BlueCross and BlueShield of Montana Medical Policy/Codes
Stem-Cell Therapy for the Treatment of Damaged Myocardium
Chapter: Surgery: Procedures
Current Effective Date: December 27, 2013
Original Effective Date: December 27, 2013
Publish Date: September 27, 2013
Description

Stem- or progenitor-cell therapy describes the use of multipotent cells of various cell lineages (autologous or allogeneic) for tissue repair and/or regeneration.  Stem-cell therapy is being investigated for the treatment of damaged myocardium resulting from acute or chronic cardiac ischemia.

Ischemia is the most common cause of cardiovascular disease and myocardial damage in the developed world.  Despite impressive advances in treatment, ischemic heart disease is still associated with high morbidity and mortality.  Current treatments for ischemic heart disease seek to revascularize occluded arteries, optimize pump function, and prevent future myocardial damage.  However, current treatments are not able to reverse existing damage to heart muscle.  Treatment with stem-cells (i.e., progenitor-cells) offers potential benefits beyond those of standard medical care, including the potential for repair and/or regeneration of damaged myocardium.  The potential sources of embryonic and adult donor cells include skeletal myoblasts marrow cells, circulating blood-derived stem-cells, endometrial mesenchymal stem-cells (MSCs), adult testis pluripotent stem-cells, mesothelial cells, adipose-derived stromal cells, embryonic cells, induced pluripotent stem-cells, and bone marrow MSCs, all of which are able to differentiate into cardiomyocyte and vascular endothelial cells. 

The mechanism of benefit following treatment with progenitor-cells is not entirely understood.  Differentiation of progenitor-cells into mature myocytes and engraftment of progenitor-cells into areas of damaged myocardium has been suggested in animal studies using tagged progenitor-cells.  However, there is controversy concerning whether injected progenitor-cells actually engraft and differentiate into mature myocytes in humans to a degree that might result in clinical benefit.  It has also been proposed that progenitor-cells may improve perfusion to areas of ischemic myocardium.  Basic science research also suggests that injected stem-cells secrete cytokines with anti-apoptotic and pro-angiogenesis properties.  Clinical benefit may result if these paracrine factors are successful at limiting cell death from ischemia or stimulating recovery.  For example, myocardial protection can occur through modulation of inflammatory and fibrogenic process.  Alternatively, paracrine factors might affect intrinsic repair mechanisms of the heart through neovascularization, cardiac metabolism and contractility, increase in cardiomyocyte proliferation, or activation of resident stem and progenitor-cells.  The relative importance of these proposed paracrine actions will depend on the age of the infarct, e.g., cytoprotective effects with acute ischemia versus cell proliferation with chronic ischemia.  Investigation of the specific factors that are induced by administration of progenitor-cells is ongoing.

There is a variety of potential delivery mechanisms for donor cells, encompassing a wide range of invasiveness.  Donor cells can be delivered via thoracotomy and direct injection into areas of damaged myocardium.  Injection of progenitor-cells into the coronary circulation can also be done using percutaneous, catheter-based techniques.  Finally, progenitor-cells can be delivered intravenously via a peripheral vein.  With this approach, the cells must be able to target damaged myocardium and concentrate at the site of myocardial damage.

Adverse effects of treatment with progenitor-cells include the risk of the delivery procedure (e.g., thoracotomy, percutaneous catheter-based, etc.) and the risks of the donor cells themselves.  Donor progenitor-cells can differentiate into fibroblasts rather than myocytes.  This may create a substrate for malignant ventricular arrhythmias.  There is also a theoretical risk that tumors, such as teratomas, can arise from progenitor-cells, but the actual risk of this occurring in humans is not known at present.

U.S. Food and Drug Administration (FDA) approval is not required in those situations in which autologous cells are processed on site with existing laboratory procedures and injected with existing catheter devices.  However, there are currently two products that require FDA approval.  MyoCell™ consists of patient autologous skeletal myoblasts that are expanded ex-vivo and supplied as a cell suspension in a buffered salt solution for injection into the area of damaged myocardium.  Since the myoblast isolation and expansion occurs at a single reference laboratory (BioHeart), this process is subject to FDA approval.  In addition, implantation may require the use of a unique catheter delivery system (MyoCath™) that also requires FDA approval.

An allogeneic human mesenchymal stem-cell (hMSC) product (Prochymal®) is being developed by Osiris Therapeutics, Inc. (Baltimore, MD) for treatment of acute MI.  Prochymal (also referred to as Procacel) is a highly pure preparation of ex vivo cultured adult hMSC isolated from the bone marrow of healthy young adult donors.  Prochymal has been granted “fast track” status by the FDA for Crohn’s disease and graft-versus-host disease (GvHD), and has orphan drug status for GvHD from the FDA and the European Medicines Agency.  Prochymal is being studied in Phase II trials for the treatment of acute MI, pulmonary disease, and type 1diabetes.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Investigational

Blue Cross and Blue Shield of Montana (BCBSMT) considers stem-cell therapy (autologous or allogeneic), including but not limited to skeletal myoblasts or hematopoietic stem-cells,  experimental, investigational and unproven as a treatment of damaged myocardium.

Infusion of growth factors (i.e., granulocyte colony stimulating factor [GCSF]) is considered experimental, investigational and unproven as a technique to increase the numbers of circulating hematopoietic stem-cells as treatment of damaged myocardium.

