The oral vitamin K antagonist warfarin is still used to prevent thromboembolic events in patients with chronic conditions such as atrial fibrillation (AF). A narrow therapeutic index with a risk for serious hemorrhage and interindividual variability in response to warfarin necessitate individualization of treatment, which has been based primarily on monitoring prothrombin time via international normalized ratio (INR) testing. Compared with the therapeutic INR range (i.e., 2 to 3), an INR greater than 4 is associated with a 25-fold higher risk of bleeding in elderly patients treated with warfarin, and the percentage time in therapeutic range (PTTR) is a widely accepted read-out for treatment effect. Complications from inappropriate warfarin dosing remain among common reasons for hospitalization due to ADRs.

Pharmacologically, warfarin is a racemic mixture of R- and S-enantiomers that differ in their patterns of metabolism and in their potency of pharmacologic effects, with S-warfarin being more potent. Warfarin dose requirements can be influenced by both modifiable (e.g., compliance, dietary vitamin K intake, therapeutic level surveillance) and nonmodifiable factors (e.g., age, gender, genetics). Candidate gene studies initially demonstrated that the CYP2C9 genotype influences warfarin clearance and alters oral anticoagulant dose requirements and bleeding risks. CYP2C9 is the principal CYP2C isoenzyme in the human liver, and it is involved in the oxidative metabolism and inactivation of S-warfarin.[1]

The two most common CYP2C9 variants with diminished enzyme activities are CYP2C9*2 (c.430 C>T, p.Arg144Cys, rs1799853) and CYP2C9*3 (c.1075 A>C, p.Ile359Leu, rs1057910). Approximately 35% of Caucasians have one or two of these variant alleles; the *2 and *3 variants are virtually nonexistent in Africans and Asians (95% express the wild-type genotype [i.e., extensive metabolizers]).

Compared with the wild-type genotype (CYP2C9*1/*1), patients with two nonfunctional variants have a reduction of enzyme activity to approximately 12% for CYP2C9*2/*2 and approximately 5% for CYP2C9*3/*3. Therefore the required dose of warfarin is lowest in homozygous carriers of the CYP2C9*3 variant and intermediate in homozygote carriers of the CYP2C9*2 variant. [1]

An important finding was the identification of an additional mechanism underlying warfarin resistance in 2004—the discovery of sequence variants in the warfarin target gene VKORC1, which encodes the vitamin K epoxide reductase complex 1. This com plex regenerates reduced vitamin K for another cycle of catalysis, which is essential for the posttranslational γ-carboxylation of vita min K–dependent clotting factors. A common noncoding variant (−1639G>A, rs9923231) was shown to be significantly associated with warfarin dose requirements. Patients with the −1639 AA genotype require lower initial warfarin doses when compared with individuals with the −1639 GG variant. As the −1639G>A polymorphism affects a VKORC1 transcription factor binding site, the functional effect of the variant is thought to be related to decreased VKORC1 transcription, leading to lower protein expression. There are major differences in the distribution of VKOCR1 haplotypes among ethnic groups, and this may explain interethnic differences in coumarin requirement. [1] GWAS in patients treated with warfarin showed two major signals in and around VKORC1 and CYP2C9 and identified a much weaker association with CYP4F2. The CYP2F4 enzyme catalyzes vitamin K oxidation and the CYP4F2*3 variant (c.1297 G>A, p.Val433Met, rs2108622) was identified to require increased warfarin dosing. Overall, VKORC1 explains approximately 25% of the variance in coumarin dose requirement, CYP2C9 explains approximately 15%, and CYP4F2 explains approximately 2%.[1]

In 2010 the US Food and Drug Administration (FDA) updated the label on warfarin, providing VKORC1 and CYP2C9 genotype specific ranges of doses, and suggested that VKORC1 and CYP2C9 genotypes be taken into consideration when the drug is prescribed. In addition, dosing algorithms are available online, including genetic and nongenetic information that can help to optimize the warfarin starting dose (see CPIC Guidelines and Table1). [1]

Table1. CPIC Recommendations on Medications Whose Adverse Effects Have Been Associated with Variability in Candidate Genes and Manifest Predominantly as Hematologic Abnormalities

Three large randomized controlled trials (RCTs) have prospectively evaluated the benefit of genotype-guided warfarin dosing. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT; ClinicalTrials.gov number, NCT01119300) trial demonstrated that PGx-guided dosing is superior to a fixed-dosing regimen for achieving therapeutic INRs, whereas the US Clarification of Optimal Anticoagulation through Genetics (COAG; NCT00839657) study failed to demonstrate an improvement in PTTR with genotype guided dosing compared with the algorithm-guided dosing control arm. Potential reasons for the differences include differences in the algorithmic strategies and control arms, as well as ancestry-related differences in the nature of variant VKORC1 alleles. The Genetic Informatics Trial (GIFT; NCT01006733) of warfarin to prevent deep venous thrombosis included 1597 patients after knee or hip arthroplasty; and the rate of a composite risk of major bleeding, INR of 4 or greater, venous thromboembolism (VTE), or death was reduced in the genotype-guided warfarin dosing arm compared with clinically guided dosing arm.

Alternative anticoagulants (e.g., the four direct oral FXa inhibitors dabigatran, apixaban, rivaroxaban, and edoxaban which are not influenced by the same polymorphisms as warfarin) have been developed, and there was a major shift toward the use of these drugs (e.g., apixaban was the second highest selling drug with 9.8 billion dollars in 2018) because they are at least as effective as warfarin for stroke prevention in patients with AF or for the treatment of VTE but are associated with a significant reduced risk of intracranial bleeding and are more convenient to administer. [2] However, because the most common ADR in all currently approved anticoagulants is bleeding, precision pharmacotherapy can help hematologists to cost-effectively guide oral anticoagulant therapy to avoid this ADR with both the availability of already identified reliable genomic markers and with the choice of different approved drugs. Efforts are underway to identify genomic markers for ADRs and efficacy of the novel, now widely used direct oral FXa inhibitors and to further expand the therapeutic armamentarium (e.g., develop drugs that do not target components of the common pathway—FXa and thrombin).

References

--------------

[1] Johnson JA, Caudle KE, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics guided warfarin dosing: 2017 update. Clin Pharmacol Ther. 2017;102(3):397–404.

[2] Mackman N, Bergmeier W, Stouffer GA, et al. Therapeutic strategies for thrombosis: New targets and approaches. Nat Rev Drug Discov. 2020;19(5):333–352.

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