A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) After Acute Myocardial Infarction
Joshua M. Hare, MD, Jay H. Traverse, MD, Timothy D. Henry, MD, Nabil Dib, MD, Robert K. Strumpf, MD, Steven P. Schulman, MD, Gary Gerstenblith, MD, Anthony N. DeMaria, MD, Ali E. Denktas, MD, Roger S. Gammon, MD, James B. Hermiller, JR, MD, Mark A. Reisman, MD, Gary L. Schaer, MD, Warren Sherman, MD J Am Coll Cardiol 2009;54:2277–86
Reviewers: Yong G. Peng MD, PhD
University of Florida, Gainesville, FL
Hong Liu, MD
UC Davis Health System, Sacramento, CA
Background and Objective
The goal of this study was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the following advantages: ease of preparation, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support.
A double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n = 53) was performed. The primary end point was incidence of treatment-emergent adverse events within 6 months.
Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points.
Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p = 0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p = 0.003) in the hMSC-treated patients. Global symptom scores in all patients (p = 0.027) and ejection fractions in the important subset of anterior MI patients were both signiﬁcantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging sub-study, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling.
Conclusion: Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients.
Using human bone marrow-derived stem cells (BMCs) as an alternative therapy to treat acute myocardial infarction (AMI) has drawn a significant interest in recent years. However, most of the published studies so far have lacked efficacy and safety profiles. Several concerns have been raised from these studies, including non-specific stem cells lodged into unwanted organ locations; significant heterogeneity among hMSCs and unpredictable stem cell proliferation post-administration; tumor genesis and stem cells that obstructed microvasculature which led to ischemia of other vital organs, etc. The current investigation was a randomized, double-blinded placebo-controlled, multi-center prospective study. There were 53 patients qualified for the study and they were randomly assigned into hMSCs versus placebo in a 2:1 ratio. Each cohort received three different doses of hMSCs (0.5, 1.6, and 5 million cells/kg) and the patients were followed for 6 months. The purpose of the study was intended to address the efficacy and safety concerns of allogeneic human mesenchymal stem cells (hMSCs) intravenously administered to patients after AMI.
The advantages of hMSCs over BMCs include the following: these cells can be delivered to the patient intravenously and they can specifically migrate into injured myocardial sites; they will not cause an anti-inflammatory response or rejection, since they lack cell surface antigens; this preparation can provide an adequate amount stem cells with therapeutic properties. The current study concluded that using hMSCs to treat patients with AMI demonstrated some efficacy and safety features in four specific areas. However, further analysis of the study reveals results that were not as convincing as they first appear for the following reasons:
- Cardiac arrhythmias may be the only area that hMSC treatment has demonstrated a favorable effect and the hMSC treatment group showed a 4-fold lower arrhythmia event rate.
- The authors suggested that pulmonary function testing, including FEV1, was significantly improved after 6 months of treatment with hMSCs. However, it does not appear from the data presented that the two groups are statistically different.
- LVEF improvement in both the hMSC and placebo groups were observed after six months. When a sub-group of patients was analyzed, the hMSC treatment group appeared to have significant LVEF improvement both by echocardiography and MRI assessment versus that of the placebo group. However, no clear criteria were given for selection of each group of patients for such a comparison. It makes one wonder if some bias factors may have contributed to these.
- Patient global symptomatic status: This evaluation certainly can be a subjective or arbitrary finding, especially if both groups have recorded similar rates of adverse events. Even though both groups presented with similar hospitalization rates (31.6% vs 23.5%), the hMSC group showed average longer hospitalization days compared to the placebo group after discharge (66 days vs 120 days).
- This preliminary study also lacks a quantitative measure to assess the amount of stem cells that were actually delivered to the injured myocardial site.
- The follow up time was too short to evaluate the efficacy and safety of such a study.
Overall, the evidence provided by this current study is weak. Further research and long-term follow up are warranted to validate the therapeutic potential of hMSCs in treating patients with AMI.