Coverage Policy Manual
Policy #: 2006015
Category: Medicine
Initiated: August 2017
Last Review: July 2018
  Myocardial Damage, Autologous Cell Therapy(progenitor, hematopoietic stem cells, myoblasts)

Description:
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 (Lee, 2004; Mathur, 2004). 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 various 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 (eg, teratomas) can arise from progenitor cells, but the actual risk in humans is currently unknown.
 
REGULATORY STATUS
The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. Hematopoietic cells are included in these regulations. FDA marketing clearance is not required when autologous cells are processed on site with existing laboratory procedures and injected with existing catheter devices. Several cell products are expanded ex-vivo and require FDA approval.
 
MyoCell® (Bioheart, 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) is similar to MyoCell®, but before injection, myoblast cells are genetically modified to release excess stromal-derived factor-1 (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 has been cleared by FDA. Implantation may require use of a unique catheter delivery system (eg, MyoCath [Bioheart]) that has been cleared by FDA.
 
An allogeneic human mesenchymal stem cell (hMSC) product (Prochymal®; Osiris Therapeutics) under investigation for the treatment of acute myocardial infarction (AMI). Prochymal® (also referred to as Provacel®; Osiris) 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 FDA for Crohn disease and graft-versus-host disease (GVHD), and has orphan drug status for GVHD from FDA and the European Medicines Agency.
 
Ixmyelocel-T (Vericel, formerly Aastrom Biosciences) is an autologous bone marrow-derived multicellular therapy produced by expanding bone marrow mononuclear cells. Ixmyelocel-T was cleared for marketing by FDA through the orphan drug process for the treatment of ischemic dilated cardiomyopathy, based on results of a phase 2b study.
MultiStem® (Athersys) is an allogeneic bone marrow‒derived adherent adult stem cell product. MultiStem® was cleared for marketing by FDA through the orphan drug process for GVHD and has received authorization from FDA for a phase 2 trial for treatment of AMI with an adventitial delivery system. In September 2016, under a Special Protocol Assessment of FDA, Athersys received approval of the design and analysis for its phase 3 trial (MultiStem Administration for Stroke Treatment and Enhanced Recovery Study-2 [MASTERS-2]) on the use of MultiStem® for treating patients who had experienced an ischemic stroke.

Policy/
Coverage:
Effective December 2011
Intracoronary artery infusion of autologous progenitor cells within the first week following acute myocardial infarction does not meet member certificate of benefit Primary Coverage Criteria for effectiveness as this therapy is being studied in clinical trials to determine effectiveness.  
 
For contracts without primary coverage criteria, intracoronary artery infusion of autologous progenitor cells within the first week following acute myocardial infarction is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Intracoronary artery infusion of autologous progenitor cells 2-3 weeks or longer following acute myocardial infarction does not meet member certificate of benefit Primary Coverage Criteria for effectiveness as this therapy was shown in a large randomized controlled trial to be ineffective.
 
For contracts without primary coverage criteria, intracoronary artery infusion of autologous progenitor cells 2-3 weeks or longer following acute myocardial infarction is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Intracoronary artery infusion of autologous progenitor cells for chronic coronary artery disease does not meet member certificate of benefit Primary Coverage Criteria for effectiveness as this therapy is being studied in clinical trials to determine effectiveness.
 
For contracts without primary coverage criteria, intracoronary artery infusion of autologous progenitor cells for chronic coronary artery disease is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Intramyocardial delivery of autologous progenitor cells does not meet member certificate of benefit Primary Coverage Criteria for effectiveness as this therapy is being studied in clinical trials to determine effectiveness.
 
For contracts without primary coverage criteria, intramyocardial delivery of autologous progenitor cells is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to December 2011
 
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.
 
Infusion of growth factors (i.e., granulocyte colony stimulating factor [GCSF]) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, infusion of growth factors (i.e., granulocyte colony stimulating factor [GCSF]) is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 

Rationale:
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.
 
