Leoncini Mario, Toso Anna, Maioli Mauro, Bellandi Francesco
G Ital Cardiol (Rome). 2013 Sep;14(9):574-84. doi: 10.1714/1311.14483.
Antiplatelet therapy with clopidogrel should be administered to patients with acute coronary syndromes and those submitted to percutaneous coronary intervention (PCI) (secondary prevention). Clopidogrel is a pro-drug which requires hepatic cytochrome P450 (CYP) metabolic activation to produce the active metabolite that inhibits platelet aggregation. CYP2C19 and CYP3A4/5 are the principal contributors in the two-step hepatic oxidation of clopidgrel. However, the response to clopidogrel is not uniform; it varies from patients platelet reactivity on standard-dose clopidogrel are at increased risk of recurrence of adverse cardiovascular events. Also drug-drug interactions that influence the function of CYP isoenzymes may affect the response to clopidogrel. Lipophilic statins, such as atorvastatin, are predominantly metabolized by CYP3A4 and may interfere with CYP activation of clopidogrel, contrary to what happens with hydrophilic statins, such as rosuvastin or pravastatin. Recently, it has been shown that in patients who presented post-PCI high on-treatment platelet reactivity on standard-dose clopidogrel during chronic treatment with clopidogrel and low-dose atorvastatin (10 mg), switching to a non-CYP3A4-metabolized statin, such as rosuvastatin or pravastatin, resulted in a significant decrease in platelet reactivity. The clinical benefit of statins is attributed to mulitple mechanisms which go beyond their lipid-lowering effects and include also antithrombotic properties. In particular, atorvastatin inhibits adenosine diphospate and thrombin-induced platelet aggregation. Moreover, pharmacodynamic studies appear to show some synergy between clopidogrel and atorvastatin: the enhancement of clopidogrel effects due to atorvastatin seems to be dose-related and independent of LDL cholesterol reduction. A recent study shows that the addition of high-dose atorvastatin (80mg) for 30 days significantly improves the pharmacodynamic effects of double-dose clopidogrel, reducing platelet reactivity and improving optimal clopidogrel response in statin naïve patients with high-on treatment platelet reactivity on standard-dose clopidogrel. These pharmacodynamic studies suggest that switching to a no CYP3A4-metabolized statin in patients with high on-treatment platelet reactivity on standard-dose clopidogre on chronic treatment with low-dose atorvastatin or administration of high-dose atorvastatin maybe two alternative strategies to avoid possible negative drug-drug interactions and to improve individual patient response to clopidogrel.
对于急性冠状动脉综合征患者以及接受经皮冠状动脉介入治疗（PCI）的患者（二级预防），应给予氯吡格雷进行抗血小板治疗。氯吡格雷是一种前体药物，需要肝脏细胞色素P450（CYP）代谢激活才能产生抑制血小板聚集的活性代谢产物。CYP2C19和CYP3A4/5是氯吡格雷两步肝脏氧化过程中的主要参与者。然而，对氯吡格雷的反应并不一致；患者对标准剂量氯吡格雷的血小板反应性各不相同，血小板反应性高的患者发生不良心血管事件复发的风险增加。此外，影响CYP同工酶功能的药物相互作用可能会影响对氯吡格雷的反应。亲脂性他汀类药物，如阿托伐他汀，主要通过CYP3A4代谢，可能会干扰氯吡格雷的CYP激活，这与亲水性他汀类药物，如瑞舒伐他汀或普伐他汀的情况相反。最近的研究表明，在接受氯吡格雷和低剂量阿托伐他汀（10毫克）长期治疗期间，PCI术后使用标准剂量氯吡格雷时出现高治疗期血小板反应性的患者，改用非CYP3A4代谢的他汀类药物，如瑞舒伐他汀或普伐他汀，可使血小板反应性显著降低。他汀类药物的临床益处归因于多种机制，这些机制超出了其降脂作用，还包括抗血栓形成特性。特别是，阿托伐他汀可抑制二磷酸腺苷和凝血酶诱导的血小板聚集。此外，药效学研究似乎显示氯吡格雷和阿托伐他汀之间存在一定协同作用：阿托伐他汀增强氯吡格雷的作用似乎与剂量相关，且与低密度脂蛋白胆固醇降低无关。最近的一项研究表明，在标准剂量氯吡格雷治疗期间出现高治疗期血小板反应性的初治他汀类药物患者中，加用高剂量阿托伐他汀（80毫克）30天可显著改善双倍剂量氯吡格雷的药效学作用，降低血小板反应性并改善氯吡格雷的最佳反应。这些药效学研究表明，对于长期接受低剂量阿托伐他汀治疗且使用标准剂量氯吡格雷时出现高治疗期血小板反应性的患者，改用非CYP3A4代谢的他汀类药物或使用高剂量阿托伐他汀可能是两种避免可能的负面药物相互作用并改善个体患者对氯吡格雷反应的替代策略。
