{"doi":"10.3389/fphar.2022.1007113","title":"Eight pharmacokinetic genetic variants are not associated with the risk of bleeding from direct oral anticoagulants in non-valvular atrial fibrillation patients","abstract":"Background: 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. Hypothesis: 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. Aim: To assess the association of eight, functional PK-related single nucleotide variants (SNVs) in five genes ( ABCB1 , ABCG2 , CYP2J2 , CYP3A4 , CYP3A5 ) with the risk of bleeding from DOACs in non-valvular AF patients. Methods: 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 p -values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. Results: In the primary analysis, none of the SNVs met the Bonferroni-corrected level of statistical significance (all p > 0.1). In exploratory analyses with other genetic models, the ABCB1 (rs4148732) GG genotype tended to be associated with the risk of bleeding from rivaroxaban [HR: 1.391 (95%CI: 1.019–1.900); p = 0.038] but not from apixaban ( p = 0.487). Conclusion: 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.","journal":"Frontiers in Pharmacology","year":2022,"id":255912,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9612,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":272503,"name":"Michael P. Dorsch","orcid":"0000-0003-2910-1879","position":1,"is_corresponding":false},{"id":104081,"name":"Geoffrey D. Barnes","orcid":"0000-0002-6532-8440","position":2,"is_corresponding":false},{"id":292022,"name":"Hao‐Jie Zhu","orcid":"0000-0002-2248-4419","position":3,"is_corresponding":false},{"id":386043,"name":"Nita A. Limdi","orcid":"0000-0002-4672-8406","position":4,"is_corresponding":false},{"id":302261,"name":"Jasmine A. Luzum","orcid":"0000-0003-3639-717X","position":5,"is_corresponding":false},{"id":743418,"name":"Alessandra M. Campos‐Staffico","orcid":"0000-0003-4172-7524","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T00:25:17.224217Z","pmid":"36506510","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}