Clinical Benefits of Stem Cells for Chronic Symptomatic Systolic Heart Failure: A Systematic Review of the Existing Data and Ongoing Trials

Abstract

The benefits of stem cell therapy for patients with chronic symptomatic systolic heart failure due to ischemic and nonischemic cardiomyopathy (ICM and NICM, respectively) are unclear. We performed a systematic review of major published and ongoing trials of stem cell therapy for systolic heart failure and compared measured clinical outcomes for both types of cardiomyopathy. The majority of the 29 published studies demonstrated clinical benefits of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs). Left ventricular ejection fraction (LVEF) was improved in the majority of trials after therapy. Cell delivery combined with coronary artery bypass grafting was associated with the greatest improvement in LVEF. Left ventricular end-systolic volume (or diameter), New York Heart Association functional classification, quality of life, and exercise capacity were also improved in most studies after cell therapy. Most ICM trials demonstrated a significant improvement in perfusion defects, infarct size, and myocardial viability. Several larger clinical trials that are in progress employ alternative delivery modes, cell types, and longer follow-up periods. Stem cells are a promising therapeutic modality for patients with heart failure due to ICM or NICM. More data are required from larger blinded trials to determine which combination of cell type and delivery mode will yield the most benefit with avoidance of harm in these patient populations.

Keywords

Systolic heart failure Stem cells Bone marrow-derived stem cells Cell therapy Ischemic cardiomyopathy (ICM)Nonischemic cardiomyopathy (NICM)

Introduction

Over the past decade, and more particularly in the past 2 years, there has been an upsurge in clinical trials investigating the effects of stem cells in patients with chronic systolic heart failure. In an attempt to determine the best strategy to improve myocardial function, several types of cells and delivery methods have been studied in patients with ischemic and nonischemic cardiomyopathy (ICM and NICM, respectively). The results of these clinical trials have been conflicting, with some showing substantial clinical improvement and others demonstrating little benefit. The heterogeneity of the reported clinical benefits seems to be related to the type of study (open-label or blinded trial) and the underlying mechanism of heart failure (ICM or NICM). Hence, in this article, we review and compare clinical outcomes of major published trials of stem cells for patients with chronic, symptomatic systolic heart failure due to ICM and NICM. We focus on variables that are of clinical importance for patients with heart failure. Additionally, we present and discuss major ongoing clinical trials of stem cell therapy for chronic heart failure.

Literature Review

A systematic review of the literature was performed. PubMed, OVID, and Cochrane Library were searched through October 16, 2015. The following key words were included in the search: heart failure, cardiomyopathy, stem cells, progenitor cells, and bone marrow. The search was completed using references manually extracted from retrieved articles. We included clinical trials in adults (18 years or older) for which any type of stem cell was given for chronic severe and symptomatic systolic heart failure from either ICM or NICM. The results were further refined to include only studies that contained patients with a left ventricular ejection fraction (LVEF) ≤45% and New York Heart Association (NYHA) functional classification II to IV. Patients with ICM had to be enrolled at least 1 month after a myocardial infarction. Only articles written in English, French, or Spanish were reviewed. There was no restriction on publication year. In order to better evaluate the effect of stem cell therapy, trials without a control group that received standard therapy alone were excluded. Also excluded were abstracts, reports from scientific sessions, and publications limited to preliminary results. For each trial, if a parameter failed to demonstrate a sustained significant improvement during the trial follow-up period, that parameter was considered as unchanged by cell therapy in our analyses. A separate search was performed using clinicaltrials.gov for ongoing and unpublished trials using the above-defined criteria. Trials that were terminated or withdrawn prior to enrollment were not included.

Search Results

The initial search of the three databases identified a total of 7,232 original articles. After excluding the duplicates and reviewing the title, abstract, or the complete article, 29 published trials that met our inclusion criteria were identified. The IMPACT-DCM and Catheter-DCM trials were analyzed and reported together in a single publication¹. For the purpose of our analysis, we considered them as two separate trials and presented the aggregate results of the NICM patients in Table 1 and the ICM patients in Table 2. The trial by Perin et al.² enrolled patients with both NICM and ICM, but since 85% of the study patients had ICM, the trial results were added to Table 3 only.

Table 1.

