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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 thromboangitis 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. Arteriogeneis 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) or other 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 stem-cell/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 granulocyte-macrophage colony-stimulating factor to mobilize peripheral blood mononuclear cells. There is some discrepancy in the literature regarding the nomenclature of cell types. Studies addressed in this policy include the use of mononuclear cells/monocytes and/or mesenchymal stem cells.
The primary outcome in stem-cell therapy trials regulated by the U.S. Food and Drug Administration (FDA) is amputation-free survival. Other 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 > 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:
Ixmyelocel-T (Aastrom Biosciences now Vericel Corp.) 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 Therapeutics 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.
Related medical policies are as follows:
POLICYTreatment of peripheral arterial disease, including critical limb ischemia, with injection or infusion of cells concentrated from bone marrow aspirate is considered investigational.
POLICY GUIDELINESInvestigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY07/21/2011: Approved by Medical Policy Advisory Committee
07/17/2012: Policy reviewed; no changes.
08/14/2013: Policy reviewed; no changes.
06/16/2014: Policy reviewed; description updated regarding devices. Policy statement unchanged.
07/23/2015: Code Reference section updated for ICD-10.
10/16/2015: Policy reviewed; description updated. No change in policy statement. Updated investigative definition in the policy guidelines section.
SOURCE(S)Blue Cross Blue Shield Association policy # 8.01.55
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.