Coverage Policy Manual
Policy #: 2011058
Category: Medicine
Initiated: August 2011
Last Review: July 2018
  Autologous Stem-cell Therapy to Treat Peripheral Arterial Disease

Description:
Critical limb ischemia due to peripheral arterial disease (PAD) results in pain at rest, ulcers, and significant risk for limb loss. Injection of hematopoietic stem cells concentrated from bone marrow is being evaluated for the treatment of critical limb ischemia when surgical or endovascular revascularization has failed.
 
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 endstage of lower extremity PAD in which severe obstruction of blood flow results in ischemic pain at rest, ulcers, and a significant risk for limb loss. The standard therapy for severe, limb-threatening ischemia is revascularization aiming to improve blood flow to the affected extremity. If revascularization has failed or is not possible, amputation is often necessary.
 
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 chemo- 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.
 
The rationale of hematopoietic stem-cell/bone marrow-cell therapy in PAD is to induce arteriogenesis by boosting the physiological repair processes. This requires large numbers of functionally active autologous precursor cells, and subsequently, a large quantity of bone marrow (e.g., 240-500 mL). 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. 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 stem-cell/bone marrow concentrate is administered either intra-arterially or through multiple injections (20 to 60) into the muscle, typically in the gastrocnemius.
 
Standard outcomes for critical limb ischemia include the Rutherford criteria for limb status, healing of ulcers, the ankle-brachial index (ABI), transcutaneous oxygen pressure (TcO2), and pain-free walking. The Rutherford criteria include ankle and toe pressure, the level of claudication, ischemic rest pain, tissue loss, nonhealing ulcer, and gangrene. The ABI measures arterial segmental pressures on the ankle and brachium, and indexes ankle systolic pressure against brachial systolic pressure (normal range 0.95 – 1.2). An increase greater than 0.1 is considered to be clinically significant. TcO2 is measured with an oxymonitor; the normal value is 70-90 mm Hg. Pain free walking may be measured by time on a treadmill, or more frequently by distance in a 400-meter walk.
 
Two devices have been identified that provide point-of-care concentration of bone marrow aspirate:
  • The SmartPReP2® Bone Marrow Aspirate Concentrate System is a microprocessor-controlled
dedicated centrifuge with decanting capability and an accessory BMAC IDE PAD Pack for
processing a patient’s bone marrow aspirate. The system is in a Phase III trial; expected
completion of the trial is in 2014. FDA product Code: JQC.
  • The MarrowStim P.A.D. kit™ (Biomet Biologics) is in a Phase III trial for the treatment of PAD
with completion expected May 2014. FDA product Code: JQC.
 
Ixmyelocel-T (Aastrom) is an expanded stem cell product where bone marrow aspirate is sent to a
processing facility to be cultured in a bioreactor and expanded over a 2-week period. The expanded cell
population is enriched with mesenchymal precursors and alternatively-activated macrophages. This
product is currently being evaluated in a pivotal Phase III trial regulated by the FDA’s Center of Biologic
Evaluation and Research.
 
Pluristem is developing allogeneic cell therapy derived from full-term placenta (PLX-PAD cells). This
product has been tested in a Phase I trial in patients with critical limb ischemia.
 
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).
  

Policy/
Coverage:
Treatment of peripheral arterial disease, including critical limb ischemia, with injection or infusion of cells concentrated from bone marrow aspirate is currently being studied in clinical trials and therefore does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, treatment of peripheral arterial disease, including critical limb ischemia, with injection or infusion of cells concentrated from bone marrow aspirate is considered investigational as this therapy is currently being studied in Phase III clinical trials to determine effectiveness.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 

Rationale:
This policy was created based on a review of literature identified through a search of the MEDLINE database through April 2011. Controlled studies and the larger case series are summarized below.
 
