Clopidogrel response significantly poorer in British South Asians

A study from Queen Mary University of London shows that British people of South Asian heritage are less likely to be able to respond to clopidogrel when prescribed the drug for acute coronary syndrome (ACS).

Clopidogrel is commonly prescribed for secondary prevention of ACS. The drug has to be converted to its active metabolite before it can take effect (as a P2Y12 platelet inhibitor). This requires the hepatic enzyme cytochrome P450 2C19 (CYP2C19) – an enzyme that is subject to genetic polymorphism. The presence of one or more loss-of-function (LOF) alleles of CYP2C19 results in ‘poor metabolisers’ and ‘intermediate metabolisers’ who are unable to activate clopidogrel.

This study set out to determine the prevalence of common CYP2C19 polymorphisms in a British–South Asian population and correlate these with recurrent myocardial infarction risk in participants prescribed clopidogrel.

DNA samples from more than 44,000 volunteers were analysed. This group had a high prevalence (57%) of intermediate or poor CYP2C19 metabolisers, with at least one LOF CYP2C19 allele.  Of note, the prevalence of poor metabolisers carrying two CYP2C19 LOF alleles was 13%.  Previously reported proportions for European and Central/South Asian populations have been 2.4% and 8.2%, respectively.

Sixty-nine percent of the cohort who were diagnosed with an acute myocardial infarction were prescribed clopidogrel. Poor metabolizers were significantly more likely to have a recurrent myocardial infarction (OR: 3.1; P = 0.019). In fact, there was a clear gradient of increased risk of recurrent myocardial infarction with increased LOF burden.

The results of this study underline the potential importance of pharmacogenetic (PGx) testing so that the genotype is known before the prescription is issued and adjustments can be made. The alternative would be to prescribe non-CYP2C19 dependent platelet inhibitors such as prasugrel or ticagrelor for everyone but the costs may be too great.

Actionable drug-genome interactions are not uncommon and routine PGx testing services have been advocated  commenting on the findings Professor David Wright said:

“This is why all services need to be delivered in a culturally competent manner. PGx evidence is biased towards the white European population and may not translate to other populations. If the profession is to assume responsibility for PGx testing it will need to ensure that all patient groups are aware of its potential limitations when their DNA is taken. I would hope that any software providing guidance following PGx testing will be routinely updated with such evidence as it would be impossible for any individual to be able to remember these differences.”

Professor Wright (University of Leicester) leads a research team focused on design and implementation of routine pharmacogenomics (PGx) services in community pharmacy.

Reference

Magavern E, Jacobs B, Warren H, et al. CYP2C19 Genotype Prevalence and Association With Recurrent Myocardial Infarction in British–South Asians Treated With Clopidogrel. JACC Adv. null2023, 0 (0) .https://doi.org/10.1016/j.jacadv.2023.100573