Policy Guidelines

There are no specific codes for this procedure, either describing the laboratory component of processing the harvested cells or implantation of cells.  In some situations, the implantation may be an added component of a scheduled coronary artery bypass graft (CABG); in other situations, the implantation may be performed as a unique indication for a cardiac catheterization procedure.

Rationale

The investigation of stem- (i.e., progenitor-) cell transplantation for the treatment of damaged myocardium is still at its preliminary stages in human subjects, in terms of investigating basic scientific issues, procedural issues, and conducting outcomes studies to determine the safety and efficacy of the techniques.

From a basic science viewpoint, it must be shown that these transplanted autologous cells can incorporate themselves into the heart, and survive, mature and electromechanically couple to each other.  For example, preliminary studies have suggested that transplanted myoblasts are potentially arrhythmogenic, and for this reason, the Investigational Device Exemption (IDE) trials discussed in the Description section require that all patients receive a cardiac defibrillator.  Patient selection criteria are still evolving.  For example, in the immediate post-infarct period, autologous cell transplant might function to alter the cardiac remodeling process that leads to subsequent cardiac dilation and congestive heart failure.  However, when autologous cell transplant is performed in patients with congestive heart failure, it may function more to stimulate myocardial regeneration.  These two different patient groups are the focus of the IDE trials.

There are also the practical issues of determining the optimal cell type, the timing of the transplantation post-infarct, and the delivery mode (directly into myocardium, intracoronary artery or sinus, or intravenous).  In addition, there are issues of harvesting the autologous cells. Hematopoietic stem-cells and skeletal myoblasts have been the focus of research, yet the ability to harvest hematopoietic stem-cells (a procedure requiring multiple bone core biopsies and general anesthesia) in the immediate post-infarct period is questionable.  One of the advantages of using skeletal myoblasts is their easy accessibility through a muscle biopsy; however, the harvested tissue must undergo culture to expand the numbers of skeletal myoblasts.  In the IDE trials, skeletal biopsy must occur three to four weeks before the anticipated implantation.

The human studies reported so far are clearly preliminary and have not attempted to evaluate long-term efficacy of stem-cell transplant.  Assmus and colleagues reported on the results of the TOPCARE-AMI, the “Transplantation Of Progenitor-cells And Regeneration Enhancement in Acute Myocardial Infarction”, study.  This study included 20 patients who had already undergone revascularization after an acute myocardial infarction (MI) and received either bone marrow-derived cells or circulating blood-derived stem-cells infused into the infarct artery during a second catheterization procedure.  Cardiac function was evaluated before and after the transplantation procedure; essentially patients served as their own control.  After four months, the authors reported an improvement in injection fraction, regional wall motion, and left ventricular end diastolic volumes.  Stamm and colleagues injected bone marrow-derived stem-cells into the peri-infarct zone in six patients who had a MI and were undergoing coronary artery bypass grafting (CABG).  All patients reported an improvement in cardiac exercise capacity and ejection fraction.  In contrast Herreros and colleagues used an intramyocardial injection of cultured myoblasts in 12 patients undergoing CABG.  The procedure was considered safe and feasible and the authors reported increased global and regional left ventricular function three months after surgery.  Strauer and colleagues reported on a clinical trial of ten patients who received intracoronary autologous bone marrow cells five to nine days after acute infarct.  This delay in treatment reflects the time needed to harvest and process the bone marrow cells.  Cardiac function in these ten patients was compared to ten contemporary control patients who refused the treatment.  At three months, the treated patients had a reduction in infarct size compared to no change in the nonrandomized control group.  Finally, Kang and colleagues used granulocyte colony stimulating factor (GCSF) to increase the number of circulating hematopoietic stem-cells in 27 patients with acute MI.  The stem-cells were harvested in a pheresis procedure and then injected into the coronary artery via a separate angioplasty and stenting procedure.  While the therapy was associated with an improvement in cardiac function, the authors noted a high rate in stent restenosis in those receiving the GCSF and the trial was stopped.

These studies focused on patients without congestive heart failure.  Smits and colleagues reported on five patients with symptomatic heart failure who were treated with direct intramyocardial injection of cultured skeletal myoblasts harvested from a quadriceps biopsy.  Compared with baseline, an improvement was noted in ejection fraction and regional wall motion.

2009 Update

2008 Blue Cross Blue Shield Association Technology Evaluation Center Assessment

In 2008, the Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) conducted a systematic review that included randomized, controlled trials of progenitor-cell therapy versus standard medical care for treatment of either acute or chronic myocardial ischemia.  The BCBSA TEC Assessment focused on the impact of progenitor-cell therapy on clinical outcomes, but also included data on physiologic outcomes such as change in left ventricular ejection fraction (LVEF).

Autologous progenitor-cell transplantation for the treatment of damaged myocardium is a rapidly evolving field, with a number of areas of substantial uncertainty.  The mechanism of benefit is not well understood.  Patient selection criteria are still evolving, and the current studies have been performed in highly selected populations.  Also, there is a lack of standardization in treatment protocols, with uncertainty in the optimal methods for harvesting of donor cells, the timing of the transplantation, and the optimal delivery mode (directly into myocardium, intracoronary artery or sinus, or intravenously).

