Importance of accounting for timing of time‐varying exposures in association studies: Hydrochlorothiazide and non‐melanoma skin cancer

Abstract Purpose Hydrochlorothiazide (HCTZ), a widely prescribed antihypertensive drug with photosensitising properties, has been linked with non‐melanoma skin cancer (NMSC) risk. However, previous analyses did not fully explore if and how the impact of past HCTZ exposures accumulates with prolonged use and/or depends on time elapsed since exposures. Therefore, we used different models to more comprehensively assess how NMSC risk vary with HCTZ exposure, and explore how the results may depend on modeling strategies. Methods We used different parametric models with alternative time‐varying exposure metrics, and the flexible weighted cumulative exposure model (WCE) to estimate associations between HCTZ exposures and NMSC risk in a population‐based cohort of HCTZ users over 65 years old, in the province of Ontario, Canada. Results Among 3844 HCTZ users, 273 developed NMSC during up to 8 years of follow‐up. In parametric models, based on all exposures, increased duration of past HCTZ use was associated with an increase of NMSC risk but cumulative dose showed no systematic association. Yet, WCE results suggested that only exposures taken 2.5–4 years in the past were associated with the current NMSC hazard. This finding led us to re‐define the parametric models, which also confirmed that any HCTZ dose taken outside this time‐window were not systematically associated with NMSC incidence. Conclusions Our analyses illustrate how flexible modeling may yield new insights into complex temporal relationships between a time‐varying drug exposure and risks of adverse events. Duration and recency of antihypertensive agents exposures must be taken into account in evaluating risk and benefits.