Background

Gastrointestinal angiodysplasias are vascular malformations that often cause red blood cell transfusion-dependent anaemia. Several studies suggest that somatostatin analogues might decrease rebleeding rates, but the true effect size is unknown. We therefore aimed to investigate the efficacy of somatostatin analogues on red blood cell transfusion requirements of patients with gastrointestinal angiodysplasias and to identify subgroups that might benefit the most from somatostatin analogue therapy.

Methods

We did a systematic review and individual patient data meta-analysis. We searched MEDLINE, Embase, and Cochrane on Jan 15, 2016, with an updated search on April 25, 2021. All published randomised controlled trials and cohort studies that reported on somatostatin analogue therapy in patients with gastrointestinal angiodysplasias were eligible for screening. We excluded studies without original patient data, single case reports, small case series (ie, <10 participants), studies in which patients had a specific aetiology of gastrointestinal angiodysplasias, and studies in which somatostatin analogue therapy was initiated simultaneously with other treatment modalities. Authors of eligible studies were invited to share individual patient data. Aggregated data was used if individual patient data were not provided. The primary outcome was the mean reduction in the number of red blood cell transfusions during somatostatin analogue therapy, compared with baseline, expressed as the incidence rate ratio (IRR) and absolute mean decrease. We defined patients as either good responders (≥50% reduction in the number of red blood cell transfusions) or poor responders (<50% reduction). A mixed-effects negative binomial regression was used to account for clustering of patients and skewness in data. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42020213985.

Findings

We identified 11 eligible studies (one randomised controlled trial and ten cohort studies) of moderate-to-high quality and obtained individual patient data from the authors of nine (82%) studies. The remaining two (18%) studies provided sufficient information in the published manuscript to extract individual patient data. In total, we analysed data from 212 patients. Somatostatin analogues reduced the number of red blood cell transfusions with an IRR of 0·18 (95% CI 0·14–0·24; p<0·0001) during a median treatment duration of 12 months (IQR 6·0–12·0) and follow-up period of 12 months (12·0–12·0), correlating with a mean absolute decrease in the number of red blood cell transfusions from 12·8 (95% CI 10·4–15·8) during baseline to 2·3 (1·9–2·9) during follow-up—ie, a reduction of 10·5 red blood cell transfusions (p<0·0001). 177 (83%) of 212 patients had a good response to somatostatin analogue therapy (defined as at least a 50% reduction in the number of red blood cell transfusions). Heterogeneity across studies was moderate (I²=53%; p=0·02). Location of gastrointestinal angiodysplasias in the stomach compared with angiodysplasias in the small bowel and colon (IRR interaction 1·92 [95% CI 1·13–3·26]; p=0·02) was associated with worse treatment response. Octreotide was associated with a better treatment response than lanreotide therapy (IRR interaction 2·13 [95% CI 1·12–4·04]; p=0·02). The certainty of evidence was high for the randomised controlled trial and low for the ten cohort studies. Adverse events occurred in 38 (18%) of 212 patients receiving somatostatin analogue therapy, with ten (5%) discontinuing this therapy because of adverse events. The most common adverse events were loose stools (seven [3%] of 212), cholelithiasis (five [2%]), flatulence (four [2%]), and administration site reactions (erythema, five [2%]).

Interpretation

Somatostatin analogue therapy is safe and effective in most patients with red blood cell transfusion-dependent bleeding due to gastrointestinal angiodysplasias. Somatostatin analogue therapy is more effective in patients with angiodysplasias located in the small bowel and colon, and octreotide therapy seems to be more effective than lanreotide therapy.

Funding

The Netherlands Organisation for Health Research and Development and the Radboud University Medical Center.

