UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)
Percutaneous coronary intervention in acute myocardial infarction: from
procedural considerations to long term outcomes
Delewi, R.
Publication date
2015
Document Version
Final published version
Link to publication
Citation for published version (APA):
Delewi, R. (2015). Percutaneous coronary intervention in acute myocardial infarction: from
procedural considerations to long term outcomes. Boxpress.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.
12
Chapter 12
Impact of intracoronary cell therapy on left
ventricular function in the setting of acute
myocardial infarction: a meta-analysis of
randomized controlled clinical trials
Ronak Delewi, Anouk Andriessen, Jan G. P. Tijssen, Felix Zijlstra, Jan J. Piek, Alexander Hirsch
ASBTRACT
ContextNumerous randomized controlled studies assessing intracoronary bone marrow cell therapy (BMC) after acute myocardial infarction (AMI) have been performed.
Objective
To systematically review the effect of autologous BMC therapy on left ventricular function by performing an up to date meta-analysis of randomized controlled trials (RCTs) including long-term follow-up.
Data sources
Trials were identified through a literature search from 1980 to June 2012 of the Pubmed, Embase, Cochrane database, and the Current Controlled Trials Register.
Study selection
Randomized clinical trials comparing intracoronary BMC infusion to control as treatment for AMI.
Data extraction
The primary endpoint was the change in left ventricular ejection fraction (LVEF) from baseline to follow-up. Secondary endpoints were changes in left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), infarct size and clinical outcomes.
Results
Improvement of LVEF in patients receiving intracoronary BMC was significantly better within 6 months (23 studies, 2.23% [95% confidence interval (CI) 1.00 to 3.47]; p < 0.001). At 12 months of follow-up, this effect sustained with 3.91% more LVEF improvement (11 studies, [95% CI 2.56 to 5.27], p <0.001). At long-term follow-up, we found a trend for better LVEF improvement in favor of cell therapy (7 studies, 1.90% [95% CI -0.43 to 4.23]; p=0.11). There was no clear effect in infarct size or LVEDV. However, we found a significant reduction in LVESV at 6 months (-4.81 ml [95% CI -7.86 to -1.76]; p<0.001 and at 12 months (-9.41 ml [95% CI -13.64 to -5.17]; p<0.001). Moreover, there was a statistically significant decrease in recurrent AMI (Relative Risk (RR) 0.44 [95% CI 0.24 to 0.79]; p =0.007), and readmission for heart failure, unstable angina or chest pain (RR 0.59 [95% CI 0.35 to 0.98]; p = 0.04) in favor of cell therapy.
12
ConclusionIntracoronary BMC treatment leads to a moderate improvement of LVEF and reduction of LVESV at 6 months that sustained at 12 months follow-up, without a clear significant effect on LVEDV, or infarct size. Furthermore, we found that intracoronary cell therapy is significantly associated with a reduction in recurrent AMI and readmission for heart failure, unstable angina or chest pain.
INTRODUCTION
Despite optimal state-of-the-art medical and revascularization therapies, the progression
and development of congestive heart failure is still considered a large burden.1 Acute
myocardial infarction (AMI) is a major cause of congestive heart failure.2 Therefore,
alternative therapies to complement primary percutaneous coronary intervention (PCI) or thrombolytic therapy in the prevention of congestive heart failure after acute myocardial infarction are being investigated.
One of the suggested therapies for myocardial dysfunction is intracoronary bone marrow cell (BMC) treatment, which was tested positive in several animal studies. From then on,
clinical trials rapidly followed to translate these exciting preclinical results to humans.3
Numerous relatively small randomized controlled studies with different types of cells,
different dosages, and follow-up durations were performed.4-36
The effect of cell therapy in AMI patients has been reviewed in de past,37-40 showing a
small significant effect after myocardial infarction of left ventricular ejection fraction (LVEF) and other endpoints as left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), and infarct size. However, these reviews did not include latest studies and follow-up. Our aim was to systematic review the effect of intracoronary injection of autologous bone marrow cell (BMC) after AMI by performing an up to date meta-analysis of randomized controlled trials (RCTs).
METHODS
literature search and study selection
We identified all published trials comparing intracoronary infusion of BMC as treatment for AMI to control by searching Pubmed, Embase, Cochrane database and
the Current Controlled Trials Register from 1980 to 1st June 2012. The following key
words were used: “bone marrow cells,” “stem cell”, “bone marrow transplantation”, “precursor cell”, “progenitor cell”, “haemopoietic marrow”, “myocardial ischemia”, “ischemia”, “ischemic heart disease”, “coronary heart disease”, “heart failure”, “cardiac”, “cardiomyo”, “ischemia” (see appendix 1). Additionally, we manually searched the conference abstracts of the American Heart Association, American College of Cardiology, European Society of Cardiology and Transcatheter Cardiovascular Therapeutics, KoreaMed, IndMed and LILACS. We also searched the references of identified studies and relevant review articles to identity additional randomized studies. To be included, trials had to: be randomized; include patients with a clinical diagnosis of acute AMI, treated with PCI; and compare a single intracoronary infusion of
12
autologous BMC (irrespective of the type and number of isolated cells) within onemonth of AMI to a comparator arm not receiving BMC (e.g. control media or plasma or standard treatment). We did not include trials where follow-up was less than 3 months or granulocyte (macrophage) colony-stimulating factor (G(M)-CSF) was administrated as co-intervention. Study selection was done by two independent reviewers (RD, AA) and disagreement was resolved by a third reviewer (AH).
Data extraction and data analysis
Data from the original publications, including markers of validity, study design, nature of the intervention, and clinical and imaging outcomes were obtained from the original publications.
