SALT LAKE CITY, UTAH. Patients on warfarin need to be monitored regularly to ensure that the INR (International Normalized Ratio) of their blood is within the therapeutic range of 2.0 to 3.0. Values lower than this increase the risk of ischemic stroke (stroke caused by blockage of small arteries), while values above about 4.0 increase the risk of serious internal bleeding and hemorrhagic stroke (stroke caused by rupture of small arteries). It is estimated that the target range of 2.0 to 3.0 is only achieved in about 50% of all patients at any one time. Not surprisingly, warfarin is the second most common drug implicated in emergency room visits for adverse drug reactions.
It is clear that any protocol that would increase the time patients spend within the therapeutic range would be most welcome. Preliminary studies have shown that certain gene variations significantly affect the rate at which warfarin is metabolized and thus the INR. The FDA recently approved a new genetic test designed to determine the presence or absence of three genes affecting warfarin metabolism [CYP2C9 *2, CYP2C9 *3, and VKORC1(C1173T)].
Researchers at the University of Utah School of Medicine now report on the first trial of genotype-guided warfarin dosing. Two hundred patients starting on warfarin were randomized into a standard treatment arm and the genotype-guided arm. Patients in the standard arm were given 10 mg/day of warfarin for the first two days, 5 mg/day for the third day, and then an adjusted dosage based on their day 3 INR value. Patients in the genotype-guided arm were given an initial dose of from 2 to 16 mg/day for two days as determined by an algorithm taking into account age, weight, gender, and the presence or absence of the variant genotypes. Dosage was halved on day 3 and then adjusted according to INR. The adjustment was calculated as the ratio of the estimated individual weekly maintenance dose determined with the algorithm to the standard weekly dose. INR measurements were made on days 0, 3, 5, 8, 21, 60, and 90.
Somewhat surprisingly, the use of the genotype algorithm did not reduce the time patients had an INR outside the therapeutic range. In both cases, patients were outside the range about 30% of the time pretty evenly split between being too high and too low. It should be pointed out that the study participants were hospitalized, so likely received better care and follow-up than if they had been outpatients. The researchers did notice that patients in the genotype arm required slightly fewer dose adjustments than did those in the standard arm. They also observed that patients who carried both the CYP2C9 and the VKORC1 variants had a greater risk of experiencing an INR greater than 4 than did those without these two gene variants. They recommend further, much larger (at least 2000 patients) trials to further evaluate their findings.
Anderson, JL, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation, Vol. 116, November 27, 2007, pp. 2563-70
Editor's comment: This study clearly shows that genotype-guided warfarin therapy does not reduce the time spent outside the recommended INR range of 2.0 to 3.0. It is possible that identifying carriers of both the gene variants may avoid some cases of overdosing, but this particular study did not have the statistical power to prove this. Says the lead investigator of the study, Dr. Jeffrey Anderson, " I think this approach has a lot of promise for the future, but it's maybe not ready for right now." Dr. Raymond Gibbons of the Mayo Clinic shares this view, "I definitely do not think doctors should rush out there and start giving genetic tests to all the patients they want to put on warfarin at the moment. Maybe one day this will happen, and yes, it does make sense, but we need evidence that it will have a real benefit, and that's not there yet."