Martí-Carvajal AJ, Gluud C, Nicola S, Simancas-Racines D, Reveiz L, Oliva P, Cedeño-Taborda J, et al.
The Cochrane database of systematic reviews. Date of publication 2015 Oct 28;volume (10):CD008548.
1. Cochrane Database Syst Rev. 2015 Oct 28;(10):CD008548. doi:
10.1002/14651858.CD008548.pub2.
Growth factors for treating diabetic foot ulcers.
Martí-Carvajal AJ(1), Gluud C, Nicola S, Simancas-Racines D, Reveiz L, Oliva P,
Cedeño-Taborda J.
Author information:
(1)Iberoamerican Cochrane Network, Valencia, Venezuela.
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.
DOI: 10.1002/14651858.CD008548.pub2
PMID: 26509249 [Indexed for MEDLINE]
