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

在过去的15年里，我们研究了接受颈动脉粥样硬化治疗的患者的认知变化， 颈动脉内膜切除术（CEA）或颈动脉血管成形术和支架植入术导致的动脉狭窄 （CAS）。使用神经认知测试，我们定义了术后认知功能障碍（CD）， 轻微脑损伤术后认知功能障碍是一系列 对大脑的伤害。早期认知功能障碍（eCD）在约25%的患者中观察到， CEA后30天内（延迟CD [dCD]）。在过去的10年里， NIH资助（RO1 AG17604），我们已经证明了1。无症状患者服用 他汀类药物再次手术后eCD显著低于未服用他汀类药物者，2.辛伐 与阿托伐他汀相比，他汀类药物也具有神经保护作用 4.患有eCD且未服用他汀类药物的患者， 死亡风险高于服用他汀类药物的eCD患者，5.促炎基因多态性 和标记物浓度与eCD增加显著相关，和6.他汀类药物是 与较低水平的促炎标志物有关。基于这些发现，我们 假设在接受CEA的无症状患者中，1.术前他汀类药物的使用 对eCD具有神经保护作用并降低早期死亡风险，2.他汀类药物的类型和剂量可能 在实现最佳神经保护方面很重要，以及3.的抗炎作用 他汀类药物可部分解释所观察到的神经保护作用。为了解决这些假设， 我们将对1000名无症状患者进行前瞻性评估， 在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获得全身炎症的标志物。患者将 术前2周和术后4周随机分配至三组之一 这取决于他们在登记时的他汀类药物状态。手臂：1.接受最佳日剂量的 将检测辛伐他汀（40 mg）、阿托伐他汀（80 mg）或瑞舒伐他汀（20 mg）， 观察，2。使用三种他汀类药物中的一种（辛伐他汀）剂量低于最佳剂量的患者 <40 mg、阿托伐他汀<80 mg或瑞舒伐他汀<20 mg）将被随机化以接受最佳剂量。 使用重新封装的盲法药物给药或保持在其次优剂量，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 设盲阿托伐他汀10 mg（次优）或阿托伐他汀80 mg（最优）。 总的来说，我们预计高剂量辛伐他汀、阿托伐他汀和瑞舒伐他汀将 对eCD和dCD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，并将反映在降低水平的全身炎症 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 临床医生试图使这种常见的程序更安全，并将阐明他汀类药物是否 在人类缺血性脑损伤中具有神经保护作用。我们的研究结果可能会指导发展 这些药物用于其他适应症。

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.