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Point of care, bone marrow mononuclear cell therapy in ischemic heart failure patients personalized for cell potency: 12-month feasibility results from CardiAMP heart failure roll-in cohort
Corresponding author at: Division of Cardiovascular Medicine, Department of Medicine and Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, H4/568 Clinical Sciences Center, 600 Highland Ave, Madison, WI 53792-3248, USA.
Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America
Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America
Division of Hematology and Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America
CardiAMP HF trial will test personalized cell therapy for heart failure patients.
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A 10 patient, open-label, roll-in cohort was performed for protocol feasibility.
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Per protocol procedures were feasible and well-tolerated in all roll-in patients.
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No significant serious adverse safety responses were observed.
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Efficacy trends were observed for functional, quality of life and echo parameters.
Abstract
Aim
Heart failure following myocardial infarction (MI) is a potentially lethal problem with a staggering incidence. The CardiAMP Heart Failure trial represents the first attempt to personalize marrow-derived cell-based therapy to individuals with cell characteristics associated with beneficial responses in prior trials. Before the initiation of the randomized pivotal trial, an open-label “roll-in cohort” was completed to ensure the feasibility of the protocol's procedures.
Methods
Patients with chronic post-MI heart failure (NYHA class II-III) receiving stable, guideline-directed medical therapy with a left ventricular ejection fraction between 20 and 40% were eligible. Two weeks prior to treatment, a ~ 5 mL bone marrow aspiration was performed to examine “cell potency”. On treatment day, a 60 mL bone marrow aspiration, bone marrow mononuclear cell (BM MNC) enrichment and transendocardial injection of 200 million BM MNC's was performed in a single, point of care encounter. Patients were then followed to assess clinical outcomes.
Results
The cell potency small volume bone marrow aspirate, the 60 mL bone marrow aspirate, and transendocardial injections were well tolerated in 10 patients enrolled. There were no serious adverse events related to bone marrow aspiration or cell delivery. Improvement in 6-min walk distance was observed at 6 months (+47.8 m, P = 0.01) and trended to improvement at 12 months (+46.4, P = 0.06). Similarly, trends to improved NYHA heart failure functional class, quality of life, left ventricular ejection fraction and recruitment of previously akinetic left ventricular wall segments were observed.
Conclusion
All CardiAMP HF protocol procedures were feasible and well tolerated. Favorable functional, echo and quality of life trends suggest this approach may offer promise for patients with post MI heart failure. The randomized CardiAMP Heart Failure pivotal trial is underway to confirm the efficacy of this approach.
Millions of Americans with chronic heart failure (HF) following myocardial infarction (MI) suffer decreased exercise capacity, poor quality of life and frequent HF-related hospitalizations. Despite advances in pharmacotherapy, coronary revascularization, and device therapy, this population of symptomatic HF patients is growing and their prognosis is particularly dismal. A tailored, precision medicine approach that selects patients with bone marrow cell characteristics linked to signals for favorable outcomes in prior cell therapy trials, and then delivers these cells at high-dose to modify post myocardial infarction adverse remodeling and improve function, offers promise for this epidemic public health problem.
Bone marrow harbors a heterogeneous mononuclear cell population that includes committed cell populations comprising endothelial progenitor cells, as well as uncommitted hematopoietic progenitor and stem cells, mesenchymal stromal/stem cells and lymphoblasts. Bone marrow mononuclear cell (BM MNC) injections have been linked to favorable functional and structural heart recovery in small [
Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia.
Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines.
Intravenous followed by X-ray fused with MRI-guided Transendocardial Mesenchymal stem cell injection improves contractility Reserve in a Swine Model of myocardial infarction.
] animal models of cardiac ischemia/infarction. This response has presumably been via paracrine factors with the potential to facilitate angiogenesis, reduce local inflammation, oxidative stress, apoptosis, and limit reactive fibrosis [
Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines.
The beneficial effects of BM MNC injections in experimental cardiac ischemia models has paved the way for post-MI chronic HF clinical trials with encouraging results [
Transendocardial autologous bone marrow in chronic myocardial infarction using a helical needle catheter: 1-year follow-up in an open-label, nonrandomized, single-center pilot study (the TABMMI study).
Prospective randomized trial of direct endomyocardial implantation of bone marrow cells for treatment of severe coronary artery diseases (PROTECT-CAD trial).
Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.
]. Three independently conducted meta-analyses of >24 randomized controlled trials testing autologous BM MNC treatment in >1800 patients have shown reductions in mortality and re-hospitalization [
Efficacy and safety of stem cell therapy in advanced heart failure patients: a systematic review with a meta-analysis of recent trials between 2017 and 2019.
]. Furthermore, sub-analyses of past trials have revealed several BM MNC markers that correlated with improved clinical outcomes in chronic ischemic heart failure patients [
Identification of bone marrow cell subpopulations associated with improved functional outcomes in patients with chronic left ventricular dysfunction: an embedded Cohort evaluation of the FOCUS-CCTRN Trial.
]. The recently initiated, randomized sham-controlled, pivotal, CardiAMP Heart Failure (HF) clinical trial (NCT02438306) was conceived using knowledge gained from prior cell therapy trials. This trial was designed to test the hypothesis that intramyocardial delivery of a high dose of autologous BM MNCs in chronic post myocardial infarction HF patients, who meet pre-specified, evidence-based bone marrow cell potency criteria, will improve exercise capacity, clinical status and contractile function [
The CardiAMP heart failure trial: a randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post-myocardial infarction heart failure: trial rationale and study design.
The CardiAMP heart failure trial: a randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post-myocardial infarction heart failure: trial rationale and study design.
]. Briefly, this is a pivotal clinical trial investigating the efficacy of transendocardial catheter delivery of autologous BM MNC in symptomatic heart failure patients due to a previous myocardial infarction (>6 months) with a left ventricular ejection fraction (LVEF) of 20–40%. This trial will assess, for the first time, an approach that selects patients with bone marrow cells identified to meet pre-specified “minimal potency criteria” determined on a screening mini-bone marrow aspirate. The trial has two stages: 1) an open-label “roll-in” cohort phase to evaluate trial safety and feasibility in 10 patients followed by 2) the randomized, sham-controlled, blinded trial phase to evaluate the safety and efficacy of the CardiAMP HF stem cell treatment in 250 patients. The primary objective of the open-label roll-in phase was to establish feasibility of the protocol procedures, assess safety and identify “best practices” prior to launching the larger, randomized, sham-controlled blinded phase of the trial. The 12-month follow-up observations for all 10 roll-in cohort patients are described herein.
2.1 Screening criteria
Human subjects institutional review board approval was obtained at all enrolling centers and all patients provided a written informed consent. This investigation conformed to the principles outlined in the Declaration of Helsinki. Eligible patients were between 21 and 90 years of age with chronic left ventricular dysfunction (EF 20–40% using contrast enhanced echocardiography and analyzed by the core lab) after a MI (>6 months) and New York Heart Association (NYHA) functional class II-III. All patients were required to be receiving clinically stable, guideline-recommended therapy for at least three months prior to enrollment. Detailed inclusion and exclusion criteria, including direction on what constitutes guideline-recommended therapy were previously reported [
The CardiAMP heart failure trial: a randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post-myocardial infarction heart failure: trial rationale and study design.
]. A proprietary cell potency assay was performed approximately 2 weeks prior to treatment. The rationale for the cell potency assay to screen patients in the larger randomized trial was previously presented [
The CardiAMP heart failure trial: a randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post-myocardial infarction heart failure: trial rationale and study design.
]. Briefly, a 5 mL bone marrow aspirate sample from the iliac crest was harvested and analyzed using flow cytometry for cell surface markers, including CD34+ hematopoietic stem cells, a cell population linked to improved outcomes in chronic ischemic heart disease [
]. Although a qualifying cell potency assay was measured in all 10 roll-in patients, investigators were masked to the cell composition results.
