Stem cell therapy for chronic ischaemic heart disease and congestive heart failure

Sheila A Fisher; Carolyn Doree; Anthony Mathur; David P Taggart; Enca Martin‐Rendon

doi:10.1002/14651858.CD007888.pub3

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Figure 1

PRISMA flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Funnel plot of comparison: 1 Stem cells versus no stem cells, outcome: 1.1 Mortality.

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Figure 4

Trial sequential analysis: Mortality at long‐term follow‐up (≥ 12 months). TSMB = trial sequential monitoring boundary; horizontal red lines indicate conventional significance threshold.

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Figure 5

Trial sequential analysis: Non‐fatal myocardial infarction at long‐term follow‐up (≥ 12 months). TSMB = trial sequential monitoring boundary; horizontal red lines indicate conventional significance threshold.

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Figure 6

Trial sequential analysis: Rehospitalisation due to heart failure at long‐term follow‐up (≥ 12 months). TSMB = trial sequential monitoring boundary; horizontal red lines indicate conventional significance threshold.

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Figure 7

Trial sequential analysis: Arrhythmias at long‐term follow‐up (≥ 12 months). TSMB = trial sequential monitoring boundary; horizontal red lines indicate conventional significance threshold.

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Figure 8

Trial sequential analysis: Composite MACE at long‐term follow‐up (≥ 12 months). TSMB = trial sequential monitoring boundary; horizontal red lines indicate conventional significance threshold.

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$Trial sequential analysis: Left ventricular ejection fraction measured by MRI at long‐term follow‐up (≥ 12 months). TSMB = trial sequential monitoring boundary; horizontal red lines indicate conventional significance threshold.$

Figure 9

Trial sequential analysis: Left ventricular ejection fraction measured by MRI at long‐term follow‐up (≥ 12 months). TSMB = trial sequential monitoring boundary; horizontal red lines indicate conventional significance threshold.

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Analysis 1.1

Comparison 1 Cells versus no cells, Outcome 1 Mortality (all‐cause).

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Analysis 1.2

Comparison 1 Cells versus no cells, Outcome 2 Non‐fatal myocardial infarction.

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Analysis 1.3

Comparison 1 Cells versus no cells, Outcome 3 Rehospitalisation due to heart failure.

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Analysis 1.4

Comparison 1 Cells versus no cells, Outcome 4 Arrhythmias.

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Analysis 1.5

Comparison 1 Cells versus no cells, Outcome 5 Composite MACE.

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Analysis 1.6

Comparison 1 Cells versus no cells, Outcome 6 MLHFQ: short term follow‐up (< 12 months).

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Analysis 1.7

Comparison 1 Cells versus no cells, Outcome 7 MLHFQ: long term follow‐up (≥ 12 months).

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Analysis 1.8

Comparison 1 Cells versus no cells, Outcome 8 Seattle Angina Questionnaire: short term follow‐up (< 12 months).

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Analysis 1.9

Comparison 1 Cells versus no cells, Outcome 9 Angina episodes per week: short term follow‐up (< 12 months).

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Analysis 1.10

Comparison 1 Cells versus no cells, Outcome 10 NYHA classification: short‐term follow‐up (< 12 months).

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Analysis 1.11

Comparison 1 Cells versus no cells, Outcome 11 NYHA classification: long term follow‐up (≥ 12 months).

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Analysis 1.12

Comparison 1 Cells versus no cells, Outcome 12 CCS class: short term follow‐up (< 12 months).

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Analysis 1.13

Comparison 1 Cells versus no cells, Outcome 13 CCS class: long term follow‐up (≥ 12 months).

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Analysis 1.14

Comparison 1 Cells versus no cells, Outcome 14 Exercise capacity: short term follow‐up (< 12 months).

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Analysis 1.15

Comparison 1 Cells versus no cells, Outcome 15 Exercise capacity: long term follow‐up (≥ 12 months).

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Analysis 1.16

Comparison 1 Cells versus no cells, Outcome 16 LVEF (%) measured by MRI: short term follow‐up (< 12 months).

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Analysis 1.17

Comparison 1 Cells versus no cells, Outcome 17 LVEF (%) measured by MRI: long term follow‐up (≥ 12 months).

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Analysis 1.18

Comparison 1 Cells versus no cells, Outcome 18 LVEF (%) measured by echocardiography: short term follow‐up (< 12 months).

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Analysis 1.19

Comparison 1 Cells versus no cells, Outcome 19 LVEF (%) measured by echocardiography: long term follow‐up (≥ 12 months).

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Analysis 1.20

Comparison 1 Cells versus no cells, Outcome 20 LVEF (%) measured by SPECT: short term follow‐up (< 12 months).

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Analysis 1.21

Comparison 1 Cells versus no cells, Outcome 21 LVEF (%) measured by SPECT: long term follow‐up (≥ 12 months).

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Analysis 1.22

Comparison 1 Cells versus no cells, Outcome 22 LVEF (%) measured by LV angiography: short term follow‐up (< 12 months).

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Analysis 1.23

Comparison 1 Cells versus no cells, Outcome 23 LVEF (%) measured by LV angiography: long term follow‐up (≥ 12 months).

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Analysis 2.1

Comparison 2 Cell dose: subgroup analysis, Outcome 1 Mortality (all‐cause): short term follow‐up (< 12 months).

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Analysis 2.2

Comparison 2 Cell dose: subgroup analysis, Outcome 2 Mortality (all‐cause): long term follow‐up (≥ 12 months).

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Analysis 2.3

Comparison 2 Cell dose: subgroup analysis, Outcome 3 NYHA classification: short term follow‐up (< 12 months).

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Analysis 2.4

Comparison 2 Cell dose: subgroup analysis, Outcome 4 CCS class: short term follow‐up (< 12 months).

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Analysis 2.5

Comparison 2 Cell dose: subgroup analysis, Outcome 5 Exercise capacity: short term follow‐up (< 12 months).

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Analysis 2.6

Comparison 2 Cell dose: subgroup analysis, Outcome 6 LVEF (%) measured by MRI: short term follow‐up (< 12 months).

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Analysis 3.1

Comparison 3 Baseline cardiac function: subgroup analysis, Outcome 1 Mortality (all‐cause): short term follow‐up (< 12 months).

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Analysis 3.2

Comparison 3 Baseline cardiac function: subgroup analysis, Outcome 2 Mortality (all‐cause): long term follow‐up (≥ 12 months).

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Analysis 3.3

Comparison 3 Baseline cardiac function: subgroup analysis, Outcome 3 NYHA classification: short term follow‐up (< 12 months).

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Analysis 3.4

Comparison 3 Baseline cardiac function: subgroup analysis, Outcome 4 NYHA classification: long term follow‐up (≥ 12 months).

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Analysis 3.5

Comparison 3 Baseline cardiac function: subgroup analysis, Outcome 5 CCS class: short term follow‐up (< 12 months).

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Analysis 3.6

Comparison 3 Baseline cardiac function: subgroup analysis, Outcome 6 Exercise capacity: short term follow‐up (< 12 months).

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Analysis 3.7

Comparison 3 Baseline cardiac function: subgroup analysis, Outcome 7 LVEF (%) measured by MRI: short term follow‐up (< 12 months).

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Analysis 4.1

Comparison 4 Route of cell administration: subgroup analysis, Outcome 1 Mortality (all‐cause): short term follow‐up (< 12 months).

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Analysis 4.2

Comparison 4 Route of cell administration: subgroup analysis, Outcome 2 Mortality (all‐cause): long term follow‐up (≥ 12 months).

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Analysis 4.3

Comparison 4 Route of cell administration: subgroup analysis, Outcome 3 NYHA classification: short term follow‐up (< 12 months).

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Analysis 4.4

Comparison 4 Route of cell administration: subgroup analysis, Outcome 4 NYHA classification: long term follow‐up (≥ 12 months).

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Analysis 4.5

Comparison 4 Route of cell administration: subgroup analysis, Outcome 5 CCS class: short term follow‐up (< 12 months).

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Analysis 4.6

Comparison 4 Route of cell administration: subgroup analysis, Outcome 6 Exercise capacity: short term follow‐up (< 12 months).

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Analysis 4.7

Comparison 4 Route of cell administration: subgroup analysis, Outcome 7 LVEF (%) measured by MRI: short term follow‐up (< 12 months).

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Analysis 5.1

Comparison 5 Cell type: subgroup analysis, Outcome 1 Mortality (all‐cause): short term follow‐up (< 12 months).

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Analysis 5.2

Comparison 5 Cell type: subgroup analysis, Outcome 2 Mortality (all‐cause): long term follow‐up (≥ 12 months).

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Analysis 5.3

Comparison 5 Cell type: subgroup analysis, Outcome 3 NYHA classification: short term follow‐up (< 12 months).

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Analysis 5.4

Comparison 5 Cell type: subgroup analysis, Outcome 4 CCS class: short term follow‐up (< 12 months).

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Analysis 6.1

Comparison 6 Participant diagnosis: subgroup analysis, Outcome 1 Mortality (all‐cause): short term follow‐up (< 12 months).

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Analysis 6.2

Comparison 6 Participant diagnosis: subgroup analysis, Outcome 2 Mortality (all‐cause): long term follow‐up (≥ 12 months).

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Analysis 6.3

Comparison 6 Participant diagnosis: subgroup analysis, Outcome 3 NYHA classification: short term follow‐up (< 12 months).

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Analysis 6.4

Comparison 6 Participant diagnosis: subgroup analysis, Outcome 4 NYHA classification: long term follow‐up (≥ 12 months).

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Analysis 6.5

Comparison 6 Participant diagnosis: subgroup analysis, Outcome 5 CCS class: short term follow‐up (< 12 months).

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Analysis 6.6

Comparison 6 Participant diagnosis: subgroup analysis, Outcome 6 Exercise capacity: short term follow‐up (< 12 months).

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Analysis 6.7

Comparison 6 Participant diagnosis: subgroup analysis, Outcome 7 LVEF (%) measured by MRI: short term follow‐up (< 12 months).

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Analysis 7.1

Comparison 7 Co‐interventions: subgroup analysis, Outcome 1 Mortality (all‐cause): short term follow‐up (< 12 months).

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Analysis 7.2

Comparison 7 Co‐interventions: subgroup analysis, Outcome 2 Mortality (all‐cause): long term follow‐up (≥ 12 months).

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Analysis 7.3

Comparison 7 Co‐interventions: subgroup analysis, Outcome 3 NYHA classification: short term follow‐up (< 12 months).

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Analysis 7.4

Comparison 7 Co‐interventions: subgroup analysis, Outcome 4 LVEF (%) measured by MRI: short term follow‐up (< 12 months).

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Analysis 8.1

Comparison 8 Sensitivity analysis: excluding studies with high/unclear risk of selection bias, Outcome 1 Mortality (all‐cause).

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Analysis 8.2

Comparison 8 Sensitivity analysis: excluding studies with high/unclear risk of selection bias, Outcome 2 Non‐fatal myocardial infarction.

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Analysis 8.3

Comparison 8 Sensitivity analysis: excluding studies with high/unclear risk of selection bias, Outcome 3 Rehospitalisation due to heart failure.

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Analysis 8.4

Comparison 8 Sensitivity analysis: excluding studies with high/unclear risk of selection bias, Outcome 4 Arrhythmias.

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Analysis 8.5

Comparison 8 Sensitivity analysis: excluding studies with high/unclear risk of selection bias, Outcome 5 Composite MACE.

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Analysis 8.6

Comparison 8 Sensitivity analysis: excluding studies with high/unclear risk of selection bias, Outcome 6 NYHA classification: short term follow‐up (< 12 months).

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Analysis 8.7

Comparison 8 Sensitivity analysis: excluding studies with high/unclear risk of selection bias, Outcome 7 NYHA classification: long term follow‐up (≥ 12 months).

