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Blue Cross and Blue Shield of Montana (BCBSMT) considers stem-cell therapy (autologous or allogeneic), including but not limited to skeletal myoblasts or hematopoietic stem-cells, experimental, investigational and unproven as a treatment of damaged myocardium.
Infusion of growth factors (i.e., granulocyte colony stimulating factor [GCSF]) is considered experimental, investigational and unproven as a technique to increase the numbers of circulating hematopoietic stem-cells as treatment of damaged myocardium.
There are no specific codes for this procedure, either describing the laboratory component of processing the harvested cells or implantation of cells. In some situations, the implantation may be an added component of a scheduled coronary artery bypass graft (CABG); in other situations, the implantation may be performed as a unique indication for a cardiac catheterization procedure.
The investigation of stem- (i.e., progenitor-) cell transplantation for the treatment of damaged myocardium is still at its preliminary stages in human subjects, in terms of investigating basic scientific issues, procedural issues, and conducting outcomes studies to determine the safety and efficacy of the techniques.
From a basic science viewpoint, it must be shown that these transplanted autologous cells can incorporate themselves into the heart, and survive, mature and electromechanically couple to each other. For example, preliminary studies have suggested that transplanted myoblasts are potentially arrhythmogenic, and for this reason, the Investigational Device Exemption (IDE) trials discussed in the Description section require that all patients receive a cardiac defibrillator. Patient selection criteria are still evolving. For example, in the immediate post-infarct period, autologous cell transplant might function to alter the cardiac remodeling process that leads to subsequent cardiac dilation and congestive heart failure. However, when autologous cell transplant is performed in patients with congestive heart failure, it may function more to stimulate myocardial regeneration. These two different patient groups are the focus of the IDE trials.
There are also the practical issues of determining the optimal cell type, the timing of the transplantation post-infarct, and the delivery mode (directly into myocardium, intracoronary artery or sinus, or intravenous). In addition, there are issues of harvesting the autologous cells. Hematopoietic stem-cells and skeletal myoblasts have been the focus of research, yet the ability to harvest hematopoietic stem-cells (a procedure requiring multiple bone core biopsies and general anesthesia) in the immediate post-infarct period is questionable. One of the advantages of using skeletal myoblasts is their easy accessibility through a muscle biopsy; however, the harvested tissue must undergo culture to expand the numbers of skeletal myoblasts. In the IDE trials, skeletal biopsy must occur three to four weeks before the anticipated implantation.
The human studies reported so far are clearly preliminary and have not attempted to evaluate long-term efficacy of stem-cell transplant. Assmus and colleagues reported on the results of the TOPCARE-AMI, the “Transplantation Of Progenitor-cells And Regeneration Enhancement in Acute Myocardial Infarction”, study. This study included 20 patients who had already undergone revascularization after an acute myocardial infarction (MI) and received either bone marrow-derived cells or circulating blood-derived stem-cells infused into the infarct artery during a second catheterization procedure. Cardiac function was evaluated before and after the transplantation procedure; essentially patients served as their own control. After four months, the authors reported an improvement in injection fraction, regional wall motion, and left ventricular end diastolic volumes. Stamm and colleagues injected bone marrow-derived stem-cells into the peri-infarct zone in six patients who had a MI and were undergoing coronary artery bypass grafting (CABG). All patients reported an improvement in cardiac exercise capacity and ejection fraction. In contrast Herreros and colleagues used an intramyocardial injection of cultured myoblasts in 12 patients undergoing CABG. The procedure was considered safe and feasible and the authors reported increased global and regional left ventricular function three months after surgery. Strauer and colleagues reported on a clinical trial of ten patients who received intracoronary autologous bone marrow cells five to nine days after acute infarct. This delay in treatment reflects the time needed to harvest and process the bone marrow cells. Cardiac function in these ten patients was compared to ten contemporary control patients who refused the treatment. At three months, the treated patients had a reduction in infarct size compared to no change in the nonrandomized control group. Finally, Kang and colleagues used granulocyte colony stimulating factor (GCSF) to increase the number of circulating hematopoietic stem-cells in 27 patients with acute MI. The stem-cells were harvested in a pheresis procedure and then injected into the coronary artery via a separate angioplasty and stenting procedure. While the therapy was associated with an improvement in cardiac function, the authors noted a high rate in stent restenosis in those receiving the GCSF and the trial was stopped.
