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 improvement in lung function, St. George s Respiratory Questionnaire score, transitional dyspnea index and lesser exacerbations than monotherapies. In addition, there are no statistically significant differences between LABA/LAMA combinations and monotherapies in terms of safety outcomes. LABA/LAMA combinations are more effective than inhaled corticosteroid/laba in preventing exacerbations in COPD patients with severe air flow limitation and previous history of exacerbations. Therefore, LABA/LAMA combinations should be considered first for patients with severe symptom, deteriorated quality of life and frequent exacerbations. Key Words: Pulmonary disease, Chronic obstructive, Long-acting β 2 -agonists, Long-acting muscarinic antagonist, Fixed dose combination Corresponding author: Soo-Jung Um, M.D. Division of Pulmonology, Department of Internal Medicine, Dong-A University Hospital, 26 Daesingongwon-ro, Seo-gu, Busan 49201, Korea Tel: +82-51-240-2769, Fax: +82-51-240-5852, E-mail: sjum@dau.ac.kr 1. 서론 만성폐쇄성폐질환 (Chronic Obstructive Pulmonary Disease, COPD) 환자의약물치료목표는증상을완화시키고악화를줄이는것이다 1. 흡입용기관지확장제는치료목표달성을위한가장중요한약물치료제이다. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 지침에서는흡입용지속성베타항진제 (Long-Acting β2-agonist, LABA) 와흡입용지속성무스카린대항제 (Long-Acting Muscarinic Antagonist, LAMA) 가중증도이상의 COPD 환자초기치료와그후지속적치료에포함되어야한다고권고하고있다 1. 한종류의기관지확장제치료로증상이호전되지않으면 LABA 와 LAMA 병용요법이필요하며, 단독요법보다이득이있다고알려져있다 2. 현재하나의흡입기에 LABA, LAMA를고정된용량으로병합한치료제가사용중이다. 네가지고정용량 LABA/LAMA 병합제제 (LABA/LAMA Fixed Dose Combination, LABA/LAMA FDC) 가시판중으로처방할수있으며, 한가지는곧출시예정이다. 본고찰에서는출판된임상자료를바탕으로 LABA/LAMA FDCs 의유용성을살펴보고어떤환자에적용할수있을지살펴보고자한다. 2. LABA/LAMA FDC 의등장배경 한종류의기관지확장제치료로 COPD 환자의증상이잘조절되지않는경우가많다. 일차의료기관에서치료중인 COPD 환자들을대상으로 24시간동안의증상변화를관찰한연구에의하면절반이상의환자가이미한가지 61
이상의약물치료중이었음에도증상이잘조절되지않았다 3. 중등증이상의증상이있는 COPD 환자에서한종류의기관지확장제보다는작용기전이다른여러기관지확장제를동시에투여하면, 더욱효과적으로주관적증상과객관적지표가향상될수있음은이미알려져있다 4. 따라서 LABA/LAMA FDC의등장은매우자연스러우며현재네종류 (Umeclidinium bromide/vilanterol trifenatate, Anoro R Ellipta R GlaxoSmithKline plc, London, UK; Glycopyrronium bromide/indacaterol maleate, Ultibro R Breezhaler R, Novartis International AG, Basel, Switzerland; Aclidinium bromide/formoterol fumarate dihydrate, Brimica R Genuair R, Almirall, S.A., Barcelona, Spain; Tiotropium bromide/olodaterol, Stiolto R Respimat R, Boehringer-Ingelheim, Ingelheim, Germany) 의 LABA/LAMA FDC가국내시판중이다 (Table 1). 