폐쇄성폐질환 (Obstructive Lung Disease) Volume 4, Number 1, January, 2016 X COPD 의치료 : 새로운치료제와병합요법 오연목 울산대학교의과대학서울아산병원호흡기내과 An inhaled long-acting bronchodi

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1 X COPD 의치료 : 새로운치료제와병합요법 오연목 울산대학교의과대학서울아산병원호흡기내과 An inhaled long-acting bronchodilator hascontributed to the treatment of COPD patients as powerfully as to have changed the disease concept of COPD from an irreversible disease to a treatable disease. Recently a new generation of inhaled long-acting bronchodilators are becoming available. Among them, a dual bronchodilator or a fixed combination of long-acting muscarinic antagonist and long-acting beta-agonist has shown at least 150% as effective as a single componentin terms of symptom improvement, health-related quality of life, lung function improvement, and exacerbation prevention. The dual bronchodilator is expected to contribute one step further to the treatment of COPD. Key Words: COPD, bronchodilator, long-acting muscarinic antagonist, long-acting beta-agonist Corresponding author: Yeon-Mok Oh, M.D., Ph.D. Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, 86, Asanbyeongwon-gil, Songpa-gu, Seoul 05505, Korea Tel: , Fax: , yeonmok.oh@gmail.com 1. 서론 최근만성폐쇄성폐질환 (chronic obstructive pulmonary disease, COPD) 치료에새로운기관지확장제가연이어나오고있어서 COPD 환자를진료하는의사와 COPD 환자에게희소식이라할것이다. COPD 는저자가수련을받던시기인 1990 년대만하더라도 ʻʻ비가역불치병ʼʼ으로인식하던질병이었다. 하지만 2000 년대흡입지속성기관지확장제 (inhaled long-acting bronchodilator) 의등장으로 COPD라는질병의개념이 ʻʻ부분가역의치료가능한병ʼʼ으로개념이전환되는큰발전이있었다. 이렇게 COPD 질병개념까지 ʻʻ치료가능한병ʼʼ으로전환시키는데기여한흡입지속성기관지확장제가지난 10여년간 COPD 환자를치료하는데널리사용되었다. 흡입지속성기관지확장제의효과는다수의임상시험으로아주잘입증이되어있으며이를반영하여 COPD 진료지침에는흡입지속성기관지확장제가 ʻʻCOPD 핵심치료제ʼʼ로기술하고있다. 우리나라진료지침과국제진료지침 (GOLD document) 에서공히호흡곤란이해결되지않는모든 COPD 환자에게흡입지속성기관지확장제를사용할것을강하게권고하고있다 1,2. 이렇게흡입지속성기관지확장제를강하게권고하는이유는이흡입제가 COPD 환자의호흡곤란증상과삶의질을개선하고운동능력을향상시키며악화와입원을줄이기때문이다. 이렇게효과가강력한흡입지속성기관지확장제가안타깝게도우리나라일선진료에서는기대한만큼사용되고있지못하다. 흡입지속성기관지확장제가기대만큼잘사용되고있지못한이유로는첫째폐활량검사결과 (FEV 1 <80%) 가있어야건강보험청구가되고둘째는흡입제사용법을교육하는데시간과노력이꽤필요하며셋째는환자가흡입제보다는경구약을선호하는경향이있기때문이다. 49

