Clopidogrel is a known platelet inhibitor, which has been widely used for the prevention of major complications of heart disease following percutaneous coronary intervention (PCI). ¹ Previous studies have shown that there was some inter-individual difference in clopidogrel response ² and resistance to clopidogrel is related with an augmented risk of major adverse cardiac events (MACE). ² Among the several risk factors that affect the response of platelet to clopidogrel therapy, smoking is linked with enhanced clopidogrel responsiveness. ³ Although various processes have been proposed (including those regarding cytochrome P450 enzyme system), the exact mechanism is still unclear. ³

Clopidogrel is taken as an inactive drug; it then passes through a two-step oxidation process with the help of cytochrome P450 (CYP) to be activated, which leads to irreversible inhibition of platelet P2Y ₁₂ adenosine diphosphate (ADP) receptor. ⁴ Smoking is identified as an inducer of CYP1A2, a major iso-enzyme controlling the first oxidation step in clopidogrel activation. ⁴

The fundamental association between coronary arterial disease (CAD) and smoking is well established. ⁴ Cessation of smoking is the only most significant intervention for prevention of CAD. ⁴ However, the “smoking paradox” is a phenomenon which has been observed in smokers on clopidogrel treatment. In these patients, the pharmacodynamics of clopidogrel was enhanced by the intensity of smoking, and smokers who received clopidogrel had low platelets reactivity. ⁵

In this study, we investigated whether smoking enhances clopidogrel responsiveness in patients with ischemic heart disease (IHD) following PCI.

This was a prospective case-control study, conducted at Al-Najaf Heart Surgery and Catheterization Center, Al-Najaf, Iraq, between August 2020–June 2022. This study was approved by the Human Research Ethics, College of Medicine, University of Kufa (KUM 364 on 10 March 2022). The study protocol was explained to all patients and only participants who provided written informed consent to enroll in the study were included. A total of 370 participants were initially included in the study, however, 46 participants were later excluded because they did not meet the study criteria. Therefore, only 324 participants who had a platelet function test two hours prior to PCI to monitor platelet responsiveness were included in the current analysis. Participants were, subsequently, divided into two study groups based on their response to clopidogrel therapy: non-responder study cohorts (case group n=111) and responder study group (control group n=213). In each of the above two study groups, participants were further subdivided according to their smoking status (smoker study group and non-smoker study group).

Table 1 shows the demographic data and clinical features of all the participants in this study. A total of 324 patients with CAD were included in the study. Among the responder study group, 51.1% of the participants in this group were smokers and 48.9% of the participants were non-smokers. In the non-responder study group, only 30.6% of the participants were smokers, versus 60.4% of the participants in this group were non-smokers, Table 1

In addition, the mean value for participants’ age in the smoker cohort was 58.58±0.75 versus 56.63±0.77 ( P value=0.07) in the non-smoker group for responder study group, whereas the mean value of the participants’ age for patients in the smoker cohort was 57.91±1.49 versus 55.20±1.05 ( P value=0.14) for non-smokers in the non-responder study cohort ( Table 1).

Overall, 77.1% of the smoker responder study group were males as compared to 72.1% non-smoker males, P=0.477. In contrast, 50% of the smoker non-responder participants were male versus 71.4% were non-smoker, P=0.029 ( Table 1).

With regards to the development of chronic illnesses, a non-significant difference was noticed in the prevalence of hypertension among the responder study cohort (67% in the smoking study sub-group versus 68.3% in the non-smoking study sub-group, P=0.772). Similarly, the prevalence of hypertension among the non-responder study group was not significantly different based on smoking status (70.6% smoking versus 64.9% non-smoking, P=0.56), Table 1.

The prevalence of diabetes mellitus was non-statistically different among the responder group (53.2% in the smoking sub-group versus 58.7% in the non-smoking study sub-group, P=0.42), as well as among the non-responder study group (55.9% in the smoking sub-group versus 48.1% in the non-smoking study sub-group, P=0.45), Table 1.

In addition, the prevalence of BMI varied insignificantly among the responder study cohort (28.84±0.47 in the smoking study sub-group versus 27.97±0.41 in the non-smoking study sub-group, P=0.16). Similarly, BMI level was not significantly different among the non-responder study cohort based on smoking status (28.91±0.50 smoking versus 30.02±1.00 non-smoking, P=0.47), Table 1.