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Analysis 8.8

Comparison 8 Sensitivity analysis: excluding studies with high/unclear risk of selection bias, Outcome 8 LVEF (%) measured by MRI: short term follow‐up (< 12 months).

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Analysis 8.9

Comparison 8 Sensitivity analysis: excluding studies with high/unclear risk of selection bias, Outcome 9 LVEF (%) measured by MRI: long term follow‐up (≥ 12 months).

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Analysis 9.1

Comparison 9 Sensitivity analysis: excluding studies with high/unclear risk of performance bias, Outcome 1 Mortality (all‐cause).

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Analysis 10.1

Comparison 10 Sensitivity analysis: excluding studies with high/unclear risk of attrition bias, Outcome 1 Mortality (all‐cause).

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Summary of findings for the main comparison. Bone marrow‐derived cell therapy for people with chronic ischaemic heart disease and congestive heart failure

Bone marrow‐derived cell therapy for people with chronic ischaemic heart disease and congestive heart failure
Patient or population: people with chronic ischaemic heart disease and congestive heart failure Settings: hospitalisation Intervention: bone marrow‐derived cell therapy Comparison: no cell therapy
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)^¶	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	No cell therapy	Bone marrow‐derived cell therapy
Mortality (all cause) Long‐term follow‐up (≥ 12 months)	102 per 1000	43 per 1000 (21 to 89)	RR 0.42 (0.21 to 0.87)	491 (9 studies)	⊕⊕⊝⊝ low^1,2	The required information size of 1899 participants to detect a RRR of 35% has not been reached.
Periprocedural adverse events	See comment	See comment	Not estimable	1695 (34 studies)	See comment	Adverse events occurring during the mapping or cell/placebo injection procedure included ventricular tachycardia (7), ventricular fibrillation (1), atrial fibrillation (1), transient complete heart block (1), transient pulmonary oedema (3), thrombus on mapping catheter tip (1), visual disturbances (2), myocardial perforation (2), limited retrograde catheter‐related dissection of the abdominal aorta (1).
Non‐fatal myocardial infarction Long‐term follow‐up (≥ 12 months)	83 per 1000	31 per 1000 (12 to 80)	RR 0.38 (0.15 to 0.97)	345 (5 studies)	⊕⊕⊝⊝ low^2,3	The required information size of 2383 participants to detect a RRR of 35% has not been reached.
Rehospitalisation due to heart failure Long‐term follow‐up (≥ 12 months)	155 per 1000	98 per 1000 (56 to 169)	RR 0.63 (0.36 to 1.09)	375 (6 studies)	⊕⊕⊝⊝ low^2,4	The required information size of 1193 participants to detect a RRR of 35% has not been reached.
Arrhythmias Long‐term follow‐up (≥ 12 months)	333 per 1000	140 per 1000 (60 to 330)	RR 0.42 (0.18 to 0.99)	82 (1 study)	⊕⊕⊝⊝ low^5,6	The required information size of 461 participants to detect a RRR of 35% has not been reached.
Composite MACE Long‐term follow‐up (≥ 12 months)	350 per 1000	224 per 1000 (133 to 378)	RR 0.64 (0.38 to 1.08)	141 (3 studies)	⊕⊕⊝⊝ low^7,8	The required information size of 431 participants to detect a RRR of 35% has not been reached.
LVEF (%) measured by MRI Long‐term follow‐up (≥ 12 months)	‐	The mean LVEF (%) measured by MRI in the intervention groups was 1.6 lower (8.7 lower to 5.5 higher).	‐	25 (1 study)	⊕⊕⊝⊝ low^6,7	The required information size of 322 participants to detect a mean difference of 4% has not been reached.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ^¶Only studies with a low risk of selection bias are included. CI: confidence interval; LVEF: left ventricular ejection fraction; MACE: major adverse clinical events; MD: mean difference; MRI: magnetic resonance imaging; NYHA: New York Heart Assocation; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio; RRR: relative risk reduction
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Six trials received full or partial commercial funding, which could have resulted in a biased assessment of the intervention effect and were therefore deemed to have a high risk of bias. One trial was not blinded (high risk of performance bias) and had a high risk of attrition bias. ²The number of observed events was low, leading to imprecision. ³Four studies received full or partial commercial funding with a high risk of bias. ⁴Five trials received full or partial commercial funding with a high risk of bias. ⁵The included trial received partial commercial funding with a high risk of bias. ⁶Only one trial with a low number of observed events was included in the analysis, leading to imprecision. ⁷All three included trials received partial commercial funding with a high risk of bias. ⁸The number of included studies was low with a low number of observed events, leading to imprecision.

Summary of findings for the main comparison. Bone marrow‐derived cell therapy for people with chronic ischaemic heart disease and congestive heart failure

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Table 1. Characteristics of study participants

Study ID	Country of study	Patient population	Mean (SD) age of participants (years)	% Male	No. randomised participants receiving intervention	No. randomised participants receiving comparator	Mean duration of follow‐up
Ang 2008	UK	CIHD (> 1 chronic myocardial scar; elective CABG)	BMMNC‐IM: 64.7 (8.7) BMMNC‐IC: 62.1 (8.7) Controls: 61.3 (8.3)	BMMNC‐IM: 71.4% BMMNC‐IC: 90.5% Controls: 90.0%	42 (21 IM, 21 IC)	21	6 months
Assmus 2006	Germany	CIHD (MI > 3 months; LV dysfunction)	BMMNC: 59 (12) CPC: 54 (12) Controls: 61 (9)	BMMNC: 89% CPC: 79% Controls: 100%	52 (28 MNC, 24 CPC)	23	3 months
Assmus 2013	Germany	CIHD (MI > 3 months; LVEF < 50%; NYHA class II or greater)	BMMNC‐LDSW: 65 (12) BMMNC‐HDSW: 58 (11) Controls‐LDSW: 60 (10) Controls‐HDSW: 63 (10)	BMMNC‐LDSW: 77% BMMNC‐HDSW: 86% Controls‐LDSW: 80% Controls‐HDSW: 90%	43 (22 LDSW, 21 HDSW)	39 (20 LDSW, 19 HDSW)	45.7 (17) months
Bartunek 2012	Belgium/ Serbia/ Switzerland	HF (LVEF 15% to 40%; ischaemic event > 2 months)	BM‐MSC: 55.3 (SE 10.4) Controls: 58.7 (SE 8.2)	BM‐MSC: 90.5% Controls: 86.7%	32	15	24 months
Chen 2006	China	CIHD (isolated, chronic LAD; LVEF < 40%)	BM‐MSC: 59.3 (6.8) Controls: 57.8 (7.2)	BM‐MSC: 88% Controls: 92%	24	24	12 months
Erbs 2005	Germany	CIHD (chronic total occlusion; myocardial ischaemia)	CPC: 63 (7) Controls: 61 (9)	CPC: 71% Controls: 86%	14	14	15 months
Hamshere 2015_IC	UK	HF (NYHA class II‐IV; no revascularisation options)	BMMNC: n/r Controls: n/r	BMMNC: n/r Controls: n/r	15	15	12 months
Hamshere 2015_IM	UK	HF (NYHA class II‐IV; no revascularisation options)	BMMNC: n/r Controls: n/r	BMMNC: n/r Controls: n/r	15	15	12 months
Heldman 2014_BMMNC	USA	CIHD (chronic MI; LV dysfunction)	BMMNC: 61.1 (8.4) Controls: 61.3 (9.0)	BMMNC: 89.5% Controls: 100%	22	10	12 months
Heldman 2014_BM‐MSC	USA	CIHD (chronic MI; LV dysfunction)	BM‐MSC: 57.1 (10.6) Controls: 60.0 (12.0)	BM‐MSC: 94.7% Controls: 90.9%	22	11	12 months
Hendrikx 2006	Belgium	CIHD (transmural MI; LV dysfunction; elective CABG)	BMMNC: 63.2 (8.5) Controls: 66.8 (9.2)	BMMNC: 100% Controls: 70%	11	12	4 months
Honold 2012	Germany	CIHD (MI > 3 months; LV regional wall motion abnormality)	CPC: 53.4 (12.3) Controls: 58.8 (7.3)	CPC: 82% Controls: 100%	23	10	60 months
Hu 2011	China	HF (MI > 3 months; LVEF < 30%; elective CABG)	BMMNC: 56.6 (9.7) Controls: 58.3 (8.9)	BMMNC: 88% Controls: 96%	31	29	12 months
Jimenez‐Quevedo 2011	Spain	Refractory angina (CCS class II‐IV)	CD133+: median 70.0 Controls: median 58.2	CD133+: 78.9% Controls: 100%	19	9	6 months
Losordo 2007	USA	Refractory angina (CCS class III‐IV)	CD34+/controls pooled: 62.4 (range 48 to 84)	CD34+/controls pooled: 80%	18 (6 LD, 6 MD 6, HD)	6	6 months
Losordo 2011	USA	Refractory angina (CCS class III‐IV)	CD34+/LD: 61.3 (9.1) CD34+/HD: 59.8 (9.2) Controls: 61.8 (8.5)	CD34+/LD: 83.6% CD34+/HD: 87.5% Controls: 89.3%	112 (56 LD, 56 HD)	56	12 months
Mathiasen 2015	Denmark	HF (NYHA class II‐III; LVEF < 45%; no revascularisation options)	BM‐MSC: 66.1 (7.7) Controls: 64.2 (10.6)	BM‐MSC: 90% Controls: 70%	40	20	6 months
Mozid 2014_IC	UK	HF (NYHA class II‐IV; no revascularisation options)	BMMNC/controls pooled (16 participants): 70 (10)	BMMNC/controls pooled (16 participants): 94%	14	2	6 months
Mozid 2014_IM	UK	HF (NYHA class II‐IV; no revascularisation options)	BMMNC/controls pooled (18 participants): 64 (9)	BMMNC/controls pooled (18 participants): 100%	10	8	6 months
Nasseri 2012	Germany	HF (LVEF < 35%; elective CABG)	CD133+: 61.9 (7.3) Controls: 62.7 (10.6)	CD133+: 93% Controls: 97%	30	30	6 months
Patel 2005	Argentina	HF (LVEF < 35%; NYHA class III‐IV; elective CABG)	CD34+: 64.8 (7.1) Controls: 63.6 (5.2)	CD34+: 80% Controls: 80%	25	25	10 years
Patel 2015	USA/Germany/India	HF (LVEF < 40%; NYHA class III‐IV)	BMAC: 58.5 (12.7) Controls: 52.7 (8.5)	BMAC: 91.7% Controls: 100%	24	6	12 months
Patila 2014	Finland	HF (LVEF 15% to 40%; NYHA class II‐IV; elective CABG)	BMMNC: median 65 (range 57 to 73) Controls: median 64 (range 58 to 70)	BMMNC: 94.7% Controls: 95.0%	20	19	12 months
Perin 2011	USA	HF (angina/HF symptoms; chronic CAD; LVEF < 40%; no revascularisation options)	BMMNC: 56.3 (8.6) Controls: 60.5 (6.4)	BMMNC: 50% Controls: 80%	20	10	6 months
Perin 2012a	USA	HF (CCS class II‐IV or NYHA class II‐III, or both; LVEF < 45%; no revascularisation options)	BMMNC: 64.0 (10.9) Controls: 62.3 (8.3)	BMMNC: 86.9% Controls: 93.7%	61	31	6 months
Perin 2012b	USA	HF (CCS class II‐IV or NYHA class II‐III, or both; LVEF < 45%; no revascularisation options)	ALDH+: 58.2 (6.1) Controls: 57.8 (5.5)	ALDH+: 90% Controls: 80%	10	10	6 months
Pokushalov 2010	Russia	HF (LVEF < 35%; no revascularisation options)	BMMNC: 61 (9) Controls: 62 (5)	BMMNC: 87% Controls: 85%	55	54	12 months
Santoso 2014	Indonesia/China	HF (NYHA class III‐IV; LVEF < 40%; no revascularisation options)	BMMNC: 58 (5.9) Controls: 60 (5.6)	BMMNC: 95% Controls: 100%	19	9	6 months
Trifunovic 2015	Serbia	CIHD (MI < 30 days; LVEF < 40%; NYHA class III‐IV; elective CABG)	BMMNC: 53.8 (10.1) Controls: 60.0 (6.8)	BMMNC: 93.3% Controls: 93.3%	15	15	Median 5 years (IQR 2.5 to 7.5)
Tse 2007	China/Australia	Refractory angina (CCS class III‐IV)	BMMNC: 65.2 (8.3) Controls: 68.9 (6.3)	BMMNC: 79% Controls: 88%	19	9	6 months
Turan 2011	Germany	CIHD (MI > 3 months; LV dysfunction)	BMMNC: 62 (10) Controls: 60 (9)	BMMNC: 52.6% Controls: 55.6%	38	18	12 months
Van Ramshorst 2009	The Netherlands	Refractory angina (CCS class II‐IV)	BMMNC: 64 (8) Controls: 62 (9)	BMMNC: 92% Controls: 80%	25	25	6 months
Wang 2009	China	Refractory angina (MI > 1 month)	CD34+: 60.6 (n/r) Controls: 60.0 (n/r)	CD34+: 56.3% Controls: 63.3%	16	16	6 months
Wang 2010	China	Refractory angina (CCS class III‐IV)	CD34+: range 42 to 80 Controls: range 43 to 80	CD34+: 51.8% Controls: 50.0%	56	56	6 months
Wang 2014	China	CIHD (LVEF < 35%)	CD133+: n/r Controls: n/r	CD133+: n/r Controls: n/r	35	35	6 months
Wang 2015	China	CIHD (multivessel disease; MI > 4 weeks; elective CABG)	BMMNC: 61.4 (7.5) Controls: 62.9 (6.9)	BMMNC: 82% Controls: 78%	45	45	6 months
Yao 2008	China	CIHD (MI > 6 months)	BMMNC: 54.8 (11.5) Controls: 56.3 (7.9)	BMMNC: 96% Controls: 96%	24	23	6 months
Zhao 2008	China	HF (LVEF < 40%; elective CABG)	BMMNC: 60.3 (10.4) Controls: 59.1 (15.7)	BMMNC: 83.3% Controls: 83.3%	18	18	6 months
ALDH: aldehyde dehydrogenase BMAC: bone marrow aspirate concentrate BMMNC: bone marrow mononuclear cells BM‐MSC: bone marrow‐derived mesenchymal stem cells CABG: coronary artery bypass grafting CCS: Canadian Cardiovascular Society CIHD: chronic ischaemic heart disease CPC: circulating progenitor cells EF: ejection fraction HD: high dose HDSW: high dose shockwave HF: heart failure IC: intracoronary IM: intramyocardial IQR: interquartile range LAD: left ventricular assist device LD: low dose LDSW: low dose shockwave LV: left ventricular LVEF: left ventricular ejection fraction MD: medium dose MI: myocardial infarction MNC: mononuclear cells n/r: not reported NYHA: New York Heart Association SD: standard deviation SE: standard error SW: shockwave

