Warfarin, with its narrow therapeutic range, requires the understanding of various influencing factors for personalized medication. Vascular senescence, marked by vascular stiffening and endothelial dysfunction, has an unclear effect on the efficacy and safety of warfarin. Based on previous studies, we hypothesized that vascular senescence increases the risk of bleeding during warfarin therapy. This study aimed to explore these effects using animal models and clinical cohorts. We established rat models of vascular senescence and calcification using d-galactose, vitamin D, and nicotine. After validating the models, we examined changes in the international normalized ratio (INR) at fixed warfarin doses (0.20 and 0.35 mg/kg). We found that vascular senescence caused significantly elevated INR values and increased bleeding risk. In the prospective clinical cohort study (NCT06428110), hospitalized warfarin patients with standard dose adjustments were divided into vascular senescence and control groups based on ultrasound and computed tomography diagnosis. Using propensity score matching to exclude the influence of confounding factors, we found that the vascular senescence group had lower steady-state warfarin doses and larger dose adjustments, with a higher probability of INR exceeding the therapeutic range. The vascular senescence group tended to experience more bleeding or thromboembolic/ischemic events during 1 year of follow-up, while there was no statistical difference. In conclusion, vascular senescence leads to unstable INR values and increases higher bleeding risk during warfarin therapy, highlighting the importance of considering vascular senescence in future precision warfarin therapies.

SIGNIFICANCE STATEMENT Many factors influence warfarin efficacy; however, the effect of vascular senescence remains unclear. This study aimed to investigate the effects of vascular senescence on the efficacy and safety of warfarin. Through both rat models and clinical cohort studies, our findings indicated that vascular senescence may compromise the stability of warfarin, presenting challenges in maintaining its efficacy and safety.

This study was sponsored by the Shanghai Municipal Health and Family Planning Commission (202040387, 20194Y0258) and the Fifth People’s Hospital of Shanghai (2020WYZD01).

The authors declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

dx.doi.org/10.1124/jpet.124.002265.

↵This article has supplemental material available at jpet.aspetjournals.org.