2005]. In this meta-analysis, 3 studies assessed bleeding risks and 8 studies assessed daily dose requirements. The analysis suggested an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Patients carrying at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele. For patients carrying at least one copy of the CYP2C9*3 allele, the mean daily warfarin dose was 37% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele.

In an observational study, the risk of achieving INR >3 during the first 3 weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype. The relative risk of overanticoagulation as measured by INR >3 during the first 2 weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele [Lindh et al., 2005].

Certain single nucleotide polymorphisms in the VKORC1 gene (especially the 1639G>A allele) have been associated with lower dose requirements for warfarin. In 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses. In this study, about 30% of the variance in warfarin dose could be attributed to variations in the VKORC1 gene alone; about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined [Wadelius et al., 2005]. About 55% of the variability in warfarin dose could be explained by the combination of VKORC1 and CYP2C9 genotypes, age, height, body weight, interacting drugs, and indication for warfarin therapy in Caucasian patients [Wadelius et al., 2005]. Similar observations have been reported in Asian patients [Takahashi et al., 2006; Veenstra et al., 2005].

Murray estimated that 1 percent of the U.S. population takes warfarin, with a dose range between 1 milligram and 20 milligrams per day. Providers and patients try to stay between that INR value of 2 and 3 for 3 to 6 months and often longer. “You can imagine what a struggle that is,” Murray said.

Though the FDA label provides guidance for doses depending on the CYP2C9 and VKORC1 genotypes, the decision memo from the Centers for Medicare & Medicaid Services (CMS) for pharmacogenomic testing for warfarin response states that testing of the variants will not be covered unless the patient is in a trial developing the evidence base for the use of the test. This is an example where medical science and medical practice do not correspond, said Murray. This is one of the drivers for why genotyping to predict warfarin dosing is not being done.

Murray briefly described the Medco-Mayo Warfarin Effectiveness Study (Epstein et al., 2010), which found that warfarin genotyping reduces



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