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ORIGINAL ARTICLE

Bone Marrow-derived Stem Cells as an Adjunctive Treatment for Acute Myocardial Infarction: a Systematic Review and Meta-analysis

R.A. Tuty Kuswardhani*, Andreas Soejitno**

* Department of Geriatric Medicine, Faculty of Medicine, Udayana University – Sanglah Hospital. Jl. Kesehatan 1 Denpasar, Bali, Indonesia. ** Faculty of Medicine, Udayana University, Denpasar, Bali, Indonesia.

Correspondence mail to: [email protected]; [email protected]

ABSTRACTAim: to confirm the beneficial effect of BMCs therapy

over placebo in AMI patients with inclusion only to the randomized double blind placebo-controlled trials.

Methods: we searched multiple database (MEDLINE, CENTRAL, CINAHL) through January 2011 for randomized, double-blind, placebo-controlled trials evaluating the efficacy and safety of BMCs for the treatment of AMI. We subsequently performed a random-effect meta-analysis to assess the eligible studies included related to the primary outcomes (mean LVEF, LVESV, and LVEDV changes from baseline) and secondary outcomes (all-cause mortality, recurrent MI, rehospitalization for HF).

Results: ten RCTs (total=906 patients) were included. BMCs therapy was proven superior to placebo regarding mean LVEF change (2.07%; 95% CI, 0.55% to 3.59%; [I2=57%; p=0.008]), LVESV (5.52 mL; 95% CI, -7.68 mL to -3.36 mL; [I2=16%; p<0.00001]), and LVEDV (3.08 mL; 95% CI, -5.57 mL to -0.58 mL; [I2=23%, p=0.02]) from baseline. BMCs therapy showed no difference with regards to mortality events when compared to placebo (OR 1.01; 95% CI, 0.35 to 2.94; [I2=0%; p=0.98]), but exerts protective effects toward recurrent MI (OR 0.45; 95% CI, 0.09 to 2.16; [I2=8%; p=0.32]) and rehospitalization for HF (OR 0.39; 95% CI, 0.08 to 1.85; [I2=0%; p=0.24]). All outcomes were sustained for a long period of time (up to 5 years).

Conclusion: the resulting meta-analysis concluded that BMCs therapy consistently improves cardiac performance parameters (LVEF, LVESV, and LVEDV) when compared to placebo, even after the establishment of primary intervention. It is also safe to use and prevents the development of recurrent MI and HF.

Key words: bone marrow-derived stem cells, acute myocardial infarction, meta-analysis.

INTRODUCTIONAcute myocardial infarction (AMI) is a serious

complication sequelae of ischemic heart disease in which the inadequate blood supply to the heart muscle reaches its critical limit and subsequently induces massive cardiac cells necrosis.1 If not treated well, AMI will usually causes necrosis of approximately one billion cardiomyocytes.2 As a concequence, cavitary dilation and negative remodeling of the left ventricle progresses and will compromise cardiac contractility significantly.3 Despite the routine use of the most advanced therapeutic strategies (e.g. PCI and CABG), the prognosis of this disease remains disconsolate and may lead to the development of heart failure.4,5

Thus, there is a clear demand of a novel therapeutic strategy which is able to restore blood supply to the ischemic area as well as regenerating the infarcted heart. Stem cell therapy would become one of the solution (see complete review on reference no.6). Stem cells are a cluster of cells characterized by their clonogenicity, self-renewal, and ability to differentiate into multiple cell lineages.6 The most trending type of stem cells used for heart regeneration is bone marrow-derived stem cells (BMCs). Bone marrow contains multiple cluster of stem cells, including hematopoeitic stem cells (HSCs), endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs).7-9 BMCs injection into the infarcted heart has been shown to enhance neovascularization, reduce negative remodeling, and improve contractile function, either in animals or in humans.10,11 In fact, there are many clinical trials which have been conducted in order to identify the efficacy and safety of BMCs therapy in AMI patients.11-13

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Vol 43 • Number 3 • July 2011 Bone Marrow-derived Stem Cells as an Adjunctive Treatment for AMI

Two meta-analyses have already shown the clear benefit of BMCs therapy over placebo for AMI and chronic ischemic heart disease patients regarding the clinical parameters such as left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), as well as the impact of delivery route and baseline LVEF to the magnitude of the outcome.14,15

However, to the best of our knowledge, there is yet no pooled study that address the long term safety of BMCs, including all-cause mortality, recurrent myocardial infarction (MI), and re-hospitalization for heart failure (HF) from valid randomized controlled trials (RCTs). In addition, the previous meta-analyses have included single blind trial which may interfere with the resulting credibility. Therefore, we performed the third meta-analysis to confirm the beneficial effect of BMCs therapy over placebo in AMI patients with inclusion only to the randomized double blind placebo-controlled trials. This study evaluates two main outcomes, i.e. those related to the clinical parametric change after therapy (primary outcome: mean LVEF, LVEDV, and LVESV change), and those which related to the long term prognosis after treatment (secondary outcome: all-cause mortality, recurrent MI, and re-hospitalization for HF).

