Pharmacological strategies to reduce exacerbation risk in COPD: A narrative review

Respiratory Research

Volumn 17, Issue 1, 2016, Pages

  Miravitlles, Marc ^a   D'Urzo, Anthony ^b   Singh, Dave ^c   Koblizek, Vladimir ^d  

^a HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

^b UNIVERSITY OF TORONTO   (Canada)

^c UNIVERSITY OF MANCHESTER   (United Kingdom)

^d CHARLES UNIVERSITY   (Czech Republic)

Author keywords

Bronchitis; Emphysema; Exacerbation; Guidelines; Phenotypes; Prevention; Risk factors; Treatment

Indexed keywords

BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; CORTICOSTEROID; LONG ACTING DRUG; MACROLIDE; MUCOLYTIC AGENT; MUSCARINIC RECEPTOR BLOCKING AGENT; PHOSPHODIESTERASE IV INHIBITOR; ANTIINFECTIVE AGENT; BRONCHODILATING AGENT; EXPECTORANT AGENT;

ARTICLE; ASTHMA; BACTERIAL INFECTION; BRONCHIECTASIS; BRONCHODILATATION; CHRONIC BRONCHITIS; CHRONIC OBSTRUCTIVE LUNG DISEASE; DISEASE EXACERBATION; DRUG INDICATION; DRUG MEGADOSE; EOSINOPHIL COUNT; HUMAN; PATIENT IDENTIFICATION; PHENOTYPE; PRACTICE GUIDELINE; PULMONARY REHABILITATION; RISK FACTOR; RISK REDUCTION; COMBINATION DRUG THERAPY; DRUG EFFECTS; LUNG; MUCOCILIARY CLEARANCE; PATHOPHYSIOLOGY; TIME FACTOR; TREATMENT OUTCOME;

ADRENAL CORTEX HORMONES; ADRENERGIC BETA-2 RECEPTOR AGONISTS; ANTI-BACTERIAL AGENTS; BRONCHODILATOR AGENTS; DISEASE PROGRESSION; DRUG THERAPY, COMBINATION; EXPECTORANTS; HUMANS; LUNG; MUCOCILIARY CLEARANCE; MUSCARINIC ANTAGONISTS; PHENOTYPE; PHOSPHODIESTERASE 4 INHIBITORS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; TIME FACTORS; TREATMENT OUTCOME;

EID: 84986563785     PISSN: 14659921     EISSN: 1465993X     Source Type: Journal    
DOI: 10.1186/s12931-016-0425-5     Document Type: Article

References (148)

1. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:1418-22.
2. Doll H, Miravitlles M. Health-related QOL in acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease: a review of the literature. Pharmacoeconomics. 2005;23:345-63.
3. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161:1608-13.
4. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57:847-52.
5. 1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med. 2001;164:358-64.
6. Qureshi H, Sharafkhaneh A, Hanania NA. Chronic obstructive pulmonary disease exacerbations: latest evidence and clinical implications. Ther Adv Chronic Dis. 2014;5:212-27.
7. Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60:925-31.
8. Miravitlles M, Murio C, Guerrero T, Gisbert R. Costs of chronic bronchitis and COPD: a 1-year follow-up study. Chest. 2003;123:784-91.
9. Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease, GOLD Executive Summary. Am J Respir Crit Care Med. 2013;187: 347-365.
10. Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, McCormick M, Haldar K, Kebadze T, Duvoix A, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184:662-71.
11. Aaron SD. Management and prevention of exacerbations of COPD. BMJ. 2014;349:g5237.
12. Aaron SD, Fergusson D, Marks GB, Suissa S, Vandemheen KL, Doucette S, Maltais F, Bourbeau JF, Goldstein RS, Balter M, et al. Counting, analysing and reporting exacerbations of COPD in randomised controlled trials. Thorax. 2008;63:122-8.
13. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J, Investigators T. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-89.
14. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, MacNee W, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363:1128-38.
15. Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543-54.
16. Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, Dusser D, Joseph E, Kattenbeck S, Koenen-Bergmann M, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369:1491-501.
17. Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS, Calverley PM, Celli BR, et al. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J. 2008;31:416-69.
18. Langsetmo L, Platt RW, Ernst P, Bourbeau J. Underreporting exacerbation of chronic obstructive pulmonary disease in a longitudinal cohort. Am J Respir Crit Care Med. 2008;177:396-401.
19. Xu W, Collet JP, Shapiro S, Lin Y, Yang T, Wang C, Bourbeau J. Negative impacts of unreported COPD exacerbations on health-related quality of life at 1 year. Eur Respir J. 2010;35:1022-30.
20. Ball P. Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest. 1995;108:43S-52S.
21. Sapey E, Stockley RA. COPD exacerbations.2: aetiology. Thorax. 2006;61:250-8.
22. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786-96.
23. Donaldson GC, Wedzicha JA. COPD exacerbations.1: Epidemiology. Thorax. 2006;61:164-8.
24. Anderson HR, Spix C, Medina S, Schouten JP, Castellsague J, Rossi G, Zmirou D, Touloumi G, Wojtyniak B, Ponka A, et al. Air pollution and daily admissions for chronic obstructive pulmonary disease in 6 European cities: results from the APHEA project. Eur Respir J. 1997;10:1064-71.
25. Ramsey SD, Hobbs FD. Chronic obstructive pulmonary disease, risk factors, and outcome trials: comparisons with cardiovascular disease. Proc Am Thorac Soc. 2006;3:635-40.
26. Evensen AE. Management of COPD exacerbations. Am Fam Physician. 2010;81:607-13.
27. Moy ML, Teylan M, Weston NA, Gagnon DR, Garshick E. Daily step count predicts acute exacerbations in a US cohort with COPD. PLoS One. 2013;8:e60400.
28. Burgel PR, Nesme-Meyer P, Chanez P, Caillaud D, Carré P, Perez T, Roche N. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest. 2009;135:975-82.
29. Kim V, Criner GJ. The chronic bronchitis phenotype in chronic obstructive pulmonary disease: features and implications. Curr Opin Pulm Med. 2015;21:133-41.
30. Miravitlles M. Cough and sputum production as risk factors for poor outcomes in patients with COPD. Respir Med. 2011;105:1118-28.
31. Oh YM, Sheen SS, Park JH, Jin UR, Yoo JW, Seo JB, Yoo KH, Lee JH, Kim TH, Lim SY, et al. Emphysematous phenotype is an independent predictor for frequent exacerbation of COPD. Int J Tuberc Lung Dis. 2014;18:1407-14.
