Chande Nilesh, Wang Yongjun, McDonald John Wd, MacDonald John K
London Health Sciences Centre - Victoria Hospital, Room E6-321A, 800 Commissioners Road East, London, ON, Canada, N6A 5W9.
Robarts Research Institute, Robarts Clinical Trials, P.O. Box 5015, 100 Perth Drive, London, ON, Canada.
Cochrane Database Syst Rev. 2015 Aug 5;8(8):CD006774. doi: 10.1002/14651858.CD006774.pub4.
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.
AUTHORS' CONCLUSIONS: 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.
溃疡性结肠炎（UC）患者的治疗选择有限。UC患者血栓形成风险增加，且观察到因血栓事件接受抗凝治疗的UC患者肠道症状有所改善，这促使人们开展试验，研究普通肝素（UFH）和低分子肝素（LMWH）在活动期UC患者中的应用。
综述关于普通肝素（UFH）或低分子肝素（LMWH）诱导溃疡性结肠炎患者缓解疗效的随机试验。
我们检索了截至2014年6月的MEDLINE、EMBASE、CENTRAL以及Cochrane IBD/FBD小组专门的试验注册库。我们还检索了关于溃疡性结肠炎的综述文章以及已识别文章的参考文献，以努力识别更多研究UFH或LMWH在溃疡性结肠炎患者中应用的随机试验。我们检索了主要胃肠病学会议的摘要，以识别以摘要形式发表的研究。
纳入比较UFH或LMWH与安慰剂或对照疗法诱导溃疡性结肠炎缓解的随机对照试验。仅以摘要形式发表的研究，若能联系作者获取更多信息则纳入。
制定了数据提取表，并用于从纳入研究中提取数据。两名作者独立提取数据。任何分歧通过协商解决。使用Cochrane偏倚风险工具评估研究质量。数据按意向性分析。主要结局为研究定义的缓解诱导。次要结局指标包括：作者定义的内镜缓解；作者定义的临床、组织学或内镜改善；不良事件的发生；出血的发生；以及通过有效工具测量的生活质量改善。对于二分结局，我们计算风险比（RR）及相应的95%置信区间。若评估相同治疗（UFH或LMWH对比安慰剂或其他疗法），则合并数据进行分析。使用GRADE标准评估支持结局的证据的总体质量。
五项研究符合纳入标准（329例患者）。三项研究（270例患者）比较了低分子肝素与安慰剂，一项研究（34例患者）比较了除标准疗法外加用LMWH，一项研究（25例患者）比较了UFH与皮质类固醇。比较UFH与皮质类固醇的研究因单盲设计被评为高偏倚风险。比较在标准疗法基础上加用LMWH与单纯标准疗法的研究因开放标签设计被评为高偏倚风险。其他三项研究被评为低偏倚风险。皮下注射LMWH在任何结局方面均未显示优于安慰剂，包括临床缓解（证据质量极低）以及临床、内镜或组织学改善。通过结肠缓释片给予高剂量LMWH在临床缓解（RR 1.39；95%CI 1.09至1.77；P = 0.008；证据质量极低）、临床改善（RR 1.28；95%CI 1.06至1.55；P = 0.01；证据质量极低）和内镜改善（RR 1.21；95%CI 1.00至1.47；P = 0.05）方面显示优于安慰剂，但在内镜缓解或组织学改善方面未显示优势。在标准疗法基础上加用LMWH在临床缓解、临床改善、内镜缓解或内镜改善方面并无益处。LMWH耐受性良好，但对生活质量无显著益处。一项比较UFH与皮质类固醇治疗重度UC的研究表明UFH在临床改善方面较差。分配到UFH组的更多患者发生直肠出血这一不良事件。
有证据表明LMWH可能对活动期UC有效。通过结肠缓释片给药时，LMWH在治疗轻至中度疾病的门诊患者方面比安慰剂更有效。这一益处需要进一步的随机对照研究予以证实。较低剂量皮下注射LMWH时未观察到同样的益处。没有证据支持使用UFH治疗活动期UC。对轻度疾病患者进一步开展UFH试验可能也是合理的。所发现的任何益处都需要与活动期UC患者直肠出血风险可能增加相权衡。