METHODS

Review Questions and Study ProtocolsThe proposed questions aimed to be answered

by our study are to what extent does BMCs therapy improves the essential clinical parameters of AMI patients, and how is the long-term role of this therapy related to all-cause mortality and complications in the same patient populations? This systematic review and the corresponding analysis are conducted under the guidance of Meta-analysis of Observational Studies in Epidemiology (MOOSE)16 and Quality of reporting of Meta-analysis (QUOROM) statements.17

Eligibility CriteriaWe determined the eligibility of the study

independently according to our inclusion criteria, i.e. (1) prospective, randomized, placebo-controlled, double blind trials; (2) assignment of participants, either to BMCs (HSCs, MSCs, EPCs, as well as bone marrow mononuclear cells/BMMNCs) or circulating progenitor cells (CPCs) treatment, and subsequent adequate allocation on the control/placebo arm; (3) only participants with AMI were included (studies with chronic myocardial infarction, HF, cardiomyopathy,

or others were excluded); (4) available outcome for LVEF, LVESV, LVEDV, as well as all-cause mortality, recurrent MI, and rehospitalization for HF (the last 3 outcomes were optional). All trials which did not fulfill the following criteria were excluded.

Search StrategyWe performed a systematic and thorough search on

MEDLINE (January 1980 to January 2011). Cochrane Central Register of Controlled Trials (CENTRAL) [January 2011], and CINAHL (January 1982 to January 2011) using the following terms: coronary-artery disease, acute myocardial infarction, bone marrow stem cells, circulating bone marrow stem cells, circulating progenitor cells, double blind, as well as combinations among these terms. In addition, we also activated search filter in MEDLINE (filter category: humans, clinical trial, RCT, comparative study, controlled clinical trial) and CINAHL (filter category: linked full text, research article, human, clinical trial). This filter system optimized the searching process by reducing the amount of irrelevant articles that would come out. Articles included were not restricted by the language, publication date, or publication status.

Data ExtractionData extracted from each trials consisted of

sample size, mean follow up duration, cell type and dose for transplantation, route of delivery, type of primary intervention, imaging technique used to evaluate primary outcomes, and description of the study quality. When multiple imaging modalities were used (e.g. echocardiography, single photon emission computed tomography [SPECT], LV angiography, magnetic resonance imaging [MRI]), MRI results were preferentially included in the analysis.

Quality AssessmentThe methodological quality of every RCTs was

benchmarked according to the criteria developed by Jüni et al29 Several aspects were evaluated, including methods of patient selection (whether or not adequate randomization applied), blinding status of outcome assessors and patients/caregivers, and methods to handle loss to follow up.

Data AnalysisThe primary outcome assessed in our study was

changes from baseline of LVEF, LVESV, and LVEDV between treatment and control groups. Whereas, the secondary outcome was aimed to evaluate the safety of BMCs treatment through calculations of all-cause mortality, recurrent MI, and rehospitalization for HF. Random effect model was chosen considering the

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heterogeneity across all RCTs. Data were measured as weighted mean difference (WMD) and their associated 95% confidence intervals (CI). Heterogeneity was determined using I2 statistic with values >50% considered high, which indicated that the variability among studies was resulted from true differences rather than due to chances. In addition, funnel plots were applied to determine the existence of publication bias. Pooled outcome results were displayed using forest plots. All statistical analyses were performed using RevMan 5.0.25 (Cochrane Collaboration, 2010).