中文翻译：

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胃肠道血管发育不良患者对生长抑素类似物反应的有效性和预测因素：系统评价和个体患者数据荟萃分析

背景

胃肠道血管发育不良是血管畸形，常导致红细胞输血依赖性贫血。几项研究表明，生长抑素类似物可能会降低再出血率，但真正的效果大小尚不清楚。因此，我们旨在研究生长抑素类似物对胃肠道血管发育不良患者红细胞输血需求的疗效，并确定可能从生长抑素类似物治疗中获益最大的亚组。

方法

我们进行了系统评价和个体患者数据荟萃分析。我们于 2016 年 1 月 15 日检索了 MEDLINE、Embase 和 Cochrane，并在 2021 年 4 月 25 日进行了更新检索。所有已发表的随机对照试验和队列研究报告了对胃肠道血管发育不良患者的生长抑素类似物治疗。我们排除了没有原始患者数据的研究、单个病例报告、小病例系列（即<10 名参与者）、患者具有胃肠道血管发育不良的特定病因的研究，以及生长抑素类似物治疗与其他治疗方式同时开始的研究。符合条件的研究的作者被邀请分享个体患者数据。如果未提供个体患者数据，则使用汇总数据。主要结果是与基线相比，生长抑素类似物治疗期间红细胞输注次数的平均减少，表示为发生率比 (IRR) 和绝对平均减少。我们将患者定义为反应良好（红细胞输血次数减少≥50%）或反应差（减少<50%）。混合效应负二项式回归用于解释患者的聚类和数据的偏度。本研究已在国际前瞻性系统评价注册 (PROSPERO) 中注册，编号为 CRD42020213985。我们将患者定义为反应良好（红细胞输血次数减少≥50%）或反应差（减少<50%）。使用混合效应负二项式回归来解释患者的聚类和数据的偏度。本研究已在国际前瞻性系统评价注册 (PROSPERO) 中注册，编号为 CRD42020213985。我们将患者定义为反应良好（红细胞输血次数减少≥50%）或反应差（减少<50%）。使用混合效应负二项式回归来解释患者的聚类和数据的偏度。本研究已在国际前瞻性系统评价注册 (PROSPERO) 中注册，编号为 CRD42020213985。

发现

我们确定了 11 项符合条件的中等到高质量研究（一项随机对照试验和十项队列研究），并从九项 (82%) 研究的作者那里获得了个体患者数据。其余两项 (18%) 研究在已发表的手稿中提供了足够的信息来提取个体患者数据。我们总共分析了 212 名患者的数据。生长抑素类似物在 12 个月（IQR 6·0-12 ·0) 和 12 个月的随访期 (12·0–12·0)，与从 12·8 起红细胞输注次数的平均绝对减少相关 (95% CI 10·4-15·8 ) 到随访期间的 2·3 (1·9–2·9)，即减少 10·5 次红细胞输注 (p<0·0001)。212 名患者中有 177 名 (83%) 对生长抑素类似物治疗有良好反应（定义为红细胞输注次数至少减少 50%）。研究间的异质性中等（我² = 53％; p=0·02）。与小肠和结肠血管发育不良相比，胃中胃肠道血管发育不良的位置（IRR 相互作用 1·92 [95% CI 1·13–3·26]；p=0·02）与较差的治疗反应相关。与兰瑞肽治疗相比，奥曲肽与更好的治疗反应相关（IRR 相互作用 2·13 [95% CI 1·12–4·04]；p=0·02）。随机对照试验的证据质量高，十个队列研究的证据质量低。接受生长抑素类似物治疗的 212 名患者中有 38 名 (18%) 发生了不良事件，其中 10 名 (5%) 因不良事件而停止该治疗。最常见的不良事件是稀便（212 例中的 7 例 [3%]）、胆石症（5 例 [2%]）、肠胃气胀（4 例 [2%]）和给药部位反应（红斑，5 例 [2%]）。

解释

生长抑素类似物治疗对大多数因胃肠道血管发育不良引起的红细胞输血依赖性出血患者是安全有效的。生长抑素类似物治疗小肠和结肠血管发育不良患者更有效，奥曲肽治疗似乎比兰瑞肽治疗更有效。

资金

荷兰卫生研究与发展组织和 Radboud 大学医学中心。