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Meta-Analysis
. 2015 Oct 28;2015(10):CD008548.
doi: 10.1002/14651858.CD008548.pub2.

Growth factors for treating diabetic foot ulcers

Arturo J Martí-Carvajal  1 , Christian Gluud, Susana Nicola, Daniel Simancas-Racines, Ludovic Reveiz, Patricio Oliva, Jorge Cedeño-Taborda
Affiliations
Meta-Analysis

Growth factors for treating diabetic foot ulcers

Arturo J Martí-Carvajal et al. Cochrane Database Syst Rev. .

Abstract

Background: Foot ulcers are a major complication of diabetes mellitus, often leading to amputation. Growth factors derived from blood platelets, endothelium, or macrophages could potentially be an important treatment for these wounds but they may also confer risks.

Objectives: To assess the benefits and harms of growth factors for foot ulcers in patients with type 1 or type 2 diabetes mellitus.

Search methods: In March 2015 we searched the Cochrane Wounds Group Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations, Ovid EMBASE and EBSCO CINAHL. There were no restrictions with respect to language, date of publication or study setting.

Selection criteria: Randomised clinical trials in any setting, recruiting people with type 1 or type 2 diabetes mellitus diagnosed with a foot ulcer. Trials were eligible for inclusion if they compared a growth factor plus standard care (e.g., antibiotic therapy, debridement, wound dressings) versus placebo or no growth factor plus standard care, or compared different growth factors against each other. We considered lower limb amputation (minimum of one toe), complete healing of the foot ulcer, and time to complete healing of the diabetic foot ulcer as the primary outcomes.

Data collection and analysis: Independently, we selected randomised clinical trials, assessed risk of bias, and extracted data in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We subjected our analyses to both fixed-effect and random-effects model analyses.

Main results: We identified 28 randomised clinical trials involving 2365 participants. The cause of foot ulcer (neurologic, vascular, or combined) was poorly defined in all trials. The trials were conducted in ten countries. The trials assessed 11 growth factors in 30 comparisons: platelet-derived wound healing formula, autologous growth factor, allogeneic platelet-derived growth factor, transforming growth factor β2, arginine-glycine-aspartic acid peptide matrix, recombinant human platelet-derived growth factor (becaplermin), recombinant human epidermal growth factor, recombinant human basic fibroblast growth factor, recombinant human vascular endothelial growth factor, recombinant human lactoferrin, and recombinant human acidic fibroblast growth factor. Topical intervention was the most frequent route of administration. All the trials were underpowered and had a high risk of bias. Pharmaceutical industry sponsored 50% of the trials.Any growth factor compared with placebo or no growth factor increased the number of participants with complete wound healing (345/657 (52.51%) versus 167/482 (34.64%); RR 1.51, 95% CI 1.31 to 1.73; I(2) = 51%, 12 trials; low quality evidence). The result is mainly based on platelet-derived wound healing formula (36/56 (64.28%) versus 7/27 (25.92%); RR 2.45, 95% 1.27 to 4.74; I(2) = 0%, two trials), and recombinant human platelet-derived growth factor (becaplermin) (205/428 (47.89%) versus 109/335 (32.53%); RR 1.47, 95% CI 1.23 to 1.76, I(2)= 74%, five trials).In terms of lower limb amputation (minimum of one toe), there was no clear evidence of a difference between any growth factor and placebo or no growth factor (19/150 (12.66%) versus 12/69 (17.39%); RR 0.74, 95% CI 0.39 to 1.39; I(2) = 0%, two trials; very low quality evidence). One trial involving 55 participants showed no clear evidence of a difference between recombinant human vascular endothelial growth factor and placebo in terms of ulcer-free days following treatment for diabetic foot ulcers (RR 0.64, 95% CI 0.14 to 2.94; P value 0.56, low quality of evidence)Although 11 trials reported time to complete healing of the foot ulcers in people with diabetes , meta-analysis was not possible for this outcome due to the unique comparisons within each trial, failure to report data, and high number of withdrawals. Data on quality of life were not reported. Growth factors showed an increasing risk of overall adverse event rate compared with compared with placebo or no growth factor (255/498 (51.20%) versus 169/332 (50.90%); RR 0.83; 95% CI 0.72 to 0.96; I(2) = 48%; eight trials; low quality evidence). Overall, safety data were poorly reported and adverse events may have been underestimated.

Authors' conclusions: This Cochrane systematic review analysed a heterogeneous group of trials that assessed 11 different growth factors for diabetic foot ulcers. We found evidence suggesting that growth factors may increase the likelihood that people will have complete healing of foot ulcers in people with diabetes. However, this conclusion is based on randomised clinical trials with high risk of systematic errors (bias). Assessment of the quality of the available evidence (GRADE) showed that further trials investigating the effect of growth factors are needed before firm conclusions can be drawn. The safety profiles of the growth factors are unclear. Future trials should be conducted according to SPIRIT statement and reported according to the CONSORT statement by independent investigators and using the Foundation of Patient-Centered Outcomes Research recommendations.

