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Enhanced clopidogrel response in smokers is reversed after discontinuation as assessed by VerifyNow assay: additional evidence for the concept of ‘smokers’ paradox'
  1. Kyung Woo Park,
  2. Si-Hyuck Kang,
  3. Jeehoon Kang,
  4. Ki-Hyun Jeon,
  5. Jin Joo Park,
  6. Jung-Kyu Han,
  7. Jin-Sin Koh,
  8. Sang Eun Lee,
  9. Han-Mo Yang,
  10. Hae-Young Lee,
  11. Hyun-Jae Kang,
  12. Bon-Kwon Koo,
  13. Byung-Hee Oh,
  14. Young-Bae Park,
  15. Hyo-Soo Kim
  1. Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul, Korea
  1. Correspondence to Professor Hyo-Soo Kim, Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, 28 Yongon-dong Chongno-gu, Seoul 110-744, Korea; hyosoo{at}


Background Previous reports on smokers' paradox to clopidogrel have only been able to show an association between cigarette smoking and enhanced response to clopidogrel therapy. No study has shown reversal of enhanced clopidogrel response after smoking cessation.

Objective To conduct a prospective observational longitudinal study in order to measure the impact of cigarette smoking on on-clopidogrel platelet reactivity (OPR).

Design From the prospective CROSS-VERIFY cohort, 810 subjects with repeated measurement of OPR at least 1 month apart were analysed. With smoking status ascertained at two time points, baseline and follow-up, study subjects were categorised into never smokers (n=628), smoking quitters (n=77) and persistent smokers (n=105). Dependent variables included OPR measured by the VerifyNow assay and the percentage of subjects with high OPR (HOPR).

Results At baseline, current smokers showed significantly lower OPR compared with never smokers, with no significant differences in OPR between future quitters and future persistent smokers within current smokers. While the OPR of never smokers and persistent smokers did not change significantly during the follow-up, the mean OPR of quitters increased significantly by 19 P2Y12 reaction units (p=0.013). The frequency of HOPR showed similar results, with an 8–10% increase in smoking quitters in contrast to no significant changes in never and persistent smokers. Both mean OPR and the frequency of HOPR showed a linear inverse relationship with the amount of smoking.

Conclusions Enhanced clopidogrel response in smokers is reversed after smoking discontinuation, suggesting a causal relationship in addition to the previously reported association between smoking and enhanced clopidogrel response.

  • Antiplatelet treatment
  • smoking
  • clopidogrel
  • coronary intervention
  • gene association
  • platelets
  • atherosclerosis
  • interventional cardiology
  • molecular biology
  • restenosis

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  • See Editorial, p 963

  • Funding This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065), and a grant from the Innovative Research Institute for Cell Therapy, Seoul National University Hospital (A062260), sponsored by the Ministry of Health and Welfare, Republic of Korea.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Seoul National University Hospital Institutes for Biomedical Research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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