Intracoronary stem cell injection improves left ventricular remodeling after acute myocardial infarction: An updated meta-analysis of randomized trials

Abstract

A recent meta-analysis by Sun et al. [1] of randomized controlled trials [2–9] of stem cell therapy after acute myocardial infarction (AMI) suggested that cell therapy had no effect on left ventricular (LV) remodeling. Results of a number of randomized trials, however, have been published to date since the meta-analysis was performed. To reassess whether intracoronary stem cell injection improves LV remodeling after AMI in which the infarct-related artery was percutaneously revascularized, we updated herein the meta-analysis [1]. We searched literature through March 2011 with the same strategy and inclusion criteria as those of the meta-analysis by Sun et al. [1]. For each study, data regarding changes frombaseline to follow-up of ejection fraction (EF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV) in both the stem cell and control groups were used to generate mean differences (MDs) for EF changes and standardized MDs (SMDs) for LVEDV change and LVESV changes (because a number of trials provided not LVEDV and LVESV but LVEDV index and LDESV index) and 95% confidence intervals (CIs). Missing standard deviations were imputed according to the Cochrane Handbook for Systematic Review of Intervention [10]. Study specific estimates were combined in both fixed and random-effect models. Between-study heterogeneity was analyzed by means of standard χ tests. Where no significant statistical heterogeneity was identified, the fixed-effect estimate was used preferentially as the summary measure. Sensitivity analyses were performed to assess the contribution of each study to the pooled estimate by excluding individual trials one at a time and recalculating the pooled MD and SMD estimates for the remaining studies. To assess publication biaswe generated a funnel plot of the logarithm of effect size versus the reciprocal of standard error for each trial. Funnel plot asymmetry (small study effects) was assessed mathematically using Egger regression test [11]. When there was an evidence of significant funnel plot asymmetry, we estimated a number of possible missing studies and the summary measure including them using the ‘trim and fill’ algorithm [12]. All analyses were conducted using Review Manager (RevMan) version 5.1 (Nordic Cochrane Centre, Copenhagen, Denmark) and Comprehensive Meta-Analysis version 2 (Biostat, Englewood, NJ). Our search identified 15 randomized controlled trials [3–9,13–20] of intracoronary stem cell injection enrolling patients with AMI in which the infarct-related artery was percutaneously revascularized. The 6-month results [2] of the Autologus Stem-Cell Transplantation in Acute Myocardial Infarction (ASTAMI) study has been updated, and the 3-year findings [13] were included in our meta-analysis. In total, our meta-analysis included data on 877 patients with AMI randomized to stem cell therapy or control. Pooled analysis demonstrated a statistically significant increase in EF changes (MD, 2.87%; 95% CI, 1.95 to 3.78%; pb0.00001; Fig. 1) and a statistically significant reduction in LVEDV changes (SMD, −0.18; 95% CI, −0.32 to −0.04; p=0.01; Fig. 2) and LVESV changes (SMD, −0.35; 95% CI, −0.49 to −0.20; pb0.00001; Fig. 2) with stem cell therapy relative to control in fixedeffect models. There was minimally trial heterogeneity (p=0.09 for EF changes; p=0.50 LVEDV changes; p=0.38 for LVESV changes) and accordingly little difference in the pooled result from random-effects modeling. Exclusion of any single trial from the analysis did not substantively alter the overall result of our analysis. There was no significant funnel plot asymmetry for EF changes (p=0.40) and LVESV changes (p=0.14). Although significant funnel plot asymmetry for LVEDV changes (p=0.01) was identified, the summary SMD including 2 possible missing studies (estimated using the ‘trim and fill’ algorism [12]) was−0.31 (95% CI,−0.45 to−0.17) that remained statistically significant. Compared with control group in the most recent meta-analysis of randomized controlled trials by Sun et al. [1], although stem cell therapy did not influence LVEDV changes (MD, −0.95 mL; 95% CI, −4.49 to 2.59 mL), patients in the cell therapy group had a significant greater reduction in LVESV changes (MD, −5.00 mL; 95% CI, −7.78 to −2.21 mL). Whereas, the results of our updated meta-analysis suggest that intracoronary stem cell injectionmay increase EF changes and reduce not only LVESV changes but also LVEDV changes over control in patients with AMI in which the infarct-related artery was percutaneously revascularized, which was robust in sensitivity analyses. Stem cell therapy is likely effective in both LV contractility and remodeling. There was no funding source for this study. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. None of the author is in any condition that may represent a potential conflict of interest. The authors of this manuscript have certified that theycomplywith thePrinciples of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1–2).