In 2002, the Therapeutic Angiogenesis by Cell Transplantation (TACT) study investigators published results of a pilot study and a small double-masked trial with 22 patients who were treated with bone marrow-mononuclear cells by intramuscular injection into the gastrocnemius of one leg and peripheral blood-mononuclear cells in the other leg as a control (randomized order) (Tateishi-Yuyama, 2002).  Patients qualified for marrow implantation if they had bilateral chronic limb ischemia, including rest pain, non-healing ischemic ulcers, or both, and were not candidates for nonsurgical or surgical revascularization. Seventeen patients (85%) had been previously treated with percutaneous angioplasty, bypass graft, or both. The patients had resting ankle-brachial index (ABI) less than 0.6 in both limbs. Patients with poorly controlled diabetes mellitus or with evidence of malignant disorder during the past 5 years were excluded from the study. About 500 mL of bone marrow cells were aspirated from the ileum, separated, and concentrated to a final volume of about 30 mL. About 3 hours after marrow aspiration the cells were implanted by intramuscular injection into the gastrocnemius. Follow-up with ABI, transcutaneous oxygen pressure (TcO2) and pain-free walking time was performed every week for 4 weeks and every 4 months thereafter. Two patients discontinued the study after randomization due to clinical worsening before 4 weeks. At 4 weeks after treatment, ABI, TcO2, and rest pain were significantly improved in legs injected with bone marrow-mononuclear cells, compared with those injected with peripheral blood-mononuclear cells. For example, ABI increased by 0.1 in the leg treated with bone marrow-mononuclear cell and by 0.02 with peripheral blood-mononuclear cells. TcO2 improved by 17.4 mm Hg with bone marrow-mononuclear cells and by 4.6 mm Hg with peripheral blood-mononuclear cells. Rest pain in legs treated with bone marrow-mononuclear cells was resolved in 16 of 20 patients, while pain in legs treated with peripheral blood-mononuclear cells remained in 17 of 20 patients. These improvements were sustained at 24 week follow-up. Digital subtraction angiography showed a marked increase in the number of visible collateral vessels in 60% of legs treated with bone marrow cells. No adverse events were reported.
 
The 2008 TACT report by the same multicenter group of investigators assessed the 3-year safety and clinical outcomes of intramuscular implantation of bone marrow-mononuclear cells in a series of 74 patients with critical limb ischemia due to atherosclerotic peripheral arterial disease (PAD) and 41 patients with thromboangiitis obliterans (TAO; Buerger’s disease) (Matoba, 2008). The ischemic limbs were not candidates for surgical or nonsurgical revascularization. Twenty-six patients (23%) had a previous bypass operation. Bone marrow cells were aspirated from the ileum, and the mononuclear cells sorted and concentrated to a final volume of 40 mL. The cells were implanted by intramuscular injection into the foot. Patients were followed every week for 4 weeks and at 6, 12, 24, and 36 months thereafter. The overall survival, amputation-free interval, adverse events, ABI, TcO2, pain scale, ulcer size, and pain-free walking distance were evaluated at each time point. Overall patient survival and amputation-free interval were defined as the primary endpoints of this study. Three-year overall survival rates were 80% in patients with atherosclerotic PAD and 100% for patients with TAO, and the median follow-up time of surviving patients was 25 months (range, 0.8 to 69 months). The 3-year amputation-free rate was 60% in atherosclerotic PAD and 91% in patients with TAO. Of the 24 amputations in patients with PAD, 83% occurred within 6 months. Multivariate analysis indicated that the severity of ischemic pain at baseline and prior repeated bypass surgery were the major determinants that negatively affected the amputation-free interval of the therapy. The ABI and transcutaneous oxygen pressure value did not significantly change, but there was a significant improvement in the leg pain scale (from 6 to 2), ulcer size (from 3.5 cm2 to 0), and pain-free walking distance (from about 25 meters to 100 meters) at 6 months.
 
Amann et al. reported a pilot study of autologous bone marrow cell transplantation in 51 consecutive patients with impending major amputation due to end-stage critical limb ischemia in 2009 (Amann, 2009). Forty-five patients (88%) had undergone a mean of two unsuccessful attempts of operative and/or percutaneous revascularization of the ischemic limb. Six patients (12%) were technically not amenable to revascularization. Critical limb ischemia was confirmed if there was angiographic proof of arterial occlusion and one of the following criteria was fulfilled: ABI less than 0.6 or TcO2 less than 30 mm Hg. Major amputation (above the ankle) had been recommended to 46 of the 51 patients (90%) by the treating vascular surgeons. For the first 12 subjects, 450-500 mL bone marrow was aspirated under general anesthesia and processed by the Ficoll method. For the remaining subjects, 240 mL bone marrow was aspirated under sedation and processed using an automated bedside density gradient centrifugation method. The final treating volume (55-85 mL) was adjusted with plasma depending on the area to be treated (whole leg, calf only, or foot), based on the localization and extent of the arterial occlusions. In addition, if a wound was present, 4-10 injections of bone marrow concentrate were given into the wound bed and the wound perimeter. Patients were seen monthly up to 6 months and at least in half-year intervals after. Minimum follow-up was 6 months, and the mean follow-up was 411 days (range 175 to 1,186 days). No patients were lost to follow-up. Improvement in perfusion and subsequent limb salvage was achieved in 30/51 patients (59%) at 6 months and 27/51 (53%) at last follow-up (mean of 411 days). Seventeen minor amputations (6 forefoot and 11 toe) were performed in the 30 patients with 24-week limb salvage. Complete wound healing was achieved in 15 of 21 patients with ischemic wounds. Perfusion, measured at 6 months with ABI and TcO2, increased in patients with limb salvage and did not change in patients who eventually underwent major amputation. Patients with limb salvage improved from a mean Rutherford category of 4.9 at baseline to 3.3 at 6 months. Analgesic consumption was reduced by 62%. Total walking distance improved in non-amputees from a median of 0 to 40 meters at 24 weeks. No unexpected long-term adverse events occurred.
 
