Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Non-Randomized, and Non-Controlled Studies
Rationale: Critical limb ischemia (CLI) is a life-threatening complication of peripheral arterial disease (PAD). In patients who are ineligible for revascularization procedures, there are few therapeutic alternatives, leading to amputations and death.
Objective: To provide a systematic review of the literature and a meta-analysis of studies evaluating safety and efficacy of autologous cell therapy for intractable PAD/CLI.
Methods and Results: We retrieved 19 randomized controlled trials (RCTs; 837 patients), 7 non-randomized trials (338 patients), and 41 non-controlled studies (1,177 patients). The primary outcome was major amputation. Heterogeneity was high and publication bias could not be excluded. Despite these limitations, the primary analysis (all RCTs) 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 ABI, TcO2, and reduced rest pain. The secondary analysis (all controlled trials; n=1,175 patients) shows there may be potential to avoid approximately 1 amputation/year for every 2 patients successfully treated. The tertiary analysis (all studies; n=2,332 patients) precisely estimated the changes in ABI, TcO2, rest pain, and walking capacity after cell therapy. Intra-muscular implantation appeared more effective than intra-arterial infusion, and mobilized peripheral blood mononuclear cells (MNCs) may outperform bone marrow-MNCs and mesenchymal stem cells. Amputation rate was improved more in trials wherein the prevalence of diabetes 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 RCTs and disappeared in RCTs 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 CLI.
- Received October 28, 2016.
- Revision received January 11, 2017.
- Accepted January 17, 2017.