RESULTS

Search ResultsThe complete process of reference searching can be

seen on Figure 1. The pooled initial search using the pre-specified terms mentioned before yielded a total of 98 articles. This is a relatively proportional number since we have activated the filter system to rule out any irrelevant references.27 of these were excluded during the first screening because it consisted of review articles (including commentaries, editorials, and letters to the editor), animal trials and in vitro studies, as well as observational studies. The 71 references left were subsequently checked and 39 were excluded because of several reasons, such as evaluating new imaging approaches, compared culture methods, used cytokines/growth factors to moblize BMCs, or assessed disease other than AMI. The remaining 32 citations were then examined in detail, in which 22 of these were again excluded. This is due to the presence of 3 non-randomized trials, 4 non-blinded (open label) trials, 11 single blind (outcome assessors only) trials, 2 ongoing trials, 1 not mentioning mean difference between primary outcomes, and 1 reference did not mention all of primary outcomes (safety evaluation only).

Therefore, the final result yielded 10 eligible studies to be included in the analysis. Publication bias analysis of all outcomes was assessed using funnel plots which are calculated based on WMDs. Several outcomes (mean LVESV changes, all-cause mortality, recurrent MI, and rehospitalization for HF) had an apparent asymmetry when assessed by funnel plots and judged visually (Figure 2B, 2D, 2E, 2F). This could be as the result of selective outcome reporting, inadequate analysis, true heterogeneity (i.e. differences in the intensity of intervention [dose and cell type provided, time from primary intervention to BMCs treatment, route of delivery], differences in the risk among studies [e.g. different cell type would exert different fatal arrhythmic potential], or differences in the outcome

measurements [e.g. different imaging techniques were used to evaluate LVESV]).18 Whereas, the rest of the outcomes displayed relatively symmetrical funnel plots (Figure 2A, 2C).

Figure 1. Flow digaram of eligible studies included in the meta-analysis. RCTs denotes randomized controlled trials, CMI denotes chronic myocardial infarction

Figure 2. The funnel plots of primary outcomes (LVEF [A], LVESV [B], LVEDV [C]) and secondary outcomes (all-cause mortality [D], recurrent MI [E], rehospitalization for HF [F]) analysed in our study.

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Characteristics of Included Studies.The baseline characteristics of all 10 included

RCTs can be seen in Table 1. They were all double-blinded trials. Of note, we included 3 follow-up studies from the previous related RCTs because they assessed the long term (up to 61 months) benefits of BMCs therapy, including its safety profiles.19-21 The number of participants in each trials were relatively small, ranging from 20 to 204 patients appropriately dispersed into control/placebo and BMCs treatment groups. The total participants were different in the primary and secondary outcomes, in which it is bigger in secondary outcome group (total: 906; BMCs 423, placebo 483) than in the primary outcome group (total: 791; BMCs 404, placebo 387). It is due to the smaller amount of patients who were willing or eligible to undergo imaging studies in order to assess the primary outcomes.

The mean follow-up durations were variable, from 4 to 61 months after therapy. All of the trials19-27, except one28, used BMCs for the treatment group. Of these, 7 RCTs used BMMNCs,19-24,26 1 RCTs used BMCs,25 and 1 RCTs used nucleated BMCs (nBMCs).27 The only RCT which did not use BMCs applied allogenic human mesenchymal stem cells (hMSCs) for the treatment group.28 It was also the only study which used allogenic stem cells, whereas the others used autologous BMCs. Cell doses infused were different across studies, with one RCTs did not mention,25 while others used cell volume units rather than number of cells.20,21,23,24,27

All cells were delivered intracoronarily (IC), except for one study28 which used intravenous infusion for cell delivery into the heart myocardium. In 9 studies, the primary prevention prior to BMCs therapy was percutaneous coronary intervention (PCI), while only one study combined thrombolytic therapy and PCI with subsequent BMCs therapy.23 No coronary artery bypass graft (CABG) surgery was identified as the primary intervention. Ultimately, a range of variability existed in the use of multiple imaging modalities to assess the primary outcomes. The most preferable modality, that is cardiac MRI, was used in 5 studies,19-21,24,27,28 whereas others applied LV angiography,23,26 standard echocardiography,22,25 or intravascular ultrasound (IVUS).23

Quality Assessment

The methodological quality of each trials can be seen on Table 2. Four RCTs fulfilled the highest standard of Jüni criteria by completing good study selections (adequate allocation and randomization, similar baseline between groups), performance and detection (adequate double-blind explanations), and attrition (zero percentage of lost to follow-up, application of intention-to-treat analysis).22,26-28 One follow-up study had no explanation regarding intention-to-treat analysis model.19 Two studies had lost to follow-up percentage of 3.75 and 10.44, respectively.23,24 Two follow-up studies did not mention

