Review and Meta-Analysis NIH Public Access Author ......Adult Bone Marrow Cell Therapy Improves Survival and Induces Long-Term Improvement in Cardiac Parameters: A Systematic Review

Adult Bone Marrow Cell Therapy Improves Survival and Induces Long-Term Improvement in Cardiac Parameters: A Systematic Review and Meta-Analysis

Vinodh Jeevanantham, MD1, Matthew Butler, MD1, Andre Saad, MD1, Ahmed Abdel-Latif, MD2, Ewa K. Zuba-Surma, PhD3, and Buddhadeb Dawn, MD1

1Division of Cardiovascular Diseases & Cardiovascular Research Institute, University of Kansas Medical Center and Hospital, Kansas City, KS 2 Division of Cardiology, University of Kentucky, Lexington, KY 3 Dept of Cell Biology, Faculty of Biochemistry, Biophysics & Biotechnology, Jagiellonian University, Krakow, Poland

Abstract

Background—Despite rapid clinical translation and widespread enthusiasm, the therapeutic

benefits of adult bone marrow cell (BMC) transplantation in patients with ischemic heart disease

(IHD) continue to remain controversial. A synthesis of the available data is critical to appreciate

and underscore the true impact of this promising approach.

Methods and Results—A total of 50 studies (enrolling 2,625 patients) identified by database

searches through January 2012 were included. Weighted Mean Differences for changes in left

ventricular (LV) ejection fraction (LVEF), infarct size, LV end-systolic volume (LVESV), and LV

end-diastolic volume (LVEDV) were estimated using random effects meta-analysis. Compared

with controls, BMC-treated patients exhibited greater LVEF (3.96%, 95% confidence interval

(CI): 2.90, 5.02; P<0.00001), and smaller infarct size (–4.03%, CI: –5.47, –2.59; P<0.00001),

LVESV (–8.91 ml, CI: –11.57, –6.25; P<0.00001), and LVEDV (–5.23 ml, CI: – 7.60, –2.86;

P<0.0001). These benefits were noted irrespective of the study design (RCT vs. Cohort study) and

the type of IHD (acute myocardial infarction vs. chronic IHD), and persisted during long-term

follow-up. Importantly, the all-cause mortality, cardiac mortality, and the incidence of recurrent

MI and stent thrombosis were significantly lower in BMC-treated patients compared with controls.

Conclusions—Transplantation of adult BMCs improves LV function, infarct size, and

remodeling in patients with IHD compared with standard therapy, and these benefits persist during

long-term follow-up. BMC transplantation also reduces the incidence of death, recurrent MI, and

stent thrombosis in patients with IHD.

Address for correspondence: Buddhadeb Dawn, MD, Division of Cardiovascular Diseases, University of Kansas Medical Center, 3901 Rainbow Blvd., Rm. 1001 Eaton, MS 3006, Kansas City, KS 66160, Tel: (913) 588-6015, Fax: (913) 588-6010, [email protected].

Conflict of Interest Disclosures: None

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NIH Public AccessAuthor ManuscriptCirculation. Author manuscript; available in PMC 2015 January 02.

Published in final edited form as:Circulation. 2012 July 31; 126(5): 551–568. doi:10.1161/CIRCULATIONAHA.111.086074.

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Keywords

bone marrow mononuclear cells; ischemic heart disease; myocardial infarction; remodeling; stem cells

Introduction

Coronary artery disease and myocardial infarction (MI) cause significant mortality,

morbidity, and economic burden1. Despite current medical and interventional therapies,

myocardial tissue lost during MI is replaced by noncontractile scar followed by remodeling

of the left ventricle (LV) and gradual progression to heart failure. Based on promising

results from preclinical studies and clinical trials, a new therapeutic approach has gained

vigorous momentum over the past decade – transplantation of adult bone marrow-derived

cells (BMCs) for heart repair. However, while BMC injection resulted in significant

improvement in LV function and structure in many studies2,3, these benefits were mixed or

absent in several others4-8. Although results from clinical trials and meta-analyses have

documented that BMC transplantation is feasible and safe7, the efficacy of this approach for

cardiac repair continues to remain unclear and controversial. In addition, the long-term

persistence of benefits of BMC transplantation remains uncertain9.

Because of the relatively small number of patients even in pooled datasets7,10, satisfactory

analysis of several key aspects of outcomes could not be achieved previously. These include

the impact of BMC transplantation on long-term patient-important clinical outcomes, and

the persistence of benefits during prolonged follow-up. While surrogate endpoints

demonstrate benefit with BMC transplantation7, understanding the clinical impact of this

new therapy on hard clinical endpoints is quintessential before mainstream application. With

the reporting of several newer clinical trials5,6,11-47 since our prior review, we sought to

systematically review the effects of adult BMC transplantation in patients with ischemic

heart disease on clinical and surrogate endpoints.

Methods

Search Strategy

We searched MEDLINE, the Web of Science, the Cochrane Central Register of Controlled

Trials, and the reference lists of retrieved reports through January 2012 for studies of BMC

transplantation in patients with ischemic heart disease (IHD) using the following terms:

“stem cells”, “progenitor cells”, “bone marrow cells”, “coronary artery disease”,

“myocardial infarction”, “acute myocardial infarction”, “ischemic cardiomyopathy”,

“cardiomyopathy”, and “heart failure”. The complete search strategy is provided in

Appendix 1.

Study Selection

Studies were included if they were: (i) randomized controlled trials or cohort studies with a

control group; (ii) conducted in patients with acute myocardial MI or chronic IHD; (iii)

conducted in patients who received percutaneous coronary intervention or thrombolysis or

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coronary artery bypass surgery; and (iv) designed such that patients in the intervention arm

received BMC therapy either via intracoronary injection or intramyocardial injection, and

patients in the control arm received standard therapy. Studies that had at least one month of

follow-up and ≥10 patients as the total sample size were included. Because we used mean

and standard deviation, studies that reported data using median and range, could not be

included. Search criteria were set to include only human studies conducted in adults ≥18

years of age.

Studies that used circulating progenitor cells following granulocyte colony-stimulating

factor (G-CSF) mobilization were excluded in order to avoid confounding direct effects of

GCSF on the myocardium and BMCs. Studies that did not report pre- and post-intervention

outcomes of interest were excluded. Studies published in languages other than English were

excluded, except those for which abstracts were available in English.

Data extraction

Three investigators (VJ, MB, and AS) independently screened all titles and abstracts to

identify studies that met the inclusion criteria and extracted relevant data using a

standardized form. The outcome measures included changes in left ventricular (LV) ejection

fraction (LVEF), infarct size, LV end-systolic volume (LVESV), and LV end-diastolic

volume (LVEDV). The clinical outcome measures included: all-cause mortality, cardiac

mortality, heart failure, stent thrombosis, in-stent restenosis, target vessel revascularization,

cerebrovascular event, and ventricular arrhythmia. Data with the longest duration of follow-

up were included for primary and secondary outcome measures. LV volumes were estimated

from LV volume indices when appropriate. Modes of imaging included echocardiography,

cardiac MRI, left ventriculography (LVG), radionuclide ventriculography (RNV), and

single-photon emission computed tomography (SPECT) (Table 1). MRI and SPECT data

were preferred over echocardiographic data for primary analysis when available. When

multiple imaging modalities were used in one study, data by each modality were extracted to

be included in subgroup analysis. Clinical trials with multiple publications with sequential

follow-up durations or different outcomes were considered as one study. For studies with

two intervention arms12,23,24,32,48 which involved two different doses (low dose and high

dose of BMCs) or different routes of administration (intracoronary and intramuscular), data

were combined using methods described in the Cochrane Handbook49.

