Efficacy and safety of stem cell therapy for acute and subacute ischemic stroke: a systematic review and meta-analysis

Abstract

The efficacy of stem cell therapy for ischemic stroke in terms of functional outcomes remains unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (PROSPERO: CRD42024503763) to assess the efficacy and safety of stem cell therapy for acute/subacute ischemic stroke, focusing on long-term outcomes. Studies of patients undergoing stem cell transplantation within 1 month of stroke onset were included. We searched five databases for publications up to January 17, 2024. Summary data were extracted from published reports. The primary outcome was the modified Rankin Scale (mRS) score. Measures of effect were risk ratios (RRs) with 95% confidence intervals (CIs). A random-effects model was used when I² was > 25%; otherwise, a fixed-effects model was used. Common serious adverse events were epilepsy, gastrointestinal disorders, and cardiac disorders. The risk of bias was assessed using the Cochrane Risk of Bias tool version 2. In total, 13 trials involving 872 (519 men) patients were included. The 1-year incidence of mRS scores 0–1 was higher in the cell-therapy group (45/195) than that in the control group (23/179; RR = 1.74 [95% CI = 1.09–2.77]; p = 0.020; I² = 0%). The 90-day incidence of mRS scores 0–2 was also higher (RR = 1.31 [95% CI = 1.01–1.70]; p = 0.044; I² = 0%). No significant differences were observed in serious adverse events or mortality. Stem cell therapy for acute/subacute ischemic stroke within 1 month of onset is safe and significantly improves long-term functional outcomes, although the mechanisms of action need to be elucidated and treatment protocols standardized to establish stem cell therapy as a standard care option for ischemic stroke.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-025-04405-6.

Introduction

Stroke remains the second leading cause of death globally¹, despite remarkable progress in its treatment. Therapeutic options for acute ischemic stroke have expanded, including the use of mechanical thrombectomy and systemic tissue plasminogen activator (tPA)^2,3. However, 3.3 million people die from ischemic stroke annually, and over 63 million years of healthy life are lost each year owing to ischemic stroke-related death and disability¹, highlighting the need for novel therapies.

Stem cell therapy has gained increasing attention since the 1990s as a potential treatment for acute stroke^4,5. Mesenchymal stem cells, bone marrow mononuclear cells, and bone marrow progenitor cells are primarily used, yielding immunomodulatory, anti-inflammatory, and neuroregenerative effects, among others⁶. Although its safety has been demonstrated in clinical trials, the efficacy of stem cell therapy remains uncertain^7–14. Recent meta-analyses have provided mixed results: one revealed no significant difference in neurological deficits¹⁵, whereas others revealed improvements in the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), or Barthel Index (BI) scores^15–25. However, the heterogeneity in study designs and inconsistent timing of stem cell administration and functional evaluation raise concerns.

To address these issues, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), including the latest large-scale trials, to evaluate the long-term efficacy and safety of stem cell therapy for acute and subacute ischemic stroke. By aligning the timing of stem cell therapy and evaluation timepoints, we aimed to minimize heterogeneity and assess the impact on disability, neurological impairment, and dependency.

Results

Screening results and eligible trials

A total of 10,067 publications were identified through the literature search and subjected to screening (Fig. 1). Of the 60 trials that qualified for primary screening of abstracts, full text for only 50 articles could be retrieved for assessment of eligibility. The reasons for exclusion were as follows: one preclinical study, reports in a language other than English or Japanese (nine studies), study designs other than RCTs (18 studies), studies that did not include patients with acute or subacute ischemic stroke (seven studies), and other reasons (two studies). Consequently, 13 studies were deemed eligible, comprising a total of 872 patients, of which 519 were male and 353 were female.

Fig. 1.

PRISMA flow diagram.

Overview of study designs, interventions, and demographics

Three of the trials were conducted in Europe, two in North America, seven in Asia, and one in both Europe and North America. Each article encompassed the entirety of the clinical trial process. These trials, ranging from phase I/II to phase III, involved 11 to 206 individuals each, and took place at a maximum of 44 research centers, reflecting the extensive scope of our investigation. Using standard treatments (rehabilitation with/without placebos) as comparators, the trials incorporated the use of autologous bone marrow stem cells and allogeneic stem cells, offering a wide array of stem cell options for analysis and evaluation. The specific doses and timing of interventions varied substantially across the studies, with durations ranging from a few days to several weeks, highlighting the need for detailed and meticulous examination of treatment protocols and regimens. Furthermore, the follow-up periods ranged from 6 months to 3.5 years, with trials encompassing participants with diverse sex (assigned at birth) and age distributions, underscoring the importance of considering demographic factors in the analysis of outcomes and results (Table 1)^{7–13,26–31}.

