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

Q: What are the key findings of this study?

The homozygous CC genotype at the ABCB1 rs1045642 locus was associated with a 2.4-fold increased risk of hemorrhagic complications in older patients with non-valvular atrial fibrillation treated with rivaroxaban.

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Non-valvular atrial fibrillation (n=94). Intervention: ABCB1 rs1045642 homozygous CC genotype vs. ABCB1 rs1045642 CT and TT genotypes. Primary outcome: Composite hemorrhagic outcome (first documented bleeding episode per patient) (OR 2.42, 95% CI 1.02-5.74, p=0.042).

Q: What does this research mean for the field?

The homozygous CC genotype at the ABCB1 rs1045642 locus is associated with an increased risk of hemorrhagic complications in older patients with non-valvular atrial fibrillation treated with rivaroxaban. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

I. V. Sychev; A. P. Kondrakhin; Sh. P. Abdullaev; П. О. Бочков; С. Н. Тучкова; Lyubov V. Selivanova; Denis S. Fedorinov; Olga A. Milovanova; Karin B. Mirzaev; Д. А. Сычев

doi:10.3390/jpm16090470

September 14, 2026Journal of Personalized MedicineOpen Access

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

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Key result

ABCB1 CC genotype is linked to ~140% higher bleeding risk with rivaroxaban in NVAF.

OR 2.42
95% CI 1.02-5.74
P=0.042
n=94

Why the study?

The role of cytochrome P450 and efflux transporter single nucleotide polymorphisms in direct oral anticoagulant safety among older adults remains clinically understudied.

Does pharmacogenetic profiling of ABCB1, CYP3A4, and CYP3A5 predict hemorrhagic complications in older patients with non-valvular atrial fibrillation treated with rivaroxaban?

Key Points

To evaluate the association of ABCB1, CYP3A4, and CYP3A5 gene variants, along with clinical factors and drug interactions, with bleeding complications in geriatric patients receiving rivaroxaban for non-valvular atrial fibrillation.
Prospectively enrolled 94 consecutive older patients (mean age 83.2 ± 9.2 years) with non-valvular atrial fibrillation receiving rivaroxaban.
Quantified rivaroxaban trough plasma concentrations (Cmin,ss) using HPLC-MS/MS and genotyped ABCB1 (rs1045642, rs2032582), CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746) using real-time PCR.
Assessed hemorrhagic complications, clinical comorbidities, and drug–drug interactions alongside HAS-BLED scores and renal excretory function.
Clinically relevant hemorrhagic complications occurred in 36.2% (n = 34) of patients, significantly associated with the homozygous CC genotype of ABCB1 rs1045642 (OR 2.42; 95% CI: 1.02–5.74; p = 0.042), whereas CYP3A4*22 and CYP3A5*3 showed no significant association.
Non-genetic factors strongly linked to bleeding included older age (88.8 ± 8.4 vs. 80.1 ± 8.7 years; p < 0.0001) and reduced eGFR (38.6 ± 16.4 vs. 57.8 ± 21.0 mL/min/1.73 m2; p < 0.0001), peaking at CKD stage 4 (OR 4.09; 95% CI: 1.73–9.70; p = 0.0009).
Bleeding odds significantly rose with co-medications including amiodarone (OR 3.61; 95% CI: 1.49–8.75; p = 0.004), NSAIDs (OR 3.21; 95% CI: 1.29–7.98; p = 0.009), and antiplatelet agents (OR 3.00; 95% CI: 1.23–7.31; p = 0.014), while rivaroxaban trough plasma levels did not differ by bleeding status (p > 0.05).

Study Design

Type

Cohort (n=94)

Blinding

Blinded outcome adjudication

Multicenter

No

Structured PICO

Does pharmacogenetic profiling of ABCB1, CYP3A4, and CYP3A5 predict hemorrhagic complications in older patients with non-valvular atrial fibrillation treated with rivaroxaban?

P

Population

94 older adults (mean age 83.2 years, 64% female) with non-valvular atrial fibrillation and CKD stages 1-4 treated with rivaroxaban, followed for a mean of 14 days during inpatient treatment.

E

Exposure

Rivaroxaban 15 or 20 mg oral once daily (tailored to clinical indications and renal function) combined with molecular genetic profiling of ABCB1, CYP3A4, and CYP3A5 loci.

O

Outcome

Composite hemorrhagic outcome (first documented bleeding episode per patient, stratified by ISTH consensus criteria into major, clinically relevant non-major, and minor bleeding) over a mean observation period of 14 days.safety

Main Result

Odds Ratio: 2.42 (95% CI 1.02–5.74)

p-value: p=0.042

In older adults with non-valvular atrial fibrillation, the ABCB1 rs1045642 CC genotype, advanced age, progressive CKD, and specific drug-drug interactions significantly increase the risk of rivaroxaban-associated hemorrhagic complications.

Limitations

Single-center design
Restricted sample size (n = 94)
Small absolute number of recorded bleeding episodes
Limited statistical power to detect the clinical effects of rare allelic variants
Statistical corrections for multiple comparisons were intentionally omitted
Composite endpoint exhibited marked heterogeneity regarding the severity of hemorrhagic events
Lacks an independent cohort for external validation
Small sample size warranting confirmation in a larger cohort
Short follow-up timeframe inherently dictated by the duration of inpatient treatment
Wide confidence intervals due to rare genotypes (e.g., TT genotype) within the studied cohort
Drug quantification confined exclusively to the systemic venous circulation, limiting assessment of tissue-specific distribution

Implication

May warrant caution with rivaroxaban in ABCB1 rs1045642 CC carriers; hypothesis-generating and requires prospective validation before clinical adoption.

Abstract

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.

Discussion

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Cite This Study

Sychev et al. (2026) conducted a cohort in Non-valvular atrial fibrillation (n=94). ABCB1 rs1045642 homozygous CC genotype vs. ABCB1 rs1045642 CT and TT genotypes was evaluated on Composite hemorrhagic outcome (first documented bleeding episode per patient) (OR 2.42, 95% CI 1.02-5.74, p=0.042). The homozygous CC genotype at the ABCB1 rs1045642 locus was associated with a 2.4-fold increased risk of hemorrhagic complications in older patients with non-valvular atrial fibrillation treated with rivaroxaban.

synapsesocial.com/papers/6aa90187eed42882c1fc198d https://doi.org/10.3390/jpm16090470

Topics

Atrial fibrillation

Persistent AF management

Anticoagulation in AF

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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

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Topics

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

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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