高剂量环利尿剂减少肝硬化的存活率

StephenW

High-Dose Loop Diuretics Reduced Survival in Cirrhosis
Faster muscle depletion and more deaths

   Contributing Writer
    September 04, 2018

A higher dose of loop diuretics was associated with more rapid skeletal muscle depletion and shorter survival in patients with liver cirrhosis, independent of the severity of disease, Japanese researchers reported.

The findings suggest that these drugs, often used to treat hepatic edema and ascites, are a critical risk factor for sarcopenia. "These results raise the important possibilities that refraining from high-dose loop diuretics for the treatment of hepatic edema and/or ascites may contribute to [preventing] skeletal muscle depletion and to improving the prognosis of patients with liver cirrhosis," wrote Makoto Shiraki, MD, PhD, of Gifu University Graduate School of Medicine in Gifu, and colleagues.

Sarcopenia, observed in 40% to 70% of liver cirrhosis patients, has been shown to worsen prognosis. In a previous study, the researchers had reported that cirrhosis patients lose skeletal muscle mass at twice the annual rate of healthy people.

In the current retrospective study, published online in Hepatology Research, the team evaluated 226 liver cirrhosis patients; median age was 64, and 137 were men. Participants were treated during 2004-2017 at Gifu University Hospital, and separated into two groups by diuretic dose (<20 mg/day and >20 mg/day).

Overall, hepatitis C virus (HCV) infection was the most common cause of cirrhosis (n=105), followed by alcohol (n=64). HCV etiology predominated in the lower-dose group (50%), and alcohol in the higher-dose patients (41%).

CT scans measured skeletal muscle at the level of the third lumbar vertebra, and the relative change in skeletal muscle area per year (ΔSMA) was calculated. The therapeutic dosage of loop diuretics inversely correlated with ΔSMA by both simple (r = –0.27, P<0.0001) and multiple regression analyses (t = –3.07, P = 0.002). During a median follow-up period of 49 months, 82 patients died – 19 in the >20 mg/day group (19/39, 48%) and 63 in the ≤20 mg/day group (63/187, 34%).

Overall survival rates were lower in the >20 mg group than in those in the ≤20 mg group: median 66 versus 97 months (P =0.002).

Multivariate analysis further revealed that higher doses were independently associated with mortality regardless of Child-Pugh class or model for end-stage liver disease score, for a hazard ratio (HR), 1.86 (95% confidence interval 1.03-3.24, P = 0.039). Another independent risk factor that emerged was a change in ΔSMA of at least –3.1% (HR 3.87, 95% CI 2.32-6.60 P<0.0001).

Asked for his perspective, Aldo J. Montano-Loza, MD, PhD, of the University of Alberta in Edmonton, Canada, who was not involved with the study, called the results "interesting," since muscle depletion is a frequent complication of cirrhosis. He cautioned, however, that the study could not determine whether it was the use of loop diuretics per se that contributed to muscle depletion and the poor outcomes or simply reflected more severe liver disease.

"While the data are consistent with the former possibility, which would have implications for pathogenesis and for clinical management, they consist only of observed associations," he told MedPage Today. "External validation of these findings in other cohorts of patients with cirrhosis is warranted."

Long-term use of loop diuretics can induce other adverse events such as hyponatremia and renal impairment, both of which are independent risk factors for mortality in patients with liver cirrhosis, Shiraki and co-authors noted. Loop diuretics impair skeletal myoblast differentiation and exercise-induced muscle hypertrophy, inhibiting skeletal myogenesis by targeting the co-transporter NKCC, which helps deliver sodium, potassium, and chloride into cells.

"The results of the present study showed an urgent need for the strategic change of the treatment of hepatic edema and/or ascites in clinical practice," the researchers wrote.

They concluded that high-dose loop diuretics should be avoided and early add-on therapy with the aquaretic selective vasopressin V2 receptor antagonist tolvaptan (Samsca) should be given to prevent sarcopenia, and called for prospective studies with more patients and longer follow-up.

Study limitations, the team said, included the retrospective and single-center design. And although diet and physical activity have been shown to be associated with skeletal muscle depletion and mortality in liver cirrhosis patients, these data were unavailable in the retrospective analysis. In addition, dose and duration of loop diuretics were decided by individual attending physicians and hence there were significant differences in baseline characteristics between patients on daily doses of >20 mg and those of ≤20 mg, potentially affecting the results.

