Unfractionated or low‐molecular weight heparin for induction of remission in ulcerative colitis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To review randomized trials examining the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis.
Background
Ulcerative colitis is a chronic inflammatory bowel disease with a relatively limited number of treatment options. Traditional therapies include 5‐aminosalicylates and corticosteroids. Azathioprine is effective for maintenance of remission of quiescent disease (Timmer 2007), but its effectiveness for remission induction in patients with active disease is questionable (Ardizzone 2006; Hawthorne 1992; Jewell 1974). Infliximab is effective for induction and maintenance of remission in patients who have failed or not tolerated other therapies (Lawson 2006; Rutgeerts 2005). Cyclosporine may be effective for treating patients with severe disease, but with significant potential for toxicity (Shibolet 2005).
There is an increased risk of thrombosis in patients with ulcerative colitis (Bernstein 2001). This may be due to an association with underlying coagulopathies (Hudson 1996; Souto 1995). Microthrombosis may also play a role in the pathogenesis of ulcerative colitis (Dhillon 1992). The finding of an improvement in bowel symptoms in ulcerative colitis patients treated with unfractionated heparin for acute thrombotic events led to hypotheses about the role of thrombosis in the pathogenesis of ulcerative colitis (Zavgorodnii 1982). Subsequently, the potential role of unfractionated heparin and low molecular weight heparins in the treatment of patients with active ulcerative colitis was investigated. However, if a benefit were to be found, it would need to be balanced against the potential for worsening of rectal bleeding in patients with active ulcerative colitis treated with anticoagulants.
Objectives
To review randomized trials examining the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials comparing UFH or LMWH with placebo or an active comparator will be considered for inclusion. Studies published as abstracts only will be included if the authors can be contacted for further information.
Types of participants
Adult patients with active ulcerative colitis defined by a combination of clinical, radiographic, endoscopic and histological criteria will be included.
Types of interventions
UFH or LMWH given by any route.
Types of outcome measures
The primary outcome measure will be the number of patients achieving clinical remission and off steroids as defined by the studies and expressed as a percentage of the number of patients randomized (intention to treat analysis). Secondary outcomes measures will include:
a) Endoscopic remission as defined by the authors;
b) Clinical, histological or endoscopic improvement as defined by the authors;
c) The occurrence of adverse events;
d) The occurrence of bleeding; and
e) Improvements in quality of life as measured by a validated instrument.
Search methods for identification of studies
See: Inflammatory Bowel Disease and Functional Bowel Disorders Group search strategy.
The MEDLINE (PUBMED), and EMBASE databases, The Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD group specialized trials register, review papers on ulcerative colitis, and references from identified papers will be searched in an effort to identify all randomized trials studying UFH or LMWH use in patients with ulcerative colitis. Abstracts from major gastroenterological meetings will be searched to identify research published in abstract form only.
Data collection and analysis
Study selection
Each author will independently review potentially relevant trials to determine their eligibility for inclusion based on the criteria identified above. Studies published in abstract form only will be included only if the authors can be contacted for further information.
Data collection
A data extraction form will be developed and used to extract data from included studies. At least 2 authors will independently extract data. Any disagreements will be resolved by consensus.
Statistical analysis
Data will be analyzed using Review Manager (RevMan 4.2.9). Data will be analyzed on an intention‐to‐treat basis, and treated dichotomously. In cross‐over studies, only data from the first arm will be included. The primary endpoint will be induction of remission, as defined by the studies. Data will be combined for analysis if they assess the same treatments (UFH or LMWH vs. placebo or other therapy). If a comparison is only assessed in a single trial, P‐values will be derived using the chi‐square test. If the comparison is assessed in more than one trial, summary test statistics will be derived using the Peto odds ratio and 95% confidence intervals (95% CI). The presence of heterogeneity among studies will be assessed using the chi‐square test (a P value of 0.10 will be regarded as statistically significant). If statistically significant heterogeneity is identified the odds ratio and 95% CI will be calculated using a random effects model.
Quality assessment
All studies will be reviewed independently by each author to assess methodological quality. The randomization method and blinding should be stated. A minimum of allocation concealment will be required for inclusion. Disagreements will be resolved by consensus.
