Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in Patients With Acute Myocardial Infarction Based on Individual Patient DataNovelty and Significance
Rationale: The meta-Analysis of Cell-based CaRdiac study is the first prospectively declared collaborative multinational database, including individual data of patients with ischemic heart disease treated with cell therapy.
Objective: We analyzed the safety and efficacy of intracoronary cell therapy after acute myocardial infarction (AMI), including individual patient data from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS, FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME; n=1252).
Methods and Results: The primary end point was freedom from combined major adverse cardiac and cerebrovascular events (including all-cause death, AMI recurrance, stroke, and target vessel revascularization). The secondary end point was freedom from hard clinical end points (death, AMI recurrence, or stroke), assessed with random-effects meta-analyses and Cox regressions for interactions. Secondary efficacy end points included changes in end-diastolic volume, end-systolic volume, and ejection fraction, analyzed with random-effects meta-analyses and ANCOVA. We reported weighted mean differences between cell therapy and control groups. No effect of cell therapy on major adverse cardiac and cerebrovascular events (14.0% versus 16.3%; hazard ratio, 0.86; 95% confidence interval, 0.63–1.18) or death (1.4% versus 2.1%) or death/AMI recurrence/stroke (2.9% versus 4.7%) was identified in comparison with controls. No changes in ejection fraction (mean difference: 0.96%; 95% confidence interval, −0.2 to 2.1), end-diastolic volume, or systolic volume were observed compared with controls. These results were not influenced by anterior AMI location, reduced baseline ejection fraction, or the use of MRI for assessing left ventricular parameters.
Conclusions: This meta-analysis of individual patient data from randomized trials in patients with recent AMI revealed that intracoronary cell therapy provided no benefit, in terms of clinical events or changes in left ventricular function.
Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01098591.
Meta-analyses of randomized and cohort cell therapy studies have reported that intracoronary or intramyocardial cell delivery was safe, and it provided 2% to 8% increases in global left ventricular (LV) ejection fraction (EF) in patients with acute myocardial infarction (AMI) or ischemic cardiomyopathy.1–4 Those meta-analyses were based on information from published articles and included different patient populations, follow-up times, and outcome measures, resulting in data heterogeneity because of inconsistent clinical definitions and parameters. In addition, publication-based meta-analyses may include studies that were later withdrawn or that contained publication errors,5 and they may exclude important trials that reported median values of skewed data. In contrast, individual patient data (IPD)-based meta-analyses contain transparent, controlled data, with unique definitions; this approach allows analyses of specific subgroups and generation of prognostic models.
Editorial, see p 1287
In This Issue, see p 1277
The largest previous relevant meta-analysis enrolled 50 studies (n=2625 patients). They reported that cardiac transplantation of adult bone marrow–derived cells provided persistent benefits, in terms of clinical outcome and LV parameters.3 However, a recent meta-analysis on intracoronary cell treatment trials, which included 30 studies (n=2037 patients), could not confirm data obtained from MRI measurements of LV function4; moreover, they were the first to report that cell therapy had no effect on clinical outcome. Both meta-analyses used aggregated data from published studies with considerable heterogeneity across the trials involved.
The ongoing meta-Analysis of Cell-based CaRdiac study (ACCRUE; NCT01098591, formerly MEta-analysis of Stem cell Studies, MESS) is a collaborative, multinational database that comprises IPD from randomized and cohort studies. The ACCRUE database was established to facilitate exploration of the clinical safety and efficacy of cell therapy in patients with ischemic heart disease (IHD) and to identify subgroups of patients predicted to benefit from cell therapy. The present study represents the first IPD-based meta-analysis of cell treatment in IHD to date. The objectives of the ACCRUE database are as follows:
To estimate the overall treatment effect of cardiac cell-based therapy on clinical outcomes, including occurrence of major adverse cardiac and cerebrovascular events (MACCE, composite of all-cause death, AMI recurrence, coronary target vessel revascularization [TVR], and stroke) and the occurrence of clinical hard end points (death, AMI recurrence, or stroke);
To analyze the effect of cell treatment on LV function and remodeling, including changes in end-diastolic volume (EDV), end-systolic volume (ESV), and EF;
To identify predictors of MACCE and of LV function and remodeling improvements in patients with IHD treated with cell therapy;
To explore the influence of patient characteristics, including cardiovascular risk factors, on the safety and efficacy of cardiac cell therapy;
To identify the characteristics of individual patients with IHD, that can predict benefit from cell therapy.
