Introduction

Warfarin (brand name Coumadin) is an anticoagulant (blood thinner). Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors and is used in the prevention and treatment of various thrombotic disorders. Warfarin is a drug with narrow therapeutic index; thus, a small change in its plasma levels may result in concentration dependent adverse drug reactions or therapeutic failure. Therefore, the dose of warfarin must be tailored for each patient according to the patient’s response, measured as INR (International Normalized Ratio), and the condition being treated.

There is a wide inter-individual variability in the dose of warfarin required to achieve target anticoagulation, and the time it takes to reach target INR. Approximately half of this variability is known to be caused by clinical or lifestyle factors (e.g., a patient’s age, weight, BMI, gender, smoking status, existing conditions, and concomitant medications) and by genetic factors (known genetic factors include variants in the VKORC1, CYP2C9, CYP4F2 genes, and the rs12777823 variant in the CYP2C gene cluster on chromosome 10) (1).

The VKORC1 and CYP2C9 genotypes are the most important known genetic determinants of warfarin dosing. Warfarin targets VKORC1, an enzyme involved in vitamin K recycling. A common variant, VKORC1, c.-1639G>A, is associated with an increased sensitivity to warfarin and lower dose requirements. The CYP2C9 enzyme metabolizes warfarin and the variants CYP2C9*2 and *3, are also associated with lower dose requirements.

The FDA-approved drug label for warfarin states that CYP2C9 and VKORC1 genotype information, when available, can assist in the selection of the initial dose of warfarin. The label provides 2 sets of warfarin dosing recommendations, for when the CYP2C9 and VKORC1 genotypes are either known (Table 1) or not known (taking into account clinical factors, the initial dose of warfarin is usually 2–5 mg once daily) (1).

In addition, the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) has published recommendations for the initial standard dose of warfarin. A dose reduction is recommended for individuals who are CYP2C9 poor and intermediate metabolizers (with the exception of intermediate metabolizers with the CYP2C9*1/*2 genotype, no dose change is required), and a dose reduction is recommended for individuals who carry 2 copies of the variant VKORC1 A allele (VKORC1, c.-1639G>A/A) (Table 2) (2, 3).

Recently, genetic variation in the CYP4F2 gene, and a variant near the CYP2C gene cluster, rs12777823, have been associated with influencing warfarin therapy. The CYP4F2*3 variant is associated with a modest increase in warfarin dose requirements in individuals with European or Asian ancestry, while in individuals with African ancestry, the rs12777823 A/G or A/A genotype is associated with decreased warfarin dose requirements.

The 2017 Update of the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing, provides warfarin dosing recommendations for adults with and without African ancestry, and also for pediatric patients (see Therapeutic Recommendations). CPIC recommends that these dosing guidelines are applied after a warfarin dose has been calculated using a validated pharmacogenetic algorithm, which includes genotype information for VKORC1, c.-1639G>A and CYP2C9*2 and *3 (Figure 1) (4)

Drug: Warfarin

Warfarin is an anticoagulant used in the prevention and treatment of venous thrombosis, pulmonary embolism, and the complications associated with atrial fibrillation and/or cardiac valve replacement. Warfarin is sometimes prescribed to reduce the risk of stroke after a myocardial infarction (MI).

Warfarin has no direct effect on an established thrombus. However, once a thrombus has occurred (e.g., deep venous thrombosis), the goal of warfarin therapy is to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may be fatal (e.g., pulmonary embolism).

Warfarin is a teratogen – an agent that can cause abnormalities in a developing fetus. Therefore, warfarin use in pregnancy is contraindicated, except in women with mechanical heart valves who have a particularly high risk of thromboembolism. If warfarin is used in pregnancy, or if a patient becomes pregnant while taking warfarin, she should be informed of the potential risks to the fetus (1).

Warfarin exposure in pregnancy can cause fetal death, neonatal death, and warfarin syndrome - a pattern of developmental abnormalities that most commonly affect bone and cartilage, causing nasal hypoplasia, and a “stippled” appearance to the ends of long bones. The risk of warfarin teratogenicity appears to be greatest between the 6^th and 12^th week of pregnancy, but toxicity before or after this period is still possible (5, 6).

Warfarin exerts its anticoagulant effect by inhibiting the enzyme encoded by VKORC1, which catalyzes the conversion of vitamin K epoxide to the active reduced form of vitamin K, vitamin K hydroquinone. Vitamin K hydroquinone is an essential cofactor in the synthesis of several clotting factors and decreased availability of vitamin K hydroquinone leads to decreased activity of the clotting factors II, VII, IX, and X, and the anticoagulant proteins C and S (7).

