Smoking Status Influence on Clopidogrel Response

Subarachnoid Hemorrhage Risk With Smoking
Subarachnoid Hemorrhage Risk With Smoking
Researchers observed a "significant inverse correlation" between P2Y12 reaction units and hemoglobin.

Current smokers and nonsmokers demonstrated a difference in P2Y12 reaction units (PRU), but not after adjustment for hemoglobin, according to a multi-cohort analysis published in JACC: Cardiovascular Interventions.

Yun Gi Kim, MD, of the Seoul National University Bundang Hospital in Seongam City, South Korea and colleagues hypothesized that the difference in PRU between current smokers and nonsmokers would be the result of the confounding effect of hemoglobin rather than a real difference in platelet activity.

“In several large scale clinical trials, nonsmokers did not benefit from clopidogrel therapy, whereas smokers showed a significant reduction in primary outcome end points related to clopidogrel treatment,” the authors wrote. “This phenomenon is called the smokers’ paradox and enhanced clopidogrel responsiveness in smokers is suggested as one of the underlying mechanisms.”

For the purposes of this study, smoking categories were defined as current smokers (those who smoked ≥100 cigarettes in their lifetime and continued to smoke within 1 month of enrollment), former smokers (those who smoked ≥100 cigarettes in their lifetime, but had not smoked within 1 month of enrollment), and “never smokers” (those who have smoked <100 cigarettes in their lifetime).

Data was collected from 3 combined cohorts (total patient population = 1314) who underwent percutaneous coronary intervention (PCI) and had VerifyNow P2Y12 assay results. The primary outcome was MACE as defined as a composite of cardiac death, myocardial infarction (MI), and ischemic stroke, between current and nonsmokers. Stent thrombosis and bleeding events were also assessed.

Researchers observed a “significant inverse correlation” between PRU and hemoglobin (r= –0.389; P<.001). Significantly higher hemoglobin levels were seen in current smokers (13.5 ± 1.6 vs 14.4 ± 1.5, P<.001), but lower PRU levels (230.1 ± 90.7 vs 212.2 ± 83.6; P<.001). However, there was no difference in PRU between nonsmokers and current smokers after adjustment for hemoglobin’s influence on PRU (224.1 [95% confidence interval: 218.7-229.5] vs 225.3 [95% confidence interval: 217.2-233.3]; P=.813).

The MACE incidence rate was not different between nonsmokers and current smokers (3.2% vs 1.9%; log-rank P=.949).

In addition, the cumulative incidence stent thrombosis (both definite and probable) and bleeding events did not differ between current and nonsmokers.

Dr Kim and colleagues pointed out that while there is evidence to support the notion of an enhanced clopidogrel response in smokers, there is also some evidence against it. Different platelet function tests produce different results, and that may be why the “smokers’ paradox” is only valid when using the VerifyNow P2Y12 assay.

“The impact of adjusting hemoglobin on the predictive value of PRU, such as MACE, should be examined. The reason for the inverse association between PRU and hemoglobin should be elucidated and corrected if possible,” they concluded.


Kim YG, Suh J-W, Kang S-H, et al. Clopidogrel responsiveness after adjusting VerifyNow P2Y12 reaction unit for the influence of hemoglobin level. JACC Cardiovasc Interv. 2016;9(16):1680-1690.  doi:10.1016/j.jcin.2016.05.036.