Meta-Analysis of Percutaneous Endomyocardial Cell Therapy in Patients with Ischemic Heart Failure by Combination of Individual Patient Data (IPD) of ACCRUE and Publication-Based Aggregate Data
Abstract
:1. Introduction
2. Methods
2.1. Search Strategy
2.2. Data Collection and IPD Management of the ACCRUE Database
2.3. Inclusion and Exclusion Criteria
2.4. Primary and Secondary Endpoints Including All Studies
2.5. Primary and Secondary Endpoints of ACCRUE IPD Studies
2.6. Statistics
2.6.1. Combined Analysis Including Harmonized IPD and Aggregate Data
2.6.2. Analysis of IPD
3. Results
3.1. Characteristics of Studies Included in the Analysis
3.2. Patient Characteristics
3.3. Procedural and In-Hospital Complications
3.4. Primary and Secondary Clinical Safety Endpoint Analyses
3.5. Primary Efficacy Endpoint Outcome
3.6. Secondary Efficacy Outcome Results
3.7. Subanalyses of ACCRUE-IPD
3.8. Subanalysis of the Cardiac Function Parameter with Risk Factors Using IPD of ACCRUE Percutaneous Endomyocardial Data
4. Discussion
4.1. Proposed Mechanisms of the Different Cell Types
4.2. Comparison with Published Trial-Based Meta-Analyses including Patients with Severe Heart Failure
4.3. Analyses of the Primary and Secondary Endpoints
5. Limitations
6. Conclusions
7. Clinical Implications
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study Name (Publ. Year) | Study Design | Sample Size (Cell Therapy/Controls) | Inclusion Criteria and Cell Delivery Mode | Cell Type and Amount | Follow-Up Period | Primary Endpoint | Imaging Modality | Intervention Device |
---|---|---|---|---|---|---|---|---|
MYSTAR (2009) [9] | RC, U | 30/30 | iCMP, HF, pIM | autol. BM-MNCs; 10–13 injection sites; 0.3 mL cells/injection; total volume: 3–3.9 mL; rest injected intracoronary; total cell number: 1.56 ± 0.4 × 109 and 1.55 ± 0.44 × 109 | 3 m | Changes in infarct size and EF | SPECT | NOGA |
ESCAPE (2010) [10] | RC, U | 55/54 | iCMP, HF, pIM | autol. BM-MNCs; 10 injection sites; 0.2 mL/injection; total cell number: 41 ± 16 × 106 | 12 m | Long-term FUP results | Echo | NOGA |
FOCUS-HF (2011) [11] | RC, U | 20/10 | iCMP, HF, pIM | autol. BM-MNCs; 15 injection sites; 0.2 mL cells/injection; total cell number: 100 × 106 cells | 6 m | Safety of pIM | Echo | NOGA |
FOCUS-CCTRN (2012) [12] | RC, MU | 61/31 | iCMP, HF, pIM | autol. BM-MNCs; 15 injection sites; 0.2 mL/injection; total cell number: 100 × 106 cells | 6 m | Change in ESV | Echo | NOGA |
PRECISE (2014) [13] | RC, MU | 21/6 | iCMP, HF, pIM | autol. ADRCs; 15 injection sites; total cell number: 42 × 106 cells in 3 mL volume | 24 m | Safety and feasibility | MRI | NOGA |
TAC-HFT (2014) [14] | RC, U | 38/21 | iCMP, HF, pIM | autol. BM-MSCs or BM-MNCs; 10 injection sites; total cell number: 100 × 106 | 12 m | 30-day SAE | MRI or CT | NOGA |
MSC-HF (2015) [15] | RC, U | 40/20 | iCMP, HF, pIM | autol. BM-MSCs; 10–15 injection sites; 0.2 mL/injection; total cell number: 77.5 ± 67.9 × 106 | 6 m | Change in ESV | MRI or CT | NOGA |
