Volume 17, Issue 9 pp. 1979-1986

Cochrane Review

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Unfractionated or low molecular weight heparin for induction of remission in ulcerative colitis: A cochrane inflammatory bowel disease and functional bowel disorders systematic review of randomized trials

Corresponding Author

Nilesh Chande MD, FRCPC

[email protected]

Gastroenterology, University of Western Ontario, London, Ontario, Canada

E1-423A, London Health Sciences Centre–Victoria Hospital, 800 Commissioners Road E., London, Ontario, N6A 5W9 CanadaSearch for more papers by this author

John K. MacDonald MA,

John K. MacDonald MA

Robarts Research Institute, London, Ontario Canada

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Josh J. Wang BSc,

Josh J. Wang BSc

Schulich School of Medicine & Dentistry (Windsor Program), University of Western Ontario, London, Ontario, Canada

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John W.D. McDonald MD, FRCPC,

John W.D. McDonald MD, FRCPC

Robarts Research Institute, London, Ontario Canada

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Nilesh Chande MD, FRCPC,

Corresponding Author

Nilesh Chande MD, FRCPC

[email protected]

Gastroenterology, University of Western Ontario, London, Ontario, Canada

E1-423A, London Health Sciences Centre–Victoria Hospital, 800 Commissioners Road E., London, Ontario, N6A 5W9 CanadaSearch for more papers by this author

John K. MacDonald MA,

John K. MacDonald MA

Robarts Research Institute, London, Ontario Canada

Search for more papers by this author

Josh J. Wang BSc,

Josh J. Wang BSc

Schulich School of Medicine & Dentistry (Windsor Program), University of Western Ontario, London, Ontario, Canada

Search for more papers by this author

John W.D. McDonald MD, FRCPC,

John W.D. McDonald MD, FRCPC

Robarts Research Institute, London, Ontario Canada

Search for more papers by this author

First published: 25 May 2011

https://doi.org/10.1002/ibd.21776

Citations: 6

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Abstract

Background:

We aimed to systematically review the efficacy of unfractionated heparin (UFH) or low molecular weight heparins (LMWH) for remission induction in patients with ulcerative colitis (UC).

Methods:

A literature search to April 2011 was performed to identify all randomized trials studying UFH or LMWH use in patients with UC. The Cochrane Risk of Bias Tool was used to assess study quality.

Results:

LMWH administered subcutaneously showed no benefit over placebo for any outcome, including clinical remission, and clinical, endoscopic, or histological improvement. High-dose LMWH administered via an extended colon-release tablet demonstrated benefit over placebo for clinical remission (odds ratio [OR] 2.73; 95% confidence interval [CI] 1.32–5.67; P = 0.007), clinical improvement (OR 2.99; 95% CI 1.30–6.87; P = 0.01), and endoscopic improvement (OR 2.25; 95% CI 1.01–5.01; 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. 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.

Conclusions:

LMWH administered by extended colon-release tablets may be effective for the treatment of active UC. 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. (Inflamm Bowel Dis 2011;)

There are a limited number of treatment options for patients with ulcerative colitis (UC). Traditional therapies include 5-aminosalicylates1, 2 and corticosteroids. Azathioprine is effective for maintenance of remission of quiescent disease,3 but its effectiveness for induction of remission in patients with active disease is questionable.4-6 Infliximab is effective for induction and maintenance of remission in patients who have failed or not tolerated other therapies.7, 8 Cyclosporine may be used for treating patients with severe disease, but with significant potential for toxicity.9

There is an increased risk of thrombosis in patients with UC.10 This may be due to an association with underlying coagulopathies.11, 12 Microthrombosis may also play a role in the pathogenesis of UC.13 The finding of an improvement in bowel symptoms in UC patients treated with unfractionated heparin (UFH) for acute thrombotic events led to hypotheses about the role of thrombosis in the pathogenesis of UC.14 Subsequently, the potential role of UFH and low molecular weight heparins (LMWH) for the treatment of patients with active UC 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 UC treated with anticoagulants. This article reviews randomized trials examining the efficacy of UFH or LMWH for induction of remission in patients with UC.

