Available online 10 April 2024, 155290

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The intricate relationship between smoking and the effects of the antiplatelet drug clopidogrel has been termed the “smoker’s paradox”. This paradox details the enhanced efficacy of clopidogrel in smokers compared to non-smokers. This review begins with an exploration of the proposed mechanisms of the smoker's paradox, particularly drawing attention to the induction of cytochrome P450 (CYP) isoenzymes via tobacco smoke, specifically the enzymes CYP1A2 and CYP2C19. Moreover, an investigation of the effects of genetic variability on the smoker’s paradox was undertaken from both clinical and molecular perspectives, delving into the effects of ethnicity and genetic polymorphisms. The intriguing role of CYP1A2 genotypes and the response to clopidogrel in smoking and non-smoking populations was examined conferring insight into the individuality rather than universality of the smoker’s paradox. CYP1A2 induction is hypothesised to elucidate the potency of smoking in exerting a counteracting effect in those taking clopidogrel who possess CYP2C19 loss of function polymorphisms. Furthermore, we assess the comparative efficacies of clopidogrel and other antiplatelet agents, namely prasugrel and ticagrelor. Studies indicated that prasugrel and ticagrelor provided a more consistent effect and further reduced platelet reactivity compared to clopidogrel within both smoking and non-smoking populations. Personalised dosing was another focus of the review considering patient comorbidities, genetic makeup, and smoking status with the objective of improving the antiplatelet response of those taking clopidogrel. In summation, this review provides insight into multiple areas of research concerning clopidogrel and the smoker’s paradox taking into account proposed mechanisms, genetics, other antiplatelet agents, and personalised dosing.

AbbreviationsACS

Acute Coronary Syndrome

CAD

Coronary Artery Disease

CHARISMA

Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance.

CKD

Chronic Kidney Disease

CURRENT-OASIS

Clopidogrel and Aspirin Optimal Dose

Usage to Reduce Recurrent Events−Seventh

Organization to Assess Strategies in, Ischemic Syndromes

C-IPA

Calculated Inhibition of Platelet Aggregation

CVD

Cardiovascular Disease

DR-IPA

Device Reported Inhibition of Platelet Aggregation

HOPR

High on-treatment Platelet Reactivity

MACCE

Major Adverse Cardiac and Cerebrovascular Events

OPR

On-Treatment Platelet reactivity

PAHs

Polycyclic Aromatic Hydrocarbons

PFT

Platelet Function Testing

PRI

Platelet Reactivity Index

PRINCE

Platelet Reactivity in Acute Non-disabling Cerebrovascular Events

TRILOGY ACS

Targeted Platelet Inhibition to Clarify the

Optimal Strategy to Medically Manage

Acute Coronary Syndromes

T2-DM

Type 2 diabetes mellitus

%INH

Percentage of Inhibition

Keywords

Smoker’s Paradox

Clopidogrel

P2Y12 Inhibitors

Acute Coronary Syndrome

Antiplatelet

Smoking

© 2024 The Author(s). Published by Elsevier GmbH.