Autologous bone marrow stem cell therapy for patients undergoing coronary artery bypass grafting: A meta‑analysis of 14 randomized controlled trials
- Authors:
- Published online on: February 15, 2019 https://doi.org/10.3892/etm.2019.7283
- Pages: 2985-2994
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Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Ischemic heart disease (IHD) remains the leading cause of morbidity and mortality worldwide (1,2). Ischemic injury to the heart muscle often results in irreversible loss of myocardial tissue, with ensuing impairment of left ventricular (LV) function. In addition to medical treatment and surgical or interventional revascularization methods, there is currently a considerable number of studies on autologous bone marrow stem cell (BMSC) therapy in combination with coronary artery bypass grafting (CABG) in the treatment of IHD (3–16). BMSC therapy is aimed at repairing the damaged myocardium, preventing ventricular remodeling and improving overall cardiac function (17).
In clinical studies, the use of BMSCs is the most popular cardiac cell-based therapy. This may be due to the fact that BMSCs are easier to obtain compared with other stem cells (e.g., circulating stem cells and cardiac stem cells), and their preparation does not require prolonged ex vivo manipulation (18). Although recent studies demonstrated that catheter-based cell delivery (e.g., NOGA™ mapping) enables increased myocardial retention of cells, this method may not be feasible in certain patients with peripheral vascular disease (19). Therefore, injection of BMSCs is a good option for patients undergoing CABG.
However, the efficacy of CABG in combination with BMSC therapy remains controversial. It has been demonstrated that CABG combined with BMSC therapy is beneficial for cardiac function, without any adverse effects, and is therefore a safe and feasible adjunct therapy in clinical practice (3,4,13,16). However, other studies reported that CABG combined with BMSC therapy had no effect on global LV function and clinical symptoms (5,7).
Several previous meta-analyses on CABG combined with BMSC therapy either had certain methodological limitations or included an insufficient number of studies (20–22). In addition, since the publication of those meta-analyses, several new randomized controlled trials (RCTs) have been published (3,13,15). Hence, the present meta-analysis was performed to re-evaluate the effectiveness of CABG combined with BMSC therapy.
Materials and methods
Trial search
The PubMed, Cochrane Library, EMBASE and Web of Science databases were searched from inception to November 22, 2017, using the key words ‘bone marrow cells OR s'tem cells’ OR ‘cell’ OR ‘progenitor cell’ OR ‘stem cell transplantation’ OR ‘cell transplantation’ OR ‘bone marrow transplantation’ OR ‘stromal cells’ and ‘coronary artery bypass’ OR ‘coronary artery bypass grafting’ OR ‘Myocardial Revascularization’. There were no language restrictions.
Inclusion criteria
Studies were included based on the following criteria: i) Participants with a clinical diagnosis of chronic IHD; ii) RCTs comparing CABG in combination with BMSC therapy and CABG alone for chronic IHD; iii) follow-up for at least 3 months after stem cell therapy.
Exclusion criteria
The exclusion criteria were as follows: i) Non-RCTs; ii) catheter-based stem cell injection methods; iii) stem cells derived from sources other than the bone marrow (e.g., c-kit+ cardiac stem cells); iv) participants with a clinical diagnosis of acute myocardial infarction; v) stem cell injection without CABG; and vi) studies with incomplete LV function data.
Risk of bias assessment
The methodological quality of the selected RCTs was independently assessed by 2 researchers (SW and LY) based on the Cochrane risk of bias criteria (23), and each quality item was rated as low-risk, high-risk or unclear-risk. The 7 items used to evaluate bias in each trial included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective reporting.
