We retrieved 19 randomized controlled trials (837 patients), 7 nonrandomized trials (338 patients), and 41 noncontrolled studies (1177 patients). The primary outcome was major
amputation. Heterogeneity was high, and publication bias could not be excluded. Despite these limitations, the primary analysis (all randomized controlled trials) showed that
cell therapy reduced the risk of
amputation by 37%, improved
amputation-free survival by 18%, and improved wound healing by 59%, without affecting mortality.
Cell therapy significantly increased ankle brachial index, increased transcutaneous
oxygen tension, and reduced rest
pain. The secondary analysis (all controlled trials; n=1175 patients) shows that there may be potential to avoid ≈1
amputation/year for every 2 patients successfully treated. The tertiary analysis (all studies; n=2332 patients) precisely estimated the changes in ankle brachial index, transcutaneous
oxygen tension, rest
pain, and walking capacity after
cell therapy. Intramuscular implantation appeared more effective than
intra-arterial infusion, and mobilized peripheral blood mononuclear cells may outperform bone marrow-mononuclear cells and mesenchymal stem cells.
Amputation rate was improved more in trials wherein the prevalence of
diabetes mellitus was high.
Cell therapy was not associated with severe adverse events. Remarkably, efficacy of
cell therapy on all end points was no longer significant in placebo-controlled randomized controlled trials and disappeared in randomized controlled trials with a low risk of bias.
CONCLUSIONS: Although this meta-analysis highlights the need for more high-quality placebo-controlled trials,
equipoise may no longer be guaranteed because autologous
cell therapy has the potential to modify the natural history of intractable
critical limb ischemia.