Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Drug Therapy of Cardiovascular Diseases
185
carry the −1639G>A polymorphism in the promoter region of the VKORC1 gene are
more sensitive to warfarin and require lower doses.
Polymorphisms in CYP2C9 and VKORC1 account for approximately 40% of
the variance in warfarin dose. 6 Current warfarin labeling suggests lower doses for
patients with certain genetic variations. Patients with the CYP 2C9*2 and CYP
2C9*3 alleles need lower warfarin maintenance doses than patients with the wildtype
allele in order to achieve their desired international normalized ratio (INR).
The two allelic variants will result in slower metabolism of warfarin. Additionally,
VKORC1 (vitamin K epoxide reductase A1) haplotype necessitates a lower warfarin
maintenance dose due to decreased expression of the messenger RNA responsible
for production of proteins necessary for VKORC1 enzyme formation. 7
Prospective randomized clinical trials are currently underway utilizing dosing
algorithms that incorporate genetic polymorphisms in CYP2C9 and VKORC1 to
determine warfarin dosages. 6 FDA-approved testing for VKORC1 and CYP2C9 variants
is available for patients on warfarin. Variations, such as missense mutations
in the gene encoding for VKORC1, cause warfarin resistance. Hence, the patient’s
genotypic variance in the two enzymes predicts response to warfarin therapy and the
amount of warfarin dose needed. 8
Clinical Application
Prospective randomized clinical trials are currently underway employing dosing
algorithms that incorporate genetic polymorphisms in CYP2C9 and VKORC1 to
determine warfarin dosages. Variations of the VKORC1 gene that might require an
adjustment in the dose of warfarin occur in up to 89% of Asians and in about onethird
of Caucasians and African Americans. More than one in ten Caucasians has a
relevant variation in CYP2C9, and the variation is less common in non-Caucasians. 9
When these genetic variations are known, warfarin can be initiated at a higher or
lower dose as appropriate. The warfarin dose calculator at www.warfarindosing.
org can also take these variations into consideration when they are known. In addition,
the dosing calculator uses clinical factors, such as drug–drug interactions, age,
weight, for determining dose.
At present, available genotype-guided warfarin initiation dosing algorithms
show limited clinical validity and utility compared with standard therapy, especially
for patients who are dosed based on their clinical information and close INR
monitoring. 10 A study with high dropout rate, which used CYP2C9 only to determine
dosing, has shown some benefit on anticoagulation control with minor bleeding
events. 11 An observational study reported a relationship between providing warfarin
genetic information to clinicians and reduced hospitalizations. 12
Other anticoagulants of minor pharmacogenomic interest include heparin, dabigatran,
rivaroxaban, and apixaban. Dabigatran was approved by the FDA in October
2010 for prevention of stroke and blood clots in people with atrial fibrillation.
Rivaroxaban was approved in November 2011 to treat atrial fibrillation and lower
the risk of blood clots after hip and knee replacements. Apixaban was approved in
December 2012 to lower the risk of stroke and dangerous blood clots in patients with
atrial fibrillation.