Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis Ford AC, Brandt LJ, Young C, Chey WD, Foxx-Orenstein AE, Moayyedi P

CRD summary The authors concluded that alosetron, cilansetron and tegaserod (drugs acting on 5-hydroxytryptamine receptors) were all effective in irritable bowel syndrome; serious adverse events were rare in trials included in this review. This was generally a well-conducted review and the authors’ conclusions are likely to be reliable.

Authors' objectives

To evaluate the effectiveness of 5-hydroxytryptamine3 (5-HT3) antagonists and 5-hydroxytryptamine4 (5-HT4) agonists in adults with irritable bowel syndrome (IBS).

Searching MEDLINE (from 1950), EMBASE (from 1980) and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched to June 2008 for studies in any language. Search terms were reported. Reference lists of identified studies were screened and abstract books of conference proceedings (2001 to 2007) were hand-searched. In addition, pharmaceutical companies were contacted and the US Food and Drug Administration (FDA) website was searched for unpublished studies.

Study selection

Randomised controlled trials (RCTs) that compared 5-HT3 antagonists or 5-HT4 agonists with placebo in adults (aged over 16 years) with irritable bowel syndrome (IBS) were eligible for inclusion. Treatment had to last at least seven days, as did follow-up. IBS could be diagnosed using physician opinion or symptom-based diagnostic criteria, with investigations to exclude organic disease if required. Studies had to report a global assessment of IBS symptoms cure or improvement or abdominal pain cure or improvement after completion of treatment (the primary review outcomes); patient self-reports were preferred. Secondary review outcomes were efficacy of individual agents, efficacy of various subgroups and adverse events.

The included trials evaluated: 5-HT3 antagonists (alosetron 0.1 to 8mg twice daily or cilansetron - reported as 3mg twice daily in text, but 2mg three times daily in trial characteristics table); 5-HT4 agonists (tegaserod 0.5 to 12mg twice daily); and mixed 5-HT3 antagonist/5-HT4 agonists (cisapride 5 to 10mg thrice daily or renzapride 1 to 4mg daily). In most included trials, females predominated. The majority of patients had diarrhoea-dominated IBS in 5-HT3 antagonist trials and constipation-dominated IBS in 5-HT4 agonist and mixed 5-HT3 antagonist/5-HT4 agonists trials. All of the included trials used Rome criteria (unspecified or I or II criteria) to diagnose IBS. Treatment duration ranged from 11 days up to 48 weeks, but treatment duration was 12 weeks in most trials.

Abstracts were screened by one reviewer. Two reviewers then independently selected studies from those identified. Disagreements were resolved by consensus.

Assessment of study quality Two reviewers independently assessed validity using the Jadad criteria (randomisation, blinding and withdrawals).

Data extraction Two reviewers independently extracted intention-to-treat (ITT) data as dichotomous outcomes using a spreadsheet to calculate relative risks (RRs) and 95% confidence intervals (CI) for persistence of symptoms (global IBS symptoms or abdominal pain). Drop-outs were assumed to be treatment failures. Some authors were contacted for clarification and additional data.

Methods of synthesis Pooled relative risks and 95% confidence intervals for the persistence of symptoms and adverse events were calculated

Page: 1 / 3 using a random-effects model. Numbers-needed-to-treat (NNT) or numbers-needed-to-harm (NNH) with 95% confidence intervals were calculated. Heterogeneity was assessed using the I 2 statistic (values less than 25% were considered to indicate a low level of heterogeneity). Subgroup analysis was used to examine the influence of IBS subtype, gender, dose and treatment duration. The possibility of publication bias was explored using funnel plots and Egger’s test.

Results of the review Twenty-nine double-blind RCTs were included (n=17,818 patients). Twenty-seven trials scored 4 or 5 on the Jadad quality scale.

5-HT3 antagonists (11 trials; 7,216 patients): Eight studies evaluated alosetron (n=4,987 patients) and three evaluated cilansetron (n=2,229 patients). 5-HT3 antagonists were associated with a statistically significant decrease in the proportion of patients with persistent symptoms compared with placebo (RR 0.78, 95% CI 0.71 to 0.86; NNT 7, 95% CI 5 to 11). Significant heterogeneity was found (I2=80%). There was no evidence of publication bias. The association remained significant with both alosetron (RR 0.79, 95% CI 0.69 to 0.90; I2=85%) and cilansetron (RR 0.75, 95% CI 0.69 to 0.82; I2=30%).

