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СпутникиРНSpaceXРоскосмосNASABackground The association between smoking and clopidogrel response has been stated in numerous studies, so the nature of this relationship remains undefined and may be confounded by methodological, hematological, and clinical factors. This study was designed to examine the relationship between smoking status and clopidogrel response between patients with coronary artery disease (CAD) who undergoing percutaneous coronary intervention (PCI). Methods In this observational analytical study, smoking status was assessed as the primary exposure variable, and responsiveness of clopidogrel was defined according to a predefined area-under-the-curve (AUC) threshold found using the Multiplate platelet function test. Patients were first classified according to smoking status (smokers vs non-smokers). Inside these groups, patients were further categorized as clopidogrel responder’s or non-responders. Baseline laboratory and clinical and features were compared between smokers and non-smokers, and a multivariable logistic regression model was tested to measure whether smoking status was independently related with responsiveness of clopidogrel after modification for main cardiovascular risk factors and hemoglobin level. Results Smokers confirmed a higher percentage of clopidogrel responders compared with non-smokers. Related to multivariable analysis, smoking status remained independently related with an increased likelihood of clopidogrel responsiveness, and level of hemoglobin similarly exhibited a significant positive relation with treatment responsiveness, whereas hypertension, age, BMI, and diabetes were not significant predicters. Conclusions Between patients undergoing PCI; smoking status was independently related with clopidogrel responsiveness; though, this result represents an observational association rather than sign of clinical benefit. The findings should be considered hypothesis-generating and justified further mechanistic and longitudinal study to explain the underlying elucidations for this design.
Research Article
Revised
[version 3; peer review: 1 approved, 1 not approved]
https://orcid.org/0000-0002-5993-9202
1, Bassim I. Mohammadhttps://orcid.org/0000-0001-6732-5940
2, Ahmed N. Rgeeb3, Dina A. Jamilhttps://orcid.org/0000-0002-0537-375X
4,5, Hayder A. Al-Aubaidyhttps://orcid.org/0000-0001-9564-0120
4https://orcid.org/0000-0002-5993-9202
1, Bassim I. Mohammadhttps://orcid.org/0000-0001-6732-5940
2, [...] Ahmed N. Rgeeb3, Dina A. Jamilhttps://orcid.org/0000-0002-0537-375X
4,5, Hayder A. Al-Aubaidyhttps://orcid.org/0000-0001-9564-0120
41 Department of Pharmacology & Therapeutics, College of Pharmacy, University of Jabbir ibn Hayyan, Al-Najaf, Iraq
2 Department of Pharmacology & Therapeutics, College of Medicine, University of Al-Qadisiyah, Al-Qadisiyah, Iraq
3 Department of Medicine (Interventional Cardiology), College of Medicine, University of Kufa, Al-Najaf, Iraq
4 Department of Microbiology, Anatomy, Physiology and Pharmacology & Centre for Cardiovascular Biology and Disease Research, School of Agriculture, Biomedicine & Environment, La Trobe University, Melbourne, VIC, 3086, Australia
5 Oceania University of Medicine, Melbourne, VIC, 3000, Australia
Ali A. R. Aldallal
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation
Bassim I. Mohammad
Roles: Conceptualization, Investigation, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation
Ahmed N. Rgeeb
Roles: Conceptualization, Methodology, Project Administration, Supervision, Writing – Original Draft Preparation
Dina A. Jamil
Roles: Investigation, Validation, Writing – Review & Editing
Hayder A. Al-Aubaidy
Roles: Conceptualization, Investigation, Project Administration, Validation, Writing – Review & Editing
OPEN PEER REVIEW
REVIEWER STATUS
Clopidogrel responsiveness, coronary artery disease, smokers’ paradox, and percutaneous intervention
Corresponding author: Hayder A. Al-Aubaidy Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright: © 2026 Aldallal AAR et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Aldallal AAR, Mohammad BI, Rgeeb AN et al. The impact of smoking status on clopidogrel responsiveness in patients with coronary artery disease who undergo percutaneous coronary intervention. [version 3; peer review: 1 approved, 1 not approved]. F1000Research 2026, 12:370 (https://doi.org/10.12688/f1000research.131820.3) First published: 05 Apr 2023, 12:370 (https://doi.org/10.12688/f1000research.131820.1) Latest published: 27 Jul 2026, 12:370 (https://doi.org/10.12688/f1000research.131820.3)
This new version of the article includes revisions made in response to the peer-review comments. The main changes include refinement of the manuscript text, clarification of the interpretation of the findings, updating and correcting the in-text citations and reference list, and improving the discussion to emphasize that the observed association between smoking status and clopidogrel responsiveness should be interpreted as hypothesis-generating rather than as evidence of clinical benefit. No new underlying or extended data have been added in this version.
