title: Methodological issues in therapeutic trials of COPD.
abstract: The recent Towards a Revolution in COPD Health (TORCH) randomised trial replicated the findings of previous trials in chronic obstructive pulmonary disease (COPD) on the apparent effectiveness of inhaled corticosteroids (ICS) in reducing exacerbation rates, but not so for mortality. In the present article, the authors review methodological issues in the TORCH and previous trials, such as patients already receiving ICS before randomisation and the absence of follow-up after study drug discontinuation, using data from two trials. First, among previous ICS users in the Canadian Optimal Therapy of COPD Trial, the hazard ratio of the first exacerbation with ICS relative to bronchodilators was 0.71 (95% confidence interval (CI) 0.53-0.96), while among those not using ICS prior to randomisation, it was 1.11 (95% CI 0.69-1.79). Secondly, the rate ratio of exacerbations with ICS was 0.78 (95% CI 0.61-0.99) prior to drug discontinuation during follow-up and 1.23 (95% CI 0.78-1.95) thereafter. Finally, a 2x2 factorial analysis of the TORCH data found a rate ratio of mortality for the salmeterol component to be 0.83 (95% CI 0.74-0.95), while for the fluticasone component it was 1.00 (95% CI 0.89-1.13). In conclusion, after proper consideration of the various methodological shortcomings in the design and analysis of randomised trials, the effectiveness of inhaled corticosteroids in treating chronic obstructive pulmonary disease remains doubtful, while the benefit observed with combination therapy may be due exclusively to the beneficial effects of the long-acting bronchodilator alone.
authors.affiliation: McGill Pharmacoepidemiology Research Unit, McGill University Health Centre, Montreal, Québec, Canada. samy.suissa@clinepi.mcgill.ca
authors.forename: S
authors.initials: S
authors.lastname: Suissa
authors.forename: P
authors.initials: P
authors.lastname: Ernst
authors.forename: K L
authors.initials: KL
authors.lastname: Vandemheen
authors.forename: S D
authors.initials: SD
authors.lastname: Aaron
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001993:Bronchodilator Agents / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006801:Humans; D053208:Kaplan-Meier Estimate; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012107:Research Design
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents