Skip to main content
Top
Published in: Respiratory Research 1/2018

Open Access 01-12-2018 | Research

Concomitant inhaled corticosteroid use and the risk of pneumonia in COPD: a matched-subgroup post hoc analysis of the UPLIFT® trial

Authors: Donald P. Tashkin, Marc Miravitlles, Bartolomé R. Celli, Norbert Metzdorf, Achim Mueller, David M. G. Halpin, Antonio Anzueto

Published in: Respiratory Research | Issue 1/2018

Login to get access

Abstract

Background

Use of inhaled corticosteroids (ICS) increases the risk of pneumonia in chronic obstructive pulmonary disease (COPD), but the magnitude of risk with different ICS remains unclear.

Methods

A post hoc analysis of the 4-year UPLIFT® trial to assess whether pneumonia risk differed by type of ICS (fluticasone propionate [FP], other ICS, or no ICS) in permanent users (defined by use until end of study) or in users at baseline (sensitivity analysis).

Results

For the permanent-users analysis, 825 patients receiving FP throughout the trial, 825 patients receiving other ICS and 825 patients not receiving ICS were matched on relevant baseline features 1:1:1. A significantly greater risk of pneumonia was observed for FP versus no ICS: the hazard ratio (HR) for risk of pneumonia was 1.33 (95% confidence interval [CI] 1.00, 1.75; p = 0.046) and the rate ratio (RR) was 1.58 (95% CI 1.05, 2.37; p = 0.028). A greater risk was also found for FP versus other ICS: HR 1.28 (95% CI 0.97, 1.68; p = 0.078) and RR 1.48 (95% CI 1.00, 2.19; p = 0.049). A higher proportion of patients on FP were hospitalized with pneumonia (7.9%) versus other ICS (6.7%) or no ICS (5.9%). Whilst other ICS use was associated with the highest number of fatal pneumonia events, the total number of fatal pneumonia incidents was low. A similar pattern was observed in the sensitivity analyses, which included 4002 patients on different treatments at baseline (FP, other ICS, and no ICS) and considered potential switches during the study.

Conclusion

The results support existing evidence of an increased pneumonia risk with FP use compared with other ICS and no ICS use in patients with COPD. Healthcare professionals should evaluate the risk–benefit ratio of using ICS when making treatment decisions with their patients.

