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Treatment Guidelines

TEST MATERIAL ONLY - PLEASE DO NOT USE THIS CONTENT TO INFORM TREATMENT

  • Guidelines, Overview 
  • Detailed Result Guidelines 
  • Warnings 

    GUIDELINES, OVERVIEW
    In 2011, the Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health's Pharmacogenomics Research Network issued a guideline related to the CYP2C9 and VKORC1 genes and warfarin therapy*. Guidelines are peer-reviewed, updated, evidence-based, and freely-accessible. They are intended to facilitate translation of pharmacogenomic knowledge from bench to bedside. They are used as the primary guide for the recommendations listed below. 


    The most common CYP2C9 & VKORC1-warfarin results are listed immediately below. Each result pair is hyperlinked, with more detailed information listed in Detailed Result Guidelines below.

    Genotypes requiring normal/high warfarin doses:

    Result in EMR Phenotype Recommended Dosing** Pharmacologic Implications Classification
    CYP2C9*1/*1,
    VKORC1 - 1639 GG
    Normal metabolism,
    Decreased sensitivity
    5-7mg/day Normal metabolism of warfarin and high/normal expression of VKORC1 leading to decreased sensitivity. Dose requirements are normal to higher than average. Strong
    CYP2C9*1/*2,
    VKORC1 - 1639 GG
    Intermediate metabolism,
    Decreased sensitivity
    CYP2C9*1/*1,
    VKORC1 - 1639 GA
    Normal metabolism,
    Intermediate sensitivity

    *Several recently published studies on warfarin pharmacogenetics [PMIDs: 24251361, 24251363, and 24251360] have called into question the appropriate implementation. These papers have prompted several opinion pieces [PMIDs: 24328463 and 24251364. The CPIC authors are evaluating the information, which will be incorporated into the next update of the CPIC guideline on warfarin.
    **The best way to estimate stable warfarin dose is to use an algorithm (https://www.warfarindosing.org which offers both high-performing algorithms). Without access to algorithms, the average dose ranges recommended in the FDA-approved warfarin product label are listed here.

    Genotypes requiring lower than average warfarin doses:

    Result in EMR Phenotype Recommended Dosing** Pharmacologic Implications Classification
    CYP2C9*1/*1,
    VKORC1-1639 AA
    Normal metabolism,
    Increased sensitivity
    3-4mg/day Normal to low metabolism of warfarin and low to normal expression of VKORC1 leading to increased sensitivity. Dose requirements are lower than average. Strong
    CYP2C9*1/*2,
    VKORC1 - 1639 GA
    Intermediate metabolism,
    Intermediate sensitivity
    CYP2C9*1/*2,
    VKORC1 - 1639 AA
    Intermediate metabolism,
    Increased sensitivity
    CYP2C9*1/*3,
    VKORC1 - 1639 GG
    Intermediate metabolism,
    Decreased sensitivity
    CYP2C9*1/*3,
    VKORC1 - 1639 GA
    Intermediate metabolism,
    Intermediate sensitivity
    CYP2C9*2/*2,
    VKORC1 - 1639 GG
    Decreased metabolism,
    Decreased sensitivity
    CYP2C9*2/*2,
    VKORC1-1639 GA
    Decreased metabolism,
    Intermediate sensitivity
    CYP2C9*2/*3,
    VKORC1 - 1639 GG
    Decreased metabolism,
    Decreased sensitivity

    *Several recently published studies on warfarin pharmacogenetics [PMIDs: 24251361, 24251363, and 24251360] have called into question the appropriate implementation. These papers have prompted several opinion pieces [PMIDs: 24328463 and 24251364. The CPIC authors are evaluating the information, which will be incorporated into the next update of the CPIC guideline on warfarin.
    **The best way to estimate stable warfarin dose is to use an algorithm (https://www.warfarindosing.org which offers both high-performing algorithms). Without access to algorithms, the average dose ranges recommended in the FDA-approved warfarin product label are listed here.

    Genotypes requiring much lower than average warfarin doses:

    Result in EMR Phenotype Recommended Dosing** Pharmacologic Implications Classification
    CYP2C9*1/*3,
    VKORC1 - 1639 AA
    Intermediate metabolism,
    Increased sensitivity
    0.5-2mg/day Decreased metabolism of warfarin and low to normal expression of VKORC1 leading to increased sensitivity. Dose requirements are much lower than average Strong
    CYP2C9*2/*2,
    VKORC1 - 1639 AA
    Decreased metabolism,
    Increased sensitivity
    CYP2C9*2/*3,
    VKORC1 - 1639 GA
    Decreased metabolism,
    Intermediate sensitivity
    CYP2C9*2/*3,
    VKORC1 - 1639 AA
    Decreased metabolism,
    Increased sensitivity
    CYP2C9*3/*3,
    VKORC1 - 1639 GG
    Decreased metabolism,
    Decreased sensitivity
    CYP2C9*3/*3,
    VKORC1 - 1639 GA
    Decreased metabolism,
    Intermediate sensitivity
    CYP2C9*3/*3,
    VKORC1 - 1639 AA
    Decreased metabolism,
    Increased sensitivity

    *Several recently published studies on warfarin pharmacogenetics [PMIDs: 24251361, 24251363, and 24251360] have called into question the appropriate implementation. These papers have prompted several opinion pieces [PMIDs: 24328463 and 24251364. The CPIC authors are evaluating the information, which will be incorporated into the next update of the CPIC guideline on warfarin.
    **The best way to estimate stable warfarin dose is to use an algorithm (https://www.warfarindosing.org which offers both high-performing algorithms). Without access to algorithms, the average dose ranges recommended in the FDA-approved warfarin product label are listed here.




    DETAILED RESULT GUIDELINES

    TEST MATERIAL ONLY - PLEASE DO NOT USE THIS CONTENT TO INFORM TREATMENT

    Result Phenotype EMR Entry Details
    CYP2C9*1/*1,
    VKORC1 - 1639 GG
    Normal metabolism,
    Decreased sensitivity
    Dose requirements are normal to higher than average. Consider using algorithm to determine dose. “Patients with the CYP2C9*1/*1 diplotype may require a higher dose of warfarin as compared to patients with the *2 or *3 CYP2C9 alleles. CYP2C9*1/*1 is considered a fully functional genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 GG genotype who are treated with warfarin or acenocoumarol may require higher dose as compared to patients with the VKORC1 AG or AA genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.