2 Table 1. 새로운흡입지속성기관지확장제 이중기관지확장제 ( 항콜린제 + 베타 - 항진제 ) 항콜린제베타 - 항진제흡입기 (device) 이름 조터나 (glycopyrronium+indacaterol 시브리 glycopyrronium 온브리즈 indacaterol 브리즈헬러 아노로 (umeclidinium+vilanterol) 인크루즈 umeclidinium vilanterol* 엘립타 듀어클리어 (aclidinium+formoterol) 에클리라 aclidinium formoterol 제뉴에어 바헬바 (tiotropium+olodaterol) 스피리바 tiotropium 스트리베르디 olodaterol 레스피맷 *vilanterol 은단일기관지확장제로는출시되지않았다. formoterol 은단일기관지확장제로 oxis 터부헬러가과거있었으나현재는철수하여없다. 하지만 COPD 를진단하는데폐활량검사가필수적이고대신할수있는검사법이없기때문에폐활량검사기계를직접잘세팅하거나아니면타병원에의뢰하여수행하거나그것도아니면타병원폐활량검사결과를환자에게가져오게하여야건강보험청구를할수있다. 또한흡입제사용법교육이처음은시간과노력이꽤필요하지만환자가한번익숙해지면오히려환자가더찾고선호하게바뀌는경우가많다. 흡입제사용법교육을회사에서제공하는동영상을환자에게진료실밖에서미리보여주어서익숙하게하면더효율적일것이다. 2. 본론 - 새로운기관지확장제와병합요법 본론에서는최근새로나왔거나나올예정인흡입지속성기관지확장제를소개하겠다 (Table 1). 이새로운흡입지속성기관지확장제중특히이중기관지확장제 (dual bronchodilator 또는병합요법이라고하기도함 ) 는그효과가기존단일기관지확장제보다 50% 이상향상되어 COPD 환자의증상및삶의질개선, 폐기능호전및악화예방등의효과가더크다. 흡입이중기관지확장제는항콜린제와베타-항진제병합요법으로서해당단일성분흡입제와비교하여효과가우수할뿐만아니라기존 COPD 약제와비교하여도효과가더우월하다. 그효과의우월성을증상및삶의질, 폐기능호전, 그리고악화예방등셋으로나누어서보겠다. 이렇게셋으로나누어살펴보는이유는과거중요하다고생각한폐기능뿐만아니라호흡곤란증상이나삶의질이환자의예후에아주중요하다는것이밝혀지게되었고악화또한환자의예후에크게영향을미치는것으로알려지게되었기때문이다. 이를반영하여최근 COPD 진료지침에는폐기능과함께호흡곤란 ( 또는삶의질 ) 점수, 그리고지난해악화횟수등을고려하여 COPD 환자를분류하고약제를선택하게권고하고있다. 1) 호흡곤란증상및삶의질개선새로운이중기관지확장제는위약과비교하여호흡곤란지수 (transition dyspnea index, TDI) 로평가한호흡곤란증상을 COPD 환자에서개선시켰다 (Figure 1A) 3-7. 이개선효과의크기는임상적으로도의미있는기준인 ʻ최소임상적의미있는차이ʼ(minimal clinically important difference, MCID) 를더넘겼다. 또한이중기관지확장제는단일기관지확장제와비교하여서도호흡곤란증상을더개선시키는것같다 (Figure 1B) 3-8. 예를들면조터나 (glycopyrronium+indacaterol) 는기존널리사용하는단일기관지확장제인 tiotropium ( 상품명스피리바 ) 과비교하여호흡곤란증상을 COPD 환자에서더개선하였다. 하지만이개선효과가크지는않았다. 삶의질개선에있어서도새로운이중기관지확장제는위약과비교하여세인트조지호흡설문 (the Saint George Respiratory Questionnaire, SGRQ) 으로평가한삶의질을 COPD 환자에서개선시켰다 3,5-7,9. 이개선효과의크기는임상적으로도의미있는기준인 ʻ최소임상적의미있는차이ʼ(minimal clinically important difference, MCID) 를넘기는경우가많았다. 또한이중기관지확장제는단일기관지확장제와비교하여서도삶의질더개선시키는것같다 3,5-8,10,11. 예를들면조터나 (glycopyrronium+indacaterol) 는기존널리사용하는단일기관지확장제인 tiotropium 50

3 Figure 1. 위약대비이중기관지확장제의호흡곤란개선효과. (A) 위약대비이중기관지확장제의호흡곤란개선효과, (B) 단일제대비이중기관지확장제의호흡곤란개선효과. 참고. 작은그래프하나는대규모임상시험을하나씩요약한결과임. 51