Adverse events were significantly increased with alosetron compared with placebo (64% versus 55%; RR 1.19, 95% CI 1.09 to 1.30; NNH 10, 95% CI 7 to 15; seven studies). There was no significant difference in serious adverse events between alosetron and placebo. Four patients developed ischaemic colitis. None of the cilansetron studies reported adverse events.

5-HT4 agonists (11 trials of tegaserod, 9,242 patients): 5-HT4 agonists were associated with a statistically significant decrease in the proportion of patients with persistent symptoms compared with placebo (55% versus 63.5%; RR 0.85, 95% CI 0.80 to 0.90; NNT 10, 95% CI 8 to 14). Significant heterogeneity was found (I2=57%). There was evidence of publication bias (asymmetrical funnel plot and Egger’s test p=0.04). There was no significant difference in adverse events between tegaserod and placebo. Two cardiovascular events were reported with tegaserod.

Mixed 5-HT3 antagonists/5-HT4 agonists (seven trials, 1,043 patients, including four trials of cisapride with 317 patients): There was no significant difference between mixed 5-HT3 antagonists/ 5-HT4 agonists and placebo in the proportion of patients with persisting IBS symptoms (64% versus 57%; I2=59%) for cisapride and renzapride whether combined or compared separately with placebo. There was no evidence of publication bias. Renzapride was associated with a statistically significant increase in diarrhoea (RR 2.17, 95% CI 1.26 to 3.74; three trials). There was no significant difference in adverse events between cisapride and placebo (three studies).

Results of other sub-group analyses were also reported.

Authors' conclusions Alosetron, cilansetron and tegaserod were all effective in the treatment of irritable bowel syndrome. Serious adverse events were rare in the eligible RCTs in this review. The authors stated that the US Food and Drug Administration considered that the risks of alosetron, cilansetron and tegaserod are sufficiently severe to require that their use is restricted.

CRD commentary The review question was clearly stated and inclusion criteria were appropriately defined. Several relevant sources were searched and attempts were made to minimise publication and language bias. However, there was evidence of publication bias for the 5-HT4 studies, suggesting a lack of small non-significant studies. Methods were used to minimise reviewer errors and bias in the selection of studies, extraction of data and assessment of validity.

Study validity was assessed and results were reported. Study details were provided and, in general, appropriate methods were used for the meta-analyses, with the use of random-effects models, assessment of heterogeneity and the conducting of various predefined subgroup analyses. However, pooling data in the presence of high heterogeneity identified for some analyses was questionable.

This was generally a well-conducted review and the authors' conclusions are likely to be reliable. Page: 2 / 3 Several of the authors disclosed that they had received consultancy and/or speakers fees from various pharmaceutical companies.

Implications of the review for practice and research Practice: The authors stated that since alosetron, cilansetron and tegaserod appear to have only a modest effect on efficacy in IBS, the risk-benefit ratio needs to be considered before they are prescribed. Despite safety concerns, the use of these drugs should be considered for patients who have failed conventional first- or second-line therapies.

Research: The authors did not state any implications for research.

Funding American College of Gastroenterology.

Bibliographic details Ford AC, Brandt LJ, Young C, Chey WD, Foxx-Orenstein AE, Moayyedi P. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis. American Journal of Gastroenterology 2009; 104(7): 1831-1843

PubMedID 19471254

DOI 10.1038/ajg.2009.223

Original Paper URL http://www.nature.com/ajg/journal/v104/n7/abs/ajg2009223a.html

Indexing Status Subject indexing assigned by NLM

MeSH Adult; Age Factors; Aged; Carbazoles /administration & dosage /adverse effects; Carbolines /administration & dosage /adverse effects; Dose-Response Relationship, Drug; Drug Administration Schedule; Education, Medical, Continuing; Female; Humans; Indoles /administration & dosage /adverse effects; Irritable Bowel Syndrome /diagnosis /drug therapy; Male; Middle Aged; Patient Satisfaction; Pyridines /administration & dosage /adverse effects; Quality of Life; Randomized Controlled Trials as Topic; Risk Assessment; Serotonin Antagonists /administration & dosage /adverse effects; Severity of Illness Index; Sex Factors; Treatment Outcome

AccessionNumber 12009107232

Date bibliographic record published 16/12/2009

Date abstract record published 16/06/2010

Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

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