Key result
CYP2C19 loss-of-function variants linked to ~53% higher ischemic stroke risk on clopidogrel.
Why the study?
To determine whether CYP2C19 loss-of-function alleles increase the risk of ischaemic stroke and myocardial infarction in UK primary care patients prescribed clopidogrel.
Does the presence of CYP2C19 loss-of-function alleles increase the risk of ischemic stroke and MI in patients prescribed clopidogrel?
Cohort (n=7,483)
Yes
Does the presence of CYP2C19 loss-of-function alleles increase the risk of ischemic stroke and MI in patients prescribed clopidogrel?
Hazard Ratio: 1.53 (95% CI 1.04–2.26)
Absolute Event Rate: 8% vs 5.2%
p-value: p=0.031
In UK primary care patients prescribed clopidogrel, carrying CYP2C19 loss-of-function variants is associated with a significantly higher risk of ischemic stroke and myocardial infarction.
Elevated stroke risk in LoF carriers on clopidogrel warrants caution; hypothesis-generating for genotype-guided therapy, should not yet change practice.
Objective To determine whether CYP2C19 loss-of-function (LoF) alleles increase risk of ischaemic stroke and myocardial infarction (MI) in UK primary care patients prescribed clopidogrel. Design Retrospective cohort analysis. Setting Primary care practices in the UK from January 1999 to September 2017. Participants 7483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36–79 years at time of first clopidogrel prescription. Interventions Clopidogrel prescription in primary care, mean duration 2.6 years (range 2 months to 18 years). Main outcome measure Hospital inpatient-diagnosed ischaemic stroke, MI or angina while treated with clopidogrel. Results 28.7% of participants carried at least one C YP2C19 LoF variant. LoF carriers had higher rates of incident ischaemic stroke while treated with clopidogrel compared with those without the variants (8 per 1000 person-years vs 5.2 per 1000 person-years; HR 1.53, 95% CIs 1.04 to 2.26, p=0.031). LoF carriers also had increased risk of MI (HR 1.14, 95% CI 1.04 to 1.26, p=0.008). In combined analysis LoF carriers had increased risk of any ischaemic event (stroke or MI) (HR 1.17, 95% CI 1.06 to 1.29, p=0.002). Adjustment for aspirin coprescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischaemic stroke by age 79 (oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers, that is, 7.1% excess stroke incidence in LoF carriers by age 79. Conclusions A substantial proportion of the UK population carry genetic variants that reduce metabolism of clopidogrel to its active form. In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischaemic events. Genotype-guided selection of antiplatelet medications may improve outcomes in patients carrying CYP2C19 genetic variants.
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Pilling et al. (2021) conducted a cohort in Patients prescribed clopidogrel (n=7,483). CYP2C19 loss-of-function (LoF) alleles vs. Without CYP2C19 LoF variants (normal metabolizers) was evaluated on Incident ischaemic stroke while treated with clopidogrel (HR 1.53, 95% CI 1.04 to 2.26, p=0.031). CYP2C19 loss-of-function variant carriers prescribed clopidogrel in primary care had a significantly higher risk of incident ischemic stroke compared to non-carriers (HR 1.53).
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