Saffioti Francesca, Gurusamy Kurinchi Selvan, Hawkins Neil, Toon Clare D, Tsochatzis Emmanuel, Davidson Brian R, Thorburn Douglas
The Royal Free Sheila Sherlock Liver Centre, Royal Free Hampstead NHS Foundation Trust and UCL Institute of Liver and Digestive Health, Pond Street, Hampstead, London, UK, NW3 2QG.
Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University of Messina, Via Consolare Valeria, 1, Messina, Messina, Italy, 98125.
Cochrane Database Syst Rev. 2017 Mar 28;3(3):CD011343. doi: 10.1002/14651858.CD011343.pub2.
Primary sclerosing cholangitis is a chronic cholestatic liver disease that is associated with both hepatobiliary and colorectal malignancies, which can result in liver cirrhosis and its complications. The optimal pharmacological treatment for patients with primary sclerosing cholangitis remains controversial.
To assess the comparative benefits and harms of different pharmacological interventions in people with primary sclerosing cholangitis by performing a network meta-analysis, and to generate rankings of available pharmacological interventions according to their safety and efficacy. Given that it was not possible to assess whether potential effect modifiers were similar across comparisons, we did not perform the network meta-analysis but instead used standard Cochrane methods.When trials begin to provide an adequate description of potential effect modifiers, we will attempt to conduct network meta-analysis.
We searched CENTRAL, MEDLINE, Embase, Science Citation Index - Expanded, the WHO International Clinical Trials Registry Platform, and randomised controlled trials registers until February 2017 to identify randomised clinical trials (RCT) on pharmacological interventions for primary sclerosing cholangitis.
We included only RCTs, irrespective of language, blinding, or publication status, in which participants were given a diagnosis of primary sclerosing cholangitis. We excluded trials that included previously liver-transplanted participants. We considered any of various pharmacological interventions compared with one other or with placebo. We excluded trials that compared different doses of various pharmacological interventions or that reported different treatment durations, except for ursodeoxycholic acid (UDCA). As UDCA is the drug most commonly investigated for primary sclerosing cholangitis, we performed a second analysis in which we stratified the dose of UDCA.
We calculated the odds ratio and the rate ratio with 95% confidence intervals (CIs) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.
We identified 22 RCTs in which 1211 participants were randomised to 13 different interventions. Most were placebo-controlled trials. Trials had few restrictions apart from an established diagnosis of primary sclerosing cholangitis, evidence of cholestasis, absence of decompensated liver disease, and absence of malignancy. However, some trials included symptomatic participants only, and others included both symptomatic and asymptomatic participants. A total of 11 RCTs (706 participants) provided data for one or more outcomes. The period of follow-up ranged from three months to three years