Chronic wounds present a real challenge to clinicians involved in wound management, not only for those health professionals who work in wound care centres, but for general practitioners and community nurses who regularly manage these types of wounds.1,2 Chronic wounds also place a financial burden on healthcare systems and, perhaps more importantly, they have devastating effects on patients and their families.3 This challenge has been increased during the COVID-19 pandemic due to a workforce shortage, repurposing of health professionals from ‘non-essential’ services such as wound care, as well as an estimated 40% drop in patient volume as patients choose not to expose themselves to the risk of infection.4 However, it is essential that patients with chronic wounds still receive appropriate care while minimising their need to visit hospital or other healthcare settings.5
Chronic wounds are classified by diagnosis, namely, venous and arterial lower limb ulcers (LUs), diabetic foot ulcers (DFUs) and pressure injuries (PIs),6 as a consequence of underlying disease such as diabetes, peripheral arterial disease or chronic venous insufficiency. The causes of chronic wounds can be observed in a persistent inflammatory response created by common components within chronic wounds.7 Evidence supports the premise that advanced age, and the presence of comorbidities frequently found in the older age group, may influence the development of chronic wounds; however, other patient-related issues, such as lifestyle choices and environment, as well as wound-specific factors, contribute to the chronic state of these wounds.8,9 The mortality rate in patients with DFUs is stated to be around 40%, which highlights the importance of appropriate diagnosis and management of both the wound and comorbidities.10
In the past few decades, wound management has greatly evolved with the introduction of a variety of local wound therapies and procedures designed to manage all type of wounds, as well as other therapies particularly targeted at chronic wounds.11 However, it has been debated that many of these dressing choices are based more on clinician experience influenced by the patient's expectations rather than scientific and clinical evidence.12,13
Chronic wounds
Many definitions of the terminology of chronic wounds mention specific timeframes of healing before a wound can be classified as chronic, such as 2–8 weeks for DFUs and four weeks to two months for VLUs; however, most references do not provide a clear timeframe to define the chronicity of wounds and do not agree on the timeline that defines an ulcer as chronic.9 It is stated that ‘such wounds may from the outset show chronic features’,14 which may advocate that chronic wounds are not defined by time/duration, but by diagnosis, suggesting that chronic wounds such as LUs, DFUs and PIs are chronic from day one.14
Lazaro et al.15 conducted a review of clinical evidence regarding the effect of elevated matrix metalloproteinases (MMPs) on wounds and stated that:
- ‘Chronic wounds present higher levels of protease activity than acute wounds’, and ‘MMP levels were higher than those recorded at any time in normally healing acute wounds’, suggesting ‘that the increased proteolytic environment in chronic wounds may impede healing’;
- ‘These factors [high levels of MMPs and decreased levels of tissue inhibitors (TIMPs)] could be used as prognosis indicators’ and ‘Inhibiting MMPs (or enhancing their inhibitors) could optimise the healing course of chronic wound’;
- ‘There is no consensus on the value of the best MMP threshold that could be used to predict general wound healing’.
The authors reiterate that decreasing high levels of these enzymes ‘might help reset wounds and put them back on the right healing trajectory, in combination with aetiological treatments and good standards of care’.15 Moreover, excess MMPs damage the basement membrane surrounding the capillaries which allow the migration of vascular endothelial cells to the wound bed, thus hindering angiogenesis.16 Furthermore, the process to break the cycle of delayed wound healing will consist of improving environmental, systemic, local and wound factors that might be contributing to a hindered healing process.15 Local chronic wound management that changes the wound microenvironment and decreases the level of MMPs shows encouraging results in the reduction of healing time, consequently improving the wound and patient outcomes.17,18
Nano-oligosaccharide factor (sucrose octasulfate dressing based on technology lipido-colloid, TLC-NOSF)
In contact with wound exudate, the TLC-NOSF wound contact layer or healing matrix forms a gel that soaks up wound exudate and decreases levels of MMPs.19 The TLC-NOSF wound contact layer or healing matrix decreases MMP levels on the wound surface, promoting wound repair and shortening time to wound healing.19 It has also been shown that, when treating neuroischaemic DFUs with a TLC-NOSF dressing, transcutaneous oxygen pressure is improved.20
Aim
The aim of this systematic review was to identify the clinical evidence available on the TLC-NOSF dressing to explore its efficacy in the management of chronic wounds, particularly lower limb ulcers, DFUs and PIs.
