Background & Aims: Carvedilol is a non-selective β-blocker (NSBBs) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal-pressure (HVPG). However, 35%-45% of patients still have insufficient HVPG-decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal-hypertension and suboptimal response to traditional-NSBBs. Methods: Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v.propranolol. Suboptimal responders (HVPG-decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4-6-weeks, repeating HVPG-measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters. Results: Of 184 eligible patients, 82 were randomized to carvedilol+simvastatin (N=41) or carvedilol+placebo (N=41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol+simvastatin (18.6±4-to-15.7±4 mm Hg, p<0.001) and carvedilol+placebo (18.9±3-to-16.9±3 mm Hg, p<0.001). The decrease was greater with carvedilol+simvastatin (2.97±2.5 vs. 2.05±1.6 mm Hg, p=0.031). An HVPG-decrease ≥20% occurred in 37% versus 15% patients respectively (OR:3.37, 95% CI=1.15-9.85; p=0.021). With test-meal, HVPG increased in both groups (p<0.01), although carvedilol+simvastatin attenuated such increment (12±8% vs. 23±16%, p<0.001). Cytokine levels (IL-6,MCP-1,MDA) decreased significantly more with carvedilol+simvastatin (p<0.01). Incidence of adverse events was similar. Conclusion: In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal-pressure reduction achieved with carvedilol-monotherapy, improves endothelial dysfunction and reduces pro-inflammatory cytokines.

中文翻译：

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卡维地洛加辛伐他汀对肝硬化伴严重门静脉高压和β阻滞剂反应不佳的血流动力学影响：一项双盲、安慰剂对照、随机试验


背景和目标：卡维地洛是一种非选择性β阻断剂（NSBBs），具有抗α1-肾上腺素能活性，比传统的NSBBs更有效地降低门静脉压力（HVPGs。然而，35%-45% 的患者仍然没有充分的 HVPG 降低。他汀类药物可改善内皮功能障碍，降低肝血管阻力，并具有多效性作用。我们研究了辛伐他汀的添加是否能提高卡维地洛对 HVPG 的疗效，用于治疗严重门静脉高压症和对传统 NSBBs 反应不佳的肝硬化。方法： 连续纳入转诊进行一级预防的肝硬化和高危静脉曲张患者。在基线时和 i.v.propranolol 后再次测量 HVPG。次优反应者 （HVPG 降低 <20%） 接受卡维地洛治疗，并随机分配至安慰剂或辛伐他汀双盲给药组。4-6 周后评估慢性 HVPG 反应，在标准流质餐后重复 HVPG 测量以估计内皮功能障碍。每次研究前均采集血浆样本以研究炎症参数。结果： 在 184 例符合条件的患者中，82 例被随机分配至卡维地洛 + 辛伐他汀组 （N=41） 或卡维地洛 + 安慰剂组 （N=41）。基线特征相似。卡维地洛 + 辛伐他汀 （18.6±4 至 15.7±4 mm Hg，p<0.001） 和卡维地洛 + 安慰剂 （18.9±3 至 16.9±3 mm Hg，p<0.001） 的 HVPG 显著降低。卡维地洛 + 辛伐他汀的降低幅度更大 （2.97±2.5 vs. 2.05±1.6 mm Hg，p = 0.031）。HVPG 降低 ≥20% 分别见于 37% 和 15% 的患者 （OR： 3.37,95% CI = 1.15-9.85;p=0.021）。试餐时，两组 HVPG 均增加 （p<0.01），尽管卡维地洛 + 辛伐他汀减弱了这种增加 （12±8% vs. 23±16%，p<0.001）。 卡维地洛 + 辛伐他汀组细胞因子水平 （IL-6 、 MCP-1 、 MDA） 显著降低幅度更大 （p<0.01）。不良事件的发生率相似。结论： 在严重门静脉高压症 （均伴有高危静脉曲张） 和对传统 NSBBs 的血流动力学反应不佳的患者中，卡维地洛联合辛伐他汀联合治疗显着增强了卡维地洛单药治疗实现的门静脉压降低，改善了内皮功能障碍并减少了促炎细胞因子。