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Many prescriptions, about 30 million, are written for warfarin each year.1 Warfarin, a vitamin K antagonist, is an oral anticoagulant with a narrow therapeutic window. Warfarin initiation is associated with an 11.8% increased risk of serious bleed during the first month of therapy due to supratherapeutic international normalized ratio (INR).2 Initiating warfarin can be difficult because of inter-patient variability in dose requirements. This inter-patient variability is explained in part by the genetic variants of warfarin metabolizing enzymes. Warfarin is metabolized through the cytochrome P450 system largely by the enzyme CYP2C9.3 Six variants of the CYP2C9 enzyme have been identified that result in decreased warfarin clearance. The two most common and most studied alleles are CYP2C9*2 and CYP2C9*3, which occur in about 10% of the caucasian population and result in as much as 37% decreased clearance of warfarin.4 Other less common variants of this enzyme include CYP2C9*5, *6, *8, and *11 in the African American population and CYP2C9*5, *9, and *11 in the caucasian population.3 Variants of this enzyme, along with variants of vitamin K epoxide reductase (VKOR), are associated with lower warfarin maintenance dose requirements.

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Warfarin inhibits VKOR, thereby reducing the amount of vitamin K produced.3 The VKORC1 variant of this enzyme is associated with up to an 88% reduction in warfarin dose requirements.5 There is debate on whether or not CYP2C9 and VKOR genotype information should be obtained to guide initial warfarin dosing. Recent studies, including the Clarification of Optimal Anticoagulation through Genetics (COAG) trial and the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial, are conflicting in whether genotype-guided warfarin dosing improves time in therapeutic INR range.6,7

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The COAG trial was a double-blind, randomized, controlled trial performed at 18 clinical centers in the United States.6 They compared a genotype-guided dosing algorithm to a clinically-guided dosing algorithm during the first five days of warfarin therapy. The genotype-guided dosing algorithm for days 1 through 3 was based on presence of CYP2C9*2, CYP2C9*3, and/or VKORC1, in addition to age, race, smoking status, body surface area, amiodarone use, target INR, and if had aDVT/PE as indication for warfarin therapy. The clinically-guided arm algorithm used the same factors except for the genotype information. For warfarin dosing on days 4 and 5, both study arms considered additional factors of diabetes, stroke, fluvastatin use, natural log INR, and doses given on days 1 through 3. After day 5, a standardized dosing algorithm was used for both groups for the remaining 23 days of the study. The primary endpoint was percentage time in therapeutic range (INR 2.0 to 3.0) from completion of the intervention period (day 4 or 5) through day 28 of therapy. There were 1,015 patients enrolled with no significant differences in baseline characteristics. After four weeks, the primary endpoint of mean percentage time in therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically-guided group (adjusted mean difference −0.2%; 95% CI, −3.4 to ...

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