REGENERATE-IHD (2017) [16] | RC, MU | 15/15 | iCMP, HF, pIM | autol. BM-MNCs; 10 injection sites; total volume: 2 mL | 12 m | Change in EF at 1 y | MRI or CT | NOGA |
C-CURE (2013) [17] | RC, MU | 21/24 | iCMP, HF, pIM | autol. BM-derived cardiopoietic stem cells; mean 18 injection sites; total: 4.5–12.7 mL; mean number of injected cells: 733 × 106 | 24 m | Feasibility and safety | Echo | NOGA |
CHART-1 (2017) [18] | RC, MU | 120/151 | iCMP, HF, pIM | autol. BM-derived cardiopoietic stem cells; median: 19 injection sites; >24 mio injected cells; median injection volume: 9.6 mL | 39 w | Hierarchical composite of 5 safety and efficacy parameters | Echo | C-Cath |
CAUSMIC (2009) [19] | RC, MU | 12/11 | iCMP, HF, pIM | autol. skeletal myoblast; 10 mio cells/injection (0.1 mL in the 30 mio cell dose group, and 0.25 mL in the 25, 100, 300 and 600 mio cell dose group) | 12 m | Safety, tolerability and feasibility | Echo | NOGA |
MESOBLAST-2 (2015) [20] | RC, MU | 45/15 | iCMP, noniCMP, HF, pIM | allog. BM-mesenchymal precursor cells; 15–20 injection sites; 0.2 mL/injection (max. 4.0 mL); 25 or 75 or 150 mio MPCs (dose escalating study) | 36 m | Safety, tolerability and feasibility | Echo | NOGA |
SEISMIC (2011) [21] | RC, MU | 26/14 | iCMP, HF, pIM | autol. skeletal myoblast; max.: 32 injection sites; 50 mio cells/mL; total: 150–800 mio cells | 6 m | Safety: SAE; efficacy: LVEF | MUGA | MyoCath™; Bioheart Inc |
MARVEL (2011) [22] | RC, MU | 14/6 | iCMP, HF, pIM | autol. skeletal myoblast; 16 injection sites; 0.25 mL/injection; total number of cells: 400 × 106 or 800 × 106 cells | 6 m | Safety: SAE; efficacy: changes in 6 min WT and MLWHF scores | Echo + MUGA | NOGA |
IXMYELOCEL-T (2016) [23] | RC, MU | 58/51 | iCMP, HF, pIM | autol. BM-origin Ixmyelocel-T; 12–17 injections sites; 0.4 mL/injection; total injection volume: 5.8–8.4 mL | 12 m | Composite of 3 safety and combined efficacy parameters | Echo | NOGA |
CCTRN-CONCERT-HF Lead-in (2021) [24] | RC, U | 9/9 | iCMP, HF, pIM | autol. BM-origin MSCs + CPCs; 150 × 106 MSCs and 5 × 106 CPCs | 3 m | Safety and feasibility | MRI or CPET | NOGA |
CCTRN-CONCERT-HF (2021) [24] | RC, MU | 93/32 | iCMP, HF, pIM | autol. BM-origin MSCs + CPCs; MSCs: 108 ± 28 × 106 and 4.3 ± CPC: 1.2 × 106; | 12 m | Safety, feasibility and efficacy | MRI | NOGA |
DREAM-HF (2021) [25] | RC, MU | 261/276 | iCMP and noniCMP, HF, pIM | allogen. BM-mesenchymal precursor cells | 30 m | Recurrent non-fatal decompensated heart failure events per 100 patients | na | NOGA |
Cell Therapy (n = 939) | Control (n = 776) | p-Value | |
---|---|---|---|
Females | 705/930 (12.5%) | 113/767 (14.7%) | 0.176 |
Hypertension | 705/878 (80.3%) | 590/736 (80.2%) | 0.950 |
Hyperlipoproteinemia | 413/491 (84.1%) | 372/424 (87.7%) | 0.129 |
Diabetes | 319/913 (34.9%) | 297/762 (27.8%) | 0.093 |
Family history of coronary heart disease | 29/108 (26.9%) | 20/87 (23.0%) | 0.536 |
Smoking | 323/616 (52.4%) | 197/460 (42.8%) | 0.005 |
History of myocardial infarction | 670/912 (73.5%) | 534/761 (70.2%) | 0.140 |