    ”Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*1/*2,
    VKORC1 - 1639 GG
    Intermediate metabolism,
    Decreased sensitivity
    Dose requirements are normal to higher than average. Consider using algorithm to determine dose. “Patients with the CYP2C9*1/*2 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 GG genotype who are treated with warfarin or acenocoumarol may require higher dose as compared to patients with the VKORC1 AG or AA genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*1/*1,
    VKORC1 - 1639 GA
    Normal metabolism,
    Intermediate sensitivity
    Dose requirements are normal to higher than average. Consider using algorithm to determine dose. “Patients with the CYP2C9*1/*1 diplotype may require a higher dose of warfarin as compared to patients with the *2 or *3 CYP2C9 alleles. CYP2C9*1/*1 is considered a fully functional genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 AG genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the VKORC1 GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*1/*1,
    VKORC1 - 1639 AA
    Normal metabolism,
    Increased sensitivity
    Likely warfarin sensitive requiring lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*1/*1 diplotype may require a higher dose of warfarin as compared to patients with the *2 or *3 CYP2C9 alleles. CYP2C9*1/*1 is considered a fully functional genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.

    ”“Patients with the VKORC1 AA genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the VKORC1 AG or GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*1/*2,
    VKORC1 - 1639 GA
    Intermediate metabolism,
    Intermediate sensitivity
    Likely warfarin sensitive requiring lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*1/*2 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 AG genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the VKORC1 GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.

    ”Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*1/*2,
    VKORC1 - 1639 AA
    Intermediate metabolism,
    Increased sensitivity
    Likely warfarin sensitive requiring lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*1/*2 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 AA genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the VKORC1AG or GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*1/*3,
    VKORC1 - 1639 GG
    Intermediate metabolism,
    Decreased sensitivity
    Likely warfarin sensitive requiring lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*1/*3 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.

    ”“Patients with the VKORC1 GG genotype who are treated with warfarin or acenocoumarol may require higher dose as compared to patients with the VKORC1 AG or AA genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*1/*3,
    VKORC1 - 1639 GA
    Intermediate metabolism,
    Intermediate sensitivity
    Likely warfarin sensitive requiring lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*1/*3 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 AG genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*2/*2,
    VKORC1 - 1639 GG
    Decreased metabolism,
    Decreased sensitivity
    Likely warfarin sensitive requiring lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*2/*2 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence the dose of warfarin.”“

    Patients with the VKORC1 GG genotype who are treated with warfarin or acenocoumarol may require higher dose as compared to patients with the VKORC1 AG or AA genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.

    ”Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*2/*2,
    VKORC1 - 1639 GA
    Decreased metabolism,
    Intermediate sensitivity
    Likely warfarin sensitive requiring lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*2/*2 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence the dose of warfarin.”“

    Patients with the VKORC1 AG genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the VKORC1 GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*2/*3,
    VKORC1 - 1639 GG
    Decreased metabolism,
    Decreased sensitivity
    Likely warfarin sensitive requiring lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*2/*3 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 GG genotype who are treated with warfarin or acenocoumarol may require higher dose as compared to patients with the VKORC1 AG or AA genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*1/*3,
    VKORC1 - 1639 AA
    Intermediate metabolism,
    Increased sensitivity
    Likely warfarin sensitive requiring much lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*1/*3 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 AA genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the VKORC1 AG or GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*2/*2,
    VKORC1 - 1639 AA
    Decreased metabolism,
    Increased sensitivity
    Likely warfarin sensitive requiring much lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*2/*2 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence the dose of warfarin.

    ”“Patients with the VKORC1 AA genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the VKORC1 AG or GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*2/*3,
    VKORC1 - 1639 GA
    Decreased metabolism,
    Intermediate sensitivity
    Likely warfarin sensitive requiring much lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*2/*3 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 AG genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the VKORC1 GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*2/*3,
    VKORC1 - 1639 AA
    Decreased metabolism,
    Increased sensitivity
    Likely warfarin sensitive requiring much lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*2/*3 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.

    ”“Patients with the VKORC1 AA genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the VKORC1 AG or GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*3/*3,
    VKORC1 - 1639 GG
    Decreased metabolism,
    Decreased sensitivity
    Likely warfarin sensitive requiring much lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*3/*3 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 GG genotype who are treated with warfarin or acenocoumarol may require higher dose as compared to patients with the VKORC1 AG or AA genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.

    ”Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*3/*3,
    VKORC1 - 1639 GA
    Decreased metabolism,
    Intermediate sensitivity
    Likely warfarin sensitive requiring much lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*3/*3 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 AG genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the VKORC1 GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.
    CYP2C9*3/*3,
    VKORC1 - 1639 AA
    Decreased metabolism,
    Increased sensitivity
    Likely warfarin sensitive requiring much lower than average doses. Consider using algorithm to determine dose. “Patients with the CYP2C9*3/*3 diplotype may require a lower dose of warfarin as compared to patients with the CYP2C9*1/*1 diplotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin.”“

    Patients with the VKORC1 AA genotype who are treated with warfarin or acenocoumarol may require a lower dose as compared to patients with the VKORC1 AG or GG genotype. Other genetic and clinical factors may also influence a patient's required dose of warfarin or acenocoumarol.”

    Algorithms are available incorporating genotype and clinical factors to predict warfarin dose requirements and provide guidance on dose adjustments based on INR.

    WARNINGS

    BOXED WARNING (Coumadin)
    Reproduced from NIH-supported DailyMed website. Based on labeling most recently submitted to FDA. Update recency is listed in the About tab.

    Warning: Bleeding Risk

  • COUMADIN can cause major or fatal bleeding (see Warnings and Precautions at DailyMed).
  • Perform regular monitoring of INR in all treated patients (see Dosage and Administration at DailyMed).
  • Drugs, dietary changes, and other factors affect INR levels achieved with COUMADIN therapy (see Drug Interactions at DailyMed).
  • Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding (see Patient Counseling Information at DailyMed).

    WARNINGS (Coumadin)
    Reproduced from NIH-supported DailyMed website. Based on labeling most recently submitted to FDA. Update recency is listed in the About tab.

    Hemorrhage
    COUMADIN can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors (see Clinical Pharmacology at DailyMed), certain concomitant drugs (see Drug Interactions at DailyMed), and long duration of warfarin therapy.

    Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.

    Drugs, dietary changes, and other factors affect INR levels achieved with COUMADIN therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs (see Drug Interactions at DailyMed).

    Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding (see Patient Counseling Information at DailyMed).

    Tissue Necrosis
    Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (<0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of COUMADIN therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.

    Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue COUMADIN therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary.

