|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/6:2014
|Return to Medical Policy Index|
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
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 unable to reverse existing heart muscle damage.(1,2) Treatment with progenitor cells (ie, stem cells) offers potential benefits beyond those of standard medical care, including the potential for repair and/or regeneration of damaged myocardium. 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 after 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 also has 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 antiapoptotic and proangiogenesis properties. Clinical benefit may result if these paracrine factors limit cell death from ischemia or stimulate recovery. For example, myocardial protection can occur through modulation of inflammatory and fibrogenic processes. Alternatively, paracrine factors may 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 depends on the age of the infarct, eg, cytoprotective effects in acute ischemia and cell proliferation in chronic ischemia. Investigation of the specific factors induced by administration of progenitor cells is ongoing.
There also are 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 also is done using percutaneous, catheter-based techniques. Finally, progenitor cells may 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 progenitor cell treatment include risks of the delivery procedure (eg, thoracotomy, percutaneous catheter-based) and 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 also is a theoretical risk that tumors, such as teratomas, can arise from progenitor cells, but the actual risk in humans is currently unknown.
U.S. Food and Drug Administration (FDA) marketing clearance is not required when 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) comprises 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. MyoCell SDF-1 (BioHeart Inc.) is similar to MyoCell®, but before injection, myoblast cells are genetically modified to release excess stromal-derived factor (SDF)-1. Increased SDF-1 levels at the site of myocardial damage may accelerate recruitment of native stem cells to increase tissue repair and neovascularization. For both products, myoblast isolation and expansion occur at a single reference laboratory (BioHeart); both products are therefore subject to FDA approval. Currently, neither product is FDA-cleared. Implantation may require use of a unique catheter delivery system, MyoCath (BioHeart Inc.), that is FDA-cleared.
An allogeneic human mesenchymal stem cell (hMSC) product (Prochymal®) is being developed by Osiris Therapeutics, Inc. (Baltimore, MD) for treatment of acute myocardial infarction (AMI).(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 disease and graft-versus-host disease (GVHD), and has orphan drug status for GVHD from FDA and the European Medicines Agency. Prochymal® is being studied in phase 2 trials for the treatment of 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 FDA for GVHD and has received authorization from FDA for a phase 2 trial for treatment of AMI 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 (ie, 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 periodically 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 review since the 2008 TEC Assessment was performed through May 7, 2014.
TREATMENT WITH PROGENITOR CELLS
The overall body of evidence is characterized by many RCTs and a number of meta-analyses of these RCTs. RCTs are mostly small in size and highly variable in terms of patient population, type of progenitor cells used, and delivery method. For the purpose of this literature review, relevant clinical trials and meta-analyses are reviewed for 3 different indications: (1) acute ischemia (MI); (2) chronic ischemia; and (3) refractory/intractable angina in patients who are not candidates for revascularization.
Systematic Reviews. The 2008 TEC Assessment reviewed a total of 10 publications from 6 unique trials enrolling 556 patients with acute ischemia.(4) 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 1 week of the acute event. The REPAIR-AMI trial (described next) 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. Primary evidence from these other trials comprised physiologic outcome measures, such as change in LVEF and change in infarct size. The primary end point 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 trials, this difference reached statistical significance; in 2 trials, there was a nonsignificant increase in favor of the treatment group. Magnitude of the incremental improvement in LVEF was not large in most cases, with 5 of 6 studies reporting an incremental change of 1% to 6% and the sixth study reporting a larger incremental change of 18%.
In 2007, Lipinski et al published a 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 end point, change in LVEF, showed a statistically significant greater improvement of 3% (95% confidence interval [CI], 1.9 to 4.1; p<0.001) for the progenitor cell group. There also was 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). At least 4 meta-analyses of bone marrow progenitor cell treatment for acute MI (AMI) 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% to 6.1%. Studies also concluded that myocardial perfusion and/or infarct size were improved in the progenitor cell treatment group, although different outcome parameters were used. All 4 meta-analyses concluded that there were no demonstrable differences in clinical outcomes for patients treated with progenitor cells.
