Canadian Thoracic Society Clinical Practice Guideline on pharmacotherapy in patients with COPD – 2019 update of evidence

References

• Bourbeau J, Bhutani M, Hernandez P, et al. CTS position statement: pharmacotherapy in patients with COPD—an update. Can J Respir Crit Care Sleep Med. 2017;1(4):222–241. doi:10.1080/24745332.2017.1395588.
   Web of Science ®Google Scholar
• Tan WC, Sin DD, Bourbeau J, et al. Characteristics of COPD in never-smokers and ever-smokers in the general population: results from the CanCOLD study. Thorax. 2015;70(9):822–829. doi:10.1136/thoraxjnl-2015-206938.
   PubMed Web of Science ®Google Scholar
• Labonté LE, Tan WC, Li PZ, et al. Undiagnosed chronic obstructive pulmonary disease contributes to the burden of health care use. Data from the CanCOLD study. Am J Respir Crit Care Med. 2016;194(3):285–298. doi:10.1164/rccm.201509-1795OC.
   PubMed Web of Science ®Google Scholar
• Colak Y, Afzal S, Nordestgaard BG, et al. Prognosis of asymptomatic and symptomatic, undiagnosed COPD in the general population in Denmark: a prospective cohort study. Lancet Respir Med. 2017;5:426–434. doi:10.1016/S2213-2600(17)30119-4.
   PubMed Web of Science ®Google Scholar
• Bhatt SP, Balte PP, Schwartz JE, et al. Discriminative Accuracy of FEV1: FVC thresholds for COPD-related hospitalization and mortality. JAMA. 2019;321(24):2438–2447. doi:10.1001/jama.2019.7233.
   PubMed Web of Science ®Google Scholar
• Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Eur Respir J. 2017;49(3):1700214.
   PubMed Web of Science ®Google Scholar
• Aaron SD, Tan WC, Bourbeau J, et al. Diagnostic instability and reversals of chronic obstructive pulmonary disease diagnosis in individuals with mild to moderate airflow obstruction. Am J Respir Crit Care Med. 2017;196(3):306–314. doi:10.1164/rccm.201612-2531OC.
   PubMed Web of Science ®Google Scholar
• Camp PG, Hernandez P, Bourbeau J, et al. Pulmonary rehabilitation in Canada: a report from the Canadian Thoracic Society COPD Clinical Assembly. Can Respir J. 2015;22(3):147–152. doi:10.1155/2015/369851.
   PubMed Web of Science ®Google Scholar
• Marciniuk DD, Brooks D, Butcher S, et al. Optimizing pulmonary rehabilitation in chronic obstructive pulmonary disease–practical issues: a Canadian Thoracic Society Clinical Practice Guideline. Can Respir J. 2010;17(4):159–168. doi:10.1155/2010/425975.
   PubMed Web of Science ®Google Scholar
• COPD Foundation. COPE survey results: low patient awareness about COPD exacerbations poses barrier to effective management. Published June 17, 2014. http://www.copdfoundation.org/About-Us/Press-Room/Press-Releases/ID/256/COPD-Foundation-Releases-Groundbreaking-COPE. Accessed December 6, 2018.
   Google Scholar
• Canadian Thoracic Society Guideline Development Process and Methodology. 2018. https://cts-sct.ca/guideline-library/methodology/. Accessed November 27, 2018.
   Google Scholar
• Brouwers M, Kho ME, Browman GP, et al. AGREE II: advancing guideline development, reporting and evaluation in healthcare. Can Med Assoc J. 2010;182(18):E839–E842.
   PubMed Web of Science ®Google Scholar
• Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an american college of chest physicians task force. Chest. 2006;129(1):174–181. doi:10.1378/chest.129.1.174.
   PubMed Web of Science ®Google Scholar
• Brouwers M, Makarski J, Kastner M, et al. The Guideline Implementability Decision Excellence Model (GUIDE-M): a mixed methods approach to create an international resource to advance the practice guideline field. Implement Sci. 2015;10:36.
   PubMed Web of Science ®Google Scholar
• Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society guideline. Chest. 2015;147(4):894–942. doi:10.1378/chest.14-1676.
   PubMed Web of Science ®Google Scholar
• Kastner M, Bhattacharyya O, Hayden L, et al. Guideline uptake is influenced by six implementability domains for creating and communicating guidelines: a realist review. J Clin Epidemiol. 2015;68(5):498–509. doi:10.1016/j.jclinepi.2014.12.013.
   PubMed Web of Science ®Google Scholar
• Gupta S, Rai N, Bhattacharrya O, et al. Optimizing the language and format of guidelines to improve guideline uptake. Can Med Am J. 2016;188(14):E362–E368. doi:10.1503/cmaj.151102.
   PubMed Web of Science ®Google Scholar
• Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med. 2012;185(4):435–452. doi:10.1164/rccm.201111-2042ST.
   PubMed Web of Science ®Google Scholar
• Pitta F, Troosters T, Spruit MA, et al. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;171(9):972–977. doi:10.1164/rccm.200407-855OC.
   PubMed Web of Science ®Google Scholar
• Johnson-Warrington V, Harrison S, Mitchell K, et al. Exercise capacity and physical activity in patients with COPD and healthy subjects classified as Medical Research Council dyspnea scale grade 2. J Cardiopulm Rehabil Prev. 2014;34(2):150–154. doi:10.1097/HCR.0000000000000038.
   Web of Science ®Google Scholar
• Zhang Y, Morgan RL, Alonso-Coello P, et al. A systematic review of how patients value COPD outcomes. Eur Respir J. 2018;52(1):1800222. doi:10.1183/13993003.00222-2018.
   PubMed Web of Science ®Google Scholar
• Yohannes AM, Alexopoulos GS. Depression and anxiety in patients with COPD. Eur Respir Rev. 2014;23(133):345–349. doi:10.1183/09059180.00007813.
   PubMedGoogle Scholar
• Müllerová H, Agusti A, Erqou S, et al. Cardiovascular comorbidity in COPD: systematic literature review. Chest. 2013;144(4):163–1178. doi:10.1378/chest.12-2847.
   Web of Science ®Google Scholar
• Maltais F, Decramer M, Casaburi R, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;189(9):e15–e62. doi:10.1164/rccm.201402-0373ST.
   PubMed Web of Science ®Google Scholar
• Nishimura K, Izumi T, Tsukino M, et al. Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. Chest. 2002;121(5):1434–1440. doi:10.1378/chest.121.5.1434.
