Key result
CYP2C19 non-carriers show ~87% fewer major events versus carriers among smokers with acute ischemic stroke.
Why the study?
Carriers of CYP2C19 loss-of-function alleles have reduced clopidogrel bioactivation, but smoking may enhance responsiveness, prompting evaluation of whether smoking modifies the impact of these alleles on clopidogrel effectiveness after acute ischaemic stroke.
Does smoking status modify the impact of CYP2C19 loss-of-function alleles on clopidogrel effectiveness after acute ischaemic stroke?
Observational (n=2,910)
Does smoking status modify the impact of CYP2C19 loss-of-function alleles on clopidogrel effectiveness after acute ischaemic stroke?
The benefit of clopidogrel in acute ischemic stroke appears confined to current smokers who are non-carriers of CYP2C19 loss-of-function alleles, suggesting that combining smoking status with genotyping may help personalize antiplatelet therapy.
Answers are grounded in this paper and cite their sources.
Smoking may modify CYP2C19 LOF effects on clopidogrel post-stroke; hypothesis-generating and should not yet change genotyping or therapy.
Carriers of CYP2C19 loss-of-function (LOF) alleles have reduced clopidogrel bioactivation, higher on-treatment platelet reactivity, and more recurrent ischaemic events. Smoking may enhance clopidogrel responsiveness. We evaluated whether smoking modifies the impact of LOF alleles on clopidogrel effectiveness after acute ischaemic stroke. This is a post-hoc analysis of the PLATELET trial (ClinicalTrials.gov NCT04072705), a prospective, observational study enrolling participants from September 2019 to March 2023. Patients receiving clopidogrel were classified as current or non-current smokers and stratified by CYP2C19 genotype (carriers of LOF alleles vs. non-carriers). The primary outcome was a 6-month composite of ischaemic or haemorrhagic stroke, myocardial infarction, or cardiovascular death. Secondary outcomes included ischaemic stroke, transient ischaemic attack, coronary revascularization, early neurological deterioration and a good functional outcome, defined as modified Rankin Scale (mRS) score 0–2 at 3 months. Safety outcomes were major bleeding and mortality. Among 2,910 participants, the primary outcome occurred in 4.8% of non-current smokers and 4.2% of current smokers. In current smokers, events were lower in non-carriers than carriers (0.6% vs 6.5%), but not in non-current smokers (4.4% vs. 5.0%). In multivariable analysis, non-carriers had a lower risk than carriers of LOF alleles only among current smokers (adjusted hazard ratio [aHR], 0.13; 95% CI; 0.02–0.70). Among the secondary outcomes, only ischaemic stroke showed lower incidence in non-carriers within the current smoking group (0.3% vs. 2.8%), with a significantly reduced risk (aHR, 0.15; 95% CI 0.03–0.85). Safety outcomes did not differ by genotype in either group. The benefit of clopidogrel was confined to current smokers who were non-carriers, with comparable safety. Combining smoking status with CYP 2C19 genotyping may help personalize antiplatelet therapy.
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Park et al. (2026) conducted an observational in acute ischaemic stroke (n=2,910). CYP2C19 non-carrier status vs. CYP2C19 loss-of-function allele carriers was evaluated on 6-month composite of ischaemic or haemorrhagic stroke, myocardial infarction, or cardiovascular death (aHR 0.13, 95% CI 0.02-0.70). Among current smokers with acute ischaemic stroke, CYP2C19 non-carriers had a significantly lower risk of the primary composite outcome compared to carriers (aHR 0.13; 95% CI 0.02-0.70).
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