Treatment of venous ulcers with growth factors: systematic review and meta-analysis

Carvalho, Magali Rezende de; Silveira, Isabelle Andrade; Oliveira, Beatriz Guitton Renaud Baptista de

doi:10.1590/0034-7167-2017-0865

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Revista Brasileira de Enfermagem

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Sumário

REVIEW • Rev. Bras. Enferm. 72 (1) • Jan-Feb 2019 • https://doi.org/10.1590/0034-7167-2017-0865 copy

Treatment of venous ulcers with growth factors: systematic review and meta-analysis

Tratamiento de úlceras venosas confactores de crecimiento: revisión sistemática y metanálisis

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

To identify evidence about the effects of growth factor application on venous ulcer healing.

Method:

Systematic review and meta-analysis, including Randomized Clinical Trials. Searches: Ovid MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL, LILACS, Web of Science, Digital Library of Theses and Dissertations; Google Scholar and list of references.

Results:

802 participants were recruited from the 10 included studies: 472 in the intervention group (growth factors) and 330 as control. The relative risk for the complete healing outcome was 1.06 [95% CI 0.92-1.22], p = 0.41. Participants who received Platelet-Rich Plasma and Epidermal Growth Factor showed a slight tendency to achieve complete healing, but without statistical relevance (p <0.05). Most of the studies were classified as moderate risk of bias.

Conclusion:

The effect of the application of growth factors for complete healing in venous ulcers is not clear, and clinical trials with methodological quality are required for more accurate recommendations.

Descriptors:
Intercellular Signaling Peptides and Proteins; Varicose Ulcer; Healing; Evidence-Based Nursing; Nursing Care

