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

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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Journal
Scientific Reports
Published
2026-07-02
DOI
https://doi.org/10.1038/s41598-026-59902-z
Primary Topic
Antiplatelet Therapy and Cardiovascular Diseases
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Won Chul Shin, Young Dae Kim, Sungwook Yu, B R Kim et al.
Scientific Reports
Antiplatelet Therapy and Cardiovascular Diseases
article

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

Won Chul Shin, Young Dae Kim, Sungwook Yu, B R Kim, Kwang‐Yeol Park, Ki-Chul Park, Jinkwon Kim, Chi-Kyung Kim, Jong-Yoon Lee, Jun Hong Lee, Jae‐Kwan Cha, Sung-Hwan Ahn, Tae‐Jin Song, H Lee, Sung-Hyuk Heo, Kyung‐Yul Lee, Hyung-Young Kim, Ye-Rim Kim, Yo Han Jung, E Kim, Jong-Ho Park, Han-Young Jung, Hee-Kwon Park, Jin-Man Jung, Hyungjong Park, Man-Seok Park, Yang-Ha Hwang, Soyoung Jeon, Jae Guk Kim, Bon-Koo Yoo, Chul-Ho Kim, Sung-Il Sohn, Sang Won Han, PLATELET Trial Investigators, Sung-Hun Kim, Sang-Jun Ahn, Dong Hoon Shin, Hyun Young Park, Tae-Hwan Park
article en

Abstract

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.

Scientific Reports
Ewha Womans University (KR), Seoul National University (KR), Inha University (KR), Yonsei University (KR), Korea University (KR), Severance Hospital (KR), Korea University Medical Center (KR), Dong-A University Hospital (KR), Seoul Metropolitan Government (KR), Kosin University Gospel Hospital (KR), Seoul National University Hospital (KR), Seoul National University Bundang Hospital (KR), Ansan University (KR), Kyungpook National University (KR), Kyung Hee University (KR), Sacred Heart Hospital (NG), Gachon University Gil Medical Center (KR), St. Mary's Hospital (US), Chonnam National University Hospital (KR), SNUH SMG-SNU Boramae Medical Center (KR), Chosun University Hospital (KR), Kangwon National University Hospital (KR), Inje University Busan Paik Hospital (KR), Kimpo University (KR), Inje University Sanggye Paik Hospital (KR), National Health Insurance Service Ilsan Hospital (KR), Hanyang University Seoul Hospital (KR), Gangnam Severance Hospital (KR), Catholic Kwandong University International St. Mary's Hospital (KR), Kyung Hee University Hospital at Gangdong (KR), Chung-Ang University Hospital (KR), National Health Insurance Service (KR), Yonsei University Health System (KR), Hallym University Chuncheon Sacred Heart Hospital (KR), Keimyung University (KR), Wonkwang University (KR)
Korea Health Industry Development Institute, Ministry of Education and Human Resources Development, Ministry of Science and ICT, South Korea, Institute for Information and Communications Technology Promotion
Good health and well-being
Openalex Percentile: Top 8%
Antiplatelet Therapy and Cardiovascular Diseases
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