2016 - Stem Cell Therapy For Chronic Ischaemic Heart Disease and Congestive HF

Stem cell therapy for chronic ischaemic heart disease and
congestive heart failure (Review)
Fisher SA, Brunskill SJ, Doree C, Mathur A, Taggart DP, Martin-Rendon E
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2014, Issue 4
http://www.thecochranelibrary.com
Stem cell therapy for chronic ischaemic heart disease and congestive heart failure (Review)
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 120
Stem cell therapy for chronic ischaemic heart disease and congestive heart failure (Review) i
[Intervention Review]
Stem cell therapy for chronic ischaemic heart disease and

congestive heart failure
Sheila A Fisher1 , Susan J Brunskill1 , Carolyn Doree1 , Anthony Mathur2 , David P Taggart3 , Enca Martin-Rendon4
1 SystematicReview Initiative, NHS Blood and Transplant, Oxford, UK. 2 Department of Clinical Pharmacology, William Harvey
Research Institute, London, UK. 3 Oxford Heart Centre, John Radcliffe Hospital, Oxford, UK. 4 Stem Cell Research Department, NHS
Blood and Transplant, Oxford, UK
Contact address: Enca Martin-Rendon, Stem Cell Research Department, NHS Blood and Transplant, John Radcliffe Hospital, Head-
ington, Oxford, OX3 9BQ, UK. Enca.Rendon@ndcls.ox.ac.uk.
Editorial group: Cochrane Heart Group.

Publication status and date: New, published in Issue 4, 2014.
Review content assessed as up-to-date: 22 May 2013.
Citation: Fisher SA, Brunskill SJ, Doree C, Mathur A, Taggart DP, Martin-Rendon E. Stem cell therapy for chronic ischaemic
heart disease and congestive heart failure. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD007888. DOI:
10.1002/14651858.CD007888.pub2.
ABSTRACT
Background
A promising approach to the treatment of chronic ischaemic heart disease (IHD) and heart failure is the use of stem cells. The last
decade has seen a plethora of randomised controlled trials (RCTs) developed worldwide which have generated conflicting results.
Objectives
The critical evaluation of clinical evidence on the safety and efficacy of autologous adult bone marrow-derived stem cells (BMSC) as a
treatment for chronic ischaemic heart disease (IHD) and heart failure.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013, Issue 3), MEDLINE (from
1950), EMBASE (from 1974), CINAHL (from 1982) and the Transfusion Evidence Library (from 1980), together with ongoing trial
databases, for relevant trials up to 31st March 2013.
Selection criteria
Eligible studies included RCTs comparing autologous adult stem/progenitor cells with no autologous stem/progenitor cells in par-
ticipants with chronic IHD and heart failure. Co-interventions such as primary angioplasty, surgery or administration of stem cell
mobilising agents, were included where administered to treatment and control arms equally.
Data collection and analysis
Two review authors independently screened all references for eligibility, assessed trial quality and extracted data. We undertook a quan-
titative evaluation of data using fixed-effect meta-analyses. We evaluated heterogeneity using the I statistic; we explored considerable
heterogeneity (I > 75%) using a random-effects model and subgroup analyses.
Stem cell therapy for chronic ischaemic heart disease and congestive heart failure (Review) 1
Main results
We include 23 RCTs involving 1255 participants in this review. Risk of bias was generally low, with the majority of studies reporting
appropriate methods of randomisation and blinding, Autologous bone marrow stem cell treatment reduced the incidence of mortality
(risk ratio (RR) 0.28, 95% confidence interval (CI) 0.14 to 0.53, P = 0.0001, 8 studies, 494 participants, low quality evidence) and
rehospitalisation due to heart failure (RR 0.26, 95% CI 0.07 to 0.94, P = 0.04, 2 studies, 198 participants, low quality evidence) in
the long term (12 months). The treatment had no clear effect on mortality (RR 0.68, 95% CI 0.32 to 1.41, P = 0.30, 21 studies,
1138 participants, low quality evidence) or rehospitalisation due to heart failure (RR 0.36, 95% CI 0.12 to 1.06, P = 0.06, 4 studies,
236 participants, low quality evidence) in the short term (< 12 months), which is compatible with benefit, no difference or harm. The
treatment was also associated with a reduction in left ventricular end systolic volume (LVESV) (mean difference (MD) -14.64 ml, 95%
CI -20.88 ml to -8.39 ml, P < 0.00001, 3 studies, 153 participants, moderate quality evidence) and stroke volume index (MD 6.52,
95% CI 1.51 to 11.54, P = 0.01, 2 studies, 62 participants, moderate quality evidence), and an improvement in left ventricular ejection
fraction (LVEF) (MD 2.62%, 95% CI 0.50% to 4.73%, P = 0.02, 6 studies, 254 participants, moderate quality evidence), all at long-
term follow-up. Overall, we observed a reduction in functional class (New York Heart Association (NYHA) class) in favour of BMSC
treatment during short-term follow-up (MD -0.63, 95% CI -1.08 to -0.19, P = 0.005, 11 studies, 486 participants, moderate quality
evidence) and long-term follow-up (MD -0.91, 95% CI -1.38 to -0.44, P = 0.0002, 4 studies, 196 participants, moderate quality
evidence), as well as a difference in Canadian Cardiovascular Society score in favour of BMSC (MD -0.81, 95% CI -1.55 to -0.07,
P = 0.03, 8 studies, 379 participants, moderate quality evidence). Of 19 trials in which adverse events were reported, adverse events
relating to the BMSC treatment or procedure occurred in only four individuals. No long-term adverse events were reported. Subgroup
analyses conducted for outcomes such as LVEF and NYHA class revealed that (i) route of administration, (ii) baseline LVEF, (iii) cell
type, and (iv) clinical condition are important factors that may influence treatment effect.
Authors conclusions
This systematic review and meta-analysis found moderate quality evidence that BMSC treatment improves LVEF. Unlike in trials where
BMSC were administered following acute myocardial infarction (AMI), we found some evidence for a potential beneficial clinical effect
in terms of mortality and performance status in the long term (after at least one year) in people who suffer from chronic IHD and heart
failure, although the quality of evidence was low.
PLAIN LANGUAGE SUMMARY

Stem cell treatment for chronic ischaemic heart disease and congestive heart failure
Those suffering from heart disease and heart failure are currently treated with drugs and, when possible, the blood supply is restored in
the heart (revascularisation) either by opening the arteries with a tiny balloon in a procedure called primary angioplasty (or percutaneous
coronary intervention (PCI)) or by heart surgery (or coronary artery bypass graft (CABG)). Revascularisation has reduced the death
rate associated with these conditions. In some people heart disease and heart failure symptoms persist even after revascularisation. Those
people may not have other treatments available to them. Recently, bone marrow stem/progenitor cells have been investigated as a new
treatment for people with heart disease and heart failure, whether they are also treated for revascularisation or not. Results from 23
randomised controlled trials, covering more than 1200 participants, to 2013 indicates that this new treatment leads to a reduction in
deaths and readmission to hospital and improvements over standard treatment as measured by tests of heart function. At present, these
results provide some evidence that stem cell treatment may be of benefit in people both with chronic ischaemic heart disease and with
heart failure. Adverse events are rare, with no long-term adverse events reported. However, the quality of the evidence is relatively low
because there were few deaths and hospital readmissions in the studies, and individual study results varied. Further research involving
a large number of participants is required to confirm these results.
Stem cell therapy for chronic ischaemic heart disease and congestive heart failure (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Bone marrow stem cells (BMSC) (intervention) compared with control (no intervention) for chronic ischaemic heart disease and congestive heart failure
Patient or population: People with chronic ischaemic heart disease and congestive heart failure
Settings: [setting]
Intervention: Bone marrow stem cells
Comparison: Control (no cells)
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Control BMSC
Mortality - Short-term 25 per 1000 14 per 1000 RR 0.68 (0.32 to 1.41) 1138 participants A combination of low
follow-up (<12 months) (9 to 35) (21 studies) low events and discordant re-
sults from one study leads
to low confidence in the
estimate of the effect. This
is likely to change with
further research
Mortality - Long-term 148 per 1000 27 per 1000 RR 0.28 (0.14 to 0.53) 494 participants As above.
follow-up ( 12 months) (8 to 78) (8 studies) low
Rehospitalisation due to 95 per 1000 33 per 1000 RR 0.36 (0.12 to 1.06) 236 participants As above.
heart failure- Short-term (5 to 101) (4 studies) low
follow-up (<12 months)
Rehospitalisation due to 92 per 1000 23 per 1000 RR 0.26 (0.07 to 0.94) 198 participants As above.
heart failure- Long-term ( 3 to 86) (2 studies) low
follow-up ( 12 months)
3
LVEF (%): mean change See comments See comments MD 4.22% (3.47 to 4.97) 746 participants LVEF measurements are
from baseline to end of (18 studies) moderate given in percentage.
study (<12 months) There is lack of appro-
priate blinding in a num-
ber of studies, which in-
creases the risk of bias
and moderate statistical
heterogeneity
LVEF (%): mean change See comments See comments MD 2.62% (0.50 to 4.73) 254 participants LVEF measurements are
from baseline to end of (6 studies) moderate given in percentage.
study (12 months) There is lack of appro-
priate blinding in a num-
ber of studies, which in-
creases the risk of bias
and moderate statistical
heterogeneity
NYHA classifica- See comments See comments MD -0.63 (-1.08 to -0.19) 486 participants NYHA Class I (1), II (2), III
tion: mean value at end (11 studies) moderate (3) and IV (4).
of study - There is lack of appropri-
Class I to IV (< 12 ate blinding in a number of
months) studies which increases
the risk of bias, and high
statistical heterogeneity
NYHA classifica- See comments See comments MD -0.91 (-1.38 to -0.44) 196 participants NYHA Class I (1), II (2), III
tion: mean value at end (4 studies) moderate (3) and IV (4).
of study - There is lack of appropri-
Class I to IV ( 12 ate blinding in a number of
months) studies which increases
the risk of bias, and high
statistical heterogeneity
*The assumed risk is provided as the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison
group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio; MD: Mean Difference.
4
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
5
BACKGROUND The procedure is currently as follows: either the bone marrow is
harvested from the recipient or stem/progenitor cells are mobilised
into circulation by a growth factor stimulant (most commonly
Description of the condition granulocyte colony-stimulating factor (G-CSF)). In the first pro-
Ischaemic heart disease (IHD) is a major cause of mortality and cedure, cells are usually collected (sometimes under general anaes-
morbidity and the main cause of congestive heart failure (CHF) in thesia) from the pelvic bone, using large suction needles. There-
Western societies (BHF 2008). Despite current therapies having after, the cells are separated from other bone marrow cells in ster-
increased the short-term survival of people suffering from myocar- ile conditions. The bone marrow harvest and separation of stem
dial infarction (MI), the number of people with CHF is rapidly cells may take several hours. In the G-CSF mobilisation proce-
increasing. In IHD, although some of the myocardium has been dure, stem/progenitor cells are collected as a blood sample and
replaced by scar tissue, the heart may prevent the death of car- then separated from other blood cells in sterile conditions. In both
diomyocytes by reducing the energy demands of contraction. This procedures, the stem/progenitor cells are infused directly into the
results in non-contracting or hibernating, but viable, myocardium. recipients coronary arteries or heart. The first procedure delivers
This is a physiological response to chronic hypoxic stress, which the cells to the coronary arteries via a special balloon-catheter dur-
is identifiable by electromechanical dissociation, and potentially ing angioplasty (e.g. percutaneous coronary intervention (PCI))
reversible by revascularisation of the hibernating myocardium in using a stop-flow technique. The second procedure administers
order to restore cardiac function. the cells into the heart muscle during an angioplasty-like proce-
As with acute MI (AMI), pharmacological therapy, angioplasty dure using electromechanical mapping and direct intramyocardial
and bypass surgery are the standard treatments offered to those injection (e.g. NOGA system) or during cardiac surgery (e.g. coro-
suffering from CHF. In the acute setting, angioplasty restores the nary artery bypass grafting (CABG)). The interval between the
normal flow in infarct-related arteries in more than 90% of those collection of the stem cells and their reinfusion varies, but as the
who have suffered MI (Grines 1999; Stone 1998). This early revas- stem cells are used fresh the time cannot be too long unless they
cularisation of the occluded artery after AMI has improved the undergo some form of culture and expansion ex vivo.
prognosis, although a significant number of people still develop The collection of the stem cells is most probably undertaken by
CHF. Preventing the progression of IHD and the development a haematologist. A specialised technician or scientist undertakes
of CHF therefore remains a challenge. In some cases, people who the separation of the stem/progenitor cells from the other bone
have already received angioplasty or bypass surgery are treated marrow cells and the cardiologist or cardiac surgeon undertakes
with maximal medical therapy, but they still present symptoms of the infusion or intramyocardial injection of the cells.
chronic myocardial ischaemia, sometimes with refractory angina. There are no adverse effects associated with the administration of
Alternative therapies for CHF, such as stem/progenitor cell trans- stem cells as a treatment for people with chronic IHD or heart
plantation, are being investigated to complement current pharma- failure. In those trials where G-CSF has been administered prior
cological therapies, primary angioplasty and cardiac surgery. This to the stem cell harvest, transient complications arising from the
approach to the treatment of CHF developed from the observa- G-CSF treatment have been described. However, no long-term
tion in animal models that mononuclear cells from bone mar- adverse effects have been reported.
row or mobilised peripheral blood were effective in cardiac re- This treatment is currently only available in research-associated
pair (Deb 2003; Orlic 2001a; Orlic 2001b; Yoon 2005). Later, it facilities, but it is conceivable that, if long-term effectiveness is
was demonstrated in the first non-randomised trials that cardiac confirmed, this procedure may be available to some or all people
function was improved when bone marrow stem/progenitor cells with chronic heart disease, since bone marrow harvest is a stan-
were transplanted into the infarcted myocardium (Assmus 2002; dard procedure used in bone marrow transplantation. The most
Strauer 2002). Although the stem cell type contributing to the effective results so far have been found in recipients with low left
repair of damaged tissue was not well defined, a study by Stamm ventricular ejection fraction (LVEF) and heart failure symptoms
(Pokushalov 2010).
2003 indicated that the delivery of CD133 progenitor cells from The costs may be high, depending on the procedures used, and
haematopoietic tissues (e.g. bone marrow and blood) into the is- currently relate to the costs of the stem/progenitor cell procedure
chaemic cardiac muscle could improve revascularisation. This has (stem cell harvest) and to the costs of the collection of the stem/
resulted in a number of larger randomised controlled trials (RCTs) progenitor cells (approximately a tenth of the overall cost of the
worldwide, for AMI (Janssens 2006; Lunde 2006; Meyer 2006; trial). The potential for a large, funded clinical trial is limited,
Schchinger 2006) and chronic heart failure (Assmuss 2006; Erbs as there are no intellectual property rights associated with this
2005; Hendrikx 2006; Patel 2006; Stamm 2007). procedure in its current form, rendering it unattractive to private
company funding.
Description of the intervention
How the intervention might work as a treatment for chronic ischaemic heart disease (IHD) and heart
failure.
The mechanisms of the beneficial effects of bone marrow-derived
stem cells (BMSC) remain unclear, and clinical trials in which
BMSC have been administered to participants with acute myocar-
dial infarction (AMI) and chronic myocardial ischaemia have pro- METHODS
duced divergent results. The type of stem cell contributing to the
repair of the damaged tissue or the amelioration of tissue damage
is still not well defined and the mechanism of action is not yet
fully understood. Bone marrow-, cord blood- or peripheral blood- Criteria for considering studies for this review
derived stem cells may exert their effects on cardiac function by
increasing vascularity via endothelial progenitor cell incorporation
into the ischaemic tissue, by generating cardiomyocytes, by mod-
Types of studies
ulating cardiac remodelling and/or, in a paracrine fashion, by pro-
ducing cytokines or other factors that may help to promote cardiac Randomised controlled trials (RCTs).
repair and limit fibrosis in the affected area (Beltrami 2003; Carr
2008; Martin-Rendon 2008a; Mathur 2004; Stuckey 2006; Yoon
2005). Types of participants
Anyone with a clinical diagnosis of IHD or congestive heart failure
(CHF), excluding people with acute myocardial infarction (AMI).
Why it is important to do this review
Stem cell therapy represents an exciting new form of treatment for
Types of interventions
many diseases. Heart disease is one of the clinical settings in which
to address this new form of therapy, although the exact clinical role Studies involving the administration of autologous adult stem cells
for stem cell therapy remains to be defined. A recent systematic on their own or in combination with co-interventions, such as
review (Martin-Rendon 2008b; Martin-Rendon 2008c) of stem cardiac surgery, as treatment for IHD or CHF.
cell treatment for AMI found that stem cell treatment may lead Participants in the comparator treatment arm of the trial received
to some improvements over conventional therapy as measured either no intervention or a placebo (e.g. the medium in which
by surrogate tests of heart function, although further trials are the stem cells were suspended or plasma). Trials where co-inter-
required to confirm that these changes translate into improvements ventions (e.g. coronary artery bypass graft (CABG), percutaneous
in long-term survival and are not accompanied by side effects. A coronary intervention (PCI), granulocyte colony-stimulating fac-
number of RCTs have been undertaken and published exploring tor (G-CSF), extracorporal shockwave therapy) were additionally
a clinical role for stem cell treatment in people with chronic IHD administered were eligible as long as the co-interventions were
and heart failure. This is a clinical group with defined treatment equal in both arms and administered to an equivalent proportion
options and problems sufficiently different from those who have of participants.
suffered an AMI to indicate the need for a new systematic review. In summary:
In addition, several RCTs have generated contradictory results. 1. Any autologous human adult stem cells
Since the use of stem/progenitor cells for cardiac tissue repair is 2. Any single dose
such a recent intervention in clinical practice, it is important that a 3. Any method of stem cell isolation
systematic review is undertaken at an early stage to assess the safety 4. Any route of administration
and efficacy of this intervention. We define safety as the absence of 5. Any co-intervention
adverse events (e.g. increased mortality and morbidity, increased 6. Repeated intervention or multiple doses.
risk of infarction, restenosis and arrhythmias), and efficacy as a
significant improvement in cardiac function, clinical outcomes
and quality of life. Types of outcome measures
We divided beneficial outcomes into clinically-based and surrogate
endpoints. At the protocol stage of this review, we had intended
to consider clinical and surrogate endpoint data at 30 days, six
months and 12 months after baseline; however, this was not possi-
OBJECTIVES
ble due to the variation in follow-up periods reported in individual
The critical evaluation of clinical evidence on the safety and effi- studies. We therefore stratified outcome data into short-term (up
cacy of autologous adult bone marrow-derived stem cells (BMSC) to 12 months) and long-term (12 months or longer) follow-up.
Primary outcomes Searching other resources
We searched the following trial registers for ongoing trials on 31
March 2013: Current Controlled Trials (ISRCTN), ClinicalTri-
Clinical als.gov, WHO International Clinical Trials Registry Platform (IC-
TRP), UMIN-CTR (Japanese Clinical Trials Registry) and the
Mortality. Hong Kong Clinical Trials Register.
We checked the reference lists of all identified eligible papers and
relevant narrative reviews. We applied no language or date restric-
Surrogate endpoints tions to any of the searches.
Left ventricular ejection fraction (LVEF).
Adverse events
Data collection and analysis
Secondary outcomes
Selection of studies
The information specialist (CD) conducted the electronic search
for potentially relevant papers and removed references that were
Clinical duplicates, clearly irrelevant and/or included in previous search
1. Morbidity (infarction, heart failure, arrhythmias); results. Two review authors (SAF, EMR) screened all titles and ab-
2. Composite outcome of morbidity and infarction; stracts identified by the review search strategy for relevance to the
3. Health-related quality of life; review question. We excluded only studies that were clearly irrele-
4. Performance status; vant at this stage, and assessed all other studies as full-text articles
for inclusion or exclusion using the criteria indicated above (type
of studies, participants, interventions and outcome measures). At
Surrogate endpoints this point, two review authors (SAF, EMR) independently assessed
eligibility using ad hoc eligibility forms, and resolving disagree-
1. Engraftment and survival of the infused stem cells; ments between them by discussion.
2. End-systolic volume;
3. End-diastolic volume;
4. Wall motion score; Data extraction and management
5. Stroke volume index. We extracted data onto tailored data extraction forms which were
created and piloted specifically for this review. Two review authors
(EMR, SAF) undertook data extraction for all eligible studies in-
dependently.
Search methods for identification of studies Aside from details relating to the quality of included studies, we
extracted the following two groups of data:
(1) Study characteristics: place of publication, date of publication,
population characteristics, setting, detailed nature of intervention,
Electronic searches
detailed nature of comparator, detailed nature of outcomes. A key
We identified relevant studies from searches of the Cochrane Cen- purpose of these data was to explain clinical heterogeneity between
tral Register of Controlled trials (CENTRAL) on The Cochrane included studies independently from analysis of the results;
Library 2013, Issue 3, and the Cochrane Heart Groups Trials (2) Results of included studies for each of the main outcomes
Register, MEDLINE (1948 to 31 March 2013), PubMed (epub- indicated in the review question. For dichotomous outcomes
lications only, 31 March 2013), EMBASE (1974 to 31 March we recorded the numbers of outcomes in treatment and control
2013) and CINAHL (1982 to 31 March 2013). We combined the groups. For continuous outcomes, we recorded the mean and stan-
MEDLINE search with RCT search filters based on the validated dard deviation.
Cochrane MEDLINE filter according to the current version of the We resolved data extraction disagreements by consensus between
Cochrane Handbook for Systematic Reviews of Interventions, section the review authors. When disagreements regarding any of the
6.4.11.1 (Higgins 2011). We also searched the databases LILACS, above were unclear, we attempted to contact authors of the origi-
KoreaMed, IndMed, PakMediNet and the Transfusion Evidence nal trials to provide further details. One review author (SAF) then
Library on 31 March 2013, using a selection of keywords. See transcribed the data into the systematic review computer software
Appendix 1 for details of the search strategies. Review Manager 5 (Review Manager 2012).
Assessment of risk of bias in included studies We did not conduct this pooling of studies by method of report-
The two review authors (SAF, EMR) undertaking the data extrac- ing of continuous measures for analyses of exercise capacity, since
tion independently assessed the risk of bias for each trial using the the assumption of consistent underlying effects does not hold for
criteria outlined in the Cochrane Handbook for Systematic Reviews standardised mean differences.
of Interventions (Higgins 2011), and resolving any disagreements Several studies reported surrogate endpoints (left ventricular
by discussion. We assessed the design, conduct and analysis of the end systolic volume (LVESV), left ventricular end diastolic vol-
trial using a three-point scale: low, high or unclear risk of bias. To ume (LVEDV), stroke volume, left ventricular ejection fraction
assess risks of bias, the authors included the following questions (LVEF)), using different measures (magnetic resonance imaging
in the Risk of bias table for each included study: (MRI), echocardiography, single-photon emission computed to-
1. Was the allocation sequence adequately generated? mography (SPECT), left ventricular angiography) and in some
2. Was allocation adequately concealed? cases, results from several different methods were reported within
3. Was knowledge of the allocated intervention adequately a single study. In this case, we used MRI data as the preferred mea-
prevented (i.e. blinded) throughout the study? sure followed by left ventricular angiography, SPECT and echocar-
4. Were incomplete outcome data adequately addressed for diography.
every outcome?
5. Were reports of the study free of selective outcome Unit of analysis issues
reporting?
In studies in which there were multiple interventions in the same
6. Was the study apparently free of other problems that could
trial, we combined the intervention trial arms for a single compar-
put it at risk of bias?
ison with the comparator (control) arm to avoid double counting
With reference to (1) to (6) above, the review authors assessed
of participants and potential correlation of results. However, for
the likely magnitude and direction of the bias and whether they
subgroup and sensitivity analyses, where the two intervention arms
considered it likely to impact on the findings.
were classified into different categories (for example, type of cell,
cell dose, route of administration of cells), we included results for
Measures of treatment effect each treatment arm in the corresponding group, with the control
group included in both groups. In order to avoid unit of analysis
We expressed dichotomous data for each arm in a particular study issues, we treated cross-over trials as parallel trials and included
as a proportion or risk and the treatment effect as a risk ratio them in the review up to the point of cross-over, i.e. first phase
(RR) with 95% confidence intervals (CIs). We expressed contin- data only.
uous data for each arm in a particular study as a mean and stan-
dard deviation, and the treatment effect as the mean difference
(MD) if outcomes were measured in the same way across trials. Dealing with missing data
For outcomes measured using different methods, we combined We attempted to contact the authors of 15 studies by email for
the treatment effect data and analysed them using the standardised clarification of methods (randomisation, allocation concealment
mean difference (SMD). We used fixed-effect models in the first and blinding), potential overlapping of studies and/or requests
instance, but random-effects models in the presence of consider- for additional data. In five cases we failed to make contact with
able heterogeneity (I greater than 75%) or for outcomes which the authors by email. Of the remaining 10 studies, we received
were measured using different methods across studies. replies from three study authors who provided additional data.
Although we intended to analyse continuous outcomes as mean In one study (Assmus 2006), results were reported for a pooled
change from baseline, several studies only reported baseline and randomised cohort and a non-randomised pilot study cohort; the
endpoint data. Where possible, we calculated the standard devia- authors of this study provided full clinical and surrogate end-
tion of the mean change from baseline based on reported confi- point data for the randomised cohort alone, as well as details
dence intervals or P values, and we used these values in the anal- of the method of randomisation. The authors of a second study
ysis. However, for several studies, insufficient information was re- (Hendrikx 2006) provided LVESV and LVEDV data (as only
ported to calculate the standard deviation. Since the mean differ- LVESV/LVEDV index values were reported). For a third study
ence based on the change from baseline can be assumed to address (Hu 2011), authors provided mean change from baseline data for
the same underlying intervention effects as an analysis based on surrogate endpoint measures.
final measures (i.e. the differences in mean final values will on
average be the same as the differences in mean change scores),
we combined studies reporting mean change from baseline values Assessment of reporting biases
with those reporting endpoint values, but presented mean change Although we believe that we made every effort to identify unpub-
and endpoint values separately as well as in combined analyses for lished studies, we assessed publication bias using a funnel plot for
clarity. the primary outcome of mortality. We accept that asymmetry, of
which publication bias may be one cause, is difficult to detect with Sensitivity analysis
the small numbers of studies (i.e. fewer than 10) often encoun- We assessed the robustness of the overall results for the primary
tered in systematic reviews. outcome of LVEF for sensitivity to the following factors:
1. Risk of bias (selection bias; performance bias; detection
Data synthesis bias; attrition bias);
We undertook meta-analyses using the Review Manager 5 soft- 2. Co-intervention or comparator;
ware (Review Manager 2012), where there were sufficient data of 3. Method of measurement (MRI, left ventricular
suitable type. We used a fixed-effect model to combine data in angiography, SPECT, echocardiography).
the first instance. Where we detected considerable heterogeneity Differences in methods of reporting for continuous outcomes
(I greater than 75%) using a fixed-effect model, we repeated the across trials led us to combine mean change from baseline and
analysis using a random-effects model. endpoint data for several outcomes (LVESV, LVEDV, stroke vol-
Although quantitative synthesis was the main method of analysis, ume index, LVEF) (see Measures of treatment effect above). We
we incorporated insights from a qualitative evaluation of studies present results separately as well as in combination to assess the
for an overall interpretation of the data. We based conclusions on sensitivity of the results to the method of reporting.
patterns of results identified across clearly-tabulated results of in-
cluded studies as well as summary measures, taking both direction
and magnitude of any effect into account.
RESULTS
Subgroup analysis and investigation of heterogeneity
We examined statistical heterogeneity using the I statistic (
Higgins 2003) and by visual inspection of forest plots. We rated
Description of studies
values of I greater than 75% as indicating a considerable level
of heterogeneity at which summary estimates should be explored
and results interpreted with caution. We explored potential rea-
sons for observed heterogeneity in comparisons with at least 10 Results of the search
studies and statistical significance in the observed effect (P < 0.05). Given that a wide variety of products and terms have been used in
We placed particular emphasis on study population, treatment, the comparator arms of the included studies, for ease of reference
outcome measurements and study quality differences between the we use the term control throughout this review to refer to the
included studies. We assessed clinical heterogeneity based on the comparator treatment arm.
data extracted on the characteristics of the included studies. We identified 7704 references from electronic database searches.
We planned subgroup analysis for mortality and LVEF (primary De-duplication and removal of all clearly irrelevant references by
clinical and surrogate endpoint outcomes) as well as for outcomes the Information Specialist (CD) excluded 5370 references. Initial
which met the above conditions for further exploration of hetero- screening of the remaining 2334 citations against inclusion cri-
geneity. Subgroup analysis considered the following factors: teria excluded a further 2225 references. Of the remaining 109
1. Dose of stem cells administered; citations, we subsequently excluded 25 references (describing 21
2. Route of cell administration; independent studies), as they did not fully meet the inclusion cri-
3. Baseline cardiac function; teria (see Excluded studies). Eight further references described six
4. Type of cell administered (mononuclear cells; circulating independent study protocols (see Ongoing studies). Nine studies
progenitor cells; haematopoietic progenitor cells; and (14 references) were published in abstract form only and although
mesenchymal stem cells); they appeared to meet the inclusion criteria, did not contain suf-
5. Participant diagnosis (chronic IHD; heart failure ficient data for inclusion; these have been identified as Studies
(secondary to IHD); intractable/refractory angina); awaiting classification. The remaining 62 citations describe a total
6. Eligibility for revascularisation. of 23 independent RCTs (see Included studies). A summary of
We regard the latter three subgroup comparisons listed above as study classification is displayed in a PRISMA flow diagram (Figure
hypothesis-generating. 1).
Figure 1. PRISMA flow diagram.
Searching of ongoing trial databases identified 837 trial records.
De-duplication and removal of clearly irrelevant trials by the In- months (Erbs 2005) and five years (Honold 2012).
formation Specialist (CD) excluded 651 records. Of the remain- Eighteen trials isolated the stem cells by bone marrow aspiration
ing 186 records, 25 ongoing trials met the eligibility criteria and and further separation of the mononuclear cells using ficoll gradi-
are shown in Ongoing studies. ent centrifugation (Ang 2008; Assmus 2006; Assmus 2012; Chen
2006; Hendrikx 2006; Hu 2011; Patel 2005; Perin 2011; Perin
Included studies 2012a; Perin 2012b; Pokushalov 2010; Tse 2007; Turan 2011;
Van Ramshorst 2009; Wang 2009; Wang 2010; Yao 2008; Zhao
Twenty-three studies met the inclusion criteria for this review and 2008). Three of these trials enriched the stem cell fraction in
included a total of 1137 participants (659 bone marrow-derived CD34-positive haematopoietic progenitors by magnetic separa-
tion (Patel 2005; Wang 2009; Wang 2010), whilst one trial en-
stem cells (BMSC) and 478 control) who were assessed for the pri-
riched the stem cell fraction in aldehyde dehydrogenase (ALDH)-
mary outcomes of the study. The mean age of participants ranged
positive haematopoietic progenitors (Perin 2012b), and one trial
from 53.4 years to 69.8 years and the proportion of men ranged
cultured the mononuclear cell population from bone marrow ex
from 50% to 100%. All trials were presented as full journal articles
with the exception of one trial (Assmus 2012) which was pub- vivo to enrich in mesenchymal progenitors (Chen 2006). In one
lished in the form of a conference abstract. Five studies (Losordo three-arm trial (Assmus 2006), bone marrow mononuclear cells
were compared with circulating progenitor cells (CPCs), and with
2007; Losordo 2011; Perin 2011; Perin 2012a; Tse 2007) were
mononuclear cells isolated from venous peripheral blood. In the
multicentre trials. Studies were based worldwide, including China
CPC arm, cells were isolated from peripheral blood by leukaphere-
(Chen 2006; Hu 2011; Wang 2009; Wang 2010; Yao 2008; Zhao
sis. In the remaining five trials, bone marrow stem cells were mo-
2008), Germany (Assmus 2006; Assmus 2012; Erbs 2005; Honold
2012; Turan 2011), the United States (Losordo 2007; Losordo bilised into circulation with granulocyte colony-stimulating factor
(G-CSF) and subsequently isolated from blood via leukapheresis
2011; Perin 2011; Perin 2012a; Perin 2012b), United Kingdom
(Erbs 2005; Honold 2012; Kang 2006; Losordo 2007; Losordo
(Ang 2008), Belgium (Hendrikx 2006), The Netherlands (Van
2011). Whilst previous trials reported severe but transient compli-
Ramshorst 2009), Russia (Pokushalov 2010), Hong Kong/Aus-
cations associated with G-CSF treatment (Kang 2006), the most
tralia (Tse 2007), Korea (Kang 2006) and Argentina (Patel 2005).
recent pilot study by Honold 2012 demonstrated that G-CSF can
Two studies included publications in Chinese (Hu 2011; Wang
2009); these studies was translated into English for this review. be safely administered to people suffering from IHD since none of
the participants included in this trial developed the type of adverse
Ten studies included participants with chronic ischaemic heart dis-
events previously associated with G-CSF treatment. Two of these
ease (IHD) (Ang 2008; Assmus 2006; Assmus 2012; Chen 2006;
trials further enriched the stem cell population in CD34-posi-
Erbs 2005; Hendrikx 2006; Honold 2012; Kang 2006; Turan
tive progenitors by magnetic separation (Losordo 2007; Losordo
2011; Yao 2008), normally defined as multivessel disease with per-
2011).
sistent ischaemia and at least 30 days from the last myocardial
infarction (MI), with the exception of one study that defines old The dose of bone marrow mononuclear cells administered var-
MI as only 14 days post-infarction (Kang 2006). Seven studies ied between 2 x 10 cells (Perin 2011) and 2 x 10 cells
included people with congestive heart failure (CHF), defined as (Assmus 2006), whilst the dose of CD34-positive cells varied be-
severe ischaemic heart failure and post-infarction heart failure (sec-
tween 1 x 10 cells (Wang 2009) to 5.6 x 10 cells (Losordo
ondary to IHD) (Hu 2011; Patel 2005; Perin 2011; Perin 2012a;
2011). The doses of ALDH-positive cells (Perin 2012b) and mes-
Perin 2012b; Pokushalov 2010; Zhao 2008) and six studies were
enchymal progenitors (Chen 2006) administered averaged 2.96
of people with intractable or refractory angina (Losordo 2007;
Losordo 2011; Tse 2007; Van Ramshorst 2009; Wang 2009; Wang x 10 cells and 5 x 10 cells respectively. In the trial where
2010). All trials maintained the participants with a standard set bone marrow mononuclear cells were compared to CPCs, the
of drugs including aspirin, clopidogrel, heparin, blockers, statins,
angiotensin converting enzyme (ACE) inhibitors, nitrates and/or dose of CPCs administered was 2.2 x 10 cells (Assmus 2006).
diuretics. Eleven trials administered the treatment via a coronary artery
Duration of follow-up ranged from three months (Assmus 2006), (intracoronarily (IC)) (Assmus 2006; Assmus 2012; Chen 2006;
four months (Assmus 2012; Hendrikx 2006), six months (Ang Erbs 2005; Honold 2012; Hu 2011; Kang 2006; Turan 2011;
2008; Hu 2011; Kang 2006; Losordo 2007; Patel 2005; Perin Wang 2009; Wang 2010; Yao 2008), whilst 11 trials delivered
2011; Perin 2012a; Perin 2012b; Tse 2007; Van Ramshorst 2009; the treatment intramyocardially (IM) (Hendrikx 2006; Losordo
Wang 2009; Wang 2010; Yao 2008; Zhao 2008), 12 months ( 2007; Losordo 2011; Patel 2005; Perin 2011; Perin 2012a; Perin
Chen 2006; Losordo 2011; Pokushalov 2010; Turan 2011), 15 2012b; Pokushalov 2010; Tse 2007; Van Ramshorst 2009; Zhao
2008). Nine out of these 11 trials aided their delivery into the One study described aortic cross-clamping during surgery with
heart muscle using electromechanical mapping of the heart. The clamp times exceeding 25 - 30 minutes (Hendrikx 2006). Aor-
other two (Hendrikx 2006; Zhao 2008) did not report whether tic cross-clamping isolates the systemic circulation during surgery
the IM delivery of stem cells was aided in any other way. Only one but causes ischaemia. Although increasing times of aortic cross-
trial had three arms comparing IC and IM delivery of stem cells clamping has been identified as a predictor of mortality, the ef-
with control (Ang 2008). fect of cross-clamping in this study was not as strong as might be
Thirteen studies (Assmus 2012; Erbs 2005; Hendrikx 2006; Hu expected. This may be due to the fact that the cause of cardiac
2011; Losordo 2007; Losordo 2011; Perin 2012a; Perin 2012b; damage is multifactorial, including coronary lesions.
Tse 2007; Van Ramshorst 2009; Wang 2010; Yao 2008; Zhao The majority of included studies reported the primary outcomes
2008) compared stem cell therapy with administration of a placebo of this review, i.e. mortality, LVEF and adverse events. One study
that consisted of a cell-free solution, either a heparin saline solu- which was published only in abstract form (Assmus 2012) did not
tion or a saline solution containing the participants own serum; report mortality, and all but four studies (Losordo 2007; Losordo
one further study (Perin 2011) used a simulated mock injection 2011; Wang 2009; Wang 2010) reported LVEF.
procedure for participants in the control arm, but without admin- For a summary details of the included studies, see the
istering a placebo solution. The remaining nine trials compared Characteristics of included studies tables.
treatment to no treatment (Ang 2008; Assmus 2006; Chen 2006;
Honold 2012; Kang 2006; Patel 2005; Pokushalov 2010; Turan
2011; Wang 2009). Excluded studies
Three studies included a three-way comparison involving two in- We excluded 21 studies (described by 25 references) from the
terventions, including intracoronary versus intramyocardial cell review following full-text assessment against the eligibility criteria
administration (Ang 2008), mononuclear cells versus circulating (see Characteristics of excluded studies tables).
progenitor cells (Assmus 2006) and high versus low cell dose In summary, the reasons for exclusion were as follows: 14 studies
(Losordo 2011). Data for both intervention arms were combined were not RCTs, four studies included participants with AMI, one
for the main analyses, although we used individual intervention trial included participants with idiopathic dilated cardiomyopathy,
trial arms for subgroup analyses where applicable. A fourth study one trial provided a review of imaging techniques for cardiac stem
(Assmus 2012) which involved a co-intervention of shockwave cell therapy, and one trial described outcomes not included in the
therapy also included an additional trial arm involving BMSC protocol of this review.
treatment, but since the co-intervention was not administered in
this treatment arm, we include only the first two treatment arms in Risk of bias in included studies
this review. One three-arm trial was also a cross-over study (Assmus
See the Characteristics of included studies tables for details of our
2006); we include only data up to the point of cross-over (three
assessment of risk of bias for each study; a summary of risk of bias
months) in this review.
is shown in Figure 2.
Figure 2. Risk of bias summary: review authors judgements about each risk of bias item for each included
study.
All trial comparisons randomised the participants. However, nine
of them (Ang 2008; Assmus 2012; Chen 2006; Erbs 2005; Honold ticipants in the control arm, or in some instances giving a mock
2012; Turan 2011; Wang 2009; Wang 2010; Yao 2008) did not injection. Four studies did not blind their participants (Ang 2008;
report the randomisation method used. In the 14 trials which re- Chen 2006; Kang 2006; Turan 2011) while the remaining seven
ported their randomisation methods, these included the use of se- studies did not report the blinding status of their participants.
quentially-numbered sealed envelopes, computer-generated ran- In one study (Wang 2009) outcome assessors were not blinded;
domisation tables using a block size of six or nine, and telephone a further four studies (Assmus 2006; Chen 2006; Honold 2012;
call-in followed by an interactive voice-response system. Kang 2006) did not report blinding of outcome assessors. Out-
come assessors were blinded in all remaining studies.
Allocation
Seven of the 23 comparisons included here described appropri-
ate methods of allocation concealment (Hendrikx 2006; Losordo Incomplete outcome data
2011; Perin 2011; Perin 2012a; Perin 2012b; Van Ramshorst One trial published in abstract form (Assmus 2012) did not re-
2009; Tse 2007), while the remaining 16 trials did not report the port the number of individuals randomised to each treatment arm
method of allocation concealment. Methods of allocation conceal- and in this study the attrition rate could not be evaluated. In all
ment included sequentially-numbered sealed envelopes, telephone other trials, withdrawals and loss to follow-up were similar in both
call-in followed by an interactive voice-response system and mask- treatment arms.
ing treatment assignment to all but one designated cell processing
team member at each centre not involved in participant care in
the case of a multicentre trial (Perin 2012a). Selective reporting
No trial reported deviations from the trial protocol, although se-
lective reporting of outcomes would be difficult to rule out.
Blinding A funnel plot for the primary outcome of mortality at short-term
Twelve studies blinded their participants (Erbs 2005; Hendrikx follow-up was symmetrical (Figure 3). However, given the very
2006; Hu 2011; Losordo 2007; Losordo 2011; Patel 2005; Perin small size of the included studies, a funnel plot is uninformative
2011; Perin 2012a; Perin 2012b; Tse 2007; Van Ramshorst 2009; to detect small study bias. Furthermore, 12 ongoing studies were
Wang 2010) by treating all the participants with G-CSF, where completed or due to be completed in advance of our search date but
this was part of the trial protocol, obtaining bone marrow aspirates we identified but no publications for them. We therefore cannot
from all participants or/and administering placebo to those par- rule out the possibility of publication bias.
Figure 3. Funnel plot of comparison: 1 Stem cells versus no stem cells, outcome: 1.1 Mortality.
In one study (Yao 2008), continuous measures were reported as