Quality Assessment

The quality of included RCTs was assessed by using criteria established by Juni et al.50, and

the quality of cohort studies was assessed by using the modified Newcastle-Ottawa scale51.

Data Analysis

Statistical analyses were performed using the Cochrane RevMan version 5, and the results

expressed as weighted mean differences (WMDs) for continuous outcomes, with 95%

confidence intervals (CIs). Data were pooled using the DerSimonian-Laird random-effects

model, but a fixed-effects model was also employed to ensure the robustness of the model

chosen and the susceptibility to outliers. Heterogeneity was analyzed using I2 statistic, with

a significance level alpha = 0.05. For I2 statistic, heterogeneity was defined as low



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(25-50%), moderate (50-75%), and high (>75%). We planned to conduct sensitivity analysis

if significant heterogeneity was found (I2 > 50%) for any one of the outcomes. For studies

that reported mean±standard deviation (SD) at baseline and follow-up, but did not report the

actual change (from baseline to follow-up) as (mean±SD), the change in SD was calculated

using a standardized formula used previously to calculate changes in mean and standard

deviation52. Peto odds ratio was calculated for clinical outcomes (all-cause mortality,

cardiac mortality, recurrent myocardial infarction, stent thrombosis, heart failure, in-stent

restenosis, target vessel revascularization, cerebrovascular event, and ventricular

arrhythmias).

Subgroup analysis and Sensitivity Analysis

Planned subgroup analyses were conducted based on: (i) type of study design (RCT vs.

Cohort study); (ii) type of IHD (acute MI vs. chronic IHD); (iii) duration of follow-up; (iv)

baseline LVEF of <43% vs. >43% (43% was the median LVEF at baseline in included

studies); and <50% vs. ≥50% (LVEF <50% represents LV dysfunction); (v) timing of BMC

transplantation after acute MI and/or PCI (<7 days vs. 7 to 30 days [7 days after acute

MI/PCI was the median in included studies]); (vi) number of cells injected (<100×106 vs.

>100×106 BMCs injected [100×106 was the median number of BMCs injected]; and

<40×106 vs. >40×106 BMCs injected); (vii) type of BMC (bone marrow mononuclear cells

[BMMNCs] vs. other select cell populations [CD133+ and CD34+ BMCs]); and (viii)

method of cell preparation (Lymphoprep vs. other Ficoll-based methods), and the use of

heparin in the final cellular suspension; (ix) location of MI (anterior vs. multiple areas); and

(x) route of injection. Sensitivity analyses were conducted to explore heterogeneity

(investigating the effects of route of injection, sample size in studies, median LVEF, and

median number of BMCs injected).

Results

Search Results

The initial search retrieved 1,724 reports, of which 1,544 were excluded based on the title

and abstract. Following the exclusion of 36 review articles and 5 reports of ongoing trials,

full-text analysis was performed on 139 reports, of which 89 were excluded because of

unrelated outcomes and the use of G-CSF and circulating progenitor cells. The remaining 50

studies (36 RCTs and 14 cohort studies enrolling a total of 2,625 patients)2-6,9,11-47,53-70 that

reported changes in LVEF, infarct size, LVESV, or LVEDV in patients who underwent

BMC transplantation compared with standard therapy were included in the final analysis

(Figure 1).

Study Characteristics

Table 1 summarizes the characteristics of included studies. The median follow-up duration

was 6 months (range: 3 months to 60 months) and the median sample size was 39 patients

(range: 10 to 391 patients). The timing of BMC transplantation in patients with acute MI

varied among the included studies (median 6.7 days; range: 1 day to 18.4 days), and the

median number of BMCs injected was 100×106 (range: 2×106 to 60×109). The median EF

of patients at baseline was 43% (range: 21% to 62%).



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Study Quality

The quality metrics of included RCTs are shown in Table 2, while Table 3 summarizes the

quality of cohort studies. All cohort studies and at least 15 RCTs failed to blind participants

and/or caregivers; 7 RCTs did not provide adequate information on blinding of participants

and caregivers; and blinding of outcome assessors was unclear in at least 3 RCTs. The loss

and adequacy of follow-up in the eligible studies are provided in Tables 2 and 3. The

follow-up was complete in most studies with shorter follow-up duration. In studies with

longer follow-up, the percent of patients lost to follow-up was acceptable. The inter-

reviewer agreement on these quality domains was greater than 90%.

Cardiac parameters.

Compared with the standard treatment group, BMC transplantation improved LVEF by

3.96% (95% confidence interval [CI]: 2.90, 5.02; P<0.00001; Figure 2), reduced infarct size

by 4.03% (CI: –5.47, –2.59; P<0.00001, Figure 3), reduced LVESV by 8.9 ml, (CI: –11.57,

–6.25; P<0.00001, Figure 4), and reduced LVEDV by 5.23 ml (CI: –7.6, –2.86; P<0.0001,

Figure 5).

Persistence of benefits during long-term follow-up

With analyses based on the duration of follow-up, the improvement in LVEF persisted for at

least more than 24 months, and improvement in infarct size, LVESV, and LVEDV persisted

for at least more than 12 months (Table 4).

Subgroup Analysis

Subgroup analysis showed that improvements in LV function, scar size, and LV volumes

were significant irrespective of the type of IHD (acute MI vs. chronic IHD), except that

BMC transplantation produced greater reduction in LVESV in patients with chronic IHD

(Table 5). The benefits of BMC therapy were similar in patients with MI in any territory

compared with those with anterior MI, although improvement in LVEDV was greater in the

latter (Table 5). The impact of baseline LVEF was analyzed separately based on the median

LVEF (43%) and the presence of LV systolic dysfunction (LVEF <50%). Results from both

analyses showed that recipients of BMC transplantation with lower LVEF at baseline

experienced significantly greater improvement in LVESV and LVEDV, with no significant

reduction in LVEDV in recipients with baseline LVEF >43% and > 50% (Table 5). In

patients with acute MI, BMC injection <7 days after acute MI and/or PCI produced similar

improvements in EF, scar size, and LVESV compared with BMC injection between 7 and

30 days. The improvement in LVEDV was also significant when cells were injected at <7

days, while BMC injection between 7 to 30 days failed to reduce LVEDV (Table 5).

Analysis based on the median BMC number (100×106) showed that injection of >100×106

BMCs produced similar improvements in EF, scar size, and EDV compared with <100×106

BMCs; while reduction in ESV was significantly greater with <100×106 BMCs. Additional

analyses utilizing progressively lower BMC numbers showed that injection of >40×106

BMCs resulted in significant improvement in all 4 primary outcome measures (LVEF, scar

size, LVESV, and LVEDV), while injection of ≤40×106 BMCs did not show improvement



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in any outcome (Table 5), indicating that 40×106 BMCs may represent the cut-off, below

which BMCs fail to exert a majority of the desired benefits.

Regarding cell types, 36 studies used BMMNCs, 5 studies used BMCs, 6 studies used

CD133+ and/or CD34+ cells, and 3 studies used MSCs and/or EPCs. Subgroup analysis

showed that while BMMNC therapy improved LVEF, scar size, and LV volumes, the

pooled effects of CD133+ and/or CD34+ cell therapy were not significantly different

compared with controls (Table 5). The reduction in scar size with BMMNC therapy was

significantly greater compared with CD133+/CD34+ cells. Analysis based on the methods

of cell preparation showed similar benefits in LVEF, scar size, and LVESV when cells were

isolated using Lymphoprep compared with other Ficoll-based methods (Table 5). Further

subgroup analysis comparing studies that used heparinized saline vs. saline-based solutions

without heparin in the final cell suspension showed greater improvement in EF and LVESV

with heparinized saline, while improvements in scar size and LVEDV were comparable with

both methods (Table 5). In 26 studies, cells were injected on the same day as BM harvest,

and in 9 studies, cells were injected by the next day (Table 1). BMCs were cultured or cell

injection was delayed for up to 48 h in 4 studies, and the time-frame was unclear in 11.