MATERIALS AND METHODS

This study is based on a previously published Cochrane systematic review.15

Trial Searching

The MEDLINE (PubMed), and EMBASE databases, the Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD group specialized trials register, review articles on UC, and references from identified papers were searched using the terms “ulcerative colitis” and “heparin” or “low molecular weight heparin” up to April 2011 in an effort to identify all randomized trials studying UFH or LMWH use in patients with UC. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only.

Randomized controlled trials comparing UFH or LMWH with placebo or an active comparator for the treatment of adult patients with UC were considered for inclusion. Active UC was defined by a combination of clinical, radiographic, endoscopic, and histological criteria. Studies published as abstracts only were included if the authors could be contacted for further information.

Outcome Measures

The primary outcome measure was 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 included:

a)
endoscopic remission as defined by the authors;
b)
clinical, histological, or endoscopic improvement as defined by the authors;
c)
adverse events;
d)
bleeding; and
e)
improvements in quality of life as measured by a validated instrument.

Quality Assessment

All studies were reviewed independently by each author to assess methodological quality. The Cochrane Risk of Bias Tool16 was used to assess study quality. Factors assessed included:

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 judgment 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 were contacted when insufficient information was provided to determine risk of bias. Studies determined to have a high risk of bias that may have affected the overall results were excluded.

Data Collection and Statistical Analysis

Each author independently reviewed potentially relevant trials to determine their eligibility for inclusion based on the criteria identified above. 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. At least two authors independently extracted data. Any disagreements were resolved by consensus.

Data were analyzed using Review Manager (RevMan 5.0.24). Data were analyzed on an intention-to-treat basis, and treated dichotomously. In crossover studies, only data from the first arm were included. Data were combined for analysis if they assessed the same treatments (UFH or LMWH vs. placebo or other therapy). If a comparison was only assessed in a single trial, P-values were derived using the chi-square test. If the comparison was assessed in more than one trial, summary test statistics were derived using the Peto odds ratio (OR) and 95% confidence intervals (95% CI). The presence of heterogeneity among studies was assessed using the chi-square test (a P-value of 0.10 was regarded as statistically significant). If statistically significant heterogeneity was identified the OR and 95% CI were calculated using a random effects model.

RESULTS

Description of Studies

The literature search identified a total of 33 studies, including eight studies published as abstracts. Of these, eight articles representing five distinct trials met the inclusion criteria and were included in the review17-21 (Table 1).

Table 1. Quality of Randomized Controlled Studies of Unfractionated Heparin and Low Molecular Weight Heparins for Treating Patients with Ulcerative Colitis

Study Reference	Intervention	Cochrane Risk of Bias Tool
Study Reference	Intervention	Adequate Sequence Generation	Allocation Concealment	Blinding	Incomplete Outcome Data Addressed	Free of Selective Reporting	Free of Other Bias
17	Tinzaparin vs. placebo	Yes	Yes	Yes	Yes	Yes	No (industry funded)
18	Parnaparin vs. placebo	Unclear	Yes	Yes	Yes	Yes	No (industry funded)
19	Reviparin vs. placebo	Yes	Yes	Yes	Yes	Yes	Yes
20	Enoxaparin vs. steroids + 5-ASA	Yes	No	No	Yes	Yes	Yes
21	UFH vs. steroids	Unclear	Unclear	No	Yes	Yes	Yes

Three randomized, blinded studies published as abstracts only were excluded after attempts to contact the authors for further details about methodology and results were not successful.22-24 Ang et al25 enrolled patients with UC and Crohn's disease. This study was excluded because separate results were not provided for patients with UC. Seven papers were excluded for being case series14, 26-29 or reports.30-32 The remaining studies were excluded as they were nonrandomized, open label studies.33-45

