Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States of America.
VA Connecticut Healthcare System, West Haven, CT, United States of America.
Contemp Clin Trials. 2021 May;104:106367. doi: 10.1016/j.cct.2021.106367. Epub 2021 Mar 24.
BACKGROUND/AIMS: The development of decompensation in cirrhosis demarcates a marked change in the natural history of chronic liver disease. HMG-CoA reductase inhibitors (statins) exert pleiotropic effects that reduce inflammation and fibrosis as well as improve vascular reactivity. Retrospective studies uniformly have associated statin utilization with improved outcomes for patients with cirrhosis. Prospective human studies have shown that statins reduce portal hypertension and reduce death in patients with decompensated cirrhosis after variceal hemorrhage when added to standard therapy with an acceptable safety profile. This proposal aims to extend these findings to demonstrate that simvastatin reduces incident hepatic decompensation events among cirrhotic patients at high risk for hepatic decompensation.
We will perform the SACRED Trial (NCT03654053), a phase III, prospective, multi-center, double-blind, randomized clinical trial at 11 VA Medical Centers. Patients with compensated cirrhosis with clinically significant portal hypertension will be stratified based upon the concomitant use of nonselective beta-blockers and randomized to simvastatin 40 mg/day versus placebo for up to 24 months. Patients will be observed for the development of hepatic decompensation (variceal hemorrhage, ascites, encephalopathy), hepatocellular carcinoma, liver-related death, death from any cause, and/or complications of statin therapy. Ancillary studies will evaluate patient-reported outcomes and pharmacogenetic corollaries of safety and/or efficacy.
Statins have a long track-record of safety and tolerability. This class of medications is generic and inexpensive, and thus, if the hypothesis is proven, there will be few barriers to widespread acceptance of the role of statins to prevent decompensation in patients with compensated cirrhosis. ClinicalTrials.gov Identifier: NCT03654053.
背景/目的：肝硬化失代偿的发展标志着慢性肝病自然史的显著变化。羟甲基戊二酰辅酶 A 还原酶抑制剂（他汀类药物）具有多种作用，可减轻炎症和纤维化，改善血管反应性。回顾性研究一致表明，他汀类药物的使用与肝硬化患者的预后改善相关。前瞻性人体研究表明，在标准治疗基础上加用心血管事件预防剂量的他汀类药物可降低肝硬化伴静脉曲张出血患者的门静脉高压，并降低死亡率。本研究旨在扩展这些发现，以证明辛伐他汀可降低高危失代偿性肝硬化患者的肝性失代偿事件发生率。
我们将开展 SACRED 试验（NCT03654053），这是一项在 11 个退伍军人事务部医疗中心进行的 III 期前瞻性多中心双盲随机临床试验。将具有临床显著门静脉高压的代偿性肝硬化患者根据同时使用非选择性β受体阻滞剂的情况进行分层，并随机分为辛伐他汀 40mg/天组或安慰剂组，治疗时间最长为 24 个月。患者将接受肝性失代偿（静脉曲张出血、腹水、肝性脑病）、肝细胞癌、与肝脏相关的死亡、任何原因导致的死亡和/或他汀类药物治疗相关并发症的观察。辅助研究将评估患者报告的结局和安全性/疗效的药物遗传学相关性。
他汀类药物具有长期的安全性和耐受性记录。这类药物是通用且廉价的，因此，如果假设得到证实，那么在广泛接受他汀类药物预防代偿性肝硬化患者失代偿的作用方面，几乎没有障碍。临床试验.gov 标识符：NCT03654053。