PubMed Disclaimer

Conflict of interest statement

Arturo Martí‐Carvajal: was employed in 2004 by Eli Lilly to run a four‐hour workshop on 'How to critically appraise clinical trials on osteoporosis and how to teach this'. He was employed in 2007 by Merck to run a four‐hour workshop 'How to critically appraise clinical trials and how to teach this'. These activities are not related to his work with The Cochrane Collaboration or any Cochrane review.

Jorge A Cedeño‐Taborda: was employed as Medical Director for Organon Venezolana SA from 2002 to 2007. In 2007 he was employed by Novartis de Venezuela as an outsourced medical adviser for the development of scientific material to support the marketing of Vildagliptine. None of these activities is related to the subject of this Cochrane review.

Christian Gluud: None known.

Susana Nicola: None known.

Daniel Simancas‐Racines: None known.

Ludovic Reveiz: None known.

Patricio Oliva: None known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Funnel plot for comparison effect of any growth factor versus placebo or no growth factor on 100% complete wound closure. P‐value (two tailed) for Egger's test = 0.43
1.1
1.1. Analysis
Comparison 1 Any growth factor versus placebo or no growth factor, Outcome 1 Complete wound closure.
1.2
1.2. Analysis
Comparison 1 Any growth factor versus placebo or no growth factor, Outcome 2 Lower limb amputation (minimum of one toe).
1.3
1.3. Analysis
Comparison 1 Any growth factor versus placebo or no growth factor, Outcome 3 Ulcer‐free days following treatment for diabetic foot ulcers (free from any recurrence).
1.4
1.4. Analysis
Comparison 1 Any growth factor versus placebo or no growth factor, Outcome 4 Adverse events (non‐serious and serious).
2.1
2.1. Analysis
Comparison 2 Any growth factor versus placebo or no growth factor (subgroup analysis of trials with follow‐up < 20 weeks versus follow‐up ≥ 20 weeks), Outcome 1 Participants with complete wound closure.
3.1
3.1. Analysis
Comparison 3 Any growth factor versus placebo or no growth factor (subgroup analysis by type of growth factor), Outcome 1 Complete wound closure.
4.1
4.1. Analysis
Comparison 4 Any growth factor versus placebo or no growth factor (sensitivity analyses considering attrition), Outcome 1 Complete wound closure.
5.1
5.1. Analysis
Comparison 5 Platelet derived wound healing formula (PDWHF) versus control, Outcome 1 Complete wound closure.
5.2
5.2. Analysis
Comparison 5 Platelet derived wound healing formula (PDWHF) versus control, Outcome 2 Lower limb amputation (minimum of one toe).
6.1
6.1. Analysis
Comparison 6 Recombinant human platelet‐derived growth factor (rHuPDGF) versus placebo, Outcome 1 Complete wound closure.
6.2
6.2. Analysis
Comparison 6 Recombinant human platelet‐derived growth factor (rHuPDGF) versus placebo, Outcome 2 Adverse event: infection.
6.3
6.3. Analysis
Comparison 6 Recombinant human platelet‐derived growth factor (rHuPDGF) versus placebo, Outcome 3 Adverse event: cellulitis.
6.4
6.4. Analysis
Comparison 6 Recombinant human platelet‐derived growth factor (rHuPDGF) versus placebo, Outcome 4 Adverse event: peripheral oedema.
6.5
6.5. Analysis
Comparison 6 Recombinant human platelet‐derived growth factor (rHuPDGF) versus placebo, Outcome 5 Adverse event: pain.
6.6
6.6. Analysis
Comparison 6 Recombinant human platelet‐derived growth factor (rHuPDGF) versus placebo, Outcome 6 Adverse event: skin ulceration.
7.1
7.1. Analysis
Comparison 7 Recombinant human basic fibroblast growth factor (rHubFBGF) versus placebo, Outcome 1 Complete wound closure.
7.2
7.2. Analysis
Comparison 7 Recombinant human basic fibroblast growth factor (rHubFBGF) versus placebo, Outcome 2 Adverse event: infection.
8.1
8.1. Analysis
Comparison 8 Recombinant human epidermal growth factor versus active control, Outcome 1 Lower limb amputation (minimum of one toe).
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD008548

References

References to studies included in this review

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Landsman 2010 {published data only}
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Robson 2002 {published data only}
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Saldalamacchia 2004 {published data only}
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References to studies excluded from this review

Acosta 2006 {published data only}
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Embil 2000 {published data only}
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References to studies awaiting assessment

Gomez‐Villa 2014 {published data only}
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References to ongoing studies

NCT00521937 {published data only}
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NCT00915486 {published data only}
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