and by nearly 70 percent when compared to cases where there is no anti-thrombotic therapy at all.

Initiation of Treatment

The International Normalized Ratio (INR), which is used to measure treatment response in patients receiving warfarin, is the ratio of the patient’s prothrombin time to a control or “normal” sample, corrected for the sensitivity of the control reagent used relative to an international standard. If the INR is either too low or too high, the patient has a three times higher risk of a clotting or bleeding event, respectively. Serious, life-threatening bleeding events (those requiring medical intervention, such as gastrointestinal or intracranial bleeding) happen in about 2 to 10 percent of patients during the first year of warfarin treatment, and approximately 1 percent of these events are fatal. Warfarin is generally underutilized, particularly in the elderly, because of concerns about bleeding events.

It is well known that certain clinical and demographic factors influence warfarin dose requirements, including age, race, sex, co-morbidities, concomitant medications, and diet. A clinician will make adjustments in the starting warfarin dose based on such known factors. Once the patient begins taking warfarin, the clinician monitors the patient closely; the monitoring is initially performed once every three to four days, then it is done weekly or every two weeks, and then, once a patient is stable, maybe every four to eight weeks. As such, warfarin dose management can already be considered “personalized medicine.” Still, a given patient’s INRs are generally in the appropriate range only 50 to 70 percent of the time. The question then, Veenstra said, is whether genomics can be used to improve warfarin management.

Warfarin Genetics

There are two genes known to be involved in outcomes related to warfarin therapy. The first, CYP2C9, codes for an enzyme that is primarily responsible for the metabolism of warfarin. Early studies identified two variants, *2 and *3, that affect the half-life of the drug. Warfarin metabolism is reduced by 40 percent in patients with the *2 variant and by 90 percent in those with the *3 variant. The prevalence of these variants in populations varies by race, occurring most often in patients of European descent and least commonly in patients of Asian descent.

Variant CYP2C9 genotypes account for about 10 percent of warfarin dosing issues. Clinical outcomes studies indicate that patients with the *2 or *3 variants have approximately twice the risk of a life-threatening bleeding event and that, during the first 90 days of therapy, that risk is



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