in most trials. Only three trials reported follow-up longer than three years. Investigators found no evidence of differences in important clinical benefits such as reduction in mortality at maximal follow-up and improvement in health-related quality of life. Primary outcomes Mortality: Effect estimates: colchicine versus placebo: odds ratio 0.44, 95% CI 0.04 to 5.07, participants = 84, one trial; penicillamine versus placebo: odds ratio 1.18, 95% CI 0.39 to 3.58, participants = 70, one trial; steroids versus placebo: odds ratio 3.00, 95% CI 0.10 to 90.96, participants = 11, one trial; ursodeoxycholic acid versus placebo: odds ratio 1.51, 95% CI 0.63 to 3.63, participants = 348, two trials, I = 0%; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial. Serious adverse events (proportion): Effect estimates: infliximab versus placebo: odds ratio not estimable (because of zero events in both arms), participants = 7, one trial; steroids versus placebo: odds ratio 20.00, 95% CI 0.93 to 429.90, participants = 11, one trial; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial. Serious adverse events (number): Effect estimates: infliximab versus placebo: rate ratio 0.80, 95% CI 0.02 to 40.44, participants = 7, one trial; penicillamine versus placebo: rate ratio 13.60, 95% CI 0.78 to 237.83, participants = 70, one trial; steroids versus placebo: rate ratio 3.32, 95% CI 0.71 to 15.62, participants = 11, one trial. Adverse events (proportion): Effect estimates: steroids versus placebo: odds ratio 20.00, 95% CI 0.93 to 429.90, participants = 11, one trial; ursodeoxycholic acid versus placebo: odds ratio 1.22, 95% CI 0.68 to 2.17, participants = 198, one trial; vancomycin versus placebo: not estimable because no events in either group, participants = 29, one trial. Adverse events (number): Effect estimates: cyclosporin versus placebo: rate ratio 2.64, 95% CI 0.99 to 7.03, participants = 26, one trial; steroids versus placebo: rate ratio 3.32, 95% CI 0.71 to 15.62, participants = 11, one trial; ursodeoxycholic acid plus metronidazole versus ursodeoxycholic acid: rate ratio 2.36, 95% CI 0.98 to 5.71, participants = 71, one trial. Health-related quality of life: ursodeoxycholic acid versus placebo: mean difference 1.30, 95% CI -5.61 to 8.21, participants = 198, one trial (Short Form (SF)-36 General Health Scale). Secondary outcomes Studies provided no evidence of differences in clinical benefits such as a reduction in the requirement for liver transplantation or a reduction in the incidence proportion of cholangiocarcinoma. One small trial (29 participants) comparing vancomycin versus placebo reported no malignancies, no liver decompensation, and no liver transplantation in either group after a very short follow-up period of 12 weeks after treatment. None of the remaining trials clearly reported other clinical benefits such as decreased development of all malignancies, colorectal cancer, liver decompensation, time to liver decompensation, time to liver transplantation, or requirement for cholecystectomy to allow comparisons between different interventions.