Warfarin is administered as a racemic mixture of the R- and S- stereoisomers. (S)-warfarin is 2–5 times more potent than (R)-warfarin and is mainly metabolized by CYP2C9. (R)-warfarin is mainly metabolized by other cytochrome P450 enzymes (8).

The initial and maintenance doses of warfarin must be tailored to each patient, and monitoring of the international normalized ratio (INR) should be performed in all patients treated with warfarin. The INR is a standardized measurement of prothrombin time, which is the time it takes for blood to clot. In healthy individuals, the INR is approximately one (range: 0.8–1.1). The goal of warfarin therapy is to achieve an INR in a target range for the condition being treated (most commonly 2–3).

The FDA-approved drug label for warfarin carries a boxed warning cautioning of the risk of bleeding, which can be fatal. Bleeding is more likely to occur within the first month, and risk factors include a high intensity of anticoagulation (INR greater than 4), age greater than or equal to 65, and a history of highly variable INRs. Other serious adverse events associated with warfarin therapy include necrosis of the skin and other tissues, particularly when used prematurely to manage thrombosis associated with heparin-induced thrombocytopenia (HIT).

Since warfarin is a drug with a narrow therapeutic index, an optimal starting dose may reduce the time taken to reach a stable INR and reduce the risk of having either a high INR (with a risk of bleeding) or a low INR (with a risk of thrombosis). Known factors that influence an individual’s response to the initial dose of warfarin include clinical and lifestyle factors (e.g., age, race, body weight, height, gender, concomitant medications—including those that compete for binding to albumin, comorbidities, diet, nutritional status) and genetic factors (e.g., CYP2C9 and VKORC1 genotypes). Therefore, the initial dose should be modified to take into account these and any additional patient-specific factors that may influence warfarin dose requirement.

The FDA-approved drug label for warfarin suggests considering a lower initial and maintenance dose of warfarin for elderly and/or debilitated patients, and in Asian patients. The drug label recommends against the routine use of loading doses because this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. However, loading doses are used in practice, and are addressed in CPIC recommendations (4).

The drug label also provides a dosing table of expected maintenance daily doses of warfarin based on CYP2C9 and VKORC1 genotypes (Table 1). The label states that if the patient’s CYP2C9 and/or VKORC1 genotypes are known, to consider these doses when selecting the initial dose of warfarin. However, CPIC states that genetics-based algorithms, such as the International Warfarin Pharmacogenetics Consortium (IWPC), predicts warfarin dose better than the table in the drug label (9).

CPIC has provided dosing recommendations that take into account whether the patients VKORC1 and CYP2C9*2 and *3 genotype is available, and a patient's self-identified ancestry (African ancestry or non-African ancestry). For patients with African ancestry, the presence of CYP2C9*5, *6, *8, and *11 alleles, and rs12777823 are also taken into account (4).

Gene: VKORC1

Genetic variation in the VKORC1 gene is the most important known genetic factor that influences warfarin dosing. Pharmacogenomic algorithms for warfarin dosing routinely include testing for VKORC1.

The VKORC1 gene encodes the vitamin K epoxide reductase enzyme, which catalyzes the rate-limiting step in vitamin K recycling (converting vitamin K epoxide to vitamin K). This enzyme is also the drug target for warfarin.

A common non-coding variant, VKORC1, c.-1639G>A (rs9923231), is associated with an increased sensitivity to warfarin and lower dose requirements (10). The polymorphism occurs in the promoter region of VKORC1 and is thought to alter a transcription factor binding site, leading to lower protein expression. As a result, patients starting warfarin therapy who are carrying at least one “A “allele at -1639 locus require lower initial and maintenance doses compared with patients carrying a G/G genotype at this locus.

The VKORC1, c.−1639G>A allele frequency varies among different ethnic groups. It is the major allele (around 90%) in Asian populations and may be one of the contributing factors for lower warfarin dosing requirements often observed in patients of Asian descent. It is also common in Caucasians (around 40%) and African-Americans (around 14%) (11-13).

Less commonly, missense mutations in VKORC1 can lead to warfarin resistance and higher dose requirements (14, 15).