32. Han MK, Agusti A, Calverley PM, Celli BR, Criner G, Curtis JL, Fabbri LM, Goldin JG, Jones PW, MacNee W, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med. 2010;182:598-604.
33. Miravitlles M, Soler-Cataluña JJ, Calle M, Molina J, Almagro P, Quintano JA, Riesco JA, Trigueros JA, Piñera P, Simón A, et al. Spanish guideline for COPD (GesEPOC). Update 2014. Arch Bronconeumol. 2014;50 Suppl 1:1-16.
34. Kankaanranta H, Harju T, Kilpelainen M, Mazur W, Lehto JT, Katajisto M, Peisa T, Meinander T, Lehtimäki L. Diagnosis and Pharmacotherapy of Stable Chronic Obstructive Pulmonary Disease: The Finnish Guidelines. Basic Clin Pharmacol Toxicol. 2015;116:291-307.
35. Koblizek V, Chlumsky J, Zindr V, Neumannova K, Zatloukal J, Zak J, Sedlak V, Kocianova J, Zatloukal J, Hejduk K, Pracharova S. Chronic Obstructive Pulmonary Disease: official diagnosis and treatment guidelines of the Czech Pneumological and Phthisiological Society; a novel phenotypic approach to COPD with patient-oriented care. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2013;157:189-201.
36. Khan JH, Lababidi HM, Al-Moamary MS, Zeitouni MO, Al-Jahdali HH, Al-Amoudi OS, Wali SO, Idrees MM, Al-Shimemri AA, Al Ghobain MO, et al. The Saudi Guidelines for the Diagnosis and Management of COPD. Ann Thorac Med. 2014;9:55-76.
37. Gupta D, Agarwal R, Aggarwal AN, Maturu VN, Dhooria S, Prasad KT, Sehgal IS, Yenge LB, Jindal A, Singh N, et al. Guidelines for diagnosis and management of chronic obstructive pulmonary disease: Joint ICS/NCCP (I) recommendations. Lung India. 2013;30:228-67.
38. Soler Cataluña JJ, Piñer Salmerón P, Trigueros JA, Calle M, Almagro P, Molina J, Quintano JA, Riesco JA, Simón A, Soriano JB, et al. Spanish COPD guidelines (GesEPOC): hospital diagnosis and treatment of COPD exacerbation. Emergencias. 2013;25:301-17.
39. Miravitlles M, Soriano JB, Ancochea J, Muñoz L, Duran-Tauleria E, Sanchez G, Sobradillo V, García-Río F. Characterisation of the overlap COPD-asthma phenotype. Focus on physical activity and health status. Respir Med. 2013;107:1053-60.
40. Hardin M, Silverman EK, Barr RG, Hansel NN, Schroeder JD, Make BJ, Crapo JD, Hersh CP. The clinical features of the overlap between COPD and asthma. Respir Res. 2011;12:127.
41. Menezes AM, Montes de Oca M, Pérez-Padilla R, Nadeau G, Wehrmeister FC, Lopez-Varela MV, Muiño A, Jardim JR, Valdivia G, Tálamo C. Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma. Chest. 2014;145:297-304.
42. Agusti A, Hurd S, Jones P, Fabbri LM, Martinez F, Vogelmeier C, Vestbo J, Rodriguez-Roisin R. FAQs about the GOLD 2011 assessment proposal of COPD: a comparative analysis of four different cohorts. Eur Respir J. 2013;42:1391-401.
43. Han MK, Muellerova H, Curran-Everett D, Dransfield MT, Washko GR, Regan EA, Bowler RP, Beaty TH, Hokanson JE, Lynch DA, et al. GOLD 2011 disease severity classification in COPDGene: a prospective cohort study. Lancet Respir Med. 2013;1:43-50.
44. Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax. 2000;55:114-20.
45. Saetta M, Di Stefano A, Maestrelli P, Turato G, Ruggieri MP, Roggeri A, Calcagni P, Mapp CE, Ciaccia A, Fabbri LM. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med. 1994;150:1646-52.
46. Hurst JR. Exacerbation phenotyping in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;184:625-6.
47. George L, Brightling CE. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease. Ther Adv Chronic Dis. 2016;7:34-51.
48. Kitaguchi Y, Komatsu Y, Fujimoto K, Hanaoka M, Kubo K. Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma. Int J Chron Obstruct Pulmon Dis. 2012;7:283-9.
49. Papi A, Romagnoli M, Baraldo S, Braccioni F, Guzzinati I, Saetta M, Ciaccia A, Fabbri LM. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;162:1773-7.
50. Montuschi P, Malerba M, Santini G, Miravitlles M. Pharmacological treatment of chronic obstructive pulmonary disease: from evidence-based medicine to phenotyping. Drug Discov Today. 2014;19:1928-35.
