Impact of Cytochrome P450 and P-glycoprotein Gene Polymorphisms on the Risk of Hemorrhagic Complications in Older Patients with Non-Valvular Atrial Fibrillation Treated with Rivaroxaban

Background: The administration of direct oral anticoagulants to older adults requires careful risk stratification against a backdrop of polypharmacy and age-related renal function decline. The role of single nucleotide polymorphisms in cytochrome P450 genes and efflux transporters in this context remains a clinically understudied issue. This study aimed to investigate the association of ABCB1, CYP3A4, and CYP3A5 allelic variants with the safety of rivaroxaban therapy in geriatric patients with non-valvular atrial fibrillation (AF). Materials and Methods: This prospective cohort study consecutively enrolled 94 patients (mean age 83.2 ± 9.2 years). Rivaroxaban trough plasma concentrations (Cmin,ss ) were quantified using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay. Real-time polymerase chain reaction was utilized for the molecular genetic profiling of the ABCB1 (rs1045642, rs2032582), CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746) loci. Comorbidity severity and the spectrum of drug–drug interactions were evaluated as additional predictors. Results: Clinically relevant hemorrhagic complications were documented in 36.2% (n = 34) of the monitored patients. A significant association was established between the homozygous CC genotype at the ABCB1 rs1045642 locus and increased bleeding propensity (odds ratio [OR] 2.42; 95% CI: 1.02–5.74; p = 0.042), whereas the alternative TT variant was associated with a pronounced protective effect. No statistically significant correlations were identified for biotransformation isoenzyme markers (CYP3A4*22, CYP3A5*3). Anticoagulant metrics were comparably distributed across groups and showed no dependence on genetic status. The leading non-genetic factors associated with hemorrhage were advanced age (p < 0.0001), progressive glomerular filtration rate decline (CKD stages 3b–4; p = 0.0009), and pharmacokinetic/pharmacodynamic interference from the co-administration of amiodarone (OR 3.61), non-steroidal anti-inflammatory drugs, and antiplatelet agents. The validated HAS-BLED score demonstrated no predictive power within the comorbid conditions of this cohort (p = 0.052). Conclusions: The ABCB1 rs1045642 (C3435T) polymorphism is associated with the occurrence of hemorrhagic events. Implementing pharmacogenetic testing of the P-glycoprotein transporter combined with a rigorous audit of renal excretory function and concomitant therapy management may optimize the safety profile of rivaroxaban in geriatric practice. These findings warrant confirmation in a larger cohort.