Annotation of CPIC Guideline for clopidogrel and CYP2C19

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Summary

The CPIC Dosing Guideline for clopidogrel recommends an alternative antiplatelet therapy for CYP2C19 poor or intermediate metabolizers (cardiovascular indications: prasugrel or ticagrelor if no contraindication; neurovascular indications: alternative P2Y12 inhibitor if clinically indicated and no contraindication.)

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Annotation

This annotation is based on the CPIC® guideline for clopidogrel and CYP2C19.

January 2022 Update

  • The 2022 update of CPIC guideline for clopidogrel has been published in Clinical Pharmacology and Therapeutics and includes expanded indications for CYP2C19 genotype-guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, and evidence from an expanded literature review.

  • This guideline is applicable to:

    • adult patients
    • pediatric patients

  • Excerpts from the 2022 clopidogrel dosing guideline:

    • "The most definitive studies showing a relationship between CYP2C19 genotype and clopidogrel response have predominantly been conducted in patients with ACS, almost all of whom underwent PCI. However, there are accumulating data showing a similar relationship between CYP2C19 no function alleles and clopidogrel response when it is used for other indications, including treatment of acute ischemic stroke or transient ischemic attack (TIA). These data, in combination with strong pharmacokinetic and pharmacodynamic data, support the use of CYP2C19 genotype-guided antiplatelet therapy when considering clopidogrel for neurovascular indications."
    • "The clinical data on which this guideline is based were obtained from studies in adults. Given the well-characterized pharmacokinetic basis for this gene-drug interaction and the presence of fully mature CYP2C19 enzyme activity after 2-3 months of age, it is reasonable to extrapolate the recommendations presented in this guideline to pediatric patients if needed."

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Table 1: Antiplatelet therapy recommendations based on CYP2C19 phenotype when considering clopidogrel for cardiovascular indications

Adapted from Tables 1 and 2 of the 2022 guideline update.

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PhenotypeGenotypeExamples of genotypesImplicationsTherapeutic recommendationsClassification of recommendationsa- ACS and/or PCIbClassification of recommendationsa - non-ACS, non-PCI cardiovascular indicationsc
CYP2C19 ultrarapid metabolizerAn individual carrying two increased function alleles*17/*17Increased clopidogrel active metabolite formation; lower on-treatment platelet reactivity; no association with higher bleeding riskIf considering clopidogrel, use at standard dose (75 mg/day)StrongNo recommendation
CYP2C19 rapid metabolizerAn individual carrying one normal function allele and one increased function allele*1/*17Normal or increased clopidogrel active metabolite formation; normal or lower on-treatment platelet reactivity; no association with higher bleeding riskIf considering clopidogrel, use at standard dose (75 mg/day)StrongNo recommendation
CYP2C19 normal metabolizerAn individual carrying two normal function alleles*1/*1Normal clopidogrel active metabolite formation; normal on-treatment platelet reactivityIf considering clopidogrel, use at standard dose (75 mg/day)StrongStrong
CYP2C19 likely intermediate metabolizerdAn individual carrying one normal function allele and one decreased function allele or one increased function allele and one decreased function allele or two decreased function alleles*1/*9, *9/*17, *9/*9Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid standard dose clopidogrel (75 mg) if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.StrongeNo recommendatione
CYP2C19 intermediate metabolizerAn individual carrying one normal function allele and one no function allele or one increased function allele and one no function allele*1/*2, *1/*3, *2/*17, *3/*17Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid standard dose (75 mg) clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.StrongNo recommendation
CYP2C19 likely poor metabolizerdAn individual carrying one decreased function allele and one no function allele*2/*9, *3/*9Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.StrongeModeratee
CYP2C19 poor metabolizerAn individual carrying two no function alleles*2/*2, *3/*3, *2/*3Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.StrongModerate

a Rating scheme described in the Supplemental Material. bACS and/or PCI includes patients undergoing PCI for an ACS or non-ACS (elective) indication. cNon-ACS, non-PCI cardiovascular indications include peripheral arterial disease and stable coronary artery disease following a recent myocardial infarction outside the setting of PCI. dThere are limited data to characterize the function of decreased function alleles. eThe strength of recommendation for “likely” phenotypes are the same as their respective confirmed phenotypes. “Likely” indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding “likely” phenotype.

