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Efficacy & safety of stem cell therapy for treatment of acute myocardial infarction: A systematic review & meta-analysis
For correspondence: Dr Jaykaran Charan, Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur 342 005, Rajasthan, India e-mail: dr.jaykaran78@gmail.com
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Received: ,
Accepted: ,
Abstract
Background & Objectives
Stem cell based therapeutic treatments have been used as a management strategy for acute myocardial infarction (AMI), a common primary factor causing death globally. We aimed to undertake a meta-analysis of studies including randomised controlled trials (RCTs) examining different stem cell preparations in AMI, as a definitive answer from this therapeutic approach is yet to emerge.
Methods
Following PROSPERO registration (CRD42024628552), a systematic search was conducted through PubMed database, Embase, Cochrane, and Web of Science. Data was analysed using RevMan 5.4.1. Primary outcomes included all-cause mortality, recurrent myocardial infarction (Re-MI), severe adverse events (SAEs), hospitalisation for heart failure, cancer incidence, and left ventricular ejection fraction (LVEF). A fixed-effect model was used to assess six outcomes: all-cause mortality, Re-MI, SAEs, heart failure hospitalisation, cancer incidence, and stroke. A model based on random effects depending on heterogeneity was used to assess LVEF.
Results
From 9,516 records, 48 studies were included for analysis based on available endpoints. No notable changes in all-cause mortality were observed between patients receiving stem cell therapy and those in the control group, according to the meta-analysis. [Risk Ratio (RR) 0.73], SAEs (RR 0.93), Re-MI (RR 0.67), HF-related hospitalisation (RR 0.79), cancer (RR 0.82), or stroke (RR 0.81). Echocardiographic LVEF improved significantly at study end [Mean difference (MD) 2.53%] and difference from baseline (MD 3.89%), with high heterogeneity (I2 - 76%). MRI-assessed LVEF showed no significant change at study end (MD 0.83%) but improved from baseline (MD 1.37%). Heterogeneity was low except for LVEF, with serious bias risk for most outcomes and very serious for Re-MI and SAEs, though their objective nature limits bias
Interpretation & conclusions
Analysis done found no significant benefit of stem cell-based therapies on clinical endpoints in AMI patients.
Keywords
Meta analysis
myocardial infarction
stem cells
stem cell therapy
systematic review
Based on the available data globally, the leading cause of mortality is cardiovascular disease1. Acute myocardial infarction (AMI) can cause persistent illness and is the cause of death among the different cardiac tissue-related diseases. Present therapy for treatment of the current episode and prevention of re-myocardial infarction (Re-MI) is not much efficacious. Each episode of MI has high mortality and there are high chances of recurrence in the survivors2. The available treatment options do not reverse tissue damage occurring during the episode, and there is a need for novel methods or interventions that may affect the pathology at the molecular level to reverse the changes in the heart due to ischemia. Numerous strategies, including gene therapy, cardiac tissue engineering, cell reprogramming, and biomaterial-based delivery methods, are being researched to treat AMI. Numerous clinical trials have explored the use of stem cell based therapeutic approaches. Stem cells are primitive, unspecialized cells capable of self-renewal throughout an organism’s lifespan. Their therapeutic potential in myocardial infarction primarily stems from their paracrine effects, which facilitates the transformation of stem cells into heart muscle and endothelial cells and triggers the stimulation and migration of the heart’s own stem cells3.
Many clinical studies were conducted to evaluate the effects of therapeutic strategies of stem cell for treating acute AMI. Several studies have reported improvements in functional parameters such as end-diastolic volume (EDV), end-systolic volume (ESV), left ventricular ejection fraction (LVEF), and infarct size (IS). Additionally, some trials have reported reductions in clinical outcomes like mortality and recurrent myocardial infarction (Re-MI); however, the findings across studies have not been consistent, with some reporting conflicting results4. Updated Cochrane review published in 2015 showed moderate evidence of no effect, with the caveat that further studies may change the scenario5.
Given the inconsistent results reported in previous studies, we undertook this systematic review and performed meta-analysis to address the research question stating: ‘What does the existing evidence reveal about the safety and effectiveness of stem cell therapies in managing acute myocardial infarction (AMI)?’ Our review seeks to include recently published trials while adhering to a methodology aligned with earlier systematic reviews5.
Materials & Methods
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Supplementary table I) while conducting this systematic review the protocol of which was registered in the PROSPERO database (number CRD42024628552). Methodological guidance was also drawn from the ‘Cochrane Handbook for Systematic Reviews of Interventions’6. Randomised Controlled Trials (RCT) satisfying all of the following requirements were included: (i) population: individuals with a myocardial infarction diagnosis,(ii) stem cells as an intervention, and (iii) comparison: inclusion of a placebo (Supplementary table II). For the syntheses, studies with the same endpoint were grouped.