Trials in Nonischemic Cardiomyopathy

Trial Name or Author (Year)	Study Type	No. Patients Treated / Control	Cell Type	Mean Cell Dose (×10⁶)	Delivery Route	Endpoint Assessed (Months)	Results
Trial Name or Author (Year)	Study Type	No. Patients Treated / Control	Cell Type	Mean Cell Dose (×10⁶)	Delivery Route	Endpoint Assessed (Months)	LVEF (Method)	LVESD or LVESV	LVEDD or LVEDV	NYHA Class	Quality of Life	6MWT	VO₂ max	BNP/NT-proBNP	Major Adverse Events	Perfusion, Infarct Size or Viability
Bocchi et al. (2010)³	Randomized, open label	23/17	CD34⁺ PBSCs	–	IC	1	↑^* (TTE)	–	EDD^ns	↓^*	↑^*	–	↑^*	↓^*	–	–
						5	↑^* (TTE)		EDD^ns	↓^*			↑^*	Ns
ABCD (2010)⁴	Randomized, open label	41/40	CD34⁺ BMCs	168	IC	36	↑^*^† (TTE)	↓^*^† ESV	EDV^ns	ns	↑^*^†	–	–	–	Death^ns	–
Vrtovec et al. (2011)⁵	Randomized, open label	28/27	CD34⁺ PBSCs	123	IC	12	↑^*^† (TTE)	–	↓^† EDD	–	–	↑^*^†	–	↓^*	^{↓^†} Death	–
Vrtovec et al. (2013)⁶	Randomized, open label	55/55	CD34⁺ PBSCs	113	IC	12	↑^† (TTE)	–	EDD^ns	–	–	↑^†	–	↓^†	^{↓^†} Death	–
						60	↑^† (TTE)		EDD^ns			↑^†		↓^†
INTRACELL (2014)⁷	Randomized, open label	20/10	BMMCs	106	TEp	3	TTE^ns	ESD^ns (TTE)	EDD^ns (TTE)	↓^*	↑^*	ns	–	–	Death^ns	–
							MRI^ns	ESV^ns (MRI)	EDV^ns (MRI)
						6	↑^* (TTE)	ESD^ns (TTE)	EDD^ns (TTE)	↓^*	↑^*	ns
						9	MRI^ns	ESV^ns (MRI)	ESV^ns (MRI)	–	–	–
						12	↑^* (TTE)	ESD^ns (TTE)	EDD^ns (TTE)	↓^*	↑^*	ns
IMPACT-DCM and Catheter-DCM (2014)^{1^‡}	Randomized, open label	18/11	Ixmyelocel-T (from BMMCs)	35–295	TEp, TEn	12	TTE^ns	ESV^ns	EDV^ns	ns	ns	ns	–	ns	MACE^ns	–
REGENERATE-DCM (2015)⁸	Randomized, single blind, placebo control	15/15	BMMCs	216	IC	3	↑^*^† (MRI or CT)	ESV^ns	EDV^ns	↓^*	↑^*	–	ns	ns	MACE^ns	–
						12	↑^*^† (MRI or CT)	ESV^ns	EDV^ns	↓^*	↑^*		↑^*	↓^*
MiHeart (2015)⁹	Randomized, double blind, placebo control	61/54	BMMCs	236	IC	6	TTE^ns	↓^* ESV	EDV^ns	↓^†	ns	ns	↓^*^†	ns	MACE^ns,	–
						12	↓^* (TTE)	↓^* ESV	↑^* EDV	ns	ns	ns	↓^*	ns	Hospitalization^ns	-

For cell type, all cells used are autologous unless specified. 6MWT, 6-min walk distance test; BMCs, bone marrow cells; BMMCs, bone marrow mononuclear cells; BNP, brain natriuretic peptide; IC, intracoronary; LVEDD, left ventricule end-diastolic diameter; LVEF, left ventricular ejection fraction; LVEDV, left ventricule end-diastolic volume; LVESD, left ventricule end-systolic diameter; LVESV, left ventricule end-systolic volume; MACE, major adverse cardiovascular events; MRI, magnetic resonance imaging; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; NYHA, New York Heart Association; PBSCs, peripheral blood stem cells; TEn, transendocardial; TEp, transepicardial; TTE; transthoracic echocardiography; VO₂max, maximal oxygen consumption.

ns: The results did not meet statistical significance for that variable.

–This variable was not studied/reported.

Significant difference (p < 0.05) from baseline (pretreatment) to posttreatment.

†

Significant difference (p < 0.05) between treatment and control group.

‡

Only the results for patients with nonischemic cardiomyopathy are presented in this table.

Table 2.