   PubMed Web of Science ®Google Scholar
• Müllerová H, Lu C, Li H, et al. Prevalence and burden of breathlessness in patients with chronic obstructive pulmonary disease managed in primary care. PLos One. 2014;9(1):e85540. doi:10.1371/journal.pone.0085540.
   PubMed Web of Science ®Google Scholar
• Calverley PM, Tetzlaff K, Dusser D, et al. Determinants of exacerbation risk in patients with COPD in the TIOSPIR study. Int J Chron Obstruct Pulm Dis. 2017;12:3391–3405. doi:10.2147/COPD.S145814.
   Web of Science ®Google Scholar
• O’Donnell DE, Hamilton AL, Webb KA. Sensory-mechanical relationships during high-intensity, constant-work-rate exercise in COPD. J Appl Physiol. 2006;101(4):1025–1035. doi:10.1152/japplphysiol.01470.2005.
   PubMed Web of Science ®Google Scholar
• Dransfield MT, Bailey W, Crater G, et al. Disease severity and symptoms among patients receiving monotherapy for COPD. Prim Care Respir J. 2010;20(1):46–53. doi:10.4104/pcrj.2010.00059.
   Google Scholar
• Troosters T, Maltais F, Leidy N, et al. Effect of bronchodilation, exercise training, and behavior modification on symptoms and physical activity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;198(8):1021–1032. doi:10.1164/rccm.201706-1288OC.
   PubMed Web of Science ®Google Scholar
• Bourbeau J, Lavoie KL, Sedeno M, et al. Behaviour-change intervention in a multicentre, randomised, placebo-controlled COPD study: methodological considerations and implementation. BMJ Open. 2016;6(4):e010109. doi:10.1136/bmjopen-2015-010109.
   Web of Science ®Google Scholar
• McCarthy B, Casey D, Devane D, et al. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;2:CD003793.
   PubMed Web of Science ®Google Scholar
• Lipson DA, Barnhart F, Brealey N, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med. 2018;378(18):1671–1680. doi:10.1056/NEJMoa1713901.
   PubMed Web of Science ®Google Scholar
• Ferguson GT, Rabe KF, Martinez FJ. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Lancet Respir Med. 2018;10:747–758. doi:10.1016/S2213-2600(18)30327-8.
   Google Scholar
• Bedard ME, Brouillard C, Pepin V, et al. Tiotropium improves walking endurance in COPD. Eur Respir J. 2012;39(2):265–271. doi:10.1183/09031936.00059511.
   PubMed Web of Science ®Google Scholar
• Beeh KM, Singh D, Di Scala L, et al. Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial. Int J Chron Obstruct Pulm Dis. 2012; 7:503–513.
   PubMed Web of Science ®Google Scholar
• Beeh KM, Wagner F, Khindri S, et al. Effect of indacaterol on dynamic lung hyperinflation and breathlessness in hyperinflated patients with COPD. COPD J Chron Obstruct Pulm Dis. 2011;8(5):340–345. doi:10.3109/15412555.2011.594464.
   Web of Science ®Google Scholar
• Beeh KM, Watz H, Puente-Maestu L, et al. Aclidinium improves exercise endurance, dyspnea, lung hyperinflation, and physical activity in patients with COPD: a randomized, placebo-controlled, crossover trial. BMC Pulm Med. 2014;14(1):209. doi:10.1186/1471-2466-14-209.
   PubMed Web of Science ®Google Scholar
• Brouillard C, Pepin V, Milot J, et al. Endurance shuttle walking test: responsiveness to salmeterol in COPD. Eur Respir J. 2008;31(3):579–584. doi:10.1183/09031936.00119007.
   PubMed Web of Science ®Google Scholar
• Cooper CB, Celli BR, Jardim JR, et al. Treadmill endurance during 2-year treatment with tiotropium in patients with COPD: a randomized trial. Chest. 2013;144(2):490–497. doi:10.1378/chest.12-2613.
   PubMed Web of Science ®Google Scholar
• Gotfried MH, Kerwin EM, Lawrence D, et al. Efficacy of indacaterol 75 mug once-daily on dyspnea and health status: results of two double-blind, placebo-controlled 12-week studies. COPD J Chron Obstruct Pulm Dis. 2012;9(6):629–636. doi:10.3109/15412555.2012.729623.
   Web of Science ®Google Scholar
• Han J, Dai L, Zhong N. Indacaterol on dyspnea in chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized placebo-controlled trials. BMC Pulm Med. 2013;13(1):26. doi:10.1186/1471-2466-13-26.
   Google Scholar
• Jiang FM, Liang ZA, Zheng QL, et al. Safety and efficacy of 12-week or longer indacaterol treatment in moderate-to-severe COPD patients: a systematic review. Lung. 2013;191(2):135–146. doi:10.1007/s00408-012-9444-2.
   Web of Science ®Google Scholar
• Jones PW, Singh D, Bateman ED, et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J. 2012;40(4):830–836. doi:10.1183/09031936.00225511.
   PubMed Web of Science ®Google Scholar
• Kaplan A. Effect of tiotropium on quality of life in COPD: a systematic review. Primary Care Respir J. 2010;19(4):315–325. doi:10.4104/pcrj.2010.00067.
   Google Scholar
• Kerwin EM, D’Urzo AD, Gelb AF, et al. Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD J Chron Obstruct Pulm Dis. 2012;9(2):90–101. doi:10.3109/15412555.2012.661492.
   Web of Science ®Google Scholar
• Kerwin EM, Gotfried MH, Lawrence D, et al. Efficacy and tolerability of indacaterol 75 mug once daily in patients aged >40 years with chronic obstructive pulmonary disease: results from 2 double-blind, placebo-controlled 12-week studies. Clin Ther. 2011;33(12):1974–1984. doi:10.1016/j.clinthera.2011.11.009.
   PubMed Web of Science ®Google Scholar
• Kinoshita M, Lee SH, Hang LW, et al. Efficacy and safety of indacaterol 150 and 300 micro g in chronic obstructive pulmonary disease patients from six Asian areas including Japan: a 12-week, placebo-controlled study. Respirology. 2012;17(2):379–389. doi:10.1111/j.1440-1843.2011.02107.x.
   PubMed Web of Science ®Google Scholar
• Maltais F, Celli B, Casaburi R, et al. Aclidinium bromide improves exercise endurance and lung hyperinflation in patients with moderate to severe COPD. Respir Med. 2011;105(4):580–587. doi:10.1016/j.rmed.2010.11.019.