In 2010, Prochazka and colleagues reported a randomized study of 96 patients with critical limb ischemia and foot ulcer (Prochazka, 2010). Patient inclusion criteria were critical limb ischemia as define by ABI equal to or less than 0.4, ankle systolic pressure equal to or less than 50 mm Hg or toe systolic pressure equal to or less than 30 mm Hg, and failure of basic conservative and revascularization treatment (surgical or endovascular). The patients were randomized into treatment with bone marrow concentrate (n=42) or standard medical care (n=54). The primary endpoints were major limb amputation during 120 days and degree of pain and function at 90- and 120-day follow-up. At baseline, the control 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% - all respectively). In addition, the control group had a higher proportion of patients with stage DIII (deep ulcers with osteitis) University of Texas Wound Classification (72% vs. 40%, respectively). 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. Forty-two of the 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. The reason for different times of follow-up for the primary outcome measure is unclear. 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 performed only in the group treated with bone marrow concentrate. In the treatment group with salvaged limbs, toe pressure and toe brachial index increased from 22.66 to 25.63 mm Hg and from 0.14 to 0.17, respectively. Interpretation of this study is limited by unequal baseline measures, lack of blinding, different periods of follow-up, different loss to follow-up and different measures at follow-up for the 2 groups.
 
Ongoing Clinical Trials
The design of the BONe Marrow Outcome Trial in Critical Limb Ischaemia (BONMOT-CLI) trial was reported in 2008 (Amann, 2008). It is an investigator-initiated, randomized, double-blinded, placebo-controlled multicenter study at 4 sites in Germany that assesses the therapeutic value of bone marrow cell-induced angiogenesis and arteriogenesis in severe, limb-threatening ischemia. Ninety patients with no option for revascularization or after failed revascularization will be randomized to 40 injections into the ischemic limb with a concentrate of autologous bone marrow cells or to sham bone marrow aspiration and 40 placebo injections. The combined primary endpoint is major amputation or persisting critical limb ischemia (no improvement) over 3 months. Secondary endpoints are death, changes in perfusion, quality of life, walking distance, minor amputations, wound healing, collateral density and cancer incidence. Post study follow-up is 2 years.
 
JUVENTAS (Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation) is a randomized, double-blind, placebo-controlled trial in the Netherlands (Sprengers, 2010). The clinical effects of repeated intra-arterial infusion of bone marrow mononuclear cells will be investigated in 110-160 patients with critical limb ischemia. Patients will receive repeated intra-arterial infusion of bone marrow-mononuclear cells or placebo into the common femoral artery. The primary outcome measure is the rate of major amputation after 6 months. Secondary endpoints include minor amputation, number and extent of leg ulcers, resolution of rest pain, perfusion, change in quality of life, and change in clinical status. Functional characteristics of the bone marrow-mononuclear cells will also be studied, and the bone marrow-mononuclear cell dysfunction will be related to clinical outcome.
 
A search of ClinicalTrials.gov in April 2011 identified a number of ongoing trials with hematopoietic stem cell/bone marrow concentrate for peripheral arterial disease, including:
 
  • A manufacturer-sponsored U.S. multicenter Phase II study on the use of autologous bone marrow cells for the treatment of critical limb ischemia due to PAD (NCT00468000). The double-blind study is expected to enroll 150 patients, randomized into two patient groups. The treatment group will receive intramuscular injections of Aastrom Biosciences TRC autologous bone marrow cell product into the affected limb; the control group will receive intramuscular injections with an electrolyte solution (without cells). The estimated completion date is listed as March 2011.
 
