Pharmacogenetics role in the safety of acenocoumarol therapy

Abstract

Vitamin K antagonists (VKAs) remain as the most prescribed drug for treatment and prevention of thrombotic disorders in many countries, despite the recent approval of the new oral anticoagulants (NOACs). Although effectiveness and safety of VKAs are tightly associated to maintaining the patient within the international normalised ratio (INR) therapeutic range (TWR), they have been likened to NOACs when patients are in good INR control (≥66% of TWR). Therefore, assessing the safety of patients should be a priority in the selection of the anticoagulation therapy. The aim of this study was to evaluate the association between CYP2C9*2, CYP2C9*3, VKORC1, CYP4F2*3, ABCB1 C3435T, APOE, CYP2C19*2 and CYP2C19*17 gene polymorphisms and treatment safety in 128 patients diagnosed with atrial fibrillation or venous thromboembolism during the initial first seven months of acenocoumarol therapy. After the first month, VKORC1-T-allele and APOE-E3/E3 genotype were independently associated to higher time above therapeutic range (TAR) and lower time below the therapeutic range (TBR). After seven months, VKORC1 T-allele predicted higher TAR, and was also associated to increased INR>4, particularly the TT-genotype (odds ratio [OR]: 32; 95% confidence interval [CI95%]: 6-175; p=810⁻⁵). C-alleles for CYP2C9*3 (OR: 5.5; CI95%: 1.8-17; p=0.003) and ABCB1 (OR: 8.9;CI95%: 1.1-70; p=0.039) independently influenced on INR>6 . Patients VKORC1-TT/ABCB1-C remained 26.8% [19.7-38.9] TAR, with associated relative risk (RR) for INR>4 1.8 higher (CI95%: 1.2-2.5; p=0.015). Patients VKORC1-TT also presented the highest risk of bleeding events (RR: 3.5;CI95%: 1.4-8.4; p=0,010). In conclusion, VKORC1, CYP2C9*3, APOE and ABCB1 genotypes should be considered in prevention of overanticoagulation and bleeding events in the initiation of acenocoumarol therapy.

Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm

“…The stable ACN dose was 31.6% higher in patients with this genotype than in the remaining patients, in agreement with findings in warfarin-anticoagulated patients [38]. We recently showed that APOE E3/E3 patients, who are TT for the APOE-rs429358 gene polymorphism, have an increased risk of overanticoagulation (INR > 4) in the initial phase of ACN treatment [45]. The present study is the first to achieve optimization of the dose prediction by adding this gene polymorphism to a pharmacogenetic algorithm.…”

FCGR2A/FCGR3A Gene Polymorphisms and Clinical Variables as Predictors of Response to Tocilizumab and Rituximab in Patients With Rheumatoid Arthritis

“…FCGR2A (rs1801274) and FCGR3A (rs396991) gene polymorphisms were analyzed by real‐time PCR using TaqMan probes. Genotyping methodology was previously described …”

“…Genotyping methodology was previously described. 36 The assay ID used for FCGR2A (rs1801274) is C 9077561 20, and for FCGR3A (rs396991) is C 25815666 10.…”

Extrapolation of acenocoumarol pharmacogenetic algorithms

“…Table 2 exhibits the distribution of clinical and genetic variables in the 189 patients in the present cohort and in the derivation cohort of the pharmacogenetic models under study. The median stable dose was 15 [10][11][12][13][14][15][16][17][18][19] mg/week in the present cohort, and the doses did not differ as a function of the indication or INR target (14 [10][11][12][13][14][15][16][17][18][19] mg/week for VTE/AF/others vs. 16 [12][13][14][15][16][17][18][19] mg/week for HVR; p = 0.192).…”

“…The genotyping methodology was previously described [18]. The Hardy-Weinberg equilibrium was determined using a specific calculator provided by the Online Encyclopedia for Genetic Epidemiology Studies [30].…”