Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis.

CONTEXT Recent studies of inhaled corticosteroid (ICS) therapy for managing stable chronic obstructive pulmonary disease (COPD) have yielded conflicting results regarding survival and risk of adverse events. OBJECTIVE To systematically review and quantitatively synthesize the effects of ICS therapy on mortality and adverse events in patients with stable COPD. DATA SOURCES Search of MEDLINE, CENTRAL, EMBASE, CINAHL, Web of Science, and PsychInfo through February 9, 2008. STUDY SELECTION Eligible studies were double-blind, randomized controlled trials comparing ICS therapy for 6 or more months with nonsteroid inhaled therapy in patients with COPD. DATA EXTRACTION Two authors independently abstracted data including study characteristics, all-cause mortality, pneumonia, and bone fractures. The I(2) statistic was used to assess heterogeneity. Study-level data were pooled using a random-effects model (when I(2) > or = 50%) or a fixed-effects model (when I(2) < 50%). For the primary outcome of all-cause mortality at 1 year, our meta-analysis was powered to detect a 1.0% absolute difference in mortality, assuming a 2-sided alpha of .05 and power of 0.80. RESULTS Eleven eligible randomized controlled trials (14,426 participants) were included. In trials with mortality data, no difference was observed in 1-year all-cause mortality (128 deaths among 4636 patients in the treatment group and 148 deaths among 4597 patients in the control group; relative risk [RR], 0.86; 95% confidence interval [CI], 0.68-1.09; P = .20; I(2) = 0%). In the trials with data on pneumonia, ICS therapy was associated with a significantly higher incidence of pneumonia (777 cases among 5405 patients in the treatment group and 561 cases among 5371 patients in the control group; RR, 1.34; 95% CI, 1.03-1.75; P = .03; I(2) = 72%). Subgroup analyses indicated an increased risk of pneumonia in the following subgroups: highest ICS dose (RR, 1.46; 95% CI, 1.10-1.92; P = .008; I(2) = 78%), shorter duration of ICS use (RR, 2.12; 95% CI, 1.47-3.05; P < .001; I(2) = 0%), lowest baseline forced expiratory volume in the first second of expiration (RR, 1.90; 95% CI, 1.26-2.85; P = .002; I(2) = 0%), and combined ICS and bronchodilator therapy (RR, 1.57; 95% CI, 1.35-1.82; P < .001; I(2) = 24%). CONCLUSIONS Among patients with COPD, ICS therapy does not affect 1-year all-cause mortality. ICS therapy is associated with a higher risk of pneumonia. Future studies should determine whether specific subsets of patients with COPD benefit from ICS therapy.

[1]  T. Seemungal,et al.  The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. , 2008, American journal of respiratory and critical care medicine.

[2]  J. R. Landis,et al.  The measurement of observer agreement for categorical data. , 1977, Biometrics.

[3]  Melonie P. Heron,et al.  Deaths: leading causes for 2003. , 2007, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[4]  I. Olkin,et al.  Improving the quality of reports of meta‐analyses of randomised controlled trials: the QUOROM statement , 2000, Revista espanola de salud publica.

[5]  M Cazzola,et al.  Outcomes for COPD pharmacological trials: From lung function to biomarkers. , 2008, Revista portuguesa de pneumologia.

[6]  Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. , 1980, Annals of internal medicine.

[7]  J. Connett,et al.  Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. , 2000, The New England journal of medicine.

[8]  Cotes Je,et al.  LONG TERM DOMICILIARY OXYGEN THERAPY IN CHRONIC HYPOXIC COR PULMONALE COMPLICATING CHRONIC BRONCHITIS AND EMPHYSEMA Report of the Medical Research Council Working Party , 1981, The Lancet.

[9]  A R Jadad,et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? , 1996, Controlled clinical trials.

[10]  T. Wilt,et al.  Use of spirometry for case finding, diagnosis, and management of chronic obstructive pulmonary disease (COPD). , 2005, Evidence report/technology assessment.

[11]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[12]  M. Woodhead Inhaled corticosteroids cause pneumonia ...or do they? , 2007, American journal of respiratory and critical care medicine.

[13]  D. Postma,et al.  Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. , 1999, The New England journal of medicine.

[14]  D. Wyss,et al.  Synergistic effect of formoterol and mometasone in a mouse model of allergic lung inflammation , 2007, British journal of pharmacology.

[15]  A. Sharafkhaneh,et al.  Update on the pharmacologic therapy for chronic obstructive pulmonary disease. , 2007, Clinics in chest medicine.

