Effect of genetic variants on bleeding with rivaroxaban in pulmonary embolism patients: A multicenter prospective cohort study

<bold>Background:</bold> The genetic feature is a critical factor for the efficacy and safety of rivaroxaban by affecting plasma concentration during extended treatment of pulmonary embolism (PE). However, the existing bleeding risk scores do not include genetic variants. The study aimed to explore whether incorporating genetic factors in the current model improved the accuracy. <bold>Methods:</bold> PE patients receiving therapeutic doses of rivaroxaban were enrolled. The primary outcome, bleeding events, was monitored over a one-year follow-up period. A genome-wide association study and candidate gene association analyses were conducted. Genetic variants were integrated into four established clinical bleeding risk scores to develop combined clinical-genetic risk assessments. <bold>Findings:</bold> This study included 3,498 patients treated with rivaroxaban. The bleeding rate during extended treatment was 4.3%. Risk factors identified for bleeding included stroke, abnormal liver function, and hypertension. In 510 patients underwent genotyping, one single-nucleotide polymorphism (SNP) ABLIM2 rs6819260 was significantly related to bleeding (OR = 8.91, 95% CI: 4.08–19.47, p = 4.22 × 10⁻⁸). Incorporating ABLIM2 rs6819260 into existing risk models significantly improved the AUC by more than 10.0%. <bold>Interpretation:</bold> Genetic variations significantly influence bleeding risk in Chinese PE patients treated with rivaroxaban during extended anticoagulation. Integrating the ABLIM2 rs6819260 SNP into bleeding risk models substantially enhances their predictive accuracy and facilitates the use of these models to guide individualized treatment decisions in clinical practice.