Database	Search strategies
Ovid MEDLINE(R) and EMBASE	(((randomized controlled trial.pt or controlled clinical trial.pt or randomized.ab. OR placebo.ab. OR clinical trial as topic.sh. ORrandomly.ab. ORtrial.ti.) not (exp animals/ not humans.sh.)) and (platelet derived endothelial cell growth factor/ OR platelet derived growth factor/ OR platelet derived growth factor a/ OR platelet derived growth factor ab/ OR platelet derived growth factor ab/ OR platelet derived growth factor b/ OR recombinant platelet derived growth factor/ OR recombinant cytokine/ OR recombinant growth factor/ ORbecaplermin/ OR recombinant fibroblast growth factor/ OR recombinant growth factor/ OR recombinant keratinocyte growth factor/ ORsprifermin/ ORvelafermin/ OR recombinant fibroblast growth factor 19/ OR transforming growth factor/ OR transforming growth factor alpha/ OR transforming growth factor beta/ OR recombinant transforming growth factor.mp. ORexp epidermal growth factor/ ORexp recombinant epidermal growth factor/ ORexp fibroblast growth factor/ ORexp platelet-rich plasma/ OR platelet-rich plasma.ab. OR autologous platelet-rich gel.mp. OR autologous platelet-rich plasma.mp.) and (exp leg ulcer/ OR venous leg ulcer.ab. OR venous ulcer.ab. OR varicose ulcer.mp.))
CINAHL	(((MH "Randomized Controlled Trials") OR (MH "Clinical Trials+") OR ("controlled clinical trial") OR (MH "Clinical Trial Registry") OR (MH "Random Assignment") OR (MH "Stratified Random Sample") OR (MH "Systematic Random Sample") OR "randomized") OR ("placebo") OR ("randomly") OR (MH "Multicenter Studies") OR (MH "Intervention Trials") OR ("trial")) AND ((MH "Platelet-Derived Growth Factor") OR ("platelet-derived growth factor") OR (MH "Platelet-Rich Plasma") OR (MH "Epidermal Growth Factors") OR (MH "Growth Substances+") OR (MH "Vascular Endothelial Growth Factors+") OR ("recombinant platelet-derived growth factor") OR ("fibroblast growth factor") OR ("recombinant fibroblast growth factor") OR ("recombinant endothelial growth factor") OR ("transforming growth factor") OR ("recombinant transforming growth factor") OR ("recombinant epidermal growth factor") OR (MH "Blood Platelets")) AND ((MH "Venous Ulcer") OR (MH "Leg Ulcer+") OR ("venous leg ulcer") OR ("varicose ulcer")))
Cochrane CENTRAL	(((MeSH descriptor: [Intercellular Signaling Peptides and Proteins] explode all trees) OR (MeSH descriptor: [Platelet-Rich Plasma] explode all trees) OR (MeSH descriptor: [Platelet-Derived Growth Factor] explode all trees) OR (MeSH descriptor: [Epidermal Growth Factor] explode all trees) OR (MeSH descriptor: [Vascular Endothelial Growth Factors] explode all trees) OR (MeSH descriptor: [Fibroblast Growth Factors] explode all trees) OR (MeSH descriptor: [Transforming Growth Factors] explode all trees) OR (recombinant growth factor:ab,ti (Word variations have been searched)) AND ((MeSH descriptor: [Varicose Ulcer] explode all trees) OR (venous leg ulcer:ab,ti (Word variations have been searched)) OR (venous ulcer*:ab,ti (Word variations have been searched)))
LILACS	((mh: "Platelet-Rich Plasma" OR tw:growth factor$ OR tw:recomb$ growth factor OR mh:"Platelet-derived growth factor" OR mh:"epidermal growth fator" OR mh:"transforming Growth Factors" OR mh:"Fibroblast Growth Factors" OR mh:"Vascular Endothelial Growth Factor" OR tw:plasma ricoemplaqueta$ OR tw:fator$ de crescimento$ OR tw: Factor$ de Crecimiento$) AND (mh:"varicose ulcer" OR tw:venous ulcer$ OR tw:venous leg ulcer$ OR tw: úlceravenosa))
	((mh:Platelet-Rich Plasma OR tw:growth factor$ OR tw:recomb$ growth factor OR tw:plasmaricoemplaqueta$ OR tw:fator$ de crescimento$ OR tw: Factor$ deCrecimiento$) AND (mh:varicose ulcer OR tw:venous ulcer$ OR tw:venous leg ulcer$ OR tw: úlceravenosa))
	((tw:growth factors OR tw:fator$ de crescimento OR tw:factor$ de crescimiento) AND (mh:varicose ulcer OR tw:venous ulcer OR tw:venous leg ulcer OR tw:úlceravenosa OR tw:úlceravaricosa))
	((growth factors OR fator$ de crescimento OR factor$ decrescimiento) AND (varicose ulcer OR venous ulcer OR venous leg ulcer OR úlceravenosa))
Web of Science	(TS=(Recombinant Fibroblast Growth Factor OR Recombinant Growth Factor OR Recombinant Keratinocyte Growth Factor OR Recombinant Fibroblast Growth Factor OR Transforming Growth Factor OR Epidermal Growth Factor OR Recombinant Epidermal Growth Factor OR Fibroblast Growth Factor OR Platelet-Rich Plasma OR Autologous platelet-rich gel OR Platelet-Derived Growth Factor OR Vascular Endothelial Growth Factor) AND TS=(varicose ulcer* OR Venous ulcer* Varicose wound* OR venous leg ulcer) AND TS=(clinical trial OR random* OR trial OR randomized clinical trial))

