Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
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.
Aaron
Shawn D
SD
The Ottawa Health Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
Vandemheen
Katherine L
KL
Fergusson
Dean
D
Maltais
François
F
Bourbeau
Jean
J
Goldstein
Roger
R
Balter
Meyer
M
O'Donnell
Denis
D
McIvor
Andrew
A
Sharma
Sat
S
Bishop
Graham
G
Anthony
John
J
Cowie
Robert
R
Field
Stephen
S
Hirsch
Andrew
A
Hernandez
Paul
P
Rivington
Robert
R
Road
Jeremy
J
Hoffstein
Victor
V
Hodder
Richard
R
Marciniuk
Darcy
D
McCormack
David
D
Fox
George
G
Cox
Gerard
G
Prins
Henry B
HB
Ford
Gordon
G
Bleskie
Dominique
D
Doucette
Steve
S
Mayers
Irvin
I
Chapman
Kenneth
K
Zamel
Noe
N
FitzGerald
Mark
M
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
D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D001993:Bronchodilator Agents; D012602:Scopolamine Derivatives; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D000420:Albuterol; D000069447:Tiotropium Bromide