Data extraction
Two reviewers (SW and LY) independently extracted the following relevant data from each study: First author; year of publication; country of origin; study population, including treatment and control group; participant characteristics, including age and sex; follow-up time; type of stem cells; dose of stem cells; route of stem cell administration; outcome measurement method; LV ejection fraction (LVEF), including baseline (LVEFbaseline), follow-up (LVEFfollow-up), and LVEF change from baseline to follow-up for the treatment (LVEFBMSC change) and control groups (LVEFcontrol change); LV end-diastolic volume (LVEDV), including baseline (LVEDVbaseline), follow-up (LVEDVfollow-up), and LVEDV change from baseline to follow-up for the treatment (LVEDVBMSC change) and control groups (LVEDVcontrol change); LV end-systolic volume (LVESV), including baseline (LVESVbaseline), follow-up (LVESVfollow-up), and LVESV change from baseline to follow-up for the treatment (LVESVBMSC change) and control groups (LVESVcontrol change); LV end-diastolic volume index (LVEDVI), including baseline (LVEDVIbaseline), follow-up (LVEDVIfollow-up), and LVEDVI change from baseline to follow-up for the treatment (LVEDVIBMSC change) and control groups (LVEDVIcontrol change); and LV end-systolic volume index (LVESVI), including baseline (LVESVIbaseline) and follow-up (LVESVIfollow-up), and LVESVI change from baseline to follow-up for the treatment (LVESVIBMSC change) and control groups (LVESVIcontrol change). Any disagreements between the reviewers were resolved by reaching a consensus.
Statistical analysis
The statistical analysis software R, version 3.4.2 was used to analyze the data. A meta-analysis was performed to calculate the mean difference (MD) LVEFchange (MD LVEFchange=LVEFBMSC change-LVEFcontrol change, LVEFBMSC change=LVEFBMSC follow-up-LVEFBMSC baseline, LVEFcontrol change=LVEFcontrol follow-up-LVEFcontrol baseline), and similarly, the MD LVEDVchange, MD LVEDVIchange, MD LVESVchange, and MD LVESVIchange, as well as their 95% confidence intervals (CIs). The majority of the studies reported the mean and standard deviation (SD). In one study (3), LV volume and ejection fraction values were expressed as mean and standard error (SE). The SE was converted into the SD by appling the formula SD=SE n, where n is the sample size. In two studies (4,7), the LV volume and ejection fraction values were expressed as the median and interquartile range. Median and interquartile range were converted into the mean and SD using the method introduced by Hozo et al (24).
In addition, the mean and SD of the LVEFBMSC change and LVEFcontrol change were not directly reported by certain studies (3,5,6,9,10,12,13,15,16). The mean of the LVEFBMSC change and LVEFcontrol change may be easily obtained by calculating the difference between the means of the LVEFbaseline and LVEFfollow-up. However, the SD of the LVEFBMSC change and LVEFcontrol change may only be effectively calculated from the LVEFbaseline and LVEFfollow-up values if the value of the correlation coefficient (Corr) is known. Therefore, the SD of LVEFBMSC change and LVEFcontrol change in the study by Hendrikx et al (11) were used to calculate the Corr values by using the following formula:
Corr=SDbaseline2+SDfollow - up2-SDchange22xSDbaselinexSDfollow - upThe calculation yielded Corr=0.6 for the BMSC and the control groups. The SD of LVEFBMSC change and LVEFcontrol change was calculated by inputting these values in the following formula:
SDchange=SDbaseline2+SDfollow - up2-2xCorrxSDbaselinexSDfollow - up.The mean and SD of the LV volume change values were calculated in the same manner.
A random-effects model was used to pool the data, and statistical heterogeneity between summary data was evaluated using I2 statistics. Egger's test was applied to examine publication bias. All tests were two-tailed and P<0.05 was considered to indicate a statistically significant difference.
Subgroup analysis
To evaluate whether the effectiveness of CABG combined with BMSC therapy in ischemic heart disease patients was influenced by the clinical characteristics, subgroup analyses were performed based on i) follow-up time (>6 or ≤6 months); ii) method to determine the outcome measure [echocardiography or cardiac magnetic resonance imaging (cMRI)]; iii) type of stem cells [bone marrow mononuclear cells (BMMNCs) or other selected cell populations (CD133+ and CD34+ cells)]; iv) route of injection [intramyocardial (IM) or intracoronary (IC)]; v) dose of stem cells [≥108 or <108 cells (108 was the median number of BMSCs injected)]; vi) baseline LVEF ≤35 or >35% (35% was the median LVEF at baseline in the included studies). Analyses were performed to evaluate whether the differences between the subgroups were statistically significant.
Sensitivity analysis
Sensitivity analysis was performed by excluding low-quality studies, trials recruiting participants with particular conditions or trials with characteristics different from the others. A sensitivity analysis of the primary outcome LVEF was performed.
