대한내과학회지 : 제 88 권제 2 호 2015 http://dx.doi.org/10.3904/kjm.2015.88.2.127 특집 (Special Review) - 심부전치료의최신지견 좌심실수축기능저하심부전증의치료 서울대학교의과대학분당서울대학교병원 1 심장혈관센터, 2 내과, 3 서울대학교의과대학내과학교실 박진주 1,2 ㆍ최동주 1,2,3 Treatment of Heart Failure with Reduced Ejection Fraction: Current Update Jin Joo Park 1,2 and Dong-Ju Choi 1,2,3 1 Cardiovascular Center and 2 Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam; 3 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea The prevalence of heart failure (HF) has been steadily increasing and it now creates an enormous social and economic burden. HF is a syndrome characterized by a high mortality rate, frequent hospitalization, a reduced quality of life, and a complex therapeutic regimen. In the last three decades, major progress in both the diagnosis and management of HF has taken place, and the pharmacologic and non-pharmacologic advances have led to a significant improvement in survival and symptoms in HF patients. After an accurate diagnosis, a proper HF management plan requires a multi-level team approach comprised of the correct combination of drug therapy, device therapy, and surgery, including heart transplantation. In this review, we focused on the pharmacologic and non-pharmacologic treatment strategies for HF with reduced ejection fraction. The goal was to develop treatment guidelines based on significant evidence derived from large clinical trials. (Korean J Med 2015;88:127-134) Keywords: Systolic heart failure; Practice guideline 서론심부전은심장기능의저하로인해체내대사에필요한양의혈액을공급하지못하는상태를말하며이는특정질병이아니라복잡한병태생리를가지고있는증후군이다. 미국심부전학회는 The American College of Cardiology Foundation/ The American Heart Association 지침에서 심실이혈액을충만시키거나구출해내는데장애를초래하는임상증후군 을 심부전이라정의하고있으며 [1] 유럽심장학회지침에서는 환자가심부전의특징적인증상및징후를가지고있으면서심장기능장애의객관적인증거를가지는임상증후군 으로정의하고있다 [2]. 심부전은진행성질환이다. 심부전의유병률은의학기술의발달및인구고령화로꾸준히증가하고있으며사회경제학적측면에서도중요한질환이다 [3]. 심부전의예후는심장질환의치료법이발달하고있음에도불구하고대체로불 Correspondence to Dong-Ju Choi, M.D., Ph.D. Cardiovascular Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 463-707, Korea Tel: +82-31-787-7007, Fax: +82-31-787-4290, E-mail: djchoi@snu.ac.kr Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 127 - 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. 88, No. 2, 2015 - 량하며심혈관계질환에서가장높은사망률을보이고있다. 심부전은좌심실구혈률을기준으로구분한다. 이전에는좌심실구혈률이저하된심부전증환자를 수축기심부전 (systolic heart failure), 좌심실수축기능이정상인환자를 확장기심부전 (diastolic heart failure) 이라고구분했지만최근에는좌심실구혈률이 40% 미만인환자들을 박출률저하심부전 (heart failure with reduced ejection fraction, HFrEF), 40% 이상의환자들을 박축률보존심부전 (heart failure with preserved ejection fraction, HFpEF) 으로분류하고있다. 심부전에서약 50% (40-71%) 정도가좌심실박출률 (ejection fraction, EF) 이보존된심부전인것으로추정된다. 환자의예후는두종류의심부전간차이가없는것으로보고되지만 [4] 현재까지는박축률저하심부전환자에서만약물치료로예후를개선하는것으로알려져있다 [1,2]. 본고에서는박축률저하심부전증치료에대해기술했다. 심부전의정의 심부전은좌심실박출률 40% 이하와초과를기준으로 HFrEF 와 HFpEF로구분할수있다. 박축률저하심부전은심박출량감소에의한무기력, 피로, 운동능력저하등을호소한다. 심부전은단일질환이아니고복합적임상증후군이다. 유럽심장학회에서는진단기준을적용하여심부전을진단하고있다 (Table 1). 