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Irish Journal of Medical Science (1971 -)

, Volume 187, Issue 3, pp 731–738 | Cite as

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

  • Lu-Fei Shen
  • Xiao-Dong Lv
  • Wen-Yu ChenEmail author
  • Qi YangEmail author
  • Zhi-Xian Fang
  • Wei-Fen Lu
Original Article

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.

Keywords

COPD Meta-analysis Roflumilast 

Notes

Authors’ 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.

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).

Compliance with ethical standards

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

  1. 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 CrossRefPubMedGoogle Scholar
  2. 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 CrossRefPubMedGoogle Scholar
  3. 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 CrossRefPubMedGoogle Scholar
  4. 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 CrossRefPubMedGoogle Scholar
  5. 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 CrossRefPubMedGoogle Scholar
  6. 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 CrossRefPubMedGoogle Scholar
  7. 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 CrossRefPubMedGoogle Scholar
  8. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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 CrossRefPubMedGoogle Scholar
  10. 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 CrossRefPubMedGoogle Scholar
  11. 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 CrossRefPubMedGoogle Scholar
  12. 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 CrossRefPubMedGoogle Scholar
  13. 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 CrossRefPubMedGoogle Scholar
  14. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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 CrossRefPubMedGoogle Scholar
  16. 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 CrossRefPubMedGoogle Scholar
  17. 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 CrossRefPubMedGoogle Scholar
  18. 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 CrossRefPubMedGoogle Scholar
  19. 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 CrossRefPubMedGoogle Scholar
  20. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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 CrossRefPubMedGoogle Scholar
  25. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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 CrossRefPubMedGoogle Scholar
  27. 27.
    Chong J, Leung B, Poole P (2013) Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev:CD002309Google Scholar
  28. 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 CrossRefPubMedGoogle Scholar

Copyright information

© Royal Academy of Medicine in Ireland 2018

Authors and Affiliations

  1. 1.Department of RespirationThe First Hospital of JiaxingJiaxingChina

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