Table 1.

Characteristics of studies.

Study	Country and region	Phase	No. of centers	No. of cases	Comparator	Type of stem cells	Dose	Timing of intervention after onset	Follow-up period	Male*	Age*	Outcome†
Chung et al., 20217	South Korea	III	4	54	Standard care alone	Autologous BM-MSCs	1 × 106/kg (max: 1.2 × 108)	Onset to randomization 20.95 ± 19.08 days Randomization to intervention 14–35 days	1 year	(I)44%, (C)67%	(I)63.03 ± 14.36 (C)64.27 ± 13.25	1–3
Moniche et al., 20239	Spain	II	4	77	Medication according to current guidelines	Autologous BM-MNCs	2 × 106/kg or 5 × 106/kg	4–7 days	6 months	(I)54% (C)66%	(L)63.0 (55–72) (H)66.0 (52–76) (C)66.0 (54–72)	1–5
Niizuma et al., 202313	Japan	II	1	35	Placebo	Allogeneic muse cells	1.5 × 107/15 ml	14–28 days	1 year	(I)80% (C)60%	(I)64.0 ± 12.1 (C) 59.2 ± 11.0	1–5
Fang et al., 201933	China	I/IIa	2	11	Placebo	Autologous BM-MSCs	5 × 106/kg ([2.5 × 106/kg]×2)	Onset to randomization < 7 days Randomization to intervention 27.0 ± 7.17 days	4 years	(I)80% (C)83%	(I)49.40 ± 10.85 (C)52.83 ± 14.95	2–5
Jaillard et al., 202012	France	I/II	1	31	Rehabilitation alone	Autologous BM-MSCs	NA	Onset to randomization < 14 days Randomization to intervention 20–29 days	2 years	(I)69% (C)73%	(I)55 (46–58) (C)53 (45–63)	2–5
Prasad et al., 201429	India	II	5	120	Conventional treatment	Autologous BM-MNCs	280.75 × 106 (SD: 162.9 × 106)	18.5 days [IQR: 9.2]	1 year	(I)68% (C)60%	(I)50.7 ± 11.6 (C)52.5 ± 12.1	1–5
Bhatia et al., 201830	India	I/II	1	20	NA	Autologous BM-MNCs	6.1 × 108	8–15 days	6 months	(I)80% (C)60%	(I)57 ± 12.2 (C)66 ± 7.3	1–3
de Celis-Ruiz et al., 202211	Spain	IIa	1	19	Placebo	Allogeneic AD-MSCs	1.0 × 107	13 days [IQR: 0.75]	2 years	(I)11% (C)30%	(I)78 (70.5–82) (C)76 (69–80.25)	1–3, 5
Savitz et al., 201932	USA	II	10	48	Placebo	Autologous BM-ALD-401 cells	3.08 × 106 (1.6 × 105– 7.5 × 107)	18.0 ± 1.9 days	1 year	(I)69% (C)79%	(I)59.3 ± 10.03 (C)62.9 ± 10.81	2–5
Houkin et al., 20248	Japan	II/III	44	206	Placebo	Allogeneic BM-multipotent progenitor cells	1.2 × 109	18–36 h	1 year	(I)54% (C)55%	(I)76.7 ± 10.4 (C)76.2 ± 10.6	1–5
Laskowitz et al., 202428	USA	II	6	73	Placebo	Allogeneic cord-blood cells	0.5–5 × 107/kg	3–10 days	1 year	(I)62% (C)62%	(I)62.6 ± 12.1 (C)64.4 ± 11.2	1–5
Lee et al., 201031	South Korea	I/II	NA	52	Standard treatment	Autologous BM-MSCs	1 × 108 ([5 × 107] ×2)	Onset to randomization 7 days Randomization to intervention 18.8–44.0 days	3.5 years (mean)	(I)50% (C)72%	(I)64.0 ± 11.6 (C)64.9 ± 14.5	2, 3
Hess et al., 201710	UK, USA	II	33	126	Placebo	Allogeneic BM-multipotent progenitor cells	1.2 × 109	37.2 ± 6.9 h	1 year	(I)54% (C)54%	(I)61.8 ± 11.4 (C)62.6 ± 11.4	1–5

AD adipose tissue-derived, BM bone marrow, IQR interquartile range, MNC mononuclear cel, MSC mesenchymal stem cell, NA not available, SD standard deviatio.