The main objective of the ACCRUE group is to use IPD to improve the quality of data used in meta-analyses of cell therapy studies in patients with chronic IHD and AMI. The first collaborative meeting was held in Vienna, 2007, with the investigators of the ASTAMI, REGENT, BOOST, Aalst (Bartunek)-study, BONAMI, REPAIR-AMI, Atsma-study, MYSTAR, STEMMI, the Hamburg and Novosibirsk intramyocardial studies, and the EUROINJECT-ONE cardiac gene therapy study. The meeting aimed to define objectives, to establish data contribution criteria, and to appoint the Independent Data Committee and Steering Committee (Online Data Supplement).
Criteria for Considering Studies for Inclusion in the ACCRUE Database
The criteria for participation in the ACCRUE database were that the data must be from randomized or cohort clinical studies, and that cardiac regeneration was induced by percutaneous administration of cells or cell-based products, or by mobilization of bone marrow–derived cells. A continuous literature search was initiated, and principal investigators and study coordinators of recently published studies were prospectively invited to contribute IPD to the database. Additional study inclusion criteria for randomized studies are included in the Online Data Supplement.
The primary outcome measure of the ACCRUE meta-analysis was the safety of the treatment, defined as the freedom from MACCE (the composite of all-cause death, AMI recurrence, stroke, and TVR). The secondary end points were freedom from the combined hard clinical end points (all-cause death, AMI recurrence, or stroke) or freedom from the individual components of MACCE. Another secondary end point was efficacy, defined as changes in LV EDV, ESV, and EF, compared with baseline.
Search Methods for Identifying Studies
Studies were prospectively identified in literature searches, and the identified investigators were invited to participate. The search methods are included in the Online Data Supplement.
Data Collection and Management
The data collection method is described in the Online Data Supplement. The corresponding authors and primary investigators of the selected studies were e-mailed or contacted personally several times with invitations to contribute original data to the central database (Figure 1). A database with predefined terms and conditions (determined and agreed on at the first investigator meeting) was sent to the participants for depositing the individual data. Authors from 39 centers responded, and data were received from 23 centers6–17 (References 18–28 in the Online Data Supplement). One center later cancelled participation and withdrew their data, referencing changes in institutional policy. The current ACCRUE database comprises 1871 IPD sets from 28 studies (15 randomized and 10 cohort cell therapy and 3 granulocyte-colony stimulating factor studies). All patients were classified as “cell-treated” (n=1203) or “control” (n=668).
In accordance with prespecified plans, analyses performed in ACCRUE differ from those performed in the individual papers. Therefore, results from the ACCRUE report may be different from those reported in the individual papers, particularly when different terms were used for event classifications or follow-up times. These issues were discussed with the corresponding authors of all papers.
All studies were approved by the local ethics committees. Additional approval was obtained for the meta-analysis. Data quality was evaluated with quality checklists from CONSORT18 and PRISMA (http://www.prisma-statement.org) statements and guidelines.
The database was controlled by the IDC. It was temporarily closed in June 2014, to perform the first statistical analysis. The current meta-analysis included data from patients with recent AMIs who were randomized to either intracoronary cell therapy or control groups (ASTAMI, Aalst, BONAMI, BOOST, CADUCEUS, FINCELL, LATE-TIME, REGENT, REPAIR-AMI, SWISS-AMI, TIME, SCAMI trials).6–17 The present analysis excluded all noncontrolled studies, the MYSTAR study with a combined delivery mode, and all randomized percutaneous intramyocardial cell-based studies in patients with chronic IHD (Figure 1).
Assessment of Risk of Bias in Included Studies
Methods for assessing the risk of bias and quality assessment are described in the Online Data Supplement.
This IPD meta-analysis was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Intervention19 and the guidelines for meta-analysis of IPD for time-to-event outcomes.20,21 Heterogeneity between the studies was tested with I2 statistics. Additional sensitivity analyses were performed to detect differences between studies. Two investigators conducted the analyses (E.N., M.G.).
Investigation of Heterogeneity and Selection Bias
The statistics for investigating heterogeneity and selection bias of the included trials are presented in the Online Data Supplement.
Normally distributed, continuous variables are presented as mean±SD. Continuous parameters with skewed distributions are expressed as the median and first interquartile range. Binary and categorical variables are given as frequencies and percentages. Associations between the number of cells/log number of cells and the changes in EDV, ESV, or EF in the cell-treated group were calculated with linear regression analysis.
All P values were based on 2-sided tests. For multiple comparisons, P values <0.01 were considered statistically significant.
