Therapeutic efficacy of CD34+ cell-involved mononuclear cell therapy for no-option critical limb ischemia: A meta-analysis of randomized controlled clinical trials

Abstract

Early-phase clinical trials in patients with critical limb ischemia (CLI) have shown positive results of mononuclear cell therapy. The current meta-analysis investigated whether cluster of differentiation (CD) 34+ mononuclear cell therapy (CD34+MCT) is effective for no-option CLI. Ten randomized controlled clinical studies of CD34+MCT for no-option CLI with 479 patients were identified and analyzed for pooled results. Compared to control groups, the CD34+MCT was associated with lower total amputation (odds ratio (OR): 0.45, p=0.01; 95% confidence interval (CI): 0.24–0.85) and a higher complete ulcer healing rate (OR: 2.80, p=0.008; 95% CI: 1.31–6.02), but showed no advantage in major amputation (OR: 0.58, p=0.11; 95% CI: 0.29–1.14) and all-cause mortality (OR: 0.82, p=0.62; 95% CI: 0.36–1.83). Studies with a high CD34+ cell dosage showed significant results in major amputation (OR: 0.38, p=0.002; 95% CI: 0.21–0.70), total amputation (OR: 0.31, p=0.0002; 95% CI: 0.17–0.57) and complete ulcer healing (OR: 7.58, p=0.0005; 95% CI: 2.40–23.88), which were not observed in the low-dose studies. However, inclusion of placebo-controlled studies showed no improvement of the CD34+MCT in total amputation (OR: 0.67, p=0.42; 95% CI: 0.25–1.79), major amputation (OR: 1.31, p=0.43; 95% CI: 0.67–2.54) or complete ulcer healing (OR: 1.52, p=0.27; 95% CI: 0.72–3.21), which were extremely significant in non-placebo-controlled studies (p<0.001). In conclusion, the significant results of CD34+MCT might not support its therapeutic benefit due to high placebo-effect risk and considerable heterogeneity caused by distinct cell doses. More sizable double-blinded, randomized, placebo-controlled trials with higher CD34+ cell dosage are needed in the future.