Methodological issues in therapeutic trials of chronic obstructive pulmonary disease

¹ McGill Pharmacoepidemiology Research Unit, McGill University Health Centre, and the Departments of Epidemiology and Biostatistics and of Medicine, McGill University, Montreal, Canada
² Ottawa Health Research Institute, University of Ottawa, Ontario, Canada

^* To whom correspondence should be addressed. E-mail: samy.suissa{at}clinepi.mcgill.ca.

	Abstract

The recent TORCH randomized trial replicated the findings of previous trials in chronic obstructive pulmonary disease (COPD) on the effectiveness of inhaled corticosteroids (ICS) in reducing exacerbation rates, but not so for mortality. We review methodological issues in these trials, such as patients already receiving ICS before randomization and the absence of follow-up after study drug discontinuation, using data from two trials. Fist, among previous ICS users in the OPTIMAL trial, the hazard ratio of the first exacerbation with inhaled corticosteroids relative to bronchodilators was 0.71 (95%CI:0.53–0.96;P=0.027), while among those not using ICS prior to randomization, it was 1.11 (95%CI:0.69–1.79;P=0.68). Second, the rate ratio of exacerbations with inhaled corticosteroids was 0.78 (95%CI: 0.61–0.99) prior to drug discontinuation 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). We conclude that after proper consideration of various methodological shortcomings in the design and analysis of randomised trials, the effectiveness of inhaled corticosteroids in treating COPD remains doubtful, while the benefit observed with combination therapy may rather be due exclusively to the beneficial effects of the long-acting bronchodilator alone.

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