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Treatment Guidelines

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

  • Guidelines, Overview 
  • Detailed Result Guidelines 
  • Contraindications 
  • Warnings 

    GUIDELINES, OVERVIEW
    In 2013, the Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health's Pharmacogenomics Research Network issued a series of guidelines related to the CYP2C19 gene and clopidogrel 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 CYP2C19-clopidogrel results are listed immediately below. Each result pair is hyperlinked, with more detailed information listed in Detailed Result Guidelines  below.

    Pediatrics: Please note that at the time of the developing these recommendations, there are no data available on the role of CYP2C19/clopidogrel in pediatric populations. However, there is no reason to suspect that CYP2C19 alleles would affect clopidogrel metabolism differently in children versus adults.

    Extensive Metabolizers:

    Result Phenotype Recommended Dosing Pharmacologic Implications Classification
    *1/*1 Extensive metabolizer Follow clopidogrel-label dosage and administration. Normal platelet inhibition and normal residual platelet aggregation. Strong


    Ultrarapid Metabolizers:

    Result Phenotype Recommended Dosing Pharmacologic Implications Classification
    *1/*17
    *17/*17
    Ultrarapid metabolizer Follow clopidogrel-label dosage and administration. Increased platelet inhibition and decreased residual platelet aggregation. Strong


    Intermediate Metabolizers:

    Result Phenotype Recommended Dosing Pharmacologic Implications Classification
    *1/*2
    *1/*3
    *2/*17
    Intermediate metabolizer Alternative antiplatelet therapy (e.g. prasugrel, ticagrelor) - if no contraindication. Reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Moderate
    Rare Genotypes, Not Specifically Covered in CPIC
    *1/*4
    *1/*5
    *1/*6
    *1/*7
    *1/*8
    *3/*17
    *4/*17
    *5/*17
    *6/*17
    *7/*17
    *8/*17
    Intermediate metabolizer Alternative antiplatelet therapy (e.g. prasugrel, ticagrelor) - if no contraindication. Reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Moderate


    Poor Metabolizers:

    Result Phenotype Recommended Dosing Pharmacologic Implications Classification
    *2/*2
    *2/*3
    *3/*3
    Poor metabolizer Recommend alternative antiplatelet therapy (e.g. prasugrel, ticagrelor) - if no contraindication. Significantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Strong
    Rare Genotypes, Not Specifically Covered in CPIC
    *2/*4
    *2/*5
    *2/*6
    *2/*7
    *2/*8
    *3/*4
    *3/*5
    *3/*6
    *3/*7
    *3/*8
    *4/*4
    *4/*5
    *4/*6
    *4/*7
    *4/*8
    *5/*5
    *5/*6
    *5/*7
    *5/*8
    *6/*6
    *6/*7
    *6/*8
    *7/*7
    *7/*8
    *8/*8
    Poor metabolizer Recommend alternative antiplatelet therapy (e.g. prasugrel, ticagrelor) - if no contraindication. Significantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Strong



