Determining the optimal dose of warfarin for frail elderly patients is a 
challenging task because of the low dose requirements in such patients, the wide 
interindividual variability of response, and the associated risk of bleeding. 
The objective of this study was to address the influence of 13 common variations 
in eight genes on the maintenance dose of warfarin in a cohort of frail elderly 
inpatients. For our study, we enrolled 300 Caucasian subjects who were hospital 
inpatients, with a mean age of 86.7 +/- 6 years. In addition to age, genetic 
variants of VKORC1, CYP2C9, CYP4F2, and EPHX1 were found to be significant 
predictor variables for the maintenance dose of warfarin, explaining 26.6% of 
dose variability. Among 132 patients in whom warfarin therapy was initiated with 
the same low-dose regimen, we studied the relative influences of genetic and 
nongenetic factors. The time to first international normalized ratio (INR) > or 
=2 was influenced by VKORC1 and CYP2C9 genotypes (P = 0.0003 and P = 0.0016, 
respectively); individuals with multiple variant alleles were at highest risk 
for overanticoagulation (INR >4) (odds ratio, 12.8; 95% confidence interval, 
2.73-60.0). In this special population of frail elderly patients with multiple 
comorbidities and polypharmacy, we demonstrated the main impact of genetic 
factors on warfarin response.