Bias in observational study of the effectiveness of nasal corticosteroids in asthma

Background: A recent observational study suggests that intranasal corticosteroids used to treat allergic rhinitis are effective at preventing asthma outcomes, such as emergency visits. The approach to data analysis may have led to biased results because of misclassification of immortal time. Objective: To illustrate the bias in the cohort approach and to present the proper time-dependent analysis by replicating the recent study using data from another source. Methods: From an existing cohort of 30,569 patients with asthma age 5 to 44 years and identified from the Saskatchewan Health databases (1975-1997), we formed the cohort of all subjects who were in the source population between January 1, 1989, and December 31, 1991. Subjects were followed to the first asthma hospitalization. All prescriptions dispensed during follow-up were identified. We replicated the time-fixed approach to data analysis used in the recent study and compared it with time-dependent approaches. Results: The cohort included 20,173 subjects, of whom 1849 were hospitalized for asthma between January 1, 1989, and December 31, 1991. The time-fixed approach misclassified more than 5000 person-years of follow-up, corresponding to 44% of the exposed person-time. As a result, the rate ratio of asthma hospitalization after any use of nasal corticosteroids (NCSs) was 0.57 by the biased time-fixed approach compared with 1.13 by the proper time-dependent approach. The time-fixed approach produced a paradoxical protective effect of NCS with I or less canisters dispensed per year (odds ratio, 0.47), which was further exaggerated when the cohort was extended to 5 years (odds ratio, 0.33). Adjusted time-dependent analyses found no protective effect, even when NCSs were dispensed regularly (rate ratio, 1.10; 95% CI, 0.54-2.21). Conclusion: The time-fixed approach to the analysis of the effectiveness of NCSs on asthma outcomes leads, by its inherent misclassification of immortal time, to a considerable exaggeration of the protective effect of these medications in preventing severe asthma exacerbations.