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A comparison of endoscopic and surgical treatment of strictures in patients with Crohn’s disease

  1. Elena Dubcenco,
  2. John K MacDonald,
  3. Brian G Feagan*

Editorial Group: Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group

Published Online: 28 MAR 2013

DOI: 10.1002/14651858.CD010428


How to Cite

Dubcenco E, MacDonald JK, Feagan BG. A comparison of endoscopic and surgical treatment of strictures in patients with Crohn’s disease (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD010428. DOI: 10.1002/14651858.CD010428.

Author Information

  1. Robarts Research Institute, Robarts Clinical Trials, London, Ontario, Canada

*Brian G Feagan, Robarts Clinical Trials, Robarts Research Institute, P.O. Box 5015, 100 Perth Drive, London, Ontario, N6A 5K8, Canada. bfeagan@robarts.ca.

Publication History

  1. Publication Status: New
  2. Published Online: 28 MAR 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Declarations of interest
 

Description of the condition

Crohn’s disease (CD) is a chronic inflammatory disease of the GI tract of unknown cause. The course of CD is characterized by periods of remissions and relapses. Traditionally, treatment has been aimed at inducing and maintaining remission of symptoms. With the recent recognition of mucosal healing as an important outcome, treatment is now focused on reducing intestinal inflammation, preventing complications, and decreasing the need for surgery. Despite modern immunosuppressive regimens many patients require treatment for stricturing disease (Himal 1981; Rutgeerts 1990; Hanauer 2004; Louis 2012).

Stricture formation defined as a constant, localized narrowing of the large or small bowel, is a common complication of CD. Strictures are often only a few centimetres in length but may be considerably longer. No drug therapy currently exists to treat fibrotic strictures. Accordingly, they usually require surgical resection or strictureplasty. However, surgery does not cure Crohn's disease. Within one year of surgical resection of all visible disease, the endoscopic recurrence rate may be as high as 90% (Rutgeerts 1984; Tytgat 1988; Olaison 1992; Borley 2002; Onali 2009). Repeated operations carry the risk of both important mortality and morbidity such as short-bowel syndrome.

 

Description of the intervention

Endoscopic treatment of strictures, such as balloon dilatation and stent placement have been used as an alternative to surgery (Williams 1991; Foster 2008; Despott 2009; Stiencker 2009; Thienpont 2010). These techniques can be used on their own or in conjunction with adjunctive medical therapies such as injection of corticosteroids. Endoscopic balloon dilatation (EBD) is performed during a regular endoscopic procedure (i.e. colonoscopy, gastroscopy, push-enteroscopy, double- or single-balloon enteroscopy) using a balloon catheter of up to 25 mm in diameter (Pohl 2007; Hirai 2010). The balloon is filled with water under visual control, and insufflated by a multi-step inflation with usually two minutes of inflation time at the maximal diameter (12 to 25 mm). Passage of the endoscope through the dilated stricture is then attempted. An additional dilatation with inflation of the balloon is performed if the first dilatation does not allow the passage of the endoscope through the strictured area. In some instances stents including self-expandable metallic stents (SEMS) are inserted endoscopically. Adjunctive techniques such as local injections of corticosteroids or balloon dilatation may be also used before or during the SEMS placement.

 

How the intervention might work

Balloon dilatation mechanically disrupts scar tissue and increases the luminal diameter. Adjunctive anti-inflammatory therapy such as intramural injection of corticosteroids is intended to blunt an inflammatory response to the tissue injury that results from dilatation and prevent re-stricturing. Although the available data indicate that endoscopic treatment relieves obstructive symptoms resulting from strictures very few randomized controlled trials (RCTs) exist (Williams 1991; Couckuyt 1995; Karstensen 2012).