A thorough and methodical search of the literature was conducted, and papers were evaluated for eligibility using established criteria for selecting and excluding studies. Two authors developed a strategy for the advanced search using keywords related to the study population (myocardial infarction), intervention (stem cells), and comparison (placebo or no treatment alongside standard care). From the beginning until October 27, 2023, two researchers (PA, RO) separately searched four main databases: Medline (PubMed), Cochrane, Web of Science, and Embase for relevant material. They did this without regard to language limitations. Supplementary material 1 lists the specific search tactics for each database. To find more research, computerized searches were supplemented by a manual screening of narrative reviews, systematic reviews, and reference lists of pertinent trials. Five reviewers independently examined the abstracts and titles for possible inclusion after deleting duplicate records. Full-text articles of the selected studies, along with any supplementary materials and protocols, were retrieved and assessed. The reasons for exclusion at each stage were systematically recorded. Detailed characteristics of the included studies are presented in table I. The type and method of administering stem cells, the length of follow up, and patient attributes such as age and gender were taken into consideration when extracting data. Although it was originally intended to get in touch with the original study authors to enquire about any missing data, this step was unnecessary because the included studies contained all the information that was needed. In studies that used a single control group to compare against multiple intervention arms, the control group’s participant count was halved to prevent duplication in the analysis.
| Study ID | Country | Patient details | Age: Mean (SD/SEM) | % Male | No. of participants in intervention (n)/comparator | Follow up | Route of cell administration | Cell type | Procedure to obtain cells | Suspension media | Dose (cells) | Comparator (placebo or control) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Angeli 2012 | Brazil | STEMI, LVEF<45% | Not reported | Not reported | 11 /11 | 12 Months | Injection intracoronary through balloon | BMMNC | Not reported | Not reported | 260(160) million BMMNC; 1.4 (1.5) % CD34+ | Medium |
| Assmus 2014 | Germany | Acute STEMI, LVEF<45% | Intervention: 57 (11) Control: 55(11) | 82%, 82% | 101/103 | 60 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | 10 ml of X VIVO 10 media | 236(174) million | Patient’s own serum |
| Attar 2023 | Iran | STEMI, LVEF < 40%. | Intervention: 53.25 (5.05); Repeated intervention: 56.05 ± 7.48 Control: 56.53 (7.95) | Intervention: 100 (%); Repeated intervention: 80% Control: 73.3 | 50/25 | 6 Months | Injection intracoronary through balloon | hWJMSC allogeneic | BM aspiration | 0.9% normal saline | 10 million | Standard treatment |
| Cao 2009 | China | STEMI | Intervention: 50.7 (1.1) Mean (SEM) Control: 51 (1) | Intervention: 95.1 (%) Control: 93.3 | 41/45 | 48 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | Heparinized saline | 50(12) million BMMNC; 1.8(0.6) % CD34+ | Heparinized saline |
| Chen 2004 | China | Acute MI | Intervention: 58 (7) Mean (SD)Control: 57 (5) | Intervention: 94 (%) Control: 97 | 34/35 | 6 Months | Injection intracoronary through balloon | BMMSC | BM aspiration | Heparinized saline | 48,000 (60,000) million | Heparinized saline |
| Choudry 2016 | Multicentre | Acute AMI | Intervention (n = 55) 56.4+10.4; Control (n = 45) 56.7+10.7 | Intervention: 84% Control: 91% | 55/45 | 12 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | 0.9% normal saline with autologous whole bone marrow | 59.8(59.9) million BMMNC; 1.9(1.5) million CD34+ | 10 mL sterile 0.9% NaCl mixed with 33 mL autologous whole bone marrow. |
| Chullikana 2015 | India | STEMI, LVEF 30-50% | Intervention 47.31 (12.1); control 47.79 (6.48) | Intervention: 100 (%) Control: 80 | 10/10 | 24 Months | Anticubital vein of forearm | BM-MSC allogeneic | BM aspiration | 35 ml of multiple electrolytes (PLASMA-LYTE A) | 2 million cells/kg body weight; 0.14% CD34+ | Multiple electrolytes injection (Plasma-Lyte A). |
| Colombo 2011 | Italy | STEMI, LVEF < 45% | Intervention: 54 (47-60) Median (Range) Control: 56 (44 - 58) | Intervention: 100 (%) Control: 100 | 5/5 | 12 Months | Injection intracoronary through balloon | CD133+ cells | BM aspiration, selection to isolate CD133-positive cells | 0.9% saline with 10% human serum albumin. | Median (range): 5.9 (4.9 to 13.5) million | Standard treatment |
| Delewi 2011 | Netherlands | STEMI | Intervention: 56 (9) Control: 55 (10) | Intervention: 84 (%) Control: 86 | 69/65 | 60 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | Heparinised saline & 4 % human serum albumin | 296 (164) million cells | Standard treatment |
| Dill 2009 | Germany | Intervention: 57 (11) Control: 55(11) | 82%, 82% | 101/103 | 24 Months | Injected intracoronary through balloon | BMMNC | BM aspiration | 10 ml of X VIVO 10 medium | 236(174) million | Standard treatment | |
