Key result
CYP2C19 loss-of-function variants increased the risk of incident ischemic stroke by 53% (HR 1.53) in primary care patients prescribed clopidogrel compared to non-carriers.
Why the study?
CYP2C19 loss-of-function variants have been linked to excess morbidity mainly in acute hospitalized cohorts, but their impact in family practice over long periods of exposure remains poorly understood.
Does carrying CYP2C19 loss-of-function variants increase the risk of ischemic stroke and MI in primary care patients prescribed clopidogrel?
Cohort (n=7,483)
Yes
Does carrying CYP2C19 loss-of-function variants increase the risk of ischemic stroke and MI in primary care patients prescribed clopidogrel?
Hazard Ratio: 1.53 (95% CI 1.04–2.26)
Absolute Event Rate: 1.91% vs 1.29%
p-value: p=0.031
In primary care patients prescribed clopidogrel, CYP2C19 loss-of-function variants are associated with a substantially higher incidence of ischemic stroke and myocardial infarction, suggesting a potential benefit for genotype-guided antiplatelet therapy.
Background The antiplatelet drug clopidogrel is commonly prescribed for stroke and myocardial infarction (MI) prevention. Clopidogrel prodrug is predominantly activated by liver enzyme CYP2C19. CYP2C19 Loss-of-function (LoF) genetic variants have been linked to excess morbidity mainly in patients hospitalized for acute ischemic events and related interventions. Little is known about the magnitude of impact of LoF variants in family practice, especially over long periods of exposure. We aimed to determine whether CYP2C19 LoF alleles increase risk of ischemic stroke and MI in primary care patients prescribed clopidogrel for up to 18 years. Methods Retrospective cohort analysis of 7,483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36 to 79 years at first clopidogrel prescription. We examined CYP2C19 LoF variant (*2-*8) associations with incident hospital-diagnosed ischemic stroke and MI in patients prescribed clopidogrel for at least 2 months using time-to-event models, with secondary analysis of the *17 gain of function variant. Results 28.7% (n=2,144/7,483) of included subjects (mean age 63 years at first clopidogrel prescription) carried at least one C YP2C19 intermediate or low metabolizer LoF variant. 1.9% of LoF variant carriers had an incident ischemic stroke whilst prescribed clopidogrel (mean 2.6 years, range 2 months to 18 years), versus 1.3% without the variants (0.6% absolute excess: Hazard Ratio 1.53: 95% CI 1.04 to 2.26, p=0.031). Additionally, 26.4% of C YP2C19 LoF variant carriers had an incident MI versus 24.1% (HR 1.14: 1.04 to 1.26, p=.008). Adjustment for aspirin co-prescription 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 ischemic stroke by age 79 (the oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers: the absolute excess stroke incidence with LoF variants was 7.1% by age 79. Conclusion In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischemic events. Genotype-guided (or routine) prescription of antiplatelet medications unaffected by CYP2C19 variants may improve outcomes in patients for whom clopidogrel is currently indicated.
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Pilling et al. (2021) conducted a cohort in Patients prescribed clopidogrel (n=7,483). CYP2C19 Loss-of-function (LoF) genetic variants vs. Non-carriers of CYP2C19 LoF variants was evaluated on Incident hospital-diagnosed ischemic stroke (HR 1.53, 95% CI 1.04 to 2.26, p=0.031). CYP2C19 loss-of-function variants increased the risk of incident ischemic stroke by 53% (HR 1.53) in primary care patients prescribed clopidogrel compared to non-carriers.
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