All analyses were based on the intention to treat. Multiple Cox regression models were used to analyze the primary outcome, stratified for the individual studies. The multiple models included cardiovascular prognostic factors for the occurrence of MACCE, such as sex, age, diabetes mellitus, hypertension, hyperlipidemia, and baseline EDV and EF values. This model was used to determine an adjusted, common treatment effect, with baseline hazards that varied across studies.20,21 To evaluate possible dependencies of the treatment effect on other prognostic factors, all possible interactions were tested within the multiple stratified Cox regression models. Factors were excluded from the analysis when data were missing in ≥50% of cases (eg, positive family anamnesis for heart disease, baseline infarct size). Adjusted hazard ratios and their 95% confidence intervals (CIs) are presented with the corresponding P values. The Kaplan–Meier method and cumulative hazards were used to display the MACCE-free, death-free, death/AMI recurrence/stroke-free, and TVR-free survival rates. Prespecified subgroup analyses for the primary end point and the secondary end point of death/AMI recurrence/stroke were performed for the following subgroup categories: age (> or ≤57 years), EF (> or ≤45%), baseline EDV (> or ≤130 mL), anterior AMI (yes or no), maximal creatine kinase (CK, > or ≤3450 U/L; CK is associated with infarct size; 3450 U/L was the median value for all patients), sex, diabetes mellitus, hypertension, hyperlipidemia, smoking, and use of MRI.
The secondary end points, changes in LV EF, EDV, and ESV, were evaluated with ANCOVA. The treatment effect was adjusted for cardiovascular risk factors, men, mode of measuring LV function, anterior location of AMI, baseline EDV, baseline EF, and time between AMI and randomization/sham intervention in controls or cell therapy in cell-treated groups; for these adjustments, the individual studies were considered a block factor. Possible interacting effects with treatment were tested within these ANCOVA models. Changes in EDV, ESV, and EF in the cell therapy and control groups are expressed as mean±SD; the mean difference from baseline was reported with SE and the relative 95% CIs were reported as effect measures.
Prespecified subgroup analyses included the effect of follow-up time and the effect of baseline EF on changes in LV function, evaluated as dichotomous variables. The numbers of patients in groups who received different subtypes of autologous cells were uneven or low; therefore, we did not perform subgroup analyses on the effect of cell types on the end points.
All statistical computations were performed with Review Manager 5.2 (The Nordic Cochrane Center, Købehvn, Denmark), and Stata/SE, version 12, for Windows (StataCorp, Houston, TX).
A systematic search for eligible trials resulted in 1533 clinical reports on cardiac cell therapies. Of these, 921 were excluded on the basis of the preclinical nature of the studies or because they were only abstracts or incomplete reports. Thus, 612 clinical studies were eligible, and 149 were selected because they used cell injections or autologous bone marrow–derived cells mobilization. A further 94 studies were excluded because they were reviews, descriptions of surgical approaches, or pilot studies for study designs or subanalyses. Finally, 55 studies were selected, and the corresponding authors were contacted. The present analysis included 12 randomized studies on intracoronary cell therapy applied after AMI (Figure 1).
Table 1 lists the study characteristics. An average of 104 patients were included in the studies (n=64 and n=40 for cell treatment and control groups). Most studies used bone marrow mononuclear cells, and MRI was used for visualizing and quantifying LV performance. Three studies assessed the timing of cell therapy (CADUCEUS, LATE-TIME, SWISS-AMI); otherwise cell therapies were performed within 2 weeks post-AMI. Most patients were randomized during the first week (65% of patients in the cell therapy and 79% of patients in the control group), and EF was measured before randomization. The quantitative baseline LV functional parameters were assessed at the time of the primary percutaneous coronary intervention (eg, FINCELL), before randomization, 1 to 3 days post-AMI (eg, REGENT), or several weeks post-AMI after resolution of myocardial stunning (eg, LATE-TIME). Thus, there were different time lapses between the delivery of cell therapy and the measurement of baseline LV function.
All patients received clinical follow-ups. Paired LV functional data measured at baseline and at follow-up were available for 1064 (624 cell therapy and 440 control) patients. Baseline LV function and follow-up events were not different for patients who lacked paired LV data for any reason (data not shown).
Infarct size data were available for 114 of 767 patients (14.9%) who received cell therapy and for 111 of 485 patients (22.9%) in the control group. Because these groups did not represent the entire population, we did not analyze changes in infarct size.
Study Quality and Risk of Bias in Included Studies
Online Table I shows the quality assessment scales of the studies on randomized intracoronary cell therapy in AMI that were included in the ACCRUE database. The internal validity scales, the results of the external validity criteria, and sensitivity analyses are described in Online Data Supplement.
Baseline Patient Characteristics
Table 2 shows the baseline clinical data, including measurements of baseline LV function parameters. No differences were observed between the 2 groups with the exception of ESV, which was lower in controls. Cardiac MRI was more often used as the imaging modality in the cell therapy group because of the higher number of patients in cell therapy group than in the control groups of the SWISS-AMI and REGENT trials (2:1 randomization).