이와같은병합제제들은새로운분말흡입기인 Breezhaler R, Ellipta R, Genuair R, Respimat R 에서 LABA와 LAMA가혼합되어분무된다. 더나아가한가지성분에의해 LABA 와 LAMA 의역할을하는새로운범주의약제도개발중이다. 1) 병합요법의생리학적기전베타항진제와무스카린길항제는다른기전으로기관지를확장시킨다. 베타항진제는기관지평활근의베타수용체와결합하여 camp 를증가시키고이는 protein kinase A를비활성화형에서활성화형으로변환시켜평활근이완을통한직접적인기관지확장효과를나타낸다. 한편무스카린길항제는신경전달물질인아세틸콜린이무스카린수용체와결합하는것을방해하는간접적인방법으로기관지확장효과를가져온다. 기관지수축은 M1, M3-수용체에의해매개되고 M2-수용체의활성화는아세틸콜린분비를감소시킨다. 아세틸콜린은 M3-수용체와결합하여 protein kinase C와세포내칼슘을증가시켜기관지를수축시킨다. 베타수용체는주로소기도에존재하며 5 M3-수용체는하부기관지를비롯하여주로기도중심부에존재한다고알려져있다 6. 따라서베타항진제와무스카린길항제병용요법은기도전반에걸쳐기관지확장효과를극대화할수있다 7. 또한기도평활근에서아드레날린경로와콜린성경로사이의보완적인상호작용이실험실연구에의해제시되기도하였다. 무스카린길항제에 β2- 항진제를첨가하면교차결합 β2- 아드레날린수용체에의한콜린성신경전달물질의조절이발생하여아세틸콜린방출이더욱감소되며이는무스카린길항제에의한기관지평활근이완을증폭시켰다 8. 아세틸콜린은기관지평활근의 post junctional M2-수용체를통해 adenylyl cyclase 를조절하여 camp 를감소시키고기도평활근수축을야기할수있다. M2- 수용체에무스카린길항제가결합하면이경로를차단하고 β2- 아드레날린수용체에결합하는 β2- 항진제를통한 camp 증가를허용하게된다 9. 2) 병합요법의임상적근거티오트로피움과포모테롤, 살메테롤, 인다카테롤등의병용요법연구에서티오트로피움단독요법보다지속성 Table 1. Currently available fixed dose LABA/LAMA combination inhalers Drug Approved dose Trade name/device Umeclidinium bromide (UME) /Vilanterol trifenatate (VIL) Glycopyrronium bromide (GLY) /Indacaterol maleate (IND) Aclidinium bromide (ACL) /Eformoterol fumarate (EFO) Tiotropium bromide (TIO) /Olodaterol (OLO) 62.5/25 μg QD Anoro R Ellipta R DPI 50/110 μg QD Ultibro R Breezhaler R DPI 15.6/27.5 μg BID Xoterna* R /Breezhaler R 400/12 μg BID Brimica R Genuair R DPI Duaklir* R /Genuair R 2.5/2.5 μg 2puff QD Stiolto R Respimat R SMI Vahelva* R /Respimat R The order of description is according to approved date. *Trade name in South Korea. LABA: long-acting β2-agonist, LAMA: long-acting muscarinic antagonist, DPI: dry powder inhaler, SMI: soft mist inhaler. 62
베타항진제를동시투여했을때폐기능향상, 호흡곤란완화, 완화제사용횟수감소등의효과가있었다 4,7,10-12. 이와같은연구들은 LABA/LAMA FDC의사용근거가되었다. 3. LABA/LAMA FDC 효과 1) 폐기능 15개무작위대조시험을메타분석한결과를보면병용요법은각각의단일요법보다항상폐기능향상효과가컸다 13. Aclidinium/Eformoterol 병용요법은각각의단일요법보다통계적으로유의한 trough FEV 1 향상효과가있었다 (+33.39 ml, 95% CI 13.40 53.38, p<0.001). Glycopyrronium/Indacaterol (+89.44 ml, 95% CI, 76.04 102.85, p<0.001), Tiotropium/Olodaterol (+54.75 ml, 95% CI, 45.70 63.80, p<0.001), Umeclidinium/Vilanterol (+83.66 ml, 95% CI, 65.65 101.67, p<0.001) 병용요법도각각의단일요법과비교할때유의하게 trough FEV 1 을향상시켰다. 병용요법에대한 23개무작위대조시험을분석한다른메타연구에서도 LABA/LAMA 병용요법이위약이나각각의단일제보다폐기능향상효과가월등하다고하였다 14. 