Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.
Cochrane Database Syst Rev. 2022 Jul 8;7(7):CD008347. doi: 10.1002/14651858.CD008347.pub4.
Peripheral arterial disease is a major health problem, and in about 1% to 2% of patients, the disease progresses to critical limb ischaemia (CLI), also known as critical limb-threatening ischaemia. In a substantial number of individuals with CLI, no effective treatment options other than amputation are available, with around a quarter of these patients requiring a major amputation during the following year. This is the second update of a review first published in 2011.
To evaluate the benefits and harms of local intramuscular transplantation of autologous adult bone marrow mononuclear cells (BMMNCs) as a treatment for CLI.
We used standard, extensive Cochrane search methods. The latest search date was 8 November 2021.
We included all randomised controlled trials (RCTs) of CLI in which participants were randomly allocated to intramuscular administration of autologous adult BMMNCs or control (either no intervention, conventional conservative therapy, or placebo).
We used standard Cochrane methods. Our primary outcomes of interest were all-cause mortality, pain, and amputation. Our secondary outcomes were angiographic analysis, ankle-brachial index (ABI), pain-free walking distance, side effects and complications. We assessed the certainty of the evidence using the GRADE approach.
We included four RCTs involving a total of 176 participants with a clinical diagnosis of CLI. Participants were randomised to receive either intramuscular cell implantation of BMMNCs or control. The control arms varied between studies, and included conventional therapy, diluted autologous peripheral blood, and saline. There was no clear evidence of an effect on mortality related to the administration of BMMNCs compared to control (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.15 to 6.63; 3 studies, 123 participants; very low-certainty evidence). All trials assessed changes in pain severity, but the trials used different forms of pain assessment tools, so we were unable to pool data. Three studies individually reported that no differences in pain reduction were observed between the BMMNC and control groups. One study reported that reduction in rest pain was greater in the BMMNC group compared to the control group (very low-certainty evidence). All four trials reported the rate of amputation at the end of the study period. We are uncertain if amputations were reduced in the BMMNC group compared to the control group, as a possible small effect (RR 0.52, 95% CI 0.27 to 0.99; 4 studies, 176 participants; very low-certainty evidence) was lost after undertaking sensitivity analysis (RR 0.52, 95% CI 0.19 to 1.39; 2 studies, 89 participants). None of the included studies reported any angiographic analysis. Ankle-brachial index was reported differently by each study, so we were not able to pool the data. Three studies reported no changes between groups, and one study reported greater improvement in ABI (as haemodynamic improvement) in the BMMNC group compared to the control group (very low-certainty evidence). One study reported pain-free walking distance, finding no clear difference between BMMNC and control groups (low-certainty evidence). We pooled the data for side effects reported during the follow-up, and this did not show any clear difference between BMMNC and control groups (RR 2.13, 95% CI 0.50 to 8.97; 4 studies, 176 participants; very low-certainty evidence). We downgraded the certainty of the evidence due to the concerns about risk of bias, imprecision, and inconsistency.
AUTHORS' CONCLUSIONS: We identified a small number of studies that met our inclusion criteria, and these differed in the controls they used and how they measured important outcomes. Limited data from these trials provide very low- to low-certainty evidence, and we are unable to draw conclusions to support the use of local intramuscular transplantation of BMMNC for improving clinical outcomes in people with CLI. Evidence from larger RCTs is needed in order to provide adequate statistical power to assess the role of this procedure.
外周动脉疾病是一个主要的健康问题，约 1%至 2%的患者疾病会进展为严重肢体缺血（CLI），也称为严重肢体缺血性疾病。在大量 CLI 患者中，除了截肢之外，没有其他有效的治疗选择，大约四分之一的这些患者在接下来的一年中需要进行大截肢。这是 2011 年首次发表的一篇综述的第二次更新。
评估自体成人间质干细胞（BMMNC）局部肌肉内移植作为 CLI 治疗方法的疗效和安全性。
我们使用了标准的、广泛的 Cochrane 检索方法。最新的检索日期为 2021 年 11 月 8 日。
我们纳入了所有将参与者随机分配至自体成人间质干细胞肌肉内给药或对照组（无干预、常规保守治疗或安慰剂）的 CLI 随机对照试验（RCT）。
我们排除了仅使用细胞培养或非自体细胞的研究，以及非随机设计的研究。
我们使用了标准的 Cochrane 方法。我们主要关注的结局指标是全因死亡率、疼痛和截肢。我们的次要结局指标包括血管造影分析、踝肱指数（ABI）、无痛行走距离、副作用和并发症。我们使用 GRADE 方法评估证据的确定性。
我们纳入了四项 RCT，共纳入 176 名临床诊断为 CLI 的患者。参与者被随机分配至接受 BMMNC 肌肉内细胞植入或对照组。对照组在研究之间有所不同，包括常规治疗、稀释的自体外周血和生理盐水。与对照组相比，BMMNC 给药与死亡率之间没有明显的关联（风险比（RR）1.00，95%置信区间（CI）0.15 至 6.63；3 项研究，123 名参与者；极低确定性证据）。所有试验均评估了疼痛严重程度的变化，但试验使用了不同形式的疼痛评估工具，因此我们无法进行数据合并。三项研究单独报告称，BMMNC 组与对照组之间在疼痛减轻方面没有差异。一项研究报告称，BMMNC 组的静息疼痛减轻程度大于对照组（极低确定性证据）。四项试验均报告了研究结束时的截肢率。我们不确定 BMMNC 组与对照组相比，截肢是否减少，因为敏感性分析后可能存在较小的效果（RR 0.52，95% CI 0.27 至 0.99；4 项研究，176 名参与者；极低确定性证据）。纳入的研究均未报告任何血管造影分析。踝肱指数的报告方式因研究而异，因此我们无法进行数据合并。三项研究报告两组之间无变化，一项研究报告 BMMNC 组的 ABI 改善（作为血流动力学改善）大于对照组（极低确定性证据）。一项研究报告了无痛行走距离，发现 BMMNC 组与对照组之间无明显差异（低确定性证据）。我们合并了随访期间报告的副作用数据，结果显示 BMMNC 组与对照组之间没有明显差异（RR 2.13，95% CI 0.50 至 8.97；4 项研究，176 名参与者；极低确定性证据）。由于对偏倚风险、不精确性和不一致性的担忧，我们降低了证据的确定性等级。
我们发现了少数符合纳入标准的研究，这些研究在对照组的使用和重要结局的测量方式上存在差异。这些试验提供的有限数据提供了极低至低确定性证据，我们无法得出支持使用自体成人间质干细胞局部肌肉内移植改善 CLI 患者临床结局的结论。需要更大规模的 RCT 证据，以提供足够的统计效力来评估该手术的作用。