51. Iwamoto H, Gao J, Koskela J, Kinnula V, Kobayashi H, Laitinen T, Mazur W. Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap. Eur Respir J. 2014;43:421-9.
52. Slats A, Taube C. Asthma and chronic obstructive pulmonary disease overlap: asthmatic chronic obstructive pulmonary disease or chronic obstructive asthma? Ther Adv Respir Dis. 2016;10:57-71.
53. Mulhall P, Criner G. Non-pharmacological treatments for COPD. Respirology. 2016;21:791-809.
54. Spruit MA, Singh SJ, Garvey C, ZuWallack R, Nici L, Rochester C, Hill K, Holland AE, Lareau SC, Man WD, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013;188:e13-64.
55. Puhan MA, Gimeno-Santos E, Scharplatz M, Troosters T, Walters EH, Steurer J. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. 2011, Issue 10. Art. No.: CD005305.
56. Zysman M, Patout M, Miravitlles M, van der Molen T, Lokke A, Hausen T, Didier A, Cuvelier A, Roche N. COPD and perception of the new GOLD document in Europe. Workshop from the Societe de pneumologie de langue francaise (SPLF). Rev Mal Respir. 2014;31:499-510.
57. Miravitlles M, Calle M, Soler-Cataluña JJ. Clinical phenotypes of COPD: identification, definition and implications for guidelines. Arch Bronconeumol. 2012;48:86-98.
58. Goh F, Shaw JG, Savarimuthu Francis SM, Vaughan A, Morrison L, Relan V, Marshall HM, Dent AG, O'Hare PE, Hsiao A, et al. Personalizing and targeting therapy for COPD: the role of molecular and clinical biomarkers. Expert Rev Respir Med. 2013;7:593-605.
59. Miravitlles M, Soler-Cataluña JJ, Calle M, Soriano JB. Treatment of COPD by clinical phenotypes: putting old evidence into clinical practice. Eur Respir J. 2013;41:1252-6.
60. Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Mölken MP, Beeh KM, Rabe KF, Fabbri LM. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364:1093-103.
61. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA, Investigators I. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med. 2008;177:19-26.
62. Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandstöm T, Taylor AF, D'Andrea P, Arrasate C, Chen H, Banerji D. 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.
63. Decramer ML, Chapman KR, Dahl R, Frith P, Devouassoux G, Fritscher C, Cameron R, Shoaib M, Lawrence D, Young D, et al. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med. 2013;1:524-33.
64. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M, O'Donnell D, McIvor A, Sharma S, 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;146:545-55.
65. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003;361:449-56.
66. 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;109:105-11.
67. Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;7:CD009285.
68. D'Urzo A, Ferguson GT, van Noord JA, Hirata K, Martin C, Horton R, Lu Y, Banerji D, Overend T. Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res. 2011;12:156.
69. Kerwin E, Hébert J, Gallagher N, Martin C, Overend T, Alagappan VK, Lu Y, Banerji D. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J. 2012;40:1106-14.
70. Jones PW, Rennard SI, Agusti A, Chanez P, Magnussen H, Fabbri L, Donohue JF, Bateman ED, Gross NJ, Lamarca R, et al. Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. Respir Res. 2011;12:55.
71. Rabe KF, Fabbri LM, Israel E, Kogler H, Riemann K, Schmidt H, Glaab T, Vogelmeier CF. Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial. Lancet Respir Med. 2014;2:44-53.
72. Bateman ED, Chapman KR, Singh D, D'Urzo AD, Molins E, Leselbaum A, Gil EG. 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;16:92.
73. Zhong N, Wang C, Zhou X, Zhang N, Humphries M, Wang C, Thach C, Patalano F, Banerji D. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. Int J COPD. 2015;10:1015-26.
74. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier C. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016. [Epub ahead of print].
75. Agarwal R, Aggarwal AN, Gupta D, Jindal SK. Inhaled corticosteroids vs placebo for preventing COPD exacerbations: a systematic review and metaregression of randomized controlled trials. Chest. 2010;137:318-25.
76. 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 Pulmon Dis. 2014;9:469-79.