Open-Label Trials in Ischemic Cardiomyopathy

Trial Name or Author (Year)	Study Type	No. Patients Treated / Control	Cell Type	Mean Cell Dose (×10⁶)	Delivery Route	Endpoint Assessed (Months)	Results
Trial Name or Author (Year)	Study Type	No. Patients Treated / Control	Cell Type	Mean Cell Dose (×10⁶)	Delivery Route	Endpoint Assessed (Months)	LVEF (Method)	LVESD or LVESV	LVEDD or LVEDV	NYHA Class	Quality of Life	6MWT	VO₂ max	BNP/NT-proBNP	Major Adverse Events	Perfusion, Infarct Size or Viability
Perin et al. (2003-4)^10,11	Nonrandomized	14/7	BMMCs	25.5	TEn	2	↑^*^† (TTE)	↓^*^† ESV	EDV^s	↓^*^†	–	–	↑^*	ns	Death^ns	↓^*^† Reversible defects (SPECT)
						4	↑^* (LV angiogram)	↓^* ESV	EDV^ns	–			–	–		↑^* Viability (NOGA^®)
						12	ns (TTE)	–	–	–			↑^*^†	ns		↓^† Reversible defects (SPECT)
Gao et al. (2006)¹²	Randomized	14/14	BMMCs	4	IC	3 days	–	–	–	–	–	–	–	↓^*	↓^{^†} CHF	–
						7 days	↑^* (TTE)	ESV^ns	EDV^ns	–		–		↓^*	admission	–
						1	↑^* (TTE)	ESV^ns	EDV^ns	–		–		–		–
						3	↑^* (TTE)	↓^* ESV	EDV^ns	–		↑^*		↓^*		↑^* Viability (PET)
						6	–	–	–	↓^*		–		–
CAuSMIC (2009)¹⁶	Randomized	12^§\|/11	SMBs	30,	TEn	3	–	ESD^ns	EDD^ns	↓^*^†	ns	–	–	–	Death^ns	↑^* Viability
				100,												(NOGA^®)
				300, or 600		6	–	ESD^ns	EDD^ns	↓^*^†	↑^†					–
						12	–	ESD^ns	EDD^ns	↓^*^†	↑^†					–
Pokushalov et al. (2010)¹³	Randomized	55/54	BMMCs	41	TEn	3	ns (TTE)	ESV^ns	EDV^ns	ns	–	–	–	↓^*^†	↓^† Death	–
						6	↑^*^† (TTE)	↓^*^† ESV	EDV^ns	↓^*^†	–	–		↓^*^†		↓^*^† Reversible defects +infarct size (SPECT)
						12	↑^*^† (TTE)	↓^*^† ESV	EDV^ns	↓^*^†	↑^*^†	↑^*^†		–		↓^*^† Reversible defects +infarct size (SPECT)
STAR-heart (2010)¹⁴	Nonrandomized	191/200	CD34⁺ BMCs	66	IC	3	↑^*^† (LV angiogram)	↓^* ESV	↓^* EDV	↓^*	–	–	↑^*	–	↓^† Death	↓^* Infarct size (LV angiogram)
						12	↑^*^† (LV angiogram)	↓^* ESV	↓^* EDV	↓^*			–			–
						60	↑^*^† (LV angiogram)	↓^* ESV	↓^* EDV	↓^*			–			–
SEISMIC (2011)¹⁷	Randomized	26/14	SMBs	596	TEn	3	ns (MUGA)	–	–	ns	ns	ns	–	–	MACE^ns	–
						6	ns (MUGA)			ns	ns	ns
C-CURE (2013)¹⁵	Randomized	21/15	Cardiopoietic cells	733	TEn	6	↑^*^† (TTE)	↓^*^† ESV	↓^* EDV	↓^*	↑^*	↑^*^†	ns	–	MACE^ns	–
						24	–	–	–	–	–	–	–
IMPACT-DCM and Catheter-DCM (2014)1^‡	Randomized	21/9	Ixmyelocel-T (expanded from BMMC)	35–295	TEp, TEn	12	ns (TTE)	ESV^ns	EDV^ns	↓^†	ns	↑^†	–	ns	↓^†MACE	–

For cell type, all cells used are autologous unless specified. LV, left ventricule; PET, position emission tomography; SPECT, single-photon emission computerized tomography; SMBs, skeletal myoblasts. See Table 1 for other abbreviations.

ns: The results did not meet statistical significance for that variable.

–This variable was not studied/reported.

Significant difference (p < 0.05) from baseline (pretreatment) to posttreatment.

†

Significant difference (p < 0.05) between treatment and control group.

‡

Only the results for patients with ischemic cardiomyopathy from these two trials are presented in this table

Different treatment doses were used in the trial.

Table 3.

