Catheter used for transendocardial cell injections.
This striking change in a very meaningful clinical outcome contrasted with the modest change in a surrogate end point at 4 months (first reported in the 2006 article), and led to the launch of the largest phase III study of stem cells for heart disease, the Effect of Intracoronary Reinfusion of Bone Marrow Derived Mononuclear Cells (BM-MNC) on All-Cause Mortality in Acute Myocardial Infarction (BAMI), a 3,000-patient, multi-center study funded by the European Union. The study will enroll patients within 3-6 days after reperfusion therapy of an acute MI if they have a left ventricular ejection fraction of 45% or less. The primary end point is a reduction in all-cause mortality, a design that will allow BAMI to use standard care as its control instead of a sham infusion.
"We discussed the end point with the EMA [European Medicines Agency], and they said that if you use only death as the end point we can do it with a state-of-the-art control. I think that is the proper way, because some people believe that intracoronary instrumentation by itself carries a risk that could also affect placebo groups," said Dr. Andreas M. Zeiher, professor and chairman of medicine at Goethe University in Frankfurt, Germany, speaking last November at the American Heart Association meeting.
Dr. Zeiher, who led the team that ran REPAIR-AMI and spearheaded organization of the BAMI trial, also stressed the need to avoid heparin when handling and administering autologous bone marrow cells to achieve optimal results. "Heparin interferes with a process that is absolutely crucial for these cells to extravasate during infusion to enter ischemic tissue," he said during a talk in March at the American College of Cardiology Scientific Session in Chicago. "Heparin in the syringe more or less completely abolishes the migratory capacity of the [bone-marrow] cells." Dr. Zeiher reviewed the methods and results of more than 20 stem-cell studies and found those that used heparin-treated bone-marrow cells had little clinical effect, when studies that avoided heparin or neutralized the drug with serum the cell treatments proved effective. REPAIR-AMI used serum to neutralize heparin, and BAMI will use bivalirudin as an anticoagulant and no heparin, he said.
In contrast to the success in REPAIR-AMI, no efficacy signal occurred in a Norwegian study of bone-marrow mononuclear cells injected into the hearts of 47 acute MI patients in the Autologous Stem-Cell Transplantation in Acute Myocardial Infarction (ASTAMI) study, which coincidently appeared in the same issue of The New England Journal of Medicine as the REPAIR-AMI report (N. Engl. J. Med. 2006;355:1199-209). The lack of success in ASTAMI juxtaposed against the efficacy signal in REPAIR-AMI (a signal later confirmed and strengthened by longer follow-up) provides an example in microcosm of the uneven road that stem cell therapy traversed over the past 11 years. Also worth noting: in ASTAMI the investigators used heparin.
"Heparin interferes with a process that is absolutely crucial for these cells to extravasate during infusion to enter ischemic tissuu," Dr. Andreas M. Zeiher said.
Dr. Zeiher’s heparin explanation for outcome differences among many stem-cell studies is "an interesting hypothesis," said Dr. Robert D. Simari, a cardiologist and professor of medicine at the Mayo Clinic in Rochester, Minn. There are likely several important differences" between the stem-cell trials that have been positive and those that have failed. Trials have differed in their design, patient populations, their stem cell products, and in the end points they have used to measure success, said Dr. Simari, who also chairs the steering committee of the Cardiovascular Cell Therapy Research Network (CCTRN), a research group of seven U.S. centers organized by the National Heart Lung and Blood Institute to run early-phase clinical trials with cell treatments.
Also in the Phase III Act: ACT34-CMI/RENEW
Another cell therapy success story now advancing to a phase III trial is led by Dr. Douglas W. Losordo using autologous CD34+ cells injected into the myocardium of patients with refractory angina. He and his associates published results last August from a phase II study with167 patients, the Double-blind, Prospective, Randomized, Placebo-controlled Study to Determine the Tolerability, Efficacy, Safety, and Dose Range of Intramyocardial Injections of G-CSF Mobilized Auto–CD34+ Cells for Reduction of Angina Episodes in Patients With Refractory Chronic Myocardial Ischemia (ACT34-CMI).
The researchers obtained the autologous cell preparation used in ACT34-CMI by first treating each patient with granulocyte colony stimulating factor daily for 4 or 5 days to mobilize their CD34+ cells. The day following the last dose of drug, each patient underwent leukopheresis to collect mononuclear cells. The cell material then underwent further ex vivo enrichment for CD34+ cells using a commercially-available magnetic cell selection device marketed by Baxter Healthcare. Patients received 100,000 CD34+ cells/kg, 500,000 CD34+ cells/kg, or placebo as intramyocardial injections at 10 sites identified by electromechanical endocardial mapping. Dr. Losordo and his associates said they used CD34+ cells because of evidence these cells, called endothelial progenitor cells, can stimulate neovascularization in ischemic tissue, and improved function in animal models of acute and chronic myocardial ischemia. The patients enrolled in ACT34-CMI all had Canadian Cardiovascular Society class III or IV chronic refractory angina despite optimal medial treatment.