TEC Assessment Index

Autologous Progenitor Cell Therapy for the Treatment of Ischemic Heart Disease

Executive Summary

Background

Ischemia is the most common cause of cardiovascular disease in the developed world. Despite impressive advances in treatment, ischemic heart disease is still associated with high morbidity and mortality. Treatment with autologous progenitor cells (i.e., stem cells) offers potential benefits beyond those of standard medical care, including the potential for repair and/or regeneration of damaged myocardium.

Objective

To determine whether treatment with autologous progenitor cells improves clinical outcomes for patients with damaged myocardium due to ischemia.

Search Strategy

MEDLINE® was searched (via PubMed) using the terms "stem cells" OR "progenitor cells" OR "bone-marrow" OR "peripheral mononuclear." These terms were cross-referenced with the terms "ischemic cardiomyopathy" OR "myocardial infarction" OR "AMI" OR "congestive heart failure" OR "CHF" OR "atherosclerotic cardiovascular disease" OR "ASCVD" OR "coronary artery disease" OR "CAD." Search was performed for the time period from January 1995 through August 2008 and was limited to English-language articles on human subjects.

Selection Criteria

Articles were selected for inclusion that had the following characteristics: full-length publications published in a peer-reviewed journal in the English language from 1995 to the present; included patients with damaged myocardium due to ischemia; randomized patients to progenitor cell treatment versus standard medical care; enrolled at least 25 patients per treatment group for acute ischemic heart disease (at least 10 patients per treatment group for chronic ischemic heart disease); and reported on one or more relevant outcome.

Main Results

A total of 15 articles met the inclusion criteria for the Assessment: 9 articles discussed patients with acute ischemic heart disease treated with progenitor cell therapy and 6 articles discussed treatment of patients with chronic ischemic heart disease. 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 was left-ventricular ejection fraction (LVEF). In all studies that reported this outcome, there was a greater increase in the LVEF for the experimental group compared with the control group. In 4 of the 6 studies of acute ischemia, and 4 of 5 studies of 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).

Author's Conclusions and Comments

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, and as a result, it is not possible to conclude with adequate certainty that progenitor cell treatment improves clinical outcomes.

The primary limitation 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 met 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.

Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether the use of autologous progenitor cell treatment for ischemic heart disease meets the Blue Cross and Blue Shield Association's Technology Evaluation Center (TEC) criteria.

1. The technology must have final approval from the appropriate governmental regulatory bodies.

Progenitor cell treatment is a procedure that does not require U.S. Food and Drug Administration (FDA) approval, although some of the devices and instruments used during the procedure may be subject to FDA approval. For all trials included in this Assessment, autologous donor cells were used, derived either from the patient’s bone-marrow cells or from circulating blood cells, thus avoiding any regulatory issues involved with allogeneic donor cell sources. Devices used during the treatment procedure are generally standard catheter-based devices approved for use in other percutaneous coronary interventions.

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

The scientific evidence does not permit conclusions to be made with adequate confidence concerning the effect of progenitor cell treatment on clinical outcomes. While the evidence is fairly strong that this treatment improves LVEF, the evidence on the impact on harder clinical outcomes is less compelling. There is only one trial with adequate numbers of clinical events for meaningful analysis, and even this trial had very low numbers of hard events such as recurrent MI and death. This trial enrolled a highly selected patient population that may not be generalizable to most patients with ischemic heart disease. The reported RRRs for the individual clinical outcomes had p values in the 0.03–0.06 range, broad confidence intervals, and point estimates of RRR that may be implausible. Uncertainty about the mechanism of action of progenitor cell treatment and lack of standardization of treatment protocols also contributes to decreased confidence in the validity of the results.

3. The technology must improve the net health outcome; and

4. The technology must be as beneficial as any established alternatives.

It cannot be determined whether progenitor cell treatment for damaged myocardium due to ischemia improves the net health outcome, or whether progenitor cell treatment for damaged myocardium due to ischemia is as beneficial as any established alternatives, since the evidence is not sufficient to permit conclusions on its effect on health outcomes.

5. The improvement must be attainable outside the investigational settings.

It cannot be determined whether any improvement is attainable outside the investigational setting since the evidence is not sufficient to permit conclusions on the effect of progenitor cell treatment for damaged myocardium due to ischemia on health outcomes.

For the above reasons, autologous progenitor cell treatment for damaged myocardium due to ischemia does not meet the TEC criteria.

TEC Assessment Index

acute; AMI; angina; ASTAMI; atherosclerosis; atherosclerotic; autologous; bone marrow; CAD; cardiology; cardiomyopathy; cardiovascular disease; cell transfer; CHF; chronic; composite; congestive heart failure; coronary artery disease; EF; ejection fraction; embryonic stem cells; engraftment; fetal cardiomyocytes; heart; infarct; intracoronary; ischemia; ischemic; left ventricular end-diastolic volume; left ventricular end-systolic volume; LVEDV; LVEF: left ventricular ejection fraction; LVESV; MACE; mesenchymal stem cells; MI; mononuclear; multipotent; muscle; myocardial; myocardial infarction; myocardium; New York Heart Association; NYHA; paracrine; PCI; percutaneous coronary intervention; peripheral blood; progenitor; QOL; quality of life; regenerate; regeneration; REPAIR-AMI; revascularization; skeletal myoblasts; totipotent; transplant; transplantation; ventricular remodeling;