Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline information
for clopidogrel and CYP2C19

last updated 09/15/2016

Summary

The CPIC Dosing Guideline for clopidogrel recommends an alternative antiplatelet therapy (e.g., prasugrel, ticagrelor) for CYP2C19 poor or intermediate metabolizers if there is no contraindication.

Annotation

September 2013 Update

Advance online publication May 2013.

  • 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.
  • Download and read:

Table 1: Antiplatelet therapy recommendations based on CYP2C19 status when considering clopidogrel for ACS patients undergoing PCI

Adapted from Tables 1 and 2 of the 2013 guideline manuscript.

Likely phenotypeGenotypesExamples of diplotypesImplications for clopidogrelTherapeutic recommendationsClassification of recommendations
Ultrarapid metabolizer (UM) (~5-30% of patients)An individual carrying two increased activity alleles (*17) or one functional allele (*1) plus one increased activity allele (*17)*1/*17, *17/*17Increased platelet inhibition; decreased residual platelet aggregation 1Clopidogrel - label recommended dosage and administrationStrong
Extensive metabolizer (EM) (~35-50% of patients)An individual carrying two functional (*1) alleles*1/*1Normal platelet inhibition; normal residual platelet aggregationClopidogrel - label recommended dosage and administrationStrong
Intermediate metabolizer (IM) (~18-45% of patients)An individual carrying one functional allele (*1) plus one loss-of-function allele (*2-*8) or one loss-of-function allele (*2-*8) plus one increased activity allele (*17) 2*1/*2, *1/*3, *2/*17Reduced platelet inhibition; increased residual platelet aggregation; increased risk for adverse cardiovascular eventsAlternative antiplatelet therapy (if no contraindication); e.g., prasugrel, ticagrelorModerate
Poor metabolizer (PM) (~2-15% of patients)An individual carrying two loss-of-function alleles (*2-*8)*2/*2, *2/*3, *3/*3Significantly reduced platelet inhibition; increased residual platelet aggregation; increased risk for adverse cardiovascular eventsAlternative antiplatelet therapy (if no contraindication); e.g., prasugrel, ticagrelorStrong

1 The CYP2C19*17 allele (rs12248560) may be associated with increased risk of bleeding.

2 The predicted metabolizer phenotype for *2-*8/*17 genotypes are provisional classifications. The currently available evidence indicates that the *17 gain-of-function allele is unable to completely compensate for the *2 loss-of-function allele [Article:20492469]; however, this data has not been consistently replicated and is therefore a provisional classification (Table S5).

An important caveat for all genotyping tests is that the "wild-type" (*1) status is reported if all other alleles that are measured are absent. Some genotype tests do not interrogate the rare loss of function alleles and therefore, if present, they may be erroneously reported as "wild type". Furthermore, in human DNA, it is always possible that a new, previously undiscovered (and therefore un-interrogated) site of variation may confer altered enzyme function in an individual, and thus lead to the rare possibility of a loss-of-function allele being erroneously called as "wild-type" (*1). The guidelines do not focus on demographic and other clinical variables, such as adherence to therapy, age, diabetes mellitus, obesity, smoking, and concomitant use of other drugs that may influence clopidogrel efficacy and clinical decision making.

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

Advance online publication June 2011.

CPIC clopidogrel guideline

Total publications: 2

Reference
1. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy: 2013 Update. Clinical pharmacology and therapeutics. 2013. Scott Stuart A, Sangkuhl Katrin, Stein C Michael, Hulot Jean-S├ębastien, Mega Jessica L, Roden Dan M, Klein Teri E, Sabatine Marc S, Johnson Julie A, Shuldiner Alan R. PubMed
2. Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450-2C19 (CYP2C19) Genotype and Clopidogrel Therapy. Clinical pharmacology and therapeutics. 2011. Scott S A, Sangkuhl K, Gardner E E, Stein C M, Hulot J-S, Johnson J A, Roden D M, Klein T E, Shuldiner A R. PubMed

Guideline History