77. 2-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;11:CD003794.
78. Anzueto A, Ferguson GT, Feldman G, Chinsky K, Seibert A, Emmett A, Knobil K, O'Dell D, Kalberg C, Crater G. Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. COPD. 2009;6:320-9.
79. Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, Wachtel A, Martinez FJ, Barnhart F, Sanford L, 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;1:210-23.
80. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003;22:912-9.
81. 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. 2003;21:74-81.
82. Agustí A, Calverley PM, Decramer M, Stockley RA, Wedzicha JA. Prevention of exacerbations in chronic obstructive pulmonary disease: knowns and unknowns. J COPD Foundation. 2014;1:166-84.
83. DiSantostefano RL, Sampson T, Le HV, Hinds D, Davis KJ, Bakerly ND. Risk of pneumonia with inhaled corticosteroid versus long-acting bronchodilator regimens in chronic obstructive pulmonary disease: a new-user cohort study. PLoS One. 2014;9:e97149.
84. Loke YK, Cavallazzi R, Singh S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax. 2011;66:699-708.
85. Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression. Am J Med. 2010;123:1001-6.
86. Magnussen H, Disse B, Rodriguez-Roisin R, Kirsten A, Watz H, Tetzlaff K, Towse L, Finnigan H, Dahl R, Decramer M, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371:1285-94.
87. Nadeem NJ, Taylor SJ, Eldridge SM. Withdrawal of inhaled corticosteroids in individuals with COPD--a systematic review and comment on trial methodology. Respir Res. 2011;12:107.
88. Rossi A, Guerriero M, Corrado A. Withdrawal of inhaled corticosteroids can be safe in COPD patients at low risk of exacerbation: a real-life study on the appropriateness of treatment in moderate COPD patients (OPTIMO). Respir Res. 2014;15:77.
89. Rossi A, van der Molen T, del Olmo R, Papi A, Wehbe L, Quinn M, Lu C, Young D, Cameron R, Bucchioni E, Altman P. INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD. Eur Respir J. 2014;44:1548-56.
90. Barrecheguren M, Esquinas C, Miravitlles M. The asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS): opportunities and challenges. Curr Opin Pulm Med. 2015;21:74-9.
91. Sin DD, Miravitlles M, Mannino DM, Soriano JB, Price D, Celli BR, Leung JM, Nakano Y, Park HY, Wark PA, Wechsler ME. What is asthma-COPD overlap syndrome (ACOS)? Towards a consensus definition from a roundtable discussion. Eur Respir J. 2016;48:664-73.
92. Christenson SA, Steiling K, van den Berge M, Hijazi K, Hiemstra PS, Postma DS, Lenberg ME, Spira A, Woodruff PG. Asthma-COPD overlap: clinical relevance of genomic signatures of Type 2 inflammation in COPD. Am J Respir Crit Care Med. 2015;191:758-66.
93. Brightling CE, McKenna S, Hargadon B, Birring S, Green R, Siva R, Berry M, Parker D, Monteiro W, Pavord ID, Bradding P. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax. 2005;60:193-8.
94. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, Wardlaw AJ, Pavord ID. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360:1715-21.
95. Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med. 2015;3:435-42.
96. Siddiqui SH, Guasconi A, Vestbo J, Jones P, Agusti A, Paggiaro P, Wedzicha JA, Singh D. Blood eosinophils: a biomarker of response to extrafine beclomethasone/formoterol in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192:523-5.
97. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685-94.
98. Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;11:CD002309.
99. Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. 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;385:857-66.
100. Wedzicha JA, Calverley PM, Rabe KF. Roflumilast: a review of its use in the treatment of COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:81-90.
101. Michalski JM, Golden G, Ikari J, Rennard SI. PDE4: a novel target in the treatment of chronic obstructive pulmonary disease. Clin Pharmacol Ther. 2012;91:134-42.
102. (FDA) FaDA: Daliresp® (roflumilast) tablets [prescribing information]. Oranienburg: Nycomed GmbH; 2011. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022522s000lbl.pdf. Accessed 27 Aug 2016.
