Description　
Peripheral arterial disease 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.  

Background
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. 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, 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 purported to have a role in the treatment of peripheral arterial disease. The primary outcome in stem cell therapy trials regulated by the U.S. Food and Drug Administration is amputation-free survival. 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 Rutherford criteria include ankle and toe pressure, level of claudication, ischemic rest pain, tissue loss, nonhealing ulcer, and gangrene. 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 mmHg). An increase of more than 0.1 mm Hg is considered clinically significant. Transcutaneous oxygen pressureis measured with an oxymonitor; a normal range is 70 to 90 mmHg. Pain-free walking may be measured by time on a treadmill or, more frequently, by distance in a 400-meter walk.

Regulatory Status
Six point-of-care concentrations of bone marrow aspirate have been cleared by the Food and Drug Administration through the 510(k) process and summarized in Table 1.

Table 1. FDA Approved Point-of-Care Concertation of Bone Marrow Aspirate Devices

Device	Manufacturer	Location	Date Cleared	510(k) No.
The SmarktPReP2® Bone Marrow Aspirate Concentrate System, SmarktPReP Platelet Concentration System	Harvest Technologies	Lakewood, CO	12/06/2010	K103340
MarrowStim Concentration System (MSC system)	Biomet Biologics, Inc	Warsaw, IN	12/18/2009	BK090008
PureBMC SupraPhysiologic Concentrating System	EmCyte Corporation®	Fort Myers, Florida	5/30/2019	K183205
Arthrex Angel System Kit	Arthrex, Inc.	Naples, Florida	5/23/2018	BK180180
Magellan® Autologous Platelet Separator System	Arteriocyte Medical Systems (Medtronic)	Memphis, TN	11/09/2004	BK040068
BioCUE Platelet Concentration Kit	Biomet Biologics Inc.	Warsaw, IN	5/26/2010	BK1000027
ART BMC System	SpineSmith Holdings LLC	Austin, TX	Not available	Not available
PXP® System	ThermoGenesis Corp.	Rancho Cordova, CA	07/10/2008	K081345

Food and Drug Administration product code: JQC.

Policy
Treatment of peripheral arterial disease, including critical limb ischemia, with injection or infusion of cells concentrated from bone marrow aspirate is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.

Policy Guidelines 
Coding
See the Codes table for details.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., people of color [African American, Asian, Black, Latino and Native American]; LGBTQIA [lesbian, gay, bisexual, transgender, queer, intersex, asexual); women; and people with disabilities [physical and invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Stem Cell Therapy in Individuals With Peripheral Arterial Disease
Clinical Context and Therapy Purpose
The purpose of stem cell therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with peripheral arterial disease (PAD).

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with PAD.

Interventions
The therapy being considered is stem cell therapy. The rationale for hematopoietic cell or 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 (e.g., 240 to 500 mL) or another source of stem cells.

Comparators
Comparators of interest include conservative management or surgical intervention. 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.

Outcomes
The general outcomes of interest are overall survival, symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related morbidity including amputation rates, improved amputation-free survival, improved wound healing, ulcer healing, and pain-free walking distance. Follow-up at 3, 6 and 12 months is of interest for stem cell therapy to monitor relevant outcomes. Longer-term follow-up is also of interest.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
At this time, the literature on stem cell therapy consists primarily of small RCTs, systematic reviews, and meta-analyses.^1,2

Systematic Reviews
Several systematic reviews have been published (Table 2). Rigato et al. (2017) published a systematic review of autologous cell therapy for PAD.³ The authors identified 19 RCTs (837 patients), 7 nonrandomized controlled studies (338 patients), and 41 noncontrolled studies (1,177 patients). There was heterogeneity across studies in setting, underlying diseases, types and doses of cells, routes of administration, and follow-up durations. Many studies were pilot or phase 2 trials and were rated as low-quality. There was an indication of publication bias. A meta-analysis of all RCTs showed a significant reduction in amputation rates, improved amputation-free survival, and improved wound healing. However, when only the placebo-controlled trials (n = 19) were analyzed, the effects were no longer statistically significant, and analysis of only RCTs with low risk of bias (n = 3) found no benefit of cell therapy.