   PubMed Web of Science ®Google Scholar
• Mroz RM, Minarowski L, Chyczewska E. Indacaterol add-on therapy improves lung function, exercise capacity and life quality of COPD patients. Adv Exp Med Biol. 2013;756:23–28. doi:10.1007/978-94-007-4549-0_4.
   Web of Science ®Google Scholar
• O’Donnell DE, Casaburi R, Vincken W, et al. Effect of indacaterol on exercise endurance and lung hyperinflation in COPD. Respir Med. 2011;105(7):1030–1036. doi:10.1016/j.rmed.2011.03.014.
   PubMed Web of Science ®Google Scholar
• Rennard SI, Scanlon PD, Ferguson GT, et al. ACCORD COPD II: a randomized clinical trial to evaluate the 12-week efficacy and safety of twice-daily aclidinium bromide in chronic obstructive pulmonary disease patients. Clin Drug Invest. 2013;33(12):893–904. doi:10.1007/s40261-013-0138-1.
   PubMed Web of Science ®Google Scholar
• Santus P, Radovanovic D, Di Marco F, et al. Faster reduction in hyperinflation and improvement in lung ventilation inhomogeneity promoted by aclidinium compared to glycopyrronium in severe stable COPD patients. A randomized crossover study. Pulm Pharmacol Ther. 2015;35:42–49. doi:10.1016/j.pupt.2015.11.001.
   PubMed Web of Science ®Google Scholar
• Satake M, Takahashi H, Sugawara K, et al. Inhibitory effect of procaterol on exercise dynamic lung hyperinflation during the 6-min walk test in stable patients with chronic obstructive pulmonary disease. Arzneim Forsch. 2011;61:8–13. doi:10.1055/s-0031-1296162.
   Web of Science ®Google Scholar
• Trivedi R, Richard N, Mehta R, et al. Umeclidinium in patients with COPD: a randomised, placebo-controlled study. [Erratum appears in Eur Respir J. 2014 Aug;44(2):555 Note: dosage error in published abstract; MEDLINE/PubMed abstract corrected; dosage error in article text]. Eur Respir J. 2014;43(1):72–81. doi:10.1183/09031936.00033213.
   PubMed Web of Science ®Google Scholar
• Yao W, Wang C, Zhong N, et al. Effect of once-daily indacaterol in a predominantly Chinese population with chronic obstructive pulmonary disease: a 26-week Asia-Pacific study. Respirology. 2014;19(2):231–238. doi:10.1111/resp.12211.
   Web of Science ®Google Scholar
• Bogdan MA, Aizawa H, Fukuchi Y, et al. Efficacy and safety of inhaled formoterol 4.5 and 9 mug twice daily in Japanese and European COPD patients: phase III study results. BMC Pulm Med. 2011;11(1):51. doi:10.1186/1471-2466-11-51.
   Google Scholar
• Braido F, Baiardini I, Cazzola M, et al. Long-acting bronchodilators improve health related quality of life in patients with COPD. Respir Med. 2013;107(10):1465–1480. doi:10.1016/j.rmed.2013.08.007.
   PubMed Web of Science ®Google Scholar
• Cheyne L, Irvin-Sellers MJ, White J. Tiotropium versus ipratropium bromide for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013; Sep 16(9):CD009552.
   Google Scholar
• Geake JB, Dabscheck EJ, Wood-Baker R, et al. Indacaterol, a once-daily beta2-agonist, versus twice-daily beta(2)-agonists or placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;1:CD010139. doi:10.1002/14651858.CD010139.pub2.
   PubMedGoogle Scholar
• Gross NJ, Nelson HS, Lapidus RJ, et al. Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients. Respir Med. 2008;102(2):189–197. doi:10.1016/j.rmed.2007.10.007.
   PubMed Web of Science ®Google Scholar
• Jones PW, Mahler DA, Gale R, et al. Profiling the effects of indacaterol on dyspnoea and health status in patients with COPD. Respir Med. 2011;05:892–899. doi:10.1016/j.rmed.2011.02.013.
   Google Scholar
• Karner C, Cates CJ. Long-acting beta(2)-agonist in addition to tiotropium versus either tiotropium or long-acting beta(2)-agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;Apr 18(4):CD008989.
   Google Scholar
• Kew KM, Mavergames C, Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;Oct 15(10):CD010177.
   Google Scholar
• Koch A, Pizzichini E, Hamilton A, et al. Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulm Dis. 2014;9:697–714.
   PubMed Web of Science ®Google Scholar
• Kornmann O, Dahl R, Centanni S, et al. Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J. 2011;37(2):273–279. doi:10.1183/09031936.00045810.
   PubMed Web of Science ®Google Scholar
• Ni H, Soe Z, Moe S. Aclidinium bromide for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;Sep 19(9):CD010509.
   Google Scholar
• Park J, Lee JS, Rhee C, et al. Effect of indacaterol on cough and phlegm in chronic obstructive pulmonary disease patients: a meta-analysis of five randomized controlled trials. J Korean Med Sci. 2015;30(10):1453–1458. doi:10.3346/jkms.2015.30.10.1453.
   Web of Science ®Google Scholar
• Chen WC, Huang CH, Sheu CC, et al. Long-acting beta2-agonists versus long-acting muscarinic antagonists in patients with stable COPD: a systematic review and meta-analysis of randomized controlled trials. Respirology. 2017;22(7):1313–1319. doi:10.1111/resp.13100.
   Web of Science ®Google Scholar
• Di Marco F, Sotgiu G, Santus P, et al. Long-acting bronchodilators improve exercise capacity in COPD patients: a systematic review and meta-analysis. Respir Res. 2018;19(1):18. doi:10.1186/s12931-018-0721-3.
   PubMed Web of Science ®Google Scholar
• Ni H, Htet A, Moe S. Umeclidinium bromide versus placebo for people with chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2017;6:CD011897. doi:10.1002/14651858.CD011897.pub2.
   Google Scholar
• Beeh KM, Korn S, Beier J, et al. Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study. Respir Med. 2014;108(4):584–592. doi:10.1016/j.rmed.2014.01.006.
   PubMed Web of Science ®Google Scholar
• Berton DC, Reis M, Siqueira AC, et al. Effects of tiotropium and formoterol on dynamic hyperinflation and exercise endurance in COPD. Respir Med. 2010;104(9):1288–1296. doi:10.1016/j.rmed.2010.05.017.
   PubMed Web of Science ®Google Scholar
• Calzetta L, Ciaprini C, Puxeddu E, et al. Olodaterol + tiotropium bromide for the treatment of COPD. Expert Rev Respir Med. 2016;10(4):379–386.