Since information regarding storage condition, especially temperature during storage was

not available in the vast majority, subgroup analysis was not performed.

Regarding the route of injection, all patients with acute myocardial infarction received

intracoronary injection of BMCs. Therefore the impact of intracoronary vs. intramyocardial

route of injection was analyzed in patients with chronic IHD. In these patients the outcomes

were not significantly different between the two routes of BMC administration (Table 5).

With regard to the design of included studies, the benefits remained significant when RCTs

and cohort studies were analyzed separately (Figures 2-5), albeit with greater magnitudes in

cohort studies compared with RCTs (Table 5).

Impact of BMC therapy on survival and clinical outcomes

Compared with patients who received standard therapy, BMC-treated patients experienced

significant decrease in all-cause mortality (OR 0.39, CI: 0.27 to 0.55, I2=14%, P<0.00001),

cardiac mortality (OR 0.41, CI: 0.22 to 0.79, I2=2%, P=0.005), recurrent MI (OR 0.25, CI:

0.11 to 0.57, I2=22%, P=0.001), and stent thrombosis (OR 0.34, CI: 0.12 to 0.94, I2=6%,

P=0.04) (Table 6). There were trends toward reduction in the incidence of heart failure (OR

0.52, CI: 0.27 to 1.00, I2=4%, P=0.05) and cerebrovascular event (OR 0.28, CI: 0.08 to 1.07,

I2=0%, P=0.06) in BMC-treated patients. The incidence of in-stent restenosis (OR 0.87, CI:

0.47 to 1.62, I2=0%, P=0.66), target vessel revascularization (OR 0.83, CI: 0.55 to 1.23,

I2=0%, P=0.35), and ventricular arrhythmias (OR 1.14, CI: 0.52 to 2.53, I2=18%, P=0.74)

were similar in BMC-treated patients compared with controls (Table 6).

Imaging modalities and outcomes

Significant differences were noted when the mean changes in LVEF, infarct size, and

LVESV were compared among studies that used echocardiography, SPECT, MRI, or LVG

for outcomes assessment. Specifically, improvement in LVEF in BMC-treated patients was

significant when echocardiography or LVG were used and showed a trend toward



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improvement with SPECT, whereas the increase was insignificant with MRI (Table 7).

Infarct scar size reduction was significant with both SPECT and LVG, but not with MRI

(Table 7). Importantly, reduction in LVESV was significant with all imaging modalities,

albeit the magnitude varied; while reduction in LVEDV was significant by

echocardiography and SPECT, but not by MRI or LVG (Table 7).

Sensitivity analysis

Heterogeneity was explored by conducting sensitivity analysis based on the route of

injection, sample size, median LVEF and median number of BMCs injected. All clinical

trials in patients with acute MI used the intracoronary route for BMC injection. Analysis

based on the route of injection, median EF and the median number of BMCs did not explain

the heterogeneity (Table 5). Analysis of studies based on sample size (<50 patients vs. ≥50

patients) did not change the results and did not explain the heterogeneity.

Publication Bias

We drew funnel plots to seek evidence of publication bias: where inconsistency was high,

the funnel plots were not interpretable; where inconsistency was low, the funnel plots were

inconclusive.

Discussion

Salient findings

Our meta-analysis of pooled data from 2,625 patients, the largest to date, demonstrate that

adult BMC transplantation results in modest yet significant improvements in LVEF, infarct

scar size, LVESV, and LVEDV. These results indicate that BMC transplantation can

improve LV function and remodeling beyond those achievable with standard therapy. The

persistence of LVEF improvement at least beyond 24 months and other enhancements at

least beyond 12 months underscores the long-standing nature of cardiac repair induced by

BMC transplantation. Importantly, and although assessed as secondary outcomes, our results

also indicate that BMC-treated patients experienced significant reduction in all-cause

mortality, cardiac mortality, recurrent MI, and stent thrombosis compared with patients who

received standard therapy. While the clinical trials included in this meta-analysis were not

designed to assess the impact of BMC transplantation on long-term clinical outcomes as

their primary outcome, these findings are highly significant from a therapeutic standpoint,

and provide a strong basis for large scale clinical trials.

BMC therapy improves LV function and remodeling

The primary objectives of cell therapy are to improve LV structure and function and

ameliorate patient symptoms. In this regard, results from individual clinical trials have been

discordant with some trials showing improvement in diverse functional and clinical

parameters with BMC transplantation, while others failing to document significant benefits.

Based on data from 2,625 patients, the current results indicate that injection of BMCs in

patients with IHD results in modest improvements in LVEF, infarct size, LVESV, and

LVEDV. The improvement in LV systolic function is noteworthy as LVEF is an important

prognostic factor in patients with acute myocardial ischemic injury71. It is also important to



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note that although the 3.96% increase in LVEF is not large, the other therapeutic options in

these patients are able to offer only similar benefits72. In addition, BMC transplantation also

improved postinfarct remodeling as evidenced by reduction in infarct scar size and LVEDV.

These benefits may translate into superior long-term prognosis in these patients. The

mechanisms underlying these benefits remain poorly understood at this time, although

enhanced angiogenesis and reduction in apoptosis through paracrine effects of growth

factors secreted by BMCs, differentiation of BMCs into cardiac cells, and activation of

cardiac stem cells have all been suggested73,74.

The sustained nature of benefits

We performed additional analysis based on duration of follow-up to examine whether the

benefits would persist during long-term follow-up. As shown in Table 4, the improvement

in LVEF was robust even beyond 24 months, while the reduction in infarct size and LV

volumes persisted for at least more than 12 months. These data indicate that the benefits of

BMC transplantation on LV structure and function are not transient.

Patient characteristics

Notwithstanding this uncertainty regarding mechanisms, we analyzed data based on pre-

defined subgroups attempting to identify the potential factors that may influence the

observed benefits. When analyzed based on the type of ischemic heart disease, BMC

transplantation in patients with chronic IHD produced greater reduction in LVESV

compared with acute MI patients who received BMC therapy (Table 5). These findings

indicate that beyond the acute setting, BMC transplantation can also effectively ameliorate

LV remodeling, which is a chronic process. Further analysis revealed similar benefits

irrespective of the location of MI, although the reduction in LVEDV was more pronounced

in patients with anterior MI.

Analysis based on the median LVEF (43%) in recipients showed significantly greater

reduction in LV volumes in patients with LVEF <43% at baseline (Table 5). These

differences in outcomes persisted when subgroup data were analyzed using a baseline LVEF

of 50%, below which LV dysfunction is considered present. Importantly, BMC therapy

failed to reduce LVEDV in patients with a baseline LVEF >43% (Table 5). Together, these

results indicate that LV remodeling outcomes are superior with lower baseline LVEF in

recipients. Although no rigid cut-off value below which BMC transplantation would be

ineffective could be determined, these data indicate that the benefits of BMC transplantation

are greater in recipients with LV dysfunction at baseline.

