EDS HM and other subtypes should be considered in patients with chronic functional GI symptoms and abdominal vascular lesions.

Running title: Network meta-analysis of pharmacological agents for treatment of CIC Word count: 3745 (excluding abstract, summary box, acknowledgements, disclosures, references, table and figure legends) Key words: bisacodyl, elobixibat, linaclotide, lubiprostone, picosulfate, polyethylene glycol, prucalopride, tegaserod, velusetrag Abbreviations: chronic idiopathic constipation (CIC) numbers needed to treat (NNT) sodium picosulfate (NaP) polyethylene glycol (PEG) complete spontaneous bowel movements (CSBM) spontaneous bowel movements (SBM) weighted mean difference (WMD) confidence interval (CI) Study Selection: Phase IIB and phase III randomized, placebo-controlled trials (RCT) of ≥4weeks' treatment for CIC in adults with Rome II or III criteria for functional constipation; trials included at least 1 of 4 endpoints. Data Extraction and Synthesis:Two investigators independently evaluated all full text articles that met inclusion criteria and extracted data for primary and secondary endpoints, risk of bias and quality of evidence.Outcomes: Primary endpoints were ≥3 complete spontaneous bowel movements (CSBM)/week and increase over baseline by ≥1 CSBM/week. Secondary endpoints were change from baseline (∆ b ) in the number of SBM/week and ∆ b CSBM/week.Results: Twenty-one RCTs (9189 patients) met inclusion and endpoint criteria: 9 prucalopride, 3 lubiprostone, 3 linaclotide, 2 tegaserod, 1 each velusetrag, elobixibat, bisacodyl and sodium picosulphate (NaP). All pre-specified endpoints were unavailable in 4 polyethylene glycol studies. Bisacodyl, NaP, prucalopride and velusetrag were superior to placebo for the ≥3 CSBM/week endpoint. No drug was superior at improving the primary endpoints on network meta-analysis. Bisacodyl appeared superior to the other drugs for the secondary endpoint, ∆ b in number of SBM/week.

Overall, the test with the highest diagnostic yield conducted in the largest number of studies was SeHCAT retention, which is not widely available in many countries outside Europe and Canada. Using different diagnostic tests, 25% (average) of patients with lower FBD with diarrhoea has evidence of idiopathic BAD. These tests serve to identify idiopathic BAD among patients with FBD with diarrhoea. Further studies are required to appraise the performance characteristics of tests for idiopathic BAD.

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