Campos-Staffico Alessandra M, Dorsch Michael P, Barnes Geoffrey D, Zhu Hao-Jie, Limdi Nita A, Luzum Jasmine A
Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States.
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
Front Pharmacol. 2022 Nov 24;13:1007113. doi: 10.3389/fphar.2022.1007113. eCollection 2022.
Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing this risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy since they are as effective and overall safer than warfarin in preventing AF-related stroke. Although patients bleed less from DOACs compared to warfarin, bleeding remains the primary safety concern with this therapy. Genetic variants known to modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs could increase the risk of bleeding. To assess the association of eight, functional PK-related single nucleotide variants (SNVs) in five genes (, , , , ) with the risk of bleeding from DOACs in non-valvular AF patients. A retrospective cohort study was carried out with 2,364 self-identified white non-valvular AF patients treated with either rivaroxaban or apixaban. Genotyping was performed with Illumina Infinium CoreExome v12.1 bead arrays by the Michigan Genomics Initiative biobank. The primary endpoint was a composite of major and clinically relevant non-major bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of the eight PK-related SNVs with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. The pre-specified primary analysis was the covariate-adjusted, additive genetic models. Six tests were performed in the primary analysis as three SNVs are in the same haplotype, and thus -values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. In the primary analysis, none of the SNVs met the Bonferroni-corrected level of statistical significance (all > 0.1). In exploratory analyses with other genetic models, the (rs4148732) GG genotype tended to be associated with the risk of bleeding from rivaroxaban [HR: 1.391 (95%CI: 1.019-1.900); = 0.038] but not from apixaban ( = 0.487). Eight functional PK-related genetic variants were not significantly associated with bleeding from either rivaroxaban or apixaban in more than 2,000 AF self-identified white outpatients.
心房颤动（AF）是缺血性中风的主要原因，治疗主要集中在通过抗凝来降低这种风险。直接口服抗凝剂（DOACs）是指南推荐的一线治疗方法，因为它们在预防与AF相关的中风方面与华法林一样有效且总体更安全。尽管与华法林相比，使用DOACs的患者出血较少，但出血仍是这种治疗的主要安全问题。已知可改变参与DOACs药代动力学（PK）的代谢酶或转运蛋白功能的基因变异可能会增加出血风险。为了评估五个基因（，，，，）中的八个与PK相关的功能性单核苷酸变异（SNV）与非瓣膜性AF患者使用DOACs出血风险之间的关联。对2364名自我认定为白人的非瓣膜性AF患者进行了回顾性队列研究，这些患者接受了利伐沙班或阿哌沙班治疗。由密歇根基因组计划生物银行使用Illumina Infinium CoreExome v12.1珠阵列进行基因分型。主要终点是主要出血和临床相关非主要出血的综合指标。采用Cox比例风险回归和时间变化分析，在未调整和协变量调整模型中评估八个与PK相关的SNV与使用DOACs出血风险之间的关联。预先指定的主要分析是协变量调整的加性遗传模型。由于三个SNV在同一单倍型中，因此在主要分析中进行了六项检验，因此低于Bonferroni校正水平8.33e-3的P值被认为具有统计学意义。在主要分析中，没有一个SNV达到Bonferroni校正的统计学意义水平（所有P>0.1）。在使用其他遗传模型的探索性分析中，rs4148732的GG基因型倾向于与利伐沙班出血风险相关[风险比：1.391（95%置信区间：1.019-1.900）；P=0.038]，但与阿哌沙班无关（P=0.487）。在2000多名自我认定为白人的AF门诊患者中，八个与PK相关的功能性基因变异与利伐沙班或阿哌沙班引起的出血均无显著关联。
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