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PostScript

LETTERS

Ondansetron and irritable bowel syndrome We read the paper by Garsed et al,1 which revives interest in 5hydroxytryptamine (5-HT) receptor antagonists as treatment for diarrhoeapredominant irritable bowel syndrome (IBS-D). As a highly prevalent functional gastrointestinal (GI) disorder,2 without a known organic pathology to target, IBS continues to be challenging to treat. Interest in agents acting on 5-HT receptors selectively is not novel, with alosetron, the most well-studied 5-HT3 antagonist, demonstrating efficacy in treating IBS-D.3 However, cases of severe constipation and ischaemic colitis led to the withdrawal of the drug. Ondansetron first demonstrated effects on GI transit over 20 years ago.4 Given the known clinical effectiveness of 5-HT3 antagonists in IBS, and the good safety profile of ondansetron, it is perhaps surprising that no randomised controlled trial has been conducted previously. At a time when licensed treatment options for IBS-D are lacking, we would like to congratulate the authors for performing this trial. The study demonstrated a significant improvement in stool form, the primary endpoint, a reduction in the number of days with urgency, and reduced urgency scores with ondansetron, compared with placebo. When applying the Food and Drug Administration (FDA) guidelines for assessing pharmacological agents in treating IBS,5 ondansetron achieved a greater percentage of stool and pain responders (41%) than placebo (17%), although this result was not statistically significant. Unfortunately, there was no significant effect on abdominal pain, with FDA pain response criteria met by 43% with ondansetron, and 40% with placebo. Adverse events were limited with both treatments, although rates of constipation were higher with ondansetron. Reassuringly, no cases of ischaemic colitis were seen, although this is not surprising given the relatively small sample size. While the findings are important and may alter clinical practice, there are some limitations of the study. As with all crossover studies, there is the problem of carryover and order effects between crossover periods, which often cannot be completely adjusted for. Despite the 2–3-week washout period between treatments, the heterogeneous, fluctuating nature of IBS,

along with high placebo response rates,6 makes it difficult to be sure that there is no carryover between treatment periods. Additionally, patient dropout rates were almost double in the arm receiving active treatment first, as compared to the arm receiving placebo first, suggesting an order effect, where patient dropout may be influenced by the sequence of treatment. These dropouts were omitted from the final analysis of the study and, hence, a true intention-to-treat analysis was not carried out. With this in mind, we feel the efficacy of ondansetron in treating IBS-D could be better judged if the authors had presented dichotomous data for pain and stool response for all 61 patients receiving ondansetron, and all 59 receiving placebo in the first treatment period, prior to crossover, with all dropouts assumed to be treatment failures. Pavit Luthra,1 Alexander C Ford1,2 1 Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, UK 2 Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK

Correspondence to Alexander C Ford, Leeds Gastroenterology Institute, Room 125, 4th Floor, Bexley Wing, St. James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK; [email protected] Competing interests None. Provenance and peer review Not commissioned; internally peer reviewed.

To cite Luthra P, Ford AC. Gut 2015;64:1181. Published Online First 20 May 2014 Gut 2015;64:1181. doi:10.1136/gutjnl-2014-307551

REFERENCES 1

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Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut 2014; 63:1617–25. Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol 2012;10:712–21. Ford AC, Brandt LJ, Young C, et al. Efficacy of 5-HT3 Antagonists and 5-HT4 Agonists in Irritable Bowel Syndrome: systematic review and meta-analysis. Am J Gastroenterol 2009;104:1831–43. Talley NJ, Phillips SF, Haddad A, et al. GR 38032F (ondansetron), a selective 5HT3 receptor antagonist, slows colonic transit in healthy man. Dig Dis Sci 1990;35:477–80. U.S Department of Health and Human Services. Food and Drug Administration. Guidance for Industry: Irritable Bowel Syndrome- Clinical Evaluation for Drugs for Treatment. http://www.fda.gov/downloads/Drugs/ Guidances/UCM205269.pdf (accessed Apr 2014). Ford AC, Moayyedi P. Meta-analysis: factors affecting placebo response rate in the irritable bowel syndrome. Aliment Pharmacol Ther 2010;32:144–58.

Gut July 2015 Vol 64 No 7

An endoscopic Mayo score of 0 is associated with a lower risk of colectomy than a score of 1 in ulcerative colitis Dear Sir, In a recent article1 we showed that correlation between histological indexes is strong for ulcerative colitis (UC). Due to the lack of intervention studies and the absence of a validated histological index, histological healing cannot be considered as a treatment goal in clinical practice for these patients. Pending these studies, we need to define the therapeutic goal for patients with UC. In the ACT 1 and 2 clinical trials,2 early mucosal healing defined by an endoscopic Mayo score (EMS) of 0–1 was associated with a lower risk of colectomy through 54 weeks of follow-up evaluation and better long-term outcomes related to symptomatic remission, corticosteroid-free symptomatic remission and corticosteroid use, and subsequent mucosal healing at weeks 30 and 54. With the exception of colectomy outcomes, an EMS of 0 at week 8 was associated with a greater proportion of patients with long-term clinical benefit.2 Among patients with clinical remission at week 8, an EMS of 0 versus 1 did not predict subsequent colectomy, symptomatic remission, corticosteroid-free remission or sustained mucosal healing.2 However, the duration of follow-up was too short, only 54 weeks, to show a statistically significant difference between an EMS of 0 and an EMS of 1 in terms of colectomy rates.2 In a French multicentre study,3 we previously showed that patients with refractory UC who achieved mucosal healing after infliximab initiation had better long-term outcomes, with significantly less colectomy and less infliximab failure after a median follow-up duration of 27 months. However, we did not compare an EMS of 0 with an EMS of 1.3 Using a well defined referral centrebased cohort, namely the Nancy IBD cohort,4 we investigated whether an EMS of 0 may be associated with better outcomes than an EMS of 1 in UC. Patients with an established diagnosis of UC were followed until January 2014. Survival curves were estimated by the Kaplan–Meier method and compared using a log rank statistic. Time to colectomy from the date of first endoscopic evaluation was calculated. Only patients with an EMS of 0 or 1 were included in the analysis. Of the 55 patients, 52.7% were women (n=29). The 1181

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Ondansetron and irritable bowel syndrome Pavit Luthra and Alexander C Ford Gut 2015 64: 1181 originally published online May 20, 2014

doi: 10.1136/gutjnl-2014-307551 Updated information and services can be found at: http://gut.bmj.com/content/64/7/1181.1

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Ondansetron and irritable bowel syndrome.

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