*(I): intervention group, (C): control group, (L): low-dose group, (H): high-dose group.

^†1. modified Rankin Scale, 2. mortality, 3. adverse events, 4. Barthel Index, 5. National Institutes of Health Stroke Scale.

Primary endpoint analysis

The primary endpoint, the mRS score, was assessed at 90, 180, and 365 days after treatment. In the cell therapy group, 36/322 patients had an mRS score of 0–1, compared with 27/257 in the control group (risk ratio [RR], 1.15 [95% confidence interval (CI), 0.72–1.84]; p = 0.55; I² = 0%) at day 90 (Fig. 2a). At day 180, an mRS score of 0–1 was observed in 19/132 patients in the cell therapy group and 15/121 patients in the control group (RR 1.10 [95% CI 0.31–3.87]; p = 0.85; I² = 33%) (Fig. 2b). At day 365, an mRS score of 0–1 was observed in 45/195 patients in the cell therapy group versus 23/179 controls (RR 1.74 [95% CI 1.09–2.77]; p = 0.0198; I² = 0%), a higher frequency in the cell therapy group (Fig. 2c). At day 90, an mRS score of 0–2 was present in 105/322 patients in the cell therapy group versus 67/257 patients in the control group (RR 1.31 [95% CI 1.01–1.70]; p = 0.0436; I² = 0%), a higher frequency in the cell therapy group (Fig. 2d). At day 180, an mRS score of 0–2 was observed in 36/122 patients in the cell therapy group and 29/111 patients in the control group (RR 1.04 [95% CI 0.69–1.58]; p = 0.84; I² = 0%) (Fig. 2e). At day 365, an mRS score 0–2 was present in 87/195 patients in the cell therapy group versus 61/179 controls (RR 1.27 [95% CI 0.98–1.65]; p = 0.08; I² = 0%) (Fig. 2f).

Fig. 2.

Forest plots comparing the risks of modified Rankin Scale (mRS) scores of 0–1 at 90, 180, and 365 days after treatment (a, b, and c), and the risks of mRS scores of 0–2 at 90, 180, and 365 days after treatment (d, e, and f).

Secondary endpoint analysis

In terms of secondary endpoints, the NIHSS scores did not differ between the cell therapy and control groups at day 90 (mean difference, – 0.08 [95% CI – 0.80 to 0.64]; p = 0.83; I² = 0%) (Fig. 3a). At day 180, the NIHSS score was significantly lower in the cell therapy group (mean difference, – 0.80 [95% CI, – 1.54 to – 0.05]; p < 0.05; I² = 0%) (Fig. 3b). At day 365, the NIHSS score did not differ between the groups (mean difference, – 0.19 [95% CI, – 1.17 to 0.80]; p = 0.71; I² = 0%) (Fig. 3c). At day 90, the BI score did not differ between the cell therapy and control groups (mean difference, – 0.40 [95% CI, – 6.24 to 5.45]; p = 0.89; I² = 0%) (Fig. 3d). The same was true at day 180 (mean difference, 0.22 [95% CI, – 9.22 to 9.65]; p = 0.96; I² = 0%) (Fig. 3e) and day 365 (mean difference, 5.67 [95% CI, – 1.17 to 12.51]; p = 0.10; I² = 0%) (Fig. 3f).

Fig. 3.

Forest plots comparing the mean differences in National Institutes of Health Stroke Scale scores at 90, 180, and 365 days after treatment (a, b, and c), the mean differences in Barthel Index scores at 90, 180, and 365 days after treatment (d, e, and f), the risks of serious adverse events up to the last follow-up (g), and the risks of mortality up to the last follow-up (h).

Cell therapy was not associated with the occurrence of serious adverse events, with an incidence of 119/330 patients in the cell therapy group and 114/279 patients in the control group (RR 0.85 [95% CI 0.70–1.04]; p = 0.11; I² = 0%) (Fig. 3g). Similarly, death from any cause was not associated with cell therapy, occurring in 34/428 cases in the cell therapy group and 56/388 cases in the control group (RR 0.72 [95% CI 0.49–1.08]; p = 0.12; I² = 0%) (Fig. 3h).