    Systemic Atheroemboli and Cholesterol Microemboli
    Anticoagulation therapy with COUMADIN may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue COUMADIN therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.

    Heparin-Induced Thrombocytopenia
    Do not use COUMADIN as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with COUMADIN may be considered after the platelet count has normalized.

    Use in Pregnant Women with Mechanical Heart Valves
    COUMADIN can cause fetal harm when administered to a pregnant woman. While COUMADIN is contraindicated during pregnancy, the potential benefits of using COUMADIN may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue COUMADIN should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines. COUMADIN exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus (see Use in Specicic Populations at DailyMed)

    Females of Reproductive Potential
    COUMADIN exposure during pregnancy can cause pregnancy loss, birth defects, or fetal death. Discuss pregnancy planning with females of reproductive potential who are on COUMADIN therapy (see Contraindications at DailyMed) as well as 'Use in Specific Populations' at the same url.

    Other Clinical Settings with Increased Risks
    In the following clinical settings, the risks of COUMADIN therapy may be increased:
  • Moderate to severe hepatic impairment
  • Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy)
  • Use of an indwelling catheter
  • Severe to moderate hypertension
  • Deficiency in protein C-mediated anticoagulant response: COUMADIN reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with COUMADIN may minimize the incidence of tissue necrosis in these patients.
  • Eye surgery: In cataract surgery, COUMADIN use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications. As COUMADIN cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue COUMADIN before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.
  • Polycythemia vera
  • Vasculitis
  • Diabetes mellitus

    Endogenous Factors Affecting INR
    The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency. The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.
  • Overview

    TEST MATERIAL ONLY - PLEASE DO NOT USE THIS CONTENT TO INFORM TREATMENT

    Warfarin is marketed under the name 'Coumadin'. Other names include Jantoven and Marevan (Image: WikiCommons:809).

    What is Warfarin?
    Warfarin is an anticoagulant. It is used to decrease the clotting ability of the blood and to help prevent harmful clots from forming in the blood vessels. It is often used to prevent or treat deep venous thrombosis, a condition in which harmful blood clots form in the blood vessels of the legs. These blood clots can travel to the lungs and cause a condition called pulmonary embolism. Warfarin is also used to prevent or treat blood clots that are caused by certain heart conditions or open-heart surgery. It may be used after a heart attack to prevent blood clots from forming. Although it will not dissolve blood clots that have already formed, warfarin may keep the clots from becoming larger and causing more serious problems.

    This medicine is available only with your doctor's prescription.

    This product is available in the following dosage forms:

  • Tablet

    **Reproduced from Mayo Clinic-supported “Patient Care & Health, Drugs and Supplements” website (Drugs and Supplements). Update recency is listed in the About tab.

    What is being tested?
    The CYP2C9 gene encodes the CYP2C9 enzyme, which is a member of the cytochrome P450 enzyme family. It is involved in the metabolism of warfarin in the body. There are different CYP2C9 gene versions, or variants, and each has a different effect on how well warfarin works in the body. The variants termed *2 and *3 may result in a non-functioning or low-functioning CYP2C9 protein. The VKORC1 gene encodes an enzyme that is involved in the blood clotting process in the body. The two versions of VKORC1 known as “G” and “A” also affect how well warfarin works in the body.

    Patients with one or more variants in either of these genes may need a lower dose of warfarin to achieve the desired effect of the drug. CYP2C9 and VKORC1 gene results, along with a patient’s individual clinical factors, are incorporated into Vanderbilt’s warfarin dose calculator, which provides the recommended initial dose of warfarin for a patient. (See Supporting Evidence)

    **Reproduced from Vanderbilt University-supported My Drug Genome website (My Drug Genome). Update recency is listed in the About tab.

    Recommendations

    FDA (Initial and Maintenance Dosing):
    The appropriate initial dosing of COUMADIN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

  • Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities
  • Genetic factors (CYP2C9 and VKORC1 genotypes) (see Clinical Pharmacology at DailyMed).

    Dosing Recommendations without Consideration of Genotype: If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

    Dosing Recommendations with Consideration of Genotype: Table 1 displays three ranges of expected maintenance COUMADIN doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants (see Clinical Pharmacology at DailyMed). If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.

    **Reproduced from NIH-supported DailyMed website. Based on labeling most recently submitted to FDA. Update recency is listed in the About tab.

    The Clinical Pharmacogenetics Implementation Consortium (CPIC):
  • The best way to estimate stable warfarin dose is to use an algorithm (https://www.warfarindosing.org which offers both high-performing algorithms). Without access to algorithms, the average dose ranges recommended in the FDA-approved warfarin product label are listed here.
  • November 2013 Update: Several recently published studies on warfarin pharmacogenetics [PMIDs: 24251361, 24251363, and 24251360] have called into question the appropriate implementation. These papers have prompted several opinion pieces [PMIDs: 24328463 and 24251364. The CPIC authors are evaluating the information, which will be incorporated into the next update of the CPIC guideline on warfarin.
  • October 2011: CPIC guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing: publication (pdf) and supplement (pdf).

    **Reproduced from NIH-supported PharmGKB website. Update recency is listed in the About tab.

    How will this affect patient healthcare?
    The Treatment Guidelines tab includes a list of guidelines based on patients' genotype.

  • PGx Studies

    TEST MATERIAL ONLY - PLEASE DO NOT USE THIS CONTENT TO INFORM TREATMENT

    Recommendations are from Clinical Pharmacogenetics Implementation Consortium November 2013 Update and October 2011 online publication, available through open access.

  • Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing.

    In addition, the following table is reproduced from Johnson et al. 2011 (Supplemental Table S3) based on PubMed search criteria:

    Type of experimental model Major findings References Level of evidence
    In vitro CYP2C9 is the primary enzyme catalyzing the metabolism and inactivation of S-warfarin. [41, 55, 56] high
    In vitro CYP2C9*2 is associated with reduced catalytic activity. Substrate affinity is not affected substantially by the *2 haplotype, but the maximum rate of metabolism (Vmax) is reduced to approximately 50% of that for CYP2C9*1 (wild-type). [55-60] high
    In vitro CYP2C9*3 is associated with significantly reduced (nearly abolished for homozygotes) function of CYP2C9. [57-59] high
    clinical Individuals with CYP2C9*2 and CYP2C9*3 exhibit impaired metabolism of S-warfarin, leading to longer half-life of the drug. [55, 58, 61-63] high
    clinical CYP2C9 variants with reduced activity (CYP2C9*5, *6, *8, and *11 alleles) variants contribute to variability in the warfarin maintenance dose for African Americans. [15, 64-67] high
    clinical Individuals with CYP2C9*2 and CYP2C9*3 haplotypes have reduced warfarin maintenance dose. [10, 11, 26, 38, 68, 69] high
    clinical Individuals with CYP2C9*2 and CYP2C9*3 are likely to require more time to achieve steady state and a stable INR due to longer half-life of the drug. [70] high
    clinical At conventional warfarin dose, individuals with CYP2C9*2 and CYP2C9*3 are at increased risk of over-anticoagulation (INR>4). [70-72] high
    clinical At conventional warfarin dose, individuals with CYP2C9*2 and CYP2C9*3 are at increased risk of life-threatening bleeding event. [68, 70, 73, 74] high
    clinical CYP2C9 rs7089580variant is associated with higher warfarin dose in African Americans. [75] moderate
    In vitro -1639G>A variant affects VKORC1 expression. [76, 77] high
    clinical VKORC1 is the target for warfarin. [45, 78] high
    clinical VKORC1: -1639G>A variant is associated with reduced maintenance dose of warfarin in caucasians, asians and blacks. It may explain much of pharmacological variability in warfarin therapy. [10, 11, 26, 38, 54, 76, 77, 79, 80] high
    clinical Multiple rare nonsynonymous SNPs in VKORC1 (V29L, D36Y, V45A, R58G, V66M, R98W, L128R) confer warfarin resistance. [45, 81-83] high
    clinical At conventional warfarin dose, individuals with VKORC1:-1639G>A have no increased risk for major or monor bleeding event in africanamericans or caucasians. [73] moderate
    clinical At conventional warfarin dose, individuals with VKORC1:-1639G>A have no difference in time to stable INR in africanamericans or caucasians. [80] moderate
    clinical VKORC1-8191 (rs61162043) variant is associated with higher warfarin dose in African Americans. [75] moderate
    clinical A variant of CYP4F2 (rs2108622, V433M) affects enzyme activity and is associated with warfarin dose, where patient with TT genotype requires approximately 1mg/day more warfarin than patients with CC genotype. [2, 3, 5, 7-10, 12-15] moderate
    clinical Variant rs339097 in CALU predicts higher warfarin dose in African Americans populations, with the G allele of rs339097 associated with 14.5% higher therapeutic warfarin dose. [19, 20] low/mod
    clinical rs11676382 in GGCX was shown to be a significant (p=0.03) predictor of residual dosing error and was associated with a 6.1% reduction in warfarin dose (95% CI: 0.6%-11.4%) per G allele. [24, 25] low/mod
    clinical rs12714145/rs7568458 in GGCX is not associated with warfarin dose . [10, 18, 25, 27, 71] low/mod
    Not ideal to be beginning the references at 41


    REFERENCES

    [1] McDonald MG, Rieder MJ, Nakano M, Hsia CK, Rettie AE. CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M variant. Mol Pharmacol 2009 Jun;75(6):1337-46.

    [2] Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P, et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008 Apr 15;111(8):4106-12.

    [3] Stec DE, Roman RJ, Flasch A, Rieder MJ. Functional polymorphism in human CYP4F2 decreases 20-HETE production. Physiol Genomics 2007 Jun 19;30(1):74-81.

    [4] Borgiani P, Ciccacci C, Forte V, Sirianni E, Novelli L, Bramanti P, et al. CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics 2009 Feb;10(2):261-6.

    [5] Singh O, Sandanaraj E, Subramanian K, Lee LH, Chowbay B. The influence of CYP4F2 rs2108622 (V433M) on warfarin dose requirement in Asian patients. Drug Metab Pharmacokinet 2010 Nov 12.

    [6] Cha PC, Mushiroda T, Takahashi A, Kubo M, Minami S, Kamatani N, et al. Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. Human molecular genetics 2010 Dec 1;19(23):4735-44.

    [7] Cen HJ, Zeng WT, Leng XY, Huang M, Chen X, Li JL, et al. CYP4F2 rs2108622: a minor significant genetic factor of warfarin dose in Han Chinese patients with mechanical heart valve replacement. British journal of clinical pharmacology 2010 Aug;70(2):234-40.

    [8] Sagreiya H, Berube C, Wen A, Ramakrishnan R, Mir A, Hamilton A, et al. Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9. Pharmacogenetics and genomics 2010 Jul;20(7):407-13. [9] Wells PS, Majeed H, Kassem S, Langlois N, Gin B, Clermont J, et al. A regression model to predict warfarin dose from clinical variables and polymorphisms in CYP2C9, CYP4F2, and VKORC1: Derivation in a

    sample with predominantly a history of venous thromboembolism. Thrombosis research 2010 Jun;125(6):e259-64.

    [10] Pautas E, Moreau C, Gouin-Thibault I, Golmard JL, Mahe I, Legendre C, et al. Genetic factors (VKORC1, CYP2C9, EPHX1, and CYP4F2) are predictor variables for warfarin response in very elderly, frail inpatients. Clinical pharmacology and therapeutics 2010 Jan;87(1):57-64.

    [11] Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, Soranzo N, et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 2009 Mar;5(3):e1000433.

    [12] Kringen MK, Haug KB, Grimholt RM, Stormo C, Narum S, Opdal MS, et al. Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction. J Biomed Biotechnol 2011;2011:739751.

    [13] Perini JA, Struchiner CJ, Silva-Assuncao E, Suarez-Kurtz G. Impact of CYP4F2 rs2108622 on the stable warfarin dose in an admixed patient cohort. Clinical pharmacology and therapeutics 2010 Apr;87(4):417-20.

    [14] Lubitz SA, Scott SA, Rothlauf EB, Agarwal A, Peter I, Doheny D, et al. Comparative performance of gene-based warfarin dosing algorithms in a multiethnic population. J Thromb Haemost 2010 May;8(5):1018-26.

    [15] Cavallari LH, Langaee TY, Momary KM, Shapiro NL, Nutescu EA, Coty WA, et al. Genetic and clinical predictors of warfarin dose requirements in African Americans. Clinical pharmacology and therapeutics 2010 Apr;87(4):459-64.

    [16] Wajih N, Sane DC, Hutson SM, Wallin R. The inhibitory effect of calumenin on the vitamin K-dependent gamma-carboxylation system. Characterization of the system in normal and warfarin-resistant rats. The Journal of biological chemistry 2004 Jun 11;279(24):25276-83.

    [17] Vecsler M, Loebstein R, Almog S, Kurnik D, Goldman B, Halkin H, et al. Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin. Thrombosis and haemostasis 2006 Feb;95(2):205-11.