| F. Aviles 2018 | SPAIN, Belgium | STEMI, LVEF ≤45% | Intervention 56(12); Control 55±8 | Intervention: 88% Control: 100 | 33/16 | 12 Months | Injected intracoronary through balloon | Cardiac stem cells- Allogenic | Human heart biopsies | saline solution with 5% human serum albumin | 35 million | Standard treatment |
| Gao 2013 | China | STEMI | Intervention: 55 (1.6 SEM)Control: 58.6 (2.4 SEM) | Intervention: 100 (%) Control: 86.4 | 21/22 | 24 Months | Injected intracoronary through balloon | BM-MSC | BM aspiration | Heparinised saline | 3.08 (0.52) million cells | Standard treatment |
| Gao 2015 | China | Acute STEMI | intervention - 57.3+/-1.3; control - 56.7+/- 1.7 | Intervention: 55%; Control 51% | 58/58 | 18 Months | Injected intracoronary through balloon | WJ-MSCS | Umbilical cord | 10 ml heparinized saline | 6 million | Placebo |
| Ge 2006 | China | STEMI | Intervention: 58 (11 SD) Control: 59 (8 SD) | Intervention: 80 (%) Control: 100 | 10/10 | 6 Months | Injected intracoronary through balloon | BMMNC | BM aspiration | Heparinized saline | 40 million cells; 4.7% CD34+ | Placebo, BM supernatant mixed with heparinized saline |
| Grajek 2010 | Poland | Anterior AMI | Intervention: 49.9 (8.4 SD) Control: 50.9 (9.3 SD) | Intervention: 87 (%) Control: 86 | 31/14 | 12 Months | Injected intracoronary through balloon | BMMNC | BM aspiration | X-vivo 15 medium & 2% autologous plasma | 410 (180) million | Standard treatment |
| Haddad 2020 | Canada | Acute STEMI, LVEF 25% - 50% | 50.5 (median age, n=37) | 89%; 82.4% in intervention and 95% in placebo | 17/20 | 8.5 yr IQR [7.9, 10.0] | Injected intracoronary through balloon | CD133+ | BM aspiration | Normal saline containing 10% autologous plasma | 10 million cells except in one patient (5.2 million) | placebo |
| Hare 2009 | USA | MI; LVEF 30-60% | Intervention: 59 (12.3); Control: 55.1 (10.2) | I: 82.4%) C: (78.9%) | 39/21 | 12 Months | Intravenous | hMSC-allogenic | BM aspiration | .9% human serum albumin, & 3.8% dimethyl sulfoxide in PlasmaLyte A | 5 million hMSCs/kg body weight | solution of 1.9% human serum albumin with 3.8% dimethyl sulfoxide in PlasmaLyte A. |
| Huikuri 2008 | Finland | STEMI | Intervention: 60 (10 SD) Control: 59 (10 SD) | Intervention: 90 (%) Control: 85 | 40/40 | 6 Months | Injected intracoronary through balloon | BMMNC | BM aspiration | Heparinised saline & 50% autologous serum | 402 (196) million cells; 2.6 (1.6) million CD34+ | Placebo (heparinised saline & 50% autologous serum) |
| Janssens 2006 | Belgium | STEMI | Intervention: 55.8 (11) Control: 57.9 (10) | Intervention: 82 (%) Control: 82 | 33/34 | 4 Months | Injected intracoronary through balloon | BMMNC | BM aspiration | Heparinised saline & 5% autologous serum albumin | 172 (72) million cells; 2(1.3) million CD34+ | Placebo heparinised saline & 50% autologous serum |
| Kaminek 2008 | Czech Republic. | Acute STEMI | intervention -54+/- 9; Control - 56+/- 9 | Control- 89%; Intervention- 86% | 31/31 | 12 Months | Injected intracoronary through balloon | BMMNC | BM aspiration | 100 million | control | |
| Kim 2018 | SOUTH KOREA | Anterior MI, LVEF ≤ 40% | Intervention 55.3 ± 8.6; control 57.8 ± 8.9 | Intervention: 100 (%) Control: 100 | 14/12 | 12 Months | Injection intracoronary through balloon | BM-MSC | BM aspiration | Heparinised saline & 5% autologous serum albumin | 72(9) million | Standard treatment |
| Laguna 2018 | SPAIN | AMI, LVEF < 50% | Intervention 62.63 (8.35); Control 64.78 (11.48) | Intervention (n=8) 87.5; Control (n=9) 88.9 | 10/10 | 9 Months | Direct intramyocardial injection | BMMNC | BM aspiration | heparinized Ringer’s lactate solution | 1 million cells per millilitre | Saline and CABG |
| Lezo J S D 2007 | Spain | Anterior STEMI | Intervention: 52 (12) Control: 55 (11) | BMMNC: 80% Control: 70% | 10/10 | 3 Months | Injected intracoronary through balloon | BMMNC | BM aspiration | 0.9% normal saline with 0.1% heparin | 900 (300) million; 17(13) million CD34+ | Heparinised saline |
| Lee 2014 | South Korea | STEMI | Intervention: 53.9 (10.5) Control: 54.2 (7.7) | Intervention: 90 (%) Control: 89.3 | 40/40 | 6 Months | Injected intracoronary through balloon | BM-MSC | BM aspiration | NR | 72 (9) million cells | Standard treatment |
| Lunde 2007 | Norway | Ant. STEMI | Intervention: 58.1 ± 8.5; Control 56.7 ± 9.6 | Intervention: 84 (%) Control: 84 | 50/50 | 6 months | Injected intracoronary through balloon | BMMNC | BM aspiration | 0.9% normal saline with 20% heparin plasma | 68 (IQR 54-130) million | Standard treatment |
| Mathur 2020 (BAMI) | Multicentre | STEMI, LVEF <45% | Intervention: 59 (11); Control 60 (11) | Intervention: 83.7 (%) Control: 77.3 | 185/190 | 24 Months | Injected intracoronary through balloon | BMMNC | BM aspiration | X-Vivo 10 medium | 25-500 million | Standard treatment |
| Meyer 2009 | Germany | STEMI | Intervention 53·4 (14·8); Control 59·2 (13·5) | Intervention 20 (67%); Control 22 (73%) | 30/30 | 5 yr | Injected intracoronary through balloon | BMMNC | BM aspiration | saline with heparin. | 2460(940) million, 9.5(6.3) million CD34+ | Standard treatment |