4 Figure 2. 이중기관지확장제 ( 예. 조터나 glycopyrronium+indacaterol) 부작용및 tiotropium 단일제 ( 상품명스피리바 ) 부작용을위약대비비교한연구. ( 상품명스피리바 ) 과비교하여삶의질을 COPD 환자에서더개선하였다. 하지만이개선효과가크지는않았다. 또한유사하게바헬바 (tiotropium+olodaterol) 도 tiotropium 단일제보다삶의질을더개선하였다. 2) 폐기능호전새로운이중기관지확장제는위약과비교하여 FEV 1 (forced expiratory volume in one second) 으로평가한폐기능을 COPD 환자에서호전시켰다 12. 이호전효과의크기는임상적으로도의미있는기준인 100 ml (minimal clinically important difference, MCID) 를훨씬넘겨서대략 ml이었다. 또한이중기관지확장제는단일기관지확장제와비교하여서도폐기능을대략 ml 더호전시켰다. 3) 악화예방새로운이중기관지확장제는위약과비교하여 COPD 악화를 30% 가량줄이는예방효과를보였다 ( 예. 조터나 ) 12. 또한이중기관지확장제는단일기관지확장제와비교하여서도더 COPD 악화를예방하는것같다. 예를들면조터나 (glycopyrronium+indacaterol) 는기존널리사용하는단일기관지확장제인 tiotropium ( 상품명스피리바 ) 과비교하여 COPD 악화를 12% 더감소시켰다 10. 악화예방은 COPD 환자치료목표중아주중요하다. 이유는악화자체로환자가나빠져서입원해야할때가있고일부환자는악화로사망에이르기도하기때문이거니와 COPD 악화가생기게되면향후악화재발위험증가및폐기능저하가속화등예후에도나쁜영향을주기때문이다. 4) 부작용및안전성새로운이중기관지확장제가단일기관지확장제보다효과가더큼을증상및삶의질개선, 폐기능호전, 그리고악화예방측면에서보여주었다. 그렇다면새로운이중기관지확장제가두성분을갖고있으니부작용도더많을것인가하는궁금증이생길수있다. 부작용이드물게일어날경우시판후상당기간이지나서문제가되는경우도있기때문이다. 다행인것은현재까지자료를보면부작용이기존기관지확장제나혼합제와비슷한것같다. 이중기관지확장제는심장부작용이나뇌혈관질환부작용면에서위약대비부작용이비슷하였다 (Figure 2) 13, 결론 2000년대들어흡입지속성기관지확장제가 COPD 환자치료에들어오면서 COPD 질병의개념을 ʻʻ치료가가능한질병ʼʼ으로전환시킬정도로크게기여하였다. 여기에더하여최근새로나온이중기관지확장제는그효과가더우월하여향후 COPD 환자치료에한걸음더나아갈것으로기대한다. 이렇게효과가잘입증된 COPD 치료제도환자에게처방이되지않으면아무소용이없기때문에진료할때 52

5 폐활량검사를더많이수행하여 COPD 환자를발굴해주시기를진심으로바란다. COPD 는유병률커서대학병원이나 3차병원에서열심히진료한다고해결할수있는병이아니다. 일선 1, 2차병원에서 COPD 환자를발굴하고치료에동참할때더나아질수있으리라기대한다. 4. 감사의글 본원고는 2015년 11월호 ʻ메디포ʼ지에실린내용과동일함을밝힌다. 두잡지에게재하는것에대해서 ʻ메디포ʼ 지및 ʻOLDʼ지의허락을득하였다. References 1. The Korean Academy of Tuberculosis and Respiratory Diseases. COPD guideline [Internet] [cited 2015 November 11]. Available from: 2. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease [Internet] [cited 2015 November 2]. Available from: org/guidelines-global-strategy-for-diagnosis-management.html 3. Bateman ED, Ferguson GT, Barnes N, Gallagher N, Green Y, Henley M, et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J 2013;42: Mahler DA, Decramer M, D'Urzo A, Worth H, White T, Alagappan VK, et al. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J 2014;43: Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med 2013;107: Singh D, Jones PW, Bateman ED, Korn S, Serra C, Molins E, et al. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. BMC Pulm Med 2014;14: D'Urzo AD, Rennard SI, Kerwin EM, Mergel V, Leselbaum AR, Caracta CF; AUGMENT COPD study investigators. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res 2014;15: Decramer M, Anzueto A, Kerwin E, Kaelin T, Richard N, Crater G, et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med 2014;2: Singh D, Ferguson GT, Bolitschek J, Grönke L, Hallmann C, Bennett N, et al. Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Respir Med 2015;109: Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandström T, Taylor AF, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med 2013;1: Buhl R, Maltais F, Abrahams R, Bjermer L, Derom E, Ferguson G, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4). Eur Respir J 2015;45: Oba Y, Sarva ST, Dias S. Efficacy and safety of long-acting β-agonist/long-acting muscarinic antagonist combinations in COPD: a network meta-analysis. Thorax doi: /thoraxjnl [Epub ahead of print] 13. Wedzicha JA, Buhl R, Lawrence D, Young D. Monotherapy with indacaterol once daily reduces the rate of exacerbations in patients with moderate-to-severe COPD: Post-hoc pooled analysis of 6 months data from three large phase III trials. Respir Med 2015;109: Wedzicha JA, Dahl R, Buhl R, Schubert-Tennigkeit A, Chen H, D'Andrea P, et al. Pooled safety analysis of the fixed-dose combination of indacaterol and glycopyrronium (QVA149), its monocomponents, and tiotropium versus placebo in COPD patients. Respir Med 2014;108:

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untitled III In What Patients Should I Use Fixed LABA/LAMA Combination in COPD? 엄수정 동아대학교의과대학내과학교실호흡기내과 Long-acting β-agonist/long acting muscarinic antagonist (LABA/LAMA) combinations are associated with a greater