Results of a phase 1, randomized, double-blind, placebo-controlled trial of bone marrow mononuclear stem cell administration in patients following ST-elevation myocardial infarction

doi:10.1016/j.ahj.2010.06.009

American Heart Journal

Volume 160, Issue 3, September 2010, Pages 428-434

https://doi.org/10.1016/j.ahj.2010.06.009 Get rights and content

Background

Initial clinical trials from Europe have demonstrated that the administration of bone marrow–derived mononuclear cells (BMCs) may improve left ventricular (LV) function in patients following ST-elevation myocardial infarction (STEMI). However, results from trials performed in the United States have not yet been presented.

Methods

We developed a phase 1, randomized, placebo-controlled, double-blind trial to investigate the effects of BMC administration in patients following STEMI on recovery of LV function using cardiac magnetic resonance imaging (cMRI). Forty patients with moderate to large anterior STEMIs were randomized to 100 million intracoronary BMCs versus placebo 3 to 10 days following successful primary angioplasty and stenting (percutaneous coronary intervention) of the left anterior descending coronary artery.

Results

Administration of BMC was safely performed in a high-risk cohort with minimal major adverse clinical event rates, and all patients remain alive to date. Left ventricular ejection fraction increased from 49.0% ± 9.5% at baseline to 55.2% ± 9.8% at 6 months by cMRI in the BMC group (P < .05), which was not different from the increase in the placebo group (48.6% ± 8.5% to 57.0% ± 13.4%, P < .05). Left ventricular end-diastolic volume decreased by 4 mL/m² in the BMC group at 6 months but increased significantly in the placebo group (17 mL/m², P < .01).

Conclusions

This phase 1 study from the United States confirms the ongoing safety profile of BMC administration in patients following STEMI. The improvement in LV ejection fraction at 6 months by cMRI in the cell therapy group was not different than the placebo group. However, BMC administration had a favorable effect on LV remodeling at 6 months.

Section snippets

Methods

The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.

Results

All 40 patients that consented to the study underwent successful bone marrow aspiration and infusion of BMCs (n = 30) or placebo (n = 10) without complication. There were no procedural complications associated with cell processing. No patient experienced a rise in troponin or procedure-related complication following the intracoronary infusion. Thirty-three patients presented with an occluded artery and TIMI 0 flow at the time of PCI, and 5 patients underwent aspiration thrombectomy. A total of

Discussion

In this phase 1 trial, we observed that cell therapy with intracoronary BMCs following moderate to large anterior STEMI can be safely performed with a low MACE rate in a high-risk patient cohort. This finding of safety is consistent with the European experience. Cell therapy was associated with a significant improvement in LVEF at 6 months following moderate to large anterior STEMI. However, we failed to demonstrate that cell therapy was superior to placebo because of the similar improvement in

Conclusions

Our phase 1 cell therapy trial using BMCs in patients with anterior STEMI confirms the ongoing safety profile of this therapy. We observed that the intracoronary infusion of 100 million BMCs was associated with a significant improvement in LV function at 6 months as measured by cMRI, but this improvement was not different than that observed in a small placebo group. However, we did demonstrate that cell therapy was associated with improved LV remodeling (LVEDV), which may have long-term