Other potential sources of bias
mean +/- standard deviation. However, visual inspection of the
Fourteen studies (Ang 2008; Assmus 2006; Erbs 2005; Hu 2011; data revealed that the standard deviations were considerably lower
Kang 2006; Losordo 2007; Losordo 2011; Perin 2011; Perin than might be expected for all continuous outcomes. This study
2012a; Perin 2012b; Tse 2007; Van Ramshorst 2009; Yao 2008; also reported P values for statistical comparisons between the base-
Zhao 2008) provided details of study funding or sponsorship. line and follow-up data using paired t-tests. However, we could
The majority of these were funded entirely by academic and/or not identify the reported significance values, either using the stan-
healthcare research grants and received no commercial sponsor- dard deviations provided, or based on an assumption that the val-
ship. Two studies acknowledged provision of equipment (Losordo ues were in fact standard errors. We therefore could not verify or
2007; Perin 2012a) and one study acknowledged receipt of con- include continuous data from this study. Only five studies (Ang
sultant fees from Biosense-Webster (Tse 2007). Full commercial 2008; Assmus 2006; Hu 2011; Kang 2006; Perin 2012a) reported
sponsorship was declared in two studies: from Baxter Heathcare loss to follow-up, which was low and comparable between differ-
(Losordo 2011) and from Aldagen Inc. (Perin 2012b). A further ent treatment arms.
study declared partial commercial funding from Baxter Heathcare
(Losordo 2007).
We identified no other sources of bias, although other potential Primary outcomes
sources of bias cannot be completely ruled out.
Effects of interventions Mortality

See: Summary of findings for the main comparison Mortality was included as an outcome in all except one study
An overview of results for the main outcomes (mortality, incidence (Assmus 2012), which was published in abstract form only. Of 22
of heart failure, LVEF and NYHA class) is given in the Summary studies which reported mortality rates during short-term follow-
of findings table. up (< 12 months), deaths were reported in nine trials (Ang 2008;
Assmus 2006; Hendrikx 2006; Hu 2011; Kang 2006; Perin 2012a; Tse 2007; Van Ramshorst 2009), left ventricular angiography
Pokushalov 2010; Van Ramshorst 2009; Zhao 2008). The remain- (Assmus 2006; Honold 2012; Perin 2011; Perin 2012b; Turan
ing 13 trials reported no deaths. A total of nine deaths (2.9%) were 2011), single-photon emission computed tomography (SPECT)
reported in 311 participants who received BMSC therapy com- (Chen 2006; Perin 2011; Van Ramshorst 2009) and echocardio-
pared with 12 deaths (5.3%) in 226 participants who received no graphy (Perin 2011; Perin 2012a; Perin 2012b; Pokushalov 2010;
stem cell therapy (risk ratio (RR) 0.68, 95% confidence interval Van Ramshorst 2009; Zhao 2008). One study (Assmus 2012) did
(CI) 0.32 to 1.41, P = 0.30; 21 trials, 1138 participants) (Analysis not report the method of LVEF measurement and in another study
1.1.1). (Patel 2005) LVEF appeared to be measured by either SPECT or
Five studies reported reasons for short-term mortality. Causes of echocardiography.
death in participants who received BMSC included perforated oe- Mean change from baseline at short-term follow-up was reported
sophageal ulcer complicated by mediastinitis seven days postoper- in 10 studies (Ang 2008; Assmus 2006; Assmus 2012; Erbs 2005;
atively (Hendrikx 2006), panperitonitis two months after enrol- Hendrikx 2006; Hu 2011; Perin 2011; Perin 2012a; Tse 2007;
ment (Kang 2006), pump failure leading to death on day 29 after Van Ramshorst 2009); the remaining eight studies (Chen 2006;
therapy (Perin 2012a), myocardial ischaemia leading to acute heart Honold 2012; Kang 2006; Patel 2005; Perin 2012b; Pokushalov
failure at 2 months (Van Ramshorst 2009), ventricular fibrilla- 2010; Turan 2011; Zhao 2008) reported baseline and endpoint
tion five hours postoperatively leading to death on day three (Zhao data only with insufficient data to calculate the standard deviation
2008), and cerebral vessel accident during six-month follow-up of the mean difference. Combined evidence across all 18 studies
(Zhao 2008). One cause of death was reported in a participant showed a significant mean difference in LVEF in participants who
who did not receive stem cell therapy, i.e. multiple organ failure received BMSC compared with those who did not receive stem cell
secondary to low cardiac output syndrome (Hendrikx 2006). The therapy (mean difference (MD) 4.22%, 95% CI 3.47% to 4.95%,
remaining four studies did not report cause of mortality. P < 0.00001; 18 trials, 746 participants). There was moderate
Eight studies (Chen 2006; Erbs 2005; Honold 2012; Losordo heterogeneity between studies (I = 53%) (Analysis 1.2).
2007; Losordo 2011; Pokushalov 2010; Tse 2007; Turan 2011) In six studies which reported LVEF at long-term follow-up, three
with long-term follow-up ( 12 months) reported mortality as (Erbs 2005; Pokushalov 2010; Van Ramshorst 2009) reported
an outcome. Deaths were reported in six studies (Chen 2006; mean change from baseline and three (Chen 2006; Honold 2012;
Erbs 2005; Honold 2012; Losordo 2011; Pokushalov 2010; Tse Turan 2011) reported baseline and endpoint values. The signifi-
2007) with a total of eight deaths (3.3%) in 241 participants cant mean difference in LVEF in participants who received BMSC
who received BMSC therapy compared with 30 deaths (18.5%) was maintained at long-term follow-up (MD 2.62%, 95% CI
in 162 participants who received no stem cell therapy; the risk 0.50% to 4.73%, P = 0.02; 6 trials, 254 participants), with mod-
of mortality over long-term follow-up was significantly lower for erate heterogeneity between studies (I = 32%) (Analysis 1.3).
those who received BMSC therapy (RR 0.28, 95% CI 0.14 to
0.53, P = 0.0001; 8 trials, 494 participants) (Analysis 1.1.2).
Reasons for mortality at long-term follow-up were reported in Adverse events
four studies. Two sudden deaths were reported in participants who
Nineteen trials (947 participants) reported adverse events as an
received stem cell therapy (Chen 2006). This study also reported
outcome, although one trial (Assmus 2012) reported adverse
four deaths in participants who did not receive stem cell therapy,
events pooled across treatment arms; only four trials did not give
due to ventricular fibrillation, sudden death, and heart failure (two
any information about adverse events(Hendrikx 2006; Losordo
people). Other reported deaths in participants in the control arm
2011; Perin 2012a; Turan 2011). Adverse events were not related
were angina followed by sudden death secondary to AMI (Erbs
to the BMSC treatment or procedure, with the exception of one
2005), progressive heart failure (Honold 2012) and AMI (Tse
trial which reported one case of haematoma during bone marrow
2007).
harvest in the BMSC treatment arm (Patel 2005), and one trial
which reported pulmonary oedema during injection of BMSC
in three cases in the treatment arm (Chen 2006). Three trials
Left ventricular ejection fraction (LVEF)
that administered G-CSF prior to BMSC enrichment (Erbs 2005;
LVEF was measured in 19 studies (Ang 2008; Assmus 2006; Honold 2012; Kang 2006) reported transient complications aris-
Assmus 2012; Chen 2006; Erbs 2005; Hendrikx 2006; Honold ing from the G-CSF treatment, as described previously in AMI
2012; Hu 2011; Kang 2006; Patel 2005; Perin 2011; Perin trials (Clifford 2012a; Clifford 2012b). Additionally, in one trial
2012a; Perin 2012b; Pokushalov 2010; Tse 2007; Turan 2011; (Perin 2011) there was one case in the treatment arm and one in
Van Ramshorst 2009; Yao 2008; Zhao 2008) with one study (Yao the control arm of periprocedural transient bundle-brance block
2008) excluded due to data inconsistencies as described above. and one post-procedural non-significant pericardial effusion in the
Measurement methods included MRI (Ang 2008; Assmus 2006; treatment arm. A variety of definitions was used to record adverse
Erbs 2005; Hendrikx 2006; Honold 2012; Hu 2011; Kang 2006; events across the studies and some trials reported adverse events
combined over both treatment arms rather than separately. No 2008), although the majority of these studies reported no inci-
long-term adverse events were reported. Adverse events reported dence of arrhythmias during follow-up in either treatment arm.
over short-term and long-term follow-up are presented as forest Four studies (Assmus 2006; Perin 2012b; Zhao 2008; Wang 2010)
plots (Analysis 1.4). observed participants with arrhythmia during follow-up, although
in one study (Wang 2010), the total number of participants with
arrhythmia was unclear. In the remaining three trials, only four
Secondary outcomes cases of arrhythmia were observed: three in participants who re-
ceived BMSC and one in a control participant.
Morbidity
Quality of life
(a) Incidence of infarction

Sixteen studies (Ang 2008; Assmus 2006; Erbs 2005; Honold (a) Angina frequency
2012; Hu 2011; Kang 2006; Losordo 2007; Perin 2011; Perin Five studies measured angina frequency: one study (Wang 2009)
2012a; Perin 2012b; Tse 2007; Van Ramshorst 2009; Wang 2009; reported mean change in number of angina episodes per week
Wang 2010; Yao 2008; Zhao 2008) reported infarction as an out- and the remaining four studies (Losordo 2007; Losordo 2011;
come at short-term follow-up. In seven studies (Assmus 2006; Pokushalov 2010; Wang 2010) reported angina frequency at short-
Erbs 2005; Honold 2012; Perin 2012a; Perin 2012b; Tse 2007; term follow-up. Combined evidence from all five studies showed a
Yao 2008) which reported participants with infarction, three cases significant mean difference in angina frequency between treatment
of infarction were reported in participants who received BMSC arms in favour of BMSC (MD -4.64, 95% CI -7.06 to -2.23, P =
compared with four cases in those who received no stem cell ther- 0.0002; 5 trials, 429 participants), with low levels of heterogeneity
apy (RR 0.57, 95% CI 0.20 to 1.59, P = 0.28; 16 trials, 737 par- between studies (I = 26%) (Analysis 1.7).
ticipants) (Analysis 1.5.1).
Of three studies (Honold 2012; Losordo 2007; Losordo 2011)
which reported infarction as an outcome at long-term follow-up, (b) Other quality of life measures
only two (Honold 2012; Losordo 2011) reported participants with Other measures of quality of life include assessments based on the
infarction; these occurred in both treatment arms (RR 0.48, 95% Seattle Angina Questionnaire (Losordo 2007; Losordo 2011; Van
CI 0.19 to 1.22, P = 0.12; 3 trials, 221 participants) (Analysis Ramshorst 2009), Minnesota Living with Heart Failure (MLHF)
1.5.2). (Perin 2011; Pokushalov 2010) and the SF-36 (Perin 2011). How-
ever, in the majority of cases, results were presented descriptively
without mean change from baseline or mean at follow-up data for
(b) Rehospitalisation due to heart failure
both treatment arms and this, together with differences in data
Five studies (Assmus 2006; Honold 2012; Losordo 2011; Perin representation (scales, summary measures), prevented any formal
2012a; Yao 2008) reported rehospitalisation due to heart failure as comparison of results.
an outcome. In four studies (Assmus 2006; Honold 2012; Perin
2012a; Yao 2008) which reported rehospitalisation at short-term
follow-up, eight participants (9.5%) in the control arm were re- Performance status
hospitalised, compared with five participants (3.3%) in the BMSC
arm, but combined evidence from meta-analysis did not show a
significant difference between trial arms (RR 0.36, 95% CI 0.12 (a) NYHA classification
to 1.06, P = 0.06; 4 trials, 236 participants) (Analysis 1.6.1). Thirteen studies measured New York Heart Association (NYHA)
However, at long-term follow-up, evidence from two studies ( classification, although one study (Ang 2008) only reported the
Honold 2012; Losordo 2011) showed a significant reduction in number of participants in class III/IV and a second study (Perin
the risk of rehospitalisation due to heart failure in participants who 2012a) did not report standard deviations for the mean NYHA
had received stem cell therapy compared with those who had not class. The absence of NYHA classification at baseline in several
(RR 0.26, 95% CI 0.07 to 0.94, P = 0.04; 2 trials, 198 participants) studies prevented a comparison of mean change from baseline be-
(Analysis 1.6.2). tween groups; we therefore compared NYHA class between groups
(c) Incidence of arrhythmias at follow-up. In the remaining 11 studies (Assmus 2006; Assmus
Incidence of arrhythmias was reported as an outcome in 15 studies 2012; Chen 2006; Honold 2012; Patel 2005; Perin 2011; Perin
(Ang 2008; Assmus 2006; Chen 2006; Hu 2011; Losordo 2007; 2012b; Pokushalov 2010; Tse 2007; Turan 2011; Zhao 2008),
Patel 2005; Perin 2011; Perin 2012b; Pokushalov 2010; Tse 2007; the mean NYHA class at short-term follow-up was significantly
Van Ramshorst 2009; Wang 2009; Wang 2010; Yao 2008; Zhao different between treatment arms, favouring BMSC therapy (MD
-1.27, 95% CI -1.33 to 1.22, P < 0.00001; 11 trials, 486 partic- model, allowing outcomes of different measurement scales to be
ipants). We noted considerable heterogeneity between studies (I combined in a meta-analysis. This method of analysis does not
= 97%); the significantly lower NYHA class in participants who allow mean change from baseline and endpoint data to be com-
received BMSC compared with those who received no stem cell bined and we therefore present separate analyses of mean change
therapy remained when we used a random-effects model (MD - from baseline and endpoint data.
0.63, 95% CI -1.08 to -0.19, P = 0.005) (Analysis 1.8). At short-term follow-up, there was no evidence for a difference in
Meta-analysis of four studies (Chen 2006; Honold 2012; mean change in exercise capacity from baseline between treatment
Pokushalov 2010; Turan 2011) using a random-effects model arms (SMD 0.22, 95% CI -0.13 to 0.58, P = 0.22; 7 trials, 464
showed that the significant improvement in NYHA class was main- participants) (Analysis 1.11.1). However, in eight studies which
tained over long-term follow-up (MD -0.91, 95% CI -1.38 to - reported endpoint values (Chen 2006; Erbs 2005; Honold 2012;
0.44, P = 0.0002; 4 trials, 196 participants), although considerable Hu 2011; Pokushalov 2010; Tse 2007; Van Ramshorst 2009;
heterogeneity (I = 89%) remained across studies (Analysis 1.9) . Wang 2010), we observed a significant difference between treat-
ment arms in favour of BMSC (SMD 0.58, 95% CI 0.15 to 1.02,
P = 0.008; 8 trials, 429 participants) (Analysis 1.11.2). There was
(b) Canadian Cardiovascular Society (CCS) angina class considerable heterogeneity across studies (I = 76%), although all
Eleven studies measured CCS angina classification, although three eight studies reported some degree of increased exercise perfor-
studies did not report sufficient data to be included in a meta-anal- mance in participants who received BMSC compared with those
ysis: one study (Ang 2008) only reported the number of partici- who received no stem cell therapy.
pants in class 2 and above, a second study (Perin 2012a) reported At long-term follow-up, one study which reported mean change
that there was no significant difference in change in CCS class from baseline showed a significant difference in exercise capacity
between the treatment groups, and a third study (Losordo 2011) in favour of BMSC (SMD 0.39, 95% CI 0.05 to 0.73, P = 0.02; 1
only reported the percentage who changed angina class in each trial, 156 participants) (Analysis 1.12.1). However, this significant
group. At short-term follow-up, four studies (Losordo 2007; Perin effect was not demonstrated in four studies which reported the
2011; Wang 2009; Wang 2010) reported mean change in CCS mean value at endpoint (SMD 0.97, 95% CI -0.33 to 2.27, P =
class from baseline, whilst four studies (Perin 2012b; Pokushalov 0.14; 4 trials, 158 participants) (Analysis 1.12.2).
2010; Tse 2007; Zhao 2008) only reported CCS class at follow-
up. Combined evidence from all eight studies incorporating both
mean change from baseline and endpoint data showed a significant Surrogate endpoints
mean difference between treatment arms in favour of BMSC (MD
-0.85, 95% CI -1.00 to -0.71, P < 0.00001; 8 trials, 379 partici-
pants). There was considerable heterogeneity between studies (I Left ventricular end-systolic volume (LVESV)
= 96%). The mean difference between treatment arms remained
LVESV was measured in 16 studies. Of these, two studies (Yao
significant under a random-effects model (MD -0.81, 95% CI -
2008; Zhao 2008) reported LVESV diameter, while two further
1.55 to -0.07, P = 0.03) (Analysis 1.10).
studies (Hendrikx 2006; Perin 2012a) reported LVESV index val-
ues (i.e. scaled by body surface area), although the authors of
(c) Exercise capacity the Hendrikx 2006 study kindly supplied LVESV data upon re-
quest. One study (Honold 2012) additionally reported LVESV
Exercise capacity was reported in 11 trials. Measures of exercise
index values in a subset of measures. Methods of LVESV mea-
capacity included an exercise tolerance test measured as metabolic
surement included MRI (Ang 2008; Erbs 2005; Hendrikx 2006;
equivalents (Chen 2006) or as time in minutes (Losordo 2007;
Honold 2012; Hu 2011; Kang 2006; Tse 2007; Van Ramshorst
Wang 2009; Wang 2010), seconds (Losordo 2011), or log seconds
2009), left ventricular angiography (Assmus 2006; Honold 2012;
(Tse 2007); a bicycle test measured as maximum O update (Erbs Turan 2011) and echocardiography (Perin 2012a; Perin 2012b;
2005; Honold 2012) or by workload (Van Ramshorst 2009); and Pokushalov 2010; Van Ramshorst 2009; Yao 2008; Zhao 2008).
by a six-minute walk test measured as distance in minutes (Hu One study (Perin 2011) did not report the method of measure-
2011; Pokushalov 2010). ment.
Mean change from baseline was reported (or could be calcu- Mean change from baseline data was reported in eight studies (Ang
lated) in seven studies (Hu 2011; Losordo 2007; Losordo 2011; 2008; Assmus 2006; Erbs 2005; Hendrikx 2006; Hu 2011; Kang
Tse 2007; Van Ramshorst 2009; Wang 2009; Wang 2010). The 2006; Tse 2007; Van Ramshorst 2009); the remaining five studies
remaining four studies (Chen 2006; Erbs 2005; Honold 2012; (Honold 2012; Perin 2011; Perin 2012b; Pokushalov 2010; Turan
Pokushalov 2010) only reported baseline and endpoint data, and 2011) only reported baseline and endpoint data (with insufficient
we could not calculate standard deviations. Results are described information to calculate standard deviations for the mean change
using the standardised mean difference with a random-effects from baseline). Combined evidence across all studies showed a
significant difference in mean LVESV between treatment arms at 2012; Turan 2011) showed that this significant effect in favour
short-term follow-up in favour of BMSC (MD -5.47 ml, 95% CI of stem cell therapy was maintained at long-term follow-up (MD
-8.81 to -2.14, P = 0.001; 13 trials, 470 participants) (Analysis 6.52, 95% CI 1.51 to 11.54, P = 0.01: 2 trials, 62 participants)
1.13). We observed moderate heterogeneity between studies (I = (Analysis 1.18).
50%). Evidence from three studies (Erbs 2005; Pokushalov 2010;
Turan 2011) demonstrated that the significant improvement in
LVESV in participants who received BMSC was maintained over Engraftment and survival of the infused stem/progenitor cells
long-term follow-up (MD -14.64 ml, 95% CI -20.88 to -8.39, P No studies reported engraftment and/or survival of the infused
< 0.00001; 3 trials, 153 participants) (Analysis 1.14). We noted cells as an outcome.
considerable heterogeneity across three studies at long-term fol-
low-up of LVESV (I = 84%). Visual inspection of the forest plots
revealed a strong and highly significant effect of the Pokushalov Subgroup analysis and investigation of heterogeneity
2010 study of people with chronic IHD and end-stage chronic
heart failure.
Mortality
We found no evidence of heterogeneity between studies for mor-
Left ventricular end-diastolic volume (LVEDV) tality (I = 0% for both short- and long-term outcomes). Subgroup
Seventeen studies measured LVEDV, with two studies (Yao 2008; analysis was precluded due to the low number of studies reporting
Zhao 2008) reporting LVEDV diameter and two further stud- the incidence of death in either treatment arm.
ies (Hendrikx 2006; Perin 2012a) reporting LVEDV index val-
ues (although LVEDV values were made available by Hendrikx
LVEF
2006 as noted above). Methods of LVEDV measurement included
MRI, left ventricular angiography, and echocardiography as de- We explored the moderate heterogeneity between studies measur-
tailed above. In one study (Patel 2005) which reported LVEDV ing LVEF at short-term follow-up using subgroup analysis (see
(but not LVESV), LVEDV appeared to be measured by either Table 1 for a summary of results). We found no significant dif-
SPECT or echocardiography. ferences between studies grouped according to cell dose (Analysis
Mean change from baseline data was reported in eight studies (Ang 2.1; 16 trials, 747 participants) or baseline cardiac function (Anal-
2008; Assmus 2006; Erbs 2005; Hendrikx 2006; Hu 2011; Kang ysis 3.1; 17 trials, 677 participants). However, the mean difference
2006; Tse 2007; Van Ramshorst 2009); the remaining six studies in LVEF in favour of BMSC, although significant both in studies
(Honold 2012; Patel 2005; Perin 2011; Perin 2012b; Pokushalov with intracoronary administration of cells (MD 3.19%, 95% CI
2010; Turan 2011) only reported baseline and endpoint data (with 2.19 to 4.19, P < 0.00001; 9 trials, 365 participants) and studies
insufficient information to calculated standard deviations for the in which cells were administered directly into the myocardium
mean change from baseline). The combined evidence across all (MD 5.30%, 95% CI 4.21 to 6.40, P < 0.00001; 10 trials, 388
studies showed no difference IN LVEDV between treatment arms participants), was significantly better when cells were administered
at short-term follow-up (MD 2.00 ml, 95% CI -2.21 to 6.21, P = intramyocardially (test for subgroup differences: P = 0.005) (Anal-
0.35; 14 trials, 490 participants) (Analysis 1.15) or at long-term ysis 4.1).
follow-up (MD -3.30 ml, 95% CI -13.11 to 6.51, P = 0.51; 3 We also found significant differences in the effect of BMSC on
trials, 170 participants) (Analysis 1.16). LVEF at short-term follow-up by type of cells administered (test
for subgroup differences: P < 0.0001) (Analysis 5.1). In particu-
lar, in two studies which administered circulating progenitor cells
Stroke volume index (mononuclear cells isolated from venous peripheral blood, not
from bone marrow aspiration), the effect of BMSC on LVEF was
Four studies (Ang 2008; Assmus 2006; Honold 2012; Turan 2011)
only marginally statistically significant (MD 1.58%, 95% CI -
reported stroke volume index (ml/m); two studies (Ang 2008;
0.01 to 3.17, P = 0.05; 3 trials, 73 participants). A comparison of
Assmus 2006) reported mean change from baseline values while
studies using mononuclear cells with those using haematopoietic
the remaining two studies (Honold 2012; Turan 2011) only re-
ported baseline and endpoint values. An additional three stud- stem cells (e.g. CD34 and ALDH cells isolated from bone
ies (Hu 2011; Perin 2012a; Van Ramshorst 2009) reported only marrow) showed that the mean difference in LVEF was signifi-
stroke volume, i.e. uncorrected for body mass index. Combined cantly better when haematopoietic stem cells were administered
evidence across all studies showed a significant improvement in (MD 8.44%, 95% CI 6.11 to 10.78, P < 0.00001; 2 trials, 40 par-
stroke volume index between treatment arms at short-term fol- ticipants) than mononuclear cells (MD 3.77%, 95% CI 2.91 to
low-up (MD 3.84, 95% CI 0.95 to 6.73, P = 0.009; 4 trials, 148 4.63, P < 0.00001; 13 trials, 606 participants) (test for subgroup
participants) (Analysis 1.17). Evidence from two studies (Honold differences: P = 0.0002).
Finally, subgroup analysis of studies categorised by participant di- stage chronic heart failure. A sensitivity analysis of the risk of long-
agnosis at baseline (chronic IHD, heart failure secondary to IHD, term mortality showed that the significantly lower risk of mortal-
and intractable/refractory angina) showed significant differences ity associated with BMSC therapy remained even when this study
in the effect of stem cell therapy on LVEF at short-term follow- was excluded from the analysis (RR 0.27, 95% CI 0.10 to 0.79,
up (test for subgroup differences: P = 0.004; 18 trials, 746 par- P = 0.02).
ticipants) (Analysis 6.1). Although the mean difference in LVEF
between treatment arms was significant for all groups of partici-
pants, we observed a significantly greater mean difference in LVEF LVEF
between treatment arms in favour of stem cell therapy in studies of A sensitivity analysis of LVEF according to the method of measure-
people with heart failure (MD 5.95%, 95% CI 4.67% to 7.23%, ment was carried out, since the limitations of some of the methods
P < 0.00001; 7 trials, 344 participants) than in studies of people used to assess LVEF are well known (Arnesen 2007). We observed
with chronic IHD (MD 3.20%, 95% CI 2.20% to 4.20%, P < a significant effect of BMSC on LVEF at short-term follow-up in
0.00001; 9 trials, 336 participants ) (test for subgroup differences: all methods of measurement with overlapping confidence inter-
P = 0.0009). vals for all analyses (MRI: MD 3.35%, 95% CI 2.17 to 4.53, P <
0.00001 (9 trials, 298 participants); left ventricular angiography:
MD 2.91%, 95% CI 1.35 to 4.47, P = 0.0003 (5 trials, 185 par-
NYHA classification ticipants); SPECT: MD 5.47%, 95% CI 2.80 to 8.14, P < 0.0001
In view of the high level of heterogeneity across studies measur- (3 trials, 124 participants); echocardiography: MD 4.78%, 95%
ing NYHA class at short-term follow-up, we conducted subgroup CI 3.36 to 6.21, P < 0.00001 (6 trials, 314 participants)) (Analysis
analyses (see Table 1 for a summary of results of subgroup analy- 7.1).
ses). There were no differences in the effect of BMSC on NYHA We also conducted a sensitivity analysis of the effect of studies at
class between studies grouped according to different cell doses high or unclear risk of bias (see Figure 2 for a summary of the
(Analysis 2.2; 10 trials, 435 participants), routes of administration risk of bias in individual studies). A significant mean difference
(Analysis 4.2; 11 trials, 486 participants) or participant diagnosis in LVEF at short-term follow-up remained when we restricted
at baseline (Analysis 6.2; 11 trials, 486 participants). However, studies to those with a low risk of selection bias (MD 3.27%, 95%
we note a significantly greater mean difference in NYHA class be- CI 1.69 to 4.84, P < 0.0001; 6 trials, 218 participants), a low
tween treatment arms in participants with lower baseline cardiac risk of performance bias (MD 5.11%, 95% CI 3.89 to 6.33, P
function (LVEF < 30%) (MD -1.41, 95% CI -1.68 to -1.14, P < 0.00001; 9 trials, 320 participants) and a low risk of detection
< 0.00001; 2 trials, 144 participants) than in participants with a bias (MD 4.58%, 95% CI 3.71 to 5.45, P < 0.00001; 14 trials,
baseline LVEF > 30% (MD -0.48, 95% CI -0.82 to -0.14, P = 588 participants) (Analysis 8.1).
0.005; 8 trials, 273 participants) (test for subgroup differences: P Differences between studies included the type of comparator
< 0.0001), although heterogeneity between studies remained high (placebo versus no placebo) and co-intervention (no co-interven-
in both comparisons (Analysis 3.2; 17 trials, 677 participants). tion, coronary artery bypass graft (CABG)) used (see Table 2 for
A comparison of the mean difference in NYHA class according a summary of placebo and co-intervention use in individual stud-
to cell type also revealed significant differences (test for subgroup ies). The significant mean difference in LVEF in favour of stem
differences: P = 0.0004) (Analysis 5.2). In particular, we observed cell therapy at short-term follow-up was also robust to the type
the greatest mean difference in NYHA class between treatment of comparator (placebo: MD 3.33%, 95% CI 2.25 to 4.41, P <
arms in one study using mesenchymal stem cells (Chen 2006) 0.00001, 9 trials, 373 participants; no placebo: MD 5.05%, 95%
(MD -1.20, 95% CI -1.58 to -0.82; 45 participants). The effect CI 4.02 to 6.09, P < 0.00001; 8 trials, 343 participants) and to the
size for this study was significantly different from that in two presence or absence of a co-intervention (no co-intervention: MD
studies using circulating progenitor cells (Assmus 2006; Honold 4.31%, 95% CI 2.97 to 5.64, P < 0.00001; 6 trials, 297 partici-
2012; 68 participants) (MD -0.02, 95% CI -0.40 to 0.36) (test for pants; CABG: MD 6.51%, 95% CI 4.76 to 8.26, P < 0.00001, 5
subgroup differences: P < 0.0001), in which there was no evidence trials, 158 participants; PCI: MD 3.35%, 95% CI 2.30 to 4.40,
of heterogeneity (I = 0%). P < 0.00001; 7 trials, 291 participants) (Analysis 9.1)
Sensitivity analysis
DISCUSSION
Mortality The incidence of heart failure secondary to ischaemic heart disease
One study (Pokushalov 2010) reported a high rate of deaths (IHD) is increasing exponentially worldwide as a consequence of
(BMSC: 6/55; no BMSC: 21/54). Although cause of death was improved standard clinical care and improved long-term survival
not reported, participants in this study had chronic IHD and end- following myocardial infarction (MI). During the last 12 years,
stem cell therapies have emerged as a new treatment for IHD and BMSC (MD -0.81, 95% CI -1.55 to -0.07, P = 0.03, 8 studies,
numerous randomised controlled trials (RCTs) have been devel- 379 participants, moderate quality evidence) at short-term
oped to treat people with left ventricular dysfunction following follow-up.
myocardial infarction and people with chronic ischaemia (Clifford
2012a; Clifford 2012b; Fisher 2013; Jeevanantham 2012). Over-
There was a significant reduction in left ventricular end
all, treatment has been shown to be safe and to have no adverse ef-
systolic volume (LVESV) at short-term (MD -5.47 ml, 95% CI -
fects. However, the clinical efficacy of this new treatment is still de-
8.81 ml to -2.14 ml, P = 0.001, 13 studies, 470 participants,
bated (Clifford 2012a; Jeevanantham 2012), as a reduction in mor-
moderate quality evidence) and long-term follow-up (MD -14.64
tality has been reported in only a handful of trials (Grajek 2010;
ml, 95% CI -20.88 ml to -8.39 ml, P < 0.00001, 3 studies, 153
Schchinger 2006; Pokushalov 2010). We have previously evalu-
participants, moderate quality evidence), but not left ventricular
ated the effect of stem cells as treatment for acute myocardial in-
end diastolic volume (LVEDV), in favour of BMSC treatment.
farction (AMI) (Clifford 2012a; Clifford 2012b; Martin-Rendon
2008b; Martin-Rendon 2008c). Here we present data on the sa-
fety and efficacy of autologous bone marrow-derived stem cells Stroke volume index was significantly improved by BMSC
(BMSC) administered to people with chronic IHD and heart fail- treatment at short-term (MD 3.84, 95% CI 0.95 to 6.73, P =
ure. 0.009, 4 studies, 148 participants, moderate quality evidence)
Twenty-three RCTs were eligible for inclusion in this review. All and long-term follow-up (MD 6.52, 95% CI 1.51 to 11.54, P =
trials compared the effect of BMSC treatment to no treatment 0.01, 2 studies, 62 participants, moderate quality evidence).
or to control. Generally, standard primary intervention included
medical therapy only, or medical therapy and revascularisation us- BMSC treatment improved LVEF significantly at short-
ing primary angioplasty (e.g. percutaneous coronary intervention term (MD 4.22%, 95% CI 3.47% to 4.97%, P < 0.00001, 18
(PCI)) or surgery (e.g. coronary artery bypass graft (CABG)). Par- studies, 746 participants, moderate quality evidence) and long-
ticipants were diagnosed with chronic IHD, generally including term follow-up (MD 2.62%, 95% CI 0.50% to 4.73%, P =
chronic symptoms of ischaemia that persisted for at least 30 days 0.02, 6 studies, 254 participants, moderate quality evidence).
since the last MI, heart failure secondary to IHD or refractory
angina. The type of cells, route of administration and dose are
detailed in Table 2. All trials reported short-term follow-up data Unlike previous reviews and meta-analyses, statistical
to 12 months, and seven studies had long-term follow-up for 12 heterogeneity was generally low or negligible for all outcomes,
months and longer. In this review, we defined mortality and left with the exception of NYHA class (I = 97%), CCS class (I =
ventricular ejection fraction (LVEF) as primary outcomes for com- 94%) and exercise capacity (I = 76%), for which results
parison with previous meta-analyses and because they are the most remained significant with a random-effects model.
common primary outcomes defined by the majority of included
studies. We also included adverse events as a primary outcome for
Results were robust to all sensitivity analyses.
this systematic review.
The main findings of the review are: There are a number of important limitations to the strength of the
conclusions derived from this review and meta-analysis.
BMSC treatment significantly reduced both mortality (RR
Firstly, the included studies are very small. Only four included
0.28, 95% CI 0.14 to 0.53, P = 0.02, 8 studies, 494 participants,
studies randomised more than 50 participants to treatment in each
low quality evidence) and rehospitalisation due to heart failure
trial arm and the majority of studies included substantially fewer
(RR 0.26, 95% CI 0.07 to 0.94, P = 0.04, 2 studies, 198
participants; there is therefore a risk of small study bias, leading to
participants, low quality evidence) at long-term follow-up.
spuriously inflated effect sizes. Secondly, whilst the number of on-
going randomised trials in this field is encouraging, several of these
The treatment was also associated with a significant appear to have been completed prior to the date of our search, but
reduction in heart failure symptoms (measured by New York we have been unable to identify any publications associated with
Heart Association (NYHA) functional class) in favour of BMSC them. We therefore cannot rule out the possibility of publication
treatment at short-term (MD -0.63, 95% CI -1.08 to -0.19, P = bias. Thirdly, the number of outcomes assessed in this systematic
0.005, 11 studies, 486 participants, moderate quality evidence) review leads us to the possibility of multiple testing and hence of
and long-term follow-up (MD -0.91, 95% CI -1.38 to -0.44, P false positive results. Our results should therefore be interpreted
= 0.0002, 4 studies, 196 participants, moderate quality with some caution. There is a clear need for large-scale, adequately-
evidence), as well as a reduction in angina symptoms (measured powered studies with well-defined participant cohorts and long-
by Canadian Cardiovascular Society (CCS) score) in favour of term follow-up to confirm the beneficial effects of BMSC in terms
of reduced mortality and rehospitalisation, and improved cardiac angina symptoms, exercise tolerance and quality of life.
function.
The observed risk ratio reduction in long-term mortality of 72%
Additional limitations include the low number of studies with represents evidence from only 39% of all included studies. In con-
long-term follow-up, and a lack of standardisation of outcome trast, an improvement in LVEF of 2.62% comes from a much
assessment methods. These limitations do not differ from those larger proportion of the included trials. This moderate improve-
found in our previous systematic review of BMSC treatment in ment in LVEF is very unlikely to explain the differential survival,
AMI trials (Clifford 2012a; Clifford 2012b). and hence the above results should be interpreted with caution.
Surprisingly, what differs from our previous review of BMSC treat- Incidence of mortality should be the primary endpoint of future
ment for AMI is the significant reduction in mortality at long- clinical trials to confirm the clinical efficacy of this treatment.
term follow-up observed in this review. This reduction in mor- Additionally, and depending on the clinical diagnosis, incidence
tality may be due to the cohort of participants included here, di- of rehospitalisation due to heart failure together with NYHA class
agnosed in some cases with refractory angina (Losordo 2011) or should be used as surrogate measures of disease progression in
with advanced heart failure (Pokushalov 2010). As stand-alone people with heart failure, whereas frequency of angina episodes and
therapy administered to people with IHD and no option of revas- CCS angina class should be measured for people with refractory
cularisation, BMSC treatment has been shown to be efficacious angina.
and it appears to reduce the incidence of mortality and improve
angina symptoms as well as NYHA class (Fisher 2013). This re- We conducted subgroup analyses for the outcomes of LEVF and
duction in mortality has been demonstrated in very few trials and NYHA class, as LVEF was measured by a high proportion of the
never in a meta-analysis of AMI studies (Clifford 2012a; Clifford trials, and we noted a high degree of statistical heterogeneity for
2012b; Martin-Rendon 2008b; Martin-Rendon 2008c). How- NYHA class. Variables included cell dosing, route of cell admin-
ever, it should be noted that the Pokushalov 2010 study of people istration or delivery, baseline cardiac function measured by LVEF,
with end-stage heart failure reported a particularly high number participant clinical diagnosis, cell type injected and method of
of deaths. Although a statistically significant beneficial effect of measurement of heart function. In summary, the results of these
BMSC on mortality remained in a sensitivity analysis after ex- subgroup analyses suggest that cell dose does not seem to have a sig-
clusion of this study, the number of observed deaths when the nificant effect on LVEF or NYHA classification, whereas intramy-
Pokushalov 2010 study was excluded was very small, leaving the ocardial injection of BMSC seems to increase the treatment effect
clinical significance of this finding unclear. for LVEF and NYHA class, and participants with lower LVEF at
baseline (LVEF below 30%) or diagnosed with congestive heart
Our previous Cochrane review evaluated stem cell treatment in failure (CHF) seem to benefit more from treatment than those
people who suffered from AMI in 33 trials and of 1765 participants with LVEF above 30% or diagnosed with chronic IHD (and not
(Clifford 2012a; Clifford 2012b). Even with the relatively large symptomatic of heart failure). The majority of trials administered
number of trials and participants included, there was insufficient bone marrow-derived mononuclear cells; few studies administered
evidence to conclude that this new treatment reduces the incidence other more enriched populations of cells such as mesenchymal
of mortality when administered following AMI. To this end, a progenitors, haemopoietic progenitor cells or circulating progen-
European Phase III multicentre RCT (the BAMI trial) has been itor cells, and hence we could only make limited comparisons be-
designed to test the clinical efficacy of BMSC therapy for AMI. tween cell types. Finally, the significant improvement in LVEF in
BMSC-treated participants over control appears to be robust to
In agreement with previous studies, we observed a moderate im- the different methods used to measure this outcome (e.g. magnetic
provement in LVEF in favour of BMSC treatment in this review. resonance imaging (MRI), single-photon emission computed to-
However, the improvement in LVEF does not adequately define mography (SPECT), LV angiography and echocardiography).
the clinical efficacy of BMSC treatment. Although global LVEF
has been used as the gold-standard surrogate to measure heart func- In summary, the results of this review may be clinically relevant, but
tion, especially in large trials in cardiology such as the CADILLAC the evidence for the reduction in the number of deaths with BMSC
trial (Stone 2002; Cox 2003), its use in cell therapy trials is con- treatment relative to controls is of low quality. Although BMSC
troversial (Traverse 2011). LVEF is a powerful predictor of mor- treatment has the potential to be used in clinical practice for people
tality in people with LV dysfunction (Solomon 2005), the typical with heart failure and for those with no other treatment option,
cohort of participants included in BMSC trials following AMI the results of this review warrant larger clinical trials to confirm the
(Clifford 2012a; Clifford 2012b). However, in the trials included present findings. To this end, the first Phase II/III and Phase III
in this review, where many of the participants have normal LVEF clinical trials for severe IHD (NCT01727063; NCT00362388;
at baseline, primary endpoints defined in individuals studies in- NCT00747708), heart failure (NCT01768702) and refractory
clude safety, mortality, incidence of heart failure, rehospitalisation angina (NCT01508910) have been designed and are currently
due to heart failure, NYHA functional class, angina episodes or ongoing. Research should also focus on a better understanding
of the best types of cells to use and why some people respond to of participants, future research should also focus on a better un-
treatment whereas others do not. derstanding of the cell therapies used (e.g. mononuclear cells, cir-
culating progenitor cells, mesenchymal stem cells or haematopoi-
etic progenitor cells) and their mechanism of action. Additionally,
AUTHORS CONCLUSIONS patient-dependent outcomes need to be more thoroughly investi-
gated, to ascertain and distinguish between responders and non-
Implications for practice responders, and to be able to tailor autologous, allogeneic or mod-
ified cell therapies to each patient group.
This review and meta-analysis show some evidence of a reduction
in mortality and rehospitalisation due to heart failure at long-term
follow-up (12 months and over) when BMSC treatment is ad-
ministered to people suffering from chronic IHD and congestive
heart failure. These results should be confirmed in larger appropri- ACKNOWLEDGEMENTS
ately powered clinical trials before developing BMSC treatment
We are in debt to Mr HJ Zhang, University of Oxford, UK, for the
for these patients as clinical practice.
translation of papers from Mandarin to English; and to Dr Brigitt
Assmus, University of Frankfurt, Germany, Dr Marc Hendrikx,
Implications for research Virga Jesse Hospital, Belgium, and Dr Sheng Liu, Fuwai Hospital,
The results of this systematic review should be confirmed in large, China for their generosity and time spent clarifying data for this
adequately-powered trials assessing the clinical relevance of the review. We would also like to thank Professors M Murphy, Suzanne
treatment. With a potential clinical effect such as a reduction in M Watt and D Roberts, NHS Blood and Transplant, for their
mortality and rehospitalisation due to heart failure in this cohort continuous support and encouragement.
REFERENCES
References to studies included in this review Assmus 2012 {published data only}

