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Warfarin Dosing Can Be a Challenge If you have patients who take warfarin, you know that achieving a stable INR can be a challenge. Too little warfarin leaves patients at risk for thrombosis. Too much can promote adverse bleeding events. On average, 50% of major bleeding events associated with warfarin use occur in the first 90 days of treatment. Achieving a stable INR often requires trial and error with frequent and costly testing. The elevated risk of bleeding complications occurring in patients with unstable INRs often sway many physicians from prescribing warfarin to patients who could greately benifit from it. Today, with genetic testing, you have another tool to make warfarin dosing safer, less costly and more effective for your patients. The AEI Brookings Joint Center for Regulatory Studies recent estimated that the use of CYP2C9 genotyping has the potential to avoid 85,000 serious bleeding events and 17,000 strokes annually and to significantly reduce health care spending. The report estimated the reduced health care spending from integreating genetic testing into warfarin therapy could be as hight as $1.1 billion annually. The Benefits of Testing: Optimal Dose, Fewer Adjustments, Faster Time to INR
The
Iverson Warfarin Dosing Panel can help you predict the optimal warfarin
dose, may shorten the time to achieve stable dosing, reduce the need
for dose adjustments, increase the time each patient spends in the
target INR range, and has the potential to improve the overall safety
and efficacy of warfarin therapy.
Right Dosage? Look to Your Patient’s Genes
There is a 10-fold inter-patient variability in the dosing required to attain a therapeutic response.2
Research has clearly shown that up to 40% of the individual variability
in warfarin response can be accounted for by variations in two enzymes:
CYP2C9 and VKORC1.3 CYP2C9 affects how warfarin is metabolized. VKORC1 affects how some patients respond to the drug.
Drug Metabolism: CYP2C9
Patients
with variations in CYP2C9 account for approximately 15% of variability
in warfarin dose response. These variations differ with racial
background. Approximately 20% of Caucasians, 5% of African-Americans
and 2% of Asians carry at least one variant copy of CYP2C9.
Patients with CYP2C9 gene variations may:
• Require more time to achieve a stable INR.
• Be at increased risk of bleeding.
• Need lower or higher doses of warfarin to achieve and maintain therapeutic INR.
Drug Response: VKORC1
Patients
with variations in VKORC1 account for up to 25% of variability in
warfarin dose response. These variations also differ with racial
background: Approximately 37% of Caucasians, 14% of African-Americans
and 89% of Asians carry at least one variant copy of VKORC1.
Patients with VKORC1 gene variations may:
• Have an increased risk for anticoagulant overdose.
• Require lower doses of warfarin to achieve and maintain therapeutic INR.
Source: AMA Personalized Health Care Report 2008: Warfarin and Genetic Testing.
A Closer Look at How Genotypes Affect Warfarin Metabolism
Warfarin
is highly effective at antagonizing the vitamin K-dependent clotting
pathway. Being a natural substance, it is given as a mixture of R and S
stereoisomers (the chemical equivalent of mirror images). S-warfarin is
three-to-five times more potent than its cousin, R-warfarin, in
inhibiting the drug’s target of action: the vitamin K epoxide reductase
complex. Phase I metabolism of S-warfarin is predominantly via the
CYP2C9 enzyme. Genetic variations in this enzyme can affect the rate at
which warfarin is inactivated and can play a major role in determining
what an individual’s maintenance dose of warfarin will be.
Patients
with some genetic variants are more likely to need lower doses of
warfarin, take a longer time to reach target INR on starting therapy
and may have an increased risk of bleeding complications. The vitamin K
epoxide reductase complex is responsible for converting vitamin K from
an oxidized to a reduced state. Reduced vitamin K is key to the
formation of many of the proteins in the clotting cascade, and without
it, overall coagulation is significantly inhibited. Warfarin inhibits
the action of the major subunit of the vitamin K epoxide reductase
complex: VKORC1. Variations in the VKORC1 subunit have been shown to be
differentially sensitive to the action of warfarin.
Together,
VKORC1 and CYP2C9 account for up to 40% of the individual variability
in warfarin response. Other important variables include age, gender,
height and weight, drug interactions and diet.3
Warfarin Dosing Facts
- More than 2 million new warfarin prescriptions are written each year in the U.S.
- There is a ten-fold variability among patients in the dose required to obtain a therapeutic response.
- On average, 50% of major bleeding events associated with warfarin use occur in the first 90 days of treatment.
- Two genes (CYP2C9 and VKORC1) account for up to 40% of individual variability in warfarin response.
- In
August 2007, the U.S. Food and Drug Administration (FDA) revised the
warfarin label to recommend genetic testing prior to initiation of
warfarin therapy.4
- 21% of patients who receive anticoagulation therapy experience major or minor bleeding events.5
References
1.
Andrew McWilliam, Randall Lutter, Clark Nardinelli. Health care savings
from personalized medicine using genetic testing: the case of warfarin
[Internet]. Working Paper 06-23, AEI-Brookings Joint Center for
Regulatory Studies. 2006 [cited 2008 Nov 21]. Available from:
http://aei-brookings.org/admin/authorpdfs/redirect-safely.php?fname=../pdffiles/WP06-23_topost.pdf
2.
Fanikos J, Grasso-Correnti N, Shah R, Kucher N, Goldhaber SZ. Major
bleeding complications in a specialized anticoagulation service. Am J
Cardiol. 2005 Aug 15;96(4):595-598.
3.
Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano
C, Jaillon P, Beaune P, Laurent-Puig P, Becquemont L, et al. Cytochrome
P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as
determinants of acenocoumarol sensitivity. Blood [Internet]. 2005
[cited 2008 Oct 24];106:135-140. Available from: http://bloodjournal.hematologylibrary.org/cgi/contne/full/106/1/135
4.
FDA Approves Updated Warfarin (Coumadin) Prescribing Information
[Internet]. U.S. Food and Drug Adminstration. 2007 [cited 2008 Oct 20].
Available from: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html
5.
American Medical Association; Arizona CERT; Critical Path Institute.
Personalized health care report 2008: warfarin and genetic testing
[Internet]. 2008 [cited 2008 Nov 21]. Available at:
http://www.azcert.org/medical-pros/warfarin_brochure.pdf
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