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：肝硬化是最常见的引起肝脏炎症和纤维化的最终共同途径。 通常由酒精或丙型肝炎和/或乙型肝炎病毒感染引起。HMG-coA 还原酶抑制剂（他汀类药物） 被认为通过改善肝内内皮功能障碍、炎症而有益于肝脏疾病 和纤维化，从而导致门静脉压力降低，因为具有临床意义。 高血压是失代偿的主要驱动因素，门静脉压力降低（在 实验性肝硬化和人类肝硬化）将防止肝功能失代偿。 目标：这项 III 期、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缓/预防肝失代偿、肝细胞癌（HCC）、需要 患有代偿性肝硬化的退伍军人的肝移植或死亡具有高失代偿风险。 具体目标： 1) 证明他汀类药物治疗肝硬化高风险患者 失代偿将减少肝失代偿、肝细胞癌、全因的发生率 死亡率和肝移植的需要；2) 评估他汀类药物暴露对健康相关的影响 代偿性肝硬化患者的生活质量；3) 探讨长期辛伐他汀对患者的影响 代偿性肝硬化患者的门脉高压。 研究设计：具有肝代偿失调高风险的代偿性肝硬化患者将被 根据是否存在静脉曲张进行分层，并随机接受辛伐他汀 40 毫克/天或 安慰剂治疗长达 24 个月，将观察患者肝功能失代偿的发生情况。 （静脉曲张出血、腹水、脑病）、HCC、肝脏相关死亡、任何原因死亡和/或 他汀类药物治疗的并发症的主要研究终点是他汀类药物治疗对减少并发症的影响。 肝失代偿和 HCC 的发生率是评估他汀类药物的效果。 治疗对死亡率、肝移植需求、健康相关生活质量的影响 失代偿性肝硬化，评估他汀类药物对门静脉高压的影响，并探讨 SLCO1B1 和 KIF6 多态性的相互作用对他汀类药物治疗的安全性和临床疗效的影响。 临床影响：估计有 35,000 名肝硬化患者正在接受持续的医疗护理 VA 医疗系统内约有 15,000 例因肝脏失代偿相关的住院治疗。 每年在 VA 的平均停留时间为 9 天 目前估计的医疗保健总支出。 对于患有肝硬化的“平均”退伍军人来说，每年大约需要 23,000 美元，是年龄的三倍 失代偿性肝硬化患者的年费用几乎是对照组的两倍， 主要与辛伐他汀住院有关，如果证明安全的话，每年费用为 25-50 美元。 减少肝脏失代偿和死亡，将为退伍军人带来巨大的健康益处，并将 一项随机对照试验将为 VA 医疗保健系统带来显着的成本节省。 对于支持他汀类药物治疗代偿性肝硬化的有效性和安全性至关重要，并将促进显着的 实践中的改变。