네가지약제간의차이는뚜렷하지않으므로환자의선호도나부작용을고려해서선택하면될것이다. 2) 호흡곤란 (Transitional Dyspnea Index, TDI) 및삶의질지표 (St. George s Respiratory Questionnaire, SGRQ) 모든 LABA/LAMA 병용요법은각각단일요법과비교할때약하지만통계적으로의미있는 TDI 상승효과가있었다. 반응군과비반응군의교차비는 Aclidinium/Eformoterol, Glycopyrronium/Indacaterol, Umeclidinium/Vilanterol 에서각각단독치료와비교하면 1.3 을초과하였다 13. SGRQ 향상도모든병합제제가각각의단일제보다효과적이었다. 단독치료에비해반응군의교차비가 1.2 에서 1.3 정도로통계학적으로유의하였으나 (p<0.01), Aclidinium/Eformoterol 의경우는통계적유의성에도달하지못하였다 (p>0.05) 13. 3) 악화감소 COPD 환자에서악화의정의는호흡기증상의변화정도가일상적인변화보다증가하여치료의변화에이르는경우로정의된다. 경증은속효성기관지확장제흡입횟수증가로호전되는경우, 중등증은항생제나전신성스테로이드를투여받아야하는경우, 중증은병원에입원해야하는경우로분류한다 1. 악화감소는 COPD 의가장중요한치료목표이며많은임상연구들이약제들의악화감소효과를연구하여보고하였다. Glycopyrronium/Indacaterol과 Salmeterol/Fluticasone 을비교한 52주무작위대조시험결과가 2016년도에발표되었다. FEV 1 은예측치의 25% 이상, 60% 미만으로비교적중증의기류제한이있으면서과거악화가 1회이상, mmrc 2점이상인중증환자가대부분인연구였다. Glycopyrronium/Indacaterol는 Salmeterol/Fluticasone와비교할때모든악화감소효과가우월하였으며 (3.59 vs. 4.03, rate ratio 0.89, 95% CI 0.83 to 0.96, p=0.003), 중등증혹은중증악화만따로분석하여도우월한감소효과를보였다 (0.98 vs. 1.19, rate ratio 0.83, 95% CI 0.75 to 0.91, p<0.001) 15. Glycopyrronium/Indacaterol 과 Tiotropium 비교연구에서는 Glycopyrronium/Indacaterol 이 Tiotropium보다모든악화를 14% 감소시키는효과가있었으나이효과는주로경증악화에서우월하게나타났고중등도이상의악화감소에는우월성을입증하지못하였다 16. 최근에시행된 16개무작위대조시험결과를분석한네트워크메타분석에의하면, LABA/LAMA FDC가중등증및중증악화예방효과가위약 (HR 0.66; 95% CI 0.57 0.77) 과 LABA (HR 0.82; 95% CI 0.73 0.93) 보다우수하였으나 LAMA (HR 0.92; 95% CI 0.84 1.00) 보다는우수한지알수없다고보고하였다 14. 따라서 LABA/LAMA의악화예방효과는대부분약제 ( 위약, LABA, LAMA, ICS/LABA) 보다우월하지만중등증이상의악화예방효과가 Tiotropium 보다우월한지에대해서는연구가더필요하다. 63
4) 심혈관부작용기관지확장제병용요법이단독요법보다효과적인것은이미발표된결과를보면알수있다. 병합요법을선택할때단독요법과비교한부작용, 특히심혈관계부작용의정도가치료결정의중요한요소일것이다. 현재까지병용요법은단독요법에비해유의한심혈관계부작용증가는없는것으로보고되고있다 17-21. 4. LABA/LAMA FDC 의적용 COPD 환자치료의중심이되는것은기관지확장제이므로모든환자에게기관지확장제치료는중요하다. 현재까지임상결과들에의하며 LABA/LAMA FDC가단독요법보다폐기능향상, 증상호전의측면에서높은효과를보였으므로처방을주저할이유는없다. 심혈관계부작용또한단독치료와비교하면차이가없거나오히려부작용이줄어드는경우도있어서약제선택의장애가되지않는다. 현재의국내외지침은폐기능즉 FEV 1 과 CAT 점수, 호흡곤란정도로표현되는환자증상의정도, 악화병력에따라서치료전략을수립하기를권고하고있다. 2014년도에개정된대한결핵및호흡기학회지침서에는증상이심하고 FEV 1 이 60% 이상인 나 그룹에서는기관지확장제단독요법을우선적으로선택하고, 증상이조절되지않거나악화가발생하는경우 LABA/LAMA FDC로단계올림치료를하도록권고하고있다. 한편 FEV 1 이 60% 미만, 과거에자주악화되었거나악화로입원한병력이있는 다 군환자에서는처음부터복합제처방혹은단일제처방후단계올림치료중에선택하도록권고하고있다. 최근개정된 GOLD 지침에서는잦은악화혹은악화로입원한적이있는그룹 D 환자에서는특별한이유가없으면 LABA/LAMA FDC를우선적으로고려하도록대폭수정된권고안을발표하였다. 또한악화의위험성이낮은그룹 B 환자에서도증상이심한경우처음부터복합제를사용하도록권고하고있다. 