The technical success rate of endoscopic intervention in Crohn's disease patients with strictures is reported as 84 to 100% while the long-term success rate based on relief of obstructive symptoms varies from 41 to 100% (Couckuyt 1995; Thomas-Gibson 2003; Singh 2005; Lavy 2007; Mueller 2010). Most of the patients who are described in these studies (up to 100%) have previously undergone surgery (Sabate 2003; Thomas-Gibson 2003; Nomura 2006; Scimeca 2011; Nanda 2012). Patients who undergo endoscopic treatment may have quiescent disease or active inflammation. Most strictures are located at the area of anastomoses. Major complications such as perforation (requiring surgery) or bleeding (requiring surgery or blood transfusion) occur in 2 to 5% of cases (Ferlitsch 2006; Stiencker 2009; Gustavsson 2012; Karstensen 2012). No deaths have been reported in the literature. Although the results of endoscopic treatment are encouraging, surgery is eventually required in up to 38% of patients because of persistent obstructive symptoms. However, multiple studies (Blomberg 1991; Williams 1991; Hoffmann 2008; Stiencker 2009; Karstensen 2012; Nanda 2012) have reported long-term benefit after endoscopic intervention in at least two thirds of patients with Crohn's strictures. Active inflammation at the site of the stricture and medical treatment during or following endoscopic treatment does not affect long-term outcomes of endoscopic treatment (East 2007; Thienpont 2010; Nanda 2012). The long-term data on efficacy of intralesional steroid injection after EBD in Crohn's disease with stricture are inconsistent (Ramboer 1995; Lavy 2007; East 2007; Di Nardo 2010). All studies that have been reported in the literature conclude that endoscopic therapy of strictures is an effective and safe alternative to surgery.

 

Why it is important to do this review

The development of a stricture in a patient with Crohn's disease is an important complication that can negatively affect quality of life. It is estimated that approximately 50% of patients with Crohn's disease affecting the ileum have stricturing disease. Bowel obstruction due to stricture may result in perforation, sepsis and death. Most patients with stricturing Crohn's disease will require surgery, usually within 7 to 10 years of diagnosis. Some patients will require multiple surgeries. A preliminary review of the literature shows that endoscopic treatment of Crohn's disease strictures may relieve symptoms without the need for surgery. Therefore, endoscopic treatment may have a substantial benefit. A systematic review of the literature is warranted to define the efficacy and safety of endoscopic interventions (i.e. balloon dilatation, intramural corticosteroid injection and stent placement) for the management of Crohn's disease strictures in comparison to surgical therapy (i.e. strictureplasty or small bowel resection).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Declarations of interest

The primary objective of this review is to evaluate the short and long-term efficacy and safety of endoscopic treatment for the management of Crohn's disease strictures.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Declarations of interest
 

Criteria for considering studies for this review

 

Types of studies

RCTs, cohort studies, case control, and case series will be considered for inclusion. Small case series (i.e. < 5 patients), meta-analyses, systematic reviews and case reports will be excluded from the analyses.

 

Types of participants

Studies that evaluate patients with Crohn's disease (either active or inactive inflammation at the area of the stricture) who have small and large bowel strictures identified by conventional clinical, radiographic and endoscopic criteria will be included. Participants of any age or gender will be eligible for inclusion. Patients with previous small and large bowel resection or strictureplasty due to Crohn's disease as well as surgery-free patients will be included. Patients with bowel strictures not related to inflammatory bowel disease will be excluded.

 

Types of interventions

Studies of endoscopic treatment of Crohn's disease strictures (i.e. balloon dilatation and stent placement), alone or with an adjunctive treatment (e.g. injection of steroids) compared to bowel resection or strictureplasty will be considered for inclusion.

 

Types of outcome measures

 

Primary outcomes

The primary outcome measure will be the subsequent need for surgery or repeated surgery for the treatment of Crohn's disease strictures.

 

Secondary outcomes

Secondary outcomes will include:

1. The rate of major complications related to the intervention: death, bleeding (requiring surgery or blood transfusion), perforation or anastomotic leak (requiring surgery), infection, any other significant adverse events leading to hospitalization (endoscopic group) or prolonged hospitalization (surgical group) and the total rate of complications;

2. The percentage of patients that needed multiple (repeated) EBD;

3. The time from primary intervention (EBD or surgery) to repeated intervention (EBD or surgery);

4. Relief of obstructive symptoms (e.g. abdominal cramps, pain, nausea, vomiting, changed bowel habits, inability to pass gas, abdominal distension). This outcome will be evaluated over both shorter (i.e. up to one year) and longer (i.e. > than one year) time horizons; and

5. Crohn's disease duration from diagnosis to EBD or surgery, disease activity where data are available; history of previous surgery; type (primary or anastomotic; single or multiple; long or short) of the stricture(s); the time of patients' follow-up; and patient demographics.