Table 1. Characteristics of study participants

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Table 2. Characteristics of study interventions

Study ID	Co‐intervention	Intervention given by:	Route of cell administration	Intervention cell type	How are cells obtained?	What were they resuspended in?	Dose administered?	Comparator arm (placebo or control)
Ang 2008	CABG	Cardiothoracic surgeon	IC or IM	BMMNC	BM aspiration (**)	Autologous serum	IM: 84 (56) million cells IC: 115 (73) million cells	No additional therapy (control)
Assmus 2006	Standard medical therapy	Cardiologist	IC	BMMNC or CPC	BM aspiration (**) for BMMNC. Vein puncture, mononuclear cell isolation by gradient centrifugation and culture for 3 days for CPC	n/r	BMMNC: 205 (110) million cells CPC: 22 (11) million cells	No additional therapy (control)
Assmus 2013	Shockwave	Cardiologist	IC	BMMNC	BM aspiration (**)	X‐VIVO 10 medium and autologous serum	HDSW: 123 (69) million cells LDSW: 150 (77) million cells	Placebo (10 mL X‐VIVO 10 medium and autologous serum)
Bartunek 2012	Standard medical therapy	Cardiologist	IC	BM‐MSC (cardiopoietic cells)	BM aspiration (**), culture for 6 days and exposure to cardiopoietic factors	Preservation solution (no details)	733 (range 605 to 1168) million cells	No additional therapy (control)
Chen 2006	Standard medical therapy	Cardiologist	IC	BM‐MSC	BM aspiration (**), culture for 7 days to select MSC	Heparinised saline	5 million cells	No additional therapy (control)
Erbs 2005	G‐CSF	Cardiologist	IC	CPC	G‐CSF infusion for 4 days prior to vein puncture, mononuclear cell isolation by gradient centrifugation and culture for 3 days for CPC	Saline and 10% autologous serum	69 (14) million cells	Placebo (cell‐free serum solution)
Hamshere 2015_IC	G‐CSF	Cardiologist	IC	BMMNC	G‐CSF infusion for 5 days and BM aspiration (**)	Autologous serum	n/r	Placebo (10 mL autologous serum)
Hamshere 2015_IM	G‐CSF	Cardiologist	IM	BMMNC	G‐CSF infusion for 5 days and BM aspiration (**)	Autologous serum	n/r	Placebo (2 mL autologous serum)
Heldman 2014_BMMNC	Standard medical therapy	Cardiologist	IM	BMMNC	BM aspiration (**)	n/r	n/r	Placebo (vehicle medium)
Heldman 2014_BM‐MSC	Standard medical therapy	Cardiologist	IM	BM‐MSC	BM aspiration (**), culture to select MSC	n/r	n/r	Placebo (vehicle medium)
Hendrikx 2006	CABG	Cardiothoracic surgeon	IM	BMMNC	BM aspiration (**)	Heparinised saline	60 (31) million cells	Placebo (heparinised saline)
Honold 2012	G‐CSF	Cardiologist	IC	CPC	G‐CSF infusion for 5 days prior to vein puncture, mononuclear cell isolation by gradient centrifugation and culture for 4 days for CPC	n/r	29 (12) million cells	No additional therapy (control)
Hu 2011	CABG	Cardiothoracic surgeon	IC	BMMNC	BM aspiration (**)	Saline solution and 20% autologous serum	132 (107) million cells	Placebo (8 mL saline; 2 mL autologous serum)
Jimenez‐Quevedo 2011	G‐CSF	Cardiologist	IM	CD133+	G‐CSF infusion for 5 days prior to leukapheresis, mononuclear cell isolation by gradient centrifugation immunomagnetic selection to isolate CD133+ cells	Normal saline solution	20 to 30 million cells	No additional therapy (control)
Losordo 2007	G‐CSF	Cardiologist	IM	CD34+	G‐CSF infusion for 5 days prior to leukapheresis, mononuclear cell isolation by gradient centrifugation immunomagnetic selection to isolate CD34+ cells	Saline solution and 5% autologous serum	LD: 0.05 million cells MD: 0.1 million cells HD: 0.5 million cells	Placebo (0.9% sodium chloride; 5% autologous plasma)
Losordo 2011	G‐CSF	Cardiologist	IM	CD34+	G‐CSF infusion for 5 days prior to leukapheresis, mononuclear cell isolation by gradient centrifugation immunomagnetic selection to isolate CD34+ cells	Saline solution and 5% autologous serum	LD: 0.1 million cells HD: 0.5 million cells	Placebo (0.9% sodium chloride; 5% autologous plasma)
Mathiasen 2015	Standard medical therapy	Cardiologist	IM	BM‐MSC	BM aspiration (**), culture for 14 to 35 days to select MSC	Phosphate buffered saline with a drop of the participant’s blood	77.5 (68) million cells	Placebo (phosphate buffered saline mixed with drop of participant’s blood)
Mozid 2014_IC	G‐CSF	Cardiologist	IC	BMMNC	G‐CSF infusion for 5 days and BM aspiration (**)	Autologous serum	86 (110) million cells	Placebo (10 mL autologous serum)
Mozid 2014_IM	G‐CSF	Cardiologist	IM	BMMNC	G‐CSF infusion for 5 days and BM aspiration (**)	Autologous serum	52 (53) million cells	Placebo (2 mL autologous serum)
Nasseri 2012	CABG	Cardiothoracic surgeon	IM	CD133+	BM aspiration (**), immunomagnetic selection to isolate CD133+ cells	Sodium chloride and 10% autologous serum	Median 5.1 million cells	Placebo (isotonic saline solution; 10% autologous serum)
Patel 2005	CABG	Cardiothoracic surgeon	IM	CD34+	BM aspiration (**), immunomagnetic selection to isolate CD34+ cells	Heparinised saline and autologous serum	Median 22 million cells	No additional therapy (control)
Patel 2015	Standard medical therapy	Cardiologist	IC	BMAC	BM aspiration (**) and concentration	Autologous serum	3700 (900) million cells	No additional therapy (control)
Patila 2014	CABG	Cardiothoracic surgeon	IM	BMMNC	BM aspiration (**)	Medium 199 containing albumin, heparin	Median 840 (range 52 to 135) million cells	Placebo (vehicle medium)
Perin 2011	Standard medical therapy	Cardiologist	IM	BMMNC	BM aspiration (**)	Saline containing 5% human serum albumin	2 million cells	No additional therapy (control)
Perin 2012a	Standard medical therapy	Cardiologist	IM	BMMNC	BM aspiration (**)	Saline containing 5% human serum albumin	100 million cells	Placebo (cell‐free suspension in same volume)
Perin 2012b	Standard medical therapy	Cardiologist	IM	ALDH+	BM aspiration (**) and cell sorting	Pharmaceutical grade human serum albumin	2.4 (1.3) million cells	Placebo (5% pharmaceutical serum albumin)
Pokushalov 2010	Standard medical therapy	Cardiologist	IM	BMMNC	BM aspiration (**)	Heparinised saline	41 (16) million cells	No additional therapy (control)
Santoso 2014	Standard medical therapy	Cardiologist	IM	BMMNC	BM aspiration (**)	Phosphate buffered saline with 10% autologous plasma	n/r	Placebo (phosphate buffered saline; 10% autologous plasma)
Trifunovic 2015	CABG	Cardiothoracic surgeon	IM	BMMNC	BM aspiration (**)	n/r	70.7 (32.4) million cells	No additional therapy (control)
Tse 2007	Standard medical therapy	Cardiologist	IM	BMMNC	BM aspiration (**)	Phosphate buffered saline with 10% autologous plasma	15 million cells	Placebo (8 ‐ 12 x 0.1 mL phosphate buffered saline with 10% autologous serum)
Turan 2011	Standard medical therapy	Cardiologist	IC	BMMNC	BM aspiration (**)	n/r	99 (25) million cells	No additional therapy (control)
Van Ramshorst 2009	Standard medical therapy	Cardiologist	IM	BMMNC	BM aspiration (**)	Phosphate buffered saline with 0.5% human serum albumin	98 (6) million cells	Placebo (0.9% sodium chloride; 0.5% human serum albumin)
Wang 2009	Standard medical therapy	Cardiologist	IC	CD34+	BM aspiration (**), immunomagnetic selection to isolate CD34+ cells	Normal saline	Range 1.0 to 6.1 million cells	No additional therapy (control)
Wang 2010	Standard medical therapy	Cardiologist	IC	CD34+	BM aspiration (**), immunomagnetic selection to isolate CD34+ cells	Saline and human serum albumin	56 (23) million cells	Placebo (saline; human serum albumin)
Wang 2014	Standard medical therapy	Cardiologist	IM	CD133+	n/r	n/r	n/r	Placebo (n/r)
Wang 2015	CABG	Cardiothoracic surgeon	IM	BMMNC	BM aspiration (**)	Heparinised saline	521 (44) million cells	Placebo (saline solution)
Yao 2008	Standard medical therapy	Cardiologist	IC	BMMNC	BM aspiration (**)	Heparinised saline	72 million cells	Placebo (0.9% sodium chloride containing heparin)
Zhao 2008	CABG	Cardiothoracic surgeon	IM	BMMNC	BM aspiration (**)	Heparinised saline	659 (512) million cells	Placebo (saline)
**BM aspiration ‐ bone marrow aspiration and isolation of bone marrow mononuclear cells by gradient centrifugation. ALDH: aldehyde dehydrogenase BM: bone marrow BMAC: bone marrow aspirate concentrate BMMNC: bone marrow mononuclear cells BM‐MSC: bone marrow‐derived mesenchymal stem cells CABG: coronary artery bypass grafting CPC: circulating progenitor cells G‐CSF: granulocyte colony‐stimulating factor HD: high dose HDSW: high dose shockwave IC: intracoronary IM: intramyocardial LD: low dose LDSW: low dose shockwave MD: medium dose MSC: mesenchymal stem cells n/r: not reported SW: shockwave