LMWH Versus Placebo

Bloom et al17

This randomized, double-blind trial included 100 patients (48 male, 52 female) with active UC. Active disease was defined by a clinical assessment of disease flare-up and a minimum score of 3 on a combined score of bowel frequency, rectal bleeding, and proctosigmoidoscopy. A histology score was added where available to give a baseline colitis activity score. The patients were randomized to tinzaparin 175 anti-Xa IU/kg/day subcutaneously for 14 days, followed by tinzaparin 4500 anti-Xa IU/day subcutaneously for 28 days (n = 48) or placebo (n = 52) subcutaneous injection daily for 42 days. Concurrent treatment with stable or increasing doses (in patients without improvement) of salicylates was allowed, but no other therapies for UC were permitted. Patients underwent a sigmoidoscopy with biopsies within 4 days prior to randomization as well as within 2 to 7 days after the end of treatment. The primary outcome measure was the degree of clinical improvement based on a change in the colitis activity score at the end of therapy compared to the baseline score. Other outcome measures included numbers and percentages of patients in each category of activity score, quality of life scores using the Inflammatory Bowel Disease Questionnaire (IBDQ) (completed by patients in English-speaking countries only), compliance with therapy, and adverse events.

Celasco et al18

This double-blind, randomized trial included 141 patients (73 male, 68 female) with mild to moderately active left-sided UC (defined by authors as a Clinical Activity Index [CAI] ≥5 and ≤12) receiving stable-dose oral aminosalicylate therapy. Patients were randomized to receive either an extended-release 210 mg parnaparin sodium (87–91 anti-Xa U/mg) tablet that targets the colon or an identical placebo tablet orally every day for 8 weeks while continuing their existing aminosalicylate regimens. Each patient underwent a colonoscopy, histologic evaluation and clinical assessment using the CAI (Rachmilewitz46) no earlier than 2 weeks prior to entry. Clinical response was also measured at 2, 4, and 8 weeks with a second colonoscopy and histologic evaluation performed at the end of treatment. The primary outcome measure was clinical remission (CAI <4) after 8 weeks of treatment. Secondary outcome measures included clinical improvement (decrease in CAI by ≥2), endoscopic healing and improvement, histologic improvement, bleeding, and adverse events.

de Bievre et al19

This randomized, double-blind trial included 29 patients (16 male, 13 female) with mild to moderately active UC (diagnosis based on Lennard-Jones criteria) and a Truelove classification severity score of 4 to 14. The patients were randomized to subcutaneous injections of reviparin 3436 IU (n = 15) or placebo (n = 14) twice daily for up to 8 weeks. All patients were concurrently treated with comparable stable doses of salicylates. Patients underwent a sigmoidoscopy with biopsies at baseline and after 8 weeks, and were seen regularly during the study. A Clinical Symptom Grading and Colitis Activity Index were calculated at each visit. If there was no improvement after 4 weeks or a clinical regression at any study visit the treatment was discontinued and corticosteroid therapy was initiated. The primary outcome measure was clinical improvement at the end of 8 weeks. Secondary outcomes included endoscopic and histologic improvements, and quality of life based on the IBDQ.

Vrij et al47 describe the same cohort of patients as de Bievre et al.19 The main focus of this study was whether clinical improvement with LMWH therapy was associated with reduced thrombin generation. Other hematological factors were also measured. Other outcome measures included the number of patients with clinical improvement after 8 weeks, endoscopic and histologic improvement, and IBDQ results.