Acute Ischemia

For acute ischemia, there were a total of ten publications from six unique studies enrolling 556 patients.  These trials had similar inclusion criteria, enrolling patients with acute ST-segment elevation MI treated successfully with percutaneous coronary intervention (PCI) and stenting, with evidence of residual myocardial dysfunction in the region of the acute infarct.  Progenitor-cell therapy was delivered via an additional PCI procedure within one week of the acute event.

The “Reinfusion of Enriched Progenitor-cells And Infarct Remodeling in Acute Myocardial Infarction” (REPAIR-AMI) trial was the largest trial, and had the largest number of clinical outcomes reported.  This was a double-blinded trial that employed a sham placebo control infusion of the patients’ own serum.  This trial enrolled 204 patients with acute ST-segment elevation MI meeting strict inclusion criteria from 17 centers in Germany and Switzerland.  At 12 months of follow-up, there were statistically significant decreases in the progenitor-cell group for MI (0 vs. 6, p<0.03) and revascularization (22 vs. 37, p<0.03) as well as for the composite outcome of death, MI, and revascularization (24 vs. 42, p<0.009).

The other trials had very few clinical events, precluding meaningful analysis of clinical outcomes.  The primary evidence from these other trials consists of physiologic outcomes measures such as change in LVEF and change in infarct size.

The primary endpoint in all six trials was change in LVEF.  In each trial, there was a greater increase in the LVEF for the progenitor-cell group compared with the control group.  In four of the six studies, this difference reached statistical significance, while in two studies there was a non-significant increase in favor of the treatment group.  The magnitude of the incremental improvement in LVEF was not large in most cases, with five of the six studies reporting an incremental change of 1% to 6%, and the final study reporting a larger incremental change of 18%.

Lipinski et al. published a quantitative meta-analysis of studies that estimated the magnitude of benefit of progenitor-cell treatment on left ventricular (LV) function and infarct size.  This analysis included ten controlled trials with a total of 698 patients.  Results for the primary endpoint, change in LVEF, showed a statistically significant greater improvement of 3% (95% CI: 1.9–4.1%, p<0.00001) for the progenitor-cell group.  There was also a statistically significant greater improvement in infarct size for the progenitor-cell group with an incremental improvement of -5.6% over the control group (95% CI: -8.7 to -2.5, p<0.001).

Chronic Ischemia

A total of six trials randomizing 231 patients were included for treatment of chronic ischemic heart disease.  Three trials randomized 125 patients to progenitor-cell therapy versus standard medical care.  The other three trials randomized 106 patients undergoing CABG to CABG plus progenitor-cell treatment versus CABG alone.  Four trials employed bone-marrow-derived progenitor-cells as the donor cell source, one trial used circulating progenitor-cells (CPC), and the final trial included both a CPC treatment group and a bone marrow-derived treatment group.

The largest trial was Assmus et al., which was a single-center, unblinded trial that enrolled 75 patients into three groups; treatment with bone marrow-derived progenitor-cells, treatment with circulating progenitor-cells, or usual medical care.

The primary physiologic measurement reported in these trials was change in LVEF.  In all six trials there was a greater improvement in LVEF for the treatment group compared with the control group, and in four of six trials, this difference reached statistical significance.  For the three trials of progenitor-cell treatment versus standard medical care, the range of incremental improvement in LVEF was 2.7%–6.0%.  For the trials of progenitor-cell treatment plus CABG versus CABG alone, the range of improvement in LVEF was 2.5%–10.1%.  Only one trial reported comparative analysis of data on the change in size of ischemic myocardium.  This trial reported that there was no difference in size of ischemic myocardium between treatment groups.

There are limited data from this group of studies on clinical outcomes, with only two studies reporting any clinical outcomes.  Assmus et al. reported on adverse cardiac events, but there were extremely small numbers of any of these clinical outcomes, and no differences between groups.

Both trials reported on change in New York Heart Association (NYHA) class between groups.  Assmus et al. also reported an improvement in mean NYHA class of 0.25 (0–4 scale) for the bone-marrow treatment group and an improvement of 0.23 for the CPC group, compared with a worsening of 0.18 for the standard medical therapy group (p<0.01).  Patel et al. reported a greater improvement in mean NYHA class for patients in the CABG plus progenitor-cell group compared to CABG alone (2.7 vs. 0.7, p value not reported), but no statistical testing for this outcome was reported.

Summary Based on 2008 TEC Assessment

For acute ischemic heart disease, the limited evidence on clinical outcomes suggests that there may be benefits in improving LVEF, reducing recurrent MI, decreasing the need for further revascularization, and perhaps even decreasing mortality.  These results indicate that progenitor-cell treatment is a promising therapy with the potential to benefit a large population of patients with ischemic heart disease.  However, the evidence to date should be viewed as preliminary rather than definitive.  There are numerous reasons why the confidence in these conclusions is not high.

The primary limitation is the small quantity of evidence on clinical outcomes, with a very small overall number of hard clinical outcomes such as recurrent MI and death across all trials.  Only one trial, REPAIR-AMI, had enough clinical outcomes for meaningful statistical analysis.  There were far more revascularization outcomes than other clinical events, and as a result, the composite outcome of major adverse cardiac events was driven almost entirely by revascularization.

All of the trials had one or more methodologic limitation.  The most common limitations were lack of double-blinding and failure to account for all randomized patients in the analysis.  The REPAIR-AMI trial was the highest methodologic quality, and was double-blinded.  However, this trial excluded 17 of 204 randomized patients from the analysis, and thus was not considered to meet the criteria for a high-quality trial.