The primary endpoint was the change in LVEF from baseline to follow-up. Secondary endpoints were changes in LVESV, LVEDV, infarct size and clinical outcomes (all cause mortality, recurrent AMI, target vessel revascularization and readmission for heart failure, unstable angina or chest pain). Per endpoint we involved only those studies in the analysis for which the information about the endpoint had been published. The quantitative information about endpoint per treatment group was obtained by extracting the mean change ± SD from the publication.
When several methods were used for outcome assessment, magnetic resonance imaging (MRI) data were preferentially included in the analysis, followed by single photon emission computed tomography (SPECT), echocardiography, and left ventricular (LV) angiography. LVESV and LVEDV were collected in ml/m² or ml when ml/m² was not available. Infarct size was preferable collected in % of LV or grams when not available. When reported or published data were incomplete, we requested additional details by correspondence, generally with the principal investigator, searched previously published Cochrane reviews, or calculated or estimated these data using the method of
the Cochrane handbook.41 If trials consisted of multiple intervention comparator arms,
we only used data from the comparator arm meeting the in- and exclusion criteria. If the multiple interventions arms all were eligible, we used the combined data if available and
if not available we separated them into different studies.15,27
Statistical analysis
Outcomes were analyzed with random-effects models. Summary results were presented as weighted mean difference (WMD) with 95% confidence interval per imaging outcome. We presented imaging outcomes split for different follow-up duration (3-6 months, 12 months and > 12 months) and different units used (ml/m² versus ml and %/LV versus grams)
We examined heterogeneity across studies by calculating an I²-value for every outcome. A standard fixed effects model (Mantel– Haenszel method) was used in the absence of heterogeneity among studies (I² value less than 50%). In the presence of heterogeneity the DerSimonian and Laird random effects model was used. Funnel plots were plotted to investigate possible publication bias. Analysis were performed using RevMan 4.2 (The Cochrane Collaboration, Copenhagen, Denmark), with statistical significance for hypothesis testing set at the 0.05, 2-tailed level.
RESUlTS
From the initial 2124 citations (Figure 1), 2025 citations were initially excluded at the title/abstract level. Fifty-four of the remaining 99 citations were RCTs, of which 24 studies were eligible for inclusion. These trials allocated 1624 patients to intracoronary cell therapy or standard therapy, ranging from 10 to 204 participants per trial. The
2124 citations identified by initial search
54 RCT's potentially eligible 99 complete articles assessed
2025 excluded (animal experiments, editorials, reviews)
45 excluded (non-randomized trials, case reports, secondary publications etc.)
Ineligible cell therapy intervention (n=15) Ineligible population (n=11) Published as abstract only (n=4) 24 RCT's included
RCT's; randomized controlled trials
Figure 1. Flow diagram of studies included in this meta-analysis
12
intervention and comparator characteristics of the included studies are shown in Table1. Ten studies included patients with anterior myocardial infarction only. Only 7 studies were double blinded and 12 studies used MRI as diagnostic modality. Follow-up ranged from 3 to 60 months. Twenty studies used mononuclear bone marrow cells for infusion (Table 2). Most trials fulfilled our markers of validity (Table 3).
Change in lVEF
The change in LVEF within 6 months was available in 23 studies (Figure 2). Improvement of LVEF within 6 months in patients receiving intracoronary cell therapy was significantly augmented compared to standard therapy (2.23% [95% confidence interval (CI) 1.00 to 3.47]; p < 0.001). At 12 months of follow-up, this effect sustained with 3.91% more LVEF improvement (eleven studies, [95% CI 2.56 to 5.27], p <0.001) in patients receiving intracoronary cell therapy. At long term follow-up, we found a trend for better LVEF improvement in favor of cell therapy (seven studies, 1.90% [95% CI -0.43 to 4.23]; p=0.11), although the number of studies was small. Assessment of publication bias using visual examination of the funnel plot of the primary publications indicated no significant publication bias (Figure 3). Moreover, exclusion of the smallest studies (cell therapy arm< 20) had little effect on the overall estimate. Improvement of LVEF in patients receiving intracoronary BMC within 6 months in 17 studies was 2.12% [95% CI 0.71 to 3.52]; p < 0.001)
lV volumes and infarct size
There was no clear difference in LVEDV between cell therapy and controls, at 6 months (-0.96 ml [95% CI -5.21 to 3.29]; p=0.66 and -1.94 ml/m² [95% CI -6.84 to 2.96]; p=0.44), at 12 months (-4.84 ml [95% CI -10.52 to 0.83]; p=0.09) and at long-term follow-up (-1.50 ml [95% CI -10.84 to 7.83]; p=0.75) (Figure 4). However, we found a significant reduction in LVESV at 6 months (-4.81 ml [95% CI -7.86 to -1.76]; p<0.001 and -0.55 ml/m² [95% CI -2.57 to 1.47]; p=0.59), at 12 months ( -9.41 ml [95% CI -13.64 to -5.17]; p<0.001) and at long-term follow-up (-5.53 ml [95% CI -10.97 to -0.08]; p=0.05) in patients receiving intracoronary cell therapy (Appendix 2). There were only 2 studies reporting on LVEDV and LVESV in ml/m² on longer term showing no benefit of cell therapy. There was a trend towards infarct size reduction in patients receiving intracoronary cell therapy at 6 months (-2.16 gram [95% CI -4.45 to 0.14], p=0.07) (Appendix 3). However, in the studies where infarct size was reported in % of LV, the difference was 0.01% ([95% CI, -1.38 to 1.40], p=0.99). Infarct size in grams or % of LV was reported in 9 of the 24 studies.
T
able 1.
