Medical Policy



Subject: Autologous Cell Therapy for the Treatment of Damaged Myocardium
Document #: MED.00117 Current Effective Date:    10/01/2017
Status: Reviewed Last Review Date:    02/02/2017

Description/Scope

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.  Other techniques of ACT involve the use of granulocyte colony stimulating factor (GCSF) to increase the volume of circulating hematopoietic stem cells to treat damaged myocardial tissue.

Position Statement

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.

Infusion of growth factors (for example, granulocyte colony stimulating factor [GCSF]) is considered investigational and not medically necessary as a technique to increase the numbers of circulating hematopoietic stem cells as treatment of damaged myocardium.

Rationale

The use of various cell types such as hematopoietic stem cells, BMMC, skeletal myoblasts, mesenchymal stem cells, 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) Premarket approval (PMA).  While FDA approval is not required for autologous cells processed on site with laboratory procedures and injected with catheter devices, specialized technologies do require FDA approval.  There are several products under investigation for the treatment of damaged myocardium.  MyoCell™ (Bioheart, Inc., Ft. Lauderdale, FL) consists of autologous skeletal myoblasts that are expanded in a laboratory and supplied as a cell suspension for injection into the damaged myocardial area.  AdipoCell™ (Bioheart, Inc., Ft. Lauderdale, FL) consists of stem cells obtained from the individual's adipose tissue and then subsequently infused into the damaged myocardium.  In addition, infusion or implantation of the manipulated autologous cell therapies may require the use of a unique catheter delivery system.  Specialized catheters to inject cells directly into the heart tissue (such as, 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 who undergo epicardial implantation of the cultured myoblasts at the time of coronary artery bypass grafting, and individuals with a prior myocardial infarction and subsequent congestive heart failure, 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). MultiStem® (Athersys, Inc., Cleveland, OH) an allogeneic bone marrow-derived adult stem cell product, which is injected into the outer layer of the affected vessels of an individual with a first time STEMI, is undergoing Phase 2 studies.  

The existing evidence on the use of stem cells to treat chronic ischemic heart disease, heart failure and acute myocardial infarction (AMI ) was evaluated in two Cochrane reviews.  In the review of chronic ischemic heart disease and heart failure, 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 myocardial infarction 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 2,732 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 a RCT (phase I and II) to evaluate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in 65 individuals with ischemic cardiomyopathy 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.  Furthermore, 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 ejection fraction.  Results suggested that transendocardial stem cell injection with MSCs or BMCs appeared to have a relatively good safety profile in individuals with chronic ischemic cardiomyopathy and left ventricular 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 randomized, pilot RCT to evaluate the safety and efficacy of adult mesenchymal stem cell 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 MSCs 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 acute myocardial infarction (MI) and received either bone marrow-derived cells 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 ejection fraction, regional wall motion, and left ventricular end diastolic volume.  Subjects in this same study were evaluated in a subsequent analysis to identify predictors of clinical outcomes after AMI following treatment with bone marrow-derived cells 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 CHR (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, left ventricular end-systolic volume, 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, randomized trial 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 heart failure 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 cell therapy.  The LVEF at 6 months was improved for the cardiopoietic cell 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 quality of life (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 stem cell therapy is an effective regenerative strategy for management of heart failure.

Duckers and colleagues (2011) reported results from the SEISMIC study, a phase IIa randomized study of percutaneous myoblasts placed along with ICD in individuals with heart failure.  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 New York Heart Failure (NYHF) 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 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 left ventricular 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, 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 heart failure and/or angina (Perin, 2012).  The primary endpoints evaluated at 6 months included changes to the left ventricular end-systolic volume (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. 

A meta-analysis by Gyöngyösi and colleagues (2015) studied the individual data of 1252 participants from 12 randomized trials 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, 0.86; 95% CI, 0.63–1.18; p=0.884).  In addition, there were no significant differences in the death rate, the ejection fraction, end-diastolic volume or systolic volume between the groups.  Previous meta-analyses have reported inconsistent results, some meta-analyses reported a benefit in those receiving cell therapy studies 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 LV end-systolic volume (LVESV).  At 12 months follow-up, there was no improvement in LVEF in any of the treatment arms compared to the control.  Major adverse cardiac events 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.

