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<p>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&#xa0;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.</p>

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Association of cytochrome P450 2C19 genotypes with effectiveness of clopidogrel in ischemic stroke by smoking status

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Hyungjong Park,
  • Hye Sun Lee,
  • Yo Han Jung,
  • Soyoung Jeon,
  • Jinkwon Kim,
  • Hee-Kwon Park,
  • Sang Won Han,
  • Young Dae Kim,
  • Jong-Ho Park,
  • Jae-Kwan Cha,
  • Hyun Young Park,
  • Sung-Il Sohn,
  • Sungwook Yu,
  • Jun Hong Lee,
  • Dong Hoon Shin,
  • Eung-Gyu Kim,
  • Kyung-Yul Lee,
  • Tae-Jin Song,
  • Sang-Jun Ahn,
  • Won Chul Shin,
  • Sung-Hun Kim,
  • Yang-Ha Hwang,
  • Sung-Hyuk Heo,
  • Chi-Kyung Kim,
  • Jin-Man Jung,
  • Bon-Koo Yoo,
  • Jong-Yoon Lee,
  • Ki-Chul Park,
  • Beom Joon Kim,
  • Han-Young Jung,
  • Tae-Hwan Park,
  • Jae Guk Kim,
  • Man-Seok Park,
  • Sung-Hwan Ahn,
  • Kwang-Yeol Park,
  • Ye-Rim Kim,
  • Chul-Ho Kim,
  • Hyung-Young Kim

摘要

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.