Apr. 3, 2002 Genetic variants in the human enzyme that metabolizes the drug warfarin, the frequently prescribed anticoagulant Coumadin, make some patients more susceptible to serious or life-threatening bleeding.
In an article in the April 3, 2002, edition of the Journal of the American Medical Association, Dr. David Veenstra, assistant professor in the University of Washington School of Pharmacy, and his colleagues say that the two genetic variants, CYP2C9*2 and CTP2C9*3, are relatively common. This is one of the first studies to show an association between genetic variants and the risk of a serious adverse drug reaction.
The patients in the retrospective cohort study attended one of two anticoagulation clinics in the Seattle area and received warfarin to prevent blood clotting due to conditions such as atrial fibrillation (irregular heart rhythm).
"After we identified these patients' genotypes, we looked back at their medical records to determine if they had had severe bleeding incidents while they were taking warfarin," Veenstra said. "We looked at two specific variants in the gene for the enzyme that helps patients metabolize warfarin."
Compared to other patients, those with at least one of the genetic variants required more time to achieve stable dosing. In other words, it took a longer period of time to determine an effective and safe dose.
Additionally, patients with at least one of the two genetic variants had a significantly increased occurrence of a serious or life-threatening bleeding incident. Veenstra says that the small numbers of patients (58) with the genetic variants in the 185-person study group suggests caution in interpreting the study's results -- but that screening for these variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in warfarin patients.
"Warfarin is a very important drug for preventing blood clots," Veenstra said, "and the risk of bleeding is still quite low in patients with a variant. However, our results suggest that these patients perhaps should be started at lower warfarin doses and followed up more frequently by their clinicians."
Testing for the genetic variants is relatively straightforward, and only requires a simple blood test, Veenstra said.
Veenstra's co-investigators include Drs. Mitchell K. Higashi, L. Midori Kondo, Ann K. Wittkowsky, Sengkeo L. Srinouanprachanh, Fred M. Farin and Allan E. Rettie, all of the University of Washington. (Dr. Higashi is now with Glaxo SmithKline).
Funding for the study came from the University of Washington NIEHS Center for Ecogenetics & Environmental Health (NIEHS is the National Institute of Environmental Health Sciences), the UW's Institute for Public Health Genetics and the PhRMA Foundation.
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