Journal of General Internal Medicine

, Volume 21, Issue 10, pp 1011–1019 | Cite as

Meta-analysis: Anticholinergics, but not β-agonists, reduce severe exacerbations and respiratory mortality in COPD

  • Shelley R. Salpeter
  • Nicholas S. Buckley
  • Edwin E. Salpeter
Original Articles


BACKGROUND: Anticholinergics and β2-agonists have generally been considered equivalent choices for bronchodilation in chronic obstructive pulmonary disease (COPD).

OBJECTIVE: To assess the safety and efficacy of anticholinergics and β2-agonists in COPD.

DESIGN: We comprehensively searched electronic databases from 1966 to December 2005, clinical trial websites, and references from selected reviews. We included randomized controlled trials of at least 3 months duration that evaluated anticholinergic or β2-agonist use compared with placebo or each other in patients with COPD.

MEASUREMENTS: We evaluated the relative risk (RR) of exacerbations requiring withdrawal from the trial, severe exacerbations requiring hospitalization, and deaths attributed to a lower respiratory event.

RESULTS: Pooled results from 22 trials with 15,276 participants found that anticholinergic use significantly reduced severe exacerbations (RR 0.67, confidence interval [CI] 0.53 to 0.86) and respiratory deaths (RR 0.27, CI 0.09 to 0.81) compared with placebo. β2-Agonist use did not affect severe exacerbations (RR 1.08, CI 0.61 to 1.95) but resulted in a significantly increased rate of respiratory deaths (RR 2.47, CI 1.12 to 5.45) compared with placebo. There was a 2-fold increased risk for severe exacerbations associated with β2-agonists compared with anticholinergics (RR 1.95, CI 1.39 to 2.93). The addition of β2-agonist to anticholinergic use did not improve any clinical outcomes.

CONCLUSION: Inhaled anticholinergics significantly reduced severe exacerbations and respiratory deaths in patients with COPD, while β2-agonists were associated with an increased risk for respiratory deaths. This suggests that anticholinergics should be the bronchodilator of choice in patients with COPD, and β2-agonists may be associated with worsening of disease control.

