Diabetic Foot Ulcer: Treatment Challenges

Reference: Armstrong DG, Orgill DP, Galiano R, Glat PM, Didomenico L, Reyzelman A, Snyder R, Li WW, Carter M, Zelen CM. A multicentre, randomised controlled clinical trial evaluating the effects of a novel autologous, heterogeneous skin construct in the treatment of Wagner one diabetic foot ulcers: interim analysis. Int Wound J. 2022;19(1):64–75. doi:10.1111/iwj.13598

Rationale: A pilot study of the application of a novel autologous, heterogeneous skin construct (AHSC) derived from a small, full-thickness skin graft, promoted formation of islands of healthy skin within venous ulcers, burns, traumatic wounds, and properly offloaded DFUs. The AHSC has not yet been tested as an adjunct to best standard of care in a large RCT of patients with DFU.

Objective: The authors conducted a planned interim healing and safety analysis of the first 50 patients who completed a planned 100-patient RCT comparing the treatment effects of AHSC covered with a nonadherent, nonabsorbent secondary dressing to the standard of care in patients with Wagner grade 1 DFU.

Methods: After institutional review board approval and with appropriate individual patient consent, 13 wound care centers in the United States enrolled 50 adult outpatients who presented with a well-perfused, uninfected Wagner grade 1 DFU that did not involve tendon, muscle, or bone in a prospective RCT comparing healing and safety outcomes during 12 weeks of DFU treatment either with standard-of-care dressing and offloading with AHSC (n = 25) or with standard of care alone (n = 25). Subjects who met the inclusion criteria and who had a qualifying DFU that decreased in area less than 30% during an initial 2-week screening period were randomized to participate in the trial. The standard of care consisted of appropriate sharp or surgical debridement, offloading of the DFU with a controlled ankle motion boot (or total contact cast if required based on foot size), gauze and foam dressings, and multilayer elastic compression. The AHSC was processed from a 1 cm × 2 cm full-thickness biopsy harvested from the leg with the index DFU and maintained at 4 °C before being spread evenly over that same DFU within 4 days of biopsy. In both groups, dressings were changed weekly. At the third weekly dressing change, the primary silicone dressing was replaced with a nonadherent wound contact dressing. All wound areas were measured weekly by investigators blinded to treatment and were assessed for healing and secondary outcomes. The primary healing end point was complete closure of the DFU without drainage after 12 weeks of study treatment, as well as confirmation of closure 2 weeks later. Secondary end points were percentage wound area reduction from baseline to 4 weeks, 6 weeks, 8 weeks, and 12 weeks; standardized valid measures of wound quality of life; wound pain; peripheral neuropathy; and adverse events (AEs). This was a planned interim analysis after completion of the first 50 patients in a continuing study involving 102 patients. The sample size was based on the assumption that a clinically important 30-percentage point difference would be statistically reproducible with 89% power to detect a difference at a significance level of less than .05 between AHSC and control group percentage healed. Intent-to-treat (ITT) analyses were performed for categorical variables using the Fisher exact test. Mann-Whitney tests were used if the data were not normally distributed. For continuous normally distributed variables, independent t tests were used.

Results: Of the 25 patients treated with AHSC, which was most commonly derived from the proximal medial calf, 2 required a second application. At 12-week follow-up, 18 patients (72%) in the AHSC group had healed, compared with 8 patients (32%) in the control group (P =.005). This result paralleled DFU percentage area reduction data. One patient in the AHSC group withdrew due to respiratory illness. Six subjects withdrew from the control group—5 due to AEs and 1 due to incarceration. No consistent differences were observed between the AHSC and control groups in terms of patient withdrawal patterns, safety, wound-related quality of life, patient-reported pain, or Semmes-Weinstein measurements of peripheral neuropathy in the index foot.

Authors' Conclusions: Topical application of the AHSC facilitated DFU closure in this interim analysis, which supports continuation of the planned 100-patient study.

Reference: Seidel D, Storck M, Lawall H, Wozniak G, Mauckner P, Hochlenert D, Wetzel-Roth W, Sondern K, Hahn M, Rothenaicher G, Krönert T, Zink K, Neugebauer E. Negative pressure wound therapy compared with standard moist wound care on diabetic foot ulcers in real-life clinical practice: results of the German DiaFu-RCT. BMJ Open. 2020;10(3):e026345. doi:10.1136/bmjopen-2018-026345

Rationale: Systematic reviews have reported insufficient unbiased evidence supporting the safety and efficacy of NPWT over SWD in the management of chronic DFU.

Objective: The German statutory health insurance funds initiated a multicenter RCT in Germany to explore the clinical superiority in terms of effectiveness and safety of NPWT compared with SWD in real-life practice treating patients with DFU.

