Diabetic foot ulceration is a serious and common complication of type 1 and type 2 diabetes, affecting 9·1–26·1 million people annually worldwide and approximately 19–34% of people with diabetes at least once in their life.1 Because the global prevalence of diabetes continues to increase substantially, with a prediction of 642 million people worldwide in 2040,2 the complex and costly management of these disabling and recurrent wounds remains a therapeutic challenge.1, 3, 4 The prognosis of patients with diabetic foot ulcers is deeply affected by the high prevalence of infection and amputation associated with these wounds. The risk of death at 5 years for a patient with a diabetic foot ulcer is 2·5 times higher than for a patient without, and up to 70% of patients could die within 5 years after amputation.1, 5 Thus, effective and safe treatments are needed that do not increase staff workload, are easy to provide, and are well received by patients.
Research in context
Evidence before this study
Management of diabetic foot ulcers is a therapeutic challenge. We searched MEDLINE and Embase on July 20, 2017, without language or date exclusions, with the terms “wound healing” AND “diabetic foot ulcers”' AND (“neuro-ischaemic” or “peripheral artery disease”) for reports of randomised controlled trials. We identified 33 papers, but no relevant study could be selected because no studies had so far assessed the superiority of any device in a cohort of patients who only had neuroischaemic ulcers. We expanded our search (again with no language or date exclusions) using the terms “wound healing” AND “diabetic foot ulcers” for meta-analyses and systematic reviews of randomised controlled trials, with a special interest in trials assessing dressing efficacy. Our search identified 146 papers from which we selected four that provided sufficient up-dated or recent evidence on wound closure and on the quality of analysed trials. Our search revealed that most trials assessing skin substitutes, growth factors, or dressings had included patients with only neuropathic ulcers or mixed populations of patients with neuropathic and neuroischaemic ulcers. According to most recent guidelines and systematic reviews, evidence to support the adoption of any particular intervention in the management of diabetic foot ulcers is poor. A strong need exists for robust evidence from studies using high-quality methods. To address this quality evidence gap, Jeffcoate and colleagues listed the key points that should ideally be included in the design and reporting of clinical studies in this field in a 2016 Personal View in The Lancet Diabetes & Endocrinology. Some positive clinical evidence has also been reported with sucrose octasulfate dressing in the management of chronic wounds with vascular involvement and protease imbalance. The results of two randomised controlled trials in patients with leg ulcers of venous or mixed origin, and of a pooled data analysis of eight real-life surveys in a variety of chronic wounds including diabetic foot ulcers, indicated a potential use of sucrose octasulfate dressings in the management of neuroischaemic diabetic foot ulcers, but the evidence needed to be established through a randomised clinical trial containing patients with diabetic foot ulcers.
Added value of this study
Our study is, to our knowledge, the first randomised double-blind controlled trial to compare two types of dressings in patients with rigorously assessed neuroischaemic diabetic foot ulcers. Sucrose octasulfate dressing along with good standard of care was significantly more effective at achieving would closure after 20 weeks of treatment than a control dressing (the same dressing without sucrose octasulfate) with similar care.
Implications of all the available evidence
Sucrose octasulfate dressings could be used in current local treatment and management of neuroischaemic diabetic foot ulcers. In the context of multidisciplinary and complex management of this condition, efficient and safe treatments that are also easy to implement by all health-care professionals are needed. Sucrose octasulfate dressings could be considered as a new standard of care.
Existing guidelines for the management of diabetic foot ulcers recommend appropriate local wound care with efficient debridement, use of wound dressings that maintain a moist environment, treatment of infection, vascular assessment and revascularisation if required, pressure relief, treatment of comorbidities, metabolic control, and patient education—however, outcomes with these management strategies are unsatisfactory.4, 6, 7, 8 Some emerging treatments have been proposed with varying degrees of success, but according to guidelines and systematic reviews, none of these interventions can be recommended over others owing to poor evidence. Only a few published studies of novel interventions were of high quality and most were susceptible to biases, including small study sizes, heterogeneous patient cohorts, and a high number of dropouts.7, 9, 10, 11
Diabetic foot ulcers are usually categorised as neuropathic, ischaemic, or neuroischaemic ulcers, the latter being diagnosed if peripheral neuropathy and peripheral artery disease are both involved. Because more accurate and frequent vascular assessment can be done today in current practice, peripheral artery disease is increasingly recognised when present and neuroischaemic ulcers are now estimated to be present in more than half the patients with diabetic foot ulcers in high-income countries.8, 12, 13, 14, 15 Unfortunately, the situation has not changed since 2011, when Armstrong and colleagues14 suggested that “peripheral artery disease in [diabetic foot ulcers] is also associated with the most severe adverse outcomes, including lower probability of healing, longer healing times, higher probability of ulcer recurrence, greater risk of amputations, and potentially higher mortality”. To date, there are no devices or drugs with proven efficacy for this indication.14
Over the past few years, knowledge of the underlying metabolic and cellular changes involved in diabetic foot ulcers and peripheral artery disease has progressed.16, 17, 18, 19, 20 Diabetic foot ulcers have a prolonged inflammatory phase with fibroblast dysfunction, impaired neovascularisation, and increased concentrations of matrix metalloproteinases.18, 19 These matrix metalloproteinases impede wound healing through degradation of growth factors and destruction of the extracellular matrix.17, 19 In neuroischaemic ulcers, this protease imbalance has been associated with poor outcomes.16, 17, 21 The potassium salt of sucrose octasulfate acts at the tissue level and has been shown to inhibit excess matrix metalloproteinases.22 Additionally, the potassium salt of sucrose octasulfate has a unique structure that interacts with growth factors and thus restores their biological functions contributing to tissue formation.22, 23, 24 Therefore, we hypothesised that a sucrose octasulfate dressing could be a potential treatment for neuroischaemic diabetic foot ulcers. Sucrose octasulfate dressings have been successfully used for the treatment of various chronic wounds.25, 26, 27 Its favourable benefit–risk ratio has been established through randomised studies of patients with leg ulcers arising from venous or mixed origins, when compared with either a control dressing or a protease modulating dressing.25, 26 Additionally, a pooled-data analysis of real-life surveys in Europe has revealed that sucrose octasulfate dressings might shorten the time to closure of chronic wounds.27 However, evidence for its usefulness in treating neuroischaemic diabetic foot ulcers is scarce. We therefore aimed to assess the efficacy of treatment with a sucrose octasulfate dressing to improve wound closure in patients with a neuroischaemic diabetic foot ulcer, compared with a control dressing without sucrose octasulfate.