Method
A search of three databases was conducted: PubMed, Google Scholar and Cochrane Library between June and August 2020. No search limitations were implemented regarding date and language to ensure exhaustive results. The inclusion criteria were as follows:
- Clinical studies evaluating TLC-NOSF dressings including randomised control trials (RCT), interventional trials (RCT, comparative, non-comparative), observational studies, case series and case reports
- Guidelines, best practice guidance, position papers and expert reviews.
The following types of publications were excluded: preclinical studies (i.e., in vivo animal model studies), editorials or letters, abstracts but no articles.
PubMed was used for the primary search. In this database, journals are selected for inclusion based on scholarly and quality criteria by literature review committees, and not electronically.21 Data about each article are entered into the database in a uniform way: author, title, date, journal name, enabling accurate retrieval in searches.21
The classical approach to identifying a research question followed by a thorough literature search using the PICO (patient/population, intervention, comparison and outcomes) process led to an appropriate study design and methodology.22 The research question was divided into four categories using this process to enable a systematic search (Table 1).
Table 1. PICO terminology
| Patient/population and/or problem | Intervention | Comparison/control (if applicable) | Outcomes or effect |
|---|---|---|---|
| Chronic ulcers | Sucrose-octasulfate | Nil | Reducing healing time |
A set methodology was used, applying suggested guidelines,23 as follows: both the singular and plural forms of terms were applied where an exact phrase was used, for example, ‘arterial ulcer’ and ‘arterial ulcers’. Truncation (stemming) was used to broaden the search to include various word endings and spellings to avoid missing any slight variation in the search term, for example, ‘reduce*’ to include ‘reduces’, ‘reduced’, etc., where singular words were used. Using a shorter term, for example, ‘reduc#’ yielded a vast number of terms which were not relevant and therefore was eliminated.
Synonyms and different terminology were also adopted to maximise the search, for example, ‘decrease’ instead of ‘reduce’ and using the term ‘bed sore’ and ‘decubitus ulcer’ for the term ‘pressure injuries’. The trade name of the dressing was included to ensure that articles using generic and/or brand names of the product were captured. Moreover, different language spelling, for example, English and American spellings, ensured that articles completed in different countries and/or from different journals were identified, for example, ‘minimise’ and ‘minimize’.
Controlled vocabulary (organised arrangement of words and phrases used to index content and/or to retrieve content through browsing or searching) was used in order to perform a complete search, i.e. Medical Subject Headings (MeSH) Terms, which, however, only provided one repeated result with terminology ‘Urgo, Start’ and nil relevant (only one result) using ‘sucrose octasulphate’ or ‘sucrose octasulfate’, which was therefore eliminated. Boolean connector ‘OR’ was used to broaden the search while Boolean connector ‘AND’ was applied to narrow the search. This resulted in a total of 21 publications identified.
Evidence collected was sorted in order to identify any unrelated work. The elimination strategy was as explained previously and mainly where the title suggested lack of relevance to the subject (for example, a different aetiology than wounds). If a doubt still existed after review of the title, the abstract and the whole article was read to identify relevance or irrelevance.
Evidence, which may be identified as lower level, for example, case presentations and expert opinion,24 was included in the final list. This rationale was followed as clinical experience represents medical knowledge that might differ from evidence derived from clinical research and may give readers different expert viewpoints.25 Furthermore, as stated by Charbonneau,26 ‘clinical judgment, then, can be understood as bringing to bear all relevant kinds of medical knowledge, along with patient goals, values, and preferences, in order to reach the best possible decision for the patient-at-hand’.
A search was also conducted using Google Scholar to identify any other available articles that might have been overlooked. The search term adapted was ‘sucrose octasulfate’ and ‘UrgoStart’, which gave 41 results. A scan was performed to eliminate titles already retrieved in the previous search and other titles which were not in line with the current search (for example, articles regarding use of sucrose octasulfate in different aetiologies and in other forms, such as ointments). This resulted in the identification of a further eight articles of interest.
