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AccuType Warfarin

AccuType Warfarin

Test Summary

AccuType® Warfarin

  

Clinical Use

  • Assist in determining optimal patient-specific dose of warfarin

  • Help reduce time required to reach optimal warfarin dose

  • Help reduce incidence of bleeding complications associated with warfarin therapy

Clinical Background

Warfarin, a derivative of coumarin, is the most widely prescribed anticoagulant for the prevention and treatment of arterial and venous thromboembolic disease, including deep vein thrombosis (DVT), pulmonary embolism (PE), ischemic stroke, myocardial infarction (MI), and atrial fibrillation. However, optimizing the warfarin dose in individual patients is complicated by 2 factors. The first factor is the drug’s narrow therapeutic range, which leads to an increased risk of thromboembolism at lower doses (international normalized ratio, INR <1.8) and an increased risk of bleeding at higher doses (INR >4).1 The second factor is the wide interindividual variability in warfarin response, which is influenced by multiple factors: some patients are more sensitive to warfarin and may require a dose of only 1 mg to achieve anticoagulation, while others require a dose of up to 20 mg.1 To achieve and maintain a stable therapeutic response, warfarin dosage is typically adjusted by trial and error based on frequent INR measurements.1 During the initial trial-and-error period, the patient is often at increased risk of bleeding, a fact that warrants a black-box warning in both Coumadin® and Jantoven® (branded generic warfarin) labels.2,3

Warfarin exerts its pharmacodynamic effect by inhibiting vitamin K epoxide reductase (VKOR), an enzyme that assists in production of vitamin K-dependent clotting factors; thus, VKOR inhibition reduces the level of vitamin K-dependent clotting factors and leads to anticoagulation. Variations in the gene encoding VKOR (VKORC1) also affect coagulation. The VKORC1 -1639G>A variant leads to reduced VKOR levels; individuals with this allele therefore tend to be more sensitive to warfarin and achieve anticoagulation at a lower dose.4

Warfarin is metabolized in the liver by the enzyme cytochrome P450 2C9, encoded by the gene CYP2C9. The rate of warfarin metabolism is influenced by vitamin K intake, ethnicity, illness, age, gender, other medications, body weight or surface area, and CYP2C9 variations.5,6 Variants of CYP2C9 (CYP2C9*2, CYP2C9*3, CYP2C9*5, and CYP2C9*6) are associated with decreased warfarin metabolism, which leads to increased warfarin sensitivity and lower dose requirements.7,8 Several studies have indicated that individuals carrying the CYP2C9*2 and/or CYP2C9*3 variant may have twice the bleeding risk during warfarin initiation and may take longer than noncarriers to achieve a stable therapeutic response with a conventional dosing approach.5,9

Together with clinical factors, VKORC1 and CYP2C9 polymorphisms account for 50% to 60% of the variability in an individual’s response to warfarin.6,10,13 The proportion of individuals carrying the VKORC1 -1639G>A allele or a CYP2C9 poor metabolizer allele varies by ethnicity (Table 1).4,7

Table 1. Distribution of Poor Metabolizer Alleles by Ethnicity4,7
Poor Metabolizer Allele Proportion Carrying Poor Metabolizer Allele (%)
Caucasians Africans Asians
VKORC1 -1639G>A 42 14 95
CYP2C9*2, *3, *5, or *6 35 3-13 2-8

 

The AccuType Warfarin assay determines a patient’s CYP2C9 and VKORC1 genotypes. This genotype information, along with the patient’s clinical and demographic data, can assist in determining a better initial warfarin dose than that estimated without genotype information or by a fixed-dose approach.11 Using genotype information to estimate warfarin dose may reduce the number and magnitude of dose adjustments needed to achieve a stable therapeutic response, resulting in fewer INR measurements and a shorter initiation period.1 One prospective study showed that CYP2C9 genotype-guided dosing reduced the incidence of minor bleeding complications by 9% during treatment initiation relative to the conventional trial-and-error approach.1 Another study showed that patients who received CYP2C9 and VKORC1 genotype testing had 28% fewer hospitalizations for bleeding or thromboembolism than controls during the first 6 months of warfarin therapy.12