Table 1. Study characteristics included in the meta-analysis

Source No. of participants

Mean follow-up duration, mo. Cell type* Cell dose Route of

deliveryType of primary

Imaging tehnique used to evaluate primary outcomes

Dill 2009 54 12 BMMNC 236+174 x 106 IC PCI Cardiac MRI

Hare 2009 34 12 hMSC (allogenic)

2.5 x 106/mL (2mL/min)

IV PCI Cardiac MRI

Herbots 2009

67 4 BMMNC 304+128 x 106 (nucleated)

IC PCI Standard echocardiography

Huikuri 2008 72 6 BMMNC 80 mL IC Thrombolytic + PCI

LV angiography, 2-D echocardiography, IVUS

Janssens 2006

60 4 BMMNC 10 mL IC PCI Cardiac MRI

Meyer 2006 59 18+6 BMMNC 128 mL IC PCI Cardiac MRI

Meyer 2009 56 61+11 BMMNC 128 mL IC PCI Cardiac MRI

Ruan 2005 20 6 BMC N/A IC PCI Standard ecocardiography

Schachinger 2006

204 4 BMMNC 236+174 x 106 IC PCI LV angiography

Wollert 2004 60 6 nBMC 128 mL IC PCI Cardiac MRI

BMC, bone marrow-derived stem cells; BMMNC, bone marrow mononuclear cells; hMSC, human mesenchymal stem cells; IC, intracoronary; IVUS, intravascular ultrasonography; LV, left ventricle/ventricular; MRI, magnetic resonance imaging; nBMC, nucleated bone marrow-derived stem cells; PCI, percutaneous coronary intervention.

* All cell type within the study were autologus, except otherwise specifiedN/A, data not available

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the blinding status of the patients/caregivers (lack of study performance).20,21 It is crucial since the patients/caregivers are usually unblinded at the end of the primary study completion.30 At last, one study had a lack explanation pertaining to the randomization method applied in the trial.25

Outcome EvaluationOn pooled data analysis, BMCs therapy after AMI

had been shown to improve LVEF by a total of 2.07% (95% CI, 0.55% to 3.59%; [I2=57%; p=0.008]; Figure 3). This was calculated from the mean LVEF change between follow-up and baseline. Every trial exerted a positive effect toward BMCs treatment, except for the negative results by Hare et al (2009) at 3 and 6 months follow-up, respectively (3 mo: -6.00% [95% CI, -12.66% to 0.66%]; 6 mo: -4.70% [95% CI, -10.34% to 0.94%]; Figure 3). Consistent with these results, if Hare et al. (Prochymal trial) was censored from the analysis, the resulting pooled data became significantly favored BMCs group with a total LVEF change of 2.60% (95% CI, 1.11% to 4.09%; [I2=33%; p=0.0006]; Figure 4]. Moreover, LVEF improvement exerted by BMCs therapy was sustained for a long period of time as proved by the consistent mean LVEF change of 3.23% (95% CI, 2.19% to 4.27%; [I2=0%; p<0.00001]) in the analysis of studies involving a minimum of 12 months follow-up period or more.19-21,28

BMCs treatment also reduced LVESV by 5.52 mL (95% CI, -7.68 mL to -3.36 mL; [I2=16%; p<0.00001];

Figure 5). There is only one RCT which reported greater reductions of LVESV in placebo by 4 mL (95% CI, -6,49 mL to 14.49%) compared with BMC group. The most optimum LVESV reduction was observed in Ruan et al (2005) during 3-month follow-up after BMCs treatment by 23.79 mL (95% CI, -44.98 mL to -2.60 mL). Whereas the second biggest amount of LVESV reduction was reported by Dill et al19 during the 12th month follow-up by 12.00 mL (95% CI, -26.90 mL to 2.90 mL). LVESV reduction was also maintained in the BMCs group for a long period of time (for a minimum of 12 months), reaching approximately 3.65 mL (95% CI, -9.12 mL to 1.82 mL; [I2=44%; p=0.19]) spare versus placebo, although the result was insignificant.