| Naseri 2018 | Tehran, Iran | STEMI, LVEF: 20-45% | Placebo group n=26: 55.5 (8.54) CD133+ group n=21: 53.14 (8.56) MNC group n=30: 51.45 (7.49) | Placebo group n=26: 88.5% CD133+ group n=21: 91.5% MNC group n=30: 90% | 51/26 | 18 Months | Direct intramyocardial injection | BMMNC; CD133+ | BM aspiration | 2 ml normal saline with 2% autologous serum. | 564.63 million (± 69.35) MNC cells; 8.19 million (± 4.26) CD133+ cells | 2 ml normal saline supplemented with 2% autologous serum. |
| Ostovaneh 2021 | MI, LVEF <45% | intervention (n=83): 54.7 (11.1); Control (n=41): 53.5 (10.2); | Placebo (n=41): 87.8% CAP-1002 group (n=83): 86.7% | 95/47 | 12 Months | Intracoronary infusion | allogeneic cardiosphere-derived cells (CDCs) [CAP-1002] | Donor hearts at the time of cardiac transplantation | NR | 25 million | ||
| Penicka 2007 | Czech Republic | Anterior STEMI, LVEF < 50% | Intervention: 61 (14) Control: 54 (10) | Intervention: 71 (%) Control: 100 | 17/10 | 24 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | NR | 2640 (IQR 1960-3300) million | Standard treatment |
| Piepoli 2010 | Italy | STEMI | intervention (n= 19) 63.1+/- 2.4; Control (n=19)- 67+/- 2.7 | 13 (68.4) in C; 13 (68.4) in BM | 19/19 | 12 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | 7 ml of PBS-EDTA buffer containing 3 ml of human albumin 5% W/V. | 248 million BMMNC, 2 million CD34+ | control |
| Plewka 2009 | Poland | STEMI, LVEF <40% | intervention: 59 (9) Contol: 56 (8) | BMMNC 68% Control: 78% | 40/20 | 24 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | heparinised saline | 144 (49) million cells | Standard treatment |
| Quyyumi 2011 | USA | Acute STEMI & LVEF ≤ 50% | CD34⁺ levels (median, IQR): HD 50.5 (45–53), MD 63 (57–66), LD 52 (51–52); treated pooled 52 (47.5–63.5), control pooled 52 (47–57). | CD34+: 100% (HD), 80% (MD), 80% (LD)Control: 87% | 16/15 | 12 Months | Injection intracoronary through balloon | CD34+ cells | BM aspiration, selection to isolate CD34+ cells | Heparinised phosphate buffered saline, 40% autologous serum & 1% human serum albumin | LD: 4.8 (0.4) million cells MD: 9.9 (0.7) million cells HD: 14.3 (1.6) million cells | Standard treatment |
| Quyyumi 2017 | USA | STEMI LVEF ≤48% | Intervention: 57.1 ± 10.1 Control: 56.4 ± 10.1 | Intervention: 85% Control: 80% | 100/95 | 6 Months | Injection intracoronary through balloon | CD34+ cells | BM aspiration, selection to isolate CD34+ cells | 10 ml phosphate buffered saline supplemented with autologous serum & human serum albumin | 14.9 ± 8 million cells (range 8 to 43.8) | phosphate buffered saline, autologous serum & HAS without cells. |
| Roman 2015 | Spain | AMI | BMMC (n=30): 54 +/- 11; G-CSF (n=30); 57 +/- 9 BMMC + G-CSF (n=29): 56 +/- 8 Control (n = 31): 57 +/- 11 | BMMC (n=30): 97%; G-CSF (n=30); 83% BMMC + G-CSF (n=29): 86% Control (n = 31): 90 | 59/61 | 12 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | heparinized saline | 560 million | |
| Roncalli 2011 | France | Acute STEMI, LVEF ≤ 45%; | BMMNC: 56 (12) Control: 55 (11) | BMMNC: 80.8% Control: 89.8% | 52/49 | 3 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | 4% human serum albumin solution | 98.3 (8.7) million cells | Standard treatment |
| Srimahachota 2011 | Thailand | STEMI, LVEF < 50% | Inervention 52 + 12.9; Control 54.1 + 14.7 | Intervention 81.8; Control 83.3 | 11/12 | 6 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | saline with 2% autologous serum | 420 (221) million cells | Standard treatment |
| Surder 2016 | Switzerland | STEMI, LVEF < 45% | BMMNC: median 55 (IQR 15) (E), 62 (IQR 15) (L) Control: median 56 (IQR 14.5) | BMMNC: 86.2% (E), 82.5 (L) Control: 83.6% | 133/67 | 12 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | 20% of autologous serum | E: 159.7 (125.8) million cells; L: 139.5 (120.5) million cells | Standard treatment |
| Tendra 2009 | Multicentre | Anterior AMI, LVEF ≤ 40% | CD34/CXCR4+: median 58 BMMNC: median 55 Control: median 59 | CD34/CXCR4+: 63.7% BMMNC: 70.6% Control: 75% | 160/40 | 6 Months | Injection intracoronary through balloon | Selected cells (S): CD34+/CXCR4+ cells Unselected cells (U): BMMNC | BM aspiration; Selected cells: immunomagnetic selection to isolate CD34+/CXCR4+ cells | Phosphate‐buffered saline | S: 1.9 million cells U: 178 million cells | Standard treatment |
| Traverse 2010 | USA | STEMI; LVEF <50% | BMMNC: median 52.5 (IQR 43 ‐ 64)Control: median 57.5 (IQR 54 ‐ 59) | BMMNC: 83.3% Control: 60% | 30/10 | 15 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | 0.9% saline solution & 5% human serum albumin | 100 million cells | 0.9% saline solution & 5% human serum albumin |
| Traverse 2011 | USA | STEMI, LVEF ≤ 45%; PCI | BMMNC: 57.6 (11) Control: 54.6 (11) | BMMNC: 79% Control: 90% | 58/29 | 6 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | 0.9% saline solution & 5% human serum albumin | 147 (17) million cells | 0.9% saline solution and 5% human serum albumin |
| Traverse 2018 | USA | anterior STEMI, LVEF ≤45% | BMC 55.9 (11) C 56.4 (10.4) | BMC 88%, C 85% | 79/41 | 12 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | 0.9% saline solution & 5% human serum albumin | 146.1(20.1) million | 5% ALBUMIN IN NS with 100 ul oh whole blood |