Timing of cell injection

Following an acute MI, the initial inflammatory myocardial milieu progressively changes to

that of a remodeled heart, and understandably the fate of injected BMCs and the outcomes

of therapy may depend on the timing of cell injection. Interestingly, when BMCs were

injected <7 days (the median interval) after acute MI and/or PCI, the improvements in

LVEF, infarct scar size, and LVESV were similar compared with BMC injection within the

7 to 30 day period; however, improvement in LVEDV was absent with delayed BMC



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injection (Table 5). These results underscore the critical need for direct comparison of

different timings of cell therapy after acute MI in prospective trials.

The impact of cell number

Since only a small fraction of injected cells is retained in the myocardium, the total number

of BMCs injected may determine the degree of cardiac recovery. While the mean changes in

LVEF, infarct size, and LVEDV were similar in patients who received >100×106 BMCs (the

median number in included studies) and <100×106 BMCs, there was a greater reduction in

LVESV in patients who received <100×106 BMCs. Upon further analysis with progressively

lower BMC numbers, none of the benefits (improvement in LVEF, and reduction in infarct

size, LVESV, and LVEDV) were observed in patients who received <40×106 BMCs, while

improvements in all four outcome parameters were evident in those who received >40×106

cells (Table 5). However, a limitation in this type of subgroup analysis is the fact that these

trials did not directly compare the effects of low vs. high dose of BMC transplantation.

Moreover, clinical factors such as the timing after MI and the route of injection may also be

responsible for the lack of benefits observed with lower number of BMCs.

Comparison of cell types

Since the initial demonstration of cardiac repair with Lin-/c-kit+ BMCs, a number of other

BMC subfractions have been used for similar purposes. In subgroup analysis, BMMNC

transplantation resulted in improvement in all four primary outcomes, whereas therapy with

CD133+ and/or CD34+ cells did not improve LVEF, scar size, or volumes (Table 5). While

this could be related to the small number of studies (reduced sample size) with these subsets,

the benefits of specific subgroups of BMMNCs need further evaluation.

It is important to note that recent studies have documented the efficacy of myocardial repair

with various adult cells from other tissues, including the heart. Indeed, the c-kit+ cardiac

stem cells (CSCs)75 are considered optimally suited for myocardial repair because of their

cardiac origin and inherent ability to differentiate into cardiac lineages. Consistent with the

efficacy of CSCs to repair infarcted myocardial tissue following intravascular delivery76 and

in the setting of an old MI77, intracoronary delivery of autologous CSCs improved LVEF by

12.3% and reduced infarct size by 30% after 1 year in patients with ischemic

cardiomyopathy in a recent trial78. In a subsequent study79, intracoronary injection of

cardiosphere-derived cells reduced infarct mass and improved regional myocardial

contractility in patients with acute MI and LV dysfunction. Thus, the efficacy of CSCs for

cardiac repair needs to be compared with BMMNCs in future trials.

The importance of cell processing methods

It has been appropriately suggested that cell processing methods impact outcomes80,81.

Therefore we performed subgroup analysis based on the specific method of density-gradient

centrifugation, and the benefits were comparable with Lymphoprep vs. other Ficoll-based

protocols (Table 5). Additional subgroup analysis showed greater improvement in LVEF

and LVESV with the use of heparin in the final BMC suspension (Table 5). Importantly,

BMCs were stored for various lengths of time, and further studies will be necessary to

directly assess the importance of additional factors in this process.



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Route of injection

In patients with acute MI, all of the included studies employed the intracoronary route.

Therefore, we analyzed the impact of cell delivery approaches in patients with chronic IHD

only. There was no significant difference between outcomes with intracoronary compared

with intramyocardial administration in patients with CIHD (Table 5). Nonetheless, in

clinical scenarios, the applicability and selection of intracoronary and intramyocardial routes

will often depend on patient characteristics and logistics.

Improvement in survival and adverse outcomes during follow-up

With the growing number of cell therapy trials, it has become critically important to

consider the overall clinical picture, which includes broader endpoints. In this light, and

although analyzed as secondary outcomes, the ability of BMC transplantation to reduce all-

cause as well as cardiac mortalities, incidence of recurrent MI, and stent thrombosis is

noteworthy. The incidence of heart failure and CVA also showed a trend toward reduction.

These data suggest that BMC transplantation may modulate other as yet unknown variables

that may influence the overall outcomes positively.

The impact of imaging modality

The potential influence of imaging modality was analyzed for all primary outcomes.

Interestingly, the improvements in LV functional parameters were more pronounced in

studies that used echocardiography or LVG compared with those using MRI. It is important

to note that the differences in mean change by MRI were uniformly directionally concordant

with other modalities, albeit not statistically significant. Thus, these results need to be

interpreted in light of the relative paucity of studies that have employed MRI for assessment

of primary outcomes (Table 1). The increasing use of MRI in newer studies may provide

additional data for effective comparison among various imaging modalities.

Safety

Our review demonstrates that BMC transplantation is safe in patients with IHD. The

incidence of in-stent restenosis, a potential concern in patients treated with intracoronary

BMC injection, was similar in BMC-treated and control patients. The incidence of other

important clinical adverse outcomes, including target vessel revascularization and

ventricular arrhythmia also did not differ between groups.

The selection of outcome variables

In this systematic review, we were able to analyze the primary variables that were reported

in a majority of studies. However, it is important to note that these variables have inherent

limitations in serving as accurate end-points of BMC therapy. For example, LVEF is known

to be load-dependent and may be influenced by hypercontractile segments in the viable

myocardium. Further, its prognostic significance diminishes with values >45%. Therefore,

in future studies, it will be important to identify a combinatorial set of parameters that will

reliably reflect the true impact of BMC therapy in patients with IHD.



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Limitations

The degree of heterogeneity observed among trials in this review is a limitation. This

heterogeneity may have resulted from the differences in imaging modalities used to

determine LV volumes and EF, BMC number and processing, timing and route of injection,

and differences in baseline characteristics among the study populations. We conducted

predetermined subgroup analyses for the mode of imaging, timing of BMC injection, and the

number of BMCs injected. However, a limitation in subgroup analysis, although pre-

defined, is that the number of studies included in one subgroup may be less than the other(s).

This could lead to smaller sample size which may result in nonsignificant association.

Nonetheless, the improvements observed across most of these subgroups (Tables 4, 5, and

7) suggest that the associations are likely valid. Sensitivity analyses based on sample size,

baseline LVEF and route of injection also did not explain the heterogeneity. Most of these

studies were conducted in small patient populations with a few exceptions, and did not focus

on broad clinical outcomes.

In conclusion, the results of our systematic review suggest that BMC transplantation in

addition to standard therapy in patients with IHD improves LV function and remodeling as

well as patient-important clinical outcomes. Further large scale randomized studies are

needed to critically evaluate the multi-faceted benefits of this promising therapeutic

approach.

Acknowledgments

The authors gratefully acknowledge Renee Falsken for expert secretarial assistance.