The Cytochrome P450 Superfamily

The cytochrome P450 superfamily (CYP450) is a large and diverse group of enzymes that form the major system for metabolizing or detoxifying lipids, hormones, toxins, and drugs in the liver. The CYP450 genes are very polymorphic and can result in reduced, absent, or increased enzyme activity.

CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, CYP3A4, and CYP1A2. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and CYP3A4. The FDA-approved drug label for warfarin states that drugs that inhibit or induce CYP2C9, CYP1A2, and/or CYP3A4 can influence warfarin exposure and increase or decrease the INR.

The influence of genetic variants in CYP2C9, CYP4F2, and the CYP2C gene cluster, is discussed below.

Gene: CYP2C9

Genetic variation in the CYP2C9 gene is a well-known genetic factor that influences warfarin dosing. Pharmacogenomic algorithms for warfarin dosing routinely include testing for CYP2C9.

The CYP2C9 gene is highly polymorphic, with over 60 star (*) alleles described and currently cataloged at the Pharmacogene Variation (PharmVar) Consortium. The CYP2C9*1 allele is the wild-type allele, and is associated with normal enzyme activity and the normal metabolizer phenotype.

The frequencies of the CYP2C9 alleles vary between different ethnic groups (16-18). In individuals of European descent, the 2 most common variant alleles associated with reduced enzyme activity are CYP2C9*2 (c.430C>T; rs1799853) and *3 (c.1075A>C; rs1057910). The *2 allele is more common in Caucasian (10-20%) than African (0-6%) populations (19). The *3 allele is less common (<10% in most populations), but rare in African populations (20).

Compared to normal metabolizers, individuals of European ancestry who carry one or two copies of *2 or *3 are more sensitive to warfarin—they require lower doses and are at a greater risk of bleeding during warfarin initiation (21-25).

In African-Americans, CYP2C9*5, *6, *8, and *11 variant alleles contribute to the variability in patient response to warfarin (26). These alleles are found more commonly in individuals with African ancestry, and collectively, are more common than the CYP2C9*2 and *3 alleles.

Gene: CYP4F2

The CYP4F2 enzyme is involved in the metabolism of vitamin K in the liver. It is a vitamin K oxidase enzyme and is an important counterpart to VKORC1, a vitamin K reductase enzyme. While VKORC1 catalyzes vitamin K recycling, CYP4F2 limits the excessive accumulation of vitamin K in the liver by catalyzing the production of hydroxylated vitamin K, which is removed from the vitamin K cycle (27).

A genetic variant CYP4F2*3 (c.1297C>T, rs2108622), has been found to influence warfarin dosing. The frequency of the variant T allele is approximately 30% in Caucasians and Asians, and approximately 7% in African-Americans (28).

The CYP4F2 enzyme with an amino acid change due to missense *3 allele is thought to be less active, leading to a rise in hepatic vitamin K. This leads to a higher dose of warfarin being required to achieve therapeutic anticoagulation (by inhibiting vitamin K-dependent clotting factors) (27).

The first studies of CYP4F2 and warfarin dosing reported that Caucasian individuals with the variant rs2108622 TT genotype required approximately 1 mg/day more warfarin than individuals with the rs2108622 CC genotype (28). Two more recent meta-analyses concluded that “T carriers” (individuals with CT or TT genotypes) require approximately an 8–11% increase in warfarin dose, compared to CC individuals. However, data did not support CYP4F2 influencing warfarin requirements in African-Americans (29, 30).

The inclusion of this CYP4F2 variant in warfarin dosing models moderately improves the accuracy of warfarin dose prediction for individuals of European or Asian ancestry, but not for individuals of African ancestry. Accordingly, CPIC recommends that the dose of warfarin should be increased by 5–10% in non-African-American individuals who carry the CYP4F2*3 variant (optional recommendation). CPIC makes no recommendation for African-Americans, stating that data do not support an impact of this variant on warfarin dosing in those of African ancestry (moderate recommendation) (4, 29, 30).

Gene: CYP2C rs12777823

The genetic variant rs12777823, located in the CYP2C gene cluster, is a non-coding variant associated with reduced warfarin dose requirements in African-Americans. The rs12777823 variant was associated with altered warfarin clearance, and individuals with this variant require a lower maintenance dose of warfarin than individuals who do not have this variant (31).

The rs12777823 variant is common in African-Americans (allele frequency 25%) and is also common in other populations; for example, Japanese (32%), and European (15%). However, the association with warfarin dose requirement has only been found for African-Americans: individuals who are heterozygous for the rs12777823 A allele require a dose reduction of warfarin by 7 mg/week, and individuals who are homozygous for the rs12777823 A allele require a dose reduction of warfarin by 9 mg/week (31). Data are lacking for the role of rs12777823 and warfarin response in other populations.

