• Shawn D Aaron, Katherine L Vandemheen, Dean Fergusson, François Maltais, Jean Bourbeau, Roger Goldstein, Meyer Balter, Denis O'Donnell, Andrew McIvor, Sat Sharma, Graham Bishop, John Anthony, Robert Cowie, Stephen Field, Andrew Hirsch, Paul Hernandez, Robert Rivington, Jeremy Road, Victor Hoffstein, Richard Hodder, Darcy Marciniuk, David McCormack, George Fox, Gerard Cox, Henry B Prins, Gordon Ford, Dominique Bleskie, Steve Doucette, Irvin Mayers, Kenneth Chapman, Noe Zamel, Mark FitzGerald, and Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium.
• The Ottawa Health Research Institute and University of Ottawa, Ottawa, Ontario, Canada.
• Ann. Intern. Med. 2007 Apr 17; 146 (8): 545555545-55.

BackgroundTreatment 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.ObjectiveTo determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone.DesignRandomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006.Setting27 academic and community medical centers in Canada.Patients449 patients with moderate or severe COPD.Intervention1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol.MeasurementsThe primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics.ResultsThe 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.LimitationsMore 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.ConclusionsAddition 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.

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