Funding Sources: This meta-analysis and publication was supported in part by NIH grant R01 HL-89939

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CLINICAL PERSPECTIVE

Although adult bone marrow cell (BMC) therapy for cardiac repair appears promising,

divergent data from smaller clinical trials have generated lingering controversy over the

nature and extent of benefits. We performed a systematic review and meta-analysis of

pooled data from 50 trials to assess the impact of BMC therapy on clinically important

end-points. Our results show that BMC therapy modestly improves left ventricular

function and remodeling in patients with IHD, and these benefits persist during long-term

follow-up. These data also suggest that BMC therapy is associated with reduced all-cause

as well as cardiac mortality, and reduced incidence of recurrent myocardial infarction

(MI) and stent thrombosis without any significant increase in adverse events. BMC

therapy seems effective for both acute MI and chronic ischemic cardiomyopathy, largely

independent of the location of MI. Patients with lower LV ejection fraction at baseline

appear to benefit more. To be effective, injection of at least 40 million BMCs seems

necessary, and the remodeling benefits seem more pronounced with earlier BMC

injection. Although BM mononuclear cells are generally more effective compared with

subpopulations, cell processing techniques deserve particular attention, because they

influence the outcomes significantly. Finally, the magnitude of changes in various

outcome parameters depends on the imaging modality, although the findings remain

directionally concordant. Thus, larger clinical trials utilizing stringent methodology and

broader array of outcomes are warranted to definitively determine the true utility of this

novel therapeutic strategy for cardiac repair.



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Figure 1. Flow diagram of eligible studies of bone marrow–derived cell (BMC) transplantation in

patients with acute myocardial infarction and chronic ischemic heart disease. GCSF

indicates granulocyte colony-stimulating factor; and RCT, randomized controlled trial. IV,

inverse variance.



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Figure 2. Forest plot of unadjusted difference in mean (with 95% confidence intervals [CIs]) change

in left ventricular ejection fraction (LVEF) in patients treated with bone marrow-derived

cells (BMCs) compared with controls. The figure shows the summary of randomized

controlled trials (RCTs) and cohort studies. Transplantation of BMCs resulted in a 3.96%

(CI: 2.90, 5.02; P<0.00001) increase in mean LVEF. The overall effect was statistically

significant in favor of BMC transplantation. WMD indicates weighted mean difference. IV,

inverse variance.



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in infarct scar size in patients treated with bone marrow-derived cells (BMCs) compared

with controls. The figure shows the summary of randomized controlled trials (RCTs) and

cohort studies. Transplantation of BMCs resulted in a 4.03% (CI: –5.47, –2.59; P<0.00001)

decrease in mean infarct scar size. The overall effect was statistically significant in favor of

BMC transplantation. WMD indicates weighted mean difference. IV, inverse variance.



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in left ventricular end-systolic volume (LVESV) in patients treated with bone marrow-

derived cells (BMCs) compared with controls. The figure shows the summary of

randomized controlled trials (RCTs) and cohort studies. Transplantation of BMCs resulted

in a 8.91 ml (CI: – 11.57, –6.25; P<0.00001) decrease in LVESV. The overall effect was

statistically significant in favor of BMC transplantation. WMD indicates weighted mean

difference. IV, inverse variance.



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in left ventricular end-diastolic volume (LVEDV) in patients treated with bone marrow-

derived cells (BMCs) compared with controls. The figure shows the summary of

randomized controlled trials (RCTs) and cohort studies. BMC transplantation resulted in a

5.23 ml (CI: – 7.60, –2.86; P<0.001) decrease in mean LVEDV. The overall effect was

statistically significant in favor of BMC transplantation. WMD indicates weighted mean

difference. IV, inverse variance.



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Tab

le 1

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of s

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us,

salin

e, in

ject

edw

ithin

8.5

h

1 ×

108

ICA

MI

Mul

tiple

NR

5.5

± 1

.3 d

RN

V

Srim

ahac

ho-t

a et

al,33

201

123

6R

CT

BM

MN

CIs

opre

p, s

alin

e+2%

auto

logo

us s

erum

,in

ject

ed s

ame

day

420

± 2

21 ×

106

ICA

MI

Mul

tiple

DE

S17

-18

%

57 ±

122

dM

RI

Stam

m e

t al,34

200

743

6C

ohor

tC

D13

3+C

liniM

acs,

inje

cted

next

day

1.08

× 1

06 to

8.3

5 ×

107

IM w

/C

AB

GC

IHD

Mul

tiple

-7.

9 w

k (m

edia

n)E

cho

Stra

uer

et a

l,2 20

0220

3C

ohor

tB

MM

NC

Fico

ll, X

-viv

o15,

hepa

rini

zed

salin

e,ov

erni

ght c

ultiv

atio

n

28 ±

22

× 1

06IC

AM

IM

ultip

leN

R8

± 2

dL

VG

Stra

uer

et a

l,69 2

005

363

Coh

ort

BM

MN

CFi

coll,

X-v

ivo1

5,he

pari

nize

d sa

line,

over

nigh

t cul

tivat

ion

90 ×

106

ICC

IHD

Mul

tiple

-82

3.5

± 9

45.5

dL

VG

Stra

uer

et a

l, 35

2010

391

60C

ohor

tB

MM

NC

Fico

ll, X

-viv

o15,

hepa

rini

zed

salin

e6.

6 ±

3.3

× 1

07IC

CIH

DM

ultip

le-

8.5

± 3

.2 y

LV

G

Suar

ez d

e L

ezo

etal

,36 2

007

203

RC

TB

MM

NC

Fico

ll-H

ypaq

ue,

hepa

rini

zed

salin

e,in

ject

ed s

ame

day

9 ±

3 ×

108

/17

± 1

3 ×

106

ICA

MI

Ant

erio

rN

R7

± 2

dL

VG

Tra

vers

e et

al,6

2010

406

RC

TB

MM

NC

Fico

ll, s

alin

e+5%

HSA

, del

iver

edw

ithin

8 h

1 ×

108

ICA

MI

Ant

erio

rD

ES

95%

3 to

10

dM

RI


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript


Sour

ceSa

mpl

e si

zeM

ean

follo

w-u

p du

rati

on

(mon

ths)

Stud

y de

sign

Cel

l typ

eB

MC

pre

para

tion

, su

spen

sion

, inj

ecti

onN

o. o

f ce

lls

tran

spla

nted

Rou

te o

f In

ject

ion

Typ

e of

IH

DL

ocat

ion

of M

ID

ES

use

Tim

e fr

om P

CI

and/

or

MI

to t

rans

plan

tati

onIm

agin

g m

odal

itie

s*

Tra

vers

e et

al,

37

2011

876

RC

TB

MC

Aut

omat

ed c

ell

proc

esso

r (S

epax

)sa

line+

5% H

SA,

inje

cted

with

in 1

2 h

1.47

± 1

7 ×

108

ICA

MI

Mul

tiple

DE

S69

-78

%

14-2

1 d

(17.

4)M

RI

Tse

et a

l,38 2

007

286

RC

TB

MM

NC

Fico

ll, P

BS+

10%

auto

logo

us s

erum

,in

ject

ed s

ame

day

1.67

± 0

.34

×10

7 (l

ow)

4.20

± 2

.80

×10

7 (h

igh)

IMC

IHD

NA

-N

AM

RI

Tur

an e

t al,39

201

132

6C

ohor

tB

MC

BM

AC

, fre

shly

isol

ated

BM

Cs

101

± 2

0 ×

106

ICA

MI

Mul

tiple

NR

7 d

LV

G

Tur

an e

t al,

4020

1162

12R

CT

BM

CB

MA

C, f

resh

lyis

olat

ed B

MC

s9.

