Stem Cell Therapy for Peripheral Arterial Disease Form

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 01|01|2026 POLICY LAST REVIEWED: 09|17|2025 OVERVIEW Peripheral arterial disease (PAD) is a common atherosclerotic syndrome associated with significant morbidity and mortality. Critical limb ischemia (CLI) 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. Use of autologous stem cells freshly harvested and allogeneic stem cells are reported to have a role in the treatment of PAD. MEDICAL CRITERIA Not applicable PRIOR AUTHORIZATION Not applicable POLICY STATEMENT Medicare Advantage Plans Treatment of peripheral arterial disease, including critical limb ischemia, with injection or infusion of stem cells from concentrated bone marrow, expanded in vitro, stimulated from peripheral blood, or from an allogeneic source, is not covered as the evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Commercial Products Treatment of peripheral arterial disease, including critical limb ischemia, with injection or infusion of stem cells from concentrated bone marrow, expanded in vitro, stimulated from peripheral blood, or from an allogeneic source, is not medically necessary as the evidence is insufficient to determine that the technology results in an improvement in the net health outcome. COVERAGE Benefits may vary between groups/contracts. Please refer to the appropriate Benefit Booklet, Evidence of Coverage or Subscriber Agreement for limitations of benefits/coverage when services are not covered/not medically necessary. BACKGROUND Peripheral Arterial Disease Peripheral arterial disease (PAD) is a common atherosclerotic syndrome associated with significant morbidity and mortality. A less common cause of PAD is Buerger disease (also called thromboangiitis obliterans), which is a nonatherosclerotic segmental inflammatory disease that occurs in younger patients and is associated with tobacco use. The 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. Physiology Two endogenous compensating mechanisms may occur with occlusion of arterial vessels: capillary growth (angiogenesis) and development of collateral arterial vessels (arteriogenesis). Capillary growth is mediated by the hypoxia-induced release of chemokines and cytokines such as vascular endothelial growth factor and occurs by sprouting of small endothelial tubes from preexisting capillary beds. The resulting capillaries are small and cannot sufficiently compensate for a large occluded artery. Arteriogenesis with collateral growth is, Medical Coverage Policy | Stem Cell Therapy for Peripheral Arterial Disease

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 2 (401) 274-4848 WWW.BCBSRI.COM

in contrast, initiated by increasing shear forces against vessel walls when blood flow is redirected from the occluded transport artery to the small collateral branches, leading to an increase in the diameter of preexisting collateral arterioles.

The mechanism underlying arteriogenesis includes the migration of bone marrow-derived monocytes to the perivascular space. The bone marrow-derived monocytes adhere to and invade the collateral vessel wall. It is not known if the expansion of the collateral arteriole is due to the incorporation of stem cells into the wall of the vessel or to cytokines released by monocytic bone marrow cells that induce the proliferation of resident endothelial cells. It has been proposed that bone marrow-derived monocytic cells may be the putative circulating endothelial progenitor cells. Notably, the same risk factors for advanced ischemia (diabetes, smoking, hyperlipidemia, advanced age) are also risk factors for a lower number of circulating progenitor cells.

Treatment Use of autologous stem cells freshly harvested and allogeneic stem cells are reported to have a potential role in the treatment of PAD. Stem cells can be administered in a variety of routes, derived from different progenitors, and be grouped with different co-factors, many of which are being studied in order to determine the best clinical option for patients. The primary outcome in stem cell therapy trials regulated by the U.S. Food and Drug Administration (FDA) is amputation-free survival, defined as time to major amputation and/or death from any cause. Other outcomes for critical limb ischemia include the Rutherford criteria for limb status, healing of ulcers, the Ankle-Brachial Index (ABI), transcutaneous oxygen pressure, and pain-free walking. The ABI measures arterial segmental pressures on the ankle and brachium and indexes ankle systolic pressure against brachial systolic pressure (normative range, 0.95 to 1.2 mm Hg).