In a meta-analysis of RCTs, Xie et al. (2018) reviewed published evidence evaluating the safety and efficacy of autologous stem cell therapy in critical limb ischemia (CLI).⁴ Cell therapy increased the probability of angiogenesis (relative risk [RR], 5.91; 95% confidence interval [CI], 2.49 to 14.02; p < .0001), increased ulcer healing (RR r ,1.73; 95% CI, 1.45 to 2.06; p < .00001), and decreased amputation rates (RR , 0.59; 95% CI, 0.46 to 0.76; p < .0001). Compared with the control group, significant improvement in the cell therapy group was also seen in Ankle-Brachial Index (ABI) (mean difference, 0.13; 95% CI, 0.11 to 0.15; p < .00001), transcutaneous oxygen tension (mean difference,12.22; 95% CI, 5.03 to 19.41; p = .0009), and pain-free walking distance (mean difference, 144.84; 95% CI, 53.03 to 236.66; p = .002).

Gao et al. (2019) reviewed 27 RCTs including 1186 patients and 1280 extremities.⁵ A majority of studies showed a high risk of bias. Meta-analysis indicated that autologous stem cell therapy was more effective than conventional therapy on the healing rate of ulcers. There was also a significant improvement in ABI, total carbon dioxide, and pain-free walking distance while a significant reduction was shown in amputation rate and rest pain scores. However, the result presented no significant improvement in major limb salvage.

Pu et al. (2022) included 12 RCTs (N = 630) in a meta-analysis of patients with atherosclerosis obliterans (the most common type of PAD).⁶ Autologous cell implantation was compared with placebo or standard care in all studies. A single injection of cell products was administered in all but 1 study in which injections were repeatedly administered. Follow-up periods ranged from 1 to 12 months. The analysis found improvements in total amputation (RR, 0.64; 95% CI, 0.47 to 0.87; p = .004; I2, 12%), major amputation (RR, 0.69; 95% CI, 0.50 to 0.94; p = .02; I2, 12%), and ABI (mean difference, 0.08; 95% CI, 0.02 to 0.13; p = .004; I2, 84%). Death and ulcer size were not improved with cell therapy. Findings of this analysis are applicable only to patients with no other therapy options. The analysis is limited by the small sample size in each trial (range, 10 to 160 patients) and heterogeneity in cell therapy methods (e.g., dosage, cell type, route of administration).

Moazzami et al. (2022) published a Cochrane review of 4 RCTs (N = 176) in patients with CLI who were treated with autologous bone marrow mononuclear cells (BM-MNCs).⁷ It was uncertain if amputations were lower (4 studies; RR, 0.52; 95% CI, 0.27 to 0.99), and mortality was not reduced with BM-MNCs (3 studies; RR, 1.0; 95% CI, 0.15 to 6.63). Data were limited by risk of bias, imprecision, and inconsistency.

Table 2. Systematic Reviews of Trials Assessing Autologous Cell Therapy for PAD

Study (Year)	Literature Search	Studies	Participants	N	Design	Results
Moazzami (2022)7	Nov 2021	4	Patients with CLI who were treated with local intramuscular transplantation of autologous adult BM-MNCs	176	RCTs	Pooled analysis of 4 RCTs found very low- to low-certainty evidence and no conclusion regarding BM-MNC for improving clinical outcomes can be drawn.
Pu (2022)6	Mar 2021	12	Patients with atherosclerosis obliterans and "no available treatment" who received autologous cell therapy	630	RCTs	Pooled analysis of 12 RCTs showed a significant improvement in total amputation, major amputation, and ABI but not all-cause death or ulcer size.
Gao (2019)5	May 2019	27	Patients with PAD or CLI who received autologous stem cell therapy	1186	RCTs	Pooled analysis of 27 RCTs showed a significant improvement in ABI, total carbon dioxide, and pain-free walking distance while significant reduction was shown in amputation rate and rest pain scores.
Rigato (2017)3	Jul 2016	67	Patients with severe intractable PAD or CLI who received autologous cell therapy	2352	RCTs, cohort	Pooled analysis of 19 RCTs showed a reduction in amputation rates, improved amputation-free survival, and improved wound healing.
Xie (2018)4	Jan 2018	23	Patients with PAD or CLI who received autologous stem cell therapy	1118	RCTs	Pooled analysis of 18 studies showed a reduction in amputation rate, ulcer healing, and pain-free walking distance (n = 512).

