Genetic polymorphisms influence pharmacokinetics and bleeding risk for DOACs in meta-analysis

BackgroundDirect oral anticoagulants (DOACs) exhibit considerable individual variability in effectiveness and bleeding risk, possibly due to genetic differences. This study assessed how genetic polymorphisms impact the pharmacokinetics (PK) and outcomes of DOACs.MethodsWe searched the PubMed, Embase, Web of Science, and Cochrane Library databases for pharmacogenomic studies related to DOACs up to October 29, 2025. Meta-analyses were performed using RevMan 5.4 for evaluated results with ≥3 studies.ResultsThirty-nine studies involving 13,300 patients were included, with 19 studies eligible for meta-analysis. For dabigatran, carriers of the CES1 rs2244613 C allele was associated with both lower trough concentration (Ctrough) and reduced bleeding risk compared with AA homozygotes. CES1 rs8192935 and ABCB1 rs4148738 were also associated with dabigatran exposure. For rivaroxaban, the ABCB1 rs1045642 TT genotype was consistently associated with lower dose-adjusted Ctrough across four subgroups. Polymorphisms in ABCB1 rs1045642 were linked to altered bleeding risk, whereas ABCB1 (rs1128503, rs4148738, rs2032582), ABCG2 rs2231142, CYP3A5 rs776746, and CYP2J2 rs890293 showed no statistically significant association with bleeding events. For apixaban, ABCG2 rs2231142 may influence PK profiles, while ABCB1 rs1045642 was associated with a reduced risk of bleeding. In the case of edoxaban, polymorphisms in SLCO1B1 may affect metabolite exposure and contribute to variability in bleeding risk.ConclusionGenetic polymorphisms in CES1, ABCB1, and SLCO1B1 are associated with variability in the PK and bleeding risk of DOACs. However, due to the observational nature, heterogeneity, and limited sample sizes of included studies, current evidence is insufficient to support genotype-guided dosing in clinical practice. Large prospective studies are needed to validate these findings.Systematic Review RegistrationPROSPERO CRD420251240030.