While the evidence for a beneficial impact on physiologic outcomes, particularly LVEF, is fairly strong, the magnitude of effect does not appear to be large.  As a result, it is not certain whether the improvement in LVEF translates to meaningful improvements in clinical outcomes.

For chronic ischemic heart disease there is only very scant evidence on clinical outcomes, and no conclusions can be drawn.  Only a handful of clinical outcome events have been reported across the included studies, too few for meaningful analysis.  Other clinical outcomes, such as NYHA class, are confined to very small numbers of patients and not reported with sufficient methodologic rigor to permit conclusions.

Additional Literature Review

In addition to the 2008 BCBSA TEC Assessment, a literature search was performed through June 2009.  Numerous small randomized, controlled trials were identified that evaluated the impact of bone marrow progenitor-cells on outcomes for patients with MI.

The majority of these studies treated patients with acute MI and reported the outcomes of LVEF and/or myocardial perfusion at three to six months.  These studies generally reported small to modest improvements in these intermediate outcomes, thus confirming the results of previous studies and the conclusions from the 2008 BCBSA TEC Assessment.  None of these new trials reported benefits in clinical outcomes such as mortality, adverse cardiac outcomes, exercise capacity, or quality of life.

At least four meta-analyses of bone marrow progenitor-cell treatment for acute MI were published over this time period, each examining between six and 13 randomized, controlled trials.  All four meta-analyses concluded that there was a modest improvement in LVEF for patients treated with progenitor-cells.  The mean estimated improvement in ejection fraction over control ranged from 2.9–6.1%.  The studies also concluded that myocardial perfusion and/or infarct size was improved in the progenitor-cell treatment group, although different outcome parameters were used.  All four of the meta-analyses concluded that there were no demonstrable differences in clinical outcomes for patients treated with progenitor-cells.

One randomized, controlled trial was identified that treated patients with chronic myocardial ischemia and that reported on a wide range of outcomes.  van Ramshorst et al. performed a randomized, double-blind trial on 50 patients with intractable angina despite optimal medical therapy who were not candidates for revascularization therapy.  Patients were injected with autologous bone marrow-derived mononuclear cells or placebo.  The main outcomes were measures of myocardial perfusion derived from SPECT (single photon emission computed tomography) scanning at rest and SPECT after exercise stress at three months post-treatment.  Secondary outcomes included LVEF, Canadian Cardiovascular Society (CCS) angina class, and Seattle Angina quality of life questionnaire measured at six months post-treatment.

There were modest improvements for most of the outcomes in favor of the experimental group compared to placebo.  For the primary outcome, a significantly greater improvement was found in the stress perfusion score for the progenitor-cell group (mean difference -2.44; 95% CI: -3.58 to -1.30, p<0.001), but no significant difference in the rest perfusion score (mean difference = 0.32; 95% CI: -0.87 to 0.23, p=0.25).  There was also a significant decrease in the mean number of ischemic segments for the progenitor-cell group (mean decrease 2.4 vs. 0.8, p<0.001).  LVEF improved slightly in the progenitor-cell group and decreased slightly in the placebo group (mean change 3% +/- 5 vs. -1% +/- 3, p=0.03).  At six months, CCS class decreased more for the progenitor-cell group (mean difference -0.79; 95% CI: -1.10 to -0.48, p<0.001) and the Seattle Angina quality of life score increased more for the progenitor-cell group (mean increase 12% vs. 6.3%, p=0.04).

One small, randomized, controlled trial compared progenitor-cells to placebo as an adjunctive treatment for patients undergoing CABG.  Zhao et al. randomized 36 patients and reported that LVEF, myocardial perfusion, and angina class were improved for the progenitor-cell group at six months.  However, there were two deaths in the progenitor-cell group versus none in the placebo; these deaths were potentially due to arrhythmias.  The authors, therefore, concluded that while there was potential benefit for bone marrow progenitor-cell treatment in this group of patients, larger studies were needed to determine the safety and arrhythmogenic potential of progenitor-cell treatment.

Summary

The new evidence corroborates previous studies in demonstrating an improvement in LVEF and myocardial perfusion for patients with myocardial ischemia treated with bone marrow-progenitor-cells.  The clinical significance of the improvement in these parameters has yet to be demonstrated, and there is very little evidence demonstrating a benefit in clinical outcomes.  Moreover, the evidence remains primarily limited to short-term effects and the long-term durability of benefit has not yet been determined.  As a result, the new evidence does not prompt reconsideration of the current policy statement, which remains unchanged.

2011 Update

The literature search update through July 2011 identified publications addressing acute ischemia, chronic ischemia, and ongoing clinical trials. 

Acute Ischemia

The literature search identified two publications with longer-term (two to three year) follow-up from the randomized trials described above.  Two year clinical outcomes from the REPAIR-AMI trial, performed according to a study protocol amendment filed in 2006, were reported in 2010.  Three of the 204 patients were lost to follow-up (two patients in the placebo group and one in the progenitor-cell group).  A total of 11 deaths occurred during the two year follow-up, eight in the placebo group and three in the progenitor-cell group.  There was a significant reduction in myocardial infarction (MI) (0% vs. 7%), and a trend toward a reduction in re-hospitalizations for heart failure (1% vs. 5%) and revascularization (25% vs. 37% - all respectively) in the active treatment group.  Analysis of combined events (all combined events included infarction), showed significant improvement with progenitor-cell therapy after acute MI.  There was no increase in ventricular arrhythmia or syncope, stroke, or cancer.  It was noted that investigators and patients were unblinded at 12 month follow-up, the sample size of the REPAIR-AMI trial was not powered to definitely answer the question of whether administration of progenitor-cells can improve mortality and morbidity after acute MI, and the relatively small sample size might limit the detection of infrequent safety events.  The authors concluded that this analysis should be viewed as hypothesis generating, providing the rationale to design a larger trial that addresses clinical endpoints.