Key words

chronic obstructive pulmonary disease COPD adrenergic β-agonists cholinergic antagonists muscarinic antagonists meta-analysis clinical outcomes mortality 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932–46.PubMedGoogle Scholar
  2. 2.
    Agusti AG. COPD, a multicomponent disease: implications for management. Respir Med. 2005;99:670–82.PubMedCrossRefGoogle Scholar
  3. 3.
    McCrory DC, Brown CD, Gelfand SE, Bach PB. Management of acute exacerbations of COPD A summary and appraisal of published evidence. Chest. 2001;119:1190–209.PubMedCrossRefGoogle Scholar
  4. 4.
    U.S. Department of Health and Human Services. COPD data fact sheet. NIH publication No. 03-5229. 2003.Google Scholar
  5. 5.
    Gan WQ, Man SF, Sin DD. Effects of inhaled corticosteroids on sputum cell counts in stable chronic obstructive pulmonary disease: a systematic review and a meta-analysis. BMC Pulm Med. 2005;5:3.PubMedCrossRefGoogle Scholar
  6. 6.
    Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med. 2002;113:59–65.PubMedCrossRefGoogle Scholar
  7. 7.
    van Grunsven PM, van Schayck CP, Derenne JP, et al. Long term effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis. Thorax. 1999;54:7–14.PubMedGoogle Scholar
  8. 8.
    Sutherland ER, Allmers H, Ayas NT, Venn AJ, Martin RJ. Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis. Thorax. 2003;58:937–41.PubMedCrossRefGoogle Scholar
  9. 9.
    Sin DD, Lacy P, York E, Man SF. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170:760–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Barnes PJ. The role of anticholinergics in chronic obstructive pulmonary disease. Am J Med. 2004;117(Suppl 12A):24S-32S.PubMedGoogle Scholar
  11. 11.
    Donohue JF, Menjoge S, Kesten S. Tolerance to bronchodilating effects of salmeterol in COPD. Respir Med. 2003;97:1014–20.PubMedCrossRefGoogle Scholar
  12. 12.
    Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax. 2003;58:399–404.PubMedCrossRefGoogle Scholar
  13. 13.
    Tashkin DP, Ashutosh K, Bleecker ER, et al. Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. A 90-day multi-center study. Am J Med. 1986;81:81–90.PubMedCrossRefGoogle Scholar
  14. 14.
    van Schayck CP, Graafsma SJ, Visch MB, Dompeling E, van Weel C, van Herwaarden CL. Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by subsensitization to salbutamol. J Allergy Clin Immunol. 1990;86:793–800.PubMedCrossRefGoogle Scholar
  15. 15.
    Rennard SI, Serby CW, Ghafouri M, Johnson PA, Friedman M. Extended therapy with ipratropium is associated with improved lung function in patients with COPD. A retrospective analysis of data from seven clinical trials. Chest. 1996;110:62–70.PubMedGoogle Scholar
  16. 16.
    Ashutosh K, Lang H. Comparison between long-term treatment of chronic bronchitic airway obstruction with ipratropium bromide and metaproterenol. Ann Allergy. 1984;53:401–6.PubMedGoogle Scholar
  17. 17.
    Tashkin DP. Is a long-acting inhaled bronchodilator the first agent to use in stable chronic obstructive pulmonary disease? Curr Opin Pulm Med. 2005;11:121–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Sestini P, Renzoni E, Robinson S, Poole P, Ram FS. Short-acting beta 2 agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2002(4): CD001495.Google Scholar
  19. 19.
    U.S. Food and Drug Administration. Labeling changes for drug products that contain salmeterol. FDA Talk Paper. 2003: T03-62.Google Scholar
  20. 20.
    U.S. Food and Drug Administration. Study of asthma-drug halted. FDA Talk Paper 2003: T03-06.Google Scholar
  21. 21.
    U.S. Food and Drug Administration. Division of Pulmonary and Allergy Drug Products Medical Officer Review. Salmeterol. 2005.Google Scholar
  22. 22.
    Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular beta2-agonist use in patients with asthma. Ann Intern Med. 2004;140:802–13.PubMedGoogle Scholar
  23. 23.
    Kraan J, Koeter GH, vd Mark TW, Sluiter HJ, de Vries K. Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. J Allergy Clin Immunol. 1985;76:628–36.PubMedCrossRefGoogle Scholar
  24. 24.
    Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet. 1990;336:1391–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Lipworth BJ. Risks versus benefits of inhaled beta 2-agonists in the management of asthma. Drug Safety. 1992;7:54–70.PubMedCrossRefGoogle Scholar
  26. 26.
