한서맥이유발될수있으며, 그회복또한빠른시간내에이루어지지않기때문에용량조절을점진적으로하는것이안전하다

3 - 대한내과학회지 : 제 90 권제 3 호통권제 667 호 Table ACC/AHA/HRS recommendations for rate control Recommendations COR LOE Control ventricular rate using a beta blocker or nondihydropyridine calcium channel antagonist for paroxysmal, I B persistent, or permanent AF IV beta blocker or nondihydropyridine calcium channel blocker is recommended to slow ventricular heart rate in the acute setting in patients without pre-excitation. In hemodynamically unstable patients, electrical cardioversion is indicated I B For AF, assess heart rate control during exertion, adjusting pharmacological treatment as necessary I C A heart rate control (resting heart rate < 80 bpm) strategy is reasonable for symptomatic management of AF IIa B IV amiodarone can be useful for rate control in critically ill patients without pre-excitation IIa B AV nodal ablation with permanent ventricular pacing is reasonable when pharmacological therapy is inadequate and IIa B rhythm control is not achievable A lenient rate-control strategy (resting heart rate < 110 bpm) may be reasonable when patients remain asymptomatic IIb B and LV systolic function is preserved Oral amiodarone may be useful for ventricular rate control when other measures are unsuccessful or contraindicated IIb C AV nodal ablation should not be performed without prior attempts to achieve rate control with medications III: harm C Nondihydropyridine calcium channel antagonists should not be used in decompensated HF III: harm C With pre-excitation and AF, digoxin, nondihydropyridine calcium channel antagonists, or amiodarone should not be III: harm B administered Dronedarone should not be used to control ventricular rate with permanent AF III: harm B COR, class of recommendation; LOE, level of evidence; AF, atrial fibrillation; bpm, beats per minute; IV, intravenous; AV, atrioventricular; LV, left ventricular; HF, heart failure. 칼슘차단제 (nondihydropyridine calcium channel blockers) 방실결절에직접작용하여전도속도를감소시킨다. 베라파밀 (verapamil) 과딜티아젬 (diltiazem) 이대표적인약제이며, 안정시심박수뿐만아니라운동중에상승하는심박수의조절에도효과적이다. 이두약제모두정맥주사가가능하여급하게심박수조절이필요한경우에효과적으로사용할수있다. 하지만심실수축력에는부정적으로작용하기때문에좌심실수축력이저하된환자에서는사용하지않도록권고된다. 디곡신 (digoxin) 심방세동환자에서안정시심박수에대한조절효과는있지만, 운동중상승하는심박수의조절에는효과가없기때문에디곡신만을사용한심박수조절은특히, 젊은환자의경우권해지지않는다. 또한, 주사제를사용하는경우에도그효과가시작되는데 1시간이상지나야하고, 최고점에도달하는데 6시간이상소요되기때문에급하게심박수를조절해야하는경우에는적절한약제가아니다 [7]. 이러한이유에서디곡신은심방세동의심박수조절에있어서 1차약제가아니다. 그럼에도불구하고심실수축을저하시키지않는몇안되는약제중하나이기때문에심부전을동반한심방세동에서보조적으로사용될수있으며, 활동시심박수조절을위해서베타차 단제나칼슘차단제 (nondihydropyridine 계 ) 를병용하는경우가흔하다. 신장으로배설되기때문에신기능이저하된경우용량조절이필요하며, 디곡신의배설을감소시키는약제들인아미오다론 (amiodarone), 프로파페논 (propafenone), 칼슘차단제 (nondihydropyridine 계 ) 등과병용할경우에는주의를요한다. 