Personalized approach of medication by indirect anticoagulants tailored to the patient-Russian context: what are the prospects?

Abstract

Indirect anticoagulants such as warfarin are the 'gold standard' for prevention and treatment of thromboembolic complications in patients at risk (in atrial fibrillation of valvular and nonvalvular etiology, the presence of artificial heart valves, orthopedic and trauma interventions, and other pathological conditions). A wide range of doses required to achieve a therapeutic effect indicates the need for a personalized approach to the appointment of warfarin. In addition to the dependence on the patient's clinical characteristics (sex, age, smoking status, diagnosis), there is a clear association between the warfarin dose and the carriage of certain allelic variants of key genes that makes it possible to apply molecular genetic testing for individual dose adjustment. This provides a more rapid target anticoagulant effect and also reduces the risk of bleeding associated with a possible overdose of warfarin. Implementation of this approach will allow more wide and safe application of indirect anticoagulants in Russia for needy patients.

Figure 1

Clinical potential of pharmacogenomics. Patients with the same diagnosis are usually treated in the same way, although their responses to drug therapy will not be the same. Pharmacogenetics has the possibility to predict those patients who are likely to have the desired response to the drug, those who are likely to have little or no benefit and those at risk for toxicity (adapted from [1]).

Figure 2

Warfarin pathway, pharmacodynamics. The coagulation cascade requires vitamin K in the reduced form as a cofactor for gamma-glutamyl carboxylase to convert inactive factors II, VII, IX, and X to the active forms. Vitamin K is oxidized during this process to vitamin K epoxide. The enzyme VKOR converts vitamin K epoxide back into reduced vitamin K. Warfarin inhibits VKOR, decreasing vitamin K availability, diminishing activatable factors II, VII, IX, and X, and thus inhibiting coagulation (adapted from [2] and [9]).

Figure 3

Metabolism of warfarin. Warfarin, an enantiomeric mixture of equal concentrations of R- and S-forms, is 93 ± 8% absorbed from the gastrointestinal tract. The rate of metabolism for S-warfarin is approximately three times (3×) faster than that for R-warfarin [2].

Figure 4

Variability in warfarin dosingat steady state. In any given patient population, the daily therapeutic warfarin dose will vary by more than an order of magnitude (adapted from [10]).

Figure 5

Factors that correlate withwarfarin dose. A number of factors affect warfarin dosing, including nongenetic factors (drug-drug interactions, environmental factors, diet, alcohol consumption, and smoking) and genetic factors. Genetic factors explain about 40% of warfarin dosing variability (adapted from [16]).

Figure 6

Effect of VKORC1 haplotypeA or B onwarfarin dosage. The asterisks denote p < 0.05 for the comparison with haplotype A/A, and the daggers denote p < 0.05 for the comparison with haplotype A/B. The T bars represent standard errors (adapted from [15]).

Figure 7

CYP2C9 polymorphisms and warfarindose. Bar graph showing the relationship of cytochrome P450 2C9 genotype and warfarin dose. *1/*1 is homozygous wild type and other labels show variants (adapted from [29]).

Figure 8

Online pharmacogenetic algorithm [65].

Figure 9

Algorithm to work withthe challenging group ofpatients.