Abdul Wahid S Fadilah, Ismail Nor Azimah, Wan Jamaludin Wan Fariza, Muhamad Nor Asiah, Abdul Hamid Muhammad Khairul Azaham, Harunarashid Hanafiah, Lai Nai Ming
Cell Therapy Center, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Kuala Lumpur, Malaysia, 56000.
Cochrane Database Syst Rev. 2018 Aug 29;8(8):CD010747. doi: 10.1002/14651858.CD010747.pub2.
Revascularisation is the gold standard therapy for patients with critical limb ischaemia (CLI). In over 30% of patients who are not suitable for or have failed previous revascularisation therapy (the 'no-option' CLI patients), limb amputation is eventually unavoidable. Preliminary studies have reported encouraging outcomes with autologous cell-based therapy for the treatment of CLI in these 'no-option' patients. However, studies comparing the angiogenic potency and clinical effects of autologous cells derived from different sources have yielded limited data. Data regarding cell doses and routes of administration are also limited.
To compare the efficacy and safety of autologous cells derived from different sources, prepared using different protocols, administered at different doses, and delivered via different routes for the treatment of 'no-option' CLI patients.
The Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), and trials registries (16 May 2018). Review authors searched PubMed until February 2017.
We included randomised controlled trials (RCTs) involving 'no-option' CLI patients comparing a particular source or regimen of autologous cell-based therapy against another source or regimen of autologous cell-based therapy.
Three review authors independently assessed the eligibility and methodological quality of the trials. We extracted outcome data from each trial and pooled them for meta-analysis. We calculated effect estimates using a risk ratio (RR) with 95% confidence interval (CI), or a mean difference (MD) with 95% CI.
We included seven RCTs with a total of 359 participants. These studies compared bone marrow-mononuclear cells (BM-MNCs) versus mobilised peripheral blood stem cells (mPBSCs), BM-MNCs versus bone marrow-mesenchymal stem cells (BM-MSCs), high cell dose versus low cell dose, and intramuscular (IM) versus intra-arterial (IA) routes of cell implantation. We identified no other comparisons in these studies. We considered most studies to be at low risk of bias in random sequence generation, incomplete outcome data, and selective outcome reporting; at high risk of bias in blinding of patients and personnel; and at unclear risk of bias in allocation concealment and blinding of outcome assessors. The quality of evidence was most often low to very low, with risk of bias, imprecision, and indirectness of outcomes the major downgrading factors.Three RCTs (100 participants) reported a total of nine deaths during the study follow-up period. These studies did not report deaths according to treatment group.Results show no clear difference in amputation rates between IM and IA routes (RR 0.80, 95% CI 0.54 