|MP 2.02.18||Progenitor Cell Therapy for the Treatment of Damaged Myocardium due to Ischemia|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/6:2013
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Progenitor cell therapy describes the use of multipotent cells of various cell lineages (autologous or allogeneic) for tissue repair and/or regeneration. Progenitor 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. (1, 2) Treatment with progenitor cells (i.e., stem 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, bone marrow cells, circulating blood-derived progenitor 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 cardiomyocytes 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 are also 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 situations in which autologous cells are processed on site with existing laboratory procedures and injected with existing catheter devices. However, there are several products that require FDA approval. MyoCell™ (BioHeart, Inc., Sunrise, FL) 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 myocardial infarction (MI). (3) Prochymal (also referred to as Provacel®) is a highly purified preparation of ex vivo cultured adult hMSCs 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 (AMI), pulmonary disease, and type 1 diabetes.
MultiStem® (Athersys) is an allogeneic bone marrow-derived adherent adult stem-cell product. MultiStem has received orphan drug status from the FDA for GVHD and has received authorization from the FDA for a Phase II trial for treatment of acute myocardial infarction with an adventitial delivery system.
Progenitor cell therapy, including but not limited to skeletal myoblasts or hematopoietic stem cells, is considered investigational as a treatment of damaged myocardium.
Infusion of growth factors (i.e., granulocyte colony stimulating factor [GCSF]) is considered investigational as a technique to increase the numbers of circulating hematopoietic stem cells as treatment of damaged myocardium.
There are no specific codes for this procedure, either describing the laboratory component of processing the harvested autologous cells, or for the implantation procedure. 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.
BlueCard/National Account Issues
Progenitor cell implantation/transplantation is a specialized service that may prompt request for an out of network referral.
The evidence review for this policy is derived in part from a 2008 TEC Assessment, (4) with the literature updated annually since the 2008 TEC Assessment using the MEDLINE database. The Assessment was a systematic review that included randomized, controlled trials (RCTs) of progenitor cell therapy versus standard medical care for treatment of either acute or chronic myocardial ischemia. The 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). The most recent literature update since the 2008 TEC Assessment was performed through March 2012.
The 2008 TEC Assessment reviewed a total of 10 publications from 6 unique studies enrolling 556 patients with acute ischemia. (4) These trials had similar inclusion criteria, enrolling patients with acute ST-segment elevation myocardial infarction (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 1 week of the acute event. The REPAIR-AMI trial (described below) is the largest trial included in the TEC Assessment and had the largest number of clinical outcomes reported. (5, 6) The other 5 trials included in the TEC Assessment 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 6 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 4 of the 6 studies, this difference reached statistical significance, while in 2 studies there was a nonsignificant increase in favor of the treatment group. The magnitude of the incremental improvement in LVEF was not large in most cases, with 5 of the 6 studies reporting an incremental change of 1% to 6% and the final study reporting a larger incremental change of 18%.
In 2007 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. (7) This analysis included 10 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% confidence interval [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, respectively, p<0.001). At least 4 meta-analyses of bone marrow progenitor cell treatment for acute MI have been published since the 2008 TEC Assessment, each examining between 6 and 13 RCTs. (8-11) All 4 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 4 of the meta-analyses concluded that there were no demonstrable differences in clinical outcomes for patients treated with progenitor cells.
A 2012 updated Cochrane review included 33 RCTs (39 comparisons with 1,765 participants) on bone marrow-derived stem-cell therapy for acute MI. (12) Twenty-five trials compared stem/progenitor cell therapy with no intervention, and 14 trials compared the active intervention with placebo. There was a high degree of statistical and clinical heterogeneity in the included trials, including variability in the cell dose, delivery and composition. Overall, stem-cell therapy was found to improve LVEF in both the short- (weighted mean difference of 1.78%) and long-term (12 to 61 months, weighted mean difference of 3.07%). Stem-cell treatment reduced left-ventricular end systolic and end-diastolic volumes at certain times and reduced infarct size in long-term follow-up. There were positive correlations between mononuclear cell dose infused and the effect on LVEF and between the timing of stem-cell treatment and the effect on LVEF. Although the quality of evidence on LVEF was rated as high, the clinical significance of the change in LVEF is unclear. The quality of evidence on health outcomes was rated as moderate. Stem/progenitor cell treatment was not associated with statistically significant changes in the incidence of mortality or morbidity (re-infarction, arrhythmias, hospital re-admission, restenosis, and target vessel revascularization), although the studies may have been underpowered to detect differences in clinical outcomes. Due to variability in outcomes measured, it was not possible to combine data on health related quality of life or performance status.