These studies focused on patients without congestive heart failure. Smits and colleagues reported on five patients with symptomatic heart failure who were treated with direct intramyocardial injection of cultured skeletal myoblasts harvested from a quadriceps biopsy. Compared with baseline, an improvement was noted in ejection fraction and regional wall motion.
2008 Blue Cross Blue Shield Association Technology Evaluation Center Assessment
In 2008, the Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) conducted a systematic review that included randomized, controlled trials of progenitor-cell therapy versus standard medical care for treatment of either acute or chronic myocardial ischemia. The BCBSA TEC Assessment focused on the impact of progenitor-cell therapy on clinical outcomes, but also included data on physiologic outcomes such as change in left ventricular ejection fraction (LVEF).
Autologous progenitor-cell transplantation for the treatment of damaged myocardium is a rapidly evolving field, with a number of areas of substantial uncertainty. The mechanism of benefit is not well understood. Patient selection criteria are still evolving, and the current studies have been performed in highly selected populations. Also, there is a lack of standardization in treatment protocols, with uncertainty in the optimal methods for harvesting of donor cells, the timing of the transplantation, and the optimal delivery mode (directly into myocardium, intracoronary artery or sinus, or intravenously).
For acute ischemia, there were a total of ten publications from six unique studies enrolling 556 patients. These trials had similar inclusion criteria, enrolling patients with acute ST-segment elevation MI treated successfully with percutaneous coronary intervention (PCI) and stenting, with evidence of residual myocardial dysfunction in the region of the acute infarct. Progenitor-cell therapy was delivered via an additional PCI procedure within one week of the acute event.
The “Reinfusion of Enriched Progenitor-cells And Infarct Remodeling in Acute Myocardial Infarction” (REPAIR-AMI) trial was the largest trial, and had the largest number of clinical outcomes reported. This was a double-blinded trial that employed a sham placebo control infusion of the patients’ own serum. This trial enrolled 204 patients with acute ST-segment elevation MI meeting strict inclusion criteria from 17 centers in Germany and Switzerland. At 12 months of follow-up, there were statistically significant decreases in the progenitor-cell group for MI (0 vs. 6, p<0.03) and revascularization (22 vs. 37, p<0.03) as well as for the composite outcome of death, MI, and revascularization (24 vs. 42, p<0.009).
The other trials had very few clinical events, precluding meaningful analysis of clinical outcomes. The primary evidence from these other trials consists of physiologic outcomes measures such as change in LVEF and change in infarct size.
The primary endpoint in all six trials was change in LVEF. In each trial, there was a greater increase in the LVEF for the progenitor-cell group compared with the control group. In four of the six studies, this difference reached statistical significance, while in two studies there was a non-significant increase in favor of the treatment group. The magnitude of the incremental improvement in LVEF was not large in most cases, with five of the six studies reporting an incremental change of 1% to 6%, and the final study reporting a larger incremental change of 18%.
Lipinski et al. published a quantitative meta-analysis of studies that estimated the magnitude of benefit of progenitor-cell treatment on left ventricular (LV) function and infarct size. This analysis included ten controlled trials with a total of 698 patients. Results for the primary endpoint, change in LVEF, showed a statistically significant greater improvement of 3% (95% CI: 1.9–4.1%, p<0.00001) for the progenitor-cell group. There was also a statistically significant greater improvement in infarct size for the progenitor-cell group with an incremental improvement of -5.6% over the control group (95% CI: -8.7 to -2.5, p<0.001).
A total of six trials randomizing 231 patients were included for treatment of chronic ischemic heart disease. Three trials randomized 125 patients to progenitor-cell therapy versus standard medical care. The other three trials randomized 106 patients undergoing CABG to CABG plus progenitor-cell treatment versus CABG alone. Four trials employed bone-marrow-derived progenitor-cells as the donor cell source, one trial used circulating progenitor-cells (CPC), and the final trial included both a CPC treatment group and a bone marrow-derived treatment group.
