Warfarin and Genetic Implications

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Warfarin and Genetic Implications

• Escher Howard-Williams
• 3/12/08

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Introduction

• What is the significance of genetic variables in
  coumadin
• Enzymes currently under investigation
• Recent NEJM Study evaluating genetic differences
  with coumadin initiation
• Recent Blood article looking at similar variables
• Current Implications and Complications

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Important Because

• Narrow therapeutic window
• INR of less than 2 is associated with an
  increased risk of thromboembolism,2 and an INR of
  4 or more is associated with an increased risk of
  bleeding
• FDA warning on package insert about genetic
  susceptibility
• UNC will soon start to test for genetic variants

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FDA Package Insert

• August 2007 states that "lower initiation doses
  should be considered for patients with certain
  genetic variations in CYP2C9 and VKORC1 enzymes."

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Clinical Scenario

• Patient comes in needing anticoagulation for
  recent PE and scrutinizes the package inserts for
  coumadin that will soon be initiated.
• Doc I want this gene test because I dont want
  to have the wrong dose of medicine
• What do we say?
• hmmm

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How Genetics Can Help

• First month is critical to reach target INR and
  is done so empirically, generally using
  standardized algorithms
• Consequently, the risk of over-anticoagulation,
  with the potential for hemorrhagic complications,
  is higher during this time than subsequently

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Genetic Variables 2 Enzymes Largely Studied

• CYP2C9 (metabolizes warfarin)
• Steady state?
• Initiation?
• VKORC1 (recycles vitamin K warfarins target)
• Initiation?
• Steady state?

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Polymorphism CYP2C9

• Polymorphisms in CYP2C9 contribute to variability
  in sensitivity to warfarin
• CYP2C9 is primarily responsible for clearance of
  the S-enantiomer of warfarin
• Patients with variants of CYP2C9 require a lower
  dose of warfarin and generally longer time to
  steady state (slow metabolizers) (?)
• They are also at higher risk for
  over-anticoagulation and serious bleeding

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These polymorphisms

• 11 wild type
• 12 heterozygote
• 13 heterozygote
• 23 compound heterozygote
• 22 homozygote
• 33 homozygote
• 5 any combination

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Vitamin K epoxide reductase

• VKORC1 recycles vitamin K epoxide to the reduced
  form of vitamin K to form factors II, VII, IX,
  and X
• VKORC1 is the target of coumadin
• VKORC1 polymorphisms are associated with a need
  for lower doses of warfarin during long term (?)

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VKORC1 Haplotypes

• VKORC1 Low-dose haplotype group (group A)
  high-dose haplotype group (group B)
• Group A/A
• Group A/B
• Group B/B

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First Study

• Genetic Determinants of Response to Warfarin
  during Initial Anticoagulation
• Schwarz, et al. Genetic Determinants of Response
  to Warfarin during Initial AnticoagulationN Engl
  J Med 2008 358 999-1008

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Patient Selection

• The study was conducted at three anticoagulation
  clinics affiliated with the Vanderbilt University
  Medical Center
• Pharmacy, Cardiology, and Arthritis and Joint
  Replacement Center
• 325 patients presenting for initiation of
  warfarin therapy were prospectively screened to
  determine eligibility

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Excluded

• Exclusion criteria were
• active cancer requiring
• potential to require or on concurrent
  chemotherapy
• active alcoholism

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Study Design

• The target INR range was determined by each
  patients physician and varied according to the
  indication for warfarin treatment
• Concurrent medications were categorized into
  groups of drugs that might potentiate or
  attenuate the anticoagulant effect of warfarin
• Amiodarone, because of its marked effects, was
  considered separately

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Data Collection

• Recorded at baseline were the patients
• age, sex, racial or ethnic background
• indication for warfarin therapy
• date of initiation of warfarin
• target INR range
• initial warfarin dose
• concomitant medications

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Genotyping

• CYP2C9 genotyping was performed with major
  variant alleles
• CYP2C91 - NORMAL
• CYP2C92
• CYP2C93
• CYP2C95
• VKORC1 genotyping
• Patients with variants (5 total) were assigned to
  the VKORC1 haplotype group A - NON-A normal

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Excluded patients

• 28 were excluded from the analysis
• 7 patients had no INR readings in the first 10
  days
• 12 patients had fewer than two INR readings,
• 6 patients had no target INR recorded or the
  target INR was outside the range of 1.8 to 3.5,
• 3 patients provided no DNA or the DNA was of poor
  quality,
• 3 patients had incomplete baseline data
  collection,
• 1 patient did not provide a blood sample,
• 1 patient did not have a recorded start date for
  warfarin, and
• 1 patient was undergoing chemotherapy. These
  exclusions