A 2012 Cochrane review included 33 RCTs (39 comparisons with 1765 participants) of bone marrow-derived stem-cell therapy for AMI.(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 cell dose, delivery, and composition. Overall, stem-cell therapy was found to improve LVEF in both the short- (<12 months; weighted mean difference [WMD], 2.9 percentage points; 95% CI, 2.0 to 3.7; I2=73%), and long-term (12-61 months; WMD, 3.8 percentage points; 95% CI, 2.6 to 4.9; I2=72%). Stem-cell treatment reduced LV 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 effect on LVEF and between the timing of stem-cell treatment and effect on LVEF. Although the quality of evidence on LVEF was rated as high, clinical significance of the change in LVEF is unclear. 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 (reinfarction, arrhythmias, hospital readmission, restenosis, target vessel revascularization), although 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.
Two 2014 systematic reviews with meta-analysis evaluated bone marrow stem-cell infusion for the treatment of AMI. Delewi et al searched the literature in February 2013 and included 16 RCTs (total N=1641).(13) De Jong et al searched the literature through August 2013 and included 22 RCTs (total N=1513).(14) Thirteen RCTs (1300 patients) appeared in both studies. In meta-analysis of placebo-controlled RCTs that reported LVEF, both studies reported statistically significant increases in LVEF with bone marrow stem-cell infusion compared with placebo: Delewi et al reported a mean difference of 2.6 percentage points (95% CI, 1.8 to 3.3; p<0.001; I2=84%) with up to 6 months of follow-up, and de Jong reported a mean difference of 2.1 percentage points (95% CI, 0.7 to 3.5; p=0.004; I2=80%) with up to 18 months of follow-up. Both studies reported statistically significant reductions in LV end systolic volumes, but only Delewi et al reported statistically significant reductions in LV end diastolic volumes. Statistical heterogeneity was substantial for all meta-analyses (I2≥55%). Based on these findings, Delewi et al concluded that intracoronary bone marrow cell infusion “is associated with improvement of LV function and remodeling in patients after STEMI.” In contrast, de Jong et al undertook additional analysis of major adverse cardiac and cerebrovascular events. With median follow-up of 6 months, there was no difference between bone marrow cell infusion and placebo in all-cause mortality, cardiac mortality, restenosis rate, thrombosis, target vessel revascularization, stroke, recurrent AMI, or implantable cardioverter defibrillator implantations. Infusion with bone marrow progenitor cells, but not bone marrow mononuclear cells, led to a statistically significant reduction in rehospitalizations for heart failure (odds ratio vs placebo, 0.14; 95% CI, 0.04 to 0.52; p=0.003). Based on these findings, de Jong et al concluded that, although safe, intracoronary infusion of bone marrow stem cells does not improve clinical outcome and clinical efficacy “needs to be defined in clinical trials.”
Key studies, including more recent RCTs not included in the meta-analyses are described next.
REPAIR-AMI trial: 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 (STEMI) meeting strict inclusion criteria from 17 centers in Germany and Switzerland.(5,6) At 12-month 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.(5,15) Three of the 204 patients were lost to follow-up (2 patients in the placebo group, 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%) in the active treatment group. Analysis of combined events (all combined events included infarction), showed significant improvement with progenitor cell therapy after 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. Also, the REPAIR-AMI trial was not powered to definitively answer the question of whether administration of progenitor cells can improve mortality and morbidity after AMI; 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 end points.
HEBE trial: In 2011, Hirsch et al reported a multicenter RCT of bone marrow or peripheral blood mononuclear cell infusion compared with standard therapy in 200 patients with AMI treated with primary PCI.(16) Mononuclear cells were delivered 3 to 8 days after MI. Blinded assessment of the primary end point, the percentage of dysfunctional LV 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; change in LV volumes, mass, or infarct size; or rates of clinical events. At 4 months, there was a similar percentage of patients with New York Heart Association (NYHA) class II or higher heart failure (19% for bone marrow, 20% for peripheral blood, 18% for control).
