Safety and efficacy of cell-based therapy on critical limb ischemia: A meta-analysis

• We systematically reviewed stem cell-based therapy on critical limb ischemia.
• We conducted trial sequential analysis to calculate the required sample size in all-cause mortality.
• The dose-response meta-analysis was applied to show the relationship between amount of stem cell and therapeutic effect.

Background aimsCritical limb ischemia (CLI) is a major health problem worldwide, affecting approximately 500–1000 people per million per annum. Cell-based therapy has given new hope for the treatment of limb ischemia. This study assessed the safety and efficacy of cellular therapy CLI treatment.MethodsWe searched the PubMed, Embase and Cochrane databases through October 20, 2015, and selected the controlled trials with cell-based therapy for CLI treatment compared with cell-free treatment. We assessed the results by meta-analysis using a variety of outcome measures, as well as the association of mononuclear cell dosage with treatment effect by dose-response meta-analysis.ResultsTwenty-five trials were included. For the primary evaluation index, cell-based therapy significantly reduced the rate of major amputation (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.32–0.60, P = 0.000) and significantly increased the rate of amputation-free survival (OR 2.80, 95% CI 1.70–4.61, P = 0.000). Trial sequence analysis indicated that optimal sample size (n = 3374) is needed to detect a plausible treatment effect in all-cause mortality. Cell-based therapy significantly improves ankle brachial index, increases the rate of ulcer healing, increases the transcutaneous pressure of oxygen, reduces limb pain and improves movement ability. Subgroup analysis indicated heterogeneity is caused by type of control, design bias and transplant route. In the dose-response analysis, there was no significant correlation between cell dosage and the therapeutic effect.ConclusionsCell-based therapy has a significant therapeutic effect on CLI, but randomized double-blind placebo-controlled trials are needed to improve the credibility of this conclusion. Assessment of all-cause mortality also requires a larger sample size to arrive at a strong conclusion. In dose-response analysis, increasing the dosage of cell injections does not significantly improve the therapeutic effects of cell-based therapy.