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Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines: Warfarin Dosing

What are the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines?

In the era of personalized medicine, we are witnessing genetic tests being incorporated into routine clinical practices. However, the extent to which pharmacogenomic tests have been qq adopted has been low, majorly due to the lack of a coherent and curated set of guidelines for their practice.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed certain guidelines that have been endorsed by several medical societies.They are designed to assist clinicians on how to use the results from genetic tests to determine the course of drug therapy for each patient. Genotype-based drug guidelines will help clinicians understand how a patient of a specific genotype would respond to or metabolize a particular drug. This will enable them to evaluate subsequent therapeutic options and to determine the dosage strength.

The Drug: Warfarin

Warfarin is a popularly used anticoagulant (commonly called a blood thinner) to prevent thromboembolic disorders. It undergoes oxidation in the liver by CYP2C9 and then inhibits the protein VKORC1 resulting in anticoagulant behavior.  Warfarin is a very effective anticoagulant, but the challenges faced in its administration stem from the fact that it has a narrow therapeutic index and there is a large degree of variation in the dose required from one individual to another. Complications that arise as a result of inappropriate warfarin dosing is a very common reason for emergency room visits.

Dosing The patient is first prescribed an initial dose based on the population average. Then a weekly measurement of the INR (International Normalized Ratio) is conducted and the dose is adjusted suitably. In the process of determining the appropriate dose, the patient not only loses a few weeks of their lives, but is also put at an increased risk of either over-anticoagulation (bleeding) or under-anticoagulation (thromboembolism).

The Genes

There are multiple genes that have been reported to affect the metabolism of the drug warfarin in the system.

CYP2C9

It is an enzyme belonging to the Cytochrome P450 family of enzymes that is found in the liver. It is the primary enzyme for metabolizing S-warfarin. Eighteen alleles of CYP2C19 have been shown to have an impact on enzyme activity.

Genetic variants

CYP2C9 has around 60 variants. The allele frequencies differ between demographic groups.

  • The wild type CYP2C9*1 is the functional allele. The homozygous wild type confers normal levels of enzyme activity.
  • The decreased function alleles CYP2C9*2 and CYP2C9*3 are more commonly observed in individuals of European ancestry. CYP2C9*2 decreases warfarin metabolism by around 30-40% and CYP2C9*3 by 80-90%. Individuals who are either homozygous or heterozygous for these alleles face an increased risk of bleeding during warfarin therapy. In these cases, the amount of drug administered must be lowered as the drug remains in circulation longer and the patient would require longer to achieve a stable INR.
  • In African populations, a more common set of decreased function alleles are found namely CYP2C9*5, *6, *8, and *11.

VKORC1

Warfarin is a vitamin K antagonist. It inhibits its target enzyme vitamin K epoxide reductase complex, subunit 1 (VKORC1).

Genetic variants

A -1639G>A polymorphism is seen to affect VKORC1 protein expression. Patients with the -1639A allele require lower doses of warfarin than -1639G/G homozygotes. The difference in the frequency of this allele across different populations explains the difference in average dose requirements between black, white and Asian populations.

CYP4F2

This enzyme is present in the liver and is an important counterpart to VKORC1. It is a vitamin K oxidase that limits the excess accumulation of vitamin K.

Genetic variants

The allele CYP4F2*3 is seen to affect enzyme activity associated with warfarin dose.

A more accurate prediction of dosing has been observed when the CYP4F2 variant was included in prediction models along with CYP2C9 and VKORC1.

CYP2C19

rs12777823 is a SNP seen to affect warfarin clearance, particularly in African American populations.

Drug-Gene Relationship:

A randomized control trial called Genetics-InFormatics Trial (GIFT) genotyped for CYP2C9*2 and *3, CYP4F2*3, and VKORC1-1639 variants. It observed a 27% reduction in composite outcome with a genotype-guided algorithm in comparison to a clinical algorithm.

 

VKORC1

CYP2C9

*1/*1*1/*2*1/*3*2/*2*2/*3*3/*3

GG

5-7 mg5-7 mg3-4 mg3-4 mg3-4 mg0.5-2 mg

AG

5-7 mg3-4 mg3-4 mg3-4 mg0.5-2 mg0.5-2 mg

AA

3-4 mg3-4 mg0.5-2 mg0.5-2 mg0.5-2 mg0.5-2 mg

Table : Three Ranges of Expected Maintenance Warfarin Doses based on CYP2C9 and VKORC1 Genotypes, adapted from the FDA drug label. (Source)

Therapeutic Recommendations

Adult Patients

Several studies have been conducted in individuals of European ancestry, African Americans, and East Asians to determine warfarin dosage based on genotyping results. The CPIC guidelines assume that the lack of literature in other populations would imply that the same guidelines would apply to them as well.

Two pharmacogenetic dosing algorithms- Gage and IWPC have been developed that provide similar dose recommendations. There is also a dose revision algorithm that can be used for refinement. These algorithms however do not include CYP4F2, CYP2C9*5, *6, *8, or *11 or rs12777823.

Overall, it can be understood that in patients with CYP2C9 genotypes that predict poor metabolism or who have increased warfarin sensitivity (VKORC1 c.-1639 A/A),  an alternate oral anticoagulant should be considered.

Pediatric Patients

Strong evidence has been established for the use of CYP2C9*2 and *3 and VKROC1 to guide warfarin therapy in children of European ancestry. A dosing tool (found at www.warfarindoserevision.com ) has been developed to estimate the same. There has however, been no other solid evidence linking gentling results to clinical outcomes for other genotypes or in other populations.

Potential Benefits and Risks Involved

Pharmacogenetic tests have the potential to shorten the time to stable INR and also avoid overdosing and under-prescribing during the initial treatment period. Achieving these benefits would essentially reduce the risk of both excessive bleeding and thromboembolic events. Since multiple alleles are involved, it is risky to rely entirely on genotyping results for individuals who may carry a rare or untested variant. Most insurance plans at the moment do not cover warfarin pharmacogenetics testing. Inconsistent results have been observed with respect to clinical outcomes for CYP2C9 and VKORC1 variants.

Additionally, testing laboratories should make an attempt to ensure that the results generated are error-free since even minor errors can adversely affect health outcomes in patients.

Caveats

The target INR for the dosing algorithm has been set to INR 2-3 for therapeutic warfarin dosing. Accommodations have to be made for other target INR doses. As the results from the genotyping tests will determine the therapeutic course of action, early testing and expedited reporting will behoove the process.

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James Watson
Xcode is a pioneer in personal genomics, focussed on enabling personalized preventive healthcare. We are dedicated to empowering physicians, wellness professionals and customers with the most validated, accurate and actionable genomic information to positively impact and improve their client's health and quality of life.