    Sovani MP, Whale CI, Tattersfield A. A benefit-risk assessment of inhaled long-acting beta2-agonists in the management of obstructive pulmonary disease. Drug Safety. 2004;27:689–715.PubMedCrossRefGoogle Scholar
  27. 27.
    Suissa S, Blais L, Ernst P. Patterns of increasing beta-agonist use and the risk of fatal or near-fatal asthma. Eur Respir J. 1994;7:1602–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Au DH, Curtis JR, Psaty BM. Risk of myocardial ischaemia and beta-adrenoceptor agonists. Ann Med. 2001;33:287–90.PubMedGoogle Scholar
  29. 29.
    Salpeter SR. Cardiovascular safety of beta(2)-adrenoceptor agonist use in patients with obstructive airway disease: a systematic review. Drugs Aging. 2004;21:405–14.PubMedCrossRefGoogle Scholar
  30. 30.
    Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis. Chest. 2004;125:2309–21.PubMedCrossRefGoogle Scholar
  31. 31.
    U.S. Food and Drug Administration Advisory Committee. Serevent, Advair, Foradil withdrawals to be considered by Advisory Committee. 2005.Google Scholar
  32. 32.
    Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Long-acting beta-agonists increase severe asthma exacerbations and asthma-related deaths: meta-analysis of randomized controlled trials. Ann Intern Med. 2006; in press.Google Scholar
  33. 33.
    National Collaborating Centre for Chronic Conditions. Chronic obstructive pulmonary disease National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax. 2004;59(Suppl 1):1–232.Google Scholar
  34. 34.
    Cooper CB, Tashkin DP. Recent developments in inhaled therapy in stable chronic obstructive pulmonary disease. BMJ. 2005;330:640–4.PubMedCrossRefGoogle Scholar
  35. 35.
    Sin DD, McAlister FA, Man SF, Anthonisen NR. Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA. 2003;290:2301–12.PubMedCrossRefGoogle Scholar
  36. 36.
    Tashkin DP, Cooper CB. The role of long-acting bronchodilators in the management of stable COPD. Chest. 2004;125:249–59.PubMedCrossRefGoogle Scholar
  37. 37.
    Pakes GE, Brogden RN, Heel RC, Speight TM, Avery GS. Ipratropium bromide: a review of its pharmacological properties and therapeutic efficacy in asthma and chronic bronchitis. Drugs. 1980;20:237–66.PubMedCrossRefGoogle Scholar
  38. 38.
    Karpel JP. Bronchodilator responses to anticholinergic and beta-adrenergic agents in acute and stable COPD. Chest. 1991;99:871–6.PubMedCrossRefGoogle Scholar
  39. 39.
    McCrory DC, Brown CD. Inhaled short-acting beta2-agonists versus ipratropium for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2001(2): CD002984.Google Scholar
  40. 40.
    Ramsey SD. Suboptimal medical therapy in COPD: exploring the causes and consequences. Chest. 2000;117(2 Suppl):33S-7S.PubMedCrossRefGoogle Scholar
  41. 41.
    Rudolf M. The reality of drug use in COPD: the European perspective. Chest. 2000;117(2 Suppl):29S-32S.PubMedCrossRefGoogle Scholar
  42. 42.
    Roche N, Lepage T, Bourcereau J, Terrioux P. Guidelines versus clinical practice in the treatment of chronic obstructive pulmonary disease. Eur Respir J. 2001;18:903–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Jadad AR, Moore A, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ. Assessing the quality or reports of randomized clinical trials. Control Clin Trials. 1996;17:1–12.PubMedCrossRefGoogle Scholar
  44. 44.
    Schultz KF, Chalmers I, Hayes RG, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408–12.CrossRefGoogle Scholar
  45. 45.
    Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.PubMedGoogle Scholar
  46. 46.
    Aalbers R, Ayres J, Backer V, et al. Formoterol in patients with chronic obstructive pulmonary disease: a randomized, controlled, 3-month trial. Eur Respir J. 2002;19:936–43.PubMedCrossRefGoogle Scholar
  47. 47.
    Anthonisen NR, Connett JE, Enright PL, Manfreda J. Hospitalization and mortality in the lung health study. Am J Respir Crit Care Med. 2002;166:333–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Boyd G. Salmeterol xinafooate in asthmatic patients under consideration for maintenance oral corticosteroid therapy. UK study group. Eur Respir J. 1995;8:1494–8.PubMedGoogle Scholar
  49. 49.
    Calverley PM, Boonsawat W, Csake Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003;22:912–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Casaburi R, Briggs DD Jr,Donohue JF, Serby CW, Menjoge SS, Witek TJ Jr. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial The US tiotropium study group. Chest. 2000;118:1294–302.PubMedCrossRefGoogle Scholar