An optimal reduction was also observed on LVEDV value. BMCs treatment reduced LVEDV by 3.08 mL (95% CI, -5.57 mL to -0.58 mL; [I2=23%, p=0.02]; Figure 6). Importantly, all results from the BOOST trial, either the main study27 or the follow-up20,21 reported greater reductions on placebo arm, compared with stem cells group (Wollert et al 27: 4.20 mL [95% CI, -3.99 mL to 12.39 mL]; Meyer et al20: 2.50mL [95% CI, -6.55 mL to 11.55 mL]; Meyer et al21: 6.40 mL [95% CI, -4.98 mL to 17.78 mL]). Another RCT reported no difference of LVEDV change between BMCs and placebo groups (0.00 mL [95% CI, -7.64 mL to 7.64 mL]). The other remaining studies favored BMCs treatment than placebo. LVEDV reduction exerted by BMCs therapy was maintained over time

Tabel 2. Quality assessment summary of RCTs included in the meta-analysis

Source

Selection Performances Detection Attrition

Was allocation

adequate?*

Was an adequate method of

randomization described?

Were group similar at the start of the

study?

Were the patients/caregivers

blinded to the intervention?

Was the outcome

ascertained blindly?

%tage was lost to follow-

up?#

intention-to-treat

analysis?

Dill 2009 Y Y Y Y Y 0 N/A

Hare 2009 Y Y Y Y Y 0 Y

Herbots 2009 Y Y Y Y Y 0 Y

Huikuri 2008 Y Y Y Y Y 3.75 Y

Janssens 2006

Y Y Y Y Y 10.44 Y

Meyer 2006 Y Y Y N/A Y 0 Y

Meyer 2009 Y Y Y N/A Y 0 Y

Ruan 2005 Y N Y Y Y 0 Y

Schachinger 2006

Y Y Y Y Y 0 Y

Wollert 2004 Y Y Y Y Y 0 Y

* Criteria for adequacy include the use of central site, numeric code, opaque envelopes, drugs prepared by pharmacy, and other appropriate

# Lost to follow-up from follow-up study or substudy was calculated from baselineN/A, data not available

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(for a minimum of 12 months to 61 months) as proven by the consistent difference of 3.08 mL (95% CI, -7.63 mL to 1.47 mL; [I2=59%; p=0.19]) among BMCs group compared with placebo.

The results of all-cause mortality indicated no difference between BMCs treatment and control group (OR 1.01; 95% CI, 0.35 to 2.94; [I2=0%; p=0.98]; Figure 7). Among 10 RCTs, only 4 trials recorded mortality events.20-22,24,26 Two patients in the BMCs treatment died from hemorrhagic shock.22,24 While the cause of the other 2 death events on BMCs treatment group was not reported.21,26 One follow-up study with 2 follow-up intervals (4 and 12 months) did not have any adverse effects explanation, either in BMCs or in control group.19 Whereas the rest of the studies have documented zero mortality events among all groups observed.

Only 4 studies had documented the recurrent MI events.20,21,23,26 Among these, BMCs therapy reduced the incidence of recurrent MI to more than a half when compared to placebo (OR 0.45; 95% CI, 0.09 to 2.16; [I2=8%; p=0.32]; Figure 8). Only 2 events (out of 201 patients) of recurrent MI were observed in the BMCs group versus 8 cases (out of 203 patients) in the placebo group for a mean follow-up duration of 22.25 months.20,21,23,26

The rehospitalization of HF was only addressed in 3 studies,20,21,26 in which 2 of them were the follow-up studies from BOOST trial.20,21 Two and six rehospitalization events out of 161 and 163 patients were reported among BMCs treatment and placebo group, respectively. Therefore, BMCs therapy significantly reduced the development of HF as commonly observed after an AMI incident (OR 0.39; 95% CI, 0.08 to 1.85; [I2=0%; p=0.24]; Figure 9).

Figure 3. Forest plot of mean LVEF changes across all RCTs

Figure 4. Forest plot of mean LVEF changes without Hare et al28

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Figure 5. Forest plot of mean LVESV changes across all RCTs

Figure 6. Forest plot of mean LVEDV changes across all RCTs

Figure 7. Forest plot of all-cause mortality across all RCTs. However, only 6 studies documented mortality events from both groups

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Figure 8. Forest plot of recurrent MI across all RCTs. Only 4 studies documented events from both groups

Figure 9. The forest plot of rehospitalization for HF. Only 3 studies documented events from all RCTs included in our study

