Effect of simvastatin on hepatic decompensation and death in subjects with high-risk compensated cirrhosis

辛伐他汀对高危代偿性肝硬化受试者肝代偿失调和死亡的影响

• 批准号: 10464880
• 负责人: David E Kaplan
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-10-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464880
• 关键词: Abdomen; Address; Age; Alcohols; Ascites; Autoimmune; Bilirubin; Blood Circulation; Cardiovascular system; Caring; Cessation of life; Cholesterol; Chronic; Chronic viral hepatitis; Cirrhosis; Clinical; Cost Savings; Data; Development; Double-Blind Method; Encephalopathies; Exposure to; Fibrosis; Fostering; Fright; Genes; Genetic; Genetic Polymorphism; Health Benefit; Health Expenditures; Healthcare Systems; Heart Diseases; Hemorrhage; Hepatic; Hepatic Encephalopathy; Hepatitis B; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatotoxicity; Hospitalization; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Individual; Infection; Inflammation; Intention; Intervention; Length of Stay; Liquid substance; Liver; Liver Fibrosis; Liver diseases; Malignant neoplasm of liver; Mediating; Medical; Multicenter Studies; Myopathy; Nitric Oxide; Outcome; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Portal Hypertension; Portal Pressure; Portal vein structure; Primary carcinoma of the liver cells; Prophylactic treatment; Prospective Studies; Quality of life; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Recurrence; Reporting; Research Design; Retrospective Studies; Rhabdomyolysis; Risk; Safety; Simvastatin; Symptoms; Testing; Time; Varicosity; Vasodilator Agents; Veterans; Virus Diseases; adverse outcome; base; care providers; chronic liver disease; clinical efficacy; clinically significant; cost; endothelial dysfunction; follow-up; health related quality of life; high risk; improved; intrahepatic; liver development; liver function; liver inflammation; liver transplantation; mortality; mortality risk; non-alcoholic fatty liver; patient population; pressure; prevent; problem drinker; prospective; prospective test; randomized placebo controlled trial; randomized trial; response; secondary endpoint; side effect; study population; vasoconstriction

Background: Cirrhosis is the final common pathway of hepatic inflammation and fibrosis caused most commonly by alcohol or viral infection with hepatitis C and/or B. HMG-coA reductase inhibitors (statins) are thought to be beneficial in liver disease by ameliorating intrahepatic endothelial dysfunction, inflammation and fibrosis, thereby leading to a reduction in portal pressure. Because clinically significant portal hypertension is the main driver of decompensation, a reduction in portal pressure (demonstrated in both experimental and human cirrhosis) will prevent hepatic decompensation. Objectives: This phase III, randomized, double-blind, placebo-controlled, multi-center study will assess whether simvastatin can delay/prevent hepatic decompensation, hepatocellular carcinoma (HCC), need for liver transplantation or death in Veterans with compensated cirrhosis at a high-risk of decompensation. Specific Aims: 1) To demonstrate that statin therapy in patients with cirrhosis at high-risk for hepatic decompensation will reduce the incidence of hepatic decompensation, hepatocellular carcinoma, all-cause mortality and need for liver transplantation; 2) to assess the impact of statin exposure on health-related quality of life in patients with compensated cirrhosis; and 3) to explore the impact of chronic simvastatin on portal hypertension in patients with compensated cirrhosis. Study Design: Patients with compensated cirrhosis at high-risk for hepatic decompensation will be stratified based upon the presence or absence of varices and randomized to simvastatin 40mg/day or placebo for up to 24 months. Patients will be observed for the development of hepatic decompensation (variceal hemorrhage, ascites, encephalopathy), HCC, liver-related death, death from any cause, and/or complications of statin therapy. The primary study endpoint is the effect of statin therapy on reducing the incidence of hepatic decompensation and HCC. Secondary endpoints are to assess the effect of statin therapy on mortality, need for liver transplantation, health related quality of life in patients with decompensated cirrhosis, to assess the impact of statins on portal hypertension, and to explore the interaction of SLCO1B1 and KIF6 polymorphisms on safety and clinical efficacy of statin therapy. Clinical Impact: There are an estimated 35,000 individuals with cirrhosis receiving ongoing medical care within the VA healthcare system. Approximately 15,000 liver decompensation-related hospitalizations occur annually in the VA with a mean length of stay of 9 days. The current estimated total healthcare expenditure for an ‘average’ Veteran with cirrhosis approximates $23,000 per year, three times greater than age- matched controls. Patients with decompensated cirrhosis have nearly double the annual costs, predominantly related to hospitalizations. Simvastatin, at a cost of $25-50 per year, if proven to safely reduce liver decompensation and death, would have tremendous health benefits for Veterans and would result in significant cost savings for the VA healthcare system. A randomized controlled trial would be essential to support the efficacy and safety of statins in compensated cirrhosis and would foster a significant change in practice.

背景：肝硬化是肝注射和纤维化的最终常见途径 通常，通过酒精或病毒感染丙型肝炎和/或B. hmg-COA降低抑制剂（他汀类药物）是 通过改善肝内内皮功能障碍，炎症，人们认为对肝病有益 和纤维化，从而导致门户压力降低。因为临床意义的门户 高血压是代偿作用的主要驱动力，降低了门户压力（两者都证明 实验性和人肝硬化）将防止肝作用。 目的：此阶段III，随机，双盲，安慰剂对照，多中心研究将评估 辛伐他汀是否可以延迟/预防肝脏癌，肝细胞癌（HCC），需要 在高风险中，肝硬化的退伍军人中的肝移植或死亡。 具体目的：1）证明肝硬化患者的他汀类药物治疗肝病患者 代偿性会减少肝脏代表性的发生率，肝细胞癌，全因 死亡率和肝移植的需求； 2）评估他汀类药物暴露对健康相关的影响 肝硬化的患者的生活质量； 3）探索慢性辛伐他汀对 完整肝硬化患者的门户高血压。 研究设计：在高危肝脏代偿上完成肝硬化的患者将是 根据静脉曲张的存在或不存在分层，并随机分为辛伐他汀40mg/天或 安慰剂长达24个月。将观察患者的发育 （静脉体出血，腹水，脑病），HCC，与肝相关的死亡，任何原因的死亡和/或 他汀类药物疗法的并发症。主要研究终点是他汀类药物治疗对减少的影响 肝脏代理和HCC的发生率。次要终点是评估他汀类药物的影响 关于死亡率的治疗，需要肝移植的需求，患者与健康相关的生活质量 肝硬化的代偿性代表，评估他汀类药物对门户高血压的影响，并探索 SLCO1B1和KIF6多态性关于他汀类药物治疗的安全性和临床效率的相互作用。 临床影响：估计有35,000名肝硬化患者接受持续的医疗服务 在VA医疗保健系统中。大约发生了15,000个与肝脏代理相关的住院 每年在VA中，平均停留时间为9天。当前估计的总医疗支出 对于一名“平均”老兵，cirhosis大约每年23,000美元，大于年龄的三倍 匹配的控件。肝硬化代表的患者的年成本几乎是一倍， 主要与住院关系有关。辛伐他汀，如果被证明是安全的，每年的费用为25-50美元 减少肝脏代表和死亡，将对退伍军人带来巨大的健康益处 VA医疗保健系统可节省大量成本。随机对照试验将是 支持他汀类药物在补偿肝硬化中的效率和安全性至关重要，并将促进重要 改变实践。