기타심박수조절을위한약제아미오다론은교감신경활성의억제작용과칼슘차단효과에의해방실결절전도속도를늦춘다. 정맥주사의경우중증환자의심방세동에서심박수조절을위해사용되고는있지만, 칼슘차단제 (nondihydrompyridine계 ) 에비해덜효과적이고, 목표에도달하는시간또한 2-3배많이소요된다 [8,9]. 고용량을부하 (loading) 할경우작용시작시간을줄일수있지만, 최근대상부전에빠진심부전이나혈압이낮은환자에서는혈역학적불안정상태를급격히악화시킬수있으므로주의를요한다. 지속성심방세동환자에서경구용아미오다론의심박수조절효과에대한자료는미미하다. 또한, 다양한독성과많은약제들과의상호작용으로인해심박수조절만을목적으로한아미오다론의사용은극히제한적이다. Wolff-Parkinson-White 증후군에동반된심방세동에서는아미오다론주사가심박수를증가시켜치명적인심실부정맥을유발시킬수있기때문에

4 - 이경석. 심방세동과항부정맥제 - 사용하면안된다 [10,11]. 요오드기 (iodine moiety) 에의한아미오다론의독성을줄이고자개발된드로네다론 (dronedarone) 은심방세동의안정시및운동중심박수모두를감소시키는것으로알려져있다. 하지만대규모연구들에서드로네다론은지속성심방세동환자에서심부전, 뇌졸중, 심혈관계사망률, 예기치않은입원등을모두증가시켰기때문에심박수조절을목적으로사용되어서는안된다. 또한, 심부전과심실수축장애가있는환자에서도심근경색, 전신색전증, 심혈관계사망의복합종점을상승시켰기때문에사용해서는안된다 [12,13]. 방실결절의절제영구형심방세동에서다른모든방법에의해심박수조절이불가능할때시도해볼수있는방법이다. 주로고주파전극도자절제술을이용하며, 방실접합부절제를통해심방과심실을전기적으로분리시키고, 영구형인공심박동기를이용하여심실을조율하기때문에심박수조절을위한투약은더이상필요치않게된다. 심방세동환자의방실결절절제이후에는박동기의존적일수있기때문에방실차단을시킨이후에박동기의작동에문제가생기면치명적일수있다. 따라서, 시간적으로가능하다면심박동기이식을적어도 4-6주전에시행함으로써안정적인박동기작동이확실한상태에서방실결절절제를시도하는것이권해진다. 율동조절방침 (rhythm control strategy) 많은심방세동환자들에서심박수를조절하고있지만, 동율동을유지하게되면상당수의환자들에서삶의질이향상되고증상의개선이분명히있기때문에율동조절이선호되는상황이있다. 심박수가적절히조절되고있음에도불구하고증상이지속되는환자, 조절약제로원하는심박수에도달할수없거나, 빈맥유발성심근병증, 처음발생한심방세동, 급성병증에병발된심방세동, 심박수조절보다는율동조절을환자가원하는경우에는율동조절방침을선택하는것이바람직하다. 심방세동은심방세동을낳는다 [14] 라는문구는이부정맥이지속적으로진행하는질환임을암시한다. 세동상태의심방은구조적재형성 (remodeling) 이점차진행되기때문에, 지금증상이없다하더라도환자가젊을수록동율동회복을기대조차할수없는상태까지진행하는것을원하지않으므로율동전환이선호되기도한다 [15-17]. 율동전환에대한지침은표 2에정리하였다. 전기적율동전환전기적율동전환이건항부정맥제를이용하건방법에관계없이, 일정기간이상지속된심방세동을동율동으로전환하고자하는경우가장우선적으로고려해야할것은뇌졸중의위험이다. 혈전색전증은심방특히, 좌심방이 (left atrial appendage) 내에이미형성되어있던혈전이분리되어발생하거나, 48시간이상지속되는심방세동에의해유발되는기절심근상태때문에동율동으로전환된후새로만들어지는혈전일수있다. 따라서, 율동전환전 3주와기절심근의회복기간인전환후 4주간항응고요법이필요하다 [18,19]. Assessment of cardioversion using transesophageal echocardiography (ACUTE) 연구결과를바탕으로경식도초음파를이용하여좌심방내혈전이없음을확인함으로써율동전환전 3주간의항응고요법을대체할수있다 [20,21]. 간과하지말아야할것은전환전 3주뿐만아니라율동전환당시의혈액응고상태가점검되어야한다는사실이다. ACUTE 연구에서는입원환자의경우헤파린정맥주사를사용했고, 외래환자의경우 5일간와파린을복용시킨후율동전환당시혈액응고상태를확인했다. 최근에는신속한항응고효과를위해저분자량헤파린이나새로운항응고제투여가대안이되고있다. 경식도초음파에서혈전이확인된경우에는율동전환을연기해야하며, 3-4주간항응고요법을시행한후경식도초음파로혈전의완전소실을확인한후재시도를할수있다 [18]. 전기적율동전환의실패는동율동회복이전혀없는경우와동율동이회복은되었지만즉시재발하는 2가지경우가있다. 전자의경우에너지의강도를높이거나전극패드의위치변경으로전기벡터를바꾸거나, 항부정맥제전처치등을시도해볼수있다. 후자의경우적절한항부정맥제전처치를하고재시도를할경우동율동지속기간을길게할수있다. 항부정맥제를이용한율동조절심방세동의재발빈도와지속시간을줄이기위해서는가역적인악화인자를찾아교정하고, 적절한항부정맥제를선택하는것이첫걸음이다. 또한, 발작성심방세동을처음경험한경우유발원인의유무를철저히조사하여제거하여야하며, 재발하기전까지항부정맥제유지요법은시작하지않는다. 이때항응고요법의유무는항부정맥제에대한반응이아닌개개인의뇌졸중위험도를바탕으로결정되어야한다 [4]. 또한, 항부정맥제의효과가절대적인것이아니고, 또한증상없는심방세동의재발이흔하기때문에주관적인증상이전

