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Role of Pharmacogenetics in Warfarin Therapy
Warfarin (Coumadin) is the most commonly prescribed oral anticoagulant for the
treatment and prevention of thromboembolic events. Approximately two million
patients in the US are initiated on warfarin therapy each year. The correct mainte-
nance dose of warfarin for a given patient is diffi cult to predict, the drug carries a
high risk of toxicity, and variability among patients means that the safe dose range
differs widely between individuals. Currently complications of warfarin therapy
account for 10.5 % of the hospital admissions for adverse drug reactions, the second
most common reason for patients to go to the emergency room. Recent pharmaco-
genetic studies indicate that the routine incorporation of genetic testing into warfa-
rin therapy protocols could substantially ease both the fi nancial and health risks
currently associated with this treatment (Reynolds et al. 2007 ). Genotype knowl-
edge of the CYP2C9 variant alleles may help the clinician to individualize warfarin
therapy with the ultimate goals of shortening the initial period of induction therapy,
reaching a stable maintenance dose earlier, and minimizing bleeding complications
in patients who are high responders and need lower warfarin doses. In 2007, the
FDA made the following recommendations:
- Lower doses of warfarin should be used in patients with genetic variations in
CYP2C9 and VKORC1 genes. - Genotyping patients in the induction phase of warfarin therapy would reduce
adverse events and improve therapy achievement of stable International
Normalized Ratio. - Existing evidence of the infl uence of CYP2C9 and VKORC1 genotypes warrants
re-labeling of warfarin to include genomic and test information.
The labeling update is a milestone that brings personalized medicine to the main-
stream. However, the FDA further emphasized that this labeling update is not a direc-
tive to physicians to use genetic tests for warfarin therapy. That kind of a label will
have to wait for outcomes data. To this end, there are numerous studies currently
ongoing looking at outcomes when genetic tests are incorporated into warfarin treat-
ment. The Harvard Partners Center for Genetics and Genomics, Medco and the Mayo
Clinic, Clinical Data and PharmaCare, and the University of Utah under the Critical
Path Initiative, are all researching the clinical utility of pharmacogenetics- based war-
farin dosing. FDA cleared Verigene Warfarin Metabolism Nucleic Acid Test
(Nanosphere Inc), which detects variants of CYP2C9 and VKORC1 genes, respon-
sible for sensitivity to warfarin. The FDA also cleared Verigene® F5/F2/MTHFR
nucleic acid test, which detects disease-associated gene mutations that can contribute
to blood coagulation disorders and diffi culties metabolizing folate (vitamin B12).
Mutations in three specifi c genes can increase an individual’s risk for dangerous
blood clots and their leading complication, and is an indication for warfarin therapy.
The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of
warfarin produces recommendations that are signifi cantly closer to the required sta-
ble therapeutic dose than those derived from a clinical algorithm or a fi xed-dose
approach (The International Warfarin Pharmacogenetics Consortium 2009 ).
4 Pharmacogenetics