非瓣膜性房颤合并肾功能不全患者利伐沙班联用药代动力学相互作用致出血的回顾性队列研究

doi:10.19803/j.1672-8629.20240399

摘要/Abstract

摘要： 目的通过筛选真实世界中非瓣膜性房颤（NVAF）合并肾功能不全[15<肌酐清除率（CL_cr）≤60 mL·min^-1]患者联用利伐沙班致出血风险增加的药代动力学相互作用（PK-DDI）药品,以促进临床合理用药。方法通过检索文献（PubMed、Web of Science、中国知网、万方数据、维普网）、说明书、2021年欧洲心律协会指南、Lexicomp数据库总结利伐沙班PK-DDI目录;采用回顾性队列研究,收集2022年11月1日至2023年10月31日在首都医科大学宣武医院住院并服用利伐沙班的NVAF合并肾功能不全患者,根据是否使用利伐沙班PK-DDI药品分为 PK-DDI组和非PK-DDI组。其中PK-DDI药品限定为P-gp和/或CYP3A4抑制剂,随访3个月,比较2组患者有效性和安全性结局。结果共计22类141种药品,根据是否需调整剂量分类,需要禁用、慎用药品65种和无需调整剂量药品76种。研究共纳入患者143例,PK-DDI 组出血发生率高于非PK-DDI组（P<0.05）,PK-DDI 组与非PK-DDI组的缺血性卒中发生率差异无统计学意义（P>0.05）。PK-DDI组主要的出血性事件为临床相关非大出血（8例,61.5%）,用药后30 d内出血发生率为38.7%,涉及药品包含胺碘酮、银杏叶提取物、氟康唑、伏立康唑、奥希替尼。结论利伐沙班PK-DDI涉及多种药品,主要靶点为 P-gp和CYP3A4。肾功能不全患者服用利伐沙班时,联用P-gp和/或CYP3A4抑制剂增加出血风险。利伐沙班应避免与银杏叶提取物、伏立康唑联用。利伐沙班与胺碘酮、氟康唑、奥希替尼联用需严密监测,如凝血酶原时间、抗凝血（Xa）因子水平或利伐沙班血药浓度。

关键词: 利伐沙班, 肾功能不全, 出血, P-gp, CYP3A4, 安全性, 非瓣膜性房颤, 凝血酶原时间, 抗Xa因子

Abstract: Objective To screen the drugs that increase the bleeding risk of pharmacokinetic drug-drug interactions (PK-DDIs) related to rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) and renal insufficiency [15<creatinine clearance(CL_cr)≤60 mL·min^-1] in the real world, and to promote the rational use of drugs in clinical practice. Methods The rivaroxaban PK-DDI catalogue was summarized by searching for the related literature from databases (PubMed, Web of Science, CNKI, Wanfang and VIP), instructions, 2021 European Heart Rhythm Association guidelines, and Lexicomp database. A retrospective cohort study was conducted to investigate NVAF patients with renal insufficiency who were admitted to Xuanwu Hospital of Capital Medical University and took rivaroxaban from November 2022 to October 2023. The patients were divided into the PK-DDI group and non-PK-DDI group. PK-DDI drugs were limited to P-gp and/or CYP3A4 inhibitors, the patients were followed up for 3 months, and the efficacy and safety outcomes of the two groups were compared. Results Sixty-five types of drugs had to be prohibited or used with caution while another 76 types of drugs did not need to be adjusted in dosage. A total of 143 patients were included in the study. The incidence of hemorrhage in the PK-DDI group was higher than in the non-PK-DDI group (P<0.05), but there was no significant difference in the incidence of ischemic stroke between the two groups (P>0.05). The common bleeding event in the PK-DDI group was clinically relevant non-major bleeding (8 cases, 61.5%), and the incidence of bleeding 30 days after treatment was 38.7%. The drugs included amiodarone, ginkgo biloba extract, fluconazole, voriconazole and ocitinib. Conclusion PK-DDIs of rivaroxaban involve a variety of drugs, and the chief targets are P-gp and CYP3A4. The combination of P-gp and/or CYP3A4 inhibitors may increase the risk of bleeding among patients with renal insufficiency who take rivaroxaban, which should never be used in combination with ginkgo biloba extract or voliconazole. When rivaroxaban is used in combination with amiodarone, fluconazole or ocitinib, such parameters should be monitored as prothrombin time (PT), anti-factor Xa levels, or blood concentrations of rivaroxaban.

Key words: Rivaroxaban, Renal Insufficiency, Hemorrhage, P-gp, CYP3A4, Safety, Non-Valvular Atrial Fibrillation, PT, Anti-Factor Xa

中图分类号:

R972

伍诗琪, 苏甦, 闫素英, 张青霞. 非瓣膜性房颤合并肾功能不全患者利伐沙班联用药代动力学相互作用致出血的回顾性队列研究[J]. 中国药物警戒, 2025, 22(4): 415-419.

WU Shiqi, SU Su, YAN Suying, ZHANG Qingxia. Bleeding Induced by Rivaroxaban Combined with PK-DDI in Patients with Nonvalvular Atrial Fibrillation and Renal Insufficiency：a Retrospective Cohort Study[J]. Chinese Journal of Pharmacovigilance, 2025, 22(4): 415-419.

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