Key studies, including studies published after the literature search was conducted for the 2012 Cochrane review, are described below.
REPAIR-AMI: This was a double-blinded trial that infused bone marrow-derived progenitor cells or a placebo control infusion of the patient’s own serum and enrolled 204 patients with acute ST-segment elevation MI meeting strict inclusion criteria from 17 centers in Germany and Switzerland. (5, 6) 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, both respectively), as well as for the composite outcome of death, MI, and revascularization (24 vs. 42, p<0.009, respectively). Two-year clinical outcomes from the REPAIR-AMI trial, performed according to a study protocol amendment filed in 2006, were reported in 2010. (5, 13) Three of the 204 patients were lost to follow-up (2 patients in the placebo group and 1 in the progenitor cell group). A total of 11 deaths occurred during the 2-year follow-up, 8 in the placebo group and 3 in the progenitor cell group. There was a significant reduction in MI (0% vs. 7%), and a trend toward a reduction in rehospitalizations 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 (AMI). 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 AMI, and the relatively small sample size might limit the detection of infrequent safety events. Thus, this analysis should be viewed as hypothesis-generating, providing the rationale to design a larger trial that addresses clinical endpoints.
HEBE: In 2011, Hirsch et al. reported a multicenter RCT of bone marrow or peripheral blood mononuclear cells compared with standard therapy in 200 patients with acute MI treated with primary percutaneous coronary intervention. (14) Mononuclear cells were delivered between 3 and 8 days after MI. Blinded assessment of the primary endpoint, the percentage of dysfunctional left ventricular segments that had improved segmental wall thickening at 4 months, found no significant difference between either of the treatment groups (38.5% for bone marrow, 36.8% for peripheral blood) and control (42.4%). There was no significant difference between the groups in LVEF, or changes in left ventricular volumes, mass or infarct size, or in rates of clinical events. At 4 months, there was a similar percentage of patients in New York Heart Association (NYHA) class II or higher (19% for bone marrow, 20% for peripheral blood, and 18% for control).
TIME: Investigators from the Cardiovascular Cell Therapy Research Network (CCTRN) reported 2012/2013 results from the randomized, double-blind, controlled, Timing in Myocardial Infarction Evaluation (TIME) trial. (15) One hundred and twenty patients with left ventricular dysfunction were randomized to placebo or to bone marrow mononuclear cell administration in the infarct-related artery at either 3 or 7 days after PCI. At 6 months there was no significant difference in LVEF or left ventricular function (assessed by magnetic resonance imaging, MRI) for the mononuclear cell groups compared to placebo. Rates of major adverse events were low in all treatment groups (11 patients underwent repeat vascularization and 6 received implantable cardioverter-defibrillators).
ASTAMI: Beitnes and colleagues reported the unblinded 3-year reassessment of 97 patients (out of 100) from the randomized ASTAMI trial. (16, 17) The group treated with bone marrow progenitor cells had a larger improvement in exercise time between baseline and 3-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 (3 infarctions and 2 deaths). These 3-year findings are similar to the 12-month results from this trial. (18)
Section Summary: Literature updates since the 2008 TEC Assessment have identified numerous small 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 LVEF and/or myocardial perfusion at 3–6 months. These studies generally reported small to modest improvements in these intermediate outcomes, although one RCT from 2011 found no benefit of stem-cell treatment for acute MI. None of the trials published after the 2008 TEC Assessment have reported benefits in clinical outcomes, such as mortality, adverse cardiac outcomes, exercise capacity, or quality of life.
