Bone Marrow Stem Cells Improve Angina Symptoms in Refractory Patients

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Intramyocardial injections of autologous bone marrow stem cells reduce angina frequency and improve exercise tolerance in “no-option” patients with refractory disease, according to results of a small, randomized trial published online July 7, 2011, ahead print in Circulation Research. The findings represent the first time a placebo-controlled trial has achieved such results, the authors say.

Researchers led by Douglas W. Losordo, MD, of Northwestern University (Chicago, IL), randomized 167 patients at 26 US centers who had chronic refractory angina and no further revascularization options in a 1:1:1 ratio to placebo or high-dose (5 × 10⁵ CD34+ cells/kg body weight) or low-dose (1 × 10⁵ CD34+ cells/kg body weight) autologous stem cells delivered by intramyocardial injection. Bone marrow stem cells were harvested following mobilization via a 5-day course of granulocyte-colony stimulating factor, after which the cells were enriched and then delivered to 10 distinct ischemic areas of myocardium identified by endocardial mapping.

PCI had previously been performed in 83% of the patients, and 28% had elevated troponin levels at some point during the mobilization and injection period, 8 of whom had elevations consistent with NSTEMI.

At 6 and 12 months, angina frequency (primary endpoint) was significantly lower in the low-dose group compared with the placebo group (table 1).

Table 1. Angina Frequency

Angina frequency was also lower in the high-dose group than in placebo-treated patients, but the difference was not statistically significant.

The low-dose group also showed greater improvement in total exercise time at 6 and 12 months compared with controls (table 2).

Table 2. Change from Baseline in Exercise Tolerance Testing

The high-dose group also achieved longer exercise times than the placebo group, but the difference was not statistically significant.

At 6 months, mean changes in the Angina Stability Scale did not differ between the placebo, low-, and high-dose groups, but the low-dose group showed a higher percentage of subjects who improved on the scale compared with controls (69.2% vs. 40.8%; P = 0.005). Compared with those receiving placebo, low-dose patients also exhibited nonsignificant but positive trends in time to onset of angina, quality-of-life testing, nitroglycerine use, and Canadian Cardiovascular Society classification.

The intramyocardial injections appeared safe, with no differences in mortality, MI, stroke, or overall MACE at 12 months among the placebo, low-dose, and high-dose groups.

Dr. Losordo and colleagues note that the study represents “the first randomized, controlled trial of stem-cell therapy in patients with refractory angina to achieve significant improvements in both angina frequency and exercise tolerance.”

Some Safety, Dosing Questions Remain

While the procedure demonstrated acceptable safety levels overall, the researchers note that 5 subjects were withdrawn from the study due to events “potentially, but not conclusively, attributable” to the intramyocardial injection protocol, and 2 myocardial perforations occurred during the injection procedure itself.

“It is possible that the rate of adverse procedural events could decrease as the technique is used more routinely,” they write. “Nevertheless, this will remain an area of careful scrutiny as therapies requiring intramyocardial delivery of therapeutics are developed.”

In addition, while the lack of a therapeutic response from the higher stem-cell dose was unexpected, the authors note, it was not unprecedented and has happened in other, similar studies. “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,” they write.

“There are all sorts of issues that are and will remain unanswered in this field for a while relating to dose response curves,” commented Warren Sherman, MD, of Columbia University Medical Center (New York, NY), in a telephone interview with TCTMD. “The logic of a higher dose doesn’t necessarily apply to this field. There are so many different variables that go into dosing, and there are issues related to the injection technique that may very well explain the unexpected dose differences that we see here.”

Definitive Trial in the Works

Dr. Sherman, who served as the principal investigator for the study at Columbia, noted that of the 2 main outcome measures, the primary endpoint of angina frequency may have been less relevant. “One might argue in terms of the primary efficacy endpoint in terms of how clinically meaningful the magnitude of the change is, but I think the stronger endpoint was exercise duration,” he said.

Dr. Sherman added that based on the current results, a larger, 300-patient study will be launched using the same protocol. “This will be very important from the standpoint of proving the concept,” he said.

While 300 patients might seem like a small number, Dr. Sherman assured that it is considered large for a cell therapy trial and that the study will be considered definitive. In addition, the endpoints are apt to be meaningful from the perspective of the US Food and Drug Administration (FDA). “The way the FDA looks at this, the emphasis is likely to be on symptom and quality-of-life changes. It’s going to be more about how they feel in this syndrome (refractory angina), as well as heart failure,” he predicted. “If this proves effective and gains approval, then that will be a great benchmark. That will be the ‘Palmaz-Schatz stent’ for refractory angina.”

 

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Source:
Losordo DW, Henry TD, Davidson C, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. 2011;Epub ahead of print.

 

 

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