   PubMed Web of Science ®Google Scholar
• Celli B, Crater G, Kilbride S, et al. Once-daily umeclidinium/vilanterol 125/25 mcg in COPD: a randomized, controlled study. Chest. 2014;145(5):981–991. doi:10.1378/chest.13-1579.
   PubMed Web of Science ®Google Scholar
• Chen X, May B, Di YM, et al. Oral Chinese herbal medicine combined with pharmacotherapy for stable COPD: a systematic review of effect on BODE index and six-minute walk test. PLoS One. 2014;9(3):e91830. doi:10.1371/journal.pone.0091830.
   Web of Science ®Google Scholar
• Jayaram L, Wong C, McAuley S, et al. Combined therapy with tiotropium and formoterol in chronic obstructive pulmonary disease: effect on the 6-minute walk test. COPD J Chron Obstruct Pulm Dis. 2013;10(4):466–472. doi:10.3109/15412555.2013.771162.
   Web of Science ®Google Scholar
• Mahler DA, Decramer M, D’Urzo A, et al. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J. 2014;43(6):1599–1609. doi:10.1183/09031936.00124013.
   PubMed Web of Science ®Google Scholar
• Maltais F, Singh S, Donald AC, et al. Effects of a combination of umeclidinium/vilanterol on exercise endurance in patients with chronic obstructive pulmonary disease: two randomized, double-blind clinical trials. [Erratum appears in Ther Adv Respir Dis. 2016 Jun;10(3):289; PMID: 27255756]. Ther Adv Respir. 2014;8(6):169–181. doi:10.1177/1753465814559209.
   PubMed Web of Science ®Google Scholar
• Rodrigo GJ, Neffen H. Comparison of indacaterol with tiotropium or twice-daily long-acting β-agonists for stable COPD: a systematic review . Chest. 2012;142(5):1104–1110. doi:10.1378/chest.11-2252.
   PubMed Web of Science ®Google Scholar
• Vincken W, Aumann J, Chen H, et al. Efficacy and safety of coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone in COPD patients: the GLOW6 study. Int J Chron Obstruct Pulm Dis. 2014; 9:215–228.
   PubMed Web of Science ®Google Scholar
• Wang L, Zhai CJ, Liu Y, et al. Umeclidinium plus vilanterol versus placebo, umeclidinium, or vilanterol monotherapies for chronic obstructive pulmonary disease: a meta-analysis of randomized controlled trials. Clin Drug Invest. 2016;36(11):865–875. doi:10.1007/s40261-016-0449-0.
   Web of Science ®Google Scholar
• Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4). [Erratum appears in Eur Respir J. 2015 Jun;45(6):1763; PMID: 26028626]. Eur Respir J. 2015;45(4):969–979. doi:10.1183/09031936.00136014.
   PubMed Web of Science ®Google Scholar
• Calzetta L, Rogliani P, Matera MG, et al. A systematic review with meta-analysis of dual bronchodilation with LAMA/LABA for the treatment of stable COPD. Chest. 2016;149(5):1181–1196. doi:10.1016/j.chest.2016.02.646.
   PubMed Web of Science ®Google Scholar
• Farne HA, Cates CJ. Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;Oct 22(10):CD008989.
   Google Scholar
• Maleki-Yazdi MR, Kaelin T, Richard N, et al. Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. Respir Med. 2014;108(12):1752–1760. doi:10.1016/j.rmed.2014.10.002.
   PubMed Web of Science ®Google Scholar
• ZuWallack R, Allen L, Hernandez G, et al. Efficacy and safety of combining olodaterol Respimat® and tiotropium HandiHaler® in patients with COPD: results of two randomized, double-blind, active-controlled studies. Int J Chron Obstruct Pulm Dis. 2014;9:1133–1144.
   PubMed Web of Science ®Google Scholar
• Kardos P, Hagedorn-Peinz I. The impact of indacaterol/glycopyrronium fixed-dose combination versus tiotropium monotherapy on lung function and treatment preference: a randomized crossover study–the FAVOR study. Int J Chron Obstruct Pulm Dis. 2018;13:69–77. doi:10.2147/COPD.S146189.
   Web of Science ®Google Scholar
• Vogelmeier C, Gaga M, Aalamian-Mattheis M, et al. Efficacy and safety of direct switch to indacaterol/glycopyrronium in patients with moderate COPD: the CRYSTAL open-label randomised trial. Respir Res. 2017;18(1):140. doi:10.1186/s12931-017-0622-x.
   PubMedGoogle Scholar
• Calzetta L, Ora J, Cavalli F, et al. Impact of LABA/LAMA combination on exercise endurance and lung hyperinflation in COPD: a pair-wise and network meta-analysis. Respir Med. 2017;129:189–198. doi:10.1016/j.rmed.2017.06.020.
   PubMed Web of Science ®Google Scholar
• Watz H, Krippner F, Kirsten A, et al. Indacaterol improves lung hyperinflation and physical activity in patients with moderate chronic obstructive pulmonary disease–a randomized, multicenter, double-blind, placebo-controlled study. BMC Pulm Med. 2014;14(1):158. doi:10.1186/1471-2466-14-158.
   PubMed Web of Science ®Google Scholar
• Watz H, Mailander C, Baier M, et al. Effects of indacaterol/glycopyrronium (QVA149) on lung hyperinflation and physical activity in patients with moderate to severe COPD: a randomised, placebo-controlled, crossover study (the MOVE study). BMC Pulm Med. 2016;16(1):95. doi:10.1186/s12890-016-0256-7.
   PubMed Web of Science ®Google Scholar
• Watz H, Beeh KM, Garcia-Aymerich J, et al. ACTIVATE: the effect of aclidinium/formoterol on hyperinflation, exercise capacity, and physical activity in patients with COPD. Int J Chron Obstruct Pulm Dis. 2017;12:2545–2558.
   PubMed Web of Science ®Google Scholar
• Troosters T, Sciurba FC, Decramer M, et al. Tiotropium in patients with moderate COPD naive to maintenance therapy: a randomised placebo-controlled trial. NPJ Prim Care Respir Med. 2014;24:14003.
   PubMed Web of Science ®Google Scholar
• Horita N, Goto A, Shibata Y, et al. Long-acting muscarinic antagonist (LAMA) plus long-acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD) (Review). Cochrane Database Syst Rev. 2017;2:CD012066.
   PubMed Web of Science ®Google Scholar
• Hoshino M, Ohtawa J, Akitsu K. Comparison of airway dimensions with once daily tiotropium plus indacaterol versus twice daily Advair® in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2015;30:128–133. doi:10.1016/j.pupt.2014.08.002.
