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Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease

Results from Two Observational Designs Free of Immortal Time Bias

Worldwide Epidemiology, GlaxoSmithKline, Greenford; National Centre for Health Outcomes Development, and Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine; Thoracic Medicine, National Heart and Lung Institute, Imperial College, London; North West Lung Centre, South Manchester University Hospital Trust, Manchester, United Kingdom; Worldwide Epidemiology, GlaxoSmithKline, Upper Providence; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Department of Heart and Lung Diseases, Hvidovre Hospital, Hvidovre, Denmark

Correspondence and requests for reprints should be addressed to Victor A. Kiri, Ph.D., Worldwide Epidemiology, GlaxoSmithKline R&D, Greenford Road, Greenford, Middlesex UB6 0HE, UK. E-mail: victor.a.kiri{at}gsk.com

Rationale: Recent cohort studies in chronic obstructive pulmonary disease (COPD) have questioned the validity of previously reported associations between inhaled corticosteroids (ICS) and reductions in mortality and rehospitalization in observational studies. Using time-dependent versions of statistical survival models, these studies have suggested immortal time bias as responsible for the proposed beneficial association. Objectives: We explored the extent of this bias in a study of patients with COPD monitored for a year from COPD discharge with two designs free of any immortal time bias in the General Practice Research Database in the United Kingdom. Methods: In Design 1, we used only patients whose treatment status was defined on the same day of discharge to obtain a matched cohort based on propensity scores, which were derived from the patient-level baseline characteristics. In Design 2, we identified all in the study cohort who experienced death or rehospitalization and then matched each case to up to four noncases by randomly sampling from the cohort risk sets without regard to treatment status. Measurements and Main Results: The propensity scores matched cohort analysis of 786 patients without a wait time found a significant risk reduction associated with use of ICS: hazard ratio, 0.69 (95% confidence interval, 0.52–0.93). The matched nested case-control analysis of 2,222 patients, designed without regard to exposure status and hence free of immortal time bias, gave a similar association with exposure to ICS in the last 6-month period: hazard ratio, 0.71 (0.56–0.90). Conclusions: We conclude that immortal time bias cannot account for the risk reduction associated with ICS exposure in observational studies.

Key Words: chronic obstructive pulmonary disease • epidemiologic methods • immortal time bias • nested case-control design • propensity scores matched cohort • time-dependent model

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