The 2008 TEC Assessment included a total of 6 trials that randomly assigned 231 patients for treatment of chronic ischemic heart disease. (4) Three trials randomly assigned 125 patients to progenitor cell therapy versus standard medical care. The other 3 trials randomly assigned 106 patients undergoing coronary artery bypass grafting (CABG) to CABG plus progenitor cell treatment versus CABG alone. Four trials employed bone marrow-derived progenitor cells as the donor cell source, 1 trial used circulating progenitor cells (CPCs), and the final trial included both a CPC treatment group and a bone marrow-derived treatment group. The primary physiologic measurement reported in these trials was change in LVEF. In all 6 trials there was a greater improvement in LVEF for the treatment group compared with the control group, and in 4 of 6 trials, this difference reached statistical significance. For the 3 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 1 trial reported comparative analysis of data on the change in size of ischemic myocardium, finding no difference in size of ischemic myocardium between treatment groups. (19) Only 2 of the 6 studies reported any clinical outcomes, and both trials reported on change in NYHA class between groups. (20, 21)
Assmus et al.: The largest trial on chronic ischemia that was included in the 2008 TEC Assessment was Assmus et al. (REPAIR-AMI Investigators), which was a single-center, unblinded trial that enrolled 75 patients into 3 groups; treatment with bone marrow-derived progenitor cells, treatment with circulating progenitor cells, or usual medical care. (20) Assmus et al. 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). This publication also reported on adverse cardiac events, but there were extremely small numbers of any of these clinical outcomes and no differences between groups.
Assmus and colleagues also reported in 2013 the CELLWAVE Phase I/II double-blind randomized trial in patients with chronic heart failure. This trial tested the hypothesis that shock wave-facilitated intracoronary cell therapy improves LVEF to a greater degree than does nonshock wave-facilitated cell therapy, due to an effect of shock wave treatment on facilitating the homing ability of progenitor cells to their target. (22) Patients were randomized to low-dose (n=42), high-dose (n=40), or sham (n=21) shock wave pre-treatments of the left ventricle. Twenty-four hours later, patients assigned to receive shock wave treatment were randomized to an intracoronary infusion of either placebo or bone marrow-derived mononuclear cells, and patients assigned to the sham shock wave treatment were given an infusion of bone marrow-derived mononuclear cells. The improvement in LVEF at 4 months was significantly greater in the groups that received shock wave + mononuclear cells (3.2%), compared with the placebo infusion group (1.0%). LVEF improved in 93% of patients receiving shock wave + mononuclear cells compared to 64% of patients who received shock wave + placebo infusion, and 64% of patients who received sham shockwave + mononuclear cells. Regional wall thickening improved significantly in the shock wave-treated mononuclear cell group (3.6%), but not in the placebo infusion group (0.6%). Symptomatic heart failure status assessed by the NYHA class showed a modest improvement with low-dose shock wave + mononuclear cells (-0.3) and with high-dose shock wave + mononuclear cells (-0.4).
STAR-Heart: 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. (23) 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 3, 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 5 years after intracoronary BMC therapy, there was a significant improvement in hemodynamics (LVEF, cardiac index), exercise capacity (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 2 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.
Section Summary. 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.
Stem-cell therapy is also being investigated in patients with intractable angina who are not candidates for revascularization.
ACT34-CMI: In 2011, Losordo et al. reported an industry-funded multicenter randomized double-blind Phase II study that included 167 patients with refractory angina and no suitable revascularization options. (24) Patients were randomized to 1 of 2 doses of mobilized autologous CD34+ cells from peripheral blood (1 x 105 or 5 x 105) or to placebo injections. The cell dose was delivered via intramyocardial injection into 10 sites identified as viable, ischemic areas of the myocardium by electromechanical endocardial mapping. One patient died during the procedure. Angina frequency was documented by daily phone calls to an interactive voice responsive system. The primary outcome was weekly angina frequency at 6 months. Angina frequency was significantly lower in the the low-dose group than in placebo-treated patients at both 6 months (6.8 vs. 10.9) and 12 months (6.3 vs. 11.0). Angina frequency in the high-dose group tended to be lower at 6 (8.3) and 12 (7.2) months, but this did not attain statistical significance. Secondary endpoints included exercise tolerance testing, use of antianginal medications, Canadian Cardiovascular Society (CCS) functional class, and health-related quality of life. Improvement in exercise tolerance was signficantly greater in low-dose patients than in placebo-treated patients at 6 (139 vs. 69 seconds) and 12 months (140 vs. 58 seconds). Exercise tolerance in the high-dose group tended to be higher at 6 (110 seconds) and 12 months (103 seconds), but this did not reach statistical significance. The time to onset of angina during treadmill exercise was not significantly different for either the low- or high-dose groups. The percentage of patients who improved on the Seattle Angina Questionnaire was greater in the low- (69.2%) and high-dose groups (67.3%) compared to controls (40.8%), and some of the measures of changes in CCS class were significantly better in both the low- and high-dose groups. Most parameters from single-proton emission computed tomography (SPECT) were not significantly different. Mortality at 12 months was 5.4% in the placebo-treated group with no deaths among cell-treated patients (p=0.107). Interpretation of these results is limited by the trend (p=0.091) for a greater percentage of patients in the control group (41.1%) to have had prior heart failure than the low- (21.8%) or high-dose (28.6%) groups. Additional study in a larger number of subjects is needed to confirm these results.
