Abstract：
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 (D-Gal), vitamin D and nicotine (VDN). 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 increasd 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 (CT) diagnosis. Using propensity score matching (PSM) 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 one 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.
摘要：
华法林,治疗范围狭窄，需要了解个性化用药的各种影响因素。血管衰老,以血管僵硬和内皮功能障碍为标志，对华法林的疗效和安全性影响不明确。根据以前的研究，我们假设血管衰老会增加华法林治疗期间出血的风险.本研究旨在使用动物模型和临床队列探索这些影响。我们使用d-半乳糖（D-Gal）建立了血管衰老和钙化的大鼠模型，维生素D和尼古丁（VDN）。验证模型后，我们检查了固定华法林剂量(0.20和0.35mg/kg)时国际标准化比率(INR)的变化.我们发现血管衰老导致INR值显着升高并增加出血风险。在前瞻性临床队列研究（NCT06428110）中，根据超声和计算机断层扫描（CT）诊断将标准剂量调整的住院华法林患者分为血管衰老组和对照组。使用倾向得分匹配(PSM)来排除混杂因素的影响，我们发现血管衰老组有较低的稳态华法林剂量和较大的剂量调整，INR超过治疗范围的可能性更高。血管衰老组在1年随访期间出现更多出血或血栓栓塞/缺血事件,而没有统计学差异。总之,血管衰老导致INR值不稳定，并增加华法林治疗期间的出血风险，强调在未来精确华法林治疗中考虑血管衰老的重要性。重要声明影响华法林疗效的因素很多，然而,血管衰老的影响尚不清楚。本研究旨在探讨血管衰老对华法林疗效和安全性的影响。通过大鼠模型和临床队列研究，我们的研究结果表明，血管衰老可能会损害华法林的稳定性，在保持其有效性和安全性方面面临挑战。
