Warfarin Pharmacogenomic Implementation: Implications for Minorities and Opportunities for Education

Recent clinical trial results cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, trials did not include many genotypes important in African Americans. We aimed to determine if omission of the CYP2C9*5, *6, *8, *11 and rs12777823G>A genotypes affects performance of pharmacogenetic dosing algorithms in African Americans. In a cohort of 274 warfarin-treated African Americans, we examined the association between CYP2C9*5, *6, *8, *11 and rs12777823G>A genotypes and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. The warfarindosing.org algorithm over-estimated doses by a median (IQR) of 1.2 (0.02 to 2.6) mg/day in rs12777823 heterozygotes (p<0.001 for predicted versus observed doses), by 2.0 (0.6 to 2.8) mg/day with the rs12777823 A homozygotes (p=0.004), and by 2.2 (0.5 to 2.9) mg/day in carriers of a CYP2C9 variant (p<0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm under-dosed warfarin by 0.8 (-2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (p<0.001) and over-dosed warfarin by 0.7 (-0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (p=0.04). Modifying the warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original warfarindosing.org (p<0.01) or IWPC (p<0.01) algorithms. These data suggest that, when providing genotype-guided warfarin dosing, it is important to account for variants prevalent in African Americans to avoid significant dosing error in this population.