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.