ABI: Ankle-Brachial Index; BM-MNC: bone marrow mononuclear cells; CLI: critical limb ischemia; PAD: peripheral arterial disease; RCT: randomized controlled trial.

Randomized and Nonrandomized Trials
Concentrated Bone Marrow Aspirate (Monocytes and Mesenchymal Stem Cells)
Intramuscular Injection
Prochazka et al. (2010) reported on a randomized study of 96 patients with CLI and foot ulcers.⁸ Patient inclusion criteria were CLI as defined by an ABI score of 0.4 or less, ankle systolic pressure of 50 mm Hg or less or toe systolic pressure of 30 mm Hg or less, and failure of basic conservative and revascularization treatment (surgical or endovascular). Patients were randomized to treatment with bone marrow concentrate (n = 42) or standard medical care (n = 54). The primary endpoints were major limb amputation during the 120 days posttreatment, and degree of pain and function at 90- and 120-day follow-ups. At baseline, the control group compared with the treatment group had a higher proportion of patients with diabetes (98.2% versus 88.1%), hyperlipidemia (80.0% versus 54.8%), and ischemic heart disease (76.4% versus 57.1%), respectively. Additionally, the control group had a higher proportion of patients (72% versus 40%) with the University of Texas Wound Classification stage DIII (deep ulcers with osteitis). For the 42 patients in the treatment group, there was a history of 50 revascularization procedures; 46 of 54 patients in the control group had a history of revascularization procedures. All 42 patients in the bone marrow group finished 90 days of follow-up, and 37 of 54 patients in the control group finished 120 days of follow-up. Differences in lengths of follow-up for the primary outcome measure were unexplained. Five patients in the bone marrow group and 8 in the control group died of causes unrelated to the therapy during follow-up. At follow-up, the frequency of major limb amputation was 21% in patients treated with bone marrow concentrate and 44% in controls. Secondary endpoints were assessed only in those treated with bone marrow concentrate. In the treatment group with salvaged limbs, toe pressure and Toe-Brachial Index score increased from 22.66 to 25.63 mm Hg and from 0.14 to 0.17, respectively. Interpretation of results is limited by unequal baseline measures, lack of blinding, differences in lengths of follow-up, differences in losses to follow-up, and differences in follow-up measures for the 2 groups.

Benoit et al. (2011) reported on a U.S. Food and Drug Administration regulated, double-blind pilot RCT of 48 patients with CLI who were randomized 2:1 to bone marrow concentrate using the SmartPrep system or to iliac crest puncture with an intramuscular injection of diluted peripheral blood.⁹ At a 6-month follow-up, the differences in the percentages of amputations between the bone marrow concentrate group (29.4%) and diluted peripheral blood group (35.7%) were not statistically significant. In a subgroup analysis of patients with tissue loss at baseline (Rutherford 5), intramuscular injection of bone marrow concentrate resulted in a lower amputation rate (39.1%) than placebo (71.4%).

Intramuscular injection with a combination of BM-MNCs and gene therapy with a vascular endothelial growth factor plasmid was tested in a 2015 European RCT assessing 32 patients.¹⁰ Controls in this trial were treated pharmacologically, and therefore the groups were not blinded to treatment. Several objective measures were improved in the BM-MNC group, but not in the control group. These measures included ABI scores, development of collateral vessels measured with angiography, and healing rates of ischemic ulcers. Amputations were performed in 25% of patients in the BM-MNC group and in 50% of patients in the control group.

