Inhaled steroids and mortality in COPD: bias from unaccounted immortal time

A recent observational study, which suggested that inhaled corticosteroids (ICS) with or without long-acting bronchodilators are effective at reducing all-cause mortality in chronic obstructive pulmonary disease (COPD) patients, may be subject to immortal time bias. This bias was assessed using a population-based cohort of 3,524 newly treated COPD patients from Saskatchewan, Canada, observed from 1990-1999. Regular users of bronchodilators or ICS were followed for 3 yrs, during which time 860 deaths occurred. Cox's proportional hazards model was used to compare the hierarchical intention-to-treat approach employed in the recent study, a technique subject to bias from two sources of immortal time, with the conventional intention-to-treat approach and the according-to-treatment approach. The adjusted rate ratio of death using the hierarchical intention-to-treat approach was 0.66 (95%) confidence interval (CI) 0.57-0.76) for ICS use relative to bronchodilator use, compared with 0.75 (95% CI 0.62-0.90) with the conventional intention-to-treat approach. Conversely, the rate ratio was 0.94 (95% CI 0.81-1.09) with the according-to-treatment approach, which accounts for both sources of immortal time. In this study, regular inhaled corticosteroid use in chronic obstructive pulmonary disease was not found to reduce all-cause mortality. Suggestion of this benefit from a previous observational study is the result of bias from unaccounted immortal time in its cohort design and analysis.