   PubMed Web of Science ®Google Scholar
• Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146(8):545–555. doi:10.7326/0003-4819-146-8-200704170-00152.
   PubMed Web of Science ®Google Scholar
• Karner C, Cates CJ. Combination inhaled steroid and long-acting beta(2)-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011;Mar 16(3):CD008532.
   Google Scholar
• Calzetta L, Matera MG, Braido F, et al. Withdrawal of inhaled corticosteroids in COPD: a meta-analysis. Pulm Pharmacol Ther. 2017;45:148–158. doi:10.1016/j.pupt.2017.06.002.
   PubMed Web of Science ®Google Scholar
• Kawayama T, Hoshino T, Ichiki M, et al. Effect of add-on therapy of tiotropium in COPD treated with theophylline. Int J Chron Obstruct Pulm Dis. 2008;3(1):137–147.
   Google Scholar
• Voduc N, Alvarez GG, Amjadi K, et al. Effect of theophylline on exercise capacity in COPD patients treated with combination long-acting bronchodilator therapy: a pilot study. Int J Chron Obstruct Pulm Dis. 2012;7:245–252.
   Web of Science ®Google Scholar
• Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695–703. doi:10.1016/S0140-6736(09)61252-6.
   PubMed Web of Science ®Google Scholar
• O’Donnell DE, Bredenbroker D, Brose M, et al. Physiological effects of roflumilast at rest and during exercise in COPD. Eur Respir J. 2012;39(5):1104–1112. doi:10.1183/09031936.00096511.
   PubMed Web of Science ®Google Scholar
• Pan L, Guo YZ, Zhang B, et al. Does roflumilast improve dyspnea in patients with chronic obstructive pulmonary disease? A meta-analysis. J Thorac Dis. 2013;5(4):422–429.
   Web of Science ®Google Scholar
• Johnson K, McEvoy CE, Naqvi S, et al. High-dose oral N-acetylcysteine fails to improve respiratory health status in patients with chronic obstructive pulmonary disease and chronic bronchitis: a randomized, placebo-controlled trial. Int J Chron Obstruct Pulm Dis. 2016;11:799–807.
   PubMed Web of Science ®Google Scholar
• Lee TM, Chen CC, Shen HN, et al. Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Clin Sci. 2009;116(6):497–505. doi:10.1042/CS20080241.
   PubMed Web of Science ®Google Scholar
• Maneechotesuwan K, Wongkajornsilp A, Adcock IM, et al. Simvastatin suppresses airway IL-17 and upregulates IL-10 in patients with stable COPD. Chest. 2015;148(5):1164–1176. doi:10.1378/chest.14-3138.
   PubMed Web of Science ®Google Scholar
• Mroz RM, Lisowski P, Tycinska A, et al. Anti-inflammatory effects of atorvastatin treatment in chronic obstructive pulmonary disease. A controlled pilot study. J Physiol Pharmacol. 2015;66(1):111–128.
   Web of Science ®Google Scholar
• Daga MK, Khan NA, Malhotra V, et al. Study of body composition, lung function, and quality of life following use of anabolic steroids in patients with chronic obstructive pulmonary disease. Nutr Clin Pract. 2014;29(2):238–245. doi:10.1177/0884533614522832.
   Web of Science ®Google Scholar
• Pan L, Wang M, Xie X, et al. Effects of anabolic steroids on chronic obstructive pulmonary disease: a meta-analysis of randomised controlled trials. PLoS One. 2014;9(1):e84855. doi:10.1371/journal.pone.0084855.
   PubMed Web of Science ®Google Scholar
• An X, Zhang AL, May BH, et al. Oral Chinese herbal medicine for improvement of quality of life in patients with stable chronic obstructive pulmonary disease: a systematic review. J Altern Complementary Med. 2012;18:731–743. doi:10.1089/acm.2011.0389.
   Web of Science ®Google Scholar
• An X, Zhang AL, Yang AW, et al. Oral ginseng formulae for stable chronic obstructive pulmonary disease: a systematic review. Respir Med. 2011;105(2):165–176. doi:10.1016/j.rmed.2010.11.007.
   PubMed Web of Science ®Google Scholar
• Liu J, Gao F, Li Z. Effect of yiqibushenhuoxue decoction on chronic obstructive pulmonary disease measured by St. George’s respiratory disease questionnaire scores and forced expiratory volume. J Tradit Chin Med. 2014;34(4):445–449. doi:10.1016/S0254-6272(15)30044-3.
   Web of Science ®Google Scholar
• Blanco I, Santos S, Gea J, et al. Sildenafil to improve respiratory rehabilitation outcomes in COPD: a controlled trial. Eur Respir J. 2013;42(4):982–992. doi:10.1183/09031936.00176312.
   PubMed Web of Science ®Google Scholar
• Goudie AR, Lipworth BJ, Hopkinson PJ, et al. Tadalafil in patients with chronic obstructive pulmonary disease: a randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med. 2014;2(4):293–300. doi:10.1016/S2213-2600(14)70013-X.
   PubMed Web of Science ®Google Scholar
• Holverda S, Rietema H, Bogaard HJ, et al. Acute effects of sildenafil on exercise pulmonary hemodynamics and capacity in patients with COPD. Pulm Pharmacol Ther. 2008;21:558–564. doi:10.1016/j.pupt.2008.01.012.
   PubMed Web of Science ®Google Scholar
• Rao RS, Singh S, Sharma BB, et al. Sildenafil improves six-minute walk distance in chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial. Indian J Chest Dis Allied Sci. 2011;53(2):81–85.
   PubMedGoogle Scholar
• Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease (review). Cochrane Database Syst Rev. 2017;9:CD002309.
   PubMedGoogle Scholar
• Zeng Z, Yang D, Huang X, et al. Effect of carbocisteine on patients with COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulm Dis. 2017;12:2277–2283. doi:10.2147/COPD.S140603.
   Web of Science ®Google Scholar
• Canadian Institute for Health Information. Inpatient Hospitalizations, Surgeries and Childbirth Indicators in 2013–14. Hospital Morbidity Database and Ontario Mental Health Reporting System. Canadian Institute for Health Information. 2015. https://secure.cihi.ca/free_products/CAD_Hospitalization%20and%20Childbirth_Infosheet_ENrev-web.pdf. Accessed June 27, 2019.
   Google Scholar
• Canadian Institute for Health Information. Which health conditions are the most expensive in 2016-17? Canadian MIS Database and Discharge Abstract Database, Canadian Institute for Health Information. 2019. https://www.cihi.ca/en/which-health-conditions-are-the-most-expensive. Accessed March 18, 2019.
   Google Scholar
• O’Donnell DE, Aaron S, Bourbeau J, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease–2007 update. Can Respir J. 2007;14(Suppl B):5B–32B. doi:10.1155/2007/926421.
   PubMed Web of Science ®Google Scholar
• O’Donnell DE, Hernandez P, Kaplan A, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease–2008 update–highlights for primary care. Can Respir J. 2008;15(Suppl A):1A–8A. doi:10.1155/2008/641965.
   PubMed Web of Science ®Google Scholar
• Global Initiative for Chronic Obstructive Lung Disease (GOLD). The Global Strategy for Diagnosis, Management and Prevention of COPD (updated 2019). 2019. https://goldcopd.org/gold-reports/. Accessed June 27, 2019.
   Google Scholar
• Burney PG, Patel J, Newson R, et al. Global and regional trends in COPD mortality, 1990-2010. Eur Respir J. 2015;45(5):1239–1247. doi:10.1183/09031936.00142414.
   PubMed Web of Science ®Google Scholar
• Institute for Health Metrics and Evaluation. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. Institute for Health Metrics and Evaluation. The Lancet. 2017;390:1151–1210.
   PubMed Web of Science ®Google Scholar
• Calverley PMA, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775–789. doi:10.1056/NEJMoa063070.
   PubMed Web of Science ®Google Scholar
• Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med. 2013;1(3):210–223. doi:10.1016/S2213-2600(13)70040-7.
   PubMed Web of Science ®Google Scholar
• Izquierdo JL, Cosio BG. The dose of inhaled corticosteroids in patients with COPD: when less is better. Int J Chron Obstruct Pulm Dis. 2018;13:3539–3547. doi:10.2147/COPD.S175047.
   PubMed Web of Science ®Google Scholar
• Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285–1294. doi:10.1056/NEJMoa1407154.
   PubMed Web of Science ®Google Scholar
• Janson C, Larsson K, Lisspers KH, et al. Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroid and long acting β2 agonist: observational matched cohort study (PATHOS). BMJ. 2013;346:f3306. doi:10.1136/bmj.f3306.
   PubMed Web of Science ®Google Scholar
• D’Urzo A, Kerwin E, Overend T, et al. Once daily glycopyrronium for the treatment of COPD: pooled analysis of the GLOW1 and GLOW2 studies. Curr Med Res Opin. 2014;30(3):493–508. doi:10.1185/03007995.2013.858618.
   PubMed Web of Science ®Google Scholar
• Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;Jul 11(7):CD009285.
   Google Scholar
• Lee SH, Lee J, Yoo KH, et al. Efficacy and safety of aclidinium bromide in patients with COPD: a phase 3 randomized clinical trial in a Korean population. Respirology. 2015;20(8):1222–1228. doi:10.1111/resp.12641.
   Web of Science ®Google Scholar
• Matera MG, Rogliani P, Cazzola M. Indacaterol for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother. 2015;16(1):107–115. doi:10.1517/14656566.2015.983076.
   Web of Science ®Google Scholar
• Oba Y, Lone NA. Comparative efficacy of long-acting muscarinic antagonists in preventing COPD exacerbations: a network metaanalysis and meta-regression. Ther Adv Respir. 2015;9(1):3–15. doi:10.1177/1753465814565624.
   PubMed Web of Science ®Google Scholar
• Pleasants RA, Wang T, Gao J, et al. Inhaled umeclidinium in COPD patients: a review and meta-analysis. Drugs. 2016;76(3):343–361. doi:10.1007/s40265-015-0532-5.
   PubMed Web of Science ®Google Scholar
• Maia IS, Pincelli MP, Leite VF, et al. Long-acting muscarinic antagonists vs. long-acting β2 agonists in COPD exacerbations: a systematic review and meta-analysis. J Bras Pneumol. 2017;43(4):302–312. doi:10.1590/s1806-37562016000000287.
   PubMed Web of Science ®Google Scholar
• Martinez FJ, Rabe KF, Ferguson GT, et al. Efficacy and safety of glycopyrrolate/formoterol metered dose inhaler formulated using co-suspension delivery technology in patients with COPD. Chest. 2017; 151(2):340–357. doi:10.1016/j.chest.2016.11.028.
   PubMed Web of Science ®Google Scholar
• Bateman ED, Chapman KR, Singh D, et al. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). Respir Res. 2015;16(1):92. doi:10.1186/s12931-015-0250-2.
   PubMed Web of Science ®Google Scholar
• Decramer M, Anzueto A, Kerwin E, 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(6):472–486. doi:10.1016/S2213-2600(14)70065-7.
   PubMed Web of Science ®Google Scholar
• Donohue JF, Singh D, Munzu C, et al. Magnitude of umeclidinium/vilanterol lung function effect depends on monotherapy responses: results from two randomised controlled trials. Respir Med. 2016;112:65–74. doi:10.1016/j.rmed.2016.01.001.
   PubMed Web of Science ®Google Scholar
• Horita N, Kaneko T. Role of combined indacaterol and glycopyrronium bromide (QVA149) for the treatment of COPD in Japan. Int J Chron Obstruct Pulm Dis. 2015;10:813–822.
   Web of Science ®Google Scholar
• Kalberg C, O’Dell D, Galkin D, et al. Dual bronchodilator therapy with umeclidinium/vilanterol versus tiotropium plus indacaterol in chronic obstructive pulmonary disease: a randomized controlled trial. Drugs R D. 2016;16(2):217–227. doi:10.1007/s40268-016-0131-2.
   PubMed Web of Science ®Google Scholar
• 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. 2016;71(1):15–25. doi:10.1136/thoraxjnl-2014-206732.
   PubMed Web of Science ®Google Scholar
• Schlueter M, Gonzalez-Rojas N, Baldwin M, et al. Comparative efficacy of fixed-dose combinations of long-acting muscarinic antagonists and long-acting beta2-agonists: a systematic review and network meta-analysis. Ther Adv Respir. 2016;10(2):89–104. doi:10.1177/1753465815624612.
   PubMed Web of Science ®Google Scholar
• Wedzicha JA, Dahl R, Buhl R, 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(10):1498–1507. doi:10.1016/j.rmed.2014.07.011.