Blinded Trials in Ischemic Cardiomyopathy

Trial Name or Author (Year)	Study Type	No. Patients Treated / Control	Cell Type	Mean Cell Dose (×10⁶)	Delivery Route	Endpoint Assessed (Months)	Results
Trial Name or Author (Year)	Study Type	No. Patients Treated / Control	Cell Type	Mean Cell Dose (×10⁶)	Delivery Route	Endpoint Assessed (Months)	LVEF (Method)	LVESD or LVESV	LVEDD or LVEDV	NYHA Class	Quality of Life	6MWT	VO₂ max	BNP/NT-proBNP	Major Adverse Events	Perfusion, Infarct Size or Viability
Patel et al. (2005)¹⁸	Randomized, single-blind	10/10	CD34⁺	22	TEp^#	1	↑^† (TTE)	–	–	–	–	–	–	–	Death^ns	–
			BMCs			3	↑^† (TTE)		–	–
						6	↑^† (TTE)		↓^* EDV	↓^*
Stamm et al. (2007)¹⁹	Randomized, double-blind	35/20	CD133⁺BMCs	5.8	TEp^#	6	↑^*^{^†} (TTE)	↓^†ESD/ESV^ns	EDD/EDV^ns	ns	–	–	–	–	Death^ns	↓^* Perfusion defects (SPECT)
						18	↑^*^† (TTE)	ESD/ESV^ns	EDD/EDV^ns	–
Zhao et al. (2008)²⁰	Randomized, double-blind	18/18	BMMCs	659	TEp^#	1	↑^*^† (TTE)	↓^* ESD	↓^* EDD	↓^*^†	–	–	–	–	Death^ns	–
						3	↑^*^† (TTE)	↓^* ESD	↓^* EDD	↓^*^†						–
						6	↑^*^† (TTE)	↓^* ESD	↓^* EDD	↓^*^†						↓^*^† Perfusion defects (SPECT)
FOCUS-HF (2011)²¹	Randomized, single-blind	20/10	BMMCs	30	TEn	3	ns (TTE, SPECT, LV angiogram) ns (TTE, SPECT, LV angiogram)	ESV^ns	EDV^ns	ns	–	–	ns	–	Death^ns	↓^* Reversible defect (SPECT)
						6		ESV^ns	EDV^ns	ns	↑^*		ns			↓^* Reversible defect (SPECT)
MARVEL-1 (2011)²⁸	Randomized, double-blind	15^§/8	SMBs	400 or	TEn	3	–	–	–	ns	ns	ns	–	ns	Death^ns	–
				800		6	ns (MUGA, TTE)			ns	ns	ns		ns
Hu et al. (2011)²²	Randomized, double-blind	31/29	BMMCs	132	Intragraft^#	6	↑^*^† (MRI)	ESV^ns	↓^*^† EDV	–	–	↑^*^†	–	↓^*^†	MACE^ns	↓^* Perfusion defect (SPECT)
FOCUS-CCTRN (2012)²³	Randomized, double blind	61/31	BMMCs	100	TEn	6	↑^† (TTE + contrast)	ESV^ns	EDV^ns	↓^*	–	–	ns	ns	MACE^ns	Perfusion defect - ns (SPECT)
Lu et al. (2013)²⁴	Randomized, double-blind	31/29	BMMCs	133.8	Intragraft^#	12	↑^*^† (MRI)	↓^*^†ESV	↓^*^† EDV	–	–	–	–	–	Death^ns	Infarct size^ns (MRI)
Cardio133 (2014)²⁵	Randomized, 30/30 double blind	CD133⁺BMCs	5.1	TEp^#	3	ns (TTE)	ESD/ESV^ns	EDD/EDV^ns	–	–	–	–	–	Adverse events^ns	–
						6	ns (TTE, MRI)	ESD/ESV^ns	EDD/EDV^ns	↓^*	↑^*	ns	ns			↓^* Perfusion defects (MRI)
Patila et al, (2014)²⁶	Randomized, 20/19 double blind	BMMCs	840	TEp^#	12	ns (MRI)	ESV - ns	EDV - ns	ns	–	–	–	ns	Death^ns	↓^† Infarct size (MRI) Viability^ns (SPECT/PET)
MSC-HF (2015)²⁷	Randomized, 39/20 double blind, sham-control	BMMSCs	77.5	TEn	6	↑^*^† (CT or MRI)	↓^*^†ESV	↑^* EDV	↓^*	↑^*	↑^*	–	ns	Death^ns	↓^* Infarct size (MRI)
Perin et al. (2015)²^¶	Randomized, double blind, sham-control	45^§/15	Allogeneic BMMSC precursors	25, 75, or 150	TEn	3	↑^*^† (TTE) (for 25 only)	ESV^ns	EDV^ns	ns	ns	ns	–	ns	HF-MACE^† (for 150 only)	Perfusion defect^ns (SPECT)
						6	ns (TTE, MUGA)	↓^*^{^†} ESV (for 150 only)	↓^*^{^†} EDV (for 150 only)	↓^* (for 25 only)	ns	ns		ns	MACE^ns
						12	ns (TTE)	ESV - ns	EDV -ns	ns	ns	ns		ns
						36	–	–	–	–	–	–		–
IxCELL-DCM (2016)²⁹	Randomized, 60/66 double blind, sham-control	Ixmyelocel-T (from BMMCs)	120	TEn	3	ns (TTE)	ESV^ns	EDV^ns	ns	–	ns	–	–	Cardiac	–
						6	ns (TTE)	ESV^ns	EDV^ns	ns		ns			events^†
						12	ns (TTE)	ESV - ns	EDV -ns	ns		ns

For cell type, all cells used are autologous unless specified. BMMSCs, bone marrow mesenchymal stem cells; MUGA, multi gated acquisition scan. See Tables 1 and 2 for other abbreviations.

ns: The results did not meet statistical significance for that variable.

