By Robert Flaumenhaft, MD, PhD

2008-07-01

Dr. Flaumenhaft indicated no relevant conflicts of interest.

Schwarz UI, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008;358:999-1008.

How much would you pay to know your patient's response to warfarin before you even gave the first dose? This question may be more than academic as accumulating data indicate that gene variants of enzymes mediating the pharmacokinetics and pharmacodynamics of warfarin are predictive of an individual patient's response to warfarin.

Studies have focused primarily on two genes. VKORC1 encodes vitamin K epoxide reductase, which recycles vitamin K epoxide to the reduced form of vitamin K and is the major target of warfarin. Individuals with different VKORC1 haplotypes require different doses of warfarin for therapeutic anticoagulation. CYP2C9 encodes cytochrome P-450 2C9, the primary enzyme required for metabolic clearance of warfarin. Polymorphisms of CYP2C9 also contribute to variability in sensitivity to warfarin. In a recent prospective study, Schwarz and colleagues evaluated the association of variants of VKORC1 and CYP2C9 with changes in INR following initiation of warfarin therapy.

Bleeding risk associated with warfarin therapy is relatively greater in the first month of therapy. Among the primary outcomes evaluated by Schwarz, et al. was the association of gene variants of VKORC1 and CYP2C9 with the first INR within therapeutic range and time to first INR >4. The rate of achieving the first INR in therapeutic range was higher by nearly 2.4-fold in patients with the A/A haplotype of VKORC1 compared with non-A haplotypes. The rate to first INR >4 was increased by >2.5-fold in patients with the A/A haplotype. Rates for achieving these endpoints were even increased in patients with a single A allele. CYP2C9 polymorphisms had less influence on initial response to warfarin. No effect on time to first therapeutic INR was detected. CYP2C9*2 and CYP2C9*3 variants were associated with somewhat shorter times to first INR >4 than the CYP2C9*1 variant. Thus, genetic variability in VKORC1 is more closely associated with initial sensitivity to warfarin than genetic variability in CYP2C9.

Warfarin remains the most widely used oral anticoagulant for patients with venous thromboembolic disease. However, its narrow therapeutic window is a substantial liability because supratherapeutic anticoagulation can result in bleeding, subtherapeutic anticoagulation is a risk for thrombosis, and there is a wide variation in individual dose requirements. The ability to predict an individual patient's response to warfarin therapy a priori could reduce the time to achieve a therapeutic INR, increase time within the therapeutic range, and potentially reduce bleeding and recurrent thrombotic episodes. This study demonstrates that genetic variants of VKORC1 constitute a significant determinant of initial response to warfarin therapy. Screening for VKORC1 haplotypes may improve warfarin dosing algorithms.

The FDA has recently updated the label of warfarin to encourage pharmacogenetic testing to help guide dosing of individuals initiating warfarin therapy. As information on the role of genetic profiling for warfarin therapy becomes available, the impact of such screening to improve efficacy and safety will be subject to increasing scrutiny. Is the screening cost-effective? Should all patients be screened? Should we test only subpopulations at substantial risk for bleeding or clotting? Can test results be obtained rapidly enough to influence initial dosing? Genetic screening to improve warfarin therapy may or may not find a role in the routine management of patients with thrombotic disease. However, it has already proven to be an important test case in the nascent field of pharmacogenetics.

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