This is a repository copy of Efficacy of drugs in chronic idiopathic constipation: a systematic review and network meta-analysis. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/150676/ Version: Accepted Version Article: Luthra, P, Camilleri, M, Burr, NE orcid.org/0000-0003-1988-2982 et al. (3 more authors) (2019) Efficacy of drugs in chronic idiopathic constipation: a systematic review and network meta-analysis. The lancet. Gastroenterology & Hepatology, 4 (11). pp. 831-844. ISSN 2468-1253 https://doi.org/10.1016/s2468-1253(19)30246-8 © 2019 Elsevier Ltd. All rights reserved. Licensed under the Creative Commons Attribution-Non Commercial No Derivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/). Reuse This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can’t change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Luthra et al. 1 of 43 Accepted 2nd July 2019 TITLE PAGE Title: Efficacy of Pharmacological Therapies in Chronic Idiopathic Constipation: Systematic Review and Network Meta-analysis. Short running head: Network Meta-analysis of Pharmacological Therapies in Constipation. Authors: Pavit Luthra MBChB1, Professor Michael Camilleri MD2, Nicholas E. Burr MBBS3,4, Professor Eamonn MM Quigley MD5, Christopher J. Black MBBS*3,4, Professor Alexander C Ford MD*3,4. *Denotes joint last author 1Centre for Gastroenterology. Royal Free Hospital, London, UK. 2Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, MN, USA. 3Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, UK. 4Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, UK. 5Division of Gastroenterology and Hepatology, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas, USA. Abbreviations: 5-HT 5-hydroxytryptamine b.i.d. twice daily Luthra et al. 2 of 43 CI confidence interval CIC chronic idiopathic constipation CSBM complete spontaneous bowel movement FDA Food and Drug Administration MeSH medical subject heading o.d. once daily PAC-QOL patient assessment of constipation quality of life RCT randomised controlled trial RR relative risk SBM spontaneous bowel movement Correspondence: Professor Alexander C. Ford Leeds Gastroenterology Institute Room 125 4th Floor Bexley Wing St. James’s University Hospital Beckett Street Leeds LS9 7TF UK email: [email protected] Telephone: 07887603665 Facsimile: 01133926968 Luthra et al. 3 of 43 Key words: CSBMs RCT comparison effectiveness treatment response Word count: 5023 Luthra et al. 4 of 43 SUMMARY Background: There are several pharmacological therapies available for the treatment of chronic idiopathic constipation (CIC), but their relative efficacy is unclear because there have been no head-to-head randomised controlled trials (RCTs). We conducted a network meta- analysis to compare their efficacies in patients with CIC. Methods: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials through June 2019 to identify RCTs assessing the efficacy of pharmacological therapies in adults with CIC. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of all treatments were reported as a pooled relative risk with 95% CIs to summarise the effect of each comparison tested, and treatments were ranked according to their P-score. Findings: We identified 33 separate eligible RCTS of pharmacological therapies, containing 17,214 patients. Based on an endpoint of failure to achieve ≥3 complete spontaneous bowel movements (CSBMs) per week, the stimulant diphenyl methane laxatives bisacodyl and sodium picosulfate, at a dose of 10mg once-daily, were ranked first at 4 weeks (RR 0.55; 95% CI 0.48 to 0.63, P-score = 0.99), and prucalopride 2mg once-daily was ranked first at 12 weeks (RR 0.82; 95% CI 0.78 to 0.86, P-score = 0.96). When failure to achieve an increase of ≥1 CSBM per week from baseline was used, again diphenyl methane laxatives at a dose of 10mg once-daily were ranked first at 4 weeks (RR 0.44; 95% CI 0.37 to 0.54, P-score = 0.99), with prucalopride 4mg once-daily ranked first at 12 weeks (RR = 0.74; 95% CI 0.66 to 0.83, P-score 0.79), although linaclotide 290g once-daily and prucalopride 2mg once-daily performed similarly. Bisacodyl was ranked last in terms of safety for total number of adverse events and abdominal pain. Luthra et al. 5 of 43 Interpretation: Almost all pharmacological therapies studied were superior to placebo, according to either failure to achieve ≥3 CSBMs per week or an increase of ≥1 CSBM per week over baseline. Although diphenyl methane laxatives were ranked first for efficacy at 4 weeks, a milder spectrum of patients may have been treated in these trials. Prucalopride was ranked first at 12 