    [18] Wadelius M, Chen LY, Eriksson N, Bumpstead S, Ghori J, Wadelius C, et al. Association of warfarin dose with genes involved in its action and metabolism. Human genetics 2007 Mar;121(1):23-34.

    [19] Voora D, Koboldt DC, King CR, Lenzini PA, Eby CS, Porche-Sorbet R, et al. A polymorphism in the VKORC1 regulator calumenin predicts higher warfarin dose requirements in African Americans. Clinical pharmacology and therapeutics 2010 Apr;87(4):445-51.

    [20] Shahin MH, Khalifa SI, Gong Y, Hammad LN, Sallam MT, El Shafey M, et al. Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients. Pharmacogenetics and genomics 2011 Mar;21(3):130-5.

    [21] Stafford DW. The vitamin K cycle. J Thromb Haemost 2005 Aug;3(8):1873-8.

    [22] Weston BW, Monahan PE. Familial deficiency of vitamin K-dependent clotting factors. Haemophilia 2008 Nov;14(6):1209-13.

    [23] Vanakker OM, Martin L, Gheduzzi D, Leroy BP, Loeys BL, Guerci VI, et al. Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity. J Invest Dermatol 2007 Mar;127(3):581-7.

    [24] Rieder MJ, Reiner AP, Rettie AE. Gamma-glutamyl carboxylase (GGCX) tagSNPs have limited utility for predicting warfarin maintenance dose. J Thromb Haemost 2007 Nov;5(11):2227-34.

    [25] King CR, Deych E, Milligan P, Eby C, Lenzini P, Grice G, et al. Gamma-glutamyl carboxylase and its influence on warfarin dose. Thrombosis and haemostasis 2010 Oct;104(4):750-4.

    [26] Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. The pharmacogenomics journal 2005;5(4):262-70.

    [27] Cha PC, Mushiroda T, Takahashi A, Saito S, Shimomura H, Suzuki T, et al. High-resolution SNP and haplotype maps of the human gamma-glutamyl carboxylase gene (GGCX) and association study between polymorphisms in GGCX and the warfarin maintenance dose requirement of the Japanese population. Journal of human genetics 2007;52(10):856-64.

    [28] Relling MV, Klein TE. CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. Clinical pharmacology and therapeutics 2011 Mar;89(3):464-7.

    [29] Anderson JL, Horne BD, Stevens SM, Grove AS, Barton S, Nicholas ZP, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007 Nov 27;116(22):2563-70.

    [30] Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clinical pharmacology and therapeutics 2008 Mar;83(3):460-70.

    [31] Epstein RS, Moyer TP, Aubert RE, DJ OK, Xia F, Verbrugge RR, et al. Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). J Am Coll Cardiol 2010 Jun 22;55(25):2804-12.

    [32] Hillman MA, Wilke RA, Yale SH, Vidaillet HJ, Caldwell MD, Glurich I, et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clinical medicine & research 2005 Aug;3(3):137-45.

    [33] Huang SW, Chen HS, Wang XQ, Huang L, Xu DL, Hu XJ, et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogenetics and genomics 2009 Mar;19(3):226-34.

    [34] Lenzini P, Wadelius M, Kimmel S, Anderson JL, Jorgensen AL, Pirmohamed M, et al. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clinical pharmacology and therapeutics 2010 May;87(5):572-8.

    [35] Millican EA, Lenzini PA, Milligan PE, Grosso L, Eby C, Deych E, et al. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood 2007 Sep 1;110(5):1511-5.

    [36] Voora D, Eby C, Linder MW, Milligan PE, Bukaveckas BL, McLeod HL, et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thrombosis and haemostasis 2005 Apr;93(4):700-5.

    [37] van Schie RM, Wadelius MI, Kamali F, Daly AK, Manolopoulos VG, de Boer A, et al. Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design. Pharmacogenomics 2009 Oct;10(10):1687-95.

    [38] Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. The New England journal of medicine 2009 Feb 19;360(8):753-64.

    [39] Hamberg AK, Wadelius M, Lindh JD, Dahl ML, Padrini R, Deloukas P, et al. A pharmacometric model describing the relationship between warfarin dose and INR response with respect to variations in CYP2C9, VKORC1, and age. Clinical pharmacology and therapeutics 2010 Jun;87(6):727-34.

    [40] Choonara IA, Haynes BP, Cholerton S, Breckenridge AM, Park BK. Enantiomers of warfarin and vitamin K1 metabolism. British journal of clinical pharmacology 1986 Dec;22(6):729-32.

    [41] Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992 Jan-Feb;5(1):54-9.

    [42] Zhang Z, Fasco MJ, Huang Z, Guengerich FP, Kaminsky LS. Human cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. Drug Metab Dispos 1995 Dec;23(12):1339-46.

    [43] Wienkers LC, Wurden CJ, Storch E, Kunze KL, Rettie AE, Trager WF. Formation of (R)-8-hydroxywarfarin in human liver microsomes. A new metabolic marker for the (S)-mephenytoin hydroxylase, P4502C19. Drug Metab Dispos 1996 May;24(5):610-4.

    [44] Ngui JS, Chen Q, Shou M, Wang RW, Stearns RA, Baillie TA, et al. In vitro stimulation of warfarin metabolism by quinidine: increases in the formation of 4'- and 10-hydroxywarfarin. Drug Metab Dispos 2001 Jun;29(6):877-86.

    [45] Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz HJ, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004 Feb 5;427(6974):537-41.

    [46] Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges. The pharmacogenomics journal 2007 Apr;7(2):99-111.

    [47] Stehle S, Kirchheiner J, Lazar A, Fuhr U. Pharmacogenetics of oral anticoagulants: a basis for dose individualization. Clinical pharmacokinetics 2008;47(9):565-94.

    [48] Limdi NA, Veenstra DL. Warfarin pharmacogenetics. Pharmacotherapy 2008 Sep;28(9):1084-97.

    [49] Waterman AD, Milligan PE, Bayer L, Banet GA, Gatchel SK, Gage BF. Effect of warfarin nonadherence on control of the International Normalized Ratio. Am J Health Syst Pharm 2004 Jun 15;61(12):1258-64.

    [50] Platt AB, Localio AR, Brensinger CM, Cruess DG, Christie JD, Gross R, et al. Can we predict daily adherence to warfarin?: Results from the International Normalized Ratio Adherence and Genetics (IN-RANGE) Study. Chest 2010 Apr;137(4):883-9.

    [51] Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clinical pharmacology and therapeutics 2008 Sep;84(3):326-31.