103. Wouters EF, Bredenbroker D, Teichmann P, Brose M, Rabe KF, Fabbri LM, Goke B. Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012;97:E1720-5.
104. White WB, Cooke GE, Kowey PR, Calverley PM, Bredenbroker D, Goehring UM, Zhu H, Lakkis H, Mosberg H, Rowe P, Rabe KF. Cardiovascular safety in patients receiving roflumilast for the treatment of COPD. Chest. 2013;144:758-65.
105. Donath E, Chaudhry A, Hernandez-Aya LF, Lit L. A meta-analysis on the prophylactic use of macrolide antibiotics for the prevention of disease exacerbations in patients with Chronic Obstructive Pulmonary Disease. Respir Med. 2013;107:1385-92.
106. Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2013;11:CD009764.
107. Uzun S, Djamin RS, Kluytmans JA, Mulder PG, van't Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. 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;2:361-8.
108. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper Jr JA, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-98.
109. Miravitlles M, Anzueto A. Antibiotic prophylaxis in COPD: Why, when, and for whom? Pulm Pharmacol Ther. 2015;32:119-23.
110. Han MK, Tayob N, Murray S, Dransfield MT, Washko G, Scanlon PD, Criner GJ, Casaburi R, Connett J, Lazarus SC, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-8.
111. Miravitlles M. Long-term antibiotics in COPD: more benefit than harm? Prim Care Respir J. 2013;22:261-2.
112. Poole P, Black PN, Cates CJ. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;8:CD001287.
113. Zheng JP, Wen FQ, Bai CX, Wan HY, Kang J, Chen P, Yao WZ, Ma LJ, Li X, Raiteri L, 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;2:187-94.
114. Tse HN, Raiteri L, Wong KY, Ng LY, Yee KS, Tseng CZ. Benefits of high-dose N-acetylcysteine to exacerbation-prone patients with COPD. Chest. 2014;146:611-23.
115. Dal Negro RI, M.; Calverly, P. Efficacy and safety of erdosteine in COPD: Results of a 12-month prospective, multinational study. Presented at the European Respiratory Society Annual Congress 2015; Amsterdam, The Netherlands, 26-30 September 2015 (Abstract PA1495). 2015.
116. Mills EJ, Druyts E, Ghement I, Puhan MA. Pharmacotherapies for chronic obstructive pulmonary disease: a multiple treatment comparison meta-analysis. Clin Epidemiol. 2011;3:107-29.
117. Pascoe SJ, Lipson DA, Locantore N, Barnacle H, Brealey N, Mohindra R, Dransfield MT, Pavord I, Barnes N. A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol. Eur Respir J. 2016;48:320-30.
118. Brightling CE, Bleecker ER, Panettieri Jr RA, Bafadhel M, She D, Ward CK, Xu X, Birrell C, van der Merwe R. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2:891-901.
119. Fukuchi Y, Tatsumi K, Inoue H, Sakata Y, Shibata K, Miyagishi H, Marukawa Y, Ichinose M. Prevention of COPD exacerbation by lysozyme: a double-blind, randomized, placebo-controlled study. Int J Chron Obstruct Pulmon Dis. 2016;11:831-8.
120. Cosio BG, Shafiek H, Iglesias A, Yanez A, Cordova R, Palou A, Rodriguez-Roisin R, Peces-Barba G, Pascual S, Gea J, et al. Oral low-dose theophylline on top of inhaled fluticasone-salmeterol does not reduce exacerbations in patients with severe COPD: A pilot clinical trial. Chest. 2016;150:123-130.
121. Watz H, Tetzlaff K, Wouters EF, Kirsten A, Magnussen H, Rodriguez-Roisin R, Vogelmeier C, Fabbri LM, Chanez P, Dahl R, et al. Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med. 2016: doi: 10.1016/S2213-2600(16)00100-4. [Epub ahead of print].
122. Ni Y, Shi G, Yu Y, Hao J, Chen T, Song H. Clinical characteristics of patients with chronic obstructive pulmonary disease with comorbid bronchiectasis: a systemic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:1465-75.
123. Bateman ED, Tashkin D, Siafakas N, Dahl R, Towse L, Massey D, Pavia D, Zhong NS. A one-year trial of tiotropium Respimat plus usual therapy in COPD patients. Respir Med. 2010;104:1460-72.
124. Powrie DJ, Wilkinson TM, Donaldson GC, Jones P, Scrine K, Viel K, Kesten S, Wedzicha JA. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J. 2007;30:472-8.
