Initial variability in the international normalized ratio (INR) response to warfarin was more strongly associated with genetic variability in the pharmacologic target of warfarin, vitamin K epoxide reductase ( VKORC1), than with cytochrome P-450 2C9 ( CYP2C9), according to a study in the March 6 issue in the New England Journal of Medicine.
Ute I. Schwarz, MD, departments of medicine and pharmacology at Vanderbilt University School of Medicine in Nashville, Tenn., and colleagues, undertook the study because while genetic variants of the enzyme that metabolizes warfarin, ( CYP2C9), and of a key pharmacologic target of warfarin, ( VKORC1), contribute to differences in patients' responses to various warfarin doses, but the role of these variants during initial anticoagulation is not clear.
Last year, the FDA approved tests for the two million patients nationwide who take warfarin to prevent blood clots from forming after a stroke, heart attack or surgery. While the test is not widely applied, the authors said their findings may refine the approach and eventually, reduce the side effects from the drug.
In 297 patients starting warfarin therapy, the investigators assessed CYP2C9 genotypes ( CYP2C9 1, 2 and 3), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the INR) and bleeding events.
The study outcomes were based on the time to the first INR within the therapeutic range, the time to the first INR of more than four, the time above the therapeutic INR range, the INR response over time and the warfarin dose requirement.
As compared with patients with the non-A/non-A haplotype, the researchers found that patients with the A/A haplotype of VKORC1 had a decreased time to the first INR within the therapeutic range and to the first INR of more than four. In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first INR within the therapeutic range, but was a significant predictor of the time to the first INR of more than four, according to the authors.
Both the CYP2C9 genotype and VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy, according to the researchers.
“This is another piece of information that says genetics may play a big role in determining not only what dose you end up on, but how quickly you get there,” said co-author Dan Roden, assistant vice chancellor for personalized medicine at Vanderbilt. “Knowing whether someone carries a variant can drive the doctor to start at a lower dose.”