Statin Neuroprotection & Cognitive Dysfunction after Carotid Endarterectomy: Safety, Feasibility, & Outcomes.

他汀类药物神经保护

• 批准号: 9176594
• 负责人: EDWARD SANDER CONNOLLY
• 金额: $ 117.29万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176594
• 关键词: Accounting; Address; Adverse effects; Angioplasty; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Blinded; Brain; Brain Injuries; Carotid Arteries; Carotid Endarterectomy; Carotid Stenosis; Cause of Death; Cerebrum; Cessation of life; Clinical; Cognition; Data; Development; Diabetes Mellitus; Dose; Encapsulated; Enrollment; Exhibits; Funding; Genetic Polymorphism; Genotype; Grant; Human; Impaired cognition; Incidence; Inflammation; Inflammatory; Injury; Intercellular adhesion molecule 1; Internal Carotid Artery Stenosis; Intervention; Ischemia; Ischemic Stroke; Lipids; Living Wills; Lovastatin; Measures; Modeling; Neurocognitive; North America; Operative Surgical Procedures; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Pravastatin; Procedures; Randomized; Randomized Controlled Trials; Regimen; Risk; Risk Factors; Safety; Serum; Simvastatin; Stenosis; Stroke; Supplementation; Surface Antigens; Telephone; Testing; Thinking; Time; Tissues; United States National Institutes of Health; arm; atorvastatin; base; cerebral ischemic injury; cognitive change; cohort; cytokine; disability; dosage; experience; high risk; inflammatory marker; mortality; neurocognitive test; neuroprotection; post-operative cognitive dysfunction; prospective; randomized trial; response; rosuvastatin

For the past 15 years, we have studied cognitive changes in patients treated for carotid artery stenosis by carotid endarterectomy (CEA) or carotid artery angioplasty and stenting (CAS). Using neurocognitive tests, we have defined post-operative cognitive dysfunction (CD), a subtle measure of cerebral injury. Post-operative cognitive dysfunction is part of a continuum of injury to the brain. Early cognitive dysfunction (eCD) is observed in ~ 25% of patients within 1 day of CEA, and less so 30 days after CEA (delayed CD [dCD]). Over the last 10 years of our NIH grant (RO1 AG17604), we have demonstrated that 1. Asymptomatic patients taking statinspre-operatively exhibit significantly less eCD than those not taking statins, 2. Simvastatin is associated with significantly less eCD than atorvastatin, 3. Statins are also neuroprotective against eCD in CAS patients, 4.Patients with eCD and not taking statins have significantly higher risk of mortality than those with eCD taking statins, 5. Pro-inflammatory polymorphisms and marker concentrations are significantly associated with increased eCD, and 6. Statins are associated with lower levels of pro-inflammatory markers. Based on these findings, we hypothesize that in asymptomatic patients undergoing CEA, 1. Pre-operative statin use is neuroprotective against eCD and lowers the risk of early mortality, 2. Statin type and dose may be important in achieving optimal neuroprotection, and 3. The anti-inflammatory effects of statins may partially account for the observed neuroprotection. To address these hypotheses, we will prospectively evaluate 1000 asymptomatic patients with a neurocognitive battery for eCD and dCD before and after CEA in a multi-center randomized trial. Lipid profiles and markers of systemic inflammation will be obtained before and after statin therapy. Patients will be randomized into one of three arms for 2 weeks pre-operatively and 4 weeks-post operatively depending on their statin status upon enrollment. Arms: 1. Patients on optimal daily doses of either simvastatin (40mg), atorvastatin (80mg) or rosuvastatin (20mg) will be tested and observed, 2. Patients on one of the three statins at less than optimal dosage (simvastatin <40mg, atorvastatin <80mg or rosuvastatin <20mg) will be randomized to receive an optimal dose or remain at their suboptimal dosage using re-encapsulated blinded medication, and 3. Patients who are not already taking statins, will be randomized to a daily dose ofreencapsulated blinded atorvastatin 10mg (suboptimal) or atorvastatin 80mg (optimal). Overall, we expect that high-dose simvastatin, atorvastatin and rosuvastatin will be neuroprotectiveagainst eCD and dCD. We think that statin neuroprotection occurs because of anti-inflammatory mechanisms and will be reflected in reduced levels of systemic inflammatory markers. The findings of this prospective randomized trial will provide important data for clinicians attempting to make this common procedure safer, and will elucidate whether statins are neuroprotective in human ischemic cerebral injury. Our results may guide the development of these agents for other indications.

在过去的 15 年里，我们研究了接受颈动脉治疗的患者的认知变化 通过颈动脉内膜切除术 (CEA) 或颈动脉血管成形术和支架置入术治疗动脉狭窄 （CAS）。通过神经认知测试，我们定义了术后认知功能障碍（CD）， 脑损伤的微妙测量。术后认知功能障碍是一系列疾病的一部分 大脑受伤。约 25% 的患者在 1 年内观察到早期认知功能障碍 (eCD) CEA 当天，以及 CEA 后 30 天（延迟 CD [dCD]）。在我们过去的 10 年里 NIH 拨款（RO1 AG17604），我们已经证明 1. 无症状患者服用 术前服用他汀类药物的患者的 eCD 明显低于未服用他汀类药物的患者，2. 辛伐他汀 与阿托伐他汀相比，eCD 显着减少，3. 他汀类药物还具有神经保护作用 对抗 CAS 患者的 eCD，4.患有 eCD 且未服用他汀类药物的患者有显着的 与服用他汀类药物的 eCD 患者相比，死亡风险更高，5. 促炎多态性 和标志物浓度与 eCD 增加显着相关，并且 6. 他汀类药物是 与较低水平的促炎标记物相关。基于这些发现，我们 假设在接受 CEA 的无症状患者中， 1. 术前使用他汀类药物 对 eCD 具有神经保护作用并降低早期死亡风险，2. 他汀类药物类型和剂量可能 对于实现最佳神经保护很重要，并且 3. 的抗炎作用 他汀类药物可能部分解释了观察到的神经保护作用。为了解决这些假设， 我们将前瞻性地评估 1000 名无症状患者的神经认知能力 一项多中心随机试验中 CEA 前后的 eCD 和 dCD。脂质谱和 在他汀类药物治疗之前和之后将获得全身炎症标志物。患者会 术前 2 周和术后 4 周被随机分入三组之一 取决于他们入组时的他汀类药物状态。手臂： 1. 接受最佳每日剂量的患者 将测试辛伐他汀 (40mg)、阿托伐他汀 (80mg) 或瑞舒伐他汀 (20mg) 观察到，2. 使用三种他汀类药物之一的患者，剂量低于最佳剂量（辛伐他汀 <40mg，阿托伐他汀 <80mg 或瑞舒伐他汀 <20mg）将被随机分配以接受最佳治疗 使用重新封装的盲法药物剂量或保持次优剂量，以及 3. 尚未服用他汀类药物的患者将被随机分配至每日剂量的重新封装的他汀类药物 盲法阿托伐他汀 10mg（次优）或阿托伐他汀 80mg（最佳）。 总体而言，我们预计大剂量辛伐他汀、阿托伐他汀和瑞舒伐他汀将 对 eCD 和 dCD 具有神经保护作用。我们认为他汀类药物的神经保护作用是由于 抗炎机制，并将反映在全身炎症水平的降低 标记。这项前瞻性随机试验的结果将为以下方面提供重要数据： 临床医生试图使这一常见手术更安全，并将阐明他汀类药物是否 对人类缺血性脑损伤具有神经保护作用。我们的结果可以指导发展 这些药物用于其他适应症。