Autologous cell therapy, including but not limited to skeletal myoblasts or hematopoietic stem cells, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

 

For contracts without primary coverage criteria, autologous cell therapy, including but not limited to skeletal myoblasts or hematopoietic stem cells, is considered investigational and is not covered.  Investigational services are an exclusion in the member benefit certificate of coverage.

 

 

 

The investigation of autologous cell transplantation for the treatment of damaged myocardium is still at its preliminary stages in human subjects, both 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 transplantation of autologous cells can incorporate themselves into the heart, 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  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 regenesis. These 2 different patient groups are the focus of the  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 intravenously). 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 3-4 weeks before the anticipated implantation.

 

The human studies reported so far are clearly preliminary and have not attempted to evaluate long-term efficacy of autologous cell transplant. Assmus and colleagues reported on the results of the TOPCARE-AMI 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 progenitor 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 4 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 6 patients who had a myocardial infarction and were undergoing 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 3 months after surgery.  Strauer and colleagues reported on a clinical trial of 10 patients who received intracoronary autologous bone marrow cells 5 to 9 days after acute infarct. This delay in treatment reflects the time needed to harvest and process the bone marrow cells. Cardiac function in these 10 patients was compared to 10 contemporary control patients who refused the treatment.  At 3 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 myocardial infarction.  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 of 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 5 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.

 

The REPAIR-AMI trial, the largest randomized, controlled trial identified, was a double-blinded trial with a sham placebo control infusion that enrolled 204 patients with acute ST-segment elevation. At 12 months of follow-up, there were statistically significant decreases in the progenitor cell group for myocardial infarction (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 ASTAMI trial, the next largest randomized, controlled trial, also reported on clinical events, but had very small numbers of clinical outcomes, precluding meaningful analysis. This trial also included the clinical outcomes of exercise time, symptoms and quality of life (QOL). There were no group differences in symptoms, or QOL. Exercise time increased in both groups, with a greater increase for the bone-marrow progenitor cell (BMC) treatment group of slightly less than 1 minute (2.1 vs. 1.3 minutes, p<0.01).

 

The most common physiologic outcome reported in other studies is left-ventricular ejection fraction (LVEF). In all studies that report this outcome, there was a greater increase in the LVEF for the experimental group.  In a majority of studies (of both acute and chronic ischemia), this difference reached statistical significance. A quantitative meta-analysis that included 10 controlled trials (randomized and nonrandomized) of patients with acute ischemia estimated the incremental improvement in LVEF to be 3.0% (95% CI: 1.9–4.1%, p<0.00001).

 

The primary limitation of research in this area is the small quantity of literature that reports on clinical outcomes, with a very small overall number of hard clinical outcomes such as recurrent MI and death across all trials. On formal quality assessment, none of the studies meet the criteria for a high-quality trial. Only one trial, REPAIR-AMI, had enough clinical outcomes for meaningful statistical analysis. This trial enrolled a highly selected patient population with acute MI, and thus may not be generalizable to the larger population of patients with acute ischemic heart disease. In the REPAIR-AMI trial, the relative risk reduction (RRR) for individual outcomes had wide confidence intervals indicating a lack of precision, and, in some cases, point estimates for RRR that may not be clinically plausible (e.g., hazard ratio for recurrent MI or death at 12 months = 0.20; 95% CI: 0.04–0.89). In addition, there were far more revascularization outcomes than other clinical events, and as a result, the composite outcome of major adverse cardiac events (MACE) was driven almost entirely by revascularization rates.

 

The evidence for a beneficial impact on physiologic outcomes, particularly LVEF, is fairly strong, but 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. The evidence for a decrease in infarct size is less robust than that for LVEF, but shows a similar pattern of incremental improvement for patients receiving progenitor cell therapy. As with LVEF, the threshold for improvement in infarct size that translates to a clinically meaningful benefit is uncertain.

 

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

 

Therefore, the evidence is insufficient to permit conclusions with adequate confidence on the effect of progenitor cell therapy on clinical outcomes for patients with ischemic heart disease. While the available evidence suggests a potential benefit on both physiologic and clinical outcomes, the limited amount of clinical outcome evidence combined with uncertainties in the patient populations, mechanism of action, and treatment delivery decreases the confidence of conclusions that can be drawn from this evidence.

 

A literature search using the MEDLINE database was conducted through June 2010.  Literature was reviewed for treatment of Acute and Chronic Ischemia and is discussed separately.

