CYP2C19 genotype prevalence and association with recurrent myocardial infarction in British-South Asians treated with clopidogrel
Key result
CYP2C19 poor metabolizer status is linked to ~3.1-fold higher recurrent MI risk on clopidogrel.
- OR 3.1
- P=0.02
- n=44,396
Why the study?
Clopidogrel remains widely prescribed for ACS and MI, yet the outcome studies supporting its licensure lacked significant South Asian representation. Furthermore, very few studies had examined CYP2C19 poor metabolizer genotypes specifically in South Asian populations or linked metabolizer diplotypes with clinical efficacy in this high-risk group.
Does the presence of a CYP2C19 poor metabolizer diplotype increase the risk of recurrent myocardial infarction in British Bangladeshi and Pakistani patients treated with clopidogrel?
Key Points
- Determine the prevalence of CYP2C19 loss-of-function genotypes in British South Asians and assess their relationship with recurrent myocardial infarction in patients treated with clopidogrel.
- Analyzed genomic and primary care records from participants in the Genes & Health cohort (N = 44,396) of British Bangladeshi and Pakistani ancestry.
- Used multivariable regression to evaluate associations between CYP2C19 diplotypes and recurrent myocardial infarction among patients prescribed clopidogrel, controlling for cardiovascular risk factors, percutaneous coronary intervention, age, and sex.
- Intermediate or poor CYP2C19 metabolizer genotypes with at least one loss-of-function allele were identified in 57% of participants, with 13% possessing two loss-of-function alleles due largely to the *2 allele present in 56% of the cohort.
- Clopidogrel was prescribed to 69% of patients diagnosed with acute myocardial infarction (N = 697; recurrent events N = 39).
- The CYP2C19 poor metabolizer diplotype was significantly associated with recurrent myocardial infarction during clopidogrel treatment (OR 3.1, p = 0.02).
Study Design
Type
Cohort (n=44,396)
Structured PICO
Does the presence of a CYP2C19 poor metabolizer diplotype increase the risk of recurrent myocardial infarction in British Bangladeshi and Pakistani patients treated with clopidogrel?
P
Population
44,396 participants of British Bangladeshi and Pakistani ancestry from the Genes & Health cohort, including 697 patients with acute myocardial infarction prescribed clopidogrel.
E
Exposure
Clopidogrel prescribed in primary care among patients carrying CYP2C19 poor metabolizer diplotypes (2 loss-of-function alleles)
C
Comparator
Clopidogrel prescribed in primary care among patients without CYP2C19 poor metabolizer diplotypes
O
Outcome
Recurrent myocardial infarction (or failed secondary prevention on clopidogrel)hard clinical
Main Result
Odds Ratio: 3.1
p-value: p=0.02
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“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.”
“This study highlights the importance of using genetics to determine who can benefit from clopidogrel after a heart attack, and how not doing so is likely to disproportionately disadvantage specific groups, such as South Asians.”
“In a study of 65,000 British Bangladeshi and Pakistani individuals, we found that 57% could not activate clopidogrel, a medicine commonly used after heart attacks or following narrowing of the coronary arteries. Thirty percent of the White European people were also not able to activate the medicine. We used electronic health records to show that those unable to activate clopidogrel had a higher risk of further heart attacks after being given the drug. This shows how real and important this issue is, making sure patients get the right medicine for the right benefit with modern genomics.”
Implication
British Bangladeshi and Pakistani individuals have a high prevalence (13%) of CYP2C19 poor metabolizer status, which triples the odds of recurrent myocardial infarction when treated with clopidogrel, supporting guideline recommendations for non-CYP2C19 dependent P2Y12 inhibitors or genotype-guided therapy in this population.
Abstract
Background Pharmacogenomics examines how genes and drugs interact to explain some of the inter-individual variability in response to medications. CYP2C19 is a hepatic enzyme involved in the metabolism of clopidogrel from a prodrug to its active metabolite. Although the European Society of Cardiology and National Institute for Care Excellence recommend ticagrelor (a non CYP2C19 dependent P2Y12 antagonist) as the antiplatelet agent of choice, clopidogrel remains widely prescribed for acute coronary syndrome and myocardial infarction. CYP2C19 poor metabolizers are known to be more common in Asian ancestry but very few studies have looked specifically at South Asian populations or linked metabolizer diplotypes with clinical efficacy data in this population. The outcome studies on which clopidogrel was licensed for efficacy and safety did not include significant South Asian representation. Furthermore, South Asians are known to have a higher prevalence of cardio-metabolic disease compared with European ancestry populations. Methods We studied the Genes & Health cohort of British Bangladeshi and Pakistani ancestry participants to look at prevalence of CYP2C19 metabolizer genotypes and correlate these with recurrent myocardial infarction risk for those who had been prescribed clopidogrel in primary care. Multivariable regression was used to test for association between known CYP2C19 diptotypes and recurrent myocardial infarction in those prescribed clopidogrel, controlling for known CVD risk factors, percutaneous coronary intervention, age, and gender. Results Genes & Health cohort participants (N = 44,396) have a high prevalence (57%) of intermediate or poor CYP2C19 metabolizers, with at least 1 loss of function allele. The prevalence of poor metabolizers carrying 2 CYP2C19 loss of function alleles is 13%, which is higher than in previously studied European (2.4%) and Central/South Asian populations (8.2%). This is primarily due to the *2 LOF allele present in 56% of the population. 69% of the cohort who were diagnosed with an acute MI were prescribed clopidogrel. The presence of the poor metabolizer diplotype is significantly associated with higher risk of recurrent MI, or failed secondary prevention on clopidogrel in this population, OR 3.1 (p = 0.02), with some subsequent ischemic events already described in this young cohort (Acute MI prescribed clopidogrel N = 697, Recurrent MI in this group N=39). Conclusions A pharmacogenomic-driven approach to clopidogrel prescribing has the potential to impact significantly on clinical management and outcomes in individuals of Bangladeshi and Pakistani ancestry. In absence of genotype guided prescribing, maximal adherence to guidelines recommending non CYP2C19 dependent P2Y12 anti-platelet therapy is likely to be disproportionately beneficial in this ethnic cohort.
Discussion
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Cite This Study
Magavern et al. (2023) conducted a cohort in Myocardial infarction / Clopidogrel therapy (n=44,396). CYP2C19 poor metabolizer diplotype (2 loss-of-function alleles) in patients prescribed clopidogrel vs. Non-poor CYP2C19 metabolizer diplotypes was evaluated on Recurrent myocardial infarction (or failed secondary prevention on clopidogrel) (OR 3.1, p=0.02). Carrying the CYP2C19 poor metabolizer diplotype (13% prevalence) was associated with higher recurrent MI risk in British-South Asians prescribed clopidogrel (OR 3.1; p=0.02).