| Wang 2014 | China | Acute STEMI | Intervention: 58 (10.2) Control: 56.1 (9.8) | Intervention: 67.9% Control: 53.3% | 28/30 | 6 Months | Injection intracoronary through balloon | BM-MSC | BM aspiration and culture of MSC | Heparinized saline | 100 million cells | Heparinized saline |
| Wen X 2012 | China | AMI | BM‐MSC: 60.4 (8.9) Control: 58.6 (10) | BM‐MSC: 58.8% Control: 61.9% | 17/21 | 3 Months | Injection intracoronary through balloon | BM‐MSC | BM aspiration | NR | 460 (160) million cells | heparinised saline |
| Wohrle 2010 | Germany | AMI | Intervention: 61.0 (8.1) Control: 61.1 (9.3) | Intervention: 90% Control: 62% | 29/13 | 36 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | 0.9% saline solution,2% human serum albumin & 0.1% autologous erythrocytes | 381 (130) million cells | 0.9% saline solution, 2% human serum albumin and 0.1% autologous erythrocytes) |
| Wollert 2017 | Germany, Norway | STEMI LVEF < 52% | 55 ± 10 | 86.6 |
loBMC (n = 38) hiBMC (n =33) loBMCi (n =25) hiBMCi (n= 31) Comparator = 26 |
6 Months | Injection intracoronary through balloon | BMMNC | BM aspiration | serum-free DMEM (Dulbecco’s modified eagle medium) | loBMC (Nucleated cells - 700 ± 290 million; CD34 cells - 2.9 ± 2.1 million); hiBMC (Nucleated cells - 2060 ± 770 million; CD34 cells - 8.2 ± 5.3 million) | Pure red blood cell suspension |
| Yao 2009 | China | STEMI, LVEF 20-39% | Intervention: 52.1 (6.3) (SD), 51.3 (7.4) (DD) Control: 52.7 (7.8) | Intervention: 83.3 & (SD), 80% (DD) Control: 91.7% | 27 (15 SD, 12 DD); Control 12 | 12 Months | Injection intracoronary through balloon | BMMNC | BM Aspiration | Heparinised plasma | SD: 410 million cells; DD: 190 (SE 120) million cells | Heparinised plasma |
| Zhang 2021 | China | STEMI | BMC: 59.3+/-9: placebo 58.6+/-11 | BMC: 95.2% Placebo: 86.36% | 21/22 | 12 Months | Injection intracoronary through balloon | BM-MSC | BM Aspiration | 2 ml normal saline | 2-5 million cells |
Outcome measure
The primary outcomes included all-cause mortality, recurrent myocardial infarction (Re-MI), serious adverse events (SAEs), hospitalisation due to heart failure, cancer incidence, and changes in LVEF assessed by MRI and echocardiography. Two researchers independently extracted the data, and a subject matter expert was consulted to settle any differences.
Statistical analysis
Authors collected and compiled the detailed outcome data from all the studies included and pooled estimates were visually represented using forest plots generated in Review Manager (RevMan) version 5.4, developed by The Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, 2020. Statistical significance was defined as a P<0.05. The dichotomous and continuous data were analysed using relative risks (RRs) and mean difference (MD) respectively with their confidence intervals (CIs). The I2 statistic was used to assess heterogeneity across studies, with values over 50 per cent considered indicative of substantial heterogeneity. Depending on the degree of heterogeneity, a fixed-effects model was used for low heterogeneity, whereas a random-effects model was employed when heterogeneity was substantial. Subgroup analyses were performed based on factors such as the timing of outcome assessment, type of stem cells used, autologous versus allogeneic sources, administration route and timing, sample size, and cell dose to identify potential sources of heterogeneity. Means and standard deviations were estimated from medians and ranges using the approach outlined by Hozo et al7 (2005). Additionally, RevMan calculator was used for conversion of data from one form to another.
Risk of bias assessment
The risk of bias for each included study was independently evaluated by two reviewers (PA, RO). Differences in opinion were resolved through discussion, and, if needed, a third reviewer was consulted. The Cochrane Collaboration’s Risk of Bias 2 (ROB-2) tool was used to assess the methodological quality of the randomized controlled trials (RCTs). Based on the assessment, studies were grouped into categories of low risk, some concerns, or high risk of bias8,9. The ROBVIS tool was utilized to graphically present the risk of bias evaluations. Potential bias from selective reporting or missing results in the synthesis was specifically evaluated through Domain 5 of the ROB-2 tool, which addresses bias due to selective outcome reporting. By using this approach, a transparent and complete evaluation of the methodological quality of the studies was achieved.
Recommendations
The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach was employed to assess the overall certainty of the synthesized evidence. For each outcome, this method evaluates the quality of evidence across multiple studies and classifies it into four levels: high, moderate, low, and very low certainty. While randomised controlled trials (RCTs) generally begin as high-certainty evidence, factors such as publication bias, indirectness, imprecision, inconsistency, and risk of bias can lead to downgrading their certainty level. On the other hand, in some circumstances, a large effect size or a dose-response connection, among other factors, might improve the certainty10-12. This was done by two independent assessors. They resolved disagreements amongst themselves and if it persisted, they followed a third independent assessor.