5 - The Korean Journal of Medicine: Vol. 90, No. 3, Table ACC/AHA/HRS recommendations for electrical and pharmacological cardioversion of AF and atrial flutter Recommendations COR LOE Prevention of thromboembolism With AF or atrial flutter for 48 h, or unknown duration, anticoagulate with warfarin for at least 3 wk before and 4 I B wk after cardioversion With AF or atrial flutter for > 48 h or unknown duration, requiring immediate cardioversion, anticoagulate as soon as I C possible and continue for at least 4 wk With AF or atrial flutter < 48 h and high stroke risk, IV heparin or LMWH, or factor Xa or direct thrombin inhibitor, I C is recommended before or immediately after cardioversion, followed by long-term anticoagulation Following cardioversion of AF, long-term anticoagulation should be based on thromboembolic risk I C With AF or atrial flutter for 48 h or unknown duration and no anticoagulation for preceding 3 wk, it is reasonable to perform TEE before cardioversion and then cardiovert if no LA thrombus is identified, provided anticoagulation is achieved before TEE and maintained after cardioversion for at least 4 wk IIa B With AF or atrial flutter 48 h or unknown duration, anticoagulation with dabigatran, rivaroxaban, or apixaban is IIa C reasonable for 3 wk before and 4 wk after cardioversion With AF or atrial flutter < 48 h and low thromboembolic risk, IV heparin, LMWH, a new oral anticoagulant, or no IIb C antithrombotic may be considered for cardioversion Direct-current cardioversion Cardioversion is recommended for AF or atrial flutter to restore sinus rhythm. If unsuccessful, cardioversion attempts I B may be repeated. Cardioversion is recommended for AF or atrial flutter with RVR, that does not respond to pharmacological therapies I C Cardioversion is recommended for AF or atrial flutter and pre-excitation with hemodynamic instability I C It is reasonable to repeat cardioversion in persistent AF when sinus rhythm can be maintained for a clinically meaningful IIa C time period between procedures Pharmacological cardioversion Flecainide, dofetilide, propafenone, and IV ibutilide are useful for cardioversion of AF or atrial flutter, provided contraindications I A to the selected drug are absent Amiodarone is reasonable for pharmacological cardioversion of AF IIa A Propafenone or flecainide ( pill-in-the-pocket ) to terminate AF out of hospital is reasonable once observed to be IIa B safe in a monitored setting Dofetilide should not be initiated out of hospital III: Harm B AF, atrial fibrillation; COR, class of recommendation; LOE, level of evidence; IV, intravenous; LMWH, low-molecular-weight heparin; TEE, transesophageal echocardiography; LA, left atrial; RVR, rapid ventricular response. 