van Ramshorst et al.: A randomized, double-blind trial of autologous bone marrow-derived mononuclear cells or placebo that included 50 patients with intractable angina despite optimal medical therapy and who were not candidates for revascularization therapy was reported in 2009. (25) The main outcomes were measures of myocardial perfusion derived from SPECT scanning at rest and SPECT after exercise stress at 3 months post-treatment. Secondary outcomes included LVEF, Canadian Cardiovascular Society (CCS) angina class, and Seattle Angina Quality-of-Life Questionnaire measured at 6 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, respectively, p=0.03). At 6 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%, respectively, p=0.04).
Section Summary. The evidence on stem-cell therapy for refractory angina includes at least 2 RCTs, including a Phase II RCT that examined 2 doses of mononuclear cells compared to placebo. Functional outcomes such as angina frequency and exercise tolerance showed modest improvements with the lower dose of mononuclear cells. Limitations of the literature include the small size of available trials, along with differences between groups at baseline that increase the uncertainty of the findings. Additional studies with a larger number of subjects are needed to determine with greater certainty whether progenitor-cell therapy improves health outcomes in patients with refractory angina.
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. (26) Issues to be resolved in these 2nd and 3rd 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.
The rationale and design of the “Swiss multicenter intracoronary stem cells study in acute myocardial infarction” (SWISS-AMI) was reported in 2010. (27) In this trial, 192 patients with AMI will be randomized to control or 1 of 2 groups treated with autologous bone marrow mononuclear cells (5 to 7 days or 3 to 4 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 4 months; secondary endpoints include changes in infarct size, regional myocardial thickness, and wall motion at 4 and 12 months. Major adverse cardiac events will be assessed at 4, 12, and 24 months.
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. (28) 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 PERFECT Phase III randomized controlled trial (NCT00950274) will assess intramyocardial bone marrow stem-cell therapy in combination with coronary artery bypass grafting. (29) The trial is expected to enroll 142 patients with completion in December 2013.
BAMI (Effect of Intracoronary Reinfusion of Bone Marrow-derived Mononuclear Cells on All-Cause Mortality in Acute Myocardial Infarction, NCT01569178) is a large Phase II trial that will be conducted in Europe. (30)
The placebo-controlled Allogeneic Heart Stem Cells to Achieve Myocardial Regeneration (ALLSTAR, NCT01458405) will assess the efficacy of allogeneic cardiosphere-derived cells in 270 patients with ventricular dysfunction after MI. (30)
Progenitor cell therapy has been tested in patients with acute ischemia, chronic ischemia, and refractory angina. For all these conditions, there is a similar pattern of outcomes, with modest improvements demonstrated on physiologic outcomes, but limited evidence on clinical outcomes. For acute ischemic heart disease, the limited evidence on clinical outcomes suggests that there may be benefits in improving left ventricular ejection fraction (LVEF), reducing recurrent myocardial infarction (MI), decreasing the need for further revascularization, and perhaps even decreasing mortality. For chronic ischemic heart disease, only a handful of clinical outcome events have been reported across the included studies, too few for meaningful analysis. For refractory angina, evidence from a Phase II randomized controlled trial (RCT) that examined 2 doses of mononuclear cells compared to placebo reported that functional outcomes such as angina frequency and exercise tolerance showed modest improvements with the lower dose of mononuclear cells.
