Pharmacogenetic testing can be used to guide cardiovascular therapies. Examples include genotyping to guide warfarin dosing and statin prescribing (Noyes et al, 2021).
Perhaps the most common usage is CYP2C19 genotyping to assist prescribers in selecting the appropriate antiplatelet therapy after percutaneous coronary intervention (PCI) and predict clopidogrel response (Duarte and Cavallari, 2021; Noyes et al, 2021).
Clopidogrel
Clopidogrel is an antiplatelet therapy that is used to prevent myocardial infarction (MI) and stroke in individuals with acute coronary syndrome (ACS) (either managed medically or with PCI), those with atherosclerotic vascular disease, and in people undergoing PCIs in general such as stent placements (Dean and Kane, 2012).
Clopidogrel is a prodrug, meaning that it is converted into its active form once it enters the body. The CYP2C19 gene encodes the CYP2C19 enzyme, and this process is needed in order for people to metabolise clopidogrel into its active form (National Institute for Health and Care Excellence (NICE), 2024). It is a P2Y12 inhibitor, which irreversibly binds to platelet P2Y12 receptor and blocks adenosine diphosphate (ADP)-mediated platelet activation and aggregation (Dean and Kane, 2012). Thrombus formation, which clopidogrel is given to prevent, involves rapidly gathering and activating platelets. It is, therefore, a platelet inhibitor.
However, as noted, its effectiveness relies on a person's ability to metabolise it. When the treatment is effective, the cytochrome P450 2C19 (CYP2C19) enzyme successfully converts clopidogrel into an active metabolite. This does not happen in all cases however and is very much dependent on a person's genes. Gene mutation can lead to people not receiving the same antiplatelet benefit or protection.
Some individuals have two loss-of-function (LOF) copies of the CYP2C19 gene (alleles), meaning that they have no CYP2C19 enzyme activity, and are classified as ‘poor metabolisers’ (PM). In these individuals, this lack of enzyme activity prevents the successful activation of clopidogrel, and thus its antiplatelet effect (Dean and Cane, 2012). Some individuals have one LOF allele. These individuals, classified as intermediate metabolisers (IM), also have trouble metabolising clopidogrel and find that its effectiveness is decreased.
In the white population, 2% of people are PM; while in the black population, 4% are PM. In the Chinese population, 14% are PM; and in Oceanians, more than half (57%) are PM (Dean and Kane, 2012). The IM phenotype is generally more common, with less than 20% of individuals of Latino descent having it, about one-fifth to one-quarter of American, European or near-Eastern descent (20–26%), 30% of those of African descent, 36% of Oceanians, more than 40% of people of Central or South Asian descent, and nearly half (more than 45%) of the East Asian population (Dean and Kane, 2012).
Pharmacogenetic testing
In these individuals, clopidogrel is not likely to be effective and an alternative may be sought if pharmacogenetic testing can be used to identify those who may be unable or less able to metabolise the drug. In these individuals, an alternative antiplatelet therapy, such as prasugrel or ticagrelor would be favourable (Dean and Kane, 2012).
Pharmacogenetic testing is not new and has been in use, particularly in the field of oncology (Mendes, 2019). However, the concept of this testing being applied to more common everyday drugs is more novel. Its use for such purposes has been somewhat controversial as there has been a lack of randomised trials to demonstrate its efficacy.
In the last few years, however, NHS Tayside and the Precision Medicine and Pharmacotherapeutics Group at the University of Dundee have formed a partnership called P4Me, which is an initiative that is developing the knowledge to implement precision medicine research into the real clinical settings based on prediction, prevention, personalisation and participation (P4) (University of Dundee, 2024).
Once an acute stroke patient is diagnosed and indicated for clopidogrel, CYP2C19 genotyping test is requested from the East of Scotland Regional Genetic Laboratory, which is based in Ninewells Hospital in Dundee (Matos, 2022). The results will be reviewed by the team, taking into consideration the patient's unique characteristics, and a personalised, optimised antiplatelet plan will be devised (Matos, 2022).
NICE (2024) has recently published new guidance regarding genotype testing to guide clopidogrel use post-ischaemic stroke or transient ischaemic attack (TIA). It discusses the use of genotype testing to identify which CYP2C19 alleles a person has to determine how effectively they can metabolise clopidogrel, providing valuable information to guide antiplatelet treatment (NICE, 2024). NICE (2024) highlights the use of genetic testing of the CYP2C19 gene either by laboratory-based or point-of-care testing.
As part of the UK's first routine CYP2C19 testing project for clopidogrel prescribing, NHS Tayside identified 2300 patients for genotyping, and nearly one-third (29%) emerged as either a PM or an IM in terms of their ability to metabolise clopidogrel (Matos, 2024; Willis, 2024).
Looking ahead
Pharmacogenetics holds much potential to individualise drug treatment regimens for many different drugs and conditions, including complex diseases such as heart failure (Duarte and Cavallari, 2021). Trials have been conducted that support pharmacogenetic testing in cardiovascular medicine, care and prescribing and guidelines do exist to support its use (Duarte and Cavallari, 2021; NICE, 2024).
However, this newest work being completed by NHS Tayside and University of Dundee is the start of bringing precision medicine into everyday prescribing (Matos, 2022; 2024; Willis, 2024). Further genotyping projects, such as the one described herein relating to genotype testing to guide clopidogrel treatment, are required before the potential of pharmacogenetic testing is fully realised in guiding prescribing practice. The future of personalised medicine does nonetheless look bright and the areas for future research are plentiful.