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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Effect of laxatives and pharmacological therapies in chronic idiopathic constipation: systematic review and meta-analysis

AC Ford and NC Suares.

Review published: 2011.

Link to full article: [Journal publisher]

CRD summary

The review found that laxatives, prucalopride, lubiprostone and linaclotide were all more effective than placebo for short-term treatment of chronic idiopathic constipation, but were associated with a greater frequency of diarrhoea. The authors' appropriate conclusions reflect the evidence base and are likely to be reliable.

Authors' objectives

To assess the effect of laxatives and pharmacological therapies in chronic idiopathic constipation.

Searching

MEDLINE (from 1950), EMBASE (from 1947) and Cochrane Central Register of Controlled Trials (CENTRAL) were searched to September 2010. There were no language restrictions. Search terms were reported. Abstract books of conference proceedings between 2002 and 2010 and reference lists of retrieved studies were searched.

Study selection

Eligible studies were randomised controlled trials (RCTs, both parallel group and first period crossover designs) that compared laxatives (osmotic or stimulant) or pharmacological therapies (prucalopride, lubiprostone or linaclotide) with placebo in adult patients (>90% of participants over the age of 16) with chronic idiopathic constipation. Chronic idiopathic constipation was required to be based on clinical symptoms, a physician's opinion or the Rome diagnostic criteria supplemented by negative investigations, where necessary. Duration of treatment had to be at least one week. Studies were required to report on the primary outcomes, failure to respond to therapy at the last point of follow-up or mean number of stools per week during therapy. Secondary outcomes included effects on individual symptoms of chronic idiopathic constipation and adverse events.

In the included studies, settings were mostly in secondary and tertiary care and two studies were in primary care. Most participants were female (range 75% to 94%). Chronic idiopathic constipation was mostly diagnosed by Rome criteria. Interventions included osmotic and stimulant laxatives, prucalopride, lubiprostone and linaclotide. Duration of therapy ranged from eight days to 20 weeks.

Two reviewers independently performed study selection. Disagreements were resolved by discussion.

Assessment of study quality

Assessment of risk of bias in the included studies was performed according to Cochrane Handbook criteria; these included randomisation method, allocation concealment, implementation of blinding, proportion of participants completing follow up, intention-to-treat (ITT) analysis and selective reporting of outcomes.

Two reviewers independently performed assessment of risk of bias. Disagreements were resolved by discussion.

Data extraction

Dichotomous data were extracted on response to therapy, effects on individual chronic idiopathic constipation symptoms and therapy-related adverse events and these were used to calculate risk ratios (RRs) with 95% confidence intervals (CIs). Continuous data were extracted on mean number of stools per week and used to calculate weighted mean differences (WMDs) with 95% CIs. Data were extracted as ITT analyses, with drop-outs assumed to be treatment failures (no response to therapy), where possible; otherwise analyses were undertaken on patients with evaluable data. Authors of studies were contacted to provide additional information on studies where required.

Two reviewers independently performed data extraction. Disagreements were resolved by discussion.

Methods of synthesis

Studies were pooled separately by different therapies (laxatives, prucalopride, lubiprostone and linaclotide) in meta-analyses. Summary effect measures were calculated using a random-effects model. NNT and the number needed to harm (NNH) with 95% CIs were calculated from the reciprocal of the risk difference of the meta-analyses.

Subgroup analysis was undertaken on type of laxative (osmotic or stimulant). Heterogeneity was assessed with I2 and X2. Significant heterogeneity was defined as a cutoff of at least 50% for I2 and a p value less than 0.10 for X2. A priori sensitivity analyses were undertaken according to dose of pharmacological therapy, risk of bias of included studies, criteria used to define chronic idiopathic constipation, duration of therapy and criteria used to define response to therapy.

Publication bias was assessed by the inspection of funnel plots for evidence of asymmetry, using the Egger and Begg tests.

Results of the review

Twenty-one RCTs were included in the review. Seven RCTs (n=1,411 participants) assessed the effects of laxatives, seven trials (n=2,639) assessed the effects of prucalopride, three trials (n=610) assessed the effects of lubiprostone and three trials (n=1,582) assessed the effects of linaclotide. Twelve of the 21 included studies were at low risk of bias.