History of coronary artery bypass graft surgery | 311/655 (47.5%) | 223/485 (57.2%) | 0.631 |
History of percutaneous coronary intervention | 476/620 (76.8%) | 325/460 (70.7%) | 0.025 |
History of previous AICD | 525/853 (61.5%) | 348/745 (46.7%) | <0.001 |
Methods for LV parameter | (n = 674) | (n = 499) | <0.001 |
Echocardiography | 407 (60.4%) | 354 (70.9%) | |
MRI | 161 (23.9%) | 74 (14.8%) | |
CT | 50 (7.4%) | 27 (5.4%) | |
SPECT | 30 (4.5%) | 30 (6.0%) | |
MUGA | 26 (3.9%) | 14 (2.8%) | |
Type of cell/placebo | |||
Autologous BM-MNCs | 211 (22.5%) | ||
Autologous BM-MSCs | 59 (6.3%) | ||
Autologous ADRCs | 21 (2.2%) | ||
Autologous BM-derived cardiopoietic stem cell | 141 (15.0%) | ||
Autologous skeletal myoblast | 26 (2.8%) | ||
Allogeneic BM-mesenchymal precursor cells | 261 (27.8%) | ||
Autologous BM-Ixmyelocel-T | 117 (12.5%) | ||
Autologous BM-MSCs + CPCs | 102 (10.9%) | ||
Placebo | 169 (21.8%) | ||
No injection (max. medical therapy) | 607 (78.2%) |
All Patients | Cell Therapy (n = 939) | Control (n = 776) | p-Value |
---|---|---|---|
Procedural complications | 26/611 (4.3%) | 1/440 (0.2%) | <0.001 |
Other in-hospital complications | 4/518 (0.8%) | 0/408 (0.0%) | 0.135 |
Follow-up events | |||
Mortality | 84/939 (8.9%) | 117/776 (15.1%) | <0.001 |
MACE | 173/939 (18.4%) | 231/776 (29.8%) | <0.001 |
AMI | 10/570 (1.8%) | 3/420 (0.7%) | 0.258 |
Stroke | 6/525 (1.1%) | 3/405 (0.7%) | 0.739 |
Coronary revascularization | 12/450 (2.7%) | 5/269 (1.9%) | 0.343 |
Hospitalization | 127/666 (19.1%) | 151/489 (30.9%) | 0.001 |
HTX or LVAD | 8/583 (1.4%) | 53/426 (12.4%) | <0.001 |
PM or AICD Impl. | 9/678 (1.3%) | 8/500 (1.6%) | 0.806 |
Non-serious AE | 94/540 (17.4%) | 115/411 (28.0%) | <0.001 |
LVF Parameter | Control (n = 187) | Cell therapy (n = 280) | p Value |
---|---|---|---|
EF (%) | |||
BL_EF | 31.2 ± 9.5 | 33.2 ± 9.8 | 0.0341 |
FUP_EF | 31.4 ± 10.5 | 36.1 ± 10.7 | <0.001 |
Delta EF | −0.4 ± 6.8 | 2.7 ± 6.7 | <0.001 |
EDV (mL) | |||
BL_EDV | 238.6 ± 80.8 | 235.1 ± 85.1 | 0.6801 |
FUP_EDV | 247.9 ± 87.7 | 237.9 ± 90.6 | 0.3021 |
Delta EDV | 9.2 ± 33.7 | 2.8 ± 38.4 | 0.1061 |
ESV (mL) | |||
BL_ESV | 169.3 ± 72.8 | 162.6 ± 76.2 | 0.3681 |
FUP_ESV | 176.6 ± 78.3 | 158.9 ± 80.7 | 0.0391 |
Delta ESV | 8.3 ± 28.9 | −3.8 ± 31.3 | < 0.001 |
(a) | ||||
---|---|---|---|---|
Changes in EF | ||||
Mean (SE) | 95% CI | p value | ||
Effect of age ≥62 | Cell therapy (n = 142) | 2.0 (0.7) | +0.6; +3.3 | 0.195 |
Control (n = 74) | −0.6 (1.0) | −2.5; +1.2 | ||
Effect of male gender | Cell therapy (n = 225) | 2.1 (0.5) | +1.0; +3.2 | <0.001 |
Control (n = 140) | −1.4 (0.7) | −2.7; −0.1 | ||
Effect of diabetes mellitus | Cell therapy (n = 65) | 1.8 (1.0) | −0.2; +3.8 | 0.072 |
Control (n = 48) | −1.7 (1.2) | −4.0; +0.6 | ||
Effect of hypertension | Cell therapy (n = 206) | 1.9 (0.6) | +0.7; +3.0 | 0.070 |
Control (n = 128) | −1.4 (0.7) | −2.8; +0.1 | ||
Effect of hyperlipidemia | Cell therapy (n = 213) | 2.4 (0.6) | +1.3; +3.5 | 0.034 |
Control (n = 135) | −1.4 (0.7) | −2.8; −0.1 | ||
