Phenprocoumon dose requirements, dose stability and time in therapeutic range in elderly patients with CYP2C9 and VKORC1 polymorphisms

Background: Dose requirements of Vitamin K antagonists are associated with CYP2C9 and VKORC1, but, compared to warfarin, less data is available about phenprocoumon. Furthermore, the effects on dose stability and anticoagulation quality are still unclear. Methods: Aim was to scrutinize phenprocoumon dose requirements, dose stability and anticoagulation quality in association to CYP2C9 and VKORC1 in a natural cohort of elderly primary care patients. As a subgroup within the IDrug study, phenprocoumon treated patients with at least two INR values within three months before enrollment (n = 209) were analyzed concerning average weekly dose, standard deviation of weekly dose (intra-subject variability), constant dose (yes/no), average INR and TTR grouped by CYP2C9 and VKORC1 (and combinations). Results: Average weekly dose per patient was 14.4 ± 5.3 mg, 11.9 ± 4.0 mg and 11.2 ± 4.3 mg in CYP2C9 wildtypes, ^∗2 and ^∗3 carriers (p <.0001) and 16.0 ± 4.2 mg, 13.3 ± 5.1 mg and 8.0 ± 2.7 mg per week in VKORC1 CC, CT and TT genotypes, respectively (p <.0001). Significant differences concerning intra-subject variability were detected among all groups (p <.0001) with the smallest variability in CYP2C9^∗3 carriers. TTR medians were 75.4%, 79.4% and 100% in wildtypes, ^∗2 and ^∗3 carriers, respectively (p = 0.0464). The proportion of patients with perfect control was highest among ^∗3 carriers, but this result was not significant (p = 0.0713). Discussion: Our analyses support the results of previous investigations regarding genotype-associated dose requirements and raise the hypothesis that dose stability and anticoagulation quality may be increased in CYP2C9^∗3 carriers. However, our data should be treated cautiously due to the small sample size.