to 1.18; three RCTs, 95 participants; low-quality evidence). Single-study data show no clear difference in amputation rates between BM-MNC- and mPBSC-treated groups (RR 1.54, 95% CI 0.45 to 5.24; 150 participants; low-quality evidence) and between high and low cell dose (RR 3.21, 95% CI 0.87 to 11.90; 16 participants; very low-quality evidence). The study comparing BM-MNCs versus BM-MSCs reported no amputations.Single-study data with low-quality evidence show similar numbers of participants with healing ulcers between BM-MNCs and mPBSCs (RR 0.89, 95% CI 0.44 to 1.83; 49 participants) and between IM and IA routes (RR 1.13, 95% CI 0.73 to 1.76; 41 participants). In contrast, more participants appeared to have healing ulcers in the BM-MSC group than in the BM-MNC group (RR 2.00, 95% CI 1.02 to 3.92; one RCT, 22 participants; moderate-quality evidence). Researchers comparing high versus low cell doses did not report ulcer healing.Single-study data show similar numbers of participants with reduction in rest pain between BM-MNCs and mPBSCs (RR 0.99, 95% CI 0.93 to 1.06; 104 participants; moderate-quality evidence) and between IM and IA routes (RR 1.22, 95% CI 0.91 to 1.64; 32 participants; low-quality evidence). One study reported no clear difference in rest pain scores between BM-MNC and BM-MSC (MD 0.00, 95% CI -0.61 to 0.61; 37 participants; moderate-quality evidence). Trials comparing high versus low cell doses did not report rest pain.Single-study data show no clear difference in the number of participants with increased ankle-brachial index (ABI; increase of > 0.1 from pretreatment), between BM-MNCs and mPBSCs (RR 1.00, 95% CI 0.71 to 1.40; 104 participants; moderate-quality evidence), and between IM and IA routes (RR 0.93, 95% CI 0.43 to 2.00; 35 participants; very low-quality evidence). In contrast, ABI scores appeared higher in BM-MSC versus BM-MNC groups (MD 0.05, 95% CI 0.01 to 0.09; one RCT, 37 participants; low-quality evidence). ABI was not reported in the high versus low cell dose comparison.Similar numbers of participants had improved transcutaneous oxygen tension (TcO₂) with IM versus IA routes (RR 1.22, 95% CI 0.86 to 1.72; two RCTs, 62 participants; very low-quality evidence). Single-study data with low-quality evidence show a higher TcO₂ reading in BM-MSC versus BM-MNC groups (MD 8.00, 95% CI 3.46 to 12.54; 37 participants) and in mPBSC- versus BM-MNC-treated groups (MD 1.70, 95% CI 0.41 to 2.99; 150 participants). TcO₂ was not reported in the high versus low cell dose comparison.Study authors reported no significant short-term adverse effects attributed to autologous cell implantation.