GCSF Therapies

The use of GCSF has been proposed as an adjunct to standard therapies to promote mobilization of stem cells and progenitor cells from the bone marrow into the circulating blood to improve repair of the damaged myocardium.  The benefits of GCSF in other fields, such as oncology, has led to research assessing the potential of GCSF in repairing myocardial tissue and improving clinical outcomes in those with damaged hearts. The results have been less than promising.

Zohnlnhöfer and colleagues (2008) reported results of a meta-analysis of 445 participants in 10 trials involving the use of GCSF stem cell mobilization after an AMI. The authors concluded the use of GCSF was safe, but infarct size was not reduced, and LVEF function was not improved.  A second meta-analysis of 6 controlled trials with 160 participants showed that treatment of AMI with GCSF did not show any significant improvement when compared to standard therapies with PCI (Fan, 2008). Some studies have reported negative findings, such as higher rate of restenosis or decreased LEVF in those receiving GCSF (Hibbert, 2014; Kang, 2004).  A Cochrane review by Moazzami and colleagues (2013) which included 7 trials and 354 individuals, reported that based on limited evidence obtained from small trials, there was a lack of benefit associated with the use of GCSF in the treatment of AMI.  Larger, quality studies are needed to evaluate potential clinical efficacy and therapy-related adverse events.

A recent double-blind, randomized placebo-controlled trial by Brenner and colleagues (2015) evaluated the use of G-CSF and Sitagliptin (GS) to placebo following AMI and successful revascularization in 174 individuals.  Individuals received the GCSF or placebo over a 5-day period and Sitagliptin or placebo over 28 days.  The absolute change in the global LVEF and RVEF between baseline (2 to 6 days post PCI) and 6 month follow-up was designated as the primary outcome.  In the intention-to-treat analysis, there was no difference in the change in the LVEF (-0.846%; 95% CI, -3.160 to 1.468; p=0.471) or in the change in the RVEF (0.298%, 95% CI, -1.315 to 1.910; p=0.716) between the treatment and control groups.  In addition, the study did not report any positive effects in the secondary clinical outcomes including regional myocardial contraction, infarct volumes and perfusion.

There are ongoing clinical trials evaluating the optimal cell types, various delivery modes, and long-term safety and effectiveness of ACT and GCSF as adjunctive therapy.  However, the current medical evidence is insufficient to allow any conclusions regarding the use of this therapy.

Background/Overview

Description of Coronary Heart Disease (CHD)

The American Heart Association (AHA) Statistics Committee and Stroke Statistics Subcommittee (Mozaffarian, 2015) 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 myocardial infarction ([MI], or heart attack) angina (chest pain), heart failure, 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.  While these stem cells do not normally result in effective myocardial regeneration, it is theorized that enhancement of this process through a form of ACT, medical augmentation of stem cell production with GCSF might result in improved cardiac regeneration or remodeling.

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.

Another method of ACT involves the infusion of growth factors, such as GCSF, with the intention of increasing the concentration of circulating hematopoietic stem cells as a treatment of damaged myocardium and enhancing recovery of the left ventricle.  GCSF is thought to also have pro-inflammatory and thrombotic effects due to its activation of neutrophils which can result in in-stent restenosis and acute coronary syndrome.  The results of some studies have raised safety concerns about the use of GCSF in individuals with acute coronary syndrome. GCSF use has been evaluated as a stand along therapy as well as an adjunctive therapy with ACT therapy.

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.

Definitions

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.

Growth factors: A group of substances produced by the body that stimulate the survival, proliferation, differentiation and function of specific cells or tissues in the body. One example is granulocyte colony stimulating factor (GCSF), which stimulates the production of a certain type of white blood cell.

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.