Primary End Point
MACCE was similar between the groups (hazard ratio, 0.86; 95% CI, 0.63–1.18; Table 3; Online Figure I). After adjusting for all confounding factors, the Cox regression showed no effect of cell therapy on MACCE-free survival (Table 3; Figure 2). The addition of anterior AMI as a confounding factor did not influence the primary outcome (Online Table II). The subgroup analysis did not reveal a prognostic factor for prevention of MACCE (Figure 2); therefore, we found no factors that influenced the success of cell therapy.
The results of the overall meta-analysis (between-trial analysis) for the primary end point were highly consistent in direction and magnitude with those obtained from the individual participant data meta-analyses (within-trial analyses); ie, there was no significant benefit with cell therapy versus controls (hazard ratio, 0.86; 95% CI, 0.63–1.18; P=0.884). No significant heterogeneity or inconsistency was found between trials (I2=0%). In addition, the funnel plot for the primary end point did not show asymmetry on visual inspection (Online Figure I), which was confirmed by a nonsignificant Egger test.
Secondary End Points
Similar to the primary end point, cell therapy did not improve clinical outcome in terms of the incidence of death, or death/AMI recurrence/stroke, and TVR (Table 3; Figure 3A, Online Figure II). No cardiovascular risk factor could be identified that influenced the clinical hard end points (death/AMI recurrence/stroke). Similarly, the hard end points were not impacted by a lower baseline EF, a higher EDV, the location of infarction, the maximal CK, or whether LV function was measured with MRI. Although we observed a trend toward differences in different subgroups, as shown in the forest plot (Figure 3B), no interaction was significant (P>0.01).
Both EDV and EF increased slightly in cell-treated and control groups (Table 3) without a decrease in ESV from baseline to follow-up. Cell therapy did not influence the changes in global EF (mean between-group difference of 0.96%; 95% CI, −0.2 to 2.1), EDV (1.2 mL; 95% CI, −3.4 to 5.8), or ESV (0.4 mL; 95% CI, −3.4 to 4.1; Table 3; Figure 4).
Table 4 summarizes the ANCOVA results (detailed data in Online Table III). The final changes in EDV, ESV, and EF were not influenced when the model included covariates of sex, age, diabetes mellitus, hypertension, hyperlipidemia, anterior AMI location, MRI imaging modality, baseline EDV, baseline EF, or timing of cell treatment. Cell therapy in older patients led to a greater increase in EDV compared with controls, with no significant changes in ESV or EF (Online Table III).
Subanalysis of Different Follow-Ups
Four studies provided a 1-year clinical follow-up data (CADUCEUS, REPAIR-AMI, SWISS-AMI, and SCAMI); the other studies reported clinical follow-ups of ≤6 months. No difference between the groups was identified at the 6-month follow-ups or at the 6- to 12-month follow-ups on MACCE, death, death/AMI recurrence/stroke, or TVR (Online Figures III–V). The majority of MACCE events were TVR at the 6-month follow-up. Trials with a planned 6-month clinical follow-up controlled the patients and performed TVR when in-stent restenosis of the infarct-related artery was documented. This resulted in an increase in the TVR incidence at 6 months, but there was no difference between groups.
Most of the LV functional measurements were performed at the 6-month follow-up; the Aalst-study, BONAMI, and REPAIR-AMI provided 3- or 4-month follow-up data; the CADUCEUS and SCAMI studies also had control measurements at 1 year. Table 5 shows the follow-up time-dependent changes in LV EDV, ESV, and EF in cell-treated and control groups. An increase was observed in EDV from baseline to the 6-month and 12-month follow-ups in both the cell therapy and control groups. Because of the relatively low numbers of patients in these subgroups, and to avoid a type I error, we did not perform statistical comparisons between the 6- and 12-month follow-up data. No difference between groups was detected on follow-up data collected at ≤6 months, or >6 months.
Subanalysis of Baseline EF Effects on Changes in LV Parameters
The subclasses of baseline EF (>50%, >45%, and >40%) showed no influence of baseline EF on the changes in EDV, ESV, or EF at the follow-up (Table 6).
Effect of the Number of Injected Cells on LV Function
Linear regression analysis showed no correlation between the number of injected cells or the log number of injected cells and the changes in EDV, EF (Online Figure VI), or ESV (data not shown) in the cell-treated group. There was, however, a large scatter in the number of cells applied (range: 12.5–4303×106).
