Medical Policy

This document addresses the use of various autologous cells, collectively known as autologous cell therapy (ACT), for the treatment of damaged myocardium. Sources for autologous cells include, but are not limited to, skeletal myoblasts, endothelial progenitor cells (EPCs), bone marrow mononuclear cells (BMMC), and mesenchymal or hematopoietic stem cells.  

Note: For information on a related topic see:

• MED.00110 Silver-based Products and Autologous Skin-, Blood- or Bone Marrow-derived Products for Wound and Soft Tissue Applications

Investigational and Not Medically Necessary:

Autologous cell therapy, including, but not limited to, skeletal myoblasts, mesenchymal stem cells or hematopoietic stem cells, is considered investigational and not medically necessary as a treatment of damaged myocardium.

The use of various cell types, such as hematopoietic stem cells, BMMC, skeletal myoblasts, mesenchymal stem cells (MSC), and circulating or bone marrow-derived EPCs are currently being evaluated in clinical trials utilizing various delivery techniques to revascularize or remodel injured myocardial (heart) tissue. The optimal cell type that can develop into functioning cardiac muscle has yet to be identified. There is also uncertainty regarding the timing of the transplantation post-infarct and the cell delivery mode (directly into myocardium, intracoronary artery or sinus, or intravenously). Additionally, there are concerns related to harvesting autologous cells safely during the immediate post-infarct period. Skeletal myoblasts may offer a unique advantage because they are easy to access through a muscle biopsy. However, the harvested tissue must undergo culture to expand the number of skeletal myoblasts. In some trials, biopsy to obtain skeletal myoblasts must occur 3 to 6 weeks before the anticipated implantation of the cultured cells.

At this time, no ACT technologies specific to the treatment of damaged myocardium have received United States (U.S.) Food and Drug Administration (FDA) approval. While FDA approval is not required for autologous cells processed on site with established laboratory procedures and injected with existing catheter devices, specialized technologies do require FDA approval. The 21st Century Cures Act (2016) established new expedited product development programs, including the regenerative medicine advanced therapy (RMAT) designation. 

According to the FDA, a drug is eligible for the RMAT designation if:

• The drug is a regenerative medicine therapy (that is, cell therapy), therapeutic tissue engineering product, human cell and tissue product, or any combination product; AND
• The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; AND
• Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition (FDA, 2020).

There are several products under investigation for the treatment of damaged myocardium. MyoCell^® (U.S. Stem Cell, Inc., Sunrise, FL) consists of autologous skeletal myoblasts that are expanded and supplied as a cell suspension for injection into the damaged myocardial area. According to the manufacturer, phase II and III trials of MyoCell are underway. Notably, in 2017 the manufacturer terminated its RMAT application for the MyoCell product. Additional progenitor cell products are being commercially developed, including the Ixmyelocel-T (Vericel Corp., Cambridge, MA), MultiStem^® (Athersys Inc., Cleveland, OH) and the CardiAMP^™ (BioCardia^® Inc., San Carlos, CA). In 2017, the manufacturer of the Ixmyelocel-T product obtained the RMAT designation for treatment of advanced heart failure (HF) due to ischemic dilated cardiomyopathy (DCM). This autologous product is produced from the individual’s own bone marrow by selectively expanding bone marrow mononuclear cells. The MultiStem is an allogeneic bone marrow-derived adult stem cell product and, as such, is not addressed in this document. The CardiAMP Cell Therapy system includes a proprietary cell processing system, to isolate, process and concentrate autologous stem cells from the bone marrow and a proprietary delivery system to percutaneously inject the cells directly into the myocardium. The manufacturer of the CardiAMP system has obtained an investigational device exemption (IDE) from the FDA for investigational use only.

Specialized catheters to inject cells directly into the heart tissue, (such as the MyoCath^™ [Bioheart, Inc., Ft. Lauderdale, FL]), are also under investigation for FDA approval. Bioheart, Inc. is currently conducting clinical trials, as part of the FDA approval process. The trials are evaluating individuals with a previous myocardial infarction (MI) who undergo epicardial implantation of the cultured myoblasts at the time of coronary artery bypass grafting and individuals with a prior MI and subsequent HF, who undergo subendocardial implantation using the MyoCath device during a catheterization procedure. All participants must receive an implantable cardiac defibrillator (ICD), based on preliminary data suggesting that the implanted myoblasts may be arrhythmogenic (cause irregular heartbeats).  

