대한내과학회지 : 제 90 권제 2 호 2016 http://dx.doi.org/10.3904/kjm.2016.90.2.115 종설 (Review) 돌연사의일차적예방을위한삽입형제세동기치료 계명대학교동산의료원심장내과 박형섭 한성욱 Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Cardiac Death Hyoung-Seob Park and Seongwook Han Division of Cardiology, Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea Implantable cardioverter-defibrillators (ICDs) are an effective treatment strategy for patients with aborted sudden cardiac death (SCD) and ventricular tachyarrhythmias. rimary prevention of SCD is a strategy involving the use of ICDs in patients who are at high risk for, but have not had, any previous events of ventricular arrhythmias or cardiac arrest. Several randomized clinical trials have demonstrated the efficacy of ICDs in the primary prevention of SCD. Therefore, ICD implantation is recommended as a standard of care by the guidelines in patients who have ischemic or nonischemic cardiomyopathy and a low left ventricular ejection fraction. However, the rates of ICD implantation as a primary prevention in Korea is quite low compared to western countries. In this review, we will summarize the results and efficacy of ICDs in the clinical trials about primary prevention of SCD, the current treatment guidelines, and the reimbursement policy of Korean health insurance. We hope that this review will help broaden the recognition of importance of ICD implantation for the primary prevention of SCD. (Korean J Med 2016;90:115-120) Keywords: Implantable cardioverter-defibrillator; Sudden cardiac death; Primary prevention 서론삽입형제세동기 (implantable cardioverter-defibrillator, ICD) 는심실세동등에의한심정지환자나구조적심장질환이있는심실빈맥환자에서이차예방을위해삽입하여이후나타나는돌연사를줄이는목적으로사용되었다 [1]. 하지만 2000 년초반부터는비록심실세동이나심정지등을경험하지않았더라도심기능이심하게저하되어있는환자군에서삽입형제세동기를삽입하는것이시작되어현재는그빈도가점차 증가하고있으며이를 ICD 삽입을통한돌연사의일차적예방이라고이야기한다. 여기에서는이러한일차적예방을위한 ICD 삽입의치료의임상결과들을통해그근거와효과를알아보고자한다. 본론허혈성심근병증에서의 ICD 를통한일차적예방 ICD 삽입은주로심실세동이나심실빈맥환자에서의이차 Correspondence to Seongwook Han, M.D., Ph.D., FACC, FHRS Division of Cardiology, Department of Internal Medicine, Keimyung University Dongsan Medical Center, 56 Dalsung-ro, Jung-gu, Daegu 41931, Korea Tel: +82-53-250-7404, Fax: +82-53-250-7034, E-mail: swhan@dsmc.or.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 - 115 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 90, No. 2, 2016 - 적예방을위해시행되다가 1990년대후반부터허혈성심장질환으로인해좌심실기능이저하된환자에서 ICD를삽입하여돌연사의빈도를줄인여러연구들이보고되었다. Table 1 은이러한연구들을정리하여보여주고있다. The Multicenter Automatic Defibrilltor Implantation Trial (MADIT) 연구 [2] 는심근경색의과거력이있으면서좌심실구혈률이 35% 이하인환자들중에서무증상의비지속성심실빈맥이있고전기생리학적검사로유발된심실빈맥이 procainamide에의해억제되지않은환자들을대상으로하였다. 