<30312EC6AFC1FD30362DBFC0BFACB8F12E687770>

Size: px

Start display at page:

Download "<30312EC6AFC1FD30362DBFC0BFACB8F12E687770>"

근형 왕
5 years ago
Views:

1 대한내과학회지 : 제 77 권제 4 호 2009 특집 (Special Review) - Updates of COPD 최근대규모만성폐쇄성폐질환임상연구의해석과적용 울산대학교의과대학서울아산병원호흡기내과및만성기도폐쇄성질환임상연구센터 이재승 오연목 Interpretation and application of recent large clinical studies in COPD Jae Seung Lee, M.D., and Yeon-Mok Oh, M.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, Seoul, Korea Chronic obstructive pulmonary disease (COPD) shows a high mortality as well as a high prevalence around the world. Recent large-scale clinical studies showed that inhaled long-acting anticholinergics, inhaled long-acting β 2 -agonists, and inhaled corticosteroid have beneficial effects on patients suffered from COPD. In addition, the combination of the two or three inhalers above shows more beneficial effects. The beneficial effects are the improvement of symptom, lung function, and quality of life as well as the reduction of exacerbation and possibly death. These beneficial effects are true not only for the patients with severe and very severe COPD but also for the patients with moderate COPD. Clinical studies also showed that mucolytics and roflumilast, a new anti-inflammatory drug have beneficial effects on the patients with COPD. According to these beneficial results proven by the recent clinical studies, the guidelines for the management of COPD might be revised to promote the usage of the beneficial drugs for the patients with COPD. The promoted usage of the COPD drugs would help the COPD patients to overcome their symptom, limitation of airflow and frequent exacerbation and also to improve their quality of life. (Korean J Med 77: , 2009) Key Words: Chronic obstructive pulmonary disease; Clinical study; Long-acting anticholinergics; Long-acting β 2 -agonist; Inhaled corticosteroid 서론만성폐쇄성폐질환 (Chronic Obstructive Pulmonary Disease: COPD) 은현재전세계적으로주요한사망원인질환중 4위를차지하고있으며, 그유병률이지속적으로증가하여 2020 년쯤에는사망원인 3위, 장애원인 5위로부상할것으로예상된다 1,2). 현재 COPD 진료지침은안정시 COPD 환자에게치료약제를증상혹은합병증을감소시키는목적으로사용할것을추천하고있다 3,4). 하지만최근대규모 COPD 임상 연구를통하여 COPD 치료약제가사망을줄일수있을것같다는희망적인증거를보여주었고, 중증 COPD (post-bronchodilator FEV 1<50% 예측치 ) 만이아니라중증도가덜한중등증 COPD (post-bronchodilator FEV 1 50~80% 예측치 ) 환자에게도여러측면에서효과를보여서악화를줄이고삶의질을향상시키며폐기능을호전시킨다는것을보여주었다. 이러한최근대규모 COPD 임상연구결과는 COPD 진료지침에변화를줄것으로기대되며 COPD 치료약제를더넓게사용하게하는기폭제가되리라생각된다