Regulatory Status Several point-of-care concentrations of bone marrow aspirate have been cleared by the FDA through the 510(k) process and are listed below: • The SmartPrep ® Bone Marrow Aspirate Concentrate System, SmartPrep Platelet Concentration System
• MarrowStim Concentration System (MSC system)
• PureBMC SupraPhysiologic Concentrating System EmCyte Corporation®
• Arthrex Angel® System Kit • Magellan® Autologous Platelet Separator System
• BioCUE® Platelet Concentration Kit (now BioCUE® Blood and Bone Marrow Aspiration (bBMA) Concentration Kit) • ART BMC/ART BMC PLUS System • PXP® System (now PXP®-1000)

For individuals who have peripheral arterial disease (PAD) who receive stem cell therapy, the evidence includes small randomized trials and systematic reviews. Relevant outcomes are overall survival, symptoms, change in disease status, morbid events, functional outcomes, quality of life, and treatment-related morbidity. The current literature on stem cells as a treatment for critical limb ischemia (CLI) 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. Three randomized controlled trials (RCTs) have been published that used granulocyte-macrophage colony-stimulating factor (GM-CSF)-mobilized peripheral blood mononuclear cells (PBMNC). The route of administration of cell therapy and the primary outcomes differed between studies. In the trial that added cell therapy to guideline-based care, there were no significant differences in progression-free survival and frequency of limb amputation at 1 year of follow-up. There was a substantial rate of subsequent surgical intervention in both arms. Well-designed RCTs with a larger number of subjects and low risk of bias are needed to evaluate the health outcomes of these various procedures. Several are in progress, including multicenter randomized, double-blind, placebo-controlled trials.

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 3 (401) 274-4848 WWW.BCBSRI.COM More data on the safety and durability of these treatments are also needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. CODING Medicare Advantage Plans and Commercial Products The following CPT code(s) are not covered for Medicare Advantage Plans and not medically necessary for Commercial Products: 0263T Intramuscular autologous bone marrow cell therapy, with preparation of harvested cells, multiple injections, one leg, including ultrasound guidance, if performed; complete procedure including unilateral or bilateral bone marrow harvest 0264T Intramuscular autologous bone marrow cell therapy, with preparation of harvested cells, multiple injections, one leg, including ultrasound guidance, if performed; complete procedure excluding bone marrow harvest 0265T Intramuscular autologous bone marrow cell therapy, with preparation of harvested cells, multiple injections, one leg, including ultrasound guidance, if performed; unilateral or bilateral bone marrow harvest only for intramuscular autologous bone marrow cell therapy RELATED POLICIES Orthopedic Applications of Stem Cell Therapy PUBLISHED Provider Update, November 2025 REFERENCES 1. Kullo IJ, Rooke TW. CLINICAL PRACTICE. Peripheral Artery Disease. N Engl J Med. Mar 03 2016; 374(9): 861-71. PMID 26962905 2. Liew NC, Lee L, Nor Hanipah Z, et al. Pathogenesis and Management of Buerger's Disease. Int J Low Extrem Wounds. Sep 2015; 14(3): 231-5. PMID 26264874 3. Krishna SM, Moxon JV, Golledge J. A review of the pathophysiology and potential biomarkers for peripheral artery disease. Int J Mol Sci. May 18 2015; 16(5): 11294-322. PMID 25993296 4. Hussain MA, Al-Omran M, Creager MA, et al. Antithrombotic Therapy for Peripheral Artery Disease: Recent Advances. J Am Coll Cardiol. May 29 2018; 71(21): 2450-2467. PMID 29793635 5. Lawall H, Bramlage P, Amann B. Treatment of peripheral arterial disease using stem and progenitor cell therapy. J Vasc Surg. Feb 2011; 53(2): 445-53. PMID 21030198 6. Fadini GP, Agostini C, Avogaro A. Autologous stem cell therapy for peripheral arterial disease meta- analysis and systematic review of the literature. Atherosclerosis. Mar 2010; 209(1): 10-7. PMID 19740466 7. Rigato M, Monami M, Fadini GP. Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies. Circ Res. Apr 14 2017; 120(8): 1326-1340. PMID 28096194 8. Xie B, Luo H, Zhang Y, et al. Autologous Stem Cell Therapy in Critical Limb Ischemia: A Meta-Analysis of Randomized Controlled Trials. Stem Cells Int. 2018; 2018: 7528464. PMID 29977308 9. Gao W, Chen D, Liu G, et al. Autologous stem cell therapy for peripheral arterial disease: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Res Ther. May 21 2019; 10(1): 140. PMID 31113463

10. Pu H, Huang Q, Zhang X, et al. A meta-analysis of randomized controlled trials on therapeutic efficacy and safety of autologous cell therapy for atherosclerosis obliterans. J Vasc Surg. Apr 2022; 75(4): 1440- 1449.e5. PMID 34788653
11. Moazzami B, Mohammadpour Z, Zabala ZE, et al. Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischaemia. Cochrane Database Syst Rev. Jul 08 2022; 7(7): CD008347. PMID 35802393
12. Procházka V, Gumulec J, Jalůvka F, et al. Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer. Cell Transplant. 2010; 19(11): 1413-24. PMID 20529449
13. Benoit E, O'Donnell TF, Iafrati MD, et al. The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design. J Transl Med. Sep 27 2011; 9: 165. PMID 21951607

