Abstract 16860: Warfarin Dosing in Patients with the CYP2C9*5 Variant
Introduction: The narrow therapeutic range of warfarin can lead to bleeding complications from trial-and-error dosing. Pharmacogenetic dosing can improve accuracy and safety of warfarin therapy in Caucasians, but is less accurate in populations of African ancestry. The cytochrome P450 2C9*5 (CYP2C9*5) SNP affects warfarin metabolism and is common in African Americans. In-vitro studies suggest CYP2C9 *5 is associated with reduced clearance of warfarin, but current dosing algorithms do not account for this variant. Quantifying the association between this SNP and warfarin requirements may improve dose prediction, especially in African Americans.
Hypothesis: The CYP2C9*5 SNP is associated with lower warfarin dose requirements.
Methods: This was a multi-centered, cross-sectional analysis of patients taking warfarin for a variety of indications. To improve statistical power, the cross-section analysis was enriched with patients known to have the CYP2C9*5 SNP. The main outcome measure was the magnitude of reduction in warfarin requirements, after adjustment for other genetic and clinical factors known to affect warfarin dose.
Results: A total of 2278 patients were genotyped. In the cross-section cohort, the CYP2C9*5SNP was present in 2.7% of African-American and 0.07% of Caucasian patients. Overall, patients with the*5 variant (N = 20) were found to have a 28% lower therapeutic dose than predicted by current pharmacogenetic dosing algorithms (P < 0.001). In the African-American subgroup, the therapeutic dose also was 28% (1.9 mg/day) lower than predicted in *5 carriers and was 4.3% (0.24 mg/day) greater than predicted in non-carriers (p<0.001).
Conclusion: Patients carrying the CYP2C9*5 SNP require a clinically relevant reduction in warfarin dose. Given the potential to improve accuracy in warfarin dose, we have incorporated these findings onto www.WarfarinDosing.org.
- © 2010 by American Heart Association, Inc.