심부전은진행성질환으로 4개의단계 (Stage A, B, C, D) 로구분하고각단계에맞춰서치료목표를설정하고치료 Table 1. Diagnostic criteria of heart failure Diagnosis of HFrEF: must meet all 3 criteria 1. Presence of typical symptoms of heart failure 2. Presence of typical signs of heart failure 3. Reduced left ventricular ejection fraction Diagnosis of HFpEF: must meet all 4 criteria 1. Presence of typical symptoms of heart failure 2. Presence of typical signs of heart failure 3. Normal to near normal left ventricular ejection fraction without LV dilation 4. Presence of structural changes (left ventricular hypertrophy/left atrium enlargement) or diastolic dysfunction HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; LV, left ventricular. 를진행하고있다. 단계 A는심부전을일으킬수있는선행질환 ( 고혈압, 당뇨, 협심증, 고지혈증, 동맥경화증 ) 이있으나아직심장에이상소견은없는상태, 단계 B는이미심장에구조적변화 ( 심장비대, 심근경색, 심장확장, 판막질환 ) 가생겼으나아직심부전의증상과징후는없는상태, 단계 C는심장에구조적변화가생겼고심부전의증상이있는상태, 단계 D는진행된경우로최대한의치료에도증상이심하고특수한치료를요하는상태이다 (Fig. 1). 심부전치료의원칙심부전의치료목적은크게증상개선및예후개선으로분류할수있다. 심부전환자들은대부분전신부종및폐울혈로인한호흡곤란을호소한다. 이에불안정한급성심부전환자 (acute heart failure) 에서는정주이뇨제를, 만성안정성심부전환자 (chronic stable heart failure) 에서는경구이뇨제를적극적으로사용하여심실충만압을적정수준으로유지시키고환자의울혈증상을완화해야한다. 이뇨제만으로울혈에의한증상이나징후가호전되지않는경우는후부하및전부하를감소시키기위해혈관확장제나심근수축력을증대시킬수있는디곡신 (digoxin) 또는카테콜라민계열의강심제를사용할수있으나예후개선효과가증명되지않아선별적으로사용해야한다. 이와함께환자의예후개선을목표로하는치료가동반되어야한다. 심부전환자에서예후개선효과가입증된약물은안지오텐신전환효소억제제 (angiotensin-converting enzyme inhibitor, ACE 억제제 ) 및안지오텐신수용체길항제 (angiotensin receptor blocker, ARB), 베타차단제 (beta blocker), 알도스테론길항제 (aldosterone antagonist) 및 ivabradine 등이다. 증상완화를위해주로사용하는약물은이뇨제및디곡신등이있다 (Fig. 2). ACE 억제제및 ARB ACE 억제제심부전환자의예후개선에서레닌- 안지오텐신-알도스테론계 (renin-angiotensin-aldosterone system, RAAS) 차단은매우중요하다. RAAS 억제를위해가장많이사용하는약제로는 ACE 억제제및 ARB 등이있다. ACE 억제제는혈액내및국소조직에서 ACE를억제하여 angiotensin II의생성을저하시키고 kininase II를억제하여혈중 bradykinin의농도를높 - 128 -
- Jin Joo Park, et al. HFrEF treatment - Figure 1. Stages in the development of heart failure and recommended therapy by stage. From Writing Committee Members, Yancy CW, Jessup M, et al. Circulation 2013:15;128:e240-e327. [1] HF, heart failure; HTN, hypertension; DM, diabetes mellitus; MI, myocardial infarction; LV, left ventricular; LVH, left ventricular hypertrophy; EF, ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; GDMT, guideline-directed medical therapy; ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin-receptor blocker; ICD, implantable cardioverter-defibrillator; HRQOL, health-related quality of life; AF, atrial fibrillation; CAD, coronary artery disease; CRT, cardiac resynchronization therapy; MCS, mechanical circulatory support. - 129 -