    DETAILED RESULT GUIDELINES

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

    Result Strength Phenotype EMR Entry Details
    *1/*1 Strong Extensive metabolizer CYP2C19 - Extensive metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two functional alleles. This means that the patient has normal platelet inhibition and normal residual platelet aggregation. The CPIC guidelines from www.pharmgkb.org suggest that clopidogrel-label dosage and administrationshould be followed.
    *1/*17 Strong Ultrarapid metabolizer CYP2C19 - Ultrarapid metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two increased-activity alleles, or one functional plus one increased-activity allele. This means that the patient has increased platelet inhibition and decreased residual platelet aggregation. The CPIC guidelines from www.pharmgkb.org suggest that clopidogrel-label dosage and administrationshould be followed.
    *17/*17 Strong Ultrarapid metabolizer CYP2C19 - Ultrarapid metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two increased-activity alleles, or one functional plus one increased-activity allele. This means that the patient has increased platelet inhibition and decreased residual platelet aggregation. The CPIC guidelines from www.pharmgkb.org suggest that clopidogrel-label dosage and administrationshould be followed.
    *1/*2 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one functional allele plus one loss-of-function allele. This means that the patient has reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. The CPIC guidelines from www.pharmgkb.org recommend alternative antiplatelet therapy (e.g. prasugrel, ticagrelor) - if no contraindication.
    *1/*3 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one functional allele plus one loss-of-function allele. This means that the patient has reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. The CPIC guidelines from www.pharmgkb.org recommend alternative antiplatelet therapy (e.g. prasugrel, ticagrelor) - if no contraindication.
    *2/*17 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one loss-of-function allele plus one increased activity allele. This means that the patient has reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. The CPIC guidelines from www.pharmgkb.org suggest alternative antiplatelet therapy (e.g. prasugrel, ticagrelor) - if no contraindication.
    *2/*2 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patient has significantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. The CPIC guidelines from www.pharmgkb.org recommend alternative antiplatelet therapy (e.g. prasugrel, ticagrelor) - if no contraindication.
    *2/*3 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patient has significantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. The CPIC guidelines from www.pharmgkb.org recommend alternative antiplatelet therapy (e.g. prasugrel, ticagrelor) - if no contraindication.
    *3/*3 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patient has significantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. The CPIC guidelines from www.pharmgkb.org recommend alternative antiplatelet therapy (e.g. prasugrel, ticagrelor) - if no contraindication.
    Rare Genotypes, Not Specifically Covered in CPIC
    Result Strength Phenotype EMR Entry Details
    *1/*4 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one functional allele plus one loss-of-function allele. This means that the patients hasreduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *1/*5 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one functional allele plus one loss-of-function allele. This means that the patients hasreduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *1/*6 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one functional allele plus one loss-of-function allele. This means that the patients hasreduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *1/*7 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one functional allele plus one loss-of-function allele. This means that the patients hasreduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *1/*8 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one functional allele plus one loss-of-function allele. This means that the patients hasreduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *2/*4 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *2/*5 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org suggest that alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *2/*6 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org suggest that alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *2/*7 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org suggest that alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *2/*8 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org suggest that alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *3/*4 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org suggest that alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *3/*5 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org suggest that alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *3/*6 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org suggest that alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *3/*7 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org suggest that alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *3/*8 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org suggest that alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *3/*17 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one loss-of-function allele plus one increased activity allele. This means that the patients hasreduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *4/*4 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *4/*5 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *4/*6 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *4/*7 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *4/*8 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *4/*17 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one loss-of-function allele plus one increased activity allele. This means that the patients hasreduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *5/*5 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *5/*6 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *5/*7 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *5/*8 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *5/*17 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one loss-of-function allele plus one increased activity allele. This means that the patients hasreduced platelet inhibition; increased residual platelet aggregation; increased risk for adverse cardiovascular events.Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *6/*6 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *6/*7 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *6/*8 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *6/*17 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one loss-of-function allele plus one increased activity allele. This means that the patients hasreduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *7/*7 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *7/*8 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *7/*17 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one loss-of-function allele plus one increased activity allele. This means that the patients hasreduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *8/*8 Strong Poor metabolizer CYP2C19 - Poor metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries two loss-of-function alleles. This means that the patients hassignificantly reduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .
    *8/*17 Moderate Intermediate metabolizer CYP2C19 - Intermediate metabolizer This patient has been tested for CYP2C19 Genotype Status. Results indicate that the individual carries one loss-of-function allele plus one increased activity allele. This means that the patients hasreduced platelet inhibition, increased residual platelet aggregation, and increased risk for adverse cardiovascular events. Guidelines adapted from CPIC at www.pharmgkb.org recommend alternative antiplatelet therapy (if no contraindication) (e.g., prasugrel, ticagrelor) .

    CONTRAINDICATIONS (Plavix)
    Reproduced from the NIH-supported DailyMed website. Based on labeling most recently submitted to FDA. Update recency is listed in the About tab (references and link removed).

    The effectiveness of Plavix is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see WARNINGS - reproduced below]. Plavix at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with Plavix at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy [see CLINICAL PHARMACOLOGY (12.5)]. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.

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


    Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function
    Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19.

    Proton Pump Inhibitors

    Avoid concomitant use of Plavix with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of Plavix.

    General Risk of Bleeding
    Thienopyridines, including Plavix, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue Plavix five days prior to surgery. In patients who stopped therapy more than five days prior to CABG the rates of major bleeding were similar (event rate 4.4% Plavix + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for Plavix + aspirin, and 6.3% for placebo + aspirin. Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7–10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.

    Discontinuation of Plavix
    Avoid lapses in therapy, and if Plavix must be temporarily discontinued, restart as soon as possible. Premature discontinuation of Plavix may increase the risk of cardiovascular events.