–This variable was not studied/reported.

Significant difference (p < 0.05) from baseline (pretreatment) to posttreatment.

†

Significant difference (p < 0.05) between treatment and control group.

Different treatment doses were used in the trial.

Seven patients enrolled in this trial had NICM.

Trials in which coronary artery bypass grafting surgery was performed.

Nonischemic Cardiomyopathy Trials: Open-Label and Blinded Trials

Eight trials included patients with NICM (Table 1). Six studies were randomized, open-label trials^1,3–7, 1 was single blinded⁸, and 1 was double blinded⁹. Five studies used autologous bone marrow or bone marrow-derived mesenchymal stem cells (BM-MSCs)^1,4,7–9, and 3 used autologous peripheral blood stem cells (PBSCs)^3,5,6. A total of 261 patients received stem cells, and 229 were used as controls. The preferred delivery route was intracoronary (IC) (6 out of 8 trials), and the administered number of stem cells ranged from 35 to 295 × 10⁶ cells. The mean endpoint assessment time was 13.4 months. Four trials demonstrated a significant improvement in LVEF when compared to the control group, with a mean LVEF change of 5.8% (range 4.6% to 7.0%) in the treated patients, and −1.3% (range −2.7% to 0.4%) in the controls (Fig. 1A). Left ventricular end-systolic volume (LVESV) was improved in only 2 trials after therapy. Quality of life was significantly improved in the majority of trials. The NYHA classification and brain natriuretic peptide (BNP) level were both improved in half of the NICM trials. Only 2 studies were able to demonstrate a significant reduction in mortality after stem cell therapy. There were only 2 trials that utilized blinding with mixed results as detailed in Table 1.

Ischemic Cardiomyopathy Trials: Open-Label Trials

There were 15 trials that included patients with ICM, 8 of which were open label (Table 2) and 11 of which were single or double blinded (Table 3). As presented in Table 2, 6 out of 8 open-label trials were randomized. Autologous bone marrow or bone marrow-derived cells were used in 6 ICM open-label trials^1,10–15, and skeletal myoblasts were administered in the other 2 studies^16,17. A total of 354 patients were treated and compared to 324 controls. The delivery mode was mixed: 5 trials utilized a transendocardial (TEn) approach, 2 trials used IC delivery, and 1 trial performed TEn or transepicardial (TEp) injections. Between 4 and 733 × 10⁶ cells were administered in these ICM trials. Endpoints were assessed at a mean time of 8.9 months. Three of the 7 ICM studies demonstrated a significant improvement in LVEF after therapy when compared to the control group, with a mean LVEF change of 6.3% in the treatment group and −1.7% in the control group (Fig. 1B). LVESV improved significantly after stem cell injections in 5 out of 7 ICM open-label trials. Quality of life was significantly improved in 3 out of 5 studies in which it was reported. Significant improvement in maximal oxygen consumption (VO₂max), NYHA classification, and 6-min walk distance test (6MWDT) was observed in almost all trials. Despite having low reported adverse event rates, a significant reduction in mortality was demonstrated in 4 out of 7 open-label studies. Moreover, all of the open-label ICM trials demonstrated an improvement in perfusion defects, myocardial viability, and/or infarct size following stem cell therapy.

Ischemic Cardiomyopathy Trials: Blinded Trials

There were 13 randomized, blinded clinical trials of patients with ICM (Table 3). Patients received autologous bone marrow cells in 10 trials^18–27, skeletal myoblasts in 1 trial²⁸, allogeneic bone marrow mesenchymal precursor cells in 1 trial², and ixmyelocel-T (ex vivo expanded autologous bone marrow cells) in 1 trial²⁹. The delivery mode for these blinded trials was TEp in 5, TEn in 6, and intragraft in the remaining 2 trials. The study patients received 5.1 to 840 × 10⁶ cells, and endpoints were assessed at a mean follow-up time of 7.3 months. When comparing 415 treated subjects to 305 controls, 5 studies demonstrated a significant improvement in LVEF when compared to the control group. Change in LVEF was assessed by transthoracic echocardiography (TTE) alone or in combination with another modality in 9 trials. Magnetic resonance imaging (MRI) alone was used for LVEF assessment in 3 trials, while computed tomography (CT) or MRI was used in 1. When MRI was used, 3 out of 5 ICM studies were able to demonstrate a significant change in LVEF. The mean change in LVEF for the blinded ICM trials that administered stem cell injections alone was 3.2% in the treatment group and −1.3% in the controls (Fig. 1B). In blinded ICM trials where concurrent coronary artery bypass grafting (CABG) and cell injection were performed, a significant improvement in LVEF was noted when compared to the controls (12.8% vs. 5.5%) (Fig. 1C). LVESV was significantly reduced in only 3 out of 11 trials after therapy, while an improvement in NYHA functional classification was reported in 5 trials. Quality of life was improved in 3 studies. However, none of these blinded trials demonstrated a significant improvement in VO₂max or mortality in the treated patients. Of the 10 trials that measured perfusion defects or infarct size, 7 reported a significant improvement.