Characteristics of
studies included in this re
vie w A uthor (y ear) (reference) Number of patients Randomization BMC vs . placebo Mean ag e (y ears) Male (%) l AD (%) Primar y inter vention Baseline l VEF (%) Imaging Modality for l VEF Assessment F ollo w-up (months)* Cao et al. (2009)(4) 86 1:1 51 94 100 PCI a) 41 ± 3 b) 41 ± 3 TTE 6, 48 Castellani et al. (2010) (5) 10 1:1 54 100 100 PCI a) 37 ± 5 b) 38 ± 7 PET 6, 12 Ge et al. (2006) (6) 20 1:1 59 90 70 PCI a) 54 ± 9 b) 58 ± 8 TTE 6 Gr ajek et al. (2010) (7)] 45 2:1 50 87 100 PCI a) 45 ± 10 b) 43 ± 7 EF-RNV 3, 6,12 Hir sch et al. (2010)(8) 134 1:1 56 84 61 PCI a) 44 ± 9 b) 42 ± 8 MRI 4 Huikuri et al. (2008) (9) 80 1:1 59 88 40 T rombol ysis follo w ed by PCI a) 59 ± 11 b) 62 ± 12 LV Angio 6 Janssens et al. (2006) (10) 67 1:1 57 82 63 PCI a) 49 ± 7 b) 47 ± 8 MRI 4, 12 K ar pov et al. (2005)(11) 44 1:1 54 82 64 PCI or trombol ysis Not re por ted SPECT 6 Lunde et al. (2006) (12-14) 100 1:1 57 84 100 PCI a) 55 ± 14 b) 54 ±12 MRI 6, 12, 36 Meluzin et al. LD (2006) (15) 44 1:1 55 95 70 PCI a) 42 ± 9 b) 42 ± 9 SPECT 3, 6, 12 Meluzin et al. HD (2006) (15) 44 1:1 55 89 73 PCI a) 41 ± 9 b) 42 ± 9 SPECT 3, 6,12 Noguier a et al. (2009)(16) 20 2:1 59 70 60 PCI or trombol ysis a) 48 ± 10 b) 48 ± 14 TTE 6 Penicka et al. (2007) (17, 18) 27 2:1 59 81 100 PCI a) 39 ± 6 b) 39 ± 4 TTE 4, 24 Piepoli et al. (2010) (19) 38 1:1 65 68 100 PCI a) 37 ± 9 b) 38 ± 10 SPECT 6, 12 Plewka et al. (2009) (20, 21) 60 2:1 56 70 100 PCI a) 35 ± 6 b) 33 ± 7 TTE 6, 12,24 Quyyumi et al. (2011) (22) 31 1:1 52 87 Not re por ted PCI a) 48 ± 10 b) 53 ± 10 MRI 6
12
A uthor (y ear) (reference) Number of patients Randomization BMC vs . placebo Mean ag e (y ears) Male (%) l AD (%) Primar y inter vention Baseline l VEF (%) Imaging Modality for l VEF Assessment F ollo w-up (months)* R oncalli et al. (2010) (23) 101 1:1 56 85 94 PCI a) 37 ± 10 b) 39 ± 9 MRI 3 Schaching er et al. (2006) (24-26) 204 1:1 56 82 70 PCI a) 48 ± 9 b) 47 ± 10 LV angio MRI 4, 12, 24 T ender a et al. NS (2009) (27) 120 2:1 56 72 100 PCI a) 34 (19-44) b) 39 (23-44) MRI 6 T ender a et al. S (2009) (27) 120 2:1 58 68 100 PCI a) 35 (12-45) b) 39 (23-44) MRI 6 T raver se et al. (2010) (28) 40 3:1 54 78 100 PCI a) 49 ± 10 b) 49 ± 9 MRI 6 T raver se et al (2011) (29) 87 2:1 57 83 91 PCI a) 49 ± 12 b) 45 ± 10 MRI 6 Tur an et al (2012) (30) 62 2:1 61 68 61 PCI a) 43 ± 10 b) 45 ± 10 LV angio 3, 12 W ohrle et al. (2010) (31, 32) 42 2:1 61 81 50 PCI a) 54 ± 9 b) 56 ± 9 MRI 6 , 12, 36 W oller t et al. (2004) (33-35) 60 1:1 56 70 64 PCI a) 50 ± 10 b) 51 ± 9 MRI 6, 18, 60 Y ao et al. (2009) (36) 24 1:1 52 88 100 PCI a) 33 ± 4 b) 32 ± 2 MRI 6, 12 BMC= bone mar row cell; EF-RNV= ejection fr action-r adionuclide ventricu logr aph y; HD ,=highdose; LAD=left anterior descending
ar ter y; LD ,=low dose; L VEF =
left ventricular ejection fr
action;
LV=
left ventricle; NS=non
selected; MRI=magnetic
resonance imaging;
PCI= percutaneous cor
onar y inter vention; PET=positr on emission tomogr aph
y; S= selected; SPECT= sing
le-photon emission computed tomogr
aph y; TTE,=tr ansthor acic echocar diogr am. a) T reatment ar m, b) Contr ol ar m * Number
s in bold is follow-up dur
ation used in this meta-anal
ysis
Data is pr
esented as mean
± standard de
viation or median with inter
quar
tile rang
T able 2. Characteristics of cell therap y inter ventions A uthor (y ear) Cell type BMC aspiration in control ar m
Sham infusion in control ar
m
Time of
BMC
administration from onset AMI
Number of
injected
cells ( x 10