2 - The Korean Journal of Medicine: Vol. 77, No. 4, 본글에서는최근발표된중요한대규모 COPD 임상연구결과를제시하여독자들의이해를돕고 COPD 환자진료에어떻게적용할지조심스럽게제안하고자한다. 최근대규모만성폐쇄성폐질환임상연구 1. 기관지확장제 (bronchodilator) 1) 흡입지속성항콜린제 (Long-acting anticholinergics) 흡입지속성항콜린제인 tiotropium 은여러임상연구에서 tiotropium 하루 1회투여가속임약 (placebo) 에비해유의하게폐기능을향상시키고악화횟수를줄이는것으로보고되어만성폐쇄성폐질환환자에서최근많이사용되고있는약제이다 5,6). 최근장기간의 tiotropium 투여효과를보기위해 5,993명의만성폐쇄성폐질환환자를대상으로 4년동안시행된전향적무작위이중맹검속임약대조임상연구인 UPLIFT (Understanding the Potential Long-term Impacts on Function with Tiotropium) 연구결과 tiotropium 투여군이속임약군에비해유의하게폐기능, 삶의질을향상시키고악화빈도를감소시켰다 7). 연구종료후 30일사망률에서는 tiotropium 투여군과속임약군과의통계적인유의한차이는없었으나 (hazard ratio, 0.89; 95% 신뢰구간, 0.79~1.02), 연구종료시점에서는 tiotropium군이 14.4%, 속임약군이 16.3% 로통계적으로유의한사망률감소를보여주었다 (hazard ratio, 0.87; 95% 신뢰구간, 0.76~0.99). 그러나 UPLIFT 연구의일차결과변수인장기간의일초간노력성호기량 (FEV 1) 의감소에는 tiotropium 투여가영향을미치지못하였다. 최근발표된메타분석 (meta-analysis) 에서 ipratropium과 tiotropium이심혈관질환으로인한사망률증가와관련있는것같다고보고하였으나 8,9), 전향적무작위임상시험인 UP- LIFT 연구에서는 tiotropium 투여가심혈관질환으로인한사망에전혀영향이없었다 7). 오히려 tiotropium 군에서유의하게낮은호흡기합병증발생률을보였으며, 심혈관계와호흡기계를포함한심각한합병증의발생이유의하게감소하였다. 이렇게메타분석과전향적연구인 UPLIFT 연구가심혈관질환에대해서상반된결과를보인것에대해서명쾌하게해석하기는어렵지만잘수행된대규모무작위시험이작은임상시험을모아서분석하는메타분석보다더신뢰할만하다는것이전문가들이받아들이는입장이라 tiotropium 이심혈관질환사망과무관한안전한약제라고받아들여도좋겠다. 2) 흡입지속성베타수용체항진제 (Long-acting β 2- agonist: LABA) 흡입지속성베타수용체항진제인 salmeterol과 formoterol 은속효성기관지확장제에비해작용시간이길며 (12시간이상 ) 장기사용에도효과가지속적으로나타난다. 12주동안의 formoterol과 ipratropium의효능비교연구에서 formoterol이속임약과 ipratropium에비해유의하게폐기능, 증상, 삶의질을향상시켰다 10). 한편, salmeterol 경우를보면, 최근보고된대규모임상연구인 TORCH (Towards a Revolution in COPD Health) 결과 salmeterol이속임약에비하여폐기능, 증상을향상시켰고악화를줄였다 11). 또한, 통계적으로유의하지않았으나 salmeterol 치료군이속임약군에비해사망률이낮았다. 3) 흡입지속성베타수용체항진제와흡입지속성항콜린제의병합요법현재의진료지침에는한가지기관지확장제로증상조절이되지않는다면용량을증량하기보다는다른종류의기관지확장제를병합하는것을추천한다 3). 이는서로다른작용기전과작용시간을가진두종류의지속성기관지확장제병합요법이단독요법에비해폐기능향상이우수하고부작용발생이적음이여러연구에서보고되었기때문이다 12-15). 베타수용체항진제, 항콜린제, 서방형 theophylline 혹은이들은병합요법중선택은증상해소와부작용에대한개인별반응정도와약제가용성에따라결정한다. 최근실시된전향적, 다기관, 무작위이중맹검연구에서 6주간의 formoterol 과 tiotropium 병합요법이 salmeterol과 fluticasone 병합요법보다폐기능향상이유의하게좋았음이보고되었는데이는기전이서로다른기관지확장제를병합하는것이더효과적임을시사한다 15). 2. 흡입코르티코스테로이드 (Inhaled corticosteroids: ICSs) 1) 흡입코르티코스테로이드단독요법만성폐쇄성폐질환의기류제한은유해입자나가스등에대한폐의비정상적인염증반응과관련되어있다. 이러한염증반응을억제하기위해대표적인항염증제인코르티코스테로이드가만성폐쇄성폐질환환자치료에사용이되었으나그효과에대해서는논란이많았다. 흡입코르티코스테로이드의만성폐쇄성폐질환환자에대해시행된장기간의대규모임상연구에는 CCLS (Copenhagen City Lung Study), EU