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Microvascular obstruction (MVO) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction following ST-elevation myocardial infarction (STEMI). We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction.
We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs or placebo / control as part of 4 randomized clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot, the multicenter French BONAMI trial and SWISS-AMI trials. A total of 327 patients had paired imaging data at 1 year. All patients received 100 to 150 million intracoronary autologous BMCs or placebo / control 3 to 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n = 210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n = 146) (P < .01). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference = 2.7%; P < .05). Similarly, left-ventricular end-diastolic (LVEDVI) and end-systolic volume indices (LVESVI) demonstrated significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo. In contrast, no improvement in LVEF or LV volumes was observed in those patients without MVO who received BMCs compared to placebo.
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Citation Excerpt :
The main characteristics of the studies are summarized in Table I. Of the 43 studies, 35 evaluated MNCs treatment in AMI4,9-11,15,16,5-8 (all STEMI patients)17-34,35-41and 8 in ICM with previous MI.42-49 All studies used autologous bone marrow–derived MNCs and delivered MNCs into the infarcted-related artery by infusion or intramyocardial injection <24 hours after the bone marrow aspiration.
Mononuclear cells (MNCs) have been tested in clinical trials across multiple cardiovascular pathologies with mixed results. Major adverse cardiac events (MACE) and markers of cardiovascular capacity have been particularly challenging to interpret because of small size. This meta-analysis is aimed to assess the efficacy of MNC therapy in randomized clinical trials to identify the markers of efficiency that could influence future trial design.
PubMed, Embase, Cochrane library, and ClinicalTrials.gov were searched from inception through November 8, 2018. Changes in left ventricular ejection fraction (LVEF) and infarct size from baseline to follow-up were selected as primary outcomes. Changes in the left ventricular end-systolic volume, left ventricular end-diastolic volume, brain natriuretic peptide/N-terminal pro–B-type natriuretic peptide, 6-minute walk test, New York Heart Association class, and MACE incidences were considered secondary outcomes.
In short-term follow-up, patients treated with MNCs demonstrated a significant increase in absolute LVEF of 2.21% (95% CI 1.59-2.83; P < .001; I² = 32%) and 6.01% (95% CI 4.45-7.57; P < .001; I² = 0%) in acute myocardial infarction (AMI) and ischemic cardiomyopathy studies, respectively. This effect was sustained in long-term follow-up. MNC therapy significantly reduced left ventricular end-systolic volume; however, infarct size, 6-minute walk test, New York Heart Association class, and MACE rates were comparable.
MNC therapy may convey a modest but sustained increase in LVEF in ischemic cardiomyopathy patients, supporting further investigation. AMI trials, however, demonstrated minimal improvement in LVEF of unclear clinical significance, suggesting a limited role for MNC therapy in AMI.
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Besides current medical and surgical revascularization therapy, novel therapeutic interventions such as administration of recombinant or purified proteins, and cell and gene therapies have been used to compensate for the loss of cardiomyocytes and to limit the process of left ventricular remodeling. These approaches have been evaluated for use both alone and as adjuncts to bypass grafting in patients who are not candidates for coronary artery surgery. Additional studies need to focus on the development of strategies for optimization of cell delivery, which include adequate cell volume, preconditioned or gene modified to optimal functional results. Induced pluripotent cells from adult somatic cells, ex vivo cell-based gene therapy, and endogenous progenitor stem cell mobilization by mobilizing drugs (alone or/and as an adjuvant with stem cell therapy) into ischemic tissues may represent new directions for cardiac repair. Recently, stem cell exosome-based therapy in clinical settings may represent a novel and viable cardio-regenerative strategy.
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: clinicaltrials.gov#: NCT00268307.

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Clinical InvestigationAcute Ischemic Heart DiseaseResults of a phase 1, randomized, double-blind, placebo-controlled trial of bone marrow mononuclear stem cell administration in patients following ST-elevation myocardial infarction

Background

Methods

Results

Conclusions

Section snippets

Methods

Results

Discussion

Conclusions

Lancet

Lancet

JACC

Am Heart J

JACC

JACC

J Am Coll Cardiol

Repair of infracted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans

Circulation

Bone marrow cells regenerate infracted myocardium

Nature

Intracoronary bone marrow–derived progenitor cells in acute myocardial infarction

N Engl J Med

Intracoronary injection of mononuclear bone marrow cells in acute wall infarction

N Engl J Med

Adult bone marrow–derived cells for cardiac repair: a systemic review and meta-analysis

Arch Int Med

Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review

Eur Heart J

Clinical Investigation
Acute Ischemic Heart Disease
Results of a phase 1, randomized, double-blind, placebo-controlled trial of bone marrow mononuclear stem cell administration in patients following ST-elevation myocardial infarction