Pharmacogenetically Guided Warfarin Therapy

Warfarin has been used as an anticoagulant for the last 60 years. Warfarin has a narrow therapeutic index (INR 2.0-3.0). Warfarin dosing is by trial and error. Underdosing leads to thrombosis and overdosing to bleeding, both of which can be lifethreatening. Warfarin is responsible a leading cause of drug related emergency admissions in the elderly (Ann Intern Med 147:755; 2007).

Warfarin is metabolized by cytochrome P450 2C9 (CYP2C9) and acts by inhibiting vitamin K epoxide reductase subunit C1 (VKORC1). Common polymorphisms in these enzmes are assocated with increased time to coagulation, risk of overanticoagulation and and risk of bleeding. The first prospective randomised study to adjust the loading and maintainence dose of warfarin according to polymorphisms of CYP2C9 and VKORC1  (Blood 118;3163;2011) has been reported. The authors showed that when the loading and maintainance dose is adjested for polymorphisms of the two enzymes, differenced in time to stable anticoagulation and risk of overanticoagulation are eliminated. This is step forward in the decreasing the risk of warfarin therapy. While one would not believe that pharmacogenetically guided dosing will hamper efficacy, documentation of clinical equivalance would help.

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