Beitnes and colleagues reported the unblinded three year reassessment of 97 patients (out of 100) from the randomized ASTAMI (Autologous Stem-cell Transplantation in Acute Myocardial Infarction) trial.  The group treated with bone marrow progenitor-cells had a larger improvement in exercise time between baseline and three year follow-up (1.5 vs. 0.6 minutes, respectively), but there was no difference between groups in change in peak oxygen consumption (3.0 mL/kg/min vs. 3.1 mL/kg/min, respectively), and there was no difference between groups in change of global LVEF or quality of life.  Rates of adverse clinical events in both groups were low (three infarctions and two deaths).  These three year findings are similar to the 12 month results from this trial.

Literature updates since the 2008 BCBSA TEC Assessment have identified numerous small randomized controlled clinical trials (RCTs) that evaluated the impact of bone marrow progenitor-cells on outcomes for patients with MI.  The majority of these studies treated patients with acute MI and reported the outcomes of left ventricular ejection fraction (LVEF) and/or myocardial perfusion at three to six months.  These studies generally reported small to modest improvements in these intermediate outcomes, thus confirming the results of previous studies and the conclusions from the 2008 BCBSA TEC Assessment.  None of these new trials reported benefits in clinical outcomes, such as mortality, adverse cardiac outcomes, exercise capacity, or quality of life.

Chronic Ischemia

Results from the acute and long-term effects of intracoronary stem-cell transplantation in 191 patients with chronic heart failure (STAR-heart) study were reported by Strauer et al. in 2010.  In this non-randomized open-label trial, 391 patients with chronic heart failure due to ischemic cardiomyopathy were enrolled; 191 patients received intracoronary bone marrow cell (BMC) therapy, and 200 patients who did not accept the treatment but agreed to follow-up testing served as controls.  The time between percutaneous coronary intervention for infarction and admission to the tertiary clinic was 8.5 years.  For the BMC therapy, mononuclear cells were isolated and identified (included CD34-positive cells, AC133-positive cells, and CD45/CD14-negative cells).  Cells were infused directly into the infarct-related artery.  Follow-up on all patients was performed at three, 12, and 60 months and included coronary angiography, biplane left ventriculography, electrocardiogram (ECG) at rest, spiroergometry, right heart catheterization and measurements of late potentials (LPs), short-term heart rate variability (HRV), and 24-hour Holter ECG.  At up to five years after intracoronary BMC therapy, there was a significant improvement in hemodynamics (LVEF, cardiac index), exercise capacity (New York Heart Association [NYHA] classification), oxygen uptake, and LV contractility compared to controls. There was also a significant decrease in long-term mortality in the BMC-treated patients (0.75% per year) compared to the control group (3.68% per year, P<0.01).  These results are encouraging, especially in regard to the mortality outcomes, since this is the first controlled trial that reports a significant mortality benefit for progenitor-cell treatment.  However, the study is limited by the potential for selection bias due to patient self-selection into treatment groups.  For example, there was a 7% difference in baseline ejection fraction between the two groups, suggesting that the groups were not comparable on important clinical characteristics.  In addition, the lack of blinding raises the possibility of bias in patient-reported outcomes such as NYHA class.  RCTs are needed to confirm these health outcome benefits for chronic ischemia.

Ongoing Clinical Trials

A 2010 critical review of cell therapy for the treatment of coronary heart disease by Wollert and Drexler described 20 ongoing cell therapy trials in patients with coronary heart disease.  Issues to be resolved in these second and third generation cell therapy trials include patient selection, cell type, procedural details, clinical endpoints, and strategies to enhance cell engraftment and prolong cell survival.  Moreover, “a large body of evidence indicates that the beneficial effects of cell therapy are related to the secretion of soluble factors acting in a paracrine manner.”  The authors suggest that the identification of specific factors promoting tissue regeneration may eventually enable therapeutic approaches based on the application of specific paracrine factors.  Updated literature reviews have also identified a number of publications that describe ongoing RCTs.

In 2010, Taljaard and colleagues reported the rationale and design of what is described as the first randomized placebo-controlled trial of “enhanced” progenitor-cell therapy for AMI.  The “ENhanced Angiogenic Cell Therapy in Acute Myocardial Infarction” trial (ENACT-AMI) is a Phase IIb, double-blind, RCT, using coronary injection of autologous early endothelial progenitor-cells for patients who have suffered large MI.  A total of 99 patients will be randomly assigned to placebo (Plasma-Lyte A), autologous mononuclear cells, or mononuclear cells transfected with human endothelial nitric oxide synthase delivered by injection into the infarct-related artery.  This trial is described as the first to include a strategy to enhance the function of autologous progenitor-cells by overexpressing endothelial nitric oxide synthase and the first to use combination gene and cell therapy for the treatment of cardiac disease.