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Outcome Measures

• Primary
• Time to first therapeutic INR
• Time to first INR gt4
• Time INR was above the therapeutic range relative
  to the complete time of follow-up
• Secondary
• average daily warfarin dose and bleeding events

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Time to first therapeutic INR and INR gt 4

• VKORC1 haplotype had a significant effect on the
  time to reach the first therapeutic INR (P0.02)
  and the time to the first INR of more than 4
  (P0.003)
• Patients with one or two VKORC1 haplotype A
  alleles had shorter times to the first INR within
  the therapeutic range and to an INR of more than
  4 than did patients with two haplotype non-A
  alleles

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Time to first therapeutic INR and INR gt 4

• In contrast, the CYP2C9 genotype did not
  significantly affect the time to the first INR
  within the therapeutic range (P0.57)
• Carriers of CYP2C92 and CYP2C93 variant alleles
  did reach a first INR of more than 4 earlier than
  did patients with the wild-type allele (P0.03)

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Association between Specific Genetic Variants and
Study Outcomes
Schwarz U et al. N Engl J Med 2008358999-1008
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Time Above Therapeutic INR

• VKORC1 haplotype had a significant effect on the
  primary outcome of the percentage of time above
  the therapeutic INR range (P0.03)
• Homozygotes for VKORC1 haplotype A spent
  significantly more time above therapeutic INR
  than patients who were homozygous for the non-A
  haplotype (18.8 vs. 9.1 P0.02).
• CYP2C9 genotype and the time above the
  therapeutic INR range was not statistically
  significant (P0.09).

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INR Response over 2 weeks related to dose

• INR response was significantly affected by the
  VKORC1 haplotype during the first 2 weeks of
  treatment (Plt0.001 for both week 1 and week 2)
• For CPYP2C9 this relationship was weaker (P0.17
  for week 1 and P0.04 for week 2).

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Average Warfarin Daily Dose and Average INR among
Patients with a VKORC1 Haplotype or CYP2C9
Genotype during Weeks 1 and 2 and from Day 29 to
the End of Follow-up
Schwarz U et al. N Engl J Med 2008358999-1008
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INR Response over 2 weeks

• THIS contrasts study by Millican et al. that
  examined the use of clinical and genetic
  variables for predicting the maintenance dose of
  warfarin in 92 patients
• Found opposite results but used different
  methodology

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Serious Bleeding

• Not related to VKORC1 or CYP2C9 but more related
  to underlying conditions and age

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Summary

• VKORC1 seemed influential in time to first
  therapeutic INR and time to INR gt4 as well as
  overall dose required
• CYP2C9 did not seem to be as influential in these
  outcomes except overall dose required at steady
  state

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Hazard Ratio for Primary Outcomes, According to
VKORC1 or CYP2C9 Variant
Schwarz U et al. N Engl J Med 2008358999-1008
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Second Study

• Millican et al. Genetic-based dosing in
  orthopedic patients beginning warfarin therapy.
  Blood. 20071101511-5.

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Millican

• The purpose of this study was to develop a
  dose-refinement nomogram to guide clinicians in
  adjusting warfarin doses based on CYP2C9.
• Will allow for, but not require, a first dose
  that is tailored to clinical and/or genetic
  factors and
• Will incorporate genetics and clinical factors
  that are independent predictors of how much the
  dose should be refined
• Studied 92 post surgical orthopedic patients

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General Results

• Clinical and genetic variables for predicting the
  maintenance dose of warfarin in 92 patients.
• Contributing factors included
• Initial warfarin dose
• INR value after three doses of warfarin
• Estimated blood loss at the time of surgery
• Smoking status
• This algorithm explained 80 of the variability
  in therapeutic dose

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Genetic Factors

• CYP2C9 significant predictor of ultimate dose
  17-31 lower and
• VKORC1 genotypes did not influence time to
  therapeutic INR with different algorithm but did
  require eventual lower therapeutic dose

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Conclusion?

• ?

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What to tell our patient?

• Soon have a pilot study here for evaluation of
  genetic factors
• Currently no true guidelines exist and data is
  inconclusive

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Why is this difficult to study?

• MEDS!
• Acute or chronic alcoholism, liver disease
• BSA
• Compliance
• Diet
• No alleles present and combinations

• Tobacco abuse??
• Increased age
• Diabetes mellitus
• Presence of malignancy
• Renal impairment
• APLA
• New Nomogram?
• Standardized Dose reduction??