00 (95% CI 0.79–1.26), suggesting no such benefit with ICS. Observational Study 2 A variation of this bias was seen in another observational study of inhaled corticosteroids (ICS) in the treatment of chronic obstructive pulmonary disease (COPD), which claimed in its title to present “results from two observational designs free of immortal time bias.”29 This claim turned out to be in fact erroneous and reflected a grave misunderstanding of immortal time bias. The authors identified, from the United Kingdom’s General Research Practice Database (GRPD), the cohort of all 4,398 patients aged 50 years and older Inhibitors,research,lifescience,medical hospitalized for COPD

from 1990 to 1999. Cohort entry was taken as the date of discharge, with 1-year follow-up until readmission to hospital for COPD

or death. Patients were considered exposed to ICS if they received a prescription of ICS on the same day of discharge. Using a propensity Inhibitors,research,lifescience,medical scores matched cohort analysis, the hazard ratio of COPD readmission or death associated with ICS use was 0.69 (95% CI 0.52–0.93), suggesting a significant 31% reduction in this outcome with ICS use. Immortal time bias is Inhibitors,research,lifescience,medical in fact introduced again with the definition of ICS exposure. It is stated that “treatment status was selleck kinase inhibitor defined on the same day of discharge,” so that all 1,091 patients who were prescribed ICS on the day of discharge were correctly classified as ICS-exposed. However, of the remaining 3,307 patients, the non-users of ICS were incorrectly taken as merely the 538 patients “who were never exposed to ICS in their entire (one-year) follow-up period.” To comply with their stated Methods, they Inhibitors,research,lifescience,medical should have used all 3,307 patients from the cohort who were not prescribed ICS on the day of discharge. By excluding the 2,769 patients who were not prescribed

ICS on the day of discharge but received an ICS later in the year of follow-up, the authors excluded a crucial component Inhibitors,research,lifescience,medical of follow-up time which is both unexposed and immortal, thus introducing a significant degree of immortal time bias in the results (Figure 2). Had the authors followed the correct method they described in the paper, namely to use “only patients Ketanserin whose treatment status was defined on the day of discharge,” they would have included all 3,307 such patients in the non-ICS group, and the rate ratio of COPD hospitalization or all-cause death with ICS would have been 1.48, not the reported 0.70.33 Figure 2 Illustration of immortal time bias in the Kiri et al. observational cohort study of inhaled corticosteroids in patients discharged with COPD.29 Observational Study 3 A further variation of this bias was seen in another observational study of ICS in COPD, also conducted using the GRPD.