Stem-cell Therapy for Peripheral Arterial Disease

Description of Procedure or Service

Background

Peripheral arterial disease (PAD) is a common atherosclerotic syndrome that is 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. 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.

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 hypoxia-induced release of chemokines and cytokines such as vascular endothelial growth factor (VEGF) and occurs by sprouting of small endothelial tubes from pre-existing capillary beds. The resulting capillaries are small and cannot sufficiently compensate for a large, occluded artery. Arteriogenesis with collateral growth is, 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 pre-existing 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 and advanced age) are also risk factors for a lower number of circulating progenitor cells.

Use of autologous stem cells freshly harvested and allogeneic stem cells are reported to have a potential role in the treatment of peripheral arterial disease. 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, transcutaneous oxygen pressure, and pain-free walking. The Ankle-Brachial Index measures arterial segmental pressures on the ankle and brachium and indexes ankle systolic pressure against brachial systolic pressure (normative range, 0.95-1.2 mm Hg). 

Regulatory Status 

Several point-of-care concentrations of bone marrow aspirate have been cleared for marketing by the FDA through the 510(k) process:

The SmartPrep® Bone Marrow Aspirate Concentrate System, SmartPrep Platelet Concentration System (Harvest Technologies, now MD Biologix)

MarrowStim™ Concentration Kit System (Biomet Biologics, Inc., now Zimmer Biomet)

PureBMC SupraPhysiologic Concentrating System (EmCyte Corporation)

Arthrex Angel® System Kit (Arthrex, Inc.)

Magellan® Autologous Platelet Separator System (Arteriocyte Medical Systems -Medtronic)

BioCUE® Platelet Concentration Kit, now BioCUE® Blood and Bone Marrow Aspiration (bBMA) Concentration Kit (Biomet Biologics, Inc., now Zimmer Biomet)

ART BMC/ART BMC PLUS System (SpineSmith Holdings, LLC, now Ceiling Biosciences)

PXP® System, now PXP®-1000 (ThermoGenesis Corp.)

Related Policies:

Orthopedic Applications of Stem Cell Therapy

Growth Factors in Wound Healing

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

Stem-cell therapy for the treatment of peripheral arterial disease is considered investigational for all applications. BCBSNC does not provide coverage for investigational services or procedures.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore, member benefit language should be reviewed before applying the terms of this medical policy.

When Stem-cell Therapy for Peripheral Arterial Disease is covered

Not applicable

When Stem-cell Therapy for Peripheral Arterial Disease is not covered

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 considered investigational.

Policy Guidelines

The evidence for stem cell therapy in individuals who have peripheral arterial disease (PAD) 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 due to PAD consists primarily of phase 2 studies using various cell preparation methods and methods of administration. Meta-analysis of these trials with the lowest risk of bias shows no significant benefit of stem cell therapy for overall survival, amputation-free survival, or amputation rates. Three randomized controlled trials have been published that use granulocytemacrophage colony-stimulating factor (GM-CSF) mobilized peripheral blood mononuclear cells (PBMNC). The route of administration of the 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 progressive-free survival and frequency of limb amputation at one year of follow-up. There was a substantial rate of subsequent surgical intervention in both arms.

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. Several are in progress, including multicenter randomized, double-blind, placebo-controlled trials. More data on the safety and durability of these treatments are also needed. The evidence is insufficient to determine that technology results in an improvement in the net health outcome.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 0263T, 0264T, 0265T

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

BCBSA Medical Policy Reference Manual [Electronic Version]. 8.01.55, 5/12/11

National Institutes of Health (NIH). Clinical Trial NCT01245335. Bone Marrow Aspirate Concentrate (BMAC) for Treatment of Critical Limb Ischemia (CLI). Retrieved on May 23, 2011 

National Institutes of Health (NIH). Clinical Trial NCT00919516. Autologous Bone Marrow Mononuclear Cell Implantation for Moderate to Severe Peripheral Arterial Disease. Retrieved on May 23, 2011 

Medical Director review 7/2011

Specialty Matched Consultant Advisory Panel review 10/2011

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). Circulation Cardiovascular interventions 2011; 4(1):26-37. Retrieved on May 31, 2012 

BCBSA Medical Policy Reference Manual [Electronic Version]. 8.01.55, 5/10/12 

Specialty Matched Consultant Advisory Panel review 10/2012

Powell RJ, Marston WA, Berceli SA, Guzman R, Henry TD, Longcore AT, Stern TP, Watling S, Bartel RL. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial. Mol Ther. 2012 Jun; 20(6):1280-6. doi: 10.1038/mt.2012.52. 

