Skip to main content
SpringerLink
Log in

Effect of roflumilast on chronic obstructive pulmonary disease: a systematic review and meta-analysis

  • Original Article
  • Published:
Irish Journal of Medical Science (1971 -) Aims and scope Submit manuscript

Abstract

Background

Randomized controlled trials (RCTs) of roflumilast effect on chronic obstructive pulmonary disease (COPD) have been reported in the last decade. The current meta-analysis was designed to systematically review and perform meta-analysis of the RCTs of roflumilast treatment in COPD.

Methods

Electronic databases including PubMed, EMBASE, Web of Science, and Cochrane clinical trials database were searched to identify RCTs of roflumilast treatment on COPD. The primary outcomes were effect of roflumilast on pre-bronchodilator FEV1, post-bronchodilator FEV1, and exacerbation rate. Secondary outcomes were effect of roflumilast on airway inflammation and adverse effect.

Results

A total of 11 RCTs were enrolled into the current analysis. Roflumilast significantly improved both pre-bronchodilator FEV1 (standardized difference in mean ± SD was 0.621 ± 0.161; 95% CI 0.306~0.936, p < 0.001) and post-bronchodilator FEV1 (standardized difference in mean ± SD was 0.563 ± 0.149, 95% CI 0.270~0.855, p < 0.001) compared with placebo. Roflumilast also significantly reduced exacerbation of COPD (standardized difference in mean ± SD 0.099 ± 0.020, 95% CI 0.061~0.138; p < 0.001) and suppressed airway inflammation (standardized difference in mean ± SD 1.354 ± 0.260, 95% CI 0.845~1.862, p < 0.001) compared with placebo. However, roflumilast significantly increased adverse effect such as diarrhea (rate ratio 2.945, 95% CI 2.453~3.536, p < 0.001) and weight loss (rate ratio 3.814, 95% CI 3.091~4.707, p < 0.001) compared with placebo.

Conclusion

These findings indicated that roflumilast treatment could improve COPD patients’ lung function and reduce exacerbation, and that inhibition of airway inflammation by roflumilast might contribute to the beneficial effect of PDE-4 inhibitors on COPD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Spurzem JR, Rennard SI (2005) Pathogenesis of COPD. Semin Respir Crit Care Med 26(02):142–153. https://doi.org/10.1055/s-2005-869535

    Article  PubMed  Google Scholar 

  2. Michalski JM, Golden G, Ikari J, Rennard SI (2012) PDE4: a novel target in the treatment of chronic obstructive pulmonary disease. Clin Pharmacol Ther 91(1):134–142. https://doi.org/10.1038/clpt.2011.266

    Article  PubMed  CAS  Google Scholar 

  3. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, Paré PD (2004) The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 350(26):2645–2653. https://doi.org/10.1056/NEJMoa032158

    Article  PubMed  CAS  Google Scholar 

  4. O'Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK (1997) Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV1. Am J Respir Crit Care Med 155(3):852–857. https://doi.org/10.1164/ajrccm.155.3.9117016

    Article  PubMed  CAS  Google Scholar 

  5. Perera WR, Hurst JR, Wilkinson TM et al (2007) Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J 29(3):527–534. https://doi.org/10.1183/09031936.00092506

    Article  PubMed  CAS  Google Scholar 

  6. Vestbo J, Hurd SS, Agusti AG et al (2013) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 187(4):347–365. https://doi.org/10.1164/rccm.201204-0596PP

    Article  PubMed  CAS  Google Scholar 

  7. Gamble E, Grootendorst DC, Brightling CE, Troy S, Qiu Y, Zhu J, Parker D, Matin D, Majumdar S, Vignola AM, Kroegel C, Morell F, Hansel TT, Rennard SI, Compton C, Amit O, Tat T, Edelson J, Pavord ID, Rabe KF, Barnes NC, Jeffery PK (2003) Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 168(8):976–982. https://doi.org/10.1164/rccm.200212-1490OC