Coding

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: 

CPT  
20200 Biopsy, muscle; superficial
20205 Biopsy, muscle; deep
20206 Biopsy, muscle; percutaneous needle
33999 Unlisted procedure, cardiac surgery [when specified as autologous cell therapy for damaged myocardium, including harvesting and preparation of cells]
   
HCPCS  
J1442 Injection, filgrastim (G-CSF), excludes biosimilars, 1 microgram
   
ICD-10 Diagnosis  
I21.01-I21.A9 Acute myocardial infarction
I22.0-I22.9 Subsequent ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction
I23.0-I23.8 Certain current complications following ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction (within the 28 day period)
I24.0-I24.9 Other acute ischemic heart disease
I25.10- I25.119 Atherosclerotic heart disease of native coronary artery
I25.2 Old myocardial infarction
I25.5-I25.6 Ischemic cardiomyopathy; silent myocardial ischemia
I25.700-I25.799 Atherosclerosis of coronary artery bypass graft(s) and coronary artery of transplanted heart with angina pectoris
I25.810-I25.89 Other forms of chronic ischemic heart disease
I25.9 Chronic ischemic heart disease, unspecified
I42.0-I42.9 Cardiomyopathy
I43 Cardiomyopathy in diseases classified elsewhere
I50.1-I50.9 Heart failure
I51.5 Myocardial degeneration
References

Peer Reviewed Publications:

  1. Assmus B, Honold J, Schächinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med. 2006; 355(12):1222-1232.
  2. Assmus B, Leistner DM, Schächinger V, et al. Long-term clinical outcome after intracoronary application of bone marrow-derived mononuclear cells for acute myocardial infarction: migratory capacity of administered cells determines event-free survival. Eur Heart J. 2014. 35(19):1275-1283.
  3. Assmus B, Schachinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation. 2002; 106(24):3009-3017.
  4. Bartunek J, Behfar A, Dolatabadi, et al. Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J Am Coll Cardiol. 2013; 61(23):2329-2338.
  5. Brenner C, Adrion C, Grabmaier U, et al. Sitagliptin plus granulocyte colony-stimulating factor in patients suffering from acute myocardial infarction: a double-blind, randomized placebo-controlled trial of efficacy and safety (SITAGRAMI trial). Int J Cardiol. 2015; 205:23-30.
  6. Duckers HJ, Houtgraaf J, Hehrlein C, et al. Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial. EuroIntervention. 2011; 6(7):805-812.
  7. Fan L, Chen L, Chen X, and Fu F. A meta-analysis of stem cell mobilization by granulocyte colony-stimulating factor in the treatment of acute myocardial infarction. Cardiovasc Drugs Ther. 2008; 22(1):45-54.
  8. Gyöngyösi M, Wojakowski W, Lemarchand P, et al.; ACCRUE Investigators. Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data. Circ Res. 2015; 116(8):1346-1360.
  9. Heldman AW, DiFede DL, Fishman J et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA. 2014; 311(1):62-73.
  10. Hendrikx M, Hensen K, Clijsters C, et al. Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation. 2006; 114(1 Suppl):I101-I107.
  11. Hibbert B, Hayley B, Beanlands RS, et al. Granulocyte colony-stimulating factor therapy for stem cell mobilization following anterior wall myocardial infarction: the CAPITAL STEM MI randomized trial. CMAJ. 2014; 186(11):E427-E434.
  12. Jakob P, Landmesser U. Current status of cell-based therapy for heart failure. Curr Heart Fail Rep. 2013; 10(2):165-176.
  13. Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet. 2006; 367(9505):113-121.
  14. Jiang M, He B, Zhang Q, et al. Randomized controlled trials on the therapeutic effects of adult progenitor cells for myocardial infarction: meta-analysis. Expert Opin Biol Ther. 2010; 10(5):667-680.
  15. Jimenez-Quevedo P, Gonzalez-Ferrer JJ, Sabate M, et al. Selected CD133⁺ progenitor cells to promote angiogenesis in patients with refractory angina: final results of the PROGENITOR randomized trial. Circ Res. 2014; 115(11):950-960.
  16. Kang HJ, Kim HS, Zhang SY, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet. 2004; 363(9411):751-756.
  17. Kang S, Yang Y, Li CJ, Gao R. Effectiveness and tolerability of administration of granulocyte colony-stimulating factor on left ventricular function in patients with myocardial infarction: a meta-analysis of randomized controlled trials. Clin Ther. 2007; 29(11):2406-2418.
  18. Lee JW, Lee SH, Young YJ, et al. A randomized, open-label, multicenter trial for the safety and efficacy of adult mesenchymal stem cells after acute myocardial infarction. J Korean Med Sci. 2014; 29(1):23-31.  
  19. Losordo DW, Schatz RA, White CJ, et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation. 2007; 115(25):3165-3172.
  20. Lunde K, Solheim S, Aakhus S, et al. Autologous stem cell transplantation in acute myocardial infarction: the ASTAMI randomized controlled trial. Intracoronary transplantation of autologous mononuclear bone marrow cells, study design and safety aspects. Scand Cardiovasc J. 2005; 39(3):150-158.
  21. Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006; 355(12):1199-1209.
  22. Mathiasen AB, Haack-Sørensen M, Jørgensen E, Kastrup J. Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina--final 3-year follow-up. Int J Cardiol. 2013; 170(2): 246-251.
  23. Menasche P. Stem cells for clinical use in cardiovascular medicine: current limitations and future perspectives. Thromb Haemost. 2005; 94(4):697-701.
  24. Penn MS, Ellis S, Gandhi S, et al. Adventitial delivery of an allogeneic bone marrow-derived adherent stem cell in acute myocardial infarction: phase I clinical study. Circ Res. 2012; 110(2):304-311.
  25. Pokushalov E, Romanov A, Chernyavsky A, et al. Efficiency of intramyocardial injections of autologous bone marrow mononuclear cells in patients with ischemic heart failure: a randomized study. J Cardiovasc Transl Res. 2010; 3(2):160-168.
  26. San Roman JA, Sánchez PL, Villa A, et al. Comparison of different bone marrow-derived stem cell approaches in reperfused STEMI. A multicenter, prospective, randomized, open-labeled TECAM Trial. J Am Coll Cardiol. 2015: 65(22):2372-2382.
  27. Schächinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol. 2004; 44(8):1690-1699.
  28. Schächinger V, Erbs S, Elsässer A, et al.; REPAIR-AMI Investigators. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J. 2006; 27(23):2775-2783.
  29. Siminiak T, Kalawski R, Fiszer D, et al. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. Am Heart J. 2004; 148(3):531-537.
  30. Strauer BE, Brehm M, Zeus T, et al. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease: the IACT Study. J Am Coll Cardiol. 2005; 46(9):1651-1658.
  31. Sürder D, Manka R, Lo Cicero V, et al. Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function four months results of the SWISS-AMI trial. Circulation. 2013; 127(19):1968-1979.
  32. Suzuki G. Translational research of adult stem cell therapy. World J Cardiol. 2015; 7(11):707-718.
  33. Tendera M, Wojakowski W. Clinical trials using autologous bone marrow and peripheral blood-derived progenitor cells in patients with acute myocardial infarction. Folia Histochem Cytobiol. 2005; 43(4):233-235.
  34. Traverse JH, Henry TD, Ellis SG, et al.; Cardiovascular Cell Therapy Research Network. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA. 2011; 306(19):2110-2119.
  35. Traverse JH, Henry TD, Pepine CJ, et al.; Cardiovascular Cell Therapy Research Network (CCTRN). Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA. 2012; 308(22):2380-2389.
  36. Traverse JH, McKenna DH, Harvey K, et al. Results of a phase 1, randomized, double-blind, placebo-controlled trial of bone marrow mononuclear stem cell administration in patients following ST-elevation myocardial infarction. Am Heart J. 2010; 160(3):428-434.
  37. Williams AR, Trachtenberg B, Velazquez DL, et al. Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Circ Res. 2011; 108(7):792-796.
  38. Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet. 2004; 364(9429):141-148.
  39. Zohlnhöfer D, Dibra A, Koppara T, et al. Stem cell mobilization by granulocyte colony-stimulating factor for myocardial recovery after acute myocardial infarction. J Am Coll Cardiol. 2008; 51(15):1429-1437.
  40. Zohlnhöfer D, Ott I, Mehilli J, et al.; REVIVAL-2 Investigators. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA. 2006; 295(9):1003-1010.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Fisher SA, Doree C, Mathur A, et al. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev. 2016;(12):CD007888.
  2. Fisher SA, Zhang H, Doree C, et al. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev. 2015;(9):CD006536.
  3. Moazzami K, Roohi A, Moazzami B. Granulocyte colony stimulating factor therapy for acute myocardial infarction. Cochrane Database Syst Rev. 2013;(5):CD008844.
  4. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics-2016 Update: a report from the American Heart Association. Circulation. 2016;133(4):e38-360.
  5. Yancy CW, Jessup M, Bozkurt B, et al.; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013; 62(16):e147-e239.
Websites for Additional Information
  1. American Heart Association. Available at: http://www.heart.org/HEARTORG/. Accessed on January 7, 2017.
  2. National Heart, Lung, and Blood Institute. What Is Heart Failure? June 22, 2015. Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/Hf/HF_WhatIs.html. Accessed on January 7, 2017.
  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 January 7, 2017.
  4. National Institute of Health. Stem Cell Basics VII. Available at: https://stemcells.nih.gov/info/basics/7.htm. Accessed on January 6, 2017.
Index