   PubMed Web of Science ®Google Scholar
• Calverley PMA, Anderson JA, Brook RD, et al. Fluticasone furoate, vilanterol, and lung function decline in patients with moderate chronic obstructive pulmonary disease and heightened cardiovascular risk. Am J Respir Crit Care Med. 2018;197(1):47–55. doi:10.1164/rccm.201610-2086OC.
   PubMed Web of Science ®Google Scholar
• GINA/GOLD. Diagnosis of diseases of Chronic Airflow Limitation: asthma, COPD and asthma-COPD Overlap Syndrome (ACOS). Published 2015. https://goldcopd.org/asthma-copd-asthma-copd-overlap-syndrome/. Accessed May 28, 2019.
   Google Scholar
• Oba Y, Lone NA. Comparative efficacy of inhaled corticosteroid and long-acting beta agonist combinations in preventing COPD exacerbations: a Bayesian network meta-analysis. Int J Chron Obstruct Pulm Dis. 2014;9:469–479.
   PubMed Web of Science ®Google Scholar
• Singh D, Nicolini G, Bindi E, et al. Extrafine beclomethasone/formoterol compared to fluticasone/salmeterol combination therapy in COPD. BMC Pulm Med. 2014;14(1):43. doi:10.1186/1471-2466-14-43.
   Google Scholar
• Stynes G, Svedsater H, Wex J, et al. Once-daily fluticasone furoate/vilanterol 100/25 mcg versus twice daily combination therapies in COPD—mixed treatment comparisons of clinical efficacy. Respir Res. 2015;16(1):25. doi:10.1186/s12931-015-0184-8.
   Google Scholar
• Vestbo J, Leather D, Diar Bakerly N, et al. Effectiveness of fluticasone furoate-vilanterol for COPD in clinical practice. N Engl J Med. 2016;375(13):1253–1260. doi:10.1056/NEJMoa1608033.
   PubMed Web of Science ®Google Scholar
• Wedzicha JA, Singh D, Vestbo J, et al. Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations. Respir Med. 2014;108(8):1153–1162. doi:10.1016/j.rmed.2014.05.013.
   PubMed Web of Science ®Google Scholar
• Singh D, Vezzoli S, Petruzzelli S, et al. The efficacy of extrafine beclomethasone dipropionate–formoterol fumarate in COPD patients who are not “frequent exacerbators”: a post hoc analysis of the FORWARD study. Int J Chron Obstruct Pulm Dis. 2017;12:3263–3271. doi:10.2147/COPD.S141416.
   Web of Science ®Google Scholar
• Ohar JA, Crater GD, Emmett A, et al. Fluticasone propionate/salmeterol 250/50 mug versus salmeterol 50 mug after chronic obstructive pulmonary disease exacerbation. Respir Res. 2014;15(1):105. doi:10.1186/s12931-014-0105-2.
   Google Scholar
• Ferguson GT, Tashkin DP, Skärby T, et al. Effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations versus formoterol in chronic obstructive pulmonary disease: the 6-month, randomized RISE (Revealing the Impact of Symbicort in reducing Exacerbations in COPD) study. Respir Med. 2017;132:31–41. doi:10.1016/j.rmed.2017.09.002.
   PubMed Web of Science ®Google Scholar
• Hedeker DG, Waternaux RD, Waternaux C. Sample size estimation for longitudinal designs with attrition: comparing time-related contrasts between two groups. J Educ Behav Stat. 1999;24(1):70–93. doi:10.3102/10769986024001070.
   Web of Science ®Google Scholar
• Horita N, Miyazawa N, Morita S, et al. Long-acting beta-agonists reduce mortality of patients with severe and very severe chronic obstructive pulmonary disease: a propensity score matching study. Respir Res. 2013;14(1):62. doi:10.1186/1465-9921-14-62.
   Google Scholar
• Oba Y, Chandran AV, Devasahayam JV. Long-acting muscarinic antagonist versus inhaled corticosteroid when added to long-acting beta-agonist for COPD: a meta-analysis. COPD J Chron Obstruct Pulm Dis. 2016;13(6):677–685. doi:10.3109/15412555.2016.1170799.
   PubMed Web of Science ®Google Scholar
• Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016;374(23):2222–2234. doi:10.1056/NEJMoa1516385.
   PubMed Web of Science ®Google Scholar
• Zhong N, Wang C, Zhou X, et al. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. Int J Chron Obstruct Pulm Dis. 2015;10:1015–1026.
   PubMed Web of Science ®Google Scholar
• Kwak MS, Kim E, Jang EJ, et al. The efficacy and safety of triple inhaled treatment in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis using Bayesian methods. Int J Chron Obstruct Pulm Dis. 2015;10:2365–2376.
   PubMed Web of Science ®Google Scholar
• Liu Y, Shi H, Sun X, et al. Benefits of adding fluticasone propionate/salmeterol to tiotropium in COPD: a meta-analysis. Eur J Intern Med. 2014;25(5):491–495. doi:10.1016/j.ejim.2014.04.007.
   Web of Science ®Google Scholar
• Rojas-Reyes MX, Garcia Morales OM, Dennis RJ, et al. Combination inhaled steroid and long-acting beta(2)-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2016;Jun 6(6):CD008532.
   Google Scholar
• Vestbo J, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet. 2017;389(10082):1919–1929. doi:10.1016/S0140-6736(17)30188-5.
   PubMed Web of Science ®Google Scholar
• Papi A, Vestbo J, Fabbri L, et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. Lancet. 2018;391(10125):1076–1084. doi:10.1016/S0140-6736(18)30206-X.
   PubMed Web of Science ®Google Scholar
• Lipson DA, Barnacle H, Birk R, et al. FULFIL trial: once-daily triple therapy for patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196(4):438–446. doi:10.1164/rccm.201703-0449OC.
   PubMed Web of Science ®Google Scholar
• Carone M, Donner CF, Jones PW. Health status measurement: an increasingly important outcome evaluation in COPD patients. Monaldi Arch Chest Dis. 2001;56(4):297–298.
   Google Scholar
• Hanania NA, Calverley PM, Dransfield MT, et al. Pooled subpopulation analyses of the effects of roflumilast on exacerbations and lung function in COPD. Respir Med. 2014;108(2):366–375. doi:10.1016/j.rmed.2013.09.018.
   PubMed Web of Science ®Google Scholar
• Luo J, Wang K, Liu D, et al. Can roflumilast, a phosphodiesterase-4 inhibitor, improve clinical outcomes in patients with moderate-to-severe chronic obstructive pulmonary disease? A metaanalysis. Respir Res. 2016;17(1):18. doi:10.1186/s12931-016-0330-y.
