View Full Version : Stem Cells May Ease Angina in Tough Cases

07-08-2011, 02:52 PM
By Crystal Phend, Senior Staff Writer, MedPage Today
Published: July 07, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Cardiac injections of hematopoietic stem cells can help relieve refractory chest pain, a large phase II study determined.

A relatively low dose of patients' own CD34-positive stem cells reduced weekly angina episodes to 6.8, compared with 10.9 among placebo-treated patients at six months (P=0.020), Douglas W. Losordo, MD, of Northwestern Memorial Hospital and Northwestern University in Chicago, and colleagues found.

Those benefits persisted out to one year, along with a substantial boost in exercise capability, they reported online in Circulation Research: Journal of the American Heart Association.

The study is the first randomized U.S. trial of stem cells for chronic angina, as research has focused more on the acute heart attack setting. Action Points
Explain that cardiac injections of hematopoietic stem cells were found to help relieve refractory chest pain in the first randomized U.S. trial of stem cells for chronic angina.

Note that the benefit in reduction in angina persisted at one year, along with a substantial boost in exercise capability.

Point out that this was a phase II study and the use of stem cells for angina may still be years away from clinical practice.
Stem cells for angina may still be years away from clinical practice, Losordo told MedPage Today, since the first pivotal phase III study isn't slated to get under way until later this year.
But the CD34-positive cells used in the study are routinely used during treatment of certain types of cancer, where they are known as hematopoietic stem cells. These cells boost both bone marrow function and blood vessel formation, which presumably cuts down on the cardiac ischemia that causes angina.

Stem cell therapies for the heart remain experimental except in South Korea, which last week became the first in the world to approve clinical use in acute myocardial infarction.

Tempered Excitement

Refractory angina is a growing problem for which stem cells could be a needed new option, Losordo explained in an interview.

"There's a large pool of patients out there who have really exhausted the currently available treatments," he said. "They've had all the bypass surgery they can have, all the angioplasty and stenting that's possible, are taking maximal and optimal medicines, and are still disabled."

But while Losordo called the results exciting, other experts contacted via email by ABC News in collaboration with MedPage Today were more circumspect.

Bernard Gersh, MD, of the Mayo Clinic in Rochester, Minn., called the results interesting but reaffirmed that "stem cell therapy should be strictly investigational other than in the setting of bone marrow transplants."

Jeff Brinker, MD, of Johns Hopkins, cited "cautious optimism" given the relatively small benefits from cardiac stem cell treatment in prior small studies.

"One should keep in mind that exercise improvement and less angina are soft endpoints and that the number of patients is relatively small," he cautioned, "so that this trial would probably not carry much scientific weight but might justify a larger controlled trial."

Steven Nissen, MD, of the Cleveland Clinic, also urged caution in interpreting the results as preliminary.

Aside from limitations as a small, phase II study, it "required highly invasive methods for administration of stem cells, which may be impractical for routine use," Nissen warned.

Favorable Results

The 167 refractory angina patients in the study got double-blind treatment with a low 1x105 or high 5x105 cells/kg dose of mobilized autologous CD34-positive stem cells, or an equal volume of placebo injected into the heart across 10 sites of ischemic but viable myocardium identified with a mapping injection catheter.

In addition to the positive primary endpoint results for angina frequency at six months, the low-dose stem cells maintained a lower weekly frequency of symptoms at 12 months (6.3 versus 11.0 episodes, P=0.035).

Exercise tolerance also rose with low-dose stem cells at six months (139 versus 69 seconds with placebo, P=0.014) and at 12 months (140 versus 58 seconds with placebo, P=0.017).

"The difference in exercise time would translate to taking somebody who now is really only able to sit and watch TV without chest pain -- so really a very sedentary lifestyle -- and make it possible for them to get up and walk without chest pain," Losordo told MedPage Today.

"Another way of looking at it is that somebody who previously was capable of walking only at a slow pace would now be able to ride a bicycle," he added.

The high-dose group also saw reduced symptom frequency and improved exercise tolerance, but neither effect was significant compared with placebo or the low dose of stem cells.

Gersh noted that this could have been a chance finding, but Losordo pointed to the consistency of the results favoring the lower dose.

"For most effective therapies, we see a positive dose-response relationship," Nissen wrote in an email. "Absence of such a relationship makes the possibility of a statistical aberration higher."

Lack of a dose-response isn't surprising or alarming in a cell-based treatment, though, according to Losordo.

After reaching a threshold dose, the effect often quickly plateaus with more cells, he explained.

Adverse Events

The treatments weren't without risk, though.

Administration of granulocyte colony stimulating factor (filgrastim/Neupogen) to boost circulating CD34+ cells for collection and injection into the heart was associated with bone pain in 20.1% of patients, angina in 17.4%, and congestive heart failure in two patients.

One patient was withdrawn from the study after a thrombus was seen on the mapping catheter. Two patients had an apparent myocardial perforation during the procedure resulting in successfully treated hemothorax in one case and cardiac tamponade and death in the other.

Overall, though, mortality rates tended to be better with stem cell treatments (0% versus 5.4% with placebo at 12 months).

Losordo cautioned that the study was underpowered for this hard endpoint since the treatment was aimed at improving function and quality of life.

One concern was that 4.6% of patients showed cardiac enzyme elevations consistent with non-ST segment elevation MI after cell mobilization and collection.

Brinker noted that these small elevations in troponin may not be clinically significant.

Losordo agreed, noting that any effects were clinically silent and similar to what is commonly seen after stenting, but added that the numbers were too small to make solid conclusions.

The study was funded by Baxter Healthcare.

Losordo reported previously being a paid consultant to Baxter Healthcare.

Several co-authors reported current or prior employment with Baxter Healthcare.

This article was developed in collaboration with ABC News.

Primary source: Circulation Research: Journal of the American Heart Association
Source reference:
Losordo DW, et al "Intramyocardial, autologous CD34+ cell therapy for refactory angina" Circ Res 2011.