Pharmacogenetics

Warfarin has a narrow therapeutic window and a large variation in dose requirements from one patient to another. Selection of initial and maintenance doses of warfarin therapy is usually based on subjective estimates of patient age, size, nutritional status and organ function.

• Genetic variation influences drug metabolism and response to therapy.
• Research has been focused on polymorphisms of genes encoding two proteins: Cytochrome P450 2C9 enzyme (CYP2C9), which is involved in the metabolic clearance of warfarin and vitamin K epoxide reductase enzyme (VKORC1), which recycles reduced vitamin K.
• Patients with CYP2C9*2 and CYP2C9*3 allelic variants and VKORC1 haplotype A/A require lower doses of warfarin to achieve anticoagulation.
• Taken together, CYP2C9 and VKORC1 genotypes explain about 30% to 40% of the total variation in the final warfarin dose.

Genetic-guided warfarin dosing could benefit patients initiating warfarin therapy. The FDA revised the labeling on warfarin in February 2010, providing genotype-specific ranges of doses and suggesting that genotypes be taken into consideration when the drug is prescribed.

However, current recommendations ADVISE AGAINST ROUTINE PHARMACOGENETIC TESTING to guide warfarin dosing as there is insufficient data indicating benefit.

• Clinical trials showed no difference in thrombotic events, major bleeding or survival.
• No difference in time to therapeutic range or time in therapeutic range.
• Not cost-effective
• Adverse outcomes also depend on other factors (transition of care, concomitant anti-platelet therapy, socioeconomic barriers)

Reference

Evidence-Based Management of Anticoagulant Therapy. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141;e152S-e184S.