Autologous Cell Therapy or Transplant
Cellular Cardiomyoplasty
Intracardiac Cell Infusion
MultiStem®
Myocardial Regeneration
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.

Document History
Status Date Action
  10/01/2017 Updated Coding section with 10/01/2017 ICD-10-CM diagnosis code changes.
Reviewed 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.  Updated Discussion, Rationale, References and Website sections.
Reviewed 02/04/2016 MPTAC review.  Updated Discussion, Rationale, Reference and Website sections.
  01/01/2016 Updated Coding section with 01/01/2016 HCPCS descriptor revision for code J1442; removed ICD-9 codes.
Revised 02/05/2015 MPTAC review. Category and number of policy changed from TRANS.00022 to MED.00117. Updated Discussion, Rationale, and Reference sections.
Reviewed 02/13/2014 MPTAC review. Updated Discussion, Rationale, Coding, References, and Web Sites.
  01/01/2014 Updated Coding section with 01/01/2014 HCPCS changes; removed J1440, J1441 deleted 12/31/2013.
Reviewed 02/14/2013 MPTAC review. Updated Discussion, Rationale, References, and Web Sites.
  01/01/2013 Updated Coding section with 01/01/2013 CPT descriptor change.
Reviewed 02/16/2012 MPTAC review. Updated Discussion, Rationale, Coding section, References, and Web Sites.
  10/01/2011 Updated Coding section with 10/01/2011 ICD-9 changes.
Reviewed 02/17/2011 MPTAC review. Updated Discussion, Rationale, References, and Websites.
Reviewed 02/25/2010 MPTAC review. Updated Rationale, References, and Websites.
Reviewed 02/26/2009 MPTAC review. 
  10/01/2008 Updated Coding section with 10/01/2008 ICD-9 changes.
Reviewed 02/21/2008 MPTAC review. References and web sites updated. The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.
  10/01/2007 Updated Coding section with 10/01/2007 ICD-9 changes.
Reviewed 03/08/2007 MPTAC review. References, web site and coding updated.
Reviewed 03/23/2006 MPTAC annual review. References updated. 
Revised 04/28/2005 MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.
Pre-Merger Organizations Last Review Date Document Number Title
Anthem, Inc. 07/28/2004 TRANS.00022 Autologous Cell Therapy for the Treatment of Damaged Myocardium
WellPoint Health Networks, Inc. 06/24/2004 2.04.28 Autologous Cell Therapy for the Treatment of Damaged Myocardium