This phase II study, in which 167 “no-option” patients with refractory angina were enrolled, provides an opportunity to make observations regarding the feasibility, safety, and efficacy for a strategy of intramyocardial injection of autologous CD34+. The primary findings of this study are that intramyocardial injection of autologous CD34+ cells was associated with a significant decrease in angina frequency and a significant improvement in exercise tolerance in patients with optimally managed but refractory angina. The significant benefit of the low dose of CD34+ cell therapy observed at the primary end point of 6 months was preserved and increased slightly in magnitude at 12 months, contrasting with prior studies of angiogenic therapies in which placebo “catch-up” was observed.20
The overall improvement in low-dose-treated patients was also supported by positive trends in time to onset of angina, quality of life testing, nitroglycerine use, and CCS classification. Our findings are consistent with our pilot study13
as well as other pilot trials of intramyocardial bone marrow cell injection in the setting of chronic myocardial ischemia.21,22
Notably, however, this is the first randomized, controlled trial of stem-cell therapy in patients with refractory angina to achieve significant improvements in both anginal frequency and exercise tolerance.
Another important observation that should not be overlooked is the demonstration of feasibility of this treatment strategy in this multicenter investigation. Each treatment required that cell mobilization, collection by leukapheresis, CD34+-cell enrichment, and lot release testing, as well as NOGA-guided intramyocardial injection, be performed locally at the investigative site. Evidence that this complex protocol could be successfully implemented at multiple treatment centers was necessary before this therapeutic approach could be considered for use on a larger scale. Successful maintenance of the study blind was also critical for the development of a phase III study.
As with any new therapy, particularly in patients with advanced cardiovascular disease, safety is a key consideration. The overall occurrence of major adverse cardiac events was no higher in patients treated with CD34+ cells than in placebo-treated patients, and key safety indices tended to favor CD34+-cell–treated subjects. The study was not powered to detect differences between groups in safety events, and consequently, these observations indicate only that there is currently no evidence for an increased risk of adverse cardiac events associated with intramyocardial CD34+ cell injection. As expected, G-CSF administration and the apheresis procedure were associated with adverse events in this patient population.23
It is worth noting that the rate of enzyme elevation consistent with the new “universal” definition of MI (4.6%) observed in this study is substantially lower than that observed in 3 large meta-analyses of patients undergoing routine percutaneous intervention.24-26
Five subjects were withdrawn from the study following mobilization and apheresis because of events potentially, but not conclusively, attributable to these procedures. Future studies may be designed to determine whether alternate strategies for the collection of CD34+ cells, including the addition of rapidly acting mobilizing agents,27
altered apheresis protocols, or bone marrow aspiration, are available and warranted. The safety of the intramyocardial injection procedure itself also requires careful consideration. The occurrence of 2 (1.2%) myocardial perforation events during the injection procedure is consistent with previous studies.28
It is possible that the rate of adverse procedural events could decrease as the technique is used more routinely; nevertheless, this will remain an area of careful scrutiny as therapies requiring intramyocardial delivery of therapeutics are developed.
This study was not powered to detect differences in efficacy between the low-dose and high-dose groups. Nevertheless, patients who received the lower dose appeared to experience greater improvement in several end points. This lack of a definitive dose-dependent response was not anticipated, but is far from unprecedented, and is consistent with the results from preclinical studies of cell therapy for myocardial ischemia29
and with an extensive body of literature indicating that the response to biological manipulations of angiogenesis is often biphasic.30
Perhaps the most notable recent clinical example is a phase II study of the antiangiogenic drug bevacizumab31
for treatment of metastatic colon cancer. The low-dose treatment, which was half the magnitude of the high-dose treatment, was associated with higher response rates and survival, and the subsequent successful phase III trial, which led to FDA approval of the drug for the condition studied, used the low dose.32
No mechanism for the inverted dose–response relationship associated with bevacizumab has been described, and the mechanism responsible for the potentially more robust effect observed in patients treated with a lower dose of intramyocardially injected CD34+ cells is also unknown. One possible explanation is that the higher dose exceeded the (as yet unidentified) optimum cell density required for promoting paracrine effects within the confined space of the myocardium.
Perfusion imaging was performed in an attempt to quantify changes in blood flow. One SPECT assessment showed improvement in low-dose patients at 6 months, and the remaining SPECT parameters did not identify significant differences between treatment groups. Does this negate the possibility that changes in blood flow were responsible for the clinical effects observed? Not necessarily. SPECT imaging was designed and validated as a tool for detecting relative reductions in blood flow that result from the obstruction of epicardial coronary arteries, whereas the mechanism responsible for the benefit of CD34+-cell therapy is believed to involve increases in capillary density and improved micro-circulation in the area around the injection sites. These improvements are likely spread around throughout the ischemic zone of the myocardium, crossing the boundaries of the standard 17-segment SPECT map; thus, the ability to detect relative changes in blood flow would be, at best, limited. Newer methods for measuring perfusion, such as quantitative positron-emission tomography imaging, may be required to document changes in absolute blood flow at the microvascular level.33
The limitations of this investigation include its status as a phase II study; thus, the findings of improvement following intramyocardial injection of autologous CD34+ cells must be replicated in a phase III investigation before definitive conclusions regarding efficacy can be made. Furthermore, the study was not powered to detect differences between doses, so observations regarding the apparently greater potency of the lower cell dose do not provide a conclusive assessment of the potential dose–response relationship.
In summary, the results from this phase II study support the safety and efficacy of intramyocardially injected autologous CD34+ cells for symptom reduction and improved exercise capacity in “no-option” patients with refractory angina. Larger-scale studies are warranted to verify these effects and to refine the methods for collecting and administering CD34+ cells to patients with disabling angina symptoms.