The rationale and design of the “Swiss Multicenter Intracoronary Stem-cells Study in Acute Myocardial Infarction” (SWISS-AMI) was also reported in 2010.  In this trial, 192 patients with AMI will be randomized to control or one of two groups treated with autologous bone marrow mononuclear cells (five to seven days or three to four weeks after the initial event).  The mononuclear cells will be infused directly into the infarct-related coronary artery.  The primary endpoint is the change in global LVEF at four months; secondary end-points include changes in infarct size, regional myocardial thickness, and wall motion at four and 12 months.  Major adverse cardiac events will be assessed at four, 12, and 24 months.

A search of the online site “ClinicalTrials.gov” in May 2011 identified a Phase II/III “Multicenter study to assess the safety and cardiovascular effects of Myocell™ implantation by a catheter delivery system in congestive heart failure patients post myocardial infarction” (MARVEL, NCT00526253).  Autologous skeletal myoblasts will be isolated, expanded in culture, and injected into the myocardium via the femoral artery.  This is a three arm randomized placebo-controlled trial with low- or high-dose active treatment (400 million or 800 million cells) compared to a control group injected with the transport media alone.  Initially, the estimated enrollment was 170 patients; the targeted completion date for the primary outcome measures (six minute walk test, quality of life, and LVEF) was listed as February 2012.  However, as of October 26, 2010, the study is ongoing, but not recruiting participants and the predicted target completion date is no longer indicated.    

Summary

Stem- or progenitor-cell therapy for the treatment of damaged myocardium is a rapidly evolving field, with a number of areas of substantial uncertainty including patient selection, cell type, and procedural details (e.g., timing and mode of delivery).

For acute ischemic heart disease, the limited evidence on clinical outcomes suggests that there may be benefits in improving LVEF, reducing recurrent MI, decreasing the need for further revascularization, and perhaps even decreasing mortality.  These results indicate that progenitor-cell treatment is a promising therapy with the potential to benefit a large population of patients with ischemic heart disease.  However, the evidence to date should be viewed as preliminary rather than definitive.  There are numerous reasons why the confidence in these conclusions is not high.  The primary limitation is the small quantity of evidence on clinical outcomes, with limited evidence across all trials on outcomes such as recurrent MI and death.  While the evidence for a beneficial impact on physiologic outcomes, particularly LVEF, is fairly strong, the magnitude of effect does not appear to be large.  As a result, it is not certain whether the improvement in LVEF translates to meaningful improvements in clinical outcomes.

For chronic ischemic heart disease, there is limited evidence on clinical outcomes.  Only a handful of clinical outcome events have been reported across the included studies, too few for meaningful analysis.  Other clinical outcomes, such as NYHA class, are confined to very small numbers of patients and not reported with sufficient methodologic rigor to permit conclusions.  Therefore, the evidence is insufficient to permit conclusions on the impact of progenitor-cell therapy on clinical outcomes for patients with chronic ischemic heart disease.

Overall, the new evidence corroborates previous studies in demonstrating an improvement in LVEF and myocardial perfusion for patients with myocardial ischemia treated with progenitor-cells.  The clinical significance of the improvement in these parameters has yet to be demonstrated, and there is very little evidence demonstrating a benefit in clinical outcome.  Moreover, the evidence remains primarily limited to short-term effects; the long-term durability of benefit has not yet been determined.  Therefore, stem-cell therapy for the treatment of damaged myocardium is considered experimental, investigational and unproven.

Coding

Disclaimer for coding information on Medical Policies         

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.          

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

Refer to the ICD-9-CM manual.

ICD-10 Codes

Refer to the ICD-10-CM manual.

