Aggarwal Sachin K, Jiang Lan, Liu Ge, Grabowska Monika E, Ong Henry H, Wilke Russell A, Feng QiPing, Wei Wei-Qi
Vanderbilt University School of Medicine, Nashville, TN, USA.
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
JACC Adv. 2024 Apr;3(4). doi: 10.1016/j.jacadv.2024.100894. Epub 2024 Mar 7.
Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to statins varies among patients and can be modeled using three distinct pharmacological properties: (1) E (baseline LDL-C), (2) ED (potency: median dose achieving 50% reduction in LDL-C); and (3) E (efficacy: maximum LDL-C reduction). However, individualized dose-response and its association with ASCVD events remains unknown.
We analyze the relationship between ED and E with real-world cardiovascular disease outcomes.
We leveraged de-identified electronic health record data to identify individuals exposed to multiple doses of the three most commonly prescribed statins (atorvastatin, simvastatin, or rosuvastatin) within the context of their longitudinal healthcare. We derived ED and E to quantify the relationship with a composite outcome of ASCVD events and all-cause mortality.
We estimated ED and E for 3,033 unique individuals (atorvastatin: 1,632, simvastatin: 1,089, and rosuvastatin: 312) using a nonlinear, mixed effects dose-response model. Time-to-event analyses revealed that ED and E are independently associated with the primary endpoint. Hazard ratios were 0.85 (p < 0.01), 0.83 (p < 0.01), and 0.87 (p = 0.10) for ED and 1.13 (p < 0.001), 1.06 (p < 0.001), and 1.15 (p = 0.009) for E in the atorvastatin, simvastatin, and rosuvastatin cohorts, respectively.
The class-wide association of ED and E with clinical outcomes indicates that these measures influence the risk for ASCVD events in patients on statins.
他汀类药物可降低低密度脂蛋白胆固醇（LDL-C），并在预防动脉粥样硬化性心血管疾病（ASCVD）方面有效。他汀类药物的剂量反应在患者之间存在差异，并且可以使用三种不同的药理学特性进行建模：（1）E（基线LDL-C），（2）ED（效力：使LDL-C降低50%的中位剂量）；以及（3）E（疗效：LDL-C的最大降低幅度）。然而，个体化的剂量反应及其与ASCVD事件的关联仍然未知。
我们分析ED和E与现实世界心血管疾病结局之间的关系。
我们利用去识别化的电子健康记录数据，在个体的纵向医疗保健背景下，识别出接受过三种最常用他汀类药物（阿托伐他汀、辛伐他汀或瑞舒伐他汀）多剂量治疗的个体。我们得出ED和E，以量化与ASCVD事件和全因死亡率的复合结局之间的关系。
我们使用非线性混合效应剂量反应模型，对3033名个体（阿托伐他汀：1632名，辛伐他汀：1089名，瑞舒伐他汀：312名）估计了ED和E。事件发生时间分析显示，ED和E与主要终点独立相关。在阿托伐他汀、辛伐他汀和瑞舒伐他汀队列中，ED的风险比分别为0.85（p<0.01）、0.83（p<0.01）和0.87（p = 0.10），E的风险比分别为1.13（p<0.001）、1.06（p<0.001）和1.15（p = 0.009）。
ED和E与临床结局的全类关联表明，这些指标会影响服用他汀类药物患者发生ASCVD事件的风险。
