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ABCB1 genotype and clinically relevant bleeding risk during extended anticoagulation therapy for pulmonary embolism:
Zhu Zhang1, Haobo Li1,2, Bingzhang Zou1,2
1National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.
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 1, 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 DOAC pharmacokinetics were assessed for associations with CRB during extended anticoagulation. In phase 2, 101 PE patients from an independent cohort underwent rivaroxaban plasma concentration measurement and genotyping for pharmacokinetic validation.
Results:
In phase 1, 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 false discovery rate correction (adjusted P = .074), although they met the gene-level false discovery rate threshold (adjusted P = .030). Among these, rs1045642 was also associated with dose-normalized peak plasma concentration in phase 2 (P = .001), without affecting recurrent venous thromboembolism or mortality. In phase 2, ABCB1 rs1045642 TT carriers had significantly higher dose-normalized peak concentrations (P = .001). Incorporating rs1045642 into 5 established bleeding scores (Kuijer, RIETE, VTE-BLEED, PE-SARD and VTE-PREDICT) consistently improved reclassification (category-free net reclassification improvement, 0.214-0.312; integrated discrimination improvement, 0.022-0.035), although the corresponding improvements in area under the receiver operating characteristic curve did not reach statistical significance.
Conclusion:
ABCB1 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.