Pharmacogenetics of Warfarin Therapy.

Abstract

A substantial burden of cardiovascular disease results from thrombosis that manifests clinically as acute coronary syndrome, stroke, and venous thromboembolism. Although antithrombotic drugs have been shown to reduce thrombotic events, there exists considerable variability in response to many of these drugs that affects the relative efficacy and safety in individual patients. Clinical, environmental, and genetic factors contribute to variability in drug response. A recent trial (1) has provided important insights into how pharmacogenomics offers an opportunity for personalized medicine through the identification of medically actionable variants to help determine an optimal dosing regimen for warfarin. Vitamin K antagonists, such as warfarin, are the most frequently prescribed oral anticoagulants used worldwide and are indicated for patients across the spectrum of cardiovascular disease, including those with or at risk for venous thromboembolism (deep venous thrombosis and pulmonary embolism), atrial fibrillation (AF),2 and mechanical heart valves. Warfarin's mechanism of action is the prevention of γ-carboxylation of the vitamin K-dependent coagulation factors prothrombin (factor II), factor VII, factor IX, and factor X. Although warfarin and other vitamin K antagonists are highly effective in reducing thromboembolism, their use is limited by multiple genetic, food, and drug interactions, as well as a narrow therapeutic index that necessitates frequent monitoring and dose adjustments, resulting in considerable bleeding risk and inconvenience. Even with frequent monitoring and dose adjustments, patients taking vitamin K antagonists spend about a third of the time outside the standard target therapeutic range [international normalized ratio (INR), 2.0–3.0]. A substantial portion of interindividual variability in the metabolism and response to warfarin is explained by genetic polymorphisms in cytochrome P450 family 2 subfamily C member 9 ( CYP2C9 ) …