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ABSTRACTBackgroundSurrogate endpoints such as laboratory parameters that are not direct measurements of, but predict, clinical benefit are approved by regulatory agencies for initial proof of efficacy. No surrogate endpoints are approved for disorders of gut–brain interaction.AimTo assess the correlation of scintigraphic colonic transit (CT) with response rates according to patient‐reported symptom‐based endpoints (composite/global symptoms, abdominal pain or stool frequency/consistency) in irritable bowel syndrome (IBS) or chronic idiopathic constipation (CIC).MethodsWe reviewed available data from, randomised controlled trials (RCTs) reporting effects on CT at 24 h and 48 h with drug versus placebo and extracted the difference in the proportions responding to drug or placebo, using rates from individual RCTs or from meta‐analyses when more than one RCT existed for a drug. We analysed associations between differences (drug vs. placebo) in CT and in response rates using Spearman correlation. Additional analyses of CT at 24 h with composite/global symptom or pain endpoints were performed with exclusion of alosetron (the only drug slowing CT).ResultsCT at 24 h correlated significantly with composite/global symptom endpoints (Rs = −0.755, p = 0.021). CT correlated with stool frequency or consistency (at 24 h, Rs = 0.506, p = 0.074; at 48 h, Rs = 0.631, p = 0.026). CT at 24 h did not correlate with abdominal pain (Rs = −0.054, p = 0.843). With the exclusion of alosetron data, CT at 24 h was non‐significantly correlated with the composite/global symptom endpoint (Rs = −0.667, p = 0.073), but not with abdominal pain (Rs = 0.377, p = 0.419).ConclusionScintigraphic CT measurement fulfils the expectation of a surrogate endpoint for symptom‐based outcomes, particularly in IBS‐D or IBS‐C and CIC.

AbstractBackgroundThere are minimal epidemiological data comparing the burden of disorders of gut brain interaction (DGBI) in the UK with other countries. We compared the prevalence of DGBI in the UK with other countries that participated in the Rome Foundation Global Epidemiology Study (RFGES) online.MethodsParticipants from 26 countries completed the RFGES survey online including the Rome IV diagnostic questionnaire and an in‐depth supplemental questionnaire with questions about dietary habits. UK sociodemographic and prevalence data were compared with the other 25 countries pooled together.Key ResultsThe proportion of participants with at least one DGBI was lower in UK participants compared with in the other 25 countries (37.6% 95% CI 35.5%–39.7% vs. 41.2%; 95% CI 40.8%–41.6%,p = 0.001). The UK prevalence of 14 of 22 Rome IV DGBI, including irritable bowel syndrome (4.3%) and functional dyspepsia (6.8%), was similar to the other countries. Fecal incontinence, opioid‐induced constipation, chronic nausea and vomiting, and cannabinoid hyperemesis (p < 0.05) were more prevalent in the UK. Cyclic vomiting, functional constipation, unspecified functional bowel disorder, and proctalgia fugax (p < 0.05) were more prevalent in the other 25 countries. Diet in the UK population consisted of higher consumption of meat and milk (p < 0.001), and lower consumption of rice, fruit, eggs, tofu, pasta, vegetables/legumes, and fish (p < 0.001).Conclusions and InferencesThe prevalence and burden of DGBI is consistently high in the UK and in the rest of the world. Opioid prescribing, cultural, dietary, and lifestyle factors may contribute to differences in the prevalence of some DGBI between the UK and other countries.

INTRODUCTION: These post hoc analyses provide clinically relevant data concerning time to response for individual irritable bowel syndrome with constipation (IBS-C) symptoms after linaclotide use. METHODS: Time-to-response data were pooled from 4 randomized controlled trials. Response time for abdominal symptoms (pain, discomfort, and bloating) and complete spontaneous bowel movements (CSBMs) were analyzed using the Kaplan-Meier method; patients were categorized as early responders (≤4 weeks), late responders (>4–12 weeks), or nonresponders. RESULTS: Among 2,350 patients (1,172 placebo and 1,178 linaclotide 290 μg), >50% of patients with IBS-C who initiated linaclotide treatment experienced a decrease of ≥30% in abdominal pain, discomfort, or bloating within 3–4 weeks (median). The median time to achieving ≥3 CSBMs was 4 weeks. Although not all linaclotide-treated patients responded within 12 weeks, a late response occurred between 4 and 12 weeks in 1 in 6 patients for abdominal pain and in approximately 1 in 10 patients for CSBM frequency. Comparisons of early responders, late responders, and nonresponders for both response definitions indicated that women, Whites, and patients with less severe baseline abdominal symptoms were more likely to respond early. DISCUSSION: Although treatment responses with linaclotide occurred in >50% of patients with IBS-C within 4 weeks of treatment initiation, benefits for individual abdominal symptoms and/or CSBM frequency can still occur between 4 and 12 weeks. A lack of improvement in one symptom does not negate the possibility of response for others, highlighting the importance of discussing all symptoms with patients and not assuming treatment futility at 4 weeks.