125. Dusser D, Bravo ML, Iacono P. The effect of tiotropium on exacerbations and airflow in patients with COPD. Eur Respir J. 2006;27:547-55.
126. Niewoehner DE, Rice K, Cote C, Paulson D, Cooper Jr JA, Korducki L, Cassino C, Kesten S. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med. 2005;143:317-26.
127. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax. 2003;58:399-404.
128. Vincken W, van Noord JA, Greefhorst AP, Bantje TA, Kesten S, Korducki L, Cornelissen PJ. Improved health outcomes in patients with COPD during 1 year's treatment with tiotropium. Eur Respir J. 2002;19:209-16.
129. Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, Menjoge SS, Serby CW, Witek Jr T. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002;19:217-24.
130. Decramer M, Anzueto A, Kerwin E, Kaelin T, Richard N, Crater G, Tabberer M, Harris S, Church A. 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;2:472-86.
131. Schermer T, Chavannes N, Dekhuijzen R, Wouters E, Muris J, Akkermans R, van Schayck O, van Weel C. Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis. Respir Med. 2009;103:542-51.
132. 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. 2000;320:1297-303.
133. Ohar JA, Crater GD, Emmett A, Ferro TJ, Morris AN, Raphiou I, Sriram PS, Dransfield MT. Fluticasone propionate/salmeterol 250/50 μg versus salmeterol 50 μg after chronic obstructive pulmonary disease exacerbation. Respir Res. 2014;15:105.
134. Anzueto A, Leimer I, Kesten S. Impact of frequency of COPD exacerbations on pulmonary function, health status and clinical outcomes. Int J Chron Obstruct Pulmon Dis. 2009;4:245-51.
135. Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg C. Effect of fluticasone propionate/salmeterol (250/50 mg) or salmeterol (50 mg) on COPD exacerbations. Respir Med. 2008;102:1099-108.
136. Seemungal T, Stockley R, Calverley P, Hagan G, Wedzicha JA. Investigating new standards for prophylaxis in reduction of exacerbations--the INSPIRE study methodology. COPD. 2007;4:177-83.
137. Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175:144-9.
138. Sharafkhaneh A, Southard JG, Goldman M, Uryniak T, Martin UJ. Effect of budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study. Respir Med. 2012;106:257-68.
139. Fukuchi Y, Samoro R, Fassakhov R, Taniguchi H, Ekelund J, Carlsson LG, Ichinose M. Budesonide/formoterol via Turbuhaler(R) versus formoterol via Turbuhaler(R) in patients with moderate to severe chronic obstructive pulmonary disease: phase III multinational study results. Respirology. 2013;18:866-73.
140. Wedzicha JA, Singh D, Vestbo J, Paggiaro PL, Jones PW, Bonnet-Gonod F, Cohuet G, Corradi M, Vezzoli S, Petruzzelli S, Agusti A. Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations. Respir Med. 2014;108:1153-62.
141. Calverley PM, Kuna P, Monsó E, Costantini M, Petruzzelli S, Sergio F, Varoli G, Papi A, Brusasco V. Beclomethasone/formoterol in the management of COPD: a randomised controlled trial. Respir Med. 2010;104:1858-68.
142. Pomares X, Monton C, Espasa M, Casabon J, Monso E, Gallego M. Long-term azithromycin therapy in patients with severe COPD and repeated exacerbations. Int J Chron Obstruct Pulmon Dis. 2011;6:449-56.
143. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178:1139-47.
144. Zheng JP, Kang J, Huang SG, Chen P, Yao WZ, Yang L, Bai CX, Wang CZ, Wang C, Chen BY, et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet. 2008;371:2013-8.
145. Decramer M, Dekhuijzen PN, Troosters T, van Herwaarden C, Rutten-van Molken M, van Schayck CP, Olivieri D, Lankhorst I, Ardia A. The Bronchitis Randomized On NAC Cost-Utility Study (BRONCUS): hypothesis and design. BRONCUS-trial Committee. Eur Respir J. 2001;17:329-36.
146. 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, et al. 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. 2005;365:1552-60.
147. Bateman ED, Rabe KF, Calverley PM, Goehring UM, Brose M, Bredenbroker D, Fabbri LM. Roflumilast with long-acting beta2-agonists for COPD: influence of exacerbation history. Eur Respir J. 2011;38:553-60.
148. 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. 2007;176:154-61.