Warfarin Sensitivity

Diagnosis

Indications for Testing

• Not enough evidence to recommend widespread adoption of genotyping
• Most useful in warfarin-naive patients but may be useful for patients with previous history of difficulty with anticoagulation
  • May also be useful with challenging patients, particularly those who might be placed on warfarin prophylactically after surgery (eg, those requiring <21 mg or >49 mg per week to maintain therapeutic INR)
    • Includes nearly half of patients

Laboratory Testing

• CYP2C9 and VKORC1 genotyping – for clinical dosing
  • Many algorithms and models for dosing are available
    • Algorithms predict maintenance dose but do not necessarily consider pharmacokinetic differences that may influence the time required to achieve a steady state
    • Algorithms typically offer no guidance regarding dosing intervals or indicate when interpretation of an international normalized ratio (INR) result is appropriate
    • Dose revision algorithms after INR response is observed are also available (Lenzini, 2010)
  • See warfarin dosing calculator for therapeutic dose estimates – other models for dosing are also available
  • Dosing equation example from Sconce, 2005
    • Dose (mg/d) = [0.628 – 0.0135 (age in years) – 0.240 (a) – 0.370 (b) – 0.241 (c) + 0.0162 (height in cm)]²
    • a = CYP2C9*2, input 0, 1, 2 based on number of alleles
    • b = CYP2C9*3, input 0, 1, 2 based on number of alleles
    • c = VKORC1, input 1 for GG, 2 for GA, 3 for AA
  • 2010 revision of the Coumadin^® label includes expected maintenance dosing based on genotype
  • Range of expected therapeutic warfarin doses based on CYP2C9 and VKORC1 genotypes

    Range of Expected Therapeutic Warfarin Doses Based on CYP2C9 and VKORC1 Genotypes†
    VKORC1	CYP2C9
    	*1/*1	*1/*2	*1/*3	*2/*2	*2/*3	*3/*3
    GG	5-7 mg	5-7 mg	3-4 mg	3-4 mg	3-4 mg	0.5-2 mg
    AG	5-7 mg	3-4 mg	3-4 mg	3-4 mg	0.5-2 mg	0.5-2 mg
    AA	3-4 mg	3-4 mg	0.5-2 mg	0.5-2 mg	0.5-2 mg	0.5-2 mg
    †Ranges are derived from multiple published clinical studies. Other clinical factors (eg, age, race, body weight, sex, concomitant medications, and comorbidities) are generally accounted for along with genotype in the ranges expressed in the table. VKORC1 -1639 G→A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3 and *3/*3 may require more prolonged time (>2-4 weeks) to achieve maximum INR effect for a given dosage regimen.

  • When dosing, also consider warfarin drug interactions
    • Cytochrome P450 drug interaction table  
  • Pharmacogenetic testing does not replace the need to monitor warfarin therapy through INR testing

Clinical Background

Warfarin (Coumadin^®) is one of the most widely used anticoagulants worldwide, with potentially severe hemorrhagic or thrombotic consequences if dosed incorrectly. The labeling for a popular formulation of warfarin was revised in August 2007 and February 2010 to include information about how the three most widely studied pharmacogenetic mutations (CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A) affect dose requirements (NDA 9-218/S-105).  These mutations account for as much as 45% of variation in warfarin response in Caucasians and 30% in African Americans.

Epidemiology

• Incidence
  • 2 million new anticoagulant-naive patients placed on warfarin annually in U.S.
  • CYP2C9*2 – Caucasians 8-19%, Asians <0-4%, African Americans 0-12%
  • CYP2C9*3 – Caucasians 5-16%, Asians 1-8%, African Americans 0-6%
  • VKORC1 sensitivity haplotypes, predicted by the -1639G>A mutation – Caucasians 37%, Asians 89%, African Americans 14%

Risk Factors

• CYP2C9 mutations reduce warfarin clearance
  • *2 allele (430C>T)
    • Reduces metabolism of S-warfarin by ~30%
    • Extends half-life – requires a longer time to achieve steady state
    • Average daily warfarin requirement reduced (see table in Diagnosis tab)
  • *3 allele (1075A>C)
    • Reduces metabolism of S-warfarin by ~80%
    • Extends half-life – requires a longer time to achieve steady state
    • Average daily warfarin requirement reduced more than with the CYP2C9*2 allele (see table in Diagnosis tab)
• VKORC1 mutations affect response to warfarin
  • Many mutations are known and exist in linkage disequilibrium
  • Genotyping to detect a common promoter mutation (-1639G>A) predicts warfarin sensitivity haplotypes
  • Average daily warfarin requirement reduced (see table in Diagnosis tab)
• Combinations of mutations from one or more genes further reduce the average daily warfarin requirement

Pathophysiology

• Warfarin prescribed for the following
  • Atrial fibrillation
    • Patients in therapeutic range ~55% of the time
  • Venous thromboembolism
  • Mechanical heart valves
  • Postoperative prophylaxis
• Warfarin inhibits production of vitamin K-dependent coagulation factors through inhibition of vitamin K epoxide reductase (VKOR)
  • Response to warfarin therapy routinely assessed through prothrombin time/international normalized ratio (INR) testing
• Warfarin is a racemic mixture of R and S enantiomers
  • S is 3-5 times more potent than R
  • S-warfarin is metabolized primarily by CYP2C9
  • Warfarin has a narrow therapeutic index that is influenced by a variety of drugs and illnesses
• Pharmacogenetics affect dosing
  • CYP2C9 genotype accounts for as much as 18% of the variability in warfarin dosing
  • VKORC1 genotype accounts for as much as 29% of the variability in warfarin dosing
  • Combining genotypes with clinical factors may account for 50-70% of variability in warfarin dosing

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Warfarin, Urine 0091230 Method: High Performance Liquid Chromatography
Warfarin, Serum or Plasma 0090805 Method: High Performance Liquid Chromatography