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Most British South Asians Unable to Respond to Clopidogrel

The majority of people of Bangladeshi and Pakistani heritage in Britain carry a common genotype that reduces their ability to metabolise clopidogrel, according to a major genetic study from Queen Mary University of London (QMUL). 

As the drug is often prescribed for secondary prevention after a first myocardial infarction (MI), and possession of this genotype might render it ineffective, it could increase their risk for recurrent MI, the researchers said.

Clopidogrel is an anti-platelet agent metabolised by a hepatic enzyme in the cytochrome P450 family, CYP2C19, whose corresponding genes are highly polymorphic, leading to genetic differences that contribute to inter-individual and inter-ethnic differences in drug pharmacokinetics, response, and toxicity .

In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of its active metabolite, and so has a lesser effect on platelet function .

The researchers explained that in studies of European populations, around 30% of individuals had been found to have genetic variants that reduced or prevented activation of clopidogrel through the production of CYP2C19. 

South Asian Populations Not Included in Genomic Studies

Yet even though people of South Asian ancestry are known to have high rates of cardiovascular disease, previous studies of genetic polymorphisms in CYP2C19 have not included UK South Asian populations, nor assessed the relationship of genetic variants with clinical efficacy in terms of the risk of recurrent MI after being prescribed clopidogrel in this population.

To explore further, the researchers studied 44,396 individuals from the Genes & Health cohort – a long-term study of 100,000 people of Bangladeshi and Pakistani origin living in East London or Bradford. Participants give saliva samples for genomic analysis that are then linked with their long-term GP and hospital records.

The study, published in JACC: Advances, found that 57% of the participants were intermediate or poor CYP2C19 metabolisers, with at least one loss-of-function CYP2C19 allele. Moreover, 13% of the poor metabolisers were carrying two CYP2C19 loss-of-function alleles, a higher proportion than that in previously studied European (2.4%) or Central/South Asian populations (8.2%).

Three-Fold Increased Risk of Recurrent MI in Poor Metabolisers

The researchers reported that more than two-thirds (69%) of participants who had been diagnosed with an acute MI had been prescribed clopidogrel. Poor metabolisers were significantly more likely to have sustained a recurrent myocardial infarction (OR: 3.1; P = 0.019), which "may relate to clopidogrel treatment failure", they said.

The authors said that given their high risk of cardiovascular disease, British people of South Asian ancestry have both a high risk of needing an antiplatelet medication and a high risk of treatment failure with clopidogrel. Their study "supports routine implementation of pharmacogenomic testing prior to prescribing clopidogrel for acute coronary syndromes", they concluded.

Lead author, Dr Emma Magavern, a clinician and researcher at QMUL, said: "Clopidogrel has been shown to prevent heart attacks mainly in people of European ancestry. For the first time we show that genetic variants that render clopidogrel ineffective are present at much higher rates (57%) in British people of Bangladeshi and Pakistani ancestry and are linked with higher risk of having another heart attack in people prescribed clopidogrel."

Personalised Pharmacogenomic Testing Urged

Dr Magavern co- authored a report from the British Pharmacological Society last year calling for personalised pharmacogenomic testing to be deployed across the NHS. The report noted that point-of-care testing was available for clopidogrel and could allow rapid genomic results when required. 

Clopidogrel is indicated for secondary prevention of atherothrombotic events including ischaemic stroke and peripheral arterial disease as well as MI, and also for primary stroke prevention in those with transient ischemic attacks, and prevention of atherothrombotic and thromboembolic events in atrial fibrillation .

The National Institute for Health and Care Excellence ( NICE ) currently recommends a point-of-care CYP2C19 test to guide treatment when performing percutaneous coronary intervention following acute coronary syndrome, and is assessing clopidogrel genotype testing following ischaemic stroke or transient ischaemic attack.

The research team noted that "systemic under-representation" of South Asians in therapeutic trials may have "obscured the intersection of risks" impacting this community. 

Fiona Miller Smith, chief executive of Barts Charity, which part-funded the research, said: "We are committed to funding health research that leads to better healthcare for all in our diverse East London population. With high rates of cardiovascular disease in the East London South Asian community, we are therefore pleased to see the outcomes of this important study, which will lead to more effective treatment for this group."

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