Effect of Vascular Senescence on the Efficacy and Safety of Warfarin: Insights from Rat Models and a Prospective Cohort Study.

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Haobin Li, Jing Liu, Qing Liang, Yan Yu, Guangchun Sun
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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, 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.

血管衰老对华法林疗效和安全性的影响:大鼠模型和前瞻性队列研究的启示。
华法林的治疗范围较窄,需要了解各种影响因素,以便进行个性化用药。以血管硬化和内皮功能障碍为标志的血管衰老对华法林的疗效和安全性的影响尚不明确。根据之前的研究,我们假设血管衰老会增加华法林治疗期间的出血风险。本研究旨在利用动物模型和临床队列探讨这些影响。我们利用 d-半乳糖(D-Gal)、维生素 D 和尼古丁(VDN)建立了大鼠血管衰老和钙化模型。在对模型进行验证后,我们检测了固定华法林剂量(0.20 和 0.35 毫克/千克)下国际标准化比率(INR)的变化。我们发现,血管衰老会导致 INR 值显著升高,增加出血风险。在前瞻性临床队列研究(NCT06428110)中,根据超声波和计算机断层扫描(CT)诊断结果,将调整标准剂量的住院华法林患者分为血管衰老组和对照组。通过倾向评分匹配(PSM)排除混杂因素的影响,我们发现血管衰老组的华法林稳态剂量较低,剂量调整幅度较大,INR超过治疗范围的概率较高。血管衰老组在一年的随访期间往往发生更多出血或血栓栓塞/缺血事件,但没有统计学差异。总之,血管衰老会导致 INR 值不稳定,并增加华法林治疗期间的出血风险,这凸显了在未来的华法林精准治疗中考虑血管衰老的重要性。意义声明 影响华法林疗效的因素很多,但血管衰老的影响仍不清楚。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,血管衰老可能会影响华法林的稳定性,给维持其疗效和安全性带来挑战。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.90
自引率
0.00%
发文量
115
审稿时长
1 months
期刊介绍: A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.
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