DESCRIPTION
Peripheral arterial disease (PAD) is a common atherosclerotic syndrome associated with significant morbidity and mortality. Development of PAD is characterized by narrowing and occlusion of arterial vessels and eventual reduction in distal perfusion. Critical limb ischemia is the end stage of lower-extremity PAD in which severe obstruction of blood flow results in ischemic pain at rest, ulcers, and a significant risk for limb loss. The standard therapy for severe, limb-threatening ischemia is revascularization aiming to improve blood flow to the affected extremity. If revascularization fails or is not possible, amputation is often necessary.
A proposed treatment for critical limb ischemia due to peripheral arterial disease is stem cell therapy. The rationale of hematopoietic cell/bone marrow-cell therapy in PAD is to induce arteriogenesis by boosting the physiologic repair processes. This requires large numbers of functionally active autologous precursor cells and, subsequently, a large quantity of bone marrow or other source of stem cells. The concentrate of bone marrow aspirate contains a mix of cell types, including lymphocytoid cells, erythroblasts, monocytoid cells and granulocytes. Following isolation and concentration, the hematopoietic cell/bone marrow concentrate is administered either intra-arterially or through multiple injections into the muscle.
POLICY
Treatment of peripheral arterial disease, including critical limb ischemia, with injection or infusion of stem cells concentrated from bone marrow, expanded in vitro, stimulated from peripheral blood, or from an allogeneic source, is considered investigational.
IMPORTANT REMINDERS
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ADDITIONAL INFORMATION
The current literature on stem cells as a treatment for critical limb ischemia due to PAD consists primarily of phase 2 studies using various cell preparation methods and methods of administration. A meta-analysis of the trials with the lowest risk of bias has shown no significant benefit of stem cell therapy for overall survival, amputation-free survival, or amputation rates. Well-designed randomized controlled trials with a larger number of subjects and low risk of bias are needed to evaluate the health outcomes of these various procedures. More data on the safety and durability of these treatments are also needed. The evidence is insufficient to determine the effects of the technology on health outcomes.
SOURCES
American Heart Association, American College of Cardiology. (2017). 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease. Retrieved January 2, 2020 from https://www.acc.org/guidelines.
BlueCross BlueShield Association. Evidence Positioning System. (2:2023). Stem cell therapy for peripheral arterial disease (8.01.55). Retrieved January 11, 2024 from www.bcbsaoca.com/eps/. (22 articles and/or guidelines reviewed)
Conte, M. S., Bradbury, A. W., Kolh, P., White, J. V., Dick, F., Fitridge, R., et al. (2019). Global vascular guidelines on the management of chronic limb-threatening ischemia. Journal of Vascular Surgery, 69 (6S), 3S–125S.e40, doi: 10.1016/j.jvs.2019.02.016. (Level 2 evidence)
Dubsky, M., Husakova, J., Bem, R., Jirkovska, A., Nemcova, A., Fejfarova, V., et al. (2022). Comparison of the impact of autologous cell therapy and conservative standard treatment on tissue oxygen supply and course of the diabetic foot in patients with chronic limb-threatening ischemia: A randomized controlled trial. Frontiers in Endocrinology, 29:13:888809. doi: 10.3389/fendo.2022.888809. (Level 3 evidence)
Gao, W., Chen, D., Liu, G., & Ran, X. (2019). Autologous stem cell therapy for peripheral arterial disease: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Research and Therapy, 10 (1), 140. (Level 1 evidence)
Horie, T., Yamazaki, S., Hanada, S., Kobayashi, S., Tsukamoto, T., Haruna, T., et al. (2018). Outcome from a randomized controlled clinical trial – improvement of peripheral arterial disease by granulocyte colony-stimulating factor-mobilized autologous peripheral-blood-mononuclear cell transplantation (IMPACT). Circulation Journal, 82 (8), 2165-2174. (Level 2 evidence)
Moazzami, B., Mohammadpour, Z., Zabala, ZE., Farokhi, E., Roohi, A., Domatova, E., et al. (2022). Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischemia (review). Cochrane Database of Systematic Reviews, 7 (7), CD008347. doi: 10.1002/14651858. (Level 3 evidence)
Peeters Weem, S., Teraa, M., de Borst, G., Verhaar, M., & Moll, F. (2015). Bone marrow derived cell therapy in critical limb ischemia: a meta-analysis of randomized placebo controlled trials. European Journal of Vascular and Endovascular Surgery, 50 (6), 775-783. (Level 2 evidence)
Pu, H., Huang, Q., Zhang, X., Wu, Z., Qiu, P., Jiang, Y., et al. (2022). A meta-analysis of randomized controlled trials on therapeutic efficacy and safety of autologous cell therapy for atherosclerosis obliterans. Journal of Vascular Surgery, 75 (4), 1440-1449. Abstract retrieved January 11, 2024 from PubMed database.
Qadura, M., Terenzi, D.C., Verma, S., Al-Omran, M., & Hess, D.A. (2017). Cell therapy for critical limb ischemia: an integrated review of pre-clinical and clinical studies. Stem Cells, 36 (2), 161-171. (Level 1 evidence)
Rigato, M., Monami, M., & Fadini, G.P. (2017). Autologous cell therapy for peripheral arterial disease: systematic review and meta-analysis of randomized, nonrandomized, and noncontrolled studies. Circulation Research, 120 (8), 1326-1340. (Level 2 evidence)
Xie, B., Luo, H., Zhang, Y., Wang, Q., Zhou, C., & Xu, D. (2018). Autologous stem cell therapy in critical limb ischemia: a meta-analysis of randomized controlled trials. Stem Cells International, 2018, 7528464. (Level 2 evidence)
ORIGINAL EFFECTIVE DATE: 12/10/2011
MOST RECENT REVIEW DATE: 2/8/2024
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