Risk of bias assessment

In terms of the risk of bias, the overall assessment revealed that five studies had a low risk, six had a medium risk, and two had a high risk. Specifically, one study was rated as high risk for “Deviations from the intended interventions”¹² and another study was rated as high risk for “Selection of the reported results”²⁶ (Fig. 4).

Fig. 4.

Risk-of-bias summary for each included trial. Green represents a low risk of bias, yellow represents some concerns, and red represents a high risk of bias.

Sensitive analysis and meta-regression

The results of the sensitivity analyses are illustrated in Supplementary Figs. S1 (sensitivity analysis 1) and S2 (sensitivity analysis 2). Although the presence of an mRS score of 0–2 90 days after treatment did not differ between the groups in sensitivity analysis 1 (RR 1.30 [95% CI 0.99–1.71]; p = 0.06; I² = 0%), all other sensitivity analyses yielded consistent results with the main analyses. Neither the univariate nor the multivariate meta-regression analyses revealed any statistically significant associations.

Discussion

This meta-analysis of RCTs of stem cell therapy for acute and subacute ischemic stroke yielded several important results. Stem cell therapy resulted in a notable increase in the number of patients with an mRS score of 0–2 at 90 days and of 0–1 at 365 days while being safe. The inclusion of a larger number of RCTs of patients who received stem cell therapy within 1 month of stroke onset favors the accuracy of our results over those of previous meta-analyses. This meta-analysis demonstrated that stem cell therapy yields a significant benefit in terms of the mRS score in the long term.

The mRS score is the most widely used measure of an individual’s inability to live an autonomous life after a stroke. The mRS score is often the primary endpoint in RCTs of cerebral infarctions, including the landmark trials that demonstrated the efficacy of recombinant tPA therapy and mechanical thrombectomy in acute stroke^32,33. This meta-analysis provides robust support for the efficacy of stem cell therapy for patients who experienced a cerebral infarction. In previous meta-analyses that demonstrated the functional efficacy of stem cell therapy, the primary outcome was the NIHSS score, and although significant differences were observed, the improvement in the NIHSS score was approximately 2 or less, indicating a significant but not clinically meaningful improvement^20–23,25. Two recent meta-analyses revealed significant reductions in mRS scores in the cell therapy groups, but as those results pertain only to differences in mean mRS values, the clinical benefit was unclear^16,18. A notable strength of the present study lies in its focus on clinically relevant outcome measures, specifically mRS 0–1 and mRS 0–2, which are more directly associated with favorable functional independence. Unlike previous studies that primarily evaluated broader or less specific endpoints, our analysis emphasizes outcomes with greater clinical significance. This approach enhances the translational relevance of our findings and provides clearer implications for patient care and therapeutic decision-making in the context of stem cell therapy for ischemic stroke.

In this study, no significant difference was observed between the stem cell therapy and control groups in achieving mRS 0–1 at 90 days, nor was there a discernible trend favoring stem cell therapy. In contrast, a significant difference in favor of the stem cell group was found for mRS 0–2 at 90 days; however, the results of the primary and sensitivity analyses were inconsistent. At 365 days, a significant improvement in mRS 0–1 was observed in the stem cell group. Although the difference in mRS 0–2 did not reach statistical significance at this time point, a favorable trend was noted. Importantly, findings for both outcomes were consistent between the primary and sensitivity analyses at 365 days, suggesting a more robust and sustained therapeutic effect over the long term.

This is in line with a previous report that has suggested that stem cell therapy may be more efficacious in the long term than that in the short term²⁹. Many of the stem cell therapies analyzed in this meta-analysis were administered intravenously. Auletta et al.³⁴ have postulated that the neuroprotective effects of the injected solution itself may contribute to the observed outcomes. However, the long-term benefits demonstrated in the present study cannot be attributed solely to these immediate neuroprotective effects. While stem cell therapy appeared to exert early benefits, the difference between groups in achieving an mRS score of 0–1 at 90 days post-treatment was not statistically significant. The mechanisms underlying the observed functional improvements at 1 year remain incompletely understood. Nonetheless, stem cells may facilitate neurological recovery through multiple pathways, including the regeneration of neurons and axons, the reorganization of synaptic connections, and the repair of disrupted neural circuits^35,36. In addition, paracrine factors secreted by bone marrow-derived mesenchymal stromal cells have demonstrated neuroprotective properties in preclinical models of ischemic stroke. These secreted factors—when administered during the acute phase—may mitigate inflammation, inhibit cell death, and support long-term tissue repair and regeneration. Angiogenesis also plays a critical role in long-term functional recovery following stroke, and stem cell therapy is actively being investigated for its pro-angiogenic potential. Furthermore, the immunomodulatory effects of stem cells may help regulate post-stroke immune responses, suppress chronic inflammation, and promote sustained neurological recovery³⁷. These mechanisms may collectively contribute to the long-term benefits observed and warrant further investigation to clarify the biological pathways involved.