TIME trial: 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.(17) One hundred twenty patients with LV 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 LV function (assessed by magnetic resonance imaging [MRI]) for the cell-infusion group compared with the placebo group. Rates of major adverse events were low in all treatment groups (11 patients underwent repeat vascularization, 6 received implantable cardioverter-defibrillators). In a 2014 letter to the editor, these investigators reported prespecified 1-year outcomes.(18) Analyzable MRI data were available for 95 (79%) of 120 randomized patients. There were no statistically significant between-group differences at 6 months or 1 year in change from baseline LVEF, regional LV function in infarct and border zones, LV volumes, infarct size, or LV mass. At 1 year, similar proportions of patients in each group experienced adverse clinical outcomes (eg, placement of implantable cardioverter-defibrillator, reinfarction, or repeat revascularization), 23% of the cell-infusion group and 22% of the placebo group.
ASTAMI trial: Beitnes et al (2009) reported the unblinded 3-year reassessment of 97 patients (of 100) from the randomized ASTAMI trial.(19,20) The group treated with bone marrow progenitor cells had a larger improvement in exercise time between baseline and 3-year follow-up compared with patients who received usual care (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, 2 deaths). These 3-year findings are similar to the 12-month results from this trial.(21)
SWISS-AMI trial: In 2013, Surder et al reported 4-month results of the open-label SWISS-AMI trial.(22,23) Two hundred patients with successfully reperfused (PCI in approximately 95%) STEMI were randomized to placebo or 1 of 2 groups treated with autologous bone marrow mononuclear cells, infused 5 to 7 days or 3 to 4 weeks after the initial event. Mononuclear cells were infused directly into the infarct-related coronary artery. Mean (SD) absolute change in LVEF from baseline to 4 months (primary efficacy end point) was -0.4 (8.8) percentage points in the control group, 1.8 (8.4) percentage points in the early infusion group, and 0.8 (7.6) percentage points in the late infusion group. Differences in LVEF compared with placebo control were 1.3 percentage points (95% CI, -1.8 to 4.3; analysis of covariance [ANCOVA], p=0.42) for the early treatment group and 0.6 percentage points (95% CI, -2.6 to 3.7; ANCOVA, p=0.73) for the late treatment group. Adverse outcomes (eg, death, MI, rehospitalization for heart failure, revascularization, or cerebral infarction) occurred with approximately equal frequency in both groups.
Evidence for this question comprises numerous small RCTs and several meta-analyses that evaluated the impact of bone marrow progenitor cells on outcomes for patients with MI. Most studies included patients with AMI and reported outcomes of LVEF and/or myocardial perfusion at 3 to 6 months. These studies generally reported small to modest improvements in these intermediate outcomes, although 2 RCTs (HEBE, TIME) found no benefit of stem-cell treatment for AMI. No trial published after the 2008 TEC Assessment has reported benefits in clinical outcomes, such as mortality, adverse cardiac outcomes, exercise capacity, or quality of life. Overall, this evidence suggests that progenitor cell treatment may be a promising intervention, but robust data on clinical outcomes are lacking. High-quality RCTs powered to detect differences in clinical outcomes are needed to answer this question.