8)
V
olume bone mar
ro w aspiration (ml) Cao et al. (2009) MN BMC No Ye s 7 da ys 5 ± 1.2 ~40 Castellani et al. (2010) Selected CD133 + BMC No No 11 – 15 da ys 0.06 (0.05-0.14) Not re por ted Ge et al. (2006) MN BMC Ye s Ye s W ithin 1 da y 0.4 ± 0.3 ~40 Gr ajek et al. (2010) MN BMC No No 4 – 6 da ys 4.1 ± 1.8 80 ± 30 Hir sch et al. (2010) MN BMC No No 3 – 7 da ys 3.0 ± 1.6 ~60 Huikuri et al. (2008) MN BMC Ye s Ye s 3 ± 2 da ys 4.0 ± 2.0 ~80 Janssens et al. (2006) MN BMC Ye s Ye s W ithin 1 da y 3.0 ± 1.3 130 ± 22 K ar pov et al. (2005) MN BMC No No 7 – 21 da ys 0.9 ± 0.5 ~100 Lunde et al. (2006) MN BMC No No 4 – 8 da ys 0.7 (0.5-1.3) ~50 Meluzin et al. LD 2006 MN BMC No No 7 ± 0.3 da ys 0.1 (0.09-0.2) ~100 Meluzin et al. HD 2006 MN BMC No No 7 ± 0.3 da ys 1 (0.9-2) ~150 Noguier a et al. (2009) MN BMC No No 6 ± 1 da ys 1 80 ± 48 Penicka et al. (2007) MN BMC No No 4 – 11 da ys 2.6 (2.0-3.3) 171 Piepoli et al. (2010) MN BMC No No 4 ± 1 da ys 4.2 ~100 Plewka et al. (2009) MN BMC No No 7 ± 2 da ys 1.4 ± 0.5 ~100 Quyyumi et al. (2011) Selected CD134 + cells No No 6 –10 da ys 0.1 ± 0.04 ~320 R oncalli et al. (2010) MN BMC No No 9 ± 1 da ys 1.0 ± 0.09 ~50 Schaching er et al. (2006) MN BMC Ye s Ye s 4 ± 1 da ys 2.4 ± 1.7 ~50 T ender a et al. NS(2009) MN BMC No No 3 – 12 da ys 1.8 50 – 70 T ender a et al. S (2009) Selected CD34 +/ CX CR4 + cells No No 3 – 12 da ys 0.02 100 – 120 T raver se et al. (2010) MN BMC Ye s Ye s 5 ± 2 da ys 1.0 50 – 70 T raver se et al. (2011) MN BMC Ye s Ye s 17 (16-20.0) 1.5 80-90 Tur an et al. (2012) MN BMC No No 7 da ys 96±32 120 W ohrle et al. (2010) MN BMC Ye s Ye s 7 ± 3 da ys 3.8 ± 1.3 128 ± 14 W oller t et al. (2004) Nucleated BMC No No 6 ± 1 da ys 25 ± 9 128 ± 33 Y ao et al. (2009) MN BMC No Ye s 4 ± 1 da ys 1.9 ± 1.2 90 ± 18 BMC= bone mar
row cells; HD=high dose; LD= low dose; MN= mononuclear
; NS= non selected; S= selected;
Data is pr
esented as mean
± standar
d de
viation or median with int
er
quartile r
12
Table 3. Methodological quality assessment of included studiesAdequate sequence generation? Allocation concealment? Double Blinding? Blinded e
valuation
primar
y endpoint?
Incomplete outcome data addressed? Free of
selecti ve repor ting? Free of other bias? Cao et al. (2009) Castellani et al. (2010) Ge et al. (2006) Grajek et al. (2010) Hirsch et al. (2010) Huikuri et al. (2008) Janssens et al. (2006) Karpov et al. (2005) Lunde et al. (2006) Meluzin et al. 2006 Noguiera et al. (2009) Penicka et al. (2007) Piepoli et al. (2010) Plewka et al. (2009) Quyyumi et al. (2011) Roncalli et al. (2010) Schachinger et al. (2006) Tendera et al. (2009) Traverse et al. (2010) Traverse et al. (2011) Turan et al. (2012) Wohrle et al. (2010) Wollert et al. (2004) Yao et al. (2009)
Figure 2. Forest plot of retrieved studies evaluating cell therapy and the difference in change left
ventricular ejection fraction from (LVEF) baseline to follow-up HD= high dose; LD, low dose; NS= non selected; S=selected
12
Clinical OutcomesWe found that cell therapy was associated with a statistically significant decrease in recurrent AMI (Relative Risk (RR) 0.44 [95% CI 0.24 to 0.79]; p= 0.007) and readmission for heart failure, unstable angina or chest pain (RR 0.59 [95% CI 0.35 to 0.98]; p = 0.04). There was a trend for difference between intracoronary cell therapy and control in all-cause mortality (RR 0.60 [95% CI 0.34 to 1.08]; p = 0.09) and target vessel revascularization (RR 0.82 [95% CI 0.63 to 1.07]; p=0.15). The number of events are summarized in Table 4.