2.2 Autologous bone marrow mononuclear cell treatment
CardiAMP HF is the first investigational cell therapy trial to test a multi-step, point of care kit to harvest, isolate and deliver high dose autologous BM MNC in post MI HF patients who were selected based on a bone marrow potency. This kit consists of tools to i) collect the 5 mL bone marrow sample for the cell potency assay, ii) harvest and process 60 mL of BM MNC for transendocardial injections and iii) deliver isolated BM MNCs using innovative, corkscrew shaped needle tipped transendocardial injection catheters that are designed to ensure high cell retention in the myocardium [
The 60 mL of bone marrow aspirate is obtained and processed at point of care (typically the cardiac catheterization laboratory) using a density-tuned dual buoy column to separate the nucleated cell fraction from the plasma phase and the buffy coat (CardiAMP™ CS, BioCardia, San Carlos, CA). As the bone marrow is being processed (<30 min), the patient is prepped for cardiac catheterization and cell delivery. Briefly, an introducer sheath is placed into a femoral artery and a left ventriculogram is performed in two orthogonal projections. Using transparency sheets affixed to the catheter-lab TV monitors, the border of the left ventricular endocardium is manually traced to provide an injection “road-map”. This patient-specific road-map is developed in conjunction with a 17-segment polar map of myocardial wall motion and thickness derived from the patient's baseline echocardiogram. Interventional cardiologists are instructed to target myocardial segments in the peri-infarct zone where the wall thickness is ≥6 mm by echocardiogram. Isolated BM MNCs are delivered in ten intramyocardial injections using the Helix™ transendocardial injection catheter and the Morph® deflectable guiding catheter (BioCardia, San Carlos, CA). Before injecting the cells, operators using the Helix® catheter were required to visually confirm needle engagement in the myocardium by i) observing appropriate, stable fixation of the Helix® screw-in catheter tip at the endocardial surface verified by x-ray fluoroscopy and ii) observing a transient “arc” or “stain” adjacent to the endocardial surface by injecting a small <0.1 mL bolus of 1:1 diluted radio-contrast through a separate contrast injection port that exits at the base of the Helix™ needle positioned outside of the myocardium.
The target total treatment dose of approximately 200 million BM MNC is the same as the Phase II TAC-HFT trial [
The CardiAMP heart failure trial: a randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post-myocardial infarction heart failure: trial rationale and study design.
The 6-min walk distance (6MWD), NYHA functional class, Minnesota Living with Heart Failure Questionnaire (MLHFQ) score were measured at baseline, and 3, 6, 9 and 12 months following treatment [
Patients’ self assessment of their congestive heart failure. Part 1 Patient perceived dysfunction and its poor correlation with maximal exercise tests.
Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
The CardiAMP heart failure trial: a randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post-myocardial infarction heart failure: trial rationale and study design.
]. An independent clinical events committee and the data safety and monitoring committee adjudicated all events and monitored the study for safety outcomes.
2.4 Core laboratories
Bone marrow analyses were performed at the Center for Cell and Gene Therapy, Baylor School of Medicine, Houston, Texas. Baseline and follow-up echocardiography analyses were performed at the independent, imaging core laboratory at Yale Cardiovascular Research Group, New Haven, CT. All Core lab analyses were masked to clinical information.
2.5 Statistical analysis
The continuous variables are summarized using descriptive statistics as mean ± standard error of the mean or percent, where appropriate. P-values for changes from baseline are calculated using the Wilcoxon signed-rank test. The authors are responsible for the design and conduct of this study, all analyses, the drafting and editing of the manuscript and its final contents.
3. Results
3.1 Procedural success
In the roll-in cohort, 14 patients were screened at three US clinical sites. Four patients were excluded due to NYHA functional class I (n = 1), LVEF exceeding 40% (n = 2) and withdrawn consent (n = 1). Thus, 10 patients met clinical screening criteria. After completion of the roll-in phase, it was revealed that 9 of these10 patients would have passed an updated cell potency assay screening threshold issued for the randomized trial. Mean age at enrollment was 67.0 ± 4.2 years (mean ± SEM) and 9 were men. At the time of study entry, 8 patients were NHYA class II, and 2 patients were NYHA class III. Baseline left ventricular ejection fraction was 28.9 ± 2.2%. Procedural success, defined as successful harvesting, processing, and delivery of at least 4 cc of concentrated BM MNC to the myocardium, was achieved in all 10 treated patients. The point of care CardiAMP CS system successfully processed 60 mL of bone marrow in 23.4 ± 2.1 min, producing a final product consisted of 6.3 mL ± 0.2 mL concentrated BM MNC suspension. Estimated total dose delivered was 192 ± 19 million BM MNC, divided evenly into 10 intramyocardial injections of 0.5 mL injectate volume each. Procedural time for the intramyocardial delivery was 38.6 ± 8.0 min. All 10 enrolled patients completed their one-year clinical and echocardiographic follow-up.
