Genomics for families

To better understand this hypothetical scenario, it is important to first be aware of what we mean when we discuss CYP2C19 and clopidogrel, and what they mean for practising pharmacy colleagues and patients.

Note that this testing is currently unavailable in the NHS but a pilot is being undertaken (as of November 2024). This webpage will be updated with more information as it becomes available and in line with content reviewing schedules.

Introducing clopidogrel and CYP2C19

Clopidogrel is an antiplatelet medicine which reduces clotting in the arteries by making platelets stick together less, reducing blood clot formation. Clopidogrel is a ‘prodrug’. This means the drug must be metabolised into an active form in the liver for the drug to be effective. The enzyme CYP2C19 is essential for this process and is coded for by a gene called CYP2C19. (Note the use of italics to refer to the gene that codes for the protein with the same name.)

Read more about clopidogrel in this GeNotes article.

What is the impact of clopidogrel pharmacogenomics?

About 1 in 3–4 people have CYP2C19 gene variants that lead to decreased enzyme activity. These are known as ‘loss of function’ or ‘no function’ variants and lead to a poor or intermediate metaboliser status). This means clopidogrel metabolism via the CYP2C19 enzyme may be less effective, and therefore clopidogrel may not work as effectively in these people.

The evidence is mounting for CYP2C19 genotype testing to guide clopidogrel use in neurovascular conditions such as ischaemic stroke. On 31 July 2024, the National Institute for Health and Care Excellence (NICE) published its diagnostic guidance for CYP2C19 genotype testing to guide clopidogrel use after ischaemic stroke or transient ischaemic attack.

The NICE impact report summarises the impact of clopidogrel pharmacogenomics in stroke, showing clopidogrel is less efficacious in poor or intermediate metabolisers. It shows that per 10,000 patients on clopidogrel who are poor or intermediate metabolisers and continue on antiplatelet treatment, 308 will have recurrent stroke events within 90 days. This is compared to 220 on dipyridamole-aspirin and 246 on ticagrelor. Explore the full report for more information.

Note: The CYP2C19 laboratory test is currently unavailable on the NHS Genomic Medicine Service for routine use. NHS England is conducting a pilot until mid-2025 to determine the optimal way of wider implementation, exploring the laboratory and the point-of-care testing methods. The CYP2C19 point-of-care tests recommended by NICE are also unavailable through any central NHS commissioning. Moreover, the prescribing actions based on pharmacogenomic results have not yet been directly implemented into UK guidelines. Professionals wishing to explore more around the scientific basis of clopidogrel pharmacogenomics can do so at the Clinical Pharmacogenomics Implementation Consortium website, which offers valuable and validated resources for evidence-based information in pharmacogenomics.

To put what we’ve learned so far into perspective, let’s examine a hypothetical patient case study to explore the role pharmacy professionals could have in genomics-informed medicines optimisation in the near future.

Important: This hypothetical scenario does not reflect current practice; currently, clopidogrel pharmacogenomic testing is not routinely implemented for ischaemic stroke patients nor offered as part of the service.

Alice is a 62-year-old retired teacher of East Asian heritage. She presented to A&E with ischaemic stroke and is now indicated for clopidogrel in the absence of atrial fibrillation.

The ward pharmacy team reviewed Alice’s case and proceeded to a patient consultation with her. They checked her drug, medical and pharmacogenomic history to complete the medication reconciliation upon admission.

This review included checks of drug interactions (prescribed and over-the-counter), contraindications, renal and hepatic function and other factors involved in medicines optimisation reviews. The pharmacy team also checked for any past pharmacogenomic results.

This provided an opportunity to review the indication for clopidogrel and offer the patient and her family an opportunity for a pharmacy consultation.

The pharmacy and medical team identified that clopidogrel could be optimised with a pharmacogenomic test and that the patient did not have any pharmacogenomic results relevant to clopidogrel and CYP2C19 in their record, so they offered the test. Note: When offering a genomic test, it is essential to check if it is routinely available in the service; pharmacists can check the National Genomic Test Directory, or refer to their regional Genomic Laboratory Hub for advice on available laboratory-led tests or the local service in case of point-of-care tests.

The pharmacist also checked that this test was implemented in the local service, clinical guidelines and medicines formulary. Pharmacogenomic tests have implications on the formulary, commissioning and shared-care arrangements because an alternative medicine may be required to be prescribed.

During the consultation, the pharmacist explored Alice’s ideas, concerns, expectations, and feelings regarding the test (see CPPE e-learning: Genomics in pharmacy: an introduction to person-centred consultations). They explained the utility and purpose of the test (that it can show if she will be able to activate the antiplatelet drug to prevent recurrent stroke), including how the information could be used in the future. They also explained that a test result showing Alice to be a poor or intermediate CYP2C19 metaboliser may mean she should be prescribed an alternative antiplatelet drug. As clopidogrel will be inadequately activated for her, treatment with clopidogrel will have a diminished effect at reducing the risk of recurrent ischaemic strokes.

As part of the consultation and to help Alice make a decision around the test, the pharmacist confirmed her ethnicity and explained that patients of East Asian heritage are statistically more likely to have a poor metaboliser CYP2C19 phenotype.

Alice was optimistic about using pharmacogenomic testing to ensure she receives the most effective treatment.

The pharmacist also considered whether they should refer Alice to have discussions with other members of the multidisciplinary team. For example, involving genetic counsellors in complex cases of genetic disease can help the patient understand better how it may affect their family. However, in this case it was not necessary, as the indication for the test was related to medicines optimisation, and not diagnostic.

Alice was found to be a CYP2C19 poor metaboliser which means she will have reduced CYP2C19 enzyme activity, leading to reduced clopidogrel activation. Therefore, her platelet on-reactivity (meaning the risk of clotting) will be higher than that of a “normal” metaboliser on clopidogrel (meaning clopidogrel will be less effective).

Using local guidance, pharmaceutical knowledge and the local formulary, the pharmacist discussed with the stroke team that this patient will likely experience reduced clopidogrel active metabolite formation. This would increase the likelihood of treatment failure and a recurrent stroke while on a long-term clopidogrel antithrombotic treatment. The pharmacist suggests using an alternative antiplatelet agent unaffected by CYP2C19 metabolism, such as dipyridamole with aspirin or ticagrelor (depending on the local formulary and guidelines). The team agreed to use an alternative as per the local formulary, and the patient was then discharged on effective long-term antithrombotic therapy.

Clear communication is essential when integrating pharmacogenomics into patient care. Pharmacists play a pivotal role in discussing the availability of genomic testing, emphasising its potential to guide safer and more effective medication use. Even when genomic test results are unavailable, it is crucial to consider how variants in CYP2C19 can affect drug response. Patients may respond differently to medications, and for some, their genetic makeup can be the determining factor in achieving therapeutic success.