이런환자들을무작위배정을통하여항부정맥제제를사용한군과 ICD 삽입군으로나누어 27개월간추적관찰한결과항부정맥제에비해 ICD 삽입군에서 54% 의사망률감소효과를보여연구가조기종료되었다. Multicenter Unsustained Tachycardia Trial (MUSTT) 연구 [3] 는좌심실구혈률이 40% 이하이면서비지속성심실빈맥이 있는관상동맥질환환자를대상으로전기생리학적검사를통해심실빈맥을유발후 procainamide에의한심실빈맥억제반응이있는경우에는약물치료를진행하였고반응이없는경우에는 ICD를삽입하였다. 5년동안의관찰기간동안심정지혹은부정맥에의한사망의위험도는 ICD를삽입한군이약물치료군에비해 76% 감소하였다. MADIT II 연구 [4] 에서는이전의연구들과는달리심근경색증의과거력이있으면서좌심실구혈률이 30% 이하이지만이전에증명된비지속성혹은지속성의심실빈맥유무와상관없이약물투여군과 ICD 삽입군으로나누어치료하여관찰하였다. 20개월간의추적관찰기간동안 ICD군에서약물투여군에비해사망률이 31% 감소하여나타났다. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) 연구 [5] 는허혈성및비허혈성심근증에의해좌심실구혈률이 35% 이하이면서 New York Heart Association (NYHA) class Table 1. Major implantable cardioverter-defibrillator trials for primary prevention of sudden cardiac death Study Population No. of patients Endpoint Hazard ratio p value MADIT I [2] Post MI NSVT LVEF 35% Inducible VT on EP study 196 Death from any cause 0.46 0.009 MUSTT [3] MADIT II [4] SCD-HeFT [5] Post MI LVEF 40% NSVT Inducible VT on EP study Post MI LVEF 30% Prior MI or NICM LVEF 35% NYHA class II/III CABG-patch [6] CABG LVEF < 36% Positive SAECG DINAMIT [7] Recent MI (within 6-40 d) LVEF 35% Impaired cardiac autonomic function DEFINITE [11] NICM LVEF < 36% PVCs, or NSVT 707 Cardiac arrest or death from arrhythmia 0.24 < 0.001 1232 Death from any cause 0.69 0.016 2521 Death from any cause 0.77 0.007 900 Death from any cause 1.07 0.64 674 Death from any cause 1.08 0.66 458 Death from any cause Sudden death from arrhythmia MADIT, Multicenter Automatic Defibrillator Trial; MI, myocardial infarction; NSVT, nonsustained ventricular tachycardia; LVEF, left ventricular ejection fraction; VT, ventricular tachycardia; EP, electrophysiology study; MUSTT, Multicenter Unsustained Tachycardia Trial; SCD-HeFT, Sudden Cardiac Death in Heart Failure Trial; NICM, nonischemic cardiomyopathy; NYHA, New York Heart Association; CABG, coronary artery bypass graft surgery; SAECG, signal-averaged electrocardiogram; DINAMIT, Defibrillator IN Acute Myocardial Infarction Trial; DEFINITE, The Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation; PVCs, premature ventricular complexes. - 116-0.65 0.20 0.08 0.006