혀없다하더라도항응고요법을중단해서는안된다. 항부정맥제의선택에있어서는약의효과에앞서안전성이먼저고려되어야하는데, 기저 QT 간격연장상태및관상동맥질환, 유의한좌심실비후, 심부전등구조적인심질환의유무와신장기능, 간기능, 환자의연령등약제의대사에영향을주는요인들모두를종합적으로하여판단해야한다. 국내에서심방세동에사용되는항부정맥제 Class IC 항부정맥제국내에서이용가능한약제는플레케나이드 (flecainide) 와프로파페논 (propafenone) 이며, 구조적인심질환이없는심방 세동에서동율동을유지하기위해사용된다. CAST (Cardiac Arrhythmia Suppression Trial) 연구에서플레케나이드는심근경색을앓았던환자에서사망률을유의하게증가시켰고, 이후허혈성심질환에서 class IC 약제의사용은금기가되었다 [22]. 또한, IC계약제들은심근수축력을저하시키기때문에심기능저하가있는경우사용하면안된다. 최근에는모든구조적심질환이있는경우까지 class IC 약제의사용을피하도록그범위가확대되었다. 심방세동을조동으로, 조동은그심방박동수를낮춤으로써 1:1 방실전도를유발할수있기때문에이들약제를사용할때는방실결절차단효과가있는약제를동시에사용하도록권고된다. 본약제들은강력

6 - Kyoung-Suk Rhee. Antiarrhythmics for atrial fibrillation - 한 Na + 통로차단제로써전도속도를저하하며, 같은기전으로 QRS파의폭을확장시킨다 [23]. 약제에의해심전도 QRS 파가기저상태에비해 50% 이상확장되는경우빈맥성심실부정맥의위험이있기때문에약제의용량을줄이거나중단해야한다. 심장외부작용으로는어지러움증, 시력저하등이있으나흔한것은아니며, 프로파페논의경우혀에금속성맛이느껴지기도한다. 프로파페논은플레케나이드와달리약한베타차단효과가있으며, 간에서 CYP2D6에의해분해되기때문에신부전환자에서사용이가능하다. 한편, 이효소에작용하는약제들을같이복용할경우프로파페논의베타차단효과가유의하게증가될수있다. 소탈롤 (sotalol) 칼륨이온통로 (IKr) 억제제이면서베타차단제이다. 강한 QT 간격연장효과로인해약 3% 에서다형심실빈맥 (torsades de pointes) 이보고되기때문에, 이식형제세동기를시술받은환자가아닌경우병원밖에서투여를시작하지않도록권고되기도한다. 소탈롤을투여하는중에심전도를통해 QT 간격연장정도를잘감시해야하며유의하게연장되는경우 (> ms) 용량을줄이거나중단해야한다. 기저 QT 간격이연장되어있는환자에서는사용금기이며, 소탈롤투여중 QT 간격을연장시키는다른약제의복용이나자몽 (grapefruit) 쥬스의섭취를금지하는철저한교육이필요하다. 소탈롤은거의다신장으로배설되기때문에신기능이저하되는상황이발생할경우혈중농도가상승할수있음을유념해야하며, 신부전환자에서투여하면안된다. 아미오다론 (amiodarone) 다양한이온통로 ( 예 : IKr, INa, IKur, Ito, ICaL, IKAch, IKs) 를차단하는 Class III 항부정맥제이다. 약물의분포용적이매우크며, 주로지방조직과간, 폐, 비장과같이혈액관류가많은장기에주로축적된다고알려져있지만실제로는거의모든조직에상당히많은양이축적된다. 일회복용시최고혈장농도에도달하는시간은 3-7시간정도로알려져있지만, 작용시작시간은빠르면 2-3일, 부하용량 (loading dose) 을투여한경우라하더라도보통 1-3주가지나야하며, 이또한개인별차이가매우큰것으로알려져있다. 따라서, 항부정맥작용뿐만아니라 QT 간격연장효과역시수일또는수주까지지연될수있다. 음식과함께복용할경우흡수율이유의하게증가되며, 위장관장애도최소화할수있다. 아미오다론은반감기역시수주정도로매우길다. 주로간에서 CYP 3A4 와 CYP2C8 효소에의해대사되어담관으로배설되고, 신장을통 해서는거의대사되지않는다. 따라서, 신부전환자에서선택할수있는항부정맥제는 class IC의프로파페논 (propafenone) 과아미오다론정도이다. 아미오다론은 CYP3A, CYP2C9, P- glycoprotein 의억제로인해다양한약제들의혈중농도를상승시킨다. 대표적경우가와파린복용환자에서 INR (international normalized ratio of prothrombin time) 의상승이며, 디곡신혈중농도를증가시켜독성을유발할수있기때문에병용할경우이들약제의용량조절이반드시필요하다. 또한, 아미오다론은전신적으로수많은부작용을일으킬수있다. 다른약제들과직접비교분석한연구들을보면발작성이거나지속성이거나심방세동에서동율동의유지및심방세동의재발방지에가장효과적인반면심각한부작용역시가장많이발생하였다 [24-27]. 아미오다론의심장에대한부작용은서맥이며, 현저한 QT 간격연장이일어날수있지만이와연관된다형심실빈맥 (torsades de pointes) 은매우드문것으로알려져있다 [28]. 심근비후, 심부전, 관상동맥질환등을가지고있는환자에서약제에의한심실빈맥유발위험이가장낮기때문에 1차로선택되는약제이다. 아미오다론이심방세동치료에있어서가장효과적이면서도 1차선택약제가될수없는이유는갑상선, 간, 폐, 눈, 피부, 신경, 근육, 등전신장기에걸쳐발생할수있는심각한부작용때문이다. 이러한독성들은대부분투약량에의존적이며, 폐섬유화등경우에따라서는치명적일수있다. 따라서, 한번시작한후장기간지속하게되는심방세동의치료에있어서아미오다론의사용여부결정은, 특히젊은환자의경우, 매우신중해야한다. 일단투여가결정되면폐, 간, 갑상선등에대한기저검사를시행해야하고, 투약을시작한후에는증상이없더라도모든환자에서이런장기들에서의이상발생유무에대한주기적인검사가반드시필요하다. 드로네다론 (dronedarone) 아미오다론의주요독성은요오드기 (iodine moiety) 에의한것으로써, 이부분을제거한아미오다론의유도체가드로네다론이다. 이약제는아미오다론이일으키는치명적인심장외부작용들은거의없고, 교감신경작용의억제, 칼슘전류, 나트륨전류, 칼륨전류차단효과등다양한전기생리학적인작용을가지고있지만기대했던항부정맥효과는아미오다론에비해떨어진다 [25]. 드로네다론은혈전색전증의위험인자를가진발작성또는지속성심방세동또는조동에서사망및심혈관계부작용의복합종점을, 주로심방세동에의한입원

