ABCB1 genotype and clinically relevant bleeding risk during extended anticoagulation therapy for pulmonary embolism: a two-phase study

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Pulmonary embolism (n=633). Intervention: ABCB1 rs1045642 variant (CT/TT carriers) vs. ABCB1 rs1045642 CC genotype. Primary outcome: Composite of major bleeding and clinically relevant non-major bleeding (HR 2.01, 95% CI 1.13-3.56, p=0.017).

Q: What does this research mean for the field?

The ABCB1 rs1045642 variant is nominally associated with an increased risk of clinically relevant bleeding and elevated peak drug concentrations during extended rivaroxaban therapy for pulmonary embolism. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Zhu Zhang; Haobo Li; Bingzhang Zou; Yu Zhang; Yuzhi Tao; Linfeng Xi; Kuangxun Li; Huiwen Li; mengjie Duo; Li Zhao; Xianbo Zuo; Zhenguo Zhai; Chen Wang

doi:10.1016/j.rpth.2026.106925

August 1, 2026Research and Practice in Thrombosis and HaemostasisOpen Access

ABCB1 genotype and clinically relevant bleeding risk during extended anticoagulation therapy for pulmonary embolism: a two-phase study

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Key result

ABCB1 variant linked to ~2-fold higher bleeding risk during extended rivaroxaban therapy for PE.

HR 2.01
95% CI 1.13-3.56
P=0.017
n=633

Figures

Graphical abstract published by Research and Practice in Thrombosis and Haemostasis — Graphical abstract · Published by Research and Practice in Thrombosis and Haemostasis · CC BY-NC-ND

Why the study?

Genetic determinants of bleeding risk during extended direct oral anticoagulant therapy for pulmonary embolism remain unclear.

Does the ABCB1 rs1045642 genotype increase the risk of clinically relevant bleeding in adult patients with pulmonary embolism receiving extended rivaroxaban therapy?

Key Points

To evaluate the association between candidate pharmacogenomic variants and clinically relevant bleeding during extended rivaroxaban treatment in patients with pulmonary embolism, and to assess whether genetic data improve existing bleeding risk models.
Phase I evaluated 633 rivaroxaban-treated patients with pulmonary embolism from a multicenter registry who completed 3 months of therapy, testing 13 candidate single nucleotide polymorphisms across 9 genes during a 1-year follow-up.
Phase II independently evaluated 101 rivaroxaban-treated patients with pulmonary embolism who underwent peak and trough plasma concentration measurements and genotyping for pharmacokinetic validation.
Risk reclassification and discrimination were assessed by incorporating the rs1045642 variant into five established clinical bleeding scores (Kuijer, RIETE, VTE-BLEED, PE-SARD, and VTE-PREDICT).
Clinically relevant bleeding occurred in 70 of 633 patients (11.1%) in Phase I, with three ABCB1 variants showing nominal associations with bleeding that met gene-level false discovery rate significance (adjusted P=0.030) but not study-wide significance (adjusted P=0.074).
In Phase II, ABCB1 rs1045642 TT carriers exhibited significantly higher dose-normalized peak rivaroxaban concentrations (P=0.001), while showing no significant differences in trough concentrations, recurrent venous thromboembolism, or all-cause mortality.
Adding rs1045642 to five clinical risk scores consistently improved category-free net reclassification improvement (0.214 to 0.312) and integrated discrimination improvement (0.022 to 0.035), although increases in area under the curve (+0.061 to +0.097) did not reach statistical significance.

Study Design

Type

Cohort (n=633)

Multicenter

Yes

Structured PICO

Does the ABCB1 rs1045642 genotype increase the risk of clinically relevant bleeding in adult patients with pulmonary embolism receiving extended rivaroxaban therapy?

P

Population

633 Chinese adult patients with pulmonary embolism continuing extended-phase rivaroxaban therapy beyond 3 months, followed for up to 1 year.

E

Exposure

Presence of the ABCB1 rs1045642 variant (CT or TT carriers) during extended anticoagulation therapy with rivaroxaban (10-20 mg once daily).

C

Comparator

Absence of the ABCB1 rs1045642 variant (CC carriers, wild-type) during extended anticoagulation therapy with rivaroxaban (10-20 mg once daily).