Ongoing Trials

We identified 13 ongoing clinical trials that are enrolling similar patients with heart failure (Table 4). All trials are randomized, 10 are double blind, and the majority utilizes a sham procedure in the control group. Nine are administering autologous cells, while the others are giving allogeneic cells [cardiosphere-derived cells in 2, mesenchymal stem cell precursors in 1, BM-MSCs in 1, and umbilical cord-derived mesenchymal stem cells (UCB-MSCs) in 1]. Even though two new delivery modes are being studied (intravenously and retrograde injections through the coronary sinus), the IC and TEn delivery modes are still used in most trials. MRI and TTE remain the favored method for left ventricular function (LVEF) and dimension assessment. Clinical outcomes such as heart failure exacerbation, recurrent hospital admission for heart failure-related symptoms, and duration of hospital stay are monitored in almost all of these studies and even constitute the primary outcome in several trials. Overall, these ongoing trials are enrolling more patients than the previous trials, have longer follow-up periods, and are mainly conducted in North America. This differs from the previously published trials that were, for the most part, performed outside of the US.

Table 4.

Ongoing Clinical Trials in Patients With Chronic and Symptomatic Systolic Heart Failure With LVEF ≥45%

Study Name or Sponsor (ClinicalTrials. gov Identifier) Country	Study Type	Patients Enrolled^*	Key Inclusion Criteria	Cell Type	Delivery Route	Follow-up (Months)	Enrollment Status	Estimated Completion Date	Expected Outcomes
	Study Type	Patients Enrolled^*	Key Inclusion Criteria	Cell Type	Delivery Route	Follow-up (Months)	Enrollment Status	Estimated Completion Date	LV Function or Dimension (Method)	6MWT or VO₂max	NYHA Class or BNP^†	Major Adverse Events	Quality of Life/HF Events	Perfusion, Infarct Size, or Viability
Nonischemic cardiomyopathy
CardioCell (NCT02467387) USA	(Phase 2a), randomized single-blind, sham-control	20	On OMT, NYHA II-III	Allogeneic BMMSCs	IV	14.8	Recruiting	December 2016	√ (MRI)	√		√
DYNAMIC (NCT02293603) USA	(Phase 1–2), randomized double-blind, placebo-control	42	On OMT, NYHA III-IV	Allogeneic CDCs	IC	12	Ongoing but not recruiting	December 2016				√	√
Nonischemic or ischemic cardiomyopathy
RIMECARD (NCT01739777) Chile	(Phase 1–2), randomized double-blind, placebo-control	30	On OMT, NYHA II-IV	Allogeneic umbilical cord derived MSCs	IV	12	Completed	June 2015	√ (n/a)	√	√	√	√
ASSURANCE (NCT00869024) USA	(Phase 1–2), randomized double-blind, sham-control	24	Nonrevascularizable, requiring LVAD placement, NYHA III-IV	BMMCs	TEp	24	Ongoing but not recruiting	December 2016	√ (PET, CT)			√	√	√
DREAM-HF/TEVA (NCT02032004) USA and Canada	(Phase 3), randomized double-blind, sham-control	1165	On OMT, NYHA II-III	Allogeneic MSC precursor	TEn	60	Recruiting	August 2018	√ (TTE)	√	√	√	√
Ischemic cardiomyopathy
REGENERATEIHD^‡ (NCT00747708) United Kingdom	(Phase 2–3) randomized double-blind, sham-control	148	On OMT, NYHA II-IV	BMCs	TEn, IC 12	Completed	May 2013	√ (CT, MRI)		√	√	√
IMPACT-CABG^‡ (NCT01033617) Canada	(Phase 2), randomized double-blind	20	Needs CABG, NYHA II-IV	CD133⁺ BMCs	Tep	6	Recruiting	September 2015	√ (TTE, MRI)		√	√	√	√
ALLSTAR^§ (NCT01458405) USA	(Phase 1–2) randomized double-blind, sham-control	274	Anterior infarct>1 <12 months prior, s/p reperfusion, with ≥15% scar, NYHA I-III	Allogeneic CDCs	IC	12	Recruiting	December 2015	√ (MRI)			√		√
Royan Institute (NCT01758406) Iran	(Phase 2), randomized double-blind, sham-control	50	On OMT, NYHA III-IV	Cardiac stem cells	IC	18	Recruiting	December 2015	√ (n/a)	√	√	√	√
ISCIC (NCT01615250) Ukraine	(Phase 1) randomized open-label	50	On OMT, NYHA II-IV	Peripheral mononuclear CD34⁺ cells	TEn	12	Recruiting	January 2016	√ (n/a)			√
CONCERT-HF (NCT02501811) USA	(Phase 2), randomized double-blind, sham-control	144	On OMT, with infarct volume >10% by MRI, NYHA II or III	BMMSC and kit⁺ cardiac stem cells	TEn	12	Not yet open for participant recruitment	February 2019	√ (MRI)	√	√	√	√	√
ATHENA I-II (NCT02052427) USA	(Phase 2), randomized double-blind, sham-control	28	On OMT, NYHA II-III	ASCs	TEn	12	Ongoing but not recruiting	May 2019	√ (TTE with contrast)	√	√	√	√	√
Focus Br (NCT00314366) USA	(Phase 1b), randomized, double blind, crossover	20	Nonrevascularizable, reversible defect on SPECT, NYHA II-IV	Aldehyde dehydrogenase-bright BMCs	TEn	18	Ongoing but not recruiting	April 2021	√ (n/a)	√	√	√	√	√

