Centre for Gastroenterology, Royal Free Hospital, London, UK.
Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, MN, USA.
Lancet Gastroenterol Hepatol. 2019 Nov;4(11):831-844. doi: 10.1016/S2468-1253(19)30246-8. Epub 2019 Aug 29.
There are several drugs available for the treatment of chronic idiopathic constipation, but their relative efficacy is unclear because there have been no head-to-head randomised controlled trials. We did a network meta-analysis to compare the efficacy of these therapies in patients with chronic idiopathic constipation.
We searched Medline, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials for randomised controlled trials published from inception to week 3 June, 2019, to identify randomised controlled trials assessing the efficacy of drugs (osmotic or stimulant laxatives, elobixibat, linaclotide, lubiprostone, mizagliflozin, naronapride, plecanatide, prucalopride, tegaserod, tenapanor, or velusetrag) in adults with chronic idiopathic constipation. Participants had to be treated for a minimum of 4 weeks, and we extracted data for all endpoints preferentially at 4 weeks, 12 weeks, or both. Trials included in the analysis reported a dichotomous assessment of overall response to therapy (response or no response to therapy). We pooled the data using a random effects model, and reported efficacy and safety of all treatments as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested. To rank treatments, we used P-scores, which measure the extent of certainty that a treatment is better than another treatment, averaged over all competing treatments.
We identified 33 eligible randomised controlled trials of drugs, comprising 17 214 patients. Based on an endpoint of failure to achieve three or more complete spontaneous bowel movements (CSBMs) per week, the stimulant diphenyl methane laxatives bisacodyl and sodium picosulfate, at a dose of 10 mg once daily, were ranked first at 4 weeks (RR 0·55, 95% CI 0·48-0·63, P-score 0·99), and prucalopride 2 mg once daily ranked first at 12 weeks (0·82, 0·78-0·86, P-score 0·96). When response to therapy was defined as falilure to achieve an increase of one or more CSBM per week from baseline, diphenyl methane laxatives at a dose of 10 mg once daily ranked first at 4 weeks (0·44, 0·37-0·54, P-score 0·99), with prucalopride 4 mg once daily ranked first at 12 weeks (0·74, 0·66-0·83, P-score 0·79), although linaclotide 290 μg once daily and prucalopride 2 mg once daily had similar efficacy (P-scores of 0·76 and 0·71, respectively). Bisacodyl ranked last in terms of safety for total number of adverse events and abdominal pain (P-score 0·08).
Almost all drugs studied were superior to placebo, according to either failure to achieve three or more CSBMs per week or or failure to achieve an increase of one or more CSBM per week over baseline. Although diphenyl methane laxatives ranked first at 4 weeks, patients with milder symptoms might have been included in these trials. Prucalopride ranked first at 12 weeks, and many of the included trials recruited patients who previously did not respond to laxatives, suggesting that this drug is likely to be the most efficacious for patients with chronic idiopathic constipation. However, because treatment duration in most trials was 4-12 weeks, the long-term relative efficacy of these drugs is unknown.
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有几种药物可用于治疗慢性特发性便秘，但由于没有头对头的随机对照试验，其相对疗效尚不清楚。我们进行了一项网状荟萃分析，以比较这些治疗方法在慢性特发性便秘患者中的疗效。
我们检索了 Medline、Embase、Embase Classic 和 Cochrane 对照试验中心注册库，以确定从开始到 2019 年 6 月第 3 周发表的评估药物（渗透或刺激性泻药、埃索美拉唑、利那洛肽、鲁比前列酮、米格列醇、那罗曲肽、普卡必利、替加色罗、替扎尼定、Tenapanor 或 Velusetrag）治疗慢性特发性便秘成人疗效的随机对照试验。参与者必须接受至少 4 周的治疗，我们优先在 4 周、12 周或两者均提取所有终点的数据。纳入分析的试验报告了总体治疗反应（治疗有反应或无反应）的二分法评估。我们使用随机效应模型汇总数据，并以汇总相对风险（RR）和 95%置信区间（CI）报告所有治疗的疗效和安全性，以总结每个比较测试的效果。为了对治疗方法进行排名，我们使用 P 分数，它衡量一种治疗方法优于另一种治疗方法的程度，在所有竞争治疗方法中平均。
我们确定了 33 项关于药物的合格随机对照试验，包括 17214 名患者。根据每周未能达到 3 次或更多完全自发性排便（CSBM）的终点，刺激性二苯甲烷类泻药比沙可啶和聚乙二醇 10mg 每日 1 次的治疗方法在第 4 周排名第一（RR 0·55，95%CI 0·48-0·63，P 分数 0·99），普卡必利 2mg 每日 1 次在第 12 周排名第一（0·82，0·78-0·86，P 分数 0·96）。当治疗反应定义为每周与基线相比增加 1 次或更多 CSBM 时，每日 10mg 剂量的二苯甲烷类泻药在第 4 周排名第一（0·44，0·37-0·54，P 分数 0·99），每日 1 次 4mg 普卡必利在第 12 周排名第一（0·74，0·66-0·83，P 分数 0·79），尽管利那洛肽 290μg 每日 1 次和普卡必利 2mg 每日 1 次的疗效相似（P 分数分别为 0·76 和 0·71）。由于总不良事件和腹痛的数量，比沙可啶的安全性最差（P 分数 0·08）。
根据每周未能达到 3 次或更多 CSBM 或每周与基线相比未能增加 1 次或更多 CSBM 的终点，几乎所有研究的药物均优于安慰剂。虽然二苯甲烷类泻药在第 4 周排名第一，但这些试验可能包括了症状较轻的患者。普卡必利在第 12 周排名第一，许多纳入的试验招募了以前对泻药无反应的患者，这表明该药对慢性特发性便秘患者可能最有效。然而，由于大多数试验的治疗持续时间为 4-12 周，这些药物的长期相对疗效尚不清楚。
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