Seattle, WA - Researchers at the University of Washington (Seattle, WA) say that two genetic variants in CYP2C9, the human enzyme responsible for metabolizing the anticoagulant warfarin (Coumadin® - DuPont Pharmaceuticals) significantly increase the risk of bleeding in some patients. Their findings appear in the April 3, 2002 issue of JAMA.1

Earlier studies had already established a link between patients who have the genetic variations CYP2C9*2 and CYP2C9*3,and low-dose requirements for warfarin, but this is one of the first studies to show an association between these variants and the risk of a serious adverse reaction to the anticoagulant, the researchers, led by Dr David L Veenstra (University of Washington), note.

The findings were based on a retrospective cohort study conducted at two anticoagulation clinics run by the University of Washington. The study included 185 patients with a complete history of warfarin exposure, who were treated with the drug for various indications from April 3, 1990 to May 31, 2001. All of the patients were white; blacks and Asians were excluded "because CYP2C9 allele frequencies are associated with ethnicity and the...clinic population, being predominantly white, could not provide a sample of sufficient size to control for potential confounding," the researchers write. The mean age of the patients at the beginning of therapy was 59.9 years; 63.8% of the patients were male. Just over half (51%) of the patients were receiving warfarin for atrial fibrillation (AF), with a mean follow-up time of 2.24 years. Patients were divided into 2 genotype groups: wild type, and variant (patients who had one or more of the CYP2C9 alleles).

In addition to having a significantly increased risk of bleeding events (hazard ratio [HR] 2.39; 95% CI 1.18-4.86) compared to patients in the wild-type group, patients in the variant group also had an increased risk of above-range international normalized ratios (INRs) (HR 1.40; 95% CI 1.03-1.90), and took longer to achieve stable dosing (HR 0.65; 95% CI 0.45-0.94).

"As genomic information becomes more readily available," the authors write, "it is likely that clinicians will need to consider new guidelines for patient management, especially when administering drugs with narrow therapeutic indexes such as warfarin. Variant CYP2C9 genotype could be considered a 'sensitivity factor' for low-dose requirements when initiating warfarin therapy, and patients with a variant genotype could be considered candidates for increased surveillance for bleeding risk. As oral versions of direct thrombin inhibitors become available, CYP2C9 genotyping could identify patients with impaired warfarin metabolism as potential candidates for these newer alternate therapies." In a JAMA press release, Veenstra said the testing for these variants is relatively straightforward, and only requires a simple blood test.