A search was also conducted through the Cochrane Library. The Cochrane Collaboration aims to produce and disseminate reliable and up-to-date information to support decision-making in health care.27 The terminology ‘UrgoStart’ in title, abstract and keyword was used to define articles specific to the research question. The same exclusion criteria were adapted and two recent publications regarding budget impact analyses in the UK were retrieved.
A description of the steps taken to complete the literature review is shown in Fig 1.
Results
A total of 21 publications were identified through PubMed, with a further eight publications through Google Scholar and two publications through Cochrane Library (n=31). Of these, seven results were omitted due to relevance or repetition. Table 2 presents the objectives/methods and main results and/or conclusions of each publication found in relation to the search findings (excluding omissions). The sequence followed:
- Importance of evidence as per the pyramid of hierarchy of evidence22
- Date (most recent to oldest).
Table 2. Results from all searches after omissions
| Author | Year | Type | Main objective method | Main results/conclusions |
|---|---|---|---|---|
| Edmonds M et al.28 | 2018 | Double-blind randomised controlled trial (RCT) performed in five European countries | Randomised, double-blind clinical trial (Explorer RCT). Intervention in non-infected neuroischaemic diabetic foot ulcer (DFU). Cohort management: TLC-NOSF versus TLC (neutral dressing). 240 patients | By week 20:Wound closure:
|
| Meaume S et al.29 | 2012 | Double-blind RCT (Challenge RCT) | Cohorts were managed with either TLC-NOSF (test group) or TLC (neutral dressing). The venous leg ulcers (VLUs) were assessed every two weeks for eight weeks. Non-infected VLUs and receiving effective compression therapy. 187 patients | Median wound area reduction by week eight:
|
| Schmutz JL et al.30 | 2008 | Open label RCT (Wound Healing Active Treatment (WHAT) RCT) | Document the effect of TLC-NOSF versus oxidised regenerated cellulose (ORC) in the local management of VLUs. 117 patients | Mean difference:
|
| Richard JL et al.31 | 2012 | Multicentre, pilot, prospective, non-controlled open-label clinical trial | Adult patients who had a non-infected neuropathic foot ulcer, 1–15cm2 in size and of 1–20 months' duration were included.The primary endpoint was the relative reduction of the wound surface area (%) at the end of the study. 33 patients |
|
| Lobmann R et al.32 | 2019 | Post hoc analyses of a double-blind RCT for cost-effectiveness (Challenge RCT) | Evaluation of the clinical outcomes associated to direct costs at 20 and 100 weeks | After 20 weeks, and with complete closure as a primary endpoint, direct treatment costs for DFU of:
|
| Lázaro-Martínez JL et al.33 | 2019 | Post hoc analyses of a double-blind RCT for impact of wound duration on the healing outcomes | Further document the impact of wound duration on the healing outcomes of the neuroischaemic DFUs included in the Explorer study and to discuss complementary pragmatic observations on the TLC-NOSF effect | Results: Whatever the wound duration subgroups analysed, higher closure rates were reported in the TLC-NOSF group than in the control group. Difference between the two treatments was reported in wounds with a duration of ≤2 months (71% versus 41%, 30 percentage points difference). Regarding wound location subgroup analyses, the outcomes were in favour of the TLC-NOSF treatment, with closure rates ranging between 43% and 61% within the TLC-NOSF group, and between 25% and 40% within the control groupConclusion: This clinical evidence supports that treating DFUs with TLC-NOSF dressing and good standard of care results in higher wound closure rates than with a neutral dressing and the same good standard of care, whatever the duration and the location of the treated wounds. The earlier the TLC-NOSF dressing is initiated in DFU treatment, the greater the benefits |
| Meaume S et al.34 | 2017 | Post hoc analyses of a double-blind RCT (Challenge) for quality of life | Report the results from the same study assessing the performance and safety of TLC-NOSF in the local management of VLU or mixed leg ulcers and determining its impact on the patient's health-related quality of life (HRQoL) | Results: In the HRQoL questionnaire (EQ-5D5L), the pain/discomfort and anxiety/depression dimensions were significantly improved in the TLC-NOSF group versus the control (pain/discomfort: 1.53±0.53 versus 1.74±0.65; p=0.022, and anxiety/depression: 1.35±0.53 versus 1.54±0.60, p=0.037)Conclusion: TLC-NOSF matrix dressing promotes faster healing of VLU and mixed leg ulcers and significantly reduces the pain/discomfort and anxiety/depression experienced by the patients |
