Aspirin for primary prevention of cardiovascular mortality: smoking exposure as a potential effect modifier—a cotinine‑based observational analysis

Serum cotinine, an objective biomarker of tobacco smoke exposure, may modify the association between regular aspirin use and atherosclerotic cardiovascular disease (ASCVD) mortality in primary prevention, but this hypothesis has not been adequately tested. We analyzed nationally representative data from NHANES 2011–2018, including 6732 adults aged ≥ 40 years without prior cardiovascular events. Regular aspirin use was defined as ≥ 15 days/month, serum cotinine was measured by mass spectrometry, and the primary outcome was ASCVD mortality. Weighted Cox models assessed associations with interaction terms for aspirin use × smoking status and aspirin use × log‑cotinine. Aspirin use was associated with improved survival in current smokers (fully adjusted HR = 0.15, 95% CI 0.03–0.76), but with worse survival in never smokers (HR = 1.86, 95% CI 1.12–3.10), and a null association in former smokers (HR = 1.65, 95% CI 0.75–3.65). A graded risk attenuation was observed across increasing cotinine tertiles ( p for linear interaction = 0.013). Significant interactions were found for both smoking status ( p < 0.05) and continuous log‑cotinine ( p = 0.009), and sensitivity analyses confirmed robustness. In conclusion, smoking exposure objectively quantified by serum cotinine significantly modifies the observed aspirin–ASCVD mortality association in this observational analysis; biomarker‑informed stratification may offer a framework for hypothesis generation, but prospective validation in randomized trials is essential before any clinical application can be considered.