Assmus B, Walter DH, Seeger FH, Leistner DM, Lutz
Ang 2008 {published data only} A, Khaled W, et al.Cardiac extracorporal shock wave
Ang KL, Chin D, Leyva F, Foley P, Kubal C, Chalil S, application to enhance the efficiency of intracoronary
et al.Randomized, controlled trial of intramuscular or cell therapy in chronic heart failure - Final results of the
intracoronary injection of autologous bone marrow cells randomized, double-blind, placebo-controlled CELLWAVE
into scarred myocardium during CABG versus CABG trial. Circulation. 2012; Vol. 126 (21 Suppl 1):Abstract
alone. Nature Clinical Practice. Cardiovascular Medicine 13050. American Heart Association 2012 Scientific
2008;5(10):66370. [PUBMED: 18711405] Sessions and Resuscitation Science Symposium, 3 - 6
Assmus 2006 {published data only} November 2012, Los Angeles, CA.
Steiner JK, Ziegler I, Assmus B, Seeger F, Walter F, Walter
Assmus B, Honold J, Schachinger V, Britten MB, Fischer-
Rasokat U, Lehmann R, et al.Transcoronary transplantation D, et al.Cardiac extracorporal shock wave-facilitated cell
of progenitor cells after myocardial infarction. The New therapy in patients with chronic heart failure (Cellwave
England Journal of Medicine 2006;355(12):122232. trial) - mechanistic insights by magnetic resonance imaging.
[PUBMED: 16990385] Circulation. 2012; Vol. 126 (21 Suppl 1):Abstract 14838.
Assmus B, Honold J, Schaechinger V, Britten MB, Fischer- American Heart Association 2012 Scientific Sessions and
Rasokat U, Lehmann R, et al.Transcoronary transplantation Resuscitation Science Symposium, 3 - 6 November 2012,
of progenitor cells for left ventricular dysfunction after Los Angeles, CA.
healed myocardial infarction: a direct comparison of
Chen 2006 {published data only}
different cell types (TOPCARE-CHD crossover trial).
Chen S, Liu Z, Tian N, Zhang J, Yei F, Duan B, et
European Heart Journal. 2006; Vol. 27 (Suppl 1):282
al.Intracoronary transplantation of autologous bone marrow
Abstract P1687. World Congress of Cardiology, 2 - 6
mesenchymal stem cells for ischemic cardiomyopathy due
September 2006, Barcelona, Spain.
to isolated chronic occluded left anterior descending artery.
Bellera Gotarda MN, Schaechinger V, Fischer-Rasokat
The Journal of Invasive Cardiology 2006;18(11):5526.
U, Honold J, Seeger FH, Dimmeler S, et al.Impaired
[PUBMED: 17090821]
microvascular function as a predictor of improvement in
patients with chronic post-infarction heart failure receiving Erbs 2005 {published data only}
intracoronary progenitor cells - results of the TOPCARE- Erbs S, Adams V, Thiele H, Emmrich F, Kluge R,
CHD Doppler substudy. Circulation. 2008; Vol. 118 (18 Kendziorra K, et al.Intracoronary transplantation of
Suppl):Abstract 3416. circulating progenitor cells after recanalisation of chronic
coronary artery occlusions: impact on coronary vasomotion College of Cardiology 2011;57(24):240915. [PUBMED:
and left ventricular remodelling. European Heart Journal. 21658561]
2005; Vol. 26 (Suppl 1):532, Abstract P3148. European Lu MJ, Zhao SH, Liu S, Zhang PH, Jiang SL, Zhang
Society of Cardiology Congress, 3 - 7 September 2005, Y, et al.Assessment of therapeutic effects of stem cell
Stockholm, Sweden. transplantation in heart failure patients with old myocardial

Erbs S, Linke A, Adams V, Lenk K, Thiele H, Diederich infarction by magnetic resonance imaging. Chinese Journal
KW, et al.Transplantation of blood-derived progenitor cells of Cardiology 2008;36(11):96974.
after recanalization of chronic coronary artery occlusion:
first randomized and placebo-controlled study. Circulation Kang 2006 {published data only}
Research 2005;97(8):75662. [PUBMED: 16151021] Kang HJ, Kim MK, Lee HY, Park KW, Lee W, Cho
Erbs S, Thiele H, Linke A, Adams V, Lenk K, Emmrich F, et YS, et al.Five-year results of intracoronary infusion of
al.Intracoronary infusion of blood-derived progenitor cells the mobilized peripheral blood stem cells by granulocyte
after recanalization of chronic coronary occlusions: long colong-stimulating factor in patients with myocardial
term effects on cardiac function and infarct size. European infarction. European Heart Journal 2012;33(24):30629.
Heart Journal. 2006; Vol. 27 (Suppl 1):274, Abstract
Kang HJ, Lee HY, Na SH, Chang SA, Park KW, Kim
P1656. World Congress of Cardiology, 2 - 6 September HK, et al.Differential effect of intracoronary infusion
2006, Barcelona, Spain. of mobilized peripheral blood stem cells by granulocyte
Thiele H, Schuster A, Erbs S, Adams V, Lenk K, Linke A, colony-stimulating factor on left ventricular function and
et al.Effects on myocardial perfusion at 3 and 15 months remodeling in patients with acute myocardial infarction
in recanalized chronic total occlusions - randomized versus old myocardial infarction: the MAGIC Cell-3-
comparison of blood-derived progenitor cells and inactive DES randomized, controlled trial. Circulation 2006;114(1
serum. Circulation. 2007; Vol. 116 (16 Suppl):Abstract Suppl):I14551. [PUBMED: 16820564]
3420. American Heart Association Scientific Sessions 2007,
3 - 7 November, Orlando, FL. Losordo 2007 {published data only}
Thiele H, Schuster A, Erbs S, Adams V, Linke A, Schuler Losordo DW, Henry TD, Schatz RA, Sup Lee J, Costa M,
G, et al.Mechanistic insights from serial cardiac magnetic Bass T, et al.Randomized, double-blind, placebo-controlled
resonance imaging at 3 and 15 months after application trial of autologous CD34+ cell therapy for refractory angina:
of blood-derived progenitor cells in recanalized chronic 2-year safety analysis. Circulation. 2010; Vol. 122 (21
coronary total occlusions (CTO). Circulation. 2006; Vol. Suppl 1):Abstract A15621. American Heart Association
114 (18 Suppl):Abstract 2616. American Heart Association Scientific Sessions, 13 - 17 November 2010, Chicago, IL.
Scientific Sessions 2006, 12 - 15 November, Chicago, IL. Losordo DW, Kearney M, Patel S, Poh K-K, Shah P, Welt F,
Thiele H, Schuster A, Erbs S, Linke A, Lenk K, Adams et al.Randomized, double-blind, placebo controlled pilot
V, et al.Cardiac magnetic resonance imaging at 3 and 15 trial of intramyocardial autologous CD34 cell therapy for
months after application of circulating progenitor cells in intractable angina. Circulation. 2006; Vol. 114 (18 Suppl):
recanalised chronic total occlusions. International Journal of Abstract 3361. American Heart Association Scientific
Cardiology 2009;135(3):28795. [PUBMED: 18584897] Sessions 2006, 12 - 15 November 2006, Chicago, IL.

Hendrikx 2006 {published data only} Losordo DW, Schatz RA, White CJ, Udelson JE,
Hendrikx M, Hensen K, Clijsters C, Jongen H, Koninckx Veereshwarayya V, Durgin M, et al.Intramyocardial
R, Bijnens E, et al.Recovery of regional but not global transplantation of autologous CD34+ stem cells for
contractile function by the direct intramyocardial intractable angina: a phase I/IIa double-blind, randomized
autologous bone marrow transplantation: results from a controlled trial. Circulation 2007;115(25):316572.
randomized controlled clinical trial. Circulation 2006; Vol. [PUBMED: 17562958]
114, issue 1 Suppl:I1017. [PUBMED: 16820557]
Losordo 2011 {published data only}
Honold 2012 {published data only} Junge CE, Motlagh D, Debelak J, Cohen A, Hammel
Honold J, Fischer-Rasokat U, Lehmann R, Leistner DM, S, Nada A, et al.Clinical parameters influencing cell
Seeger FH, Schachinger V, et al.G-CSF stimulation and mobilization and impact of mobilization ability on efficacy
coronary reinfusion of mobilized circulating mononuclear outcomes: An analysis from ACT34-CMI. Circulation.
proangiogenic cells in patients with chronic ischemic heart 2012; Vol. 126 (21 Suppl 1):Abstract 12015. American
disease: Five-year results of the TOPCARE-G-CSF trial. Heart Association 2012 Scientific Sessions and Resuscitation
Cell Transplantation 2012;21(11):232537. Science Symposium, 3 - 6 November 2012, Los Angeles,
Hu 2011 {published data only} CA.

Hu S, Liu S, Zheng Z, Yuan X, Li L, Lu M, et al.Isolated Livingston D, Motlagh D, Debelak J, Cohen A, Story K,
coronary artery bypass graft combined with bone marrow Hammel S, et al.Phase 2 study of intramyocardial injection
mononuclear cells delivered through a graft vessel for of autologous CD34+ cells to treat subjects with refractory
patients with previous myocardial infarction and chronic chronic myocardial ischemia (CMI): Factors influencing
heart failure: a single-center, randomized, double-blind, mobilization and apheresis. Blood. 2009; Vol. 114:Abstract
placebo-controlled clinical trial. Journal of the American 3227. 51st Annual Meeting of the American Society of
Hematology, ASH, 5 - 8 December 2009, New Orleans, heart failure: the FOCUS-CCTRN trial. JAMA 2012;307
LA. (16):171726.
Losordo DW, Henry T, Schatz RA, Lee JS, Costa M, Bass Willerson JT, Perin EC, Ellis SG, Pepine CJ, Henry TD,
T, et al.Autologous CD34+ cell therapy for refractory Zhao DX, et al.Intramyocardial injection of autologous
angina: 12 month results of the phase II ACT34-CMI bone marrow mononuclear cells for patients with chronic
study. Circuation. 2009; Vol. 120 (18 Suppl):Abstract ischemic heart disease and left ventricular dysfunction (First
5638. American Heart Association Scientific Sessions 2009, Mononuclear Cells injected in the US [FOCUS]): Rationale
14 - 18 November 2009, Orlando, FL. and design. American Heart Journal 2010;160(2):21523.

Losordo DW, Henry TD, Davidson C, Sup Lee J, [PUBMED: 20691824]
Costa MA, Bass T, et al.ACT34-CMI Investigators.
Perin 2012b {published data only}
Intramyocardial, autologous CD34+ cell therapy for
Perin EC, Silva GV, Zheng Y, Fernandez MR, Moore W,
refrectory angina. Circulation Research 2011;109(4):
Coulter S, et al.First in man transendocardial injection of
42836.
autologous aldehyde dehydrogenase-bright cells in heart
Povsic TJ, Losordo DW, Story K, Junge CE, Schatz RA,
failure patients (FOCUS-Bright). Circulation. 2009; Vol.
Harrington RA, et al.Cardiac biomarker elevation during
120 (18 Suppl):Abstract 3502. American Heart Association
stem cell mobilisation, apheresis and intramyocardial
Scientific Sessions 2009; 14 - 18 November 2009; Orlando,
delivery is common but does not impact incidence of long-
FL.
term MACE: An analysis from ACT34-CMI. Circulation.
Perin EC, Silva GV, Zheng Y, Gahremanpour A, Canales
2012; Vol. 126 (21 Suppl 1):Abstract 11770. American
J, Patel D, et al.Randomized, double-blind pilot study
Heart Association 2012 Scientific Sessions and Resuscitation
of transendocardial injection of autologous aldehyde
Science Symposium, 3 - 6 November 2012, Los Angeles,
dehydrogenase-bright stem cells in patients with ischemic
CA.
heart failure. American Heart Journal 2012;163(3):415-21,
Povsik TJ, Losordo DW, Story K, Junge CE, Schatz RA,
421.e1. [PUBMED: 22424012]
Harrington RA, et al.Incidence and clinical significance of
cardiac biomarker elevation during stem cell mobilization, Pokushalov 2010 {published data only}
apheresis, and intramyocardial delivery: An analysis from Pokushalov E, Romanov A, Artemenko S, Cherniavskiy
ACT34-CMI. American Heart Journal 2012;164(5): A, Larionov P, Terehov I, et al.Efficacy of intramyocardial
68997.e3. injections of autologous bone marrow mononuclear stem
Patel 2005 {published data only} cells in patients with ischemic heart failure: Long term
Patel AN, Geffner L, Vina RF, Saslavsky J, Urschel HC results: ACC poster contributions. Journal of the American
Jr, Kormos R, et al.Surgical treatment for congestive heart College of Cardiology. 2010; Vol. 55 (10 Suppl 1):A24:
failure with autologous adult stem cell transplantation: a Abstract E228. Amercan College of Cardiologys 59th
prospective randomized study. The Journal of Thoracic and Annual Scientific Session and i2 Summit: innovation in
Cardiovascular Surgery 2005;130(6):16318. [PUBMED: Intervention, 14 - 16 March 2010, Atlanta, GA.

16308009] Pokushalov E, Romanov A, Artemenko S, Larionov P,
Cherniavskiy A. Efficiency of intramyocardial injections of
Perin 2011 {published data only} autologous bone marrow mononuclear stem cells in patients
Perin EC, Silva GV, Fernandes MR, Henry T, Moore W, with ischemic heart failure: Long-term results. Journal of
Coulter S, et al.FOCUS-HF: The first US randomized Cardiac Failure. 2009; Vol. 15 (6 Suppl 1):S44, Abstract
blinded controlled trial of transendocardial injection 138. 13th Annual Scientific Meeting of the Heart Failure
of bone marrow mononuclear cells in chronic severe Society of America, 13 - 16 September 2009, Boston, MA.
ischemic heart failure patients. Journal of the American Pokushalov E, Romanov A, Cherniavskiy A, Artemenko S,
College of Cardiology. 2009; Vol. 53 (10 Suppl):A193, Larionov P, Terehov I, et al.Efficiency of intramyocardial
Abstract 1051-191. American College of Cardiology 58th injections of autologous bone marrow mononuclear
Annual Scientific Session and i2 Summit: Innovation in stem cells in patients with ischemic heart failure: Long-
Intervention, 29 - 31 September 2009, Orlando, FL. term results. American Journal of Cardiology. 2009;

Perin EC, Silva GV, Henry TD, Cabreira-Hansen MG, Vol. 104 (6 Suppl 1):74D - 75D, Abstract TCT-194.
Moore WH, Coulter SA, et al.A randomized study of Transcatheter Cardiovascular Therapeutics Symposium, 21
transendocardial injection of autologous bone marrow - 25 September 2009, San Francisco, CA.
mononuclear cells and cell function analysis in ischemic Pokushalov E, Romanov A, Chernyavsky A, Larionov
heart failure (FOCUS-HF). American Heart Journal 2011; P, Terekhov I, Artyomenko S, et al.Efficiency of
161(6):107887.e3. [PUBMED: 21641354] intramyocardial injections of autologous bone marrow
Perin 2012a {published data only} mononuclear cells in patients with ischemic heart failure: a

Perin EC, Willerson TJ, Pepine CJ, Henry TD, Ellis randomized study. Journal of Cardiovascular Translational
SG, Zhao DX, et al.Cardiovascular Cell Therapy Research Research 2010;3(2):1608. [PUBMED: 20560030]
Network CCTRN. Effect of transendocardial delivery of Romanov A, Pokushalov E, Artemenko S, Larionov P,
autologous bone marrow mononuclear cells on functional Terehov I, Kliver E, et al.Efficiency of intramyocardial
capacity, left ventricular function, and perfusion in chronic injections of autologous bone marrow mononuclear stem
cells in patients with ischemic heart failure: long-term [PUBMED: 20100336]

results.. European Heart Journal. 2009; Vol. 30 (Suppl Tse HF, Thambar S, Kwong YL, Rowlings P, Bellamy
1):504, Abstract P3097. European Society of Cardiology G, McCrohon J, et al.Prospective randomized trial of
Congress 2009, 29 August - 2 September 2009, Barcelona, direct endomyocardial implantation of bone marrow
Spain. cells for treatment of severe coronary artery diseases
Romanov A, Pokushalov E, Cherniavskiy A, Artemenko S, (PROTECT-CAD trial). European Heart Journal 2007;28
Larionov P, Terehov I, et al.Efficiency of intramyocardial (24):29983005. [PUBMED: 17984132]
injections of autologous bone marrow mononuclear cells in
patients with ischemic heart failure: A randomized study. Turan 2011 {published data only}

Heart Rhythm. 2010; Vol. 7 (5 Suppl 1):S348: Abstract Turan RG, Bozdag-T I, Ortak J, Kische S, Akin I,
P05-82. 31st Annual Scientific Sessions of the Heart Schneider H, et al.Improved functional activity of bone
Rhythm Society, 12 - 15 May 2010, Denver, Colorado. marrow derived circulating progenitor cells after intra
Romanov A, Pokushalov E, Cherniavskiy A, Larionov P, coronary freshly isolated bone marrow cells transplantation
Artemenko S, Terekhov I, et al.Efficiency of intramyocardial in patients with ischemic heart disease. Stem Cell Reviews
injections of autologous bone marrow mononuclear stem 2011;7(3):64656. [PUBMED: 21188654]
cells in patients with ischemic heart failure: long-term Turan RG, Bozdag-Turan I, Ortak J, Akin I, Kische S,
results. European Journal of Heart Failure. 2009; Vol. 8 Schneider H, et al.Improved mobilization of the CD34(+)
(Suppl 2):ii705, Abstract 1401. Heart Failure Congress, 30 and CD133(+) bone marrow-derived circulating progenitor
May - 2 June 2009, Nice, France. cells by freshly isolated intracoronary bone marrow cell
Romanov A, Pokushalov E, Cherniavskiy A, Larionov P, transplantation in patients with ischemic heart disease. Stem
Terekhov I, Kilver E, et al.Efficiency of intramyocardial Cells and Development 2011;20(9):1491501. [PUBMED:
injections of autologous bone marrow mononuclear cells in 21190450]
patients with ischemic heart failure: A randomized study.
European Journal of Heart Failure. 2010; Vol. 9 (Suppl 1): Van Ramshorst 2009 {published data only}
S60-S61, Abstract 404. Heart Failure Congress 2010. 29 Rodrigo S, Van Ramshorst J, Beeres SL, Al Younis I,
May - 1 June 2010, Berlin, Germany. Dibbets-Schneider P, De Roos A, et al.Intramyocardial
Romanov A, Pokushalov E, Cherniavskiy A, Larionov injection of bone marrow mononuclear cells in chronic
P, Terekhov I, Poveschenko O, et al.Efficiency of myocardial ischemia patients after previous placebo
intramyocardial injections of autologous bone marrow injection improves myocardial perfusion and anginal
mononuclear cells in patients with ischemic heart failure: symptoms: An intra-patient comparison. American Heart
a randomized study. European Heart Journal. 2010; Vol. Journal 2012;164(5):7718.
31 (Abstract Supplement):323, Abstract 2024. European Rodrigo S, Van Ramshorst J, Beeres SL, Dibbets-Schneider
Society of Cardiology Congress, 28 August - 1 September P, De Roos A, Fibbe WE, et al.Intramyocardial injection
2010, Stockholm, Sweden. of bone marrow mononuclear cells in patients with
Romanov A, Pokushalov E, Prokhorova D, Cherniavskiy A, chronic myocardial ischemia: An intra-patient comparison.
Artemenko S, Shirokova N, et al.Cardiac resynchronization Circulation 2011;124(Suppl 1).
therapy and bone marrow transplantation in patients with Rodrigo S, Van Ramshorst J, Beeres SL, Dibbets-Schneider
ischemic heart failure and electro-mechanical dyssynchrony. P, Stokkel M, Fibbe WE, et al.Intramyocardial bone marrow
A randomized study. European Heart Journal. 2010; Vol. cell injection in patients with chronic myocardial ischemia:
31 (17 Suppl 1):591; Abstract 3476. European Society Results long term follow-up. Circulation. 2011; Vol. 124
of Cardiology Congress, 28 August - 1 September 2010, (21 Suppl 1):Abstract A15175. American Heart Association
Stockholm, Sweden. Scientific Sessions, 12 - 16 November 2011, Orlando, FL.
Romanov AB, Pokushalov E, Cherniavskiy A, Kliver E, Rodrigo S, Van Ramshorst J, Beeres SL, Dibbets-Schneider
Karaskov A, Dib N. Efficiency of intramyocardial injections P, Stokkel M, Zwaginga JJ, et al.Intramyocardial bone
of autologous bone marrow mononuclear cells in patients marrow cell injection in patients with chronic myocardial
with ischemic heart failure: A randomized study. Journal ischemia: Results long term follow-up. European Heart
of the American College of Cardiology. 2011; Vol. 57 (14 Journal. 2011; Vol. 32:820, Abstract P4671. European
Suppl 1):Abstract E241. 60th Annual Scientific Session and Society of Cardiology Congress 2011, 27 - 31 August 2011,
Expo ACC. 11, 2 - 5 April 2011, New Orleans. Paris, France.
Van Ramshorst J, Antoni ML, Beeres SL, Roes SD, Delgado
V, Rodrigo SF, et al.Intramyocardial bone marrow-derived
Tse 2007 {published data only} mononuclear cell injection for chronic myocardial ischemia:
Chan CW, Kwong YL, Kwong RY, Lau CP, Tse HF. the effect on diastolic function. Circulation, Cardiovascular
Improvement of myocardial perfusion reserve detected Imaging 2011;4(2):1229. [PUBMED: 21209073]

by cardiovascular magnetic resonance after direct Van Ramshorst J, Bax JJ, Beeres SL, Dibbets-Schneider
endomyocardial implantation of autologous bone marrow P, Roes SD, Stokkel MP, et al.Intramyocardial bone
cells in patients with severe coronary artery disease. marrow cell injection for chronic myocardial ischemia:
Journal of Cardiovascular Magnetic Resonance 2010;12:6. a randomized controlled trial. JAMA 2009;301(19):
19972004. [PUBMED: 19454638] Beeres 2007a {published data only}
Van Ramshorst J, Bax JJ, Beeres SL, Dibbets-Schneider P, Beeres SL, Bax JJ, Dibbets-Schneider P, Stokkel MP, Fibbe
Roes SD, Stokkel MPM, et al.Intramyocardial injection WE, Van der Wall EE, et al.Intramyocardial injection of
of bone marrow-derived mononuclear cells for chronic autologous bone marrow mononuclear cells in patients with
myocardial ischemia: a randomized, double-blind, placebo- chronic myocardial infarction and severe left ventricular
controlled trial. European Heart Journal. 2009; Vol. dysfunction. American Journal of Cardiology 2007;100(7):
30 (Suppl 1):452, Abstract 2819. European Society of 10948. [PUBMED: 17884369]
Cardiology Congress, 29 August - 2 September 2009,
Beeres 2007b {published data only}
Barcelona, Spain.
Beeres SL, Bengel FM, Bartunek J, Atsma DE, Hill JM,
Van Ramshorst J, Bax JJ, Beeres SL, Roes SD, Dibbets P,
Vanderheyden M, et al.Role of imaging in cardiac stem cell
De Roos A, et al.Intramyocardial autologous bone marrow
therapy. Journal of the American College of Cardiology 2007;
cell injection in no-option patients with refractory angina
49(11):113748. [PUBMED: 17367656]
pectoris and documented ischemia: A randomized, double
blinded, placebo-controlled trial. Journal of the American Chang 2006 {published data only}
College of Cardiology. 2009; Vol. 53 (10 Suppl):A340, Chang SA, Kim HK, Lee HY, Kang HJ, Kim YJ, Zo JH,
Abstract 1041-145. American College of Cardiology 58th et al.Restoration of synchronicity of the left ventricular
Annual Scientific Session and i2 Summit: Innovation in myocardial contraction with stem cell therapy: New insights
Intervention, 29 - 31 March 2009, Orlando, FL. into the therapeiutic implication of stem cell therapy in
myocardial infarction. Circulation. 2006; Vol. 114
Wang 2009 {published data only} (18 Suppl):Abstract 2718. American Heart Association
Wang S-H, Cui J-Y, Lu M, Wang X, Li, X-M, Tan C, et Scientific Sessions 2006; 12 - 15 November 2006, Chicago,
al.Intracoronary transplantation with autologous bone IL.
marrow CD34+ stem cells for angina: a randomized
controlled clinical analysis. Journal of Clinical Rehabilitative Charwat 2010 {published data only}
Tissue Engineering Research 2009;13(14):26236. Charwat S, Lang I, Dettke M, Graf S, Nyolczas N,
Hemetsberger R, et al.Effect of intramyocardial delivery of
Wang 2010 {published data only} autologous bone marrow mononuclear stem cells on the
Wang S, Cui J, Peng W, Lu M. Intracoronary autologous regional myocardial perfusion. NOGA-guided subanalysis
CD34+ stem cell therapy for intractable angina. Cardiology of the MYSTAR prospective randomised study. Thrombosis
2010;117(2):1407. [PUBMED: 20975266] and Haemostasis 2010;103(3):56471. [PUBMED:
20076851]
Yao 2008 {published data only}
Yao K, Huang R, Qian J, Cui J, Ge L, Li Y, et Chin 2010 {published data only}
al.Administration of intracoronary bone marrow Chin SP, Poey AE, Chang SK, Wong CY, Lam KH, Cheong
mononuclear cells on chronic myocardial infarction SK. Safety and efficacy of autologous mesenchymal stem
improves diastolic function. Heart (British Cardiac Society) cells for the treatment of end-stage dilated cardiomyopathy
2008;94(9):114753. [PUBMED: 18381377] - a comparison of intracoronary and direct intramyocardial
injection. European Heart Journal. 2010; Vol. 31 (17
Zhao 2008 {published data only}
Suppl 1):79-80, Abstract P601. European Society of
Zhao Q, Sun Y, Xia L, Chen A, Wang Z. Randomized
Cardiology Congress, Stockholm, Sweden, 28 August - 1
study of mononuclear bone marrow cell transplantation
September 2010.
in patients with coronary surgery. The Annals of Thoracic
Surgery 2008;86(6):183340. [PUBMED: 19021989] Gu 2011 {published data only}
Gu X, Xie Y, Gu J, Sun L, He S, Xu R, et al.Repeated
References to studies excluded from this review intracoronary infusion of peripheral blood stem cells with
G-CSF in patients with refractory ischemic heart failure-
Beeres 2006 {published data only} -a pilot study. Circulation Journal 2011;75(4):95563.
Beeres SL, Bax JJ, Dibbets-Schneider P, Stokkel MP, Fibbe [PUBMED: 21325723]
WE, Van der Wall EE, et al.Sustained effect of autologous Haack-Sorensen 2013 {published data only}
bone marrow mononuclear cell injection in patients with Haack-Sorensen M, Friis T, Mathiasen AB, Jorgensen
refractory angina pectoris and chronic myocardial ischemia: E, Hansen L, Dickmeiss E, et al.Direct intramyocardial
twelve-month follow-up results. American Heart Journal mesenchymal stromal cell injections in patients with severe
2006;152(4):684.e116. [PUBMED: 16996834] refractory angina: one-year follow-up. Cell Transplantation
2013;22(3):5218.
Beeres 2007 {published data only}
Beeres SL, Bax JJ, Zeppenfeld K, Dibbets-Schneider P, Kakuchaya 2010 {published data only}
Stokkel MP, Fibbe WE, et al.Feasibility of trans-endocardial Kakuchaya T. Influence of bone-marrow derived progenitor
cell transplantation in chronic ischaemia. Heart (British stem cells on cardiac remodelling in a placebo-controlled
Cardiac Society) 2007; Vol. 93, issue 1:1134. [PUBMED: clinical trial involving patients with congestive heart
17170348] failure. Heart Surgery Forum. 2010; Vol. 13:S121. 20th
World Congress of the World Society of Cardio-Thoracic marrow cell transplantation. Journal of the American
Surgeons, WSCTS Chennai, India, 20 - 23 October 2010. College of Cardiology. 2011; Vol. 57(14 Suppl 1):Abstract
E103.
Kang 2006b {published data only}
Kang H-J, Kim H-S, Na S-H, Zhang S-Y, Kang WJ, Youn Rivas-Plata 2010 {published data only}
T-J, et al.Six months follow up results of granulocytes- Rivas-Plata A, Castillo J, Pariona M, Chunga A. Bypass
colony stimulating factor based stem cell therapy in patients grafts and cell transplant in heart failure with low ejection
with myocardial infarction: MAGIC cell randomized fraction. Asian Cardiovascular & Thoracic Annals 2010;18
controlled trial. Korean Circulation Journal 2006;36(2): (5):4259. [PUBMED: 20947595]
99107.
Stamm 2007a {published data only}
Lai 2009 {published data only}
Stamm C, Kleine HD, Choi YH, Dunkelmann S, Lauffs
Ang KL, Lai VK, Rathbone WE, Harvey NH, Gaiinanes M.
JA, Lorenzen B, et al.Intramyocardial delivery of CD133+
Randomized controlled trial on the cario protective effect of
bone marrow cells and coronary artery bypass grafting for
bone marrow cells in patients undergoing coronary artery
chronic ischemic heart disease: safety and efficacy studies.
bypass graft surgery. European Journal of Heart Failure.
The Journal of Thoracic and Cardiovascular Surgery 2007;
2009; Vol. 8:ii707.
133(3):71725. [PUBMED: 17320570]
Lai VK, Ang KL, Rathbone W, Harvey NJ, Galinanes
M. Randomized controlled trial on the cardioprotective Tuma 2011 {published data only}
effect of bone marrow cells in patients undergoing coronary Tuma J, Fernandez-Vina R, Carrasco A, Castillo J, Cruz
bypass graft surgery. European Heart Journal 2009;30(19): C, Carrillo A, et al.Safety and feasibility of percutaneous
23549. [PUBMED: 19561024] retrograde coronary sinus delivery of autologous bone
Maureira 2012 {published data only} marrow mononuclear cell transplantation in patients with
Maureira P, Tran N, Djaballah W, Angioi M, Bensoussan chronic refractory angina. Journal of Translational Medicine
D, Didot N, et al.Residual viability is a predictor of the 2011;9:183. [PUBMED: 22029669]
perfusion enhancement obtained with the cell therapy of
Vicario 2004 {published data only}
chronic myocardial infarction: a pilot multimodal imaging
Vicario J, Campo C, Piva J, Faccio F, Gerardo L, Becker
study. Clinical Nuclear Medicine 2012;37(8):73842.
C, et al.One-year follow-up of transcoronary sinus
[PUBMED: 22785499]
administration of autologous bone marrow in patients with
Perin 2003 {published data only} chronic refractory angina. Cardiovascular Revascularization

Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa Medicine : Including Molecular Interventions 2005;6(3):
AL, Mesquita CT, et al.Transendocardial, autologous bone 99107.
marrow cell transplantation for severe, chronic ischemic
Vicario J, Campos C, Piva J, Faccio F, Gerardo L, Becker
heart failure. Circulation 2003;107(18):2294302. C, et al.Transcoronary sinus administration of autologous
[PUBMED: 12707230] bone marrow in patients with chronic refractory stable
Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, angina Phase 1. Cardiovascular Radiation Medicine 2004;5
Silva GV, et al.Improved exercise capacity and ischemia (2):716. [PUBMED: 15464943]
6 and 12 months after transendocardial injection of
autologous bone marrow mononuclear cells for ischemic Wang 2006 {published data only}
cardiomyopathy. Circulation 2004;110(11 Suppl 1): Wang WM, Sun NL, Liu J, Zhang P, Liu KY, Wang Q,
II2138. [PUBMED: 15364865] et al.[Effects of intracoronary autologous bone marrow
mononuclear cells transplantation in patients with anterior
Peruga 2009 {published data only}
myocardial infarction]. Zhonghua Xin Xue Guan Bing Za
Peruga J, Plewka M, Kasprzak J, Jezewski T, Wierzbicka A,
Zhi 2006;34(2):1036. [PUBMED: 16626572]
Robak T, et al.Intracoronary administration of stem cells
in patients with acute myocardial infarction - angiographic
follow-up. Kardiologia Polska 2009;67(5):47784.
References to studies awaiting assessment
[PUBMED: 19521932]
Pokushalov 2011 {published data only} Bartunek 2012 {published data only}

Pokushalov E, Romanov A, Corbucci G, Prohorova D, Bartunek J, Behfar A, Dolatabadi D, Ostojic M, Dens
Chernyavsky A, Larionov P, et al.Cardiac resynchronization J, Vanderheyden M, et al.Cardiopoietic stem cell therapy
therapy and bone marrow cell transplantation in patients in heart failure: The multicenter randomized c-cure trial.
with ischemic heart failure and electromechanical Circulation. 2012; Vol. 126 (Suppl 1):Abstract 18117.
dyssynchrony: a randomized pilot study. Journal of American Heart Association 2012 Scientific Sessions and
Cardiovascular Translational Research 2011;4(6):76778. Resuscitation Science Symposium, 3 - 6 November 2012,
[PUBMED: 21547598] Los Angeles, CA.
Pokushalov E, Romanov A, Prohorova D, Artemenko S, Bartunek J, Dolatabadi D, Vanderheyden M, Dens J,
Cheriniavskiy A, Karaskov A, et al.Cardiac resynchronization Ostojic M, Behfar A, et al.Cardiopoietic mesenchymal stem
therapy in patients with ischemic heart failure after bone cells for treatment of ischemic cardiomyopathy: First-in-
man phase II multicentre clinical trial. European Heart Results of the CARDIO133 trial. Journal of the American
Journal. 2011; Vol. 32:815. College of Cardiology. 2012; Vol. 59 (13 Suppl 1):E864.
Bartunek J, Wijns W, Dolatabadi D, Vanderheyden M, Nasseri BA, Klose K, Ebell W, Dandel M, Kukucka M,
Dens J, Ostojic M, et al.C-cure multicenter trial: Lineage Gebker R, et al.Improved regional contractile function and
specified bone marrow derived cardiopoietic mesenchymal reduced scar size after clinical cell therapy with CD133-
stem cells for treatment of ischemic cardiomyopathy. positive cells. Interactive Cardiovascular and Thoracic
Journal of the American College of Cardiology. 2011; Vol. Surgery. 2013; Vol. 16 (2):S233. 3rd EACTS Meeting on
57 (14 Suppl 1):E200. Cardiac and Pulmonary Regeneration, 14 - 15 December
2012, Berlin, Germany.
Cuzzola 2007 {published data only}
Cuzzola M, Irrera G, Pontari A, Callea I, Pucci G, Shihong 2012 {published data only}
Martinelli G, et al.Progenitor cell trafficking in patients Shihong W. Intracoronary autologous CD34+ stem cell
with infarcted myocardium undergoing autologous bone therapy for intractable angina. Heart. 2012; Vol. 98:
marrow mononuclear cell injection. Interim analysis of E423.
a double blind randomised phase II clinical trial. Bone Tuma 2010 {published data only}
Marrow Transplantation. 2007; Vol. 39 (Suppl 1s):S215. Tuma J, Fernandez R, Cruz C, Carrillo A, Erchilla J, Inga
European Group for Blood and Marrow Transplantation L, et al.Long term benefit of autologous bone marrow
Annual Congress, Lyon, France, 25 - 28 March 2007. transplantation by retrograde technique in terminal heart
failure (LIBERTY study). Journal of the American College
Jimenez-Quevedo 2011 {published data only} of Cardiology. 2010; Vol. 56 (13 Suppl 1):B71.

Jimenez-Quevedo P, Gonzalez FJ, Llorente L, Sabate M,
Garcia MX, Hernandez-Antolin R, et al.Selected CD133+ Zverev 2006 {published data only}
endothelial progenitor cells to create angiogenesis in no- Zverev O, Boldueva S, Nemkov A, Shloydo E, Tsurupa
option patients: The design of the PROGENITOR S, Rigkova D, et al.Improvement of cardiomyocyte
randomized trial. European Heart Journal. 2011; Vol. 32: function after transplantation of autologous bone marrow
816: Abstract P4654. mesenchymal stem cells in patients with non-acute ischemic
Jimenez-Quevedo P, Gonzalez-Ferrer JJ, Sabat M, Garcia- heart disease. European Heart Journal. 2006; Vol. 27
Mol X, Llorent L, Hernandez-Antoli R, et al.Selected (Suppl 1):276: Abstract P1663. World Congress of
CD133+ endothelial progenitor cells to create angiogenesis Cardiology; 2 - 6 September 2006; Barcelona, Spain..
in no-option patients: Preliminary 3-months results of the
References to ongoing studies
progenitor trial. Circulation. 2012; Vol. 126: 21 (Suppl 1):
American Heart Association 2012 Scientific Sessions and
ACTRN12611000219987 {published data only}
Resuscitation Science Symposium, 3 - 6 November 2012,
ACTRN12611000219987. A study of the effect of direct
Los Angeles, CA.
endomyocardial injection of autologous bone marrow cells
Jimenez-Quevedo P, Gonzalez-Ferrer JJ, Sabate M, Garcia-
on left ventricular ejection function in patients with end-
Moll X, Alfonso F, Hernandez-Antolin R, et al.Selected
stage ischaemic heart failure. apps.who.int/trialsearch/
CD133+ endothelial progenitor cells to create angiogenesis
Trial.aspx?TrialID=ACTRN12611000219987 (accessed 21
in no-option patients: Preliminary results of safety and
August 2012).
feasibility. Journal of the American College of Cardiology.
2012; Vol. 60:B112. EUCTR2009-016364-36-NL {published data only}
EUCTR2009-016364-36-NL. Injection of autologous
Kakuchaya 2011 {published data only} bone marrow cells into damaged myocardium of no-option
Kakuchaya T, Golukhova E, Eremeeva M, Chigogidze N, patients with ischemic heart failure: a randomized placebo
Aslanidi I, Shurupove I, et al.Accurate design of randomized controlled trail. - Cell therapy for ischemic heart failure.
placebo-controlled clinical trials for assessment of stem cell apps.who.int/trialsearch/trial.aspx?trialid=EUCTR2009-
effects on cardiac regeneration. European Heart Journal. 016364-36-NL (accessed 1 April 2013).
2011; Vol. 32:290: Abstract P1758.
EUCTR2011001117-13-GB {published data only}
Minjie 2011 {published data only} EUCTR2011001117-13-GB. Research study aiming at
Minjie L, Shihua Z, Sheng L, Shiliang J, Gang Y. Effects of investigating the potential effectiveness and safety of a
autologous bone marrow mononuclear cells transplantation treatment for chronic advanced heart failure of ischemic
through coronary artery bypass grafting in patients with origin. The treatment is based on patient own stem cells
old myocardial infarction assessed by MRI: A randomised, that will be collected and guided to the cardiac cells lineage
double-blind, placebo-controlled pilot trial. Heart. 2011; before being injected into the heart muscle. apps.who.int/
Vol. 97:A137A138. trialsearch/trial.aspx?trialid=EUCTR2011-001117-13-GB
Nasseri 2012 {published data only} (accessed 1 April 2013).

Nasseri BA, Kikucha M, Dandel M, Ebell W, Hetzer R, ISRCTN71717097 {published data only}
Stamm C. Autologous CD133+ bone marrow cells and ISRCTN71717097. Bone-marrow derived stem cell
bypass grafting for regeneration of ischemic myocardium: transplantation in patients undergoing left ventricular
restoration surgery for dilated ischaemic end-stage (bone marrow or mesenchymal) in chronic ischemic left
heart failure: a randomised blinded controlled trial ventricular dysfunction and heart failure secondary to
(TransACT 2). apps.who.int/trialsearch/Trial.aspx?TrialID= myocardial infarction (TAC-HFT) trial: A randomized,
ISRCTN71717097 (accessed 21 October 2010). double-blind, placebo-controlled study of safety and
ISRCTN75217135 {published data only} efficacy. American Heart Journal 2011;161(3):48793.
ISRCTN75217135. A pilot study to evaluate the efficacy of NCT00790764 {published data only}
combined transplantation of progenitor cells and coronary NCT00790764. Phase II combination stem cell therapy
artery bypass grafting (TOPCABG) N/A. apps.who.int/ for the treatment of severe coronary ischemia (CI).
trialsearch/trial.aspx?trialid=ISRCTN75217135 (accessed clinicaltrials.gov/show/NCT00790764 (accessed 21
21 October 2010). October 2010).
NCT00285454 {published data only} NCT00820586 {published data only}
NCT00285454. Cell repair in heart failure. NCT00820586. Intramyocardial delivery of autologous
clinicaltrials.gov/show/NCT00285454 (accessed 21 bone marrow. clinicaltrials.gov/show/NCT00820586
October 2010). (accessed 21 October 2010).
Tura BR, Martino HF, Gowdak LH, Dos Santon RR, Donndorf P, Kaminski A, Tiedemann G, Kindt G, Steinhoff
Dohmann HF, Krieger JE, et al.Multicenter randomized G. Validating intramyocardial bone marrow stem cell
trial of cell therapy in cardiopathies - MiHeart study. Trials therapy in combination with coronary artry bypass grafting,
2007;8:2. the PERFECT Phase III randomized multicentre trial:
NCT00418418 {published data only} study protocol for a randomized controlled trial. Trials
NCT00418418. Combined CABG and stem-cell 2012;13:99.
transplantation for heart failure. clinicaltrials.gov/show/ NCT01033617 {published data only}
NCT00418418 (accessed 21 October 2010). NCT01033617. IMPACT-CABG Trial: IMPlantation of
NCT00644410 {published data only} Autologous CD133+ sTem Cells in Patients Undergoing
Mathiasen AB, Jorgensen E, Qayyum E, Haack-Sorensen CABG. clinicaltrials.gov/show/NCT01033617 (accessed 21
M, Ekblond A, Kastrup J. Rationale and design of the October 2010).
first randomized, double-blind, placebo-controlled trial NCT01074099 {published data only}
of intramyocardial injection of autologous bone-marrow NCT01074099. Feasibility study of BMAC enhanced
derived Mesenchymal Stromal Cells in chronic ischemic CABG. clinicaltrials.gov/show/NCT01074099 (accessed 21
Heart Failure (MSC-HF Trial). American Heart Journal October 2010).
2012;164(3):28591. NCT01150175 {published data only}
NCT00690209 {published data only} NCT01150175. Direct endomyocardial injection of
NCT00690209. By pass surgery with stem cell therapy autologous bone marrow cells to treat ischaemic heart
in chronic ischemic cardiopathy. clinicaltrials.gov/show/ failure (END-HF). clinicaltrials.gov/show/NCT01150175
NCT00690209 (accessed 21 October 2010). (accessed 21 October 2010).
Mozid A, Arnous S, Yeo C, Brookman P, Preston M, NCT01214499. Prospective, controlled and randomized
Archbold A, et al.Head-to-head comparison of different clinical trial on cardiac cell regeneration with laser and
delivery methods of autologous bone marrow progenitor autologous bone marrow stem Cclls, in patients with
cells in chronic ischaemic heart failure. European Heart coronary disease and refractory angina. clinicaltrials.gov/
Journal. 2011; Vol. 32 (16 Suppl 1):456. European Society show/NCT01214499 (accessed 21 October 2010).
of Cardiology Congress, Stockholm, Sweden, 28 August - 1 NCT01267331 {published data only}
September 2010. NCT01267331. Cell therapy in patients with chronic
Yeo C, Locca D, Wong J, Burchell T, Preston M, Brookman ischemic heart disease undergoing cardiac surgery.
P, et al.Ejection fraction and NYHA class in heart failure in clinicaltrials.gov/show/NCT01267331 (accessed 21 August
the REGENERATE-IHD stem cell study: A comparison 2012).
between the intramyocardial intracoronary arms. American NCT01299324 {published data only}
Journal of Cardiology. 2009; Vol. 104 (6 Suppl 1): NCT01299324. Retrograde delivery of BMAC (bone
190D191D. marrow aspirate concentrate) for congestive heart failure.
Yeo C, Mathur A. Autologous bone marrow-derived stem clinicaltrials.gov/show/NCT01299324 (accessed 21 August
cells for ischemic heart failure: REGENERATE-IHD trial. 2012).
Regenerative Medicine 2009;4(1):11927. NCT01337011 {published data only}
NCT00768066 {published data only} NCT01337011. Intra-coronary versus intramyocardial
Trachtenberg B, Velazquez DL, Williams AR, McNiece I, application of enriched CD133pos autologous bone marrow
Fishman J, Nguyen K, et al.Rational and design of the derived stem cells (AlsterMACS). clinicaltrials.gov/show/
transendocardial injection of autologous human cells NCT01337011 (accessed 21 August 2012).
NCT01354678 {published data only} Additional references
NCT01354678. Intramyocardial multiple precision
injection of bone marrow mononuclear cells in myocardial Arnesen 2007
ischemia (IMPI). clinicaltrials.gov/show/NCT01354678 Arnesen H, Lunde K, Aakhus S, Forfang K. Cell therapy in
(accessed 21 August 2012). myocardial infarction. Lancet 2007;369(9580):21423.
NCT01442129 {published data only} Assmus 2002
NCT01442129. The effect of intramyocardial injection Assmus B, Schachinger V, Teupe C, Britten M, Lehmann
of mesenchymal precursor cells on myocardial function in R, Dobert N, et al.Transplantation of progenitor cells and
patients undergoing LVAD implantation. clinicaltrials.gov/ regeneration enhancement in acute myocardial infarction
ct2/show/NCT01442129 (accessed 21 August 2012). (TOPCARE-AMI). Circulation 2002;106(24):300917.
NCT01508910 {published data only}
Assmuss 2006
Povsic TJ, Junge C, Nada A, Schatz RA, Harrington
Assmuss B, Honold J, Schachinger V, Britten MB, Fischer-
RA, Davidson CA, et al.A phase 3, randomized, double-
Rasokat U, Lehmann R, et al.Transcoronary transplantation
blinded, active-controlled, unblinded standard of care
of progenitor cells after myocardial infarction. New England
study assessing the efficacy and safety of intramyocardial
Journal of Medicine 2006;355(12):122232.
autologous CD34+ cell administration in patients with
refractory angina: Design of the RENEW study. American Beltrami 2003
Heart Journal 2013;165(6):85461. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F,
Povsic TJ, Losordo DW, Story K, Junge CE, Schatz RA, Chimenti S, et al.Adult cardiac stem cells are multipotent
Harrington RA, et al.A phase 3, randomized, partially and support myocardial regeneration. Cell 2003;114(6):
blinded, active-controlled, study assessing the efficacy 76376.
and safety of intramyocaridal autologous CD34+ cell BHF 2008
administration in patients with refractory angina: Design British Heart Foundation. Coronary Heart Disease
of the RENEW study. Circulation. 2012; Vol. 126 (21 statistics. www.heartstats.org (last updated 27th March
Suppl 1):Abstract 11777. American Heart Association 2012 2009) (date accessed 20 November 2008).
Scientific Sessions and Resuscitation Science Symposium, 3
- 6 November 2012, Los Angeles, CA. Carr 2008
Carr CA, Stuckey DJ, Tatton L, Tyler DJ, Hale SJ, Sweeney
D, et al.Bone marrow-derived stromal cells home to and
NCT01615250. Implantation of peripheral stem cells
remain in the infarcted rat heart but fail to improve
in patient with ischemic cardiomyopathy (ISCIC).
function: an in vivo cine-MRI study. American Journal of
clinicaltrials.gov/show/NCT01615250 (accessed 21 August
Physiology. Heart and Circulatory Physiology 2008;295(2):
2012).
H53342.
Clifford 2012a
NCT01660581. Intracardiac CD133+ cells in patients with
Clifford DM, Fisher SA, Brunskill SJ, Doree C, Mathur
no-option resistant angina (Regent Vsel). clinicaltrials.gov/
A, Watt S, et al.Stem cell treatment for acute myocardial
show/NCT01660581 (accessed 21 August 2012).
infarction. Cochrane Database of Systematic Reviews 2012,
NCT01666132 {published data only} Issue 2. [DOI: 10.1002/14651858.CD006536.pub3]
NCT01666132. METHOD - Bone marrow derived
mononuclear cells in chronic ischemic disease. Clifford 2012b
clinicaltrials.gov/show/NCT01666132 (accessed 21 August Clifford DM, Fisher SA, Brunskill SJ, Doree C, Mathur
2012). A, Clarke MJ, et al.Long-term effects of autologous bone
marrow stem cell treatment in acute myocardial infarction:
factors that may influence outcomes. PLoS ONE 2012;7
NCT01727063. Cell therapy in severe chronic ischemic
(5):e37373.
heart disease (MiHeart). clinicaltrials.gov/show/
NCT01727063 (accessed 1 April 2013). Cox 2003
NCT01768702 {published data only} Cox DA, Stone GW, Grines CL, Stuckey T, Cohen DJ,
NCT01768702. Safety and efficacy of autologous Tcheng JE, et al.Outcomes of optimal or stent-like
cardiopoietic cells for treatment of ischemic heart failure. balloon angioplasty in acutemyocardial infarction: the
(CHART-1). clinicaltrials.gov/show/NCT01768702 CADILLAC trial. Journal of the American College of
(accessed 1 April 2013). Cardiology 2003;42(6):9717.
NTR2516 {published data only} Deb 2003
NTR2516. Injection of autologous bone marrow cells Deb A, Wang S, Skelding JKA, Miller D, Simper D, Caplice
into damaged myocardium of no-option patients with NM. Bone marrow-derived cardiomyocytes are present in
ischemic heart failure, a randomized placebo-controlled adult human heart: A study of gender-mismatched bone
trial. apps.who.int/trialsearch/trial.aspx?trialid=NTR2516 marrow transplantation patients. Circulation 2003;107(9):
(accessed 21 October 2010). 12479.
Fisher 2013 Martin-Rendon 2008b
Fisher SA, Doree C, Brunskill JS, Mathur A, Martin- Martin-Rendon E, Brunskill SJ, Hyde CJ, Stanworth SJ,
Rendon E. Bone marrow stem cell treatment for ischemic Mathur A, Watt SM. Autologous bone marrow stem cells
heart disease patients with no option of revascularization: a to treat acute myocardial infarction: A systematic review.
systematic review and meta-analysis. PLoS ONE 2013;8(6): European Heart Journal 2008;29(15):180718.
e64669. Martin-Rendon 2008c
Grajek 2010 Martin-Rendon E, Brunskill S, Dore C, Hyde C, Watt SM,
Grajek S, Popiel M, Gil L, Breborowicz P, Lesiak M, Czepczy Mathur A, et al.Stem cell treatment for acute myocardial
ski R, et al.Influence of bone marrow stem cells on left infarction. Cochrane Database of Systematic Reviews 2008,
ventricle perfusion and ejection fraction in patients with Issue 4. [DOI: 10.1002/14651858.CD006536.pub2]
acute myocardial infarction of anterior wall: randomized Mathur 2004
clinical trial: Impact of bone marrow stem cell intracoronary Mathur A, Martin JF. Stem cells and repair of the heart.
infusion on improvement of microcirculation. European Lancet 2004;364(9429):18392.
Heart Journal 2010;31(6):691702. Meyer 2006
Grines 1999 MeyerGP, Wollert KC, Lotz J, Steffens J, Lippolt P, Fichtner
Grines CL, Cox DA, Stone GW, Garcia E, Mattos LA, S, et al.Intracoronary bone marrow cell transfer after
Giambartolomei A, et al.Coronary angioplasty with or myocardial infarction: eighteen months follow-up data
without stent implantation for acute myocardial infarction. from the randomized, controlled BOOST (BOne marrOw
Stent primary angioplasty in myocardial infarction study transfer to enhance ST-elevation infarct regeneration) trial.
group. New England Journal of Medicine 1999;341(26): Circulation 2006;113(10):128794.
194956. Orlic 2001a
Higgins 2003 Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I,
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Anderson SM, et al.Bone marrow cells regenerate infarcted
Measuring inconsistency in meta-analyses. BMJ 2003;327 myocardium. Nature 2001;410(6829):7015.
(7414):55760. Orlic 2001b
Higgins 2011 Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk
Higgins JPT, Green S (editors). Cochrane Handbook I, Quaini F, et al.Mobilized bone marrow cells repair
for Systematic Reviews of Interventions Version 5.1.0 the infarcted heart, improving function and survival.
[updated March 2011]. The Cochrane Collaboration, Proceedings of the National Academy of Sciences USA 2001;98
2011. Available from www.cochrane-handbook.org. (18):103449.
Patel 2006
Janssens 2006
Patel AN, Geffner L, Vina RF, Saslavsky J, Urschel HC
Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C,
Jr, Kormos R, et al.Surgical treatment for congestive heart
Desmet W, et al.Autologous bone marrow-derived stem-cell
failure with autologous adult stem cell transplantation:
transfer in patients with ST-segment elevation myocardial
a prospective randomized study. Journal of Thoracic and
infarction: double-blind, randomised controlled trial.
Cardiovascular Surgery 2006;130(6):16318.
Lancet 2006;367(9505):11321.
Review Manager 2012
Jeevanantham 2012 Copenhagen: The Nordic Cochrane Centre, The Cochrane
Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba- Collaboration. Review Manager (RevMan). Version 5.2.
Surma EK, Dawn B. Adult bone marrow cell therapy Copenhagen: The Nordic Cochrane Centre, The Cochrane
improves survival and induces long-term improvement in Collaboration, 2012.
cardiac parameters: a systematic review and meta-analysis.
Schchinger 2006
Circulation 2012;126(5):55168.
Schchinger V, Erbs S, Elssser A, Haberbosch W,
Lunde 2006 Hambrecht R, Hlschermann H, et al.Intracoronary
Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, bone marrow-derived progenitor cells in acute myocardial
Egeland T, et al.Intracoronary injection of mononuclear infarction. New England Journal of Medicine 2006;355(12):
bone marrow cells in acute myocardial infarction. New 121021.
England Journal of Medicine 2006;355(12):1199209. Solomon 2005
Martin-Rendon 2008a Solomon SD, Anavekar N, Skali H, McMurray JJ,
Martin-Rendon E, Sweeney D, Lu FJ, Girdlestone J, Swedberg K, Yusuf S, et al.Influence of ejection fraction on
Navarrete C, Watt SM. 5-Azacytidine-treated human cardiovascular outcomes in a broad spectrum of heart failure
mesenchymal stem/progenitor cells derived from umbilical patients. Circulation 2005;112(24):373844.
cord, cord blood and bone marrow do not generate Stamm 2003
cardiomyocytes in vitro at high frequencies. Vox Sanguinis Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C,
2008;95(2):13748. Klinge H, et al.Autologous bone marrow-derived stem cell
transplantation for myocardial infarction. Lancet 2003;361 autologous intracoronary mononuclear bone marrow cell
(9351):456. transplantation in humans. 2002 Circulation;106(15):
Stamm 2007 19138.
Stamm C, Kleine HD, Choi YH, Dunkelmann S, Lauffs JA, Stuckey 2006
Loranzen B, et al.Intramyocardial delivery of CD133+ bone Stuckey DJ, Carr CA, Martin-Rendon E, Tyler DJ,
marrow cells and coronary artery bypass grafting for chronic Willmott C, Cassidy PJ, et al.Iron particles for noninvasive
ischemic heart disease: safety and efficacy studies. Journal of monitoring of bone marrow stromal cell engraftment into,
Thoracic and Cardiovascular Surgery 2007;133(3):71725. and isolation of viable engrafted donor cells from, the heart.
Stone 1998 Stem Cells 2006;24(8):196875.
Stone GW, Brodie BR, Griffin JJ, Morice MC, Constantini Traverse 2011
C, St Gor FG, et al.Prospective, multicenter study of the Traverse JH, Henry TD, Moye LA. Is the measurement of
safety and feasibility of primary stenting in acute myocardial left ventricular ejection fraction the proper end point for
infarction: in-hospital and 30 day results of the PAMI stent cell therapy trials? An analysis of the effect of bone marrow
pilot trial. Primary angioplasty in myocardial infarction mononuclear stem cell administration on left ventricular
stent pilot trial investigators. Journal of the American College ejection fraction after ST-segment elevation myocardial
of Cardiology 1998;31(1):2330. infarction when evaluated by cardiac magnetic resonance
Stone 2002 imaging. American Heart Journal 2011;162(4):6717.
Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Yoon 2005
Griffin JJ, et al.Comparison of angioplasty with stenting, Yoon YS, Wecker A, Heyd L, Parks JS, Tkebuchava T,
with or without abciximab, in acute myocardial infarction. Kusano K, et al.Clonally expanded novel multipotent stem
New England Journal of Medicine 2002;346(13):95766. cells from human bone marrow regenerate myocardium
Strauer 2002 after myocardial infarction. Journal of Clinical Investigation
Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez 2005;115(2):32638.

A, Sorg RV, et al.Repair of infarcted myocardium by Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Ang 2008
Methods Type of study: Parallel RCT.

Type of publication: Full paper.
Source of funding: British Heart Foundation (grant PG04050).
Study setting: Leicester, UK.
Number of centres: One.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: 21 intramyocardial (IM) 21 intra-
coronary (IC), 21 Control (C).
Number (N) of participants analysed (primary outcome) in each arm: 17 IM, 16 IC, 15 C.
Participants Description: Hospitalised participants undergoing elective cardiac surgery with at least 1
myocardial scar.
Age distribution (SD) in each arm: 64.7 (8.7) years IM, 62.1 (8.7) years IC, 61.3 (8.3)
years C.
Sex (% male) in each arm: 71.4% IM, 90.5% IC, 90% C.
Number of diseased vessels: multivessel.
Time from symptom onset to initial treatment: At least 6 weeks.
Statistically significant baseline imbalances between the groups? No
Interventions Intervention arms: IM and IC.

Type of stem cells: BMSC (mononuclear fraction)
Summary of stem cell isolation and type and route of delivery: Bone marrow aspiration
followed by density gradient centrifugation to enrich in mononuclear cells, infused via
the coronary artery (IC) or injected into the myocardium (IM).
Dose of stem cells: 86 (56) x 10 cells IM and 115 (73) x 10 cells IC.
Timing of stem cell procedure: Concomitant to CABG
G-CSF details: Not applicable
Comparator arm: Control, no placebo
Outcomes Primary outcomes: Improvement in systolic function of scar segments 6 mths after treat-
ment.
Secondary outcomes: Reductions in infarct size, global end-diastolic volume and end-
systolic volume, and improvement in stroke volume and LVEF. Postoperative compli-
cations, troponin I levels within 24 hours of surgery and clinical evaluation (assessment
of functional status and adverse events).
Outcome assessment points: Baselina and 6 months
Method(s) of outcome measurement: MRI
Notes
Risk of bias
Bias Authors judgement Support for judgement
Ang 2008 (Continued)
Random sequence generation (selection Unclear risk No method for generation of random se-
bias) quences was reported.
Allocation concealment (selection bias) Unclear risk No method of allocation concealment was
reported.
Blinding of participants and personnel High risk Participants and clinicians were not
(performance bias) blinded.
All outcomes
Blinding of outcome assessment (detection Low risk Outcomes assessors were blinded.
bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk Reasons for loss to follow-up and with-
All outcomes drawals were given, with attrition rates sim-
ilar in both treatment arms
Selective reporting (reporting bias) Low risk All outcomes mentioned in the Methods
were reported in results, although it would
be difficult to rule out selective reporting
Other bias Low risk No other sources of bias were identified.
Assmus 2006
Methods Type of study: Cross-over RCT with 3 arms.

Type of publication: Full paper
Source of funding:Supported by the Deutsche Forschungsgemeinschaft (FOR 501-1:
WA 146/2-1) The Foundation Leducq Transatlantic Network of excellence for Cardiac
Regeneration, The European Union European Vascular Genomics Network (LSHM-
CT-2003-503254) and the Alfried Krupp Stiftung.
Study setting:Frankfurt, Germany
Number of centres: One
Length of follow-up: 3 months
Number (N) of participants randomised to each arm: 28 in BMSC arm; 24 in CPC arm
and 23 in control arm.
Number (N) of participants analysed (primary outcome) in each arm: 24 in BMSC arm;
19 in CPC arm and 18 in control arm.
Participants Description: Hospitalised participants who have suffered from MI at least 3 months
previously.
Age distribution in each arm: 59 12 years old in BMSC arm; 54 12 years old in CPC
arm and 61 9 years old in control arm
Sex (% male) in each arm: 89% in BMSC arm; 79% in CPC arm and 100% in control
arm.
Number of diseased vessels: 1 (n = 7), 2 (n = 13), 3 (n = 8) in BMSC arm; 1 (n = 7), 2 (n
= 4), 3 (n = 12) in CPC arm and 1 (n = 2), 2 (n = 9), 3 (n = 12) in control arm
Assmus 2006 (Continued)
Time from symptom onset to initial treatment: Previous MI at least 3 months earlier. 100%
participants with previous MI.
Statistically significant baseline imbalances between the groups? No.
Interventions Intervention arm: BMSC and CPCs

Type of stem cells: BMSC, bone marrow mononuclear cells; CPCs, circulating progenitor
cells.
Summary of stem cell isolation and type and route of delivery: BMSC arm: 50 ml of bone
marrow aspirate was obtained under local anaesthesia on the morning of cell transplan-
tation. Mononuclear cells were isolated by Ficoll-gradient centrifugation. CPC arm:
Mononuclear cell fraction was isolated by Ficoll-gradient centrifugation of 270 mL of
venous blood and cultured for 3 days ex vivo. In both arms of the trial cells were delivered
intracoronarily.
Dose of stem cells: BMSC arm: 2.05 1.1 x 10 mononuclear cells. On average less than
1% were CD34-positive cells. CPC arm: 2.2 1.1 x 10 mononuclear cells. No measure
of CD34-positive cells in this fraction.
Timing of stem cell procedure: At least 3 months after last MI. In some cases concomitant
PCI
G-CSF details: No G-CSF administered.
Comparator arm: No cell infusion.
Outcomes Primary outcomes: Absolute change in global LVEF as measured by quantitative LV

angiography 3 months after cell infusion.
Secondary outcomes: 1. Quantitative variables relating to the regional LV function of the
target area, as well as LV volumes derived from serial LV angiograms.
2. Functional status assessed by NYHA classification.
3. Event-free survival defined as freedom from death, MI, stroke or rehospitalisation for
worsening heart failure.
4. Causes of rehospitalisation.
Outcome assessment points: Baseline and 3 months.
Method(s) of outcome measurement: LV angiography and MRI.
Notes
Risk of bias
Random sequence generation (selection Low risk Randomisation was performed using com-
bias) puterised simple random allocation with
known N. No blockwise randomisation
was performed
reported.
Blinding of participants and personnel High risk Clinicians were not blinded. Blinding of
(performance bias) participants was not reported
All outcomes
Blinding of outcome assessment (detection Low risk Quantitative analysis of angiograms was
bias) performed by an investigator who was
All outcomes blinded to the individual participants treat-
ment. The same for the MRI analysis
All outcomes drawals were given, with similar attrition
rates in both treatment arms
Assmus 2012

Type of publication: Abstract.
Source of funding: Not reported.
Study setting: Germany.
Number (N) of participants randomised to each arm: Not reported.
32 in control arm.
Participants Description: Hospitalised participants presenting post-infarction heart failure.

Age distribution in each arm: Not reported.
Sex (% male) in each arm: Not reported.
Number of diseased vessels: Not reported.
Time from symptom onset to initial treatment: Not reported.
Interventions Intervention arm: BMSC and shock wave.

Type of stem cells: Not reported.
Dose of stem cells: BMSC arm: Not reported.
Timing of stem cell procedure: 24 hours following shock wave.
Comparator arm: No cell infusion, only shock wave.
Outcomes Primary outcomes: None reported/

Secondary outcomes: LVEF, NYHA, AE, extent of myocardial scar tissue, systolic wall
thickening, mortality, hospitalisation.
Method(s) of outcome measurement: MRI for LVEF.
Notes
Risk of bias
reported.
Blinding of participants and personnel Unclear risk The trial was reported as double-blind
(performance bias) but it was unclear whether this included
All outcomes clinicians and/or participants
Blinding of outcome assessment (detection Unclear risk The trial was reported as double-blind
bias) but it was unclear whether this included
All outcomes clinicians and/or participants
Incomplete outcome data (attrition bias) Unclear risk The number randomised to each treatment
All outcomes arm was not stated and attrition rates could
not be determined
Chen 2006

Study setting: China.
Number (N) of participants randomised to each arm: 24 in BMSC arm and 24 in control
arm.
23 in control arm.
Participants Description: Hospitalised participants with severe ischaemic heart failure due to an iso-
lated chronic occluded left anterior descending artery.
Age distribution in each arm: 59.3 6.8 years old in BMSC arm; 57.8 7.2 years old in
control arm.
Sex (% male) in each arm: 88% in BMSC arm; 92% in control arm.
Time from symptom onset to initial treatment: 14 days following successful PCI.
Chen 2006 (Continued)
Interventions Intervention arm: BMSC and control.

Type of stem cells: Mesenchymal stem cells. 60 ml of autologous bone marrow were
aspirated under local anaesthesia from the ilium of all participants during the morning of
the 8th day after the PCI procedure and were then cultured for 7 days. BM mesenchymal
stem cells were harvested and washed three to four times with heparinised saline. 2 hours
before transplantation, the stem cell suspension was mixed with heparin, filtered and
prepared for implantation. Cell viability was > 92%.
Dose of stem cells: BMSC arm: 5 x 10 cells
Timing of stem cell procedure: 14 days following successful PCI and 7 days after bone
marrow aspiration
Comparator arm: Not described.
Outcomes Primary outcomes: None reported

Secondary outcomes: reversible defects, metabolic equivalents, exercise, LVEF, NYHA,
mortality.
Method(s) of outcome measurement: SPECT.
Notes
Risk of bias
reported.
Blinding of participants and personnel High risk Participants and clinicians were not
(performance bias) blinded.
All outcomes
Blinding of outcome assessment (detection Unclear risk Not reported.

bias)
All outcomes
Chen 2006 (Continued)
Erbs 2005

Source of funding: Supported by Heart Center Leipzig GmbH, University of Leipzig
Study setting: Leizpig, Germany.
Number (N) of participants randomised to each arm: BMSC arm: 14; Control arm: 14.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 12;
Control arm: 11.
Participants Description: Participants with chronic total artery occlusion with clinical signs of my-
ocardial ischaemia and local wall motion abnormalities.
Age distribution in each arm: BMSC arm: 63 7 years old; Control arm: 61 9 years
old.
Sex (% male) in each arm: BMSC arm: 71%; Control arm: 86%.
Number of diseased vessels: BMSC arm: 1 (n = 8), 2 (n = 4), 3 (n = 2); Control arm: 1 (n
= 6), 2 (n = 5), 3 (n = 3).
Time from symptom onset to initial treatment: Complete total obstruction - defined as an
obstruction of a native coronary artery for more than 30 days with no luminal continuity
and with TIMI flow grade 0 or 1.
Interventions Intervention arm: BMSC.