Current pharmacogenomic dosing algorithms do not include rs12777823 status, but analysis has shown that the addition of this variant improves the dosing algorithm published by the IWPC by 21% for African-Americans (31).

CPIC has stated that for African-Americans, a dose reduction of 10–25% in individuals with the rs12777823 A/G or A/A genotype is recommended (moderate recommendation). For non-African-Americans, CPIC recommends that rs12777823 should not be considered, even if the result is available (4).

Genetic Testing

The NIH’s Genetic Testing Registry (GTR) provides a list of tests for “warfarin response,” and the VKORC1, CYP2C9, and CYP4F2 genes.

The VKORC1 and CYP2C9 genotypes are important genetic determinants of warfarin dosing. The contribution of VKORC1 to the variation in dose requirement is larger (approximately 30%) than the contribution of CYP2C9 (usually less than 10%) (32). The variants that are routinely tested for are CYP2C9*2, CYP2C9*3, and VKORC1, c.−1639G>A. These variants are used in the FDA table to guide therapy, and also in the IWPC algorithm.

Currently, routine lab tests do not test for the presence of rs12777823. Other variants that are not routinely tested for include the CYP2C9*5, *6, *8 and *11 alleles, the genes CYP4F2, EPHX1, and GGCX (which all have a role in the vitamin K cycle), and the gene CALU (a cofactor in the VKOR complex) (26, 33).

In African-Americans, the influence of the CYP2C9*5, *6, *8 and *11 alleles are thought to be as significant as the influence of the CYP2C9*2 and*3 alleles on warfarin dosing in Caucasians. Requesting testing of these additional CYP2C9 alleles, and including these genotypes in an expanded dosing algorithm improves warfarin dose prediction in African-Americans, while maintaining high performance in European-Americans (34).

Individuals who are most likely to benefit from genetic testing are those who have yet to start warfarin therapy. However, genotype-guided warfarin dosing is controversial and is generally not carried out preemptively. Some studies have reported that, in general, the current use of genotype-guided dosing algorithms did not improve anticoagulation control in the first few weeks of warfarin therapy (35-41); however, a recent study found genotype-guided warfarin dosing did improve the safety of starting warfarin, compared to clinically guided dosing (42).

Therapeutic Recommendations based on Genotype

This section contains excerpted¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

Nomenclature

Pharmacogenetic Allele Nomenclature: International Workgroup Recommendations for Test Result Reporting (43).

Guidelines for the description and nomenclature of gene variations are available from the Human Genome Variation Society (HGVS).

Nomenclature for Cytochrome P450 enzymes is available from Pharmacogene Variation (PharmVar) Consortium.

Acknowledgments

The author would like to thank the following experts for reviewing this summary:
Saeed Alzghari, MS, MBA (HOM), PharmD, BCPS, Director of Clinical Pharmacy, Gulfstream Genomics, Dallas, TX, USA; Bernard Esquivel, MD, PhD, MHA, President of the Latin American Association for Personalized Medicine, Mexico City, Mexico; Christine M. Formea, PharmD, BCPS, FCCP, FASHP, Pharmacogenomics Medication Therapy Management Pharmacist and Assistant Professor of Pharmacy, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; Inge Holsappel, Pharmacist at the Royal Dutch Pharmacists Association (KNMP), the Hague, the Netherlands (for reviewing the information regarding the guidelines of the DPWG); George P. Patrinos, Associate Professor of Pharmacogenomics and Pharmaceutical Biotechnology, Department of Pharmacy, University of Patras, Patras, Greece; Chakradhara Rao S Uppugunduri, Maître-assistant at the CANSEARCH Laboratory, Department of Pediatrics, University of Geneva, Geneva, Switzerland.

Second edition (2016):

The author would like to thank Brian F. Gage, MD, MSC, Professor of Medicine, Washington University, St. Louis, MO, USA; and Sol Schulman, MD, Clinical Fellow in Medicine, Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, for reviewing this summary.

First edition (2012):

The Pharmacogenomics Knowledgebase: http://www.pharmgkb.org

The Clinical Pharmacogenetics Implementation Consortium: http://www.pharmgkb.org/page/cpic

Version History

To view the 2016 version of this summary (Created: June 8, 2016) please click here.

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