Results
Search results
A total of 1,785 studies were identified from the electronic database search. Deduplication and removal of all clearly irrelevant studies excluded 151 articles. Initial screening of the remaining 1,627 studies against the inclusion criteria excluded a further 1,602 studies (animal experiments, case reports, meeting abstracts, insufficient data and reviews). In the remaining 23 studies, the full text was assessed for eligibility, subsequently excluding 9 studies: 2 studies used c-kit+ cardiac stem cells rather than BMSCs, 4 studies did not provide complete LV function data, 2 studies were replicated and no CABG was performed in 1 study. The final analysis included 14 independent RCTs. A flow chart depicting the study selection process is presented in Fig. 1.
Study characteristics
A total of 14 studies met the inclusion criteria for the present meta-analysis, including a total of 596 participants who were assessed for the primary outcomes of the study. The ‘treatment group’ (n=316) included participants who had received CABG combined with BMSC therapy, while the ‘control group’ (n=280) included patients who had only received CABG. The mean follow-up period was 11 months. The mean age of the participants ranged from 53.8 to 66.8 years, and the percentage of male patients ranged from 70 to 100%. A total of 5 studies were performed in China, 2 in Germany and 1 each in the USA, UK, Canada, Serbia, Finland, France and Belgium; the Canadian study was a multicenter trial (15 patients in Montreal and 18 in Toronto) (3). The baseline characteristics of the included studies are summarized in Table I.
Risk of bias assessment
Of the 14 studies, 9 (64.2%) adequately generated their randomisation sequence, 5 (35%) concealed allocation, 7 (50%) blinded participants and personnel, 6 (42.9%) blinded outcome assessment and 6 studies had a low risk of bias regarding selective reporting. All of the studies had a low risk of bias regarding missing outcome data. The detailed information on risk of bias is provided in Figs. 2 and 3.
LVEFchange
All 14 studies, including a total of 537 participants, reported on the change in LVEF after the treatment. In the treatment group, the mean change in the LVEF from baseline to follow-up was 8.46%. In the control group, the mean change in the LVEF from baseline to follow-up was 4.22%. The difference in the change of the LVEF between the treatment and control groups was statistically significant (MD=4.36%; 95% CI: 1.90–6.81%; P<0.01; Fig. 4).
LVEDVchange
A total of 7 studies with 224 participants reported on the change in LVEDV after the treatment. There was no significant difference in the overall change of LVEDV from baseline to follow-up between the treatment and control groups (MD=−6.27 ml; 95% CI: −22.34 to 9.80 ml; P=0.44; Fig. 5).
LVEDVIchange
A total of 4 studies with 159 participants reported on the change in LVEDVI after the treatment. There was no significant difference in the overall change of LVEDVI from baseline to follow-up between the treatment and control groups (MD=−15.11 ml/m2; 95% CI: −31.53 to 1.30 ml/m2; P=0.07; Fig. 6).
LVESVchange
A total of 5 studies with 156 participants reported a change in LVESV after the treatment. There was no significant difference in the overall change of LVESV from baseline to follow-up between the treatment and control groups (MD=−11.52 ml; 95% CI: −26.97 to 3.93 ml; P=0.14; Fig. 7).
LVESVIchange
A total of 4 studies with 159 participants reported a change in LVESVI after the treatment. There was no significant difference in the overall change of LVESVI from baseline to follow-up between the treatment and control groups (MD=−16.56 ml/m2; 95% CI: −37.75 to 4.63 ml/m2; P=0.13; Fig. 8).
Publication bias
To exclude potential publication bias, funnel plots (Fig. 9) and Egger's test for publication bias was performed. No publication bias was evident for the 14 studies included in the LVEF meta-analysis (Egger's test P=0.48 for the MD of LVEFchange).
Subgroup analysis
The subgroup analysis did not reveal any significant differences within subgroups based on follow-up period, type of stem cells, route of cell administration, dose of stem cells and baseline LVEF (Table II). However, the measurement method for the LVEF (echocardiography or cMRI) affected the effectiveness of CABG combined with BMSC injection in IHD patients (P<0.01; Table II).