  51. 51.
    Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002;19:217–24.PubMedCrossRefGoogle Scholar
  52. 52.
    Chapman KR, Arvidsson P, Chuchalin AG, et al. The addition of salmeterol 50 microg bid to anticholinergic treatment in patients with COPD: a randomized, placebo controlled trial. Chronic obstructive pulmonary disease. Can Respir J. 2002;9:178–85.PubMedGoogle Scholar
  53. 53.
    Colice GL. Nebulized bronchodilators for outpatient management of stable chronic obstructive pulmonary disease. Am J Med. 1996;100:11S-18S.PubMedCrossRefGoogle Scholar
  54. 54.
    Combivent Inhalation Solution Study Group. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. The COMBIVENT inhalation solution study group. Chest. 1997;112:1514–21.Google Scholar
  55. 55.
    Cook D, Guyatt G, Wong E, et al. Regular versus as-needed short-acting inhaled beta-agonist therapy for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163:85–90.PubMedGoogle Scholar
  56. 56.
    Donohue JF, van Noord JA, Bateman ED, et al. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest. 2002;122:47–55.PubMedCrossRefGoogle Scholar
  57. 57.
    Friedman M, Serby CW, Menjoge SS, Wilson JD, Hilleman DE, Witek TJ Jr. Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest. 1999;115:635–41.PubMedCrossRefGoogle Scholar
  58. 58.
    Mahler DA, Wire P, Horstman D, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;166:1084–91.PubMedCrossRefGoogle Scholar
  59. 59.
    Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med. 2005;143:317–26.PubMedGoogle Scholar
  60. 60.
    Rossi A, Kristufek P, Levine BE, et al. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Chest. 2002;121:1058–69.PubMedCrossRefGoogle Scholar
  61. 61.
    Rutten-van Molken M, Roos B, Van Noord JA. An empirical comparison of the St George’s Respiratory Questionnaire (SGRQ) and the Chronic Respiratory Disease Questionnaire (CRQ) in a clinical trial setting. Thorax. 1999;54:995–1003.PubMedCrossRefGoogle Scholar
  62. 62.
    Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J. 2003;21:74–81.PubMedCrossRefGoogle Scholar
  63. 63.
    Taylor J, Kotch A, Rice K, et al. Ipratropium bromide hydrofluoroalkane inhalation aerosol is safe and effective in patients with COPD. Chest. 2001;120:1253–61.PubMedCrossRefGoogle Scholar
  64. 64.
    van Noord JA, de Munck DR, Bantje TA, Hop WC, Akveld ML, Bommer AM. Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Eur Respir J. 2000;15:878–85.PubMedCrossRefGoogle Scholar
  65. 65.
    Wadbo M, Lofdahl CG, Larsson K, et al. Effects of formoterol and ipratropium bromide in COPD: a 3-month placebo-controlled study. Eur Respir J. 2002;20:1138–46.PubMedCrossRefGoogle Scholar
  66. 66.
    Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003;361:449–56.PubMedCrossRefGoogle Scholar
  67. 67.
    Calverley PM, Boonsawat W, Zhong N, Peterson S, Olsson H. Author’s correction: maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003;24:1075.Google Scholar
  68. 68.
    Appleton S, Poole S, Smith B, Veale A, Bara A. Long-acting beta2-agonists for chronic obstructive pulmonary disease patients with poorly reversible air-flow limitation. Cochrane Database Syst Rev. 2002(3):CD001104.Google Scholar
  69. 69.
    U.S. Food and Drug Administration. NDA 21-395 Clinical briefing document. Spiriva (Tiotropium bromide) inhalation powder for COPD. 2002.Google Scholar
  70. 70.
    Vincken W, van Noord JA, Greefhorst AP, et al. Improved health outcomes in patients with COPD during 1 yr’s treatment with tiotropium. Eur Respir J. 2002;19:209–16.PubMedCrossRefGoogle Scholar
  71. 71.
    Oostenbrink JB, Rutten-van Molken MP, Al MJ, Van Noord JA, Vincken W. One-year cost-effectiveness of tiotropium versus ipratropium to treat chronic obstructive pulmonary disease. Eur Respir J. 2004;23:241–9.PubMedCrossRefGoogle Scholar

Copyright information

© Society of General Internal Medicine 2006

Authors and Affiliations

  • Shelley R. Salpeter
    • 1
    • 2
  • Nicholas S. Buckley
    • 3
  • Edwin E. Salpeter
    • 4
  1. 1.Department of MedicineStanford University School of MedicineStanfordUSA
  2. 2.Department of MedicineSanta Clara Valley Medical CenterSan JoseUSA
  3. 3.International Baccalaureate ProgramSequoia High SchoolRedwood CityUSA
  4. 4.Center for Radiophysics and Space ResearchCornell UniversityIthacaUSA

Personalised recommendations