[16]  N. Zhong,et al.  The Efficacy and Safety of Combination Salmeterol (50 μg)/Fluticasone Propionate (500 μg) Inhalation Twice Daily Via Accuhaler in Chinese Patients With COPD , 2007 .

[17]  S. Suissa Medications to modify lung function decline in chronic obstructive pulmonary disease: some hopeful signs. , 2008, American journal of respiratory and critical care medicine.

[18]  T. Lasserson,et al.  Combined corticosteroid and long-acting beta-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. , 2007, The Cochrane database of systematic reviews.

[19]  M. Weatherall,et al.  Dose–response relationship for risk of non‐vertebral fracture with inhaled corticosteroids , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[20]  A. Anzueto,et al.  COPD is associated with increased mortality in patients with community-acquired pneumonia , 2006, European Respiratory Journal.

[21]  P. Lange,et al.  Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial , 1999, The Lancet.

[22]  N. Anthonisen,et al.  The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial , 2005 .

[23]  Bartolome Celli,et al.  Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. , 2007, The New England journal of medicine.

[24]  A. Gonzalez,et al.  Inhaled corticosteroid use in chronic obstructive pulmonary disease and the risk of hospitalization for pneumonia. , 2007, American journal of respiratory and critical care medicine.

[25]  C. Begg,et al.  Operating characteristics of a rank correlation test for publication bias. , 1994, Biometrics.

[26]  Michele Tarsilla Cochrane Handbook for Systematic Reviews of Interventions , 2010, Journal of MultiDisciplinary Evaluation.

[27]  L. Boulet,et al.  Ambulatory use of inhaled beta(2)-agonists for the treatment of asthma in Quebec : a population-based utilization review. , 2001, Chest.

[28]  H. Nelson,et al.  Enhanced synergy between fluticasone propionate and salmeterol inhaled from a single inhaler versus separate inhalers. , 2003, The Journal of allergy and clinical immunology.

[29]  M. Cazzola,et al.  To add, or not to add an inhaled corticosteroid in moderate COPD: that is the question. , 2008, Chest.

[30]  R. Hubbard,et al.  Use of inhaled corticosteroids and the risk of fracture. , 2006, Chest.

[31]  I. Olkin,et al.  Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement , 1999, The Lancet.

[32]  L. Mcgarvey,et al.  Inflammation in chronic obstructive pulmonary disease: implications for new treatment strategies. , 2007, Current medicinal chemistry.

[33]  D. Sin,et al.  The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. , 2008, American journal of respiratory and critical care medicine.

[34]  C. Vogelmeier,et al.  Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. , 2007, American journal of respiratory and critical care medicine.

[35]  A. Jemal,et al.  Trends in the leading causes of death in the United States, 1970-2002. , 2005, JAMA.

[36]  T. Lasserson,et al.  Inhaled corticosteroids for stable chronic obstructive pulmonary disease. , 2007, The Cochrane database of systematic reviews.

[37]  Gil C Grimes,et al.  Medications for COPD: a review of effectiveness. , 2007, American family physician.

[38]  N. Zhong,et al.  The efficacy and safety of combination salmeterol (50 microg)/fluticasone propionate (500 microg) inhalation twice daily via accuhaler in Chinese patients with COPD. , 2007, Chest.

[39]  K. Lohr,et al.  Efficacy and Safety of Inhaled Corticosteroids in Patients With COPD: A Systematic Review and Meta-Analysis of Health Outcomes , 2006, The Annals of Family Medicine.

[40]  W. MacNee,et al.  Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper , 2004, European Respiratory Journal.

[41]  P. Calverley,et al.  Maintenance therapy with budesonide and formoterol in chronicobstructive pulmonary disease , 2003, European Respiratory Journal.

[42]  D. Postma,et al.  Long-Term Treatment with Inhaled Budesonide in Persons with Mild Chronic Obstructive Pulmonary Disease Who Continue Smoking , 1999 .

[43]  M. O. Turner Inhaled corticosteroids and pneumonia in COPD: an association looking for evidence. , 2008, American journal of respiratory and critical care medicine.

[44]  R. Sansores,et al.  Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease , 2003, European Respiratory Journal.

[45]  R. Hubbard,et al.  Inhaled corticosteroids and the risk of fracture in chronic obstructive pulmonary disease. , 2007, QJM : monthly journal of the Association of Physicians.

[46]  D. Altman,et al.  Assessing Risk of Bias in Included Studies , 2008 .

[47]  J. Rello,et al.  Implications of COPD in patients admitted to the intensive care unit by community-acquired pneumonia , 2006, European Respiratory Journal.