Gupta et al. (2017) evaluated the efficacy and safety of intramuscular adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeutics Research, Bangalore, India) in a phase II prospective, open-label dose-ranging study.¹¹ Ninety patients were nonrandomly allocated to 3 groups: 1 million cells/kg body weight (n = 36), 2 million cells/kg body weight (n = 36), and standard of care (SOC; n = 18). Compared with the SOC group, greater reduction in rest pain and healing of ulcers were seen in the 2 million cells/kg body weight group (0.3 units per month [standard error (SE), 0.13]; 95% CI, -0.55 to -0.05; p = .0193 and 11.0% decrease in size per month [SE, 0.05%]; 95% CI, 0.80 to 0.99; p = .0253, respectively) and in the 1 million cells/kg body weight group (0.23 per month [SE, 0.13]; 95% CI, -0.49 to 0.03; p = .081 and 2.0% decrease in size per month [SE, 0.06%]; 95% CI, 0.87 to 1.10; p = .6967, respectively). Limitations of this study included the geographically and ethnically homogenous cohort and a lack of clearly defined methods for cohort selection. Additionally, patients in the cell administration groups had lower ABI values and larger ulcers indicating potential investigator bias to allocate more severe patients to the treatment groups.

Dubsky et al. (2022) compared standard therapy with BM-MNC in patients with CLI and diabetic foot.¹² Forty patients with no-option chronic limb-threatening ischemia and no available treatment options were randomized to no treatment or BM-MNC for 12 weeks. Transcutaneous oxygen pressure (a marker of wound healing) had greater improvement in the BM-MNC group compared with no treatment (difference, 21.8 mm Hg; p = .034). There were more healed ulcers at 12 weeks in the BM-MNC group (31.3% vs. 0%; p = .48). The amputation rate and amputation-free survival was not different between groups. Although short-term improvements in outcomes were seen in this trial, the trial is limited by its small sample size, lack of placebo comparator, and single-center design.

Intra-Arterial Injection
The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation trial was a randomized, double-blind, placebo-controlled study (2015) from Europe.¹³ This foundation-supported trial evaluated the clinical effects of repeated intra-arterial infusion of BM-MNCs in 160 patients with nonrevascularizable CLI. Patients received a repeated intra-arterial infusion of BM-MNCs or placebo (autologous peripheral blood erythrocytes) into the common femoral artery. The primary outcome measure (rate of major amputation after 6 months) did not differ significantly between groups (19% for BM-MNCs vs. 13% controls). Secondary outcomes of QOL, rest pain, ABI score, and transcutaneous oxygen pressure improved to a similar extent in both groups, reinforcing the need for a placebo control in this type of trial. Results from a long-term follow-up analysis of 109 of the participants found that improvements in self-reported QOL persisted for a median of 35 months in both groups, who remained blinded to treatment assignment.¹⁴ The percentages of patients undergoing amputation also remained similar in the 2 groups (25.9% for the BM-MNC group vs. 25.3% for the control group).

Results from the multicenter Intraarterial Progenitor Cell Transplantation of Bone Marrow Mononuclear Cells for Induction of Neovascularization in Patients with Peripheral Arterial Occlusive Disease trial (2011) were reported.¹⁵ In this double-blind, phase 2 trial, 40 patients with CLI who were not candidates or had failed to respond to interventional or surgical procedures were randomized to intra-arterial administration of BM-MNC or placebo. The cell suspension included hematopoietic, mesenchymal, and other progenitor cells. After 3 months, both groups were treated with BM-MNC in an open-label phase. Twelve patients received additional treatment with BM-MNC between 6 months and 18 months. The primary outcome measure (a significant increase in the ABI score at 3 months) was not achieved (from 0.66 at baseline to 0.75 at 3 months). Limb salvage and amputation-free survival rates differed between groups. There was a significant improvement in ulcer healing (ulcer area, 1.89 cm2 vs. 2.89 cm2) and reduced pain at rest (an improvement on a 10-point visual analog scale score of »3 vs. 0.05) following intra-arterial BM-MNC administration.

Section Summary: Concentrated Bone Marrow Aspirate (Monocytes and Mesenchymal Stem Cells)
There is preliminary evidence of benefit to the use of intramuscular concentrated bone aspirate injection in CLI patients. Randomized controlled trials and a non-randomized comparative study have been published.^9,8,10,11 Two RCTs have been published with intra-arterial injection of concentrated bone marrow aspirate.^13,15 The RCTs did not find support for their respective primary outcome measures; the rate of major amputation after 6 months or a significant increase in the ABI score at 3 months.