Effect of smoking | Cell therapy (n = 145) | 1.7 (0.7) | +0.4; +3.0 | 0.102 |
Control (n = 79) | −0.1 (0.9) | −1.8; +1.8 | ||
Effect of baseline EF ≤ 45% | Cell therapy (n = 226) | 2.3 (0.5) | +1.2; +3.3 | 0.151 |
Control (n = 152) | −0.7 (0.7) | −2.0; +0.6 | ||
(b) | ||||
Changes in EDV | ||||
Mean (SE) | 95% CI | p value | ||
Effect of age ≥ 62 | Cell therapy (n = 129) | 3.3 (3.8) | −4.2; +10.9 | 0.102 |
Control (n = 69) | 9.4 (5.3) | −0.9; +19.8 | ||
Effect of male gender | Cell therapy (n = 201) | −1.6 (3.1) | −7.7; +4.5 | 0.732 |
Control (n = 129) | 7.7 (83.9) | −10.5; +31.3 | ||
Effect of diabetes mellitus | Cell therapy (n = 51) | −7.9 (6.1) | −19.9; +4.1 | 0.073 |
Control (n = 40) | 0.5 (6.9) | −13.0; +14.1 | ||
Effect of hypertension | Cell therapy (n = 183) | −0.5 (3.2) | −6.9; +5.8 | 0.214 |
Control (n = 116) | 9.8 (4.1) | +1.8; +17.8 | ||
Effect of hyperlipidemia | Cell therapy (n = 191) | −0.56 (3.2) | −6.3; +6.2 | 0.283 |
Control (n = 123) | 8.1 (4.0) | +0.3; +15.9 | ||
Effect of smoking | Cell therapy (n = 127) | −4.6 (3.9) | −12.2; +3.1 | 0.108 |
Control (n = 72) | 3.2 (5.2) | −6.9; +13.3 | ||
Effect of baseline EF ≤ 45% | Cell therapy (n = 201) | −1.2 (3.1) | −7.3; +5.0 | 0.152 |
Control (n = 137) | 9.4 (3.8) | +1.0; +16.8 | ||
(c) | ||||
Changes in ESV | ||||
Mean (SE) | 95% CI | p value | ||
Effect of age ≥62 | Cell therapy (n = 129) | −3.3 (3.0) | −9.2; +2.7 | 0.282 |
Control (n = 69) | 8.0 (4.1) | +0.1; +16.1 | ||
Effect of male gender | Cell therapy (n = 201) | −7.1 (2.4) | −11.9; −2.3 | 0.004 |
Control (n = 129) | 8.0 (3.0) | +2.0 +13.9 | ||
Effect of diabetes mellitus | Cell therapy (n = 51) | −11.2 (4.8) | −20.7; −1.8 | 0.020 |
Control (n = 40) | 5.7 (5.4) | −5.0; +16.3 | ||
Effect of hypertension | Cell therapy (n = 183) | −6.1 (2.5) | −11.1; −1.1 | 0.020 |
Control (n = 116) | 9.6 (3.2) | +3.3; +15.9 | ||
Effect of hyperlipidemia | Cell therapy (n = 191) | −6.4 (2.5) | −11.3; −1.5 | 0.011 |
Control (n = 123) | 8.6 (3.1) | +2.5; +14.7 | ||
Effect of smoking | Cell therapy (n = 127) | −8.7 (3.0) | −14.7; −2.8 | 0.634 |
Control (n = 72) | 1.2 (4.0) | −6.7; +9.1 | ||
Effect of baseline EF ≤ 45% | Cell therapy (n = 201) | −7.3 (2.4) | −12.2; −2.5 | 0.003 |
Control (n = 137) | 8.5 (3.0) | +2.7; +14.3 |
Type of Cell | Studies | Proposed Mechanisms |
---|---|---|
Autologous BM-MNC [9,10,11,12,14,16] | MYSTAR, ESCAPE, FOCUS-HF, FOCUS-CCTRN, REGENERATE-HD, TAC-HFT | Secretion of angiogenic chemokines and cytokines, and ability to recruit cells and promote cell survival; upregulation of endogenous cytokine expression |
Autologous BM-MSCs [15] | MSC-HF | Multipotent stem cells, paracrine stimulation of resident cardiac stem cells |
Autologous ADRCs [13] | PRECISE | Mixed, multipotent population of cells, differentiating into multiple cell lineages, such as cardiomyocytes, endothelial and smooth muscle cells; secretion of growth factors and cytokines |
Autologous BM-derived cardiopoietic stem cell [17,18] | C-CURE, CHART-1 | Nuclear translocation of cardiac transcription factors; increase in Nkx2.5, Flk-1, Gata-6, and Fog-1 |
