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Hemoglobin levels may explain apparent enhanced response to clopidogrel by smokers
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Adjusting the influence of hemoglobin appears to nullify differences in P2Y12 reaction units between nonsmokers and current smokers, suggesting that cigarette smokers do not have a heightened response to clopidogrel, according to recent findings.
In the study, researchers evaluated three cohorts: the Seoul National University Bundang Hospital (SNUBH) retrospective cohort and the CILON-T and HOST-ASSURE cohorts, both of which were originally multicenter, randomized trials.
From these cohorts, they identified patients who had available VerifyNow P2Y12 assay (Accriva Diagnostics) results and underwent primary PCI (SNUBH, n = 459; CILON-T, n = 715; HOST-ASSURE, n = 1,357). After application of exclusion criteria, the final combined cohort was 1,314 patients.
Before PCI, patients in all cohorts received 100 mg aspirin and 75 mg clopidogrel daily for a minimum of 7 days, and blood samples were collected for baseline testing including complete blood count.
After antiplatelet treatment, residual platelet function was assessed using the VerifyNow P2Y12 assay, with the results expressed as P2Y12 reaction units (PRU). Platelet function was also evaluated using blood samples taken after PCI and at discharge. The researchers performed univariate linear regression analysis to determine the regression coefficient between hemoglobin and PRU, and applied a general linear model to determine the effect of smoking on clopidogrel responsiveness while controlling for the effect of hemoglobin.
Negative association
They found a negative association between PRU and hemoglobin (r = –0.389; P < .001). They calculated an unstandardized regression coefficient of –21.4, indicating that PRU is reduced by 21.4 for each 1 mg/dL increase in hemoglobin levels. Disparities in PRU were seen across quartiles of hemoglobin (P < .001). Current smokers had lower PRU vs. nonsmokers (230.1; 95% CI, 224-235.9 vs. 212.2; 95% CI, 203.7-220.7; P < .001). Conversely, smokers demonstrated higher hemoglobin levels vs. nonsmokers (13.5 vs. 14.4; P < .001). A Kaplan-Meier survival curve analysis showed no difference in the incidence rate of MACE in smokers vs. nonsmokers (3.2% vs. 1.9%; log-rank P = .949).
Although the unadjusted analysis demonstrated a significantly higher PRU in the nonsmokers vs. the current smokers, an analysis adjusting the effect of hemoglobin found no difference in PRU between nonsmokers and current smokers (224.1; 95% CI, 218.7-229.5 vs. 225.3; 95% CI, 217.2-233.3).
No smoking benefit
In a related editorial, Dirk Sibbing, MD, and Lisa Gross, MD, of the Medizinische Klinik in Munich, wrote that although this study has limitations and further studies on larger cohorts are needed, these findings are important in explaining the “smoker’s paradox” of clopidogrel response.
edge, the findings by Kim [and colleagues] 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,” Sibbing and Gross wrote. – by Jennifer Byrne
Disclosure: The researchers and Gross report no relevant disclosures. Sibbing reports financial ties with AstraZeneca, Bayer Vital, Daiichi Sankyo, Eli Lilly, Merck Sharpe and Dohme, Pfizer and Roche Diagnostics.
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