- Hyoung-Seob Park, et al. ICDs for primary prevention of SCD - II, III의심부전이있는환자들을대상으로하였다. 환자들은기존의치료군과 amiodarone 사용군그리고 ICD 삽입군으로나누어치료를하였으며 45.5개월의추적관찰동안 ICD 치료는사망률을 23% 낮추는효과를보였으나 amiodarone의사용은위약에비해사망률을감소시키지못하였다. 위와같이대부분의연구가 ICD 삽입을통해사망률의감소를보여준반면, Coronary Artery Bypass Graft Patch (CABG- Patch) 연구 [6] 는다른결과를보여주었다. 이연구는관상동맥질환을가지고좌심실구혈률이 36% 미만이면서평균신호심전도의이상을가진환자들을관상동맥우회수술만받는군과수술에추가적으로 ICD를삽입한군으로나누어 32개월동안추적관찰하였다. 추적관찰기간동안대조군의사망률은 24%, ICD 군은 27% 로양군간의사망률의차이는보이지못하였다. 또한 Defibrillator IN Acute Myocardial Infarction Trial (DINAMIT) 연구 [7] 에서는심근경색증발생후 6-40일이면서좌심실구혈률이 35% 이하이고심장의자율신경기능이저하된환자들을대상으로하여 ICD를삽입한군과삽입하지않은군을비교하였다. 평균 30개월의관찰기간동안 ICD 삽입은사망률의차이를보이지않아심근경색발생후 40 일이내의조기에 ICD를일차적예방의목적으로삽입하는것은이득이없는것으로나타났다. 위의결과들을토대로하여 2012년개정된 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS) 치료지침 [8] 에서는심근경색발생후 40일이경과한허혈성심부전으로좌심실구혈율이 35% 이하이면서 NYHA class II, III의증상을보이거나좌심실구혈율이 30% 이하이면서 NYHA class I의증상을보일때 ICD 삽입을권고하고있다 (Class I, Level of Evidence B). 또한이전의심근경색증에의한비지속성심실빈맥이있으면서좌심실구혈률이 40% 이하일경우에는전기생리학적검사에서심실세동이나지속적인심실빈맥이유발된경우에 ICD 삽입을권고한다 (Class I, Level of Evidence B). 현재국내에서의심근경색증환자일차예방을위한 ICD 인정기준은심근경색발생후 40일이경과한허혈성심부전으로적절한약물치료에도불구하고 NYHA class II, III의증상을보이고 1년이상생존이예상되는환자의경우에서심구혈률이 30% 이하이거나, 심구혈률이 31-35% 로비지속성심실빈맥이있으며임상전기생리학적검사에서지속성심실빈맥이유발된경우이다. 비허혈성심근병증에서의 ICD 를통한일차적예방허혈성심근병증의경우와는달리비허혈성심근병증에서 ICD의일차적예방효과에대해서는아직까지이견이있다. Cardiomyopathy Trial (CAT) 연구 [9] 에서는확장성심근병증으로좌심실구혈률이 30% 이하인환자를 ICD 삽입군과대조군으로나누어추적관찰하였다. 평균 5.5년의추적관찰기간동안양군간에사망률의차이는보이지않았다. Amiodarone Versus Implantable Cardioverter-Defibrillator (AMIOVIRT) 연구 [10] 에서는좌심실구혈률이 35% 이하인비허혈성심근병증환자중무증상의비지속성심실빈맥이있는환자를대상으로하여 amiodarone 투여군과 ICD 삽입군으로나누어치료를하여 3년간관찰한결과전체사망률은양군간에차이가없었다. CAT와 AMIOVIRT 연구의결과에서보면비허혈성심근병증에서일차적예방을위한 ICD 삽입은사망률의감소효과를보이지못하였다. 하지만두연구모두대상환자수가많지않고비허혈성심근병증으로진단후초기에 ICD 삽입이이루어져초기치료이후적절한약물치료를통해심기능이증가할수있는가능성을염두에두지못한제한점을가지고있었다. 이러한고려를통해심기능이호전된환자들을배제하고연구를진행하였다면더좋은결과를보여주었을것으로사료된다. 최근의몇몇연구들은 ICD 삽입을통한효과에대해서보고를하고있다. The Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) 연구 [11] 는비허혈성심근병증환자이면서좌심실구혈률이 36% 미만인환자중에서심실기외수축또는비지속성심실빈맥을보인환자를대상으로한연구였다. 총 458명의환자를대상으로평균 29 개월동안추적관찰한결과 ICD 삽입군은표준약물치료군에비해부정맥에의한급사율을통계적으로유의하게 80% 감소시켰다. 전체사망률도 34% 감소시켰으나통계적유의성은얻지못하였다. DEFINITE 연구의결과도 Table 1에서같이보여주고있다. 위와같이비허혈성심근병증환자에서의 ICD 삽입의유용성은각연구마다차이를보인다. 하지만여러전향적연구를메타분석한결과 [12] 에의하면 ICD 삽입을통해약물치료에비해 31% 의사망률감소를얻을수있었다. 그외에 SCD-HeFT 연구중비허혈성심근병증을환자만을추가적으로분석한경우에도사망률에대한이득은전체환자군에서의결과와비슷한경향을보였다. - 117 -