See the authors' detailed response to the review by Anastasios Apostolos
See the authors' detailed response to the review by Bogumił Ramotowski
Cardiovascular disease is a chief global health burden and remains to be one of the leading causes of morbidity and mortality globally.1,2 Clopidogrel is often prescribed in dual antiplatelet treatment for prevention of large-scale adverse cardiac events in patients undergoing percutaneous coronary intervention (PCI). Though, Substantial inter-individual variability in clopidogrel responsiveness has been steadily documented, and decreased platelet inhibition has been related with poorer cardiovascular outcomes.3,4 The variability has been well reported across pharmacodynamic studies and meta-analytic evidence and emphasizes the clinical relevance of elucidating the contributors to clopidogrel response variability.5,6
One of the factors hypothesized to predict platelet reactivity and therefore clopidogrel pharmacodynamic response has been smoking, as a number of studies have found that smokers may be more responsive to clopidogrel compared to non-smokers, a phenomenon commonly referred to as the “smoking paradox” in the context of antiplatelet therapy response.7,8 Although several mechanistic descriptions have been suggested, the basis of this association still remains under-estimated and seems to be due to biochemical and pharmacodynamic differences rather than any clinical benefit.6
Clopidogrel is a prodrug that undergoes biotransformation through sequential cytochrome P450 (CYP)-mediated oxidative steps to give its active thiol metabolite, which irreversibly inhibits the platelet P2Y12 receptor.9,10 Cigarette smoking has been shown to induce cytochrome P450 1A2 (CYP1A2) activity, potentially enhancing clopidogrel bioactivation, which may result in reduced on-treatment platelet reactivity among smokers.11,12 Nonetheless, there has been documented inter-ethnic and population-based variation in platelet reactivity which suggests that the association between smoking status and clopidogrel responsiveness may vary across different clinical and demographic settings.13
However, smoking presents a large preventable risk factor for cardiovascular morbidity and mortality, and its deleterious systemic effects greatly outshine theoretical pharmacodynamic relationships noted in analytical studies.1,2 Thus, findings from studies that have investigated smoking-related variation in responsiveness to clopidogrel should be viewed as hypothesis-generating and background rather than suggestive about therapeutic benefit.
While the ‘smoker’s paradox’ has been extensively studied in Western and East Asian populations, data regarding clopidogrel responsiveness in Middle Eastern patients remains scarce. Given the potential inter-ethnic variability in cytochrome P450 polymorphisms, it is crucial to investigate whether this phenomenon persists in this specific demographic.
Therefore, the objective of this study was to investigate the relationship between smoking and clopidogrel response in patients with CAD during PCI by means of smoking status as main exposure factor with multiple-variable test for major cardiovascular risk factors and haemoglobin level adjustment in addition to modulating them through a multi-variables approach. The present study was designed to explore this association without implying causality, with the aim of generating scientifically meaningful hypotheses, but by developing scientifically meaningful hypotheses and a more balanced methodological interpretation of the results that would give a more solid ground of the relationship.
This observational analytical study examined patients with confirmed CAD undergoing PCI at Annajaf Heart Surgery and Catheterization Center, Najaf, Iraq, between November 2018 and March 2019. All study patient received dual antiplatelet treatment as ordered by clinical guidelines for stable CAD patients undergoing PCI2 with aspirin and clopidogrel prior to PCI. Patients were excluded if they had:
• acute coronary syndrome
• thrombocytopenia
• significant hepatic or renal dysfunction
• recent blood transfusion
• active bleeding
• patients were receiving medications known to interfere with platelet function or clopidogrel metabolism and pharmacodynamic response.4
Demographic, clinical, and laboratory data was collected at baseline from medical records and direct patient interview. Smoking status was determined by self-report from patients and classified as current smoker or non-smoker according to definitions used in previous cardiovascular and pharmacodynamic studies.1
Patients who are on clopidogrel as maintenance treatment or subsequent a loading dose in accordance with PCI practice standards. Platelet reactivity was measured using the Multiplate® impedance aggregometry system, which is used to quantify the area under the aggregation curve (AUC) after adenosine diphosphate (ADP) stimulation, and is widely used in the evaluation of platelet activity on treatment in patients receiving clopidogrel.4
The blood samples from the patients were collected in hirudinized tubes and then analyzed.