  • A manufacturer-sponsored Phase III trial with bone marrow aspirate concentrate with the SmartPReP2® system for the treatment of critical limb ischemia (NCT01245335). This is a U.S. pivotal randomized double-blind safety and efficacy trial comparing bone marrow aspirate concentrate with placebo injection into ischemic tissue of the lower extremity in 210 patients. The study start date is listed as January 2011; the expected study completion date is June 2014.
 
Summary
Based on initial evidence from case series and small randomized trials, injection of bone marrow concentrate may hold promise as a treatment for critical limb ischemia due to peripheral arterial disease. However, well-designed and well-conducted randomized controlled trials are needed to evaluate the health outcomes of this procedure. A number of trials are in progress, including several large randomized double-blind placebo controlled trials. Results from these trials are needed to adequately evaluate the impact on net health outcome of this procedure. Further information on the safety and durability of the treatment is also needed.
 
2012 Update
A literature search was conducted through September 2012.  There was no new information identified that would prompt a change in the coverage statement.
 
Results from the multi-center PROVASA trial (Intraarterial Progenitor Cell Transplantation of Bone Marrow Mononuclear Cells for Induction of Neovascularization in Patients with Peripheral Arterial Occlusive Disease) were reported in 2011 (Walter, 2011). In this double-blind Phase II trial, 40 patients with critical limb ischemia who were not candidates or had failed to respond to interventional or surgical procedures were randomized to intra-arterial administration of bone marrow-derived mononuclear cells (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 and 18 months. The primary outcome measure, a significant increase in the ABI 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 the groups. There was a significant improvement in ulcer healing (ulcer area 1.89 cm2 vs. 2.89 cm2) and reduced pain at rest (improvement of about 3 vs. 0.05) following intra-arterial BM-MNC administration. This is the only randomized controlled trial to report intra-arterial administration of BM-MNC.
Interim analysis results from 46 patients was reported from the RESTORE-CLI study in 2011 (Powell, 2011).  The RESTORE-CLI is a manufacturer-sponsored U.S. multicenter Phase II study on the use of autologous bone marrow cells for the treatment of critical limb ischemia due to PAD(NCT00468000).  The authors report in the interim analysis that intramuscular injections of autologous bone marrow-derived cells are safe for the treatment of patients with lower extremity critical limb ischemia.  The interim results of 46 of 86 patients indicated an improvement in amputation-free survival and time to first occurrence of treatment failure compared to placebo.  According to the authors, a larger Phase III trial is planned based on these interim results.
 
A search of online site ClinicalTrials.gov in October 2012 identified a number of ongoing trials with hematopoietic stem cell/bone marrow concentrate for peripheral arterial disease, including a manufacturer-sponsored Phase III trial with bone marrow aspirate concentrate with the SmartPReP2® system for the treatment of critical limb ischemia (NCT01245335). This is a U.S. pivotal randomized double-blind safety and efficacy trial comparing bone marrow aspirate concentrate with placebo injection into ischemic tissue of the lower extremity in 210 patients. The study start date is listed as January 2011; the expected study completion date is June 2014.
 
2013 Update
A literature search was conducted using the MEDLINE database through September 2013.  No new information was identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
A 2011 Cochrane review identified 2 small studies with a total of 57 patients that met the review’s inclusion criteria for local intramuscular transplantation of autologous mononuclear cells (monocytes) for critical limb ischemia (CLI) (Moazzami, 2011). Studies were excluded that used mesenchymal stem cells (MSCs) or bone marrow aspirate. In one of the studies, intramuscular injection of bone marrow-derived mononuclear cells was compared with standard conservative treatment. In the second study, peripheral blood derived mononuclear cells were collected following injections of granulocyte colony-stimulating factor and transplanted by intramuscular injections. Both studies showed a significant reduction in amputations with treatment with monocytes, but larger randomized controlled trials are needed to adequately evaluate the effect of treatment with greater certainty.
 
In 2012, Liu et al. reported a meta-analysis of 6 randomized trials (333 patients) that evaluated mononuclear cell transplantation in patients with CLI (Liu, 2012). Cell therapy was found to decrease the incidence of amputation in patients with CLI with an odds ratio (OR) of 0.37. The rate of amputation free survival was increased in patients with Rutherford class 5 CLI (OR: 3.28) but was not significantly different in patients with Rutherford class 4. Following is a description of some of the randomized controlled trials (RCTs) that were included in the meta-analysis.
 
