title: Benefits and risks of adjunctive inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis.
abstract: BACKGROUND
  Several clinical trials have evaluated the benefits associated with adding an inhaled corticosteroid (ICS) to a long-acting bronchodilator in the treatment of severe or very severe (stage III or IV) chronic obstructive pulmonary disease (COPD).
  
  
  OBJECTIVE
  We conducted a meta-analysis to elucidate the benefits and risks associated with adjunctive ICS treatment in patients with severe or very severe COPD.
  
  
  METHODS
  A systematic literature search of MEDLINE, EMBASE, and the Cochrane Collaboration's Central Register of Controlled Clinical Trials (from initiation through April 2008) was conducted by 2 investigators working independently. A search strategy using key medical subject headings and text key words was performed using the Cochrane Collaboration's Highly Sensitive Search Strategy for MEDLINE and the McMaster University Health Information Research Unit EMBASE search strategy. To be included in this meta-analysis, studies had to be randomized controlled trials; compare the use of ICS in combination with long-acting beta-agonists (LABAs) or tiotropium with long-acting bronchodilator monotherapy; include only subjects with COPD and forced expiratory volume in 1 second (FEV(1)) <80% and an FEV(1)/forced vital capacity ratio <70%; follow up patients for a minimum of 24 weeks; and report data on either mortality or exacerbations. We evaluated 3 efficacy end points (exacerbations, mortality, and change in St. George's Respiratory Questionnaire [SGRQ] score), 2 tolerability end points (pneumonia and oral candidiasis), and study withdrawals. Rate ratios and relative risks (RRs) were calculated using a random effects model. Statistical heterogeneity was addressed using the Q statistic and I(2) value. The Egger weighted regression statistic and visual inspection of funnel plots were used to assess publication bias.
  
  
  RESULTS
  A total of 9 studies met the inclusion criteria (N = 7,992 subjects). Seven trials provided exacerbation rates and 8 trials provided data on overall mortality. Change in SGRQ score from baseline was reported in 6 trials while pneumonia and oral candidiasis were reported in 5 and 6 studies, respectively. The incidence of patient withdrawal was reported in 8 studies. Exacerbations (rate ratio, 0.82; 95% CI, 0.72-0.92) and SGRQ score (weighted mean difference, -1.98 points; 95% CI, -2.56 to -1.40) were reduced with adjunctive ICS treatment but mortality was not affected (rate ratio, 0.86; 95% CI, 0.73-1.02). Both pneumonia (RR, 1.68; 95% CI, 1.28-2.21) and oral candidiasis (RR, 2.93; 95% CI, 1.94-4.42) were increased with adjuvant ICS treatment. Patient study withdrawal for any reason (RR, 0.83; 95% CI, 0.74- 0.93) was less likely with adjuvant ICS treatment. On visual inspection of the funnel plots, publication bias could not be ruled out for either efficacy or tolerability end point analysis. However, inspection of the Egger weighted regression statistic suggested the low likelihood of publication bias for all end points.
  
  
  CONCLUSIONS
  Addition of an ICS to a LABA was associated with a reduced risk for exacerbations but an increased risk for pneumonia and oral candidiasis compared with long-acting bronchodilator monotherapy in this meta-analysis of 9 randomized controlled trials. While measured patient-perceived health and well-being increased to a statistically significant level, this did not translate into a clinically meaningful level for all patients with combination treatment. Lower risk of study withdrawal was observed in adjuvant ICS patients. The benefits and risks associated with adjunctive ICS treatment will need to be assessed when making decisions regarding its use.
authors.affiliation: University of Connecticut School of Pharmacy, Storrs, Connecticut, USA.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Sobieraj
authors.forename: C Michael
authors.initials: CM
authors.lastname: White
authors.forename: Craig I
authors.initials: CI
authors.lastname: Coleman
mesh_terms: D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D016032:Randomized Controlled Trials as Topic; D012129:Respiratory Function Tests; D012602:Scopolamine Derivatives / Q000627:therapeutic use; D012720:Severity of Illness Index; D000069447:Tiotropium Bromide
chemical_list: D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D005938:Glucocorticoids; D012602:Scopolamine Derivatives; D000069447:Tiotropium Bromide