0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Articles |

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, the GLUCOLD (Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease) Study Group
[+] Article and Author Information

For a complete list of the GLUCOLD Study Group investigators, see the Appendix.


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


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@lumc.nl). Data set: Available from Dr. Sterk (p.j.sterk@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@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.


Ann Intern Med. 2009;151(8):517-527. doi:10.7326/0003-4819-151-8-200910200-00004
Text Size: A A A

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.

Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

Total number of randomly assigned patients who adhered to therapy (>70% medication use) per treatment group. For each stage of the study (0, 6, and 30 months), we list the number of patients who underwent bronchoscopy among those remaining in the study.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Pathologic outcomes.

Adjusted mean change in log-transformed bronchial cell counts (per 10−7 m2 lamina propria) over time during treatment with fluticasone, 500 µg twice daily, for 30 months; fluticasone, 500 µg twice daily, for 6 months plus placebo for 24 months; fluticasone, 500 µg twice daily, and salmeterol, 50 µg twice daily, for 30 months; and placebo, twice daily, for 30 months in patients with chronic obstructive pulmonary disease. Error bars represent 95% CIs.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Clinical outcomes.

Adjusted mean change and 95% CI over time during treatment with fluticasone, 500 µg twice daily, for 30 months; fluticasone, 500 µg twice daily, for 6 months followed by placebo for 24 months; fluticasone, 500 µg twice daily, and salmeterol, 50 µg twice daily, for 30 months; and placebo, twice daily, for 30 months in patients with moderately severe chronic obstructive pulmonary disease. Changes in methacholine PC20 are expressed as mean doubling doses. CCQ = Chronic COPD [chronic obstructive pulmonary disease] Questionnaire; MRC = Medical Research Council; methacholine PC20 = provocative concentration of methacholine that causes a 20% decrease in FEV1.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Correlation between pathologic and clinical outcomes.

Correlation of changes (30 months minus baseline) in postbronchodilator FEV1 (% predicted) and log-transformed methacholine PC20 with changes in log-transformed CD4+ cell count per 10−7 m2 and changes in log-transformed mast cell numbers per 10−7 m2 in the lamina propria of bronchial biopsies from patients with chronic obstructive pulmonary disease treated with fluticasone or placebo for 30 months. Methacholine PC20 = provocative concentration of methacholine that causes a 20% decrease in FEV1.

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Submit a Comment

Summary for Patients

Effect of Treatment With Fluticasone With and Without Salmeterol on Airway Inflammation and Lung Function in Patients With Chronic Obstructive Pulmonary Disease

The summary below is from the full report titled “Effect of Fluticasone With and Without Salmeterol on Pulmonary Outcomes in Chronic Obstructive Pulmonary Disease. A Randomized Trial.” It is in the 20 October 2009 issue of Annals of Internal Medicine (volume 151, pages 517-527). The authors are T.S. Lapperre, J.B. Snoeck-Stroband, M.M.E. Gosman, D.F. Jansen, A. van Schadewijk, 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, and the GLUCOLD (Groningen Universities Corticosteroids in Obstructive Lung Disease) Study Group.

Read More...

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Related Point of Care
Topic Collections

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)