Comparison of ACCRUE Data With Results From Nonparticipating Studies
Online Table IV summarizes the results from currently published randomized cell-therapy trials in patients with recent AMI who did not contribute to the ACCRUE database. The reported mean EF, SD, and the number of included patients are shown (References 29–47 in the Online Data Supplement). These 19 studies included 503 patients (mean=27) in the cell-treated group and 352 patients (mean=19) in the control group. In contrast, the ACCRUE intracoronary arm included 767 patients (mean=64) in the cell-treated group and 485 patients (mean=40) in the control group. The ACCRUE database currently represents >70% of all clinical cardiac regeneration studies and ≈60% of all intracoronary cell studies; it includes all major randomized studies, except the HEBE trial, the Cao, and the Chen studies (References 36, 40, and 45 in the Online Data Supplement).
The ACCRUE is the first IPD database to facilitate meta-analyses of cardiac cell therapy. The database currently comprises a pool of 1871 IPD from 15 randomized cardiac regeneration studies; 12 of these studies (with 1252 IPD) involved intracoronary cell delivery in patients with recent AMIs. This first meta-analysis of the ACCRUE selecting these 12 randomized studies on intracoronary administration of reparative cells shows no effect of cell therapy on clinical events or changes in LV function or remodeling. On the basis of original data, we could not identify predictive factors or patient characteristics that might indicate patients most likely to benefit from cell therapy.
An important feature of this ACCRUE, which is rarely seen in other meta-analyses, is its prospective nature, following the Cochrane guidelines for planning and conducting an IPD meta-analysis. The prospective data collection of ACCRUE allows the uniform definitions of end points, follow-up periods, and adverse events; this approach ensured the most unbiased, and thus, the most reliable results, and increased the robustness and accuracy of the findings.
However, some caution should be taken with the interpretation of our results. The negative and, for the health community, disappointing results are not surprising. Six of the included studies (including about two thirds of the study patients), which comprised the largest and most homogeneous clinical populations (ASTAMI, BONAMI, REGENT, TIME, LATE-TIME, SWISS-AMI), reported no benefit from autologous cell-based, intracoronary regenerative treatment.8,9,11,15–17 One of the 3 similarly large studies which were not included in the ACCRUE database (HEBE) also reported a negative outcome.
Potentially, the efficacy of cell therapy could be affected by differences among the studies included in the ACCRUE database. For example, differences in the types of injected cells and the timing of cell administration (acute phase of AMI versus convalescent AMI) may affect the outcomes. We did not evaluate these factors separately because the individual subgroups would have comprised statistically unacceptably low number of patients. However, the ANCOVA analysis showed that, when the time to cell/control therapy was considered as an independent covariate, it did not significantly affect the changes in EDV, ESV, or EF. An additional factor that might influence changes in LV function could be the time that baseline EF was measured (if not the same day as the cell therapy). This timing may be consequential, considering that, in the natural course of the reperfused AMI, during the first week, rapid changes were observed in the EF, and the size of late enhancement in serial MRI.22 Moreover, there was a time-dependent component in the regenerative function of the different types of harvested autologous comorbid bone marrow–origin cells.23
Adverse Events, LV Function, and LV Remodeling Related to Intracoronary Cell Therapy
Intracoronary administration of cells proved to be safe, with a low procedural complication rate (2.2%). The composite in-hospital complications were similar between groups. The mortality and incidence of hard clinical end points were noticeably low among the patients with ST-segment–elevation myocardial infarction in both groups. This finding may have resulted from the carefully selected patients and the relatively high baseline EFs. Subanalyses of different follow-ups did not change the outcome difference between treated and control patients; the negative results were consistent. We point out that a placebo effect has been observed in blinded randomized trials, although this effect might be less significant than in nonrandomized studies. Because the placebo effect is additive to the control treatment effect, it can reduce the observed treatment effect size and the statistical power of the study.
Most patients underwent MRI scanning, which is regarded the gold standard for assessing LV function. Similar to our results, de Jong et al4 found that the beneficial effect of cell therapy on LV EF and infarct size disappeared, when MRI was used for quantitative imaging. In addition, both studies found that the baseline EF did not affect the improvement in LV function compared with time.4 Also our data were consistent with a previous study, where serial cardiac MRIs of patients with reperfused first AMIs showed a gradual increase in LV EDV during the first year after the AMI.22
In contrast with previous meta-analyses3,4 we did not assess infarct size at follow-up because the majority of trials did not measure infarct size before cell therapy; therefore, no change between baseline and follow-up could be reported. Instead, we added the maximal CK as a confounding factor that could influence the outcome because maximal CK is highly associated with infarct size.24
In contrast with previous meta-analyses, we found no association between the number of cells delivered and the outcomes. It should be mentioned, however, that the numbers of cells used for intracoronary cell therapy varied widely, even without considering trials that assessed the importance of cell number on the clinical or functional outcome. Previous studies reported only the mean or median numbers of injected cells/group. Therefore, the results of those analyses should be considered less exact than results from this ACCRUE study.
