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Therapies

Clopidogrel

Some individuals have genetic variants in the CYP2C19 gene, which can have an impact on the efficacy of clopidogrel.

Clinical context

Clopidogrel is a commonly prescribed antiplatelet medicine used in coronary artery disease, peripheral vascular disease and after ischaemic strokes or transient ischaemic attacks. It is prescribed to prevent further vascular events.

Clopidogrel and pharmacogenomics

  • Clopidogrel is a prodrug that needs to be converted to its active metabolite by two steps of oxidative metabolism, which involves several CYP450 enzymes (such as CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4). Of all the CYP450 enzymes, CYP2C19 makes the greatest contribution to both steps of oxidation.
  • Alleles of the CYP2C19 gene are categorised into functional groups based on predicted phenotype, which determines the impact on the conversion of clopidogrel to its activated metabolite.
  • Patients with two loss-of-function CYP2C19 alleles have significantly decreased enzyme activity, rendering clopidogrel activation via CYP2C19 ineffective. These patients are classified as CYP2C19 poor metabolisers.
  • One loss-of-function CYP2C19 allele also confers reduced enzyme activity, decreasing clopidogrel effectiveness (through reduced activation). These patients are classified as intermediate metabolisers.
  • Prevalence of CYP2C19 loss-of-function alleles can vary significantly across diverse ancestry groups. About 20%–30% of White individuals in the UK have at least one loss-of-function variant in CYP2C19 (and are therefore poor or intermediate metabolisers), but this number increases to about 50%–60% in East Asian populations.
  • Conversely, some CYP2C19 alleles can cause significantly enhanced enzymatic function, with affected patients being described as rapid or ultra-rapid metabolisers. However, this phenotypic status has no associated prescribing recommendations, as standard dose clopidogrel is still deemed safe and effective.
  • CYP2C19 intermediate and/or poor metabolisers who receive clopidogrel experience reduced platelet inhibition and are therefore at increased risk of major adverse cardiovascular and cerebrovascular events.
  • Patients with CYP2C19 intermediate and/or poor metaboliser status should be considered for alternative antiplatelet agents unaffected by CYP2C19 genotype status, such as prasugrel or ticagrelor.
  • The evidence for genotype-based prescribing in neurovascular conditions such as stroke is mounting. NICE on the topic is forthcoming.

Genomic testing for CYP2C19 variation

  • There are currently no NHS guidelines that mandate CYP2C19 pharmacogenomic testing prior to commencing clopidogrel therapy for cardiovascular disease.
  • There are existing Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines on management for patients in whom CYP2C19 test results are available and/or in whom the clinician chooses to order CYP2C19 pharmacogenomic testing.
  • CYP2C19 genotype-guided therapy could identify patients who would benefit most from alternative antiplatelet therapy, such as prasugrel or ticagrelor, based on a recent meta-analysis. These therapies have different adverse effect profiles (such as increased bleeding risk) and cost implications. Ultimately, the selection of testing and therapy will depend on individual treatment goals.
  • In patients with acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) and a CYP2C19 intermediate or poor metaboliser phenotype, clopidogrel should be avoided, if possible. It is advised instead to prescribe prasugrel or ticagrelor at the standard dose. A simplified summary of the CPIC 2022 recommendations is presented below in table 1.

Table 1: Summary of CPIC 2022 recommendations when considering clopidogrel for cardiovascular indications, based on CYP2C19 phenotype

Phenotype Therapeutic recommendations Classification of recommendation for ACS or PCI
CYP2C19 rapid metaboliser Use standard dose clopidogrel Strong
CYP2C19 normal metaboliser Use standard dose clopidogrel Strong
CYP2C19 intermediate or ‘likely intermediate’ metaboliser Avoid clopidogrel if possible Strong
CYP2C19 poor or ‘likely poor’ metaboliser Prescribe standard dose prasugrel or ticagrelor if no contraindication Strong
  • Always check the latest guidelines if using genotypic information to guide your prescribing.
  • Please note that this table does not include the examples of the CYP2C19 diplotypes associated with each phenotype, which can be found in the resources section below.
  • If, as a prescriber, you follow the CPIC guidelines and alter a prescription or dose, please refer to the CPIC website to use the most up-to-date version of the relevant guideline.
  • Ensure that the rationale for using a CYP2C19-guided prescription is clearly stated in the medical notes and on the prescription, and is explained to the patient.
  • Consider adding the information about the CYP2C19 phenotype to the patient’s medical summary, to help ensure that it will be passed on to other prescribers (for example, in secondary care).
  • For more information about genomic testing for CYP2C19 variants and how the identification of variants affects patient management, see Results: Patient with a known CYP2C19 genotype and coronary artery disease requiring clopidogrel.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 13/07/2023
  • Next review due: 13/07/2025
  • Authors: Dr Azara Janmohamed, Dr Spoorthy Kulkarni
  • Reviewers: Charlotte Barker, Professor Bill Newman