Effect of Fluticasone With and Without Salmeterol on Pulmonary Outcomes in Chronic Obstructive Pulmonary Disease

doi:10.1059/0003-4819-151-8-200910200-00004

Effect of Fluticasone With and Without Salmeterol on Pulmonary Outcomes in Chronic Obstructive Pulmonary Disease

A Randomized Trial

Thérèse S. Lapperre, MD;
Jiska B. Snoeck-Stroband, MD;
Margot M.E. Gosman, PhD, MD;
Désirée F. Jansen, PhD;
Annemarie van Schadewijk, MSc;
Henk A. Thiadens, PhD, MD;
Judith M. Vonk, PhD;
H. Marike Boezen, PhD;
Nick H.T. ten Hacken, PhD, MD;
Jacob K. Sont, PhD;
Klaus F. Rabe, PhD, MD;
Huib A.M. Kerstjens, PhD, MD;
Pieter S. Hiemstra, PhD;
Wim Timens, PhD, MD;
Dirkje S. Postma, PhD, MD;
Peter J. Sterk, PhD, MD; and
the GLUCOLD (Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease) Study Group*

From Leiden University Medical Center, Leiden; University Medical Center Groningen, Groningen; and Amsterdam Medical Centre, Amsterdam, The Netherlands.

Abstract

Background: Inhaled corticosteroids (ICSs) and long-acting β₂-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD).

Objective: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD.

Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847)

Setting: 2 university medical centers in The Netherlands.

Patients: 114 steroid-naive current or former smokers with moderate to severe COPD.

Measurements: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months.

Intervention: Random assignment by minimization method to receive fluticasone propionate, 500 µg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 µg twice daily, and salmeterol, 50 µg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29).

Results: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3⁺ cells (−55% [95% CI, −74% to −22%]; P = 0.004), CD4⁺ cells (−78% [CI, −88% to 60%]; P < 0.001), CD8⁺ cells (−57% [CI, −77% to −18%]; P = 0.010), and mast cells (−38% [CI, −60% to −2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV₁ decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3⁺ cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV₁ level.

Limitations: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months.

Conclusion: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects.

Primary Funding Source: Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, GlaxoSmithKline of The Netherlands, University Medical Center Groningen, and Leiden University Medical Center.