 

Search methods for identification of studies

 

Electronic searches

A computer aided search will be conducted from the following databases:

1. MEDLINE (1980 to November 2012);
2. Pubmed (1980 to November 2012);
3. EMBASE (1980 to November 2012); and
4. The Cochrane Library (1980 to November 2012).

 

Searching other resources

We will also search abstracts submitted to major gastroenterology meetings (1980 to November 2012) published in the following journals:

a) Gastroenterology;
b) Gut;
c) American Journal of Gastroenterology;
d) Canadian Journal of Gastroenterology;
e) Gastrointestinal Endoscopy;
f) European Journal of Gastroenterology and Hepatology;
g) Surgical Endoscopy;
h) Endoscopy;
i) Surgical Laparoscopy, Endoscopy and Percutaneous Techniques;
j) Gastrointestinal Endoscopy Clinics of North America;
k) Surgical Laparoscopy and Endoscopy;
l) Diagnostic and Therapeutic Endoscopy;
m) Surgery;
n) American Journal of Surgery;
o) Annals of Surgery; and
p) British Journal of Surgery.

Reference lists from retrieved articles and review articles will be searched to identify additional studies that may have been missed by the database searches.

 

Data collection and analysis

 

Selection of studies

All studies identified by the electronic searches will be independently assessed by two authors (ED and JKM) and relevant studies will be selected based on the inclusion criteria described above. Studies published in abstract form will only be included if the authors can be contacted for further information. Any disagreement among authors will be resolved by discussion and consensus.

 

Data extraction and management

A standardized data extraction form will be designed and used to extract information on relevant features and results of the included studies. Two authors (ED and JKM) will independently extract data from the included studies. Data to be extracted will include:

1. Study design features (e.g. methods used for random allocation, allocation concealment, and blinding; intention-to-treat analysis, inclusion and exclusion criteria);

2. Patient characteristics (e.g. patient demographics);

3. Details of the intervention (e.g. endoscopic balloon dilatation versus strictureplasty or small bowel resection or both);

4. Outcomes (e.g. proportion of patients with relief of symptoms, relapse of obstructive symptoms, development of complications, adverse events and subsequent need for surgery);

5. Number of subjects lost to follow-up or dropping out and reasons for withdrawal; and

6) Definitions of symptom relief and recurrence.

 

Assessment of risk of bias in included studies

Two authors (ED and JKM) will independently assess the risk of bias of included RCTs using the Cochrane risk of bias tool (Higgins 2011). Factors to be assessed will include:

  1. sequence generation (i.e. was the allocation sequence adequately generated?);
  2. allocation sequence concealment (i.e. was allocation adequately concealed?);
  3. blinding (i.e. was knowledge of the allocated intervention adequately prevented during the study?);
  4. incomplete outcome data (i.e. were incomplete outcome data adequately addressed?);
  5. selective outcome reporting (i.e. are reports of the study free of suggestion of selective outcome reporting?); and
  6. other potential sources of bias (i.e. was the study apparently free of other problems that could put it at a high risk of bias?).

A judgement of 'Yes' indicates low risk of bias, 'No' indicates high risk of bias, and 'Unclear' indicates unclear or unknown risk of bias. Disagreements were resolved by consensus. Study authors will be contacted for additional information if any items are assessed as unclear.

The methodological quality of cohort and case control studies will be assessed using the Newcastle-Ottawa Scale (Wells 2013).

We will use the GRADE approach to rate the overall quality of evidence for the primary outcomes and selected secondary outcomes of interest. Randomized trials start as high quality evidence, but may be downgraded due to: (1) limitations in design and implementation (risk of bias), (2) indirectness of evidence, (3) inconsistency (unexplained heterogeneity), (4) imprecision (sparse data), and (5) reporting bias (publication bias). The overall quality of evidence for each outcome will be determined after considering each of these elements, and categorized as high quality (i.e. further research is very unlikely to change our confidence in the estimate of effect); moderate quality (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low quality (i.e. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate); or very low quality (i.e. we are very uncertain about the estimate) (Guyatt 2008; Schünemann 2011).

