Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Supplementary Figure 1.
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Odds ratio of major amputation in patients with CLI treated with cell therapy versus no cell therapy (Random Effect Model): Placebocontrolled RCTs only.
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Supplementary Figure 2.
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Odds ratio of ulcer in patients with CLI treated with cell therapy versus no cell therapy (Random Effect Model): Placebo-controlled RCTs only.
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Supplementary Figure 3.
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Odds ratio of improvement in ABI (>0.1 or >15%) in patients with CLI treated with cell therapy versus no cell therapy (Random Effect Model): Placebo-controlled RCTs only.
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Supplementary Figure 4.
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Odds ratio of all-cause mortality in patients with CLI treated with cell therapy versus no cell therapy (Random Effect Model): Placebocontrolled RCTs only.
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Supplementary Figure 5.
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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Supplementary Figure 6.
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Funnel plot for major amputation
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Supplementary Figure 7.
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Funnel plot for complete ulcer healing
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Supplementary Figure 8.
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Funnel plot for improvement in ABI
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Supplementary Figure 9.
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Funnel plot for improvement in ABI (excluding study by Teraa et al)
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Supplementary Figure 10.
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Funnel plot for all-cause mortality
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Appendix 1.
11
PRISMA Checklist.
Section/topic
#
Checklist item
Reported page #
TITLE Title
1
Identify the report as a systematic review, meta-analysis, or both.
Title page
2
Provide a structured summary including, as applicable: background; Abstract page objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
ABSTRACT Structured summary
INTRODUCTION Rationale 3 Objectives
4
METHODS Protocol and 5 registration Eligibility criteria
6
Information sources
7
Search
8
on
Describe the rationale for the review in the context of what is already known. Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
Introduction section Introduction section
Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
N/A Method section Method section
Method section, appendices 3&4 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in Method systematic review, and, if applicable, included in the meta-analysis). section Data collection 10 Describe method of data extraction from reports (e.g., piloted forms, Method process independently, in duplicate) and any processes for obtaining and confirming section data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding Method sources) and any assumptions and simplifications made. section Risk of bias in 12 Describe methods used for assessing risk of bias of individual studies, and Method individual how this information is to be used in any data synthesis. section studies Summary 13 State the principal summary measures (e.g., risk ratio, difference in means). Method measures section Synthesis of 14 Describe the methods of handling data and combining results of studies, if Method results done, including measures of consistency (e.g., I2) for each meta-analysis. section Risk of bias 15 Specify any assessment of risk of bias that may affect the cumulative Method across studies evidence (e.g., publication bias, selective reporting within studies). section
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Additional analyses
12
16 Describe methods of additional analyses (e.g., sensitivity or subgroup Method analyses, meta-regression), if done, indicating which were pre-specified. section
RESULTS Study selection Study characteristics
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
Risk of bias 19 Present data on risk of bias of each study and, if available, any outcome within studies level assessment (see item 12).
Results individual studies
of 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
Synthesis results
of 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.
Risk of bias 22 Present results of any assessment of risk of bias across studies (see Item 15). across studies Additional analysis
23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).
DISCUSSION Summary of 24 Summarize the main findings including the strength of evidence for each evidence main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
Results and Discussion section Results and Discussion section Results and Discussion section, table 2, supplementary figures 6-10 Results and Discussion section, table 2, figures 1-4, supplementary figures 6-10 Results and Discussion section, table 2 Results and Discussion section, table 2 Results and Discussion section, table 2 Results and Discussion section Results and Discussion section Conclusion section N/A
Adapted from: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Appendix 2.
Study flow diagram.
13
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Appendix 3.
14
PubMed database search strategy.
The following search terms were used in the PubMed database: ‘’critical limb ischaemia’’ OR ‘’critical limb ischemia’’ OR ‘’peripheral artery disease’’ OR ‘’peripheral arterial disease’’ OR ‘’peripheral vascular disease’’ OR ‘’peripheral arteriosclerosis’’ OR ‘’arteriosclerosis obliterans’’ AND ‘’stem cell’’ OR ‘’bone marrow concentrate’’ OR ‘’bone marrow derived mononuclear cell’’ OR ‘’peripheral blood derived mononuclear cell’’ OR ‘’peripheral mononuclear cell’’ OR ‘’granulocyte colony stimulating factor’’ OR ‘’GCSF’’ OR ‘’CD34’’ OR ‘’CD133’’ OR ‘’mesenchymal stromal cell’’ OR ‘’mesenchymal stem cell’’ OR ‘’adipose tissue derived stem cell’’ OR ‘’umbilical cord derived mononuclear cell’’ OR ‘’umbilical cord derived mesenchymal stem cell’’ OR ‘’umbilical cord derived mesenchymal stromal cell’’ OR ‘’umbilical cord stem cell’’ OR ‘’hematopoietic stem cell’’ OR ‘’haematopoietic stem cell’’ OR ‘’endothelial progenitor cell’’ OR ‘’circulating angiogenic cell’’ OR ‘’outgrowth endothelial cell’’.
Liew, Bhattacharya, Shaw, Stansby: Cell Therapy for Critical Limb Ischaemia
Appendix 4: ID #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14 #15 #16 #17 #18 #19 #20 #21 #22 #23 #24 #25 #26
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Cochrane Library database search strategy.
Search MeSH descriptor: [Stem Cell Transplantation] explode all trees MeSH descriptor: [Peripheral Blood Stem Cell Transplantation] explode all trees MeSH descriptor: [Hematopoietic Stem Cell Mobilization] explode all trees MeSH descriptor: [Bone Marrow Cells] explode all trees MeSH descriptor: [Granulocyte Colony-Stimulating Factor] explode all trees MeSH descriptor: [Mesenchymal Stem Cell Transplantation] explode all trees MeSH descriptor: [Mesenchymal Stromal Cells] explode all trees MeSH descriptor: [Leukocytes, Mononuclear] explode all trees MeSH descriptor: [Cord Blood Stem Cell Transplantation] explode all trees MeSH descriptor: [Bone Marrow Transplantation] explode all trees bone marrow cell endothelial progenitor cell circulating angiogenic cell adipose derived stem cell mononuclear cell bone marrow concentrate (BM-MNC* or PB-MNC* or M-PB-MNC* or BM-MSC* or AT-MSC* or ADSC* or UC-MSC* or EPC* or CAC* or OEC*):ti,ab,kw MeSH descriptor: [Arteriosclerosis Obliterans] explode all trees MeSH descriptor: [Arteriosclerosis] explode all trees MeSH descriptor: [Atherosclerosis] explode all trees MeSH descriptor: [Arterial Occlusive Diseases] explode all trees MeSH descriptor: [Peripheral Vascular Diseases] explode all trees critical limb isch* or CLI #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 #18 or #19 or #20 or #21 or #22 or #23 #24 and #25