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.

Aim: To 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.

Methods: A 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.

Results: Fifty-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").

Conclusions: In 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.