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 4 (401) 274-4848 WWW.BCBSRI.COM

14. Skóra J, Pupka A, Janczak D, et al. Combined autologous bone marrow mononuclear cell and gene therapy as the last resort for patients with critical limb ischemia. Arch Med Sci. Apr 25 2015; 11(2): 325-31. PMID 25995748
15. Gupta PK, Krishna M, Chullikana A, et al. Administration of Adult Human Bone Marrow-Derived, Cultured, Pooled, Allogeneic Mesenchymal Stromal Cells in Critical Limb Ischemia Due to Buerger's Disease: Phase II Study Report Suggests Clinical Efficacy. Stem Cells Transl Med. Mar 2017; 6(3): 689-699. PMID 28297569
16. Dubský M, Husáková J, Bem R, et al. 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. Front Endocrinol (Lausanne). 2022; 13: 888809. PMID 36105404
17. Teraa M, Sprengers RW, Schutgens RE, et al. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo- controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial. Circulation. Mar 10 2015; 131(10): 851-60. PMID 25567765
18. Peeters Weem SM, Teraa M, den Ruijter HM, et al. Quality of Life After Treatment with Autologous Bone Marrow Derived Cells in No Option Severe Limb Ischemia. Eur J Vasc Endovasc Surg. Jan 2016; 51(1): 83-9. PMID 26511056
19. Walter DH, Krankenberg H, Balzer JO, et al. Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA). Circ Cardiovasc Interv. Feb 01 2011; 4(1): 26-37. PMID 21205939
20. Powell RJ, Comerota AJ, Berceli SA, et al. Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia. J Vasc Surg. Oct 2011; 54(4): 1032-41. PMID 21684715
21. Powell RJ, Marston WA, Berceli SA, et al. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial. Mol Ther. Jun 2012; 20(6): 1280-
22. PMID 22453769
23. Norgren L, Weiss N, Nikol S, et al. PACE: randomized, controlled, multicentre, multinational, phase III study of PLX-PAD for critical limb ischaemia in patients unsuitable for revascularization: randomized clinical trial. Br J Surg. Jan 31 2024; 111(2). PMID 38294084
24. Poole J, Mavromatis K, Binongo JN, et al. Effect of progenitor cell mobilization with granulocyte- macrophage colony-stimulating factor in patients with peripheral artery disease: a randomized clinical trial. JAMA. Dec 25 2013; 310(24): 2631-9. PMID 24247554
25. McDermott MM, Ferrucci L, Tian L, et al. Effect of Granulocyte-Macrophage Colony-Stimulating Factor With or Without Supervised Exercise on Walking Performance in Patients With Peripheral Artery Disease: The PROPEL Randomized Clinical Trial. JAMA. Dec 05 2017; 318(21): 2089-2098. PMID 29141087
26. Horie T, Yamazaki S, Hanada S, et al. 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). Circ J. Jul 25 2018; 82(8): 2165-2174. PMID 29877199
27. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. Mar 21 2017; 69(11): e71-e126. PMID 27851992
28. Valentine EA, Ochroch EA. 2016 American College of Cardiology/American Heart Association Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Perioperative Implications. J Cardiothorac Vasc Anesth. Oct 2017; 31(5): 1543-1553. PMID 28826846
29. Gornik HL, Aronow HD, Goodney PP, et al. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. Jun 18 2024; 83(24): 2497-2604. PMID 38752899

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 5 (401) 274-4848 WWW.BCBSRI.COM

29. Tendera M, Aboyans V, Bartelink ML, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J. Nov 2011; 32(22): 2851-906. PMID 21873417
30. Aboyans V, Ricco JB, Bartelink MEL, et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries Endorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J. Mar 01 2018; 39(9): 763-816. PMID 28886620
31. Mazzolai L, Teixido-Tura G, Lanzi S, et al. 2024 ESC Guidelines for the management of peripheral arterial and aortic diseases. Eur Heart J. Sep 29 2024; 45(36): 3538-3700. PMID 39210722

32. Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb- threatening ischemia. J Vasc Surg. Jun 2019; 69(6S): 3S-125S.e40. PMID 31159978

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