| Augustin M et al.35 | 2016 | Post hoc RCT cost and outcome analyses (Challenge RCT) | Evaluating the cost-effectiveness of TLC-NOSF in VLUs compared with a similar neutral foam dressing Cost-effectiveness analysis from the perspective of the German statutory health care system was performed using a decision tree model for a period of eight weeks | Effect-adjusted costs after eight weeks of treatment:
|
| Münter KC et al.36 | 2017 | Pooled data analyses from observational surveys performed in France and Germany | Determine whether the clinical trials' results translate into routine management Pooled data from eight real-life observational studies (10,220 patients)The two main indicators used were time to wound closure and time to 50% reduction of the PUSH score | Results: The overall closure rate with TLC-NOSF was 30.8 % (95%CI: 29.9–31.7%). Overall the average time to complete closure was 112.5 days (95%CI: 105.8-119.3) for leg ulcers, 98.1 days (95%CI: 88.8-107.5) for DFUs and 119.5 days (95%CI: 94.6-144.3) for pressure injuries Time-to-closure is substantially shorter for chronic wounds treated with the TLC-NOSF dressing as a first-line intervention versus second-line interventionConclusion: Results indicates that using TLC-NOSF dressings in routine wound management can reduce the healing time of leg ulcers (LUs), DFUs and pressure ulcers (PUs). These data also suggest that the earlier the decision to use this dressing, the shorter the time to closure, whatever the severity and the nature of these chronic wounds |
| Dissemond J et al.37 | 2020 | German Prospective, multicentre, observational study | Study with two polyabsorbent TLC-NOSF dressings (UrgoStart Plus Pad and UrgoStart Plus Border). 1140 patients | By the final visit, 48.5% of wounds had healed and 44.8% had improved regardless of wound aetiology or proportions of sloughy and granulation tissue at the start of treatmentConclusion: Results complete the evidence on the good healing properties and safety profile of these dressings, especially in non-selected patients treated in current practice, and regardless of the characteristics of wounds and patients. They support the use of the dressings as a first-line intervention and until wound healing in the management of chronic wounds, in association with appropriate standard of care |
| Sigal ML et al.38 | 2019 | Prospective multicentre open-label non-comparative clinical trials | Pathology: mixed or VLUs Two prospective, multicentric clinical studies: A: debridement stage (37 patients) B: granulation stage (51 patients). In both studies, the primary outcome was the relative wound area reduction (RWAR) at week 12 | Results at week 12:
|
| Allaert FA.39 | 2014 | Prospective, multicentre non-comparative observational study | Assess the healing of wounds after sequential treatment combining TLC-Ag for four weeks and TLC-NOSF for the four following weeks. The primary endpoint was the relative decrease in surface area of the wound at eight weeks measured by planimetry | After sequential treatment:
|
| Schaper NC et al.40 | 2019 | International practice guidelines | Basic principles of prevention, classification and treatment of diabetic foot disease, based on the six International Working Group on the Diabetic Foot (IWGDF) Guideline chapters | Regarding TLC-NOSF:
|
| Arroyo AA et al.41 | 2012 | Cost-effectiveness study | Compares the use of TLC-NOSF in 1000 patients versus the most commonly used products for treating wounds. This comparison is made using a cost-effectiveness model (Markov model) | From the calculations made it has been concluded that the cost to treat a LU was:
|
| Betts A et al.42 | 2018 | Budget impact analyses | A budget impact model in diabetic foot patients eligible for UrgoStart | Over the five-year period, using UrgoStart instead of a neutral dressing could save £251.7 million for the National Health Service (NHS) while also avoiding 26.1 million days with ulceration for patients. |
| Betts A et al.43 | 2018 | Budget impact analyses | Markov model with the perspective of the NHS in the UK, with a cohort of 1000 patients and base-case time horizon of one year. | Sensitivity analysis showed a cost saving for UrgoStart of £274.25 and a 0.03 gain in quality-adjusted-life years, per patient |