Systematic Reviews. The 2008 TEC Assessment included a total of 6 trials that randomly assigned 231 patients with 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 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 trials of progenitor cell treatment versus standard medical care, the range of incremental improvement in LVEF was 2.7% to 6.0%. For trials of progenitor cell treatment plus CABG versus CABG alone, the range of improvement in LVEF was 2.5% to 10.1%. Only 1 trial reported comparative analysis of data on the change in size of ischemic myocardium, finding no difference.(24) Only 2 of 6 trials reported any clinical outcomes, and both trials reported on change in NYHA class between groups, discussed next.(25,26)
In 2014, Fisher et al published a Cochrane review of autologous stem-cell therapy for chronic ischemic heart disease and congestive heart failure.(27) Literature was searched through March 2013, and 23 RCTs (total N=1255) were included. Overall quality of the evidence was considered low because there were few events of interest (deaths and hospital readmissions). In long-term (≥12 months), but not short-term (<12 months), follow-up, there were statistically significant reductions in all-cause mortality (relative risk [RR], 0.3; 95% CI, 0.1 to 0.5; p<0.001; I2=0%) and rehospitalizations due to heart failure (RR=0.3; 95% CI, 0.1 to 0.9; p=0.039; I2=0%) in patients who received stem-cell infusion compared with controls (no stem-cell infusion). Statistically significant improvements in LVEF and in NYHA classification in stem-cell groups were observed at both 6 months and 1 year or later. Evidence was considered of moderate quality for these outcomes, but statistical heterogeneity was moderate to substantial. Additional research in larger studies is required to confirm these results.
Representative individual RCTs are discussed next.
Assmus et al (2006): The largest trial on chronic ischemia that was included in the 2008 TEC Assessment was Assmus et al (REPAIR-AMI Investigators).(25) This was a single-center, open-label trial that enrolled 75 patients into 3 groups: treatment with bone marrow-derived progenitor cells, treatment with CPCs, or usual medical care. Improvements in mean NYHA class (0-4 scale) were 0.25 for the bone-marrow treatment group and 0.2 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.
CELLWAVE: Assmus et al (2013) reported a phase 1/2 double-blind randomized trial in patients with chronic heart failure.(28) 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. Patients were randomized to low-dose (n=42), high-dose (n=40), or sham (n=21) shock wave pretreatments 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. Improvement in LVEF at 4 months was significantly greater in groups that received shock wave plus mononuclear cells (3.2 percentage points; 95% CI, 2.0 to 4.4), compared with the placebo infusion group (1.0 percentage point; 95% CI, -0.3% to 2.2%; p=0.02). LVEF improved in 93% of patients receiving shock wave plus mononuclear cells compared with 64% of patients who received shock wave plus placebo infusion, and 64% of patients who received sham shockwave plus 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 NYHA class showed a modest improvement with low-dose shock wave plus mononuclear cells (-0.3) and with high-dose shock wave plus mononuclear cells (-0.4).
STAR-Heart: Results from the intracoronary stem-cell transplantation in patients with chronic heart failure (STAR-heart) trial were reported by Strauer et al in 2010.(29) In this nonrandomized 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 undergo follow-up testing served as controls. Mean time between PCI for infarction and admission to the tertiary clinic was 8.5 years. For BMC therapy, mononuclear cells were isolated and identified (included CD34-positive cells, AC133-positive cells, 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 measurement of late potentials, short-term heart rate variability, and 24-hour Holter ECG. At up to 5 years after intracoronary BMC therapy, there was significant improvement in hemodynamics (LVEF, cardiac index), exercise capacity (NYHA classification), oxygen uptake, and LV contractility compared with controls. There also was a significant decrease in long-term mortality in the BMC-treated patients (0.75% per year) compared with the control group (3.68% per year, p<0.01). These results are encouraging, especially in regard to the mortality outcomes, because this is the first controlled trial that reported 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 at baseline. Additionally, 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.
For chronic ischemic heart disease, there is limited evidence on clinical outcomes. The studies reviewed reported only a handful of clinical outcome events, too few for meaningful analysis. Other clinical outcomes, such as change in 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 also is being investigated in patients with intractable angina who are not candidates for revascularization.
