title: Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
abstract: BACKGROUND
  Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied.
  
  
  OBJECTIVE
  To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone.
  
  
  METHODS
  Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006.
  
  
  METHODS
  27 academic and community medical centers in Canada.
  
  
  METHODS
  449 patients with moderate or severe COPD.
  
  
  METHODS
  1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol.
  
  
  METHODS
  The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics.
  
  
  RESULTS
  The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo.
  
  
  CONCLUSIONS
  More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists.
  
  
  CONCLUSIONS
  Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041.
authors.affiliation: The Ottawa Health Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Aaron
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Vandemheen
authors.forename: Dean
authors.initials: D
authors.lastname: Fergusson
authors.forename: François
authors.initials: F
authors.lastname: Maltais
authors.forename: Jean
authors.initials: J
authors.lastname: Bourbeau
authors.forename: Roger
authors.initials: R
authors.lastname: Goldstein
authors.forename: Meyer
authors.initials: M
authors.lastname: Balter
authors.forename: Denis
authors.initials: D
authors.lastname: O'Donnell
authors.forename: Andrew
authors.initials: A
authors.lastname: McIvor
authors.forename: Sat
authors.initials: S
authors.lastname: Sharma
authors.forename: Graham
authors.initials: G
authors.lastname: Bishop
authors.forename: John
authors.initials: J
authors.lastname: Anthony
authors.forename: Robert
authors.initials: R
authors.lastname: Cowie
authors.forename: Stephen
authors.initials: S
authors.lastname: Field
authors.forename: Andrew
authors.initials: A
authors.lastname: Hirsch
authors.forename: Paul
authors.initials: P
authors.lastname: Hernandez
authors.forename: Robert
authors.initials: R
authors.lastname: Rivington
authors.forename: Jeremy
authors.initials: J
authors.lastname: Road
authors.forename: Victor
authors.initials: V
authors.lastname: Hoffstein
authors.forename: Richard
authors.initials: R
authors.lastname: Hodder
authors.forename: Darcy
authors.initials: D
authors.lastname: Marciniuk
authors.forename: David
authors.initials: D
authors.lastname: McCormack
authors.forename: George
authors.initials: G
authors.lastname: Fox
authors.forename: Gerard
authors.initials: G
authors.lastname: Cox
authors.forename: Henry B
authors.initials: HB
authors.lastname: Prins
authors.forename: Gordon
authors.initials: G
authors.lastname: Ford
authors.forename: Dominique
authors.initials: D
authors.lastname: Bleskie
authors.forename: Steve
authors.initials: S
authors.lastname: Doucette
authors.forename: Irvin
authors.initials: I
authors.lastname: Mayers
authors.forename: Kenneth
authors.initials: K
authors.lastname: Chapman
authors.forename: Noe
authors.initials: N
authors.lastname: Zamel
authors.forename: Mark
authors.initials: M
authors.lastname: FitzGerald
mesh_terms: D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000368:Aged; D000420:Albuterol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000730:Androstadienes / Q000009:adverse effects / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002423:Cause of Death; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D000068298:Fluticasone; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D010349:Patient Compliance; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D011788:Quality of Life; D000068299:Salmeterol Xinafoate; D012602:Scopolamine Derivatives / Q000009:adverse effects / Q000627:therapeutic use*; D000069447:Tiotropium Bromide; D016896:Treatment Outcome
chemical_list: D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D001993:Bronchodilator Agents; D012602:Scopolamine Derivatives; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D000420:Albuterol; D000069447:Tiotropium Bromide