Results
The screening process via the PRISMA flowchart13 can be visualized in flowchart figure 1. After a systematic search across four databases, we identified 9516 records initially, retrieved 218 full texts and selected 48 articles for comprehensive review and quantitative synthesis.
- PRISMA flow diagram illustrating the study selection process according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines.
We extracted all relevant results reported across the included studies. It included data from different measures, time points, and analyses. However, to prevent unit of analysis issue, endpoints reported at the longest follow up were considered for the analysis and a subgroup analysis was done based on trial duration.
Mortality
All-cause mortality was reported in 30 clinical trials14-42 having 2879 participants (1633 in stem cell and 1246 in control). The findings demonstrated that stem cell therapy had no significant effect on reducing all-cause mortality in patients with AMI (RR = 0.73; 95% CI: 0.50–1.05; P = 0.09) with uniform findings among the studies (I2 = 0%; Fig. 2). Furthermore, subgroup analyses stratified by the timing of outcome assessment revealed no significant differences, further supporting the absence of a clear mortality benefit associated with stem cell therapy (trial period up to 6 months, trial period up to 12 months, trial period more than 12 months; Supplementary Fig. 1A), cell type (mononuclear, mesenchymal, both; Supplementary Fig. 1B), route of administration (intracoronary, direct intramyocardial, antecubital vein of forearm; Supplementary Fig. 1C), autogenic vs. allogenic; Supplementary Fig. 1D), time of cell administration (administration < 24 h, administration 1 - 21 days, not mentioned; Supplementary Fig. 1E), sample size (<100 and ≥100) Supplementary Fig. 1F), and dose of cell administered (< 500 million and ≥ 500 million; Supplementary Fig. 1G).
- This forest plot shows all-cause mortality incidence between stem cell therapy and control groups, with pooled effect estimates.
Serious adverse events
SAEs were reported in 12 trials14,17,21,13-25,29,31-33,41,43 having 1161 participants (571 in the stem cell intervention group and 590 in control group). There was no significant difference in the occurrence of SAEs between the stem cell group and the control group [RR = 0.93 (0.76-1.14) P=0.51, I2=0%; Supplementary Fig. 2A. No significant differences were obtained on subgroup analysis based on time of assessment (Supplementary Fig. 2B), cell type (Supplementary Fig. 2C), route of administration (Supplementary Fig. 2D), autogenic vs. allogenic (Supplementary Fig. 2E), time of cell administration (Supplementary Fig. 2F), sample size (Supplementary Fig. 2G), and dose of cell administered (Supplementary Fig. 2H).
Recurrent-myocardial infarction
Incidences of re-MI were reported in 18 trials14,16,18,20-23,25-28,32,34,35,37,44,45 having 1981 participants (1158 in intervention group and 823 in control). Stem cell treatment has no favourable effect on preventing myocardial infarction [RR = 0.67 (0.43 – 1.05), P=0.08, I2 = 0%; Fig. 3]. No significant differences were obtained on subgroup analysis based on time of assessment (Supplementary Fig. 3A), cell type (Supplementary Fig. 3B), route of administration (Supplementary Fig. 3C), time of cell administration (Supplementary Fig. 3D), sample size (Supplementary Fig. 3E), and dose of cell administered (Supplementary Fig. 3F).
- This forest plot presents the overall effect of stem cell therapy on the incidence of re-myocardial infarction.
Hospitalisation due to heart failure
Nineteen trials14,15,18-20,22,26,27,29,31-34,37,39,40,44,46,47 reported occurrences of hospitalisation caused by heart failure (total participants = 1641, 928 in the stem cell group vs. 713 in the control group). No significant difference in hospitalisation due to heart failure was observed between the intervention and control groups [RR = 0.79 (0.52–1.20), P = 0.27, I2 = 0%; Fig. 4]. No significant differences were obtained on subgroup analysis based on time of assessment (Supplementary Fig. 4A), cell type (Supplementary Fig. 4B), route of administration (Supplementary Fig. 4C), autogenic vs. allogenic (Supplementary Fig. 4D), time of cell administration (Supplementary Fig. 4E), sample size (Supplementary Fig. 4F), and dose of cell administered (Supplementary Fig. 4G).
- This forest plot presents effect of stem cell therapy on hospitalisation due to heart failure in comparison with control.
Cancer incidence
Cancer incidences were reported in six trials14,20,22,25,28,48 having 807 participants (411 in cell group, 396 in control). No extra cancer incidences were reported in the stem cell group compared to control [RR = 0.82 (0.43 – 1.55) P=0.54, I2 = 0%; Fig. 5]. No significant differences were obtained on subgroup analysis based on the time of assessment (Supplementary Fig. 5A), cell type (Supplementary Fig. 5B), route of administration (Supplementary Fig. 5C), autogenic vs. allogenic (Supplementary Fig. 5D), time of cell administration (Supplementary Fig. 5E), sample size (Supplementary Fig. 5F), and dose of cell administered (Supplementary Fig. 5G). In this analysis, studies with a follow up period of 12 months or longer had a median duration of 24 months (range: 18–104 months); see table I for details.
- This forest plot shows the cancer incidence between stem cell therapy recipients and control participants.