DISCUSSIONOur analyses have shown a consistent LVEF

improvement and sustained reductions of LVESV and LVEDV among BMCs treatment group compared with placebo, even across a long-term follow-up period (mean 13.3 months, median 12 months, range 4 to 61 months). These 3 parameters are very critical to control as LVEF is a strong predictor of all-cause mortality and rehospitalization for HF after AMI.31 Thus, preserving the LVEF through primary intervention and adjunctive therapy like BMCs would be very beneficial to prevent the serious complications and death. Whereas LVESV and LVEDV represent the loading capacity of the heart. As has been explained before, during AMI, there is a massive cardiomyocytes loss from the ventricular wall and the formation of fibrous scar tissues among the necrotic cells.6 This condition leads to the acute physiological compensation by cavitary dilation or enlargement of the left ventricle (negative remodeling), thus increasing its loading capacity (LVESV and LVEDV). If neglected, the patient will develop HF.3 Once again, BMCs therapy had protected the heart by reducing LVESV and LVEDV and was sustained for up to 5 years.21

LVEF improvement after BMCs treatment in our study was lower than in the previous meta-analysis

(2.60% vs. 3.66%).14 This is perhaps due to the limited study included (10 vs. 20) with 3 follow-up studies assessing the long term BMCs benefits. Moreover, the inclusion of Prochymal trial significantly reduced the pooled WMD LVEF result. However, despite low increment, further LVEF improvement after AMI is associated with better outcome. In fact, the mean LVEF improvement 6 months after mechanical reperfusion therapy in AMI patients was only 2.5%.32 Therefore, an additon of 2-4% LVEF improvement would likely to exert multiple beneficial effects to the patient.

The protective mechanism of BMCs therapy in the heart remains elusive. Some studies suggested that BMCs will transdifferentiate into cardiomyocytes and replace the old one during its migration to the myocardium.7,10,33 Another hypothesis is that BMCs would undergo cell fusion with the existing cardiomyocyes and regenerate them, thus preventing the massive cell necroses as commonly observed in AMI.34-36 However, given that only a small fraction (1.3 to 2.6%) of BMCs still retained in the infarct area, it is likely that BMCs exert its function through paracrine signaling.37 Paracrine effects have been reported to stimulate endogenous stem cell activation and mobilization to the infarct zone, prevent apoptotic cell death, as well as induce neovascularization

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and myogenesis.10,37,38 Indeed, an observation using C-acetate PET in AMI patients receiving BMCs demonstrated increased metabolic activies in the infarcted region.39

Limitation of The Study and Recommendation for Further Research

A quite low degree of variability has been observed in our analysis. Furthermore, funnel plots from several outcomes indicate the possibility of publication bias. This could be explained by the uniformity of the trials included in our study. Due to the inclusion of double blind RCTs only, most of them have similar characteristics of interventions and outcome assessment (e.g. the use of BMMNC in 70% of the RCTs, the use of intracoronary delivery in 90% of the study included, the use of cardiac MRI in 60% of the study). Moreover, we included 3 folow-up studies from the previous RCTs which definitely possess the same characteristics with the prior corresponding study when involved in several outcomes evaluation.19-21 However, consistent findings favoring the use of BMCs therapy over placebo exist either in the primary or secondary outcomes. These results are in accordance with the two previous meta-analyses,14,15 therefore we cautiously generalize them as valid enough, which is further supported by the objective criteria using the inclusion of only double-blind RCTs.

There is a significant limitation in the analysis of secondary outcomes, primarily the recurrent MI and rehospitalization for HF subgroups. Since only 3 to 4 RCTs adequately addressed the problems, the results of these analysis should be critically appraised. However, the inclusion of the follow-up study from REPAIR-AMI consistently demonstrated similar outcomes among the other trials.

According to these two main problems (i.e. potential publication bias and limited data availability), we recommend that further research should adhere to the standard operational procedure in designing their methods, for instance, the use of double blind technique instead of single-blinded study, uniform LVEF baseline, identical cell type, dose, and methods of preparation, as well as the timing and route of delivery. This uniformity will reduce the heterogeneity and thus minimizing the bias resulting from chances and validate the results further.

CONCLUSIONBMCs therapy significantly improves cardiac

clinical parameters among patients with AMI when compared with placebo. These effects include, a

consistent LVEF improvement and reductions of LVESV and LVEDV which all are the predictors of subsequent AMI complications, like HF. Futhermore, analysis of secondary outcomes concluded that BMCs therapy is safe to use and protects the patients from recurrent MI and rehospitalization for HF. All of these results were sustainable in the long-term period of follow-up. This present study recommends the use of BMCs treatment as an adjunctive therapy to the established primary intervention currently available (i.e. PCI and thrombolytic therapy).

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bone marrow-derived stem cells as an adjunctive treatment ... · used for heart regeneration is...

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