    Patients with Recent Transient Ischemic Attack (TIA) or Stroke
    In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and Plavix has not been shown to be more effective than Plavix alone, but the combination has been shown to increase major bleeding.

    Thrombotic Thrombocytopenic Purpura (TTP)
    TTP, sometimes fatal, has been reported following use of Plavix, sometimes after a short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.

    Cross-Reactivity among Thienopyridines Hypersensitivity including rash, angioedema or hematologic reaction have been reported in patients receiving Plavix, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines.

  • Overview

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

    Clopidogrel is an anti-platelet pro-drug marketed as 'Plavix' by Sanofi and Bristol-Myers Squibb

    What is Clopidogrel?

  • Clopidogrel (Plavix - Sanofi/BMS) is a thienopyridine prodrug. It used to inhibit thrombi in coronary artery disease, peripheral vascular disease, cerebrovascular disease, and to prevent myocardial infarction.
  • Clopidogrel relies on hepatic biotransformation to form an active metabolite, which selectively and irreversibly inhibits the purinergic P2RY12 receptor and thus platelet aggregation for the platelet’s life span (~10 days).
  • Only 15% of the prodrug is available for transformation to the active agent; the remaining 85% is hydrolyzed by esterases to inactive forms. Conversion to its active metabolite requires two sequential oxidative steps involving several CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5. Paraoxonase 1 (PON1) may also be involved in clopidogrel activation.

    What is being tested?

  • Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of clopidogrel. Several loss-of-function CYP2C19 alleles have been identified. These impair the formation of active metabolites, resulting in reduced platelet inhibition. CYP2C19 loss-of-function alleles also confer increased risks for serious adverse cardiovascular events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype–directed antiplatelet therapy, and refined recommendations for specific CYP2C19 alleles.
  • Like many other CYP450 superfamily members, the CYP2C19 gene is highly polymorphic, with >25 known variant alleles. The wild-type CYP2C19*1 allele is associated with functional CYP2C19-mediated metabolism. The most common CYP2C19 loss-of-function allele is *2 (c.681G>A; rs4244285), with allele frequencies of ~15% in Caucasians and Africans, and 29–35% in Asians.
  • Other CYP2C19 variant alleles with reduced or absent enzymatic activity have been identified (e.g., *3–*8); however, their frequencies are typically below 1%, with the exception of CYP2C19*3 (c.636G>A; rs4986893) in Asians (with an allele frequency of 2–9%).
  • The hepatic CYP2C19 enzyme also contributes to the metabolism of a large number of clinically relevant drugs such as antidepressants, benzodiazepines, mephenytoin, and some proton pump inhibitors.

    Recommendations

  • FDA (Boxed Warning): The effectiveness of Plavix is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Plavix at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with Plavix at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.

  • The Clinical Pharmacogenetics Implementation Consortium (CPIC): CPIC updated its Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy in 2013. Guidelines for antiplatelet therapy were developed based on interpretation of the available literature by the authors and experts in the field, and cover 25 known alleles.

  • The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group evaluated therapeutic dose recommendations for clopidogrel based on the CYP2C19 genotype. For the CYP2C19 PM and IM phenotype they conclude an increased risk for reduced response to clopidogrel and recommend to consider an alternative drug. Prasugrel is not or to a much smaller extent metabolized by CYP2C19 but is associated with an increased bleeding risk compared to clopidogrel.

    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 based the Clinical Pharmacogenetics Implementation Consortium from 2013, available through open access:

    Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update.
    SA Scorr et al, 2013. Clinical Pharmacology & Therapeutics.

    In addition, the following table is reproduced from Scott et al. (2013) based on PubMed search criteria:

    Model Major Findings Refs (links below) Level of Evidence*
    In vitro CYP2C19*2 (c.681G>A; rs4244285) is a common polymorphism that results in a splicing defect and nonfunctional CYP2C19 protein. 1 High
    In vitro The CYP2C19*3 - *8 variant alleles result in loss-of-function. 2-7 High
    In vitro/In vivo CYP2C19*17 (c.-806C>T; rs12248560) is a common polymorphism that results in increased activity as a consequence of enhanced transcription. 8-10 High
    In vitro CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5 are involved in the hepatic metabolism of clopidogrel. 11-16 High
    In vitro CYP2C19 contributes substantially to both oxidative steps of clopidogrel metabolism during the formation of its active metabolite. 15 High
    Clinical CYP2C19*2 is associated with reduced formation of active metabolites (pharmacokinetics) in healthy subjects treated with clopidogrel. 17-23 High
    Clinical CYP2C19*2 is associated with reduced formation of active metabolites (pharmacokinetics) in ACS/PCI patients treated with clopidogrel. 24, 25 High
    Clinical CYP2C19*2 is associated with higher on-treatment platelet reactivity (pharmacodynamics) in healthy subjects treated with clopidogrel. 17-21, 26-29 High
    Clinical CYP2C19*2 is associated with higher on-treatment platelet reactivity (pharmacodynamics) in ACS/PCI patients treated with clopidogrel. 24, 25, 29-59 High
    Clinical CYP2C19*2 is associated with adverse cardiovascularoutcomes (e.g., cardiovascular death, myocardial infarction,stroke, stent thrombosis) in ACS/PCI patients treated withclopidogrel. 20, 29, 33, 44, 48, 55, 58-69 High
    Clinical CYP2C19*3 (and possibly other loss-of-function alleles) is associated with lower formation of active metabolites (pharmacokinetics) in healthy subjects treated with clopidogrel 18-20, 33 High
    Clinical CYP2C19*3 (and possibly other loss-of-function alleles) isassociated with higher on-treatment platelet reactivity(pharmacodynamics) in healthy subjects treated withclopidogrel. 18-20, 28 High
    Clinical CYP2C19*3 (and possibly other loss-of-function alleles) isassociated with higher on-treatment platelet reactivity(pharmacodynamics) in ACS/PCI patients treated withclopidogrel 34, 37, 38, 43-47, 49, 53, 57-59, 70 High
    Clinical CYP2C19*3 (and possibly other loss-of-function alleles) isassociated with adverse cardiovascular outcomes (e.g.,cardiovascular death, myocardial infarction, stroke, stentthrombosis) in ACS/PCI patients treated with clopidogrel. 20, 44, 49, 58-60, 63, 64 High
    Clinical CYP2C19*17 is associated with lower on-treatment plateletreactivity (pharmacodynamics) in ACS/PCI patients treatedwith clopidogrel. 39, 51, 71-75 Moderate
    Clinical CYP2C19*17 is associated with enhanced clopidogrel response and an increased bleeding risk in ACS/PCI patients treated with clopidogrel. 51, 72-74, 76 Moderate
    Clinical CYP2C19 loss-of-function alleles are not associated withadverse cardiovascular outcomes in coronary patients withlow frequencies of PCI and with other indications (e.g., atrialfibrillation) treated with clopidogrel. 77, 78 High
    Clinical ACS/PCI patients with CYP2C19 reduced metabolizer genotypes have reduced risks of primary outcome with prasugrel compared to clopidogrel. However, for CYP2C19 EMs, the risks with prasugrel and clopidogrel are not significantly different. 79 High
    Clinical ACS/PCI patients with CYP2C19 reduced metabolizergenotypes have reduced risks of primary outcome withticagrelor compared to clopidogrel, which was less significantamong CYP2C19 EMs and most pronounced among patientsundergoing PCI. 78, 80 High
    ACS: acute coronary syndrome; EM: extensive metabolizer; PCI: percutaneous coronary intervention* See above for description of ‘Levels of Evidence Linking Genotype to Phenotype’.

    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 Clopidogrel, 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 clopidogrel? 
  • What is being tested? 
  • How will this affect my healthcare? 

    BACKGROUND
  • Why test for genetic interactions with clopidogrel? 
  • How will this affect my treatment? 

    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 thiopurines? 
  • 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 clopidogrel, are there similar health implications for my family? 
  • Are there likely to be emotional consequences relevant to clopidogrel for my family? 

    OVERVIEW
    What is clopidogrel?
    Clopidogrel is also called Plavix. It is a drug used by doctors to treat or prevent strokes and heart attacks. Clopidogrel works by preventing the blood from clotting so that it flows easier through the body. Clopidogrel is sometimes called a 'blood thinner'.

    What is being tested?
    People react differently to medicine and some of those different reactions can be related to their genes. People with certain differences in their genes might not respond to particular medications as well as others. The gene involved in how people use clopidogrel is called CYP2C19. This test will look for some of the genetic differences in the CYP2C19 gene that can make people less responsive to clopidogrel.