Type of stem cells: mobilised bone marrow mononuclear cells.
Summary of stem cell isolation and type and route of delivery: All participants subcutaneously
injected twice a day with filgrastin (G-CSF, 300 microg) over 4 days in order to increase
the amount of CPCs in the blood. At day 4, 400 ml of venous blood were collected
from all participants, MNC were purified and ex vivo-cultured for 4 days in endothelial-
specific medium to select CPCs. MNCs were isolated from 400 ml of venous blood
by density gradient centrifugation (Histopaque-1077). Immediately after isolation, total
MNC were plated on gelatine-coated cell culture flasks with a cell density of 1 x 10
cells/cm. Cells were maintained for 4 days in endothelial basal medium supplemented
with EGM SingleQuots and 10% human serum, collected from each individual partic-
ipant. Additionally the cell culture medium was supplemented with ascorbic acid (final
concentration 75 ng/mL) and hydrocortisone (0.2 microg/mL). After 4 days of culture
nonadherent cells were removed by a thorough washing with PBS and the adherent
cells were detached with trypsin/EDTA. The collected cells were washed twice with PBS
containing 2 mmol/L EDTA and resuspended in a final volume of 20 ml physiological
NaCl supplemented with 10% autologous participant serum. Cells were administered
intracoronarily.
Dose of stem cells: 69 14 x 10 CPCs (range 22 x 10 to 200 x 10 ).
Timing of stem cell procedure: 10 1 days following successful recanalisation.
G-CSF details: 300mg of G-CSF administered for 4 days to all participants
Comparator arm: Placebo, cell-free serum solution.
Erbs 2005 (Continued)
Outcomes Primary outcomes: LV function

Secondary outcomes: Assessment of coronary endothelial function, myocardial viability
(number of myocardial segments with hybernation), regional wall motion, LV mass
(myocardial mass; infarct size). Clinical outcomes, restenosis, coronary endothelium
function, myocardial viability, number of hibernating segments in myocardium.
Outcome assessment points: Baseline, 3 and 15 months.
Method(s) of outcome measurement: MRI.
Notes
Risk of bias
reported.
Blinding of participants and personnel Low risk Neither the interventionalist nor the clini-
(performance bias) cal investigator were aware of whether par-
All outcomes ticipants received CPCs or serum. All par-
ticipants received G-SCF and cells were iso-
lated from all participants
Blinding of outcome assessment (detection Low risk Image analysis assessors remained blinded
bias) after the results at 3 months follow-up.
All outcomes Other assessors were blinded to 3 months
only
Hendrikx 2006

Study setting: Hasselt, Belgium.
Control arm: 10.
Participants Description: Elective CABG surgery; transmural myocardial infarction on ECG and
akinesia or dyskinesia in part of the left ventricle as shown by angiography.
Age distribution in each arm: BMSC arm: 63.2 8.5 years old; Control arm: 66.8 9.2
years old.
Number of diseased vessels: BMSC arm: 1 (n = 0), 2 (n = 2), 3 (n = 8); Control arm: 1 (n
= 1), 2 (n = 2), 3 (n = 7).
Time from symptom onset to initial treatment: BMSC arm: 217 (162) days and control
arm: 213 (145) days between occurrence of MI and time of CABG (and treatment).
Interventions articipanIntervention arm: BMSC.

Type of stem cells: BMSC, bone marrow mononuclear cells.
Summary of stem cell isolation and type and route of delivery: 40 mL of bone marrow was
aspirated under local anaesthesia from the participants iliac crest, the day before surgery.
BMSC were immediately isolated by density gradient centrifugation using Lymphoprep.
Isolated cells were washed twice with saline and subsequently resuspended in X-Vivo
15 medium (Cambrex) supplemented with 2% autologous serum. This cell suspension
was transferred to Teflon bags at a concentration of approximately 1 x 10 cells/mL for
overnight cultivation. The next day, cells were harvested and washed 3 times before finally
being suspended in 10 mL heparinised saline. 10 mL of cell suspension were injected
into the border zone of the infarct with 29-gauge myoinjector syringes containing 0.
5 mL of cell suspension. Multiple punctures were performed with prevent needles to
make injections parallel to the epicardium and avoid delivery of cells into the ventricular
cavity.
Dose of stem cells: 60.25 (31.35) x 10 cells with > 95% viability and over 73% recov-
ery. Containing 1.42 (0.99)% CD34-positive cells and 76.37 (44.47) CFU-GM/ 10
mononuclear cells.
Timing of stem cell procedure: Approximately 24 hours following bone marrow aspiration;
217 (162) days post-AMI
G-CSF details: None.
Comparator arm: Placebo; a similar volume of heparinised saline was injected in the
control group
Outcomes Primary outcomes: global LVEF change and regional wall thickening changes in the infarct
area.
Secondary outcomes:Changes in metabolic activity measured by thallium scintigraphy.
Hendrikx 2006 (Continued)
Notes
Risk of bias
Random sequence generation (selection Low risk 1:1 randomisation was carried out using se-
bias) quentially-numbered sealed envelopes
Allocation concealment (selection bias) Low risk Sealed envelopes.
Blinding of participants and personnel Low risk Both groups had bone marrow aspirated.
(performance bias) The BM group had bone marrow isolated
All outcomes the day before surgery from the iliac crest.
The control group had bone marrow aspi-
rated from the sternum during the opera-
tion
The surgeon conducting surgery was un-
aware whether cells or only saline was in-
jected
Blinding of outcome assessment (detection Low risk Cardiac MR images were analysed by an
bias) investigator blinded to treatment assign-
All outcomes ment. For Thallium Scintigraphy, 2 inves-
tigators independently analysed data, and
were blinded to treatment assignment
Honold 2012

Control arm: 9.
Participants Description: Hospitalised participants with CAD and a previous MI at least 3 months
prior to cell therapy with a well demarcated LV regional wall motion abnormality.
Age distribution in each arm: BMSC arm: 53.4 12.3 years old; Control arm: 58.8 7.
3 years old.
Number of diseased vessels: BMSC arm: 1 (n = 10), 2 (n = 6), 3 (n = 6); Control arm: 1
(n = 4), 2 (n = 2), 3 (n = 4).
Time from symptom onset to initial treatment: At least 3 months from previous MI.
Interventions Intervention arm: BMSC

Type of stem cells: EPC from bone marrow aspirates.
Summary of stem cell isolation and type and route of delivery: G-CSF was administered to
the participants for 5 days. 270 ml of peripheral blood was drawn. Mononuclear cells
were isolated using a Ficoll gradient centrifugation and cells were resuspended in X-vivo
15 medium with 1 ng/ml carrier-free human recombinant VEGF, atorvastin and 20%
human serum drawn from each individual participant. Cells were cultured ex vivo for 4
days to enrich in endothelial progenitor cells (uptake of LDL).
Dose of stem cells: 29 12 x 10 .
Timing of stem cell procedure: % days following G-SCF administration and 4 days fol-
lowing bone marrow aspiration and cell culture
G-CSF details: Yes, 5 days prior to cell isolation.
Comparator arm: no placebo.
Outcomes Primary outcomes: Safety and efficacy.

Secondary outcomes: Global and regional LV function and volumes after 3 months, de-
termined by both LV angiography and MRI. Clinical parameters like functional NYHA
class, cardiopulmonary exercise testing, and N-terming aprohormone of BNP serum
levels were obtained during a 5-year follow-up period.
Notes
Risk of bias
Honold 2012 (Continued)
reported.
Blinding of participants and personnel Unclear risk Blinding of clinicians and participants was
(performance bias) not reported.
All outcomes
Blinding of outcome assessment (detection Unclear risk MRI independent observers were blinded;
bias) blinding was not reported for other out-
All outcomes comes
Hu 2011

Source of funding: Key project in the National Science and Technology Pilar programme
during the Eleventh 5-year plan period (2006BAJ01A09), Basic scientific research fund
of the National Scientific Institute 2009-2011
Study setting: Beijing, China.
Control arm: 28.
Participants Description: People between 18 and 75 years of age, suitable for CABG with CHF due
to severe ischaemic cardiomyopathy.
years old.
Sex (% male) in each arm: 93.3% (both arms pooled).
Number of diseased vessels: BMSC arm: 3; Control arm: 3.
Time from symptom onset to initial treatment: At least 3 month from last MI.
Statistically significant baseline imbalances between the groups? No
Hu 2011 (Continued)

Type of stem cells: BMSC from bone marrow aspirates.
Summary of stem cell isolation and type and route of delivery: After anaesthesia but before
CABG, 60 ml of BM was aspirated from the participants iliac crest and diluted with
normal saline solution. The mononuclear cells were isolated using Ficoll density gradient
centrifugation according to good manufacturing practice regulations and resuspended in
10 ml of saline solution. The cell suspension was filtered by a 70-um cell strainer before
transplantation. The cells were counted under a light microscope and the viability was
assessed by trypan blue dye. The final suspension of BMMNCs contained 10 ml MN
cells. Cells were delivered via the grafted vessel (saphenous vein graft).
Dose of stem cells: mean 13.17 10.66 x 10 .
Timing of stem cell procedure: Within 24 hours and during CABG.
G-CSF details: No.
Comparator arm: The placebo solution was a mixture of 8 ml of saline solution and 2 ml
of the participants own serum
Outcomes Primary outcomes: Changes in LVEF.

Secondary outcomes: LVEDV index (MRI); LVESV index (MRI); wall motion score index
(Echo); perfusion score (SPECT), 6-mins walking test and BNP value.
Notes
Risk of bias
Random sequence generation (selection Low risk A randomisation table was generated by
bias) statistical software.
reported.
Blinding of participants and personnel Low risk The study processes were blinded to sur-
(performance bias) geons, participants, co-ordinators and in-
All outcomes vestigators who were responsible for partic-
ipant assessments.
Blinding of outcome assessment (detection Low risk The study processes were blinded to sur-
bias) geons, participants, co-ordinators and in-
All outcomes vestigators who were responsible for partic-
ipant assessments.
Hu 2011 (Continued)
Kang 2006

Source of funding: Supported by a grant from Stem Cell Research Center, Republic of
Korea (SC3150, to Dr Y-B Park)
Study setting: Seoul, Korea.
Control arm: 16.
Participants Description: People with new STEMI over 14 days ago who were successfully revascu-
larised with DES (Drug Eluting Stents) in the culprit lesion (defined in the paper as old
MI).
years old.
Number of diseased vessels: BMSC arm: 1 (n = 6); 2 (n = 7); 3 (n = 3); Control arm: 1 (n
= 5); 2 (n = 3); 3 (n = 8).
Time from symptom onset to initial treatment: > 14 days post-MI.

Type of stem cells: Mobilised BMSC using G-SCF for 3 days.
Summary of stem cell isolation and type and route of delivery: Following G-CSF treatment
for 3 days by apheresis. Peripheral blood stem cells were mobilised by daily injection of
G-CSF at 10 g/Kg body weight for 3 days. PBSC were then collected on day 4 with
COBE spectra apheresis system using mononuclear cell collection methods. Cell dose
infused were 1 - 2 x 10 monocytes per participant. Cells were infused via the coronary
artery using an over-the-wire balloon catheter.
Dose of stem cells: 1 - 2 x 10 monocytes per participant.
Timing of stem cell procedure: BMSC arm: 514 524 days after revascularisation; Control
arm: 960 832 days after revascularisation
G-CSF details: Daily injection of G-CSF at 10 g/Kg body weight for 3 days
Comparator arm: Control participants did not received G-CSF or placebo.
Outcomes Primary outcomes: The primary endpoint to evaluate efficacy was the change in LVEF.
Secondary outcomes: Changes in LV volume, myocardial perfusion measured by coronary
flow reserve (CFR), and the development of major adverse cardiac events: death, new
MI, revascularisation, or hospitalisation because of aggravation of ischaemia or heart
Kang 2006 (Continued)
failure.
Notes
Risk of bias
Random sequence generation (selection Low risk A randomisation table was used.
bias)
reported.
Blinding of participants and personnel High risk Not blinded.

(performance bias)
All outcomes
Blinding of outcome assessment (detection Unclear risk Angiography conducted by independent

bias) blinded specialist but other blinding not
All outcomes reported (after randomisation, study pro-
cesses were not blinded)
Losordo 2007

Source of funding: Supported in part by NIH grants and by a grant from Baxter Healthcare.
Biosense-Webster provided the mapping and injection catheters for this study at no extra
cost
Study setting: USA.
Number of centres: multicentre.
Number (N) of participants randomised to each arm: BMSC HD arm: 6; BMSC MD arm:
6; BMSC LD arm: 6 and Control arm: 6.
Number (N) of participants analysed (primary outcome) in each arm: BMSC HD arm: 6;
BMSC MD arm: 6; BMSC LD arm: 6 and Control arm: 6
Participants Description: Participants with CCS class III - IV symptomatic of chronic refractory
angina.
Age distribution in each arm: Mean 62.4 (range 48 to 84 years) for all groups.
Sex (% male) in each arm: 80% for all arms.
Number of diseased vessels: not reported.
Time from symptom onset to initial treatment: not reported, not applicable.
Statistically significant baseline imbalances between the groups? None reported.
Interventions Intervention arm: Low Dose (LD), Medium Dose (MD) and High Dose (HD) of CD34+
cells.
Type of stem cells: CD34+ cells from mobilised peripheral blood.
Summary of stem cell isolation and type and route of delivery: G-CSF was given to all
participants at 5 g/kg for 5 days. Leukoapheresis was performed on the 5th day for
collection of mononuclear cells. The cells were stored overnight at 4C, and the following
morning the CD34+ fraction was purified on a commercially available device (isolex 300i,
Baxter Healthcare) according to manufacturers instructions. Cells were then subjected
to testing and were required to meet lot-release criteria. Once passed, the participants
underwent NOGA electromechanical mapping and intramyocardial injection of CD34+
cells suspended in saline plus 5% autologous serum, versus cell diluent using the NOGA
Myostar catheter. The dose was divided into 10 injections of 0.2 mL per injection.
Dose of stem cells: 5 x 10 CD34 cells/kg (LD), 1 x 10 CD34 cells/kg (MD) and 5 x 10
CD34 cells/kg (HD).
Timing of stem cell procedure: On day 6 following G-CSF administration and within 24
hours of cell isolation
G-CSF details: G-CSF was given to all participants at 5 g/kg for 4 - 5 days
Comparator arm: Placebo. G-CSF was given to all participants at 5 g/kg for 4 - 5 days.
No cells were injected, only saline (0.9 % NaCl) with 5% autologous plasma
Outcomes Primary outcomes: Not reported.

Secondary outcomes: Safety analysis (AEs), Efficacy (angina frequency, NTG use, exercise
tolerance, CCS class, SPECT perfusion imaging, QOL testing).
Method(s) of outcome measurement: Angina frequency and CCS angina class.
Notes
Losordo 2007 (Continued)
Risk of bias
Random sequence generation (selection Low risk Randomisation codes were established by
bias) the study statistician
reported.
Blinding of participants and personnel Low risk All participants were administered G-CSF
(performance bias) 4 - 5 days prior to treatment. All had
All outcomes CD34+ cells collected and all were injected
with a solution in a syringe that was iden-
tical for treatment and control
Blinding of outcome assessment (detection Low risk Randomisation codes were only revealed to
bias) the stem cell laboratory technician respon-
All outcomes sible for separating the cells into aliquots or
preparing the placebo material
Incomplete outcome data (attrition bias) Low risk All randomised participants were included
All outcomes at follow-up.
Losordo 2011
Methods Type of study:Parallel RCT.

Source of funding: Baxter Healthcare sponsored the study and was responsible for the
conduct of the investigation, with oversight provided by the principle investigator and
the scientific advisory board
Study setting: USA.
Number of centres: 26 centres.
Number (N) of participants randomised to each arm: BMSC HD arm: 56; Control arm:
56.
Number (N) of participants analysed (primary outcome) in each arm: BMSC HD arm: 56;
Control arm: 55.
Participants Description: Participants with CCS class III - IV symptomatic of chronic refractory
angina.
Age distribution in each arm: BMSC HD arm: 59.8 9.2 yrs; Control arm: 61.8 8.5.
Sex (% male) in each arm: BMSC HD arm: 87.5%; Control arm: 89.3%.
Number of diseased vessels: not reported.
Time from symptom onset to initial treatment: At least 40 days from previous MI.
Statistically significant baseline imbalances between the groups? Yes, Cardiovascular risk
factors (HTN, smoking, DM); angina episodes per week
Interventions Intervention arm: Low Dose (LD) and High Dose (HD) of CD34+ cells.
Type of stem cells: CD34+ cells from mobilised peripheral blood.
Summary of stem cell isolation and type and route of delivery: G-CSF was given to all par-
ticipants at 5 g/kg for 4 - 5 days. On day 5 leukapheresis was performed. The following
day mononuclear cells were collected and CD34+ cells enriched using a commercially
available device (Isolex 300im) magnetic cell separation system. Cell suspension with
> 70% viability and > 50% CD34+ cells were given at 2 doses of body weight with a
maximum of 100 kg. Cell suspension was diluted in saline (0.9 % NaCl) with 5% autol-
ogous plasma. Cells were injected into the myocardium. The injection was performed
by NOGA mapping and at 10 sites (0.2 cc/ site) using a NOGA Myostar catheter.
Dose of stem cells: 1 x 10 CD34 cells/kg and 5 x 10 CD 34 cells/kg.
Timing of stem cell procedure: At least 3 months following MI.
G-CSF details: G-CSF was given to all participants at 5 g/kg for 4 - 5 days
Comparator arm: Placebo. G-CSF was given to all participants at 5 g/kg for 4 - 5 days.
No cells were injected, only saline (0.9 % NaCl) with 5% autologous plasma
Outcomes Primary outcomes: Angina frequency 6 months after treatment.

Secondary outcomes: Secondary efficacy endpoints included exercise tolerance testing, use
of antianginal medication, CCS functional class, health-related QOL (Seattle Angina
Questionnaire, SF-36 Survey, Dyspnea Questionnaire, Euro 5 Questionnaire); combined
rate of MACE, SPECT, cardiac MRI (in a sub-study). Safety endpoints included adverse
event reporting, chest Xray and echo and lab screening.
Method(s) of outcome measurement: CCS functional class
Notes
Risk of bias
Random sequence generation (selection Low risk Participants were randomly assigned to 1 of
bias) 3 treatment groups via a telephone call-in
and an interactive voice-response system.
Allocation concealment (selection bias) Low risk The cell-processing laboratory at each cen-
tre was responsible for making the ran-
domisation call and preparing the CD34+
cells or control injection accordingly
Blinding of participants and personnel Low risk All participants were administered G-CSF
(performance bias) 4 - 5 days prior to treatment. All had
All outcomes CD34+ cells collected and all were injected
with a solution in a syringe that was iden-

tical for treatment and control
Blinding of outcome assessment (detection Low risk Double-blind study. An independent com-
bias) mittee conducted the analysis. All study
All outcomes personnel remained blinded until the end
of the study
Patel 2005

Study setting: Rosario, Argentina.
Control arm: 10.
Participants Description: Participants with documented ischaemic heart failure requiring revasculari-
sation, undergoing off-pump CABG.
years old.
Time from symptom onset to initial treatment: At least 7 days after the last MI, all partici-
pants had history of MI and revascularisation by PCI.
Interventions Intervention arm: CD34+ cells.

Type of stem cells: CD34+ cells.
Summary of stem cell isolation and type and route of delivery: BM was harvested from the
iliac bone in a sterile fashion after achievement of general anaesthesia. To minimise the
anaesthetic time, a special multihold harvest needle with a 60 mL syringe was designed.
It was introduced into the iliac bone between both posterior iliac spines at both sides.
500 - 600 mL of BM with a minimal number of puncture sites harvested. At least 250
mL BM must be harvested to continue with the protocol. Harvested BM was placed in
a blood bag with 10,000 U of heparin sulfate and 400 microm of lysine acetylsalicylate
Patel 2005 (Continued)
to avoid platelet clumping. The BM was filtered on a 500 microm filter followed by
a 200 microm filter. The resulting solution was mixed with hydroethylstarch 6%. The
supernatant was centrifuged at 400 g for 15 mins. The cellular pellet was resuspended in
PBS. The cell solution was mixed 3:1 with a solution of 155 mmol/L NH Cl, 10 mmol/
L KHCO3 and 0.1 mmol/L EDTA and set for 5 mins at room temperature. Solution was
then centrifuged at 400 g for 10 mins. The pellet was washed with PBS and resuspended.
The cell suspension was placed over Ficoll Paque (1.077 density) 4:1 and centrifuged
at 400 g for 30 mins. The upper layer was aspirated, leaving the mononuclear cell layer
at the interphase. The interphase cells were transferred to a new conical tube with PBS
and centrifuged at 300 g for 10 mins. The supernatant was completely removed, and
the cell pellet was resuspended in PBS. Cell counts were performed, and the magnetic
labeling with Isolex 300i was performed to obtain an enriched product of at least 70%
CD34+ cells. The resulting cell solution was resuspended in 30 mL of the participants
own plasma and 10,000 U of heparin sulphate. 30 ml of cell preparation were delivered
in 1 ml aliquots over a 2-second period. The injections into the myocardium were spaced
1cm apart and spaced to avoid coronary vessels. Injections were 3 - 5 mm in depth.
Dose of stem cells: Median of 22 x 10 CD34+ cells.
Timing of stem cell procedure: At least 7 days following the last MI.
G-CSF details: No.
Comparator arm: Control , no placebo.

Secondary outcomes: Global LVEF, LVEDV, NYHA class.
Outcome assessment points: Baselina and 1, 3 and 6 months.
Method(s) of outcome measurement: SPECT or Echocardiography.
Notes
Risk of bias
Random sequence generation (selection Low risk A person who did not participate in the trial
bias) had the choice of picking a coloured ball
(red = BMSC arm; blue = control arm)
Allocation concealment (selection bias) Unclear risk A person who did not participate in the trial
had the choice of picking a coloured ball
(red = BMSC arm; blue = control arm)
Blinding of participants and personnel Low risk The clinicians were not blinded, but the
(performance bias) study was blinded for the participants and
All outcomes reviewers of the imaging studies (cardiolo-
gists)
Blinding of outcome assessment (detection Low risk The study was blinded for the participants
bias) and reviewers of the imaging studies (car-
All outcomes diologists)
Patel 2005 (Continued)
Perin 2011

Source of funding:No extramural funding was used to support this work; the authors have
no disclosures, no funding and no relationship with industry to report.
Study setting: Texas and Minneapolis, USA.
Number of centres: Two.
Control arm: 10.
Participants Description: People with ischaemic heart failure (HF) and no option of revascularisation.
Age distribution in each arm: BMSC arm: 56.3 8.6 years old; control arm: 60.5 6.4
years old.

Type of stem cells: BMSC.
Summary of stem cell isolation and type and route of delivery: 50 ml of BM was aspirated
from the posterior iliac crest, approximately 4 hours before the cells were injected into the
heart. Mononuclear cells were isolated using a density gradient centrifugation, washed in
heparinised saline containing 5% human serum albumin and passed through a mesh. 3 x
10 cells were resuspended in 3 ml saline containing serum albumin (5%). 3ml were pre-
served for further studies. 3 hours after bone marrow aspiration, participants underwent
an electromechanical mapping to select myocardial segments for cell injection. Cells were
injected into viable myocardium (> 6.9 mV unipolar voltage). Electromechanical maps
comprised an average of 87 16 points. Each injection of 2 million cells was delivered
in a volume of 0.2 mL. Participants received an average of 15 cell injections in a mean
of 6 1 segments.
Dose of stem cells: 2 x 10 cells.
Timing of stem cell procedure: Within 24 hours of harvesting the bone marrow.
G-CSF details: None.
Comparator arm: Electromechanical mapping using the NOGA system, intramyocardial
injection. A simulated injection procedure was performed, but no placebo material was
Perin 2011 (Continued)
administered to participants in this arm.
Outcomes Primary outcomes: Safety of cell injections was assessed at 3 time points: i) early safety
(periprocedural and up to 2 weeks); 2) at 3 months, and 3) at 6 months. Major adverse
events were adjudicated (hospitalisation, arrhythmia, exacerbation of congestive HF,
acute coronary syndrome, MI, stroke or death).
Secondary outcomes: Efficacy: at 3 and 6 months, functional status was assessed by MVO ,
SPECT and 2-D echocardiography. At 6 months, participants also underwent coronary
and LV angiography and electromechanical mapping. Quality of life was assessed at
baseline and 6-month follow-up.
Method(s) of outcome measurement: Not applicable.
Notes
Risk of bias
Random sequence generation (selection Low risk Numbered sealed envelopes were used.
bias)
Allocation concealment (selection bias) Low risk Numbered sealed envelopes were used.
Blinding of participants and personnel Low risk Clinicians were not blinded, but partici-
(performance bias) pants received a simulated mock injection
All outcomes procedure (although unclear whether BM
aspiration undertaken in control group)
Blinding of outcome assessment (detection Low risk Efficacy studies were read by an indepen-
bias) dent blinded investigator. Blinding was
All outcomes maintained until the end of the assessment
Perin 2012a

Source of funding: NHLBI under co-operative agreement 5 U01 HL087318-04. In part by
NHLBI contracts N01-HB37164 and HHSN268201000008C awarded to the Molec-
ular and Cellular Therapeutics Facility, University of Minnesota and NO1-HB-37163
and HHSN268201000007C awarded to the Cell Processing Facility , Baylor College
of Medicine and Nationall Centre for Research Resources CTSA grant UL1 TR000064
awarded to the University of Florida. The CCTRN also acknowledges its industry part-
ners, Biosafe, Biologics Delivery Systems Group and Cordis Corporation for their con-
tributions of equipment and technical support during the conduct of the trial. [Full
details and conflict of interest declarations in the paper]
Study setting: USA.
Number of centres: Five.
Control arm: 28.
Participants Description: People with chronic IHD and LV dysfunction who have no other revascu-
larisation options.
Age distribution in each arm: BMSC arm: 63.95 10.90 years old; Control arm: 62.32
8.25 years old.
Sex (% male) in each arm: BMSC arm: 86.89%; Control arm: 93.65%.

Type of stem cells: BMSC
Summary of stem cell isolation and type and route of delivery: Approx. 80 - 100 mL of BM
was aspirated from the iliac crest using standard techniques. The aspirate was processed
using Ficoll with a closed, automated cell processing system (Sepax). Composition of
CD34 and CD133 cells was determined by flow cytometry.Cells passed stipulated lot
release criteria, included viability (> 70%) and sterility. The target dose was 100 x 10
total BMCs. The BMC final product was suspended in normal saline containing 5%
human serum albumin and adjusted to a concentration of 100 x 10 cells in 3 mL
distributed into 3 1 mL syringes. The placebo group received a cell-free suspension in
the same volume. Mean (SD) volume of BM harvested was 93.7 (8.3) mL. Total dose of
100 x 10 contained an average of 2.6% of CD34 cells and 1.2% of CD133 cells. Cells
were delivered by intramyocardial injection. The cell-containing or cell-free preparation
was delivered to viable myocardial regions identified during electromechanical mapping
of the LV endocardial surface (NOGA).
Dose of stem cells: 100 x 10 BMSC.
Timing of stem cell procedure: Within 12 hours of cell harvest.
G-CSF details: No.
Comparator arm: Approx. The placebo group received a cell-free suspension in the same
volume. Mean (SD) volume of BM harvested was 93.7 (8.3) mL
Perin 2012a (Continued)
Outcomes Primary outcomes:

1. Change in LVESV.
2. Change in maximal oxygen consumption.
3. Change in defect size on SPECT.
Secondary outcomes: BM mononuclear cell characteristics, LVESV, LVEDV, myocardial
oxygen consumption, % reversibility, LVEF, clinical improvement at 6 months; change in
CCS anginal score, NYHA class, decrease in weekly need for antianginal meds; MACEs.
Method(s) of outcome measurement: Echocardiography and SPECT.
Notes
Risk of bias
Random sequence generation (selection Low risk Randomisation was computer-generated

bias) and used variable block sizes of 6 or 9, ran-
domly selected and stratified by centre
Allocation concealment (selection bias) Low risk Treatment assignment was masked to all
but 1 designated cell processing team mem-
ber at each centre not involved in partici-
pant care
Blinding of participants and personnel Low risk All caregivers and participants were masked
(performance bias) to treatment.
All outcomes
Blinding of outcome assessment (detection Low risk Double-blind study: MACEs were as-
bias) sessed by 2 independent cardiologists not
All outcomes affiliated with any clinical site and masked
to treatment assignment
Perin 2012b

Source of funding: This work was supported solely by Aldagen, Inc, Durham, NC
Study setting: Texas, USA.
Number (N) of participants analysed (primary outcome) in each arm:BMSC arm: 10;
Control arm: 10.
Participants Description: Advanced ischaemic heart failure and no other option for revascularisation.
years old.
Time from symptom onset to initial treatment: At least 1 month from the last MI.
Interventions Intervention arm: ALDH+ cells.

Type of stem cells: ALDH+ cells.
Summary of stem cell isolation and type and route of delivery: 100 mL ( 20) BM was har-
vested from the iliac crest under local anaesthesia unless institutional guidelines required
general anaesthesia. BM cells were depleted of CD15 and glycophoris A-expresing cells
using immunomagnetic beads (EasySep). The cells were reacted with ALDH substrate
and ALDH bright (+) cells were isolated by using a cell sorter (MoFlo or FACSAria)
. After centrifugation, the cells were resuspended in 3.5 mL 5% pharmaceutical grade
human serum albumin. The final products were transferred to a 3 mL fluorinated ethy-
lene propylene bag with a needles entry port. ALDH (+) cells were administered in-
tramyocardially via a NOGA Myostar catheter. Cells comprised a mean of 0.74% /0 0.
28% of the nucleared BM cells in the unprocessed aspirates from participants (median 0.
73%, range 0.35% to 1.16%). Cell injections were targeted to areas of the myocardium
identified as ischaemic or SPECT and as viable by EMM.
Dose of stem cells: 15 injections in a volume of 0.2 mL per injection. Mean number of
nucleated cells administered to the treatment group was 2.94 1.58 x 10 cells (median
2.78 x 10 , range 0.53 - 5.42 x 10 ). When the total cell doses were corrected for the
proportion of ALDH (+) cells in the cell product, the mean number of ALDH (+) cells
administered to the cell treatment group was 2.37 1.31 x 10 (median 2.27 x 10
, range 0.35 - 4.42 x 10 ).
Timing of stem cell procedure: Products manufactured at Aldagen were administered within
50 - 55 hours of BM aspiration, whereas those produced locally at the University of
Texas were administered within 30 - 36 hours of aspiration.
G-CSF details: No.
Comparator arm: Control participants underwent the same procedures but received
transendocardial injections of placebo solution (5% albumin) instead of the cell prepa-
ration
Outcomes Primary outcomes: Safety, assessed by MACE and hospitalisations: periprocedural (up to
2 weeks) and 6 months.
Secondary outcomes: Efficacy, evaluated by clinical status, LVEF, perfusion on SPECT
imaging and MVO .
Perin 2012b (Continued)

Notes
Risk of bias
Random sequence generation (selection Low risk Computer-generated randomised

bias) sequence.
Allocation concealment (selection bias) Low risk Computer-generated randomised

sequence.
Blinding of participants and personnel Low risk Placebo used; all personnel involved were
(performance bias) blinded. Personnel involved in the har-
All outcomes vesting procedure acted independently of
the study team, thus maintaining blinding.
Control participants underwent an iden-
tical bone marrow harvest procedure, in-
cluding insertion of the needle, except that
BM was not aspirated. Control partici-
pants received transendocardial injections
of placebo solution instead of cell prepara-
tion
Blinding of outcome assessment (detection Low risk Double-blinded trial. two blinded, in-
bias) dependent echocardiologists reviewed the
All outcomes echocardiograms and the average of the 2
readings was reported
Pokushalov 2010

Study setting: Russia.
Control arm: 33 at the end of study.
Participants Description: Chronic myocardial infarction and end-stage chronic heart failure.
old.
Number of diseased vessels: BMSC arm: 1 (n = 2); 2 (n = 1); 3 (n = 52); Control arm: 1
(n = 3); 2 (n = 3); 3 (n = 48).
Time from symptom onset to initial treatment: A history of MI > 12 months before enrol-
ment.

Summary of stem cell isolation and type and route of delivery: On the day of surgery, BM
was aspirated from the iliac crest under local anaesthesia by the standard technique.
MNBMC were isolated by Ficoll density gradient centrifugation. Three washing steps
were performed and the cells were resuspended in heparinised saline for further use.
Cell viability was tested by Trypan Blue (exclusion method) and estimated at more than
98% for each transplant. Intramyocardial injection. Non-fluroscopic mapping with the
NOGA system via femoral artery access and retrograde aortic approach using a 7-Fr
NOGA Star catheter. An area of interest located by technetium-99m tetrofosmin SPECT
was delineated in detail by means of NOGA mapping; it included ischaemic but viable
myocardium. Immediately before injection, the catheter was positioned perpendicularly
to endocardium with excellent loop stability and the extension of the needle to induce
premature ventricular contraction. Ten successive intramyocardial injections (roughly 0.
2 ml each) were administered into the infarction border zone.
Dose of stem cells: 41 16 x 10 BMSC, with 2.5 (1.6)% being CD34-positive cells.
Timing of stem cell procedure: Within 24 hours after cell harvesting.
G-CSF details: No.
Comparator arm: Not reported.
Outcomes Primary outcomes: Efficacy of the intramyocardial injection of autologous bone marrow
mononuclear cells, measured by change in myocardial perfusion defects at rest and under
pharmacological stress.
Secondary outcomes: Safety of the intramyocardial BMMC therapy, quality of life, CCS
angina class, NYHA functional class, LV functions, life-threatening arrhythmias, mor-
tality between 2 groups, NOGA change in voltage assessed by NOGA follow-up endo-
cardial mapping.
Pokushalov 2010 (Continued)
Notes
Risk of bias
Random sequence generation (selection Low risk Randomisation was carried out using an
bias) electronic system.
reported.
All outcomes
Blinding of outcome assessment (detection Low risk SPECT imaging done by consensus of 2
bias) readers blinded to the type of the study
All outcomes (baseline or follow-up) and clinical data;
other blinding not reported
Tse 2007

Source of funding:This study was partially supported by the Sun Chieh Yeh Heart Foun-
dation Fund; S K Ye Medical Foundation Grant (project no 203217) and The Research
Grants Council of Hong Kong (HKU 7357/02M). Two authors received consultant fee
from Biosense-Webster, CA, USA. All other authors declare that they have no conflict
of interest
Study setting: Hong Kong (China) and Newcastle (Australia).
Number of centres: Two.
Control arm: 9.
Tse 2007 (Continued)
Participants Description: People with severe CAD who had failed conventional therapy.
years old.