    Article  PubMed  Google Scholar 

  8. Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF (2007) Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 62(12):1081–1087. https://doi.org/10.1136/thx.2006.075937

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bateman ED, Rabe KF, Calverley PM et al (2011) Roflumilast with long-acting beta2-agonists for COPD: influence of exacerbation history. Eur Respir J 38(3):553–560. https://doi.org/10.1183/09031936.00178710

    Article  PubMed  CAS  Google Scholar 

  10. Fabbri LM, Calverley PM, Izquierdo-Alonso JL et al (2009) Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 374(9691):695–703. https://doi.org/10.1016/S0140-6736(09)61252-6

    Article  PubMed  CAS  Google Scholar 

  11. Meltzer EO, Chervinsky P, Busse W, Ohta K, Bardin P, Bredenbröker D, Bateman ED (2015) Roflumilast for asthma: efficacy findings in placebo-controlled studies. Pulm Pharmacol Ther 35(Suppl):S20–S27. https://doi.org/10.1016/j.pupt.2015.10.006

    Article  PubMed  CAS  Google Scholar 

  12. Bardin P, Kanniess F, Gauvreau G, Bredenbröker D, Rabe KF (2015) Roflumilast for asthma: efficacy findings in mechanism of action studies. Pulm Pharmacol Ther 35(Suppl):S4–10. https://doi.org/10.1016/j.pupt.2015.08.006

    Article  PubMed  CAS  Google Scholar 

  13. Lee SD, Hui DS, Mahayiddin AA et al (2011) Roflumilast in Asian patients with COPD: a randomized placebo-controlled trial. Respirology 16(8):1249–1257. https://doi.org/10.1111/j.1440-1843.2011.02038.x

    Article  PubMed  Google Scholar 

  14. Wells JM, Jackson PL, Viera L, Bhatt SP, Gautney J, Handley G, King RW, Xu X, Gaggar A, Bailey WC, Dransfield MT, Blalock JE (2015) A randomized, placebo-controlled trial of roflumilast. Effect on proline-glycine-proline and neutrophilic inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 192(8):934–942. https://doi.org/10.1164/rccm.201503-0543OC

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Higgins J, Thompson S, Deeks J, Altman D (2002) Statistical heterogeneity in systematic reviews of clinical trials: a critical appraisal of guidelines and practice. J Health Serv Res Policy 7(1):51–61. https://doi.org/10.1258/1355819021927674

    Article  PubMed  Google Scholar 

  16. Calverley PM, Rabe KF, Goehring UM et al (2009) Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 374(9691):685–694. https://doi.org/10.1016/S0140-6736(09)61255-1

    Article  PubMed  CAS  Google Scholar 

  17. O'Donnell DE, Bredenbroker D, Brose M, Webb KA (2012) Physiological effects of roflumilast at rest and during exercise in COPD. Eur Respir J 39(5):1104–1112. https://doi.org/10.1183/09031936.00096511

    Article  PubMed  CAS  Google Scholar 

  18. Zheng J, Yang J, Zhou X, Zhao L, Hui F, Wang H, Bai C, Chen P, Li H, Kang J, Brose M, Richard F, Goehring UM, Zhong N (2014) Roflumilast for the treatment of COPD in an Asian population: a randomized, double-blind, parallel-group study. Chest 145(1):44–52. https://doi.org/10.1378/chest.13-1252

    Article  PubMed  CAS  Google Scholar 

  19. Martinez FJ, Calverley PM, Goehring UM et al (2015) Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 385(9971):857–866. https://doi.org/10.1016/S0140-6736(14)62410-7

    Article  PubMed  CAS  Google Scholar 

  20. Lee JS, Hong YK, Park TS, Lee SW, Oh YM, Lee SD (2016) Efficacy and safety of roflumilast in Korean patients with COPD. Yonsei Med J 57(4):928–935. https://doi.org/10.3349/ymj.2016.57.4.928