The largest trial was Assmus et al., which was a single-center, unblinded trial that enrolled 75 patients into three groups; treatment with bone marrow-derived progenitor-cells, treatment with circulating progenitor-cells, or usual medical care.
The primary physiologic measurement reported in these trials was change in LVEF. In all six trials there was a greater improvement in LVEF for the treatment group compared with the control group, and in four of six trials, this difference reached statistical significance. For the three trials of progenitor-cell treatment versus standard medical care, the range of incremental improvement in LVEF was 2.7%–6.0%. For the trials of progenitor-cell treatment plus CABG versus CABG alone, the range of improvement in LVEF was 2.5%–10.1%. Only one trial reported comparative analysis of data on the change in size of ischemic myocardium. This trial reported that there was no difference in size of ischemic myocardium between treatment groups.
There are limited data from this group of studies on clinical outcomes, with only two studies reporting any clinical outcomes. Assmus et al. reported on adverse cardiac events, but there were extremely small numbers of any of these clinical outcomes, and no differences between groups.
Both trials reported on change in New York Heart Association (NYHA) class between groups. Assmus et al. also reported an improvement in mean NYHA class of 0.25 (0–4 scale) for the bone-marrow treatment group and an improvement of 0.23 for the CPC group, compared with a worsening of 0.18 for the standard medical therapy group (p<0.01). Patel et al. reported a greater improvement in mean NYHA class for patients in the CABG plus progenitor-cell group compared to CABG alone (2.7 vs. 0.7, p value not reported), but no statistical testing for this outcome was reported.
Summary Based on 2008 TEC Assessment
For acute ischemic heart disease, the limited evidence on clinical outcomes suggests that there may be benefits in improving LVEF, reducing recurrent MI, decreasing the need for further revascularization, and perhaps even decreasing mortality. These results indicate that progenitor-cell treatment is a promising therapy with the potential to benefit a large population of patients with ischemic heart disease. However, the evidence to date should be viewed as preliminary rather than definitive. There are numerous reasons why the confidence in these conclusions is not high.
The primary limitation is the small quantity of evidence on clinical outcomes, with a very small overall number of hard clinical outcomes such as recurrent MI and death across all trials. Only one trial, REPAIR-AMI, had enough clinical outcomes for meaningful statistical analysis. There were far more revascularization outcomes than other clinical events, and as a result, the composite outcome of major adverse cardiac events was driven almost entirely by revascularization.
All of the trials had one or more methodologic limitation. The most common limitations were lack of double-blinding and failure to account for all randomized patients in the analysis. The REPAIR-AMI trial was the highest methodologic quality, and was double-blinded. However, this trial excluded 17 of 204 randomized patients from the analysis, and thus was not considered to meet the criteria for a high-quality trial.
While the evidence for a beneficial impact on physiologic outcomes, particularly LVEF, is fairly strong, the magnitude of effect does not appear to be large. As a result, it is not certain whether the improvement in LVEF translates to meaningful improvements in clinical outcomes.
For chronic ischemic heart disease there is only very scant evidence on clinical outcomes, and no conclusions can be drawn. Only a handful of clinical outcome events have been reported across the included studies, too few for meaningful analysis. Other clinical outcomes, such as NYHA class, are confined to very small numbers of patients and not reported with sufficient methodologic rigor to permit conclusions.
Additional Literature Review
In addition to the 2008 BCBSA TEC Assessment, a literature search was performed through June 2009. Numerous small randomized, controlled trials were identified that evaluated the impact of bone marrow progenitor-cells on outcomes for patients with MI.
The majority of these studies treated patients with acute MI and reported the outcomes of LVEF and/or myocardial perfusion at three to six months. These studies generally reported small to modest improvements in these intermediate outcomes, thus confirming the results of previous studies and the conclusions from the 2008 BCBSA TEC Assessment. None of these new trials reported benefits in clinical outcomes such as mortality, adverse cardiac outcomes, exercise capacity, or quality of life.
