Review Question
We reviewed the evidence about the effects of unfractionated or low-molecular weight heparin on induction of remission in patients with ulcerative colitis, with the medical literature up to June 17, 2014.
Background
What is ulcerative colitis?
Ulcerative colitis is a chronic inflammatory bowel disease characterized by recurrent episodes of active disease, which commonly affect the rectum or colon or both. Patients with active disease may experience abdominal cramping, urgency to pass stools, and bloody diarrhea. When the symptoms stop, the patients enter a 'remission phase' of ulcerative colitis.
What is heparin?
Heparin is a family of medications that reduce the body's natural ability to form clots. Unfrationated and low-molecular heparins are sub-types of heparins that are currently available for clinical use. In theory, decreasing clot formation may help to improve symptoms of ulcerative colitis.
Study Characteristics
The researchers identified five studies that included a total of 329 patients. Three studies (270 patients) compared low molecular weight heparin to placebo (e.g. a sugar pill), one study (34 patients) compared low molecular weight heparin in addition to standard therapy, and one study (25 patients) compared unfractionated heparin to steroids. The study comparing unfractionated heparin to steroids and the study that compared the addition of low molecular weight heparin to standard therapy to standard therapy alone was judged to be of low quality. The three placebo-controlled studies were judged to be of high quality.
Key Results
In one small study, unfractionated heparin was worse than steroids for inducing clinical improvement (i.e. reduction of symptoms) in people with severe ulcerative colitis. In addition, rectal bleeding was more frequent among people who received unfractionated heparin. In another small study low molecular weight heparin used with standard therapy provided no additional benefit over standard therapy alone in adults with active ulcerative colitis.
Low molecular weight heparin administered by injection showed no benefit over placebo for any outcome, including clinical remission (very low quality of evidence), clinical improvement and endoscopic improvement (i.e. healing of inflammation). High dose low molecular weight heparin administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission, clinical improvement. and endoscopic improvement. This result suggests that high dose low molecular weight heparin administered by extended-release capsules may be effective for the treatment of active ulcerative colitis. However, this result needs to be verified by future clinical trials.
There is evidence to suggest that LMWH may be effective for the treatment of active UC. When administered by extended colon-release tablets, LMWH was more effective than placebo for treating outpatients with mild to moderate disease. This benefit needs to be confirmed by further randomized controlled studies. The same benefits were not seen when LMWH was administered subcutaneously at lower doses. There is no evidence to support the use of UFH for the treatment of active UC. A further trial of UFH in patients with mild disease may also be justified. Any benefit found would need to be weighed against a possible increased risk of rectal bleeding in patients with active UC.
There are a limited number of treatment options for patients with ulcerative colitis (UC). An increased risk of thrombosis in UC coupled with an observation that UC patients being treated with anticoagulant therapy for thrombotic events had an improvement in their bowel symptoms led to trials examining the use of unfractionated heparin (UFH) and low molecular weight heparins (LMWH) in patients with active UC.
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.
We searched MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD/FBD group specialized trials register up to June 2014. We also searched review papers on ulcerative colitis and references from identified papers in an effort to identify additional randomized trials studying UFH or LMWH use in patients with ulcerative colitis. We searched abstracts from major gastroenterological meetings to identify research published in abstract form.
Randomized controlled trials comparing UFH or LMWH to placebo or a control therapy for induction of remission in ulcerative colitis were included. Studies published in abstract form only were included if the authors could be contacted for further information.
A data extraction form was developed and used to extract data from included studies. Two authors independently extracted data. Any disagreements were resolved by consensus. The Cochrane Risk of Bias tool was used to assess study quality. Data were analyzed on an intention-to-treat basis. The primary outcome was induction of remission, as defined by the studies. Secondary outcomes measures included: endoscopic remission as defined by the authors; clinical, histological or endoscopic improvement as defined by the authors; the occurrence of adverse events; the occurrence of bleeding; and improvements in quality of life as measured by a validated instrument. We calculated the risk ratio (RR) and corresponding 95% confidence interval for dichotomous outcomes. Data were combined for analysis if they assessed the same treatments (UFH or LMWH versus placebo or other therapy). The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria.
Five studies were eligible for inclusion (329 patients). Three studies (270 patients) compared low molecular weight heparin to placebo, one study (34 patients) compared LMWH in addition to standard therapy, and one study (25 patients) compared UFH to corticosteroids. The study comparing UFH to corticosteroids was rated at high risk of bias due to a single-blind design. The study that compared the addition of LMWH to standard therapy to standard therapy alone was rated at high risk of bias due to open-label design. The other three studies were rated as low risk of bias. LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission (very low quality of evidence), and clinical, endoscopic, or histological improvement. High dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (RR 1.39; 95% CI 1.09 to 1.77 ; P = 0.008; very low quality of evidence), clinical improvement (RR 1.28; 95% CI 1.06 to 1.55; P = 0.01; very low quality of evidence), and endoscopic improvement (RR 1.21; 95% CI 1.00 to 1.47 ; P = 0.05) but not endoscopic remission or histologic improvement. LMWH was not beneficial when added to standard therapy for clinical remission, clinical improvement, endoscopic remission or endoscopic improvement. LMWH was well-tolerated but provided no significant benefit for quality of life. One study examining UFH versus corticosteroids for the treatment of severe UC demonstrated the inferiority of UFH for clinical improvement. More patients assigned to UFH had rectal hemorrhage as an adverse event.