Stroke incidence
Stroke incidences were reported in eight trials14,18,22,24,25,31,34,37 (1121 participants, 610 stem cell group, and 511 control group). No statistically significant difference was observed in stroke incidences reported in the stem cell group compared to control [RR = 0.81 (0.41 – 1.60), P = 0.55, I2 = 0%; Fig. 6]. No significant differences were observed in subgroup analyses based on time of assessment (Supplementary Fig. 6A), cell type (Supplementary Fig. 6B), route of administration (Supplementary Fig. 6C), autogenic vs. allogenic (Supplementary Fig. 6D), time of cell administration (Supplementary Fig. 6E), and sample size (Supplementary Fig. 6F).
- Forest plot comparing the incidence of stroke between patients receiving stem cell therapy and controls.
Left ventricular ejection fraction
a) LVEF measured by echocardiography (end of the study)
End of the study, LVEF measured by echocardiography was reported by 1915,17,19-21,23,28,33,40,43,46,49-55 clinical trials with 20 comparisons (909 participants, 480 in the stem cell group, and 429 in the control group). LVEF (%) at the study’s end was significantly higher in the treatment group compared to controls [MD = 2.53 (0.95–4.10); P < 0.001], with high heterogeneity (I2 = 76%, P < 0.001; Supplementary Fig. 7A). Significant results were observed in subgroup analyses based on trial duration (up to 12 months, and >12 months; (Supplementary Fig. 7B), cell type (mesenchymal; (Supplementary Fig. 7C), administration route (intracoronary; (Supplementary Fig.7D), autologous vs. allogeneic cells (Supplementary Fig.7E), timing of cell administration (administration <24 hand 1-21 days; Supplementary Fig.7F), sample size (<100; Supplementary Fig. 7G) and dose administered (<500 million; Supplementary Fig. 7H).
b) LVEF measured by echocardiography (difference from the baseline)
Differences from baseline LVEF were reported in 8 clinical trials15,19,20,23,50,52-54 with nine comparisons (486 participants, 251 in the stem cell group, and 235 in the control group). The difference from baseline LVEF was significantly greater in the stem cell group as compared to the control group [MD=3.89 (2.32 – 5.46), P <0.001]. The trials exhibited high heterogeneity (I2 = 80%, P<0.001; Supplementary Fig. 8A). Significant differences were obtained on subgroup analysis based on time of assessment (Supplementary Fig. 8B), cell type (Supplementary Fig. 8C), route of administration (Supplementary Fig. 8D), autogenic vs. allogenic (Supplementary Fig. 8E), time of cell administration (Supplementary Fig. 8F), and sample size (Supplementary Fig. 8G).
LVEF measured by MRI
a) LVEF measured by MRI (end of the study)
End of the study, LVEF measured by MRI was reported by 19 clinical trials16,18,24,26,31-33,35,37,39,41,44,45,48,50,54,56,57, reporting 24 comparisons with control (1340 participants, 809 in the stem cell group, and 531 in the control group). LVEF (%) at the end of the study was not significantly different from that of the control group [MD=0.83 (-0.73 – 2.38), P = 0.3]. The trials exhibited high heterogeneity (I2 = 60%, P<0.001; Supplementary Fig. 9A). No significant differences were obtained on subgroup analysis based on time of assessment (Supplementary Fig. 9B), cell type (Supplementary Fig. 9C), route of administration (Supplementary Fig. 9D), autogenic vs. allogenic (Supplementary Fig. 9E), time of cell administration (Supplementary Fig. 9F), sample size (Supplementary Fig. 9G), and dose of cell administered (Supplementary Fig. 9H).
b) LVEF measured by MRI (difference from the baseline)
Differences from baseline LVEF were reported in 22 clinical trials16,18,22,24,26,31,32,34,37,39,41-45,47,48,50,54,56,57 with 25 comparisons (1499 participants, 886 in the stem cell group, and 613 in the control group). Difference from baseline LVEF was significantly more in stem cell group as compared to control group [MD=1.37 (0.39 – 2.35), P =0.01]. The trials had a high heterogeneity (I2 =56%, P<0.001; Supplementary Fig. 10A). Similar significant differences were obtained on subgroup analysis based on time of assessment (trial period up to 12 months (Supplementary Fig. 10B), cell type (mesenchymal; Supplementary Fig. 10C), route of administration (intravenous; Supplementary Fig. 10D), autogenic vs. allogenic (Supplementary Fig. 10E), time of cell administration (1-21 days; Supplementary Fig. 10F), sample size (<100; Supplementary Fig. 10G), and dose of cell administered (Supplementary Fig. 10H).
Risk of bias of the included studies
The risk of bias in the different studies is elaborated in figure 7. Around 28 studies were having high risk of bias. Most of these studies were either open blind or information about blinding and allocation concealment was missing, and there were dropouts in almost all studies (Supplementary table III). Most of the outcomes were very objective in nature; hence, the risk of bias, even if it existed, might have had limited influence on the overall results for these clinical outcomes. (Fig. 7).
- This visual representation uses a ‘traffic light’ system (green = low risk, yellow = some concerns, red = high risk) to show the risk of bias for each included study.
