An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients

Abstract

The objective of this study was to assess the relative influence of VKORC1 and CYP2C9 genetic variants on several clinical outcomes related to warfarin treatment. We conducted a retrospective cohort analysis of 172 anticoagulation clinic patients followed from warfarin initiation. We assessed the following clinical outcomes: time to stable dose; time in, above, and below therapeutic range; the probability of overanticoagulation (international normalized ratio [INR] >5); frequency of anticoagulation clinic visits; and the contribution of genetics to maintenance dose. Patients with CYP2C9 variants, compared to those without, achieved stable dose 48% later (p < 0.01), spent a higher proportion of time above range in the first month of therapy (14% vs. 25%, p = 0.07), and had a higher odds ratio (OR) of an INR >5 (OR: 4.15, p = 0.03). In contrast, the only statistically significant effect with VKORC1 was a higher odds of an INR >5 (OR: 4.47, p = 0.03) for patients homozygous for the VKORC1 low-dose haplotype (AA) compared to heterozygotes. We did not detect an influence of CYP2C9 nor VKORC1 on the frequency of clinic visits. CYP2C9 alone, VKORC1 alone, and a combination of genetic and clinical factors explained 12%, 27%, and 50%, respectively, of the variation in warfarin maintenance dose. In conclusion, genetic variation in VKORC1 appears to have a different influence than CYP2C9 on anticoagulation-related outcomes such as bleeding events and time in therapeutic range. This difference may be due, in part, to pharmacokinetics factors (e.g. drug half-life), which are influenced primarily by CYP2C9; these findings should be confirmed in additional studies.

Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study

“…1). These findings are consistent with two recent studies [26,42], but are at odds with the findings of Schwarz et al [25]. This may reflect the different loading dose regimens used between the two populations, with the higher loading doses in our population being reflected in the effect of CYP2C9 variation initially.…”

Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy

“…Furthermore, several studies published to date have described the contribution of genetic variations to initial warfarin response variability in patients whose treatment was initiated with respective anticoagulation clinic regimens, likely with similar INR response-monitoring schedules as WRAPID. 22,23,43 Thus, we believe that pharmacogenetics-based initiation, particularly with the use of loading doses, should result in a safe and similar rise to optimal anticoagulation responses among VKORC1 and CYP2C9 genotype groups. Supportive of the role of genotype-guided initiation for warfarin therapy, a recent study suggested that genotyping for patients in whom therapy was being initiated significantly reduced the hospitalization rate for bleeding or thromboembolic events compared with a control group.…”

“…Such pooling of CYP2C9*2 and *3 variants has been used previously by other studies for similar reasons. 8,41,43 In particular, these studies demonstrated that among patients whose therapy was initiated with standard dosing protocols, CYP2C9 variant carriers spent more time above therapeutic INR, had an elevated risk of overanticoagulation, and a lower dose requirement overall.…”

Editor´s choice articles 2006–2008

“…In an important study, Meckley et al (31) showed that genetic variation in the vitamin K-epoxide reductase VKORC1 appears to have a different influence than the cytochrome P450-enzyme CYP2C9 on anticoagulation-related outcomes such as bleeding events and time in therapeutic range. Nonetheless, they found that this difference may be due, in part, to pharmacokinetics factors (e.g.…”