3 - Jae Seung Lee, et al. Interpretation and application of recent large clinical studies in COPD - ROSCOP (European Respiratory Society Study on Chronic Obstructive Pulmonary Disease) 연구, ISOLDE (Inhaled Steroids in Obstructive Lung Disease in Europe) 연구와 LHS-2 (the Lung Health Study-2) 연구가있다 16-19). 네연구모두에서흡입코르티코스테로이드단독투여는만성폐쇄성질환의폐기능감소를완화시키지못하였다. 그러나여러연구에서코르티코스테로이드정규치료가중증만성폐쇄성폐질환환자의악화횟수를감소시키고삶의질을증가시킴을보고하였다. 이를근거로현재의만성폐쇄성폐질환진료지침에서는중증 (GOLD 3기 ) 이상이거나반복악화의병력 (3년에 3회이상 ) 이있는환자에는흡입코르티코스테로이드의정규치료가추천된다 3). 상기대규모임상연구 4개와 TRISTAN (TRial of Inhaled STeroid ANd long acting β 2-agonist) 연구그리고 Szafranski의연구, Calverley의연구등에서분석한대상자를모두합하여분석한 ISEEC (Inhaled Steroid Effects Evaluation in COPD) 연구에서흡입코르티코스테로이드가속임약에비해모든원인의사망률을감소시킬수있음을보여주었다 20). 그러나 ISEEC 연구에서도흡입코르티코스테로이드가초기 6개월에는폐기능을향상시키지만이후일초간노력성호기량 (FEV 1) 감소를완화시키지는못했다. 최근시행된 EUROSCOP 연구의사후분석 (pot-hoc analysis) 에서흡입코르티코스테로이드가심혈관질환발생을감소함을보여주어, 흡입코르티코스테로이드가만성폐쇄성폐질환의전신염증반응을감소시킬수있음을시사하였다 21). 2) 흡입코르티코스테로이드와지속성베타수용체항진제병합요법코르티코스테로이드와지속성베타수용체항진제는약리적으로병합투여를통해항염증효과와기관지확장효과의상승작용 (synergy) 을나타날수있어중증만성폐쇄성폐질환환자에서많이사용되고있다. 여러연구에서 salmeterol/fluticasone 또는 formoterol/budesonide 병합투여가속임약이나각각의단독투여보다폐기능을향상시키고악화를줄이는것으로보고하였다 11,22-24). 최근의대규모임상연구에서는코르티코스테로이드와지속성베타수용체항진제의병합투여로사망률을감소시킬가능성을보여주고있다. 최근대규모환자를대상으로 3년간의약제투여효과를비교한 TORCH study 결과통계적유의성은도달하지않았으나 salmeterol/fluticasone 투여군이속임약군에비해사망률이 17.5% 감소하였다 (p=0.052) 11). 또한 TORCH 사후분석 (posthoc analysis) 에서 salmeterol/fluticasone 투여군에서속임약군 에비해 FEV 1 감소가적어만성폐쇄성폐질환의진행을막을수있음을시사하였다 25). 최근 salmeterol/fluticasone 병합투여와 tiotropium 단독투여의효과를비교하는 INSPIRE (Investigating New Standards for Prophylaxis in Reduction of Exacerbation) 연구결과가보고되었다 26). INSPIRE 연구는중증이상의만성폐쇄성폐질환환자를대상으로시행한연구로써 salmeterol/fluticasone 투여군이 tiotropium 투여군에비해일차결과변수인악화빈도에는유의한차이가없었으나이차결과변수중하나인사망률이유의하게낮았다. 3) 지속성항콜린제와흡입코르티코스테로이드 / 지속성베타수용체항진제의병합최근서로다른작용기전을가진기관지확장제인지속성항콜린제와지속성베타수용체항진제에흡입코르티코스테로이드세가지모두를병합해서투여하는것에대한관심이증가하고있다. UPLIFT 연구에서는 tiotropium 투여군과속임약군모두에서 60% 이상의환자에서흡입코르티코스테로이드와지속성베타수용체항진제의병용투여가허용이되었는데, tiotropium 투여군이속임약군에비해유의하게폐기능, 삶의질을향상시키고악화빈도를감소시켰다 7). 449명의중등증에서중증만성폐쇄성폐질환환자를대상으로 1년간시행된캐나다의 OPTIMAL 연구에서는 tiotropium 과 salmeterol/fluticasone 병합군이 tiotropium과속임약투여군보다악화빈도는유의한차이를보이지않았으나, 폐기능과삶의질에있어서는유의한향상을보였으며, 병원입원빈도를감소하였다. 그러나 tiotropium 과 salmeterol 병합군은 tiotropium 과속임약군과비교시폐기능이나입원빈도에차이를보여주지못했다 27). 또한 tiotropium 단독투여와 tiotropium과 budesonide/formoterol 병합투여간의효과를비교하기위해중등증- 고도중증 (GOLD II-IV) 만성폐쇄성폐질환환자 660명을대상으로시행된 CLIMB (Evaluation of Efficacy and Safety of Symbicort as an Add-on Treatment to Spiriva in Patients With Severe COPD) 연구결과 tiotropium과 budesonide/formoterol 병합투여가 tiotropium 단독투여에비해유의한폐기능과삶의질이향상되었고, 악화는감소함을보여주었다 28). 3. 기타약제 1) 점액용해제만성폐쇄성폐질환의병인에서산화스트레스가중요한요인으로알려져항산화효과를가진점액용해제인 N-ace