Figure 3. Funnel plot of included studies (primary publications)
Figure 4. Forest plot of retrieved studies evaluating cell therapy and the difference in change left
ventricular end diastolic volume (LVEDV) from baseline to follow-up
12
Table 4. Clinical outcomes evaluated at the longest available follow-upAll cause
mortality myocardial Recurrent infarction
Target vessel
revascularisation Readmission for heart failure, unstable angina,
chest pain Author (year) therapyCell
N=943 Control N=681 Cell therapy N=943 Control N=681 Cell therapy N=943 Control N=681 Cell therapy N=943 Control N=681 Cao et al. (2009) 0 1 - 0 1 1 0 Castellani et al. (2010) - - - 0 3 Ge et al. (2006) - - - -Grajek et al. (2010) 1 0 1 1 3 4 1 1 Hirsch et al. (2010) 0 0 0 1 4 4 0 1 Huikuri et al. (2008) 0 1 0 2 - 0 1 Janssens et al. (2006) 1 1 0 1 2 1 2 1 Karpov et al. (2005) - - - -Lunde et al. (2006) 1 1 1 2 12 9 2 1 Meluzin et al. LD 2006 - 1 2 -* 1 0 Meluzin et al. HD 2006 - 0 2 -* -Noguiera et al. (2009) - - 1 0 -Penicka et al. (2007) 3 0 2 0 5 4 2 4 Piepoli et al. (2010) 2 4 - 1 1 4 4 Plewka et al. (2009) 2 2 1 1 5 3 1 5 Quyyumi et al. (2011) 1 0 0 0 2 1 2 1 Roncalli et al. (2010) 1 0 6 2 12 11 4 2 Schachinger et al. (2006) 3 8 0 7 19 28 1 5 Tendera et al. NS (2009) 1 1 1 2 13 7 -Tendera et al. S (2009) 1 1 2 2 12 7 -Traverse et al. (2010) 0 0 0 1 0 1 -Traverse et al (2011) 0 1 1 0 1 2 1 0 Turan et al. (2012) - - - -Wohrle et al. (2010) 1 1 0 0 7 3 2 0 Wollert et al. (2004) 2 2 1 1 6 4 2 3 Yao et al. (2009) 0 0 0 1 0 1 -Total 2.1 % 20/943 24/3.5%681 17/1.8%943 28/4.1%681 105/11.1%943 92/13.5%681 26/2.8%943 32/4.7%681
DISCUSSION
In the present meta-analysis, we found that BMC treatment leads to a slightly better improvement of LVEF and reduction of LVESV at 6 months, which was sustained at 12 months follow-up, without a clear significant effect on LVEDV or infarct size. Furthermore, we found that intracoronary cell therapy is significantly associated with a reduction in recurrent AMI, and readmission for heart failure, unstable angina or chest pain.
In the past years, earlier reports have presented a meta-analysis regarding BMC cell therapy after MI.(37-40) Our analysis differs from previously published meta-analysis. First, other meta-analysis also included studies that administered G(M)-CSF or bone marrow derived cells from the peripheral blood group and/or included both acute and chronic myocardial infarction patients making the results more heterogeneous. Second, all meta-analyses pooled different outcome measures for LVEDV, LVESV, and infarct size used in the trials. We have chosen to present these outcomes separately, because this is more precise. Third, our meta-analysis is more up to date containing a larger number of studies and latest follow-up. However, our results are globally in agreement with the results of the previous meta-analyses, namely that cell therapy results in a slightly better significant improvement of LVEF compared to controls, without a clear significant effect on LVEDV or infarct size.
There has been a lot of controversy regarding high risk subgroups benefitting more from cell therapy, appropriate cell storage, cell dosage and cell type. Unfortunately this meta-analysis does not answer these relevant questions but bundles all trials with a high degree of heterogeneity.
Finally the question remains whether a small increase of LVEF is clinically meaningful. However as Reffelman et al. stated when putting the moderate increases of cardiac volumes in perspective with existing therapy, we appear to be in the range of effects observed with reperfusion therapy, pharmacotherapeutic interventions influencing
the renin-angiotensin-aldosterone pathway, and beta-blockers after AMI.42 More
importantly, we found that intracoronary cell therapy is associated with a significant reduction in recurrent AMI and readmission for heart failure, unstable angina or chest pain. The mechanism behind these significant reductions remains unclear and could be biased due to the low number of clinical events or placebo effect (in case of readmission for heart failure, unstable angina or chest pain). It has been suggested that BMC therapy alters the process of restenosis development and/or atherosclerotic disease progression via enhanced reendothelialization and potential vascular repair. Also, it has been hypothesized that BMC leads to greater recovery of coronary blood flow reserve which is inversely associated with atherosclerotic disease progression, which may in turn explains
12
the lower rate of recurrent MI.24 However, these hypotheses are highly speculative and
should further be investigated.
We feel that intracoronary bone marrow cell treatment still holds promise and should be investigated in a large clinical trial with clinical outcomes as primary endpoint. The large BAMI trial, funded by the European Union, will investigate BMC therapy in a RCT with a primary clinical endpoint.”
This meta-analysis shows that there is little space for more small randomized controlled trial assessing intracoronary BMCs in acute myocardial infarction with surrogate primary endpoints.
CONClUSION
Intracoronary bone marrow cell treatment leads to a moderate improvement of LVEF and reduction of LVESV at 6 months, that sustained at 12 months follow-up, without a clear significant effect on LVEDV, or infarct size. Furthermore, we found that intracoronary cell therapy is significantly associated with a reduction in recurrent AMI and readmission for heart failure, unstable angina or chest pain.
REFERENCE lIST
1. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De SG, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Stafford R, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J. Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation 2010;121:948-54.
2. Karasek J, Widimsky P, Ostadal P, Hrabakova H, Penicka M. Acute heart failure registry from high-volume university hospital ED: comparing European and US data. Am J Emerg Med 2012;30 695-05.
3. Lovell MJ, Mathur A. Cardiac stem cell therapy: progress from the bench to bedside. Heart 2010;96:1531-37.
4. Cao F, Sun D, Li C, Narsinh K, Zhao L, Li X, Feng X, Zhang J, Duan Y, Wang J, Liu D, Wang H. Long-term myocardial functional improvement after autologous bone marrow mononuclear cells transplantation in patients with ST-segment elevation myocardial infarction: 4 years follow-up. Eur Heart J 2009;30:1986-94.
5. Castellani M, Colombo A, Giordano R, Pusineri E, Canzi C, Longari V, Piccaluga E, Palatresi S, Dellavedova L, Soligo D, Rebulla P, Gerundini P. The role of PET with 13N-ammonia and 18F-FDG in the assessment of myocardial perfusion and metabolism in patients with recent AMI and intracoronary stem cell injection. J Nucl Med 2010;51:1908-16. 6. Ge J, Li Y, Qian J, Shi J, Wang Q, Niu Y, Fan B, Liu X, Zhang S, Sun A, Zou Y. Efficacy
of emergent transcatheter transplantation of stem cells for treatment of acute myocardial infarction (TCT-STAMI). Heart 2006;92:1764-67.
