Warfarin Dosing (CYP2C9/VKORC)

Warfarin is the most commonly prescribed oral anticoagulant. It is used to prevent harmful clotting after heart attack, stroke or major surgery.

The therapeutic dose of Warfarin for each patient can vary greatly and be hard to predict. If the dose is incorrect, excessive bleeding can occur with too much, while too little may result in harmful clot formation.

Traditionally, doctors would use the patient’s sex, age, weight and medical history to determine the initial Warfarin dose. However, these characteristics do not account for the major sources of variation in doses required. Therefore, a clinician will need to perform blood tests (ie INR) for many weeks or even months to determine the patient’s true individual dose. As such, this can be a lengthy trial and error process, during which the patient may be at an increased risk of an adverse reaction until the correct dose is found.

The major functional components that influence the Warfarin dose are:

1. How rapidly the patient can metabolise (or clear) Warfarin. (Metabolism)
2. How much Warfarin is required to inhibit the clotting process? (Action)

Warfarin Clearance (metabolism)

Warfarin is metabolized by the Cytochrome p450 2C9 enzyme (CYP2C9). Up to 35% of patients have inherited a form of the enzyme with reduced activity. When this deficiency is present in a patient, Warfarin is cleared more slowly, leading to high blood levels, which then increases the risk of excessive bleeding.

Two genetic variants can lead to a reduced activity of CYP2C9. They are known as CYP2C9*2 and CYP2C9*3.

Warfarin Action

Warfarin inhibits the formation of active clotting factors by inhibiting vitamin K epoxide reductase complex subunit 1 (VKORC1). DNA sequence differences in the VKORC1 gene increase or decrease the amount of warfarin required to inhibit the formation of clotting factors.

Pharmacogenetics and Warfarin Dose Variability

Since CYP2C9 and VKORC1 act independently, the total genomic based Warfarin variability is presently believed to be at least 50%. Variants in these genes lead not only to variable initial Warfarin dose sensitivity but also to delays in achieving a stable maintenance dose.

How to Use these Tests

CYP2C9 and VKORC1 gene testing can now explain why certain people require a lower or higher dose of Warfarin to get its full benefits. It is also anticipated that this genetic information can help doctors determine each patient’s individual Warfarin dose more quickly and precisely.

Adjustment of induction and maintenance Warfarin doses based on CYP2C9 & VKORC1 genotype can be determined by genetic testing pre-induction and up to four days post induction. As such, standard induction regimes do not need to be postponed until the genetic test results are available. Simply send a sample for gene testing at, or prior to, commencement of treatment. Test results can then be applied to select maintenance dose on or shortly after days four or five.

Advantages of Genotyping in Predicting Warfarin Maintenance Doses

By determining the genotype of CYP2C9 and VKORC1 a clinician can now more accurately set the Warfarin maintenance dose thereby minimizing possible adverse reactions such as excessive bleeding or harmful clot formation. By using genotyping information a patient’s Warfarin therapeutic steady state level is reached more quickly thereby reducing the period of trial and error.

Test Information

Normal (Wild-type) Genotype

• CYP2C9 *1/*1
• VKORC1 GG

References

• Sconce et al. Blood (2005) 106:2329-33
• Reider et al N Eng J Med (2005) 352:2285-93
• D’Andrea et al Blood (2005) 105:645-49
• Peyvandi et al Clin Pharm Ther (2004) 75:198-203
• Aquilante et al Clin Pharm Ther (2006) 79:291-302