One of the objectives of this meta-analysis was to reveal prognostic factors for clinical events or identify patients who might benefit from cell therapy. We did not achieve this objective, despite the fact that intracoronary treatment arm of the ACCRUE database included large randomized studies (mean of 104 patients per study) with remarkably low between-trial heterogeneity, when compared with the previous largest reported meta-analysis.3,4 Because we used common definitions of primary end points throughout the studies, the heterogeneity for clinical end points was 0% among studies. In contrast to previously published meta-analysis, which showed up to 87% heterogeneity among studies, our meta-analysis showed little or no heterogeneity among studies for continuous parameters of the secondary end points, ie, the heterogeneities were 0% for ΔEDV, 11% for ΔESV, and 48% for ΔEF. This highlighted the accuracy of a large-scale IPD-based meta-analysis in characterizing any potential effect in different clinical subgroups and its pivotal role in fully exploring the clinical relevance and adequacy of cell therapy for treating IHD. However, according to de Jong et al,4 >30 000 patients should be included in a study to identify an effect of cell therapy, when mortality is ≈2%.
Advantages of the IPD-Based Meta-Analysis
This ACCRUE IPD-based meta-analysis overcame the major limitations of systematic reviews and conventional meta-analyses. Those approaches extract aggregated data from available publications according to a predefined study protocol, and the random effects are determined by calculating the weighted means (eg, relative risk) of randomized trials. Accordingly, publication-based meta-analyses must exclude some important trials, where group differences are expressed as the median and interquartile range (eg, BONAMI, HEBE, MYSTAR, REGENT). Online Table IV shows the heterogeneity among reports of LV functional data from studies that were not included in the ACCRUE database. All but 1 study (Ruan et al, Reference 47, in the Online Data Supplement) were included in a recent intracoronary cell therapy AMI meta-analysis.4 When no original data were available, they recalculated the mean differences and 95% CIs or SDs with meta-analysis software and a standardized formula. Thus, these recalculated data were partially discrepant with the published or original data; eg, Plewka et al showed changes in EF from baseline to follow-up of 10±9% in the cell therapy group versus 5±8% in controls (Reference 35 in the Online Data Supplement); in contrast; the calculated random-effect meta-analysis data showed EF changes of 9±5.8% versus 5±4.9%, or 9±7% versus 5±3.4% in cell-treated versus control groups, respectively.3,4 In contrast, the present IPD meta-analysis included raw data; thus, we could calculate accurate real means with SDs, mean differences with SEs and CIs; moreover, these calculations were not influenced by the limited information gained from the publications.
Limitations of the ACCRUE Database
A major limitation of the presented study was the combination of several different cell types (bone marrow mononuclear cells, CD133+ -enriched bone marrow–derived cells or CD34+CXCR selected cells, or cardiosphere-derived cells). As in all previous meta-analyses, we assumed that the potency was comparable among different cell types. In fact, different cell population exert heterogeneous effects, depending on the amount of time passed since AMI.23 In addition, when various clinically used cell types were compared directly in the same mouse infarct model, the rank order of efficacy was cardiosphere-derived cells>>bone marrow mononuclear cells.25 Only 2% of the ACCRUE database comprised heart-derived cells; thus, heart cells were not well-represented in the present analysis. In addition, intracoronary infusion of allogeneic mesenchymal stem cells resulted in a 6.28% increase in EF, as reported by de Jong et al.4 Our meta-analysis contained only studies with autologous cells, which in turn, increased its homogeneity.
Another limitation was that the ACCRUE database included fewer studies and patients than the total number of available published studies. Thus, this study did not include all studies that would be typically incorporated into a conventional meta-analysis. This lack was partly because of the resistance from centers to provide individual data, and partly because of the temporary closure of the database, which precluded studies that were published later.
Most previous large medical IPD-based meta-analysis studies were company sponsored. Those studies implemented a generalized electronic case report form, and the database and data were monitored by external monitoring companies. Therefore, extraction of standardized data from case report forms was a priori facilitated. However, to date, no company-sponsored studies on cell-based cardiac regeneration with intracoronary cell delivery have been conducted and controlled centrally. To date, no financial support was available for the effort of providing and formatting data in accordance with the ACCRUE database. In addition, data that did not represent the entire population could not be assessed, such as medication during follow-up, or data on stent thrombosis. However, the statistical analysis revealed a remarkably low heterogeneity across the trials in this ACCRUE study (I2, 0% to 48%), compared with previous, largest meta-analyses (I2, up to 87%),3,4 because of the prespecified baseline and outcome parameters.