7. Grajek S, Popiel M, Gil L, Breborowicz P, Lesiak M, Czepczynski R, Sawinski K, Straburzynska-Migaj E, Araszkiewicz A, Czyz A, Kozlowska-Skrzypczak M, Komarnicki M. Influence of bone marrow stem cells on left ventricle perfusion and ejection fraction in patients with acute myocardial infarction of anterior wall: randomized clinical trial: Impact of bone marrow stem cell intracoronary infusion on improvement of microcirculation. Eur Heart J 2010;31:691-702.
8. Hirsch A, Nijveldt R, van der Vleuten PA, Tijssen JG, van der Giessen WJ, Tio RA, Waltenberger J, ten Berg JM, Doevendans PA, Aengevaeren WR, Zwaginga JJ, Biemond BJ, van Rossum AC, Piek JJ, Zijlstra F. Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood compared with standard therapy in patients after acute myocardial infarction treated by primary percutaneous coronary intervention: results of the randomized controlled HEBE trial. Eur Heart J 2011;32:1736-47.
9. Huikuri HV, Kervinen K, Niemela M, Ylitalo K, Saily M, Koistinen P, Savolainen ER, Ukkonen H, Pietila M, Airaksinen JK, Knuuti J, Makikallio TH. Effects of intracoronary injection of mononuclear bone marrow cells on left ventricular function, arrhythmia risk profile, and restenosis after thrombolytic therapy of acute myocardial infarction. Eur Heart J 2008;29:2723-32.
12
10. Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, Kalantzi M, Herbots L, Sinnaeve P, Dens J, Maertens J, Rademakers F, Dymarkowski S, Gheysens O, Van CJ, Bormans G, Nuyts J, Belmans A, Mortelmans L, Boogaerts M, Van de Werf F. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 2006;367:113-21.
11. Karpov RS, Popov SV, Markov VA, Suslova TE, Ryabov VV, Poponina YS, Krylov AL, Sazonova SV. Autologous mononuclear bone marrow cells during reparative regeneratrion after acute myocardial infarction. Bull Exp Biol Med 2005;140:640-43.
12. Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grogaard HK, Bjornerheim R, Brekke M, Muller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 2006;355:1199-209.
13. Beitnes JO, Hopp E, Lunde K, Solheim S, Arnesen H, Brinchmann JE, Forfang K, Aakhus S. Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomised, controlled study. Heart 2009;95:1983-89.
14. Beitnes JO, Gjesdal O, Lunde K, Solheim S, Edvardsen T, Arnesen H, Forfang K, Aakhus S. Left ventricular systolic and diastolic function improve after acute myocardial infarction treated with acute percutaneous coronary intervention, but are not influenced by intracoronary injection of autologous mononuclear bone marrow cells: a 3 year serial echocardiographic sub-study of the randomized-controlled ASTAMI study. Eur J Echocardiogr 2011;12:98-106. 15. Meluzin J, Janousek S, Mayer J, Groch L, Hornacek I, Hlinomaz O, Kala P, Panovsky R,
Prasek J, Kaminek M, Stanicek J, Klabusay M, Koristek Z, Navratil M, Dusek L, Vinklarkova J. Three-, 6-, and 12-month results of autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction. Int J Cardiol 2008;128:185-92. 16. Nogueira FB, Silva SA, Haddad AF, Peixoto CM, Carvalho RM, Tuche FA, Soares VE,
Sousa AL, Rabischoffsky A, Mesquita CT, Borojevic R, Dohmann HF. Systolic function of patients with myocardial infarction undergoing autologous bone marrow transplantation. Arq Bras Cardiol 2009;93:374-72.
17. Penicka M, Horak J, Kobylka P, Pytlik R, Kozak T, Belohlavek O, Lang O, Skalicka H, Simek S, Palecek T, Linhart A, Aschermann M, Widimsky P. Intracoronary injection of autologous bone marrow-derived mononuclear cells in patients with large anterior acute myocardial infarction: a prematurely terminated randomized study. J Am Coll Cardiol 2007;49:2373-74.
18. Skalicka H, Horak J, Kobylka P, Palecek T, Linhart A, Aschermann M. Intracoronary injection of autologous bone marrow-derived mononuclear cells in patients with large anterior acute myocardial infarction and left ventricular dysfunction: a 24- month follow up study. Bratisl Lek Listy 2012;113:220-227.
19. Piepoli MF, Vallisa D, Arbasi M, Cavanna L, Cerri L, Mori M, Passerini F, Tommasi L, Rossi A, Capucci A. Bone marrow cell transplantation improves cardiac, autonomic, and
functional indexes in acute anterior myocardial infarction patients (Cardiac Study). Eur J Heart Fail 2010;12:172-80.
20. Plewka M, Krzeminska-Pakula M, Lipiec P, Peruga JZ, Jezewski T, Kidawa M, Wierzbowska-Drabik K, Korycka A, Robak T, Kasprzak JD. Effect of intracoronary injection of mononuclear bone marrow stem cells on left ventricular function in patients with acute myocardial infarction. Am J Cardiol 2009;104:1336-42.
21. Plewka M, Krzeminska-Pakula M, Peruga JZ, Lipiec P, Kurpesa M, Wierzbowska-Drabik K, Korycka-Wolowiec A, Kasprzak JD. The effects of intracoronary delivery of mononuclear bone marrow cells in patients with myocardial infarction: a two year follow-up results. Kardiol Pol 2011;69:1234-40.