LMWH in Addition to Standard Therapy

Zezos et al20

This nonblinded trial included 34 patients (22 male, 12 female) with active UC (including six patients hospitalized at entry). Patients were randomized to two groups. The “standard therapy group” received corticosteroids and aminosalicylates (n = 18). The “heparin therapy group” received similar standard therapy plus enoxaparin 100 anti-Xa IU/kg subcutaneously daily for 12 weeks (n = 16). For all patients, corticosteroids were initially administered either intravenously (prednisolone 50 to 75 mg/day) or orally (methylprednisolone 32 to 48 mg/day) depending on disease severity. After initial response, intravenous corticosteroids were switched to oral, and oral corticosteroids were tapered in a dose-reduction schedule over 12 weeks. Aminosalicylates were given in steady doses (2–4 g/day) throughout the study. Patients underwent a colonoscopy at baseline and were seen at regular intervals for clinical and biochemical assessments during the study. Another colonoscopy was performed at the end of treatment. Disease activity was assessed with the Simple Clinical Colitis Activity Index (SCCAI) at each study visit. Endoscopic disease severity was assessed with a modified endoscopic grading system (scored 0–18). Histologic disease activity was scored from 0–12 based on four features (ulcers, erosion, crypt abscess, cryptitis). The primary outcome measures were the percentages of patients with complete response (coexisting clinical and endoscopic remission, with SCCAI score ≤2 and endoscopic score ≤3) and partial response (≥50% reduction of SCCAI score and a reduction in endoscopic score by at least 1 grade) after 12 weeks of therapy. Other outcome measures included compliance and tolerability to therapy, withdrawals, adverse events, change in clinical, endoscopic, and histological disease activity and laboratory parameters of inflammation and coagulation.

UFH Versus Corticosteroids

Panes et al21

This randomized, single-blind trial included 25 patients (12 male, 13 female) with moderate to severely active UC requiring hospitalization, with a Seo activity index of at least 150, and a sigmoidoscopic score of at least 2 on a 0–3 scale. Patients were stratified by disease severity (moderate disease, Seo index 150–220; and severe disease, Seo index >220). Patients were randomized to a continuous infusion of UFH (n = 12; adjusted to achieve a prolongation of activated partial thromboplastin time [APTT] of 1.5–2 times control) or a single daily dose of 6-methylprednisolone 0.75 mg/kg/day (moderate disease) or 1 mg/kg/day (severe disease) plus a placebo infusion (n = 13). Physician assessors were blinded to the assigned therapies. Patients with significant improvement (decrease in Seo index >70 points) or remission (Seo index <100) were discharged from hospital on 12,500 U of UFH twice daily or a tapering dose of steroids until week 12 of the study. Patients were seen regularly during hospital admission and after discharge. A sigmoidoscopy was performed at baseline and at weeks 4 and 8. The primary outcome measure was clinical improvement (decrease in Seo index >70 points) at day 10. Patients not achieving this outcome or with worsening clinical disease (increase in Seo index >70 points) at any point were considered treatment failures and withdrawn from the study. Secondary outcome measures included amount of rectal bleeding and changes in inflammatory markers on serial serology.

Effects of Interventions

LMWH Versus Placebo

Clinical remission

In Bloom et al,17 4/48 patients (8.3%) assigned to LMWH and 4/52 patients (7.7%) assigned to placebo achieved clinical remission during the study period (OR 1.09; 95% CI 0.26–4.63; P = 0.91). In Celasco et al,18 55/71 (77.5%) patients assigned to LMWH achieved clinical remission after 8 weeks of treatment compared to 39/70 patients (55.7%) in the placebo group (OR 2.73; 95% CI 1.32–5.67; P = 0.007). The studies were not pooled for analysis because the parenteral LMWH administered in Bloom et al and the nonparenteral LMWH administered in Celasco et al exhibit different therapeutic profiles, locally and systemically.17, 18