    [52] Linder MW, Bon Homme M, Reynolds KK, Gage BF, Eby C, Silvestrov N, et al. Interactive modeling for ongoing utility of pharmacogenetic diagnostic testing: application for warfarin therapy. Clin Chem 2009 Oct;55(10):1861-8.

    [53] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. The New England journal of medicine 2009 Sep 17;361(12):1139-51.

    [54] Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee MT, et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood 2010 May 6;115(18):3827-34.

    [55] Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 1994 Feb;4(1):39-42.

    [56] Yamazaki H, Inoue K, Shimada T. Roles of two allelic variants (Arg144Cys and Ile359Leu) of cytochrome P4502C9 in the oxidation of tolbutamide and warfarin by human liver microsomes. Xenobiotica 1998 Feb;28(2):103-15.

    [57] Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 2002 Apr;12(3):251-63.

    [58] Kirchheiner J, Brockmoller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clinical pharmacology and therapeutics 2005 Jan;77(1):1-16.

    [59] Ho PC, Abbott FS, Zanger UM, Chang TK. Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes. The pharmacogenomics journal 2003;3(6):335-42.

    [60] Tang C, Shou M, Rushmore TH, Mei Q, Sandhu P, Woolf EJ, et al. In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics. Pharmacogenetics 2001 Apr;11(3):223-35.

    [61] Lindh JD, Holm L, Andersson ML, Rane A. Influence of CYP2C9 genotype on warfarin dose requirements--a systematic review and meta-analysis. European journal of clinical pharmacology 2009 Apr;65(4):365-75.

    [62] Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999 Feb 27;353(9154):717-9.

    [63] Daly AK, King BP. Contribution of CYP2C9 to variability in vitamin K antagonist metabolism. Expert Opin Drug Metab Toxicol 2006 Feb;2(1):3-15.

    [64] Redman AR, Dickmann LJ, Kidd RS, Goldstein JA, Ritchie DM, Hon YY. CYP2C9 genetic polymorphisms and warfarin. Clin Appl Thromb Hemost 2004 Apr;10(2):149-54.

    [65] Tai G, Farin F, Rieder MJ, Dreisbach AW, Veenstra DL, Verlinde CL, et al. In-vitro and in-vivo effects of the CYP2C9*11 polymorphism on warfarin metabolism and dose. Pharmacogenetics and genomics 2005 Jul;15(7):475-81.

    [66] Scott SA, Jaremko M, Lubitz SA, Kornreich R, Halperin JL, Desnick RJ. CYP2C9*8 is prevalent among African-Americans: implications for pharmacogenetic dosing. Pharmacogenomics 2009 Aug;10(8):1243-55.

    [67] Limdi N, Goldstein J, Blaisdell J, Beasley T, Rivers C, Acton R. Influence of CYP2C9 Genotype on warfarin dose among African American and European Americans. Per Med 2007 May 1;4(2):157-69.

    [68] Margaglione M, Colaizzo D, D'Andrea G, Brancaccio V, Ciampa A, Grandone E, et al. Genetic modulation of oral anticoagulation with warfarin. Thrombosis and haemostasis 2000 Nov;84(5):775-8.

    [69] Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000 Sep 1;96(5):1816-9.

    [70] Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. Jama 2002 Apr 3;287(13):1690-8.

    [71] Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2008 Jun 23.

    [72] Peyvandi F, Spreafico M, Siboni SM, Moia M, Mannucci PM. CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulant therapy. Clinical pharmacology and therapeutics 2004 Mar;75(3):198-203.

    [73] Limdi NA, McGwin G, Goldstein JA, Beasley TM, Arnett DK, Adler BK, et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin. Clinical pharmacology and therapeutics 2008 Feb;83(2):312-21.

    [74] Ogg MS, Brennan P, Meade T, Humphries SE. CYP2C9*3 allelic variant and bleeding complications. Lancet 1999 Sep 25;354(9184):1124.

    [75] Perera MA, Gamazon E, Cavallari LH, Patel SR, Poindexter S, Kittles RA, et al. The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans. Clinical pharmacology and therapeutics 2011 Mar;89(3):408-15.

    [76] Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. The New England journal of medicine 2005 Jun 2;352(22):2285-93.

    [77] Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Human molecular genetics 2005 Jul 1;14(13):1745-51.

    [78] Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature 2004 Feb 5;427(6974):541-4.

    [79] Cooper GM, Johnson JA, Langaee TY, Feng H, Stanaway IB, Schwarz UI, et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 2008 Aug 15;112(4):1022-7.

    [80] Schelleman H, Chen Z, Kealey C, Whitehead AS, Christie J, Price M, et al. Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clinical pharmacology and therapeutics 2007 May;81(5):742-7.

    [81] Harrington DJ, Underwood S, Morse C, Shearer MJ, Tuddenham EG, Mumford AD. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1. Thrombosis and haemostasis 2005 Jan;93(1):23-6.

    [82] Bodin L, Horellou MH, Flaujac C, Loriot MA, Samama MM. A vitamin K epoxide reductase complex subunit-1 (VKORC1) mutation in a patient with vitamin K antagonist resistance. J Thromb Haemost 2005 Jul;3(7):1533-5.

    [83] Harrington DJ, Gorska R, Wheeler R, Davidson S, Murden S, Morse C, et al. Pharmacodynamic resistance to warfarin is associated with nucleotide substitutions in VKORC1. J Thromb Haemost 2008 Oct;6(10):1663-70.
  • Patient FAQs

    TEST MATERIAL ONLY - PLEASE DO NOT USE THIS CONTENT TO INFORM TREATMENT

    Elsewhere on MyResults.org, we have compiled a list of resources to help patients understand Pharmacogenomics and Warfarin, as well as a range of videos, recommended websites, and other patient-friendly content. Immediately below, we have reproduced relevant sections addressing common questions your patients may have.
    Should your patient need to discuss genetic testing and/or results in more detail, the National Society of Genetic Counselors has developed a directory to help locate nearby genetic counseling services.

    OVERVIEW
  • What is Warfarin? 
  • What is being tested? 
  • How will this affect my healthcare? 

    BACKGROUND
  • Why test for genetic interactions with Warfarin? 
  • How will this affect my treatment? 
  • Can taking Warfarin cause any problems?  
  • Are any other complications associated with Warfarin?  
  • Who is affected? 
  • Do different populations respond differently to Warfarin? 
  • Do reactions to Warfarin and other drugs run in my family? 
  • Is there a difference between being a carrier and being predisposed to a particular drug response? 
  • Why do genetic differences make people respond to warfarin differently? 

