Protocol for Improvement of Therapy With Warfarin

Overview

Atrial Fibrillation (AF) is the most common supraventricular arrhythmia in clinical practice. The presence of AF, as an independent factor, increases mortality by up to two times. One in every six cerebrovascular accidents (CVA) occurs in patients with AF, generating an annual risk of around 7% per year, which represents an increase of up to seven times in relation to the risk in the general population, leading to the need for start anticoagulant therapy. Warfarin is still the Oral Anticoagulant (OC) of choice, being the most used in several clinical situations. The variability of response to anticoagulants is related to pharmacokinetic and pharmacodynamic factors, adherence to treatment, age, diet, body mass index (BMI), liver function, body deposition of vitamin K, individual drug metabolism, drug interactions, comorbidities, in addition to of genetic factors. It is estimated that the annual risks associated with the use of OCs are between 2% and 8% for bleeding. The clinical benefit and risk of OAC therapy are associated with the time in which the values of therapeutic - TTR (time in therapeutic range). Measuring the quality of anticoagulation assesses whether therapy is being maintained within this range. Increased TTR is associated with a decrease in thromboembolic and/or hemorrhagic events. In the context of OCs, pharmacogenetics is the science that predicts the response to drugs, based on individual genetic markers. By understanding the relationship between the genotype and the response to a drug, pharmacogenomics has the potential to help healthcare professionals to predict the therapeutic dose of warfarin by genotyping patients for several Single Nucleotide Polymorphisms (SNPs) that affect metabolism or sensitivity to warfarin. Therefore, the main objectives of genotype-guided therapy are to improve the safety and efficacy of anticoagulant therapy. In Brazil, more specifically in the Brazilian Northeast, the use of a dose predictor algorithm is not common, which leads to high rates of complications and consequently increases the length of hospital stay. As a result, there is an increasing need to implement therapeutic technologies applied to precision health, explore studies on genetic polymorphisms and therapies guided by pharmacogenomics, aiming to understand the individual genetic effect on the metabolism of drugs such as warfarin.

Atrial Fibrillation (AF) is the most common supraventricular arrhythmia in clinical practice. Patients with AF have a 5 times greater risk of causing stroke, especially ischemic stroke, than any other cardiovascular disease. This arrhythmia causes stasis and changes in the thrombosis-antithrombosis balance, which can form thrombi and embolize systemically, reaching the brain and causing stroke, leading to the need to start anticoagulant therapy. Warfarin is still the Oral Anticoagulant (OAC) of choice, being the most used in various clinical situations. With sensitivity to the drug varying in each person, treatment needs to be monitored regularly using the International Normalized Ratio (INR). The known genetic variants that have the greatest impact on the response to warfarin are the variants in the warfarin target, VKORC1, carriers of this variant require a lower dose of warfarin, and the enzyme encoded by CYP2C9, which is the most important when it comes to of involvement with the pharmacokinetics of warfarin. Polymorphisms in the CYP2C9 and VKORC1 genes are responsible for approximately 12 and 24%, respectively, of the variation in warfarin dose among. patients of European descent. Therefore, in the presence of one or more polymorphisms in one of these genes, it is necessary to adjust the warfarin doses. Previous studies have indicated that pharmacogenetic algorithms generally predict warfarin dose more accurately than other dosing methods. In Brazil, more specifically in the Brazilian Northeast, the use of a dose predictor algorithm is not common, which leads to high rates of complications and consequently increases the length of hospital stay. As an objective, the present study plans to implement a pharmacogenetic algorithm protocol for predicting warfarin dose, guided by genotype, versus a clinical protocol based only on drug dosage, in the population with atrial fibrillation, and to evaluate the superiority of the treatment.