Individuals Suitable for Testing

  • Individuals scheduled for, or receiving, warfarin therapy

Method

  • PCR amplification of VKORC1 promoter and exons 3, 5, and 7 of CYP2C9

  • Single-nucleotide primer extension

  • Fluorescent detection of extension products

Interpretive Information

The VKORC1 -1639G>A mutation and the CYP2C9 variants CYP2C9*2, CYP2C9*3, CYP2C9*5, and CYP2C9*6 are independently associated with increased sensitivity to warfarin; individuals with one or more of these mutations may require a lower warfarin dose to achieve an appropriate degree of anticoagulation.2 Table 2 provides a range of therapeutic warfarin doses predicted based on genotype and other clinical factors. Clinicians may consider these ranges when selecting the initial dose.2 A number of genotype-based algorithms have been developed to assist in determining patient-specific doses.6,13-15 One such dosing algorithm is available at the WarfarinDosing.org Web site (http://www.WarfarinDosing.org).15

Table 2. Range of Expected Therapeutic Warfarin Doses Based on CYP2C9 and VKORC1 Genotypesa,b

VKORC1

Genotype

CYP2C9 Genotype
*1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3
GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg
AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg
AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

a Ranges are derived from multiple published clinical studies. Other clinical factors (eg, age, race, body weight, sex, concomitant medications, and comorbidities) are generally accounted for along with genotype in the ranges expressed in the table. VKORC1 –1639G>A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen.
b From Coumadin package insert.2

Warfarin sensitivity may be affected by genetic variations other than those tested for in this assay as well as by clinical factors such as age, race, body weight or surface area, sex, tobacco use, concomitant medications, and comorbid medical conditions. Assistance with the interpretation of results is available by calling 1-866-GENE-INFO (1-866-436-3463).

References

  1. Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther. 2008;83:460-470.

  2. Coumadin [package insert]. New York, NY: Bristol-Myers Squibb; 2011. http://packageinserts.bms.com/pi/pi_
    coumadin.pdf. Updated October, 2011. Accessed February 20, 2013.

  3. Jantoven [package insert]. Minneapolis, MN: Upsher-Smith Laboratories; 2010. http://www.upsher-smith.com/wp-content/uploads/2011/06/Jantoven_PI.pdf. Accessed November 21, 2011.

  4. Oldenburg J, Bevans CG, Fregin A, et al. Current pharmacogenetic developments in oral anticoagulation therapy: the influence of variant VKORC1 and CYP2C9 alleles. Thromb Haemost. 2007;98:570-578.

  5. Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives. Thromb Res. 2007;120:1-10.

  6. Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. 2008;84:326-331.

  7. Kirchheiner J, Brockmoller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther. 2005;77:1-16.

  8. Voora D, Eby C, Linder MW, et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost. 2005;93:700-705.

  9. Higashi MK, Veenstra DL, Kondo M, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002;287:1690-1698.

  10. Caldwell MD, Berg RL, Zhang KQ, et al. Evaluation of genetic factors for warfarin dose prediction. Clin Med. 2007;5:8-16.

  11. International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360:753-764.

  12. Epstein RS, Moyer TP, Aubert RE, et al. Warfarin genotyping reduces hospitalization rates: results from the MM-WES (Medco-Mayo Warfarin Effectiveness Study). J Am Coll Cardiol. 2010;55:2804-2812.

  13. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005;106:2329-2333.

  14. Zhu Y, Shennan M, Reynolds KK, et al. Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes. Clin Chem. 2007;53:1199-1205.

  15.  WarfarinDosing. Barnes-Jewish Hospital at Washington University Medical Center. http://www.Warfarin
    Dosing.org. Accessed February 20, 2013.
     

This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.

Content reviewed 02/2013
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