| National Institue for Health and Care Excellence (NICE)44 | 2019 | NICE medical technologies guidance | NICE guidance on UrgoStart for treating leg ulcers and DFUs | Recommendations support the case for adopting UrgoStart dressings to treat DFUs and VLUs in the National Health Service (NHS) because they are associated with increased wound healing compared with non-interactive dressings |
| Conde-Montero E et al.45 | 2020 | Interventional, prospective, single-arm, monocentre study | Outpatients with venous leg ulcers treated with autologous punch grafting, TLC-NOSF dressing and multi-type compression therapy. The primary outcome was the percentage of healed wounds by week 12. 42 patients with 51 ulcers | Despite poor wound healing prognosis at baseline (47% of recurrent ulcers, with a mean duration of 15 months and a mean area of 12.6cm2), wound healing was achieved in 47 ulcers (92%) after a mean period of treatment of 25±13 days. A relative wound area reduction >75% was also reached in three additional ulcers by the last evaluation visit |
| Galea E and Khatib M.46 | 2020 | Case report | Mechanism of action through two cases | New treatment modalities, such as UrgoStart, are proving effective in reducing healing times and enhancing HRQoL |
| Blasco García C et al.47 | 2012 | Case report | Clinical cases with chronic wounds of vascular origin and pressure ulcers. Cases required an initial debridement with polyacrylate fibre dressings with TLC. A polyurethane foam dressing with TLC-NOSF was applied in the granulation phase | The use of TLC-NOSF was considered to have delivered good results with a maximum healing time of 27 days of treatment in these difficult-to-heal wounds. It was also noted that the dressings did not cause any periwound maceration. |
| Piťhová P48 | 2018 | Case report | Management of diabetic foot ulcers with sequential management including TLC-NOSF | The sequential wound management using dressing with cleansing and antibacterial effect (polyacrylate fibres with silver – UrgoClean Ag) in the first phase and inhibition of MMPs with TLC-NOSF in the second phase can be very effective in the treatment of non-healing ulcerations |
| Stryja J49 | 2018 | Case report | Experience with UrgoStart used in a treatment of a non-healing ulceration on a left external ankle in a 60-year old patient with type 2 diabetes and underlying critical ischaemia of her leg | Positive outcomes in the case after using sucrose octasulfate dressing |
| Venerová J50 | 2018 | Case report | Complex therapy of chronic plantar neuroischaemic ulcer in patient with diabetes | Positive outcomes in the case after using sucrose octasulfate dressing |
| Galea E51 | 2018 | Summary of evidence | Evaluate effectiveness of TLC-NOSF in the management of chronic wounds through results of previously published RCTs and explore the methods and results of a recent RCT (Explorer) on the specific management of neuroischaemic DFUs | UrgoStart is a safe and reliable option in the management of chronic wounds in general. Moreover, the Explorer Study has provided clinicians with robust evidence regarding the benefits and efficacy of UrgoStart in the management of diabetic neuroischaemic foot ulcers |
TLC—technology lipido-colloid; NOSF—nano-oligosaccharide factor
Discussion
This systematic review has identified a number of publications from different levels of importance (as per the hierarchy of evidence). Of the RCTs listed,28,29,30,31 it is of importance to note that two are performed double-blind.28,29 This process provides a strategy to minimise risks of bias which may influence the results of the investigation.52 The quality of many studies evaluating the efficacy of wound care products is frequently low due to risk of bias of open-label studies.53 Apart from adequate allocation concealment, blinding of outcome assessors, intention-to-treat analysis, and use of patient-oriented outcomes are particularly important.51
The RCTs20,21,34,35 and the post hoc analyses of RCTs32,33 regarding the use of the TLC-NOSF dressing not only assessed the efficacy of the dressing in reducing healing time and improving financial benefits, but also established the positive effects of the dressing on patients' health-related quality of life (HRQoL).34 Guidelines published by the International Working Group on the Diabetic Foot (IWGDF)40 and the National Institute for Health and Care Excellence (NICE)44 recommend the use of the TLC-NOSF dressing in different chronic wounds—these recommendations are based on high-level RCTs showing the beneficial aspects of this chronic wound treatment option.
