Association between non-steroidal anti-inflammatory drugs and keratinocyte carcinomas of the skin among participants in the Veterans Affairs Topical Tretinoin Chemoprevention Trial.

PURPOSE: Observational studies have reported significant negative associations between sporadic non-steroidal anti-inflammatory drug (NSAID) use and keratinocyte carcinoma (KC) while reporting null results for regular use. This pattern may be partially explained by the operational expression of NSAID exposure and analytic model assumptions. Our goals were to quantify the association between NSAIDs and KC and to explore the impact of exposure metrics and modeling assumptions on observed associations.

METHODS: We conducted a prospective cohort study by linking data from the Veterans Affairs Topical Tretinoin Chemoprevention Trial and the VA Pharmacy Benefits Management database. NSAID use was categorized according to cyclooxygenase selectivity, timing of initiation, and frequency of use. Data were analyzed using time-varying and time-fixed multivariable-adjusted Cox proportional hazard models [Correction made here after initial online publication]. Simulated null data were generated and analyzed to explore potential biases introduced by the models and the exposure metrics.

RESULTS: During a median follow-up time of 2 years for basal cell carcinoma and 2.5 years for squamous cell carcinoma, 472 occurrences of BCC and 309 occurrences of SCC were observed. Time-fixed analyses of NSAID exposure metrics produced significant negative associations, whereas time-varying analyses produced null results. Analysis of simulated null data revealed the potential for strong bias in the time-fixed analyses.

CONCLUSIONS: This study did not identify a negative association between NSAIDs and KC. The disparity between the time-fixed and the time-varying analyses highlights the extent to which operational definitions of drug exposures and reliance on time-fixed methods may introduce bias.