Table 2. Characteristics of study interventions

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Table 3. Summary of outcome reporting

Study ID

Primary outcomes

Secondary outcomes

All‐cause mortality

Non‐fatal MI

Hospital readmission for HF

Composite MACE^a

Arrhythmias

NYHA class

CCS class

Angina frequency

Exercise tolerance

Quality of life

LVEF^b

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

PR*

Total (%) analysed^c

1637

(85.8)

1010

(53.0)

881

(46.2)

461 (24.2)

482

(25.3)

495

(26.0)

288 (15.1)

201

(10.5)

959

(50.3)

363

(19.0)

741

(38.9)

346

(18.1)

608

(31.9)

142 (7.4)

428

(22.4)

82 (4.3)^d

535

(28.1)

227

(11.9)

197

(10.3)^e

151

(7.9)^e

439

(23.0)^f

110

(5.8)^f

CCS: Canadian Cardiovascular Society; FR: full reporting, outcome included in analysis; HF: heart failure; LT: long‐term follow‐up (≥ 12 months); LVEF: left ventricular ejection fraction; MACE: major adverse clinical events; MI: myocardial infarction; NR: outcome not reported; NYHA: New York Heart Association; PR: partial reporting with insufficient information on outcome reported for inclusion in analysis; PR*: no incidence of outcome observed; ST: short‐term follow‐up (< 12 months)

^aComposite measure of mortality, reinfarction, or rehospitalisation for heart failure.
^bLVEF measured by any method.
^cTotal number of participants included in meta‐analysis of outcome (% of total number of participants from all included studies).
^dNo meta‐analysis was performed, as only one study reported values suitable for inclusion.
^eMinnesota Living with Heart Failure Questionnaire.
^fTotal number analysed given for LVEF measured by magnetic resonance imaging.

Table 3. Summary of outcome reporting

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Table 4. Clinical (dichotomous) outcomes

Study ID	Number of analysed participants		All‐cause mortality events			Non‐fatal MI events			Hospital readmission for HF			Composite MACE^a			Arrhythmia events
Study ID	Cells	No cells	Cells	No cells	Length of follow‐up	Cells	No cells	Length of follow‐up	Cells	No cells	Length of follow‐up	Cells	No cells	Length of follow‐up	Cells	No cells	Length of follow‐up
Ang 2008	42	19	1	1	6 mths^a	0	0	6 mths	n/r	n/r	n/r	n/r	n/r	n/r	0	0	6 mths
Assmus 2006	52	23	0	1	3 mths	1	0	3 mths	1	1	3 mths	1	1	3 mths	0	1	3 mths
Assmus 2013	43	39	6	8	45.7 (17) mths	1	4	45.7 (17) mths	8	13	45.7 (17) mths	14	19	45.7 (17) mths	6	13	45.7 (17) mths
Bartunek 2012	21	15	1	2	24 mths	n/r	n/r	n/r	6	4	24 mths	n/r	n/r	n/r	n/r	n/r	n/r
Chen 2006	22	23	2	4	12 mths	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	0	0	6 mths
Erbs 2005	13	12	0	1	15 mths	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r
Hamshere 2015_IC	15	15	0	0	12 mths	1	0	12 mths	0	0	12 mths	1	0	12 mths	1	1	12 mths
Hamshere 2015_IM	15	15	0	0	12 mths	0	0	12 mths	1	1	12 mths	1	1	12 mths	0	1	12 mths
Heldman 2014_BMMNC	19	10	0	0	12 mths	0	0	12 mths	0	1	12 mths	0	1	12 mths	n/r	n/r	n/r
Heldman 2014_BM‐MSC	19	11	1	1	12 mths	0	0	12 mths	0	0	12 mths	1	1	12 mths	n/r	n/r	n/r
Hendrikx 2006	11	12	1	1	4 mths	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r
Honold 2012	23	9	0	1	60 mths	1	2	60 mths	0	2	60 mths	n/r	n/r	n/r	n/r	n/r	n/r
Hu 2011	31	29	1	2	12 mths	0	0	6 mths	n/r	n/r	n/r	3	4	6 mths	1	0	12 mths
Jimenez‐Quevedo 2011	19	9	1	1	6 mths	0	0	6 mths	n/r	n/r	n/r	n/r	n/r	n/r	1	1	6 mths
Losordo 2007	18	6	0	0	12 mths	0	0	12 mths	n/r	n/r	n/r	n/r	n/r	n/r	0	1	12 mths
Losordo 2011	112	56	0	3	12 mths	6	7	12 mths	3	4	12 mths	n/r	n/r	n/r	n/r	n/r	n/r
Mathiasen 2015	40	20	1	1	6 mths	0	0	6 mths	6	2	6 mths	n/r	n/r	n/r	3	1	6 mths
Mozid 2014_IC	14	2	0	1	6 mths	0	0	6 mths	1	0	6 mths	1	1	6 mths	0	0	6 mths
Mozid 2014_IM	10	8	0	3	6 mths	0	0	6 mths	0	0	6 mths	0	3	6 mths	2	2	6 mths
Nasseri 2012	30	30	1	3	34 mths^b	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r
Patel 2005	25	25	3	10	10 yrs	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	0	0	6 mths
Patel 2015	22	6	5	2	12 mths	n/r	n/r	n/r	2	0	12 mths	n/r	n/r	n/r	0	0	12 mths
Patila 2014	13^c	17^c	0	0	Median 60 mths	0	0	Median 60 mths	1	1	Median 60 mths	n/r	n/r	n/r	n/r	n/r	n/r
Perin 2011	20	10	0	0	6 mths	0	0	6 mths	n/r	n/r	n/r	n/r	n/r	n/r	0	0	6 mths
Perin 2012a	61	31	1	0	6 mths	1	0	6 mths	3	5	6 mths	n/r	n/r	n/r	n/r	n/r	n/r
Perin 2012b	10	10	0	0	6 mths	1	0	6 mths	n/r	n/r	n/r	n/r	n/r	n/r	3	2	6 mths
Pokushalov 2010	55	54	6	21	12 mths	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	0	0	12 mths
Santoso 2014	19	9	0	2	23 (8) mths	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	1	1	6 mths
Trifunovic 2015	15	15	2	4	Median 5 yrs	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r
Tse 2007	19	9	0	1	19 (9) mths	0	1	3 mths	n/r	n/r	n/r	n/r	n/r	n/r	0	0	6 mths
Turan 2011	38	18	0	0	12 mths	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r
Van Ramshorst 2009	25	25	1	0	6 mths	0	0	6 mths	n/r	n/r	n/r	n/r	n/r	n/r	0	0	6 mths
Wang 2009	16	16	0	0	6 mths	0	0	6 mths	n/r	n/r	n/r	n/r	n/r	n/r	0	0	6 mths
Wang 2010	56	56	0	0	6 mths	0	0	6 mths	n/r	n/r	n/r	n/r	n/r	n/r	0	1	6 mths^d
Wang 2014	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r
Wang 2015	45	45	0	0	6 mths	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r	n/r
Yao 2008	24	23	0	0	6 mths	0	1	6 mths	1	2	6 mths	n/r	n/r	n/r	0	0	6 mths
Zhao 2008	18	18	2	0	6 mths	0	0	6 mths	n/r	n/r	n/r	n/r	n/r	n/r	1	0	6 mths
HF: heart failure; MACE: major adverse clinical events; MI: myocardial infarction; n/r: not reported ^aAng 2008: participants followed up for six months; mortality reported as “death within 30 days of treatment”. ^bNasseri 2012: deaths reported “beyond follow‐up period” occurred at 31 and 34 months. ^cPatila 2014: mortality rates reported in 20/19 participants at 12 months and 13/17 participants at 60 months. ^dWang 2010: values are for ventricular arrhythmia (atrial arrhythmia also reported but unclear whether any participant overlap).

Table 4. Clinical (dichotomous) outcomes

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Table 5. Periprocedural adverse events