(i) under standardized laboratory conditions;
(ii) as stated in a manufacturer’s directive8; and
(iii) according to previously published protocols.
All patients were categorized as being clopidogrel non-responders, AUC > the predefined assay threshold, and any AUC < the threshold was classified as clopidogrel responsiveness, which confirmed previous Multiplate-based pharmacodynamic studies.7
Baseline variables collected were age, sex, BMI, diabetes mellitus and hypertension. Hemoglobin levels were taken into account as a possible covariate to ensure that all associations considered with cardiovascular risk profile and platelet assay activity.
Smoking status was analyzed as the primary exposure variable and responsiveness of clopidogrel as the primary outcome. We then compared baseline features of smoker’s vs non-smokers using the independent Student’s t-test for continuous variables and the chi square test for categorical variables. The effect of smoking status on clopidogrel responsivity was explored using a multivariable logistic regression model. The multivariable logistic regression model included smoking, age, sex, BMI, diabetes mellitus, hypertension, and hemoglobin as covariates. Adjusted odds ratios (AOR) were reported with 95% confidence intervals (CI), and was considered statistically relevant when p-value was less than 0.05.
A total of 324 patients with CAD undergoing PCI were involved in the study, of whom 143 (44.1%) were current smokers and 181 (55.9%) were non-smokers. Baseline demographic, clinical, and laboratory characteristics stratified by smoking status are presented in Table 1. Smokers were slightly older than non-smokers; the distribution of sex, BMI, diabetes mellitus, and hypertension were broadly comparable between groups. Hemoglobin levels differed significantly between smokers and non-smokers, supporting the inclusion of this variable in the multivariable analytical model. The differences further supported, in Table 1, the need for analytical adjustment of the variable table for potential confounding factors.
The mean AUC values of smokers against non-smokers determined by Multiplate assay were similar between smokers and non-smokers.
However, more patients in the smoking group responded to clopidogrel more than non-smoking patients. This pattern at unadjusted level, though, indicated a probable association between smoking status and a greater propensity for clopidogrel responsiveness Table 2.
After accounting for age, sex, BMI, diabetes mellitus, hypertension, and hemoglobin, smoking status was independently related with clopidogrel responsiveness. Smokers were found to have a higher adjusted probability of being categorized as responders. Responses were positively related with hemoglobin level as well, implying a possible hematological contribution to variability in platelet reactivity behavior. In contrast, age, BMI, hypertension and diabetes were not significant predictors in the adjusted model. Inclusive, the multivariable results suggest that the link of smoking status with clopidogrel responsiveness persists beyond crude baseline differences, and thus, the results should be interpreted with caution and in the framework of an observational analytical design. The results of the multivariable logistic regression analysis are presented in Table 3.
This study investigated the relationship between smoking status and clopidogrel responsiveness in patients with CAD undergoing PCI. The main finding of this study was that smokers were more likely to be classified as clopidogrel responders than nonsmokers; this relationship, when accounting other significant clinical covariates such as hemoglobin level, was nonetheless significant. These observations generally converge with previous pharmacodynamic and meta-analytic reports reporting lower on-treatment platelet reactivity and greater clopidogrel responsiveness in smokers—the so-called “smoking paradox”.5,7,8 Crucially, previous outcome-based studies suggest that this association should be interpreted as a pharmacodynamic relationship rather than evidence of clinical benefit and that it does not change prognosis in smokers.6
Our findings align with previous reports of the smoker’s paradox. However, this study is among the first to confirm these pharmacodynamic changes specifically within an Iraqi cohort, suggesting that the biochemical effect of smoking on clopidogrel metabolism transcends ethnic differences previously observed between Caucasian and Asian populations.
Although mean ADP-test AUC values did not differ significantly between smokers and non-smokers, responder classification is based on a prespecified threshold and therefore reflects the distribution of values around that cut-off rather than differences in group means alone. In the present study, sensitivity analyses using alternative cut-offs (45 U and 55 U) confirmed that the association between smoking status and clopidogrel responsiveness was robust and not driven solely by the choice of threshold. These findings are consistent with previous discussions in the literature regarding the limitations of dichotomizing continuous pharmacodynamic measures.14,15
A number of other mechanistic approaches have been suggested to explain this association. Clopidogrel, a prodrug, necessitates the sequential oxidative activation of CYP to produce its active thiol metabolite, which irreversibly inhibits the platelet P2Y12 receptor.10,16 Cigarette smoking is known to induce CYP1A2 activity amongst smokers and the metabolic activation and platelet inhibition that results from this process contributes to the differential responses in residual platelet reactivity.11,17,18 However, the interrelationship of smoking status and response of antiplatelet may differ across populations and genetic backgrounds, given that population level and inter-ethnic variability in platelet reactivity has also been reported.13,19 All these data together support a biochemical and pharmacokinetic interpretation instead of the causal or advantageous impact of smoking.20
In this study, the level of hemoglobin was linked with responsiveness to clopidogrel. This is consistent with reports in the literature indicating that various hematological parameters can affect platelet function measurements and mediate variations in the intensity of antiplatelet response.8 Though, the clinical significance of this association remains uncertain and needs to be examined into further scrutiny among larger cohorts, with future follow-up studies and an event-based outcome.