weeks, and many of the included trials recruited patients who had previously failed laxatives, suggesting that this drug is likely to be the most efficacious for patients with CIC. However, since treatment duration in most trials was 4 to 12 weeks, the long term relative efficacy of these drugs is unknown. Funding: None. Luthra et al. 6 of 43 RESEARCH IN CONTEXT Evidence before this study Chronic idiopathic constipation (CIC) affects as many as 14% of the general population. Randomised controlled trials (RCTs) demonstrate that laxatives and other newer pharmacological therapies are effective for the treatment of CIC. However, there is limited information concerning their relative efficacy. A previous systematic review and network meta-analysis of RCTs was published in 2017, but the literature search was done in 2015, and more RCTs have been published in the intervening 4 years, as well as trials of newer drugs. Added value of this study We have conducted a contemporaneous systematic review and network meta-analysis of RCTs reporting the effect of pharmacological therapies in CIC. Analyses according to different efficacy endpoints and duration of therapy were conducted, as well as effect on quality of life and adverse events. Implications of all the available evidence Diphenyl methane laxatives were ranked first for efficacy at 4 weeks, when failure to achieve either ≥3 CSBMs per week or an increase of ≥1 CSBM per week over baseline were used to define response to therapy, and were superior to almost all other treatments. However, trials of these drugs may have recruited a milder spectrum of patients, who were not laxative resistant. At 12 weeks of treatment, prucalopride 2mg or 4mg o.d. were ranked first, and appeared superior to several other drugs and dosages. As most RCTs were of 4 to 12 weeks duration, the longer term efficacy of these treatments is unknown. Luthra et al. 7 of 43 INTRODUCTION Chronic idiopathic constipation (CIC) is a chronic functional disorder of the lower gastrointestinal tract, characterised by persistently difficult, infrequent, or incomplete defecation, in the absence of any physiological abnormality. (1) The condition is common; a previous meta-analysis of cross-sectional community-based surveys estimated the prevalence worldwide at 14%. (2) As many as one-in-five people with symptoms compatible with CIC will consult a physician, (3) and the impact on quality of life for patients is comparable with that for organic conditions, such as chronic obstructive pulmonary disease, diabetes, and depression. (4) In a burden of illness study in the USA, constipation accounted for 3 million ambulatory visits and 800,000 emergency room visits. (5) Costs in the USA are estimated to be between $2000 and $7500 per patient per year. (6) Patients with CIC are often told to increase their dietary fibre intake in order to alleviate symptoms, but randomised controlled trial (RCT) evidence to support this strategy is lacking. (7) Although both osmotic and stimulant laxatives are beneficial for the treatment of CIC, (8) many patients report dissatisfaction with their efficacy and safety. (9) Other pharmacological therapies for the disorder have therefore been developed. Agonists at the 5- hydroxytryptamine-4 (5-HT4) receptor, such as tegaserod, naronapride, prucalopride, and velusetrag increase colonic motility and transit. (10, 11) Secretagogues such as lubiprostone, linaclotide, and plecanatide are drugs that act by stimulating intestinal fluid secretion, thereby accelerating gastrointestinal transit. (12, 13) Elobixibat is an inhibitor of the ileal bile acid transporter, which leads to delivery of bile acids into the colon, where they are deconjugated and increase colonic motility and secretion. (14) Finally, mizagliflozin and tenapanor are drugs that act on sodium-glucose co-transporters and sodium-hydrogen exchangers, respectively. Both drugs appear to have effects on stool consistency in healthy volunteers. (15, 16) Luthra et al. 8 of 43 Many of these pharmacological therapies, including osmotic and stimulant laxatives, have been tested in placebo-controlled trials, but their relative efficacy was unknown, until recently, because head-to-head trials are lacking. A network meta-analysis, published in 2017, (17) attempted to circumvent this limitation in the available evidence by making indirect treatment comparisons between all active therapies tested in placebo-controlled trials, up to March 2015. These included prucalopride, tegaserod, velusetrag, lubiprostone, linaclotide, bisacodyl, sodium picosulfate, and elobixibat.