Pharmacogenetics of anticoagulants

Abstract

Warfarin, acenocoumarol, and phenprocoumon are among the major anticoagulant drugs worldwide. Because of their low therapeutic index and serious adverse reactions (ADRs), their wide use, and their varying kinetics and pharmacogenetic dependence, it is of great importance to explore further possibilities to forecast the dose beyond conventional INR measurements. Here, we describe particulars of the relative pharmacogenetic influence on the kinetics of these agents, the population distribution of genetics risk groups, and novel data on clinical features with influence on dose requirement and ADR risk. The usefulness of genetic information prior to and soon after start of therapy is also discussed. The current renewed focus on these issues is caused not only because of new genetic knowledge and genotyping facilities but also because of the high rate of serious ADRs. Application of these measures in the care of patients with anticoagulant therapy is important awaiting new therapeutic principles to be introduced, which may take long time still.

Figure 1

Cumulative incidence of severe bleeding and the composite of severe bleeding and all-cause mortality in the warfarin-treated WARG cohort [5].

Figure 2

Cumulative incidence or severe bleeding in warfarin-treated users and non-users of drugs potentially interacting with warfarin. Data from the WARG cohort [5].

Figure 3

Combined CYP2C9 and VKORC1 genotype frequencies. The striped bar (1/4 of the Caucasian population) indicates individuals without any variant alleles (CYP2C9*2, CYP2C9*3 or VKORC1 A), while the solid bars represent genotypes with one or more variant alleles (3/4 of the population).

Figure 4

Warfarin dose predictions based on the patient's sex, age, CYP2C9 and VKORC1 genotype, and use of interacting drugs. “Drugs” refer to the number of concomitantly used drugs potentially interacting with warfarin, causing an increased INR (drugs lowering INR are not included in the algorithm).