Study's ID	Authors and year of publication	Growth Factor tested	Number of Participants		Frequency of Application	Masking	Risk of Bias
Study's ID	Authors and year of publication	Growth Factor tested	Test	Control	Frequency of Application	Masking	Risk of Bias
A	Somani et al, 2017⁽¹⁸18 Somani A, Rai R. Comparison of Efficacy of Autologous Platelet-rich Fibrin versus Saline Dressing in Chronic Venous Leg Ulcers: A Randomised Controlled Trial. J Cutan Aesthet Surg [Internet]. 2017 [cited 2017 Oct 15];10(1):8-12. Available from: http://dx.doi.org/10.4103/JCAS.JCAS_137_16 http://dx.doi.org/10.4103/JCAS.JCAS_137_... ⁾	PRP	9	6	1 X a week	Does notreport	Moderate
B	Aguirre et al, 2015⁽¹⁹19 Aguirre JJ, Anitua E., Francisco S, Cabezas AI, Orive G, Algorta J. Efficacy and safety of plasma rich in growth factors in the treatment of venous ulcers: a randomized clinical trial controlled with conventional treatment. Clinical Dermatology [Internet]. 2015 [cited 2017 Oct 15];3(1):13-20. Available from: https://www.clinicaldermatology.eu/materiale_cic/816_3_1/6983_efficacy/article.htm https://www.clinicaldermatology.eu/mater... ⁾	PRP	12	11	1 X a week	Does notreport	Moderate
C	Robson et al, 2004⁽²⁰20 Robson M, Hanfnt J, Garner W, Jenson J, Serena T, Payne WG, et al. Healing of Chronic Venous Ulcers Is Not Enhanced by the Addition of Topical Repifermin (KGF-2) to standardized Care. J Appl Res [Internet]. 2004 [cited 2017 Oct 15];4(2):302-11. Available from: http://www.jrnlappliedresearch.com/articles/Vol4Iss2/robson-Jar-spring.pdf http://www.jrnlappliedresearch.com/artic... ⁾	KGF	60µg - 123 120µg - 112	117	Exchange: 2 X a week	Double-blind	Moderate
D	Senet et al, 2003⁽²¹21 Senet P, Bon F-X, Benbunan M, Bussel A, Traineau R, Calvo F, et al. Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers. J Vasc Surg [Internet]. 2003 [cited 2017 Oct 15];38(6):1342-8. Available from: http://dx.doi.org/10.1016/S0741-5214(03)00908-X http://dx.doi.org/10.1016/S0741-5214(03)... ⁾	PRP	8	7	3 X a week	Double-blind	Moderate
E	Wieman-1a, 2001⁽²²22 Wieman TJ. Efficacy and Safety of Recombinant Human Platelet-Derived Growth Factor-BB (Becaplermin) in Patients with Chronic Venous Ulcers. Wounds [Internet]. 2003 [cited 2017 Oct 15];15(9):257-64. Available from: http://www.woundsresearch.com/article/1931 http://www.woundsresearch.com/article/19... ⁾	PDGF	35	36	Exchange: daily	Double-blind	Moderate
F	Wieman-1b, 2001⁽²²22 Wieman TJ. Efficacy and Safety of Recombinant Human Platelet-Derived Growth Factor-BB (Becaplermin) in Patients with Chronic Venous Ulcers. Wounds [Internet]. 2003 [cited 2017 Oct 15];15(9):257-64. Available from: http://www.woundsresearch.com/article/1931 http://www.woundsresearch.com/article/19... ⁾	PDGF	32	32	Exchange: 2 X week	Double-blind	Moderate
G	Robson et al, 2001⁽²³23 Robson MC, Phillips TJ, Falanga V, Odenheimer DJ, Parish LC, Jensen JL, et al. Randomized trial of topically applied repifermin (recombinant human keratinocyte growth factor-2) to accelerate wound healing in venous ulcers. Wound Repair Regen [Internet]. 2001 [cited 2017 Oct 15];9(5):347-52. Available from: http://dx.doi.org/10.1046/j.1524-475x.2001.00347.x http://dx.doi.org/10.1046/j.1524-475x.20... ⁾	KGF	20µg - 32 60µg - 32	31	Exchange: 2 X week	Double-blind	Moderate
H	Stacey et al, 2000⁽²⁴24 Stacey MC, Mata SD, Trengove NJ, Mather CA. Randomised double-blind placebo controlled trial of topical autologous platelet lysate in venous ulcer healing. Eur J Vasc Endovasc Surg [Internet] 2000 [cited 2017 Oct 15];20(3):296-301. Available from: http://dx.doi.org/10.1053/ejvs.2000.1134 http://dx.doi.org/10.1053/ejvs.2000.1134... ⁾	PRP	42	44	Exchange: 2 X week	Double-blind	Moderate
I	Robson et al, 1995⁽²⁵25 Robson MC, Phillip LG, Cooper DM, Lyle WG, Robson LE, Odom L, et al. Safety and effect of transforming growth factor-ß2 for treatment of venous stasis ulcers. Wound Repair Regen [Internet]. 1995 [cited 2017 Oct 15];3(2):157-67. Available from: http://dx.doi.org/10.1046/j.1524-475X.1995.30207.x http://dx.doi.org/10.1046/j.1524-475X.19... ⁾	TGF-β	12	Control 1- 12 Control 2 - 12	Exchange: 3 X week	Blindevaluator	Low
J	Falanga et al, 1992⁽²⁶26 Falanga V, Eaglstein WH, Bucalo B, Katz MH, Harris B, Carson P. Topical use of human recombinant epidermal growth factor (h-EGF) in venous ulcers. J Dermatol Surg Oncol. 1992;18(7):604-6.⁾	EGF	23	22	Exchange: 2 X dia	Double-blind	High risk
	Total		472	330

