Impact of drug exposure definitions on observed associations in pharmacoepidemiology research

Abstract

BACKGROUND A variety of methods used to define exposure in pharmacoepidemiological studies. Although each method has known biases, the relative effect of these biases on an observed association has not been fully examined. OBJECTIVE To explore the influence of different exposure definitions on estimates, using the association between metformin and all-cause mortality as a proto-typical model. METHODS New users of oral anti-hyperglycemic drugs identified using administrative health databases from Alberta, Canada between 1998 and 2010. Drug exposure was described using definitions that are commonly used in observational studies. All analyses included the same covariates of age, gender, and a comorbidity score, and subjects not exposed to metformin served as the reference group. The measure of association assessed using a Cox Proportional Hazards model for cohort studies and conditional logistic regression for case-control studies. RESULTS We identified 64,293 new oral anti-hyperglycemic drugs users; mean age 68.9 years, 33,131 (52%) males, and 24,745 (39%) deaths during a mean follow-up of 6 years. In adjusted models, the association between metformin and mortality ranged from 0.23 (95% CI 0.22–0.25) to 0.96 (95% CI 0.93–0.99). Most metformin exposure definitions, however, provided estimates in the 0.6–0.8 reduction range, aligning with the results of previous observational studies. CONCLUSIONS The variety of exposure definitions tested in this analysis produced a wide range of associations between metformin and mortality risk. Therefore, pharmacoepidemiological studies should include sensitivity analyses using at least two exposure definitions with complementary risks of bias to improve the validity of study results.