O

Outcome

Composite of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) (together termed clinically relevant bleeding, CRB) defined by ISTH criteria, evaluated from month 3 to 12 after PE diagnosis, adjudicated by a blinded central committee.safety

Main Result

Hazard Ratio: 2.01 (95% CI 1.13–3.56)

p-value: p=0.017

The ABCB1 rs1045642 variant is nominally associated with higher peak plasma concentrations of rivaroxaban and increased clinically relevant bleeding during extended therapy in patients with pulmonary embolism, suggesting a potential role for pharmacogenomics in bleeding risk stratification.

Limitations

Observational design susceptible to unmeasured confounding and channeling bias in dose selection
No genetic association survived study-wide FDR correction
Phase 2 did not validate bleeding outcomes
Small number of major bleeding events and nonsignificant AUC improvements limit conclusions regarding predictive utility
Cohort was exclusively Han Chinese, requiring replication in other populations
Observational design remains susceptible to unmeasured confounding and channeling bias in dose selection.
No association survived study-wide false discovery rate (FDR) correction.
Phase 2 did not validate bleeding outcomes.
Small number of major bleeding events and nonsignificant AUC improvements limit conclusions regarding predictive utility.
Exclusively Han Chinese cohort requires replication in other populations before clinical implementation.

Implication

ABCB1 rs1045642 carriers may face higher bleeding risk on extended rivaroxaban; hypothesis-generating for pharmacogenomic risk models pending validation.

Abstract

Background Extended direct oral anticoagulant (DOAC) therapy reduces recurrent venous thromboembolism, but clinically relevant bleeding (CRB) remains a safety concern. DOACs exhibit substantial pharmacokinetic variability among individuals, and genetic determinants of bleeding risk during extended anticoagulation remain unclear. Objectives To explore the association between pharmacogenomic variants and CRB during extended rivaroxaban therapy and explore their potential contribution to bleeding risk prediction in patients with pulmonary embolism (PE). Methods In Phase I, 633 rivaroxaban-treated PE patients from the multicenter registry with genome-wide genotyping data were included. Thirteen candidate single nucleotide polymorphisms across 9 genes previously reported to influence DOACs pharmacokinetics were assessed for associations with CRB during extended anticoagulation. In Phase II, 101 PE patients from an independent cohort underwent rivaroxaban plasma concentration measurement and genotyping for pharmacokinetic validation. Results In Phase I, 70 patients (11.1%) experienced CRB during the 1-year follow-up. Three ABCB1 variants showed nominal associations with CRB; none remained significant after study-wide FDR correction (adjusted P=0.074), although they met the gene-level FDR threshold (adjusted P=0.030). Among these, rs1045642 was also associated with dose-normalized peak plasma concentration in Phase II (P = 0.001), without affecting recurrent VTE or mortality. In Phase II, ABCB1 rs1045642 TT carriers had significantly higher dose-normalized peak concentrations (P=0.001). Incorporating rs1045642 into five established bleeding scores (Kuijer, RIETE, VTE-BLEED, PE-SARD and VTE-PREDICT) consistently improved reclassification (cfNRI 0.214–0.312; IDI 0.022–0.035), although the corresponding improvements in AUC did not reach statistical significance. Conclusion ABCB 1 rs1045642 showed a nominal association with CRB and higher rivaroxaban peak plasma concentration during extended therapy. Adding this genotype to existing bleeding scores improved risk reclassification but not overall discrimination, and its clinical utility requires independent prospective validation.

Discussion

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Cite This Study

Zhang et al. (2026) conducted a cohort in Pulmonary embolism (n=633). ABCB1 rs1045642 variant (CT/TT carriers) vs. ABCB1 rs1045642 CC genotype was evaluated on Composite of major bleeding and clinically relevant non-major bleeding (HR 2.01, 95% CI 1.13-3.56, p=0.017). The ABCB1 rs1045642 variant (CT or TT carriers) was nominally associated with a 2-fold increased risk of clinically relevant bleeding (HR 2.01) during extended rivaroxaban therapy for pulmonary embolism.

synapsesocial.com/papers/6ad0fcd03afa093ea9ad0067 https://doi.org/10.1016/j.rpth.2026.106925

Topics

Pulmonary embolism

Anticoagulation in AF

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ABCB1 genotype and clinically relevant bleeding risk during extended anticoagulation therapy for pulmonary embolism: a two-phase study

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Topics

ABCB1 genotype and clinically relevant bleeding risk during extended anticoagulation therapy for pulmonary embolism: a two-phase study

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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