Cell therapy for heart disease: Trial sequential analyses of two Cochrane reviews

Abstract

Meta-analyses of cell therapy trials for heart disease have yielded discrepant results. To resolve limitations associated with meta-analyses, such as imprecision and accumulation of random errors, we conducted trial sequential analysis (TSA). Randomized controlled trials that administered autologous bone marrow-derived cells to patients who suffered acute myocardial infarction (AMI) or heart failure (HF) were included. TSA has been applied to two clinical outcomes, all-cause mortality and hospitalization for HF, and to left ventricular ejection fraction (LVEF), as a surrogate of heart function. The results suggest that there is evidence of reduction of the risk of mortality and hospitalization in HF, but insufficient evidence to determine treatment effect in AMI. Moreover, the treatment does not improve LVEF by more than a mean difference of 4% when administered to either AMI or HF patients. The required number of participants to include in a meta-analysis to detect treatment effect was also estimated.

Meta-Analyses of Human Cell-Based Cardiac Regeneration Therapies

“…A recent study has suggested that systematic reviews of cell therapies for heart disease are most likely underpowered to detect changes in LVEF of ≤4%. 23 This suggests that the results for LVEF from the systematic reviews and meta-analyses included here (Table 5) may be neither detectable nor clinically relevant and justify the selection of better surrogate outcomes to evaluate treatment effect. In contrast, this study found that the available evidence shows conclusively that cell therapy reduces mortality (risk ratio [RR], 0.42; 95% confidence interval, 0.27-0.64) in patients with CIHD/HF but that AMI studies are considerably underpowered to detect a similar effect size.…”

“…In contrast, this study found that the available evidence shows conclusively that cell therapy reduces mortality (risk ratio [RR], 0.42; 95% confidence interval, 0.27-0.64) in patients with CIHD/HF but that AMI studies are considerably underpowered to detect a similar effect size. 23 In a single RCT, the transitivity assumption states that treatment options are randomized in the same group of patients in the same trial. In other words, it is equally likely that any patient could have been given any of the treatment options.…”

“…The accumulation of these errors occurs when (1) a low number of trials with a low number of participants is included in the meta-analyses, (2) multiple reviews and review updates are conducted (multiple statistical testing), and (3) when the meta-analyses are underpowered or of insufficient quality. Recently, Fisher et al 23 have used trial sequential analysis with cumulative data from 2 Cochrane reviews and meta-analyses to address some of these limitations. Trial sequential analysis helps to reduce the likelihood of observing random errors (type I and type II errors) and estimates the information size, the total number of participants required in a meta-analysis to be confident about its findings.…”

Peripheral Blood Mononuclear Cell Secretome for Tissue Repair

“…However, three recent meta-analyses generated contradictory results. Fisher et al reported that autologous cell therapy may reduce the risk of mortality and re-hospitalization in patients with H F [14,15]. Gyöngyösi et al showed that intracoronary stem cell therapy following AMI provides no clinical benefits or reduction in mortality [16].…”

Mesenchymal stromal cell therapy as treatment for ischemic heart failure: the MSC-HF study

“…Bone marrow and blood mononuclear cells (MNC), hematopoietic progenitor cells (HPC) or mesenchymal stromal cells (MSC) have been administered to patients who have suffered a recent myocardial infarction (MI) as well as those with symptomatic ischemic HF (3). However, it is still unclear whether cell-based therapies represent an effective treatment for these patients (3)(4)(5)(6)(7). There is also a need to define the optimal cell therapy approach: the best cell type to be used in the clinic, the best delivery system and the patient group who would benefit most from these treatments.…”