CARE Gastroenterology Faculty Update from DDW 2013

Chronic Constipation & Canadian Perspectives from DDW 2013

The treatment of chronic constipation (CC) is an ongoing area of consideration for the CARE Gastroenterology Faculty with new treatments on the market, and a further pipeline of promising therapies on the horizon. Currently, there are a high number of referrals received by GI specialists for colon cancer investigation in patients with unresolved CC. This influx of referrals has not only a negative impact on resources, but can also be very unsettling for the patient who is being investigated for cancer unnecessarily. It is important to use available CC therapies as they have the ability to effectively treat CC when other therapies (fibre, diet and exercise, laxatives) fail. Resolving constipation with these therapies will eliminate the need for further investigation, and in turn, decrease the number of patients being referred to specialists. The following DDW 2013 abstract features one of these available therapies, prucalopride, a highly selective 5HT4 agonist for the treatment of CC. Prucalopride has been proven to effectively treat CC and improve quality of life. 


Abstract# Su2069: How Effective Is Prucalopride for the Treatment of Chronic Constipation? A Systematic Review and Meta-Analysis

Background: Chronic constipation is a challenging, albeit common, condition that impairs quality of life and, because of its high prevalence and chronicity, consumes significant healthcare resources. Our understanding of the pathophysiology of constipation remains incomplete, and available therapies have limited efficacy. Prucalopride is the first selective, high-affinity 5-HT4 agonist, with a predominantly enterokinetic effect, translating into significant clinical efficacy.

Methods: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials as well as abstracts from the major American, European and Asian meetings were searched up to November 2012. Large (≥ 250 patients) randomized controlled trials (RCTs) in adult patients with CC, treated with prucalopride, were included. Risk of bias for RCTs was assessed as described in the Cochrane handbook. Relative risks (with 95% CI) were computed using a random effects model in order to provide a more conservative estimate. The outcomes assessed were the number of patients with an average increase of ≥ 3 SCBM (spontaneous complete bowel movements) (at both 4 and 12 weeks), the number of patients with an average increase of ≥1 SCBM (at 12 weeks), the number of patients rating their treatment as extremely or quite a bit effective, improvement of ≥ 1 point (out of four) on the  PAC-QOL satisfaction score from baseline, as well as the use of laxative (both oral and enemas). Results were analyzed only if data were available from at least three RCTs for each variable considered.

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Results: Five studies, comparing different doses of prucalopride to placebo, were identified. They included more than 2,500 patients, most of whom were female (up to 92.5%). All studies were at low risks of bias. The results are shown below.

Conclusions/Key Take Away: Prucalopride is effective for treating CC and also significantly improves quality of life. The two regimens tested (i.e., 2 mg and 4 mg daily) provide a similar clinical benefit, with no evidence of dose-response effect.

Prucalopride is an enterokinetic which increases colonic peristalsis though stimulation of serotonin (5HT4) receptors in the gut. Canadian approval in early 2012 was based on data, including findings from three pivotal trials which demonstrated that prucalopride was effective in improving bowel function, constipation related symptoms, and quality of life in women with CC in whom laxatives have failed. Although the studies recruited both women and men, due to the larger proportion of women included, approval at this time is only for women. This abstract further confirms the outcome of the previous pivotal trials, in showing that patients with significant constipation symptoms had improved bowel movement frequency and satisfaction over placebo, including achieving the primary endpoint of ≥ 3 SCBM per week (the validated patient-reported outcome mandated by the FDA and European authorities, which equates to complete normalization of bowel function). Prucalopride is a highly selective 5-HT4 agonist with minimal cross-reactivity with other receptors, in contrast to previous 5HT4 agonists (cisapride and tegaserod) which had significant stimulation of other serotonin receptors or cardiac ion channels, leading to cardiovascular side effects. Other therapies discussed at DDW this year potentially on the horizon for Canada include luminally active pro-secretory agents such as linaclotide (an agonist of guanylate cyclase C). For more information on the use of linaclotide, refer to the abstracts below presented at DDW 2013.
— CARE Gastroenterology Faculty

Additional Abstracts that Hold Our Attention:
 

Sa1151:  Effect of Linaclotide in the Treatment of Irritable Bowel Syndrome and Chronic Constipation: a Meta-Analysis 

Mo2054: Assessing Abdominal and Bowel Symptoms Using Adequate Relief Based Thresholds: Results From 2 Phase 3 Trials of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation

Su2033: Determining the Minimum Duration for Initial Treatment with Linaclotide in IBS-C Patients: Results From Pooled Phase 3 Trials