Despite meticulous titration of anticoagulation therapy and careful attention to confounding medications, serious bleeding complications occur in some patients who receive warfarin.
How best to predict the risk of bleeding in patients who receive warfarin?
Despite meticulous titration of anticoagulation therapy and careful attention to confounding medications, serious bleeding complications occur in some patients who receive warfarin. However, without warfarin, these patients may experience strokes and the inevitable sequelae.
GENETIC TESTING FOR PROBLEM ALLELES
Genetic testing might make the future of anticoagulation with vitamin K antagonists safer; these tests can detect 2 genetic variations that increase the risk of bleeding in patients who take warfarin. In fact, the FDA recently approved updated prescribing information for warfarin that alerts health care providers to the availability of these tests.1
A meta-analysis that included 9 studies and 2775 patients found that those who carry only 1 allele for CYP2C9*2 required 17% less warfarin to achieve a therapeutic effect than patients who do not have this allele.2 Patients with the CYP2C9*3 allele needed 37% less warfarin than those without this gene variant. In one study, the likelihood of an international normalized ratio greater than 3 in the first 2 weeks of therapy was doubled in the cohort with these problem alleles.1 Overall, about 30% to 35% of patients carry the CYP2C9*2 and CYP2C9*3 alleles; these patients should probably be treated with lower doses of warfarin than those who do not have these genetic variations.
A variant of the VKORC1 gene also increases the risk of bleeding complications with warfarin. Having both the CYP2C9 and VKORC1 alleles further increases risk.
Some of the studies of these alleles were performed in select populations (Swedish, white), and it may not be possible to extrapolate from the results to predict risk in all patients. More studies need to be performed in disparate populations before screening for these alleles becomes routine.
THE TRUE COST OF SCREENING
The price of testing for the genetic variations ranges from $125 to $500, depending on the laboratory. However, consider the far greater costs of warfarin-induced bleeding complications.
The number of warfarin prescriptions increased from 21 million in 1998 to 31 million in 2004. Warfarin was the leading cause of fatal adverse drug events in 2003 and 2004, and it is responsible for about 29,000 emergency department visits each year as a result of excessive bleeding.3 Thus, genetically informed dosage adjustments may save a great deal of money by preventing costly complications (eg, hemorrhagic strokes) and, more important, may save lives.
US Food and Drug Administration. FDA approves updated warfarin (Coumadin) prescribing information. Available at:
. Accessed November 7, 2007.
Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis.
Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action.
Arch Intern Med