Trial registration

Post hoc analysis of UPLIFT®. ClinicalTrials.​gov number: NCT00144339. Retrospectively registered September 2, 2005.
Appendix
Available only for authorised users
Literature
1.
go back to reference NICE National Clinical Guideline Centre. Chronic obstructive pulmonary disease in over 16s: diagnosis and management 2010. NICE National Clinical Guideline Centre. Chronic obstructive pulmonary disease in over 16s: diagnosis and management 2010.
2.
go back to reference Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Am J Respir Crit Care Med. 2017;195:557–82.CrossRef Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Am J Respir Crit Care Med. 2017;195:557–82.CrossRef
3.
go back to reference Barnes PJ. Inhaled corticosteroids in COPD: a controversy. Respiration. 2010;80:89–95.CrossRef Barnes PJ. Inhaled corticosteroids in COPD: a controversy. Respiration. 2010;80:89–95.CrossRef
4.
go back to reference Miravitlles M, Cosio BG, Arnedillo A, Calle M, Alcazar-Navarrete B, Gonzalez C, et al. A proposal for the withdrawal of inhaled corticosteroids in the clinical practice of chronic obstructive pulmonary disease. Respir Res. 2017;18:198.CrossRef Miravitlles M, Cosio BG, Arnedillo A, Calle M, Alcazar-Navarrete B, Gonzalez C, et al. A proposal for the withdrawal of inhaled corticosteroids in the clinical practice of chronic obstructive pulmonary disease. Respir Res. 2017;18:198.CrossRef
5.
go back to reference Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68:1029–36.CrossRef Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68:1029–36.CrossRef
6.
go back to reference Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;(3):CD010115. Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;(3):CD010115.
7.
go back to reference Price D, Yawn B, Brusselle G, Rossi A. Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD. Prim Care Respir J. 2013;22:92–100.CrossRef Price D, Yawn B, Brusselle G, Rossi A. Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD. Prim Care Respir J. 2013;22:92–100.CrossRef
8.
go back to reference Babu KS, Kastelik JA, Morjaria JB. Inhaled corticosteroids in chronic obstructive pulmonary disease: a pro-con perspective. Br J Clin Pharmacol. 2014;78:282–300.CrossRef Babu KS, Kastelik JA, Morjaria JB. Inhaled corticosteroids in chronic obstructive pulmonary disease: a pro-con perspective. Br J Clin Pharmacol. 2014;78:282–300.CrossRef
9.
go back to reference 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.CrossRef 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.CrossRef
10.
go back to reference Latorre M, Novelli F, Vagaggini B, Braido F, Papi A, Sanduzzi A, et al. Differences in the efficacy and safety among inhaled corticosteroids (ICS)/long-acting beta2-agonists (LABA) combinations in the treatment of chronic obstructive pulmonary disease (COPD): role of ICS. Pulm Pharmacol Ther. 2015;30:44–50.CrossRef Latorre M, Novelli F, Vagaggini B, Braido F, Papi A, Sanduzzi A, et al. Differences in the efficacy and safety among inhaled corticosteroids (ICS)/long-acting beta2-agonists (LABA) combinations in the treatment of chronic obstructive pulmonary disease (COPD): role of ICS. Pulm Pharmacol Ther. 2015;30:44–50.CrossRef
11.
go back to reference Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775–89.CrossRef Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775–89.CrossRef
12.
go back to reference Singh S, Loke YK. An overview of the benefits and drawbacks of inhaled corticosteroids in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2010;5:189–95.CrossRef Singh S, Loke YK. An overview of the benefits and drawbacks of inhaled corticosteroids in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2010;5:189–95.CrossRef
13.
go back to reference 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.CrossRef 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.CrossRef
14.
go back to reference Weatherall M, Clay J, James K, Perrin K, Shirtcliffe P, Beasley R. Dose-response relationship of inhaled corticosteroids and cataracts: a systematic review and meta-analysis. Respirology. 2009;14:983–90.CrossRef Weatherall M, Clay J, James K, Perrin K, Shirtcliffe P, Beasley R. Dose-response relationship of inhaled corticosteroids and cataracts: a systematic review and meta-analysis. Respirology. 2009;14:983–90.CrossRef
15.
go back to reference Tashkin DP, Murray HE, Skeans M, Murray RP. Skin manifestations of inhaled corticosteroids in COPD patients: results from lung health study II. Chest. 2004;126:1123–33.CrossRef Tashkin DP, Murray HE, Skeans M, Murray RP. Skin manifestations of inhaled corticosteroids in COPD patients: results from lung health study II. Chest. 2004;126:1123–33.CrossRef
