Strategies and Therapies for Outcomes Prevention in Cirrhosis: The STOP-C Liver Cirrhosis Network

项目摘要/摘要： 肝硬变及其并发症，包括肝细胞癌，是越来越常见的病因 美国的发病率和死亡率。本申请的中心假设是(1)创造 对代偿性肝硬变患者的前瞻性队列研究将促进新的 基于我们收集的临床、行为、代谢和生物标志物数据来预测临床的预测模型 失代偿，(2)这个队列可以验证，然后得到更大的电子健康记录的补充 基于(EHR)的虚拟队列，后者将使电子肝硬变表型和 随后对单独使用降脂剂的安全性和有效性的真实数据进行分析 肝硬变患者的多重结局和(3)长期他汀类药物治疗将在以下方面提供临床益处 预防肝脏失代偿和肝细胞癌的作用不依赖于其降脂作用。为了调查这些 假设，我们为队列研究和基于他汀类药物的肝脏临床试验提出了独特的方法。 肝硬化网络(LCN)。在目标1a中，我们将创建一个具有高度表型的患者的预期队列 代偿性NASH、ALD、胆汁淤积性和隐源性肝硬变，以方便询问 新疾病预测因子的生物样本、患者报告的行为和结果以及临床数据 进展，并通过血清脂蛋白的测定了解复杂的相互作用 肝硬变和脂代谢。在目标1b中，我们将创建一个覆盖LCN范围、基于EHR的大型患者虚拟队列 代偿性肝硬变的电子表型及其临床前瞻性验证 并发症与我们的面对面队列，并评估不同类别的使用，安全性和有效性 在这个庞大的现实世界虚拟队列中，降脂药物对结果的影响。在目标2中，我们建议研究 他汀类药物预防NAFLD或ALD患者临床失代偿的安全性和有效性 同时探索他汀类药物的潜在多效性机制。在这项试验中，患有和不患有心绞痛的患者 已确定的非肝性降脂适应症将随机分为普伐他汀与阿利洛单抗(第1组)。 或安慰剂(第2层)。这种以他汀类药物为基础的临床试验的创新方法将承认 患者的降脂治疗的基线适应症，并提供一种替代的降脂途径 抑制PCSK9，具有类似或更强的降低低密度脂蛋白的效力，但缺乏他汀类药物的促多发性作用， 允许对他汀类药物可能影响结果的机制进行新的洞察，而不受其影响 在血脂上。在整个队列和干预试验中，我们将研究脂蛋白代谢、炎症 标记，并收集微生物组和生物标本，以供未来的翻译研究更好地理解 肝硬变疾病进展背后的机制以及普伐他汀和阿利洛单抗的任何潜在影响 对临床结果的影响。因此，这些创新策略利用队列和临床试验设计来 最大化获得的知识，改善肝硬变患者的临床结果。

Project Summary/Abstract: Cirrhosis and its complications including hepatocellular carcinoma (HCC) are increasingly common causes of morbidity and mortality in the United States. The central hypotheses of this application are that (1) the creation of a prospective cohort study of patients with compensated cirrhosis will facilitate the generation of novel prediction models based on the clinical, behavioral, metabolic, and biomarker data we collect to predict clinical decompensation, (2) this cohort can validate and then be supplemented by a larger electronic health record (EHR)-based virtual cohort, the latter of which will enable validation of electronic cirrhosis phenotypes and subsequent analysis of real-world data on the safety and effectiveness of individual lipid-lowering agents on multiple outcomes among patients with cirrhosis and (3) long-term statin therapy will provide clinical benefits in preventing hepatic decompensation and HCC independent of its lipid lowering effect. To investigate these hypotheses, we propose unique approaches to both the cohort study and statin-based clinical trial for the Liver Cirrhosis Network (LCN). In Aim 1a, we will create a prospective cohort of highly phenotyped patients with compensated NASH, ALD, cholestatic and cryptogenic cirrhosis, in order to facilitate the interrogation of biospecimens, patient reported behaviors and outcomes, and clinical data for novel predictors of disease progression, and to understand through serum lipoproteins measurement the complex interaction between cirrhosis and lipid metabolism. In Aim 1b, we will create a large LCN-wide EHR-based virtual cohort of patients with compensated cirrhosis, prospectively validate electronic phenotypes for cirrhosis and its clinical complications with our in-person cohort, and evaluate the use, safety and effectiveness of different classes of lipid lowering medications upon outcomes in this large real-world virtual cohort. In Aim 2, we propose to study the safety and efficacy of statins in preventing clinical decompensation among patients with NAFLD or ALD cirrhosis while exploring the potential pleiotropic mechanisms of statins. In this trial, patients with and without an established non-hepatic indication for lipid lowering will be randomized to pravastatin v. alirocumab (stratum 1) or placebo (stratum 2), respectively. This innovative approach to the statin-based clinical trial will acknowledge the patient's baseline indication for lipid-lowering therapy, and offer an alternative lipid lowering pathway in PCSK9 inhibition, which has similar or greater LDL-lowering potency but lacks the pleotropic effects of statins, to allow for novel insights into mechanisms by which statins might impact outcomes independent of its effects on lipids. Throughout the cohort and interventional trials, we will study lipoprotein metabolism, inflammatory markers, and collect microbiome and biospecimens for future translational research to better understand the mechanisms behind disease progression in cirrhosis and for any potential impact of pravastatin and alirocumab on clinical outcomes. These innovative strategies therefore leverage both cohort and clinical trial designs to maximize the knowledge gained and improve clinical outcomes among patients with cirrhosis.