Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Korea.
Clin Pharmacol Ther. 2019 Jul;106(1):182-194. doi: 10.1002/cpt.1361. Epub 2019 Feb 25.
Simultaneous competition for cytochrome P450 (CYP) 2C19 and CYP3A4 might diminish clopidogrel's antiplatelet effect by impacting its metabolic activation. This pharmacoepidemiologic study investigated whether proton pump inhibitors (PPIs) and CYP3A4-metabolized statins individually and jointly increase thrombotic events by attenuating clopidogrel's effectiveness. From Korean nationwide claims data (2007-2015), we selected 59,233 patients who initiated clopidogrel and statins after coronary stenting and compared thrombotic risks by PPI or CYP3A4-metabolized statin use or both. PPIs were associated with increased thrombotic risks (hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45), unlike CYP3A4-metabolized statins (HR 1.03, 95% CI 0.98-1.07). PPIs with high CYP2C19-inhibitory potential were more relevant than those with low potential (HR 1.28, 95% CI 1.02-1.61). Joint effects of PPIs and CYP3A4-metabolized statins were nonsignificant (relative excess risk due to interaction -0.14, 95% CI -0.34 to 0.07). Concurrent PPIs were associated with increased thrombotic risks in patients receiving clopidogrel and statins; CYP3A4-metabolized statins did not exacerbate PPI-associated risks.
同时竞争细胞色素 P450（CYP）2C19 和 CYP3A4 可能会通过影响其代谢激活来降低氯吡格雷的抗血小板作用。这项药物流行病学研究调查了质子泵抑制剂（PPIs）和 CYP3A4 代谢的他汀类药物是否单独和联合通过减弱氯吡格雷的有效性来增加血栓事件。从韩国全国索赔数据（2007-2015 年）中，我们选择了 59233 名在冠状动脉支架置入术后开始使用氯吡格雷和他汀类药物的患者，并通过使用 PPI 或 CYP3A4 代谢的他汀类药物或两者来比较血栓形成风险。与 CYP3A4 代谢的他汀类药物（HR 1.03，95%CI 0.98-1.07）不同，PPIs 与增加的血栓形成风险相关（HR 1.27，95%CI 1.12-1.45）。与 CYP2C19 抑制潜力低的 PPI 相比，具有高 CYP2C19 抑制潜力的 PPI 更相关（HR 1.28，95%CI 1.02-1.61）。PPIs 和 CYP3A4 代谢的他汀类药物的联合作用不显著（交互归因的相对超额风险-0.14，95%CI-0.34 至 0.07）。同时使用 PPI 与接受氯吡格雷和他汀类药物的患者血栓形成风险增加相关；CYP3A4 代谢的他汀类药物不会加剧 PPI 相关风险。
