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

背景：肝硬化是最常见的肝脏炎症和纤维化的最终共同途径 通常通过酒精或丙型和/或B型肝炎病毒感染。HMG-CoA还原酶抑制剂（他汀类）是 认为通过改善肝内内皮功能障碍、炎症 和纤维化，从而导致门静脉压力降低。因为具有临床意义的门户 高血压是失代偿的主要驱动力，门静脉压力降低（在两种情况下都有表现）。 实验和人肝硬化）将防止肝代偿失调。 目的：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迟/预防肝失代偿、肝细胞癌（HCC），是否需要 肝移植或死亡的退伍军人与代偿性肝硬化在高风险的失代偿。 具体目的：1）证明他汀类药物治疗肝硬化高危患者， 失代偿将降低肝失代偿、肝细胞癌、全因性肝癌的发生率 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疾病的影响 代偿期肝硬化患者的生活质量; 3）探讨慢性辛伐他汀对 代偿期肝硬化门静脉高压症 研究设计：代偿性肝硬化患者，肝功能失代偿的高风险， 根据是否存在静脉曲张分层，并随机接受辛伐他汀40 mg/天或 安慰剂长达24个月。将观察患者是否发生肝功能失代偿 （静脉曲张出血、腹水、脑病）、HCC、肝脏相关死亡、全因死亡，和/或 他汀类药物治疗的并发症主要研究终点是他汀类药物治疗对减少 肝失代偿和HCC的发生率。次要终点是评估他汀类药物的作用 治疗对死亡率、肝移植需求、健康相关生活质量的影响 失代偿期肝硬化，评估他汀类药物对门静脉高压的影响，并探讨 SLCO 1B 1和KIF 6多态性对他汀类药物治疗的安全性和临床疗效的相互作用。 临床影响：估计有35，000名肝硬化患者正在接受治疗 在VA医疗保健系统中。大约有15，000例肝失代偿相关的住院治疗 每年在弗吉尼亚州，平均停留时间为9天。目前估计的医疗总开支 对于一个患有肝硬化的“平均”退伍军人来说，每年大约23,000美元，是年龄的三倍- 匹配的控制。失代偿性肝硬化患者的年费用几乎是正常人的两倍， 主要与住院有关。辛伐他汀，每年25 -50美元，如果证明安全 减少肝脏失代偿和死亡，将对退伍军人产生巨大的健康益处， 为VA医疗保健系统节省大量成本。随机对照试验将是 对于支持他汀类药物治疗代偿期肝硬化的疗效和安全性至关重要， 实践中的变化。

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.