Moreover, several studies have suggested that statins may enhance the therapeutic efficacy of MT and r-tPA^38,39. Accordingly, the combination of stem cell therapy with established treatments may yield additive or even synergistic effects. However, in the absence of robust clinical evidence supporting the efficacy of stem cell therapy in acute stroke, it has not yet been approved as a standard treatment worldwide. Instead, it is limited to administration in clinical studies. However, this meta-analysis has revealed that stem cell therapy contributes to an improved prognosis at 1 year. In contrast to previous meta-analyses, this meta-analysis was focused on the acute and subacute phases of stroke to minimize heterogeneity and because the effect of stem cell therapy is expected to vary depending on the timing of administration³⁴. Taken together, we propose that a clinical trial be conducted with patient outcomes after 1 year as the primary endpoints, with a view to establish stem cell therapy as the standard of care for acute and subacute ischemic stroke. Currently, the treatment for stroke after 24 h is not standardized. The results of this study suggest that stem cell therapy may become the standard of care within 1 month of stroke onset.

The strengths of this study include the integration of the latest large-scale RCTs, providing the most comprehensive and reliable evidence on the efficacy and safety of stem cell therapy to date. Furthermore, whereas the lack of consistency in the timing of outcome evaluations was an issue in previous meta-analyses, this meta-analysis is characterized by the unified timing of evaluations (90 days, 180 days, and 1 year later). Additionally, by including only patients who received stem cell therapy within 1 month of stroke onset, this study minimized heterogeneity related to the timing of treatment, thereby enhancing the accuracy and consistency of the results.

This study has several limitations. First, the limited number of available studies represents a significant constraint, potentially affecting the robustness and generalizability of the conclusions. Second, heterogeneity could not be entirely eliminated. Although we restricted inclusion to patients who received stem cell therapy within one month of cerebral infarction onset—and overall heterogeneity was generally moderate, particularly for the mRS score at 180 days—subgroup analyses based on cell type could not be meaningfully conducted due to the small number of studies and participants (data not shown). Additionally, considerable variability existed in stroke type and size, as well as in the methods of stem cell administration and dosage. To address these sources of variation, future clinical trials and meta-analyses with more narrowly defined inclusion criteria are warranted.

In conclusion, this systematic review and meta-analysis suggests that stem cell therapy administered within 1 month of ischemic stroke onset may offer some benefit in improving functional outcomes at specific time points—for example, a higher incidence of mRS 0–2 at 90 days and mRS 0–1 at 1 year. These findings support the potential of stem cell therapy as a promising adjunctive treatment. However, given the limited number of studies, heterogeneity in cell types, and inconsistencies in follow-up durations, these results should be interpreted with caution. Further research is needed to clarify the underlying mechanisms contributing to the observed benefits and to identify patient populations most likely to respond favorably to stem cell therapy.

Methods

Search strategy and selection criteria

Before we initiated this systematic review and meta-analysis, the study protocol was registered on PROSPERO (registration number: CRD42024503763). This study was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 reporting guidelines⁴⁰.

The inclusion criteria for this study were as follows: (i) participants were patients diagnosed with ischemic stroke; (ii) more than one patient who underwent stem cell transplantation within 1 month of stroke onset was included in the study, irrespective of the transplantation method or stem cell source; (iii) the comparison group received conventional medical therapy; (iv) the study was a RCT; (v) the study was available in English. We excluded publications with incomplete information or no extractable data, as the results of such studies could not be verified.

The following databases were searched by YM: CENTRAL, MEDLINE (via PubMed), Embase, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. Each database was searched using the following search scheme: patients AND intervention AND study design (Supplementary Table S1). Any conflicts in the results of the literature search and data extraction were resolved through consultation with the other authors. The search was conducted for data published in the databases from inception to January 17, 2024.

