AUTHOR=Campos-Staffico Alessandra M. , Dorsch Michael P. , Barnes Geoffrey D. , Zhu Hao-Jie , Limdi Nita A. , Luzum Jasmine A. 

TITLE=Eight pharmacokinetic genetic variants are not associated with the risk of bleeding from direct oral anticoagulants in non-valvular atrial fibrillation patients

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.1007113

DOI=10.3389/fphar.2022.1007113

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Hypothesis:</bold> 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.</p><p><bold>Aim:</bold> To assess the association of eight, functional PK-related single nucleotide variants (SNVs) in five genes (<italic>ABCB1</italic>, <italic>ABCG2</italic>, <italic>CYP2J2</italic>, <italic>CYP3A4</italic>, <italic>CYP3A5</italic>) with the risk of bleeding from DOACs in non-valvular AF patients.</p><p><bold>Methods:</bold> 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 <italic>p</italic>-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant.</p><p><bold>Results:</bold> In the primary analysis, none of the SNVs met the Bonferroni-corrected level of statistical significance (all <italic>p</italic> &gt; 0.1). In exploratory analyses with other genetic models, the <italic>ABCB1</italic> (rs4148732) GG genotype tended to be associated with the risk of bleeding from rivaroxaban [HR: 1.391 (95%CI: 1.019–1.900); <italic>p</italic> = 0.038] but not from apixaban (<italic>p</italic> = 0.487).</p><p><bold>Conclusion:</bold> 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.</p>