Fifteen trials reported the source of funding; three were funded by parties without vested interest in results of the trial, and 12 were funded in part or in full by drug companies.
AUTHORS' CONCLUSIONS: Evidence is currently insufficient to show differences in effectiveness measures such as mortality, health-related quality of life, cirrhosis, or liver transplantation between any active pharmacological intervention and no intervention. However, trials were at high risk of bias and included small numbers of participants, had short follow-up periods, and reported few clinical outcomes. An urgent need exists to identify an effective medical treatment for primary sclerosing cholangitis through well-designed RCTs with adequate follow-up that aim to identify differences in outcomes important to people with primary sclerosing cholangitis.
原发性硬化性胆管炎是一种慢性胆汁淤积性肝病，与肝胆及结肠恶性肿瘤相关，可导致肝硬化及其并发症。原发性硬化性胆管炎患者的最佳药物治疗仍存在争议。
通过进行网状Meta分析，评估不同药物干预对原发性硬化性胆管炎患者的相对获益和危害，并根据安全性和有效性对现有药物干预进行排名。鉴于无法评估各比较中潜在效应修饰因素是否相似，我们未进行网状Meta分析，而是采用了标准的Cochrane方法。当试验开始充分描述潜在效应修饰因素时，我们将尝试进行网状Meta分析。
我们检索了Cochrane中心对照试验注册库（CENTRAL）、医学期刊数据库（MEDLINE）、荷兰医学文摘数据库（Embase）、科学引文索引扩展版（Science Citation Index - Expanded）、世界卫生组织国际临床试验注册平台（WHO International Clinical Trials Registry Platform）以及随机对照试验注册库，检索截至2017年2月，以识别关于原发性硬化性胆管炎药物干预的随机临床试验（RCT）。
我们仅纳入RCT，无论语言、是否设盲或发表状态如何，其中参与者被诊断为原发性硬化性胆管炎。我们排除了纳入过肝移植参与者的试验。我们考虑了将任何一种药物干预与其他干预或安慰剂进行比较的试验。我们排除了比较不同剂量的各种药物干预或报告不同治疗持续时间的试验，但熊去氧胆酸（UDCA）除外。由于UDCA是原发性硬化性胆管炎研究最常用的药物，我们进行了第二项分析，对UDCA的剂量进行了分层。
我们使用Review Manager基于现有参与者分析，采用固定效应和随机效应模型计算了比值比和率比以及95%置信区间（CI）。我们根据Cochrane评估偏倚风险，使用序贯试验分析控制随机误差风险，并使用GRADE评估证据质量。
我们识别出22项RCT，其中1211名参与者被随机分配至13种不同干预措施。大多数是安慰剂对照试验。除了确诊原发性硬化性胆管炎、胆汁淤积证据、无失代偿性肝病以及无恶性肿瘤外，试验几乎没有其他限制。然而，一些试验仅纳入有症状的参与者，其他试验则纳入了有症状和无症状的参与者。共有11项RCT（706名参与者）提供了一个或多个结局的数据。大多数试验的随访期为三个月至三年。只有三项试验报告随访期超过三年。研究者未发现证据表明在最大随访期死亡率降低和健康相关生活质量改善等重要临床获益方面存在差异。主要结局死亡率：效应估计值：秋水仙碱与安慰剂比较：比值比0.44，95%CI 0.04至5.07，参与者 = 84，一项试验；青霉胺与安慰剂比较：比值比1.18，95%CI 0.39至3.58，参与者 = 70，一项试验；类固醇与安慰剂比较：比值比3.00，95%CI 0.10至90.96，参与者 = 11，一项试验；熊去氧胆酸与安慰剂比较：比值比1.51，95%CI 0.63至3.63，参与者 = 348，两项试验，I = 0%；万古霉素与安慰剂比较：因两组均无事件发生无法估计，参与者 = 29，一项试验。严重不良事件（比例）：效应估计值：英夫利昔单抗与安慰剂比较：比值比无法估计（因两组均无事件发生），参与者 = 7，一项试验；类固醇与安慰剂比较：比值比20.00，95%CI 0.93至429.90，参与者 = 11，一项试验；万古霉素与安慰剂比较：因两组均无事件发生无法估计，参与者 = 29，一项试验。严重不良事件（数量）：效应估计值：英夫利昔单抗与安慰剂比较：率比0.80，95%CI 0.02至40.44，参与者 = 7，一项试验；青霉胺与安慰剂比较：率比13.60，95%CI 0.78至237.83，参与者 = 70，一项试验；类固醇与安慰剂比较：率比3.32，95%CI 0.71至15.62，参与者 = 11，一项试验。不良事件（比例）：效应估计值：类固醇与安慰剂比较：比值比20.00，95%CI 0.93至429.90，参与者 = 11，一项试验；熊去氧胆酸与安慰剂比较：比值比1.22，95%CI 0.68至2.17，参与者 = 198，一项试验；万古霉素与安慰剂比较：因两组均无事件发生无法估计，参与者 = 29，一项试验。不良事件（数量）：效应估计值：环孢素与安慰剂比较：率比2.64，95%CI 0.99至7.03，参与者 = 26，一项试验；类固醇与安慰剂比较：率比3.32，95%CI 0.71至15.62，参与者 = 11，一项试验；熊去氧胆酸加甲硝唑与熊去氧胆酸比较：率比2.36，95%CI 0.98至5.71，参与者 = 71，一项试验。健康相关生活质量：熊去氧胆酸与安慰剂比较：平均差值1.30，95%CI -5.61至8.21，参与者 = 198，一项试验（简短健康调查问卷（SF）-36总体健康量表）。次要结局研究未提供证据表明在诸如肝移植需求减少或胆管癌发病率降低等临床获益方面存在差异。一项比较万古霉素与安慰剂的小型试验（29名参与者）在治疗后12周的极短随访期后报告两组均无恶性肿瘤、无肝失代偿且无肝移植。其余试验均未明确报告其他临床获益，如所有恶性肿瘤、结直肠癌、肝失代偿的发生率降低，肝失代偿时间、肝移植时间或胆囊切除术需求，因此无法在不同干预措施之间进行比较。
15项试验报告了资金来源；3项由对试验结果无既得利益的机构资助，12项部分或全部由制药公司资助。
目前证据不足，无法表明任何积极药物干预与不干预在死亡率、健康相关生活质量、肝硬化或肝移植等有效性指标上存在差异。然而，试验存在较高偏倚风险，参与者数量少，随访期短，且报告的临床结局较少。迫切需要通过设计良好且有充分随访的RCT来确定原发性硬化性胆管炎的有效药物治疗方法，这些试验旨在识别对原发性硬化性胆管炎患者重要的结局差异。