- 대한내과학회지 : 제 88 권제 2 호통권제 654 호 2015 - 여서혈관을확장시키며교감신경계의활성을저하시키고염분배설을촉진시키는작용을한다. 또한장기적으로는조직의증식, 섬유화, 혈관내피세포의기능조절, 혈전의형성및나아가서는죽상경화증의진행예방에도관여한다 [5]. ACE 억제제는심부전환자의예후를개선한첫번째약제이며 [6,7] 이미여러대규모임상연구에서심부전증상을개선시키고사망및재입원율을감소시켰다 [7,8]. 뿐만아니라무증상의좌심실기능저하환자들에서도심부전의진행을막고사망률을낮추는것으로알려져있다. 저용량과고용량을비교하면고용량에서더큰효과가있기에약의부작용이발생하지않는범위 ( 기침의유무, 혈압, 혈청크레아티닌, 혈청칼륨값을확인 ) 에서증량을시도해야한다 [9]. ACE 억제제는사용금기나부작용이없는한좌심실수축기능장애가있는모든환자뿐만아니라심부전 A단계환자에서도투여되어야한다. ACE 억제제를사용하는경우에는 ACE 억제제를소량으로시작해야하며 2주간격으로용량을 2배로증량하여목표용량 (target dose) 까지도달한다 (Table 2). 하지만환자가부작용등으로 ACE 억제제증량을못견디는경우환자가견딜수있는최대용량을유지한다. ACE 억제제사용시혈액전해질농도 ( 혈청 K + ), urea, creatinine, 혈압등을정기적으로측정해야한다. Creatinine의상승폭이기준치에비교하여 < 50% 이거나 2.3 mg/dl까지는 ACE 억제제사용용량을유지하고 Cr이 50%, 기준치대비 100% 의경우는사 Figure 2. Treatment options for patients with heart failure with reduced ejection fraction. From McMurray JJ, Adamopoulos S, Anker SD, et al. Eur J Heart Fail 2012;14:803-869. [2] ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; NYHA, New York Heart Association; MR antagonist, mineralocorticoid receptor antagonist; LVEF, left ventricular ejection fraction; HR, heart rate; CRT-P, cardiac resynchronization therapy pacemaker; CRT-D, cardiac resynchronization therapy defibrillator; ICD, implantable cardioverter-defibrillator; H-ISDN, hydralazine and isosorbide dinitrate; LVAD, left ventricular assist device. a Diuretics may be used as needed to relieve the signs and symptoms of congestion but they have not been shown to reduce hospitalization or death. b Should be titrated to evidence-based dose or maximum tolerated dose below the evidence-based dose. c Asymptomatic patients with an LVEF 35% and a history of myocardial infarction should be considered for an ICD. d If mineralocorticoid receptor antagonist not tolerated, an ARB may be added to an ACE inhibitor as an alternative. e European Medicines Agency has approved ivabradine for use in patients with a heart rate 75 b.p.m. May also be considered in patients with a contraindication to a beta-blocker or beta-blocker intolerance. f Indication differs according to heart rhythm, NYHA class, QRS duration, QRS morphology and LVEF. g Not indicated in NYHA class IV. h Digoxin may be used earlier to control the ventricular rate in patients with atrial fibrillation-usually in conjunction with a beta-blocker. i The combination of hydralazine and isosorbide dinitrate may also be considered earlier in patients unable to tolerate an ACE inhibitor or an ARB. - 130 -
- 박진주외 1 인. 좌심실수축기능저하심부전증의치료 - Table 2. Evidence-based doses of ACE-inhibitor or ARB used in key randomized trials of heart failure (or after myocardial infarction) Starting dose Target dose ACE inhibitor Captopril, mg tid 6.25 50 Enalapril, mg bid 2.5 10-20 Lisinopril, mg qd 2.5-50 20-35 Ramipril 2.5 mg qd 5 mg bid Trandolapril, mg qd 0.5 4 ARB Candesartan, mg qd 4 or 8 32 Valsartan, mg bid 40 160 Losartan, mg qd 50 150 ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. 용중인 ACE 억제제의용량을절반으로감량하고혈액검사를다시시행한뒤사용해야한다. 만약혈청 K + 6.0 mmol/l 이거나 Cr이 > 100% 증가하거나 > 4.0 mg/dl이면 ACE 억제제사용을중단하고전문가에게자문을구해야한다. 하지만 ACE 억제제의중단이필요할경우는매우드물며치료중단시심부전이임상적으로악화될수있으므로약제중단전에반드시전문가에게조언을구해야한다. ACE 억제제는과거에치명적인부작용 ( 혈관부종, 무뇨증, 진행되는신부전 ) 이있었거나임신부에서는사용하지않도록해야한다. 