Sensitivity analysis
A sensitivity analysis, in which the trials with relatively low-quality data by Maureira et al (8) and Zhao et al (14) were excluded, indicated that the results were not markedly affected by the exclusion [LVEFchange (MD=4.01%; 95% CI: 1.47–6.56%; P<0.01)].
Discussion
The present meta-analysis demonstrated that BMSC therapy may improve cardiac function during CABG in patients with IHD. The change of LVEF from baseline to follow-up in the treatment group (CABG + BMSCs) increased by 4.36% compared with that in the control group (CABG alone). The LVESVchange and LVEDVchange were reduced in the treatment group, but the difference from the control group was not statistically significant. Sensitivity analyses that excluded low-quality studies and studies that only included patients with particular medical conditions did not alter these results. Furthermore, these results were generally consistent, regardless of the follow-up time, type of stem cells, route of cell injection (IM or IC), dose of stem cells and baseline LVEF. However, the difference in the measurement method of LVEF (echocardiography or cMRI) affected the results (P<0.0001).
At present, the mechanisms of the efficacy of BMSC therapy in patients undergoing CABG remains elusive, and it may be multifactorial. Certain studies suggested that BMSCs may exert their beneficial effect by paracrine stimulation, cell fusion and transdifferentiation (25–28). Rota et al (29) demonstrated in rats that c-kit+ BMSCs engraft in proximity to the infarcted myocardium and differentiate into cells of the cardiogenic lineage, forming functionally competent cardiomyocytes and vascular structures. In addition, the effect of certain cytokines, including vascular endothelial growth factor (VEGF), has been indicated to restore coronary vessels and myocytes via angiogenesis following experimental infarction. BMSCs express a number of cytokines, including VEGF, insulin-like growth factor and platelet-derived growth factor, which stimulate the regeneration and proliferation of residual normal myocytes and intrinsic myocardial stem cells (endogenous stem cells) for cell regeneration and fusion (30,31).
In the present meta-analysis, 10 studies provided short-term follow-up (≤6 months) and 4 studies reported long-term follow-up (>6 months) data, but only 1 study provided 5-year follow-up data. There was no significant difference regarding the improvement in the LVEF between the short-term and long-term follow-up. A systematic review and meta-analysis by Jeevanantham et al (32) indicated that adult BMSC therapy improves the LVEF in patients with IHD compared with standard treatment, and these benefits persist at least beyond 24 months (32). Similarly, Nesteruk et al (33) indicated that the LVEF in the stem cell therapy group improved at 5 years compared with that in the CABG alone group. These data suggest that the benefits of BMSC therapy on cardiac function are not short-lived.
With regard to the methods for measuring the LVEF (echocardiography or cMRI), the subgroup analysis demonstrated that the choice of method affected the determined effectiveness of CABG combined with BMSC injection in IHD patients (P<0.0001). cMRI and echocardiography have important diagnostic value in assessing cardiac function, and perform similarly regarding the method of calculaton in the measurement of the cardiac ejection fraction. However, echocardiographic measurements may be affected by the ultrasonographer, whereas MRI is more reliable and accurate for measuring cardiac function.
Regarding the type of BMSC therapy, 2 of the 4 studies that included CD133+ or CD34+ cells in the meta-analysis had an unfavorable MD. However, only 1 of the 10 studies using BMMNCs/BMCs had an unfavorable MD. These results suggest that using BMMNCs/BMCs may lead to a more noticeable improvement in the LVEF compared with CD133+ or CD34+ cells. However, this result may be limited by the small sample size of the cohort treated with CD133+ or CD34+ cells, and accordingly, the conclusions may only be preliminary. Autologous cell preparations are medical products characterized by complexity in terms of differences in cell isolation protocols and storage of cell products, and the methods for assessing outcome may be inhomogeneous. These factors may affect the role of CD133+ or CD34+ cell therapy in improving cardiac function. Therefore, the function of CD133+ or CD34+ cells in improving LVEF and the underlying mechanisms and remain to be further elucidated.