Procedural Codes: 33999
References
  1. Menasche, P., Hagege, A.A., et al.  Myoblast transplantation for heart failure.  Lancet (2001 January 27) 357(9252):279-80.
  2. Penn, M.S., Francis, G.S., et al.  Autologous cell transplantation for the treatment of damaged myocardium.  Progress in Cardiovascular Disease (2002 July-August) 45(1):21-32.
  3. Strauer, B.E., Brehm, M., et al.  Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans.  Circulation (2002 October 8) 106(15):1913-8.
  4. Assmus, B., Schachinger, V., et al.  Transplantation Of Progenitor-cells And Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI).  Circulation (2002 December 10) 106(24):3009-17.
  5. Tse H.F., Kwong Y.L., et al.  Angiogenesis in ischemic myocardium by intra-myocardial autologous bone marrow mononuclear cell implantation.  Lancet (2003) 361(9351):47-9.
  6. Stamm, C., Westphal, B., et al.  Autologous bone-marrow stem-cell transplantation for myocardial regeneration.  Lancet (2003 January 4) 361(9351):45-6.
  7. Abbott, J.D., and F.J. Giordano.  Stem-cells and cardiovascular disease.  Journal of Nuclear Cardiology (2003 July-August) 10(4):403-12.
  8. Forrester, J.S., Price, M.J., et al.  Stem-cell repair of infarcted myocardium: an overview for clinicians.  Circulation (2003 September 2) 108(9):1139-45.
  9. Herreros, J., Prosper, F., et al.  Autologous intramyocardial injection of cultured skeletal muscle-derived stem-cells in patients with non-acute myocardial infarction.  European Heart Journal (2003 November) 24(22):2012-20.
  10. Smits, P.C., van Geuns, R.J., et al.  Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up.  Journal of the American College of Cardiology (2003 December 17) 42(12):2063-9.
  11. Wollert, K.C., Meyer, G.P., J., et al.  Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomized controlled clinical trial.  Lancet (2004) 364(9429):141-8.
  12. ClinicalTrials.gov – Stem-cell Study for Patients with Heart Disease (NCT00081913) (2004 January).  Available at <www.clinicaltrials.gov> (accessed - 2007 August 14).
  13. Kang, H.J., Kim, H.S., et al.  Effects of intracoronary infusion of peripheral blood stem-cells mobilized with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomized clinical trial.  Lancet (2004 March 6) 363(9411):751-6.
  14. Lee, M.S., and R.R. Makkar.  Stem-cell transplantation in myocardial infarction: a status report.  Annals of Internal Medicine (2004 May 4) 140(9):729-37.
  15. Chen, S.L., Fang, W.W., et al.  Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem-cell in patients with acute myocardial infarction.  American Journal of Cardiology (2004 July 1) 94(1):92-5.
  16. Mathur, A., and J.F. Martin.  Stem-cells and repair of the heart.  Lancet (2004 July 10-16) 364(9429):183-92.
  17. Erbs, S., Linke, A., et al.  Transplantation of blood-derived progenitor-cells after recanalization of chronic coronary artery occlusion.  Circulation Research (2005 October 14) 97:756-62.
  18. Mouquet, F., Pfister, O., et al.  Restoration of cardiac progenitor-cells after myocardial infarction by self-proliferation and selective homing of bone marrow-derived stem-cells.  Circulation Research (2005 November 25) 97(11):1090-2.
  19. Patel, A.N., Geffner, L., et al.  Surgical treatment for congestive heart failure with autologous adult stem-cell transplantation: a prospective randomized study.  Journal of Thoracic and Cardiovascular Surgery (2005 December) 130(6):1631-8.
  20. Janssens, S., Dubois, C., et al.  Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomized controlled trial.  Lancet (2006 January 14) 367(9505):113-21.
  21. ClinicalTrials.gov – MYOHEART (MYOgenesis Heart Efficiency And Regeneration Trial (NCT00054678) (2006 March).  Available at www.clinicaltrials.gov (accessed – 2009 August 14).
  22. ClinicalTrials.gov – Autologous Cultured Myoblasts (BioWhittaker) Transplanted via Myocardial Injection (NCT0050765) (2006 March).  Available at <www.clinicaltrials.gov> (accessed – 2007 August 14).
  23. Zohlnhofer, 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.  Journal of the American Medical Association (2006 March 1) 295(9):1003-10.
  24. Meyer, G.P., Wollert, K.C., et al.  Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial.  Circulation (2006 March 14) 113(10):1287-94.
  25. Schaefer, A., Meyer, G.P., et al.  Impact of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: results from the BOOST trial.  European  Heart Journal (2006 April) 27(8):929-35.
  26. Murry, C.E., Reinecke, H., et al.  Regeneration gaps: observations on stem-cells and cardiac repair.  Journal of the American College of Cardiology (2006 May 2) 47(9):1777-85.
  27. Bartunek, J., Dimmeler, S., et al.  Task force of the European Society of Cardiology.  The consensus of the task force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem-cells for repair of the heart.  European Heart Journal (2006 June) 27(11):1338-40.
  28. Uemura, R., Xu, M., et al.  Bone marrow stem-cells prevent left ventricular remodeling of ischemic heart through paracrine signaling.  Circulation Research (2006 June 9) 98(11):1414-21.
  29. Hendrikx, M., Hensen, K., et al.  Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation.  Circulation (2006 July 4) 114(1 supplement):I-101-7.
  30. Kang, H.J., Lee, H.Y., et al.  Differential effect of intracoronary infusion of mobilized peripheral blood stem-cells by granulocyte colony-stimulating factor on left ventricular function and remodeling in patients with acute myocardial infarction versus old myocardial infarction.  Circulation (2006 July 4) 114(1 supplement):I-145-51.
  31. ClinicalTrials.gov – Safety and Effects of Implanted (Autologous) Skeletal Myoblasts (MyoCell) Using an Injection Catheter = SEISMIC Trial (NCT00375817) (2006 September).  Available at www.clinicaltrials.gov (accessed – 2009 August 14).
  32. Assmus, B., Honold, J., Schachinger, V., et al.  Transcoronary transplantation of progenitor-cells after myocardial infarction.  New England Journal of Medicine (2006 September 21) 355(12):1222-32.
  33. Lunde, K., Solheim, S., et al.  Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction.  New England Journal of Medicine (2006 September 21) 355(12):1199-209.
