Abstract
BackgroundVitamin 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.ObjectiveThe authors aim to develop an algorithm comprised of clinical and genetic factors to explain the variability in the therapeutic dose of acenocoumarol among Chilean patientsMethodologyDNA 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).ResultsThe 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.ConclusionWe 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.
Highlights
Cardiovascular diseases (CVD) have been highlighted as a health priority by several institutions worldwide, including the World Health Organization (WHO) through its Global Action Plan for the Prevention and Control of Non-communicable Diseases 2013–2020
In order to achieve that, we have investigated the association of relevant single nucleotide polymorphisms (SNPs) (Table 1) with acenocoumarol dosage
Our model showed no association between weekly therapeutic dose (WTD) and CYP4F2 or ApoE polymorphisms, which are included in the Spanish study (Borobia et al, 2012)
Summary
Cardiovascular diseases (CVD) have been highlighted as a health priority by several institutions worldwide, including the World Health Organization (WHO) through its Global Action Plan for the Prevention and Control of Non-communicable Diseases 2013–2020. Oral anticoagulants are indicated for patients who survive a cardiovascular disease in order to prevent new thromboembolic conditions (WHO, 2013). Called vitamin K antagonists (VKA), include drugs such as warfarin, acenocoumarol, and phenprocoumon. VKA are highly effective antithrombotic agents used to prevent complications associated with atrial fibrillation, artificial heart valves, and thromboembolic diseases (such as deep venous thrombosis and pulmonary embolism). Major bleeding is the most concerning adverse effect of anticoagulant therapy, but the risk of bleeding associated with VKA is difficult to estimate. 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
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