2008 Update
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.
 
2010 Update
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.
 
Acute Ischemia
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).
 
Chronic Ischemia
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.
 
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 (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.
    • The MyoHeart™ trial (Myogenesis Heart Efficiency and Regeneration Trial; NCT00054678) is described as MyoCell™ implantation using the MyoCath celivery catheter system. It lists an estimated enrollment of 20 subjects with estimated completion in 2007. It is currently described as ongoing, but not recruiting participants.
    • The autologous cultured myoblast (BioWhittaker) transplanted via myocardial injection trial (NCT00050765) is a study of MyoCell™ implantation by epicardial injection during CABG surgery. This study was posted in 2002 with estimated enrollment of 15 subjects; estimated completion was 2006. As of June 2010, the study is not yet open for participant recruitment.
    • NCT00526253 is 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). Autologous skeletal myoblasts will be isolated, expanded in culture, and injected into the myocardium via the femoral artery. This is a 3-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. Estimated enrollment is 390 patients; the targeted completion date for the primary outcome measures (6 min. walk test, quality of life, and LVEF) is listed as February 2010.
 
Summary
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.
 
2011 Update
 
Results of the LateTIME study, a randomized, double-blind, placebo-controlled trial was recently published (Traverse, 2011).  The LateTIME trial assessed the effects of intracoronary delivery of autologous bone marrow cells on left ventricular function, two to three weeks following acute myocardial infarction. A total of 87 patients were randomized to receive intracoronary infusion of either autologous bone marrow cells or placebo.  Changes in left ventricular ejection fraction and wall motion in the infarct and surrounding areas were measured at baseline and 6 months by cardiac MRI. Left ventricular volume and infarct size was also measured. The authors concluded that in patients with MI and Left ventricular dysfunction, infusion of autologous bone marrow cells, 2 to 3 weeks following MI did not improve left ventricular function compared to placebo.
 
An accompanying editorial (Hare, 2011) published in The Journal of the American Medical Association discusses the fact that the 2 to 3 week timeframe used in the LateTIME trial may have been outside a “window in which ‘injury signals’ that recruit and retain stem cells are released”. An ongoing clinical trial, the “TIME” trial (NCT00684021) will assess the effects of bone marrow cell infusion in patients with predominantly ST-segment elevation MI at 3 days and 7 days post myocardial infarction.
 
The MARVEL study, discussed above in the 2010 Update, is currently ongoing (NCT00526253). Additionally the BAMI trial, a study planned to enroll 3000 patients to assess all-cause mortality will provide additional important information (Hare, 2011).
 
The coverage statement has been changed, as a result of the published findings in the LateTIME trial and the currently ongoing trials assessing autologous bone marrow cell infusion post myocardial infarction.
 
2012 Update
A literature search was conducted using the MEDLINE database through June 2012. There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the relevant identified literature.
 
A 2012 updated Cochrane review included 33 RCTs (39 comparisons with 1,765 participants) on 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 the cell dose, delivery and composition. Overall, stem-cell therapy was found to improve LVEF in both the short- (weighted mean difference of 1.78%) and long-term (12 to 61 months, weighted mean difference of 3.07%). Stem-cell treatment reduced left ventricular end systolic and end diastolic volumes at certain times and reduced infarct size in long-term follow-up. There were positive correlations between mononuclear cell dose infused and the effect on LVEF and between the timing of stem-cell treatment and the effect on LVEF. Although the quality of evidence on LVEF was rated as high, the clinical significance of the change in LVEF is unclear. The quality of evidence on health outcomes was rated as moderate. Stem/progenitor cell treatment was not associated with statistically significant changes in the incidence of mortality or morbidity (re-infarction, arrhythmias, hospital re-admission, restenosis, and target vessel revascularization), although the studies may have been underpowered to detect differences in clinical outcomes. Due to variability in outcomes measured, it was not possible to combine data on health related quality of life or performance status.
 