Summary of finding table
Overall certainty of evidence remains low or very low for most outcomes. Grade assessment is shown in table II.
| Certainty assessment | No. of patients | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | Cell | No cell | Relative (95% CI) | Absolute (95% CI) | ||
| Mortality | ||||||||||||
| 30 | randomised trials | seriousa | not serious | not serious | seriousb | none | 44/1633 (2.7%) | 51/1246 (4.1%) | RR 0.73 (0.50 to 1.05) | 11 fewer per 1,000 (from 20 fewer to 2 more) | ⨁⨁◯◯ Low | CRITICAL |
| SAE frequency | ||||||||||||
| 12 | randomised trials | very seriousc | not serious | not serious | seriousb | none | 121/571 (21.2%) | 143/590 (24.2%) | RR 0.93 (0.76 to 1.14) | 17 fewer per 1,000 (from 58 fewer to 34 more) | ⨁◯◯◯ Very low | CRITICAL |
| Re MI frequency | ||||||||||||
| 18 | randomised trials | very seriousd | not serious | not serious | seriousb | none | 29/1158 (2.5%) | 33/823 (4.0%) | RR 0.67 (0.43 to 1.05) | 13 fewer per 1,000 (from 23 fewer to 2 more) | ⨁◯◯◯ Very low | CRITICAL |
| Heart Failure Frequency | ||||||||||||
| 19 | randomised trials | seriouse | not serious | not serious | seriousb | none | 37/928 (4.0%) | 39/713 (5.5%) | RR 0.78 (0.50 to 1.20) | 12 fewer per 1,000 (from 27 fewer to 11 more) | ⨁⨁◯◯ Low | CRITICAL |
| Stroke frequency | ||||||||||||
| 8 | randomised trials | seriousa | not serious | not serious | seriousb | none | 13/610 (2.1%) | 14/511 (2.7%) | RR 0.81 (0.41 to 1.60) | 5 fewer per 1,000 (from 16 fewer to 16 more) | ⨁⨁◯◯ Low | CRITICAL |
| Cancer incidence | ||||||||||||
| 6 | randomised trials | not serious | not serious | not serious | seriousb | none | 15/411 (3.6%) | 18/396 (4.5%) | RR 0.82 (0.43 to 1.55) | 8 fewer per 1,000 (from 26 fewer to 25 more) | ⨁⨁⨁◯ Moderate | CRITICAL |
aonly 33.3% of trials have low risk of bias; bConfidence interval crosses the point if no difference; conly 25% of trials have low risk of bias; donly 22% of trials have low risk of bias. CI, confidence interval; MD, mean difference; RR, risk ratio
Publication bias
Outcomes with fewer than 10 trials were not eligible for publication bias assessment. For outcomes with ≥10 trials (mortality, SAE, Re-MI, hospitalisation due to heart failure, and LVEF differences), publication bias was evaluated and reported in supplementary figure 11.
Discussion
This systematic review and meta-analysis (SRMA) evaluated the efficacy and safety of stem cell therapy in patients with acute myocardial infarction (AMI). Based on the findings from 48 eligible studies, stem cell treatment did not demonstrate a significant improvement over standard care in major clinical outcomes, including all-cause mortality, serious adverse events (SAEs), recurrent myocardial infarction, hospitalisations due to heart failure, stroke incidence, or cancer occurrence. These results are consistent with the most current Cochrane review, which found that stem cell treatment does not enhance clinical outcomes for individuals with AMI after examining 41 trials58.
Despite significant heterogeneity, our analysis showed a favourable change in LVEF as evaluated by echocardiography after the study and as a change from baseline in terms of functional outcomes. After the research, LVEF, as determined by MRI, did not significantly differ; however, it did demonstrate a notable improvement over baseline, albeit with significant heterogeneity. In this study, the improvement in LVEF (difference from baseline, measured by echocardiography) was 3.89 per cent, which falls below the five per cent threshold commonly cited in the literature as the Minimal Clinically Important Difference (MCID) for LVEF improvement59,60. This suggests that while the observed change may be statistically significant, its clinical relevance may be limited. These findings are consistent with the Cochrane review, further reinforcing the uncertainty regarding the clinical relevance of LVEF improvements. Overall, both our analysis and the Cochrane review suggest that stem cell therapy does not provide clinically meaningful benefits in the treatment of AMI. While modest improvements in LVEF were observed, their significance remains unclear due to high heterogeneity across studies.
The stem cell type, delivery method and timing, follow up periods, sample size, and cell dosage differed among the included trials. Subgroup analysis was performed to evaluate how these parameters affected the final outcome. Subgroup analysis based on sample size showed no significant differences in outcome direction between the two groups. Cell dose showed no overall effect, except for LVEF by echocardiography: doses <500 million improved outcomes, while >500 million, reported in one study, showed no effect—possibly by chance. However, a previous study reported improved LVEF with doses >500 million61.
The overall quality of the evidence is moderate, reflecting some concerns about bias and confidence intervals, including the possibility of no effect. Seven outcomes were analysed, with heterogeneity observed in only one - LVEF. Subgroup analyses were performed to investigate differences based on cell type, dosage, and sample size. A few studies were excluded due to unclear reporting of stem cell characteristics. In this SRMA, it was found that in patients with AMI, the use of stem cells had no significant effect on mortality, current MI, or heart failure-related hospitalisations, except for LVEF. The evidence is of moderate quality; further clinical trials may change the estimate.
This meta-analysis suggests that stem cell therapy does not significantly impact mortality, current MI, or heart failure-related hospitalisations in AMI patients. While improvements in LVEF were noted, their clinical significance remained uncertain. The findings highlight the necessity of further large-scale, rigorously designed trials with long term follow-up to determine the potential role of stem cell therapy in AMI treatment.
Financial support & sponsorship
This review was commissioned by the Indian Council of Medical Research (ICMR) under the project titled “EOI -2023-000306: Evidence Synthesis for the Use of Stem Cell Therapy: Conducting Systematic Review and Meta-analysis.” The Department of Health Research (DHR), Government of India.
Conflicts of Interest
None.
Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation
The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript and no images were manipulated using AI.
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