4 - 대한내과학회지 : 제 77 권제 4 호통권제 590 호 tylcysteine (NAC) 의만성폐쇄성폐질환에대한효과를알아보기위한 3년간의전향적무작위배정, 속임약대조연구인 BRONCUS (Bronchitis Randomized on NAC) 연구에서 NAC 는 FEV 1 감소, 악화빈도, 삶의질에영향을주지못했다. 하지만하위집단 (subgroup) 분석에서는흡입코르티코스테로이드를복용하지않는환자에서는악화를낮출가능성이있으며이차분석에서는폐의과팽창을줄일수있는가능성을보여주었다 29). 한편, 만성폐쇄성폐질환환자 709명을대상으로 1년간시행된 PEACE 연구에서는흡입코르티코스테로이드사용과는관계없이 carbocysteine 투여로만성폐쇄성폐질환악화빈도를낮추고삶의질을향상시켰다 30). 2) Roflumilast 항염증제인흡입코르티코스테로이드가여러연구를통해서 COPD 환자의폐기능을향상시키고악화를줄이는것이확인되었다. 이에따라서코르티코스테로이드는외새로운항염증제에대한연구도시행되었다. 이가운데 phosphodiesterease-4 (PDE4) 차단제인 roflumilast가흡입코르티코스테로이드의대체제로많이연구되었다. 중등증에서중증만성폐쇄성폐질환환자 1,413명을대상으로 6개월간시행된임상연구에서 roflumilast가일초간노력성호기량을유의하게향상시키고악화를줄였다 31). 이후 1,513명의중증- 고도중증 COPD 환자를대상으로 1년간시행된임상연구에서 roflumilast는유의하게폐기능을향상시켰고, 고도중증 COPD (postbronchodilator FEV 1<30% 예측치 ) 환자에서는악화의빈도를낮추었다 32). 최근대규모임상연구의해석과적용 1. 해석앞서소개한여러 COPD 치료약제가대규모임상연구를통해서 COPD 환자에게유익한효과가있음을보여주었다. 또한, 기전이다른약제를두개나세개를함께사용하는경우효과가더큼을보여주었다. 이러한 COPD 치료약제가보여준유익한효과에는증상과폐기능개선뿐아니라삶의질호전과악화감소가있었다. 게다가 tiotropium 이나 salmeterol/fluticasone 는 COPD 환자에게투여하였을때사망을감소시킬가능성까지있어서 COPD 치료영역에새로운희망을보여주었다. 이러한유익한효과는중증 COPD 환자 만이아니라상대적으로중증도가덜한중등증 COPD 환자에게까지효과가있다는것도최근의대규모임상연구에서잘보여주고있다. 2. 적용이상의 COPD 치료약제를실제 COPD 환자진료에어떻게응용하여적용할것인가? 저자는조심스럽게아래와같이제안을하고싶다. 1) 중등증및중증이상의 COPD 환자치료에기관지확장제두종류 ( 흡입지속성항콜린제및흡입지속성베타수용체항진제 ) 를흡입코르티코스테로이드와함께사용한다. 2) 1) 의세약제에추가하여 COPD 악화가잦은환자에게는점액용해제를사용한다 ( 잦은악화라함은지난 2년간 2 번이상악화를의미한다 ). 3) 1) 의약제중흡입코르티코스테로이드대신 roflumilast를사용할수있다 (roflumilast는아직국내에서구할수없다 ). 결론본글에서상세하게다룬대규모 COPD 임상연구결과는앞으로 COPD 진료영역에많은영향을미칠것같다. 이러한임상연구결과를근거로 COPD 진료지침이 COPD 환자에게약제를더많이그리고더넓게사용하는방향으로개정될것으로기대한다. 그리하여 COPD 환자에게유익하다고증명된여러약제를더많이그리고넓게사용함으로써환자에게도움을것이라고생각한다. COPD의효과적치료방법에는상기약제외에도호흡재활, 산소요법, 폐용적축소술등이있어서이러한방법도적응증에맞추어 COPD 환자에게더널리사용하기를추천한다. 그리고 COPD 치료에빠질수없는중요한방법인금연에대해서는아무리강조하여도지나치지않을것이다. 본글에서는다루지않았지만최근대규모임상연구에의해서금연약제가담배를중단하는데효과가있음이잘입증되었으니환자진료에적용해보기바란다 33,34). 결론적으로다시강조하면 COPD를치료할수있는여러가지효과적인약제가최근임상연구를통해서잘입증되었고이러한임상연구의성과를 COPD 환자진료에적용하여환자에게실제로유익한효과가나타나도록노력을경주해야할시점이라하겠다