At least four meta-analyses of bone marrow progenitor-cell treatment for acute MI were published over this time period, each examining between six and 13 randomized, controlled trials. All four meta-analyses concluded that there was a modest improvement in LVEF for patients treated with progenitor-cells. The mean estimated improvement in ejection fraction over control ranged from 2.9–6.1%. The studies also concluded that myocardial perfusion and/or infarct size was improved in the progenitor-cell treatment group, although different outcome parameters were used. All four of the meta-analyses concluded that there were no demonstrable differences in clinical outcomes for patients treated with progenitor-cells.
One randomized, controlled trial was identified that treated patients with chronic myocardial ischemia and that reported on a wide range of outcomes. van Ramshorst et al. performed a randomized, double-blind trial on 50 patients with intractable angina despite optimal medical therapy who were not candidates for revascularization therapy. Patients were injected with autologous bone marrow-derived mononuclear cells or placebo. The main outcomes were measures of myocardial perfusion derived from SPECT (single photon emission computed tomography) scanning at rest and SPECT after exercise stress at three months post-treatment. Secondary outcomes included LVEF, Canadian Cardiovascular Society (CCS) angina class, and Seattle Angina quality of life questionnaire measured at six months post-treatment.
There were modest improvements for most of the outcomes in favor of the experimental group compared to placebo. For the primary outcome, a significantly greater improvement was found in the stress perfusion score for the progenitor-cell group (mean difference -2.44; 95% CI: -3.58 to -1.30, p<0.001), but no significant difference in the rest perfusion score (mean difference = 0.32; 95% CI: -0.87 to 0.23, p=0.25). There was also a significant decrease in the mean number of ischemic segments for the progenitor-cell group (mean decrease 2.4 vs. 0.8, p<0.001). LVEF improved slightly in the progenitor-cell group and decreased slightly in the placebo group (mean change 3% +/- 5 vs. -1% +/- 3, p=0.03). At six months, CCS class decreased more for the progenitor-cell group (mean difference -0.79; 95% CI: -1.10 to -0.48, p<0.001) and the Seattle Angina quality of life score increased more for the progenitor-cell group (mean increase 12% vs. 6.3%, p=0.04).
One small, randomized, controlled trial compared progenitor-cells to placebo as an adjunctive treatment for patients undergoing CABG. Zhao et al. randomized 36 patients and reported that LVEF, myocardial perfusion, and angina class were improved for the progenitor-cell group at six months. However, there were two deaths in the progenitor-cell group versus none in the placebo; these deaths were potentially due to arrhythmias. The authors, therefore, concluded that while there was potential benefit for bone marrow progenitor-cell treatment in this group of patients, larger studies were needed to determine the safety and arrhythmogenic potential of progenitor-cell treatment.
The new evidence corroborates previous studies in demonstrating an improvement in LVEF and myocardial perfusion for patients with myocardial ischemia treated with bone marrow-progenitor-cells. The clinical significance of the improvement in these parameters has yet to be demonstrated, and there is very little evidence demonstrating a benefit in clinical outcomes. Moreover, the evidence remains primarily limited to short-term effects and the long-term durability of benefit has not yet been determined. As a result, the new evidence does not prompt reconsideration of the current policy statement, which remains unchanged.
The literature search update through July 2011 identified publications addressing acute ischemia, chronic ischemia, and ongoing clinical trials.
The literature search identified two publications with longer-term (two to three year) follow-up from the randomized trials described above. Two year clinical outcomes from the REPAIR-AMI trial, performed according to a study protocol amendment filed in 2006, were reported in 2010. Three of the 204 patients were lost to follow-up (two patients in the placebo group and one in the progenitor-cell group). A total of 11 deaths occurred during the two year follow-up, eight in the placebo group and three in the progenitor-cell group. There was a significant reduction in myocardial infarction (MI) (0% vs. 7%), and a trend toward a reduction in re-hospitalizations for heart failure (1% vs. 5%) and revascularization (25% vs. 37% - all respectively) in the active treatment group. Analysis of combined events (all combined events included infarction), showed significant improvement with progenitor-cell therapy after acute MI. There was no increase in ventricular arrhythmia or syncope, stroke, or cancer. It was noted that investigators and patients were unblinded at 12 month follow-up, the sample size of the REPAIR-AMI trial was not powered to definitely answer the question of whether administration of progenitor-cells can improve mortality and morbidity after acute MI, and the relatively small sample size might limit the detection of infrequent safety events. The authors concluded that this analysis should be viewed as hypothesis generating, providing the rationale to design a larger trial that addresses clinical endpoints.
