Stem-cell treatment for cardiac disease recently launched into advanced clinical trials, as a flurry of early-phase studies over the last year collectively confirmed the treatment as safe but left its efficacy unresolved.
At least two phase III trials are now underway and others are possibly imminent. But until these pivotal studies begin to yield outcome results in about 4 years, stem-cell treatment remains a question mark – an appealing idea fueled by hints of effectiveness but also dogged by failures that prompt skepticism about its future.
Photos courtesy Texas Heart Institute
Dr. Emerson C. Perin injects autologous bone marrow cells into an acute MI patient.
The gush of recent early-phase studies also hint at possible explanations for the variability in the success of stem cell treatment. The studies examined a broad range of cell types and patients. (Click here to see a chart of the studies.) The results imply that select types of bone marrow cells may be more effective as therapy and that the number and potency of stem cells decrease with age.
Clinical testing of stem cells for heart disease has hit its stride more than a decade after the first-in-human report in 2001 of a patient treated following an acute myocardial infarction (Dtsch. Med. Wochenschr. 2001;126:932-8), which was followed by the first randomized clinical trial, also in myocardial infarction patients, reported in 2004 (Lancet 2004;364:141-8).
"So far, stem-cell treatment has been safe in all the areas where it’s been used. I’m very satisfied" with the progress, said Dr. Emerson C. Perin, an interventional cardiologist and medical director of the Stem Cell Center at the Texas Heart Institute and one of the U.S. researchers who has worked longest on stem-cell clinical studies. Those working on clinical investigations of stem cells "haven’t done anything stupid to kill it, and we’ve gone from a crawl to a walk," he said in an interview.
Development of stem cell therapies "has been on a normal track; each step takes time. It’s very similar to what happened with fibrinolytic therapy for treating acute myocardial infarctions" in the 1980s and 1990s, said Dr. Timothy D. Henry, an interventional cardiologist, director of research at the Minneapolis Heart Institute Foundation, and another very active stem cell researcher. "It was a good 10 years before we got lytics up and going. People want [stem cells] to be a magic bullet. I think some people have put unrealistic expectations on stem cells, but it’s like any other treatment. You need to do a trial and find out the relative risks and benefits, and that takes time," he said in an interview.
Electromechanical mapping of a patient's heart identifies the sites for transendocardial cell injections.
A different take on the past decade of stem-cell work came from another researcher in the field, Dr. Eduardo Marbán. "The pace of progress has been disappointingly slow, marked by numerous examples of clinical studies prematurely undertaken without benefit of adequate preclinical data. We are lucky that no one has been killed," said Dr. Marbán, professor and director of the Cedars-Sinai Heart Institute in Los Angeles. But despite whatever role luck may have played, Dr. Marbán agreed on the bottom line: "The major accomplishment of the 11-year experience has been the convincing demonstration that most forms of cell therapy are safe, if administered via the intracoronary route." Then he added the elephant in the room: "Efficacy is another matter.
record. Why subject patients to risk in receiving a cell product that has not been extensively validated in vitro and in small and large animals? Yet this has been done over and over again" by investigators running clinical trials of stem cells and other cells for heart disease, Dr. Marbán said in an interview.
Making It to Phase III: REPAIR-AMI/BAMI
The recent surge of study results, and the path to phase III may be best exemplified by the landmark phase II trial done by German investigators, the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial (N. Engl. J. Med. 2006;355:1210-21). The multicenter German study randomized 204 patients an average of 4 days following an acute myocardial infarction (MI) to receive either an intracoronary infusion of autologous bone marrow cells processed to enrich for progenitor cells, or placebo.
Last November, at the annual Scientific Sessions of the American Heart Association, the group presented 5-year follow-up results for 200 of the 204 patients. Helped by the lengthy follow-up, the researchers found that the stem-cell treatment cut the cumulative rate of death, recurrent MI, or need for revascularization from 64% in the control arm to 42%, a statistically significant difference in a prespecified end point of the study.