Objectives The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) showed no difference in the composite endpoint of stroke, myocardial infarction, or death between carotid artery stenting (CAS) and carotid endarterectomy (CEA) in patients with symptomatic or asymptomatic carotid stenosis (CS). We compared restenosis or occlusion, and repeat revascularization, between CAS and CEA over 2 years of follow-up. Methods Restenosis, occlusion, and repeat revascularization were assessed at 1, 6, 12 and 24 months post-randomization. Hemodynamically significant restenosis (≥70% diameter reduction) was defined by a peak systolic velocity (PSV) ≥300 cm/second on standardized duplex ultrasonography (DUS), occlusion by an absence of flow within the target artery on DUS, and repeat revascularization by any additional procedure (CEA, angioplasty or CAS) performed on the index artery. Studies were performed in CREST-certified laboratories and interpreted in the CREST Ultrasound Core Lab. Patients included in this report were those who received their assigned treatment within 30 days of randomization and had an ultrasound reviewed at the Core Lab (n=2191). Treatment differences were assessed using proportional hazards models adjusting for age, sex, and symptomatic status. Results In the analytic cohort, 1086 patients received CAS and 1105 received CEA. Over 2 years 113 patients developed restenosis, 56 (rate 5.8%) in the CAS group and 57 (rate 5.8%) in the CEA group; and 8 developed an occlusion, 3 (rate 0.3 %) in the CAS group and 5 (rate 0.5%) in the CEA group. The combined restenosis-occlusion rate was 6.0% (n=58) for CAS and 6.3% (n=62) for CEA (HR=0.90, 95% CI=0.63-1.29, p=0.58). Forty-three patients of the 2191 underwent repeat revascularization (20 CAS, 23 CEA, p=0.69) of which 28 had restenosis by our criteria and so were included ( Figure ). Stroke occurred in 13 (4 CAS; 9 CEA) of the 120 patients with restenosis or occlusion; 1 of the 4 CAS strokes occurred after restenosis was detected, and 5 of 9 CEA strokes occurred after restenosis was detected. Conclusions This analysis of carotid restenosis is the largest reported to date from any randomized clinical trial. Restenosis and occlusion were infrequent and similar up to 2 years following CAS or CEA among 2191 patients. The rates of revascularization likewise did not differ between CAS and CEA. Follow-up out to 10 years is ongoing. Figure. Kaplan-Meier curves of restenosis and occlusion over 2 years.

LINKED CONTENTThis article is linked to Nelson et al and Vasant papers. To view these articles, visit https://doi.org/10.1111/apt.16437 and https://doi.org/10.1111/apt.16440

SummaryBackgroundAlthough bloating is a highly prevalent and troublesome symptom in irritable bowel syndrome with constipation (IBS‐C), treatment is empirical with no specific guidelines for its management.AimTo conduct a pairwise and network meta‐analysis, using a frequentist approach, of Food and Drug Administration‐licensed drugs for IBS‐C comparing their efficacy for abdominal bloating as a specific endpoint.MethodsWe searched the medical literature through December 2020 to identify randomised controlled trials (RCTs) in IBS‐C, with abdominal bloating reported as a dichotomous assessment. Efficacy of each drug was reported as a pooled relative risk (RR) with 95% confidence intervals (CIs) to summarise effect of each comparison tested. Treatments were ranked according to their P‐score.ResultsWe identified 13 eligible RCTs, containing 10 091 patients. Linaclotide 290 µg o.d., lubiprostone 8 µg b.d., tenapanor 50 mg b.d. and tegaserod 6 mg b.d. were all superior to placebo for abdominal bloating in patients with IBS‐C, in both pairwise and the network meta‐analyses. Linaclotide demonstrated the greatest improvement in abdominal bloating in both pairwise and network meta‐analysis (RR of failure to achieve an improvement in abdominal bloating = 0.78; 95% CI 0.74‐0.83, number needed to treat = 7, P‐score 0.97). Indirect comparison revealed no significant differences between individual drugs.ConclusionsWe found all licensed drugs for IBS‐C to be superior to placebo for abdominal bloating. Linaclotide appeared to be the most efficacious at relieving abdominal bloating. Further research is needed to assess long‐term efficacy of these agents and to better understand the precise mechanism of improving bloating.

Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.