ACT34-CMI trial: In 2011, Losordo et al reported an industry-funded multicenter, randomized double-blind phase 2 trial that included 167 patients with refractory angina and no suitable revascularization options.(30) Patients were randomized to 1 of 2 doses of mobilized autologous CD34+ cells from peripheral blood (1´105 or 5´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. Weekly 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). Weekly 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 end points 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. Time to onset of angina during treadmill exercise was not significantly different between either transplanted group and the placebo group. 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 with controls (40.8%), and some 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 between either transplanted group and the placebo group. 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 patients is needed to confirm these results.
van Ramshorst et al: A randomized double-blind trial of autologous bone marrow-derived mononuclear cell or placebo infusion was reported in 2009.(31) Fifty patients who had intractable angina despite optimal medical therapy and were not candidates for revascularization therapy were enrolled. The main outcomes were measures of myocardial perfusion derived from SPECT scanning at rest and SPECT after exercise stress at 3 months posttreatment. Secondary outcomes included LVEF, 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 with placebo. For the primary outcome, a significantly greater improvement was found in 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 at-rest perfusion score (mean difference, -0.32; 95% CI, -0.87 to 0.23; p=0.25). There also was 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 [SD] change, 3%  vs -1% , 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).
Evidence on stem-cell therapy for refractory angina includes at least 2 RCTs, including a phase 2 RCT that examined 2 doses of mononuclear cells compared with 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 uncertainty of the findings. Additional, larger studies are needed to determine with greater certainty whether progenitor-cell therapy improves health outcomes in patients with refractory angina.
TREATMENT WITH G-CSF
The body of evidence on the use of granulocyte colony stimulating factor (G-CSF) as a treatment for coronary heart disease is smaller compared with that for the use of stem cells. A few RCTs on treatment of acute ischemia report physiologic outcomes. Additionally, meta-analyses of the available trials have been published.
Moazzami et al (2013) published a Cochrane review of G-CSF for AMI.(32) Literature was searched in November 2010, and 7 small, placebo-controlled RCTs (total N=354) were included. Overall risk of bias was considered low. All-cause mortality did not differ between groups (RR=0.6; 95% CI, 0.2 to 2.8; p=0.55; I2=0%). Similarly, change in LVEF, LV end systolic volume, and LV end diastolic volume did not differ between groups. Evidence was insufficient to draw conclusions about the safety of the procedure. The study indicated a lack of evidence for benefit of G-CSF therapy in patients with AMI.
Subsequent to the Cochrane review, Achilli et al published 6-month(33) and 3-year(34) results of their multicenter, placebo-controlled RCT, STEM-AMI. Sixty consecutive patients with first anterior STEMI, who underwent primary PCI within 12 hours after symptom onset and had LVEF of 45% or less were enrolled. Patients were randomized 1:1 to G-CSF 5 mg/kg body weight administered subcutaneously starting within 12 hours after PCI and continuing twice daily for 5 days, or placebo. Standard STEMI care was provided to all patients. Among cardiac MRI outcomes (LVEF, LV end systolic volume, LV end diastolic volume) at 6 months and 3 years, only LV end diastolic volume at 3 years was statistically significantly improved in the G-CSF group compared with placebo. At 3 years, there was no statistical difference in clinical outcomes, including death, reinfarction, target vessel restenosis or revascularization, heart failure, and stroke. The study was likely underpowered to detect statistically significant differences in most of these parameters.
The small number of trials that use G-CSF as a treatment for acute ischemia (MI) generally do not report an improvement in physiologic or clinical outcomes, and a Cochrane review of 7 placebo-controlled trials reported a lack of evidence for benefit. This evidence is not supportive of the use of G-CSF in the treatment of acute 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.(35) Issues to be resolved in these second- and third-generation cell therapy trials include patient selection, cell type, procedural details, clinical end points, 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 suggested 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 also have identified other publications that describe ongoing RCTs.
Taljaard et al (2010) reported the rationale and design of what is described as the first randomized placebo-controlled trial of “enhanced” progenitor cell therapy for AMI.(36) The “enhanced angiogenic cell therapy in acute myocardial infarction” trial (ENACT-AMI; NCT00936819) is a phase 2, double-blind, RCT using coronary injection of autologous early endothelial progenitor cells for patients who have suffered large MI. One hundred patients will be randomized 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. Estimated completion is December 2016.