Beitnes and colleagues reported the unblinded three year reassessment of 97 patients (out of 100) from the randomized ASTAMI (Autologous Stem-cell Transplantation in Acute Myocardial Infarction) trial. The group treated with bone marrow progenitor-cells had a larger improvement in exercise time between baseline and three year follow-up (1.5 vs. 0.6 minutes, respectively), but there was no difference between groups in change in peak oxygen consumption (3.0 mL/kg/min vs. 3.1 mL/kg/min, respectively), and there was no difference between groups in change of global LVEF or quality of life. Rates of adverse clinical events in both groups were low (three infarctions and two deaths). These three year findings are similar to the 12 month results from this trial.
Literature updates since the 2008 BCBSA TEC Assessment have identified numerous small randomized controlled clinical trials (RCTs) that evaluated the impact of bone marrow progenitor-cells on outcomes for patients with MI. The majority of these studies treated patients with acute MI and reported the outcomes of left ventricular ejection fraction (LVEF) and/or myocardial perfusion at three to six months. These studies generally reported small to modest improvements in these intermediate outcomes, thus confirming the results of previous studies and the conclusions from the 2008 BCBSA TEC Assessment. None of these new trials reported benefits in clinical outcomes, such as mortality, adverse cardiac outcomes, exercise capacity, or quality of life.
Results from the acute and long-term effects of intracoronary stem-cell transplantation in 191 patients with chronic heart failure (STAR-heart) study were reported by Strauer et al. in 2010. In this non-randomized open-label trial, 391 patients with chronic heart failure due to ischemic cardiomyopathy were enrolled; 191 patients received intracoronary bone marrow cell (BMC) therapy, and 200 patients who did not accept the treatment but agreed to follow-up testing served as controls. The time between percutaneous coronary intervention for infarction and admission to the tertiary clinic was 8.5 years. For the BMC therapy, mononuclear cells were isolated and identified (included CD34-positive cells, AC133-positive cells, and CD45/CD14-negative cells). Cells were infused directly into the infarct-related artery. Follow-up on all patients was performed at three, 12, and 60 months and included coronary angiography, biplane left ventriculography, electrocardiogram (ECG) at rest, spiroergometry, right heart catheterization and measurements of late potentials (LPs), short-term heart rate variability (HRV), and 24-hour Holter ECG. At up to five years after intracoronary BMC therapy, there was a significant improvement in hemodynamics (LVEF, cardiac index), exercise capacity (New York Heart Association [NYHA] classification), oxygen uptake, and LV contractility compared to controls. There was also a significant decrease in long-term mortality in the BMC-treated patients (0.75% per year) compared to the control group (3.68% per year, P<0.01). These results are encouraging, especially in regard to the mortality outcomes, since this is the first controlled trial that reports a significant mortality benefit for progenitor-cell treatment. However, the study is limited by the potential for selection bias due to patient self-selection into treatment groups. For example, there was a 7% difference in baseline ejection fraction between the two groups, suggesting that the groups were not comparable on important clinical characteristics. In addition, the lack of blinding raises the possibility of bias in patient-reported outcomes such as NYHA class. RCTs are needed to confirm these health outcome benefits for chronic ischemia.
Ongoing Clinical Trials
A 2010 critical review of cell therapy for the treatment of coronary heart disease by Wollert and Drexler described 20 ongoing cell therapy trials in patients with coronary heart disease. Issues to be resolved in these second and third generation cell therapy trials include patient selection, cell type, procedural details, clinical endpoints, and strategies to enhance cell engraftment and prolong cell survival. Moreover, “a large body of evidence indicates that the beneficial effects of cell therapy are related to the secretion of soluble factors acting in a paracrine manner.” The authors suggest that the identification of specific factors promoting tissue regeneration may eventually enable therapeutic approaches based on the application of specific paracrine factors. Updated literature reviews have also identified a number of publications that describe ongoing RCTs.
