CAM 80155

Stem-cell Therapy for Peripheral Arterial Disease

Category:Therapy   Last Reviewed:May 2019
Department(s):Medical Affairs   Next Review:May 2020
Original Date:May 2013    

Description
Critical limb ischemia due to peripheral arterial disease results in pain at rest, ulcers, and significant risk for limb loss. Injection or infusion of stem cells, either concentrated from bone marrow, expanded in vitro, stimulated from peripheral blood, or from an allogeneic source, is being evaluated for the treatment of critical limb ischemia.

For individuals who have peripheral arterial disease who receive stem cell therapy, the evidence includes small randomized trials, systematic reviews, and case series. 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 peripheral arterial disease 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. 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 the effects of the technology on health outcomes.  

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 mm Hg). 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 mm Hg. Pain-free walking may be measured by time on a treadmill or, more frequently, by distance in a 400-meter walk.

Regulatory Status
Two point-of-care concentration of bone marrow aspirate has 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

Biomet Biologics, Inc

Warsaw, IN

12/18/2009

BK090008

FDA product code: JQC.

Related Policies
20116 Recombinant and Autologous Platelet-Derived Growth Factors as a Treatment of Wound Healing and Other Conditions
20218 Progenitor Cell Therapy for the Treatment of Damaged Myocardium Due to Ischemia
80152 Orthopedic Applications of Stem-Cell Therapy

Policy
Treatment of peripheral arterial disease, including critical limb ischemia, with injection or infusion of cells concentrated from bone marrow aspirate is considered INVESTIGATIONAL.

Policy Guidelines
Beginning in July 2011, there are specific CPT category III codes for this therapy:

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.

The CPT codes were constructed to allow reporting of the complete procedure and harvesting by a single physician (code 0263T) or separate reporting when the cell harvesting and therapy injections are performed by separate physicians (0264T and 0265T). 

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of 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 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 technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical uses 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. RCTs 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.

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 PAD.

The question addressed in this evidence review is: does stem cell therapy improve the net health outcome in patients with PAD?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest are 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 (eg, 240-500 mL) or another source of stem cells. The SmartPReP2 Bone Marrow Aspirate Concentrate System (Harvest Technologies) has been developed as a single-step point-of-care, bedside centrifugation system for the concentration of stem cells from bone marrow. The system is composed of a portable centrifuge and an accessory pack that contains processing kits including a functionally closed dual-chamber sterile processing disposable container. The SmartPReP2 system is designed to concentrate a buffy coat of 20 mL from whole-bone marrow aspirate of 120 mL.

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 or bone marrow concentrate is administered either intra-arterially or through multiple injections (20 to 60) into the muscle, typically in the gastrocnemius. Other methods of concentrating stem cells include the in vitro expansion of bone marrow‒derived stem cells or use of a granulocyte-macrophage colony-stimulating factor to mobilize peripheral blood mononuclear cells.

Comparators
Comparators of interest include conservative management, rehabilitation protocols 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.

Timing
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.

Setting
Patients with PAD are managed by vascular surgeons and cardiologists in an outpatient clinical setting.

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

a.     To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs
b.     In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c.     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.  

At this time, the literature on stem cell therapy consists primarily of small RCTs, systematic reviews and meta-analyses, retrospective reviews, and case series.1,2 Systematic reviews, controlled studies, and the larger case series are described next. 

Systematic Reviews
Rigato et al (2017) published a systematic review of autologous cell therapy for the peripheral arterial disease.3 They identified 19 RCTs (837 patients), 7 nonrandomized controlled studies (338 patients), and 41 noncontrolled studies (1177 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 a 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 a 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=5.91, confidence interval [CI]: 2.49-14.02, p<0.0001), ulcer healing (relative risk=1.73, CI: 1.45-2.06, p<0.00001), and a reduction in amputation rates (relative risk=0.59, CI: 0.46-0.76, p<0.0001). Compared with the control group, significant improvement in the cell therapy group was also seen in ankle-brachial index (mean difference=0.13, CI=0.11-0.15, p<0.00001), transcutaneous oxygen tension (mean difference=12.22, CI=5.03-19.41, p=0.0009), and pain-free walking distance (mean difference=144.84, CI=53.03-236.66, p=0.002).