3.2 Safety
The bone marrow aspiration procedures during screening and treatment procedures, as well as the transendocardial injection procedures were well tolerated in all patients. Minor, transient discomfort was reported at the site of bone marrow aspirate in 2 of 10 patients. There were no serious adverse events (SAE's) or major adverse cardiovascular events (MACE) reported peri-procedurally or at 30-day follow-up.
At 12-month follow-up, 5 SAE's were reported, including recurrent acute myocardial infarction in 2 patients at days 217 and 245 post treatment, 2 episodes of VT with ICD intervention in 2 patients and hospitalization for decompensated heart failure in 1 patient. These events were considered unlikely to be causally linked to the experimental procedure or device by the local investigator(s) or by the independent events committee.
3.3 Exploratory efficacy outcomes
At baseline, mean 6MWD was 334.5 m ± 26.8 m This increased by +47.8 m at 6 months (P = 0.01) and + 46.4 m relative to baseline at 12 months (P = 0.06; Fig. 1). At 12 months, 6MWD was overall observed to be improved over baseline in 8 of 10 patients.
Fig. 16 min walk distance. A. Box and whisker plots of 6-min walk distance (6MWD) results at 3, 6, 9 and 12 months. B. Similar plots showing change in 6MWD over 12 months compared to baseline. The bottom whisker, bottom edge of the box, top edge of the box, and top whisker indicate the 5th, 25th, 75th, and 95th percentiles. The black square symbol represents the median value (50th percentile). m = meters.
Improvement of New York Heart Association Functional Heart Failure Class (NYHA HF) was observed in the overall cohort at 3- and 6-months follow-up (respectively P = 0.015, and P = 0.037, Fig. 2). One patient was admitted for decompensated heart failure at 9-months. At baseline, two patients were classified with NYHA HF class III and eight patients with NYHA HF class II. At 12-months, three patients were reduced to class I NYHA HF functional class (P = 0.183).
Fig. 2Fig. 2. New York Heart Association (NYHA) heart failure functional class. A. shows distribution in NYHA heart failure functional class at baseline, 3, 6, 9 and 12 months. B. shows change in functional class over 12 months.
By 12-months, the Minnesota Living with Heart Failure Questionnaire (MLHFQ) score was improved in 7 of 10-patients. Baseline mean MLHFQ score was 33.5 ± 8.2. Overall, MLHFQ score improved −10.5 at six months and − 10.0 at twelve months (30% relative improvement vs. baseline, P = 0.33; Fig. 3).
Fig. 3Minnesota Living with Heart Failure Questionnaire (MLHFQ). A. Box and Whisker plots of MLHFQ score at baseline, 3, 6, 9 and 12 months. B. Similar plots showing change in MLHFQ over 12 months compared to baseline. The bottom whisker, bottom edge of the box, top edge of the box, and top whisker indicate the 5th, 25th, 75th, and 95th percentiles. The black square symbol represents the median value (50th percentile).
Consistent with the observed clinical improvements, there was recruitment of previously akinetic myocardial segments. On average, treated patients had 6.1 ± 0.92 akinetic myocardial segments at baseline (6/17). Transendocardial BM MNC injection in adjacent contracting myocardial segments resulted in progressive recruitment of +1.1 myocardial segments at 6-months (18% recruitment of akinetic myocardial tissue, P = 0.08) and + 1.9 myocardial segments at 12-months (31.1% recruitment of akinetic myocardial tissue; P = 0.04). Recruitment of previously akinetic myocardial tissue into contractile tissue was observed in 8 out of 10 patients treated with BM MNC by 12-months. Furthermore, total wall motion score significantly and progressively improved at 6-and 12-months by 3.0 and 6.7 points, respectively (an 8.2% and 16.2% improvement of total wall motion score; P = 0.01 at both time points). Improvement of wall motion score index (WMSI) was observed in all ten patients treated with CardiAMP HF BM MNC therapy at 6 months (Fig. 4), and with further improvement at 12 months (p = 0.016). Left ventricular ejection fraction (LVEF%) increased by a mean of +4.1% ± 2.1% at 12 months follow-up, but this was not statistically significant (Fig. 4; P = 0.18). Of note, LVEF% was improved numerically, in 7 of 10 subjects compared to baseline.