  34. Schachinger, V., Erbs, S., et al.  REPAIR-AMI Investigators.  Intracoronary bone marrow-derived progenitor-cells in acute myocardial infarction.  New England Journal of Medicine (2006 September 21) 355(12):1210-21.
  35. Schachinger, V., Erbs, S., et al.  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.  European Heart Journal (2006 December) 27(23):2775-83.
  36. Assmus, B., Honold, J., et al.  Transcoronary transplantation of progenitor-cells after myocardial infarction.  New England Journal of Medicine (2006 December) 355(12):1222-32.
  37. Stamm, C., Kleine, H.D., et al.  Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies.  Journal of Thoracic and Cardiovascular Surgery (2007 March) 133(3):717-25.
  38. Mazhari, R., and J.M. Hare.  Advances in cell-based therapy for structural heart disease.  Progress in Cardiovascular Diseases (2007 May-June) 49(6):387-95.
  39. Losordo, D.W., Schatz, R.A., et al.  Intramyocardial transplantation of autologous CD34+ stem-cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial.  Circulation (2007 June 26) 115(25):3165-72.
  40. Lunde, K., Solheim, S., et al.  Exercise capacity and quality of life after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: results from the Autologous Stem-cell Transplantation in Acute Myocardial Infarction (ASTAMI) randomized controlled trial.  American Heart Journal (2007 October) 154(4):710.e1-8.
  41. Lipinski, M.J., Biondi-Zoccai, G.G., et al.  Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction.  Journal of the American College of Cardiology (2007 October 30) 50(18):1761-7.
  42. Martin-Rendon, E., Brunskill, S.J., et al.  Autologous bone marrow stem-cells to treat acute myocardial infarction: a systematic review.  European Heart Journal (2008 August) 29(15):1807-18.
  43. Kang, S., Yang, Y.J., et al.  Effects of intracoronary autologous bone marrow cells on left ventricular function in acute myocardial infarction: a systematic review and meta-analysis.  Coronary Artery Disease (2008 August) 19(5):327-35.
  44. Meluzin, J., Janousek, S., et al.  Three-, 6-, and 12-month results of autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction.  International Journal of Cardiology (2008 August 18) 128(2):185-92.
  45. Progenitor-cell therapy for treatment of myocardial damage due to ischemia.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2008 September) 23(4):1-36.
  46. Huikuri, H.V., Kervinen, K., et al.  Effects of intracoronary injection of mononuclear bone marrow cells on left ventricular function, arrhythmia risk profile, and restenosis after thrombolytic therapy of acute myocardial infarction.  European Heart Journal (2008 November) 29(22):2723-32.
  47. Zhao, Q., Sun, Y., et al.  Randomized study of mononuclear bone marrow cell transplantation in patients with coronary surgery.  Annals of Thoracic Surgery (2008 December) 86(6):1833-40.
  48. Herbots, L., D’hooge, J., et al.  Improved regional function after autologous bone marrow-derived stem-cell transfer in patients with acute myocardial infarction.  European Heart Journal (2009 March) 30(6):662-70.
  49. Singh, S., Arora, R., et al.  Stem-cells improve left ventricular function in acute myocardial infarction.  Clinical Cardiology (2009 April) 32(4):176-80.
  50. Lipiec, P., Krzeminska-Pakula, M., et al.  Impact of intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction on left ventricular perfusion and function.  European Journal of Nuclear Medicine and Molecular Imaging (2009 April) 36(4):587-93.
  51. van Ramshorst, J., Bax, J.J., et al.  Intramyocardial bone marrow cell injection for chronic myocardial ischemia.  Journal of the American Medical Association (2009 May 20) 301(19):1997-2004.
  52. Zhang, S.N., Sun, A.J., et al.  Intracoronary autologous bone marrow stem-cells transfer for patients with acute myocardial infarction: a meta-analysis of randomized controlled trials.  International Journal of Cardiology (2009 August 14) 136(2):178-85.
  53. Beitnes, J.O., Hopp, E., et al.  Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomized, controlled study.  Heart (2009 December) 95(24):1983-9.
  54. Hare, J.M., Traverse, J.H., et al.  A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem-cells (prochymal) after acute myocardial infarction.  Journal of the American College of Cardiology (2009 December 8) 54(24):2277-86.
  55. Assmus, B., Rolf, A., et al.  Clinical outcome 2 years after intracoronary administration of bone-marrow-derived progenitor-cells in acute myocardial infarction.  Circulartory Heart Failure (2010 January) 3(1):89-96.
  56. Taljaard, M., Ward, M.R., et al.  Rationale and design of Enhanced Angiogenic Cell Therapy in Acute Myocardial Infarction (ENACT-AMI): the first randomized placebo-controlled trial of enhanced progenitor-cell therapy for acute myocardial infarction.  American Heart Journal (2010 March) 159(3):354-60.
  57. Wollert, K.C., and H. Drexler.  Cell therapy for the treatment of coronary heart disease: a critical appraisal.  National Review of Cardiology (2010 April) 7(4):204-15.
  58. Surder, D., Schwitter, J., et al.  Cell-based therapy for myocardial repair in patients with acute myocardial infarction: rationale and study design of the SWiss multicenter Intracoronary Stem-cell Study in Acute Myocardial Infarction (SWISS-AMI).  American Heart Journal (2010 July) 160(1):58-64.
  59. Strauer, B.E., Yousef, M., et al.  The acute and long-term effects of intracoronary Stem-cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study.  European Journal of Heart Failure (2010 July) 12(7):721-9.
  60. ClinicalTrials.gov – To Assess Safety and Effects of Myoblast Implantation Into Myocardium Post Myocardial Infarction (MARVEL) Trial (NCT00526253) (2010 October 26).  Available at www.clinicaltrials.gov (accessed – 2011 August 25).
  61. Autologous Cell Therapy for the Treatment of Damaged Myocardium.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2011 June) Medicine 2.02.18.
History
September 2013  New 2013 BCBSMT medical policy.
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Stem-Cell Therapy for the Treatment of Damaged Myocardium