 

Measures of treatment effect

Review Manager 5 will be used to perform statistical analysis. The extracted data from the original studies will be used to construct two by two tables. All data will be analyzed on an intention-to-treat basis. The relative risk (RR) with 95% confidence intervals (95% CI) will be calculated for dichotomous outcomes.

For continuous outcomes, the mean difference (MD) and 95% CI will be calculated when continuous outcomes are measured using the same units. The standardized mean difference (SMD) and 95% CI will be calculated when different scales are used to evaluate the same outcome.

 

Unit of analysis issues

Although some studies may report more than one efficacy outcome or complication or adverse event per subject, the primary analysis will consider only the proportion of subjects who experience at least one event. Separate analyses will be conducted for comparisons between balloon dilatation versus bowel resection and balloon dilatation versus strictureplasty. Cross-over trials and cluster randomized trials are not likely to be encountered for this intervention.

 

Dealing with missing data

An intention-to-treat analysis will be used. Patients who drop out or have missing outcome data will be considered treatment failures. Where possible, authors will be contacted to provide missing data. A sensitivity analysis using per protocol data will be performed to assess the impact of our assumptions on the effect estimates.

 

Assessment of heterogeneity

We will assess heterogeneity by visual inspection of forest plots and by calculating the Mantel-Haenstzel Chi2 test (a P value of 0.10 will be considered statistically significant) and the I2 statistic (Higgins 2003). An I2 of 25% will be considered to indicate low heterogeneity, 50% moderate or substantial heterogeneity and 75% high heterogeneity (Higgins 2003). We will conduct sensitivity analyses to investigate heterogeneity. For example, if a pooled analysis shows statistically significant heterogeneity and a visual inspection of the forest plot identifies studies that may contribute to this heterogeneity the analysis will be repeated excluding these studies to see if this explains the heterogeneity.

 

Assessment of reporting biases

If an appropriate number of studies are included in the review, we will assess the possibility of publication bias using funnel plots and Egger's test (Egger 1997).

 

Data synthesis

Data from individual trials will be pooled for meta-analysis if the interventions, patient groups and outcomes are sufficiently similar (determined by consensus). Data will not be pooled for meta-analysis if a high degree of heterogeneity is detected (i.e. I2 > 75%). A fixed-effect model (Mantel Haenstzel) will be used to pool data in the absence of heterogeneity. A random-effects model will be used if there is statistically significant heterogeneity (P < 0.10) or substantial heterogeneity (I2 statistic > 50%). For dichotomous outcomes a pooled RR and 95% CI will be calculated. For continuous outcomes a pooled MD and 95% CI will be calculated.

 

Subgroup analysis and investigation of heterogeneity

We plan to perform subgroup analyses for the following, where reported:

  1. Endoscopic balloon dilatation group: a) Single procedure subgroup and b) Multiple (2 or more) procedures subgroup; and
  2. Surgical intervention group: a) Strictureplasty subgroup and b) Small bowel resection subgroup.

 

Sensitivity analysis

In addition to a per protocol analysis, potential sensitivity analyses will include the exclusion of: (1) unpublished studies; and (2) studies of low methodological quality.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Declarations of interest

Funding for the IBD/FBD Review Group (September 1, 2010 - August 31, 2015) has been provided by the Canadian Institutes of Health Research (CIHR) Knowledge Translation Branch (CON - 105529) and the CIHR Institutes of Nutrition, Metabolism and Diabetes (INMD); and Infection and Immunity (III) and the Ontario Ministry of Health and Long Term Care (HLTC3968FL-2010-2235).

Miss Ila Stewart has provided support for the IBD/FBD Review Group through the Olive Stewart Fund.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Declarations of interest

Elena Dubcenco has no known conflicts of interest. Brian Feagan has received lecture fee(s) from: GlaxoSmithKline, Procter & Gamble Pharmaceuticals, Salix Pharmaceuticals Inc, Shire Pharmaceuticals Inc, Tillotts Pharma AG and Merck. John MacDonald has served as a consultant for Tillotts Pharma AG. All of these financial activities are outside the submitted work.

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Declarations of interest
  8. Additional references
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