그리고수축기혈압이낮은경우, 혈청 creatinine이높은경우 (Cr > 3 mg/dl), 양측성신동맥협착, 고칼륨혈증 (K + > 5.5 mmol/l) 인경우에는특별한주의가필요하다. ACE 억제제는기침을유발할수있으므로환자가마른기침을호소할경우 ACE 억제제를 ARB 제제로대체하는것을고려해야한다. 심부전환자에서 ACE 억제제의효과는 drug-class specific 이라고생각되지만모든 ACE 억제제에대한임상시험결과가없으므로가능하면임상시험에서효과가입증된약제를선택하는것을추천한다. ARB ARB는안지오텐신수용체-1 (AT-1 receptor) 을직접차단하고 bradykinin을증가시키지않아 ACE 억제제에비해부작용이적으며환자들의순응도가높다. 고령의심부전환자를대상으로 captopril 과 losartan을비교한연구 (ELITE-II) 에 서 losartan은 ACE 억제제보다부작용의빈도가낮았지만사망개선효과에서는차이가없었다 [10]. Valsartan 및 candesartan은심부전환자의입원율과사망률을감소시켰다 [11,12]. ACE 억제제및 ARB 병합요법은 CHARM-Added 연구에서는총사망률을감소시켰지만 Val-HeFT 연구에서는사망률감소에영향을주지못했다. ACE 억제제와 ARB를병합하여사용한 ONTARGET 고혈압연구에서는 ACE 억제제와 ARB를병합하여사용할경우신장기능이상이증가하는것을보고하였다 [13]. 현재심부전환자에서 ACE 억제제와 ARB 병합요법의임상적이득이명확하지않고부작용만증가시키는상황에서 ACE 억제제및 ARB 병합요법은신중하게접근해야할것이다. ARB는박축률저하심부전환자에서 ACE 억제제와동등한심혈관질환억제효과가있다. 따라서 ACE 억제제를부작용때문에투여할수없는경우 ARB를사용해야한다. ARB는신장기능이상및고칼륨혈증, 저혈압등에대해 ACE 억제제와같은주의가필요하다. 베타차단제베타차단제는심부전환자의예후를개선시킨두번째약제이다. 1991년 SOLVD 연구에서 ACE 억제제가심부전환자에서생존율을향상시킨다는것을보고하고약 5년이지나서야여러대규모임상연구에서베타차단제또한생명연장및심부전악화방지효과를입증했다. 현재 bisoprolol [14], sustained-release metoprolol (succinate) [15], cavedilol [16-18], nebivolol [19] 등 4가지약제만이박축률저하심부전에서예후개선효과를입증하였으며심부전환자에서사용이가능하다 (Table 3). ACE 억제제와달리베타차단제는 class effect 가없다. Propranolol 또는 atenolol 같은 1세대베타차단제및 short-acting metoprolol tartate는심부전환자에서예후를개선하지못했기에사용을피해야한다. 베타차단제를시작하기전 ACE 억제제를먼저사용하는것을추천한다. 하지만 ACE 억제제를투여중인환자에서베타차단제를추가하는최적의시점은알려져있지않다. 베타차단제를시작하기위해서반드시고용량의 ACE 억제제나안지오텐신수용체차단제를사용하고있어야할필요가없으며저용량의 ACE 억제제를사용하고있다고해도가능한빨리베타차단제를추가하는것이좋다 [20]. 베타차단제는아주낮은용량으로부터시작하고조금씩증량하여 - 131 -
- The Korean Journal of Medicine: Vol. 88, No. 2, 2015 - Table 3. Evidence-based doses of beta-blockers used in key randomized trials of heart failure (or after myocardial infarction) Starting dose Target dose Bisoprolol, mg qd 1.25 10 Carvedilol, mg bid 3.125 20-50 Metorpolol succinate, mg qd 12.5 200 Nebivolol, mg qd 1.25 10 수주에서수개월후목표용량에도달하게한다. 베타차단제를증량하는동안울혈이발생하는지확인해야하며, 울혈이발생하는경우우선이뇨제를추가하거나이미이뇨제를사용하고있는경우에는이뇨제를증량해야한다. 만약베타차단제복용중심부전이악화되는경우 (acute decompensation heart failure) 에도가능하면베타차단제를유지하고먼저이뇨제를추가또는증량한다. 하지만낮은심박출량 (low cardiac output) 이심부전악화의원인인경우에는베타차단제를감량하거나일시적으로중단하고 phosphodiesterase 억제제 (milrinone) 같은강심제를투여한다. 환자가안정되면퇴원전베타차단제를재개하는것을고려한다. Aldosterone 길항제 (mineralocorticosteroid receptor antagonist) Renin-angiotensin-aldosterone system의마지막단계는 aldosterone의유리이다. ACE 억제제를사용할경우 aldosterone을억제하는효과는 20% 미만이므로 aldosterone 수용체를직접차단하는약제가개발되었다. Aldosterone은나트륨저류, 마그네슘및칼슘소실, 교감신경계항진, 섬유화의증가, 부교감신경계억제및압수용체기능부전등의기전으로심부전의병태생리에중요한역할을하는것으로알려져있다 [5]. 박출률저하심부전환자 (EF < 35%) 1,663명을대상으로시행한 Randomized Aldactone Evaluation Study 연구에의하면기존치료에 spironolactone을추가시전체사망률을 29%, 심부전악화로인한재입원율을 36% 감소시켰다고한다 [21]. Spironolactone은특히 ACE 억제제또는 ARB와병용해서사용시치명적인고칼륨혈증을유발할수있다. Spironolactone 을투여전혈액검사를시행해야신장기능이상및전해질불균형이있는지확인해야한다. GFR > 30 ml/min/1.73 cm 2 및혈청 K + < 5.0 meq/dl인경우에약제를사용한다. Spironolactone 을시작하면신장기능및혈청칼리움농도를 1-2주후반드시평가해야하며 1개월이후에도정기적으로검사 Table 4. Evidence-based doses of mineralocorticoid receptor antagonists in key randomized trials of heart failure Starting dose Target dose Spironolactone, mg qd 25 25-50 Eplerone, mg qd 25 50 하여용량을조절해야한다. 