Boncoraglio Giorgio Battista, Ranieri Michela, Bersano Anna, Parati Eugenio A, Del Giovane Cinzia
Department of Neurology, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Via Celoria 11, Milano, Italy, 20133.
Cochrane Database Syst Rev. 2019 May 5;5(5):CD007231. doi: 10.1002/14651858.CD007231.pub3.
Stroke is a leading cause of morbidity and mortality worldwide, with very large healthcare and social costs, and a strong demand for alternative therapeutic approaches. Preclinical studies have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in people with ischemic stroke is lacking. This is the first update of the Cochrane review published in 2010.
To assess the efficacy and safety of stem cell transplantation compared with control in people with ischemic stroke.
We searched the Cochrane Stroke Group Trials Register (last searched August 2018), CENTRAL (last searched August 2018), MEDLINE (1966 to August 2018), Embase (1980 to August 2018), and BIOSIS (1926 to August 2018). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched August 2018). We also contacted individuals active in the field and stem cell manufacturers (last contacted August 2018).
We included randomized controlled trials (RCTs) that recruited people with ischemic stroke, in any phase of the disease (acute, subacute or chronic), and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation, regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as neurologic impairment or functional outcome) at longer term follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections, and neoplastic transformation).
Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data. If needed, we contacted study authors for additional information. We performed random effects meta-analyses when two or more RCTs were available for any outcome. We assessed the certainty of the evidence by using the GRADE approach.
In this updated review, we included seven completed RCTs with 401 participants. All tested adult human non-neural stem cells; cells were transplanted during the acute, subacute, or chronic phase of ischemic stroke; administered intravenously, intra-arterially, intracerebrally, or into the lumbar subarachnoid space. Follow-up ranged from six months to seven years. Efficacy outcomes were measured with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), or Barthel Index (BI). Safety outcomes included case fatality, and were measured at the end of the trial.Overall, stem cell transplantation was associated with a better clinical outcome when measured with the NIHSS (mean difference [MD] -1.49, 95% confidence interval [CI] -2.65 to -0.33; five studies, 319 participants; low-certainty evidence), but not with the mRS (MD -0.42, 95% CI -0.86 to 0.02; six studies, 371 participants; very low-certainty evidence), or the BI (MD 14.09, 95% CI -1.94 to 30.13; three studies, 170 participants; very low-certainty evidence). The studies in favor of stem cell transplantation had, on average, a higher risk of bias, and a sample size of 32 or fewer participants.No significant safety concerns associated with stem cell transplantation were raised with respect to death (risk ratio [RR] 0.66, 95% CI 0.39 to 1.14; six studies, participants; low-certainty evidence).We were not able to perform the sensitivity analysis according to the quality of studies, because all of them were at high risk of bias.
AUTHORS' CONCLUSIONS: Overall, in participants with ischemic stroke, stem cell transplantation was associated with a reduced neurological impairment, but not with a better functional outcome. No obvious safety concerns were raised. However, these conclusions came mostly from small RCTs with high risk of bias, and the certainty of the evidence ranged from low to very low. More well-designed trials are needed.
中风是全球发病和死亡的主要原因，医疗和社会成本巨大，对替代治疗方法有强烈需求。临床前研究表明，移植到大脑中的干细胞可带来功能改善。然而，迄今为止，缺乏缺血性中风患者干细胞移植获益的证据。这是对2010年发表的Cochrane综述的首次更新。
评估与对照相比，干细胞移植对缺血性中风患者的疗效和安全性。
我们检索了Cochrane中风组试验注册库（最后检索时间为2018年8月）、CENTRAL（最后检索时间为2018年8月）、MEDLINE（1966年至2018年8月）、Embase（1980年至2018年8月）和BIOSIS（1926年至2018年8月）。我们手工检索了潜在相关的会议论文集，筛选了参考文献列表，并检索了正在进行的试验和研究注册库（最后检索时间为2018年8月）。我们还联系了该领域的活跃人士和干细胞制造商（最后联系时间为2018年8月）。
我们纳入了招募缺血性中风患者的随机对照试验（RCT），疾病处于任何阶段（急性、亚急性或慢性），且通过计算机断层扫描或磁共振成像扫描确认有缺血性病变。我们纳入了所有类型的干细胞移植，无论细胞来源（自体移植、同种异体移植或异种移植；胚胎、胎儿或成人；来自脑或其他组织）、细胞给药途径（全身或局部）和剂量。主要结局是长期随访（至少六个月）时的疗效（以神经功能缺损或功能结局评估）。次要结局包括术后安全性结局（死亡、神经功能缺损恶化、感染和肿瘤转化）。
两位综述作者独立应用纳入标准，评估试验质量和偏倚风险，并提取数据。如有需要，我们联系研究作者获取更多信息。当有两个或更多RCT可用于任何结局时，我们进行随机效应荟萃分析。我们使用GRADE方法评估证据的确定性。
在本次更新的综述中，我们纳入了7项完成的RCT，共401名参与者。所有试验均使用成人非神经干细胞；细胞在缺血性中风的急性、亚急性或慢性阶段进行移植；通过静脉、动脉、脑内或腰蛛网膜下腔给药。随访时间为六个月至七年。疗效结局采用美国国立卫生研究院卒中量表（NIHSS）、改良Rankin量表（mRS）或Barthel指数（BI）进行测量。安全性结局包括病死率，在试验结束时进行测量。总体而言，用NIHSS测量时，干细胞移植与更好的临床结局相关（平均差[MD] -1.49，95%置信区间[CI] -2.65至-0.33；五项研究，319名参与者；低确定性证据），但用mRS测量时不相关（MD -0.42，95% CI -0.86至0.02；六项研究，371名参与者；极低确定性证据），用BI测量时也不相关（MD 14.09，95% CI -1.94至30.13；三项研究，170名参与者；极低确定性证据）。支持干细胞移植的研究平均偏倚风险较高，且样本量为32名或更少参与者。在死亡方面，未提出与干细胞移植相关的重大安全问题（风险比[RR] 0.66，95% CI 0.39至1.14；六项研究，参与者；低确定性证据）。我们无法根据研究质量进行敏感性分析，因为所有研究的偏倚风险都很高。
总体而言，在缺血性中风参与者中，干细胞移植与神经功能缺损减轻相关，但与更好的功能结局无关。未提出明显的安全问题。然而，这些结论大多来自偏倚风险高的小型RCT，证据的确定性从低到极低。需要更多设计良好的试验。