6 ±

3.2

× 1

07IC

AM

IM

ultip

leN

R7

days

LV

G

Woh

rle

et a

l,43 2

010

426

RC

TB

MM

NC

Fico

ll, s

alin

e+2%

albu

min

, inj

ecte

d at

6 h

(med

ian)

381

± 1

30 ×

106

ICA

MI

Mul

tiple

DE

S28

-31

%

6.3

± 0

.8 d

MR

I

Yao

et a

l,44 2

008

476

RC

TB

MM

NC

Fico

ll-H

ypaq

ue,

hepa

rin-

trea

ted

plas

ma,

inje

cted

sam

e da

y

180

×10

6IC

CIH

DM

ultip

leD

ES

57-

58%

13 ±

8 m

onth

sM

RI

Yao

et a

l,48 2

009

3912

RC

TB

MM

NC

Fico

ll-H

ypaq

ue,

hepa

rin-

trea

ted

plas

ma,

inje

cted

sam

e da

y

1.9

± 1

.2 ×

108

(sin

gle

tran

sfus

ion)

2.0

± 1

.4 ×

108

(rep

eat t

rans

fusi

on)

ICA

MI

Ant

erio

rD

ES

33-

47%

3 to

7 d

repe

at a

t 3 m

onth

sM

RI

Yer

ebak

an e

t al,

45 2

011

5518

Coh

ort

CD

133+

Clin

iMac

s, in

ject

edne

xt d

ay6

× 1

06IM

w/

CA

BG

CIH

CM

ultip

le-

>14

day

s (2

-1,2

15w

eeks

)E

cho

You

sef

et a

l,46 2

009

124

60C

ohor

tB

MM

NC

Fico

ll, h

epar

iniz

edsa

line

6.1

± 3

.9 ×

107

ICA

MI

Mul

tiple

NR

7 ±

2 d

LV

G

Zha

o et

al,47

200

836

6R

CT

BM

MN

CFi

coll,

hep

arin

ized

salin

e, in

ject

ed s

ame

day

6.59

± 5

.12

× 1

08IM

w/

CA

BG

CIH

DM

ultip

le-

NA

Ech

o

Abb

revi

atio

ns: A

MI,

acu

te m

yoca

rdia

l inf

arct

ion;

BM

C, b

one

mar

row

cel

ls; B

MM

NC

, bon

e m

arro

w m

onon

ucle

ar c

ells

; BM

PC, b

one

mar

row

ste

m c

ells

; CA

BG

, cor

onar

y ar

tery

byp

ass

graf

t; C

IHD

, chr

onic

isch

emic

hea

rt d

isea

se; D

ES,

dru

g-el

utin

g st

ent;

Ech

o,

echo

card

iogr

aphy

; EF,

eje

ctio

n fr

actio

n; H

SA, h

uman

ser

um a

lbum

in; I

C, i

ntra

coro

nary

; IM

, int

ram

uscu

lar;

IS,

infa

rct s

ize;

LV

G, l

eft v

entr

icul

ogra

phy;

MI,

myo

card

ial i

nfar

ctio

n; M

RI,

mag

netic

res

onan

ce im

agin

g; M

SC, m

esen

chym

al s

tem

cel

ls; N

A, n

ot a

vaila

ble;

NR

, not

re

port

ed; P

BS,

pho

spha

te-b

uffe

red

salin

e; P

CI,

per

cuta

neou

s co

rona

ry in

terv

entio

n; P

ET

, pos

itron

em

issi

on to

mog

raph

y; R

CT

, ran

dom

ized

con

trol

led

tria

l; R

NV

, rad

ionu

clid

e ve

ntri

culo

grap

hy; S

PEC

T, s

ingl

e ph

oton

em

issi

on c

ompu

ted

tom

ogra

phy;

Vol

, LV

vol

ume(

s).

* The

imag

ing

mod

ality

use

d fo

r pr

imar

y ou

tcom

es a

sses

smen

t in

our

met

a-an

alys

is


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript


Tab

le 2

Qua

lity

asse

ssm

ent s

cale

for

the

rand

omiz

ed c

ontr

olle

d tr

ials

incl

uded

in th

e m

eta-

anal

ysis

Sele

ctio

nP

erfo

rman

ceD

etec

tion

Att

riti

on

Sour

ce o

f bi

asW

as a

lloca

tion

ade

quat

e?*

Was

an

adeq

uate

m

etho

d of

ra

ndom

izat

ion

desc

ribe

d?

Wer

e gr

oups

si

mila

r at

the

st

art

of t

he

stud

y?

Wer

e th

e pa

tien

ts/

care

give

rs b

linde

d to

the

inte

rven

tion

?

Was

the

out

com

e as

cert

aine

d bl

indl

y?

Wha

t pe

rcen

t w

as lo

st t

o fo

llow

-up?

Wer

e al

l pat

ient

s an

alyz

ed in

the

gr

oup

to w

hich

th

ey w

ere

assi

gned

(i

nten

tion

-to-

trea

t an

alys

is)?

Ang

et a

l,12 2

008

YN

YY

Y8%

N

Ass

mus

et a

l,53 2

006

YN

YN

Y8.

6%Y

Cao

et a

l,15 2

009

YY

YN

RY

0Y

Che

n et

al,55

200

4Y

NY

YY

0Y

Col

ombo

et a

l,16 2

011

YY

YY

Y0

Y

Ge

et a

l,57 2

006

YY

YN

Y0

Y

Gra

jek

et a

l.1720

10Y

YY

NY

0N

Hen

drik

x et

al,58

200

6Y

YY

NY

0Y

Her

bots

et a

l,18 2

009

YY

YY

Y1%

Y

Hua

ng e

t al,19

200

6 (a

bstr

act o

nly)

NA

NA

NA

NA

NA

NA

NA

Hui

kuri

et a

l,20 2

008

YY

YY

Y3.

7%Y

Lun

de e

t al,4,

13,1

4,61

200

6, 2

008,

200

9Y

YY

NY

0Y

Jans

sens

et a

l,59 L

ance

t 200

6Y

YY

YY

10%

Y

Lip

iec

et a

l,21 2

009

YY

YN

Y5%

N

Mel

uzin

et a

l,23,2

4 20

06, 2

008

YN

YN

RY

9%N

Mey

er e

t al,9,

67,6

8,70

200

6Y

YY

YY

0Y

Nog

ueir

a et

al 25

200

9Y

YY

NY

0Y

Peni

cka

et a

l,5 20

07Y

YN

RN

RN

R11

%N

Piep

oli e

t al,27

201

0Y

YY

NR

NR

0Y

Plew

ka e

t al,28

200

9Y

NY

NR

Y0

Y

Poku

shal

ov e

t al,29

201

0Y

YY

NY

24%

Y

Quy

yum

i et a

l,30 2

011

YN

YN

Y8%

N


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript


Sele

ctio

nP

erfo

rman

ceD

etec

tion

Att

riti

on

Sour

ce o

f bi

asW

as a

lloca

tion

ade

quat

e?*

Was

an

adeq

uate

m

etho

d of

ra

ndom

izat

ion

desc

ribe

d?

Wer

e gr

oups

si

mila

r at

the

st

art

of t

he

stud

y?

Wer

e th

e pa

tien

ts/

care

give

rs b

linde

d to

the

inte

rven

tion

?

Was

the

out

com

e as

cert

aine

d bl

indl

y?

Wha

t pe

rcen

t w

as lo

st t

o fo

llow

-up?

Wer

e al

l pat

ient

s an

alyz

ed in

the

gr

oup

to w

hich

th

ey w

ere

assi

gned

(i

nten

tion

-to-

trea

t an

alys

is)?