Expanded Monocytes and Mesenchymal Stem Cells
Interim and final results from the industry-sponsored phase 2, randomized, double-blind, placebo-controlled RESTORE-CLI trial, which used cultured and expanded monocytes and mesenchymal stem cells (MSCs) derived from bone marrow aspirate (ixmyelocel-T), were reported by Powell et al. (2011, 2012).^16,17 Seventy-two patients with CLI received ixmyelocel-T (n = 48) or placebo with sham bone marrow aspiration (n = 24) and were followed for 12 months. There was a 40% reduction in any treatment failure (due primarily to differences in doubling of total wound surface area and de novo gangrene), but no significant differences in amputation rates at 12 months.

Granulocyte-Macrophage Colony-Stimulating Factor Mobilization
Poole et al. (2013) reported on the results of a phase 2, double-blind, placebo-controlled trial of granulocyte-macrophage colony-stimulating factor (GM-CSF) in 159 patients with intermittent claudication due to PAD.¹⁸ Patients were treated with subcutaneous injections of GM-CSF or placebo 3 times weekly for 4 weeks. The primary outcome (peak treadmill walking time at 3 months) increased by 109 seconds (296 to 405 seconds) in the GM-CSF group and by 68 seconds (308 to 376 seconds) in the placebo group (p = .08). Changes in the physical functioning subscale score of the 36-Item Short-Form Health Survey and distance score of the Walking Impairment Questionnaire were significantly better in patients treated with GM-CSF. However, there were no significant differences between the groups in ABI score, Walking Impairment Questionnaire distance or speed scores, claudication onset time, or 36-Item Short-Form Health Survey Mental Component or Physical Component Summary scores. The post hoc exploratory analysis found that patients with more than a 100% increase in progenitor cells (CD34-positive/CD133-positive) had a significantly greater increase in peak walking times (131 seconds) than patients who had less than a 100% increase in progenitor cells (60 seconds).

McDermott et al. (2017) reported results from an RCT of 210 patients with PAD that evaluated whether GM-CSF combined with supervised treadmill exercise improves 6-minute walk distance (6MWT) compared with exercise alone and compared with GM-CSF alone and to determine whether GM-CSF alone improves 6MWT more than placebo and whether exercise improves 6MWT more than an attention control intervention.¹⁹ Supervised exercise consisted of treadmill exercise 3 times weekly for 6 months. Participants were randomized to 1 of 4 groups: supervised exercise + GM-CSF (exercise + GM-CSF) (n = 53), supervised exercise + placebo (exercise alone) (n = 53), attention control + GM-CSF (GM-CSF alone) (n = 53), attention control + placebo (n = 51). The attention control consisted of weekly educational lectures by clinicians for 6 months. The primary outcome was change in 6MWT distance at a 12-week follow-up, with a minimum clinically important difference of 20 meters. Ninety-three percent of patients completed a 12-week follow-up. At follow-up, exercise + GM-CSF did not significantly improve 6MWT distance more than exercise alone (p = .61) or more than GM-CSF alone (Hochberg-adjusted p = .052). Use of GM-CSF alone did not improve a 6MWT more than attention control + placebo (p = .91). Exercise alone improved a 6MWT compared with attention control + placebo (Hochberg-adjusted p = .02).

Horie et al. (2018) reported results from an RCT (IMPACT: Improvement of Peripheral Arterial Disease by Granulocyte Colony-Stimulating Factor-Mobilized Autologous Peripheral-Blood-Mononuclear Cell Transplantation) of 107 patients with PAD characterized as Buerger disease that evaluated the efficacy and safety of GM-CSF-mobilized peripheral blood mononuclear cell (PBMNC) transplantation compared with SOC (Tables 3 and 4).²⁰ Participants were randomized to guideline-based SOC or SOC plus intramuscular weight-based PBMNC administration. After disease progression or completion of a 1-year follow-up, 17 patients in the control group underwent cell therapy. Furthermore, 21 patients underwent revascularization after completion of the protocol treatment period or after discontinuation of the study (12 in the cell therapy group, 9 in the control group; 18 patients underwent percutaneous transluminal angioplasty, 2 had bypass surgery, and 1 had thrombectomy). Serious adverse events occurred in 20% of the cell therapy group compared with 11.3% of the control group (p = .28). Leukopenia, alkaline phosphatase elevation, and hyperuricemia were determined to be adverse events related to GM-CSF administration. This study was limited by a small number of advanced cases (Fontaine stage IV cases 20.4%), a high-risk group of hemodialysis patients, and a high number of patients who did not complete treatment (cell therapy group: 38.5%; control group: 50.9%).

