目的:本研究的目的是评估吸烟对氯吡格雷和普拉格雷治疗的药代动力学和药效学(PD)的影响。
背景:主要随机试验数据表明,与吸烟者相比,非吸烟者从氯吡格雷治疗中获益较少或没有获益(即,“吸烟者悖论”)。
方法:悖论是一种前瞻性,随机化,双盲,双假人,安慰剂对照,客观评估的非吸烟者(n=56)和稳定性冠心病患者接受阿司匹林治疗的吸烟者(n=54)的交叉研究.患者随机接受氯吡格雷(每天75毫克)或普拉格雷(每天10毫克)10天,并在14天的冲洗后交叉。通过使用VerifyNowP2Y12和血管扩张剂刺激的磷蛋白磷酸化测定来评估PD。氯吡格雷和普拉格雷代谢物水平,细胞色素P4501A2活性,CYP2C19基因型,并确定了安全参数。
结果:在氯吡格雷治疗期间,器械报告的血小板聚集抑制(IPA)在非吸烟者中的趋势低于吸烟者(最小二乘平均治疗差异±SE:7.7±4.1%;p=0.062).在接受氯吡格雷治疗的吸烟者中,器械报告的IPA显著低于接受普拉格雷治疗的吸烟者(最小二乘平均治疗差异:31.8±3.4%;p<0.0001)。在氯吡格雷治疗期间,与吸烟者相比,非吸烟者计算的IPA较低,P2Y12反应单位和血管扩张剂刺激的磷蛋白磷酸化和血小板反应性指数较高(分别为p=0.043,p=0.005和p=0.042).无论吸烟状况如何,普拉格雷治疗后都存在更大的抗血小板作用(所有比较p<0.001)。
结论:PARADOX显示相对于吸烟者,非吸烟者的氯吡格雷活性代谢物暴露和氯吡格雷的PD效应较低。与氯吡格雷相比,无论吸烟状况如何,普拉格雷与更大的活性代谢物暴露和PD效应相关。氯吡格雷治疗的非吸烟者抗血小板反应较差可能为吸烟者的悖论提供了解释。吸烟状况对服用阿司匹林并患有稳定型冠状动脉疾病的受试者的普拉格雷和氯吡格雷治疗的影响;NCT01260584。
OBJECTIVE: The goal of this
study was to evaluate the effect of smoking on the pharmacokinetics and pharmacodynamics (PD) of clopidogrel and prasugrel therapy.
BACKGROUND: Major randomized
trial data demonstrated that nonsmokers experience less or no benefit from clopidogrel treatment compared with smokers (i.e., the \"smokers\' paradox\").
METHODS: PARADOX was a prospective, randomized, double-blind, double-dummy, placebo-controlled, crossover
study of objectively assessed nonsmokers (n = 56) and smokers (n = 54) with stable coronary artery disease receiving aspirin therapy. Patients were randomized to receive clopidogrel (75 mg daily) or prasugrel (10 mg daily) for 10 days and crossed over after a 14-day washout. PD was assessed by using VerifyNow P2Y12 and vasodilator-stimulated phosphoprotein phosphorylation assays. Clopidogrel and prasugrel metabolite levels,
cytochrome P450 1A2 activity, CYP2C19 genotype, and safety parameters were determined.
RESULTS: During clopidogrel therapy, device-reported inhibition of platelet aggregation (IPA) trended lower in nonsmokers than smokers (least squares mean treatment difference ± SE: 7.7 ± 4.1%; p = 0.062). Device-reported IPA was significantly lower in clopidogrel-treated smokers than prasugrel-treated smokers (least squares mean treatment difference: 31.8 ± 3.4%; p < 0.0001). During clopidogrel therapy, calculated IPA was lower and P2Y12 reaction units and vasodilator-stimulated phosphoprotein phosphorylation and platelet reactivity index were higher in nonsmokers than in smokers (p = 0.043, p = 0.005, and p = 0.042, respectively). Greater antiplatelet effects were present after prasugrel treatment regardless of smoking status (p < 0.001 for all comparisons).
CONCLUSIONS: PARADOX demonstrated lower clopidogrel active metabolite exposure and PD effects of clopidogrel in nonsmokers relative to smokers. Prasugrel was associated with greater active metabolite exposure and PD effects than clopidogrel regardless of smoking status. The poorer antiplatelet response in clopidogrel-treated nonsmokers may provide an explanation for the smokers\' paradox. (The Influence of Smoking Status on Prasugrel and Clopidogrel Treated Subjects Taking Aspirin and Having Stable Coronary Artery Disease; NCT01260584).