The literature was independently screened by two authors (TO and ST) using Rayyan software (https://www.rayyan.ai/). After duplicates were manually excluded using the “Detect duplicates” algorithm in Rayyan, primary screening of study titles and abstracts was performed, and those that did not meet the inclusion criteria were excluded. Secondary screening was performed by reading the full text to identify studies that met the inclusion criteria. Reasons for exclusion were noted throughout. As an additional step, we also screened the references of the studies included in the secondary screening.

Data analyses

The following data were extracted from the included studies by TO and ST: the title; first author’s name; year of publication, country where the study was conducted; study design; number of centers; enrolment start and end dates; type of stroke; sample size; baseline patient characteristics (e.g., mean age, sex, and activities of daily living [ADLs]); route, timing, frequency, and dose of stem cell therapy; type of stem cells; comparator(s); definition of “control” group; trial phase; outcome measures; follow‑up duration; eligibility criteria; source(s) of funding or other material support for the study; authors’ financial relationships and other potential conflicts of interest; outcome results; and information related to the risk-of-bias assessment. When the necessary data could not be extracted from the published article or registered information, we requested these directly from the authors. Only studies with the same time points for outcome evaluation were pooled for analysis to reduce variability, thereby enhancing the consistency and reliability of the results. Additionally, we planned to perform separate analyses based on cell types; however, as mesenchymal stem cells or similar cell types were analyzed in all 13 studies, this was not necessary.

The risk of bias of the included studies was assessed using the Cochrane “Risk of Bias” tool version 2⁴¹. Two authors (TO and ST) independently evaluated each outcome. Conflicts arising between them were solved by including the other authors.

Pairwise meta-analyses of the included studies were conducted to compare the outcomes and measures of effect between stem cell therapy and standard care (placebo). The primary outcome was the mRS score. The secondary outcomes were the NIHSS score as a nervous-system outcome, the BI score as an ADL outcome, and severe adverse events and death as safety outcomes.

We sought to summarize the effect estimates as follows. The measures of effect were RRs (95% CIs) for mRS scores, adverse events, and death, and mean differences for NIHSS and BI scores. The I-squared statistic (I²) was used to calculate the heterogeneity among the included studies. A random-effects model was used when I² was larger than 25%; otherwise, a fixed-effects model was used.

To evaluate the reliability of the results, a sensitivity analysis was conducted by excluding studies with a high risk of bias (sensitivity analysis 1). Furthermore, sensitivity analyses were performed on studies in which all participants received stem cell therapy within 30 days of the stroke onset (sensitivity analysis 2). A subgroup analysis based on stem cell type was attempted; however, the number of studies available for each cell type was limited to two or three, rendering the analysis infeasible due to insufficient statistical power. Meta-regression analyses were performed using a random-effects model. In the univariate meta-regression, baseline age, sex (proportion of male participants), and NIHSS score were included as explanatory variables. Although the interval from stroke onset to cell administration was initially considered, it was ultimately excluded from the analysis due to inconsistent reporting across studies. The outcome variables analyzed were the proportions of patients achieving mRS scores of 0–1 and 0–2 at 90, 180, and 365 days post-treatment. Additionally, a multivariate meta-regression was conducted using the same model specifications, simultaneously incorporating the aforementioned explanatory variables. Statistical analyses were performed using R version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria).

Electronic supplementary material

Below is the link to the electronic supplementary material.

Author contributions

TO, the principal investigator, conceived of the study. All authors contributed to the content and writing of the manuscript. TO wrote the first draft of the manuscript. ST and YM contributed to the curation and performed statistical analysis. TO, ST, and YM collected the data. KO and MF provided oversight for the research activities. KH and MF verified the trial data. All authors contributed to the scientific content of the manuscript, critically reviewed it, and approved the final version. All authors had final responsibility for the decision to submit for publication.

Funding

There was no funding source for this study. The funders of the trials included in this meta-analysis had no role in study design, data collection, data analysis, data interpretation, or writing of this report.

Data availability

All data produced or analyzed throughout this investigation are encompassed within this published manuscript.

Declarations

Competing interests

TO received a travel allowance from Healios. KH received consulting fees from Healios. ST, YM, KO, and MF declare no conflicts of interests.

Disclosures

TO received a travel allowance from Healios. KH received consulting fees from Healios. ST, YM, KO, and MF declare no conflicts of interests.