ABSTRACT: BACKGROUND:Peripheral arterial disease (PAD) is a common cause of disability and mortality. The reconstruction of blood circulation presents to be the key to treatment, which can be achieved by surgery and interventional therapy. Since 40% patients have lost the chance for the therapy, a new method is needed to reduce the amputation and mortality rate for "no-option" patients. The objective of our systematic review and meta-analysis was to evaluate the efficacy and safety of autologous implantation of stem cells in patients with PAD critically, compared with active controls and placebo. METHODS:Randomized controlled trials (RCTs) of autologous implantation of stem cells compared with placebo and control for PAD were included. Electronic medical databases including MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), the Chinese Biomedical Literature Database, China National Knowledge Infrastructure (CNKI), and ClinicalTrials.gov were searched from initial period to September 2018. Independently, two reviewers screened citations, extracted data, and assessed the risk of bias according to the criteria of the Cochrane handbook. The quality of evidence was evaluated by GRADE evidence profile. The primary outcomes consisted of amputation rate, major amputation rate, ulcer healing rate, and side effects. The second outcomes included ankle-brachial index (ABI), transcutaneous oxygen tension (TcO2), pain-free walking distance (PFWD), and rest pain score. Statistical analysis was conducted via RevMan 5.3 and Stata 12.0. RESULTS:According to the twenty-seven RCTs, 1186 patients and 1280 extremities were included and the majority of studies showed a high risk of bias. Meta-analysis indicated that autologous stem cell therapy was more effective than conventional therapy on the healing rate of ulcers [OR?=?4.31 (2.94, 6.30)]. There was also significant improvement in ABI [MD?=?0.13 (0.10, 0.17)], TcO2 [MD?=?0.13 (0.10, 0.17)], and PFWD [MD?=?178.25 (128.18, 228.31)] while significant reduction was showed in amputation rate [OR?=?0.50 (0.36, 0.69)] and rest pain scores [MD?=?-?1.61 (-?2.01, -?1.21)]. But the result presented no significant improvement in major limb salvage [0.66 (0.42, 1.03)]. Besides, stem cell therapy could reduce the amputation rate [OR?=?0.50 (0.06, 0.45] and improve the ulcer healing rate [OR?=?4.34 (2.96, 6.38] in DM subgroup. Eight trials reported the side effects of autologous stem cell therapy, and no serious side effects related to stem cells were reported. GRADE evidence profile showed all the quality evidence of outcomes were low. CONCLUSIONS:Based on the review, autologous stem cell therapy may have a positive effect on "no-option" patients with PAD, but presented no significant improvement in major limb salvage. However, the evidence is insufficient to prove the results due to high risk of bias and low-quality evidence of outcomes. Further researches of larger, randomized, double-blind, placebo-controlled, and multicenter trials are still in demand.
