Mega trials in COPD--clinical data analysis and design issues

The TORCH and UPLIFT randomised controlled trials have provided important data on the benefits of COPD treatments, but also some lessons in study design and data analysis that we will here review. Firstly, it is fundamental that the study question be answerable by the study design. The question in the TORCH study was aimed at a comparison with 'usual care', but the placebo group was not 'usual care'. Secondly, TORCH and UPLIFT were among the first trials to follow the intent-to-treat principle, fundamental to avoid bias in randomised trials. However, this principle was followed for the mortality outcome, but not for lung function, so that the findings related to lung function decline are subject to bias from regression to the mean. Finally, a re-analysis of the TORCH study (performed to fully exploit the data as a 2 × 2 factorial trial) shows that a mortality benefit is entirely accounted for by the effect of the long-acting beta-agonist salmeterol, with no effect attributable to the inhaled corticosteroid fluticasone component of the combination therapy. Together, these data suggest that long-acting bronchodilators, including anticholinergics such as tiotropium and beta-agonists, are associated with lower mortality of patients with COPD, but not inhaled corticosteroids. With COPD one of the major causes of morbidity and mortality worldwide, mega trials such as TORCH and UPLIFT are much needed, but must achieve the utmost scientific rigour in their design and analysis.