Abstract
The purpose of this study was to identify the renin–angiotensin system (RAS)-related genetic factors associated with bleeding and develop the bleeding risk scoring system in patients receiving direct oral anticoagulants (DOACs). This study was a retrospective analysis of prospectively collected samples from June 2018 to May 2020. To investigate the associations between RAS-related genetic factors and major bleeding, we selected 16 single nucleotide polymorphisms (SNPs) from five genes (namely, AGT, REN, ACE, AGTR1, and AGTR2). Multivariable logistic regression analysis was employed to investigate the independent risk factors for bleeding and to develop a risk scoring system. A total of 172 patients were included in the analysis, including 33 major bleeding cases. Both old age (≥65 years) and moderate to severe renal impairment (CrCl < 50 mL/min) increased the risk of bleeding in the multivariable analysis. Among RAS-related polymorphisms, patients carrying TT genotype of rs5050 and A allele of rs4353 experienced a 3.6-fold (95% CI: 1.4–9.3) and 3.1-fold (95% CI: 1.1–9.3) increase in bleeding, respectively. The bleeding risk increased exponentially with a higher score; the risks were 0%, 2.8%, 16.9%, 32.7%, and 75% in patients with 0, 1, 2, 3, and 4 points, respectively. Although this study is limited to a retrospective study design, this is the first study to suggest RAS-related genetic markers and risk scoring systems, including both clinical and genetic factors, for major bleeding in patients receiving DOAC treatment.
Highlights
Direct oral anticoagulants (DOACs) are widely used for anticoagulation therapy to reduce the risk of stroke or systemic embolism in patients with non-valvular atrial fibrillation and to prevent or treat several types of thromboembolic events, including venous thromboembolism [1,2]
This study aimed to identify the renin–angiotensin system (RAS)-related genetic factors associated with major bleeding and to develop the bleeding risk scoring system in Korean patients receiving DOACs
As the incidence of major bleeding was low, a case-cohort study approach was applied; patients at Ewha Womans University Mokdong Hospital were enrolled as the cohort, and additional cases were recruited from all hospitals
Summary
Direct oral anticoagulants (DOACs) are widely used for anticoagulation therapy to reduce the risk of stroke or systemic embolism in patients with non-valvular atrial fibrillation and to prevent or treat several types of thromboembolic events, including venous thromboembolism [1,2]. Two classes of DOACs are currently available—direct thrombin inhibitors (dabigatran) and direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) [3]. Bleeding is the most severe and common complication of anticoagulation treatment [4]. In a large retrospective observational study, the incidence rate of major bleeding was 3.5%, 5.3%, and 3.5% per person-year in the dabigatran, rivaroxaban, and apixaban groups, respectively [5]. All DOACs showed lower risks of intracranial hemorrhage than warfarin, they had similar or higher risks of gastrointestinal (GI) bleeding [6–9].
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