Progenitor cell therapy for the treatment of damaged and ischemic 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). The accumulating evidence on this therapy indicates that progenitor cell therapy is a promising intervention, but that the ultimate effects on health outcomes are still uncertain. The clinical significance of the improvement in the physiologic 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, progenitor (stem) cell therapy for the treatment of damaged or ischemic myocardium is considered investigational.
Medicare National Coverage
There is no national coverage determination.
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- Hare JM, Traverse JH, Henry TD et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 2009; 54(24):2277-86.
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- Hirsch A, Nijveldt R, van der Vleuten PA et al. Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood compared with standard therapy in patients after acute myocardial infarction treated by primary percutaneous coronary intervention: results of the randomized controlled HEBE trial. Eur Heart J 2011; 32(14):1736-47.
- Traverse JH, Henry TD, Pepine CJ et al. 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):2380-9.
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- Lunde K, Solheim S, Aakhus 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. Am Heart J 2007; 154(4):710 e1-8.
- 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):I101-7.
- Assmus B, Honold J, Schachinger V et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 2006; 355(12):1222-32.
- Patel AN, Geffner L, Vina RF et al. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study. J Thorac Cardiovasc Surg 2005; 130(6):1631-8.
- Assmus B, Walter DH, Seeger FH et al. Effect of shock wave-facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: the CELLWAVE randomized clinical trial. JAMA 2013; 309(15):1622-31.
- Strauer BE, Yousef M, Schannwell CM. The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail 2010; 12(7):721-9.
- Losordo DW, Henry TD, Davidson C et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res 2011; 109(4):428-36.
- van Ramshorst J, Bax JJ, Beeres SL et al. Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial. JAMA 2009; 301(19):1997-2004.
- Wollert KC, Drexler H. Cell therapy for the treatment of coronary heart disease: a critical appraisal. Nat Rev Cardiol 2010; 7(4):204-15.
- Surder D, Schwitter J, Moccetti T et al. Cell-based therapy for myocardial repair in patients with acute myocardial infarction: rationale and study design of the SWiss multicenter Intracoronary Stem cells Study in Acute Myocardial Infarction (SWISS-AMI). Am Heart J 2010; 160(1):58-64.
- Taljaard M, Ward MR, Kutryk MJ 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. Am Heart J 2010; 159(3):354-60.
- Donndorf P, Kaminski A, Tiedemann G et al. Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT Phase III randomized multicenter trial: study protocol for a randomized controlled trial. Trials 2012; 13:99.
- Marban E, Malliaras K. Mixed results for bone marrow-derived cell therapy for ischemic heart disease. JAMA 2012; 308(22):2405-6.
|CPT||No specific CPT codes|
|ICD-9 Diagnosis||Investigational for all uses|
|ICD-10-CM (effective 10/1/14)||Investigational for all diagnoses|
|ICD-10-PCS (effective 10/1/14)||No specific code found for intracoronary infusion of stem cells|
|30243AZ||Transfusion, central vein, percutaneous, embryonic stem cells|
|30243X0, 30243X1, 30243Y0, 30243Y1||Transfusion, central vein, percutaneous, cord blood and hematopoietic stem cells, code list|
|Type of Service||Surgery|
|Place of Service||Inpatient|
|04/16/04||Add policy to Medicine section, Cardiology subsection||New policy|
|03/15/05||Replace policy||Policy updated with literature search. No change in policy statement. Reference 13 added|
|12/14/05||Replace policy||Policy updated with literature search. No change in policy statement.|
|02/15/07||Replace policy||Policy updated with literature search; reference numbers 14-20 added; no change in policy statement|
|07/10/08||Replace policy||Description, Rationale, and Reference sections completely revised, based on 2008 TEC Assessment. No change in policy statement|
|07/09/09||Replace policy||Policy updated with literature search; references 29-38 added. No change to policy statements|
|07/08/10||Replace policy||Policy updated with literature search through May 2010; references added, deleted, and reordered; policy statements unchanged|
|6/9/11||Replace policy||Policy updated with literature search through April 2011; references added and reordered; policy statements unchanged|
|06/14/12||Replace policy||Policy updated with literature search through March 2012; references 12, 14, 22 added and references reordered; 1 reference removed; policy statements unchanged|
|6/13/13||Replace policy||Policy updated with literature search through May 15, 2013; references 15, 22, 29 and 30 added and references reordered; policy statements unchanged|