Fig. 4Echocardiogram Wall Motion Score Severity Index (WMSI) and Left Ventricular Ejection Fraction (LVEF). A. Box and Whisker plots of WMSI at baseline, 3, 6, 9 and 12 months. B. Similar plots showing change in WMSI over 12 months compared to baseline. C. Box and Whisker plots of LVEF at baseline, 3, 6, 9 and 12 months. D. Similar plots showing change in LVEF over 12 months compared to baseline. The bottom whisker, bottom edge of the box, top edge of the box, and top whisker indicate the 5th, 25th, 75th, and 95th percentiles. The black square symbol represents the median value (50th percentile).
CardiAMP HF is the first investigational cell therapy trial to test a patient-centered treatment approach that includes (i) a screening bone marrow cell potency assay designed to select patients who are likely to yield BM MNC with a high density of therapeutically potent cells, (ii) a clinically efficient, point-of-care bone marrow cell processing platform that permits cell processing within the cardiac catheterization laboratory in less than 30 min, and (iii) an innovative transendocardial catheter-based cell delivery system with a helix-shaped injection needle designed to maximize cell retention and ensure a high local BM MNC dose. The 12-month follow-up results of the open-label, roll-in cohort suggest that treatment with transendocardial injection of high dose autologous BM MNC is feasible and well tolerated in patients with medically optimized but still symptomatic chronic ischemic HF with reduced ejection fraction. The investigational treatment procedure, which includes bone marrow aspiration, cell processing and catheter injection, was performed on average in <70 min. This is well within an acceptable range for a time-constrained cardiac catheterization laboratory. This point of care approach is not only clinically appealing, it would be more cost efficient than other autologous cell harvest and treatment approaches that require shipping cells to an off-site clean room facility for processing.
Results from the roll-in cohort show trends toward favorable improvements in clinical performance scores including NYHA heart failure functional class, 6MWD, MLHFQ score and echocardiographic parameters. The observed clinical improvements correlated with the echocardiographic results, which demonstrated a mean 31% recruitment of dysfunctional/akinetic myocardial segments and a mean increase in global contractile function. The ongoing 250 patient randomized pivotal trial is specifically designed to confirm these observations.
Several investigators have shown that bone marrow cell sub-populations secrete factors that modulate inflammation, attenuate fibrosis, regulate cell differentiation and survival, and initiate angiogenesis and/or vasculogenesis by recruiting endogenous cells, such as macrophages [
]. Additionally, these cells secrete extracellular membrane vesicles that harbor cardio-reparative factors including RNA/microRNAs, growth factor and cytokine proteins and lipids [
]. The symptom and ambulatory functional improvement trends in the CardiAMP HF roll-in cohort are consistent with the observations from the TAC-HFT17 and the TABMMI [
Transendocardial autologous bone marrow in myocardial infarction induced heart failure, two-year follow-up in an open-label phase I safety study (the TABMMI study).
Transendocardial autologous bone marrow in chronic myocardial infarction using a helical needle catheter: 1-year follow-up in an open-label, nonrandomized, single-center pilot study (the TABMMI study).
] chronic ischemic heart failure trials that used a similar bone marrow harvest and delivery method. Potential mechanisms underlying these symptom and functional improvements could include increased contractile and vascular reserve, which has been observed in animal ischemic heart disease models [
Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines.
Intravenous followed by X-ray fused with MRI-guided Transendocardial Mesenchymal stem cell injection improves contractility Reserve in a Swine Model of myocardial infarction.
CardiAMP HF is the first cell therapy trial to use a pre-specified cell potency assay to prospectively identify likely therapeutic responders. For instance, CD34+ circulating cell titer, a key component of the cell potency assay, has been linked to improved prognosis in cardiovascular patients after acute MI, whereas CD34+ cell expression correlated with favorable clinical outcome of autologous bone marrow treatment in patients with chronic ischemic heart disease [
Identification of bone marrow cell subpopulations associated with improved functional outcomes in patients with chronic left ventricular dysfunction: an embedded Cohort evaluation of the FOCUS-CCTRN Trial.