16.
go back to reference Woods CP, Argese N, Chapman M, Boot C, Webster R, Dabhi V, et al. Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol. Eur J Endocrinol. 2015;173:633–42.CrossRef Woods CP, Argese N, Chapman M, Boot C, Webster R, Dabhi V, et al. Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol. Eur J Endocrinol. 2015;173:633–42.CrossRef
17.
go back to reference Ernst P, Gonzalez AV, Brassard P, Suissa S. Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia. Am J Respir Crit Care Med. 2007;176:162–6.CrossRef Ernst P, Gonzalez AV, Brassard P, Suissa S. Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia. Am J Respir Crit Care Med. 2007;176:162–6.CrossRef
18.
go back to reference Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009;34:641–7.CrossRef Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009;34:641–7.CrossRef
19.
go back to reference Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300:2407–16.CrossRef Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300:2407–16.CrossRef
20.
go back to reference Calverley PMA, Stockley RA, Seemungal TAR, Hagan G, Willits LR, Riley JH, et al. Reported pneumonia in patients with COPD: findings from the INSPIRE study. Chest. 2011;139:505–12.CrossRef Calverley PMA, Stockley RA, Seemungal TAR, Hagan G, Willits LR, Riley JH, et al. Reported pneumonia in patients with COPD: findings from the INSPIRE study. Chest. 2011;139:505–12.CrossRef
21.
go back to reference Crim C, Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, et al. Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD. Ann Am Thorac Soc. 2015;12:27–34.CrossRef Crim C, Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, et al. Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD. Ann Am Thorac Soc. 2015;12:27–34.CrossRef
22.
go back to reference Tricco AC, Strifler L, Veroniki AA, Yazdi F, Khan PA, Scott A, et al. Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis. BMJ Open. 2015;5:e009183.CrossRef Tricco AC, Strifler L, Veroniki AA, Yazdi F, Khan PA, Scott A, et al. Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis. BMJ Open. 2015;5:e009183.CrossRef
23.
go back to reference Festic E, Scanlon PD. Incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. A double effect of inhaled corticosteroids? Am J Respir Crit Care Med. 2015;191:141–8.CrossRef Festic E, Scanlon PD. Incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. A double effect of inhaled corticosteroids? Am J Respir Crit Care Med. 2015;191:141–8.CrossRef
24.
go back to reference Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med. 2009;169:219–29.CrossRef Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med. 2009;169:219–29.CrossRef
25.
go back to reference 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.CrossRef 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.CrossRef
26.
go back to reference Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA, et al. 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.CrossRef Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA, et al. 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.CrossRef
27.
go back to reference 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.CrossRef 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.CrossRef
28.
go back to reference Morjaria JB, Rigby A, Morice AH. Inhaled corticosteroid use and the risk of pneumonia and COPD exacerbations in the UPLIFT study. Lung. 2017;195:281–8.CrossRef Morjaria JB, Rigby A, Morice AH. Inhaled corticosteroid use and the risk of pneumonia and COPD exacerbations in the UPLIFT study. Lung. 2017;195:281–8.CrossRef
29.
go back to reference Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543–54.CrossRef Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543–54.CrossRef
30.
go back to reference Decramer M, Celli B, Tashkin DP, Pauwels RA, Burkhart D, Cassino C, et al. Clinical trial design considerations in assessing long-term functional impacts of tiotropium in COPD: the UPLIFT trial. COPD. 2004;1:303–12.CrossRef Decramer M, Celli B, Tashkin DP, Pauwels RA, Burkhart D, Cassino C, et al. Clinical trial design considerations in assessing long-term functional impacts of tiotropium in COPD: the UPLIFT trial. COPD. 2004;1:303–12.CrossRef
31.
go back to reference Halpin DM, Dahl R, Hallmann C, Mueller A, Tashkin D. Tiotropium HandiHaler(®) and Respimat(®) in COPD: a pooled safety analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:239–59.PubMedPubMedCentral Halpin DM, Dahl R, Hallmann C, Mueller A, Tashkin D. Tiotropium HandiHaler(®) and Respimat(®) in COPD: a pooled safety analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:239–59.PubMedPubMedCentral