The existing evidence on the use of stem cells to treat chronic ischemic heart disease, HF and acute myocardial infarction (AMI) was evaluated in two Cochrane reviews. In the review of chronic ischemic heart disease and HF, there is low quality evidence that stem cell treatment improves left ventricular ejection fraction (LVEF) or reduces mortality in the short term, or that therapy reduces the incidence of non-fatal MI or improves New York Heart Association (NYHA) functional status in the long term (Fisher, 2016). In AMI, a total of 41 randomized controlled trials (RCTs) with 2732 individuals were included in the review. The authors noted there was no clinically relevant improvement in morbidity, quality of life/performance or LVEF reported with ACT over controls. The authors summarized that the evidence was insufficient to allow for any conclusions to be drawn and that further adequately powered trials are needed (Fisher, 2015).

Heldman (2014) conducted an RCT (phase I and II) to evaluate the safety of transendocardial stem cell injection with autologous MSCs and bone marrow mononuclear cells (BMCs) in 65 individuals with ischemic cardiomyopathy (CM) and LVEF of less than 50%. Study investigators compared MSCs (n=19) with the placebo group (n=11), and BMCs (n=19) with the placebo group (n=10). Participants were followed for a period of 1 year. No participants experienced treatment-associated serious adverse events when evaluated at 30 days. At 1 year, the rate of adverse events was 31.6% (95% confidence interval [CI]; 12.6% to 56.6%) for MSCs, 31.6% (95% CI; 12.6%-56.6%) for BMCs, and 38.1% (95% CI; 18.1%-61.6%) for placebo. At 1 year follow-up, the Minnesota Living With Heart Failure scores significantly improved in individuals treated with MSCs (-6.3; 95% CI; -15.0 to 2.4; p=0.02) and with BMCs (-8.2; 95% CI; -17.4 to 0.97; p=0.005), but not in individuals in the placebo group (0.4; 95% CI; -9.45 to 10.25; p=0.38). Additionally, the 6-minute walk distance increased with MSCs only (p=0.03). No changes were observed in left ventricular chamber volume and LVEF. Results suggested that transendocardial stem cell injection with MSCs or BMCs appeared to have a relatively good safety profile in individuals with chronic ischemic CM and left ventricular (LV) dysfunction. Study authors emphasized that the study was hampered by several limitations including small sample size, and no definitive conclusions regarding the safety and clinical effects can be made. Larger, well-designed studies are necessary to further assess the safety and efficacy of this therapeutic approach. 

Lee (2014) conducted a pilot RCT to evaluate the safety and efficacy of adult MSC treatment following AMI. Participants were randomized to the group treated with autologous BM-derived MSCs at 1 month (n=33) or the control group (n=36). The primary endpoint was any change in LVEF assessed at 6 months. Individuals in the BM-derived MSC treatment group experienced significant improvement in the LVEF at 6 months compared with the control group (p=0.037). There was no incidence of toxicity during intracoronary administration of MSCs, and no significant adverse cardiovascular events were observed during follow-up. Study authors concluded that intracoronary infusion of human BM-derived MSCs at 1 month was relatively safe, well-tolerated, and resulted in fair improvement in LVEF, when assessed at 6 months of follow-up.