In 2011, Hirsch et al. reported a multicenter RCT of bone marrow or peripheral blood mononuclear cells compared with standard therapy in 200 patients with acute MI treated with primary percutaneous coronary intervention (Hirsch, 2011). Mononuclear cells were delivered between 3 and 8 days after MI. Blinded assessment of the primary endpoint, the percentage of dysfunctional left ventricular segments that had improved segmental wall thickening at 4 months, found no significant difference between either of the treatment groups (38.5% for bone marrow, 36.8% for peripheral blood) and control (42.4%). There was no significant difference between the groups in LVEF, or changes in left ventricular volumes, mass or infarct size, or in rates of clinical events. At 4 months, there was a similar percentage of patients in New York Heart Association (NYHA) class II or higher (19% for bone marrow, 20% for peripheral blood, and 18% for control).
 
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.
 
2013 Update
A literature search conducted using the MEDLINE database through June 2013 did not reveal any new information that would prompt a change in the coverage statement.
 
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 (Traverse, 2012). One hundred and twenty patients with left ventricular dysfunction were randomized to placebo or to bone marrow mononuclear cell administration in the infarct-related artery at either 3 or 7 days after PCI. At 6 months there was no significant difference in LVEF or left ventricular function (assessed by MRI) for the mononuclear cell groups compared to placebo. Rates of major adverse events were low in all treatment groups (11 patients underwent repeat vascularization and 6 received implantable cardioverter-defibrillators).
 
Ongoing Clinical Trials
Numerous ongoing clinical trials are discussed in earlier updates. Three additional ongoing trials were identified.
 
The PERFECT Phase III randomized controlled trial (NCT00950274) will assess intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting (Donndorf, 2012). 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 II trial that will be conducted in Europe (Marban, 2012).
 
The placebo-controlled Allogeneic Heart Stem Cells to Achieve Myocardial Regeneration (ALLSTAR, NCT01458405) will assess the efficacy of allogeneic cardiosphere-derived cells in 270 patients with ventricular dysfunction after MI (Marban, 2012).
    
2014 Update
 
A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
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.
 
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.”
Key studies, including more recent RCTs not included in the meta-analyses are listed below:
 
In a 2014 letter to the editor, these investigators reported prespecified 1-year outcomes (Travers, 2014). 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.
 
 
SWISS-AMI: In 2013, Surder et al reported 4-month results of the open-label SWISS-AMI trial (Surder, 2013). Two hundred patients with successfully re-perfused (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 (the 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 acute MI and reported outcomes of LVEF and/or myocardial perfusion at 3-6 months. These studies generally reported small to modest improvements in these intermediate outcomes, although 2 RCTs (HEBE and TIME) found no benefit of stem-cell treatment for acute MI. 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.
 
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.
 
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.
Representative individual RCTs are discussed below.
 
A brief overview has shown 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 G-CSF as a treatment for coronary heart disease is smaller compared to 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 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.
 
Subsequent to the Cochrane review, Achilli et al published 6-month (Achilli, 2010) and 3-year (Achilli, 2014) 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, and 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
 
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 (CTSN) 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). Estimated enrollment is 100 patients, and trial completion is expected June 2014.
 
Summary
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 ischemicheart disease, limited evidence on clinical outcomes suggests that there may be benefits in improving left ventricular ejection fraction (LVEF), reducing recurrent myocardial infarction (MI), decreasing the need for further revascularization, and perhaps even decreasing mortality. For chronic ischemic heart disease, only a handful of clinical outcome events have been reported across the included studies, too few for meaningful analysis. For refractory angina, evidence from a Phase 2 randomized controlled trial (RCT) 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 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 one 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 (ACCF, 2013). Progenitor cell therapy is not recommended.
 
