Effect of Smoking Cessation on the Pharmacokinetics and Pharmacodynamics of Clopidogrel after PCI: The Smoking Cessation Paradox Study

Abstract

Background Cigarette smoking is associated with enhanced clopidogrel effect and platelet inhibition. However, the effect of smoking cessation on clopidogrel pharmacokinetics (PK) and pharmacodynamics (PD) is unknown. We aimed to determine the effect of smoking cessation, confirmed by cotinine measurement, on clopidogrel PK and PD after percutaneous coronary intervention (PCI). Methods and Results Following successful PCI, patients treated with 75 mg/day clopidogrel who reported smoking ≥10 cigarettes/day with NicAlert urine cotinine level 6 were enrolled. Clopidogrel and its metabolite concentrations, VerifyNow P2Y12 reaction units (PRUs), and NicAlert levels were measured in the study group before and at 30 days after smoking cessation and in a control group. CYP1A2 and CYP2C19 genotypes were determined. At 30-day visit (n = 87), 45 patients continued smoking, whereas 42 patients stopped smoking. Baseline PRUs were similar between groups. At 30 days, the smoking cessation group had higher PRUs (150.5 ± 68.6 vs. 118.4 ± 65.9, p = 0.03), greater absolute PRU change (27.7 ± 39.8 vs. −12.9 ± 55.4, p = 0.0002), greater change of PRUs adjusted for baseline platelet reactivity (38.6 ± 10.0, p < 0.01), greater risk of high platelet reactivity (HPR) (odds ratio: 10.14 [1.52–67.5], p = 0.017), and a trend towards decreased H3 clopidogrel metabolite levels (−3.41 ng/mL [−11.00 to 0.54 ng/mL], p = 0.072). CYP2C19 LoF carriers who stopped smoking had the highest PRUs, whereas those with the wild type who continued smoking had the lowest PRUs (p < 0.008). Conclusion Smoking cessation in clopidogrel-treated patients after PCI is associated with increased platelet reactivity and greater risk of HPR. Alternative P2Y12 inhibitors may be considered in selected patients who stop smoking after PCI.

Tobacco use disorder and cardiovascular health

“…Smoking has strong prothrombotic effects which may reduce the efficacy of anti-thrombotic drugs, requiring more sustained use of anticoagulant drugs in patients after coronary revascularization or with severe CHD in general. Conversely, smoking enhances the conversion of clopidogrel to its active metabolite, enhancing the anti-platelet effect of this drug [19,61]. Because of the prothrombotic effects of smoking, the risk of myocardial infarction and stroke is higher in women taking estrogen-containing oral contraceptives.…”

Correlation Between Smoking Paradox and Heart Rhythm Outcomes in Patients With Coronary Artery Disease Receiving Percutaneous Coronary Intervention

“…The role of smoking on clopidogrel activity remains controversial. Some studies have concluded current smokers may have a higher clopidogrel metabolite exposure and pharmacodynamic effects than non-smokers (30), while cessation of smoking in clopidogrel-treated patients after PCI increased both VerifyNow P2Y12 platelet reaction units (PRUs) and platelet activity (31,32). Another study postulated the lower PRUs were due to higher hemoglobin levels in current smokers than non-smokers, and there was no difference of PRUs after adjustment for hemoglobin (33).…”

Association Between Smoking and the Antiplatelet Effect of Clopidogrel

“…В исследовании B. Ramotowski et al прекращение курения, зафиксированное у пациентов европеоидной расы с помощью определения уровня котинина в моче системой Accutest NicAlert, было ассоциировано с повышением реактивности тромбоцитов на фоне лечения клопидогрелом [40]. В этом и других исследованиях функция тромбоцитов оценивалась с помощью основанной на принципе оптической трансмиссии тест-системы VerifyNow P2Y12, в которой в качестве активаторов агрегации используются аденозиндифосфат (АДФ) и простагландин Е1.…”

“…Также наблюдалась взаимосвязь между эффектом отказа от курения и носительством аллелей, приводящих к потере функции: носители мутаций, ассоциированных с потерей функции (CYP2C19*2), бросившие курить, имели более высокий уровень реактивности тромбоцитов на фоне приёма клопидогрела, в то время как носители аллели дикого типа, продолжавшие курить, являлись подгруппой с наиболее низкой остаточной активностью тромбоцитов [40]. K. W. Park et al оценили функцию тромбоцитов у 810 пациентов из Кореи, получавших клопидогрел.…”

“…По данным B. Ramotowski et al, отказ от курения пациентов, принимающих клопидогрел после перенёсенного ЧКВ, ассоциирован с повышением остаточной реактивности тромбоцитов, в связи с чем у отдельных пациентов, получающих клопидогрел и бросивших курить после ЧКВ, может быть рассмотрено применение альтернативных антагонистов P2Y12 [40].…”