22. Quyyumi AA, Waller EK, Murrow J, Esteves F, Galt J, Oshinski J, Lerakis S, Sher S, Vaughan D, Perin E, Willerson J, Kereiakes D, Gersh BJ, Gregory D, Werner A, Moss T, Chan WS, Preti R, Pecora AL. CD34(+) cell infusion after ST elevation myocardial infarction is associated with improved perfusion and is dose dependent. Am Heart J 2011;161:98-105. 23. Roncalli J, Mouquet F, Piot C, Trochu JN, Le CP, Neuder Y, Le TT, Agostini D, Gaxotte V,
Sportouch C, Galinier M, Crochet D, Teiger E, Richard MJ, Polge AS, Beregi JP, Manrique A, Carrie D, Susen S, Klein B, Parini A, Lamirault G, Croisille P, Rouard H, Bourin P, Nguyen JM, Delasalle B, Vanzetto G, Van BE, Lemarchand P. Intracoronary autologous mononucleated bone marrow cell infusion for acute myocardial infarction: results of the randomized multicenter BONAMI trial. Eur Heart J 2011;32:1748-57.
24. Assmus B, Rolf A, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Tillmanns H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Tonn T, Dimmeler S, Dill T, Zeiher AM, Schachinger V. Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction. Circ Heart Fail 2010;3:89-96. 25. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J,
Corti R, Mathey DG, Hamm CW, Suselbeck T, Werner N, Haase J, Neuzner J, Germing A, Mark B, Assmus B, Tonn T, Dimmeler S, Zeiher AM. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J 2006;27:2775-83. 26. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J,
Corti R, Mathey DG, Hamm CW, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006;355:1210-21.
27. Tendera M, Wojakowski W, Ruzyllo W, Chojnowska L, Kepka C, Tracz W, Musialek P, Piwowarska W, Nessler J, Buszman P, Grajek S, Breborowicz P, Majka M, Ratajczak MZ. Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial. Eur Heart J 2009;30:1313-21.
12
28. Traverse JH, McKenna DH, Harvey K, Jorgenso BC, Olson RE, Bostrom N, Kadidlo D, Lesser JR, Jagadeesan V, Garberich R, Henry TD. Results of a phase 1, randomized, double-blind, placebo-controlled trial of bone marrow mononuclear stem cell administration in patients following ST-elevation myocardial infarction. Am Heart J 2010;160:428-34.
29. Traverse JH, Henry TD, Ellis SG, Pepine CJ, Willerson JT, Zhao DX, Forder JR, Byrne BJ, Hatzopoulos AK, Penn MS, Perin EC, Baran KW, Chambers J, Lambert C, Raveendran G, Simon DI, Vaughan DE, Simpson LM, Gee AP, Taylor DA, Cogle CR, Thomas JD, Silva GV, Jorgenson BC, Olson RE, Bowman S, Francescon J, Geither C, Handberg E, Smith DX, Baraniuk S, Piller LB, Loghin C, Aguilar D, Richman S, Zierold C, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moye LA, Simari RD. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA 2011;306:2110-19.
30. Turan RG, Bozdag T, Turan CH, Ortak J, Akin I, Kische S, Schneider H, Rauchhaus M, Rehders TC, Kleinfeldt T, Belu C, Amen S, Hermann T, Yokus S, Brehm M, Steiner S, Chatterjee T, Sahin K, Nienaber CA, Ince H. Enhanced mobilization of the bone marrow-derived circulating progenitor cells by intracoronary freshly isolated bone marrow cells transplantation in patients with acute myocardial infarction. J Cell Mol Med 2012;16:852-64. 31. Wohrle J, Merkle N, Mailander V, Nusser T, Schauwecker P, von SF, Schwarz K, Bommer
M, Wiesneth M, Schrezenmeier H, Hombach V. Results of intracoronary stem cell therapy after acute myocardial infarction. Am J Cardiol 2010;105:804-12.
32. Woehrle J, von Scheidt F, Markovic S, Schauwecker P. Intracoronary stem cell therapy in patiens with acute myocardial infarction - 36 months results of a randomized, double-blind, placebo controlled trial wih serial MRI follow-ups [abstract]. J Am Coll Cardiol 2012 ;59:E346. 2012.
33. Meyer GP, Wollert KC, Lotz J, Steffens J, Lippolt P, Fichtner S, Hecker H, Schaefer A, Arseniev L, Hertenstein B, Ganser A, Drexler H. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation 2006;113:1287-94.
34. Meyer GP, Wollert KC, Lotz J, Pirr J, Rager U, Lippolt P, Hahn A, Fichtner S, Schaefer A, Arseniev L, Ganser A, Drexler H. Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial. Eur Heart J 2009;30:2978-84.
35. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141-48.
36. Yao K, Huang R, Sun A, Qian J, Liu X, Ge L, Zhang Y, Zhang S, Niu Y, Wang Q, Zou Y, Ge J. Repeated autologous bone marrow mononuclear cell therapy in patients with large myocardial infarction. Eur J Heart Fail 2009;11:691-98.
37. Martin-Rendon E, Brunskill SJ, Hyde CJ, Stanworth SJ, Mathur A, Watt SM. Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J 2008;29:1807-18.
38. Lipinski MJ, Biondi-Zoccai GG, Abbate A, Khianey R, Sheiban I, Bartunek J, Vanderheyden M, Kim HS, Kang HJ, Strauer BE, Vetrovec GW. Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. J Am Coll Cardiol 2007;50:1761-67. 39. Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA, Zuba-Surma
EK, Al-Mallah M, Dawn B. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med 2007;167:989-997.
40. Clifford DM, Fisher SA, Brunskill SJ, Doree C, Mathur A, Watt S, Martin-Rendon E. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev 2012;2:CD006536. 41. Higgins JTP, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version
5.1.0 [updated March 2011]. The Cochrane Collaboration 2011.