Clinical improvement

In Bloom et al,17 15/48 patients (31.3%) assigned to LMWH and 20/52 patients (38.5%) assigned to placebo improved clinically over the study period (OR 0.73, 95% CI 0.32–1.66, P = 0.45) during the study period. Over the study duration, the mean colitis activity score changed from 7.6 to 6.84 (−10.0%) in the LMWH group and from 7.4 to 6.44 (−13.0%) in the placebo group. In Celasco et al,18 61/71 (85.9%) patients assigned to LMWH and 47/70 (67.1%) patients assigned to the placebo improved clinically (OR 2.99; 95% CI 1.30–6.87; P = 0.01). The mean CAI decreased from 6.22 to 2.02 in LMWH patients compared to a decrease from 6.64 to 2.96 in placebo patients over the treatment period. In de Bievre et al,19 12/15 patients (80%) assigned to LMWH and 11/14 patients (78.6%) assigned to placebo clinically improved over the study period (OR 1.09; 95% CI 0.18–6.58; P = 0.92). The mean CAI decreased from 9.87 at baseline to 5 at week 8 in the LMWH group and from 9.14 to 6 in the placebo group. The mean Colitis Symptom Grading decreased from 8.33 at baseline to 4 in the LMWH group and from 6.36 to 4 in the placebo group. The definitions of clinical improvement in Bloom et al, Celasco et al, and de Bievre et al were not sufficiently similar to pool data for meta-analysis.17-19

Endoscopic improvement

In Celasco et al,18 59/71 (83.1%) patients in the LMWH group and 48/70 (68.6%) patients in the placebo group improved endoscopically over the study duration (OR 2.25; 95% CI 1.01–5.01; P = 0.05). The mean Endoscopic Index decreased from 5.93 to 2.47 in the LMWH group and from 6.24 to 3.44 in the placebo group. In de Bievre et al,19 9/15 patients (60.0%) assigned to LMWH and 8/14 patients (57.1%) assigned to placebo improved endoscopically over the study period (OR 1.13; 95% CI 0.26–4.94; P = 0.88). The mean Endoscopic Grading System decreased from 9.64 at baseline to 7.36 after 8 weeks in the LMWH group and from 9.46 to 7.63 in the placebo group. The grading scales used in these two studies were not sufficiently similar to justify pooling the data for analysis.

Endoscopic remission

In Celasco et al,18 15/71 (21.1%) patients in the LMWH group and 11/70 (15.7%) patients in the placebo group achieved endoscopic remission over the study duration (OR 1.44; 95% CI 0.61–3.39; P = 0.41). This outcome was not reported in de Bievre et al.19

Histological improvement

In Celasco et al,18 33/71 (46.5%) patients in the LMWH group and 32/70 (45.7%) patients in the placebo group improved histologically over the study duration (OR 1.03; 95% CI 0.53–2.00; P = 0.93). The mean Histological Score decreased from 4.83 to 2.64 in the LMWH group and from 5.28 to 3.39 in the placebo group. In de Bievre et al,19 10/15 patients (66.7%) assigned to LMWH and 7/14 patients (50%) assigned to placebo improved histologically over the study period (OR 2.00; 95% CI 0.45–8.96; P = 0.37). The mean Histological Grading System decreased from 2.93 at baseline to 2.00 after 8 weeks in the LMWH group and from 3.93 to 3.11 in the placebo group. The grading scales used in these two studies were not sufficiently similar to justify pooling the data for analysis.

Adverse events

In Bloom et al,17 0/48 patients (0%) assigned to LMWH and 1/52 patients (1.9%) assigned to placebo developed significant rectal hemorrhage. Other adverse events considered severe in the LMWH group included one patient with colitis not otherwise specified and two patients with aggravated UC; in the placebo group one patient had aggravated UC and one developed nausea. Overall, 29/48 patients (60.4%) in the LMWH group and 28/52 patients (53.8%) in the placebo group reported at least one adverse event. No serious adverse events were reported in either the LMWH or placebo groups in de Bievre et al,19 including no reports of rectal hemorrhage. In Celasco et al18, 22/71 (31.0%) patients in the LMWH group and 23/70 (32.9%) patients in the placebo group experienced at least one adverse event during the study, although none were serious. Bloody stools indicative of rectal bleeding were absent in 48/71 (67.6%) patients in the LMWH group and 35/70 (50.0%) patients in the placebo groups at 8 weeks compared to 2/71 (28.2%) and 3/70 (42.9%) at week 0, respectively.