Study's ID	Intervention	Control	Complete Healing		Follow-up Time
Study's ID	Intervention	Control	Intervention	Control	Follow-up Time
A	PRP	Saline Solution	5/9	0/6	4 weeks
B	PRP + compression therapy	Silicone dressing + compression therapy	5/12	0/11	8 weeks
C	KGF 60mg or 120mg + compression therapy	Placebo + compression therapy	60µ- 72/123 120µg- 58/112	72/117	26 weeks
D	FrozenPRP + compression therapy	Saline Solution + compressiontherapy	1/8	1/7	12 weeks
E	PDGF + compression therapy	Placebo gel + compression therapy	12/35	12/36	16 weeks
F	PDGF + compression therapy	Placebo gel + compression therapy	18/32	14/32	16 weeks
G	KGF 20 mg or 60mg + compression therapy	Placebo + compression therapy	20µg - 10/32 60µg - 12/32	9/31	12 weeks
H	FrozenPRP + compression therapy	PBS Solution+ compressiontherapy	33/42	34/44	36 weeks
I	Collagen matrix containing TGF-β + compression therapy	Controle 1: Matriz de colágeno + terapia compressiva Controle 2: gaze petrolada + terapia compressiva	4/12	Control 1- 4/12 Control 2- 3/12	6 weeks
J	EGF + compression therapy	Placebo + compression therapy	6/23	2/22	10 weeks
	Total		236/472	151/330

COMPARISON BETWEEN TREATMENT WITH GROWTH FACTORS OR STANDARD TREATMENT/PLACEBO FOR VENOUS ULCERS FOR COMPLETE HEALING OUTCOME
Population: Patients with venous ulcers. Intervention: Growth Factors. Setting: Hospital or outpatient. Comparator: Standard treatment/placebo.
Outcomes	Relative Risk (95% CI)	Number of Participants (studies)	Quality of the evidence (GRADE)	Comment
Growth Factors Versus Standard Treatment/Placebo follow-up time: 4 to 36 weeks	RR 1.06 (0.92-1.22)	802 participants (10 studies)	⊕⊕⊕⊝ Moderate	1 point deduction: 6 RCTs did not detail the method of randomization and/or allocation and 2 RCTs did not blind the evaluator.
PRP versus Control follow-up time: 4 to 36 weeks	RR 1.26 (0.97-1.63)	139 participants (4 studies)	⊕⊕⊕⊝ Moderate	1 point deduction: 2 RCTs did not detail the randomization and/or allocation process and RCTs did not blind the evaluator.
KGF versus placebo follow-up time: 12-26 weeks	RR 0.93 (0.78-1.11)	447 participants (2 studies)	⊕⊕⊕⊝ Moderate	1 point deduction: 2 RCTs did not detail the method of randomization and allocation.
PDGF versus Placebo follow-up time: 16 weeks	RR 1.17 (0.78-1.74)	135 participants (2 studies)	⊕⊕⊕⊝ Moderate	1 point deduction: 2 RCTs did not detail the method of randomization and secrecy of allocation.
TGF versus Control follow-up time: 6 weeks	RR 1.14 (0.41-3.15)	36 participants (1 study)	⊕⊕⊕⊝ Moderate	1 point deduction: Wide CI.
EGF versus Placebo follow-up time: 10 weeks	RR 2.87 (0.65-12.73)	45 participants (1 study)	⊕⊕⊝⊝ Low	1 point deduction: 1 RCT did not detail the process of secrecy RCT allocation; 1 point deduction: Wide CI.
Evidence levels from the GRADE Working Group High quality: Future research is unlikely to change our confidence in the estimated effect. Moderate quality: Future research is likely to have a significant impact on our confidence in the estimated effect and may change this estimate. Low quality: Future research is very likely to have a significant impact on our confidence in the estimated effect and change the estimate. Very low quality: there are many uncertainties about the estimate.

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[1] Corresponding Author: Magali Rezende de Carvalho E-mail: magalirecar@gmail.com