Genetic Tests Offer New Approach to Warfarin Dosing

Researchers from the Stanford, California-based International Warfarin Pharmacogenetics Consortium reported in the February 19 New England Journal of Medicine a new way to estimate a starting dose of warfarin. This new way is based on a patient’s genetic information. The genetic information is not useful if the patient is already on a stable dose of warfarin with INRs in the therapeutic range but may be useful when a patient is first starting warfarin.

Warfarin works by interfering with the production of proteins that promote blood clotting. Vitamin K is required to make several proteins involved in blood clotting, and warfarin interferes with vitamin K function in the liver. In this study, the researchers determined if the patients had variants of two genes that are known to affect the metabolism of warfarin. The first, CYP2C9, affects how the liver processes warfarin. The second, VKORC1, activates vitamin K. The researchers then used their data to create a method to predict a more appropriate dose of warfarin for each of the more than 4,000 patients in the study. The researchers developed this new method in a group of just over 1,000 patients.

The researchers found that up to 46% of people prescribed warfarin required a dose that is higher or lower than average. Their study showed incorporating genetic information into prescribing patterns may help doctors adjust warfarin doses for these patients. While the research isn’t the first to show so, it is the largest and most ethnically diverse such study so far, with more than 5,000 patients. “This algorithm [the new approach] will flag the 10 to 30 percent of people in whom determining the ideal dose will be difficult by standard dosing methods,” said researcher Russ Altman, MD, PhD, professor of bioengineering, genetics and medicine at Stanford University School of Medicine.

A number of questions must be answered before this type of genetic testing is ready for routine use. First, no studies have shown that using this genetic information actually benefits the patient – reduces bleeding or thrombosis. In the study, using a fixed dose of warfarin to start therapy was off by about 13 milligrams (mg) per week from the ideal dose determined over time, which was on average 35 mg per week. Using clinical data, the predicted starting doses for warfarin were off by about 10 mg from the ideal weekly dose, yet even with the genetic information the predictions were still off by an average of 8.5 mg, only marginally better.

Second, these genetic tests are expensive and slow to perform; they are usually only available after the patient is already started on warfarin. Incorporating this kind of genetic information in a standard office visit will be a challenge for many clinicians, and the time lag between obtaining a DNA sample and getting a useful result can now vary from days to weeks.

In a discussion of the results, the researchers acknowledge the study did not address some of the practical aspects of using genetic test results for prescribing warfarin. Their data did not show whether the new approach could affect outcomes such as less time needed to achieve therapeutic effect, a decrease in the number of times a patient would have abnormal results of monitoring tests, or a decline in the risks of blood clots or bleeding. They noted, however, that this study is one step toward individualizing treatment for those patients who might need an adjusted dose and provides a basis for future studies that are needed to determine whether the use of genetic tests affects outcomes.

The warfarin label recommends—but does not require—genetic testing for patients newly prescribed warfarin. Food and Drug Administration (FDA) officials have said a dearth of data prevents such a requirement.

In a commentary accompanying the warfarin consortium’s findings, the FDA’s Janet Woodcock, PhD and Lawrence Lesko, MD explain that trials produce data to show whether having genetic information hastens determining the proper dose of warfarin and reduces office visits. But they also point out that the majority of people prescribed the drug won’t benefit from such research.

“Given the expected volume of genetic information and the relative paucity of randomized controlled trials involving marketed drugs, we need clear thinking about what is required for the adoption of pharmacogenetic testing,” Woodcock and Lesko write.

Sources

TE Klein et al. Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data. New England Journal of Medicine 2009; 360: 753-764.

Janet Woodcock, M.D. and Lawrence J. Lesko, Ph.D. Pharmacogenetics — Tailoring Treatment for the Outliers. New England Journal of Medicine 2009; 360: 811-813.

Press release. Patients' genetic profiles can help avoid incorrect dosing of a common, dangerous drug, say Stanford scientists. Stanford University School of Medicine. Available online at http://med.stanford.edu/news_releases/2009/february/warfarin.html through http://med.stanford.edu. Issued February 18, 2009. Accessed March 3, 2009.

Deborah Levenson. FDA Takes a Step Toward Widespread Personalized Medicine. Clinical Laboratory News 2007; 33(10). Available online at http://www.aacc.org/publications/cln/2007/Oct/Pages/inside1_1007.aspx through http://www.aacc.org. Accessed March 3, 2009.