Iverson Genetic Diagnostics

Warfarin Sensitivity Test

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Overview

• Clinical Challenges of Warfarin Safety• Warfarin Dosing & Inter-Individual Variation• Case Study• Warfarin Dosing Algorithms• Why Test?• Iverson Services & Solutions

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Clinical Challenge: Warfarin Safety

• Widely prescribed dangerous drug.

– 2 million on warfarin, 30 million Rx a year.– 43,000 ER visits a year, 2nd to Insulin for ER adverse drug reaction (ADR)– 87,000 major bleeding events a year.– 17,000 strokes a year.– 10,000 deaths a year.

Source: FDA, AEI-Brookings Joint Center, and The Joint Commission

• 2006 FDA Black Box Warning Bleeding Risk.

• 2007 FDA updates warfarin label with genotypic information.

• 2008 The Joint Commission issues new goal 3E on Anticoagulant Safety.

FDA and Joint Commission

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Adverse Drug Reactions

• Healthcare cost –

− Average cost of bleeding episode: $16,000 or 6 hosp days.

− Average cost of clotting episode: $ 40,000.

− Including genetic information would save

$ 1.1 billion a year. Source: AEI-Brookings Joint Center

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Risks of Warfarin ADRStrongly Depend on INR Value

• INR below 2 = high risk of stroke• INR above 4 = high risk of hemorrhage

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Current Methodsfor Warfarin Dosing

• Initial dose can be modified by age, gender, body mass, co-morbidities.

• This will predict only 17-21% of the inter-individual variation.

• Subsequent dosing based on INR.

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Genetics & Warfarin Dosing

• Single base pair changes in DNA sequence lead to reduced activities in two genes.

• These two genes play a key role in the patient’s response to Warfarin.

− Response – VKORC1 (1386)− Metabolism – CYP2C9 *2 & *3

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Vitamin K Epoxide Reductase 1 (VKORC1)

• Variations explain up to 25% of patient variability in Warfarin dose response.

• Approximately 37% of Caucasians, 14% of African-Americans, and 89% of Asians carry at least one variant copy.

• Patients with certain VKORC1 variations have an increased risk for anticoagulant overdose, and may require lower doses of Warfarin to achieve and maintain therapeutic INR.

Warfarin Dose & VKORC1

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Cytochrome P450 2C9 (CYP2C9)

• Variations explain approximately 15% of patient variability in Warfarin dose response.

• Approximately 20% of Caucasians, 5% of African-Americans, and 2% of Asians carry at least one variant copy.

• Patients with CYP2C9 gene variations require more time to achieve stable INR, are at an increased risk of bleeding, and may require lower doses of Warfarin to achieve and maintain therapeutic INR.

Warfarin Dose & CYP2C9

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Case Study

• Patient profile:

− 65 years old − White male− 260 LBS, 5’9” tall− Taking Lipitor®− Diagnosis: Deep Vein

Thrombosis

• Therapeutic dose:

5.6 mg/day using available clinical data and existing algorithms.

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Case Study Cont’d• Now we genotype this patient:

– CYP2C9 *3/*3– VKORC1 A/A

• Resulting optimal warfarin dose:− Loading dose: 4.1 mg− Therapeutic dose: 1.8 mg/day

Without genotype data, this patient would have INR value >4,

with potential hemorrhage, and slow return to therapeutic INR

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Web-Based WarfarinDosing Algorithm

• Use with or without genotype data.

• Use before or after initial warfarin dose. − (up to 5 doses)

• Allows incorporation of INR results to adjust dose.

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Why Test for Warfarin Sensitivity ?

• Clinical factors only explain 17-21% of dose variability.

• Adding genetic information explains up to 55% of dose variability.

• Adding in INR3 explains 79% of response variability.

• Genotypes will help shorten the time to stable INR.

• Knowing the genotype helps avoid ADR / AE.

• Satisfies new 2009 Joint Commission requirement.Personalized Medicine:Each patient on warfarin receives the right dose the first time.

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Iverson Operates a CLIA Certified Laboratory

• The laboratory is CLIA (Clinical Laboratory Improvement Amendment) certified for high-complexity molecular testing

• Our facilities allow us to provide the very highest in quality testing in the fastest possible turn-around time.

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Iverson Provides each Organization with Tools and Training

Clinical and Administrative

• Test kit workstations• Pre-populated lab requisitions• Iverson billing/insurance protocol• List of credentialed insurance

carriers• Clinical discussion

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Questions?

Iverson Genetic Diagnostics, Inc.19805 North Creek Parkway, Suite 200

Bothell, Washington 98011

Tel: (425) 318-1332 Fax: (425) 318-1795

Vincent Lecca, Business Deveolpment/Central U.S.

512.627.7723

www.iversongenetics.com