    GENETIC TEST
  • What is the test? 
  • What will the test result mean? 
  • How is the test being performed? 
  • Will it hurt? 
  • Is it safe? 
  • How long will I have to wait for results? 
  • Is this a standard test? 
  • What type of test is this? 
  • Will I need to have this test done more than once? 

    TREATMENT
  • How will this test affect my treatment? 
  • How will this result be used? 
  • Will I be referred to a specialist? 
  • Is there anything else I should know? 

    PRIVACY & SHARING
  • Should I tell other healthcare providers about my test result? 
  • Who will see my test results? 
  • Should I tell other healthcare providers about my test result? 
  • Should my other family members be tested to see how they might respond to warfarin? 
  • Will this affect my health insurance? 
  • Who can I contact if they have any more questions? 
  • Is it there a risk to my privacy? 

    RISKS
  • What should I do if I have concerns about genetic test results? 
  • Is there a reason why I may be a specific risk?  
  • Are there any implications for having children? 
  • If I am found to have a specific gene variant, am I at increased risk? 
  • Can I expect to experience emotional consequences related to my test result? 
  • Can I expect to experience social consequences related to my test result? 
  • Can I expect to experience an increase in anxiety? 
  • Are there any implications in terms of discrimination arising from the test result?  
  • If I am found to be at increased risk for responding poorly to warfarin, are there similar health implications for my family? 
  • Are there likely to be emotional consequences for my family? 

    OVERVIEW
    What is Warfarin?
    Warfarin is also called Coumaden. It is a drug used by doctors to treat or prevent blood clots, and is most often prescribed to those at risk of deep vein thrombosis, pulmonary embolism, and stroke. Warfarin works by thinning the blood to keep it from clotting so that it flows easier through the body. Warfarin is sometimes called a 'blood thinner'.

    What is being tested?
    A genetic test can look at gene differences (called variants) that affect how your body breaks down the drug warfarin. People react differently to medicine, and some of those different reactions can be related to their genes. Certain variants are linked to a slower drug effect, while other variants may lead to faster drug effects in the body. Variants in two genes in particular - CYP2C9 and VKORC1 - are involved in how people process warfarin. This test will look for some of the genetic differences in the CYP2C9 and VKORC1 genes that can make people respond more rapidly or more slowly to warfarin.

    How will this affect my healthcare?
    Reaching just the right dose of warfarin can be difficult. Deciding on the right dose is affected by many clinical factors including age, sex, weight, height, smoking status, and interacting medications.

    Your doctor will use your genetic test information together with your clinical factors to better predict the best warfarin dose for you. This test can help to your doctor to decide on the best starting dose of warfarin for you. It is also possible that your doctor will not to do anything different.

    You should follow your doctor's instructions on taking any medication. Do not change your medications on your own before speaking with your doctor. If you have any questions about your test results or the medications you are on, please talk with your doctor.

    Why test for genetic interactions with Warfarin?
    By performing a test on your DNA, we may be able to anticipate how you will respond to warfarin and to modify your treatment accordingly. The dose that patients receive depends on their age, gender, race, and weight. In addition, genetic factors dictate an individual's response to the drug. Calculators are available to doctors to help determine the correct dose for each patient.

    How will this affect my treatment?
    If genetic testing does indicate that you may not respond optimally to treatment with warfarin, your doctor should change your prescription.

    Can taking Warfarin cause any problems?
    For the majority of people taking warfarin will not cause any problems. The most common side effect, found in 1-3% of people taking warfarin, is bleeding, which can become serious.

    Are any other complications associated with Warfarin?
    Large doses of warfarin can cause necrosis, severe damage to the skin and tissue. Although rare, taking warfarin can also damage organs, including the pancreas, spleen, and liver.

    Who is affected?Genetic differences that affect how people respond to warfarin are relatively common. As outlined immediately below, there is a relationship between ancestry and risk of warfarin sensitivity.

    Do different populations respond differently to Warfarin?
    Variants in two genes in particular - CYP2C9 and VKORC1 - are involved in how people process warfarin.

    For CYP2C9, the two most common versions of the gene are CYP2C9*2 and CYP2C9*3:

  • CYP2C9*2 is found in 8-19% of Caucasians, in 0-12% of African Americans, and in 0-4% Asians.
  • CYP2C9*3 is found in 5-16% of Caucasians, in 0-6% of African Americans, and in 1-8% of Asians.

    Warfarin sensitivity related to the VKORC1 gene is associated with a generic mutation called 1639G>A. This is found in 89% of Asians, 37% of Caucasians, and 14% of African Americans.

    Do reactions to Warfarin and other drugs run in my family?
    We typically inherit two gene copies from each parent. If you have a genetic difference that affects how you respond to warfarin, it is likely to have been inherited from one or both of your parents, and it is possible you will pass this to your children. However, this is not always the case, and a large variety of inheritance scenarios are possible. If you are concerned about this, we strongly advise you to discuss with your doctor or healthcare provider.

    Is there a difference between being a carrier and being predisposed to a particular drug response?
    You may carry a genetic a difference that does not affect how you response to warfarin, but may affect how your children might respond. A full discussion of the relevant scenarios/implications are beyond the scope of this site, however, and we recommend you discuss with your doctor or healthcare provider if this is a concern.

    Why do genetic differences make people respond to warfarin differently?
    The CYP2C9 gene codes for a protein involved in the breakdown (metabolism) of warfarin. People with variations in this gene may metabolize warfarin more slowly, resulting in slower clearance of the drug and accumulation in the body over time. They may require a lower dose of the drug.

    The VKORC1 gene codes for the protein that warfarin targets. A variation in this gene may result in a protein change that may be more sensitive or less sensitive (or resistant) to the anticoagulant effect of warfarin. Depending on the variant present, the person tested may need a lower or higher initial dose of warfarin.

    GENETIC TEST

    What is the test?
    This test may help your doctor decide on the dose of warfarin you should receive. As mentioned in the Overview, the test specifically focuses on two genes - CYP2C9 and VKORC1. The amount of warfarin you need will depend on the type of CYP2C9 and VKORC1 you have inherited. However, the dose you receive will also greatly depend upon your health, age, gender, diet, and other medications.

    NOTE: The test only looks for the more common types of CYP2C9 and VKORC1, and may not test for rare types that could be involved in your personal response to warfarin.

    What will the test result mean?
    Genetic testing for warfarin sensitivity may be used to help determine your response to warfarin and to help select appropriate doses. It does this by identifying variations in certain genes. Certain variations in the VCORC1 or CYP2C9 genes may result in a protein change that affect how individuals are more sensitive or less sensitive (or resistant) to the blood-thinning effect of warfarin. Depending on the variant present, the person tested may need a lower or higher initial dose of warfarin.