For cell type, all cells used are autologous unless specified. ASCs, adipose-derived stem cells; CABG, coronary artery bypass grafting; CDCs, cardiosphere-derived cells; CS, coronary sinus; CT, computed tomography; HF, heart failure; IV, intravenous; MSCs, mesenchymal stem cells; OMT, optimal medical therapy. See Tables 1–2 for other abbreviations.

n/a: nonavailable.

As of October 16, 2015.

†

Stands for BNP or NT-proBNP.

‡

Partial results have been published.

Some patients enrolled will be NYHA class I.

Discussion

When compared to previously published reviews^30–33, this systematic review provides a broad contemporary perspective of the role of stem cells in patients with heart failure due to ICM or NICM. Stem cell therapy has been evaluated in a wide spectrum of cardiac disease, including acute ST-elevation myocardial infarction, ICM, and NICM. Prior reviews have often focused only on a part of that spectrum, such as stem cell therapy in patients with ICM and/or myocardial infarction. This review is unique in that it broadens the scope of analysis to include trials of both ICM as well as NICM. In terms of data reported, reviews have often focused specifically on left ventricular function (LVEF and LVESV) and mortality post procedure. Our review includes additional parameters that are important in the management of chronic heart failure, including quality of life, NYHA functional classification, BNP level, and exercise capacity. These parameters are usually reported in clinical trials, but are often underrepresented in systematic reviews.

Impact on Cell Therapy on Left Ventricular Function and Dimension

There was a significant improvement in LVEF from pretreatment values in cell therapy-treated patients in 16 of the 28 trials presented^{3–8,12–15,18–20,22–24,27}. In 14 of the 28 trials, there was a significant improvement in LVEF when compared to the control group (4 out of 8 NICM studied^4–6,8, and 10 out of 20 ICM studies^{13–15,18–20,22–24,27}). This difference could have resulted from some of the trials being underpowered to demonstrate significance between group differences. Patients who received stem cells in combination with CABG for ICM had the greatest improvement in mean LVEF compared to the control group (12.8%) followed by NICM patients (5.8%), and ICM patients who received cell therapy alone (without CABG) (5.1%).

LVESV or diameter reduction was observed in more than half of the trials, suggesting that cell therapy may help reverse cardiac remodeling in these patients with heart failure. Additionally, a significant change in LVESV or diameter after cell injection correlated with an improvement in LVEF in most trials. This association was especially noticeable for ICM studies in which 13 out of 17 reported concordant results for both variables^{1,12–15,20,21,24–27}. However, left ventricular end-diastolic volume (LVEDV) or diameter (LVEDD) did not appear to be as useful as indicators of therapy response, as they remained unchanged in the majority of trials (reduced in 1 out of 8 NICM trials⁵, and 6 out of 19 ICM trials^{14,15,18,20,22,24}), and had poor correlation with a change in LVEF after therapy.

Impact of Cell Therapy on Subjective and Objective Markers of Heart Failure

Overall, NYHA functional classification and quality of life were improved in the majority of trials after cell therapy. Open-label trials were more likely to demonstrate an improvement in NYHA classification after treatment compared to blinded trials. This could be due to a “placebo effect” in the open-label-treated group³⁴. The confounding effect of a “placebo effect” should be less pronounced in the ongoing trials given their use of a single- or double-blind design (with many employing a sham-treated control group) (Table 4).

