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Cytochrome p450 Genotyping for Assessment of Individuals Prior to Initiation of Clopidogrel Bisulfate (Plavix®)
Pharmacogenetic Testing to Determine Drug Sensitivity (AmeriHealth Administrators)
Genetic Testing Prior to Initiation of Clopidogrel Bisulfate (Plavix®)
On March 12, 2010, the US Food and Drug Administration approved a new label for clopidogrel bisulfate (Plavix®), which included a Black Box Warning that discussed the diminished effectiveness of clopidogrel bisulfate in individuals with an impaired ability to convert the drug into its active form. This warning was the third FDA labeling change relative to this issue in one year. The Black Box Warning was included in the labeling based on the concern that antiplatelet utility of clopidogrel bisulfate is dependent upon its activation by the cytochrome P450 system. Explicit in the March 2010 labeling change was the assertion that individuals with genetic polymorphisms that diminish CYP2C19 function metabolize clopidogrel (Plavix
) poorly and have higher rates of cardiovascular events after acute coronary syndrome (ACS) and percutaneous coronary interventions (PCIs) than individuals with normal CYP2C19 function.
In order to provide analysis and context to the Black Box Warning, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) convened a writing committee. A report of their findings, assessment, and recommendations for practice was co-published by the ACCF and AHA in July 2010. The consensus opinion report indicates that because of genetic polymorphisms, individuals with decreased CYP2C19 function metabolize clopidogrel bisulfate poorly and have higher rates of cardiovascular events after acute coronary syndrome (ACS) and percutaneous coronary interventions (PCIs) than individuals with normal CYP2C19 function. Tests are available to identify individuals with genetic polymorphisms, and "alternative treatment strategies should be considered in poor metabolizers of the drug."
As discussed in the ACCF/AHA analysis, there are three major CYP2C19 genetic polymorphisms. Polymorphism CYP2C19*1 corresponds to normal function; the other two alleles, CYP2C19*2 and CYP2C19*3, represent loss-of-function alleles. The presence of these polymorphisms explains most of the reduced function in individuals who are poor metabolizers. The analysis notes that CYP2C19 alleles*2 and*3 represent 85% and 99% of the nonfunctional alleles in whites and Asians, respectively. Poor metabolizers have two loss-of-function alleles, whereas individuals with one copy of a loss-of-function allele are considered intermediate metabolizers. Intermediate metabolizers may also have decreased active metabolite levels and reduced antiplatelet effects when treated with clopidogrel bisulfate, but the Black Box Warning only refers to poor metabolizers.
ACCF/AHA additionally notes that the FDA labeling for clopidogrel bisulfate (Plavix®) was first revised in May 2009, and this labeling indicated that "poor metabolizer status is associated with diminished response to clopidogrel" and that "the optimal dose for poor metabolizers has yet to be determined." A subsequent FDA-labeling revision in late 2009 advised that clopidogrel should be avoided "in patients with impaired CYP2C19 function due to known genetic polymorphisms or due to drugs that inhibit CYP2C19 activity."
The newest FDA labeling (March 2010) for clopidogrel bisulfate suggests that there are many retrospective, prospective randomized, and cohort studies that substantiate increased major adverse cardiac event (MACE) rates in individuals with genetic polymorphisms. This labeling does not advise that physicians avoid the use of clopidogrel bisulfate for individuals who are known to have genetic CYP2C19 polymorphisms, but now indicates that physicians should "consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers (FDA
Drug Safety Communication
The ACCF/AHA collaborative document includes "Recommendations for Practice" discussion points. In sum, they indicate that more studies and trials are needed at this time because the predictive value of genetic testing is currently very limited, and because there is insufficient evidence to recommend such testing as routine. The practice recommendations indicate that the physician should use clinical judgement and assess any specific individual factors that may place an individual's risk as moderate or high for poor outcomes: this includes persons undergoing elective high-risk PCI for treatment of extensive and/or very complex disease. Moreover, if a person is identified as a potentially poor metabolizer, other treatments should be considered, ie, alternative dosing or use of other, available agents, such as prasugrel (Effient®), if not contraindicated for the individual.
Coverage is subject to the terms, conditions, and limitations of the member's contract.
COMMERCIAL AND MEDICARE ADVANTAGE MEMBERS
CYP 450 phenotyping for CYP2C19 prior to initiation of clopidogrel (Plavix®) is medically necessary and, therefore, covered when:
The individual is at risk for adverse events and therefore requires assessment for CYP2C19 *2 and *3 alleles before undergoing treatment with clopidogrel bisulfate (Plavix®) in order to identify his or her risk of poorly metabolizing clopidogrel and his or her likelihood of exhibiting poor response to the drug;
The individual is likely to be undergoing elective high-risk percutaneous coronary interventions (PCIs) for treatment of extensive and/or very complex coronary disease.
Subject to the terms and conditions of the applicable benefit contract, Cytochrome p450 genotyping for assessment of individuals prior to initiation of clopidogrel bisulfate (Plavix®) is covered under the medical benefits of the Company's products when the medical necessity criteria listed in this medical policy are met.
There is no Medicare coverage determination addressing this service; therefore, the Company policy is applicable.
US FOOD AND DRUG ADMINISTRATION (FDA) STATUS
Genetic testing is a laboratory procedure and is historically not regulated by the US Food and Drug Administration (FDA). Clinical Laboratory Improvement Amendments (CLIA) establishes quality standards for all laboratory testing. However, recently, the FDA is reported to be involved in the evaluation of the service of genetic testing.
Aleil B, Jacquemin L, De Poli F, et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study.
JACC Cardiovasc Interv.
Angiolillo DJ, Shoemaker SB, Desai B, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study.
Campo G, Fileti L, Valgimigli M, et al. Poor response to clopidogrel: current and future options for its management.
J Thromb Thrombolysis.
Campo G, Valgimigli M, Gemmati D, et al. Poor responsiveness to clopidogrel drug-specific or class-effect mechanism? Evidence from a clopidogrel-to-ticlopidine study.
J Am Coll Cardiol.
Food and Drug Administration. FDA Drug Safety Communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. Available at:
. Accessed July 31, 2013.
Frere C, Cuisset T, Morange PE, et al. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome.
Am J Cardiol.
Gladding P, Webster M, Ormiston J, et al. Antiplatelet drug nonresponsiveness.
Am Heart J.
Gladding P, Webster M, Zeng I, et al. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial.
JACC Cardiovasc Interv.
Gladding P, Webster M, Zeng I, et al. The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel: the PRINC (Plavix Response in Coronary Intervention) trial.
JACC Cardiovasc Interv.
Gurbel PA, Antonino MJ, Bliden KP, et al. Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target.
Holmes DR, Dehmer GJ, Sanjay K, et al. ACCF/AHA Clopidogrel Clinical Alert. Approaches to the FDA “Boxed Warning”: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association.
J Am Coll Cardiol.
2010;56;321-341. Available at:
. Accessed July 31, 2013.
MacPhee IA, Holt DW. A pharmacogenetic strategy for immunosuppression based on the CYP3A5 genotype.
Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention.
Eur Heart J.
Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement.
Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events.
N Engl J Med.
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes.
N Engl J Med.
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Code number(s) and Code narrative(s)
HCPCS Level II
G0452: Molecular pathology procedure; physician interpretation and report
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