Ram

shor

st e

t al,41

,42

2009

YY

YY

Y18

%Y

Rua

n et

al,65

200

5Y

NY

YY

0Y

Scha

chin

ger

et a

l,3,56

,66

2006

YY

YY

Y0

Y

Silv

a et

al,32

200

9Y

YY

NY

0Y

Srim

ahac

hota

et a

l,33 2

011

NY

YN

Y0

Y

Suar

ez d

e L

ezo

et a

l,36 2

007

YY

YN

RY

0Y

Tra

vers

e et

al,6

2010

YY

YY

Y0

Y

Tra

vers

e et

al,

3720

11Y

NY

NY

1.1%

Y

Tur

an e

t al,

40 2

011

YN

YN

Y0

Y

Tse

et a

l,38 2

007

YY

YY

Y7%

Y

Woh

rle

et a

l,43 2

010

YY

YY

Y4.

7%Y

Yao

et a

l,44 2

008

YN

YN

Y0

Y

Yao

et a

l,48 2

009

YY

YN

RY

13%

N

Zha

o et

al,47

200

8Y

YY

NY

5.5%

Y

* ‘Ade

quat

e’ m

eans

the

use

of c

entr

al s

ite, n

umer

ic c

ode,

opa

que

enve

lope

s, d

rugs

pre

pare

d by

pha

rmac

y, a

nd o

ther

app

ropr

iate

pro

cedu

res

as d

escr

ibed

by

Juni

et a

l. 50

. NA

, not

ava

ilabl

e; N

R, n

ot

repo

rted

.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript


Tab

le 3

Mod

ifie

d N

ewca

stle

-Otta

wa

Qua

lity

Ass

essm

ent S

cale

for

the

Coh

ort S

tudi

es in

clud

ed in

the

met

a-an

alys

is

Sele

ctio

nO

utco

me

Sour

ceR

epre

sent

ativ

enes

s of

the

exp

osed

co

hort

Sele

ctio

n of

th

e no

nexp

osed

co

hort

Asc

erta

inm

ent

of e

xpos

ure

Inci

dent

dis

ease

Com

para

bilit

yA

sses

smen

t of

out

com

eL

engt

h of

fol

low

-up

Ade

quac

y of

fol

low

-up

Aka

r et

al,11

2009

BA

AA

BB

AA

Bar

tune

k et

al,54

2005

AA

AA

AB

AA

Kat

rits

is e

t al,60

2005

AA

AA

AA

AA

Man

gina

s et

al,22

BA

AA

BN

RA

A

Moc

ini e

t al,62

2006

AA

AA

AA

AA

Perm

et a

l,6364

2003

, 200

4A

AA

NR

AA

AA

Riv

as-P

lata

et

al,31

201

0B

AA

AA

NR

AA

Stam

m e

t al,34

2007

BA

AA

CA

AB

Stra

uer

et a

l,2

2002

AA

AA

AB

AA

Stra

uer

et a

l,69

2005

AA

AA

AB

AA

Stra

uer

et a

l,35

2010

AA

AA

AB

AA

Tur

an e

t al,39

2011

AA

AA

AA

AA

Yer

ebak

an e

t al

, 45 2

011

AA

AA

AA

AB

You

sef

et a

l,46

2009

AA

AA

AA

AA

* Se

lect

ion:

(1)

Rep

rese

ntat

iven

ess

of th

e ex

pose

d co

hort

: A, t

ruly

rep

rese

ntat

ive

of th

e av

erag

e pa

tient

with

isch

emic

hea

rt d

isea

se; B

, som

ewha

t rep

rese

ntat

ive

of th

e av

erag

e pa

tient

with

isch

emic

hea

rt

dise

ase;

C, s

elec

ted

grou

p; a

nd D

, no

desc

ript

ion

of th

e de

riva

tion

of th

e co

hort

. (2)

Sel

ectio

n of

the

none

xpos

ed c

ohor

t: A

, dra

wn

from

the

sam

e co

mm

unity

as

the

expo

sed

coho

rt; B

, dra

wn

from

a

diff

eren

t sou

rce;

and

C, n

o de

scri

ptio

n of

the

deri

vatio

n of

the

none

xpos

ed c

ohor

t. (3

) A

scer

tain

men

t of

expo

sure

: A, s

ecur

e re

cord

(eg

, sur

gica

l rec

ords

); B

, str

uctu

red

inte

rvie

w; C

, wri

tten

self

-rep

ort;

and

D, n

o de

scri

ptio

n. (

4) D

emon

stra

tion

that

out

com

e of

inte

rest

was

not

pre

sent

at s

tart

of

stud

y: A

, yes

; B, n

o.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Jeevanantham et al. Page 31†

Com

para

bilit

y: C

ompa

rabi

lity

of c

ohor

ts o

n th

e ba

sis

of th

e de

sign

or

anal

ysis

: A, s

tudy

con

trol

s fo

r co

mor

bidi

ties;

B, s

tudy

con

trol

s fo

r ad

ditio

nal r

isk

fact

ors

(suc

h as

age

and

sev

erity

of

illne

ss);

and

C,

not d

one.

‡ O

utco

me:

(1)

Ass

essm

ent o

f ou

tcom

e: A

, ind

epen

dent

blin

d as

sess

men

t; B

, rec

ord

linka

ge; C

, sel

f-re

port

; and

D, n

o de

scri

ptio

n. (

2) W

as f

ollo

w-u

p lo

ng e

noug

h fo

r ou

tcom

es to

occ

ur: A

, yes

; B, n

o. (

3)

Ade

quac

y of

fol

low

-up

of c

ohor

ts: A

, com

plet

e fo

llow

-up—

all s

ubje

cts

acco

unte

d fo

r; B

, sub

ject

s lo

st to

fol

low

-up

unlik

ely

to in

trod

uce

bias

(sm

all n

umbe

r lo

st),

fol

low

-up

rate

hig

her

than

90%

, or

desc

ript

ion

prov

ided

of

thos

e lo

st; C

, fol

low

-up

rate

90%

or

low

er (

sele

ct a

n ad

equa

te p

erce

ntag

e) a

nd n

o de

scri

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Table 4

Unadjusted difference in mean change in parameters in BMC-treated patients compared with controls based

on the duration of follow-up

Follow-up duration Difference in mean 95% Confidence Interval P value

LVEF

0 – 3 months 4.78 3.22 to 6.34 <0.00001

4 – 6 months 3.47 2.35 to 4.59 <0.00001

7 – 12 months 5.93 4.56 to 7.30 <0.00001

13 – 24 months 2.14 0.25 to 4.02 <0.03

> 24 months 6.91 3.37 to 10.45 0.0001

Infarct size

0 – 3 months –6.19 –9.73 to –2.64 0.0006

4 – 6 months –2.94 –4.60 to –1.29 0.0005

7 – 12 months –5.60 –9.67 to –1.53 0.007

> 12 months –2.39 –2.78 to –2.01 <0.00001

LVESV

0 – 3 months –9.33 –13.66 to –5.00 <0.00001

4 – 6 months –5.68 –7.83 to –3.54 <0.00001

7 – 12 months –14.52 –19.35 to –9.68 <0.00001

> 12 months –9.47 –14.51 to –4.44 0.0002

LVEDV

0 – 3 months –2.92 –7.09 to 1.26 0.17

4 – 6 months –2.90 –4.92 to –0.89 0.005

7 – 12 months –7.65 –12.48 to –2.83 0.002

> 12 months –4.37 –7.84 to –0.90 0.01

Abbreviations: BMC, bone marrow cells; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume


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Table 5

Subgroup analysis examining the impact of study design, type of ischemic heart disease, timing of

transplantation, number of BMCs transplanted, and route of BMC transplantation, and left ventricular ejection

fraction at baseline on outcome variables.