Assmus and colleagues (2002) reported on the results of the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) study. This study included 20 individuals who had already undergone revascularization after an AMI and received either BMCs or circulating blood-derived progenitor cells infused into the infarct artery during a second catheterization procedure. Cardiac function was evaluated before and after the transplantation procedure. After 4 months, the authors reported an improvement in LVEF, regional wall motion, and LV end diastolic volume (LVEDV). Subjects in this same study were evaluated in a subsequent analysis to identify predictors of clinical outcomes after AMI following treatment with BMCs or circulating blood-derived progenitor cells (Assmus, 2014). Subjects were followed for a mean period of 58 months. Seven subjects in the BMC group versus 15 subjects in the placebo group died (p=0.08) and 5 BMC subjects versus 9 placebo subjects required rehospitalization for instent restenosis of the infarct vessel (p=0.023). Univariate analysis demonstrated that the predictors of adverse events in the placebo group were age, the CADILLAC risk score, treatment with aldosterone antagonists and diuretics, changes in LVEF, LV end-systolic volume (LVESV), and N-terminal pro-Brain Natriuretic Peptide (p=0.01 for all) at 4 months in all subjects, as well as the placebo group. However, in the treatment group, only two outcomes were associated with significant improvements.

Mathiasen (2013) evaluated the long-term safety and efficacy of intramyocardial injection of autologous bone-marrow derived mesenchymal stromal cells (BMMSCs) in individuals with severe but stable coronary artery disease (CAD) and refractory angina (n=31) over a follow-up period of 3 years. Subjects had no additional revascularization options available to them. Investigators injected BMMSCs into an ischemic region of the heart. Study results demonstrated statistically significant improvements in total exercise time (p=0.0016), angina class (p<0.0001), the weekly occurrence of angina attacks (p<0.0001), and treatment with nitroglycerine (p=0.0017). In terms of the Seattle Angina Questionnaire, participants experienced significant improvements in several measures, including the physical limitation score, angina stability score, angina frequency score, and quality of life (QOL) score (p<0.0001 for each measure). Results also demonstrated significantly reduced hospital admissions for the following conditions:  stable angina (p<0.0001), revascularization (p=0.003) and overall cardiovascular disease (p<0.0001).

Results from the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) prospective, multi-center, blinded, RCT were reported by Bartunek and colleagues (2013). The primary endpoint of the study was feasibility and safety of autologous BM-derived cardiopoietic stem cell therapy at 2 years follow-up. A total of 319 individuals with chronic ischemic HF were screened at 9 centers, and 47 individuals were randomized to receive standard of care or standard of care plus BM-derived cardiopoietic stem cell therapy. In the cell therapy arm, bone marrow was harvested and MSCs were isolated and expanded by exposure to cardiogenic cocktail treatments. The cardiopoietic MSCs were injected endoventricularly with guidance from electromechanical mapping of the participants’ hearts. Cardiopoietic stem cell expansion successfully met pre-determined criteria for 75% (n=21 individuals) and successful delivery occurred for all cases transplanted. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic MSC therapy. The LVEF at 6 months was improved for the cardiopoietic MSC treatment group with a 7% increase from 27.5% (95% CI; 25.5% to 29.5%) at baseline to 34.5% (95% CI; 32.5% to 36.6%) (n=21, p<0.0001). LVEF was unchanged in the control group (n=15) from baseline 27.8% (95% CI; 25.8% to 29.8%) to 28.0% (95% CI; 26.1% to 30.6%) at 6 months. Other indicators, including the 6-minute walk test and composite scores such as QOL, cardiac function, and clinical endpoints improved with cell therapy, compared with standard of care. The study authors concluded the trial was not powered as a therapeutic efficacy trial. A full 30% of the participants, for whom adequate cells could not be obtained, were dropped from the analysis. Comparative effectiveness trials will be required to determine if cardiopoietic MSC therapy is an effective regenerative strategy for management of HF.

Duckers and colleagues (2011) reported results from the SEISMIC study, a phase IIa RCT of percutaneous myoblasts placed, along with ICD, in individuals with HF. A total of 26 individuals were randomized to the treatment group that involved ICD and myoblasts, and 14 participants were randomized to the control group that involved optimal medical treatment. The trial was designed to examine the safety and feasibility of the MyoCell transplantation procedure. There was no significant difference in the global LVEF at 6 months follow-up. There were no significant differences between the treatment and control groups with regard to the NYHA classification and 6-minute walk test results. The study authors concluded the data demonstrated the feasibility of myoblast implantation, but the results were not superior to standard optimal medical treatment and ICD placement.

