CYP2C9 Polymorphism and Unstable Anticoagulation with Warfarin in Patients Within the First 3 Months Following Heart Valve Replacement

Abstract

Background. Warfarin dose requirements are partly determined by common single nucleotide polymorphisms in VKORC1 and CYP2C9 genes. Objectives. The aim of this study was to investigate how the presence of allelic variants in CYP2C9 affects the stability of anticoagulation in patients within the first 3 months following elective heart valve replacement. Material and Methods. In a case-control study we compared 18 consecutive carriers of CYP2C9*2 and/or *3 and 25 well-matched patients with the wild type CYP2C9*1/*1 genotype. The former group was randomly assigned to use coagulometers or monitor international normalized ratio (INR) in local outpatient clinics. Subjects receiving drugs potently interfering with warfarin were ineligible. Anticoagulation with the baseline warfarin regimens based on pharmacogenetic algorithm was assessed by time in the therapeutic INR range (TTR) within the first 3 months following implantation. Results. Carriers of the CYP2C9*2 and/or *3 genotypes were characterized by lower estimated warfarin dose (median, 21 [interquartile range, 21-35] vs. 35 [28-42] mg/week, p = 0.02) and actual (27.8 ± 13.2 vs. 46.3 ± 13.9 mg/week, p < 0.001), together with lower TTR values (56 [38.6-74.9] vs. 75.4 [58.1-83.6] %, p = 0.03) and longer time above the therapeutic range (13.8 [4.9-34.5] vs. 4.5 [0-15.3] %, p = 0.047) than patients with the CYP2C9*1/*1 genotype. There were no differences in the estimated and actual warfarin doses, TTR values and adverse events between the self-testing and standard-care subgroups. Conclusions. The presence of CYP2C9*2 and/or *3 genotypes is associated with unstable warfarin treatment in patients after heart valve replacement, regardless of the type of INR testing (Adv Clin Exp Med 2015, 24, 4, 607-614).

Polymorphism of the CYP2C9 and VKORC1 genes in patients on the public health system of a municipality in Southern Brazil

“…Although no significant association was observed between median TTR and the polymorphisms analyzed, this data may be a consequence of either sample size or chronic patients, since another study has already shown this association. 13 In a cohort study conducted in Canada with 1059 patients taking warfarin, the average time in the therapeutic interval was 56% (± 25%) in the three months after start of treatment and 70% (± 21%) in the 3 to 12 months interval. Independent predictors of inadequate anticoagulation control were chronic kidney disease, heart failure, dyslipidemia and age.…”

Effect of Oridonin on Cytochrome P450 Expression and Activities in HepaRG Cell

“…In previous studies, CYP3A4, as the most important metabolism enzymes, not only accounts for up to 30% of the total hepatic CYP450s proteins but also involved in almost 50% metabolism of therapeutic drugs [27]. CYP2C9 has played a key role in the process of a variety of drugs, especially in those with a narrow therapeutic range, such as phenytoin sodium and warfarin [28-30]. Meanwhile, these 2 enzymes have been proved to play an important part in the biotransformation of anticancer agents in vivo.…”

Identification of environmental and genetic factors that influence warfarin time in therapeutic range

“…However, the literature is very controversial (Apostolakis et al, 2013Pokorney et al, 2015. Among the genetic factors, polymorphisms in the CYP2C9 and VKORC1 genes have already been associated with TTR (Park et al, 2015(Park et al, , 2017Wypasek et al, 2015;Bryk et al, 2018). More recently, a GWAS reported that two SNPs (rs17791091 and rs4379440) in ASPH gene are associated with TTR (Eriksson et al, 2016).…”