Study ID	Periprocedural adverse events
Ang 2008	2 deaths (1 control, 1 intracoronary cell therapy) occurred within 30 days of treatment. Reasons were not given, but neither was considered to be related to cell therapy.
Assmus 2006	In‐hospital events: MI occurred in 1 CPC participant and ventricular arrhythmia detected during monitoring in 1 control participant.
Assmus 2013	n/r (only safety of shockwave procedure reported)
Bartunek 2012	In the cell therapy group, 1 participant had ventricular tachycardia during procedure which was resolved by cardioversion, and 1 participant had blurred vision after intervention (participant had pre‐existing ophthalmic migraines). Other reported adverse events (gastrointestinal, hepatobiliary, respiratory, thoracic, mediastinal, and peripheral vascular disorders) were not considered to be related to cell therapy.
Chen 2006	3 participants in cell therapy group experienced a transient episode of pulmonary oedema during the injection of stem cells. No sustained arrhythmias were monitored during the procedure.
Erbs 2005	1 cell therapy and 1 control participant reported headache, and 1 control participant developed fever during G‐CSF stimulation. G‐CSF resulted in comparable increases in serum C‐reactive protein levels and blood leukocyte count in both CPC and control groups (returned to baseline values within 4 days after G‐CSF). Neither G‐CSF injection nor intracoronary transplantation of CPC caused any elevation in troponin T levels.
Hamshere 2015_IC	n/r
Hamshere 2015_IM	n/r
Heldman 2014_BMMNC	No participant had significant postprocedural pericardial effusion. Small transient increases in CK‐MB and serum troponin I were observed. There were no treatment emergent serious adverse events among any of participants who received cell therapy.
Heldman 2014_BM‐MSC	No participant had significant postprocedural pericardial effusion. Small transient increases in CK‐MB and serum troponin I were observed. There were no treatment emergent serious adverse events among any of participants who received cell therapy.
Hendrikx 2006	1 cell therapy participant died on postoperative day 7 from a perforated oesophageal ulcer complicated by mediastinitis. 1 control participant died on the 5th postoperative day from multiorgan failure secondary to low cardiac output syndrome.
Honold 2012	Mild cephalgies and episodes of mild to moderate bone and muscular pain were reported during 5‐day course of G‐CSF. No participant developed chest pain episodes or clinical signs of decompensated HF. No novel ischaemia‐related ECG changes were observed during G‐CSF treatment and after intracoronary CPC infusion. Troponin T levels remained unchanged. Moreover, no specific G‐CSF‐mediated severe complications occurred. Intracoronary infusions were successfully performed without any procedural complications.
Hu 2011	2 participants (unclear which treatment arm) had neurological complications but recovered and were discharged. No participants had arrhythmia.
Jimenez‐Quevedo 2011	G‐CSF treatment was well tolerated, all participants presented bone pain as the only symptom. After cell injection, none of the participants had a significant rise in creatine phosphokinase, symptoms, ECG changes, or echocardiographic abnormalities.
Losordo 2007	13 participants reported transient increase in angina frequency after administration of G‐CSF. There were no cardiac enzyme elevations, MIs, acute coronary syndromes, or deaths. 1 participant in the placebo group developed ventricular tachycardia during the mapping procedure. No arrhythmias were detected by implantable cardioverter defibrillator, LifeVest, or Holter monitoring in any participant during or after the injection procedure.
Losordo 2011	Administration of G‐CSF was associated with bone pain (20.1%), angina (17.4%), CHF (2 participants), and 8 participants had troponin elevations consistent with non‐STEMI. In 1 participant a thrombus was observed on the mapping catheter tip as it was removed. 2 participants experienced an apparent myocardial perforation during the injection procedure (1 resulted in haemothorax, which was successfully treated; 1 resulted in cardiac tamponade; this participant died after unsuccessful pericardiocentesis procedure). Elevated troponin levels were observed in 28% of participants at some point during the mobilisation and injection period, all of which were minor and subclinical except for those mentioned above.
Mathiasen 2015	1 participant with a history of episodic ventricular tachycardia developed ventricular tachycardia during the NOGA mapping procedure. Another participant experienced double vision and dizziness during the injection procedure; cerebral‐CT afterwards was normal, but the incident was diagnosed as a minor stroke by the neurologist. 1 participant from the treatment group suffered a stroke 12 days after treatment.
Mozid 2014_IC	The most common side effects from G‑CSF were bone pain (22%) and low grade pyrexia (65%) (reported in all G‐CSF groups combined). Bleeding from the arterial access site did not differ significantly between the 2 intervention arms. All episodes were minor and resolved with conservative treatment within 24 h of the procedure. As expected, there were increases in troponin and creatine kinase levels postprocedure in both arms.
Mozid 2014_IM	The most common side effects from G‑CSF were bone pain (22%) and low grade pyrexia (65%) (reported in all G‐CSF groups combined). There were 3 cases of arrhythmia during the intramyocardial procedure that required treatment. Of these, 1 participant developed atrial fibrillation, which reverted to sinus rhythm within 24 h of the procedure. Another participant developed transient complete heart block periprocedure requiring temporary pacing only. The final participant suffered an episode of pulseless ventricular tachycardia following intramyocardial injection, which was successfully cardioverted with a single 200 J external defibrillation and remained haemodynamically stable afterwards. 1 participant died from suspected acute LV failure 6 days after discharge. Bleeding from the arterial access site did not differ significantly between the two intervention arms. All episodes were minor and resolved with conservative treatment within 24 h of the procedure. As expected, there were increases in troponin and creatine kinase levels postprocedure in both arms.
Nasseri 2012	2 participants in the placebo group died early postoperatively: 1 died on day 8 after developing Candida sepsis following LV failure despite intra‐aortic balloon pump and catecholamine treatment and mechanical assist device implantation, and 1 died on day 22 (reason not given).
Patel 2005	1 participant in the OPCAB plus stem cell therapy group had a haematoma at the bone marrow harvest site. There were no other adverse events in either group (i.e. neurologic, haematologic, vascular, death, or infection events). No participants had any postoperative arrhythmias.
Patel 2015	5 participants who received BMAC experienced “non‐serious adverse events possibly related to the procedure”. Procedure‐related complications included haematomas at the catheterisation site and elevated serum creatinine levels.
Patila 2014	There were no differences between treatment groups in participants’ haemodynamics, arterial blood gases, systemic vein oxygen level, blood glucose, acid–base balance, lactate, haemoglobin, body temperature, and diuresis, as well as medications needed. Perioperative measures are reported in detail in Lehtinen 2014.
Perin 2011	No perforations or arrhythmias were associated with cell injection procedures. Postprocedural transient left bundle‐branch block (resolved in 24 h) was seen in 1 treated and 1 control participant. 1 treated participant had non‐significant pericardial effusion. No sustained ventricular arrhythmias were observed by Holter monitoring in any participant. Transient fever but no sepsis occurred in 1 control participant.
Perin 2012a	1 participant experienced a limited retrograde catheter‐related dissection of the abdominal aorta (withdrawn from study). 1 participant experienced recurrent ventricular tachycardia with hypotension (and received only a small volume of cell product).
Perin 2012b	No major adverse clinical cardiac events were associated with the cell injection procedures, including no perforations. Electromechanical mapping–related ventricular tachycardia occurred in 2 control participants, and ventricular fibrillation occurred in 1 control participant. No deaths occurred, and HF was not exacerbated in any participant. Holter monitoring showed no sustained ventricular arrhythmia in any participant.
Pokushalov 2010	No periprocedural complications occurred in participants who received cell therapy. 2‐dimensional echocardiography did not reveal postprocedural pericardial effusion. Creatine kinase activity and peak troponin T level remained unaltered. No new periprocedural arrhythmias were recorded during 24 h of consecutive electrocardiographic monitoring. An implantable cardioverter defibrillator was implanted to 2 participants with ventricular tachycardia prior to cell injections.
Santoso 2014	There were no acute procedural‐related complications, including stroke, transient ischaemic attack, ECG changes, sustained ventricular or atrial arrhythmias, and elevation of CPK‐MB. There was also no echocardiographic evidence of pericardial effusion in any participant within the first 24 h of the procedure.
Trifunovic 2015	The early postoperative course was uneventful in both groups with no significant differences between them with regard to adverse side effects during hospital stay. There were no significant differences in cardiac‐specific enzymes activities after the operation or the number of atrial fibrillation episodes or appearance of pericardial effusion between the groups.
Tse 2007	There were no acute procedure‐related complications, including stroke, transient ischaemic attack, ECG changes, sustained ventricular or atrial arrhythmias, elevation of CPK‐MB, or echocardiographic evidence of pericardial effusion within the first 24 h after the procedure.
Turan 2011	There was no inflammatory response or myocardial reaction (white blood cell count, C‐reactive protein, CK, troponin) after cell therapy. There were no immediate pre‐ or postprocedure adverse complications, new electrocardiographic changes, or significant elevations in CK or troponin, and no inflammatory response was observed in participants with bone marrow cell transplant.
Van Ramshorst 2009	In the placebo group, a greater than 0.5‐centimetre pericardial effusion was detected on 2‐dimensional echocardiography in an asymptomatic participant 2 days after the injection procedure, and pericardiocentesis was subsequently performed.
Wang 2009	No periprocedural adverse events; cardiac proteins in normal range.
Wang 2010	No increase in angina frequency or usage of sublingual NTG was observed in participants of either group. There were no cardiac enzyme elevations, MIs, acute coronary syndromes, or deaths. No participants from either group developed ventricular tachycardia during the cell or saline infusion procedure. No arrhythmias were detected by Holter monitoring in any participant during or after the infusion process.
Wang 2014	n/r
Wang 2015	Predischarge arrhythmias were reported (as number of events) in both cell therapy and control participants.
Yao 2008	Intracoronary application of BMC was performed without any acute or long‐term side effects. There was no inflammatory response or myocardial reaction (i.e. white blood cell count, C‐reactive protein, and creatinine phosphokinase) after cell therapy.
Zhao 2008	In the perioperative period, sporadic ventricular premature beats and self terminating bouts of rapid atrial fibrillation were observed in both groups. However, 2 participants developed VF, and 1 died in the BMMNC group: 1 participant developed VF on the 5th day postoperatively but was successfully resuscitated and VF well‐controlled, and the other developed refractory VF 5 hours' postoperatively with death on postoperative day 3. There were no ventricular arrhythmias in the control group.
AMI: acute myocardial infarction BM: bone marrow BMAC: bone marrow aspirate concentrate BMC: bone marrow cells BMMNC: bone marrow mononuclear cells CHF: congestive heart failure CK‐MB: creatine kinase‐MB CPC: circulating progenitor cells CPK‐MB: creatine phosphokinase‐MB CT: computed tomography ECG: electrocardiogram G‐CSF: granulocyte colony‐stimulating factor HF: heart failure LV: left ventricular MI: myocardial infarction MSC: mesenchymal stem cells non‐STEMI: non‐ST elevation myocardial infarction n/r: not reported NTG: nitroglycerine OPCAB: off‐pump coronary artery bypass PCI: percutaneous coronary intervention ULN: upper limit of normal VF: ventricular fibrillation

Table 5. Periprocedural adverse events

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Table 6. Quality of life and performance measures