   PubMed Web of Science ®Google Scholar
• Luo P, Li S, Chen Y, et al. Efficiency and safety of roflumilast combined with long-acting bronchodilators on moderate-to severe stable chronic obstructive pulmonary disease patients: a meta-analysis. J Thorac Dis. 2016;8(9):2638–2645. doi:10.21037/jtd.2016.09.12.
   Web of Science ®Google Scholar
• Martinez FJ, Calverley PM, Goehring UM, et al. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet. 2015;385(9971):857–866. doi:10.1016/S0140-6736(14)62410-7.
   PubMed Web of Science ®Google Scholar
• Yan JH, Gu WJ, Pan L. Efficacy and safety of roflumilast in patients with stable chronic obstructive pulmonary disease: a meta-analysis. Pulm Pharmacol Ther. 2014;27(1):83–89. doi:10.1016/j.pupt.2013.04.004.
   PubMed Web of Science ®Google Scholar
• Martinez FJ, Rabe KF, Calverley MA, et al. Determinants of response to roflumilast in severe chronic obstructive pulmonary disease pooled analysis of two randomized trials. Am J Respir Crit Care Med. 2018;198(10):1268–1278. doi:10.1164/rccm.201712-2493OC.
   PubMed Web of Science ®Google Scholar
• Shen LF, Lv XD, Chen WY, et al. Effect of roflumilast on chronic obstructive pulmonary disease: a systematic review and meta-analysis. Irish J Med Sci. 2018;187(3):731–738. doi:10.1007/s11845-018-1738-9.
   PubMed Web of Science ®Google Scholar
• Ayfer Aytemur Z, Baysak A, Ozdemir O, et al. N-acetylcysteine in patients with COPD exacerbations associated with increased sputum. Wien Klin Wochenschr. 2015;127(7-8):256–261. doi:10.1007/s00508-014-0692-4.
   Web of Science ®Google Scholar
• Cazzola M, Calzetta L, Page C, et al. Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis. Eur Respir Rev. 2015;24(137):451–461. doi:10.1183/16000617.00002215.
   PubMed Web of Science ®Google Scholar
• Poole P, Chong J, Cates CJ. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;Jul 29(7):CD001287.
   Google Scholar
• Shen Y, Cai W, Lei S, et al. Effect of high/low dose N-acetylcysteine on chronic obstructive pulmonary disease: a systematic review and meta-analysis. COPD J Chron Obstruct Pulm Dis. 2014;11:351–358. doi:10.3109/15412555.2013.858315.
   Web of Science ®Google Scholar
• Tse HN, Raiteri L, Wong KY, et al. Benefits of high-dose N-acetylcysteine to exacerbation-prone patients with COPD. Chest. 2014;146(3):611–623. doi:10.1378/chest.13-2784.
   PubMed Web of Science ®Google Scholar
• Zheng JP, Wen FQ, Bai CX, et al. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2014;2(3):187–194. doi:10.1016/S2213-2600(13)70286-8.
   PubMed Web of Science ®Google Scholar
• Dal Negro RW, Wedzicha JA, Iversen M, et al. Effect of erdosteine on the rate and duration of COPD exacerbations: the RESTORE study. Eur Respir J. 2017;50(4):1700711. doi:10.1183/13993003.00711-2017.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Rogliani P, Calzetta L, et al. Impact of mucolytic agents on COPD exacerbations: a pair-wise and network meta-analysis. COPD J Chron Obstruct Pulm Dis. 2017; 14(5):552–563. doi:10.1080/15412555.2017.1347918.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Calzetta L, Page C, et al. Impact of erdosteine on chronic bronchitis and COPD: a meta-analysis. Pulm Pharmacol Ther. 2018;48:185–194. doi:10.1016/j.pupt.2017.11.009.
   Web of Science ®Google Scholar
• Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189(12):1503–1508. doi:10.1164/rccm.201402-0207OC.
   PubMed Web of Science ®Google Scholar
• Ni W, Shao X, Cai X, et al. Prophylactic use of macrolide antibiotics for the prevention of chronic obstructive pulmonary disease exacerbation: a meta-analysis. PLoS One. 2015;10(3):e0121257. doi:10.1371/journal.pone.0121257.
   PubMed Web of Science ®Google Scholar
• Simpson JL, Powell H, Baines KJ, et al. The effect of azithromycin in adults with stable neutrophilic COPD: a double blind randomised placebo controlled trial. PLoS One. 2014;9(8):e105609. doi:10.1371/journal.pone.0105609.
   Web of Science ®Google Scholar
• Uzun S, Djamin RS, Kluytmans JA, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2(5):361–368. doi:10.1016/S2213-2600(14)70019-0.
   PubMed Web of Science ®Google Scholar
• Devereux G, Cotton S, Fielding S, et al. Effect of theophylline as adjunct to inhaled corticosteroids on exacerbations in patients with COPD a randomized clinical trial. JAMA. 2018;320(15):1548–1559. doi:10.1001/jama.2018.14432.
   Web of Science ®Google Scholar
• Bremner PR, Birk R, Brealey N, et al. Single-inhaler fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol plus umeclidinium using two inhalers for chronic obstructive pulmonary disease: a randomized noninferiority study. Respir Res. 2018;19(1):19. doi:10.1186/s12931-018-0724-0.
   PubMedGoogle Scholar
• Feldman GJ, Sousa AR, Lipson DA, et al. Comparative efficacy of once-daily umeclidinium/vilanterol and tiotropium/olodaterol therapy in symptomatic chronic obstructive pulmonary disease: a randomized study. Adv Ther. 2017;34(11):2518–2533. doi:10.1007/s12325-017-0626-4.
   PubMed Web of Science ®Google Scholar
• Kerwin E, Ferguson GT, Sanjar S, et al. Dual bronchodilation with indacaterol maleate/glycopyrronium bromide compared with umeclidinium bromide/vilanterol in patients with moderate-to-severe COPD: results from two randomized, controlled, cross-over studies. Lung. 2017;195(6):739–747.
   PubMed Web of Science ®Google Scholar
• Landis SH, Suruki R, Hilton E, et al. Stability of blood eosinophil count in patients with COPD in the UK Clinical Practice Research Datalink. COPD J Chron Obstruct Pulm Dis. 2017;14(4):382–388. doi:10.1080/15412555.2017.1313827.
   PubMed Web of Science ®Google Scholar
• Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543–1554. doi:10.1056/NEJMoa0805800.
   PubMed Web of Science ®Google Scholar