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

Study (Year)

Literature Search

Studies

Participants

N

Design

Results

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)

CLI: critical limb ischemia; PAD: peripheral arterial disease, RCT: randomized controlled trial.

The following discussion concerns some RCTs included and not included in the meta-analyses. A number of these RCTs were described as pilot or phase 2 studies.

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 ulcer.5 Patient inclusion criteria were CLI as defined by an Ankle-Brachial Index (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 treatment group had a higher proportion of patients with diabetes (98.2% vs 88.1%), hyperlipidemia (80.0% vs 54.8%), and ischemic heart disease (76.4% vs 57.1%), respectively. Additionally, the control group had a higher proportion of patients (72% vs 40%) with 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 eight 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 two 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.6 At 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%). Power analysis indicated that 210 patients were needed to achieve 95% power in a planned pivotal trial.

Intramuscular injection with a combination bone marrow mononuclear cells (BM-MNCs) and gene therapy with a vascular endothelial growth factor plasmid were tested in a 2015 European RCT assessing 32 patients.7 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. They 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.8 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 see in the 2 million cells/kg body weight group (0.3 units per month [standard error (SE): 0.13], CI: -0.55 to -0.05, p=0.0193 and 11.0% decrease in size per month [SE: 0.05%], CI: 0.80-0.99, p=0.0253, respectively) and in the 1 million cells/kg body weight group (0.23 per month [SE: 0.13], CI: -0.49 to 0.03, p=0.081 and 2.0% decrease in size per month [SE: 0.06%], CI: 0.87-1.10, p=0.6967, 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 ankle-brachial pressure index values and larger ulcers indicating potential investigator bias to allocate more severe patients to the treatment groups.

Section Summary: Concentrated Bone Marrow Aspirate (Monocytes and MSCs) - Intramuscular Injection
RCTs, a non-randomized comparative study and a retrospective chart review have been published. There is preliminary evidence of benefit to the use of intramuscular concentrated bone aspirate injection outcomes in CLI patients.

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 (NCT00371371).9 This foundation-supported trial evaluated the clinical effects of repeated intra-arterial infusion of BM-MNCs in 160 patients with nonrevascularizable CLI. Patients received 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 pressureimproved to a similar extent in both groups, reinforcing the need for placebo control in this type of trial. Results from a long-term follow-up analysis of 109 of the participants found improvements in self-reported QOL persisted for a median of 35 months in both groups, who remained blinded to treatment assignment.10 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.11 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 three 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 did differ between groups. There was a significant improvement in ulcer healing (ulcer area, 1.89 cm2vs 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, respectively.

Section Summary: Concentrated Bone Marrow Aspirate (Monocytes and MSCs) - Intra-Arterial Injection
Two RCTs have been published. The RCTs did not find support for their respective primary outcome measures; the rate of major amputation after six months or a significant increase in the ABI score at three months.

Adverse Events
Jonsson et al (2012) reported a high incidence of serious adverse events in patients treated with peripheral blood mononuclear cells, causing the investigators to terminate the study.12 Of nine patients, two had myocardial infarction believed to be related to the bone marrow stimulation, one of whom died. Another patient had a minor stroke one week after stem cell implantation.

Expanded Monocytes and MSCs
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 MSCs derived from bone marrow aspirate (ixmyelocel-T), were reported by Powell et al (2011, 2012).13,14 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 results of a phase 2, double-blind, placebo-controlled trial of GM-CSF in 159 patients with intermittent claudication due to PAD.15 Patients were treated with subcutaneous injections of GM-CSF or placebo three times weekly for four 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=0.08). 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 100% increase in progenitor cells (60 seconds).