National Institutes of Health (NIH). Clinical Trial NCT01049919. Safety and Efficacy Study of Autologous Concentrated Bone Marrow Aspirate (cBMA) for Critical Limb Ischemia (CLI). 

National Institutes of Health (NIH). Clinical Trial NCT00951210. Safety of Intramuscular Injections (IM) of Allogeneic PLX-PAD Cells for the Treatment of Critical Limb Ischemia (CLI). 

Liu FP, Dong JJ, Sun SJ et al. Autologous bone marrow stem cell transplantation in critical limb ischemia: a meta-analysis of randomized controlled trials. Chin Med J 2012; 125(23):4296-300.

BCBSA Medical Policy Reference Manual [Electronic Version]. 8.01.55, 5/9/13

Specialty Matched Consultant Advisory Panel review 10/2013

Poole J, Mavromatis K, Binongo JN et al. Effect of progenitor cell mobilization with granulocytemacrophage colony-stimulating factor in patients with peripheral artery disease: a randomized clinical trial. JAMA 2013; 310(24):2631-9.

McDermott MM, Guralnik JM, Criqui MH, Ferrucci L, Zhao L, Liu K, Domanchuk K, Spring B, Tian L, Kibbe M, Liao Y, Lloyd Jones D, Rejeski WJ.

Bartel RL, Booth E, Cramer C et al. From bench to bedside: review of gene and cell-based therapies and the slow advancement into phase 3 clinical trials, with a focus on Aastrom's Ixmyelocel-T. Stem Cell Rev 2013; 9(3):373-83.

BCBSA Medical Policy Reference Manual [Electronic Version]. 8.01.55, 5/22/14

Specialty Matched Consultant Advisory Panel review 11/2014

Senior Medical Director review 11/2014

BCBSA Medical Policy Reference Manual [Electronic Version]. 8.01.55, 5/21/15

Specialty Matched Consultant Advisory Panel review 10/2015

Senior Medical Director review 10/2015

BCBSA Medical Policy Reference Manual [Electronic Version]. 8.01.55, 1/14/16

Specialty Matched Consultant Advisory Panel review 10/2016

Medical Director review 10/2016

BCBSA Medical Policy Reference Manual [Electronic Version]. 8.01.55, 7/2017

Medical Director review 7/2017 

Specialty Matched Consultant Advisory Panel review 10/2017

Medical Director review 10/2017

BCBSA Medical Policy Reference Manual [Electronic Version]. 8.01.55, 2/2018

Specialty Matched Consultant Advisory Panel review 10/2018

Medical Director review 10/2018

BCBSA Medical Policy Reference Manual [Electronic Version]. 8.01.55, 2/2018

Specialty Matched Consultant Advisory Panel review 10/2019

Medical Director review 10/2019

BCBSA Medical Policy Reference Manual [Electronic Version]. 8.01.55, 2/2020

Specialty Matched Consultant Advisory Panel review 10/2020

Medical Director review 10/2020

BCBSA Medical Policy Reference Manual [Electronic Version]. 8.01.55, 2/2021

Specialty Matched Consultant Advisory Panel review 10/2021

Medical Director review 10/2021

Specialty Matched Consultant Advisory Panel review 10/2022

Medical Director review 10/2022

Specialty Matched Consultant Advisory Panel review 10/2023

Medical Director review 10/2023

Kullo IJ, Rooke TW. CLINICAL PRACTICE. Peripheral Artery Disease. N Engl J Med. Mar 03 2016; 374(9): 861-71. PMID 26962905

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

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

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

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

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

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

Xie B, Luo H, Zhang Y, et al. Autologous Stem Cell Therapy in Critical Limb Ischemia: A MetaAnalysis of Randomized Controlled Trials. Stem Cells Int. 2018; 2018: 7528464. PMID 29977308