Autologous skeletal myoblast [19,21,22] | CAUSMIC, SEISMIC, MARVEL | Myogenic phenotype; increase in graft survival; intrinsic resistance to hypoxia; up-regulation of pro-angiogenic, anti-apoptotic, heart development and extracellular matrix remodeling genes; and secretion of growth factors |
Allogeneic BM-mesenchymal precursor cells [20,25] | MESOBLAST-2, DREAM-HF | Multipotent nonhematopoietic stem cells, enrichment of the Stro-1/Stro-3+ population of mesenchymal lineage precursors, extensive proliferation, differentiation in vitro into different cell types, secretion of multiple paracrine factors and a decrease in apoptosis |
Autologous BM-Ixmyelocel-T [23] | Ixmyelocel-T | Has the regenerative properties of MSCs, but a 200 times higher number of M2 macrophages and 50 times higher number of CD90+ MSCs |
Autologous BM-MSCs + CPCs [24] | CCTRN-CONCERT-HF Lead-in, CCTRN-CONCERT-HF | CPCs differentiate into endothelial cells, and release paracrine signals, combining the 2 different cell types results into a complementary impact on secretome production |
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Gyöngyösi, M.; Pokushalov, E.; Romanov, A.; Perin, E.; Hare, J.M.; Kastrup, J.; Fernández-Avilés, F.; Sanz-Ruiz, R.; Mathur, A.; Wojakowski, W.; et al. Meta-Analysis of Percutaneous Endomyocardial Cell Therapy in Patients with Ischemic Heart Failure by Combination of Individual Patient Data (IPD) of ACCRUE and Publication-Based Aggregate Data. J. Clin. Med. 2022, 11, 3205. https://doi.org/10.3390/jcm11113205
Gyöngyösi M, Pokushalov E, Romanov A, Perin E, Hare JM, Kastrup J, Fernández-Avilés F, Sanz-Ruiz R, Mathur A, Wojakowski W, et al. Meta-Analysis of Percutaneous Endomyocardial Cell Therapy in Patients with Ischemic Heart Failure by Combination of Individual Patient Data (IPD) of ACCRUE and Publication-Based Aggregate Data. Journal of Clinical Medicine. 2022; 11(11):3205. https://doi.org/10.3390/jcm11113205
Chicago/Turabian StyleGyöngyösi, Mariann, Evgeny Pokushalov, Aleksander Romanov, Emerson Perin, Joshua M. Hare, Jens Kastrup, Francisco Fernández-Avilés, Ricardo Sanz-Ruiz, Anthony Mathur, Wojcieh Wojakowski, and et al. 2022. "Meta-Analysis of Percutaneous Endomyocardial Cell Therapy in Patients with Ischemic Heart Failure by Combination of Individual Patient Data (IPD) of ACCRUE and Publication-Based Aggregate Data" Journal of Clinical Medicine 11, no. 11: 3205. https://doi.org/10.3390/jcm11113205
APA StyleGyöngyösi, M., Pokushalov, E., Romanov, A., Perin, E., Hare, J. M., Kastrup, J., Fernández-Avilés, F., Sanz-Ruiz, R., Mathur, A., Wojakowski, W., Martin-Rendon, E., Pavo, N., Pavo, I. J., Hemetsberger, R., Traxler, D., Spannbauer, A., & Haller, P. M. (2022). Meta-Analysis of Percutaneous Endomyocardial Cell Therapy in Patients with Ischemic Heart Failure by Combination of Individual Patient Data (IPD) of ACCRUE and Publication-Based Aggregate Data. Journal of Clinical Medicine, 11(11), 3205. https://doi.org/10.3390/jcm11113205