Methods: An independent scientific institute conducted the study from 2011 to 2014 at 40 qualified diabetic hospital or outpatient clinics, hiring research nurses to support additional study documentation needs. Patients 18 years of age and older with statutory health insurance fund contracts and a Wagner grade 2, 3, or 4 DFU of at least 4 weeks’ duration were enrolled. Patients were included without regard to venous insufficiency status. Those at high risk of bleeding or with exposed or damaged blood vessels were excluded, as were those undergoing NPWT during the prior 6 weeks, those unable of adhere to the study protocol, and those unable to give informed consent. The goal was complete wound closure. Qualifying patients were randomized to undergo NPWT or receive SWD within 6 hours after clinically appropriate revascularization, DFU cleansing, debridement, or amputation of the affected foot part below the upper ankle joint. Risk factors for delayed healing documented on enrollment were impaired circulation, neuropathy, index wound infection, and limited glycemic control. Within each study site, DFU randomization was stratified by Wagner-Armstrong stage—either less than Wagner-Armstrong grade 2c or greater than or equal to Wagner-Armstrong grade 2c. Negative pressure wound therapy was administered using intermittent or continuous CE-marked devices (ie, devices that bear the symbol of free trade capacity in the European Union). Standard wound dressing was defined as site-specific standard wound care. Treating physicians were not blinded to DFU treatment. Healing outcomes were assessed based on wound photographs using the Wound Healing Analyzing Tool (WHAT) by individuals blinded to treatment. The primary outcome was complete wound closure at 16 weeks, with final follow-up of 6 months. Blinded investigators used the WHAT to evaluate photographs for the secondary outcomes of wound area, tissue type, and percentage area reduction at weeks 1, 3, 5, 12, and 16. Planned analyses compared outcomes in subgroups of index DFU larger or smaller than the median DFU area. A sample size of 162 patients per group was needed for statistical significance of a 15-percentage point difference between NPWT and SWD groups, based on a type 1 error of α = .05 and a type 2 error of ß = .20. Fisher exact test analysis of the 16-week NPWT superiority primary outcome hypothesis was conducted on the modified ITT sample of those who underwent at least 1 treatment after baseline. The log-rank test was used to measure differences in time to healing. Bonferroni-Holm corrections were used for repeated
continuous variable t tests. Factors recognized to delay DFU healing were analyzed using binary logistic regression to identify their effects on wound closure.

Results: Of 181 patients initially randomized to NPWT and 187 randomized to SWD, 171 patients underwent at least 1 NPWT treatment and 174 received SWD, respectively, thus qualifying for the ITT analyses. At baseline, similar proportions of patients in the 2 groups were at risk of index DFU nonhealing. In comparable numbers of patients undergoing NPWT or receiving SWD, the index DFU site was revascularized or amputated before study enrollment. Intent-to-treat analyses revealed similar continuous increases in patient quality of life and wound granulation tissue during the study. Fibrin and necrotic tissue values in the DFU decreased throughout the study, with smaller wound areas reported by clinical investigators than by the blinded WHAT assessments. Index DFU area, pain, and volume decreased throughout the study, with no significant difference between the NPWT and SWD groups in terms of patients’ pain and quality of life, or in terms of percentage of DFUs for which complete closure was achieved after 16 weeks or 6 months, time to complete closure, or recurrence. Patients in the SWD group experienced fewer AEs compared with patients in the NPWT group (P =.007), with no difference in resections, amputations, or serious AEs related to treatment. Baseline presence of arterial disease (P =.026) and symptoms related to DFU infection (P <.037) delayed healing, but these variables were similar for NPWT and SWD; thus, they did not influence treatment effects. In the subgroup analysis, large wounds treated with NPWT closed faster than large wounds dressed with SWD. Lack of adherence to the protocol, temporary changes in the randomized therapy, and incomplete documentation limited the ability to draw clear conclusions about effectiveness.

Authors' Conclusions: As evaluated in real-life German clinical practice, NPWT was not found to be superior to SWD. This study serves as the basis for future similar studies with more rigorous quality control.

The investigators who conducted these difficult studies are to be commended for their courage and integrity.^5,6 The RCT evaluating AHSC reported significant efficacy of the skin construct on Wagner grade 1 DFU, with all investigators and subjects adhering to the assigned study protocol.⁵ This study reported a greater rate of healing with AHSC than with a topical standard of care, including substandard⁷ “4 × 4 gauze pads” but not hydrogel or honey dressings. The efficacy of the AHSC remains to be tested on Wagner grades 2, 3, and 4 DFUs or compared with evidence-based hydrogel³ or honey⁴ dressings. In the German RCT, no consistent differences were found in healing or other outcomes for patients with a Wagner grade 2, 3, or 4 DFU managed with NPWT as compared with SWD; that study did not include topical hydrogel or honey dressings.⁶ Among patients with a DFU larger than the study median area, per-protocol patients in the NPWT group (<1 in 4 of ITT NPWT subjects) were more likely to heal at 16 weeks; however, the effect was not sustained, and this small subset of conscientious investigators and patients may not represent real-world DFU results. The more striking result is that even in the context of an RCT, most of the time wound care professionals followed their opinions rather than their randomly assigned protocols. Future studies could optimize outcomes and encourage wound care professionals to follow protocols by using remotely guided evidence-based protocols⁸ and by providing feedback about measured DFU progress to professional caregivers.⁹ Patients expect wound care professionals to do what works by using interventions with evidence of efficacy and safety. Neither Armstrong et al⁵ nor Seidel et al⁶ explored what the experimental intervention added to an evidence-based standard of topical dressing for DFUs. Future RCTs comparing ways to close the DFU healing gap could help improve patient outcomes and provide a more accurate comparison if all groups were subject to rigorous management of all risk factors for delayed DFU healing, including using the best evidence-based topical hydrogel³ or honey dressing⁴ on the DFU. Using less-effective, substandard care control interventions in any clinical study is a disservice to patients and poor use of valuable clinical resources.