The PERFECT phase 3 randomized controlled trial (NCT00950274) will assess intramyocardial bone marrow stem-cell therapy in combination with CABG.(37) The trial is expected to enroll 142 patients with completion in December 2014.
BAMI (Effect of Intracoronary Reinfusion of Bone Marrow-Derived Mononuclear Cells on All-Cause Mortality in Acute Myocardial Infarction, NCT01569178) is a large phase 3 trial that will be conducted in Europe.(38) Expected enrollment is 3000 patients with completion in May 2018.
The MARVEL phase2/3 trial (NCT00526253) is a double-blind RCT of MyoCell. Approximately 170 patients with congestive heart failure at least 2 months after MI were randomized into 1 of 3 treatment groups: MyoCell at a dose of 400 or 800 million cells or control (HypoThermasol, acellular biopreservation media), administered by injection catheter via femoral artery directly into the myocardium. Final data collection for the primary outcomes, 6-minute walk test and quality of life, was February 2014.
CCTRN and the Cardiothoracic Surgical Trials Network are co-sponsoring a phase 2 double-blind RCT of mesenchymal precursor cell injection (bone marrow-derived) during placement of a left ventricular assist device (LVAD; NCT01442129). Thirty patients from U.S centers who are scheduled to have a LVAD implanted as either bridge-to-transplant or destination have been randomized to active treatment or sham control. Primary outcomes include intervention-related adverse events and ability to tolerate wean from LVAD support for 30 minutes without signs or symptoms of hypoperfusion at 90 days. Although the trial is listed as active, estimated completion date was March 2014.
Osiris is conducting a phase 2, double-blind, placebo-controlled RCT of Prochymal® in patients who have had a first acute MI (within 7 days) (NCT00877903). Estimated enrollment is 220 patients with trial completion in February 2016.
Researchers in London are conducting a phase 2, double-blind, placebo-controlled RCT of autologous bone marrow-derived stem-cell infusion for acute anterior MI (REGENERATE-AMI; NCT00765453).(39) Estimated enrollment is 100 patients, and trial completion is expected June 2014.
The phase 1/2 placebo-controlled Allogeneic Heart Stem Cells to Achieve Myocardial Regeneration (ALLSTAR, NCT01458405) trial will assess the efficacy of allogeneic cardiosphere-derived cells in 270 patients with ventricular dysfunction after MI.(38) Estimated enrollment is 274 with completion in December 2015.
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 impacts on clinical outcomes. For acute ischemic heart disease, limited evidence on clinical outcomes suggests that there may be benefits in improving left ventricular ejection fraction, reducing recurrent myocardial infarction, 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 2 randomized controlled trial that examined 2 doses of mononuclear cells compared with 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 several areas of uncertainty, including patient selection, cell type, and procedural details (eg, timing and mode of delivery). Accumulating evidence on this therapy suggests that progenitor cell therapy is may be a promising intervention, but that ultimate effects on health outcomes are still uncertain. Clinical significance of improvements in physiologic parameters has yet to be demonstrated, and there is very little evidence demonstrating benefit in clinical outcome. Moreover, evidence remains primarily limited to short-term effects; although 1 meta-analysis reported durable (≥1 year) improvements in congestive heart failure classification, this result requires replication, and other durable improvements in clinical outcomes (death, hospitalizations for heart failure) were based on low-quality evidence. Therefore, progenitor (stem) cell therapy for the treatment of damaged or ischemic myocardium is considered investigational.
Practice Guidelines and Position Statements
American College of Cardiology Foundation/American Heart Association
In 2013, ACCF and AHA issued joint guidelines for the management of STEMI.(40) Progenitor cell therapy is not recommended.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- Lee MS, Makkar RR. Stem-cell transplantation in myocardial infarction: a status report. Ann Intern Med 2004; 140(9):729-37.
- Mathur A, Martin JF. Stem cells and repair of the heart. Lancet 2004; 364(9429):183-92.
- 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.
- Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Progenitor cell therapy for treatment of myocardial damage due to ischemia. TEC Assessments 2008; Volume 23, Tab 4.
