Effects of cigarette smoking on clopidogrel [Neurosurgery Wiki]

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====== Effects of cigarette smoking on clopidogrel ======

Smoking induces cytochrome P450 1A2 ([[CYP1A2]]), a hepatic enzyme involved in the metabolism of [[clopidogrel]]. Clopidogrel shows better inhibition of [[platelet]] aggregation in [[smoker]]s than nonsmokers
((Bliden KP, Dichiara J, Lawal L, Singla A, Antonino MJ, Baker BA, Bailey WL,
Tantry US, Gurbel PA. The association of cigarette smoking with enhanced platelet
inhibition by clopidogrel. J Am Coll Cardiol. 2008 Aug 12;52(7):531-3. doi:
10.1016/j.jacc.2008.04.045. PubMed PMID: 18687246.
))
and smokers are less likely to be hyporesponders than nonsmokers
((Matetzky S, Shenkman B, Guetta V, Shechter M, Beinart R, Goldenberg I, Novikov
I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with
increased risk of recurrent atherothrombotic events in patients with acute
myocardial infarction. Circulation. 2004 Jun 29;109(25):3171-5. Epub 2004 Jun 7. 
Erratum in: Circulation. 2011 Oct 25;124(17):e459. Bienart, Roy [corrected to
Beinart, Roy]. PubMed PMID: 15184279.
)).

Cho et al. investigated the association between smoking status and post-clopidogrel platelet reactivity in patients with acute myocardial infarction. Differences in the clinical situation and timing of the platelet test could explain the differences with the Bliden study
((Cho JH, Jeong YH, Ahn YJ, Kang MK, Koh JS, Kim IS, Park Y, Hwang SJ, Kwak CH, 
Hwang JY. The impact of smoking on post-clopidogrel platelet reactivity in
patients with acute myocardial infarction. Korean Circ J. 2010 Mar;40(3):119-24. 
doi: 10.4070/kcj.2010.40.3.119. Epub 2010 Mar 24. PubMed PMID: 20339496; PubMed
Central PMCID: PMC2844977.
)).

[[Cigarette smoking]] seems to positively modify the beneficial effect of [[clopidogrel]] on angiographic and [[clinical outcome]]s. A study of Desai et al., demonstrates that common clinical factors that influence the [[metabolism]] of [[clopidogrel]] might impact its clinical [[effectiveness]]
((Desai NR, Mega JL, Jiang S, Cannon CP, Sabatine MS. Interaction between
cigarette smoking and clinical benefit of clopidogrel. J Am Coll Cardiol. 2009
Apr 14;53(15):1273-8. doi: 10.1016/j.jacc.2008.12.044. PubMed PMID: 19358940;
PubMed Central PMCID: PMC2675920.
)).

However, whether it influences the association between [[CYP2C19]] genetic variants and clopidogrel efficacy is not clear.

2961 patients from the [[CHANCE trial]] were involved in a substudy and successfully genotyped for both two [[single nucleotide polymorphism]]s of [[CYP2C19]] (*2 and *3). [[Cox regression]] model was used to evaluate the interactions between CYP2C19 *2 and *3 carrier status and clopidogrel efficacy stratified by smoking status.

There were marginal significant interactions between CYP2C19 *2 and *3 [[allele]]s carrier status and antiplatelet treatment regimen for the risk of recurrent stroke and composite events (p = 0.054, p = 0.051, respectively) among smokers, but not in non-smokers. Among smokers, clopidogrel plus aspirin decreased the recurrence rate of stroke compared with aspirin alone in noncarriers (3.8% vs 11.8%, hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.15-0.65, p = 0.002), but not in carriers. Similar results were also found for the recurrence rate of composite events in smokers. No significant difference was found for hemorrhage events in all groups.

Among patients with minor [[stroke]] or [[TIA]], marginal significant interactions between CYP2C19 *2 and *3 alleles carrier status and clopidogrel efficacy were found in smokers, but not in non-smokers. Among smokers, clopidogrel plus aspirin might decrease the recurrence rate of stroke in noncarriers of *2 and *3 alleles of CYP2C19 compared with aspirin alone. However, more caution should be taken to interpret this findings for several limitations in the study
((Wang T, Pan Y, Lin J, Anand R, Wang D, Johnston SC, Meng X, Li H, Zhao X, Liu 
L, Wang Y, Wang Y; CHANCE investigators. Influence of smoking on CYP2C19 genetic 
variants and clopidogrel efficacy in patients with minor stroke or TIA. Eur J
Neurol. 2019 Apr 11. doi: 10.1111/ene.13962. [Epub ahead of print] PubMed PMID:
30974489.
)).