Results: Patient with a known CYP2C19 genotype and coronary artery disease requiring clopidogrel

A 70-year-old man with known coronary artery disease has been diagnosed with acute myocardial infarction secondary to stent thrombosis after percutaneous coronary intervention. This is despite him being on clopidogrel, an antiplatelet commonly prescribed after acute coronary syndrome. Since diagnosis he has had pharmacogenomic testing, which has identified him as having the CYP2C19 diplotype allele associated with CYP2C19 poor metaboliser status.

• Clopidogrel is a prodrug that needs to be converted to its active metabolite. This happens in two stages involving several cytochrome P450 (CYP) enzymes, such as CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4. Of these, CYP2C19 makes the greatest contribution to both stages.
• Alleles of the CYP2C19 gene are categorised into functional groups based on predicted phenotype, which determines the impact on clopidogrel conversion to its active 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). Individuals with one loss-of-function CYP2C19 allele are classified as intermediate metabolisers.
• CYP2C19 intermediate metabolisers and CYP2C19 poor metabolisers who receive clopidogrel have reduced platelet inhibition and are at increased risk of major adverse cardiovascular and cerebrovascular events.
• Patients with CYP2C19 intermediate or poor metaboliser status should therefore be considered for alternative antiplatelet agents not affected by CYP2C19 genotype status, such as prasugrel or ticagrelor.

• At the time of writing, there is no standardised NHS guidance on altering prescriptions according to CYP2C19 phenotype. However, Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines (see the resources list below) provide management recommendations for those who have test results for CYP2C19 genetic variants (see the resources list below).
• The clinician needs to consider the pharmacogenomic results in the context of the patient’s wider medical history, their concurrent medicines and the availability of safe and effective alternatives.
• In patients with acute coronary syndrome or percutaneous coronary intervention and a CYP2C19 intermediate or poor metaboliser phenotype, clopidogrel should be avoided, if possible, and it is advised to prescribe prasugrel or ticagrelor instead at the standard dose.
• Please refer to the CPIC website and use the latest, 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 also 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 clinicians

• CPIC: Guideline for clopidogrel and CYP2C19
• National Library of Medicine: Clopidogrel therapy and CYP2C19 genotype
• PharmGKB: Annotation of CPIC guideline for clopidogrel and CYP2C19

References:

• Djordjevic N. ‘Genotyping genetic variants of CYP2C19 for precision antiplatelet dosing: State of the art and future perspectives’. Expert Opinion on Drug Metabolism & Toxicology 2022: volume 18, issue 12, pages 817–830. DOI: 10.1080/17425255.2022.2166486
• Galli M, Benenati S, Capodanno D and others. ‘Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: A systematic review and meta-analysis’. The Lancet 2021: volume 397, issue 10,283, pages 1,470–1,483. DOI: 10.1016/S0140-6736(21)00533-X
• Pereira NL, Rihal C, Lennon R and others. ‘Effect of CYP2C19 genotype on ischemic outcomes during oral P2Y₁₂inhibitor therapy: A meta-analysis’. Journal of the American College of Cardiology: Cardiovasc Interventions 2021: volume 14, issue 7, pages 739–750. DOI: 10.1016/j.jcin.2021.01.024

For patients

• Cincinnati Children’s Hospital Medical Center: Patient education for pharmacogenetic testing
• Cincinnati Children’s Hospital Medical Center: Your CYP2C19 genetic test results and what they mean (CYP2C29 intermediate metabolizer) (PDF, four pages)
• Cincinnati Children’s Hospital Medical Center: Your CYP2C19 genetic test results and what they mean (CYP2C19 poor metabolizer) (PDF, four pages)