Quality of life

Bloom et al17 reported the subscores of the different domains of the IBDQ, and found no significant differences in any domain between the LMWH and placebo groups from the start to the end of treatment. In de Bievre et al19 there were no significant differences in the mean IBDQ score in the LMWH versus placebo group at baseline (LMWH 132.1, placebo 141.2, P = 0.57) or at the end of treatment (LMWH 162.1, placebo 173.1, P = 0.71).

LMWH in Addition to Standard Therapy

Clinical remission

In Zezos et al,20 5/16 patients (31.3%) assigned to LMWH in addition to standard therapy with corticosteroids and aminosalicylates and 7/18 patients (38.9%) assigned to standard therapy alone achieved clinical remission during the study period (OR 0.71; 95% CI 0.17–2.95; P = 0.64).

Clinical improvement

In Zezos et al,20 14/16 patients (87.5%) assigned to LMWH in addition to standard therapy with corticosteroids and aminosalicylates and 14/18 patients (77.8%) assigned to standard therapy alone improved clinically during the study period (OR 2.00; 95% CI 0.31–12.75; P = 0.46).

Endoscopic remission

In Zezos et al,20 5/16 patients (31.3%) assigned to LMWH in addition to standard therapy with corticosteroids and aminosalicylates and 7/18 patients (38.9%) assigned to standard therapy achieved endoscopic remission during the study period (OR 0.71; 95% CI 0.17–2.95; P = 0.64).

Endoscopic improvement

In Zezos et al,20 11/16 patients (68.9%) assigned to LMWH in addition to standard therapy and 11/18 patients (61.1%) assigned to standard therapy alone improved endoscopically during the study period (OR 1.40; 95% CI 0.34–5.79; P = 0.64).

Adverse events

In Zezos et al,20 no severe adverse events, including no significant rectal bleeding complications, occurred in patients in either the LMWH + standard therapy group nor in the standard therapy group.

Histological improvement, quality of life

These outcomes were not reported in Zezos et al.20

UFH Versus Corticosteroids

Clinical improvement

In Panes et al,21 0/12 patients (0%) assigned to UFH and 9/13 patients (69.2%) assigned to corticosteroids improved clinically over the study period (OR 0.02; 95% CI 0–0.40; P = 0.01).

Adverse events

In Panes et al,21 three patients assigned to UFH were withdrawn from the study due to an increase in rectal bleeding. In two of these patients the bleeding was controlled after stopping the UFH, but the third patient required urgent surgery. No other adverse events occurred in this group. One patient in the corticosteroid group required urgent surgery following the development of toxic megacolon. No other severe adverse events were reported.

Clinical remission, endoscopic remission, endoscopic improvement, histological improvement, quality of life

These outcomes were not reported in Panes et al.21

DISCUSSION

There are a limited number of effective treatments for remission induction in active UC. An increased risk of thrombosis in patients with UC and reports suggesting an improvement in UC symptoms while on anticoagulant therapy led to randomized controlled studies of heparin and LMWH in active UC. However, an increased risk of rectal bleeding due to anticoagulant therapy would need to be considered as a potential complication of treatment, and balanced against any therapeutic benefit.

There are four articles representing three distinct randomized, placebo-controlled double blind studies evaluating LMWH in the treatment of outpatients with mild-moderate active UC.17-19, 47 Two of these studies showed no benefit for adjuvant LMWH therapy over placebo in a variety of outcome measures, including clinical remission, clinical improvement, endoscopic improvement, histological improvement, or quality of life.17-19 However, the results of Celasco et al18 showed statistically significant benefit for LMWH over placebo in achieving clinical remission and improvement, endoscopic improvement, and reduced rectal bleeding when administered by extended colon-release tablets.