Study ID	No. analysed participants		Performance assessment	Mean follow‐up		No. analysed participants		Quality of life assessment	Mean follow‐up
Study ID	Cells	No cells	Performance assessment	ST	LT	Cells	No cells	Quality of life assessment	ST	LT
Ang 2008	21	21	NYHA class (SR)^a	6 mths	n/r	‐	‐	‐	‐	‐
Ang 2008	21	21	CCS class (SR)^b	6 mths	n/r	‐	‐	‐	‐	‐
Assmus 2006	43	18	NYHA class (EP)	3 mths	n/r	‐	‐	‐	‐	‐
Assmus 2013	43	39	NYHA class (EP/MC)	4 mths	n/r	‐	‐	‐	‐	‐
Bartunek 2012	21	15	NYHA class (SR)^c	6 mths	n/r	21	15	MLHFQ (SR)^c	6 mths	n/r
Bartunek 2012	21	15	6MWT (distance) (EP)	6 mths	n/r	‐	‐	‐	‐	‐
Chen 2006	22^d	23^d	NYHA class (EP)	6 mths	12 mths	‐	‐	‐	‐	‐
Chen 2006	22^d	23^d	ETT (METs) (EP)	6 mths	12 mths	‐	‐	‐	‐	‐
Erbs 2005	12	10	Bike test (max O₂ update) (EP)	3 mths	15 mths	‐	‐	‐	‐	‐
Hamshere 2015_IC	15	15	NYHA class (EP)	6 mths	12 mths	‐	‐	‐	‐	‐
Hamshere 2015_IC	15	15	CCS class (EP)	6 mths	12 mths	‐	‐	‐	‐	‐
Hamshere 2015_IM	15	15	NYHA class (EP)	6 mths	12 mths	‐	‐	‐	‐	‐
Hamshere 2015_IM	15	15	CCS class (EP)	6 mths	12 mths	‐	‐	‐	‐	‐
Heldman 2014_BMMNC	17	16	NYHA class (SR)^e	n/r	12 mths	15	19	MLHFQ (MC)	6 mths	12 mths
Heldman 2014_BMMNC	15^f	19^f	6MWT (distance) (MC)	6 mths	12 mths	‐	‐	‐	‐	‐
Heldman 2014_BM‐MSC	17	16	NYHA class (SR)^e	n/r	12 mths	19^g	19^g	MLHFQ (MC)	6 mths	12 mths
Heldman 2014_BM‐MSC	18^h	19^h	6MWT (distance) (MC)	6 mths	12 mths	‐	‐	‐	‐	‐
Honold 2012	21^j	10^j	NYHA class (EP)	3 mths	60 mths	‐	‐	‐	‐	‐
Honold 2012	12^k	5^k	Bike test (sec) (EP)	3 mths	12 mths	‐	‐	‐	‐	‐
Hu 2011	30	27	6MWT (distance) (EP/MC)	6 mths	n/r	‐	‐	‐	‐	‐
Jimenez‐Quevedo 2011	19	9	CCS class (median)^m	6 mths	n/r	n/r	n/r	SAQ (median)^m	6 mths	n/r
Jimenez‐Quevedo 2011	15	7	ETT (time; METs) (median)^m	6 mths	n/r	19	9	Angina frequency (median)ⁿ	6 mths	n/r
Losordo 2007	18	6	CCS class (MC)	6 mths	n/r	18	6	SAQ (SR)^p	6 mths	n/r
Losordo 2007	18	6	ETT (time) (MC)	6 mths	n/r	17	6	Angina frequency (EP/MC)	6 mths	n/r
Losordo 2011	109^q	53^q	CCS class (SR)^r	6 mths	12 mths	109^q	53^q	SAQ (MC)	6 mths	12 mths
Losordo 2011	109^q	53^q	ETT (time) (MC)	6 mths	12 mths	109	53	Angina frequency (EP)	6 mths	n/r
Mathiasen 2015	40	40	NYHA class (SR)^s	6 mths	n/r	40	40	KCCQ‐QOL (SR)^s	6 mths	n/r
	40	40	CCS class (SR)^s	6 mths	n/r	40	40	SAQ (SR)^s	6 mths	n/r
	40	40	6MWT (SR)^s	6 mths	n/r	40	40	Angina frequency (SR)^s	6 mths	n/r
Mozid 2014_IC	14	2	NYHA class (EP)	6 mths	n/r	‐	‐	‐	‐	‐
Mozid 2014_IC	14	2	CCS class (SR)	6 mths	n/r	‐	‐	‐	‐	‐
Mozid 2014_IM	10	8	NYHA class (EP)	6 mths	n/r	‐	‐	‐	‐	‐
Mozid 2014_IM	10	8	CCS class (SR)	6 mths	n/r	‐	‐	‐	‐	‐
Nasseri 2012	28	26	NYHA class (EP/MC)^t	6 mths	n/r	28	26	MLHFQ^u	6 mths	n/r
	28	26	6MWT^u	6 mths	n/r	‐	‐	‐	‐	‐
	28	26	CCS class (EP/MC)^t	6 mths	n/r	‐	‐	‐	‐	‐
Patel 2005	10	10	NYHA class (EP/MC)^t	6 mths	n/r	‐	‐	‐	‐	‐
Patel 2015	17	4	NYHA class (EP)^t	n/r	12 mths	17	4	MLHFQ (SR)	n/r	12 mths
Patel 2015	17	4	CCS class (SR)	n/r	12 mths	‐	‐	‐	‐	‐
Patila 2014	20	19	NYHA class (EP/MC)	n/r	12 mths^v	20	19	SF‐36^w	n/r	60 mths
Perin 2011	20	10	NYHA class (EP)	6 mths	n/r	17	9	MLHFQ (EP)	6 mths	n/r
Perin 2011	20	10	CCS class (EP/MC)	6 mths	n/r	13	10	SF‐36 (physical/mental) (EP)	6 mths	n/r
Perin 2012a	55	30	NYHA class (MC)	6 mths	n/r	‐	‐	‐	‐	‐
	44	22	CCS class (MC)	6 mths	n/r	‐	‐	‐	‐	‐
	51	29	6MWT (distance) (EP)	6 mths	n/r	‐	‐	‐	‐	‐
Perin 2012b	10	10	NYHA class (EP)	6 mths	n/r	‐	‐	‐	‐	‐
Perin 2012b	10	10	CCS class (EP)	6 mths	n/r	‐	‐	‐	‐	‐
Pokushalov 2010	53^x	46^x	NYHA class (EP)	6 mths	12 mths	53^x	46^x	MLHFQ (EP)	6 mths	12 mths
	53^x	46^x	CCS class (EP)	6 mths	12 mths	53^x	46^x	Angina frequency (EP)	6 mths	12 mths
	53^x	46^x	6MWT (distance) (EP)	6 mths	12 mths	‐	‐	‐	‐	‐
Santoso 2014	19	9	NYHA class (EP)^y	6 mths	n/r	‐	‐	‐	‐	‐
Santoso 2014	19	9	6MWT (distance) (EP)^y	6 mths	n/r	‐	‐	‐	‐	‐
Trifunovic 2015	15	15	NYHA class (EP)	6 mths	12 mths	‐	‐	‐	‐	‐
Trifunovic 2015	15	15	6MWT (distance) (EP)	6 mths	12 mths	‐	‐	‐	‐	‐
Tse 2007	19	9	NYHA class (EP)^t	6 mths	n/r	‐	‐	‐	‐	‐
	19	9	CCS class (EP)^t	6 mths	n/r	‐	‐	‐	‐	‐
	19	9	Treadmill test (time; METs) (EP/MC)	6 mths	n/r	‐	‐	‐	‐	‐
Turan 2011	33	16	NYHA class (EP)	6 mths	12 mths	‐	‐	‐	‐	‐
Van Ramshorst 2009	24	25	CCS class (EP)	6 mths	n/r	24	25	SAQ (EP/MC)	6 mths	n/r
Van Ramshorst 2009	24	25	Bike test (workload) (EP/MC)	6 mths	n/r	‐	‐	‐	‐	‐
Wang 2009	16	16	CCS class (MC)	6 mths	n/r	16	16	Angina frequency (MC)	6 mths	n/r
Wang 2009	16	16	ETT (min) (MC)	6 mths	n/r	‐	‐	‐	‐	‐
Wang 2010	56	56	CCS class (EP/MC)	6 mths	n/r	56	56	Angina frequency (EP/MC)	6 mths	n/r
Wang 2010	56	56	ETT (min) (EP/MC)	6 mths	n/r	‐	‐	‐	‐	‐
Wang 2014	n/r	n/r	NYHA class (SR)	6 mths	n/r	‐	‐	‐	‐	‐
Wang 2014	n/r	n/r	5MWT (distance) (SR)	6 mths	n/r	‐	‐	‐	‐	‐
Zhao 2008	16	18	NYHA class (EP)	6 mths	n/r	‐	‐	‐	‐	‐
Zhao 2008	16	18	CCS class (EP)	6 mths	n/r	‐	‐	‐	‐	‐
CCS: Canadian Cardiovascular Society; EP: endpoint; ETT: exercise tolerance test; KCCQ‐QOL: Kansas City Cardiomyopathy Questionnaire – Quality of Life; LT: long term; MC: mean change from baseline; MET: metabolic equivalent test (mL/kg/min); MLHFQ: Minnesota Living with Heart Failure Questionnaire; n/r: not reported; NYHA: New York Heart Association; SAQ: Seattle Angina Questionnaire; SF‐36: 36‐Item Short Form Health Survey; SR: summary results; ST: short term; 5MWT: 5‐minute walk test; 6MWT: 6‐minute walk test ^aReported as number of participants in NYHA class III/IV. ^bReported as number of participants in CCS class II or greater. ^cReported graphically as percentage of participants showing improvement or deterioration. ^d20/19 at 12 months. ^eReported as number who improved/did not change/deteriorated. ^f17/19 at 12 months. ^g16/19 at 12 months. ^h16/19 at 12 months. ^j20/6 at 5 years. ^k10/5 at 12 months. ^mReported as median absolute difference with 95% confidence interval. ⁿMedian time to onset of angina also reported. ^pResults presented graphically. ^q106/50 at 12 months. ^rReported as percentage of participants changed. ^sResults presented graphically with P values for differences between groups. ^tCalculated from frequency data. ^uUnclear whether mean or median values are reported. ^vAlso reported: median values at 60 months. ^wReported graphically for each of eight components of SF‐36 at 60 months. ^x49/33 at 12 months. ^yReported as difference between groups at endpoint.

Table 6. Quality of life and performance measures

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Table 7. Surrogate (continous) outcome: LVEF

Study ID	No. randomised participants		No. analysed participants		Baseline LVEF: Mean (SD)		Mean follow‐up of LVEF
Study ID	Cells	No cells	Cells	No cells	Cells	No cells	ST	LT
Measured by MRI
Ang 2008	42	21	18	7	IM: 25.4 (8.1) IC: 28.5 (6.5)	20.9 (8.9)	6 mths	‐
Assmus 2013	43	39	15	12	n/r	n/r	4 mths	‐
Erbs 2005	14	14	12^a	11^a	51.0 (12.1)	55.8 (12.4)	3 mths	15 mths
Hendrikx 2006	11	12	10	10	42.9 (10.3)	39.5 (5.5)	4 mths	‐
Honold 2012	23	10	9	4	33.4 (SEM 12.7)	23.3 (SEM 7.2)	3 mths	12 mths
Hu 2011	31	29	31^b	28^b	23.5 (6.7)	24.8 (5.2)	6 mths	12 mths
Mathiasen 2015	40	20	40	20	28.2 (9.3)	25.1 (8.5)	6 mths	‐
Nasseri 2012	30	30	26	22	27 (6)	26 (6)	6 mths	‐
Patila 2014	20	19	18	7	37.1 (9.5)	38.5 (13.5)	‐	60 mths
Santoso 2014	19	9	19	9	23.6 (8.4)	26.8 (8.8)	6 mths	‐
Tse 2007	19	9	18	8	51.9 (8.5)	45.7 (8.3)	6 mths	‐
Van Ramshorst 2009	25	25	22	18	56 (12)	54 (10)	6 mths	‐
Wang 2014	35	35	35	35	29 (7)	28 (6)	6 mths	‐
Measured by echocardiography
Bartunek 2012	32	15	21	15	27.5 (95% CI 25.5, 29.5)	27.8 (95% CI 25.9, 29.8)	6 mths	‐
Hu 2011	31	29	24	18	36.0 (1.2)	34.7 (1.4)	‐	12 mths
Perin 2011	20	10	20	10	37.0 (10.6)	39.0 (9.1)	6 mths	‐
Perin 2012a	61	31	54	28	34.7 (8.8)	32.3 (8.6)	6 mths	‐
Perin 2012b	10	10	10	10	36.1 (10.9)	32.1 (10.6)	6 mths	‐
Pokushalov 2010	55	54	53^c	46^c	27.8 (3.4)	26.8 (3.8)	6 mths	12 mths
Trifunovic 2015	15	15	15	15	35.3 (3.9)	36.5 (5.3)	6 mths	12 mths
Van Ramshorst 2009	25	25	24	25	50 (5)	52 (5)	6 mths	‐
Wang 2015	45	45	45	45	39.3 (6.2)	38.2 (8.0)	6 mths	‐
Zhao 2008	18	18	16	18	35.8 (7.3)	36.7 (9.2)	6 mths	‐
Measured by SPECT
Chen 2006	24	24	22^d	23^d	26 (6)	23 (8)	6 mths	12 mths
Perin 2011	20	10	20	10	41.5 (11.2)	43.0 (10.4)	6 mths	‐
Van Ramshorst 2009	25	25	24	25	53 (12)	54 (12)	6 mths	12 mths
Measured by LV angiography
Assmus 2006	52	23	43	18	BMMNC: 41 (11) CPC: 39 (10)	43 (13)	3 mths	‐
Assmus 2013	43	39	41	38	LDSW: 37.2 (95% CI 31.7, 42.7) HDSW: 32.4 (95% CI 26.9, 37.9)	LDSW: 29.9 (95% CI 24.0, 35.7) HDSW: 32.3 (95% CI 26.5, 38.1)	4 mths	‐
Honold 2012	23	10	21	5	37.5 (SEM 12.9)	37.6 (SEM 7.5)	3 mths	‐
Perin 2011	20	10	20	10	37.5 (8.2)	40.0 (3.2)	6 mths	‐
Perin 2012b	10	10	10	10	38.0 (17.5)	41.9 (11.8)	6 mths	‐
Turan 2011	38	18	33	16	46 (10)	46 (10)	3 mths	12 mths
95% CI: 95% confidence interval; BMMNC: bone marrow mononuclear cells; CPC: circulating progenitor cells; HDSW: high‐dose shockwave; IC: intracoronary; IM: intramyocardial; LDSW: low‐dose shockwave; LT: long term; LV: left ventricular; LVEF: left ventricular ejection fraction; SD: standard deviation; SEM: standard error of the mean; SPECT: single‐photon emission computed tomography; ST: short term ^a12/10 at 15 months. ^b25/25 at 12 months. ^c20/19 at 12 months. ^d49/33 at 12 months.