LateTIME, a phase II randomized, double-blind, placebo-controlled trial, investigated the impact of intracoronary infusion of autologous BMC in individuals with LVEF less than or equal to 45% after percutaneous stent placement (Traverse, 2011). A group of 87 participants were randomized to BMC infusion or placebo. BMC treatment was provided 2 to 3 weeks after the initial MI and primary study endpoints were improvement in global and regional LV function. The mean LVEF change from baseline to 6 months was not different in the BMC treatment group (48.7% to 49.2%), compared with the placebo group (45.3% to 48.8%). The authors concluded that delivery of BMC 2 to 3 weeks following MI is not effective.

In a companion trial to the LateTIME, the TIME trial prospectively evaluated the effect of BMC therapy during the first week after stenting with primary percutaneous coronary intervention (PCI). The double-blind, placebo-controlled trial randomized 120 participants (LVEF ≤ 45% after PCI) to BMC therapy at day 3 or day 7 (Traverse, 2012). All participants had autologous BMCs isolated after undergoing bone marrow aspiration. A second randomization assigned individuals to receive 150 x 10⁶ total nucleated cells (70-80% of BMCs) or to placebo. Infusions of BMCs or placebo were administered in the infarct-related artery within 12 hours of aspiration. Change from baseline and at 6 months in global LVEF and regional LV function measured by MRI, were the primary endpoints. At 6 months, there was no significant BMC treatment versus placebo effect demonstrated by improved LVEF.  

Similarly, the FOCUS-CCTRN (First Mononuclear Cells injected in the United States conducted by the CCTRN [Cardiovascular Cell Therapy Research Network]), a phase II randomized, double-blind, placebo-controlled trial investigated the safety and efficacy of transendocardial-delivered BMCs in participants with chronic ischemic heart disease and LV dysfunction with HF and/or angina (Perin, 2012). The primary endpoints evaluated at 6 months included changes to the LVESV on echocardiography, maximal oxygen consumption, and reversibility on single photon emission tomography (SPECT). There were no statistically significant differences between BMC versus placebo for all of the primary endpoints (Perin, 2012). 

A meta-analysis by Gyöngyösi and colleagues (2015) studied the individual data of 1252 participants from 12 RCTs involving intracoronary cell therapy after AMI. The overall results of the analysis of the primary end-point, freedom from major adverse cardiac and cerebrovascular events (MACCE), was found to be highly consistent, in direction and magnitude, with the results of the within-trial analysis. The results showed there was no significant difference between the MACCE rates of those who received cell therapy versus those in the control groups (14.0% versus 16.3%; hazard ratio [HR], 0.86; 95% CI; 0.63–1.18; p=0.884). In addition, there were no significant differences in the death rate, LVEF, LVEDV or LVESV between the groups. Previous meta-analyses have reported inconsistent results; some meta-analyses reported a benefit in those receiving cell therapy while other meta-analyses did not report a benefit. The authors noted that, while previous meta-analyses used information from published articles resulting in data heterogeneity, this study used individual participant data in their analysis.

San Roman and colleagues (2015) conducted a four-arm multicenter, prospective, randomized, open-labeled trial comparing the efficacy of BMMC (n=30), G-CSF mobilization (n=30) and both therapies (n=29) to standard therapy (n=31) in AMI. Following infarct-related artery revascularization, individuals received treatment based on the regimen assigned to each treatment group. The primary endpoint was the absolute change (baseline to 12 months) in global LVEF and in LVESV. At 12 months follow-up, there was no improvement in LVEF in any of the treatment arms, compared to the control, and MACE were not significantly different between the groups. The reported 4% overall improvement in LVEF was comparable to improvements reported in contemporary randomized reperfusion trials with a similar testing population.

Description of Coronary Heart Disease (CHD)

The American Heart Association (AHA) Statistics Committee and Stroke Statistics Subcommittee (Mozaffarian, 2016) reported an estimated 85.6 million adults in the U.S. suffer from one or more types of coronary vascular disease (CVD). Of these, 15.5 million have coronary heart disease (CHD), which includes MI (heart attack), angina (chest pain), HF, stroke and congenital cardiovascular defects. CHD occurs when the flow of blood through one or more of the coronary arteries becomes inadequate. This results in oxygen deprivation in the heart muscle, and may eventually result in heart attack or even death. CVD is the most common cause of death compared to other major causes of death in the U.S.

