Risk Factors for Rivaroxaban-Related Bleeding Events—Possible Role of Pharmacogenetics: Case Series

Abstract

Non-vitamin K antagonist oral anticoagulants’ interindividual trough concentration variability affects efficacy and safety, especially in bleeding events. Rivaroxaban is metabolised via CYP3A4/5-, CYP2J2-, and CYP-independent mechanisms and is a substrate of two transporter proteins: ABCB1 (MDR1, P‑glycoprotein) and ABCG2 (BCRP; breast-cancer-resistance protein). The polymorphisms of these genes may possibly affect the pharmacokinetics of rivaroxaban and, consequently, its safety profile. Rivaroxaban variability may be associated with age, liver and kidney function, concomitant illness and therapy, and pharmacogenetic predisposition. This case series is the first, to our knowledge, that presents multiple risk factors for rivaroxaban-related bleeding (RRB) including age, renal function, concomitant diseases, concomitant treatment, and pharmacogenetic data. It presents patients with RRB, along with their complete clinical and pharmacogenetic data, as well as an evaluation of possible risk factors for RRB. Thirteen patients were carriers of ABCB1, ABCG2, CYP2J2, and/or CYP3A4/5 gene polymorphisms. Possible drug–drug interactions with increased bleeding risk were identified in nine patients. Six patients had eGFR <60 mL/min/1.73 m2. Our data suggest a possible role of multiple factors and their interactions in predicting RRB; however, they also indicate the need for further comprehensive multidisciplinary research to enable safer use of this product based on a personalised approach.

Gene polymorphism as a cause of hemorrhagic complications in patients with non-valvular atrial fibrillation treated with oral vitamin K-independent anticoagulants

“…Rivaroxaban is a widely used oral anticoagulant that prevents the formation of fibrin clots by selective, reversible inhibition of factor Xa. 9 , 24 , 28 , 45 After oral administration, the drug is rapidly absorbed, and the maximum plasma concentration is reached within 2–4 h. The bioavailability of rivaroxaban is high but varies depending on the dosage: for example, when taking 10 mg of rivaroxaban, the absolute bioavailability ranges from 80% to 100%; however, if 20 mg of the drug is taken on an empty stomach, the bioavailability decreases to 66% and significantly increases during meals. 46 The degree of the drug binding to blood plasma proteins is approximately 92–95%.…”

“… 9 , 24 Age, renal pathology, and concomitant drug therapy may affect the individual variability of rivaroxaban concentration. 45 In patients with renal insufficiency, the concentration of the drug increases, which leads to the prolongation of the prothrombin time. 46 …”

Common P-glycoprotein (ABCB1) polymorphisms do not seem to be associated with the risk of rivaroxaban-related bleeding events

“…We expected the four ABCB1 polymorphisms to be in a strong pairwise LD, and we planned to classify the subjects based on the "load" of variant alleles across them as: i) 0-2 variant alleles, but no locus is variant homozygous (i.e., wild-type or a maximum of 2 heterozygous loci); ii) 2-5 variant alleles, i.e, at least one variant homozygous locus to a maximum of 5 variant alleles (2 variant + 1 heterozygous or 1 variant + 3 heterozygous loci); iii) 6-8 variant alleles (17,20,(25)(26)(27)(28). We further expected that distribution of patients across these categories would be 30%, 50% and 20%, respectively, and that 15-20% would experience bleeding over the first 6 months of treatment (18,33).…”

“…Genomic DNA was extracted from whole blood using the QIAamp DNA Mini Kit (Qiagen, Hilden, Germany), according to the manufacturer’s instructions. Pharmacogenetic analyses were performed by using specific TaqMan DME and SNP Assays on 7500 Real-Time PCR System (Thermo Fisher Scientific, Waltham, USA) for genotyping of CYP2J2 , CYP3A4 , CYP3A5 , ABCB1 , and ABCG2 gene variants ( 28 ). Only for the ABCB1 triallelic locus c.2677G>T/A (rs2032582) genotyping was performed by the real-time PCR on the LightCycler v 2.0 device (Roche Diagnostics, Germany), as described by von Arjomand-Nahad et al ( 29 ).…”

Pharmacogenetics and pharmacokinetics of rivaroxaban in patients with atrial fibrillation and chronic kidney disease

“…Ограничения исследования Настоящее исследование имеет ряд ограничений: относительно небольшая выборка пациентов, анализ только минимальной концентрации ривароксабана без исследования его пиковой концентрации, ограниченное число исследуемых генов и их полиморфных вариантов, отсутствие среди включенных пациентов носителей определенных генотипов. Также в нашем исследовании были исследованы только по одному полиморфному варианту генов CYP3А4/5 и CYP2J2, не были изучены полиморфные варианты rs2242480, rs2246709, rs3735451 гена СУР3А4, rs7515289 и rs11572325 гена CYP2J2, хотя имеются данные о влиянии данных вариантов на концентрацию ривароксабана [29].…”