• Plavix Smoker's Paradox Debunked? Hemoglobin confounds platelet level readings, study suggests

    Lower platelet reactivity among cigarette smokers on clopidogrel (Plavix) was not actually a sign of enhanced drug response but confounding by hemoglobin levels, a study found.

    As in subanalyses of the large clinical trials suggesting the antithrombotic protection offered by the drug was limited to smokers — dubbed the smoker’s paradox — smokers had lower platelet reactivity measured by the P2Y12 reaction unit (PRU; 212.2 versus 230.1, P<0.001).

    Smokers also had higher hemoglobin levels (14.4 versus 13.5 for non-smokers, P<0.001), Jung-Won Suh, MD, of Seoul National University Bundang Hospital in Korea, and colleagues reported online in JACC: Cardiovascular Interventions.

    PRU levels were inversely correlated with hemoglobin levels (r=-0.389, P<0.001), regardless of smoking status.

    After taking into account that relationship between hemoglobin and PRU, there was no longer any difference in PRU between smokers and non-smokers (225.3 versus 224.1, P=0.813).

    “Because PRU, hemoglobin, and smoking status are closely associated, hemoglobin should be considered as a covariate when evaluating the influence of smoking on clopidogrel responsiveness. To the best of our knowledge, this is the first study that took hemoglobin level into account before defining the relationship between smoking status and clopidogrel responsiveness.”

    “The observed difference in PRU between non-smokers and current smokers is largely attributable to the difference in hemoglobin level,” they concluded. “Our data suggest that cigarette smoking does not improve clopidogrel responsiveness.”

    “It is possible that hemoglobin concentration might have an influence on PRU value that is unrelated to intrinsic platelet reactivity. However, further investigation is needed to clarify the underlying mechanism,” Suh and colleagues wrote.

    For now, “enhanced clopidogrel responsiveness in cigarette smokers is not confirmed in this study and the concept of the smokers’ paradox needs further validation.”

    Dirk Sibbing, MD, and Lisa Gross, MD, both of the German Center for Cardiovascular Research in Munich, commended the investigators for their “important study” in an accompanying editorial.

    “The results lend support to the hypothesis that hemoglobin levels are a key driver for the observed ex-vivo phenomenon (new smoker’s paradox) of lower on-treatment platelet reactivity levels and/or an enhanced response to adenosine diphosphate inhibitors like clopidogrel in active smokers in most of the studies published so far,” they added.

    However, the duo cited the results of the COPTER trial, which found that patients on chronic clopidogrel, prasugrel (Effient), or ticagrelor (Brilinta) all had platelet reactivity levels that tracked brief periods of smoking cessation and resumption.

    These data “emphasize the inconsistency that still exists in this field of research,” they concluded.

    Suh and colleagues’ study incorporated data from three trials: SNUBH (n=459), CILON-T (n=715), and HOST-ASSURE (n=1,357). Their final cohort included 1,314 patients who underwent PCI and had VerifyNow P2Y12 assay results available.

    Prior studies have had conflicting results over whether smokers respond better to clopidogrel therapy, they noted, though they commented that the “smoker’s paradox” has really been valid only when the VerifyNow P2Y12 assay was used as a platelet function test.

    Furthermore, they found that rates of adverse events — including stent thrombosis and bleeding events — were no different between smokers and non-smokers.

    The investigators acknowledged that their study was limited by its retrospective nature and its reliance on self-reported smoking status.

    Another major limitation was the “lack of pharmacokinetic data on clopidogrel active metabolite generation among smokers versus nonsmokers,” contributed Sibbing and Gross. “It must be emphasized that most of the studies investigating the issue of smoking and drug response focused on pharmacodynamic testing with different platelet function assays.”

    The editorialists also pointed out the relatively small sample size and the study’s focus on clopidogrel-treated patients, leaving out those on prasugrel and ticagrelor.

    Nonetheless, “despite the existing gaps in knowledge, the findings by [the investigators] are important because they sound a note of caution toward a possible ‘benefit’ of smoking on antiplatelet drug response, which was suggested by some prior studies.”



    The study was sponsored by government grants from the Republic of Korea.

    Suh and Gross disclosed no relevant conflicts of interest.

    Sibbing reported speaking and consulting for Eli Lilly, Merck Sharp & Dohme, Pfizer, Daiichi Sankyo, Bayer Vital, AstraZeneca, and Roche Diagnostics; as well as receiving research grants from Roche Diagnostics.


    JACC: Cardiovascular Interventions


    Kim YG, et al “Cigarette smoking does not enhance clopidogrel responsiveness after adjusting VerifyNow P2Y12 reaction unit for the influence of hemoglobin level” JACC Cardiovasc Interv 2016; DOI: 10.1016/j.jcin.2016.05.036.


    JACC: Cardiovascular Interventions


    Sibbing D, Gross L “Smoking and clopidogrel response revisited: Hemoglobin levels explaining the Smoker’s Paradox” JACC Cardiovasc Interv 2016; DOI; 10.1016/j.jcin.06.042.

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