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Updated: May 14, 2026
Predicting Amputation using Local Circulating Mononuclear Progenitor Cells in Angioplasty-treated Patients with Critical Limb Ischemia
Published on: September 22, 2020
Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized
Martin Teraa1, Ralf W Sprengers, Yolanda van der Graaf
1*Department of Nephrology and Hypertension †Department of Vascular Surgery ‡Department of Radiology §Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands.
Insights
Bone marrow (BM)-derived cell therapy shows promise for critical limb ischemia (CLI) by improving perfusion and reducing amputation rates. However, results vary, highlighting the need for placebo-controlled trials to confirm efficacy in CLI patients.
Area of Science:
- Regenerative Medicine
- Vascular Surgery
- Cell Therapy
Background:
- Critical Limb Ischemia (CLI) represents the advanced stage of peripheral arterial disease.
- Standard treatments like bypass surgery or endovascular revascularization are not suitable for all CLI patients, often leaving amputation as the sole option.
- Bone marrow (BM)-derived cell therapy has emerged as a potential strategy to promote neovascularization and enhance limb perfusion in CLI.
Purpose of the Study:
- To conduct a meta-analysis of randomized controlled trials (RCTs) evaluating BM-derived cell therapy against standard care (with or without placebo) in CLI patients.
- To summarize the efficacy of BM-derived cell therapy for improving outcomes in CLI.
Main Methods:
- A systematic literature search was performed across Medline, Embase, and the Cochrane Controlled Trials Register.
- Data from 12 RCTs involving 510 CLI patients were critically appraised and meta-analyzed using a random-effects model.
- Primary endpoints included major amputation rates and amputation-free survival.
Main Results:
- BM-derived cell therapy demonstrated significant benefits in subjective and surrogate objective endpoints, including pain scores, walking distance, ankle-brachial index, and transcutaneous oxygen levels (all P < 0.00001).
- Overall RCTs indicated a reduced risk of major amputation (RR = 0.58; P = 0.004).
- However, placebo-controlled RCTs showed a non-significant reduction in major amputation rates (RR = 0.78; P = 0.46), and amputation-free survival did not differ significantly between groups (RR = 1.16; P = 0.22).
Conclusions:
- BM-derived cell therapy holds promise for CLI patients, with observed improvements in various clinical and physiological markers.
- A notable divergence exists between results from placebo-controlled and non-placebo-controlled RCTs, underscoring the importance of placebo controls in future trial designs.
- Further large-scale, well-designed, placebo-controlled RCTs with long-term follow-up are essential to validate the durability and efficacy of BM-derived cell therapy in CLI.
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.