The mean level of HbA1c was statistically significantly different in the responder study cohort (14.6±0.55 in the smoking sub-group versus 13.12±0.38 in the non-smoking study sub-group, P=0.029), While it was not significant within the non-responder study cohort (14.3±0.31 in the smoking sub-group versus 12.96±0.39 in the non-smoking study sub-group, P=0.33), Table 1.

Likewise, the mean level of AUC was statistically significantly different in the responder study group (17±8 in the smoking sub-group versus 45±6 in the non-smoking study sub-group, P=0.005). A statistically significant difference was noted within the non-responder study cohort (62±3 in the smoking sub-cohort as compared to 95±7 in the non-smoking study sub-cohort, P=0.008), Table 1.

Smoking status increased the response to clopidogrel therapy as manifested by the response to platelet function test with an odd’s ratio of 0.4213 (95% C.I. 0.259-0.684), P=0.0002, Table 2.

The current study compared the clopidogrel response to smoking status in patients with CAD who were prepared to undertake a PCI procedure. In this study, we took into consideration all the modifiable and the non-modifiable risk factors such as the presence of chronic condition (hyperglycemia, hypertension, and hemoglobin level). We could not find a significant difference between smoking participants versus non-smoking participants in the responder study cohort nor in the non-responder study cohort. These findings were comparable to the findings of other studies. ^{7 , 8}

Additionally, this study illustrated a significantly higher hemoglobin level among the smoking participants when compared to the non-smoking patients, although Yun Gi Kim and his team found evidence that the AUC measured by Multiplate Analyzer was not affected by hemoglobin level. ⁹ While there was a significantly lower AUC among the smoker participants as compared to the non-smoker in both study groups, these results are consistent with ^{5 , 10} and contrary to results by Kim et al., 2016. ⁹

However, it is worth mentioning that cessation of smoking represents the first action for the secondary prevention of the development of ischemic events in people with CVD diseases because it lowers the risk of thrombotic cardiovascular processes. ^{11 , 12} Although quitting smoking is the best strategy to lower thrombotic risk and save money on healthcare, many people with established CVD disease refuse to quit smoking. Accordingly, determining the best antiplatelet treatment plan for these patients is crucial. ^{11 , 12}

We also revealed that smoking enhanced clopidogrel responsiveness by 0.42 in responder study group and non-responder study groups. Previous studies concluded that smoking incudes enzyme activation of cytochrome P450 (primarily 2B6 and 1A2 isoenzymes), which are crucial for the biotransformation of the medication clopidogrel. ^{5 , 13} Smoking increases clopidogrel’s anti-aggregative action and platelet inhibition since it speeds up the drug's metabolism. Platelet P2Y ₁₂ receptors may become more numerous and expressed when exposed to nicotine, which may improve their sensitivity to clopidogrel. ^{5 , 13} Clopidogrel should be the drug of choice when it comes to long term prevention of CVD disease in smoker patients because of the larger number of clopidogrel responders and aspirin non-responders. ¹⁴ This is especially important for patients who, in accordance with recommended practices, depend on a single antiplatelet therapy, typically aspirin, for their protection against the development of atherosclerosis and do not have a clinical rationale for a combined antiplatelet treatment in combination with clopidogrel.

The absence of clinical follow-up for outcome and complications and a genetic investigation to assess patients who did not respond to clopidogrel are among the study’s first limitations.

The inability to measure cotinine plasma levels to accurately depict smokers' health is a second limitation of our study. However, most studies addressing the smoking paradox and the increased cardiovascular risk associated with smoking have this drawback.

There is a marked variance in AUC between smoker and non-smoker participants in the responder study group as well as among the non-responder study group. Our results propose that cigarette smoking enhances clopidogrel responsiveness. These results suggest potential benefits of clopidogrel therapy based on the smoking paradox, but this theory needs further investigations.

The authors declare that all data were generated in-house and that no paper mill was used. The authors responsibilities were as follows: Author Contributions: “Conceptualization, A.A., A.R., B.M., and H.A.; methodology, A.A., D.J., B.M., and A.R.; investigation, H.A., A.R., A.A., and B.M.; writing—original draft preparation, A.A., B.M., and A.R.; review and editing, H.A., and D.J.; supervision, B. M, and A.R. Authors have read and agreed to the final version of the manuscript.”