Summary of stem cell isolation and type and route of delivery: BM was harvested via pos-
terior iliac crest puncture under local anaesthesia. A total of 40 mL of BM blood was
aspirated, and an adequate trephine biopsy was performed. BMMNC were isolated by
Ficoll density gradient centrifugation. BM cells were washed twice in phosphate-buffered
saline, resuspended in phosphate-buffered saline enriched wit 10% autologous plasma to
either 1 or 2 x 10 MNC/mL and returned directly to cardiac catheterisation laboratory
for use. BM suspensions were tested by flow cytometry with directly conjugated antibod-
ies against CD34. Intramyocardial injection. Non-fluoroscopic LV electromechanical
mapping (NOGA) to identify the foci of ischaemic myocardium. During the procedure,
systemic anticoagulation was achieved with intravenous heparin to maintain an activated
clotting time of 250 - 300 s throughout the procedure. The targeted injection regions
were selected by matching the area of ischaemic myocardium identified by SPECT. After
completion of the LV electromechanical mapping, the mapping catheter was replaced
by a modified mapping catheter incorporated with a 27G needle at the tip that could be
used for direct endomyocardial injection.
Dose of stem cells: 1.5 x 10 BMNC.
Timing of stem cell procedure: Within 3 - 4 hours from cell harvest.
G-CSF details: No.
Comparator arm: In the placebo group the participants received cell-free phosphate
buffered saline with 10% autologous serum. 8 - 12 injections of 0.1 mL of placebo
preparation were delivered evenly in each ischaemic region
Outcomes Primary outcomes: Change from baseline in total exercise time on a modified Bruce
protocol at 6 months follow-up.
Secondary outcomes: Changes in LVEF, NYHA, and CCS angina classification and sum
of different scores on SPECT, global LVEF, LVEDV and LVESV by MRI.
Method(s) of outcome measurement: SPECT and MRI.
Notes
Risk of bias
Random sequence generation (selection Low risk Randomisation table: randomisation was
bias) constrained, stratified on the study centre
and conducted via a system of sealed and
Tse 2007 (Continued)
numbered envelopes provided to each in-

vestigative centre
Allocation concealment (selection bias) Low risk Sealed numbered envelopes were provided
from the study centre (centralised) to each
investigational centre
Blinding of participants and personnel Low risk After randomisation the study processes
(performance bias) were blinded to participants (placebo). No
All outcomes details of the blinding of clinicians given
Blinding of outcome assessment (detection Low risk After randomisation the study processes
bias) were blinded to study co-ordinators and in-
All outcomes vestigators responsible for participants as-
sessment. Blinding was maintained until
the end of the study
Turan 2011

Number (N) of participants randomised to each arm:BMSC arm: 38; Control arm: 18.
Control arm: 16.
Participants Description: People with IHD.

old.
Number of diseased vessels: BMSC arm: 1.5 0.5; Control arm: 2.0 0.6.
Time from symptom onset to initial treatment: Transmural myocardial infarction (MI) 28
14 months before treatment.
Turan 2011 (Continued)

Summary of stem cell isolation and type and route of delivery: 120 ml bone marrow was
aspirated from the participants own iliac crest, mononuclear cells were isolated using
Harvest BMAC System (Germany) (most probably by density gradient centrifugation)
and concentrated into 20 ml of cell suspension. Cell transplantation was performed via
the coronary artery using 4 fractional infusions parallel to balloon inflation over 2 - 4
mins of 5 ml cell suspension. Cells were infused directly into the infarcted artery via an
angioplasty balloon catheter that was inflated at a low pressure and was located within
the previously stented coronary artery. Intracoronary infusion. After undergoing arterial
puncture, all participants received 7500 - 10,000 units of heparin. Cell transplantation
was performed via the intracoronary administration route using 4 fractional infusions
parallel to balloon inflation over 2 - 4 mins of 5 ml of cell suspension. All cells were infused
directly into the infarcted zone through the infarct-related artery via an angioplasty
balloon catheter, which was inflated at a low pressure (4 atm) and was located within the
previously stented coronary segments. This prevented back flow of cells and produced
stop flow beyond the site of balloon inflation to facilitate high pressure infiltration of
cells into the infarcted zone with prolonged contact time for cellular migration.
Dose of stem cells: 99 x 10 ( 25) mononuclear cells.
Timing of stem cell procedure: Within 24 hours from cell harvest.
G-CSF details: No.
Comparator arm: No placebo.
Outcomes Primary outcomes: Change in global EF as well as the size of infarcted area measured by
left ventriculography.
Secondary outcomes: Functional activity of BMSC immediately pre- and 3, 6 and 12
months after procedure; functional status assessed by NYHA classification and brain
natriuretic peptide level in peripheral blood in both groups.
Method(s) of outcome measurement: Left ventriculography.
Notes
Risk of bias
reported.
Blinding of participants and personnel Unclear risk Not reported for clinicians, no placebo
(performance bias) given to participants
All outcomes
Turan 2011 (Continued)
Blinding of outcome assessment (detection Low risk Haemodynamic investigations and lab re-
bias) sults were obtained independently by 2 in-
All outcomes vestigators
Van Ramshorst 2009

Source of funding: This study is an academia-initiated exploratory Phase II study. No
external sponsor was involved in study design, data collection, data analysis, data inter-
pretation or writing of the report. No external funding was applicable for this study
Study setting: Leiden, The Netherlands.
Control arm: 25.
Participants Description: People suffering from severe angina, ineligible for PCI or CABG.
old.
Time from symptom onset to initial treatment: At least 6 months from the last MI.

Summary of stem cell isolation and type and route of delivery: BM was aspirated from
the iliac crest under local anaesthesia and placed in a heparinised Hanks balanced salt
solution. The MNC were isolated using Ficoll density gradient centrifugation, washed
in phosphate-buffered saline with 0.5% human serum albumin and resuspended in
phosphate-buffered saline with 0.5% human serum albumin. The final suspension of
BMMNC contained 40 x 10 mL. The filtered bone marrow was checked for the presence
of clots and the BM cell population was analysed by fluorescence-activated cell sorting
using anti-CD34 and anti-CD35 antibodies. Intramyocardial injection. During cell
isolation and randomisation, a 3D electromechanical map of the LV was obtained using
the NOGA system. The ischaemic regions on SPECT were visually matched with the
Van Ramshorst 2009 (Continued)
3D electromechanical map based on anatomical landmarks including LV long axis,

position of apex, mitral valve area, aortic valve location and basal inferoseptal point.
Cross-referencing was also performed using fluoroscopic identification of anterior, septal,
lateral and inferior orientations.
Dose of stem cells: The cell suspension contained 98 6 x 10 BM cells with a cell viability
of 98% (1%) and a CD34+ cell fraction of 2.4% (0.9%).
Timing of stem cell procedure: Within 2 hours of BM aspiration.
G-CSF details: No.
Comparator arm: Participants had bone marrow aspiration and received an intramyocar-
dial injection
Outcomes Primary outcomes: Summed stress score (myocardial perfusion).

Secondary outcomes: LVEF (and LV stroke volume, LVESV, LVEDV), CCS angina class,
Seattle Angina Questionnaire QOL score.
Also reported: exercise capacity.
Notes
Risk of bias
Random sequence generation (selection Low risk Sequentially-numbered sealed envelopes

bias) provided by the Department of Medical
Statistics and Bioinformatics. A block size
of 4 was used without further stratification
Allocation concealment (selection bias) Low risk Sequentially-numbered sealed envelopes

provided by the Department of Medical
Statistics and Bioinformatics
Blinding of participants and personnel Low risk A blinded syringe with either cell suspen-
(performance bias) sion or placebo was brought to the cath
All outcomes lab. All participants had BM aspirated.
They were unaware of group assignment.
A placebo was used
Blinding of outcome assessment (detection Low risk Participants, study co-ordinators and inves-
bias) tigators involved in participant assessments
All outcomes were unaware of group assignment
Van Ramshorst 2009 (Continued)
Wang 2009

Study setting: Beiging, China.
Control arm: 16.
Participants Description: Angina, no AMI in 1 month prior to transplantation.

Age distribution in each arm: BMSC arm: 60.6; Control arm: 60.
Time from symptom onset to initial treatment: At least 1 month from the last AMI, angina.
Interventions Intervention arm: CD34+ cells.

Type of stem cells: CD34+ cells.
Summary of stem cell isolation and type and route of delivery: 150 ml of BM was aspirated
from the iliac crest. CD34+ cells were enriched by a cell separation device under GMP
conditions. CD34+ cells were resuspended in normal saline and kept at room tempera-
ture. Cells were transported to the Cath lab. Cells were delivered using a microcatheter
following PCI.
Dose of stem cells: 1.0 - 6.1 x10 CD34+ cells.
Timing of stem cell procedure: Unclear, not reported.
G-CSF details: No.
Comparator arm: No cells were harvested, PCI only, no placebo.

Secondary outcomes: Myocardial perfusion defect area, wall motion, angina frequency
change, Nitrate triglycerine dose change, angina classification by CCS class.
Method(s) of outcome measurement:
Notes
Risk of bias
Wang 2009 (Continued)
reported.
All outcomes
Blinding of outcome assessment (detection High risk Specified in the text that they are not
bias) blinded.
All outcomes
Wang 2010

Study setting: China.
Control arm: 56.
Participants Description: Intractable angina, no revascularisation.

Age distribution in each arm: BMSC arm: 42 - 80 years old; Control arm: 43 - 80 years
old.
Sex (% male) in each arm: BMSC arm: 51.79%; Control arm: 50%.
Number of diseased vessels: 3.
Interventions Intervention arm: CD34 + cells.

Type of stem cells: CD34 + cells.
Summary of stem cell isolation and type and route of delivery: 120 - 150ml bone marrow
aspirates from the posterior iliac crest were obtained from all participants. CD34+ cells
were isolated by labelling with the appropriate CD34 antibody and separating them
magnetically using a CLINIMACS (Myltenyi Biotec). CD34+ cells were resuspended in
15 ml of saline + human serum albumin . Only the saline+human serum albumin was
infused in the control group, using the same protocol as in the BMSC group. The cell
Wang 2010 (Continued)
were infused into the coronary artery using a GE Innoca 2000 DSA with 3000 units
of heparin. Approximately 1 - 2 hours after cell separation, 10 ml of cells and 5 ml of
saline were infused into the left coronary artery and right coronary artery separately by
an over-the-wire balloon.
Dose of stem cells: 5.6 2.3 x 10 CD34 cells.
Timing of stem cell procedure: Within 2 hours of cell harvest.
G-CSF details: No.
Comparator arm: Only the saline+human serum albumin was infused in the control
group, using the same protocol as in the BMSC group
Outcomes Primary outcomes: Safety (mortality and morbidities).

Secondary outcomes: Arrythmias, angina frequency, nitroglycerine use, exercise tolerance,
CCS class, perfusion effect or myocardial perfusion.
Method(s) of outcome measurement: Number of deaths
Notes
Risk of bias
reported.
Blinding of participants and personnel Low risk All participants and researchers were un-
(performance bias) aware of the treatments. No details about
All outcomes clinicians
Blinding of outcome assessment (detection Low risk All participants and researchers were un-
bias) aware of the treatments
All outcomes
Yao 2008

Source of funding: This work was supported by Shanghai Scientific Research Fund
(06DJ14001), Program for Shanghai Outstanding Medical Academic Leader (LJ06008
and National Key Program (2006CB943704)
Study setting: Shanghai, China.
Control arm: 23.
Participants Description: People hospitalised with a history of transmural MI and revascularisation

plus stent implantation at least 6 months earlier.
9 years old.
Number of diseased vessels: BMSC arm; 1 (67%); 2 (29%); 3 (4%); Control arm: 1 (70%)
; 2 (26%); 3 (4%).
Time from symptom onset to initial treatment: At least 6 months from last MI. 13 8
months before entry into study.

Summary of stem cell isolation and type and route of delivery: BM (95 (20) ml) was collected
under local anaesthesia from the posterior superior iliac spine. BMC were isolated and
enriched with the use of Ficoll-Hypaque gradient centrifugation procedures. BM aspi-
rates were diluted with 0.9% NaCl (1:5) and mononuclear cells were isolated by density
gradient centrifugation using Ficoll (800 g x 25 mins). Mononuclear cells were washed
(800 g x 5 mins) 3 times with phosphate buffered saline and then resuspended in 16 ml
of heparin-treated plasma at a density of 2.4 (1.2 x 10 ) cells/ml at room temperature.
Before intracoronary injection, the mononuclear cells were filtered (Falcon) and counted.
These cells were used for therapy. To ensure that a certain % of stem cells were present
in the infused MNC, a 1-ml suspension was subjected to FACS analysis after incubation
with anti-human monoclonal antibodies: anti-human CD34 conjugated with FITC, or
CD133 antibodies conjugated with APC. The FACS analysis revealed that 2.4% (0.9%)
of BMC was positive for CD34 and 0.75% (0.2%) was positive for CD133. Intracoro-
nary infusion. An over-the-wire angioplasty balloon catheter was inserted into the stent
previously implanted during the acute reperfusion procedure. The balloon was inflated
with low pressure (2 - 4 atm) to completely block blood flow for 2 mins and repeated 5
times. During each balloon inflation, 3 ml of BMC suspensions were infused distal to
the occluding balloon into the infarct-related artery.
Dose of stem cells: 7.2 x 10 cells.
Timing of stem cell procedure: within 6 hours after bone marrow puncture.
G-CSF details: No.
Comparator arm: Placebo. The placebo solution consisted of 0.9% NaCl containing
heparin
Yao 2008 (Continued)
Outcomes Primary outcomes: Improvement of LV function.

Secondary outcomes: LVEF, LVED diameter, LVES diameter (Echo).
LVEF, LVESV, LVEDV, infarct size (MRI).
Myocardial perfusion (SPECT); mortality and morbidities.
Method(s) of outcome measurement: Echocardiography, MRI and SPECT.
Notes
Risk of bias
reported.
All outcomes
Blinding of outcome assessment (detection Low risk Outcome assessors (MRI, echocardiogra-
bias) phy, SPECT) were blinded to the assigned
All outcomes therapy
Selective reporting (reporting bias) Low risk All outcomes mentioned in the methods
were reported in results; although it would
Zhao 2008

Source of funding: Shanghai Medical Development Research Fund, Grant Number 2000I-
2D002
Study setting: Shanghai , China.
Control arm: 18
Participants Description: People with ischaemic heart failure admitted for elective CABG.
7 years old.
Number of diseased vessels: multivessel, 2 or more.

Summary of stem cell isolation and type and route of delivery: After heparinisation and
median sternotomy, BM (about 30 mL) was aspirated from the sternum by a special
suction appliance in both groups. The MNBMC were immediately isolated by density
gradient centrifugation using Ficoll. Isolated cells were washed twice with heparinised
saline and subsequently resuspended in 5 mL saline. The cells were counted and the
viability was assessed by trypan blue dye exclusion. The cell suspension was filtered by a
70-micron cell strainer before transplantation. During CABG, intramyocardial injection
in and around the infarct area at 10 points (approximately 0.5 ml per injection) with a
29-gauge syringe.
Dose of stem cells: 6.59 5.12 x 10 (cell viability 96.48% 3.10%).
Timing of stem cell procedure: within 24 hours following cell harvest.
G-CSF details: No.
Comparator arm: Placebo, saline.
Outcomes Primary outcomes: Death, MI and recurrence of heart failure.

Secondary outcomes: Echo: infarction wall thickness; infarction wall motion velocity;
LVED/LVES diameter; global LVEF; LV shortening fraction; mitral valve regurgitation.
SPECT: LV SRS; infarcted area SRS; clinical parameters; NYHA, CCS classification;
24-hour Holter analysis.
Method(s) of outcome measurement: Echocardiography and SPECT.
Notes
Risk of bias
Zhao 2008 (Continued)
Random sequence generation (selection Low risk Randomisation was achieved by using a se-
bias) quence of random numbers generated by a
computer.
reported.
All outcomes
Blinding of outcome assessment (detection Low risk The results were analysed by 2 independent
bias) experienced observers; investigators (Echo,
All outcomes SPECT) were blinded to the randomisa-
tion scheme
AE adverse events; ALDH: aldehyde dehydrogenase; AMI: acute myocardial infarction; APC: allophycocyanin ;BMMNC bone marrow
mononuclear cells; BMSC bone marrow stem cells; CABG coronary artery bypass grafting; BNP brain natriuretic peptide; CAD:
coronary artery disease; CCS Canadian Cardiovascular Society; DM: diabetes mellitus; CPC circulating progenitor cells; EF:
ejection fraction; EMM: electromechanical mapping; EPC endothelial progenitor cells; FITC: fluorescein isothiocyanate; HTN:
hypertension; IM intramuscular; IC intracoronary; LVEF left ventricular ejection fraction, LVEDV left ventricular end diastolic
volume; LVESV left ventricular end systolic volume; MACE major adverse clinical events; MLHF Minnesota Living with Heart
Failure; MRI magnetic resonance imaging; MVO myocardial oxygen consumption; NTG: nitroglycerine; NYHA New York Heart
Association; PBS: phosphate buffered saline; PBSC: peripheral blood stem cell; PCI percutaneous coronary intervention; RCT
randomised controlled trial; SPECT: single-photon emission computed tomography; STEMI: ST elevation myocardial infarction;
VEGF: vascular endothelial growth factor.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Beeres 2006 Non-RCT, no control arm included.
Beeres 2007 Non-RCT, no control arm included.
Beeres 2007a Non-RCT, no control arm included.
Beeres 2007b Review of imaging techniques for cardiac stem cell therapy.
Chang 2006 AMI.
Charwat 2010 AMI.
Chin 2010 Non-RCT, no control arm included.
Gu 2011 Non-RCT.
Haack-Sorensen 2013 Non-RCT, no control arm included.
Kakuchaya 2010 24 participants with ischaemic dilated cardiomyopathy and 26 with idiopathic dilated cardiomyopathy
Kang 2006b AMI.
Lai 2009 Primary outcome measures for cardiac enzymes, not in the protocol
Maureira 2012 Non-RCT.
Perin 2003 Non-RCT.
Peruga 2009 AMI.
Pokushalov 2011 Non-RCT for cell therapy.
Rivas-Plata 2010 Non-RCT.
Stamm 2007a Non-RCT
Tuma 2011 Non RCT, no control arm
Vicario 2004 Non-RCT.
Wang 2006 Not clear whether this is an RCT and chronic ischaemic heart disease
AMI acute myocardial infarction; RCT randomised controlled trial.
Characteristics of studies awaiting assessment [ordered by study ID]
Bartunek 2012
Methods Bone marrow-derived cariopoietic cells, based on cardiac lineage commitment of mesenchymal stem cells. Bone
marrow mesechymal cells are isolated from bone marrow aspirates and cultured in vitro. The cells are induced to
express cardiac-specific markers by culturing them in a cocktail of cytokines. Cells are delivered intramyocardially
into viable myocardium using electromechanical mapping (e.g. NOGA system) administered in 9 - 26 injections
Participants Participants (n = 48) with ischaemic heart failure due to chronic ischaemic heart disease, with LVEF 15 - 40%.
Randomised to cardiopoietic mesechymal cells (c-MSC) (n = 21) and control (n = 15)
Age: 55.7 10.4 years old in the treatment arm and 59.5 8 years old in the control arm
Male: 95% in treatment arm and 91% in control arm.
Interventions Treatment arm: c-MSC.

Control arm: not reported.
Dose of cells: 7.33 x 10 cells were delivered intramyocardially.
Outcomes LVEF, LVESV, LVEDV, 6-minute walk test (exercise), quality of life, oxygen consumption, NYHA class, heart failure-
related hospitalisation and mortality
Duration: 6 months
Method of measurement: Echocardiography
Notes
Cuzzola 2007
Methods Bone marrow mononuclear cells (BMMNC) were isolated from bone marrow aspirates and injected intramyocardially
during cardiac surgery (CABG)
Participants Participants eligible for inclusion had an acute MI at least 6 months prior to the treatment and LVEF lower than
35%
Age: not reported.
Male: not reported.
Interventions Treatment arm: BMMNC + CABG

Control arm: placebo + CABG
Dose of cells: not reported
Outcomes Safety and LVEF

Duration: 12 months
Method of measurement: not reported.
Notes
Jimenez-Quevedo 2011
Methods Participants were treated with G-CSF for 4 days. CD133+ cells were isolated from peripheral blood during apheresis
using the CliniMacs technology (Miltenyi Biotec) to obtain 20 - 30 x 10 cells. The cells were injected transendo-
cardially guided by electromechanical mapping with the NOGA system
Participants Participants with angina class II - IV, and ischaemic viable myocardium demonstrated by SPECT, with no option of
revascularisation
Age: 64 10.7 years old.
Male: 86%.
Interventions Treatment arm: Dose of CD133+ cells : 30 x 10 cells.

Control arm: not clear what they received.
Outcomes Duration: 3 months.

Primary outcome: Safety.
Notes
Kakuchaya 2011
Methods Method of cell isolation: not reported.

Route of delivery: intramyocardial and Intracoronary.
Participants 50 participants, no details given of age, male to female ratio

24 with ischaemic dilated cardiomyopathy; 26 with idiopathic dilated cardiomyopathy
Interventions Treatment arm: CD133+ cells.

Control arm: placebo.
Outcomes Increase in LVEF and perfusion defects reduction..

Duration: 6 months
Notes
Minjie 2011
Methods No details of cell isolation or cell dose or cell delivery method given
Participants 50 participants with old miocardial infarction (OMI).

Age: 57.48 7.98 years old.
Male: 94%.
Interventions Treatment arm: BMSC + CABG.

Control arm: CABG alone.
Outcomes Primary: LVEF measured and scar size.

Method of measurement: MRI.
Duration: 12 months.
Minjie 2011 (Continued)
Notes Full details will be required to assess this trial
Nasseri 2012
Methods No details of cells isolation.
Participants 60 participants with chronic HF and LVEF < 35%.

Age: 62 (37 - 78) years old.
Male: 97.5%.
Interventions Treatment arm: CABG and BMSC CD133+ cells.

Control arm: CABG and placebo injection.
Dose of cells: 5.6 x 10 cells (range 2 - 13 x 10 ), cells were delivered intramyocardially in 20 injections
Outcomes LVEF and HF symptoms.

Duration: 6 months.
Method of measurement: MRI and 2D Echo.
Notes
Shihong 2012
Methods CD34+ cells were isolated from 120 - 150 ml of bone marrow aspirates by cell selection. Cells were administered via
the coronary artery
Participants 112 participants with refractory angina, randomised to CD34+ cells treatment (n = 56) or placebo arm (n = 56)
Age: 42 - 80 years old in BMSC arm and 43 - 80 years old in the control arm
Male: 51.7% in BMSC arm and 50% in control arm.
Interventions Treatment arm: CD34+ cells.

Control arm: placebo (saline).
Dose of cells: not reported.
Outcomes Angina episodes, consumption of nitroglycerine, exercise time, CCS (angina) class and myocardial perfusion
Duration: 6 months.
Method of measurement: CCS class and SPECT.
Notes
Tuma 2010
Methods BMMNCs were isolated from bone marrow. Cells were delivered via the coronary artery
Participants 40 participants, 20 with ischaemic heart failure (IHF) and 20 with non-ischaemic heart failure (nIHF)
Age: 67 years old IHF and 64 years old nIHF.
Male: not reported.
Tuma 2010 (Continued)
Interventions Treatment arm: BMMNCs.

Control arm: no placebo.
Dose of cells: 12 x 10 cells were administered intracoronarily.
Outcomes NYHA class, LVEF, LVESV, LVEDV.

Duration: 48 months.
Method of measurement: not reported.
Notes
Zverev 2006
Methods MSCs were isolated form bone marrow and cultured in vitro. BMMNCs were isolated also from bone marrow. Cells
were delivered via the coronary artery
Participants 69 participants, randomised to MSC (n = 18), BMMNC (n = 38) and control (n = 13)
Age: not reported.
Male: not reported.
Interventions Treatment arms: MSC and BMMNC.

Control arm: no placebo.
Dose of cells: 12 x 10 cells were administered intracoronarily.
Outcomes Angina episodes, nitroglycerine consumption, myocardial viability and perfusion, LVEF
Duration: 9 months.
Method of measurement: SPECT and echocardiography.
Notes
AE: adverse events; AMI: acute myocardial infarction; BMMNC: bone marrow mononuclear cells; BMSC: bone marrow stem cells;
BNP: brain natriuretic peptide; CABG: coronary artery bypass grafting; CCS: Canadian Cardiovascular Society; CPC: circulating
progenitor cells; EPC: endothelial progenitor cells; G-CSF: granulocyte colony-stimulating factor; HF: heart failure; IM: intra-
muscular; IC: intracoronary; LVEF: left ventricular ejection fraction; LVEDV: left ventricular end diastolic volume; LVESV: left
ventricular end systolic volume; MACE: major adverse clinical events; MRI: magnetic resonance imaging; MSC: mesenchymal stem
cells; MVO : myocardial oxygen consumption; NYHA: New York Heart Association; PCI: percutaneous coronary intervention;
RCT: randomised controlled trial; SPECT: single-photon emission computed tomography.
Characteristics of ongoing studies [ordered by study ID]
ACTRN12611000219987
Trial name or title A study of the effect on heart function of direct myocardial injection of autologous bone marrow for treatment
of patients with end-stage ischaemic heart failure
Methods A randomised, blinded, parallel, placebo-controlled, safety/efficacy study
Participants End-stage ischaemic heart failure:

1. Age 18 - 80 years.
2. CCS classification II - IV angina and/or NYHA classification II - III heart failure symptoms.
3. Received stable and best cardiac medical therapy including diuretics, long-acting nitrates, beta-
blocker, and angiotensin-converting enzyme inhibitors without control of symptoms.
4. Not suitable for conventional revascularisation (due to diffuse disease, chronic total occlusion, lack of
graftable vessels or any combination thereof ).
5. LVEF < 40% by echocardiography.
6. Recent coronary angiogram (within the last 6 months) to document the coronary anatomy and insure
the presence of coronary artery disease (CAD) that is not amenable to standard revascularisation procedures.
7. Serum creatinine less than 250 mmol/L, normal liver function, and normal blood count: white blood
cell (WBC) count, granulocytes, platelet count, haemoglobin (Hb).
8. Reversible perfusion defect on SPECT.
9. Hemodynamically stable.
10. Participant is willing to comply with specified follow-up evaluations.
Interventions Treatment arm 1: Endomyocardial injection of autologous bone marrow mononuclear cells (10 to 12 injections
of 0.1 ml of bone marrow of concentration of 10 cells per mL at each predetermined target site) via NOGA
electromechanical mapping system
Treatment arm 2: Blinded placebo percutaneous endomyocardial injection.
Outcomes Primary outcome:

LVEF measured by MRI (6 months).
Secondary outcomes:
1. Incidence of adverse events (6 months).
2. Clinical status (NYHA, CCS, anginal attacks, 6-minute walk test) (3/6 months).
3. Exercise capacity (modified Bruce protocol treadmill test; MVO
measurement) (3/6 months).
4. Myocardial perfusion imaging (SPECT) (6 months).
Starting date May 2011
Contact information Department of Medicine, The University of Hong Kong, MR 1928, Block K, Queen Mary Hospital, 102
Pokfulam Road, Hong Kong (Principal Investigator: Dr HF Tse). Contact: Dr Suku Thambar (melissa.
chaplin@hnehealth.nsw.gov.au)
Notes
EUCTR2009-016364-36-NL
Trial name or title Injection of autologous bone marrow cells into damaged myocardium of no-option patients with ischaemic
heart failure: a randomised placebo controlled trail. - cell therapy for ischaemic heart failure
Methods A randomised, double-blind, cross-over, placebo-controlled trial
Participants Ischaemic heart failure:

1. Ischaemic heart failure NYHA class 3 or 4 despite optimal pharmacological and non- pharmacological
therapy.
2. No candidate for (repeat) surgery (revascularisation, valve repair or ventricular reconstruction).
3. No candidate for (repeat) percutaneous revascularisation.
4. Optimal resynchronisation therapy, or no candidate for resynchronisation therapy.
5. Male or female, > 18 years and < 75 years old.
6. Life expectancy more than 6 months.
7. Able to perform an exercise tolerance test prior to therapy.
8. Able and willing to undergo all the tests used in this protocol including the travelling involved.
9. Written informed consent.
Interventions Treatment arm 1: Intracardiac administration of bone marrow mononuclear cells

Treatment arm 2: Intracardiac administration of placebo.
Outcomes Primary outcomes:

1. Left ventricular global ejection fraction as assessed by Gated SPECT.
2. LV regional wall motion by echocardiography.
3. FDG-SPECT for assessment of viability and hibernation.
4. Myocardial innervation imaging (MIBG-SPECT) for assessment of myocardial innervation.
5. Exercise capacity by bicycle exercise testing with VO
measurement.
6. Quality of Life assessed using the MLHF questionnaire.
Secondary outcomes:
Safety (incidence of arrhythmias via Holter monitoring, inflammation and myocardial damage)
Starting date July 2010
Contact information None identified
Notes
EUCTR2011001117-13-GB
Trial name or title Efficacy and safety of bone marrow-derived mesenchymal cardiopoietic cells (C3BS-CQR-1) for the treatment
of chronic advanced ischaemic heart failure
Methods A phase III, randomised, parallel, double-blind, sham-controlled safety/efficacy/pharmacoeconomic study
Participants Congestive heart failure:

1. Age 18 and < 80 years.
2. Systolic dysfunction with LVEF 30% as assessed by echocardiography.
3. Ischaemic heart failure without known need for revascularisation.
4. MLHFQ score > 30.
EUCTR2011001117-13-GB (Continued)
5. Ability to perform a 6-minute walk test > 100 m and 400 m.

6. History of hospitalisation for HF within 12 months prior to screening.
7. NYHA Class III or IV despite optimal standard of care or INTERMACS class 4, 5, 6 or 7.
8. Use of ACE inhibitor and/or ARB; and beta blocker, for at least 3 months prior to screening visit,
unless intolerant or contraindicated.
9. Stable dosing of ACE inhibitor, ARB, beta blocker, aldosterone blocker, and diuretics for at least 1
month prior to screening visit, defined as 50% change in total dose of each agent.
10. Willing and able to give written informed consent.
Interventions Treatment arm 1: autologous bone marrow-derived cardiopoietic stem cells

Treatment arm 2: Sham control.

Efficacy (9 months) based on a hierarchical composition of:
1. All-cause mortality.
2. Worsening of heart failure events requiring intensive care with intravenous diuretics or inotropic
support or readmission.
3. Change in MLHFQ total score.
4. Change in 6-minute walk distance.
5. Change in LVESV as assessed by echocardiography.
6. Change in LVEF as assessed by echocardiography.
Secondary outcomes:
1. Occurrence of the following clinical events: death and cause of death, readmissions and cause of
readmission, cardiac transplantation, myocardial infarction, stroke (12/24 months).
2. Incidence of serious adverse events [12/24 months]
3. Incidence of non-serious adverse events (12 months).
4. Time to all-cause mortality (12 months).
5. Worsening of heart failure events requiring intensive care with intravenous diuretics or inotropic
support or readmission (12 months).
6. Aborted sudden death events, defined as resuscitated sudden death or appropriate AICD firing for
severe ventricular tachyarrhythmias (12 months).
7. Additional tertiary (explorative) outcomes including the effect of each of the components of the
composite endpoint at 39 and 52 weeks.
Starting date February 2013
Contact information Cardio3 BioSciences SA, Mont-Saint-Guibert, 1435, Belgium. Contact: infor@c3bs.com
Notes
ISRCTN71717097
Trial name or title Bone-marrow derived stem cell transplantation in patients undergoing left ventricular restoration surgery for
dilated ischaemic end-stage heart failure: a randomised blinded controlled trial (TransACT 2)
Methods A double-blind randomised placebo-controlled trial.
ISRCTN71717097 (Continued)
Participants End-stage heart failure:

1. Previous anterior myocardial infarction (with evidence of large surgically excludible scar at cardiac
MRI).
2. Significant LV dilation (LVESV index greater than or equal to 60 ml/m).
3. LVEF less than or equal to 35%.
4. NYHA class III/IV and 1 episode of congestive heart failure (CHF) requiring medical attention.
5. Elective left ventricular restoration surgery indicated.
6. Elective CABG indicated to bypass stenoses or occlusions of coronary arteries.
7. Participant aged 16 years and< 80 years old, either sex.
Interventions Treatment arm 1: Surgical ventricular restoration and transplantation of autologous CD133+
Treatment arm 2: Surgical ventricular restoration and injection of placebo, i.e. autologous plasma
Outcomes Primary Outcome:

Regional LV thickening of the affected segments 6 months after surgery
Secondary Outcomes:
1. Mid-term generic and cardiac-specific health status and quality of life, measured at baseline and 6
months follow-up.
2. End systolic volume and stroke volume quantified by cardiac MRI, measured at baseline (3 - 5 days
postoperatively) and 6 months follow-up.
3. Myocardial injury throughout the duration of the study by measuring troponin I levels (24 hours pre-
operatively, surgery, 4, 12, 24 hours postoperatively, 6 weeks and 6 months follow-up).
Starting date August 2009.
Contact information University of Bristol, Bristol Royal Infirmary. Contact: Mr R Ascione (r.ascione@bristol.ac.uk)
Notes
ISRCTN75217135
Trial name or title A pilot study to evaluate the efficacy of combined transplantation of progenitor cells and coronary artery
bypass grafting (TOPCABG)
Methods RCT
Participants 10 participants undergoing CABG.
Interventions Treatment arm 1: stem cells (5 participants).

Treamment arm 2: heparinised saline (5 participants).
Outcomes Primary outcome: to show improvements in myocardial function, regional wall motion and myocardial per-
fusion
Starting date January 2004
ISRCTN75217135 (Continued)
Contact information Southampton University Hospitals NHS Trust, Level D, East Wing, Southampton General Hospital, Tremona
Road, Southampton SO16 6YD. Contact: Mr D Varghese (dvarghese@btinternet.com).
Notes Completed/not recruiting but no publications identified.
NCT00285454
Trial name or title Cell repair in heart failure
Methods A phase I/II, parallel, randomised, double-blind, placebo-controlled, single-centre study
Participants Ischaemic heart failure and no revascularisation options:

1. Symptomatic ischaemic multivessel coronary artery disease not suitable for standard revascularisation
procedures such as CABG, PCI, LVAD, or heart transplant.
2. Area of reversible inducible ischaemia (> 10% of LV on SPECT) performed not more than 6 months
prior to study treatment.
3. LVEF < 45% on optimal medical therapy.
4. NYHA class II - IV stable on optimal medical therapy for at least 30 days.
5. Written informed consent and agree to attend hospital appointments for 1 year.
6. Men and women 18 to 80 years of age.
Interventions Treatment arm 1: Autologous bone marrow mononuclear cells. 5% HSA.

Treatment arm 2: Placebo: 5% HSA.
Route of administration: retrograde coronary venous delivery The total dose of bone marrow mononuclear
cells or placebo will be divided into 2, each administered as a 10 ml bolus into selected coronary veins. There
will be significant participant heterogeneity regarding size of ischaemic viable territory present and anatomy of
venous system. The aim is to treat 2 veins, individual SPECT and venogram results will be used to direct the
venous anatomy to be targeted. An attempt will be made to cover as large an area as possible of a participants
ischaemic viable territory. The total dose of cells will remain constant between participants
Outcomes Primary Outcomes:

1. Safety (up to one year).
2. Efficacy.
Co-primary endpoints at 180 Days
1. Perfusion (MIBI SPECT).
2. Function (CMR).
Secondary Outcomes:
1. Efficacy (180 days).
2. Perfusion (CMR).
3. Function (ECHO, SPECT).
4. Exercise (VO
Max).
5. QOL.
Starting date January 2008
NCT00285454 (Continued)
Contact information The Department of Gene Therapy, The National Heart and Lung Institute, Imperial College London (Prin-
cipal Investigator: EWF Alton) and The Royal Brompton Hospital, London, UK (Principal Investigator: JR
Clague). Contact: Amanda Heini-Green, (a.heinl-green@imperial.ac.uk); Eric Alton (e.alton@imperial.ac.
uk).
Notes Estimated completion date: December 2008.

The recruitment status of this study is unknown because the information has not been verified recently
NCT00362388
Trial name or title Cell therapy in chronic ischaemic heart disease
Methods A phase III, parallel, multicentre, randomised, double-blind, placebo-controlled study
Participants Severe, chronic IHD:

1. Diagnosis of chronic, severe, diffuse, multivessel atherosclerotic coronary artery disease (CAD) referred
for CABG.
2. Echocardiogram-assessed LVEF between 25% and 55% (Simpsons rule).
3. Angina (or equivalent) functional class II to IV (CCS) despite maximally tolerated medical therapy.
4. Abnormal myocardial perfusion tests: i. Cardiac scintigraphy ii. Magnetic resonance imaging iii.
Dobutamine-atropine stress-echocardiogram.
5. Non-candidates for PCI due to ANY of the following: i. High risk lesion ii. Extensive lesion iii.
Diffuse, small vessel disease.
6. Non-candidates for a complete CABG, or candidates for a complete CABG in whom, according to an
expert panel, there is a high probability of failure of the grafts due to the extension and severity of the
disease, with diffuse, small vessel involvement.
7. Signed, written informed consent, according to the National Guidelines for Clinical Trials.
Interventions Treatment arm 1: Intramyocardial injection of autologous BMC.

Treatment arm 2: placebo.
Co-intervention: CABG

1. Reduction in the ischaemic score (global/regional) (12 months).
2. Increase in LVEF (12 months).
Secondary Outcomes: All-cause and cardiovascular mortality during the first year
1. Increase in VO
max.
2. Increase in quality of life.
3. Reduction in angina/heart failure functional class (12 months).
4. Percentage of participants with a 5% increase in LVEF (6 and 12 months).
Starting date January 2006.
Contact information Heart Institute (InCor), Hospital das Clinicas, University of So Paulo Medical School, So Paulo, SP, Brazil,
05403-900 (Principal Investigator: Prof. Sergio A. de Oliveira)
Notes Study terminated due to low enrolment.
NCT00418418
Trial name or title Combined CABG and stem-cell transplantation for heart failure
Methods A phase II, prospective, randomised, double-blind, placebo-controlled study
Participants Symptomatic heart failure with low LVEF scheduled to coronary bypass operation:
1. Symptomatic heart failure.
2. Scheduled for CABG.
3. Aged 18 to 75 years.
4. Informed consent obtained.
5. People of either gender, evaluated in cardiovascular laboratory and scheduled for CABG with moderate
heart failure, will be eligible.
6. NYHA II - IV symptoms.
7. LVEF in screening echocardiography 15% to 45%.
8. Optimal heart failure medication and coronary medication before operation, containing at least 2
heart failure drugs: must have ACE inhibitor, or AT II blocker, and/or beta-blocker together with diuretics,
digitalis or aldosterone antagonist, and coronary medication: a statin and anticoagulation, either aspirin or
clopidogrel.
Interventions Treatment arm 1: Coronary bypass operation performed via sternotomy during cardiac arrest. Bone marrow
aspirated from the iliac crest (100 ml). During the operation, the aspirate is transported to the stem cell
laboratory, where the sample is centrifugated through Ficoll. During cardiac arrest, stem cells are directly
injected to myocardium. The amount of the cells varies individually (5 - 1000 x 10 cells), the cells are diluted
in autologous serum (5 ml)
Treatment arm 2: Identical procedure, with intramyocardial injection of autologous serum
Outcomes Primary Outcomes: Does a bone marrow transplantation therapy increase the ejection fraction of the heart
measured with MRI, when compared with placebo treatment? (12 months).
Secondary Outcomes: Does a bone marrow transplantation therapy increase any cardiac function parameter
measured by an echocardiography, MRI or PET ischaemia area, when compared with no treatment group?
(6/12 months).
Does a bone marrow transplantation therapy improve BNP-value? (3/6/12 months).
Does a bone marrow transplantation therapy decrease hospitalisation or the days stayed in hospital?
Do pericardial fluid growth factor concentrations correlate to left ventricular function improvement? (up to
12 months).
Does autologous cardiac stem cell quality correlate to left ventricular function improvement? (3/6/12 months)
Starting date October 2006
Contact information Department of Cardiothoracic Surgery, Helsinki University, Meilahti Hospital, Finland (Principal Investiga-
tor). Contact: (ari.harjula@hus.fi); Dr T Patila (tommi.patila@hus.fi)

NCT00644410
Trial name or title Autologous mesenchymal stromal cell therapy in heart failure
Methods A phase I/II, randomised, parallel, double-blind (participant, caregiver, investigator, outcome assessor) safety/
efficacy study

1. aged 30 - 80 years.
2. LVEF < 45%.
3. NYHA class II or III.
Interventions Treatment arm 1: Mesenchymal stromal cells 20 - 40 ml administered by electromechanical mapping (NOGA-
XP) and intramyocardial injections with the 8F-sized Myostar mapping-injection catheter
Treatment arm 2: Saline placebo.

