Clopidogrel and Pharmacogenomic Testing

VHA Pharmacy Benefits Management Services, Medical Advisory Panel and VISN Pharmacist Executives

January 2012

The following recommendations are based on medical evidence, clinician input, and expert opinion. The content of the document is dynamic and will be revised as new information becomes available. The purpose of this document is to assist practitioners in clinical decision-making, to standardize and improve the quality of patient care, and to promote cost-effective drug prescribing. The clinician should utilize this guidance and interpret it in the clinical context of the individual patient. Individual cases that are outside the recommendations should be adjudicated at the local facility according to the policy and procedures of its P&T Committee and Pharmacy Services.

Why wouldpharmacogenomic testing be important for guiding clopidogrel therapy?

Clopidogrel given with aspirin is a mainstay of therapy in patients with Acute Coronary Syndrome (ACS) as well as those undergoing percutaneous coronary interventions (PCI). In March 2010the FDA approved a new label for clopidogrel with a “boxed warning” about the diminished effectiveness of clopidogrel in patients with impaired ability to convert the drug into its active metabolite. This could explain why patients still may have recurrent atherothrombotic events despite dual antiplatelet therapy. Other potential contributing factors include potential drug interactions, genetic factors influencing conversion of the prodrug clopidogrel and potential impact of dosing and duration for clopidogrel/aspirin therapy.

Which genotypes are associated with suboptimal clopidogrel response?

Multiple studies have demonstrated that both heterozygotes and homozygotes for loss-of-function CYP2C19 alleles have lower levels of the active clopidogrel metabolite and exhibit diminished platelet inhibition.It is important to note that approximately 2% of the population is homozygous for the loss of function allele. Additionally, certain ethnic groups, such as Asian, seem to be predisposed to the condition. Correlation between lab markers and clinical outcomes has been seen in observational studies. Prospective randomized control trials are ongoing to evaluate the efficacy of therapeutic interventions on clinical outcomes.

Is it possible to overcome low responsiveness with larger clopidogrel doses?

There have been several published trials which have investigated this issue. However, the trials are often underpowered to look at clinical outcomes, and efficacy is limited to laboratory assays of platelet aggregation or measured blood levels of the active clopidogrel metabolite.Recently, Mega, et al. published the results of the ELEVATE-TIMI 56 trial. This study investigated whether higher doses of clopidogrel could improve the response in patients who carried loss of function alleles. The outcomes of this study demonstrated that increasing the maintenance dose of clopidogrel, in patients who are heterozygotes for the CYP2C19 allele, would produce changes in platelet reactivity equivalent to patients who are non-carriers of the allele. These findings concur with those of CLOVIS-2, where an increase of clopidogrel loading doses to 900 mg produced equivalent response in heterozygote CYP2C19 loss of function alleles but not in homozygous patients. In the GRAVITAS trial, patients with high platelet reactivity, as measured by the Verify Now assay, did not demonstrate a decrease in platelet reactivity with higher doses of clopidogrelthat was associated with improved clinical outcomes. Several additional trials are ongoing which may help to answer this question more fully.

Does higher clopidogrel dosing in patients with loss of function CYP2C19 alleles equate to increased adverse events?

There has not been an increase in bleeding events in patients given a higher clopidogrel dose based on their genetic typing. However, the duration of the trials, one to six months on average, do not allow correlation to longer periods of therapy used frequently in ACS, high risk PCI or other indications.

Is the risk the same for both heterozygotes and homozygotes for loss-of-function CYP2C19 alleles?

Currently available evidence from observational studies supports patients who are homozygotes for the loss of function alleles may demonstrate an increased risk for developing adverse clinical outcomes due to lower levels of the active clopidogrel metabolite. Additionally, patients who are heterozygotes for the loss of function allele,patients with diabetes and those with higher body mass index may be at increased risk for adverse clinical outcomes.

Should all patients be tested for loss-of-function CYP2C19 alleles?

Routine genetic testing in patients undergoing PCI for loss of function alleles is not recommended.Consensus statements from the American College of Cardiology and the American Heart Association do not support mandatory testing in all patients receiving clopidogrel therapy (see below). Consideration for genomic testing might include those patients with thrombotic events despite use of clopidogrel (although these patients might be considered for other antiplatelet agents), and those identified by the ACC/ AHA:

6.1.2. Clopidogrel Genetic Testing: Recommendations

CLASS IIb

1. Genetic testing might be considered to identify whether a patient athigh risk for poor clinical outcomes is predisposed to inadequateplatelet inhibition with clopidogrel (829). (Level of Evidence: C)

2. When a patient predisposed to inadequate platelet inhibition withclopidogrel is identified by genetic testing, treatment with an alternateP2Y12 inhibitor (e.g., prasugrel or ticagrelor) might be considered(829). (Level of Evidence: C)

CLASS III: NO BENEFIT

1. The routine clinical use of genetic testing to screen patients treatedwith clopidogrel who are undergoing PCI is not recommended (829).(Level of Evidence: C)

References

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  2. Gladding P, Webster M, Zeng I,et al. The pharmacogeneticsand pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv. 2008Dec;1(6):620-7.
  3. Geisler T, Schaeffeler E, Dippon J, et al. CYP2C19 and nongenetic factors predict poorresponsiveness to clopidogrel loading dose after coronary stent implantation.Pharmacogenomics. 2008 Sep;9(9):1251-9.
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  7. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM,Braunwald E, Sabatine MS. Genetic variants in ABCB1 and CYP2C19 andcardiovascular outcomes after treatment with clopidogrel and prasugrel in theTRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010 Oct16;376(9749):1312-9.
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