WARFARIN Study Purpose

The purpose of the WARFARIN Study is to determine the utility of genetic testing in reducing the incidence of adverse events, including both bleeding and thromboembolism, associated with the initiation of warfarin therapy.

Clinical Issues with Warfarin Therapy

Warfarin is the most widely prescribed anticoagulant for the prevention and treatment of arterial and venous thromboembolic diseases including deep vein thrombosis (DVT), pulmonary embolism (PE), ischemic stroke, myocardial infarction (MI), and atrial fibrillation. Warfarin therapy is complicated by a narrow therapeutic range: individuals with international normalized ratio (INR) values <1.8 are at risk for recurrent thromboembolism, while those with INR values >4 are at risk for increased bleeding.

Additionally, a wide variation in response among individuals is seen, e.g., some patients may require a dose of 1 mg to achieve anticoagulation, while others require a dose of up to 20 mg. This large range makes determining the correct dose difficult and leads to a significant incidence of adverse events, ie, bleeding and thromboembolism, especially during the initiation of warfarin therapy.

Warfarin Response Test

Mutations in the VKORC1 gene are associated with either decreased or increased responsiveness (sensitivity) to warfarin. Likewise, mutations in CYP2C9 have been shown to be associated with decreased warfarin metabolism. Specifically, the common promoter polymorphism -1639G>A in VKORC1 and genetic variants of CYP2C9, CY2C9*2 (RI44C), and CYP2C9*3 (I359L) are independently associated with increased responsiveness to warfarin therapy.

Together, VKORC1 and CYP2C9 polymorphisms, along with well known clinical factors, account for approximately 60% of an individual's response to warfarin. Approximately 42%-46% of Caucasians, 3%-13% of Africans, and 90%-95% of Asians carry at least one copy of the -1639G>A allele. Likewise, approximately 33% of Caucasians, 3%-13% of Africans, and 2%-8% of Asians are positive for at least one of the CYP2C9 poor metabolizer variants.

The assay determines the variants of VKORC1 and CYP2C9 (CY2C9*2 and CYP2C9*3) and is designed to assist in initial dosing and maintenance dosing.

Results and Dosing

Test results include the suggested starting dose and maintenance dose of warfarin based on the genotype data and other clinical factors. The algorithm used for determining the dose can be accessed at www.warfarindosing.org. Using the algorithm, measured INR data can be input to more accurately determine subsequent warfarin doses.