Laxatives: Compared to placebo, laxatives were associated with a significantly lower rate of failure to respond to therapy (RR 0.52, 95% CI 0.46 to 0.60; seven studies) with an NNT of 3 (95% CI 2 to 4). Subgroup analyses according to type of laxative reported significant benefits for osmotic and stimulant laxatives when compared to placebo. There was no evidence of significant heterogeneity. Sensitivity analyses indicated that treatment effects remained similar. Laxatives significantly reduced individual chronic idiopathic constipation symptoms. Compared to placebo, mean number of stools per week was significantly higher with laxatives (WMD 2.55, 95% CI 1.53 to 3.57; six studies); subgroup analyses confirmed the benefits separately for both osmotic and stimulant laxatives. Significant heterogeneity (I2=100%) was identified in the analyses. Compared to placebo, laxatives were associated with significantly more frequent diarrhoea (RR 13.75, 95% CI 2.82 to 67.14; two studies) with an NNH of 3 (95% CI 2 to 6).

Prucalopride: Compared to placebo, prucalopride was associated with a significantly lower rate of failure to respond to therapy (RR 0.82, 95% CI 0.76 to 0.88; seven studies) with significant heterogeneity (I2=60%) between studies and an NNT of 6 (95% CI 5 to 9). When sensitivity analyses were undertaken, there was no longer evidence of significant heterogeneity. Prucalopride was associated with a significantly greater risk of adverse events such as headache, nausea and diarrhoea.

Lubiprostone: Compared to placebo, lubiprostone was associated with a significantly lower rate of failure to respond to therapy (RR 0.67, 95% CI 0.56 to 0.80; three studies) with an NNT of 4 (95% CI 3 to 7). Lubiprostone was associated with a significantly greater risk of adverse events such as nausea and diarrhoea. No significant heterogeneity was found in the analyses.

Linaclotide: Compared to placebo, linaclotide was associated with a significantly lower rate of failure to respond to therapy (RR 0.84, 95% CI 0.80 to 0.87; three studies) with an NNT of 6 (95% CI 5 to 8). A significantly higher proportion of patients on linaclotide reported a decrease in severity of abdominal discomfort and bloating. Linaclotide was associated with a significantly greater risk of diarrhoea (RR 3.08, 95% CI 1.27 to 7.48; three studies). No significant heterogeneity was found in the analyses.

Where funnel plots were able to be generated, there was generally no evidence of significant asymmetry that might indicate publication bias.

Authors' conclusions

Laxatives, prucalopride, lubiprostone and linaclotide are all superior to placebo for treatment of chronic idiopathic constipation, but were associated with a greater frequency of diarrhoea.

CRD commentary

The review addressed a clear research question. Inclusion criteria appeared appropriate. Several relevant sources were searched to identify studies, there were no language restrictions, search terms were appropriate and attempts were made to find unpublished studies by searching conference abstracts; these minimised the risk of language and publication biases. Appropriate methods were used during the review process to select studies, extract data and assess studies for risk of bias. Twelve studies (out of 21) were at low risk of bias. Studies were synthesised in meta-analyses separately according to type of therapy. Pooled analyses were assessed for heterogeneity. Where heterogeneity was demonstrated, attempts made to explain the findings. Appropriate sensitivity analyses were performed to determine the robustness of the results according to study quality and other factors and to explain any heterogeneity that was identified. Publication bias was appropriately assessed using formal tests and little evidence of it was found.

The authors' appropriate conclusions reflect the evidence base and are likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that guidelines for management of chronic idiopathic constipation should be updated to reflect the effectiveness of laxatives and pharmacological therapies.

Research: The authors stated that research was required to assess long-term safety effects of laxatives and pharmacological therapies. Large studies based in primary care settings, particularly with head-to-head comparisons, were required.

Funding

Not stated.

Bibliographic details

Ford AC, Suares NC. Effect of laxatives and pharmacological therapies in chronic idiopathic constipation: systematic review and meta-analysis. Gut 2011; 60(2): 209-218. [PubMed: 21205879]

Indexing Status

Subject indexing assigned by NLM

MeSH

Alprostadil /adverse effects /analogs & derivatives /therapeutic use; Benzofurans /adverse effects /therapeutic use; Chronic Disease; Constipation /drug therapy; Diarrhea /chemically induced; Humans; Laxatives /adverse effects /therapeutic use; Peptides /adverse effects /therapeutic use; Randomized Controlled Trials as Topic; Treatment Outcome

AccessionNumber

12011000835

Database entry date

14/09/2011

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.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 21205879

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