engleski

The risk factors for bleeding events in patients taking rivaroxaban – possible role of pharmacogenetics

Background: Rivaroxaban has large interindividual trough concentration variability effecting its efficacy and safety. It is a substrate of ABCB1, ABCG2, CYP2J2, CYP3A4, transporters and enzymes responsible for its transport or metabolism. This variability could be associated to protein-coding genes polymorphisms, drug-drug interactions, age, liver and kidney function. Aim: Evaluate possible risk factors (genes polymorphisms, drug-drug interactions, age, liver and kidney function) for rivaroxaban-associated bleeding adverse reactions. Patients and Methods: Presented patients, with rivaroxaban-associated bleeding, are part of a large case-controlled study population (funded by the Croatian Science Foundation: Pharmacogenomics in Prediction of Cardiovascular Drugs Adverse Reaction). Data on bleeding, concomitant medications, liver and kidney function, and red blood cell count was collected. Pharmacogenetic analysis was performed on 7500 Real-Time PCR System (Applied Biosystems, USA) using specific TaqMan® DME Assay and TaqMan® SNP Assay reagents (Applied Biosystems, USA) for genotyping of relevant pharmacogenes: CYP3A4*1B, *22, CYP3A5*3, CYP2J2*7, ABCB1 (c.1236C>T, c.3435C>T), and ABCG2 (c.421C>A). Results: Thirteen patients (median age 74 years, range 61-80) with rivaroxaban-associated bleeding were analysed: gastrointestinal (N = 7), epistaxis (N = 4), haematuria (N = 1) and gynaecological bleeding (N = 1). In 8/13 drug-drug interactions with increased bleeding risk were found. Two patients had eGFR > 90, while five patients had eGFR < 60. One patient was CYP3A4*22 homozygote, two were CYP2J2*7 heterozygous, two patients had ABCB1 T/T genotype, and three ABCG2 C/A genotype. Three patients who experienced bleeding did not have investigated risk factors. Conclusion: Our results indicate the need for more detailed medical examination prior to rivaroxaban treatment, with emphasis on renal function, particularly in the elderly, with more attention paid to concomitant therapy (possible drug-drug interactions). Due to the small number of patients no pharmacogenetic conclusion might be stated, but findings indicate the need of further research.

drug safety ; interactions ; multidisciplinary ; pharmacogenetic ; risk factors ; rivaroxaban ; rivaroxaban-related bleeding

nije evidentirano