    For some, this testing may be used to help determine an appropriate dose because you previously took warfarin and either experienced inappropriate clotting or bleeding episodes while on warfarin, or had to go through many dose adjustments to reach a stable anticoagulant ("blood-thinning") effect.

    How is the test being performed?
    Testing is performed on your DNA, usually extracted from a blood sample. For many patients, your hospital or treatment center may already have some of your DNA stored in a biobank. You may be asked for an additional sample or be asked to give us permission to do testing on the existing samples.

    Will it hurt?
    For some patients, we may need an additional blood sample. Taking blood may cause some pain, bleeding or bruising at the spot where the needle enters your body. Rarely, taking blood may cause fainting or infection.

    Is it safe?
    There is a risk that you may experience pain or bleeding if you need to give an additional blood sample. Risks concerning privacy are discussed under Privacy & Sharing.

    How long will I have to wait for results?
    Unfortunately, we cannot give an accurate estimate for the time you will have to wait for results - this will depend on the resources available at the center where you receive treatment.

    Is this a standard test?
    Although increasingly more common, this test is not yet standard, and is typically offered as part of a research study.

    What type of test is this?
    Is this test intended to confirm a diagnosis? No
    Is this test intended to predict a family history of disease? No
    Is this test intended to check if I am a carrier for a particular disease? No
    Is this test intended to screen for genetic disorders? No
    Is this test intended to screen for disorders related to pregnancy? No
    Is this test intended to screen for disorders related to newborns? No

    Will I need to have this test done more than once?
    No, you should not need to have this test done more than once. You will need to keep track of your testing result in order to share with all of your doctors, including those you see at other medical care centers.

    TREATMENT

    How will this test affect my treatment?

    For most people tested, it is likely that your treatment options will stay the same and that you will begin treatment with warfarin as scheduled, or you will maintain you treatment with warfarin . If this is not the case, your doctor will either change your recommended dose of warfarin or recommend a new treatment.

    How will this result be used?


    Genetic testing for warfarin sensitivity may be used to help determine your response to warfarin and to help select appropriate doses. It does this by identifying variations in certain genes. Certain variations in the VCORC1 or CYP2C9 genes may result in a protein change that affect how individuals are more sensitive or less sensitive (or resistant) to the blood-thinning effect of warfarin. Depending on the variant present, the person tested may need a lower or higher initial dose of warfarin.

    For some, this testing may be used to help determine an appropriate dose because you previously took warfarin and either experienced inappropriate clotting or bleeding episodes while on warfarin, or had to go through many dose adjustments to reach a stable anticoagulant ('blood-thinning') effect.

    The result will be put into your medical record for your doctor to have access to use when deciding about prescribing warfarin. Your doctor may:
  • Do other tests to see how you might respond to warfarin
  • Do nothing and continue with your planned course of treatment
  • Switch your dose if you are on warfarin and having difficulty with control

    Regardless of your genetic makeup, your response to warfarin therapy will still need to be monitored with regular PT/INR tests.

    Will I be referred to a specialist?
    It is unlikely that you will be referred to a specialist, but you may request an appointment with a genetic counselor.

    Is there anything else I should know?
    You should follow your doctor's instructions when taking any medication. Do not change your medications on your own before speaking with your doctor.

    PRIVACY & SHARING

    Should I tell other healthcare providers about my test result?
    If your doctor who prescribes medication for you doesn't already know about your test result, we do recommend that you share this information with him/her. However, what you decide to do with your results is up to you.

    Who will see my test results?
    People who have access to your medical record will be able to see your genetic test result. This may include health professionals such as doctors, nurses, pharmacists, and genetic counselors. However, health professionals from other centers or hospitals will likely not have access to your results.

    Should I tell other healthcare providers about my test result?
    If your doctor who prescribes medication for you doesn't already know about your test result, you should share this information with him/her.

    Should my other family members be tested to see how they might respond to warfarin?
    You may want to share your test results with your family, since they might have the same genetic variant as you.

    Will this affect my health insurance?
    No, your health insurance will not be affected by this test result.

    Who can I contact if they have any more questions?
    You can contact your local center, where you received the test.

    Is it there a risk to my privacy?
    Research that uses information from medical records and that involves genetic testing can affect your privacy. Your participation in this research will be held strictly confidential, and only coded numbers will be used to identify specimens and research records. While it is impossible to absolutely guarantee that information in our secure system will never be known by others, we are taking every possible precaution to see that this does not happen.

    RISKS

    What should I do if I have concerns about genetic test results?
    If you are concerned about genetic test results you have received, you should discuss your concerns with your doctor. Your doctor should be able to explain results to you, and may recommend you to a genetic counselor or another doctor that can further help you understand your results.

    Is there a reason why I may be a specific risk?
    Testing is recommended for all individuals undergoing or considering undergoing treatment with warfarin.

    Are there any implications for having children?
    No.

    If I am found to have a specific gene variant, am I at increased risk?
    For some individuals, there gene test result may indicate that they are at an increased risk of responding poorly to warfarin. Testing is done to help guide your doctor chose the best treatment for you.

    Can I expect to experience emotional consequences related to my test result?
    A range of reactions are possible and normal. Some patients may experience anxiety or other negative reactions related to their use/potential use of warfarin. If this is the case, please discuss with your doctor, who can address your concerns and refer you another health professional if required.

    Can I expect to experience social consequences related to my test result?
    We do not anticipate any social consequences related to use/potential use of warfarin. As always, however, if you do experience any negative social reactions, please discuss with your doctor who can address your concerns.

    Can I expect to experience an increase in anxiety?
    Many individual experience increased anxiety related to genetic testing. Again, please discuss with your doctor if this is the case./p>

    Are there any implications in terms of discrimination arising from the test result?
    Health insurance companies are prevented by law from discriminating against you based on your genetic test results. However, the same law does not apply to long-term disability insurance or to life insurance.

    If I am found to be at increased risk for responding poorly to warfarin, are there similar health implications for my family?
    If results indicate that you may respond poorly to warfarin, your family may be more likely to have a similar response should warfarinever be considered an option for them. As such, you may want to discuss your results with your family.

    Are there likely to be emotional consequences for my family?
    Similar to patients, family members may experience a range of reactions, which is normal. We recommend that if you discuss any questions or problems with your healthcare provider.

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    When was this content last updated?
    May 14, 2015.

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