In 2011, Benoit et al. reported an FDA-regulated double-blind pilot RCT of 48 patients with CLI who were randomized in a 2:1 ratio to bone marrow concentrate using the SmartPReP system or iliac crest puncture with intramuscular injection of diluted peripheral blood (Benoit, 2011). At 6-month follow-up, the difference in the percentage of amputations between the cell therapy group and controls (29.4% vs. 35.7%, respectively) did not achieve statistical significance. 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 than placebo (39.1% vs. 71.4%, respectively). Power analysis indicated that 210 patients would be needed to achieve 95% power in a planned pivotal trial.
 
Expanded Monocytes and Mesenchymal Stem Cells
Interim and final results from the industry-sponsored Phase II randomized double-blind placebo-controlled RESTORE-CLI trial, which utilized cultured and expanded monocytes and MSCs derived from bone marrow aspirate (ixmyelocel-T), were reported by Powell et al. in 2011 and 2012 (Powell, 2011; Powell, 2012). 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 difference in amputations at 12 months.
 
A 2011 study by Lu et al. was a randomized double-blind safety and feasibility study of 41 patients with bilateral diabetic CLI and foot ulcer who were injected intramuscularly with expanded bone marrow MSCs or bone marrow-derived monocytes in one limb and normal saline in the other limb (Lu, 2011). At 24 weeks after treatment, outcomes (painless walking time, ankle-brachial index, transcutaneous oxygen pressure, and magnetic resonance angiography) were significantly improved in both experimental groups compared to injection with normal saline. Outcomes on some outcome measures were modestly improved for treatment with MSCs compared to mononuclear cells. Ulcer healing at 24 weeks occurred in 100% of experimental limbs with a faster rate of healing in the MSC-treated limbs. No cell-treated limbs underwent amputation, compared to 6 of 37 control limbs.
 
Ongoing Clinical Trials
A 2012 update on clinical trials evaluating the effect of biologic therapy in patients with critical limb ischemia (CLI) describes several products that are currently in Phase II or Phase III trials (Powell, 2012). The U.S. Food and Drug Administration (FDA) recommends that the primary efficacy endpoint in a Phase III 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 (about 500) may be needed to evaluate clinical outcomes (Powell, 2012).
The design of the BONe Marrow Outcome Trial in Critical Limb Ischaemia (BONMOT-CLI) trial was reported in 2008 (Amann, 2008). It is an investigator-initiated, randomized, double-blinded, placebo-controlled multicenter study at 4 sites in Germany that assesses the therapeutic value of bone marrow cell-induced angiogenesis and arteriogenesis in severe, limb-threatening ischemia. Ninety patients with no option for revascularization or after failed revascularization will be randomized to 40 injections into the ischemic limb with a concentrate of autologous bone marrow cells or to sham bone marrow aspiration and 40 placebo injections. The combined primary endpoint is major amputation or persisting critical limb ischemia (no improvement) over 3 months. Secondary endpoints are death, changes in perfusion, quality of life, walking distance, minor amputations, wound healing, collateral density and cancer incidence. Post study follow-up is 2 years.
JUVENTAS (Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation) is a randomized, double-blind, placebo-controlled trial in the Netherlands (Sprengers, 2010). The clinical effects of repeated intra-arterial infusion of bone marrow mononuclear cells will be investigated in 110-160 patients with critical limb ischemia. Patients will receive repeated intra-arterial infusion of bone marrow-mononuclear cells or placebo into the common femoral artery. The primary outcome measure is the rate of major amputation after 6 months. Secondary endpoints include minor amputation, number and extent of leg ulcers, resolution of rest pain, perfusion, change in quality of life, and change in clinical status. Functional characteristics of the bone marrow-mononuclear cells will also be studied, and the bone marrow-mononuclear cell dysfunction will be related to clinical outcome.
A search of online site ClinicalTrials.gov in April 2013 and a 2012 review by Powell, (Powell, 2012) identified a number of ongoing trials with concentrated or expanded stem cells for peripheral arterial disease, including:
  • A manufacturer-sponsored U.S. multicenter Phase III study on the use of autologous bone marrow cells for the treatment of critical limb ischemia due to PAD. Completion of this study of ixmyelocel-T (REVIVE) is expected mid-2015 (NCT01483898).
  • A manufacturer-sponsored Phase III trial with bone marrow aspirate concentrate with the SmartPReP2® system for the treatment of critical limb ischemia (NCT01245335). This is a U.S. pivotal randomized double-blind safety and efficacy trial comparing bone marrow aspirate concentrate with placebo injection into ischemic tissue of the lower extremity in 210 patients. The study start date is listed as January 2011; the expected study completion date is June 2014.
  • A manufacturer-sponsored sham-controlled Phase III trial of Biomet Biologic’s MarrowStim P.A.D. kit™ (NCT01049919) is currently recruiting. The study has an estimated enrollment of 152 patients with completion expected May 2014.
  • A Phase I study of placenta-derived mesenchymal-like stromal cells (PLX-PAD) by Pluristem has been completed (NCT00951210) A Phase II study in patients with CLI is expected to begin in 2013. A Phase II study of PLX-PAD for the treatment of intermittent claudication (NCT01679990) is currently recruiting with a target enrollment of 150 patients and completion in December 2015.
 