요약하면증상이심하면서잦은악화를경험한환자나심한호흡곤란을호소하는환자에게는초기치료로, 이외의경우는단계올림치료로 LABA/LAMA FDC를권고하고있다 (Figure 1). 5. ICS (Inhaled Corticosteroid)/LABA 와 LABA/LAMA ICS/LABA 는 COPD 치료의주된역할을해왔으나개정된지침에서는더이상초기치료로권고하지않고있다. ICS를 LABA와병용하면 LABA 단독보다 COPD 환자의악화를줄인다 22. 하지만 LABA/LAMA FDC인 Glycopyrronium/Indacaterol 과 ICS/LABA인 Fluticasone/Salmeterol 을 52주간투여하여비교한연구에서 Glycopyrronium/Indacaterol 이 Fluticasone/Salmeterol 보다유의하게악화를감소시켰다 15. 2017년이전의 GOLD 지침에서는그룹 C, D 즉악화위험성이높은환자에게만 ICS/LABA 가초기치료로허용되었으나실제로는 ICS 처방이광범위하게이루어지고있었고이에따른폐렴과골다공증등부작용의우려가있었다. 이런상황에서개정된 GOLD지침에서는 ICS/LABA 가 Figure 1. Summary of GOLD and Korean COPD guidelines for long acting beta agonist and muscarinic antagonist combination treatment. Symptomatic means CAT 10 or MRC 2. Exacerbator means at least 2 exacerbations in the previous year or hospitalized experience. GOLD: Global Initiative for Chronic Obstructive Lung Disease, Tx: treatment. 64
초기치료에서배제됨으로써일선진료의들에게 COPD 치료가기관지천식과는다르다는인식을심어주고 ICS 남용을막고자하는의도가있다고생각된다. ICS/LABA 는중복증후군 (Asthma COPD Overlap Syndrome, ACOS) 환자들에게는여전히유효하며혈액내호산구수치가 ICS 처방의생화학적지표로서유용하게사용될수있다. 하지만이러한고려도반드시악화의위험도가높은환자즉잦은악화나악화로입원한병력이있는환자에서만고려할수있다는것이중요하다. 아직까지는 ICS 반응군을예측하는효과적인지표는없으므로치료제선택의어려움이있을수있다. 향후지속적인연구가필요한분야라고생각한다. 6. 결론 LABA/LAMA 는 COPD 환자의폐기능을향상시키고증상을호전시키며악화를예방한다. 이러한효과는각각의단일제와비교해도통계적으로유의하게나타났다. 개정된진료지침에서는증상이심하거나악화의위험성이높은환자에게기관지확장제단일요법보다는 LABA/LAMA 치료를우선적으로고려하도록하고있고, ICS/LABA 는악화의위험이높은환자중일부환자에서사용하는것으로역할이축소되었다. 향후 ICS/LABA가효과적인환자군을규명할연구가필요할것이다. References 1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, Management, and prevention of chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease; 2016. 2. Malerba M, Morjaria JB, Radaeli A. Differential pharmacology and clinical utility of emerging combination treatments in the management of COPD--role of umeclidinium/vilanterol. Int J Chron Obstruct Pulmon Dis 2014;9:687-95. 3. Miravitlles M, Worth H, Soler Cataluña JJ, Price D, De Benedetto F, Roche N, et al. Observational study to characterise 24-hour COPD symptoms and their relationship with patient-reported outcomes: results from the ASSESS study. Respir Res 2014;15:122. 4. van Noord JA, Aumann JL, Janssens E, Smeets JJ, Verhaert J, Disse B, et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J 2005;26:214-22. 5. Carstairs JR, Nimmo AJ, Barnes PJ. Autoradiographic visualization of beta-adrenoceptor subtypes in human lung. Am Rev Respir Dis 1985;132:541-7. 