Horie et al (2018) reported an RCT of 107 patients with PAD characterized as Buerger disease that evaluated the efficacy and safety of GM-CSF-mobilized peripheral blood mononuclear cell transplantation compared with SOC.16 Participants were randomized to guideline-based SOC or SOC plus intramuscular weight based peripheral blood mononuclear cell administration. After disease progression or completion of 1-year follow-up, 17 patients in the control group underwent the 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=0.28). Leukopenia, alkaline phosphatase elevation, and hyperuricemia were determined to be adverse events related to GM-CSF administration. This study was limited a small number of advanced cases (Fontaine stage IV cases (20.4%)), a high-risk group of hemodialysis patients and by the high number of patients who did not complete treatment (cell therapy group: 38.5%; control group: 50.9%).

Table 3. Key Characteristics RCT Intramuscular GM-CSF PBMNCs for CLI  

 

 

 

 

 

Treatment

Study (Year)

Countries

Sites

Dates

Participants

Active

Comparator

Horie (2018)16

IMPACT

Japan

17

2009-2013

Patients with PAD, Fontaine classification II-IV (n=107)

  • Intramuscular GM-CSF, single dose of 200μg/m2 per day for 4 days (n=52)
  • Guideline based Standard of care1 (n=55)

CLI: critical limb ischemia; GM-CSF: granulocyte-macrophage colony-stimulating factor; PAD: peripheral arterial disease; PBMNC: peripheral blood mononuclear cell; RCT: randomizedcontrolled trial.

Includes the use of lipid, antihypertensive, antidiabetic, antithrombotic drugs, exercise, and prostanoids.

Table 4. Results of RCT Intramuscular GM-CSF PBMNCs for CLI- 1 Year Follow-Up  

Study (Year)

PFS (95% CI)

Frequency of major limb amputation

New ulcer or gangrene

Serious AE (%)

Horie (2018)16 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

0.07

 

1.00

0.28

AE: adverse events; CI: confidence intervals; CLI: critical limb ischemia; PFS: progression-free survival;

The purpose of the gap table (see Table 5) is to display notable gaps identified in each study.

Two RCTs have been published. 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 PFS and frequency of limb amputation at one year of follow-up. There was a substantial rate of subsequent surgical intervention in both arms.

Summary of Evidence
For individuals who have PAD who receive stem cell therapy, the evidence includes small randomized trials, systematic reviews, and case series. The relevant outcomes are overall survival, symptoms, change in disease status, morbid events, functional outcomes, QOL, 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. 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. Two RCTs have been published that used granulocyte colony-stimulating factor mobilized peripheral mononuclear cells. 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 PFS and frequency of limb amputation at one year of follow-up. There was a substantial rate of subsequent surgical intervention in both arms.

For individuals who have peripheral arterial disease who receive stem cell therapy, the evidence includes small randomized trials, systematic reviews, retrospective reviews, and case series. The 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 peripheral arterial disease 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. Two randomized controlled trials have been published that used granulocyte colony-stimulating factor mobilized peripheral mononuclear cells. 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 progression-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 the effects of the technology on health outcomes.

PRACTICE GUIDELINES AND POSITION STATEMENTS
American Heart Association and American College of Cardiology
The guidelines from the American Heart Association and American College of Cardiology (2016) provided recommendations on the management of patients with lower-extremity peripheral arterial disease (PAD), including surgical and endovascular revascularization for critical limb ischemia (CLI).17,18 Stem cell therapy for PAD was not addressed.  

European Society of Cardiology
The European Society of Cardiology (2011) guidelines on the diagnosis and treatment of PAD did not recommend for or against stem cell therapy for PAD.19 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).20

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable. 

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 5. A search of ClinicalTrials.gov in January 2018 and reviews by Powell (2012)21 and Bartel et al (2013),22 identified a number of ongoing trials assessing concentrated, expanded, or stimulated stem cells for PAD (see Table 5).