AUTHORS' CONCLUSIONS: Mostly low- and very low-quality evidence suggests no clear differences between different stem cell sources and different treatment regimens of autologous cell implantation for outcomes such as all-cause mortality, amputation rate, ulcer healing, and rest pain for 'no-option' CLI patients. Pooled analyses did not show a clear difference in clinical outcomes whether cells were administered via IM or IA routes. High-quality evidence is lacking; therefore the efficacy and long-term safety of autologous cells derived from different sources, prepared using different protocols, administered at different doses, and delivered via different routes for the treatment of 'no-option' CLI patients, remain to be confirmed.Future RCTs with larger numbers of participants are needed to determine the efficacy of cell-based therapy for CLI patients, along with the optimal cell source, phenotype, dose, and route of implantation. Longer follow-up is needed to confirm the durability of angiogenic potential and the long-term safety of cell-based therapy.
血管再通术是严重肢体缺血（CLI）患者的金标准治疗方法。在超过30%不适合或先前血管再通治疗失败的患者（“无选择”CLI患者）中，肢体截肢最终不可避免。初步研究报告了自体细胞疗法治疗这些“无选择”患者CLI的令人鼓舞的结果。然而，比较不同来源自体细胞的血管生成能力和临床效果的研究数据有限。关于细胞剂量和给药途径的数据也很有限。
比较不同来源、采用不同方案制备、以不同剂量给药并通过不同途径递送的自体细胞治疗“无选择”CLI患者的疗效和安全性。
Cochrane血管信息专家（CIS）检索了Cochrane血管专业注册库、Cochrane对照试验中心注册库（CENTRAL）、MEDLINE Ovid、Embase Ovid、护理及相关健康文献累积索引（CINAHL）、补充和替代医学数据库（AMED）以及试验注册库（2018年5月16日）。综述作者检索了截至2017年2月的PubMed。
我们纳入了涉及“无选择”CLI患者的随机对照试验（RCT），比较特定来源或自体细胞治疗方案与另一种来源或自体细胞治疗方案。
三位综述作者独立评估试验的纳入资格和方法学质量。我们从每个试验中提取结局数据并汇总进行荟萃分析。我们使用风险比（RR）及95%置信区间（CI）或均值差（MD）及95%CI计算效应估计值。
我们纳入了7项RCT，共359名参与者。这些研究比较了骨髓单个核细胞（BM-MNCs）与动员外周血干细胞（mPBSCs）、BM-MNCs与骨髓间充质干细胞（BM-MSCs）、高细胞剂量与低细胞剂量以及肌肉注射（IM）与动脉内（IA）细胞植入途径。我们在这些研究中未发现其他比较。我们认为大多数研究在随机序列生成、不完整结局数据和选择性结局报告方面存在低偏倚风险；在患者和人员盲法方面存在高偏倚风险；在分配隐藏和结局评估者盲法方面存在不清楚的偏倚风险。证据质量大多为低至极低，偏倚风险、不精确性和结局的间接性是主要的降级因素。三项RCT（100名参与者）报告在研究随访期间共有9例死亡。这些研究未按治疗组报告死亡情况。结果显示IM和IA途径之间的截肢率无明显差异（RR 0.80，95%CI 0.54至1.18；三项RCT，95名参与者；低质量证据）。单项研究数据显示BM-MNC治疗组和mPBSC治疗组之间的截肢率无明显差异（RR 1.54，95%CI 0.45至5.24；150名参与者；低质量证据），高细胞剂量和低细胞剂量之间也无明显差异（RR 3.21，95%CI 0.87至11.90；16名参与者；极低质量证据）。比较BM-MNCs与BM-MSCs的研究未报告截肢情况。低质量证据的单项研究数据显示BM-MNCs和mPBSCs之间愈合溃疡的参与者数量相似（RR 0.89，95%CI 0.44至1.83；49名参与者），IM和IA途径之间也相似（RR 1.13，95%CI 0.73至1.76；41名参与者）。相比之下，BM-MSC组中似乎比BM-MNC组有更多参与者愈合溃疡（RR 2.00，95%CI 1.02至3.92；一项RCT，22名参与者；中等质量证据）。比较高细胞剂量与低细胞剂量的研究人员未报告溃疡愈合情况。单项研究数据显示BM-MNCs和mPBSCs之间静息痛减轻的参与者数量相似（RR 0.99，95%CI 0.93至1.06；104名参与者；中等质量证据），IM和IA途径之间也相似（RR 1.22，9%CI 0.91至1.64；32名参与者；低质量证据）。一项研究报告BM-MNC和BM-MSC之间静息痛评分无明显差异（MD 0.00，95%CI -0.61至0.61；37名参与者；中等质量证据）。比较高细胞剂量与低细胞剂量的试验未报告静息痛情况。单项研究数据显示BM-MNCs和mPBSCs之间踝臂指数（ABI；较治疗前增加>0.1）升高的参与者数量无明显差异（RR 1.00，95%CI 0.71至1.40；104名参与者；中等质量证据），IM和IA途径之间也无明显差异（RR 0.93，95%CI 0.43至2.00；35名参与者；极低质量证据）。相比之下，BM-MSC组的ABI评分似乎高于BM-MNC组（MD 0.05，95%CI 0.01至0.09；一项RCT，37名参与者；低质量证据）。高细胞剂量与低细胞剂量比较中未报告ABI情况。IM和IA途径改善经皮氧分压（TcO₂）的参与者数量相似（RR 1.22，95%CI 0.86至1.72；两项RCT，62名参与者；极低质量证据）。低质量证据的单项研究数据显示BM-MSC组的TcO₂读数高于BM-MNC组（MD 8.00，95%CI 3.46至12.54；37名参与者），mPBSC治疗组高于BM-MNC治疗组（MD 1.70，95%CI 0.41至2.99；150名参与者）。高细胞剂量与低细胞剂量比较中未报告TcO₂情况。研究作者报告自体细胞植入未产生明显的短期不良反应。
大多为低质量和极低质量的证据表明，对于“无选择”CLI患者，不同干细胞来源和自体细胞植入的不同治疗方案在全因死亡率、截肢率、溃疡愈合和静息痛等结局方面无明显差异。汇总分析未显示细胞通过IM或IA途径给药在临床结局上有明显差异。缺乏高质量证据；因此，不同来源、采用不同方案制备、以不同剂量给药并通过不同途径递送的自体细胞治疗“无选择”CLI患者的疗效和长期安全性仍有待证实。未来需要更多参与者的RCT来确定基于细胞的疗法对CLI患者的疗效，以及最佳细胞来源、表型、剂量和植入途径。需要更长时间的随访来确认血管生成潜力的持久性和基于细胞疗法的长期安全性。