Table 2: Antiplatelet therapy recommendations based on CYP2C19 phenotype when considering clopidogrel for neurovascular indications

Adapted from Tables 1 and 3 of the 2022 guideline update.

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PhenotypeGenotypeExamples of genotypesImplicationsTherapeutic recommendationsClassification of recommendationsaOther Considerations
CYP2C19 ultrarapid metabolizerAn individual carrying two increased function alleles*17/*17Increased clopidogrel active metabolite formation; lower on-treatment platelet reactivityNo recommendationNo recommendation
CYP2C19 rapid metabolizerAn individual carrying one normal function allele and one increased function allele*1/*17Normal or increased clopidogrel active metabolite formation; normal or lower on-treatment platelet reactivityNo recommendationNo recommendation
CYP2C19 normal metabolizerAn individual carrying two normal function alleles*1/*1Normal clopidogrel active metabolite formation; normal on-treatment platelet reactivityIf considering clopidogrel, use at standard dose (75 mg/day)Strong
CYP2C19 likely intermediate metabolizercAn individual carrying one normal function allele and one decreased function allele or one increased function allele and one decreased function allele or two decreased function alleles*1/*9, *9/*17, *9/*9Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsConsider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.ModeratedAlternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA.e
CYP2C19 intermediate metabolizerAn individual carrying one normal function allele and one no function allele or one increased function allele and one no function allele*1/*2, *1/*3, *2/*17, *3/*17Reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsConsider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.ModerateAlternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA.e
CYP2C19 likely poor metabolizercAn individual carrying one decreased function allele and one no function allele*2/*9, *3/*9Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid clopidogrel if possible. Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.ModeratedAlternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA.e
CYP2C19 poor metabolizerAn individual carrying two no function alleles*2/*2, *3/*3, *2/*3Significantly reduced clopidogrel active metabolite formation; increased on-treatment platelet reactivity; increased risk for adverse cardiac and cerebrovascular eventsAvoid clopidogrel if possible. Consider an alternative P2Y12 inhibitor at standard dose if clinically indicated and no contraindication.ModerateAlternative P2Y12 inhibitors not impacted by CYP2C19 genetic variants include ticagrelor and ticlopidine. Prasugrel is contraindicated in patients with a history of stroke or TIA.e

aNeurovascular disease includes acute ischemic stroke or transient ischemic attack, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms. bRating scheme described in the Supplemental Material. cThere are limited data to characterize the function of decreased function alleles. dThe strength of recommendation for “likely” phenotypes are the same as their respective confirmed phenotypes. “Likely” indicates the uncertainty in the phenotype assignment, but it is reasonable to apply the recommendation for the confirmed phenotype to the corresponding “likely” phenotype. eGiven limited outcomes data for genotype-guided anti-platelet therapy for neurovascular indications, selection of therapy should depend on individual patient treatment goals and risks for adverse events.

September 2013 Update

  • The 2013 update of CPIC guidelines regarding clopidogrel have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC). Literature published between 1966 to January 2013 was reviewed. The updated therapeutic recommendations are more focused to patients with acute coronary syndromes undergoing percutaneous coronary intervention (ACS/PCI) than the original guideline, with additional updates involve refined recommendations for variant and novel CYP2C19 alleles beyond *2.
  • At the time of the development of this recommendation, there are no data available on the possible role of CYP2C19 in clopidogrel response in pediatric patient populations; however, there is no reason to suspect that CYP2C19 variant alleles would affect clopidogrel metabolism differently in children as compared with adults.
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The American Society of Health-System Pharmacists (ASHP) has endorsed the Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy.

August 2011

PharmGKB ID

PA166104948