    How will this affect my healthcare?
    If testing shows that you might be less responsive to clopidogrel, you may be prescribed a different medication by your doctor. Your doctor may also use this information to decide on which dose to take. It is also possible that your doctor will not to do anything different.

    If you have any questions about your test results or the medications you are on, please talk with your doctor.

    You should follow your doctor's instructions on taking any medication. Do not change your medications on your own before speaking with your doctor.

    Why test for genetic interactions with clopidogrel?
    By performing a test on your DNA, we may be able to anticipate how you will respond to clopidogrel and to adjust your treatment accordingly.

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

    Can taking clopidogrel cause any problems?
    For the majority of people taking clopidogrel will not cause any problems. However, in a small proportion of people, a change in dosing or medication may be recommended to prevent bleeding and other adverse events.

    Are any other complications associated with clopidogrel?
    A minority of individuals can experience severe complications after taking clopidogrel, with excessive bleeding a possibility.

    Who is affected?Up to 50% of people have a genetic difference that either increases or reduces how they metabolize clopidogrel, which may warrant a change in treatment.

    Do different populations respond differently to clopidogrel?
    Genetic differences in clopidogrel response are relatively widespread across populations. However, individuals of Asian ancestry may be the most likely to have a genetic difference affecting their response to clopidogrel.

    Do reactions to clopidogrel 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 clopidogrel, 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 clopidogrel, 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 clopidogrel differently?
    Clopidogrel must be activated by CYP450 enzymes in our body in order to work. The instructions on how the CYP450 enzymes work is determined by the CYP2C19 gene. So, differences in the CYP2C19 gene will make people use clopidogrel differently. For some people, the genetic difference makes the CYP450 enzymes work less well. If the CYP450 enzymes don’t activate the clopidogrel in the body, it will make clopidogrel less effective for the person taking it.

    GENETIC TEST

    What is the test?
    People react differently to medicine and some of those different reactions can be related to their genes. People with certain differences in their genes might not respond to particular medications as well as other people. The gene involved in how people use clopidogrel is called, CYP2C19. This test will look for some of the genetic differences in the CYP2C19 gene that can make people less responsive to clopidogrel.

    What will the test result mean?
    This test will tell us how you will likely respond to clopidogrel. Most people are 'normal metabolizers'. You might also be a 'poor metabolizer', 'intermediate metabolizer', or 'ultra-rapid metabolizer':

  • Normal metabolizers are people who would respond to clopidogrel as expected.
  • Poor metabolizers are people where clopidogrel will not work as well to treat their condition. Therefore, someone who is a poor metabolizer may need to use a different drug or may need a larger dose of medication to get the same benefits.
  • Intermediate metabolizers are people who may process or use clopidogrel a bit slower than expected, but can still experience some benefit from the drug. This means that some people who are found to be an intermediate metabolizer of clopidogrel may have a slower response to clopidogrel.
  • Rapid metabolizers are people who may process or use clopidogrel faster than other people. This means that people who are found to be a rapid metabolizer of clopidogrel may have an improved response to this medication.

    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 clopidogrel as scheduled, or you will maintain you treatment with Clopidogrel. If this is not the case, your doctor will either change your recommended dose of clopidogrel or recommend a new treatment.

    How will this result be used?

    The result will be put into your medical record for your doctor to use when deciding about prescribing you clopidogrel. Your doctor may:

  • Do other tests to see how you might respond to clopidogrel
  • Do nothing and continue with your planned course of treatment
  • Change your dosage of clopidogrel
  • Give you another medication that is not clopidogrel to treat your condition
  • You should follow your doctor's instructions when taking any medication. Do not change your medications on your own before speaking with your doctor.

    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 clopidogrel?
    You may want to share your test results with your family, since they might have the same genetic variant as you. If you are a 'poor metabolizer' of clopidogrel, they may want to consider being tested also.

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

    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 clopidogrel (needing more or less of the drug), or of developing side-effects such as bleeding. 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 clopidogrel. 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 clopidogrel. 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.

    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 clopidogrel, are there similar health implications for my family?
    If results indicate that you may respond poorly to clopidogrel, your family may be more likely to have a similar response should clopidogrel ever 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 relevant to clopidogrel 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.

    About

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

    When was this content last updated?
    May 04, 2015.

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