통증을동반한여성형유방 (gynecomastia) 발생시약물사용을중단해야한다 (Table 4). 최근새로운알도스테론길항제인 eplerenone은 EPHESUS 연구에서심근경색 14일이내인좌심실박출률 40% 환자에서 1년내사망률을 13.6% 에서 11.8% 로감소시켰다 [22]. Eplerenone은아직우리나라에서사용할수없다. Ivabradine 박출률저하심부전환자에서빈맥은감소한심박출량을보상해주는효과가있지만시간이지나면서좌심실의충만장애를가져오고심근산소소모량을증가시키며관상동맥의관류시간을단축시켜장기적으로심부전을악화시킬수있다. Ivabradine 은심박조율기에있는 funny channel (If) 을선택적으로억제하여순수하게심장박동수만감소시키고혈압또는심근수축력에는영향을미치지않는다. SHIFT 연구에서는 18세이상의기저심박수가분당 70회이상이며좌심실박출률이 35% 이하인 6,558명의환자들을대상으로 ivabradine의효과를분석하였다 [23]. 피험자의 90% 정도가이미베타차단제나 ACE 억제제또는 ARB를복용중이었다. Ivabradine 은심혈관사망이나심부전악화에따른재입원율을 18% 낮추었다 (p < 0.0001). 최근개정된유럽심장학회심부전권고안에서는 ACE 억제제 /ARB, 베타차단제및 mineralocorticoid receptor 길항제 (eplerenone/spironolactone) 3 제요법을사용했음에도불구하고 (i) 심부전증상이지속되면서 (ii) left ventricular ejection fraction이 35% 이하이고 (iii) 정상동율동이면서 (iv) 심박수가 70 bpm을초과하는환자에게는 ivabradine을추가하는것을권고하고있다. 디곡신 디곡신은 200년전부터임상에서사용되기시작하여심부전환자에서가장오래전부터사용되어온약제이다. 디곡신은좌심실박축률을증가시키고교감신경계의활성도를저하시켜심부전환자에서증상을완화시킨다. DIG 연구에 - 132 -
- Jin Joo Park, et al. HFrEF treatment - 서는디곡신이동조율심부전환자의심부전악화로인한입원을감소시켰지만예후는개선시키지못했다 [24]. 심부전증상이없는박출률저하환자에서디곡신효과는아직명확하게밝혀져있지않다. 현재디곡신은정상동률동이면서 ACE 억제제등다른약제의투여에도불구하고심부전증이지속되거나심방세동이동반되어맥박수를조절하기위해투여할수있다. 일반적인유지투여용량은 0.125 mg/day를권장하고있다. 심장재동기 (cardiac resynchronization therapy) ACE 억제제, 베타차단제, 알도스테론길항제등에반응을하지않는심부전환자에서심장재동기화를고려할수있다. COMPANION 연구결과심장재동기화치료만으로총사망률을 24% (p = 0.06) 감소시켰으며재동기화치료와제세동기를같이사용한군에서는 36% (p = 0.003) 감소시켰다 [25]. CARE-HF 연구에서는약물사용군보다재동기화군에서 36% 의총사망률감소를보여주었다 [26]. 심장재동기화는좌심실박출률이 35% 이하이고동조율, 적절한약물치료에도불구하고 New York Heart Association (NYHA) Class II-IV이거나심장비동시성 ( 심전도상 QRS 간격이 120 ms 이상 ) 인심부전환자에서시행되어야한다. Implantable cardioverter defibrillator (ICD) 급사는심부전환자사망의주원인이다. 심실확장과심실기능의저하가있는심부전환자에서비지속성혹은지속성심실빈맥이흔히관찰되며이런환자에서심장성사망률은특히높다. 심장제세동기는급성심장사를더효과적으로감소시킬수있기때문에치명적인빈맥성부정맥을가진모든환자에서삽입형심장제세동기 (ICD) 삽입을고려해야한다. 심장이식약물치료에불응하는 Stage D 말기심부전환자에서가장근본적인치료는심장이식이다. 심장이식은 1967년 Dr. Barnard 에의해처음으로성공적으로시행된이래 [27] 1983년강력하고안전한면역억제제인 cyclosporine이미국식품의약국 (FDA) 의사용승인을얻으면서예후가크게개선되었다. 현재성인에서심장이식후 1, 3, 5년생존율은각각 87.8%, 78.5%, 71.7% 로보고되고있다 [28]. 심장이식술이적용되는환자에 는심인성쇼크로강심제또는기계적보조치료를요하는말기심부전환자, 관상동맥성형술및관상동맥우회술이불가능하고어떠한치료에도반응하지않는협심증환자, 고주파치료및 ICD에반응하지않는악성심실성부정맥환자등이있다 [29]. 심장이식술은말기심부전환자중고위험군환자에서만예후를개선한다. Deng 등 [30] 은심장이식대기자중고위험군환자 (heart failure survival score [HFSS] 7.19) 에서만예후가개선되는반면중등 (7.20 HFSS < 8.10) 및저위험군 (HFSS 8.10) 환자에서는예후개선효과가없다고보고하였다. 그러므로말기심부전환자중심장이식으로예후개선이가능한환자를선별해야한다. 결 박출률저하심부전증의치료는심부전의병태생리적기전이점차밝혀지면서약물및비약물적치료에서눈부신발전을보여주었으며심부전환자의치료목표는단순증상호전이아니라생존율개선이다. 현재많은약제들이임상시험을통해개발되고있으며이를통해심부전환자의생존율이개선될것으로기대된다. 이와같은상황에서임상의는약물적요법의장단점을잘이해하고적절한치료방법을선택해야환자의증상이호전되고생존율이향상될것이다. 론 중심단어 : 수축기심부전 ; 진료지침 REFERENCES 1. Writing Committee Members, Yancy CW, Jessup M, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:e240-e327. 2. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803-869. 3. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971;285:1441-1446. 4. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, - 133 -
