Anticoagulation endpoints with clinical implementation of warfarin pharmacogenetic dosing in a real-world setting: A proposal for a new pharmacogenetic dosing approach

Abstract

Achieving therapeutic anticoagulation efficiently with warfarin is important to reduce thrombotic and bleeding risks and is influenced by genotype. Utilizing data from a diverse population of 257 patients who received VKORC1 and CYP2C9 genotype-guided warfarin dosing, we aimed to examine genotype-associated differences in anticoagulation endpoints and derive a novel pharmacogenetic nomogram to more optimally dose warfarin. We observed significant differences across patients with 0, 1, or ≥2 reduced-function VKORC1 or CYP2C9 alleles, respectively, in time to achieve therapeutic international normalized ratio (INR) (7.8 ± 5.8, 7.2 ± 4.7, and 5.4 ± 4.6 days, P = 0.0004) and mean percentage of time in therapeutic range in the first 28 days (22.2, 27.8, and 32.2%, P = 0.0127) with use of existing pharmacogenetic algorithms. These data suggest that more aggressive dosing is necessary for patients with 0 to 1 VKORC1/CYP2C9 variants to more efficiently achieve therapeutic anticoagulation. Herein, we provide a novel kinetic/pharmacodynamic-derived dosing nomogram optimized for a heterogeneous patient population.

Figure 1

Box plots of daily warfarin dose during hospitalization by genetic subgroups for all study participants. The diamonds represent means and lines within boxes represent medians. The upper and lower boundaries of the boxes mark the 3rd and 1st quartile. The whiskers above the boxes represent the smaller value of the maximum and 3rd quartile plus 1.5 multiplied by the interquartile range, whereas the whiskers below the boxes represent the larger value of the minimum and 1st quartile minus 1.5 multiplied by the interquartile range. Circles represent outliers.

Figure 2

Kaplan-Meier time-to-event function estimates for patients with 0, 1, or ≥2 reduced-function alleles

Figure 3

Percentage of time in INR range (as calculated by Rosendaal method)(45) that is i) above 3 (red) ii) below 2 (blue) and iii) within 2-3 (green) for patients with 0, 1, and ≥2 variant alleles

Figure 4

A-C) Comparison of warfarin maintenance doses for a 70-year old individual calculated using our nomogram vs. dose recommendations shown on the FDA-approved label for warfarin (Coumadin®) (29) as stratified by VKORC1 and CYP2C9 genotypes. Error bar indicates the recommended dose range from the label.