2014 Update
A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2013 meta-analysis by Teraa et al. included 12 randomized controlled trials with a total of 510 patients
with critical limb ischemia (Teraa, 2013). Eight of the trials had fewer than 50 patients. Meta-analysis of all of the trials showed significant improvements with bone marrow-derived cell therapy on both subjective and objective intermediate endpoints (pain score, pain-free walking distance, ankle-brachial index, and
transcutaneous oxygen measurements) and on amputation rates (relative risk [RR] of .58). Overall, there
were 38 amputations in the experimentally-treated limbs compared to 62 amputations for control limbs.
However, when only placebo-controlled trials were included, no effect on major amputation rates was
identified (RR of .78 to .92).
 
In 2013, Poole et al reported results of a phase II double-blind, placebo-controlled study of granulocytemacrophage colony-stimulating factor (GM-CSF) in 159 patients with intermittent claudication due to peripheral arterial disease (Poole, 2013). Patients were treated with subcutaneous injections of GM-CSF or placebo 3 times a week for 4 weeks. The primary outcome, peak treadmill walking time at 3 months, increased by 109 seconds (from 296 to 405 seconds) in the GM-CSF group and by 56 seconds (from 308 to 376 seconds) in the placebo group (p=.08). Changes in the physical functioning subscore of the SF-36 and distance score of the walking impairment questionnaire (WIQ) were significantly better in patients treated with GM-CSF. However, there were no significant differences between the groups in the ankle brachial index, the WIQ distance and speed scores, claudication onset time, or mental or physical
component scores of the SF-36. Post-hoc exploratory analysis found a that patients with a greater than
100% increase in progenitor cells (CD34+/CD133+) had a significantly greater increase in peak walking
time than patients who had less than 100% increase in progenitor cells (131 seconds vs 60 seconds).
 
An ongoing and unpublished clinical trial; PROPEL (Progenitor cell release plus exercise to improve functional performance in peripheral artery disease) is a placebo-controlled trial of a combination of 12 weeks of treadmill training plus granulocytemacrophage colony stimulating factor (GM-CSF) (Domanchuk, 2013)).  A total of 240 patients will be randomized to 1 of 4 arms of the study: GM-CSF plus supervised treadmill exercise; GM-CSF plus attention control; placebo plus supervised exercise; placebo plus attention control. The primary outcome is change in distance for the six-minute walk at 12 weeks. Secondary outcomes include change in brachial artery flow-mediated dilation, change in maximal treadmill walking time, and change in circulating CD34+ cells.
 
A search of online site ClinicalTrials.gov in April 2014 and reviews by Powell in 2012 and Bartel in
2013 (Bartel, 2013) identified a number of ongoing trials with concentrated or expanded stem cells for peripheral arterial disease, including:
  • A manufacturer-sponsored U.S. multicenter Phase III study on the use of autologous expanded   bone marrow cells for the treatment of critical limb ischemia due to PAD. This study has completed enrollment of 41 patients and completion of this study of ixmyelocel-T (REVIVE) is expected mid-2015 (NCT01483898). This study was last verified in July 2013.
  • A manufacturer-sponsored Phase III trial with bone marrow aspirate concentrate with the SmartPReP2® system for the treatment of critical limb ischemia (NCT01245335). This is a U.S. pivotal randomized double-blind safety and efficacy trial comparing bone marrow aspirate concentrate with placebo injection into ischemic tissue of the lower extremity in 210 patients. The study start date is listed as January 2011; the expected study completion date is June 2014
November 2016.
  • A manufacturer-sponsored sham-controlled Phase III trial of Biomet Biologic’s MarrowStim P.A.D. kit™ (NCT01049919) is currently recruiting. The study has an estimated enrollment of 152 patients with completion expected May 2014 2015.
  • A Phase I study of placenta-derived mesenchymal-like stromal cells (PLX-PAD) by Pluristem has been completed (NCT00951210). The study had an enrollment of 12, the results have not been posted. A Phase II study in patients with CLI is expected to begin in 2013. A Phase II study of PLX-PAD for the treatment of intermittent claudication (NCT01679990) is currently recruiting with a target enrollment of 150 patients and completion in December 2015.
 
