Results: Patient with a known CYP2C19 genotype requiring antiplatelet therapy following an ischaemic stroke or transient ischaemic attack

A 64-year-old man has been admitted to hospital with right-sided weakness and slurred speech. Their CT head demonstrates a left middle cerebral artery (MCA) infarction, confirming an ischaemic stroke. You plan to prescribe clopidogrel as their definitive antiplatelet therapy from two weeks post infarction. However, you note that in the past he has previously undergone pharmacogenomic testing, which shows he is a CYP2C19 poor metaboliser.

• Clopidogrel is a prodrug that needs to be converted to its active metabolite. This happens in two stages involving several cytochrome P450 (CYP) enzymes, with the greatest contribution from CYP2C19.
• People have two copies of the CYP2C19 gene and a variant in either copy can affect the function of the CYP2C19 enzyme. For people taking clopidogrel, this means that genetic variation in CYP2C19 can impact on the conversion of clopidogrel to its active metabolite.
• The functional activity of each allele can be combined to predict the CYP2C19 phenotype of an individual patient.
• 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 CYP2C19 poor metaboliser status should be considered for alternative antiplatelet agents not affected by CYP2C19 genotype status.
• Diagnostic guidance from the National Institute for Health and Care Excellence (NICE) states that individuals who carry CYP2C19 loss-of-function variants (so poor and intermediate metabolisers) are at increased risk of recurrent stroke when treated with clopidogrel.

• NICE recommends that CYP2C19 genotype testing should be used in people who have just had an ischaemic stroke or transient ischaemic attack (TIA) to identify patients with CYP2C19 loss-of-function variants so they can be offered alternative antiplatelet drugs to lower their risk of blood clots.
• When determining which antiplatelet medicine to use, prescribers should refer to local and national stroke guidelines.
  • The effectiveness of other antiplatelet agents, such as dipyridamole, aspirin and ticagrelor, are not known to be impacted by an individual’s CYP2C19 metaboliser status.
• You should 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.
• 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 information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.

For clinicians

• CPIC: Guideline for clopidogrel and CYP2C19
• National Library of Medicine: Clopidogrel therapy and CYP2C19 genotype
• NICE: CYP2C19 genotype testing to guide clopidogrel use after ischaemic stroke or transient ischaemic attack (Diagnostics guidance DG59)
• 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)