Allegretti Andrew S, Israelsen Mads, Krag Aleksander, Jovani Manol, Goldin Alison H, Schulman Allison R, Winter Rachel W, Gluud Lise Lotte
Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, USA, MA 02114.
Cochrane Database Syst Rev. 2017 Jun 14;6(6):CD005162. doi: 10.1002/14651858.CD005162.pub4.
Hepatorenal syndrome is a potentially reversible renal failure associated with severe liver disease. The disease is relatively common among people with decompensated cirrhosis. Terlipressin is a drug that increases the blood flow to the kidneys by constricting blood vessels. The previous version of this systematic review found a potential beneficial effect of terlipressin on mortality and renal function in people with cirrhosis and hepatorenal syndrome.
To assess the beneficial and harmful effects of terlipressin versus placebo/no intervention for people with cirrhosis and hepatorenal syndrome.
We identified eligible trials through searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, and Science Citation Index Expanded, and manual searches until 21 November 2016.
Randomised clinical trials (RCTs) involving participants with cirrhosis and type 1 or type 2 hepatorenal syndrome allocated to terlipressin versus placebo or no intervention. We allowed co-administration with albumin administered to both comparison groups.
Two review authors independently extracted data from trial reports and undertook correspondence with the authors. Primary outcomes were mortality, hepatorenal syndrome, and serious adverse events. We conducted sensitivity analyses of RCTs in which participants received albumin, subgroup analyses of participants with type 1 or type 2 hepatorenal syndrome, and Trial Sequential Analyses to control random errors. We reported random-effects meta-analyses with risk ratios (RR) and 95% confidence intervals (CI). We assessed the risk of bias based on the Cochrane Hepato-Biliary Group domains. We graded the quality of the evidence using GRADE.
We included nine RCTs with a total of 534 participants with cirrhosis and ascites. One RCT had a low risk of bias for mortality and a high risk of bias for the remaining outcomes. All included trials had a high risk of bias for non-mortality outcomes. In total, 473 participants had type 1 hepatorenal syndrome. Seven RCTs specifically evaluated terlipressin and albumin. Terlipressin was associated with a beneficial effect on mortality when including all RCTs (RR 0.85, 95% CI 0.73 to 0.98; 534 participants; number needed to treat for an additional beneficial outcome (NNTB) 10.3 people; low-quality evidence). Trial Sequential Analysis including all RCTs also found a beneficial effect of terlipressin. Additional analyses showed a beneficial effect of terlipressin and albumin on reversal of hepatorenal syndrome (RR 0.63, 95% CI 0.48 to 0.82; 510 participants; 8 RCTs; NNTB 4 people; low-quality evidence). Terlipressin increased the risk of serious cardiovascular adverse events (RR 7.26, 95% CI 1.70 to 31.05; 234 participants; 4 RCTs), but it had no effect on the risk of serious adverse events when analysed as a composite outcome (RR 0.91, 95% CI 0.68 to 1.21; 534 participants; 9 RCTs; number needed to treat for an additional harmful outcome 24.5 people; low-quality evidence). Non-serious adverse events were mainly gastrointestinal, including diarrhoea (RR 5.76, 95% CI 2.19 to 15.15; 240 participants; low-quality evidence) and abdominal pain (RR 1.54, 95% CI 0.97 to 2.43; 294 participants; low-quality evidence).We identified one ongoing trial on terlipressin versus placebo in participants with cirrhosis, ascites, and hepatorenal syndrome type 1.Three RCTs reported funding from a pharmaceutical company. The remaining trials did not report funding or did not receive funding from pharmaceutical companies.
AUTHORS' CONCLUSIONS: This review suggests that terlipressin may be associated with beneficial effects on mortality and renal function in people with cirrhosis and type 1 hepatorenal syndrome, but it is also associated with serious adverse effects. We downgraded the strength of the evidence due to methodological issues including bias control, clinical heterogeneity, and imprecision. Consequently, additional evidence is needed.
肝肾综合征是一种与严重肝病相关的潜在可逆性肾衰竭。该疾病在失代偿期肝硬化患者中相对常见。特利加压素是一种通过收缩血管来增加肾脏血流量的药物。本系统评价的上一版发现特利加压素对肝硬化合并肝肾综合征患者的死亡率和肾功能有潜在有益影响。
评估特利加压素与安慰剂/无干预措施相比，对肝硬化合并肝肾综合征患者的有益和有害影响。
我们通过检索Cochrane肝胆组对照试验注册库、Cochrane图书馆中的Cochrane对照试验中心注册库（CENTRAL）、MEDLINE、Embase和科学引文索引扩展版，并进行手工检索，直至2016年11月21日，以识别符合条件的试验。
随机临床试验（RCT），纳入肝硬化合并1型或2型肝肾综合征的参与者，分为特利加压素组与安慰剂组或无干预措施组。我们允许两组比较均联合使用白蛋白。
两位综述作者独立从试验报告中提取数据，并与作者进行沟通。主要结局为死亡率、肝肾综合征和严重不良事件。我们对参与者接受白蛋白的RCT进行了敏感性分析，对1型或2型肝肾综合征的参与者进行了亚组分析，并进行了试验序贯分析以控制随机误差。我们报告了采用风险比（RR）和95%置信区间（CI）的随机效应荟萃分析。我们根据Cochrane肝胆组领域评估偏倚风险。我们使用GRADE对证据质量进行分级。
我们纳入了9项RCT，共534例肝硬化合并腹水的参与者。1项RCT在死亡率方面偏倚风险低，在其余结局方面偏倚风险高。所有纳入试验在非死亡率结局方面偏倚风险高。共有473名参与者患有1型肝肾综合征。7项RCT专门评估了特利加压素和白蛋白。纳入所有RCT时，特利加压素对死亡率有有益影响（RR 0.85，95%CI 0.73至0.98；534名参与者；额外有益结局的需治疗人数（NNTB）为10.3人；低质量证据）。包括所有RCT的试验序贯分析也发现特利加压素具有有益影响。进一步分析表明，特利加压素和白蛋白对肝肾综合征的逆转有有益影响（RR 0.63，95%CI 0.48至0.82；510名参与者；8项RCT；NNTB 4人；低质量证据）。特利加压素增加了严重心血管不良事件的风险（RR 7.26，95%CI 1.70至31.05；234名参与者；4项RCT），但作为复合结局分析时，对严重不良事件风险无影响（RR 0.91，95%CI 0.68至1.21；534名参与者；9项RCT；额外有害结局的需治疗人数24.5人；低质量证据）。非严重不良事件主要为胃肠道事件，包括腹泻（RR 5.76，95%CI 2.19至15.15；240名参与者；低质量证据）和腹痛（RR 1.54，95%CI 0.97至2.43；294名参与者；低质量证据）。我们确定了一项正在进行的关于特利加压素与安慰剂对比治疗肝硬化、腹水和1型肝肾综合征参与者的试验。3项RCT报告有制药公司资助。其余试验未报告资助情况或未接受制药公司资助。
本综述表明，特利加压素可能对肝硬化合并1型肝肾综合征患者的死亡率和肾功能有有益影响，但也与严重不良反应相关。由于包括偏倚控制、临床异质性和不精确性等方法学问题，我们降低了证据的强度。因此，需要更多证据。