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
A 2011 Cochrane review, updated in 2014, identified 2 small studies with a total of 57 patients that met the review’s inclusion criteria for local intramuscular transplantation of autologous mononuclear cells (monocytes) for critical limb ischemia (CLI) (Moazzami, 2011; 2014).  Studies were excluded that used mesenchymal stem cells (MSCs) or bone marrow aspirate. In one of the studies, intramuscular injection of bone marrow-derived mononuclear cells (BM-MNCs) was compared with standard conservative treatment. In the second study, peripheral blood-derived mononuclear cells were collected following injections of granulocyte-macrophage colony-stimulating factor (GM-CSF) and transplanted by intramuscular injections. Both studies showed a significant reduction in amputations with treatment with monocytes, but larger randomized controlled trials (RCTs) are needed to adequately evaluate the effect of treatment with greater certainty. No additional studies were found for the 2014 update of this systematic review.
 
Intra-Arterial Injection
JUVENTAS (Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial
Supplementation) is a randomized double-blind, placebo-controlled trial from Europe (NCT00371371) (Teraa, 2015). This foundation-supported trial evaluated the clinical effects of repeated intra-arterial infusion of BMMNCs in 160 patients with non-revascularizable critical limb ischemia. Patients received repeated intraarterial infusion of BM-MNCs or placebo (autologous peripheral blood erythrocytes) into the common femoral artery. The primary outcome measure, the rate of major amputation after 6 months, was not significantly different between the two groups (19% for BM-MNCs vs 13% controls). Secondary outcomes of quality of life, rest pain, ABI, and transcutaneous oxygen pressure improved to a similar extent in both groups, reinforcing the need for a placebo control in this type of trial.
 
Practice Guidelines and Position Statements
The European Society of Cardiology published 2011 guidelines on the diagnosis and treatment of PADs (Tendera, 2011). The guidelines did not recommend for or against stem cell therapy for PAD. The guidelines provided the following information: Stem cell and gene therapy for revascularization is a novel therapy that is currently being evaluated to stimulate neovascularization. For autologous cell transplantation, bone marrow and peripheral blood are rich sources of stem and progenitor cells. At this time, it is unclear which of the many different cell types is the most promising. At present, angiogenic gene and stem cell therapy are still being investigated, and it is too early to make firm recommendations.
   
2016 Update
A literature search conducted through April 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2015, Peeters Weem and colleagues reported a meta-analysis of 10 double-blind placebo-controlled RCTs on bone marrow-derived cell therapy in CLI (Peeters Weem, 2015). There were a total of 499 patients included in the metaanalysis, with a range of 10-160 patients per study. The studies varied in the route of administration (2 intra-arterial and 8 intramuscular) and in the cell type used (BM-MNCs, MSCs, Ixmyocel-T, CD34+ cells or CD133+ cells). Many of the studies were considered to be pilot or phase 2 studies and were rated as low study quality. Meta-analysis found no significant differences between the experimental and control groups for the primary outcomes of major amputation rate (relative risk [RR]: 0.91), survival (RR: 100), or amputation free survival (RR:1.03). There were modest improvements compared to placebo in the ankle brachial index, transcutaneous oxygen, and pain score, with a mean decrease of 1.3 in the cell therapy group and 0.6 in the controls. There was no difference between the percentage of healed ulcers.
 
Skora and colleagues reported on an intramuscular injection with a combination BM-MNCs and gene therapy with a vascular endothelial growth factor (VEGF) plasmid was tested in a European RCT with 32 patients (Skora, 2015). Controls in this study were treated pharmacologically and were 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 included the ankle-brachial index, development of collateral vessels measured with angiography, and healing of ischemic ulcers. Amputations were performed in 25% of patients in the BM-MNC group and 50% of patients in the control group.
 
2018 Update
A literature search was conducted through June 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
American Heart Association and American College of Cardiology
The 2016 guidelines from the American Heart Association and 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 (CLI), (AHA and ACC, 2017). Stem cell therapy for PAD was not addressed.
 
European Society of Cardiology
The 2011 European Society of Cardiology guidelines on the diagnosis and treatment of PAD did not recommend for or against stem cell therapy for PAD. 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), (ESC, 2017).