The objective changes in exercise capacity, measured by the 6MWDT and VO₂max, were also more likely to be improved in the open-label studies. These two variables were only reported together in three trials^9,15,25, and only one trial was able to demonstrate similar results for both parameters; both remained unchanged after therapy. The 6MWDT was more often improved when compared to the control group than the VO₂max was after cell therapy, suggesting that the 6MWDT may be a better marker of improvement following cell therapy. The change in the 6MWDT and VO₂max did not differ between NICM and ICM patients.

Although the BNP level was significantly improved in half of the open-label trials, this was observed in only 2 of the blinded trials^8,22. This discordance could be due to the fact that some of the trials were underpowered to demonstrate significant changes in BNP level. An additional possibility is that cell therapy did not change the volume status of these patients.

Impact of Cell Therapy on Myocardial Perfusion Imaging

Perfusion defect size, infarct size, and myocardial viability were only assessed in ICM trials. Overall, these parameters were improved after stem cell therapy. Several assessment methods were used. The more commonly adopted one was single-photon emission computed tomography (SPECT), followed by MRI, and both yielded similar results for detection of perfusion imaging change. Myocardial viability assessed by SPECT, NOGA^® mapping, or position emission tomography (PET) was reported to be significantly improved in 3 of the 5 trials in which it was measured^10,12,16. Perfusion defect size, infarct size, and myocardial viability were all assessed within 12–36 months of therapy. There is only 1 trial that reported data beyond 1 year, and therefore the benefits of stem cells on myocardial perfusion after that time remain unclear. More data are needed to confirm these benefits and to determine which imaging modality is most accurate at identifying such perfusion changes.

Stem Cell Type and Number

Most of the trials presented here administered autologous BM-MSCs with mixed results. All 3 trials that employed PBSCs (CD34⁺)^3,5,6 as well as the C-CURE trial¹⁵, which used cardiopoietic cells that were grown from bone marrow cells, demonstrated overall beneficial results. However, the 3 trials that administered skeletal myoblasts^16,17,28 were small studies that yielded overall negative results. There was no clear association between the number of cells administered and the improvement in clinical outcome. At this time, it remains unclear which cell type and what cell number are most beneficial for patients with chronic systolic heart failure. Ongoing trials should help clarify these important points.

Delivery Mode

The three preferred delivery modes were TEn, IC, and TEp. While IC was mainly used for NICM patients, TEn and TEp and intragraft were favored for ICM. Patients who had cells infused via an IC or intragraft routes were more likely to have an increased LVEF compared to the other techniques. This observation differs from existing data suggesting that TEn would be superior to IC delivery in terms of myocardial retention rates, improvement in LVEF, BNP level, and exercise capacity³⁵. Of the 8 trials that administered cells by IC, 4 did not use a flow occlusion technique^3,5,6,9. In the remaining trials, 3 had simultaneous proximal balloon inflation during infusion^8,12,14 and 1 had coronary sinus balloon inflation for distal flow interruption⁴. The only IC trial that failed to show a significant improvement in LVEF did not use a flow-obstruction technique⁹, suggesting that a flow-occlusion technique might be favorable to cell retention and local effect.

Limitations

The interpretation of these trials' results is limited by the fact that cell therapy for heart failure is relatively new, and as such, most trials are either pilot studies or early phase II trials, with a small sample size. The heterogeneity and overall small number of trials in this review limit our ability to perform detailed subgroup analyses that could provide clinically important information. For example, it is certainly possible that cell preparation techniques used in some of the trials may have impacted results; however, the small number of these studies, the heterogeneity of preparation techniques, and insufficient information on the details of cell preparation preclude drawing meaningful conclusions on this subject. The follow-up time of these studies also tended to be short, especially for the blinded ICM trials. A small group of trials registered on clinicaltrials.gov was terminated early due to lack of funding or administrative problems, and thus their results were not published. Additionally, our results could be limited by “publication bias,” in which negative studies were not published. These missing negative trials could exaggerate the perceived benefits of cell therapy for patients with heart failure. Our search for ongoing trials was limited to trials listed on clinicaltrials.gov. Hence, it is possible that there are other pertinent ongoing trials not listed on clinicaltrials.gov website. This may be the case for trials performed outside the US.

Conclusions

This review suggests that stem cells are a promising therapeutic modality for patients with severe symptomatic heart failure due to ICM and NICM. However, larger randomized, double-blind clinical trials with longer follow-up periods are needed to determine which combination of cell type, delivery mode, and subset of patients would most optimally demonstrate safety and efficacy. Future studies will also clarify which outcome variables are most appropriate to assess efficacy of these novel therapies. The surge of new trials should help clarify these questions.

Footnotes

Acknowledgment

Dr. Schaer serves on the steering committee of the ixCELL trial. Otherwise, the other authors declare no conflicts of interest.

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