Li Hui, He Xiaoshuang, Guan Yingyun, Lu Qiuya, Fang Jie, Bian Xiaolan
Department of Pharmacy Ruijin Hospital, Shanghai Jiaotong University School of Medicine Shanghai China.
Department of Laboratory Medicine Ruijin Hospital, Shanghai Jiaotong University School of Medicine Shanghai China.
J Am Heart Assoc. 2025 Jun 17;14(12):e040698. doi: 10.1161/JAHA.124.040698. Epub 2025 Jun 5.
Rivaroxaban is a first-line agent for venous thromboembolism prophylaxis and treatment. However, its pharmacokinetics, pharmacodynamics, and bleeding risk exhibit significant interindividual variability. Known nongenetic factors alone cannot fully explain this variability, and the impact of genetic polymorphisms remains debated.
From December 29, 2021, to May 11, 2023, 310 patients with venous thromboembolism treated with rivaroxaban were enrolled in this observational study from a tertiary hospital in Shanghai, China, based on predefined criteria. We assessed relationships between rivaroxaban concentrations, anti-Factor Xa levels, and coagulation parameters; examined the impact of 12 genes on concentrations and anti-Factor Xa levels; and followed up for at least 3 months to identify bleeding risk factors.
Rivaroxaban plasma concentration was significantly related to anti-Factor Xa levels (R=0.697), activated partial thromboplastin time (R=0.134), prothrombin time (R=0.123), and international normalized ratio (R=0.116). Peak concentrations were associated with (rs776746, =0.023), ( rs76292544, =0.034), and ( rs1045642, =0.012); trough concentrations were linked to (rs776746, =0.045), (rs76292544, =0.014), and (rs2231142, =0.029); peak anti-Factor Xa levels were associated with (rs1738023, =0.022; rs1738025, =0.035) and (rs7212506, =0.044). However, these genetic associations were not significant after Bonferroni correction. Hemorrhage risk factors were anemia, pulmonary embolism, and the TT genotype of (rs76292544).
Pharmacogenetic monitoring and hemorrhage risk assessment may contribute to optimize its efficacy and safety. Larger-scale, global multicenter clinical trials are required to validate the potential gene loci for testing, including (rs776746), (rs76292544), (rs1045642), and (rs2231124), with particular focus on (rs76292544).
利伐沙班是静脉血栓栓塞预防和治疗的一线药物。然而，其药代动力学、药效学和出血风险存在显著的个体间差异。仅已知的非遗传因素无法完全解释这种差异，基因多态性的影响仍存在争议。
从2021年12月29日至2023年5月11日，根据预先定义的标准，在中国上海一家三级医院对310例接受利伐沙班治疗的静脉血栓栓塞患者进行了这项观察性研究。我们评估了利伐沙班浓度、抗Xa因子水平和凝血参数之间的关系；研究了12个基因对浓度和抗Xa因子水平的影响；并进行了至少3个月的随访以确定出血风险因素。
利伐沙班血浆浓度与抗Xa因子水平（R = 0.697）、活化部分凝血活酶时间（R = 0.134）、凝血酶原时间（R = 0.123）和国际标准化比值（R = 0.116）显著相关。峰值浓度与（rs776746，P = 0.023）、（rs76292544，P = 0.034）和（rs1045642，P = 0.012）相关；谷浓度与（rs776746，P = 0.045）、（rs76292544，P = 0.014）和（rs2231142，P = 0.029）相关；峰值抗Xa因子水平与（rs1738023，P = 0.022；rs1738025，P = 0.035）和（rs7212506，P = 0.044）相关。然而，经过Bonferroni校正后，这些基因关联并不显著。出血风险因素为贫血、肺栓塞和（rs76292544）的TT基因型。
药物遗传学监测和出血风险评估可能有助于优化其疗效和安全性。需要进行更大规模的全球多中心临床试验来验证用于检测的潜在基因位点，包括（rs776746）、（rs76292544）、（rs1045642）和（rs2231124），尤其要关注（rs76292544）。