7 - 대한내과학회지 : 제 90 권제 3 호통권제 667 호 횟수를줄임으로써, 감소시켰지만 [29], 심부전이나좌심실기능이저하된환자에서는사망률을증가시켰기때문에, NYHA (New York Heart Association) III 또는 IV 수준의심부전이나 4주이내에대상부전이있었던심부전이나좌심실기능저하가있는경우사용금기이다 [13]. 만성심방세동환자에서는뇌졸중, 심혈관계에의한사망, 입원등의복합종점을증가시키기때문에동율동이회복및유지되지않은지속성심방세동환자에서의드로네다론사용역시금기이다 [12]. 드로네다론의주요심장부작용은서맥과 QT 간격연장이며, 이와연관된다형심실빈맥 (torsades de pointes) 은드물게보고된다 [30]. 간에서 CYP3A4에의해대사되며, CYP2D6 와 P-glycoprotein 에대해중등도의억제효과가있기때문에디곡신혈중농도를높이며, 다비가트란 (dabigatran) 및강력한 CYP3A4 억제제 ( 케토코나졸, 마크로라이계항생제등 ) 들과의병용은금기이다. CYP3A4 의중등도억제효과가있는베라파밀, 딜티아젬과의병용은가능하지만이들약제의용량조절을고려해야한다. 또한, 투여시작첫 6개월이내발생하는중증간독성의보고가있기때문에특히, 첫 6개월-1년간은간효소의주기적인감시가필요하다. 중심단어 : 심방세동 ; 항부정맥제 ; 심박수조절 ; 율동전환 REFERENCES 1. Wolf PA, Benjamin EJ, Belanger AJ, Kannel WB, Levy D, D Agostino RB. Secular trends in the prevalence of atrial fibrillation: the Framingham Study. Am Heart J 1996;131: European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, 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). Eur Heart J 2010;31: Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the An Ticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001;285: January CT, Wann LS, Alpert JS, et al 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. Circulation 2014;130: Olshansky B, Rosenfeld LE, Warner AL, et al. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol 2004;43: Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362: Jordaens L, Trouerbach J, Calle P, et al. Conversion of atrial fibrillation to sinus rhythm and rate control by digoxin in comparison to placebo. Eur Heart J 1997;18: Siu CW, Lau CP, Lee WL, Lam KF, Tse HF. Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation. Crit Care Med 2009;37: Hofmann R, Steinwender C, Kammler J, Kypta A, Leisch F. Effects of a high dose intravenous bolus amiodarone in patients with atrial fibrillation and a rapid ventricular rate. Int J Cardiol 2006;110: Nebojša M, Dragan S, Nebojša A, et al. Lethal outcome after intravenous administration of amiodarone in patient with atrial fibrillation and ventricular preexcitation. J Cardiovasc Electrophysiol 2011;22: Badshah A, Mirza B, Janjua M, Nair R, Steinman RT, Cotant JF. Amiodarone induced torsade de pointes in a patient with Wolff-Parkinson-White syndrome. Hellenic J Cardiol 2009; 50: Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365: Køber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358: Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation 1995;92: de Vos CB, Pisters R, Nieuwlaat R, et al. Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. J Am Coll Cardiol 2010;55: Cosio FG, Aliot E, Botto GL, et al. Delayed rhythm control of atrial fibrillation may be a cause of failure to prevent recurrences: reasons for change to active antiarrhythmic treatment at the time of the first detected episode. Europace 2008;10: Van Gelder IC, Haegeli LM, Brandes A, et al. Rationale and current perspective for early rhythm control therapy in atrial fibrillation. Europace 2011;13: Jaber WA, Prior DL, Thamilarasan M, et al. Efficacy of anticoagulation in resolving left atrial and left atrial appendage thrombi: a transesophageal echocardiographic study. Am Heart J 2000;140:

8 - 이경석. 심방세동과항부정맥제 You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e531S e575s. 20. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001;344: Weigner MJ, Thomas LR, Patel U, et al. Early cardioversion of atrial fibrillation facilitated by transesophageal echocardiography: short-term safety and impact on maintenance of sinus rhythm at 1 year. Am J Med 2001;110: Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324: Aliot E, Capucci A, Crijns HJ, Goette A, Tamargo J. Twentyfive years in the making: flecainide is safe and effective for the management of atrial fibrillation. Europace 2011;13: Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352: Piccini JP, Hasselblad V, Peterson ED, Washam JB, Califf RM, Kong DF. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009;54: AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003;42: Freeman BL, Hardy MA. Multiplanar phalangeal and metatarsal osteotomies for hallux rigidus. Clin Podiatr Med Surg 2011;28:329-44, viii. 28. Kirchhof P, Franz MR, Bardai A, Wilde AM. Giant T-U waves precede torsades de pointes in long QT syndrome: a systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation. J Am Coll Cardiol 2009; 54: Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360: Huemer M, Sarganas G, Bronder E, Klimpel A, Garbe E, Haverkamp W. Torsade de pointes tachycardia in a patient on dronedarone therapy. Pharmacotherapy 2015;35:e61-e

Table 1. Common medication dosage for rate control of atrial fibrillation 약물 정주 경구상용용량 s Metoprolol tartrate 2분에걸쳐 mg 투여, 3회까지 mg BID M

Table 1. Common medication dosage for rate control of atrial fibrillation 약물 정주 경구상용용량 s Metoprolol tartrate 2분에걸쳐 mg 투여, 3회까지 mg BID M 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