6. Mak JC, Barnes PJ. Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung. Am Rev Respir Dis 1990;141:1559-68. 7. Cazzola M, Molimard M. The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther 2010;23:257-67. 8. Brichetto L, Song P, Crimi E, Rehder K, Brusasco V. Modulation of cholinergic responsiveness through the [beta]- adrenoceptor signal transmission pathway in bovine trachealis. J Appl Physiol (1985) 2003;95:735-41. 9. Spina D. Pharmacology of novel treatments for COPD: are fixed dose combination LABA/LAMA synergistic? Eur Clin Respir J 2015;2. doi: 10.3402/ecrj.v2.26634. 10. Mahler DA, D'Urzo A, Bateman ED, Ozkan SA, White T, Peckitt C, et al. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison. Thorax 2012;67:781-8. 11. van Noord JA, Aumann JL, Janssens E, Verhaert J, Smeets JJ, Mueller A, et al. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest 2006;129:509-17. 12. van Noord JA, Aumann JL, Janssens E, Smeets JJ, Zaagsma J, Mueller A, et al. Combining tiotropium and salmeterol in COPD: Effects on airflow obstruction and symptoms. Respir Med 2010;104:995-1004. 13. Calzetta L, Rogliani P, Matera MG, Cazzola M. A systematic review with meta-analysis of dual bronchodilation With LAMA/LABA for the treatment of stable COPD. Chest 2016;149:1181-96. 14. Oba Y, Sarva ST, Dias S. Efficacy and safety of long-acting β-agonist/long-acting muscarinic antagonist combinations 65
66 in COPD: a network meta-analysis. Thorax 2016;71:15-25. 15. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med 2016;374:2222-34. 16. 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;1:199-209. 17. 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;45:969-79. 18. Mahler DA, Kerwin E, Ayers T, FowlerTaylor A, Maitra S, Thach C, et al. FLIGHT1 and FLIGHT2: efficacy and safety of QVA149 (Indacaterol/Glycopyrrolate) versus its monocomponents and placebo in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;192:1068-79. 19. 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;42:1484-94. 20. Celli B, Crater G, Kilbride S, Mehta R, Tabberer M, Kalberg CJ, et al. Once-daily umeclidinium/vilanterol 125/25 mcg in COPD: a randomized, controlled study. Chest 2014;145:981-91. 21. 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;14:178. 22. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-89.