Enhanced Clopidogrel Response in Smokers Is Reversed After Discontinuation as Assessed by VerifyNow Assay: Additional Evidence for the Concept of ‘Smokers’ Paradox’

Study Questions:

What is the impact of cigarette smoking on on-clopidogrel platelet reactivity (OPR)?


From the prospective CROSS-VERIFY cohort, 810 subjects with repeated measurement of OPR at least 1 month apart were analyzed. With smoking status ascertained at two time points, baseline and follow-up, study subjects were categorized 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).


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.


The authors concluded that enhanced clopidogrel response in smokers is reversed after smoking discontinuation.


This study suggests that smoking cessation resulted in reversal of the enhanced response to clopidogrel in smokers. At baseline, current smokers had significantly lower OPR compared with never smokers. Among those who were actively smoking at baseline, those who stopped smoking thereafter (quitters) showed an increase in OPR, in contrast to persistent smokers whose OPR did not change significantly at follow-up. Furthermore, there was a linear relationship between the amount of cigarette smoking and the antiplatelet effect of clopidogrel. The data should not be construed to mean that smoking improves the effectiveness of antiplatelet therapy. The slight increase in platelet inhibition has not been associated with improved outcomes, and is unlikely to offset the greatly increased risk of a thrombotic event from smoking. Further investigation is warranted to elucidate the true clinical implications of this phenomenon, but for now, smoking should be strongly discouraged.

Keywords: Risk, Follow-Up Studies, Platelet Aggregation Inhibitors, Cardiovascular Diseases, Blood Platelets, Drugs, Chinese Herbal, Tobacco Use Disorder, Smoking Cessation

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