The benefit of LMWH described by Celasco et al may be due to the decision to study a LMWH administered via extended colon-release tablets rather than through the conventional subcutaneous route. Oral LMWH is absorbed in the gastrointestinal tract, has enhanced efficacy in targeting GI lesions, and exerts a weaker systemic antithrombotic effect.48 Taken together, these factors allowed Celasco et al18 to administer a much higher dose of LMWH with a decreased risk of bleeding (18,000–19,000 anti-Xa IU vs. 4500 anti-Xa IU Bloom et al vs. 3436 anti-Xa IU de Bievre et al) and deliver the drug directly to the diseased colon rather than have the drug systemically distributed to unaffected tissues.

The two studies with negative findings enrolled relatively small numbers of patients, and may have lacked the power to detect a statistically significant difference between LMWH and placebo. However, the large difference in effect size between these studies weakens this hypothesis. Lastly, but of note, five of the eight Celasco et al investigators worked as consultants or employees for the firm that provided all study funding and developed the extended colon-release technology. Despite being a well-designed trial with thorough outcome reporting and analysis, the heavy degree of industry involvement is a potential source of bias which weakens the conclusions one can draw from the study.18 Industry-funded studies may be more likely to be associated with positive results for the products made by the company funding the research.49, 50

No benefit was found with the addition of LMWH to standard therapy in Zezos et al,20 in which participants and evaluators were not blinded to treatment allocation. However, LMWH was well tolerated in all of these studies, without any reports of significant rectal bleeding in those patients assigned to LMWH. Two other placebo-controlled studies published as abstracts only also demonstrated no benefit for LMWH over placebo.23, 24

Only one of the included studies evaluated UFH monotherapy for active UC. This study included inpatients with severe disease and corticosteroids were used as the comparator. The UFH-treated patients had a significantly lower rate of clinical improvement than those who received steroids (0% versus 69%). Increased rectal bleeding also occurred in 3 of 12 patients given UFH. Although this study was limited by its single-blind design, in that only the physician examiners were blinded to treatment allocation, the results strongly suggest inferiority of UFH compared to corticosteroids in this patient population. Furthermore, this study shows that UFH used as monotherapy does not provide any benefit for the treatment of moderate or severe exacerbations of UC.21 Whether or not UFH would be effective for treating patients with milder disease is not known. A single randomized, placebo-controlled trial testing UFH in this setting has been published in abstract form only, but the final results have not been published.22

In conclusion, there is no evidence to support the use of UFH or LMWH given subcutaneously for the treatment of active UC. LMWH given orally by colon extended-release tablets may be beneficial as a therapy for UC, and further study into this treatment is warranted. The pathophysiology of UC and the possible link between microthrombosis and immune activation in the colon should also be further investigated, and may identify other therapeutic targets which could be important in developing novel treatments for UC.

Acknowledgements

This article is based on a Cochrane Review published in The Cochrane Library 2010, Issue 10 (see www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the review.

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Citing Literature

Volume17, Issue9

September 2011

Pages 1979-1986

Unfractionated or low molecular weight heparin for induction of remission in ulcerative colitis: A cochrane inflammatory bowel disease and functional bowel disorders systematic review of randomized trials

Abstract

Background:

Methods:

Results:

Conclusions:

MATERIALS AND METHODS

Trial Searching

Outcome Measures

Quality Assessment

Data Collection and Statistical Analysis

RESULTS

Description of Studies

LMWH Versus Placebo

Bloom et al17

Celasco et al18

de Bievre et al19

LMWH in Addition to Standard Therapy

Zezos et al20

UFH Versus Corticosteroids

Panes et al21

Effects of Interventions

LMWH Versus Placebo

Clinical remission

Clinical improvement

Endoscopic improvement

Endoscopic remission

Histological improvement

Adverse events

Quality of life

LMWH in Addition to Standard Therapy

Clinical remission

Clinical improvement

Endoscopic remission

Endoscopic improvement

Adverse events

Histological improvement, quality of life

UFH Versus Corticosteroids

Clinical improvement

Adverse events

Clinical remission, endoscopic remission, endoscopic improvement, histological improvement, quality of life

DISCUSSION

Acknowledgements

REFERENCES

Citing Literature

References

Related

Information