Article and Author Information

Note: Drs. Lapperre and Snoeck-Stroband contributed equally to the study and the manuscript. Drs. Postma and Sterk also contributed equally to the study, the study supervision, and the manuscript.
Acknowledgment: The authors thank the patients for their cooperation in our study.
Grant Support: By the Netherlands Asthma Foundation (grant 3.4.93.96.3), GlaxoSmithKline of The Netherlands, University Medical Center Groningen, and Leiden University Medical Center.
Potential Conflicts of Interest: Consultancies: N.H.T. ten Hacken (Nycomed, Chiesi, Boehringer Ingelheim, GlaxoSmithKline), K.F. Rabe (GlaxoSmithKline), H.A.M. Kerstjens (GlaxoSmithKline, AstraZeneca, Nycomed), D.S. Postma (Altana, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Teva). Honoraria: D.S. Postma (AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Nycomed, Teva, Top Institute Pharma), P.J. Sterk (GlaxoSmithKline). Grants received: M.M.E. Gosman (Glaxo Wellcome), N.H.T. ten Hacken (GlaxoSmithKline, AstraZeneca, Nycomed, Novartis, Boehringer Ingelheim), K.F. Rabe (GlaxoSmithKline), H.A.M. Kerstjens (GlaxoSmithKline, AstraZeneca, Nycomed, Novartis, Boehringer Ingelheim), P.S. Hiemstra (GlaxoSmithKline), P.J. Sterk (GlaxoSmithKline, Innovative Medicines Initiative).
Reproducible Research Statement: Study protocol: Available at www.clinicaltrials.gov. Statistical code: Available from Dr. Sont (j.k.sont{at}lumc.nl). Data set: Available from Dr. Sterk (p.j.sterk{at}amc.nl).
Requests for Single Reprints: Dirkje S. Postma, MD, PhD, Department of Pulmonology, University Medical Center Groningen and University of Groningen, Box 30.001, 9700 RB Groningen, The Netherlands; e-mail, d.s.postma{at}int.umcg.nl.
Current Author Addresses: Drs. Lapperre, Rabe, and Hiemstra and Ms. van Schadewijk: Department of Pulmonology, Box 9600, 2300RC Leiden, University Medical Center, Leiden, The Netherlands.
Drs. Snoeck-Stroband and Sont: Department of Medical Decision Making, Box 9600, 2300RC Leiden, Leiden University Medical Center, Leiden, The Netherlands.
Dr. Gosman: Department of Neurology, University Hospital Nijmegen, Reinier Postlaan 4, 6525 GC Nijmegen, The Netherlands.
Dr. Jansen: Faculty of Medicine, Box 30.001 NL-9700-RB, University Medical Center Groningen, Groningen, The Netherlands.
Dr. Thiadens: Department of Public Health and Primary Care, Postzone V-0-P, Box 9600, 2300RC Leiden, University Medical Center, Leiden, The Netherlands.
Drs. Vonk and Boezen: Department of Epidemiology E3.29, Box 30.001, University Medical Center Groningen, Groningen, The Netherlands.
Drs. ten Hacken, Kerstjens, and Postma: Department of Pulmonary Diseases, Box 30.001 NL-9700-RB, University Medical Center Groningen, Groningen, The Netherlands.
Dr. Timens: Department of Pathology, Box 30.001 NL-9700-RB, University Medical Center Groningen, Groningen, The Netherlands.
Dr. Sterk: Department of Respiratory Medicine, F5-259, Academic Medical Centre, University of Amsterdam, Box 22700, NL-1100 DE, Amsterdam, The Netherlands.
Author Contributions: Conception and design: J.B. Snoeck-Stroband, H.A. Thiadens, H.M. Boezen, N.H.T. ten Hacken, J.K. Sont, H.A.M. Kerstjens, P.S. Hiemstra, W. Timens, D.S. Postma, P.J. Sterk.
Analysis and interpretation of the data: T.S. Lapperre, J.B. Snoeck-Stroband, D.F. Jansen, H.A. Thiadens, J.M. Vonk, H.M. Boezen, N.H.T. ten Hacken, J.K. Sont, K.F. Rabe, H.A.M. Kerstjens, P.S. Hiemstra, W. Timens, D.S. Postma.
Drafting of the article: T.S. Lapperre, J.B. Snoeck-Stroband, M.M.E. Gosman, D.F. Jansen, H.M. Boezen, J.K. Sont, K.F. Rabe, P.S. Hiemstra, W. Timens, D.S. Postma, P.J. Sterk.
Critical revision of the article for important intellectual content: T.S. Lapperre, J.B. Snoeck-Stroband, M.M.E. Gosman, H.A. Thiadens, J.M. Vonk, N.H.T. ten Hacken, K.F. Rabe, H.A.M. Kerstjens, P.S. Hiemstra, W. Timens, D.S. Postma, P.J. Sterk.
Final approval of the article: T.S. Lapperre, J.B. Snoeck-Stroband, M.M.E. Gosman, D.F. Jansen, H.A. Thiadens, J.M. Vonk, H.M. Boezen, N.H.T. ten Hacken, J.K. Sont, K.F. Rabe, H.A.M. Kerstjens, P.S. Hiemstra, W. Timens, D.S. Postma, P.J. Sterk.
Provision of study materials or patients: T.S. Lapperre, J.B. Snoeck-Stroband, N.H.T. ten Hacken, K.F. Rabe, H.A.M. Kerstjens, D.S. Postma.
Statistical expertise: T.S. Lapperre, J.B. Snoeck-Stroband, D.F. Jansen, J.M. Vonk, H.M. Boezen, J.K. Sont, D.S. Postma.
Obtaining of funding: P.S. Hiemstra, W. Timens, D.S. Postma, P.J. Sterk.
Administrative, technical, or logistic support: T.S. Lapperre, J.B. Snoeck-Stroband, H.M. Boezen, K.F. Rabe, H.A.M. Kerstjens, D.S. Postma.
Collection and assembly of data: T.S. Lapperre, J.B. Snoeck-Stroband, M.M.E. Gosman, A. van Schadewijk, H.A. Thiadens, J.M. Vonk, N.H.T. ten Hacken, J.K. Sont, K.F. Rabe, P.S. Hiemstra, W. Timens, D.S. Postma.
↵* For a complete list of the GLUCOLD Study Group investigators, see the Appendix.