Acenocoumarol Pharmacogenetic Dosing Algorithms and Their Application in Two Bulgarian Patients with Low Anticoagulant Requirements.

BACKGROUND: The anticoagulant therapy with acenocoumarol is generally associated with a high risk of bleeding and thromboembolic events. PURPOSE: We applied eight already existing acenocoumarol dosing algorithms to Bulgarian patients with low acenocoumarol dose requirements and investigated which of these algorithms would predict most precisely the dose anticoagulant. MATERIALS AND METHODS: Two patients with Bulgarian origin were referred to the outpatient clinical laboratory of "St. Ekaterina" University Hospital for Cardiovascular Surgery and Cardiology, Sofia, Bulgaria. After obtaining written informed consent, both patients were genotyped for polymorphisms in genes for Cytochrome P450 2C9 (CYP2C9), Vitamin K epoxide reductase (VKORC1), Apolipoprotein E (APOE), and Cytochrome P450 4F2 (CYP4F2). RESULTS: All applied acenocoumarol dosing algorithms predicted relatively similar doses of coumarin anticoagulant in both patients. However, van Schie et al.'s algorithm allowed more accurate calculation of the optimal dose in our patients with extremely low acenocoumarol requirements. Genotyping of selected polymorphic variants in CYP2C9 and VKORC1 showed that both patients were compound heterozygotes for CYP2C9 (CYP2C9*2/*3) and homozygotes for both variants in VKORC1 (VKORC1 1173 T/T, and VKORC1-1639 A/A). This combination of genotypes suggested high sensitivity to acenocoumarol leading to the low anticoagulant dose requirements (0.25 and 1 mg/day, respectively) needed to reach the target International Normalized Ratio of 2.5-3.5. CONCLUSIONS: The genotyping of polymorphic variants in VKORC1 and CYP2C9, together with clinical and demographic parameters, can serve for more precise definition of the individual starting and maintenance doses of coumarin derivatives in each patient.

Estimation and validation of acenocoumarol dosing algorithms in Bulgarian patients with cardiovascular diseases.

Aim & Methods: A total of 169 Bulgarian patients were genotyped for CYP2C9*2,*3, VKORC1-1639G>A and VKORC11173C>T. The effect of genetic and nongenetic factors on acenocoumarol dose variability was tested in a derivation cohort of patients and the obtained algorithm was validated in a test cohort. RESULTS & DISCUSSION: It was found that VKORC-1639G>A (25.5%), CYP2C9*2 (7.8%), CYP2C9*3 (6.1%), age (13.6%) and diagnosis (6.0%) significantly affected acenocoumarol dose variability in the derivation cohort. These factors with additional factors, such as sex (0.1%, p = 0.76), weight (2.6%, p = 0.14) and amiodarone use (3.0%, p = 0.059) accounted for 46.5% and 23.0% of the dose variability for genetic and clinical models, respectively. CONCLUSION: Based on the results of this investigation, validated clinical and pharmacogenetic algorithms for the prediction of a stable anticoagulant dose were developed, specifically designed for the Bulgarian population.