25‐Hydroxyvitamin D concentrations and risk of venous thromboembolism in the general population with 18 791 participants

Summary Background Vitamin  D has potential antithrombotic effects, suggesting that vitamin  D analogs could be used as adjunctive antithrombotic agents. However, epidemiologic evidence of an association between reduced 25‐hydroxyvitamin  D concentrations and the risk of venous thromboembolism is lacking. Objectives To test the hypothesis that reduced plasma 25‐hydroxyvitamin  D concentrations are associated with an increased risk of venous thromboembolism in the general population. Methods We prospectively studied 18 791 participants from the C openhagen C ity H eart S tudy and the C openhagen G eneral P opulation S tudy. During up to 30 years of follow‐up, 950 participants were diagnosed with venous thromboembolism. Plasma 25‐hydroxyvitamin  D concentrations were adjusted for seasonal variation. Results The cumulative incidence of venous thromboembolism as a function of age increased with decreasing tertiles of seasonally adjusted plasma 25‐hydroxyvitamin  D (log‐rank trend: P  = 4 × 10 −4 ). On comparison of participants in the lowest and the highest tertile of plasma 25‐hydroxyvitamin  D concentrations, the crude risk estimate in a model adjusted for age and sex was a 37% (95% confidence interval [CI] 15–64%) increased risk of venous thromboembolism. The corresponding risk increase in a model adjusted for age, sex, body mass index, smoking and cancer was 26% (95% CI 5–51%), and in a multivariable‐adjusted model also including physical activity, hormone replacement therapy, menopausal status, oral contraception use and lipid‐lowering therapy it was 28% (95% CI 6–53%). Furthermore, corresponding risk increases with attempts to correct for regression dilution bias were 103% (95% CI 37–202%), 70% (95% CI 14–155%) and 73% (95% CI 15–160%) in the three models, respectively. Conclusion In these large general population studies, we observed a stepwise increasing risk of venous thromboembolism with decreasing tertiles of seasonally adjusted plasma 25‐hydroxyvitamin  D concentrations.