Table 7. Surrogate (continous) outcome: LVEF

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Comparison 1. Cells versus no cells

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (all‐cause) Show forest plot	37		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Short term follow‐up (< 12 months)	33	1637	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.26, 0.87]
1.2 Long term follow‐up (≥ 12 months)	21	1010	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.25, 0.58]
2 Non‐fatal myocardial infarction Show forest plot	25		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Short term follow‐up (< 12 months)	20	881	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.17, 2.15]
2.2 Long term follow‐up (≥ 12 months)	9	461	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.17, 0.93]
3 Rehospitalisation due to heart failure Show forest plot	16		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Short term follow‐up (< 12 months)	10	482	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.36, 1.12]
3.2 Long term follow‐up (≥ 12 months)	10	495	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.36, 1.04]
4 Arrhythmias Show forest plot	24		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Short term follow‐up (< 12 months)	22	959	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.33, 1.45]
4.2 Long term follow‐up (≥ 12 months)	7	363	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.22, 0.97]
5 Composite MACE Show forest plot	9		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Short term follow‐up (< 12 months)	8	288	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.18, 1.42]
5.2 Long term follow‐up (≥ 12 months)	5	201	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.41, 1.12]
6 MLHFQ: short term follow‐up (< 12 months) Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 Mean value at endpoint	2	125	Mean Difference (IV, Random, 95% CI)	‐29.52 [‐33.76, ‐25.27]
6.2 Mean change from baseline	2	72	Mean Difference (IV, Random, 95% CI)	‐9.07 [‐22.09, 3.95]
6.3 Combined	4	197	Mean Difference (IV, Random, 95% CI)	‐18.96 [‐31.97, ‐5.94]
7 MLHFQ: long term follow‐up (≥ 12 months) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 Mean value at endpoint	1	82	Mean Difference (IV, Random, 95% CI)	‐36.5 [‐42.21, ‐30.79]
7.2 Mean change from baseline	2	69	Mean Difference (IV, Random, 95% CI)	‐7.63 [‐16.35, 1.09]
7.3 Combined	3	151	Mean Difference (IV, Random, 95% CI)	‐17.80 [‐39.87, 4.26]
8 Seattle Angina Questionnaire: short term follow‐up (< 12 months) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

8.1 Mean value at endpoint	1	49	Mean Difference (IV, Random, 95% CI)	5.0 [‐3.21, 13.21]
8.2 Mean change from baseline	2	211	Mean Difference (IV, Random, 95% CI)	9.34 [2.62, 16.07]
8.3 Combined	2	211	Mean Difference (IV, Random, 95% CI)	9.34 [2.62, 16.07]
9 Angina episodes per week: short term follow‐up (< 12 months) Show forest plot	5		Mean Difference (IV, Random, 95% CI)	Subtotals only

9.1 Mean value at endpoint	4	396	Mean Difference (IV, Random, 95% CI)	‐6.96 [‐11.99, ‐1.93]
9.2 Mean change from baseline	3	167	Mean Difference (IV, Random, 95% CI)	‐1.77 [‐14.61, 11.08]
9.3 Combined	5	428	Mean Difference (IV, Random, 95% CI)	‐5.11 [‐11.30, 1.09]
10 NYHA classification: short‐term follow‐up (< 12 months) Show forest plot	17		Mean Difference (IV, Random, 95% CI)	Subtotals only

10.1 Mean value at endpoint	16	658	Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.84, ‐0.00]
10.2 Mean change from baseline	4	239	Mean Difference (IV, Random, 95% CI)	‐0.56 [‐1.49, 0.36]
10.3 Combined	17	741	Mean Difference (IV, Random, 95% CI)	‐0.44 [‐0.84, ‐0.05]
11 NYHA classification: long term follow‐up (≥ 12 months) Show forest plot	9		Mean Difference (IV, Random, 95% CI)	Subtotals only

11.1 Mean value at endpoint	9	346	Mean Difference (IV, Random, 95% CI)	‐0.57 [‐1.03, ‐0.10]
11.2 Mean change from baseline	1	39	Mean Difference (IV, Random, 95% CI)	‐2.2 [‐2.70, ‐1.70]
11.3 Combined	9	346	Mean Difference (IV, Random, 95% CI)	‐0.81 [‐1.23, ‐0.39]
12 CCS class: short term follow‐up (< 12 months) Show forest plot	13		Mean Difference (IV, Random, 95% CI)	Subtotals only

12.1 Mean value at endpoint	10	486	Mean Difference (IV, Random, 95% CI)	‐0.32 [‐0.82, 0.18]
12.2 Mean change from baseline	6	318	Mean Difference (IV, Random, 95% CI)	‐0.62 [‐1.40, 0.17]
12.3 Combined	13	608	Mean Difference (IV, Random, 95% CI)	‐0.43 [‐0.92, 0.06]
13 CCS class: long term follow‐up (≥ 12 months) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

13.1 Mean value at endpoint	3	142	Mean Difference (IV, Random, 95% CI)	‐0.58 [‐2.04, 0.88]
14 Exercise capacity: short term follow‐up (< 12 months) Show forest plot	16		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

14.1 Mean value at endpoint	11	563	Std. Mean Difference (IV, Random, 95% CI)	0.56 [0.19, 0.93]
14.2 Mean change from baseline	9	535	Std. Mean Difference (IV, Random, 95% CI)	0.33 [0.05, 0.61]
15 Exercise capacity: long term follow‐up (≥ 12 months) Show forest plot	8		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

15.1 Mean value at endpoint	5	178	Std. Mean Difference (IV, Random, 95% CI)	1.14 [0.04, 2.25]
15.2 Mean change from baseline	3	227	Std. Mean Difference (IV, Random, 95% CI)	0.34 [0.07, 0.62]
16 LVEF (%) measured by MRI: short term follow‐up (< 12 months) Show forest plot	12		Mean Difference (IV, Random, 95% CI)	Subtotals only

16.1 Mean value at endpoint	10	352	Mean Difference (IV, Random, 95% CI)	3.01 [‐0.05, 6.07]
16.2 Mean change from baseline	9	308	Mean Difference (IV, Random, 95% CI)	4.05 [2.55, 5.55]
16.3 Combined	12	439	Mean Difference (IV, Random, 95% CI)	2.92 [1.03, 4.82]
17 LVEF (%) measured by MRI: long term follow‐up (≥ 12 months) Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

17.1 Mean value at endpoint	4	110	Mean Difference (IV, Random, 95% CI)	2.37 [‐1.54, 6.29]
17.2 Mean change from baseline	3	97	Mean Difference (IV, Random, 95% CI)	3.83 [‐0.42, 8.08]
17.3 Combined	4	110	Mean Difference (IV, Random, 95% CI)	4.38 [0.82, 7.93]
18 LVEF (%) measured by echocardiography: short term follow‐up (< 12 months) Show forest plot	9		Mean Difference (IV, Random, 95% CI)	Subtotals only

18.1 Mean value at endpoint	8	388	Mean Difference (IV, Random, 95% CI)	5.16 [2.87, 7.44]
18.2 Mean change from baseline	3	161	Mean Difference (IV, Random, 95% CI)	3.47 [1.59, 5.34]
18.3 Combined	9	470	Mean Difference (IV, Random, 95% CI)	5.71 [4.29, 7.13]
19 LVEF (%) measured by echocardiography: long term follow‐up (≥ 12 months) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

19.1 Mean value at endpoint	3	154	Mean Difference (IV, Random, 95% CI)	7.69 [6.47, 8.92]
19.2 Mean change from baseline	1	82	Mean Difference (IV, Random, 95% CI)	6.1 [‐1.27, 13.47]
19.3 Combined	3	154	Mean Difference (IV, Random, 95% CI)	7.96 [6.39, 9.54]
20 LVEF (%) measured by SPECT: short term follow‐up (< 12 months) Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

20.1 Mean value at endpoint	4	145	Mean Difference (IV, Random, 95% CI)	2.41 [‐2.65, 7.46]
20.2 Mean change from baseline	1	30	Mean Difference (IV, Random, 95% CI)	‐2.3 [‐17.33, 12.73]
20.3 Combined	4	145	Mean Difference (IV, Random, 95% CI)	5.22 [2.60, 7.85]
21 LVEF (%) measured by SPECT: long term follow‐up (≥ 12 months) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

21.1 Mean value at endpoint	2	88	Mean Difference (IV, Random, 95% CI)	0.37 [‐2.30, 3.04]
21.2 Mean change from baseline	1	49	Mean Difference (IV, Random, 95% CI)	4.0 [‐6.48, 14.48]
21.3 Combined	2	88	Mean Difference (IV, Random, 95% CI)	0.28 [‐2.48, 3.03]
22 LVEF (%) measured by LV angiography: short term follow‐up (< 12 months) Show forest plot	6		Mean Difference (IV, Random, 95% CI)	Subtotals only

22.1 Mean value at endpoint	6	265	Mean Difference (IV, Random, 95% CI)	3.18 [0.39, 5.97]
22.2 Mean change from baseline	4	181	Mean Difference (IV, Random, 95% CI)	1.72 [0.50, 2.95]
22.3 Combined	6	250	Mean Difference (IV, Random, 95% CI)	2.00 [0.53, 3.46]
23 LVEF (%) measured by LV angiography: long term follow‐up (≥ 12 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

23.1 Mean value at endpoint	1	49	Mean Difference (IV, Random, 95% CI)	6.0 [0.81, 11.19]

Comparison 1. Cells versus no cells

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Comparison 2. Cell dose: subgroup analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (all‐cause): short term follow‐up (< 12 months) Show forest plot	30		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 < 107 cells	6	334	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.02, 1.63]
1.2 107 < 108 cells	18	771	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.15, 0.79]
1.3 ≥ 108 cells	8	487	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.35, 1.94]
2 Mortality (all‐cause): long term follow‐up (≥ 12 months) Show forest plot	16		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 < 107 cells	4	297	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.10, 1.09]
2.2 107 < 108 cells	7	330	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.17, 0.53]
2.3 ≥ 108 cells	5	236	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.30, 1.26]
3 NYHA classification: short term follow‐up (< 12 months) Show forest plot	15		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 < 107 cells	4	149	Mean Difference (IV, Random, 95% CI)	‐0.29 [‐0.94, 0.36]
3.2 107 < 108 cells	8	309	Mean Difference (IV, Random, 95% CI)	‐0.65 [‐1.22, ‐0.08]
3.3 ≥ 108 cells	4	241	Mean Difference (IV, Random, 95% CI)	‐0.41 [‐0.72, ‐0.11]
4 CCS class: short term follow‐up (< 12 months) Show forest plot	9		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 < 107 cells	4	288	Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.92, 0.19]
4.2 107 < 108 cells	5	160	Mean Difference (IV, Random, 95% CI)	‐0.54 [‐1.40, 0.32]
5 Exercise capacity: short term follow‐up (< 12 months) Show forest plot	10		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 107 < 108 cells	7	357	Std. Mean Difference (IV, Random, 95% CI)	0.56 [‐0.03, 1.14]
5.2 ≥ 108 cells	3	161	Std. Mean Difference (IV, Random, 95% CI)	0.43 [0.10, 0.77]
6 LVEF (%) measured by MRI: short term follow‐up (< 12 months) Show forest plot	9		Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 107 < 108 cells	7	199	Mean Difference (IV, Random, 95% CI)	5.23 [3.91, 6.54]
6.2 ≥ 108 cells	3	101	Mean Difference (IV, Random, 95% CI)	2.37 [‐0.92, 5.66]