Table 3. Key Characteristics of RCT with Intramuscular GM-CSF -Mobilized PBMNCs for PAD

				Treatment
Study (Year)	Countries	Sites	Dates	Participants	Active	Comparator
Horie (2018)20 IMPACT	Japan	17	2009 to 2013	Patients with PAD, Fontaine classification II-IV (n = 107)	Intramuscular GM-CSF, single dose of 200 μg/m2 per day for 4 days (n = 52)	Guideline based standard of care1 (n = 55)

GM-CSF: granulocyte-macrophage colony-stimulating factor; PAD: peripheral arterial disease; PBMNC: peripheral blood mononuclear cells; RCT: randomized controlled trial.
1 Includes the use of lipid, antihypertensive, antidiabetic, antithrombotic drugs, exercise, and prostanoids.

Table 4. Results of RCT with Intramuscular GM-CSF -Mobilized PBMNCs for PAD

Study (Year)	PFS (95% CI)	Frequency of major limb amputation	New ulcer or gangrene	Serious AE
Horie (2018)20 IMPACT
Cell Therapy group	0.42 (0.13 – 1.36)	6.0%	18%	20.0%
Control group	0.62 (0.28 – 1.36)	5.7%	15.1%	11.3%
p-value	.07	1.00	.80	.28

AE: adverse events; CI: confidence intervals; GM-CSF: granulocyte-macrophage colony-stimulating factor; PAD: peripheral arterial disease; PBMNC: peripheral blood mononuclear cells; PFS: progression-free survival; RCT: randomized controlled trial.
The purpose of the limitations tables (see Tables 5 and 6) is to display notable limitations identified in the study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 5. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-upe
Horie (2018)20 IMPACT		3-fixed dosing was used (not weight-based)

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. 
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 6. Study Design and Conduct Limitations

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Horie (2018)20 IMPACT		1,2,3 — open-label trial

      
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Granulocyte-Macrophage Colony-Stimulating Factor Mobilization
Three RCTs have been published.^18,19,20 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 PFS and frequency of limb amputation at 1 year of follow-up.²⁰ There was a substantial rate of subsequent surgical intervention in both arms.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Heart Association and the American College of Cardiology
In 2016, the guidelines from the American Heart Association and the American College of Cardiology provided recommendations on the management of patients with lower-extremity peripheral arterial disease (PAD), including surgical and endovascular revascularization for critical limb ischemia.^21,22 Stem cell therapy for PAD was not addressed.

Global Vascular Guideline
In 2019, a Global Vascular Guideline on management of chronic limb-threatening ischemia summarized the available literature on therapeutic angiogenesis for various etiologies.²³ The guideline was a joint venture of the Society for Vascular Surgery, the European Society for Vascular Surgery, and the World Federation of Vascular Societies. Based on a moderate level of evidence, the guideline recommended that therapeutic angiogenesis in patients with chronic limb-threatening ischemia should be limited to the context of a clinical trial (strong recommendation). The authors noted that Phase 3 clinical trials are planned or underway so additional data may be forthcoming in the future.