The review by Powel (2012) evaluated the effects of biologic therapy in patients with CLI, describing several products in phase 2 or 3 trials.21 The U.S. Food and Drug Administration recommended that the primary efficacy endpoint in a phase 3 CLI trial should be amputation-free survival. When the probability of this outcome is combined with the comorbid burden of CLI patients and variable natural history, large numbers of patients (≈500) may be needed to evaluate clinical outcomes.21

Table 5. Summary of Key Trials  

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

 

 

 

NCT01049919a

MarrowStim PAD Kit for the Treatment of Critical Limb Ischemia (CLI) in Subjects With Severe Peripheral Arterial Disease (PAD) (MOBILE)

152

May 2020

NCT03304821

Granulocyte-Macrophage Stimulating Factor (GM-CSF) in Peripheral Artery Disease: the GPAD-3 Study

176

Jun 2022

Unpublished

 

 

 

NCT01483898a

An Efficacy and Safety Study of Ixmyelocel-T in Patients With Critical Limb Ischemia (CLI) (REVIVE)

 

594

Apr 2014

(last update posted Aug 2018)

NCT01245335a

Pivotal Study of the Safety and Effectiveness of Autologous Bone Marrow Aspirate Concentrate (BMAC) for the Treatment of Critical Limb Ischemia Due to Peripheral Arterial Disease

97

Nov 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)

NCT01408901

PROgenitor Cell Release Plus Exercise to Improve functionaL Performance in PAD: The PROPEL Study23

210

Aug 2017

 

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)

172

April 2018

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):445-453. 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):10-17. 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. Prochazka V, Gumulec J, Jaluvka F, et al. Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer. Cell Transplant. Jun 2010;19(11):1413-1424. PMID 20529449
  6. Benoit E, O'Donnell TF, Jr., 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 
  7. Skora 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):325-331. PMID 25995748
  8. 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
  9. 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):851-860. PMID 25567765
  10. 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):83-89. PMID 26511056
  11. 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 1 2011;4(1):26-37. PMID 21205939
  12. Jonsson TB, Larzon T, Arfvidsson B, et al. Adverse events during treatment of critical limb ischemia with autologous peripheral blood mononuclear cell implant. Int Angiol. Feb 2012;31(1):77-84. PMID 22330628
  13. 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):1032-1041. PMID 21684715
  14. 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):1280-1286. PMID 22453769
  15. 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):2631-2639. PMID 24247554
  16. 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
  17. 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
  18. 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
  19. European Stroke Organisation, Tendera M, Aboyans V, 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- 2906. PMID 21873417
  20. 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. Aug 26 2017. PMID 28886620
  21. Powell RJ. Update on clinical trials evaluating the effect of biologic therapy in patients with critical limb ischemia. J Vasc Surg. Jul 2012;56(1):264-266. PMID 22633422
  22. 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. Jun 2013;9(3):373-383. PMID 23456574
  23. Domanchuk K, Ferrucci L, Guralnik JM, et al. Progenitor cell release plus exercise to improve functional performance in peripheral artery disease: the PROPEL Study. Contemp Clin Trials. Nov 2013;36(2):502-509. PMID 24080099

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-9-CM Procedure 99.79 Therapeutic apheresis or other injection, administration or infusion of other therapeutic or prophylactic substance, other (includes harvest of stem cells)
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 and Blue Shield Association technology assessment program (TEC) and other non-affiliated 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 2014 Forward     

05/01/2019 

Annual review, no change to policy intent. Updating background, regulatory status, rationale and references. 

05/08/2018 

Annual review, no change to policy intent. Updating description, rationale and references. 

05/23/2017 

Annual review, no change to policy intent. 

05/03/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

06/01/2015 

Annual review, no change to policy intent. Updating rationale and references, adding coding. 

05/26/2014

Annual review. Added related policies and policy guidelines. Updated background, regulatory status, rationale and references. No change to policy intent.


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