Background: Critical Limb Ischemia (CLI) is the most advanced stage of peripheral arterial disease and is usually treated with bypass surgery or endovascular revascularization. However, a considerable proportion of CLI patients are not eligible to these treatment strategies and amputation is often the only option left. In the past decade, research has focused on bone marrow (BM)–derived cell-based strategies that aim at neovascularization to improve limb perfusion. Individual studies did not convincingly prove efficacy of BM-derived cell therapy in CLI patients thus far.
Objectives: Perform a meta-analysis of all randomized controlled trials (RCTs) available that studied BM-derived cell therapy compared to standard care with or without placebo in CLI patients and provide summary efficacy data on this approach.
Methods: A systematic search in the electronic databases of Medline, Embase, and the Cochrane Controlled Trials Register was performed. All studies were critically appraised and data were extracted and meta-analyzed using a random-effects model. Major amputation and amputation-free survival were considered as the primary endpoints.
Results: A total of 12 RCTs jointly including 510 CLI patients were identified and analyzed. The meta-analysis showed beneficial effects of BM-derived cell therapy on both subjective and surrogate objective endpoints, that is, pain score, pain-free walking distance, ankle-brachial index, and transcutaneous oxygen measurements (all P < 0.00001). Overall, the RCTs showed reduced amputation rates in the therapeutic arms of the included trials with a relative risk (RR) on major amputation of 0.58 [95% confidence interval (CI), 0.40–0.84; P = 0.004]. However, when only the placebo-controlled RCTs were considered, the beneficial effect on major amputation rates was considerably reduced and nonsignificant (RR = 0.78; 95% CI, 0.40–1.51; P = 0.46). Amputation-free survival did not significantly differ between the BM treated and the control group (RR = 1.16; 95% CI, 0.92–1.48; P = 0.22).
Conclusions: This meta-analysis underlines the promising potential of BM-derived cell therapy in CLI patients. Importantly, the results of placebo-controlled and non–placebo-controlled RCTs seem to diverge, which stresses the necessity to use placebo in the control arms of these trials. Future well-designed larger placebo-controlled RCTs are needed and should include long-term follow-up data to assess durability of treatment effects.