]. Prior studies have similarly identified cell biomarkers, such as CD34+, in the cell graft that predicted favorable outcomes for autologous cell therapy for recent acute MI [
]. The cell potency assay screen used in this trial establishes a quality control on the cells used to prepare the treatment product, a feature that is remarkably lacking in all minimally manipulated autologous cell therapy trials to date. In addition, this prognostic and predictive enrichment approach may accentuate the therapeutic effect with reduced biovariability, improve the power of the underlying trial and potentially reduce the number needed to treat in clinical practice.
The primary outcome for the actively enrolling 250 patient randomized, sham-controlled stage of the trial is an outcome composite based on a 3-tiered Finkelstein Schoenfeld hierarchical analysis, where the tiers are (1) all-cause death, including cardiac death equivalents such as heart transplant or left ventricular assist device placement, ordered by time to event; (2) non-fatal major adverse coronary and cerebrovascular events, excluding those deemed procedure-related occurring within the first seven days post-procedure (heart failure hospitalization, stroke or myocardial infarction) and ordered by time to event, and (3) change from baseline in 6MWD at 12 months. The Finkelstein Schoenfeld procedure, which has been used in other cardiovascular disease trials, is a ranked analysis that first compares each subject to each other subject for the occurrence of first-tier events and then compares patient outcomes for subsequent tiers. This method permits combining categorical endpoints such as death, with continuous endpoints such as 6MWD.
6MWD is a robust tool to evaluate functional capacity and predict survival in moderate to severe heart failure patients [
]. The first observation for change in 6MWD in the roll-in cohort appears to compare favorably with prior established HF therapies. For example, the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial randomized 453 medically-refractory, mainly NYHA class II-III heart failure patients to cardiac resynchronization therapy (CRT) versus control, and demonstrated improved 6MWD of +39 m versus +10 m in the control group (p = 0.001) at 6-months [
]. In the COMPANION CRT trial, which enrolled almost 90% patients with EF < 35% and NYHA class III heart failure, 6MWD increased by +40 m at 6-months in the CRT group. The data obtained from these and other CRT trials contributed to Food and Drug Administration approval and widespread adoption of this therapy. Compared to the improvement in 6MWD at 6-months in the MIRACLE and COMPANION CRT trials of +39 m and + 40 m at 6-months, respectively, the improvement in the CardiAMP-HF roll-in cohort was +48 m; however, the small sample size and open-label design of the roll-in cohort prevents drawing firm conclusions. However, it does support the need to complete enrollment and follow-up of the randomized, sham-controlled pivotal trial.
4.1 Limitations
It is important to emphasize that this was a safety and feasibility cohort that was not powered for efficacy outcomes. Although investigators were careful to ensure that these treatment refractory heart failure patients were on clinically stable, guideline-recommended therapy for at least 3 months prior to enrollment, it is possible, although unlikely, that some of the observed efficacy of the cell therapy was attributable to continued medical optimization. Additionally, patient-reported responses are known to be subjective and they include a true therapeutic effect and a placebo effect. In an open trial, if patients assigned to an intervention procedure have an expectation that the intervention is beneficial, this might bias their reporting (and bias their physician's interpretation) of symptoms, thus artifactually increasing the rate and/or magnitude beneficial responses. Furthermore, placebo effects are known to be larger for invasive than non-invasive treatments, as documented in a recent landmark trial (ORBITA) that revealed that sham percutaneous coronary intervention for chronic ischemic heart disease improved patient-reported outcomes [
]. For these reasons, the CardiAMP HF randomized trial utilizes a blinded, sham-controlled design.
5. Conclusions
Twelve-month follow-up data from the 10 patient CardiAMP HF open label, roll-in cohort confirms feasibility and suggests potentially favorable responses in the clinical and imaging outcomes, including recruitment of dysfunctional myocardial segments with improved global systolic function. The ongoing randomized stage of the CardiAMP HF trial is enrolling 250 patients in a sham-controlled pivotal trial at up to 40 U.S. sites to confirm the effects observed in the roll-in stage. Success in this pivotal trial has potential to lead to the first cell therapeutic product for patients with chronic post MI heart failure.
Source of funding
CardiAMP HF is a clinical trial funded by BioCardia Inc., San Carlos, CA, Maryland Stem Cell Research Fund (2016-MSCRFP-2804) and Centers for Medicare and Medicaid.