Change in LVESV, measured by MRI or computed tomography (1/3/56/12 months)
Secondary outcomes:
1. LVEF, LVESV, LVEDV, wall thickness, systolic wall thickening measured by MRI or CT.
2. Myocardial scar tissue measured by MRI.
3. Safety of treatment.
4. Clinical symptoms.
5. Functional capacity.
6. Weekly angina attacks.
7. Use of short-term nitroglycerine.
8. Quality of life.
Starting date September 2008
Contact information Cardiac Stem Cell Laboratory and Catheterisation Laboratory 2014, Rigshospitalet, Copenhagen University
Hospital, Copenhagen, Denmark (Dr AB Mathiasen (abbe@dadlnet.dk)
Notes Estimated completion date: September 2013.
NCT00690209
Trial name or title Bypass surgery with stem cell therapy in chronic ischaemic cardiopathy
Methods A phase II, parallel, randomised, single-blind (participant) controlled study
Participants Ischaemic heart disease:

1. Aged 18 - 75 years.
2. Chronic IHD.
3. LVESV > 140 ml.
4. Poor global contractile function (LVEF < 40%).
5. Substantial amount of residual viability (> 30% of left ventricle).
Interventions Treatment arm 1: surgical revascularisation alone.

Treatment arm 2: surgical revascularisation associated with autologous bone marrow-derived stem cells injec-
tion in viable territories
Outcomes Primary outcome: Evolution of left ventricular volumes and contractility.

Secondary outcome: Functional status.
Starting date May 2008
Contact information Departments of CardiacSurgery, Cardiology and Radiology, University Hospital, Clermont-Ferrand, France
(Principal Investigator: Dr J Lipiecki. Contact: Patrick Lacarin (placarin@chu-clermontferrand.fr).
Notes Estimated completion date: June 2011.

NCT00747708
Trial name or title Bone marrow derived adult stem cells for chronic heart failure (REGEN-IHD)
Methods A phase II/III, randomised, parallel, double-blind (participant, investigator, outcome assessor), safety/efficacy
study
Participants Chronic ischaemic heart failure:

1. Symptomatic, with a diagnosis of heart failure secondary to ischaemic heart disease who are on optimal
heart failure treatment and no further treatment options available.
2. Participant has been considered for an implantable defibrillator in keeping with NICE guidelines.
Interventions Treatment arm 1: G-CSF injections followed by bone marrow aspiration. Intramyocardial injections of bone
marrow-derived stem/progenitor cells or placebo infusion through a percutaneous route
Treatment arm 2: G-CSF injections followed by bone marrow aspiration. Intramyocardial injections of placebo
infusion through a percutaneous route

Change in global LVEF (12 months).
Secondary Outcomes:
Change in quality of life (6 months).
Occurence of MACE (12 months).
Change in NT-proBNP (6 months).
change in NYHA class (12 months).
Contact information London Chest Hospital, Barts and the London NHS Trust, London, UK (Prinicpal Investigator: Anthony
Mathur)
Notes Estimated completion date: May 2013.
NCT00768066
Trial name or title The transendocardial autologous cells (hMSC or hBMC) in ischaemic heart failure Ttial (TAC-HFT)
Methods A phase I/II, randomised, parallel, double-blind (participant, investigator), safety/efficacy study

1. Diagnosis of chronic ischaemic left ventricular dysfunction secondary to MI.
2. Be a candidate for cardiac catheterisation.
3. Been treated with appropriate maximal medical therapy for heart failure or post-infarction left
ventricular dysfunction.
4. Ejection fraction 50%.
5. Able to perform a metabolic stress test.
Interventions Treatment arm 1: 40 million autologous human mesenchymal cells/mL delivered in either a dose of 0.25 mL
per injection for a total of 1 x 10 hMSCs x 10 injections or a dose of 0.5 mL per injection for a total of 2 x 10
x 10 injections. The injections will be administered transendocardially during cardiac catheterisation using
the Biocardia Helical Infusion Catheter
Treatment arm 2: 40 million autologous human bone marrow cells/mL delivered in either a dose of 0.25 mL
per injection for a total of 1 x 10 hBMCs x 10 injections or a dose of 0.5 mL per injection for a total of 2 x 10
x 10 injections. The injections will be administered transendocardially during cardiac catheterisation using
the Biocardia Helical Infusion Catheter
Treatment arm 3: 0.5 mL injections of phosphate-buffered saline (PBS) and 1% HSA x 10 injections. The
injections will be administered transendocardially during cardiac catheterisation using the Biocardia Helical
Infusion Catheter

Incidence of TE-SAE define as composite of death, non-fatal MI, stroke, hospitalisation for worsening heart
failure, cardiac perforation, pericardial tamponade, ventricular arrhythmias > 15 sec. or with haemodynamic
compromise or atrial fibrillation (1 month)
Secondary outcomes:
1. Infarct scar size and regional LV function (MRI) (6/12 months).
2. Wall thickening, LVEF, LVESV, LVEDV (MRI, echocardiogram) (6/12 months).
3. Myocardial perfusion (MRI) (6/12 months).
4. Peak VO
by treadmill determination (6/12 months).
5. 6-minute walk test (6/12 months).
6. NYHA functional class (6/12 months).
7. MLHF questionnaire (6/12 months).
8. Incidence of MACEs (6/12 months).
9. Ectopic tissue formation (6/12 months).
10. 48-hour ambulatory ECG recordings (6/12 months).
11. Haematology, clinical chemistry and urinalysis values (6/12 months).
12. Pulmonary function (forced expiratory volume in 1 second) (6/12 months).
13. Serial troponin and CK-MB values (6/12 months).
14. Post-cardiac catheterisation echocardiogram (day 1 post-catheterisation).
Contact information University of Miami Miller School of Medicine, Miami, Florida, US 33136 (Principal Investigators: Dr JM
Hare, Dr AW Heldman, Dr JP Zambrano)
Notes Estimated completed date: August 2012.
NCT00790764
Trial name or title Phase II combination stem cell therapy for the treatment of severe coronary ischaemia
Methods A phase II,randomised, placebo-controlled, safety/efficacy study
Participants Severe coronary ischaemia:

1. Age 18 to 80.
2. Men or women.
3. Angina pectoris: CCS Class III or IV or symptoms consistent with angina equivalent (dyspnoea) CCS
Class III or IV (Functional Class).
4. Chronic coronary artery disease in at least 1 epicardial vessel with stenosis > 70% by coronary
angiography within the last 6 months.
5. Stable medical therapy for at least 1 month.
6. Reversible perfusion defects by SPECT.
7. Not a candidate for coronary artery by-pass surgery due to poor targets or small vessels and not a
candidate for percutaneous intervention due to small vessels or unreachable coronary lesions due to
complicated anatomy.
Interventions Enrolled individuals (60) will be divided in 2 treatment groups for the infusion of the cell /placebo product:
1. Treatment Group A (30 individuals, including patients and placebo controls) will receive the product by
intracoronary infusion.
2. Treatment Group B (30 individuals, including patients and placebo controls) will receive the product by
transendocardial injections. In turn, each Treatment Group will consist of 2 subgroups of individuals that
will receive the infusion of 1 of the 2 doses established of the cell product:
3. In treatment SubGroup 1, 10 individuals will receive the low dose of the cell product and 5 individuals
will receive the placebo product.
4. In treatment SubGroup 2, 10 individuals will receive the high dose of the cell product and 5
individuals will receive the placebo product.
For the cell product, proper aliquots of each cell type will be taken to fulfill the doses established for this
protocol. The 2 aliquots will be mixed and resuspended to a final volume of 3 ml in the Final Suspension
Medium which consists of Dulbeccos Phosphate Buffered Saline (DPBS), containing 5% HSA
For placebo, 3 ml of the Final Suspension Medium which consists of Dulbeccos Phosphate Buffered Saline
(DPBS), containing 5% HSA will be transferred to a 5 ml syringe
Outcomes Primary Outcome: Safety as measured by laboratory assessments, ECG and temperature (2 weeks).
Secondary Outcome: Efficacy as measured by SPECT scan, MUGA scan and 2D echoradiogram (6 months)
Starting date November 2008.
Contact information TCA Cellular Therapy, Covington, Louisiana, United States, 70433 (Principal Investigator: Dr Patrick
Lacarin)
Notes Estimated completion date: November 2011.

NCT00820586
Trial name or title Intramyocardial delivery of autologous bone marrow.
Methods A phase II, parallel, randomised, double-blind (participant, investigator), safety/efficacy study
Participants Refractory angina:

1. Participants > 21 years old.
2. Participants with functional class (CCS) III or IV angina.
3. Participants with LVEF < 30%.
4. Attempted best tolerated medical therapy.
5. Clinical signs and symptoms of myocardial ischaemia with reversible ischaemia on perfusion imaging.
6. Participant deemed to be a poor candidate or at high surgical risk.
7. Participant must be able to complete a minimum of 2 minutes but no more than 10 minutes exercise
test (Bruce Protocol).
8. Participant (or their legal guardian) understands the nature of the procedure and provides written
consent prior to the procedure.
10. Participant must develop angina and a horizontal or down-sloping ST-segment depression of < 1 mm
during exercise, compared to pre-exercise ST segment, 80 ms from the J point or moderate angina with or
without the above ST segment changes.
Angiographic inclusion criteria:
1. Severe obstruction (lumen diameter stenosis > 70%) in a coronary or surgical conduit felt to be solely
or partially responsible for angina and myocardial ischaemia.
2. There must be at least 1 coronary or surgical conduit with < 70% diameter stenosis.
3. Poor candidate for PCI of treatment zone.
4. Poor candidates for surgical revascularisation procedures, such as inadequate target coronary anatomy
or lack of potential surgical conduits.
Interventions Treatment arm 1: Direct intramyocardial percutaneous delivery of autologous total bone marrow-derived total
mononuclear cells or selected CD34+ bone marrow-derived cells
Treatment arm 2: Not specified.

Incidence of major adverse cardiac events (MACE), defined as a combined endpoint of death, acute MI (Q-
wave and non-Q wave), revascularisation procedures (percutaneous or surgical), and periprocedural compli-
cations (i.e., left ventricular perforation with haemodynamic consequences requiring pericardiocentesis, and
stroke) (1/3/6/12 months)
Secondary Outcomes:
1. Change in CCS angina classification score from baseline (12 months).
2. Changes in the quality of life, as assessed according to the Seattle Angina Questionnaire.
3. Change in exercise duration and exercise tolerance using standardised treadmill exercise testing from
baseline (6/12 months).
4. Cumulative number of hospitalisations for coronary ischaemia and CHF (12 months).
5. SPECT-chances in global and regional radionuclide perfusion at rest, peak stress, and redistribution
from baseline (1/6/12 months).
6. Change in angiographic collateral score (6 months).
7. Change in global and regional myocardial contractility (assessed by echocardiography) from baseline
(6/12 months).
Contact information Antonio Colombo, Director of Invasive Cardiology Unit, IRCCS San Raffaele, Milan, Italy
Notes Estimated completion date: February 2012.

This study has suspended participant recruitment (due to lack of further funding support)
NCT00950274
Trial name or title Intramyocardial transplantation of bone marrow stem cells in addition to coronary artery bypass graft (CABG)
surgery (PERFECT)
Methods A phase III, randomised, parallel, double-blind (participant, caregiver, investigator, outcomes assessor) efficacy
study
Participants Chronic ischaemic coronary artery disease:

1. Coronary artery disease after myocardial infarction with indication for CABG surgery.
2. Currently reduced global LVEF assessed at site by cardiac MRI at rest (25% LVEF 50%).
3. Presence of a localised akinetic/hypokinetic/hypoperfused area of LV myocardium for defining the
target area.
4. Informed consent of the participant.
5. Aged 18 and < 80 years.
6. Not pregnant and do not plan to become pregnant during the study. Women with childbearing
potential must provide a negative pregnancy test within 1 - 7 days before OP and must be using oral or
injectable contraception (non-childbearing potential is defined as post-menopausal for at least 1 year or
surgical sterilisation or hysterectomy at least 3 months before study start).
Interventions Treatment arm 1: Intramyocardial injection of 5 mL CD133+ cells (0.5 - 5 x 10 cells) suspended in physio-
logical saline + 10% autologous serum intramyocardially during CABG surgery
Treatment arm 2: Intramyocardial injection of 5 mL of physiological saline + 10% autologous serum intramy-
ocardially during CABG surgery

LVEF at rest, measured by MRI (6 months).
Secondary Outcomes:
1. Change in LVEF as assessed by MRI and echocardiography (early postoperatively and 6 months).
2. Regional contractility in the AOI/Change in LVESD, LVEDD as assessed by echocardiography (early
postoperatively (discharge), 6 months).
3. Physical exercise capacity determined by 6-minute walk test (early postoperatively (discharge), 6
months).
4. NYHA and CCS class (early postoperatively (discharge), 6 months).
5. MACE (cardiac death, myocardial infarction, secondary intervention/reoperation, ventricular
arrhythmia) (6 months).
6. QoL-score: MLHF Questionnaire, SF-36 Questionnaire, EQ-5D Questionnaire (3 months, 6
months).
Starting date July 2009.
Contact information University of Rostock, Germany, 18057 (Principal Investigator: Dr G Steinhoff (gustav.steinhoff@med.uni-
rostock.de))
NCT01033617
Trial name or title IMPACT-CABG Trial: IMPlantation of Autologous CD133+ sTem cells in patients undergoing CABG
Methods A phase II, parallel, randomised, double-blind (participant, caregiver, investigator, outcomes assessor), placebo-
controlled safety/efficacy study
Participants Myocardial infarct; heart failure:

1. Age 18 years, and 75 years.
2. People with severe chronic ischaemic cardiomyopathy manifested by CCS class II or greater angina,
and/or NYHA class II or greater, and who have undergone diagnostic coronary angiography demonstrating
70% diameter narrowing of at least 2 major coronary arteries or branches or 50% diameter narrowing
of the left main coronary artery.
3. A significant left ventricular systolic dysfunction evaluated by echocardiography or LV angiography
(LVEF 45% but 25%) due to prior myocardial infarction. This area of left ventricular dysfunction
should be akinetic or severely hypokinetic, not dyskinetic or aneurismal, when assessed by echocardiography
or LV angiogram. This territory should be irrigated by 1 or a branch of the 3 major vascular territories (i.e.
right coronary artery, left circumflex, or left anterior descending artery distribution) that will be bypassed
during the surgical procedure.
4. No contraindications or exclusions (see below).
5. Willingness to participate and ability to provide informed consent.
Interventions Treatment arm 1: Autologous CD133+ stem cells (total 2 ml with 10 - 15 injections) injected into the
myocardium
Treatment arm 2: Placebo solution containing plasma injected into the myocardium

1. Freedom from MACE: cardiac death, myocardial infarct, repeat coronary bypass grafting or
percutaneous intervention of bypassed artery (6 months).
2. Freedom from major arrhythmia: sustained ventricular tachycardia or survived sudden death (6
months).
Secondary Outcomes:
1. Regional myocardial perfusion and function assessed by magnetic resonance scans (6 months).
2. Device performance endpoint: Feasibility to produce from 100 ml of bone marrow aspiration a final
cell product that contains a target CD133+ cells higher than 0.5 million with a purity superior to 30% and
a recovery superior to 10% (baseline).
3. Symptom severity and quality of life after CABG surgery (6 months).
Starting date December 2009.
Contact information Centre de recherche du CHUM (CRCHUM), Montreal, Quebec, Canada, H2W 1T8 (Principal Inves-
tigators: Dr N Noiseux, Dr S Mansour, Dr D-C Roy). Contact: Nicolas Noiseux, MD, MSc, FRCSC, (
noiseuxn@videotron.ca).
Notes Estimated completion date: July 2013.

This study is currently recruiting participants.
NCT01074099
Trial name or title Feasibility study of BMAC enhanced CABG
Methods A phase I/II randomised, single-blind (participant) safety/efficacy study

1. Age > 18 years and ability to understand the planned treatment.
2. People with ischaemic congestive heart failure requiring bypass surgery.
3. Congestive heart failure with LVEF 40%.
4. Serum bilirubin, SGOT and SGPT 2.5 time the upper level of normal.
5. Serum creatinine < 3.0 or no dialysis.
6. NYHA performance status 3.
7. Negative pregnancy test (in women with childbearing potential).
8. Participant has read and signed the IRB-approved Informed Consent form
9. Hematocrit 28.0%, WBC count 14,000, Platelet count 50,000, Creatinine 3.0 mg/Dl, and/
or no dialysis, INR 1.6 unless on Coumadin, or PTT < 1.5 x control (to avoid bleeding complications).
Participants on Coumadin will be corrected prior to the procedure and must have an INR < 1.6 at the time
of randomisation/surgery.
Interventions Treatment arm 1: 60 mL of bone marrow drawn, concentrated in a SmartPRep2 centrifuge and concentrated
nucleated cells injected into areas of ischaemic myocardium during CABG
Treatment arm 2: CABG only.

1. Change in cardiac status (classification) (12 months).
2. NYHA or CCS classification evaluation.
Secondary Outcome: Safety as measured by frequency and severity of adverse events (12 months
Starting date February 2011.
Contact information Harvest Technologies, University of Utah (Principal Investigator: Amit Patel, MD)
Notes Study terminated (pilot results in change to protocol, new study needed)
NCT01150175
Trial name or title Direct endomyocardial injection of autologous bone marrow cells to treat ischaemic heart failure (END-HF)
Methods A phase II, randomised, double-blind (participant, investigator), parallel safety/efficacy study

1. Age 18 - 80 years old.
2. CCS Class II - IV angina and/or NYHA class II - III HF symptoms.
3. Received stable and best cardiac medical therapy including long-acting nitrates, beta-blocker, and
ACE inhibitors without control of symptoms.
4. Not suitable for conventional revascularisation by their referring cardiologist.
5. LVEF < 40% by echocardiography.
6. Recent coronary angiogram (within the last 6 months) to document the coronary anatomy and insure
the presence of CAD that is not amenable to standard revascularisation procedures.
7. Creatinine < 250 mmol/L, normal liver function, and normal blood count: WBC, granulocytes;
platelet count, Hb.
8. Reversible perfusion defect on SPECT.
9. Able to walk on treadmill.
10. Haemodynamically stable.
12. All participants give written informed consent.
Interventions Treatment arm 1: Endomyocardial injection of autologous bone marrow cells.

Treatment arm 2: Endomyocardial injection of plasma.

MRI ejection fraction changed from baseline (6 months).
Secondary Outcomes:
Changes in exercise duration and MVO using standardised treadmill testing (modified Bruce protocol) from
baseline (6 months)
Contact information University of Hong Kong (Principal Investigator: Prof HF Tse). Contact: Dr T Santoso (tsantoso@cbn.net.id)
.

NCT01214499
Trial name or title Prospective, controlled and randomised clinical trial on cardiac cell regeneration with laser and autologous
bone marrow stem sells, in patients with coronary disease and refractory angina
Methods A phase II, randomised, single-blind (outcome assessor), parallel safety/efficacy study
Participants Coronary disease and refractory angina:

1. Aged > 18 years of age.
2. At least 1 area of myocardial ischaemia or chronic myocardial infarction of the left ventricle
demonstrated by any imaging technique not amenable to conventional revascularisation and angina
refractory to medical treatment.
3. LVEF > 25% measured in the 6 months prior to the procedure.
4. Participants must be mentally competent to give consent for inclusion in the clinical trial.
Interventions Treatment arm 1: Transmyocardial revascularisation (TMR) with Holmium YAG laser plus the participants
own stem cells extracted from bone marrow
Treatment arm 2: Transmyocardial revascularisation (TMR) with Holmium YAG laser

NYHA classification for angina (12 months).
Secondary Outcomes:
1. The demographic, intra and postoperative variables (12 months).
2. Percentage of ischaemic area (SPECT) and maximum effort capacity before the occurrence of the
angina (12 months).
3. LVEF, LVESV, LVEDV will be examined through an echocardiogram and a pre- and postoperative
cardiac magnetic resonance imaging study (12 months).
4. The EQ-5D questionnaire (standardised instrument for use as a measure of health outcome) will be
completed for the subjective assessment of the quality of life that the participant perceives to have (12
months).
Starting date October 2010.
Contact information Cardiovascular Surgery Service, Hospital Universitario de La Princesa, Madrid, Spain, 28006 (Principal
Investigator: Dr GR Copa (guillermoreyescopa@yahoo.es)).
Notes Estimated completion date: October 2012.

NCT01267331
Trial name or title Cell therapy in patients with chronic ischaemic heart disease undergoing cardiac surgery
Methods A phase I/II, randomised, double-blind (participant, caregiver), parallel safety/efficacy study
Participants Severe, chronic ischaemic disease:

1. Aged between 18 and 75 years.
2. Scheduled to undergo CABG.
3. At least 3 months since last episode of myocardial infarction.
4. Echocardiogram-assessed LVEF between 15% and 40% (Simpsons rule).
5. Abnormal wall motion of at least 1 segment due to prior myocardial infarction shown by
echocardiography or left ventriculography.
6. Abnormal myocardial perfusion in infarcted area by SPECT.
7. Willingness to participate and ability to provide written informed consent.
Interventions Treatment arm 1: Direct intramyocardial injection of autologous bone marrow mononuclear cells during
CABG
Treatment arm 2: Between 10 and 15 placebo injections that consist of saline and 5% HSA during CABG

Major adverse cardiac events (6 months)/
Secondary Outcomes:
Left ventricular function (global function, regional myocardial perfusion and function assessed by magnetic
resonance imaging and echocardiogram (6 months))
Starting date December 2010
Contact information Chinese PLA General Hospital, Beijing, China (Principal Investigator: Dr C Gao (gaochq301@yahoo.com)
and Dr L Zhang (drzhanglin@gmail.com)).
Notes Estimated completion date: June 2013
NCT01299324
Trial name or title Retrograde delivery of BMAC (bone marrow aspirate concentrate) for congestive heart failure
Methods A phase I, randomised, open-label, cross-over safety study.

1. Age 18 years and ability to understand the planned treatment.
2. People with congestive heart failure.
3. LVEF 40% by echocardiogram, per ECHO completed 30 days prior to treatment.
4. Symptomatic heart failure NYHA class III or IV.
5. Able to comply with all study-related visits.
6. Able to tolerate study procedures, including bone marrow aspiration, SPECT.
7. Able to give informed consent.
8. Negative for HcG with a serum pregnancy test.
9. Participants with controlled diabetes mellitus (HbA1c < 9.0%).
10. Hematocrit 28.0%, WBC count 14,000, Platelet count 50,000.
11. Life expectancy of 6 months or more in the opinion of the investigator
12. Participants requiring high-dose corticosteroid therapy (more than 7.5 mg/day) with 1 month before
the aspiration or 6 months after the infusion.
13. Serum bilirubin, ALT, AST 2.5 time the upper level of normal.
14. Controlled blood pressure (systolic blood pressure 140 and a diastolic blood pressure of 90
mmHG) and established anti-hypertensive therapy as necessary prior to entry into the study.
15. Participant has received stable, standard medical therapy for at least 1 month with no new medications
to treat the disease introduced in the last 3 months.
16. Pre-existing condition (e.g. thromboembolic risk, diabetes, hypercholesterolaemia are adequately
controlled in the opinion of the investigator).
17. Fertile participants (male and female) must agree to use an appropriate form of contraception while
participating in the study.
Interventions Treatment arm 1: Infusion of autologous BMAC nucleated cells into the coronary sinus
Treatment arm 2: Control (no infusion)

Number of participants with adverse events as a measure of safety and tolerability (12 months).
Secondary Outcomes:
1. Effect of the infusion of bone marrow nucleated cells on the clinical course of angina (as measured by
QOL questionnaire, MLHF questionnaire, NYHA and CCS classification and SPECT) (12 months).
2. Effect of the infusion of bone marrow nucleated cells on the clinical course of heart failure (as measured
by QOL questionnaire, MLHF questionnaire, NYHA and CCS classification and SPECT) (12 months).
Starting date February 2011.
Contact information Harvest Technologies (Dr Amit Patel, Principal Investigator). Contact: Kevin Benoit (pkbenoit@harvesttech.
com)
Notes Estimated completion date: October 2014.
NCT01337011
Trial name or title Intra-coronary versus intramyocardial application of enriched CD133pos autologous bone marrow derived
stem cells (AlsterMACS)
Methods A phase I/II, parallel, randomised, single-blind (participant) study
Participants Chronic ischaemic cardiomyopathy:

1. Aged 18 to 80 years old.
2. Both genders.
3. Reduced LVEF as evaluated by routine clinical angiogram, echocardiography or MRI ( 45%) due to
ischaemic heart disease.
4. Symptomatic heart failure NYHA II on optimal therapy.
5. Coronary artery in the target region that can be used for cell infusion.
6. Participant has been informed of the nature of the clinical trial and agrees to its provision and has
provided written informed consent.
Interventions Treatment arm 1: Intracoronary administration of autologous CD133+ stem cells

Treatment arm 2: Intramyocardial administration of autologous CD133+ stem cells
Outcomes Primary Outcome: Change in LVEF measured via echocardiography (6 months).

Secondary Outcomes:
1. The application of CD133pos cells into the coronary system or intra-myocardial via the NOGA
system is safe and feasible; the route of application of CD133pos cells has no effect on MACE (5 years).
2. Decrease of brain natriuretic peptide (6/12 months).
3. Improvement of 6-minute walk (6/12 months).
4. Improvement of peak oxygen consumption (6/12 months).
5. The application of CD133pos cells intra-myocardial is equally effective to the intracoronary
application route regarding LV function (6/12 months).
6. Improvement of LV function as measured by cardiacMRI (6/12 months).
Contact information Asklepios proresearch, ASKLEPIOS Klinik St. Georg, Hamburg, Germany, 20099 (Principal Investigator:
Dr Martin Bergmann (mar.bergmann@asklepios.com)).
NCT01354678
Trial name or title Intramyocardial multiple precision injection of bone marrow mononuclear cells in myocardial ischaemia
(IMPI)
Methods A phase I, parallel, randomised, double-blind (participant, caregiver, investigator), safety/efficacy study

1. Participants with coronary artery disease (CAD) and HF II - III NYHA class.
2. MI > 6 months before the study.
3. LVEF < 35%.
4. Absence of indication to coronary revascularisation.
5. Optimal pharmacological therapy no less than 8 weeks.
6. Heart transplantation is contraindicated.
7. Partcicipants with implantable cardioverter-defibrillator (ICD) or cardiac resynchronisation therapy
defibrillator (CRT-D).
8. Participants giving informed consent.
Interventions Treatment arm 1: Intramyocardial multiple precision injection of bone marrow mononuclear cells
Treatment arm 2: Intramyocardial multiple precision injection with placebo.
Outcomes Primary Outcome: Change in global LVEF and regional wall motion score index (6/12 months).
Secondary Outcomes: Incidence of the major adverse cardiac events (6/12 months)
Starting date May 2011.
Contact information Almazov Federal Center of Heart, Blood and Endocrinology (Principal Investigator: Prof EV Shlyakhto).
Contact: Prof DS Lebedev (lebedevdmitry@mail.ru); Prof OM Moiseeeva (moiseeva@almazovcentre.ru).
Notes Estimated completion date: May 2015.
NCT01442129
Trial name or title The effect of intramyocardial injection of mesenchymal precursor cells on myocardial function in patients
undergoing LVAD Implantation
Methods A phase II, randomised, parallel, multicentre, double-blind (participant, caregiver, investigator, outcomes
assessor), safety/efficacy study
Participants Heart failure, cardiomyopathy and ventricular dysfunction:

1. Signed informed consent, inclusive of release of medical information, and Health Insurance Portability
and Accountability Act (HIPAA) documentation.
2. Aged 18 years or older.
3. If the participant or partner is of childbearing potential, he or she must be willing to use adequate
contraception (hormonal or barrier method or abstinence) from the time of screening and for a period of at
least 16 weeks after procedure.
4. Women of childbearing potential must have a negative serum pregnancy test at screening.
5. Admitted to the clinical centre at the time of randomisation.
6. Clinical indication and accepted candidate for implantation of an FDA-approved implantable, non-
pulsatile LVAD as a bridge to transplantation or for destination therapy.
Interventions Treatment arm 1: Intramyocardial injection of 25 million mesenchymal precursor cells at the time of LVAD
implantation
Treatment arm 2: Injection of control solution during LVAD implantation.

Intervention-related adverse events (90 days).
Secondary Outcomes:
Functional status and ventricular function (90 days).
Starting date April 2012.
Contact information Multicentre study (Study Chairs: Dr T Gardner, Christiana Care Health Services; Dr P O-Gara, Brigham
and Womens Hospital)
Notes Estimated completion date: March 2014.
NCT01508910
Trial name or title Efficacy and safety of targeted intramyocardial delivery of auto CD34+ stem cells for improving exercise
capacity in subjects with refractory angina (RENEW)
Methods A phase III, randomised, parallel, double-blind (participant, investigator), safety/efficacy study
Participants Refractory angina and chronic myocardial ischaemia:

1. Men or women who are 21 - 80 years of age at the time of signing the informed consent.
2. Participants with CCS class III or IV chronic refractory angina.
3. Participants without control of their angina symptoms in spite of maximal tolerated doses of anti-
angina drugs. Participants must be on optimal therapy for their angina and must have been on a stable anti-
anginal medication regimen for at least 4 weeks before signing the informed consent form.
4. Participants with obstructive coronary disease unsuitable for conventional revascularisation due to
unsuitable anatomy or comorbidity as determined at the site and confirmed by an independent adjudication
committee.
5. Participants must have evidence of inducible myocardial ischaemia.
6. Participants must experience angina episodes.
7. Participants must be able to complete 2 exercise tolerance tests on the treadmill within 3 weeks of
randomisation.
8. If a woman of childbearing potential, she must not be pregnant and must agree to employ adequate
birth control measures for the duration of the study.
Interventions Treatment arm 1: Targeted intramyocardial delivery of 1 x 10 Auto-CD34+ cells after G-CSF mobilisation
and apheresis
Treatment arm 2: Targeted intramyocardial delivery of placebo after G-CSF mobilisation and apheresis

Change from baseline in total exercise time on exercise tolerance test (ETT) using the Modified Bruce Protocol
(12 months).
Secondary Outcomes:
1. Angina frequency (episodes per week) (3/6/12 months).

2. Change from baseline in total exercise time on ETT (6 months).
3. Incidence of MACEs and other serious adverse events in all participants (24 months).
Contact information Baxter Healthcare Corporation (Study Director: Dr A Nada). Contact: Lauren Davis, Clinical Project Manager
(lauren.davis@ppdi.com)
NCT01615250
Trial name or title Implantation of peripheral stem cells in patients with ischaemic cardiomyopathy (ISCIC)
Methods A phase I, randomised, parallel, open-label safety/efficacy study
Participants Ischaemic cardiomyopathy:

1. People with ischaemic cardiomyopathy and HF II-IV NYHA class.
2. MI > 6 months before the study.
3. LVEF < 35%.
4. Absence effect of coronary revascularisation during 6 months.
5. Optimal pharmacological therapy no less than 8 weeks.
6. Heart transplantation is contraindicated.
7. Participants with implantable cardioverter-defibrillator (ICD) or cardiac resynchronisation therapy
defibrillator (CRT-D).
8. Participants giving informed consent.
Interventions Treatment arm 1: Intramyocardial implantation of peripheral mononuclear cells with CD34+ stem cells in
participant with ischaemic cardiomyopathy after preparatory course of shock-wave therapy
Treatment arm 2: Cardiospec shock-wave therapy only.

Change in global LVEF and regional wall motion score index (6/12 months).
Secondary Outcomes:
Incidence of MACEs (6/12 months).
Contact information Odessa Regional Clinical Hospital, Odessa, Ukraine, 65025 (Principal Investigator: Prof II Karpenko (ar-
card2@gmail.com))
Notes Estimated completion date: January 2016.
NCT01660581
Trial name or title Intracardiac CD133+ cells in patients with no-option resistant angina (Regent Vsel)
Methods A phase II, randomised, parallel, double-blind (participant, investigator), efficacy study
Participants Stable angina:

1. Stable angina CCS II - IV despite maximum pharmacotherapy for at least 2 weeks since last
medications change.
2. Presence of 1 myocardial segment with ischaemia features in Tc-99m SPECT.
3. Participants disqualified from revascularisation procedures by Heart Team.
4. Aged > 18 and < 75 years old.
5. Participant must provide written informed consent for participation in study.
Interventions Treatment arm 1: Intramyocardial injection (electromechanical mapping-based) of autological CD133+ cells,
isolated from bone marrow
Treatment arm 2: Intramyocardial injection (electromechanical mapping-based) of placebo - 0.9% NaCl plus
0.5% solution of participants serum

Myocardial perfusion change (4 months).
Secondary Outcomes:
1. Global and segmental contractility change and myocardial perfusion change (MRI: 4 months;
echocardiography: 4/12 months).
2. Exercise tolerance (4/12 months).
3. Occurrence of symptomatic angina (1/4/6/12 months).
4. Quality of life (1/4/6/12 months).
5. Occurrence of ventricular arrhythmia (1/4/6/12 months).
6. Occurrence of in-stent restenosis and progression of atherosclerotic lesions in remained coronary artery
segments (4 months).
Starting date June 2012
Contact information Samodzielny Publiczny Szpital Kliniczny nr 7 l skiego Uniwersytetu Medycznego w Katowicach Grno
l skie Centrum Medyczne im. prof. Leszka Gieca, Katowice-Ochojec, Silesian, Poland, 40-635 (Principal
Investigator: Prof W Wojakowski (wojtek.wojakowski@gmail.com))
NCT01666132
Trial name or title METHOD - bone marrow derived mononuclear cells in chronic ischaemic disease
Methods A phase I/II, randomised, cross-over, open-label, safety/efficacy study
Participants Chronic ischaemic heart disease:

1. Chronic cardiac ischaemic disease at least 4 months after 1 or more myocardial infarctions in a stable
phase of the disease without option for revascularisation.
2. LVEF at echocardiography 40%.
3. Significant regional LV wall motion dysfunction in the infarct-related territory.
4. Symptoms NYHA II - IV or CCS II - III (at least class III according to one of the 2 classifications).
5. Participant agrees to comply with all follow-up evaluations.
6. Age > 18 years old.
7. Participant has been informed of the nature of the clinical trial and agrees to its provision and has
provided written informed consent.
Interventions Treatment arm 1: Intramyocardial, NOGA-guided injection on BM cells.

Treatment arm 2: Combination of intramyocardial, NOGA-guided injection of BM cells and intracoronary
injection of those cells
Treatment arm 3: Initially no intervention; cross-over to therapy 6 months after enrolment

Troponin samples (1 day after cell injection).
Number of participants with adverse events at short term (within 1 week after cell injection).
Number of participants with adverse events at mid/long term (up to 12 months after cell injection).
Secondary Outcomes:
Change in LVEF (6 months) (Designated as safety issue: Yes).
First 10 participants + following randomisation phase (n = 54); assessment of short-term safety (1 week) and
adverse events (within 1 year).
Change in Vo2 max (6 months).
Contact information Cardiocentro Ticino, Lugano, Switzerland, 6900 (Principal Investigator: Dr T Moccetti). Contact: Dr D
Suerder (daniel.suerder@cardiocentro.org)
Notes Estimated completion date: February 2014.
NCT01727063
Trial name or title Cell therapy in severe chronic ischaemic heart disease (MiHeart)
Methods A phase II/III, randomised, parallel, double-blind (participant, investigator), safety/efficacy study
Participants Chronic ischaemic heart disease:

1. Symptoms of angina or angina equivalent.
2. Documented coronary artery disease (invasive angiography).
3. Documented myocardial ischaemia (stress echo, cardiac scintigraphy, or MRI).
4. Unsuitable for complete myocardial revascularisation (PCI or CABG) OR even if a complete
procedure is feasible, it is anticipated that myocardial perfusion may not be restored due to poor distal beds.
Interventions Treatment arm 1: Intramyocardial injection of autologous bone marrow-derived cells

Treatment arm 2: Saline injection.

Increase in myocardial perfusion assessed by MRI (1/6/12 months).
Secondary Outcomes:
1. Improvement in LV function assessed by MRI (1/6/12 months).