The authors reported having no conflicts of interest.

Montano-Loza reported having no conflicts of interest.

StephenW

高剂量环利尿剂减少肝硬化的存活率
更快的肌肉耗尽和更多的死亡

   贡献作家
    2018年9月4日

日本研究人员报告说，较高剂量的袢利尿剂与肝硬化患者骨骼肌耗竭更快，生存期更短有关，与疾病的严重程度无关。

研究结果表明，这些常用于治疗肝性水肿和腹水的药物是肌肉减少症的重要危险因素。 “这些结果提出了重要的可能性，即抑制高剂量袢利尿剂治疗肝性水肿和/或腹水可能有助于[预防]骨骼肌耗竭和改善肝硬化患者的预后，”Makoto Shiraki写道，岐阜大学岐阜大学医学研究生院博士，同事。

在40％至70％的肝硬化患者中观察到的肌肉减少症已被证实会恶化预后。在之前的一项研究中，研究人员报告说，肝硬化患者的骨骼肌质量减少了两倍于健康人的年增长率。

在目前的肝脏病学研究在线发表的回顾性研究中，该团队评估了226例肝硬化患者;中位年龄为64岁，其中137岁为男性。参与者在2004 - 2017年期间在岐阜大学医院接受治疗，并通过利尿剂量（<20mg /天和> 20mg /天）分成两组。

总体而言，丙型肝炎病毒（HCV）感染是肝硬化最常见的原因（n = 105），其次是酒精（n = 64）。 HCV病因在低剂量组（50％）中占主导地位，而在较高剂量组中则为酒精（41％）。

CT扫描测量第三腰椎水平的骨骼肌，并计算每年骨骼肌面积的相对变化（ΔSMA）。通过简单（r = -0.27，P <0.0001）和多元回归分析（t = -3.07，P = 0.002），袢利尿剂的治疗剂量与ΔSMA呈负相关。在49个月的中位随访期间，82名患者死亡 - > 20 mg /天组中的19名（19 / 39,48％）和≤20mg /天组中的63名（63 / 187,34％） 。

> 20 mg组的总生存率低于≤20mg组：中位数66对97个月（P = 0.002）。

多变量分析进一步显示，无论Child-Pugh类别或终末期肝病评分模型，较高剂量与死亡率独立相关，风险比（HR）为1.86（95％置信区间1.03-3.24，P = 0.039） 。出现的另一个独立危险因素是ΔSMA的变化至少为-3.1％（HR 3.87,95％CI 2.32-6.60 P <0.0001）。

在被问及他的观点时，加拿大埃德蒙顿阿尔伯塔大学的医学博士Aldo J. Montano-Loza没有参与这项研究，称结果“有趣”，因为肌肉耗竭是肝硬化的常见并发症。 。然而，他警告说，该研究无法确定是否使用袢利尿剂本身导致肌肉耗竭和不良后果或仅仅反映更严重的肝脏疾病。

“尽管这些数据与之前的可能性一致，这可能会对发病机制和临床管理产生影响，但它们只包括观察到的相关性，”他告诉MedPage Today。 “需要在其他肝硬化患者队列中对这些发现进行外部验证。”

长期使用袢利尿剂可以诱发其他不良事件，如低钠血症和肾功能损害，这两者都是肝硬化患者死亡的独立危险因素，Shiraki及其合着者指出。袢利尿剂通过靶向共转运蛋白NKCC来抑制骨骼成肌细胞分化和运动诱导的肌肉肥大，抑制骨骼肌生成，这有助于将钠，钾和氯化物输送到细胞中。

研究人员写道：“本研究的结果显示，临床实践中急需治疗肝水肿和/或腹水的战略性改变。”

他们得出结论，应该避免使用高剂量袢利尿剂，应该给予早期的附加疗法，使用aquaretic选择性加压素V2受体拮抗剂tolvaptan（Samsca）来预防肌肉减少症，并要求进行更多患者和更长时间随访的前瞻性研究。

该团队表示，研究局限包括回顾性和单中心设计。尽管已显示饮食和身体活动与肝硬化患者的骨骼肌耗竭和死亡率相关，但这些数据在回顾性分析中是不可获得的。此外，袢利尿剂的剂量和持续时间由个体主治医师决定，因此每日剂量> 20 mg和≤20mg患者的基线特征存在显着差异，可能影响结果。

作者报告没有利益冲突。

据报道，Montano-Loza没有利益冲突。