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. de Mey C, Nassr N, Lahu G (2011) No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study. BMC Clin Pharmacol 11(1):7. https://doi.org/10.1186/1472-6904-11-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Rennard SI, Calverley PM, Goehring UM et al (2011) Reduction of exacerbations by the PDE4 inhibitor roflumilast—the importance of defining different subsets of patients with COPD. Respir Res 12(1):18. https://doi.org/10.1186/1465-9921-12-18

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Barnes NC, Saetta M, Rabe KF (2014) Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast. BMC Pulm Med 14(1):9. https://doi.org/10.1186/1471-2466-14-9

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hanania NA, Calverley PM, Dransfield MT et al (2014) Pooled subpopulation analyses of the effects of roflumilast on exacerbations and lung function in COPD. Respir Med 108(2):366–375. https://doi.org/10.1016/j.rmed.2013.09.018

    Article  PubMed  Google Scholar 

  25. Rennard SI, Sun SX, Tourkodimitris S, Rowe P, Goehring UM, Bredenbröker D, Calverley PM (2014) Roflumilast and dyspnea in patients with moderate to very severe chronic obstructive pulmonary disease: a pooled analysis of four clinical trials. Int J Chron Obstruct Pulmon Dis 9:657–673. https://doi.org/10.2147/COPD.S55738

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Samyshkin Y, Kotchie RW, Mork AC et al (2014) Cost-effectiveness of roflumilast as an add-on treatment to long-acting bronchodilators in the treatment of COPD associated with chronic bronchitis in the United Kingdom. Eur J Health Econ 15(1):69–82. https://doi.org/10.1007/s10198-013-0456-5

    Article  PubMed  Google Scholar 

  27. Chong J, Leung B, Poole P (2013) Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev:CD002309

  28. Martinez FJ, Rabe KF, Sethi S, Pizzichini E, McIvor A, Anzueto A, Alagappan VKT, Siddiqui S, Rekeda L, Miller CJ, Zetterstrand S, Reisner C, Rennard SI (2016) Effect of roflumilast and inhaled corticosteroid/long-acting beta2-agonist on chronic obstructive pulmonary disease exacerbations (RE(2)SPOND). A randomized clinical trial. Am J Respir Crit Care Med 194(5):559–567. https://doi.org/10.1164/rccm.201607-1349OC

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This study was supported by the Funds from the Key Discipline of Jiaxing Respiratory Medicine Construction Project (No. 04-Z-11), the Early Diagnosis and Comprehensive Treatment of Lung Cancer Innovation Team Building Project, the Clinical Research Project in Medical Committee of Zhejiang Province (No. 2013ZYC-A89), and the Talent Cultivation in Science and Technology Innovation Project of The First Hospital of Jiaxing (No. 2016-CX-04).

Author information

Author notes

  1. Liu-Fei Shen and Xiao-Dong Lv contributed equally to this work.

Authors and Affiliations

  1. Department of Respiration, The First Hospital of Jiaxing, No. 1882 South Zhonghuan Road, Jiaxing, 314000, China

    Lu-Fei Shen, Xiao-Dong Lv, Wen-Yu Chen, Qi Yang, Zhi-Xian Fang & Wei-Fen Lu

Authors
  1. Lu-Fei Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Dong Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen-Yu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhi-Xian Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei-Fen Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Liu-Fei Shen and Xiao-Dong Lv have made substantial contributions to conception and design of the study; Wen-Yu Chen searched literature; Qi Yang extracted data from the collected literature; Zhi-Xian Fang and Wei-Fen Lu contributed to the analysis of data; Liu-Fei Shen wrote the manuscript; Xiao-Dong Lv revised the manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Wen-Yu Chen or Qi Yang.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shen, LF., Lv, XD., Chen, WY. et al. Effect of roflumilast on chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ir J Med Sci 187, 731–738 (2018). https://doi.org/10.1007/s11845-018-1738-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11845-018-1738-9

Keywords

Search

Navigation