A Pharmacogenetically Guided Acenocoumarol Dosing Algorithm for Chilean Patients: A Discovery Cohort Study.

BACKGROUND: Vitamin K antagonists (VKA) are used as prophylaxis for thromboembolic events in patients with cardiovascular diseases. The most common VKA are warfarin and acenocoumarol. These drugs have a narrow therapeutic margin and high inter-individual response variability due to clinical and pharmacogenetic variables. OBJECTIVE: The authors aim to develop an algorithm comprised of clinical and genetic factors to explain the variability in the therapeutic dose of acenocoumarol among Chilean patients. METHODOLOGY: DNA was obtained from 304 patients as a discovery cohort with an international normalized ratio (INR) range of 2.0-3.0. The non-genetic (demographic and clinical) variables were also recorded. Genotype analyses were performed using real-time PCR for VKORC1 (rs9923231), VKORC1 (rs7294), GGCx (rs11676382), CYP4F2 (rs2108622), ABCB1 (rs1045642), CYP2C9*2 (rs1799853), ApoE (rs429358), and CYP2C9*3 (rs1057910). RESULTS: The clinical variables that significantly influenced the weekly therapeutic dose of VKA were age, sex, body mass index (BMI), and initial INR, collectively accounting for 19% of the variability, and the genetic variables with a significant impact were VKORC1 (rs9923231), CYP2C9*2 (rs1799853), and CYP2C9*3 (rs1057910), explaining for another 37% of the variability. CONCLUSION: We developed an algorithm that explains 49.99% of the variability in therapeutic VKA dosage in the Chilean population studied. Factors that significantly affected the dosage included VKORC1, CYP2C9*2, and CYP2C9*3 polymorphisms, as well as age, sex, BMI, and initial INR.

Functionally Significant Coumarin-Related Variant Alleles and Time to Therapeutic Range in Chilean Cardiovascular Patients.

Despite the development of new oral agents over the last decade, vitamin K antagonists (VKAs) remain the most widely used anticoagulants for treating and preventing thromboembolism worldwide. In Chile, the Ministry of Health indicates that acenocoumarol should be used in preference to any other coumarin. Complications of inappropriate dosing are among the most frequently reported adverse events associated with this medication. It is well known that polymorphisms in pharmacokinetic and pharmacodynamic proteins related to coumarins (especially warfarin) influence response to these drugs. This work analyzed the impact of CYP2C19*2 (rs4244285), CYP1A2*1F (rs762551), GGCx (rs11676382), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), CYP4F2 (rs2108622), VKORC1 (rs9923231), VKORC1 (rs7294), CYP3A4*1B (rs2740574), and ABCB1 (rs1045642) polymorphisms on time to therapeutic range for oral anticoagulants in 304 Chilean patients. CYP2C9*3 polymorphisms were associated with time to therapeutic range for acenocoumarol in Chilean patients, and the CYP4F2 TT genotype, MDR1 A allele, CYP1A2 A allele, and CYP3A4T allele are promising variants that merit further analysis. The presence of polymorphisms explained only 4.1% of time to therapeutic range for acenocoumarol in a multivariate linear model. These results improve our understanding of the basis of ethnic variations in drug metabolism and response to oral anticoagulant therapy. We hope that these findings will contribute to developing an algorithm for VKA dose adjustment in the Chilean population in the near future, decreasing the frequency of stroke, systemic embolism, and bleeding-related adverse events.

Anticoagulation Management With Coumarinic Drugs in Chilean Patients.

Warfarin and acenocoumarol are used in various cardiovascular disorders to improve the prognosis of patients with thromboembolic disease. However, there is a lack of substantial efficacy and safety data on antithrombotic prophylaxis in several countries, particularly in Latin America. The aim of this study was to provide information about the efficacy of anticoagulants in Chilean patients. Data were collected from databases of the Western Metropolitan Health Service, Santiago, Chile. We identified 6280 records of patients receiving anticoagulant treatment. The three most common diagnoses were rhythm disorder (43.7%), venous thrombosis (22%), and valvular prosthesis (10.7%). The majority of patients (98.5%) received acenocoumarol while 1.5% of patients received warfarin, at weekly therapeutic doses of 13.6 mg and 30.4 mg, respectively. For total diagnoses, the median time in the therapeutic range was 50%. However, better results, 66.7%, were observed when a telemedicine strategy was used only in Santiago Province. Our findings emphasize that in Chile, where the number of patients receiving anticoagulant treatment increases every year, telemedicine, by committed teams, improves the use of oral anticoagulants and is able to increase quality indicators of anticoagulant treatment care.