In 2010, Taljaard and colleagues reported the rationale and design of what is described as the first randomized placebo-controlled trial of “enhanced” progenitor-cell therapy for AMI. The “ENhanced Angiogenic Cell Therapy in Acute Myocardial Infarction” trial (ENACT-AMI) is a Phase IIb, double-blind, RCT, using coronary injection of autologous early endothelial progenitor-cells for patients who have suffered large MI. A total of 99 patients will be randomly assigned to placebo (Plasma-Lyte A), autologous mononuclear cells, or mononuclear cells transfected with human endothelial nitric oxide synthase delivered by injection into the infarct-related artery. This trial is described as the first to include a strategy to enhance the function of autologous progenitor-cells by overexpressing endothelial nitric oxide synthase and the first to use combination gene and cell therapy for the treatment of cardiac disease.
The rationale and design of the “Swiss Multicenter Intracoronary Stem-cells Study in Acute Myocardial Infarction” (SWISS-AMI) was also reported in 2010. In this trial, 192 patients with AMI will be randomized to control or one of two groups treated with autologous bone marrow mononuclear cells (five to seven days or three to four weeks after the initial event). The mononuclear cells will be infused directly into the infarct-related coronary artery. The primary endpoint is the change in global LVEF at four months; secondary end-points include changes in infarct size, regional myocardial thickness, and wall motion at four and 12 months. Major adverse cardiac events will be assessed at four, 12, and 24 months.
A search of the online site “ClinicalTrials.gov” in May 2011 identified a Phase II/III “Multicenter study to assess the safety and cardiovascular effects of Myocell™ implantation by a catheter delivery system in congestive heart failure patients post myocardial infarction” (MARVEL, NCT00526253). Autologous skeletal myoblasts will be isolated, expanded in culture, and injected into the myocardium via the femoral artery. This is a three arm randomized placebo-controlled trial with low- or high-dose active treatment (400 million or 800 million cells) compared to a control group injected with the transport media alone. Initially, the estimated enrollment was 170 patients; the targeted completion date for the primary outcome measures (six minute walk test, quality of life, and LVEF) was listed as February 2012. However, as of October 26, 2010, the study is ongoing, but not recruiting participants and the predicted target completion date is no longer indicated.
Stem- or progenitor-cell therapy for the treatment of damaged myocardium is a rapidly evolving field, with a number of areas of substantial uncertainty including patient selection, cell type, and procedural details (e.g., timing and mode of delivery).
For acute ischemic heart disease, the limited evidence on clinical outcomes suggests that there may be benefits in improving LVEF, reducing recurrent MI, decreasing the need for further revascularization, and perhaps even decreasing mortality. These results indicate that progenitor-cell treatment is a promising therapy with the potential to benefit a large population of patients with ischemic heart disease. However, the evidence to date should be viewed as preliminary rather than definitive. There are numerous reasons why the confidence in these conclusions is not high. The primary limitation is the small quantity of evidence on clinical outcomes, with limited evidence across all trials on outcomes such as recurrent MI and death. While the evidence for a beneficial impact on physiologic outcomes, particularly LVEF, is fairly strong, the magnitude of effect does not appear to be large. As a result, it is not certain whether the improvement in LVEF translates to meaningful improvements in clinical outcomes.
For chronic ischemic heart disease, there is limited evidence on clinical outcomes. Only a handful of clinical outcome events have been reported across the included studies, too few for meaningful analysis. Other clinical outcomes, such as NYHA class, are confined to very small numbers of patients and not reported with sufficient methodologic rigor to permit conclusions. Therefore, the evidence is insufficient to permit conclusions on the impact of progenitor-cell therapy on clinical outcomes for patients with chronic ischemic heart disease.
Overall, the new evidence corroborates previous studies in demonstrating an improvement in LVEF and myocardial perfusion for patients with myocardial ischemia treated with progenitor-cells. The clinical significance of the improvement in these parameters has yet to be demonstrated, and there is very little evidence demonstrating a benefit in clinical outcome. Moreover, the evidence remains primarily limited to short-term effects; the long-term durability of benefit has not yet been determined. Therefore, stem-cell therapy for the treatment of damaged myocardium is considered experimental, investigational and unproven.
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