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Published ahead of print on May 18, 2005, doi:10.1164/rccm.200502-210OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 4, August 2005, 460-464

A more recent version of this article appeared on August 15, 2005
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Submitted on February 10, 2005
Accepted on May 11, 2005

Inhaled Corticosteroids in COPD: Results from Two Observational Designs Free of Immortal-time Bias

Victor A Kiri1*, Neil B Pride2, Joan B Soriano3, and Jorgen Vestbo4

1 Worldwide Epidemiology, GlaxoSmithKline, London, Middlesex, United Kingdom; National Centre for Health Outcomes Development, London School of Hygiene and Tropical Medicine, London, United Kingdom, 2 National Heart and Lung Institute, Thoracic Medicine, Imperial College, London, United Kingdom, 3 Worldwide Epidemiology, GlaxoSmithKline, Upper Providence, PA, USA; Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, 4 Nort West Lung Centre, South Manchester University Hospital Trust, Manchester, United Kingdom; Department of Heart and Lung Diseases, Hvidovre Hospital, Hvidovre, Denmark

* To whom correspondence should be addressed. E-mail: Victor.A.Kiri{at}gsk.com.

Rationale: Recent cohort studies in 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 COPD patients followed for a year from COPD discharge with two designs free of any immortal-time in the General Practice Research Database (GPRD) in the UK. 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 4 non-cases 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 (HR) 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 six-month: HR of 0.71 (0.56-0.90). Conclusions: We conclude that immortal-time bias can not account for the risk reduction associated with ICS exposure in observational studies.
Key words: epidemiologic methods, immortal time bias, propensity scores-matched cohort, nested case-control design, time-dependent model




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