2. Improvement in angina functional class determined using the CCS classification (1/6/12 months).
Contact information Heart Institute, Sao Paulo, SP, Brazil 05403-000 (Principal Investigator: Prof LHW Gowdak). Contact:
Meyrielli A Vieira (meyri.vieira@incor.usp.br); Prof LHW Gowdak (luis.gowdak@incor.usp.br)
NCT01768702
Trial name or title Safety and efficacy of autologous cardiopoietic cells for treatment of ischaemic heart failure. (CHART-1)
Methods A phase III, randomised, parallel, double-blind (participant, outcomes assessor), safety/efficacy study

1. Age 18 and < 80 years.
2. Systolic dysfunction with LVEF 30% as assessed by echocardiography.
3. Ischaemic heart failure without known need for revascularisation.
4. MLHFQ score > 30.
5. Ability to perform a 6-minute walk test > 100 m and 400 m.
6. History of hospitalisation for HF within 12 months prior to screening.
7. NYHA Class III or IV despite optimal standard of care or INTERMACS class 4, 5, 6 or 7.
8. Use of ACE inhibitor and/or ARB and beta blocker, for at least 3 months prior to screening visit,
unless intolerant or contraindicated.
9. Stable dosing of ACE inhibitor, ARB , beta blocker, aldosterone blocker,and diuretics for at least 1
month prior to screening visit, defined as 50% change in total dose of each agent.
10. Willing and able to give written informed consent.
Interventions Treatment arm 1: Injection of C3BS-CQR-1 cardiopoietic cells using the C-Cath injection catheter
Treatment arm 2: Mimic injection procedure through insertion of a sham catheter. No injection actually
performed

Efficacy between groups post-index procedure: change between groups from baseline in a hierarchical com-
posite outcome comprising, from most to least severe outcome, days to death from any cause, number of
worsening of heart failure events, change in score for the MLHF questionnaire (10-point deterioration, no
meaningful change,10-point improvement), change in 6-minute walk distance (40 m deterioration, no mean-
ingful change, 40 m improvement) and change in LVESV (15 mL deterioration, no meaningful change, 15
mL improvement), and LVEF (4% absolute deterioration, no meaningful change, 4% absolute improvement)
(39 weeks).
Secondary Outcomes:
1. Efficacy (time to all-cause mortality, time to worsening of heart failure, and time to aborted sudden
death) and safety (number and cause of deaths and readmissions, number of cardiac transplantations,
number of myocardial infarctions, number of strokes. Incidence of serious AEs and non-serious AEs)
between groups post-index procedure (52/104 weeks).
2. Efficacy and safety between groups post-index procedure (time to all-cause mortality, time to
cardiovascular mortality, and rate of worsening heart failure requiring outpatient IV therapy for heart failure
or readmission for heart failure, and other) (39/52 weeks post-index).
Starting date November 2012.
Contact information Multicentre study: Cardio3 Biosciences (Study Chairs: Dr A Terzic, Mayo Clinic, Division of Cardiovascular
Diseases, Rochester, MN, USA and Dr J Bartunek, OLV Ziekenhuiz Aalst, Belgium). Contact: Dr Christian
Homsy (chomsy@c3bs.com)
Notes Estimated completion date: March 2017.
NTR2516
Trial name or title Injection of autologous bone marrow cells into damaged myocardium of no-option patients with ischaemic
heart failure; a randomised placebo-controlled trial
Methods A randomised, parallel, double-blinded, placebo-controlled trial
Participants Heart failure:

1. Ischaemic heart failure NYHA class 2, 3 or 4 despite optimal pharmacological and non-
pharmacological therapy.
2. No candidate for (repeat) surgery (revascularisation, valve repair or ventricular reconstruction).
3. No candidate for (repeat) percutaneous revascularisation.
4. Optimal resynchronisation therapy or no candidate for resynchronisation therapy.
5. Men or women, > 18 years and < 75 years old.
6. Life expectancy > 6 months.
7. Able to perform an exercise tolerance test prior to therapy.
8. Able and willing to undergo all the tests used in this protocol including the travelling involved.
9. Written informed consent.
Interventions Treatment arm 1: Intramyocardial injection of autologous bone marrow-derived mononuclear cells via NOGA
mapping
Treatment arm 2: Intramyocardial injection of placebo via NOGA mapping.

Change in LVEF relative to baseline (3 months).
Secondary outcomes:
1. NYHA grading of heart failure.
2. Quality of life.
3. Exercise capacity.
4. CCS score.
5. Regional myocardial perfusion at 3 months follow-up.
6. Viability and sympatic innervation at 3 months follow-up.
7. Occurence of arrhythmias.
8. Pericardial effusion > 5 mm (echo).
9. Myocardial damage.
10. Severe inflammation.
NTR2516 (Continued)
Contact information Leiden University Medical Center, Department of Cardiology, PO Box 9600, 2300 RC, Leiden, The Nether-
lands (Principal Investigator: Dr DE Atsma)
ACE: angiotensin converting enzyme; AE: adverse events; AICD: automatic implantable cardioverter defibrillator; AMI: acute my-
ocardial infarction; ARB: angiotensin receptor blocker; AST: aspartate transaminase ;BMAC: bone marrow aspirate concentrate;
BMMNC: bone marrow mononuclear cells; BMSC: bone marrow-derived stem cells; BNP: brain natriuretic peptide; CABG: coro-
nary artery bypass grafting; CCS: Canadian Cardiovascular Society; CMR: cardiac magnetic resonance; CPC: circulating progenitor
cells; ECG: electrocardiogram; EDTA: ethylene-diamine-tetraacetic acid; EPC: endothelial progenitor cells; G-CSF: granulocyte-
colony stimulating factor; HcG: human chorionic gonadotrophin; HSA: human serum albumin; IC: intracoronary; IM: intramus-
cular; InterMACS: Interagency Registry for Mechanically Assisted Circulatory Support; LVAD: left ventricular assist device; LVEF:
left ventricular ejection fraction, LVEDV: left ventricular end diastolic volume; LVESV: left ventricular end systolic volume; MACE:
major adverse clinical events; MLHFQ: Minnesota Living with Heart Failure Questionnaire; MRI: magnetic resonance imaging;
MSC: mesenchymal stem cells; MUGA: multigated radionuclide angiography: MVO : myocardial oxygen consumption; NYHA:
New York Heart Association; PCI: percutaneous coronary intervention; PET: positron emission tomography ; RCT: randomised
controlled trial; SGOT: serum aspartic aminotransferase; SGPT: serum glutamate pyruvate transaminase ;SPECT: single-photon
emission computed tomography; WBC: white blood cell.
DATA AND ANALYSES
Comparison 1. Stem cells versus no stem cells
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Mortality (any) 22 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Short-term follow-up (< 21 1138 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.32, 1.41]
12 months)
1.2 Long-term follow-up ( 8 494 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.14, 0.53]
12 months)
2 LVEF (%): Short-term follow- 18 Mean Difference (IV, Fixed, 95% CI) Subtotals only
up (< 12 months)
2.1 Mean change from 10 435 Mean Difference (IV, Fixed, 95% CI) 2.93 [2.02, 3.83]
baseline
2.2 Mean at endpoint 8 311 Mean Difference (IV, Fixed, 95% CI) 7.03 [5.70, 8.36]
2.3 Combined 18 746 Mean Difference (IV, Fixed, 95% CI) 4.22 [3.47, 4.97]
3 LVEF (%): Long-term follow-up 6 Mean Difference (IV, Fixed, 95% CI) Subtotals only
( 12 months)
3.1 Mean change from 3 153 Mean Difference (IV, Fixed, 95% CI) 5.68 [1.65, 9.71]
baseline
3.2 Mean at endpoint 3 101 Mean Difference (IV, Fixed, 95% CI) 1.45 [-1.04, 3.94]
4 Adverse effects 18 999 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.67, 1.44]
12 months)
12 months)
5 Infarction 17 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
12 months)
12 months)
6 Rehospitalisation due to heart 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
failure
12 months)
12 months)
7 Angina episodes per week: short 5 Mean Difference (IV, Fixed, 95% CI) Subtotals only
term follow-up (<12 months)
7.1 Mean change from 1 32 Mean Difference (IV, Fixed, 95% CI) -3.60 [-12.80, 5.60]
baseline
7.2 Mean value at endpoint 4 397 Mean Difference (IV, Fixed, 95% CI) -4.72 [-7.22, -2.22]
7.3 Combined 5 429 Mean Difference (IV, Fixed, 95% CI) -4.64 [-7.06, -2.23]
8 NYHA Classification: short- 11 Mean Difference (IV, Random, 95% CI) Subtotals only
term follow-up (< 12 months)
8.1 Mean value at endpoint 11 486 Mean Difference (IV, Random, 95% CI) -0.63 [-1.08, -0.19]
9 NYHA Classification: long-term 4 Mean Difference (IV, Random, 95% CI) Subtotals only
9.1 Mean value at endpoint 4 196 Mean Difference (IV, Random, 95% CI) -0.91 [-1.38, -0.44]
10 CCS class: short-term follow- 8 Mean Difference (IV, Random, 95% CI) Subtotals only
up (< 12 months)
10.1 Mean change from 4 198 Mean Difference (IV, Random, 95% CI) -1.26 [-2.06, -0.46]
baseline
10.2 Mean value at endpoint 4 181 Mean Difference (IV, Random, 95% CI) -0.55 [-1.54, 0.45]
10.3 Combined 8 379 Mean Difference (IV, Random, 95% CI) -0.81 [-1.55, -0.07]
11 Exercise capacity: short-term 11 Std. Mean Difference (IV, Random, 95% CI) Subtotals only
follow-up (< 12 months)
11.1 Mean change from 7 464 Std. Mean Difference (IV, Random, 95% CI) 0.22 [-0.13, 0.58]
baseline
11.2 Mean value at endpoint 8 429 Std. Mean Difference (IV, Random, 95% CI) 0.58 [0.15, 1.02]
12 Exercise capacity: long-term 5 Std. Mean Difference (IV, Random, 95% CI) Subtotals only
12.1 Mean change from 1 156 Std. Mean Difference (IV, Random, 95% CI) 0.39 [0.05, 0.73]
baseline
12.2 Mean value at endpoint 4 158 Std. Mean Difference (IV, Random, 95% CI) 0.97 [-0.33, 2.27]
13 LVESV (ml): short-term 13 Mean Difference (IV, Fixed, 95% CI) Subtotals only
baseline
13.2 Mean at endpoint 5 224 Mean Difference (IV, Fixed, 95% CI) -13.72 [-20.46, -6.
97]
13.3 Combined 13 470 Mean Difference (IV, Fixed, 95% CI) -5.47 [-8.81, -2.14]
14 LVESV (ml): long-term follow- 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
up ( 12 months)
baseline
14.2 Mean at endpoint 2 131 Mean Difference (IV, Fixed, 95% CI) -17.25 [-24.66, -9.
85]
14.3 Combined 3 153 Mean Difference (IV, Fixed, 95% CI) -14.64 [-20.88, -8.
39]
15 LVEDV (ml): short-term 14 Mean Difference (IV, Fixed, 95% CI) Subtotals only
15.1 Mean change from 8 246 Mean Difference (IV, Fixed, 95% CI) 3.45 [-1.30, 8.19]
baseline
15.2 Mean at endpoint 6 244 Mean Difference (IV, Fixed, 95% CI) -3.36 [-12.49, 5.77]
15.3 Combined 14 490 Mean Difference (IV, Fixed, 95% CI) 2.00 [-2.21, 6.21]
16 LVEDV (ml): long-term 3 Mean Difference (IV, Fixed, 95% CI) Subtotals only
baseline
16.2 Mean at endpoint 2 148 Mean Difference (IV, Fixed, 95% CI) -3.88 [-15.70, 7.93]
16.3 Combined 3 170 Mean Difference (IV, Fixed, 95% CI) -3.30 [-13.11, 6.51]
17 Stroke volume index: short 4 Mean Difference (IV, Fixed, 95% CI) Subtotals only
term follow-up (<12 months)
17.1 Mean change from 2 86 Mean Difference (IV, Fixed, 95% CI) 2.33 [-1.26, 5.92]
baseline
18 Stroke volume index: long term 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
follow-up (12 months)
Comparison 2. Cell dose: subgroup analysis
No. of No. of
1 LVEF (%): short-term follow-up 16 747 Mean Difference (IV, Fixed, 95% CI) 4.01 [3.28, 4.74]
(< 12 months)
1.1 Dose < 10 3 95 Mean Difference (IV, Fixed, 95% CI) 5.48 [2.74, 8.23]
1.2 Dose 10 to 10 11 426 Mean Difference (IV, Fixed, 95% CI) 4.12 [3.22, 5.01]
1.3 Dose 10 to 10 5 226 Mean Difference (IV, Fixed, 95% CI) 3.38 [2.00, 4.77]
2 NYHA Classification: short- 10 435 Mean Difference (IV, Random, 95% CI) -0.63 [-1.08, -0.19]
2.1 Dose < 10 3 95 Mean Difference (IV, Random, 95% CI) -0.53 [-1.20, 0.14]
2.2 Dose 10 to 10 6 264 Mean Difference (IV, Random, 95% CI) -0.74 [-1.40, -0.07]
2.3 Dose 10 to 10 2 76 Mean Difference (IV, Random, 95% CI) -0.49 [-1.15, 0.18]
Comparison 3. Baseline cardiac function: subgroup analysis
No. of No. of
(< 12 months)
1.1 Baseline LVEF <30% 4 228 Mean Difference (IV, Fixed, 95% CI) 5.40 [3.81, 6.99]
1.2 Baseline LVEF 30-50% 11 386 Mean Difference (IV, Fixed, 95% CI) 4.36 [3.28, 5.45]
1.3 Baseline LVEF >50% 2 63 Mean Difference (IV, Fixed, 95% CI) 4.65 [2.47, 6.84]
2.1 Baseline LVEF < 30% 2 144 Mean Difference (IV, Random, 95% CI) -1.41 [-1.68, -1.14]
2.2 Baseline LVEF 30 - 50% 8 273 Mean Difference (IV, Random, 95% CI) -0.48 [-0.82, -0.14]
Comparison 4. Route of cell administration: subgroup analysis
No. of No. of
(< 12 months)
1.1 Intracoronary 9 365 Mean Difference (IV, Fixed, 95% CI) 3.19 [2.19, 4.19]
1.2 Intramyocardial 10 388 Mean Difference (IV, Fixed, 95% CI) 5.30 [4.21, 6.40]
2.1 Intracoronary 5 255 Mean Difference (IV, Random, 95% CI) -0.40 [-0.85, 0.04]
2.2 Intramyocardial 6 231 Mean Difference (IV, Random, 95% CI) -0.83 [-1.43, -0.23]
Comparison 5. Cell type: subgroup analysis
No. of No. of
(< 12 months)
1.1 Mononuclear cells 13 606 Mean Difference (IV, Fixed, 95% CI) 3.77 [2.91, 4.63]
1.2 Circulating progenitor 3 73 Mean Difference (IV, Fixed, 95% CI) 1.58 [-0.01, 3.17]
cells
1.3 Haematopoietic 2 40 Mean Difference (IV, Fixed, 95% CI) 8.44 [6.11, 10.78]
progenitor cells
1.4 Mesenchymal stem cells 1 45 Mean Difference (IV, Fixed, 95% CI) 6.0 [3.08, 8.92]
2.1 Mononuclear cells 7 351 Mean Difference (IV, Random, 95% CI) -0.60 [-1.12, -0.08]
2.2 Circulating progenitor 2 68 Mean Difference (IV, Random, 95% CI) -0.02 [-0.40, 0.36]
cells
2.3 Haematopoietic stem cells 2 40 Mean Difference (IV, Random, 95% CI) -0.88 [-3.04, 1.27]
2.4 Mesenchymal stem cells 1 45 Mean Difference (IV, Random, 95% CI) -1.2 [-1.58, -0.82]
Comparison 6. Participant diagnosis: subgroup analysis
No. of No. of
(< 12 months)
1.1 Chronic ischaemic heart 9 336 Mean Difference (IV, Fixed, 95% CI) 3.20 [2.20, 4.20]
disease
1.2 Heart failure (secondary 7 344 Mean Difference (IV, Fixed, 95% CI) 5.95 [4.67, 7.23]
to ischaemic heart disease)
1.3 Intractable/refractory 2 66 Mean Difference (IV, Fixed, 95% CI) 4.02 [1.72, 6.31]
angina
2.1 Chronic ischaemic heart 5 255 Mean Difference (IV, Random, 95% CI) -0.40 [-0.85, 0.04]
disease
2.2 Heart failure (secondary 5 203 Mean Difference (IV, Random, 95% CI) -0.92 [-1.57, -0.26]
to ischaemic heart disease)
2.3 Intractable/refractory 1 28 Mean Difference (IV, Random, 95% CI) -0.38 [-0.75, -0.01]
angina
Comparison 7. Method of measurement: sensitivity analysis
No. of No. of
1 LVEF (%): short-term follow-up 16 Mean Difference (IV, Fixed, 95% CI) Subtotals only
(< 12 months)
1.1 Measured by MRI 9 298 Mean Difference (IV, Fixed, 95% CI) 3.35 [2.17, 4.53]
1.2 Measured by left 5 186 Mean Difference (IV, Fixed, 95% CI) 2.91 [1.35, 4.47]
ventricular angiography
1.3 Measured by SPECT 3 124 Mean Difference (IV, Fixed, 95% CI) 5.47 [2.80, 8.14]
1.4 Measured by 6 314 Mean Difference (IV, Fixed, 95% CI) 4.78 [3.36, 6.21]
echocardiography
Comparison 8. Risk of bias: sensitivity analysis
No. of No. of
(< 12 months)
1.1 Low risk of selection bias 6 218 Mean Difference (IV, Fixed, 95% CI) 3.27 [1.69, 4.84]
1.2 Low risk of performance 9 320 Mean Difference (IV, Fixed, 95% CI) 5.11 [3.89, 6.33]
bias
1.3 Low risk of detection bias 14 588 Mean Difference (IV, Fixed, 95% CI) 4.58 [3.71, 5.45]
Comparison 9. Co-intervention/comparator sensitivity analysis
No. of No. of
(< 12 months)
1.1 Placebo 9 373 Mean Difference (IV, Fixed, 95% CI) 3.33 [2.25, 4.41]
1.2 No placebo 8 343 Mean Difference (IV, Fixed, 95% CI) 5.05 [4.02, 6.09]
1.3 No co-intervention 6 297 Mean Difference (IV, Fixed, 95% CI) 4.31 [2.97, 5.64]
received
1.4 Co-intervention: CABG 5 158 Mean Difference (IV, Fixed, 95% CI) 6.51 [4.76, 8.26]
1.5 Co-intervention: PCI 7 291 Mean Difference (IV, Fixed, 95% CI) 3.35 [2.30, 4.40]
ADDITIONAL TABLES
Table 1. LVEF and NYHA class: subgroup analysis
Factor Subgroup LVEF NYHA
No. MD (95% P I No. MD (95% P I

studies CI) studies CI)
Cell dose < 10 3 5.48 (2.74, < 0.0001 0% 3 -0.53 (-1. 0.12 93%
8.23) 20, 0.14)
10 - 10 11 4.12 (3.22, < 0.00001 73% 6 -0.74 (-1. 0.03 96%

5.01) 40, -0.07)
> 10 5 3.38 (2.00, < 0.00001 0% 2 -0.49 (-1. 0.15 80%

4.77) 15, 0.18)
Test for subgroup dif- P = 0.38 P = 0.86

ferences:
Route IC 9 3.19 (2.19, < 0.00001 43% 5 -0.40 (-0. 0.08 82%
of admin- 4.19) 85, 0.04)
istration
IM 10 5.30 (4.21, < 0.00001 52% 6 -0.83 (-1. 0.007 97%
6.40) 43, -0.23)

ferences:
Base- < 30% 4 5.40 (3.81, < 0.00001 44% 2 -1.41 (-1. <0.00001 57%
line cardiac 6.99) 68, -1.14)
function
(LVEF)
Table 1. LVEF and NYHA class: subgroup analysis (Continued)
30% - 11 4.36 (3.28, < 0.00001 56% 8 -0.48 (-0. 0.005 85%
50% 5.45) 82, -0.14)
> 50% 2 4.65 (2.47, < 0.0001 7% NA

6.84)
Test for subgroup dif- P = 0.57 P < 0.0001

ferences:
Cell type MNC 13 3.77 (2.91, < 0.00001 19% 7 -0.60 (-1. 0.02 97%
4.63) 12, -0.08)
CPC 3 1.58 (-0. 0.05 67% 2 -0.02 (-0.40 0.92 0%

01, 3.17) to 0.36)
HSC 2 8.44 (6.11, < 0.00001 52% 2 -0.88 (-3. 0.42 97%
10.78) 04, 1.27)
MSC 1 6.00 (3.08, < 0.0001 NA 1 -1.20 (-1. <0.00001 NA

8.92) 58, -0.82)
Test for subgroup dif- P < 0.0001 P = 0.0004

ferences:
Participant CIHD 9 3.20 (2.20, < 0.00001 21% 5 -0.40 (-0. 0.08 83%
diagnosis 4.20) 85, 0.04)
HF 7 5.95 (4.67, < 0.00001 61% 5 -0.92 (-1. 0.006 97%

7.23) 57, -0.26)
IRA 2 4.02 (1.72, 0.0006 0% 1 -0.38 (-1. 0.05 NA

6.31) 16, -0.25)

ferences:
CIHD: chronic ischaemic heart disease; CPC: circulating progenitor cells; HF: heart failure (secondary to ischaemic heart disease);
HSC: haematopoietic stem cells; IC: intracoronary; IM: intramyocardial; IRA: intractable/refractory angina; MNC: mononuclear
cells; MSC: mesenchymal stem cells.
Table 2. Summary characteristics of studies
Number of par- Baseline LVEF

Mean Method ticipants Baseline func- (%) Method
Trial Co- Type dose of assessed for pri- tional Class Mean (SD) (s) Dura-
inter- of (SD) stem Com- mary outcome used tion of
ven- stem of cells cell para- to trial
tion cell isola- tor mea- (months)
tion arm sure
and LVEF
route
of de-
livery
Con- Con- SC Con-

SC trol SC trol arm trol
arm arm arm arm arm
Ang Medi- 115 BM as- CABG 8 7 28.5 20.9 MRI 6

2008 cal BMMNC(73) x pira- NYHA: NYHA: (6.5) (8.9)
IC ther- 10 tion*, NR NR
apy cells IC CCS: CCS:
and 2.3 2.7
CABG
Ang Medi- 84 (56) BM as- CABG 10 7 25.4 20.9 MRI 6

2008 cal BMMNCx 10 pira- NYHA: NYHA: (8.1) (8.9)
IM ther- cells tion*, NR NR
apy IM CCS: CCS:
and 2.7 2.7
CABG
Ass- Medi- 2. BM as- PCI in 24 18 41 (11) 43 (13) LVA 3

mus cal BMMNC05 (1. pira- a pro- NYHA: NYHA:
2006 ther- 1) x 10 tion*, por- 2.2 (0. 1.91
BMSC apy cells IC tion of 6) (0.7)
and partici- CCS: CCS:
PCI pants NR NR
Ass- Medi- CPC 2.2 (1. Leuka- PCI in 19 18 39 (10) 43 (13) LVA 3
mus cal 1) x 10 phere- a pro- NYHA: NYHA:
2006 ther- cells sis, por- 2.2 (0. 1.91
CPC apy IC tion of 8) (0.7)
and partici- CCS: CCS:
PCI pants NR NR
Ass- Medi- NR NR BM as- PCI + 37 32 NR NR MRI 4

mus cal pira- SW + NYHA: NYHA:
2012 ther- tion*, placebo 2.3 (0. 2.1 (0.
apy + IC 6) 3)
Table 2. Summary characteristics of studies (Continued)
PCI + CCS: CCS:

SW NR NR
Chen Medi- MSC 5 x 10 BM as- PCI, 22 at 6 23 at 6 26 (6) 23 (8) 12

2006 cal cells pira- no months, months, NYHA: NYHA: SPECT
ther- tion*, placebo 20 19 2.7 (0. 2.9 (0.
apy + IC at 12 at 12 8) 6)
PCI months months CCS: CCS:
NR NR
Erbs Medi- CPC 69 (14) Leuka- PCI + 12 at 3 11 at 3 51.0 55.8 MRI 15

2005 cal x 10 phere- G-CSF months; months; NYHA: NYHA: (12.1) (12.4)
ther- cells sis, IC + infu- 12 10 NR NR
apy, sion at 15 at 15 CCS: CCS:
PCI of cell- months months NR NR
and G- free
CSF serum
Hen- Medi- 62. BM as- CABG 10 10 42.9 39.5 MRI 4

drikx cal BMMNC25 (31. pira- + saline NYHA: NYHA: (10.3) (5.5.)
2006 ther- 35) tion*, NR NR
apy x 10 IM CCS: CCS:
and cells NR NR
CABG
Hon- Medi- EPC 29 (12) Leuka- G-CSF 9 4 33.4 23.3 MRI 60

old cal x 10 phere- + PCI, NYHA: NYHA: (12.7) (7.2)
2012 ther- cells sis, cul- no 1.9 (0. 2.0 (0.
apy + ture ex placebo 7) 7)
G-CSF vivo, CCS: CCS:
+ PCI IC NR NR
Hu Medi- 13. BM as- CABG 31 28 22.78 24.95 MRI 6

2011 cal BMMNC17 (10. pira- + NYHA: NYHA:
ther- 66) tion*, placebo NR NR
apy x 10 IC (0.8 CCS: CCS:
and cells saline NR NR
CABG + 0.2
partic-
ipants
own
serum)
Kang Medi- NR Leuka- PCI, 15 16 48.5 45.1 MRI 6

2006 cal BMMNC phere- no G- NYHA: NYHA: (12.9) (10.2)
ther- sis, IC CSF, NR NR
apy, no CCS: CCS:
PCI placebo NR NR
and G-
CSF
Medi- 2.2 (2. Leuka- G- 18 6 NR NR - 6

Losordo
cal CD34+ 5) x 10 phere- CSF+ NYHA: NYHA:
2007
ther- cells sis and injec- NR NR
apy CD34+ selection of CCS: CCS:
+ cells/ tion of saline NR NR
G-CSF kg CD34 with
by 5% au-
MACS, tolo-
IM gous
(EMM) plasma
Medi- 1 x 10 Leuka- G- 54 at 6 53 at 6 58.9 59.8 Echo 12

Losordo
cal CD34+ phere- CSF months; months; NYHA: NYHA: (14.2) (14.5) or
2011
ther- cells CD34+ sis and + injec- 53 50 NR NR SPECT
LD
apy cells/ selection of at 12 at 12 CCS: CCS:
+ kg tion of saline months months NR NR
G-CSF CD34 with
by 5% au-
MACS, tolo-
IM gous
(EMM) plasma
Medi- 5 x 10 Leuka- B-CSF 55 at 6 53 at 6 60.6 59.8 Echo 12

Losordo
cal CD34+ phere- + injec- months; months; NYHA: NYHA: (13.3) (14.5) or
2011
ther- cells CD34+ sis and tion of 53 50 NR NR SPECT
HD
apy cells/ selec- saline at 12 at 12 CCS: CCS:
+ kg tion of with months months NR NR
G-CSF CD34 5% au-
by tolo-
MACS, gous
IM plasma
(EMM)
Patel Medi- 22 x 10 BM 10 10 29.4 30.7 6

2005 cal CD34+ aspira- CABG, NYHA: NYHA: (3.6) (2.5) SPECT
ther- cells CD34 tion* no 3.5 3.4 Echo
apy cells and placebo CCS: CCS:
and selec- NR NR
CABG tion of
CD34
by
MACS,
IM
(EMM)
Perin Medi- 2 x 10 BM Mock 20 10 37.0 39,0 Echo () 6

2011 cal BMMNC aspira- injec- NYHA: NYHA: (10.6) (9.1)
ther- BMMNCtion*, tion 2.3 (0. 2.6 (0.
apy
IM but no 2) 3)
(EMM) placebo CCS: CCS:
ad- 3.0 (0. 3.0 (0.
minis- 2) 3)
tered
Perin Medi- 100 x BM Injec- 54 28 34.7 32.2 Echo 6

2012a cal BMMNC10 aspiration of NYHA: NYHA: (8.8) (8.6)
ther- tion*, saline NR NR
apy BMMNCIM with CCS: CCS:
(EMM) 5% NR NR
HSA
Perin Medi- 2.94 BM Injec- 10 10 36.1 32.1 Echo () 6

2012b cal ALDH+ (1.58) aspiration of NYHA: NYHA: (10.9) (10.6)
ther- cells x 10 tion*, saline 2.5 (0. 2.6 (0.
apy selec- with 5) 5)
ALDH+ tion of 5% CCS: CCS:
cells ALDH+ HSA 2.0 (0. 2.5 (0.
cells 5) 5)
by cell
sorting
IM
(EMM)
Medi- 41 BM No ad- 53 at 6 46 at 6 27.8 26.8 Echo 12

Pokushalov
cal BMMNC(16) aspira- di- months, months, NYHA: NYHA: (3.4) (3.8)
2010
ther- x 10 tion*, tional 49 33 3.3 (0. 3.5 (0.
apy IM ther- at 12 at 12 2) 1)
BMMNC(EMM) apy months months CCS: CCS:
3.1 (0. 3.5 (0.
4) 5)
Tse Medi- 10 - 20 BM Injec- 19 9 51.9 45.3 MRI 6

2007 cal BMMNCx 10 aspiration of NYHA: NYHA: (8.5) (8.3)
ther- tion*, saline 2.8 (0. 2.8 (0.
apy BMMNCIM with 8) 4)
(EMM) 10% CCS: CCS:
HSA 3.3 (0. 3.1 (0.
5) 3)
Turan Medi- 99 (25) BM as- PCI, 33 16 46 (10) 46 (10) LVA 12

2011 cal BMMNCx 10 pira- no NYHA: NYHA:
ther- cells tion*, placebo 2.4 (0. 2.5 (0.
apy IC 4) 9)
and CCS: CCS:
PCI NR NR
Van Medi- 98 (6) BM Injec- 24 25 56.0 54.0 MRI 6

cal BMMNCx 10 aspiration of NYHA: NYHA: (12.0) (10.0)
Ramshorst
ther- tion*, saline NR NR
2009
apy BMMNCIM with 0. CCS: CCS:
(EMM) 5% 3.0 (0. 2.9 (0.
HSA 6) 7)
Wang Medi- 1.0 - 6. BM PCI, 16 16 NR NR - 6m

2009 cal CD34+ 1 x 10 aspira- no NYHA: NYHA:
ther- cells tion* placebo NR NR
apy + CD34 and CSS: CSS:
PCI cells selec- NR NR
tion of
CD34
by
MACS,
IC
Wang Medi- 5.6 (2. BM Injec- 56 56 NR NR - 6

2010 cal CD34+ 3) x 10 aspiration of NYHA: NYHA:
ther- cells tion* saline NR NR
apy CD34 and with CSS: CSS:
cells+ selec- HSA 3.3 3.5
tion of (24.7) (26.2)
CD34
by
MACS,
IC
Yao Medi- 7. BM as- PCI in 24 26 44.4 42.5 MRI 6

2008 cal BMMNC2 x 10 pira- a pro- NYHA: NYHA: (5.5) (7.3) Echo
ther- cells tion* , por- NR NR
apy IC tion of CSS: CSS:
and partici- NR NR
PCI pants +
injec-
tion of
0.9%
saline
and
hep-
arin
Zhao Medi- 6.59 BM as- CABG 16 18 35.8 36.7 Echo 6

2008 cal BMMNC(5.12) pira- + injec- NYHA: NYHA: (7.3) (9.2)
ther- x 10 tion* , tion of 3.33 3.40
apy cells IM 0.9% (0.48) (0.50)
and saline CSS:3. CSS:3.
CABG and 22 (0.
hep- 43) 30 (0.

arin 46)
BM: bone marrow; BMMNC: bone marrow mononuclear cell(s); CABG: coronary artery bypass graft; CCS: Canadian Cardiolovascular
Society functional classification of angina; CPC: circulating progenitor cells; Echo: echocardiography; EMM: ElectroMechanical
Maping, usually using the commercially available NOGA system; EPC: endothelial progenitor cells; G-CSF: granulocyte colony
stimulating factor; HSA: human serum albumin; IC: intracoronary; IM: intramyocardial; LVA: left ventricular angiography; LVEF:
left ventricular ejection fraction; MACS: magnetic activated cell sorting; MRI: magnetic resonance imaging; MSC: mesenchymal
stem cells; NR: Not reported; NYHA: New York Heart Association functional classification of heart failure; PCI: percutaneous
coronary intervention; SC: stem cells; SD: standard deviation; SPECT: single-photon emission computed tomography; SW: shock
wave.
(*): BM aspiration: bone marrow was harvested by aspiration and mononuclear cells were isolated by Ficoll density gradient centrifu-
gation;
(): in the meta-analysis, controls from the Losordo 2011 trial were divided into 2 equal groups to enable separate analysis of each of
the BMSC treatment groups.
( ) LVEF was measured by ECHO, SPECT and LVA or ECHO and LVA. Results from ECHO are reported here.
CONTRIBUTIONS OF AUTHORS
Sheila Fisher: methodology expert, eligibility screening, data extraction and quality assessment, data analysis and preparation of the
final report.
Carolyn Doree: information specialist, design and implementation of search strategies, initial eligibility screening and data verification,
comments on the final report.
Susan Brunskill: methodology expert, development of the protocol, comments on the final report.
Anthony Mathur: clinical content expert (clinical cardiology), preparation of the final report.
David P Taggart: clinical content expert (cardiac surgery), comments on the final report.
Enca Martin-Rendon: scientific content expert, eligibility screening, data extraction and quality assessment, preparation of the final
report. Corresponding author who takes the global responsibility of this review.
DECLARATIONS OF INTEREST
Professor Anthony Mathur is the lead investigator of the ongoing BAMI trial. Dr Martin-Rendon works at the Stem Cell Research
Laboratory, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK.
SOURCES OF SUPPORT
Internal sources
NHS Blood and Transplant, Research and Development., UK.
William Harvey Research Institute, UK.
External sources
NIHR, UK.
National Institute for Health Research (NIHR) under its Programme Grant Scheme (RP-PG-0310-1001, EMR).
Oxford BRC, UK.
Oxford Biomedical Research Centre Programme (SAF, CD and SJB).
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

Several outcomes listed in the protocol for this review were based on those of a previous review of AMI (Clifford 2012a) and were not
as relevant for IHD and congestive heart failure. Secondary outcomes were therefore restricted to those most relevant to this review. In
particular, we considered re-operation, length of hospital stay, restenosis, target vessel revascularisation and wall motion score index to
be less relevant to the current review; they were rarely reported in individual studies and were not included in this review.
Difference in time points for the outcomes - new stratifications used for the outcomes (as detailed in the Types of outcome measures
section).

2016 - Stem Cell Therapy For Chronic Ischaemic Heart Disease and Congestive HF

Diunggah oleh

Informasi Dokumen

Judul Asli

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

2016 - Stem Cell Therapy For Chronic Ischaemic Heart Disease and Congestive HF

Diunggah oleh

Hak Cipta:

Format Tersedia

Stem cell therapy for chronic ischaemic heart disease and

congestive heart failure (Review)

Fisher SA, Brunskill SJ, Doree C, Mathur A, Taggart DP, Martin-Rendon E

Stem cell therapy for chronic ischaemic heart disease and

Editorial group: Cochrane Heart Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Assumed risk Corresponding risk

GRADE Working Group grades of evidence

Description of the intervention

In one study (Yao 2008), continuous measures were reported as

Effects of interventions Mortality

(a) Incidence of infarction

Characteristics of included studies [ordered by study ID]

Methods Type of study: Parallel RCT.

Interventions Intervention arms: IM and IC.

Bias Authors judgement Support for judgement

Other bias Low risk No other sources of bias were identified.

Methods Type of study: Cross-over RCT with 3 arms.

Interventions Intervention arm: BMSC and CPCs

Outcomes Primary outcomes: Absolute change in global LVEF as measured by quantitative LV

Bias Authors judgement Support for judgement

Other bias Low risk No other sources of bias were identified.

Methods Type of study: Parallel RCT.

Participants Description: Hospitalised participants presenting post-infarction heart failure.

Interventions Intervention arm: BMSC and shock wave.

Outcomes Primary outcomes: None reported/

Bias Authors judgement Support for judgement

Other bias Low risk No other sources of bias were identified.

Methods Type of study: Parallel RCT.

Statistically significant baseline imbalances between the groups? No.

Interventions Intervention arm: BMSC and control.

Outcomes Primary outcomes: None reported

Bias Authors judgement Support for judgement

Blinding of outcome assessment (detection Unclear risk Not reported.

Other bias Low risk No other sources of bias were identified.

Methods Type of study: Parallel RCT.

Interventions Intervention arm: BMSC.

Outcomes Primary outcomes: LV function

Bias Authors judgement Support for judgement

Other bias Low risk No other sources of bias were identified.

Methods Type of study: Parallel RCT.

Interventions articipanIntervention arm: BMSC.

Bias Authors judgement Support for judgement

Allocation concealment (selection bias) Low risk Sealed envelopes.

Other bias Low risk No other sources of bias were identified.

Methods Type of study: Parallel RCT.

Interventions Intervention arm: BMSC

Outcomes Primary outcomes: Safety and efficacy.

Bias Authors judgement Support for judgement

Other bias Low risk No other sources of bias were identified.

Methods Type of study: Parallel RCT.

Interventions Intervention arm: BMSC

Outcomes Primary outcomes: Changes in LVEF.

Bias Authors judgement Support for judgement

Other bias Low risk No other sources of bias were identified.

Methods Type of study: Parallel RCT.

Interventions Intervention arm: BMSC.

Bias Authors judgement Support for judgement

Blinding of participants and personnel High risk Not blinded.

Blinding of outcome assessment (detection Unclear risk Angiography conducted by independent

Other bias Low risk No other sources of bias were identified.

Methods Type of study: Parallel RCT.