Does “smoker’s paradox” exist in clopidogrel-treated Turkish patients with acute coronary syndrome

Abstract

Previously conducted studies revealed that smoking enhanced the efficacy of clopidogrel by increasing formation of the active metabolite (AM) from the prodrug through induction of the cytochrome CYP1A2. The expression of cytochrome enzymes depends on genotype and no data exists in literature conducted in Turkish patients comparing the clopidogrel responsiveness between active smokers and non-active smokers treated with clopidogrel. In this study, our aim was to investigate the clopidogrel responsiveness in clopidogrel-treated Turkish acute coronary syndrome (ACS) patients according to their smoking status. We retrospectively enrolled 258 patients who were hospitalized due to ACS. Clinical variables of the patients, especially smoking status were recorded. Clopidogrel resistance was evaluated by using adenosine diphosphate (ADP) induced platelet aggregometry. Clopidogrel resistance was detected as a change in maximal aggregation ≤20% from baseline. A total of 139 patients were active smokers while 12 were former smokers. 107 patients did not have a history of smoking. Ten of the smokers were hyporesponsive to clopidogrel, whereas 36 of non-smokers were hyporesponsive to clopidogrel (p < 0.001). Receiver-operating characteristic curve analysis demonstrated that Au-min value >612.5 predicted the clopidogrel resistance with a sensitivity of 60% (OR: 100.65, %95 CI = 19.996-506.615 p < 0.001). Results of this study demonstrated that ADP responses were lower in smokers receiving clopidogrel and aspirin than in non-smokers receiving the same drug regimen. This finding indicates that smoking was related to an enhanced clopidogrel responsiveness in Turkish patients hospitalized due to ACS, suggesting that "smoker's paradox" probably exists in Turkish ACS patients.

Platelet-to-lymphocyte ratio but not neutrophil-to-lymphocyte ratio predicts high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndrome

“…Enhanced clopidogrel response in smokers, defined as the smokers’ paradox, is not universal but was observed only in cytochrome P450 CYP1A2 A-allele carriers which indicate a genotype-dependent impact of smoking on clopidogrel responsiveness. [ 26 ] In our study, the existence of smokers’ paradox was also confirmed. Hypertension and diabetes were also considered to be other risk factors for HPR in recently conducted studies; however, in our study, we did not observe such kind of relationships.…”

Influence of smoking on the antiplatelet effect of clopidogrel differs according to clopidogrel dose: Insights from the GRAVITAS trial

“…An analysis of the CROSS‐VERIFY (Measuring Clopidogrel Resistance to Assure Safety After PCI using VerifyNow) cohort not only found that smokers had significantly lower OTR that non‐smokers at baseline, but also that the level of OTR and frequency of high OTR in patients who quit smoking ( n = 77) rose significantly compared to persistent smokers at 1 month ( n = 105) . A slightly larger study ( n = 139 smokers) recently reported a lower rate of high OTR on clopidogrel among smokers compared to non‐smokers, and a separate study of patients with acute coronary syndrome found active smoking to be independently associated with lower risk of high OTR (OR 0.51, P = 0.02) . Further, our results are consistent with the PARADOX (The Influence of Smoking Status on the Pharmacokinetics and Pharmacodynamics of Clopidogrel and Prasugrel) study, which randomly assigned smokers ( n = 54) and nonsmokers ( n = 56) with stable coronary artery disease to clopidogrel 75 mg or prasugrel 10 mg for 10‐days, followed by a 14‐day washout and treatment cross‐over .…”

“…Cigarette smoking enhances the generation of the active metabolite of clopidogrel by inducing CYP1A2 activity . Several studies suggest that there may be a “smokers’ paradox,” as although smoking has many negative effects on cardiovascular health, smokers have greater platelet inhibition and lower rates of high OTR when compared to non‐smokers on clopidogrel . Consistent with this observation, the CLARITY—TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy—Thrombolysis in Myocardial Infarction 28), CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance), and CURRENT‐OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Symptoms) trials all suggested that the clinical benefit of clopidogrel might be greater in smokers compared to non‐smokers .…”

The role of CYP2C19 genotyping to guide antiplatelet therapy following ischemic stroke or transient ischemic attack

“…There is evidence to suggest that cigarette smoking is associated with improved responsiveness to clopidogrel, resulting in decreased clopidogrel on-treatment platelet reactivity. This is known as the ‘smokers paradox,’ the concept that active smokers treated with clopidogrel have more major adverse cardiovascular event (MACE) reduction compared with non-smokers treated with clopidogrel [ 84 ]. There is conjecture regarding the mechanism which underpins this phenomena, but one hypothesis is that smoking can induce enzymes of the P450 cytochrome system meaning that smokers are exposed higher levels of clopidogrel’s active metabolite, relative to non-smokers [ 85 , 86 , 87 , 88 ].…”