Comparison 2. Cell dose: subgroup analysis

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Comparison 3. Baseline cardiac function: subgroup analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (all‐cause): short term follow‐up (< 12 months) Show forest plot	28		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 < 30%	11	508	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.09, 0.59]
1.2 30 ‐ 50%	13	642	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.36, 2.11]
1.3 > 50%	4	271	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.11, 3.35]
2 Mortality (all‐cause): long term follow‐up (≥ 12 months) Show forest plot	16		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 < 30%	9	426	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.20, 0.64]
2.2 30 ‐ 50%	7	289	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.27, 1.21]
3 NYHA classification: short term follow‐up (< 12 months) Show forest plot	15		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 < 30%	6	273	Mean Difference (IV, Random, 95% CI)	‐0.40 [‐1.22, 0.43]
3.2 30 ‐ 50%	9	420	Mean Difference (IV, Random, 95% CI)	‐0.32 [‐0.54, ‐0.10]
4 NYHA classification: long term follow‐up (≥ 12 months) Show forest plot	9		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 < 30%	5	202	Mean Difference (IV, Random, 95% CI)	‐0.66 [‐1.28, ‐0.04]
4.2 30 ‐ 50%	4	144	Mean Difference (IV, Random, 95% CI)	‐0.98 [‐1.72, ‐0.25]
5 CCS class: short term follow‐up (< 12 months) Show forest plot	8		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 < 30%	4	213	Mean Difference (IV, Random, 95% CI)	‐0.25 [‐1.47, 0.97]
5.2 30 ‐ 50%	4	150	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.31, 0.09]
6 Exercise capacity: short term follow‐up (< 12 months) Show forest plot	7		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 < 30%	4	225	Std. Mean Difference (IV, Random, 95% CI)	0.96 [0.37, 1.56]
6.2 30 ‐ 50%	3	127	Std. Mean Difference (IV, Random, 95% CI)	0.38 [‐0.57, 1.33]
7 LVEF (%) measured by MRI: short term follow‐up (< 12 months) Show forest plot	9		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 < 30%	6	290	Mean Difference (IV, Random, 95% CI)	1.54 [‐1.96, 5.03]
7.2 30 ‐ 50%	3	60	Mean Difference (IV, Random, 95% CI)	3.31 [0.88, 5.75]

Comparison 3. Baseline cardiac function: subgroup analysis

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Comparison 4. Route of cell administration: subgroup analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (all‐cause): short term follow‐up (< 12 months) Show forest plot	33		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Intramyocardial	22	1049	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.21, 1.03]
1.2 Intracoronary	12	607	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.21, 1.23]
2 Mortality (all‐cause): long term follow‐up (≥ 12 months) Show forest plot	21		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Intramyocardial	13	652	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.17, 0.50]
2.2 Intracoronary	8	358	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.30, 1.09]
3 NYHA classification: short term follow‐up (< 12 months) Show forest plot	17		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 Intramyocardial	11	445	Mean Difference (IV, Random, 95% CI)	‐0.48 [‐0.99, 0.03]
3.2 Intracoronary	6	296	Mean Difference (IV, Random, 95% CI)	‐0.38 [‐0.76, 0.00]
4 NYHA classification: long term follow‐up (≥ 12 months) Show forest plot	9		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 Intramyocardial	4	181	Mean Difference (IV, Random, 95% CI)	‐1.09 [‐1.76, ‐0.41]
4.2 Intracoronary	5	165	Mean Difference (IV, Random, 95% CI)	‐0.61 [‐0.92, ‐0.30]
5 CCS class: short term follow‐up (< 12 months) Show forest plot	13		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 Intramyocardial	10	434	Mean Difference (IV, Random, 95% CI)	‐0.33 [‐0.87, 0.22]
5.2 Intracoronary	3	174	Mean Difference (IV, Random, 95% CI)	‐1.00 [‐2.87, 0.86]
6 Exercise capacity: short term follow‐up (< 12 months) Show forest plot	11		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 Intramyocardial	6	310	Std. Mean Difference (IV, Random, 95% CI)	0.78 [0.19, 1.36]
6.2 Intracoronary	5	253	Std. Mean Difference (IV, Random, 95% CI)	0.33 [‐0.06, 0.72]
7 LVEF (%) measured by MRI: short term follow‐up (< 12 months) Show forest plot	12		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 Intramyocardial	8	309	Mean Difference (IV, Random, 95% CI)	2.18 [‐0.41, 4.77]
7.2 Intracoronary	5	137	Mean Difference (IV, Random, 95% CI)	3.72 [0.86, 6.57]

Comparison 4. Route of cell administration: subgroup analysis

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Comparison 5. Cell type: subgroup analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (all‐cause): short term follow‐up (< 12 months) Show forest plot	33		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Mononuclear cells	20	966	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.28, 1.04]
1.2 Circulating progenitor cells	3	104	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.01, 7.48]
1.3 Haematopoietic progenitor cells	8	464	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.05, 1.46]
1.4 Mesenchymal stem cells	3	126	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.03, 7.59]
2 Mortality (all‐cause): long term follow‐up (≥ 12 months) Show forest plot	19		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Mononuclear cells	12	540	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.25, 0.70]
2.2 Haematopoietic progenitor cells	4	302	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.10, 0.69]
2.3 Mesenchymal stem cells	3	111	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.15, 1.57]
3 NYHA classification: short term follow‐up (< 12 months) Show forest plot	15		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 Mononuclear cells	12	547	Mean Difference (IV, Random, 95% CI)	‐0.42 [‐0.86, 0.02]
3.2 Haematopoietic progenitor cells	3	94	Mean Difference (IV, Random, 95% CI)	‐0.47 [‐1.95, 1.02]
4 CCS class: short term follow‐up (< 12 months) Show forest plot	13		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 Mononuclear cells	8	366	Mean Difference (IV, Random, 95% CI)	‐0.39 [‐0.99, 0.21]
4.2 Haematopoietic progenitor cells	5	242	Mean Difference (IV, Random, 95% CI)	‐0.54 [‐1.55, 0.46]

Comparison 5. Cell type: subgroup analysis

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Comparison 6. Participant diagnosis: subgroup analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (all‐cause): short term follow‐up (< 12 months) Show forest plot	33		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Chronic IHD	11	550	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.26, 1.62]
1.2 HF (secondary to IHD)	15	645	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.14, 0.82]
1.3 Refractory/intractable angina	7	442	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.11, 3.35]
2 Mortality (all‐cause): long term follow‐up (≥ 12 months) Show forest plot	21		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Chronic IHD	9	389	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.27, 0.99]
2.2 HF (secondary to IHD)	9	401	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.19, 0.58]
2.3 Refractory/intractable angina	3	220	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 0.91]
3 NYHA classification: short term follow‐up (< 12 months) Show forest plot	16		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 Chronic IHD	6	296	Mean Difference (IV, Random, 95% CI)	‐0.43 [‐0.78, ‐0.07]
3.2 HF (secondary to IHD)	10	417	Mean Difference (IV, Random, 95% CI)	‐0.47 [‐1.02, 0.09]
4 NYHA classification: long term follow‐up (≥ 12 months) Show forest plot	9		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 Chronic IHD	3	105	Mean Difference (IV, Random, 95% CI)	‐0.66 [‐0.91, ‐0.42]
4.2 HF (secondary to IHD)	6	241	Mean Difference (IV, Random, 95% CI)	‐0.92 [‐1.47, ‐0.37]
5 CCS class: short term follow‐up (< 12 months) Show forest plot	13		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 HF (secondary to IHD)	8	363	Mean Difference (IV, Random, 95% CI)	‐0.25 [‐0.90, 0.40]
5.2 Refractory/intractable angina	5	245	Mean Difference (IV, Random, 95% CI)	‐0.78 [‐1.44, ‐0.11]
6 Exercise capacity: short term follow‐up (< 12 months) Show forest plot	11		Std. Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 Chronic IHD	4	114	Std. Mean Difference (IV, Random, 95% CI)	0.48 [‐0.26, 1.22]
6.2 HF (secondary to IHD)	4	260	Std. Mean Difference (IV, Random, 95% CI)	0.79 [0.04, 1.53]
6.3 Refractory/intractable angina	3	189	Std. Mean Difference (IV, Random, 95% CI)	0.26 [‐0.03, 0.55]
7 LVEF (%) measured by MRI: short term follow‐up (< 12 months) Show forest plot	10		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 Chronic IHD	6	178	Mean Difference (IV, Random, 95% CI)	2.58 [‐0.16, 5.31]
7.2 HF (secondary to IHD)	4	195	Mean Difference (IV, Random, 95% CI)	2.50 [‐1.97, 6.97]

Comparison 6. Participant diagnosis: subgroup analysis

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Comparison 7. Co‐interventions: subgroup analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (all‐cause): short term follow‐up (< 12 months) Show forest plot	33		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Co‐interventions	8	432	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.32, 1.70]
1.2 No co‐interventions	25	1205	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.13, 0.72]
2 Mortality (all‐cause): long term follow‐up (≥ 12 months) Show forest plot	21		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Co‐interventions	6	312	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.26, 0.88]
2.2 No co‐interventions	15	698	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.19, 0.56]
3 NYHA classification: short term follow‐up (< 12 months) Show forest plot	17		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 Co‐interventions	6	233	Mean Difference (IV, Random, 95% CI)	‐0.57 [‐1.20, 0.05]
3.2 No co‐interventions	11	508	Mean Difference (IV, Random, 95% CI)	‐0.37 [‐0.87, 0.13]
4 LVEF (%) measured by MRI: short term follow‐up (< 12 months) Show forest plot	12		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 Co‐interventions	5	179	Mean Difference (IV, Random, 95% CI)	2.01 [‐0.26, 4.29]
4.2 No co‐interventions	7	260	Mean Difference (IV, Random, 95% CI)	3.55 [0.82, 6.27]

Comparison 7. Co‐interventions: subgroup analysis

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Comparison 8. Sensitivity analysis: excluding studies with high/unclear risk of selection bias

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (all‐cause) Show forest plot	15		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Short term follow‐up (< 12 months)	14	744	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.32, 1.50]
1.2 Long term follow‐up (≥ 12 months)	9	491	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.21, 0.87]
2 Non‐fatal myocardial infarction Show forest plot	11		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Short term follow‐up (< 12 months)	6	288	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.05, 4.58]
2.2 Long term follow‐up (≥ 12 months)	5	345	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.15, 0.97]
3 Rehospitalisation due to heart failure Show forest plot	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Short term follow‐up (< 12 months)	3	234	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.32, 1.32]
3.2 Long term follow‐up (≥ 12 months)	6	375	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.36, 1.09]
4 Arrhythmias Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Short term follow‐up (< 12 months)	6	224	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.18, 3.21]
4.2 Long term follow‐up (≥ 12 months)	1	82	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.18, 0.99]
5 Composite MACE Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Short term follow‐up (< 12 months)	2	59	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Long term follow‐up (≥ 12 months)	3	141	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.38, 1.08]
6 NYHA classification: short term follow‐up (< 12 months) Show forest plot	5		Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 Combined	5	277	Mean Difference (IV, Random, 95% CI)	‐0.26 [‐0.59, 0.07]
7 NYHA classification: long term follow‐up (≥ 12 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 Combined	1	39	Mean Difference (IV, Random, 95% CI)	‐2.2 [‐2.70, ‐1.70]
8 LVEF (%) measured by MRI: short term follow‐up (< 12 months) Show forest plot	7		Mean Difference (IV, Random, 95% CI)	Subtotals only

8.1 Combined	7	249	Mean Difference (IV, Random, 95% CI)	2.92 [0.67, 5.17]
9 LVEF (%) measured by MRI: long term follow‐up (≥ 12 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

9.1 Combined	1	25	Mean Difference (IV, Random, 95% CI)	‐1.60 [‐8.70, 5.50]

Comparison 8. Sensitivity analysis: excluding studies with high/unclear risk of selection bias

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Comparison 9. Sensitivity analysis: excluding studies with high/unclear risk of performance bias

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (all‐cause) Show forest plot	26		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Short term follow‐up (< 12 months)	25	1216	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.29, 1.16]
1.2 Long term follow‐up (≥ 12 months)	13	624	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.21, 0.86]

Comparison 9. Sensitivity analysis: excluding studies with high/unclear risk of performance bias

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Comparison 10. Sensitivity analysis: excluding studies with high/unclear risk of attrition bias

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (all‐cause) Show forest plot	32		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Short term follow‐up (< 12 months)	28	1449	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.26, 0.89]
1.2 Long term follow‐up (≥ 12 months)	17	883	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.25, 0.60]

Comparison 10. Sensitivity analysis: excluding studies with high/unclear risk of attrition bias

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