The results of this IPD meta-analysis revealed some important discrepancies from previous meta-analyses. Our findings highlighted the lack of consistent efficacy in cell-based cardiac regeneration with intracoronary delivery in patients with diverse cardiovascular risk factors. Although the ACCRUE database continues to recruit data, it cannot replace large-volume, prospective randomized studies, such as the ongoing BAMI trial (ClinicalTrials.gov Identifier: NCT01569178) or the CCTRN network.26,27
Sources of Funding
TIME and LateTIME were supported by a grant from the National Heart, Lung, and Blood Institute under the cooperative agreement 5 UM1 HL087318-01. Part of the study was supported by European Union structural funds (Innovative Economy Operational Program POIG.01.01.02-00-109/09-00) to Dr Wojakowski.
From the Cardiology Department, Medical University of Vienna, Vienna, Austria (M.G., N.P., J.B.-K., I.J.P., G.M.); Third Department of Cardiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland (W.W., M.T.); Inserm, UMR1087, CNRS UMR6291, University of Nantes, Nantes, France (P.L.); Cardiology Department, Rikshospitalet University Hospital, Oslo, Norway (K.L.); Cardiovascular Center, OLV Hospital, Aalst, Belgium (J.B.); Cedars-Sinai Heart Institute, Los Angeles, CA (E.M., T.D.H., K.M.); Cardiology Division, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany (B.A.); Minneapolis Heart Institute, Abbott Northwestern Hospital, Minneapolis, MN (J.H.T.); Coordinating Center for Clinical Trials, University of Texas School of Public Health, Houston (L.A.M.); Cardiology Division, Cardiovascular Center, University Hospital Zurich, Switzerland (D.S.); Fondazione Cardiocentro Ticino, Lugano, Switzerland (D.S., R.C.); Heart Clinic Hirslanden Zurich, Switzerland (R.C.); Medical Research Center, Institute of Clinical Medicine, Department of Internal Medicine, University of Oulu, Finland (H.H., J.M.); Cardiology Department, University of Ulm, Ulm, Germany (J.W.); Clinic of Emergency Medicine, Military Medical Academy, Belgrade, Serbia (S.O.); Cardiology Division, Institute CARDIOMET, CIC Biotherapies, University Hospital of Toulouse, France (J.R.); State Research Institute of Circulation Pathology, Novosibirsk, Russian Federation (E.P., A.R.); Cardiology Department, Rigshospitalet, Copenhagen University, Copenhagen, Denmark (J.K.); Asklepios Klinik St. Georg, Hamburg, Germany (M.W.B.); Cardiology Department, Leiden University Medical Center, Leiden, The Netherlands (D.E.A.); Cardiology Department, Odense University Hospital, Denmark (A.D.); Cardiology Department, University of Debrecen, Hungary (I.E.); Cardiology Department, University of Tirgu Mures, Romania (I.B., T.B.); University Clinic for Cardiology, Skopje, Republic of Macedonia (H.P.); Medical Centre, Hungarian Defense Forces, Budapest, Hungary (N.N.); Karolinska Institute, Stockholm, Sweden (C.S.); Invasive Cardiology, National Research Council Institute of Clinical Physiology (CNR-IFC), Pisa, Italy (S.B.); Internal Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany (E.P.N.); and Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Research Network, 10th Military Research Hospital and Polyclinic, Bydgoszcz, Poland (E.P.N.).
Other investigators of the Meta-Analysis of Cell-based CaRdiac stUdiEs group included are as follows: Rayyan Hemetsberger, Dietmar Glogar, Sasko Kedev, Erik Jørgensen, Yongzhong Wang, and Rasmus S. Ripa. Cardiovascular Cell Therapy Research Network Acknowledgments: Carl J. Pepine, James T. Willerson, David X.M. Zhao, Stephen G. Ellis, John R. Forder, R. David Anderson, Antonis K. Hatzopoulos, Marc S. Penn, Emerson C. Perin, Jeffrey Chambers, Kenneth W. Baran, Ganesh Raveendran, Charles Lambert, James D. Thomas, Ray F. Ebert, and Robert D. Simari.
In January 2015, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.7 days.
* A full list of author affiliations and additional investigators participating in the ACCRUE database can be found in the Appendix.
This article was sent to Sumanth D. Prabhu, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
The online-only Data Supplement is available with this article at http://circres.ahajournals.org/lookup/suppl/doi:10.1161/CIRCRESAHA.116.304346/-/DC1.
- Nonstandard Abbreviations and Acronyms
- meta-Analysis of Cell-based CaRdiac stUdiEs
- acute myocardial infarction
- confidence interval
- creatine kinase
- end-diastolic volume
- ejection fraction
- end-systolic volume
- ischemic heart disease
- individual patient data
- left ventricular
- major adverse cardiac and cerebrovascular events
- target vessel revascularization
- Received May 7, 2014.
- Revision received February 13, 2015.