European Society of Cardiology
In 2011, the European Society of Cardiology guidelines on the diagnosis and treatment of PAD did not recommend for or against stem cell therapy for PAD.²⁴ However, in 2017, updated guidelines, published in collaboration with the European Society of Vascular Surgery, stated: “Angiogenic gene and stem cell therapy are still being investigated with insufficient evidence in favour of these treatments.” The current recommendation is that stem cell/gene therapy is not indicated in patients with chronic limb-threatening ischemia (class of recommendation: III; Level of evidence: B).²⁵

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Table 7. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03968198	Autologous Transplantation of Adipose Tissue Derived Mesenchymal Stroma/Stem Cells (ASC) in Patients With Critical Limb Ischemia	43	Jul 2023
NCT03304821	Granulocyte-Macrophage Stimulating Factor (GM-CSF) in Peripheral Artery Disease: the GPAD-3 Study	176	Sep 2022
NCT02685098	A Clinical and Histological Analysis of Mesenchymal Stem Cells in Amputation (CHAMP)	16	May 2026
NCT02805023a	Phase 1/2, Double Blind Randomized Placebo Controlled Study to Assess the Safety and Efficacy of BGC101 (EnEPC) in the Treatment of PAD & CLI	50	Dec 2023
Unpublished
NCT02551679a	A Randomized Double Blind Placebo Controlled Clinical Study to Assess Blood-Derived Autologous Angiogenic Cell Precursor Therapy in Patients With Critical Limb Ischemia (ACP-CLI)	95	Dec 2020 (status unknown; last update Jan 2020)
NCT04466007	Multicenter, Randomized, Dose-search, Parallel, Double-blind, and Placebo-controlled Clinical Trial to Evaluate the Safety and Efficacy of Intramuscular Administration of Allogeneic Adipose Tissue Adult Mesenchymal Stem Cells in Diabetic Patients With Critical Limb Ischemia Without Possibility of Revascularization	90	Sep 2022
NCT01745744	Clinical Trial Phase I / II, Multicentre, Open, Randomized Study of the Use of Mesenchymal Stem Cells From Adipose Tissue (CeTMAd) as Cell Regeneration Therapy in Critical Chronic Ischemic Syndrome of Lower Limb in Nondiabetic Patients	33	July 2018
NCT00498069a	Feasibility Study of the Safety and Activity of Autologous Bone Marrow Aspirate Concentrate (BMAC) for the Treatment of Critical Limb Ischemia Due to Peripheral Arterial Occlusive Disease	48	Mar 2015
NCT02538978a	Safety and Effectiveness of the SurgWerksTM-CLI Kit and VXPTM System for the Rapid Intra-operative Aspiration, Preparation and Intramuscular Injection of Concentrated Autologous Bone Marrow Cells Into the Ischemic Index Limb of Rutherford Category 5 Non-Reconstructable Critical Limb Ischemia Patients	224	Mar 2019 (last update posted 2016 not yet recruiting)
NCT01679990a	A Phase II, Randomized, Double-Blind, Multicenter, Multinational, Placebo-Controlled, Parallel- Groups Study to Evaluate the Safety and Efficacy of Intramuscular Injections of Allogeneic PLX-PAD Cells for the Treatment of Subjects With Intermittent Claudication (IC)	180	Feb 2019 (last update Feb 2019)
NCT03042572	Allogeneic Mesenchymal Stromal Cells for Angiogenesis and Neovascularization in No-option Ischemic Limbs; A Double-blind, Randomized, Placebo-controlled Trial	60	Jul 2021 (unknown status; last update May 2018)
NCT01049919a	MarrowStim PAD Kit for the Treatment of Critical Limb Ischemia (CLI) in Subjects With Severe Peripheral Arterial Disease (PAD) (MOBILE)	153	Feb 2020 (terminated; primary endpoint not met)
NCT03809494a	Clinical Study of the Use of an Autologous Blood Filtration Device in the Treatment of Critical Limb Ischemia	2	Nov 2020 (Terminated)

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

References

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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): 1280-6. PMID 22453769
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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
25. 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 arteriesEndorsed 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

Coding Section

Codes	Number	Description
CPT	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
ICD-9-CM Diagnosis		Investigational for all relevant codes
ICD-10-CM (effective 10/01/15)		Investigational for all relevant codes
ICD-10-PCS (effective 10/01/15)		ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this therapy.
	6A550ZT, 6A550ZV	Pheresis, extracorporeal separation of blood products, stem cells — code by hematopoietic or cord blood

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2024 Forward     

01012024  NEW POLICY

05/17/2024 Annual review, no change to policy intent.