CPT/HCPCS:
0263TIntramuscular 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
0264TIntramuscular 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
0265TIntramuscular 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

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Amann B, Ludemann C, Ruckert R et al.(2008) Design and rationale of a randomized, double-blind, placebo-controlled phase III study for autologous bone marrow cell transplantation in critical limb ischemia: the BONe Marrow Outcomes Trial in Critical Limb Ischemia (BONMOT-CLI). Vasa 2008; 37(4):319-25.

Amann B, Luedemann C, Ratei R et al.(2009) Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease. Cell Transplant 2009; 18(3):371-80.

Bartel RL, Booth E, Cramer C et al.(2013) 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.

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Domanchuk K, Ferrucci L, Guralnik JM et al.(2013) Progenitor cell release plus exercise to improve functional performance in peripheral artery disease: the PROPEL Study. Contemp Clin Trials 2013; 36(2):502-9.

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Jonsson TB, Larzon T, Arfvidsson B et al.(2012) Adverse events during treatment of critical limb ischemia with autologous peripheral blood mononuclear cell implant. Int Angiology 2012; 31(1):77-84.

Lawall H, Bramlage P, Amann B.(2011) Treatment of peripheral arterial disease using stem and progenitor cell therapy. J Vasc Surg 2011; 53(2):445-53.

Liu FP, Dong JJ, Sun SJ et al.(2012) 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.

Lu D, Chen B, Liang Z et al.(2011) Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract 2011; 92(1):26-36.

Matoba S, Tatsumi T, Murohara T et al.(2008) Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (Therapeutic Angiogenesis by Cell Transplantation [TACT] trial) in patients with chronic limb ischemia. Am Heart J 2008; 156(5):1010-8.

Moazzami K, Majdzadeh R, Nedjat S.(2011) Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia. Cochrane Database Syst Rev 2011; (12):CD008347.

Moazzami K, Moazzami B, Roohi A, et al.(2014) Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia. Cochrane Database Syst Rev. 2014;12:CD008347. PMID 25525690

Peeters Weem SM, Teraa M, de Borst GJ, et al.(2015) Bone Marrow derived Cell Therapy in Critical Limb Ischemia: A Meta-analysis of Randomized Placebo Controlled Trials. Eur J Vasc Endovasc Surg. Oct 9 2015. PMID 26460286

Peeters Weem SM, Teraa M, den Ruijter HM, et al.(2015) Quality of Life After Treatment with Autologous Bone Marrow Derived Cells in No Option Severe Limb Ischemia. Eur J Vasc Endovasc Surg. Oct 26 2015. PMID 26511056

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

Poole J, Mavromatis K, Binongo JN et al.(2013) 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.

Powell RJ, Comerota AJ, Berceli SA et al.(2011) 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 2011; 54(4):1032-41.

Powell RJ, Marston WA, Berceli SA et al.(2012) Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial. Mol Ther 2012; 20(6):1280-6.

Powell RJ.(2012) Update on clinical trials evaluating the effect of biologic therapy in patients with critical limb ischemia. J Vasc Surg 2012; 56(1):264-6.

Prochazka V, Gumulec J, Jaluvka F et al.(2010) Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer. Cell Transplant 2010; 19(11):1413-24.

Prochazka V, Gumulec J, Jaluvka F et al.(2010) Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer. Cell Transplantation 2010; 19(11):1413-24.

Skora J, Pupka A, Janczak D, et al.(2015) 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

Sprengers RW, Moll FL, Teraa M et al.(2010) Rationale and design of the JUVENTAS trial for repeated intra-arterial infusion of autologous bone marrow-derived mononuclear cells in patients with critical limb ischemia. J Vasc Surg 2010; 51(6):1564-8.

Tateishi-Yuyama E, Matsubara H, Murohara T et al.(2002) Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002; 360(9331):427-35.

Tendera M, Aboyans V, Bartelink M, et al.(2011) ESC Guidelines on the Diagnosis and Treatment of Peripheral Artery Diseases. Eur Heart J. 2011; 32(22):2851-2906. PMID 21873417

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Teraa M, Sprengers RW, van der Graaf Y et al.(2013) Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials. Ann Surg 2013; 258(6):922-9.

Teraa M, Sprengers RW, van der Graaf Y et al.(2013) Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials. Ann Surg 2013; 258(6):922-9.

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Walter DH, Krankenberg H, Balzer JO et al.(2011) 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.


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