- Accepted February 19, 2015.
- © 2015 American Heart Association, Inc.
- Jeevanantham V,
- Butler M,
- Saad A,
- Abdel-Latif A,
- Zuba-Surma EK,
- Dawn B.
- de Jong R,
- Houtgraaf JH,
- Samiei S,
- Boersma E,
- Duckers HJ.
- Bartunek J,
- Vanderheyden M,
- Vandekerckhove B,
- Mansour S,
- De Bruyne B,
- De Bondt P,
- Van Haute I,
- Lootens N,
- Heyndrickx G,
- Wijns W.
- Wollert KC,
- Meyer GP,
- Lotz J,
- Ringes-Lichtenberg S,
- Lippolt P,
- Breidenbach C,
- Fichtner S,
- Korte T,
- Hornig B,
- Messinger D,
- Arseniev L,
- Hertenstein B,
- Ganser A,
- Drexler H.
- Roncalli J,
- Mouquet F,
- Piot C,
- et al
- Tendera M,
- Wojakowski W,
- Ruzyłło W,
- Chojnowska L,
- Kepka C,
- Tracz W,
- Musiałek P,
- Piwowarska W,
- Nessler J,
- Buszman P,
- Grajek S,
- Breborowicz P,
- Majka M,
- Ratajczak MZ
- Wöhrle J,
- Merkle N,
- Mailänder V,
- Nusser T,
- Schauwecker P,
- von Scheidt F,
- Schwarz K,
- Bommer M,
- Wiesneth M,
- Schrezenmeier H,
- Hombach V.
- Miettinen JA,
- Ylitalo K,
- Hedberg P,
- et al
- Sürder D,
- Schwitter J,
- Moccetti T,
- et al
- Traverse JH,
- Henry TD,
- Pepine CJ,
- et al
- Traverse JH,
- Henry TD,
- Ellis SG,
- et al
- Stroup DF,
- Berlin JA,
- Morton SC,
- Olkin I,
- Williamson GD,
- Rennie D,
- Moher D,
- Becker BJ,
- Sipe TA,
- Thacker SB.
- Higgins JPT,
- Green S.
- Tudur Smith C,
- Williamson PR.
- Engblom H,
- Hedström E,
- Heiberg E,
- Wagner GS,
- Pahlm O,
- Arheden H.
- Cogle CR,
- Wise E,
- Meacham AM,
- et al
- Reiter R,
- Swingen C,
- Moore L,
- Henry TD,
- Traverse JH.
- Li TS,
- Cheng K,
- Malliaras K,
- Smith RR,
- Zhang Y,
- Sun B,
- Matsushita N,
- Blusztajn A,
- Terrovitis J,
- Kusuoka H,
- Marbán L,
- Marbán E.
- Simari RD,
- Moyé LA,
- Skarlatos SI,
- Ellis SG,
- Zhao DX,
- Willerson JT,
- Henry TD,
- Pepine CJ.
Novelty and Significance
What Is Known?
Previous meta-analyses of randomized, cardiac cell-based therapy studies have shown moderate, but significant improvements in clinical outcome and left ventricular function.
Those meta-analyses suggested that the beneficial effects were gained by increases in the number of cells delivered, by timing cell therapy for delivery 5 to 8 days post–myocardial infarction, or by selecting patients with decreased ejection fraction.
What New Information Does This Article Contribute?
These meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) represent the first prospective meta-analysis in this field to be based on individual patient data (IPD), rather than on the aggregated data used in conventional meta-analyses.
These IPD-based meta-analysis of randomized studies found that intracoronary administration of autologous reparative cells had no effect on major adverse cardiac and cerebrovascular events or on left ventricular performance or remodeling.
Our results were not influenced by the timing of cell therapy, by the number of injected cells, or by the baseline cardiac ejection fraction.
This meta-analysis was based on a collaborative, multinational database (ACCRUE) that comprised IPD from randomized and cohort studies. The ACCRUE database was established to facilitate explorations of the clinical safety and efficacy of cell therapy in patients with ischemic heart disease and to identify subgroups of patients predicted to benefit from cell therapy. The ACCRUE database represents the most comprehensive source of evidence available to date. The present prospective study was the first to analyze data in the ACCRUE database on patients with recent acute myocardial infarctions. We included IPD from 12 randomized studies, and found that intracoronary autologous cell administration provided no benefit on overall clinical outcome. Moreover, we found no benefit on left ventricular performance or remodeling. Because the data pool comprised IPD, we could apply prespecified definitions of baseline and outcome parameters that accommodated multiple points of view and represented both clinical and functional end points. We tested the stability of these clinical and quantitative end points in several sensitivity analyses and found consistent results. This approach provided robust and justified conclusions.