42. Reffelmann T, Konemann S, Kloner RA. Promise of blood- and bone marrow-derived stem cell transplantation for functional cardiac repair: putting it in perspective with existing therapy. J Am Coll Cardiol 2009;53:305-308.
12
SUPPlEMENTARy DATA
Appendix 1 Search terms
Search terms used for Pubmed
1. “Myocardial Ischemia”[Mesh]
2. (myocard*[tiab] OR subendocard*[tiab] OR transmural[tiab] OR cardiac[tiab] OR
cardial[tiab] OR heart[tiab]) AND infarct*[tiab]
3. myocardial[tiab] AND ischaemia*[tiab]
4. myocardial[tiab] AND ischemia*[tiab]
5. heart[tiab] AND ischaemia*[tiab]
6. heart[tiab] AND ischemia*[tiab]
7. ischaemic heart disease*[tiab]
8. ischemic heart disease*[tiab]
9. heart attack*[tiab]
10. coronary disease*[tiab] OR coronary heart disease*[tiab] OR coronary artery disease*[tiab] 11. coronary occlusi*[tiab] 12. ami[tiab] 13. coronary stenosis*[tiab] 14. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13
15. “Stem Cell Transplantation”[Mesh] 16. “Bone Marrow Transplantation”[Mesh] 17. “Bone Marrow Cells”[Mesh]
18. “Stem Cells”[Mesh] 19. stem cell*[tiab] 20. bone marrow*[tiab] 21. progenitor cell*[tiab] 22. precursor cell*[tiab]
23. hematopoetic cell*[tiab] OR haematopoetic cell*[tiab] OR hematopoietic cell*[tiab] OR haematopoietic cell*[tiab] OR hemopoietic cell*[tiab] OR haemopoietic cell*[tiab] 24. hematopoetic marrow*[tiab] OR haematopoetic marrow*[tiab] OR hematopoietic
marrow*[tiab] OR haematopoietic marrow*[tiab] OR hemopoietic marrow*[tiab] OR haemopoietic marrow*[tiab]
25. #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 26. #14 AND #25
27. (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti] NOT (animals[mh] NOT (animals[mh] AND humans [mh])) 28. #26 AND #27
Search terms used for Embase
1. exp ischemic heart disease/
2. ((myocard* or subendocard* or transmural or ardiac or cardial or heart) and infarct*).ti,ab.
3. (myocardial and ischaemia*).ti,ab.
4. (myocardial and ischemia*).ti,ab.
5. (heart and ischemia).ti,ab.
6. (heart and ischaemia).ti,ab.
7. “ischemic heart disease”.ti,ab.
8. “ischaemic heart disease”.ti,ab.
9. “heart attack”.ti,ab.
10. (coronary disease* or coronary heart disease* or coronary artery disease*).ti,ab. 11. “coronary occlus*”.ti,ab.
12. ami.ti,ab.
13. coronary stenosis.ti,ab.
14. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 15. exp stem cell transplantation/
16. exp stem cell mobilization/ 17. exp bone marrow transplantation/ 18. exp bone marrow cell/
19. exp stem cell/ 20. stem cell*.ti,ab. 21. bone marrow.ti,ab. 22. progenitor cell*.ti,ab. 23. precursor cell*.ti,ab.
24. (hematopoetic or haematopoetic or hematopoietic or haematopoietic or hemopoietic or haemopoietic).ti,ab.
25. 24 and cell*.ti,ab. 26. 24 and marrow.ti,ab.
27. 15 or 16 or 17 or 19 or 20 or 21 or 22 or 23 or 25 or 26 28. 14 and 27
29. controlled clinical trial/ 30. random*.tw.
31. randomized controlled trial/ 32. follow-up.tw.
33. double blind procedure/ 34. placebo*.tw.
35. placebo/ 36. factorial*.ti,ab.
12
38. (singl*adj blind*).ti,ab. 39. assign*.ti,ab. 40. allocat*.ti,ab. 41. volunteer*.ti,ab. 42. crossover procedure/ 43. single blind procedure/44. (crossover* or cross-over*).ti,ab. 45. or/29-44
46. 28 and 45
47. (exp animals/ or nonhuman/) not human/ 48. 46 not 47
Search terms used for The Cochrane Library
1. MeSH descriptor myocardial Ischemia explode all trees
2. (myocard* or subendocard* or transmural* or cardiac or cardial or heart) and (infarct* or ischem* or ischaem*)
3. heart attack*
4. coronary disease* or coronary heart disease* or coronary artery disease*
5. coronary occlus* or coronary stenosis*
6. ami[tiab]
7. (#1 OR #2 OR #3 OR #4 OR #5 OR #6)
8. MeSH descriptor Stem Cell Transplantation explode all trees
9. MeSH descriptor Bone Marrow Transplantation explode all trees
10. MeSH descriptor Bone Marrow Cells explode all trees 11. MeSH descriptor Stem Cells explode all trees
12. stem cell* or bone marrow* 13. progenitor cell* or precursor cell*
14. hematopoetic or haematopoetic or hematopoietic of haematopoietic or hemopoietic or haemopoietic
15. (#14 AND (cell* or marrow*))
16. (#8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #15) 17. (#7 AND #16)
Search terms used for LILACs, INMED, KOREAMED and mRCT
lIlACs, INMED, kOREAMED, mRCT
((marrow cell$ OR stem cell$ OR progenitor cell$ OR precursor cell$) AND (infarct$ OR coronar$ OR myocard$ OR heart attack$ OR heart failure OR cardiac$ OR cardiomyo$ OR ischemia))
Appendix 2. Forest plot of retrieved studies evaluating cell therapy and the difference in change left ventricular end systolic volume (lVESV)