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

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

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

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

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

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

Gupta PK, Krishna M, Chullikana A, et al. Administration of Adult Human Bone MarrowDerived, 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

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

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, doubleblind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intraarterial Supplementation (JUVENTAS) trial. Circulation. Mar 10 2015; 131(10): 851-60. PMID 25567765

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

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

McDermott MM, Ferrucci L, Tian L, et al. Effect of Granulocyte-Macrophage ColonyStimulating 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

Horie T, Yamazaki S, Hanada S, et al. Outcome from a Randomized Controlled Clinical Trial - Improvement of Peripheral Arterial Disease by Granulocyte Colony-Stimulating FactorMobilized Autologous Peripheral-Blood-Mononuclear Cell Transplantation (IMPACT). Circ J. Jul 25, 2018; 82(8): 2165-2174. PMID 29877199

Specialty Matched Consultant Advisory Panel review 10/2024

Medical Director review 10/2024

Policy Implementation/Update Information

7/19/11 New policy implemented. Treatment of peripheral arterial disease, including critical limb ischemia, with injection or infusion of cells concentrated from bone marrow aspirate is considered investigational. Medical Director review 7/2011. (mco)

11/8/11 Specialty Matched Consultant Advisory Panel review 10/2011.No changes to Policy Statements. (mco) 6/29/12 References updated. No changes to Policy Statement. (mco)

11/13/12 Specialty Matched Consultant Advisory Panel review 10/2012. No changes to Policy Statements. (mco)

6/11/13 Description section updated and Related Policies added. Policy Guidelines updated. References updated. No changes to Policy Statements. (mco)

11/12/13 Specialty Matched Consultant Advisory Panel review 10/2013. No changes to Policy Statements. (mco)

7/15/14 References updated. No changes to Policy Statements. (mco) 

1/13/15 References updated. Related Policies added. Specialty Matched Consultant Advisory Panel review 11/2014. Senior Medical Director review 11/2014. No changes to Policy statements. (td)

7/1/15 References updated. Policy Statements remain unchanged. (td)

12/30/15 References updated. Specialty Matched Consultant Advisory Panel review 10/29/2015. Medical Director review 10/2015. (td)

4/29/16 Policy Guidelines section updated. References updated. (td)

11/22/16 Specialty Matched Consultant Advisory Panel review 10/2016. Medical Director review 10/2016. (jd)

7/28/17 Policy revised with updated language clarification under the “When Not Covered” section, to include “stem cells from concentrated bone marrow, expanded in vitro, stimulated from peripheral blood, or from an allogeneic source is considered investigational.” No change to policy intent. Medical Director review 7/2017. (jd)

11/10/17 Minor revisions to Policy Guidelines. Specialty Matched Consultant Advisory Panel review 10/2017. Medical Director review 10/2017. (jd)

11/9/18 References updated. Specialty Matched Consultant Advisory Panel review 10/2018. Medical Director review 10/2018. (jd)

2/26/19 Description section and regulatory status updated. Policy guidelines updated with minor revisions and references updated. (jd)

10/29/19 Specialty Matched Consultant Advisory Panel review 10/2019. Medical Director review 10/2019. (jd)

2/25/20 Minor revisions and updates to the Description section, regulatory status, policy guidelines, and reference section. No change to policy intent. (jd)

11/10/20 Specialty Matched Consultant Advisory Panel review 10/2020. Medical Director review 10/2020. (jd)

11/2/21 Description section and references updated. Specialty Matched Consultant Advisory Panel review 10/2012. Medical Director review 10/2021. (jd)

11/1/22 References updated. Specialty Matched Consultant Advisory Panel review 10/2022. Medical Director review 10/2022. (tm)

11/7/23 Description section, Regulatory Status, Policy Guidelines and References updated. Specialty Matched Consultant Advisory Panel review 10/2023. Medical Director review 10/2023. (tm)

11/13/24 Description and References updated. Specialty Matched Consultant Advisory Panel review 10/2024. Medical Director review 10/2024. (tm)