- 대한내과학회지 : 제 90 권제 2 호통권제 666 호 2016 - 따라서비허혈성심근병증환자에서도적절환환자를선택하여 ICD를삽입한다면사망률의감소효과를얻을수있을것으로생각된다. 이런연구결과들을바탕으로 ACCF/AHA/HRS 치료지침 [8] 에서는비허혈성심근병증으로좌심실구혈률이 35% 이하이면서 NYHA class II, III인환자들에게 ICD 삽입을권고하고있다 (Class I, Level of Evidence B). 하지만국내의 ICD 인정기준은비허혈성심부전으로 3개월이상의약물치료에도불구하고 NYHA class II, III의증상을보이고 1년이상생존이예상되는환자의경우에서심구혈률이 30% 이하일때인정을해주고있으며심구혈률이 31-35% 일경우에는비지속성심실빈맥이있으면서전기생리학적검사에서지속성심실빈맥이유발되는경우에한해인정하고있다. Cardiac resynchronization therapy with defibrillator (CRT-D) 삽입을통한돌연사의일차적예방앞서 ICD 삽입만을통한일차적예방의효과에대해서기술하였지만 CRT-D 가심부전환자에서의일차적예방효과가어느정도인지에대한연구도있었다. Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) 연구 [13] 는허혈성혹은비허혈성심근병증에의해좌심실구혈률이 35% 이하이면서 NYHA class III 또는 IV의심부전이있고 QRS 간격이 120 msec 이상인환자를대상으로하여적적한약물치료, Cardiac resynchronization therapy with pacemaker (CRT-P) 삽입군그리고 CRT-D 삽입군으로나누어사망혹은입원까지의시간을일차유효성평가변수로하여추적관찰하였다. 일차유효성평가변수의측면에서는약물치료군에비해 CRT-P 와 CRT-D 삽입군모두사건발생을줄이는효과를보여주었다. 하지만전체사망률로보았을경우에는약물치료군에비해 CRT-P 의경우에는통계적으로유의한사망률의감소를보여주지못하였으나 CRT-D의삽입은사망률을 36% 감소시켰다. 기타질환에서의돌연사의일차적예방돌연사의예방을위해 ICD를삽입하여야하는질환들은그외에도비후성심근병증 (hypertrophic cardiomyopathy, HCM), 긴 QT (long QT) 증후군, 브루가다 (Brugada) 증후군, 부정맥호발성우심실심근병증등여러질환이있다. HCM 환자들은증상이없는경우가많고임상적으로처음나타나는증상이돌연사로나타나는경우가있다. HCM 환자에서의돌연사는심실성부정맥과연관되는것으로알려 져있고이는심근허혈, 심방세동등의여러가지원인에의해서유발될수있다. 돌연사의위험인자를가진환자의경우에는많게는연간 6% 의사망률을보고하고있다 [14]. HCM 에서돌연사의위험인자에대해서는여러관찰연구에서언급하고있지만이를종합하여 2003년에 American College of Cardiology (ACC)/European Society of Cardiology (ESC) 에서발표된전문가의견 [14] 에서는돌연사의 7가지주요위험인자를제시하였다. 이들은심실세동에의한심정지, 자발적심실성빈맥, 돌연사의가족력, 원인을알수없는실신, 좌심실중격의비후가 30 mm 이상, 운동중의비정상적혈압반응, 홀터 (holter) 모니터상의비지속성빈맥이다. ACCF/AHA/HRS 치료지침 [8] 에서는이러한주요위험인자중 1개이상을가지고있을경우에는 ICD 삽입의적응증이된다고제시하고있다 (Class IIa, Level of Evidence C). 국내에서는 HCM 환자에서이차적인예방으로의 ICD 삽입뿐만아니라일차적인예방을위한 ICD 삽입을다음 5개의위험인자중에서두가지이상에해당되는경우에인정하는데그위험인자들은 (1) 실신의증상 (2) 급사의가족력 (3) 좌심실중격의과도한비후 (> 30 mm) (4) 24시간활동중전도에서나타난비지속성심실빈맥 (5) 운동부하검사상혈압증가반응이없는경우 ( 충분한운동부하에도혈압상승이 < 20 mmhg 인경우 ) 이다. 브루가다증후군에서심실세동으로인한심정지의병력이있는환자에서 ICD 삽입을해야하는것은이견이없다. 하지만브루가다패턴의심전도만가지고 ICD 삽입등의치료를결정하는것은아직논란이많다. 이런브루가다증후군환자에서돌연사의위험도를평가하는것이매우중요하며이는 ICD 삽입만이브루가다증후군에서돌연사를예방할수있는유일한방법이기때문이다. 대부분연구 [15,16] 에서자발적인 I형브루가다패턴의심전도를가지고실신의병력이있는환자들은이후부정맥관련심장사건발생의고위험군으로분류하고있다. 최근발표된 HRS/European Heart Rhythm Association (EHRA)/Asica Pacific Heart Rhythm Society (APHRS) 전문가의견서 [17] 및 ACCF/AHA/HRS 치료지침 [8] 에의하면자발적인 I형패턴의브루가다심전도를가지고심실성부정맥에의해나타났을가능성이높은실신의과거력이있는경우 ICD 삽입을권고하고있다 (Class IIa, Level of Evidence C). 따라서브루가다증후군환자에서실신의과거력은매우중요하며국내 ICD 인정기준은 실신이있는브루가다증후군환자에서, 충분한평가로도실신의원인을알수없거나, 임상전기생리학적검사에서심실세동또는빈 - 118 -