5 - 이재승외 1 인. 만성폐쇄성폐질환임상연구의해석과적용 - 중심단어 : 만성폐쇄성폐질환 ; 임상연구 ; 지속성항콜린제 ; 지속성베타수용체항진제 ; 흡입코르티코스테로이드 감사의글 본글은보건복지가족부지원에의하여이루어진것임 (A040153). REFERENCES 1) Lopez AD, Shibuya K, Rao C, Mathers CD, Hansell AL, Held LS, Schmid V, Buist S. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J 27: , ) World Health Organization. Report world health. Available from: 3) Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: updated Available from: 4) Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS, Calverley PM, Celli BR, Jones PW, Mahler DA, Make B, Miravitlles M, Page CP, Palange P, Parr D, Pistolesi M, Rennard SI, Rutten van Molken MP, Stockley R, Sullivan SD, Wedzicha JA, Wouters EF; American Thoracic Society/European Respiratory Society Task Force on outcomes of COPD. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J 31: , ) Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, Menjoge SS, Serby CW, Witek T Jr. A long term evaluation of once daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 19: , ) O Donnell DE, Fluge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, Magnussen H. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 23: , ) Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M; UPLIFT Study Investigators. A 4 year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 359: , ) Lee TA, Pickard AS, Au DH, Bartle B, Weiss KB. Risk for death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med 149: , ) Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and metaanalysis. JAMA 300: , ) Dahl R, Greefhorst LA, Nowak D, Nonikov V, Byrne AM, Thomson MH, Till D, Della Cioppa G; Formoterol in Chronic Obstructive Pulmonary Disease I Study. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164: , ) Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; Investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 356: , ) Cazzola M, Centanni S, Santus P, Verga M, Mondoni M, di Marco F, Matera MG. The functional impact of adding salmeterol and tiotropium in patients with stable COPD. Respir Med 98: , ) van Noord JA, Aumann JL, Janssens E, Smeets JJ, Verhaert J, Disse B, Mueller A, Cornelissen PJ. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J 26: , ) van Noord JA, Aumann JL, Janssens E, Verhaert J, Smeets JJ, Mueller A, Cornelissen PJ. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest 129: , ) Rabe KF, Timmer W, Sagkriotis A, Viel K. Comparison of a combination of tiotropium plus formoterol to salmeterol plus fluticasone in moderate COPD. Chest 134: , ) Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Longterm effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 353: , ) Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, Ohlsson SV. Long term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking: European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Med 340: , ) Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 320: , ) Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 343: , ) Sin DD, Anderson JA, Anthonisen NR, Buist AS, Burge PS, Calverley PM, Connett JE, Lindmark B, Pauwels RA, Postma DS, Soriano JB, Szafranski W, Vestbo J. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax 60: , ) Lofdahl C G, Postma DS, Pride NB, Boe J, Thoren A. Possible protection by inhaled budesonide against ischaemic cardiac events in mild COPD. Eur Respir J 29: , ) Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C. Combined salmeterol and fluticasone in the