Outcome Difference in mean (95% confidence interval) P value for subgroup

differences

Acute MI Chronic IHD

LVEF 3.48 (2.05 to 4.91) 4.94 (3.27 to 6.61) 0.19

Infarct scar size –3.73 (–5.29 to –2.18) –6.09 (–7.96 to –4.21) 0.06

LVESV –5.91 (–8.31 to –3.50) –16.34 (–23.98 to –8.70) 0.01

LVEDV –3.76 (–6.38 to –1.15) –7.81 (–13.8 to –1.83) 0.22

Anterior wall MI MI in any territory

LVEF 3.37 (1.48 to 5.26) 4.37 (2.91 to 5.82) 0.41


LVESV –8.15 (–12.03 to –4.27) –10.08 (–14.56 to –5.60) 0.52

LVEDV –13.73 (–22.2 to –5.27) –3.14 (–5.87 to –0.41) 0.02

Baseline LVEF <43 % Baseline LVEF ≥43%

LVEF 4.83 (3.37 to 6.29) 3.61 (2.05 to 5.18) 0.26


LVESV –13.93 (–18.27 to –9.59) –4.70 (–7.34 to –2.07) 0.0004

LVEDV –10.01 (–14.59 to –5.43) –2.19 (–6.08 to 1.69) 0.01

Baseline LVEF <50 % Baseline LVEF ≥50 %

LVEF 4.06 (2.87 to 5.24) 3.75 (0.81 to 6.69) 0.85


LVESV –9.88 (–12.91 to –6.86) –4.49 (–8.73 to –0.26) 0.04

LVEDV –7.18 (–10.69 to –3.68) –1.05 (–5.42 to 3.31) 0.03

BMCs injected <7 d after acute MI and/or PCI BMCs injected 7 to 30 d after acute MI and/or PCI

LVEF 3.91 (1.40 to 6.42) 0.43

Infarct scar size 2.68 (0.87 to 4.48) –4.78 (–7.91 to –1.64) 0.55

LVESV –3.56 (–6.0 to –1.12) –7.48 (–12.24 to –2.72) 0.35

LVEDV –4.89 (–7.48 to –2.3)–7.14 (–12.29 to –1.99)

–0.12 (–4.48 to 4.24) 0.04

No. of BMCs <100 × 106 No. of BMCs ≥100 × 106

LVEF 4.69 (3.22 to 6.16) 3.54 (2.04 to 5.04) 0.28


LVESV –13.46 (–18.78 to –8.15) –4.52 (–6.67 to –2.37) 0.002

LVEDV –5.1 (–9.45 to –0.76) –4.52 (–8.30 to –0.75) 0.84

No. of BMCs <40 × 106 No. of BMCs ≥40 × 106


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Outcome Difference in mean (95% confidence interval) P value for subgroup

differences

LVEF 1.88 (–0.49 to 4.25) 4.19 (3.06 to 5.32) 0.09

Infarct scar size –3.48 (–10.13 to 3.17) –4.22 (–5.73 to –2.71) 0.83

LVESV –13.59 (–32.68 to 5.49) –7.78 (–10.21 to –5.35) 0.55

LVEDV –7.30 (–20.31 to 5.72) –4.31 (–6.60 to –2.03) 0.66

BMMNC CD133+/CD34+

LVEF 3.84 (2.68 to 5.00) 3.05 (–0.19 to 6.29) 0.65

Infarct scar size –3.47 (–4.86 to –2.07) 0.94 (–2.85 to 4.74) 0.03

LVESV –9.13 (–12.08 to –6.17) –16.53 (–40.47 to 7.41) 0.55

LVEDV –6.47 (–9.00 to –3.94) –8.01 (–25.02 to 9.00) 0.86

Other Ficoll-based methods Lymphoprep

LVEF 3.94 (2.57 to 5.31) 4.44 (2.06 to 6.82) 0.72


LVESV –9.75 (–13.83 to –5.68) –6.46 (–8.88 to –4.05) 0.17

LVEDV –7.5 (–11.46 to –3.54) –9.54 (–27.93 to 8.85) 0.83

No heparin Heparinized Saline

LVEF 2.58 (1.22 to 3.95) 6.15 (4.30 to 8.01) 0.002


LVESV –4.84 (–8.4 to –1.27) –13.07 (–19.17 to –6.96) 0.02

LVEDV –6.41 (–12.29 to –0.52) –4.43 (–7.05 to –1.80) 0.55

IC - Chronic IHD IM - Chronic IHD

LVEF 3.43 (0.33 to 6.53) 4.94 (3.27 to 6.12) 0.40

Infarct scar size –3.99 (–8.3 to 0.32) –3.42 (–10.23 to 3.39) 0.89

LVESV –19.24 (–37.92 to –0.56) –15.64 (–24.95 to –6.33) 0.74

LVEDV –12.91 (–27.96 to 2.14) –6.39 (–12.78 to 0.00) 0.43

RCTs Cohort studies

LVEF 3.35 (2.19 to 4.50) 5.68 (3.54 to 7.82) 0.06


LVESV –6.58 (–9.30 to –3.86) –17.50 (–26.20 to –8.80) 0.02

LVEDV –4.15 (–6.78 to –1.52) –8.9 (–15 to –2.81) 0.16

Abbreviations: BMC, bone marrow cells; CIHD, chronic ischemic heart disease; IC, intracoronary; IM, intramyocardial; MI, myocardial infarction; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; PCI, percutaneous coronary intervention; RCT, randomized controlled trial.


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Table 6

Clinical outcomes in BMC-treated patients compared with patients receiving standard therapy

Outcome Peto OR 95% Confidence Interval P value

All-cause mortality 0.39 0.27 to 0.55 <0.00001

Cardiac deaths 0.41 0.22 to 0.79 0.005

Recurrent MI 0.25 0.11 to 0.57 0.001

Heart failure 0.52 0.27 to 1.00 0.05

Stent thrombosis 0.34 0.12 to 0.94 0.04

In-stent restenosis 0.87 0.47 to 1.62 0.66

TVR 0.83 0.55 to 1.23 0.35

CVA 0.28 0.08 to 1.07 0.06

VT / VF 1.14 0.52 to 2.53 0.74

Abbreviations: BMC, bone marrow cell; CVA, cerebrovascular accident; MI, myocardial infarction; OR, odds ratio; TVR, target vessel revascularization; VF, ventricular fibrillation; VT, ventricular tachycardia.


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Table 7

Unadjusted differences in mean change in parameters in BMC-treated patients compared with controls based

on the mode of imaging

Difference in mean 95% Confidence Interval P value for Z P value for subgroup differences

LVEF

Echo 3.61 2.18 to 5.04 <0.00001 0.001

SPECT 2.60 −0.35 to 5.55 0.08

MRI 1.17 −0.60 to 2.95 0.20

LVG 7.08 4.77 to 9.38 0.0001

Infarct size

SPECT –2.41 –2.78 to –2.03 <0.00001 0.04

MRI –1.48 –1.48 to 0.91 0.22

LVG –7.01 –10.66 to–3.36 0.0002

LVESV

Echo –15.81 –23.75 to –7.87 <0.0001 <0.0001

SPECT –7.02 –11.19 to –2.85 0.001

MRI –2.38 –3.89 to –0.87 0.002

LVG –14.44 –21.61 to –7.27 <0.0001

LVEDV

Echo –7.66 –13.08 to –2.25 0.006 0.08

SPECT –14.79 –24.22 to –5.35 0.002

MRI –2.39 –6.84 to 2.06 0.29

LVG –3.08 –10.25 to 4.10 0.4

Abbreviations: Echo, echocardiography; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVG, left ventriculography; MRI, magnetic resonance imaging; SPECT, single photon emission computed tomography.


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