The economic benefits of using the TLC-NOSF dressing is shown in different publications, for example, costs for the TLC-NOSF dressing in 2019 were €5,882.87 compared with €8,449.39 for the neutral dressing (cost-effectiveness: €6,277.58 versus €10,375.56, respectively).32 The NICE guidelines also state that: ‘the use of TLC-NOSF could be associated with cost savings of £541 per patient per year for leg ulcers and £342 per patient per year for DFUs'. It concluded that, if 25% of patients with a DFU switched from a non-interactive dressing to TLC-NOSF, this would save the NHS up to £5.4 million per year’.44 The pooled data analyses36 from numerous observational surveys on thousands of patients, as well as the list of case reports retrieved, add the perspective of using the dressing in the reality of daily clinical practice. This approach, sometimes referred to as a ‘naturalistic’ design, allows in-depth, multifaceted explorations of complex issues in their real-life settings.54 It should also be noted that the authors indicate that better results are achieved when the TLC-NOSF dressing is used as a first-line treatment as early as possible.36
In a recently published review of evidence regarding the efficacy of MMP-inhibiting wound dressings in the treatment of chronic wounds,55 the results demonstrated ‘a clear trend towards shorter healing times, if an earlier treatment with MMP-inhibiting dressings was initiated’. It also states that ‘the use of TLC-NOSF dressings is indicated for chronic wounds such as DFUs and VLUs, as also recognised by health technology institutions and international working groups’, while highlighting that no recommendation is given by these institutions for other MMP modulating/inhibiting wound dressings. Furthermore, in a recent publication by Dixon and Edmonds,56 it is stated that ‘sucrose octasulfate (UrgoStart) target and reduce the actions of matrix metalloproteinases and therefore reduce time to wound healing’.
Limitations
The main limitation in this review may be attributed to the fact that some data might have been overlooked due to the lack of inclusion of other databases, such as EMBASE and CINAHL. However, it should be noted that the focus was predominantly on freely available databases and searches that would be available to a broader audience and the majority of health professionals not affiliated with an education faculty. The aim was to reduce potential bias in the review process by avoiding limitation to publication language.
Conclusion
Wound care practitioners have a variety of products and procedures that they might use in their daily practice of managing chronic wounds. Clinicians need to base clinical decisions on the best available evidence and decide on how best to apply it to the individual patient. Evidence supporting clinical practice should be patient-oriented, highlighting outcomes of importance to patients and HRQoL, rather than just disease-oriented evidence.
The list of evidence in this systematic review describes all levels of evidence regarding a TLC-NOSF dressing which is intended for the management of chronic wounds. Based on the clinical evidence provided, it may be suggested that the TLC-NOSF dressing can provide clinicians with an evidence-based option for the management of chronic wounds which may be beneficial in reducing healing times, enhancing patients' HRQoL and providing economic benefits. However, it should be stressed that the dressing is only one part of the standard of care. Aetiological, environmental, and patient evaluation and control still remain essential for holistic management which is necessary to achieving the best clinical outcomes for patients presenting with chronic wound, recognising that a patient is a person with a specific medical, psychological, social and private status, which needs to be assessed, analysed and investigated as a whole.
Reflective questions
- What are the factors that make a wound chronic?
- What are advantages/disadvantages of including Google Scholar in search methodologies to help identify any other available articles that might have been overlooked?
- When we look at the efficacy of dressings, why do we need to include reduction of healing time and improving financial benefits, as well as the positive effects on patients' health-related quality of life?
- As part of the standard of care in wound management, how and why is it important to recognise that a patient is a person with a specific medical, psychological, social and private status, which needs to be assessed, analysed and investigated as a whole?