 

The 2010 literature update identified 2 publications with longer-term (2-3 year) follow-up from the randomized trials described above (Beitnes, 2009) (Assmus, 2010). Two-year clinical outcomes from the REPAIR-AMI trial, performed according to a study protocol amendment filed in 2006, were reported in 2010 (Schachinger, 2006). 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 myocardial infarction (0% vs. 7%), and a trend towards 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 acute 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 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. The authors concluded that this analysis should be viewed as hypothesis generating, providing the rationale to design a larger trial that addresses clinical end points.

 

Beitnes and colleagues reported the unblinded 3-year reassessment of 97 patients (out of 100) from the randomized ASTAMI trial (Beitnes, 2009) (Lunde, 2006). The group treated with bone marrow progenitor cells had a larger improvement in exercise time between baseline and 3-year follow-up, but there was no difference between groups in change in peak oxygen consumption, 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 (Lunde, 2007).

 

One small, randomized, controlled trial was reported in 2008 that compared progenitor cells to placebo as an adjunctive treatment for patients undergoing CABG (Zhao, 2008). Zhao et al. randomized 36 patients and reported that LVEF, myocardial perfusion, and angina class were improved for the progenitor cell group at 6 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.

 

One controlled trial was identified that reported on a wide range of outcomes in patients with chronic myocardial ischemia who were injected with autologous bone marrow-derived mononuclear cells or placebo (van Ramshorst, 2009). This randomized, double-blind trial included 50 patients who had intractable angina despite optimal medical therapy and were not candidates for revascularization therapy. 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 but no significant difference in the rest perfusion score.  There was also a significant decrease in the mean number of ischemic segments for the progenitor cell group. LVEF improved slightly in the progenitor cell group and decreased slightly in the placebo group. At 6 months, CCS class decreased more for the progenitor cell group and the Seattle Angina quality of life score increased more for the progenitor cell group.

 

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 (Wollert, 2010).  Issues to be resolved in these 2nd and 3rd 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 suggest that the identification of specific factors promoting tissue regeneration may eventually enable therapeutic approaches based on the application of specific paracrine factors.

 

Talijaard and colleagues reported the rationale and design of what is described as the first randomized place-controlled trial of enhanced progenitor cell therapy for acute myocardial infarction (Taljaard, 2010). The “enhanced angiogenic cell therapy in acute myocardial infarction” trial (ENACT-AMI) is a phase IIb, double-blind, randomized controlled trial, using coronary injection of autologous early endothelial progenitor cells for patients who have suffered large myocardial infarction. A total of 99 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.

 

Also listed on ClinicalTrials.gov as of June 2010 are two Phase I studies and one Phase II study sponsored by BioHeart, Inc.

 

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 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. 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.

 

 

 

 

 

 

 

 

 

Stem-cell therapy is also being investigated in patients with intractable angina who are not candidates for revascularization. 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 (Losordo, 2011). 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 congestive 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.

 

 

 

 

 

 

    

 

 

 

A 2012 Cochrane review included 33 RCTs (39 comparisons with 1765 participants) of bone marrow-derived stem-cell therapy for acute MI (Clifford, 2012). 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, 2.9 percentage points [95% CI, 2.0 to 3.7]; I2=73%), and long-term (12 to 61 months; weighted mean difference, 3.8 percentage points [95% CI, 2.6 to 4.9; I2=72%). 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 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.

 

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) (Delewi, 2014). De Jong et al searched the literature through August 2013 and included 22 RCTs (total N=1513) (du Jong, 2013). 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 (MACCE). 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.”

 

 

 

 

 

 

In 2014, Fisher et al published a Cochrane review of autologous stem cell therapy for chronic ischemic heart disease and congestive heart failure (Fisher, 2014). 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.

 

 

Moazzami et al (2013) published a Cochrane review of granulocyte colony-stimulating factor (G-CSF) for AMI (Moazzami, 2013). 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 (relative risk, 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.

 

 

 

 

 

 

 

 

 

 

 

 

 

ischemic cardiomyopathy (NYHA II-III and LVEF less than or equal to 45%) who were ineligible for revascularization (Perin, 2014). Patients were randomized 3:1 to receive autologous ADRC or placebo control in double-blind fashion. Patients were followed for up to 18 months for efficacy outcomes. There was no statistical difference in LVEF or LV volumes (assessed by echocardiography). Although some measures of exercise capacity improved more in ADRC-treated patients compared with controls (eg, maximal oxygen consumption [MVO2]), there were no statistical changes from baseline SPECT stress and rest total severity scores in either group.