|Additive value of adult bone-marrow-derived cell transplantation to conventional revascularization in chronic ischemic heart disease: a systematic review and meta-analysis
|Zhao Q, Ye X
The authors concluded that the myocardial injection of selected cells derived from bone marrow, after surgical revascularisation, might benefit patients with chronic ischaemic heart disease and severely impaired left ventricular ejection fraction. There were differences between trials, uncertainty about the analysis, and a small number of included participants, and the authors' conclusions should be treated with caution.
To investigate the impact of the transplantation of cells derived from bone marrow, on chronic ischaemic heart disease, after coronary artery bypass grafting or percutaneous coronary intervention.
MEDLINE, EMBASE, The Cochrane Library, Current Controlled Trials and BIOSIS Previews were searched for articles, in any language, from January 1990 to May 2011. Search terms were reported. The reference lists of retrieved articles and relevant reviews were handsearched.
Randomised controlled trials (RCTs) comparing intramyocardial or intracoronary injection of any dose and type of cells derived from the patient's own bone marrow were eligible for inclusion if this transplantation was compared with no such transplantation (placebo or plasma). Participants had to have a clinical diagnosis of chronic ischaemic heart disease and to have undergone a successful revascularisation by coronary artery bypass grafting or percutaneous coronary intervention. Trials with co-interventions were permitted if these were applied equally to all groups in the trial. Trials had to report the left ventricular ejection fraction (LVEF). Published or unpublished trials were eligible.
All participants had treated myocardial infarction, resulting in chronic irreversible myocardial scarring. In most trials of coronary artery bypass grafting, cells were injected into the myocardium. In trials of percutaneous coronary intervention, cells were delivered by intracoronary perfusion. The types of cells were unselected, selected or circulating progenitor cells; the specific type and dosage varied between trials. Where reported, the mean time from myocardial infarction to cell delivery ranged from more than six weeks to 81 months. Trials lasted from three to 12 months. Three trials had two intervention groups and a control group. These groups varied by cell type, cell delivery or acute versus old myocardial infarction.
Two reviewers independently selected the trials for the review.
Assessment of study quality
The quality of included trials was assessed according to criteria adapted from Juni, et al. This covered randomisation, allocation concealment, completeness of follow-up and blinding of outcome assessment.
Two reviewers independently assessed the quality of included trials, with disagreements resolved by consensus.
The change in mean LVEF, left ventricular end-systolic volume and left ventricular end-diastolic volume were extracted for each group and used to calculate mean differences with 95% confidence intervals for each trial. Outcome data from echocardiography, single-photon-emission computed tomography and magnetic resonance imaging (MRI) were considered to be equivalent. Where more than one measure was reported, MRI data were used. Authors were contacted where there were missing data.
Two reviewers independently extracted these data.
Methods of synthesis
Weighted mean differences and 95% confidence intervals were pooled from the individual trial data. Where trials reported different units, standardised mean differences were used. Statistical heterogeneity was assessed using Ι². Subgroup analyses were planned for the route of cell delivery, cell type, storage duration, dose of transplanted cells and baseline LVEF. Publication bias was assessed in funnel plots.
Results of the review
Ten RCTs were included in the review, with 422 patients. The allocation of participants was adequate in eight trials and the randomisation method was described in five. All trials had comparable groups at baseline. The patients or caregivers were blinded in only three trials. Nine trials had blinded outcome assessment and intention-to-treat analyses were performed in all trials. Loss to follow-up ranged from none to 20%. Follow-up was usually at three to six months.
Transplantation significantly improved the LVEF by 5.58% (95% CI 2.19 to 8.98; Ι²=86%; seven comparisons; n=232 patients) at three to four months follow-up and by 3.76% (95% CI 0.12 to 7.41; Ι²=88%; eight comparisons; n=250) at six months follow-up, compared with control. It significantly improved overall by 4.59% (95% CI 2.22 to 6.95; Ι²=87%). Statistical heterogeneity was high for all of these outcomes.
Transplantation significantly reduced left ventricular end-systolic volume (WMD -0.36, 95% CI -0.70 to -0.02; Ι²=21%) and left ventricular end-diastolic volume (WMD -0.38, 95% CI -0.76 to -0.01; Ι²=30%) at six months. These benefits were not observed at three to four months follow-up. Statistical heterogeneity for these analyses was low.
Subgroup analyses found that the impact of transplantation on LVEF was significantly associated with the primary intervention, route of cell delivery, cell type and baseline LVEF, but not with cell dose and duration of storage.
The myocardial injection of selected cells derived from bone marrow, after surgical revascularisation, might benefit patients with chronic ischaemic heart disease and severely impaired LVEF.
The review addressed a clear question with well-defined inclusion criteria. Several relevant databases were searched, with no language or publication restrictions, minimising the risk of language and publication biases. Publication bias was assessed, but there were few trials for a funnel plot, and bias cannot be ruled out. Appropriate steps were taken in study selection, data extraction and quality assessment to minimise the risk of reviewer error and bias. The quality of included trials was assessed, using an appropriate tool, and was generally good, but the trials were small, with few participants overall, which weakened the evidence.
No information was provided on the control groups or co-interventions, making it difficult to ascertain what transplantation was being compared with and to identify other interventions that might have affected the results. The trials focused on short-term (up to six months) outcomes in participants with old myocardial infarction, and it is unclear how applicable the results may be to patients with acute myocardial infarction, or over the long term (more than six months). Where trials had multiple treatment arms, the control group was double counted, which could have affected the reliability of the results. For most of the outcomes, high levels of statistical heterogeneity were reported, and it might not have been appropriate to combine the data in meta-analyses.
Given the differences between trials, uncertainty about the analysis, and the small number of included participants, the authors' conclusions should be treated with caution.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors stated that larger RCTs were needed to investigate the effects of cell transplantation in patients with chronic ischaemic heart disease over the long term.
Zhao Q, Ye X. Additive value of adult bone-marrow-derived cell transplantation to conventional revascularization in chronic ischemic heart disease: a systematic review and meta-analysis. Expert Opinion on Biological Therapy 2011; 11(12): 1569-1579
Subject indexing assigned by NLM
Adult; Angioplasty, Balloon, Coronary; Chi-Square Distribution; Chronic Disease; Combined Modality Therapy; Coronary Artery Bypass; Evidence-Based Medicine; Humans; Myocardial Ischemia /complications /physiopathology /therapy; Randomized Controlled Trials as Topic; Recovery of Function; Stem Cell Transplantation; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left /etiology /physiopathology /therapy; Ventricular Function, Left
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This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.