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

背景：肝硬变是肝脏炎症和纤维化的最终共同途径，是引起肝脏炎症和纤维化的主要原因 通常由酒精或病毒感染丙型和/或乙肝引起，HMG-CoA还原酶抑制剂(他汀类)是 被认为通过改善肝内皮细胞功能障碍、炎症而有益于肝病 和纤维化，从而导致门脉压力的降低。因为临床上有重要意义的门户 高血压是失代偿的主要驱动力，即门脉压力降低(在两种情况下都表现为 实验性和人类肝硬变)将防止肝脏失代偿。 目标：这项第三阶段的随机、双盲、安慰剂对照、多中心研究将评估 辛伐他汀能否延缓/预防肝脏失代偿，即肝细胞癌，需要 肝移植或死亡的退伍军人代偿性肝硬变失代偿风险高。 具体目的：1)证实他汀类药物治疗肝硬变高危患者 失代偿将降低肝脏失代偿、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 3)探讨慢性辛伐他汀对代偿性肝硬变患者生活质量的影响 代偿性肝硬变患者的门脉高压症。 研究设计：具有肝脏失代偿高危风险的代偿性肝硬化患者将 根据静脉曲张的存在或不存在进行分层，随机服用辛伐他汀40 mg/天或 安慰剂最长可达24个月。将观察患者肝脏失代偿的发展情况。 (静脉曲张出血、腹水、脑病)、肝细胞癌、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。主要的研究终点是他汀类药物治疗在减少 肝功能失代偿和肝细胞癌的发生率。次要终点是评估他汀类药物的效果 慢性肝炎患者死亡率、肝移植需求、健康相关生活质量的治疗 评估他汀类药物对门静脉高压症的影响，并探讨他汀类药物对失代偿性肝硬变的影响。 SLCO1B1和KIF6基因多态性对他汀类药物安全性和临床疗效的影响 临床影响：估计有35,000名肝硬变患者正在接受持续的医疗护理 在退伍军人管理局的医疗保健系统中。大约有15,000人因肝脏失代偿而住院 每年在退伍军人事务部居住，平均停留时间为9天。目前估计的医疗保健总支出 对于患有肝硬变的退伍军人来说，平均每年大约23,000美元，是年龄的三倍- 配对的对照组。失代偿期肝硬变患者的年费用几乎翻了一番， 主要与住院有关。辛伐他汀，每年花费25-50美元，如果被证明是安全的 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 为退伍军人管理局医疗保健系统节省了大量成本。随机对照试验将是 对支持他汀类药物在代偿性肝硬变中的有效性和安全性至关重要，并将促进显著的 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.