be required. Kawai et al ascertained 250 cases of bleeding during long term warfarin therapy and 250 controls receiving long term warfarin therapy without bleeding in BioVU.32 A candidate gene analysis (CYP2C9, CYP4F2, and VKORC1) identified CYP2C9*3 as a risk factor for bleeding with an odds ratio for major bleeding of 2.05 (95% confidence interval (CI) 1.04–4.04). The association between bleeding and CYP4F2 variants seen in an administrative database study33 was not replicated, and larger numbers may be required. Importantly, major bleeding was not a common outcome in the randomized controlled trials (RCTs), discussed further below, comparing genotype-guided therapy to conventional therapy for warfarin,34,35 although a trend toward less bleeding was seen in the largest of these trials (10/501 cases vs 4/514 cases). Another key point raised in particular by studies of warfarin pharmacogenomics, including the RCTs, is the need for ancestral diversity. Genetically-informed algorithms performed worse than conventional care in African-American (AA) subjects,34 likely reflecting the fact that different variants contribute to variable dose requirements in AAs.24,36–38