- Schachinger V, Erbs S, Elsasser A et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006; 355(12):1210-21.
- Schachinger V, Erbs S, Elsasser A 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. Eur Heart J 2006; 27(23):2775-83.
- Lipinski MJ, Biondi-Zoccai GG, Abbate A et al. Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. J Am Coll Cardiol 2007; 50(18):1761-7.
- Singh S, Arora R, Handa K et al. Stem cells improve left ventricular function in acute myocardial infarction. Clin Cardiol 2009; 32(4):176-80.
- Kang S, Yang YJ, Li CJ et al. Effects of intracoronary autologous bone marrow cells on left ventricular function in acute myocardial infarction: a systematic review and meta-analysis for randomized controlled trials. Coron Artery Dis 2008; 19(5):327-35.
- Martin-Rendon E, Brunskill SJ, Hyde CJ et al. Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J 2008; 29(15):1807-18.
- Zhang SN, Sun AJ, Ge JB et al. Intracoronary autologous bone marrow stem cells transfer for patients with acute myocardial infarction: a meta-analysis of randomised controlled trials. Int J Cardiol 2009; 136(2):178-85.
- Clifford DM, Fisher SA, Brunskill SJ et al. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev 2012; 2:CD006536.
- Delewi R, Hirsch A, Tijssen JG et al. Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis. Eur Heart J 2014; 35(15):989-98.
- de Jong R, Houtgraaf JH, Samiei S et al. Intracoronary stem cell infusion after acute myocardial infarction: a meta-analysis and update on clinical trials. Circ Cardiovasc Interv 2014; 7(2):156-67.
- Assmus B, Rolf A, Erbs S et al. Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction. Circ Heart Fail 2010; 3(1):89-96.
- 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.
- Traverse JH, Henry TD, Pepine CJ et al. One-year follow-up of intracoronary stem cell delivery on left ventricular function following ST-elevation myocardial infarction. JAMA 2014; 311(3):301-2.
- 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):1199-209.
- Beitnes JO, Hopp E, Lunde K et al. Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomised, controlled study. Heart 2009; 95(24):1983-9.
- 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.
- Surder 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. Circulation 2013; 127(19):1968-79.
- 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.
- 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.
- Fisher SA, Brunskill SJ, Doree C et al. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev 2014; 4:CD007888.
- 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. Circulation 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.
- Moazzami K, Roohi A, Moazzami B. Granulocyte colony stimulating factor therapy for acute myocardial infarction. Cochrane Database Syst Rev 2013; 5:CD008844.
- Achilli F, Malafronte C, Lenatti L et al. Granulocyte colony-stimulating factor attenuates left ventricular remodelling after acute anterior STEMI: results of the single-blind, randomized, placebo-controlled multicentre STem cEll Mobilization in Acute Myocardial Infarction (STEM-AMI) Trial. Eur J Heart Fail 2010; 12(10):1111-21.
- Achilli F, Malafronte C, Maggiolini S et al. G-CSF treatment for STEMI: final 3-year follow-up of the randomised placebo-controlled STEM-AMI trial. Heart 2014; 100(7):574-81.
- Wollert KC, Drexler H. Cell therapy for the treatment of coronary heart disease: a critical appraisal. Nat Rev Cardiol 2010; 7(4):204-15.
- 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.
- Hamshere S, Choudhury T, Jones DA et al. A randomised double-blind control study of early intracoronary autologous bone marrow cell infusion in acute myocardial infarction (REGENERATE-AMI). BMJ Open 2014; 4(2):e004258.
- O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61(4):e78-140.
|CPT||No specific CPT codes|
|ICD-9 Diagnosis||Investigational for all uses|
|ICD-10-CM (effective 10/1/15)||Investigational for all diagnoses|
|ICD-10-PCS (effective 10/1/15)||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|
|6/12/14||Replace policy||Policy updated with literature review through May 7, 2014; references 13-14, 22, 27, 32-34, and 39-40 added; policy statements unchanged|