6 - The Korean Journal of Medicine: Vol. 77, No. 4, treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 361: , ) Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, Peterson S, Olsson H. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 21:74 81, ) Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronicobstructive pulmonary disease. Eur Respir J 22: , ) Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW, Vestbo J, Knobil K, Yates JC, Calverley PM. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH Study. Am J Respir Crit Care Med 178: , ) Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA; INSPIRE Investigators. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 177:19 26, ) Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M, O Donnell D, McIvor A, Sharma S, Bishop G, Anthony J, Cowie R, Field S, Hirsch A, Hernandez P, Rivington R, Road J, Hoffstein V, Hodder R, Marciniuk D, McCormack D, Fox G, Cox G, Prins HB, Ford G, Bleskie D, Doucette S, Mayers I, Chapman K, Zamel N, FitzGerald M; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 146: , ) Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, Kessler R. Efficacy and tolerability of budesonide/formoterol added to tiotropium in COPD patients. Am J Respir Crit Care Med 2009 [Epub ahead of print] 29) Decramer M, Rutten van Molken M, Dekhuijzen PN, Troosters T, van Herwaarden C, Pellegrino R, van Schayck CP, Olivieri D, Del Donno M, De Backer W, Lankhorst I, Ardia A. Effects of N acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost Utility Study, BRONCUS): a randomised placebo controlled trial. Lancet 365: , ) Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L, Bai CX, Wang CZ, Wang C, Chen BY, Shi Y, Liu CT, Li Q, Wang ZS, Huang YJ, Luo ZY, Chen FP, Yuan JZ, Yuan BT, Qian HP, Zhi RC, Zhong NS. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo controlled study. Lancet 371: , ) Rabe KF, Bateman ED, O Donnell D, Witte S, Bredenbroker D, Bethke TD. Roflumilast: an oral anti inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 366: , ) Calverley PM, Sanchez Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1 year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 176: , ) Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR; Varenicline Phase 3 Study Group. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained release bupropion for smoking cessation: a randomized controlled trial. JAMA 296:56 63, ) Nides M, Oncken C, Gonzales D, Rennard S, Watsky EJ, Anziano R, Reeves KR. Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7 week, randomized, placebo and bupropion controlled trial with 1 year follow up. Arch Intern Med 166: ,

untitled

untitled DOI: 10.4046/trd.2009.67.1.1 ISSN: 1738-3536(Print)/2005-6184(Online) Tuberc Respir Dis 2009;67:1-7 CopyrightC2009. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 호흡기내과의사를위한