Importantly, these findings should not be interpreted as supporting smoking as a therapeutic modifier. Smoking is a significant preventable risk factor for cardiovascular morbidity and mortality and yet its adverse systemic effects have far surpassed any hypothesized pharmacodynamic associations in its pharmacodynamic basis based on an analytical assessment. Hence, the results of the current study need to be considered to be hypothesis-generating and interpreted in a cautious, clinically appropriate way.1,2,6
Several limitations of the present study should be acknowledged. First, smoking status was determined based on self-reported information and clinical documentation without biochemical verification (e.g., cotinine), which may have resulted in some degree of misclassification. Second, although the study did not include longitudinal follow-up or assessment of major adverse cardiovascular events, its primary objective was to investigate pharmacodynamic variability in clopidogrel response rather than clinical outcomes. Outcome-based studies have already shown that smoking-related enhancement of platelet inhibition does not translate into improved prognosis; therefore, the absence of outcome data in the present study does not diminish its mechanistic and pharmacological relevance. Third, variability in clopidogrel dosing and concomitant therapies may have introduced residual confounding. Finally, unmeasured factors, including genetic polymorphisms affecting clopidogrel metabolism and inflammatory status, could have influenced platelet reactivity. Consequently, the findings should be interpreted as hypothesis-generating and warrant confirmation in larger, prospective, outcome-based investigations.
Smoking status was independently associated with clopidogrel responsiveness after adjustment for major cardiovascular risk factors and hemoglobin level. These findings suggest that pharmacodynamic variability in platelet response to clopidogrel may be influenced by clinical and hematological factors.
Nevertheless, the findings denote an observational association, should not be interpreted as evidence of clinical benefit or therapeutic advantage related to smoking. For future planning studies, prospective besides mechanistic research are reasonable to clarify the causal pathways and to place these remarks within a wider clinical and public health setting.
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.”
The authors thank members of the Pharmacology and Therapeutic Department of University of Kufa.
The author(s) declared that no grants were involved in supporting this work.
Published: 27 Jul 2026, 12:370
Published: 23 Aug 2023, 12:370
Published: 05 Apr 2023, 12:370
© 2026 Aldallal AAR et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Current Reviewer Status: ?
Key to Reviewer Statuses VIEW HIDE
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 2
VERSION 2
PUBLISHED 23 Aug 2023
Revised
Reviewer Report 27 Nov 2023
Anastasios Apostolos, Department of Cardiology, Faculty of Medicine, University of Patras, University Hospital of Patras & First Department of Cardiology, Medical School, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
Not Approved
VIEWS 0
Is the work clearly and accurately presented and does it cite the current literature?
No
Is the study design appropriate and is the work technically sound?
No
Are sufficient details of methods and analysis provided to allow replication by others?
No
If applicable, is the statistical analysis and its interpretation appropriate?
Partly
Are all the source data underlying the results available to ensure full reproducibility?
Partly
Are the conclusions drawn adequately supported by the results?
No
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Interventional cardiolgoy
CloseReviewer Report 19 Sep 2023
Bogumił Ramotowski, Department of Cardiology, Centre of Postgraduate Medical Education, Warsaw, Poland
Approved
VIEWS 0
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Clopidogrel responsiveness in smokers
CloseVersion 1
VERSION 1
PUBLISHED 05 Apr 2023
Reviewer Report 24 Jul 2023
Bogumił Ramotowski, Department of Cardiology, Centre of Postgraduate Medical Education, Warsaw, Poland
Approved with Reservations
VIEWS 0
Is the work clearly and accurately presented and does it cite the current literature?
Partly
Is the study design appropriate and is the work technically sound?
No
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?
Partly
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?
Partly
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Clopidogrel responsiveness in smokers
Close