Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysisBMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g2688 (Published 28 April 2014) Cite this as: BMJ 2014;348:g2688
- Alexandra N Nowbar, cardiovascular scientist,
- Michael Mielewczik, postdoctoral biologist,
- Maria Karavassilis, clinical medical student,
- Hakim-Moulay Dehbi, statistician,
- Matthew J Shun-Shin, academic clinical fellow in cardiology,
- Siana Jones, cardiovascular physiologist,
- James P Howard, physician,
- Graham D Cole, BHF clinical research training fellow,
- Darrel P Francis, professor of cardiology
- on behalf of the DAMASCENE writing group
- 1International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London W2 1LA, UK
- Correspondence to: A N Nowbar
- Accepted 24 March 2014
Objective To investigate whether discrepancies in trials of use of bone marrow stem cells in patients with heart disease account for the variation in reported effect size in improvement of left ventricular function.
Design Identification and counting of factual discrepancies in trial reports, and sample size weighted regression against therapeutic effect size. Meta-analysis of trials that provided sufficient information.
Data sources PubMed and Embase from inception to April 2013.
Eligibility for selecting studies Randomised controlled trials evaluating the effect of autologous bone marrow stem cells for heart disease on mean left ventricular ejection fraction.
Results There were over 600 discrepancies in 133 reports from 49 trials. There was a significant association between the number of discrepancies and the reported increment in EF with bone marrow stem cell therapy (Spearman’s r=0.4, P=0.005). Trials with no discrepancies were a small minority (five trials) and showed a mean EF effect size of −0.4%. The 24 trials with 1-10 discrepancies showed a mean effect size of 2.1%. The 12 with 11-20 discrepancies showed a mean effect of size 3.0%. The three with 21-30 discrepancies showed a mean effect size of 5.7%. The high discrepancy group, comprising five trials with over 30 discrepancies each, showed a mean effect size of 7.7%.
Conclusions Avoiding discrepancies is difficult but is important because discrepancy count is related to effect size. The mechanism is unknown but should be explored in the design of future trials because in the five trials without discrepancies the effect of bone marrow stem cell therapy on ejection fraction is zero.
Notes added at proof stage: The institution of t07, t08, t21, and t49 is recently reported to have identified evidence of misconduct46 and has notified the city prosecutor. The institution of the SCIPIO trial31 is recently reported to have requested that the publication be retracted.47
Contributors: DPF and GDC designed the study, examined the trials, and drafted and revised the paper. MM designed the study, performed the search, examined the trials, and drafted and revised the paper. ANN performed the search, examined the trials, analysed the data, and drafted and revised the paper. MJS and HD examined the trials, analysed the data, and revised the paper. JPH and SJ examined the trials and revised the paper. MK performed the search and revised the paper. DPF is guarantor.
Funding: This study was not funded by any external organisation. All authors are associated with Imperial College London. For full disclosure, we report that DPF is supported by a British Heart Foundation senior clinical research fellowship FS/10/038 and GDC is a British Heart Foundation clinical research training fellow (FS/12/12/29294). Neither the institution nor any funder had any role in devising, conducting, analysing or reporting this study.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: Not required.
Data sharing: The complete list of identified discrepancies is shown in appendices 1-3. These are freely available from the corresponding author in editable form on request. We welcome and will make public any corrections or updates from readers.
Transparency declaration: The guarantor affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
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