Description of Technologies

From a basic science viewpoint, it must be shown that autologous cells, when transplanted into the heart, can (1) truly regenerate myocardium by incorporating themselves into the native tissue, surviving, differentiating, and ultimately electromechanically coupling to each other, or (2) serve as a trophic factor leading to survival of injured myocardial tissue and improved cardiac function through tissue preservation and ventricular remodeling. For example, preliminary studies have suggested that transplanted myoblasts are potentially capable of producing disorderly or irregular heart rhythms.  

ACT for the treatment of damaged heart muscle involves the transplantation of various types of cells into a damaged heart with the goal of replacing damaged heart muscle or to assist in the healing process. Various types of ACT have been researched to either stimulate regeneration of the heart muscle or modify ventricular remodeling post-infarct. For example, it is thought that after an MI an increased number of hematopoietic stem cells are released into the circulation and then engrafted into the heart.  

In humans, skeletal myoblasts, harvested from a muscle biopsy, or hematopoietic stem cells, harvested from the bone marrow or peripheral blood, or mesenchymal stem cells, harvested from the bone marrow have also been investigated as cell sources for ACT. The harvested cells can be transplanted in a variety of ways, frequently as an adjunct to coronary artery bypass surgery; for example, either by injecting directly into the nonfunctional heart muscle, or injecting into a coronary artery or coronary sinus. It is thought that through the release of chemokines released by the heart, circulating hematopoietic stem cells might have a natural homing ability to reach damaged myocardium.

The proposed benefits of ACT for the treatment of damaged myocardium are improved heart function, restored myocardial viability and potentially extended lifespan. However, several of the published clinical trials report physiological measures as intermediate outcomes; hence, it is uncertain how this technology may improve net health outcomes. In addition, there are known risks related to the various methods utilized to harvest and transplant autologous cells, including pain, hemorrhage, cardiac arrest, and death.

Autologous cell therapy (ACT): A medical treatment involving the transplantation of various types of cells harvested from the individual and then returned to them in a unique manner. This treatment may involve one or several types of cells and has been proposed for a wide variety of conditions.

Hematopoietic stem cells: A type of cell from which blood cells are created.

Mesenchymal stem cells: A type of bone marrow derived cell from which muscles are created. It is a term that is currently used to define non-blood adult stem cells from a variety of tissues, although it is not clear that mesenchymal stem cells from different tissues are the same.

Myocardium: The medical term for the heart muscle.

Progenitor cells: Primitive cells capable of replication, differentiation and formation into mature cells.

Remodeling: The overstretching of viable cardiac cells to maintain cardiac output.

Skeletal myoblasts: A type of cell from which skeletal muscle fibers are created.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
For the following procedure and diagnosis codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary:

Peer Reviewed Publications:

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39. Naseri MH, Madani H, Ahmadi Tafti SH, et al. COMPARE CPM-RMI Trial: intramyocardial transplantation of autologous bone marrow-derived CD133+ cells and MNCs during CABG in patients with recent MI: A phase II/III, multicenter, placebo controlled, randomized, double-blind clinical trial. Cell J. 2018; 20(2):267-277.
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49. Sawa Y, Yoshikawa Y, Toda K, et al. Safety and efficacy of autologous skeletal myoblast sheets (TCD-51073) for the treatment of severe chronic heart failure due to ischemic heart disease. Circ J. 2015; 79(5):991-999.
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3. National Heart, Lung, and Blood Institute. What is Coronary Artery Disease? June 22, 2016. Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/Cad/CAD_WhatIs.html. Accessed on September 25, 2020.

Autologous Cell Therapy or Transplant (ACT)
CardiAMP
Cellular Cardiomyoplasty
Intracardiac Cell Infusion
Ixmyelocel-T
Myocardial Regeneration
MultiStem
Myocath
Myocell

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.