33.
go back to reference Biggadike K. Fluticasone furoate/fluticasone propionate - different drugs with different properties. Clin Respir J. 2011;5:183–4.CrossRef Biggadike K. Fluticasone furoate/fluticasone propionate - different drugs with different properties. Clin Respir J. 2011;5:183–4.CrossRef
34.
go back to reference Vestbo J, Leather D, Diar Bakerly N, New J, Gibson JM, McCorkindale S, et al. Effectiveness of fluticasone furoate-vilanterol for COPD in clinical practice. N Engl J Med. 2016;375:1253–60.CrossRef Vestbo J, Leather D, Diar Bakerly N, New J, Gibson JM, McCorkindale S, et al. Effectiveness of fluticasone furoate-vilanterol for COPD in clinical practice. N Engl J Med. 2016;375:1253–60.CrossRef
35.
go back to reference Vestbo J, Anderson JA, Brook RD, Calverley PM, Celli BR, Crim C, et al. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet. 2016;387:1817–26.CrossRef Vestbo J, Anderson JA, Brook RD, Calverley PM, Celli BR, Crim C, et al. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet. 2016;387:1817–26.CrossRef
36.
go back to reference Morice AH, Hart SP. Increased propensity for pneumonia with fluticasone in COPD. Am J Respir Crit Care Med. 2018;197:1229–30.CrossRef Morice AH, Hart SP. Increased propensity for pneumonia with fluticasone in COPD. Am J Respir Crit Care Med. 2018;197:1229–30.CrossRef
37.
go back to reference Lipson DA, Barnacle H, Birk R, Brealey N, Locantore N, Lomas DA, et al. FULFIL trial: once-daily triple therapy for patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196:438–46.CrossRef Lipson DA, Barnacle H, Birk R, Brealey N, Locantore N, Lomas DA, et al. FULFIL trial: once-daily triple therapy for patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196:438–46.CrossRef
38.
go back to reference Janson C, Stratelis G, Miller-Larsson A, Harrison TW, Larsson K. Scientific rationale for the possible inhaled corticosteroid intraclass difference in the risk of pneumonia in COPD. Int J Chron Obstruct Pulmon Dis. 2017;12:3055–64.CrossRef Janson C, Stratelis G, Miller-Larsson A, Harrison TW, Larsson K. Scientific rationale for the possible inhaled corticosteroid intraclass difference in the risk of pneumonia in COPD. Int J Chron Obstruct Pulmon Dis. 2017;12:3055–64.CrossRef
39.
go back to reference Yawn BP, Li Y, Tian H, Zhang J, Arcona S, Kahler KH. Inhaled corticosteroid use in patients with chronic obstructive pulmonary disease and the risk of pneumonia: a retrospective claims data analysis. Int J Chron Obstruct Pulmon Dis. 2013;8:295–304.CrossRef Yawn BP, Li Y, Tian H, Zhang J, Arcona S, Kahler KH. Inhaled corticosteroid use in patients with chronic obstructive pulmonary disease and the risk of pneumonia: a retrospective claims data analysis. Int J Chron Obstruct Pulmon Dis. 2013;8:295–304.CrossRef
40.
go back to reference Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, 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.CrossRef Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, 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.CrossRef
41.
go back to reference Mullerova H, Chigbo C, Hagan GW, Woodhead MA, Miravitlles M, Davis KJ, et al. The natural history of community-acquired pneumonia in COPD patients: a population database analysis. Respir Med. 2012;106:1124–33.CrossRef Mullerova H, Chigbo C, Hagan GW, Woodhead MA, Miravitlles M, Davis KJ, et al. The natural history of community-acquired pneumonia in COPD patients: a population database analysis. Respir Med. 2012;106:1124–33.CrossRef
42.
go back to reference Gomez-Junyent J, Garcia-Vidal C, Viasus D, Millat-Martinez P, Simonetti A, Santos MS, et al. Clinical features, etiology and outcomes of community-acquired pneumonia in patients with chronic obstructive pulmonary disease. PLoS One. 2014;9:e105854.CrossRef Gomez-Junyent J, Garcia-Vidal C, Viasus D, Millat-Martinez P, Simonetti A, Santos MS, et al. Clinical features, etiology and outcomes of community-acquired pneumonia in patients with chronic obstructive pulmonary disease. PLoS One. 2014;9:e105854.CrossRef
Metadata
Title
Concomitant inhaled corticosteroid use and the risk of pneumonia in COPD: a matched-subgroup post hoc analysis of the UPLIFT® trial
Authors
Donald P. Tashkin
Marc Miravitlles
Bartolomé R. Celli
Norbert Metzdorf
Achim Mueller
David M. G. Halpin
Antonio Anzueto
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2018
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-018-0874-0

Other articles of this Issue 1/2018

Respiratory Research 1/2018 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.