The Role Of Drug Indication On Incidence Rate Heterogeneity: A Large-Scale, Systematic Evaluation Across An International Network Of Observational Databases.

Purpose: Incidence rate estimates are sensitive to a range of factors, including age, sex, and geographical setting (data source). The magnitude of the impact of drug indication on incidence rates remains underexplored. Methods: We conducted an observational cohort study using 13 healthcare databases to estimate the incidence rates of 73 health outcomes across 8 drug classes with multiple indications. We calculated incidence rates for each drug-outcome pair and performed random-effects meta-analyses to pool results across databases. Then, we conducted variance components analysis to find the proportions of variability attributed to database, age, sex, and indication. We reported the median of the variance components across all 73 health outcomes as a measure of the magnitude of differences across indications, age, sex, and database, per drug class. Results: Adjusting for database, age, and sex differences, the drug classes with the highest median VC were trimethoprim (0.49), SGLT-2 inhibitors (0.26), and beta blockers (0.10), while the drug class with the lowest VC was GLP-1 agonists (<0.01). Within each drug class, and adjusting for all other factors, age was frequently the strongest contributor to incidence variation (for 5/8 drug classes, the highest class-wide median VC was the age median VC), followed by database, indication, then biological sex. Conclusion: This study showed that for some drug classes, there exists substantial variation in incidence rates estimates across indications even after accounting for heterogeneity due to age, biological sex, and data source. As many drugs have multiple indications in clinical practice, it may be important to consider drug indication when estimating incidence rates in observational studies for the purpose of patient safety evaluations.