2015 Update
A literature search conducted through June 2015 did not reveal any new information that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
Gyöngyösi et al (2015) conducted an individual patient data meta-analysis of 12 RCTs (N=1252) on autologous intracoronary cell therapy after AMI, including the REPAIR-AMI and ASTAMI trials reviewed below, using a collaborative, multinational database, ACCRUE (meta-Analysis of Cell-based CaRdiac study; NCT01098591) (Gyongyosi, 2015).  All patients had STEMI treated with PCI. Mean (SD) baseline LVEF was approximately 46% (12%). Most studies used bone marrow mononuclear cells and administered cell therapies within 2 weeks after AMI. Median follow-up duration was 6 months. Eight trials had low risk of bias, and 4 single-blind (assessor) trials had medium-low risk of bias. Adjusted (for cardiovascular risk factors) random effects meta-analyses showed no effect of cell therapy on the primary end point, MACCE (major adverse cardiac and cerebrovascular events, a composite of all-cause death, AMI recurrence, coronary target vessel revascularization, and stroke) (186 events; 14.0% cell therapy vs 16.3% control; hazard ratio [HR]: 0.86; 95% CI: 0.63 to 1.18; I2=0%); death (21 events; 1.4% cell therapy vs 2.1% control); or a composite of clinical hard end points (death, AMI recurrence, and stroke; 45 events; 2.9% cell therapy vs 4.7% control). Compared with controls, changes in LVEF, end-diastolic volume, or end-systolic volume were not observed. The study was limited by variation in the time from AMI to cell delivery (median: 6.5 days) and in imaging modality for assessing cardiac function (magnetic resonance imaging [MRI], single-proton emission computed tomography [SPECT], angiography, echocardiography).
 
Several small RCTs have been published recently. Pätilä et al (2014) randomized 39 patients with ischemic heart failure (NYHA II-III) who were scheduled for elective CABG to double-blind, intra-operative myocardial injections of bone marrow mononuclear cells (BMMC) or placebo (Patila, 2014).  Patients had been optimized on medical therapy for 1-3 months before randomization. At 1-year follow-up, there was no statistical difference in LVEF or wall thickening (assessed by MRI) or viability by positron emission tomography (PET) and SPECT scan. Statistically significant reductions in scar volume and transmural scar were observed in patients who received BMMC compared with controls. Perin et al (2014)
investigated transendocardial injections of adipose-derived regenerative cells (ADRC) in 27 patients with
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.
 
July 2017
A literature search conducted using the MEDLINE database through June 2017 did not reveal any new literature that would prompt a change in the coverage statement. In 2016, Povsic et al reported on the industry-sponsored Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells (RENEW) trial (Povsic, 2016). This 3-arm multicenter trial compared outcomes from intramyocardial administration of autologous CD34+ cells using exercise capacity at 3, 6, or 12 months. Patients underwent cell mobilization with G-CSF for 4 days followed by apheresis. The peripheral cell product was shipped to central processing facility (Progenitor Cell Therapy) for selection of CD34+ cells. The study was terminated after enrollment of 112 of a planned 444 patients prior to data analysis due to strategic considerations. The progenitor cell group had greater exercise capacity than the standard therapy group, but was no better than the double-blinded placebo group, consistent with a placebo effect. In addition, with only 122 participants, the study was not adequately powered to detect a between-group difference.
 
2018 Update
A literature search was conducted through June 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
The STAR-Heart trial evaluated stem cell therapy for chronic heart failure due to ischemic cardiomyopathy. This nonrandomized open-label study, reported by Strauer et al, evaluated 391 patients with chronic heart failure (Strauer, 2010). In this trial, 191 patients received intracoronary BMC therapy, and 200 patients who did not accept the treatment agreed to undergo follow-up testing served as controls. Mean time between percutaneous coronary intervention 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. At up to 5 years after intracoronary BMC therapy, there was a significant improvement in hemodynamics (LVEF, cardiac index), exercise capacity (NYHA classification), oxygen uptake, and left ventricular 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). However, the trial was limited by the potential for selection bias (patient self-selection into treatment groups). For example, there was a 7% difference in baseline ejection fraction rates between 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.

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