- 대한내과학회지 : 제 88 권제 2 호통권제 654 호 2015 - Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355:251-259. 5. Yoo BS. Pharmacological treatment of heart failure. Korean J Med 2011;81:716-719. 6. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429-1435. 7. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325:293-302. 8. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-153. 9. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensinconverting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999;100:2312-2318. 10. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial-the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582-1587. 11. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675. 12. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensinconverting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767-771. 13. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372: 547-553. 14. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13. 15. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-2007. 16. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-1658. 17. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 2002;106:2194-2199. 18. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 2001;357:1385-1390. 19. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215-225. 20. Funck-Brentano C, van Veldhuisen DJ, van de Ven LL, et al. Influence of order and type of drug (bisoprolol vs. enalapril) on outcome and adverse events in patients with chronic heart failure: a post hoc analysis of the CIBIS-III trial. Eur J Heart Fail 2011;13:765-772. 21. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-717. 22. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21. 23. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875-885. 24. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-533. 25. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329-1338. 26. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-1549. 27. Barnard CN. The operation. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. S Afr Med J 1967;41:1271-1274. 28. Stehlik J, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Heart Transplant Report-2011. J Heart Lung Transplant 2011;30:1078-1094. 29. Mancini D, Lietz K. Selection of cardiac transplantation candidates in 2010. Circulation 2010;122:173-183. 30. Deng MC, De Meester JM, Smits JM, Heinecke J, Scheld HH. Effect of receiving a heart transplant: analysis of a national cohort entered on to a waiting list, stratified by heart failure severity. Comparative Outcome and Clinical Profiles in Transplantation (COCPIT) Study Group. BMJ 2000;321: 540-545. - 134 -