Declaration of Competing Interest
ANR: Research support to the U. Wisconsin-Madison from Fujifilm Cellular Dynamics, BioCardia, Biologics Delivery Systems, Johnson & Johnson and Cellular Logistics Inc., NIH/NHLBI 1U01HL148690-01, NIH 5T32HL007936-15. Consultant for Cellular Logistics Inc., Blue Rock Therapeutics Inc.
CJP: Research or educational support to the University of Florida-Amarin; AMGEN; Alnylam; AstraZeneca; BioCardia, Inc.; Biologic Delivery Systems, Johnson & Johnson, Brigham and Women's Hospital via NHLBI; CSL Behring; LLC & Duke University for DCRI; DoD CDMRPPR161603; Capricor Inc.; Cytori Theraputics; GE Health Care; McJunkin Family Foundation; PCORnet; Mesoblast, Inc.; NIH/NHLBI 1 R01 HL146158-01, R01 HL132448 and UM1 HL087366; Pfizer; and Sanofi US Services, Inc., Consultant-BioCardia Inc.; Caladrius Biosciences, Inc.; Imbria Pharmaceuticals, Inc.; Ironwood Pharmaceuticals, Inc.; Mesoblast, Inc.; Milestone Pharmaceuticals; Novartis Pharmaceuticals; Takeda Pharmaceutical USA, Inc.; Verily Life Sciences LLC; and XyloCor Therapeutics, Inc.
HJD and PAA are employees of BioCardia.
PH is a consultant and has equity ownership in Cellular Logistics Inc.
PVJ is a consultant for BioCardia, Inc., Precigen, Inc., Astra Zeneca, Inc; and Founder and Chief Technical Officer, Domicell, Inc.
Acknowledgements
The authors acknowledge the outstanding contributions of the following: Adrian Gee and April Durett of the Center for Cell & Gene Therapy, Baylor College of Medicine, Texas Children's Hospital in Houston; Maria Cabreira of the Stem Cell Center, Texas Heart Institute, Houston, for their support of CardiAMP HF stem cell studies. In addition, Mary Jo Rizzo, Lavanya Bellumkonda, Lissa Sugeng, and Alexandra Lansky of the Yale Echo Core Lab, Yale Cardiovascular Research Group, New Haven CT, for the echocardiographic image analysis in the CardiAMP HF study. We acknowledge the contributions of Gary Gerstenblith MD at Johns Hopkins University School of Medicine, John Hiemenz MD and John Wingard MD at U. Florida College of Medicine for bone marrow aspiration, and Thomas Cook PhD at U. Wisconsin-Madison for Biostatistics Expertise.
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Long-term effects of bone marrow mononuclear cell transplantation on left ventricular function and remodeling in rats.
Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia.
Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines.
Intravenous followed by X-ray fused with MRI-guided Transendocardial Mesenchymal stem cell injection improves contractility Reserve in a Swine Model of myocardial infarction.
Transendocardial autologous bone marrow in chronic myocardial infarction using a helical needle catheter: 1-year follow-up in an open-label, nonrandomized, single-center pilot study (the TABMMI study).
Prospective randomized trial of direct endomyocardial implantation of bone marrow cells for treatment of severe coronary artery diseases (PROTECT-CAD trial).
Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.
Efficacy and safety of stem cell therapy in advanced heart failure patients: a systematic review with a meta-analysis of recent trials between 2017 and 2019.
Identification of bone marrow cell subpopulations associated with improved functional outcomes in patients with chronic left ventricular dysfunction: an embedded Cohort evaluation of the FOCUS-CCTRN Trial.
The CardiAMP heart failure trial: a randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post-myocardial infarction heart failure: trial rationale and study design.
Patients’ self assessment of their congestive heart failure. Part 1 Patient perceived dysfunction and its poor correlation with maximal exercise tests.
Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
Transendocardial autologous bone marrow in myocardial infarction induced heart failure, two-year follow-up in an open-label phase I safety study (the TABMMI study).
Transendocardial autologous bone marrow in chronic myocardial infarction using a helical needle catheter: 1-year follow-up in an open-label, nonrandomized, single-center pilot study (the TABMMI study).
Intravenous followed by X-ray fused with MRI-guided Transendocardial Mesenchymal stem cell injection improves contractility Reserve in a Swine Model of myocardial infarction.
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