Effectiveness of most common adjuvant wound treatments (skin substitutes, negative pressure wound therapy, hyperbaric oxygen therapy, platelet-rich plasma/fibrin, and growth factors) for the management of hard-to-heal diabetic foot ulcers: a meta-analysis of randomized controlled trials for the development of the Italian Guidelines for the Treatment of Diabetic Foot Syndrome.

aimTo assess the effects of several adjuvant therapies (AT) commonly used in the treatment of diabetic foot ulcers (DFU). The present meta-analysis was designed to support the development of the Italian Guidelines for the Treatment of Diabetic Foot Syndrome.

methodsA Medline and Embase search were performed up to May 20th, 2024 collecting all RCTs including diabetic patients or reporting subgroup analyses on diabetic patients with DFU comparing AT with placebo/standard of care (SoC), with a duration of at least 12 weeks. Prespecified endpoints were: ulcer healing (principal), time-to-healing, major and minor amputation, serious adverse events (SAE), and all-cause mortality. AT assessed were: growth factors (GF), Platelet-rich plasma and fibrin (PRP/F), skin substitutes (SS), negative pressure wound therapy (NPWT), and hyperbaric oxygen therapy (HBOT). Mantel-Haenzel Odds ratios and 95% confidence intervals (MH-OR, 95% CIs) were either calculated or extracted directly from the publications. Weighted mean differences and 95% CIs were calculated for continuous variables.

resultsFifty-one studies fulfilled all inclusion criteria (3, 5, 27, 8, and 8 with GF, PRP/F, SS, NPWT, and HBOT, respectively). Participants treated with any of the explored AT had a significantly higher ulcer healing rate (MH-OR ranging from 2.17 to 4.18) and shorter time-to-healing in comparison with SoC/placebo. Only PRP/F and HBOT showed a significantly lower risk of major amputation (MH-OR: 0.32(0.11;0,93; p = 0.04 and 0.28(0.10;0,79; p = 0.02, respectively), despite a higher risk of SAE. No other significant effects on the above-reported prespecified endpoints were observed. For the primary endpoint, the quality of evidence was rated as "high" for all the AT, except for NPWT ("moderate").

conclusionsIn conclusion, AT can actively promote wound healing and shorten time-to-healing in patients with DFU. HBOT and PRP/F also showed a reduction of the risk of major amputation, despite a higher rate of SAE.