- 박형섭외 1 인. 삽입형제세동기를통한돌연사의일차예방 - 맥이유발되는경우이다. 긴 QT 증후군에서의 ICD 치료는베타차단제를사용한약물치료후에도반복적으로실신혹은심실빈맥이나타날때적응이되므로 [8] 이를일차적예방으로단정지어말하기는힘들것같다. 미국의치료지침이나국내 ICD 인정기준에서는긴 QT 증후군환자로실신에대한충분한평가로도원인을알수없는실신의경력이있고베타차단제치료에도재발하거나약물치료를지속할수없는경우에 ICD를삽입해야한다고제시하고있다. 결 여러전향적인연구를통해돌연사의일차적예방을위한 ICD 삽입의돌연사와사망률의감소효과가증명이되었으며이를기반으로만들어진치료지침과보험규정이돌연사고위험군에서일차적예방을위한 ICD 삽입을권고하는것이치료의표준 (standard of care) 임을명시하고있다. 현재국내에서도그건수가점점증가하는추세에있지만아직도한국에서일차적예방을위한 ICD 삽입술의빈도가외국에비해서매우낮다. 동양과서양의문화적차이로인해환자들이시술을거부하는것이그이유중하나이지만상당수의환자들이급사의예방에대해서적절히권고받고있지못하다는것이큰이유일것이다. 따라서심부전환자에서돌연사위험에대해시기적절한평가가중요하고, 치료지침에따른 ICD 삽입의권고가반드시고려되어야한다. 론 중심단어 : 삽입형제세동기 ; 돌연사 ; 일차적예방 REFERENCES 1. European Heart Rhythm Association; Heart Rhythm Society, Zipes DP, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006;48:e247-e346. 2. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933-1940. 3. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341:1882-1890. 4. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877-883. 5. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-237. 6. Bigger JT Jr. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med 1997;337:1569-1575. 7. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter defibrillator after acute myocardial infarction. N Engl J Med 2004;351:2481-2488. 8. Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/ AHA/HRS focused update incorporated into the ACCF/ AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2013;61:e6-75. 9. Bänsch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation 2002;105:1453-1458. 10. Strickberger SA, Hummel JD, Bartlett TG, et al. Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemicdilated cardiomyopathy and asymptomaticnonsustained ventricular tachycardia-- AMIOVIRT. J Am Coll Cardiol 2003;41:1707-1712. 11. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151-2158. 12. Desai AS, Fang JC, Maisel WH, Baughman KL. Implantable defibrillators for the prevention of mortality in patients with nonischemic cardiomyopathy: a meta-analysis of randomized controlled trials. JAMA 2004;292:2874-2879. 13. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-2150. 14. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clin- - 119 -
- The Korean Journal of Medicine: Vol. 90, No. 2, 2016 - ical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003;42:1687-1713. 15. Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation 2003;108:3092-3096. 16. Priori SG, Gasparini M, Napolitano C, et al. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimulation predictive value) registry. J Am Coll Cardiol 2012;59:37-45. 17. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932-1963. - 120 -