A total of 3 previous meta-analyses (20–22) have analyzed the effect of CABG in combination with BMSC therapy in patients with IHD. The present results differ from those of the previous meta-analyses in several aspects. In the meta-analysis study by Donndorf et al (22) reported that the improvement in the LVEF (MD of LVEFchange of 5.40%) tended to be more prominent; however, their study only included 6 trials (4 RCTs and 2 cohorts; Table III presents the studies that were included in previous meta-analyses) with a total of 179 patients, whereas the present study included 14 RCTs with a total of 596 participants. Therefore, the present results may be more reliable. The meta-analysis by Qin et al (20) indicated that BMSC therapy significantly improved the LVEF and reduced the LVEDV and LVESV; however, their study only indicated the MD of the post-treatment LVEF values between the BMSC and the CABG alone groups, whereas in the present meta-analysis, the MD of LVEF change from follow-up to baseline between the BMSC and CABG groups was calculated. Therefore, the present results may be more reliable. Ali-Hassan-Sayegh et al (21), who included 9 studies (6 RTCs and 3 cohorts) with a total of 335 patients, obtained similar results compared with the present meta-analysis for the LVEFchange (MD=4.06%, 95% CI: 0.41 to 7.72%; P<0.01) and LVEDVchange (MD=7.06 ml, 95% CI: 8.58 to 22.7 ml; P=0.30). Our study demonstrated, with markedly narrower CIs, that CABG in combination with BMSC therapy may improve cardiac function. Compared with the previous meta-analysis studies, a large number of additional studies was included and more thorough analyses were performed. The addition of large RCTs provided more reliable estimates of the effects of CABG combined with BMSC therapy. Furthermore, the LVEDVI and LVESVI were only determined in 4 trials included in the present study (3,4,11,16). Although this is a small sample, these indexes are more reflective regarding the heart function compared with LVEDV and LVESV, as each individual's body surface area is different. In addition, the majority of the studies reported on the LVEDV and LVESV as clinical outcomes, so their data were extracted separately. This may be one of the reasons for the difference in LVEDV and LVESV not being statistically significant. Therefore, future meta-analyses must include more studies to obtain significant results.
The present meta-analysis was based on a comprehensive search strategy, including a systematic rigorous approach to the evaluation of RCTs investigating the effectiveness of BMSC therapy in combination with CABG in IHD patients. A detailed subgroup analysis was performed to explore differences in LVEFchange. Although the results of the present study appear promising regarding the efficacy of BMSC therapy, there were also certain limitations: First, there was significant heterogeneity in the present meta-analysis, which may be attributable to the dose and type of BMSC therapy, the timing of CABG combined with BMSC therapy after myocardial ischemia, the baseline LVEF, method of cell processing and outcome measurement methods, and these factors may affect the efficacy of BMSC therapy. Furthermore, the CIs were relatively wide, most likely due to the small number of studies and the relatively sparse subjects in all outcomes. Finally, the follow-up was relatively short in most studies, and the sustained efficacy of BMSC therapy for patients undergoing CABG remains to be further demonstrated. The results of the present meta-analysis should be confirmed in large, adequately powered RCTs assessing the efficacy of BMSC therapy, and outcome measures should be standardised (e.g. LVEF, LVEDV and LVESV). Future research should also focus on the mechanisms of action of BMSC therapy to further confirm the results of meta-analyses in IHD patients.
In conclusion, based on the present evidence, autologous BMSC therapy for patients undergoing CABG appears to be associated with an improvement in LV function. This improvement is beyond that achieved by CABG alone. Therefore, BMSC therapy may be beneficial as an adjuvant therapy for patients undergoing CABG.
Acknowledgements
Not applicable.
Funding
This study was supported by the National Natural Science Foundation of China (grant no. 81770300), the International Cooperation Exchange Project of Gansu province (grant no. 18YF1WA046), the Science and Technology Projects of Lanzhou, China (grant no. 2016-2-57) and CAS ‘Light of West China’ Program granted to MZ.
Availability of data and materials
All the datasets generated and analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
SW and LY analyzed the patient data and were the major contributors in the preparation of the manuscript. QB and AW analyzed part of the patient data. XS and YD performed the literature search and extracted the data. XD and XL were responsible for the statistical analysis. YZ, PY and KY made substantial contributions to the conception of the study. MZ and YC drafted the manuscript. All the authors have read and approved the final version of this manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests to disclose.
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