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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 sways many physicians from prescribing warfarin to patients who could greatly benefit 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 recently 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 integrating genetic testing into warfarin therapy could be as height as $1.1 billion annually.¹

The Benefits of Testing: Optimal Dose, Fewer Adjustments, Faster Time to INR

The Iverson Warfarin Dosing Panel can help 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. 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.

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

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

The AMA, the Critical Path Institute, and the Arizona Center for Education and Research on Therapeutics have collaborated to develop the brochure "Personalized health care report 2008: Warfarin and genetic testing." The brochure is designed for physicians and other health care providers who commonly prescribe warfarin but who may not have had exposure to pharmacogenomics and genetic testing.

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