IWGDF guidance on use of interventions to enhance the healing of chronic ulcers of the foot in diabetes

Abstract

There is a clear need for evidence to substantiate the use of particular interventions in the management of chronic ulcers of the foot in diabetes. Following the completion of the latest of three systematic reviews undertaken over the last 10 years for the International Working Group on the Diabetic Foot (IWGDF) 1-3, the authors have formulated guidance on the use of interventions to enhance the healing of foot ulcers in diabetes, based on the evidence from all three reviews. The guidance is based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system of rating both the quality of the evidence and the strength of the recommendations. 1 Recommendations can be made to support an intervention, but also against the use of a particular intervention if there is no strong supporting evidence to justify its adoption. The guidance is divided into ten categories – the same as those used to group different types of intervention in the systematic reviews. The term debridement is here defined as the removal of surface debris, slough and necrotic and infected matter with the aim of leaving clean, viable tissue. Even though professional opinion is united in support of the use of debridement to clean the surface of the wound when possible, the experimental evidence to justify debridement in general and of any particular method of debridement is not strong. Debridement may be undertaken using physical (e.g. surgical, sharp or hydro-debridement), biological (larvae), autolytic (hydrogels) or biochemical (enzymes) methods. There is surprisingly little evidence on sharp or surgical debridement with only a single article included in one of the previous systematic reviews and that being a subgroup analysis from another trial 6. Despite this, the majority of national guidelines emphasize that sharp debridement 7-9 is an essential part of good wound care, taking relative contraindications such as severe ischemia into account. The available evidence from the three systematic reviews undertaken by the IWGDF, as published earlier in this journal, suggest that the use of hydrogels 10-12 as a means of debridement may have some benefit in terms of wound healing when compared with saline moistened gauze, but the risk of bias in the published studies was high – a conclusion supported by a Cochrane review 13. Similarly, the use of enzymatic or hydro-debridement cannot be supported by the available evidence, which is limited to one study on each method that qualified for inclusion 14, 15. The use of larval therapy is equally unsupported in these three reviews with only four small studies identified, each of which had a high risk of bias 16-19. Of interest, two recent large Randomised Controlled Trials (RCTs) of the use of larval therapy in venous leg ulcers have failed to demonstrate a benefit in terms of healing 20, 21. This does not mean that debridement is ineffective but simply that the studies have not been performed that provide robust evidence to support a strong recommendation. In general, however, clinicians should not adopt newer, more expensive, interventions unless they have been shown to have a greater impact on wound healing than existing methods. The three systematic reviews performed have looked at a number of different topical preparations designed to improve the healing of ulcers of the foot in diabetes. In general, the evidence to support the adoption of any particular intervention is poor, because the available studies are small and at high risk of bias. The results of an earlier positive study on a carboxymethylcellulose dressing 22 were not born out by a more recent large single blind RCT with low risk of bias 23. There is increasing interest in the use of surface antiseptics or antimicrobials, and although healing may not be the most obvious outcome measure to evaluate these agents, it is important that it is assessed in order to demonstrate the contribution it may make to the healing process. A single study reporting the use of antibiotic beads after transmetatarsal amputation found that this intervention had no impact on the incidence of wound healing 24. Honey has been used for centuries as an antimicrobial agent, and its appeal as a potential target for the management of chronic wounds is obvious. There is, however, little evidence to support its use for either the promotion of healing or the prevention of secondary infection. Over the three systematic reviews, only three small controlled studies on the use of honey were identified, and none showed convincing evidence of benefit when compared with an iodine-containing dressing 25-27. A Cochrane review of honey-based dressings in all wound types 28 concluded that health services may wish to consider avoiding routine use of honey dressings until sufficient evidence of effect is available – a conclusion that is endorsed by the results of the current review. Other topical antimicrobials, such as silver-based or iodine-based dressings and applications, are also used frequently. Only one controlled trial of a silver-based dressing was identified in all three systematic reviews 29, and this demonstrated no convincing evidence of benefit. Similarly, a recent Cochrane review found no evidence of benefit from the use of antiseptic preparations in terms of either healing or secondary infection in any studies of infected or contaminated wounds 30. Similarly, a single large high-scoring multicentre RCT that compared a non-adherent dressing with an iodine-impregnated dressing and a carboxymethylcellulose hydrofibre dressing was reported in the 2012 review. This showed no difference between the three products in terms of either wound healing or the incidence of new infection 23. The conclusion for the whole group of topical interventions is that there was either insufficient or no evidence to justify the use of any of the preparations considered in preference to any other. In the absence of any specific indication, practitioners should use the dressing/application with the lowest acquisition cost but that supports moist wound healing while controlling any exudate. In our systematic reviews, we reported two RCTs 31, 32 of methodologically good quality on systemic hyperbaric oxygen therapy. The larger study 32, which included patients both with and without (severe) peripheral arterial disease, demonstrated a significantly improved outcome in the intervention group, who were more likely to heal within 12 months. In a post-hoc analysis, ulcer healing in the patients treated with hyperbaric oxygen therapy was associated with baseline trans cutaneous oxygen pressure levels, but not with ankle brachial index or toe blood pressure 33. Of note, the second RCT that also observed improved wound healing 31 included only patients with non-reconstructable critical limb ischemia. It remains therefore to be determined which group of patients will benefit most from systemic hyperbaric oxygen therapy. This is underscored by a large retrospective cohort study of patients treated in 83 centres located in 31 states of the USA 34. Data were included if patients had been treated according to reimbursement guidelines from Centers for Medicare and Medicaid Services, which require that patients have ‘an adequate lower-extremity arterial flow’ as determined by the clinician. Using propensity score-adjusted models, the authors concluded that hyperbaric oxygen therapy did not appear to be useful for the prevention of amputation and did not improve the likelihood that a wound would heal in these patients. Although the design and inclusion criteria of this study have been criticized, it highlights the need for further studies to determine which patient group might benefit most from this treatment and to establish cost-effectiveness. Negative pressure wound therapy (NPWT) is a technique for applying continuous or intermittent negative pressure to wounds via a material that fills the wound. Optimal use of this technique requires knowledge of the influence of different pressure levels, the different materials that can be put in the wound and the interface materials (those in direct contact with the wound surface). One theory behind the use of NPWT is that by extracting wound exudate, the frequency of dressing changes can be reduced and wounds can therefore be kept cleaner and with reduced malodour. Moreover, NPWT appears to stimulate granulation tissue formation 35, 36 and contraction of the wound 35. It is also suggested that NPWT may increase tissue perfusion by mechanical means and may also encourage offloading by making ambulation difficult 35. NPWT is generally useful in stimulating the healing process but does not result in complete epithelialisation. Potential adverse effects of NPWT have been described, including wound maceration, retention of dressings and wound infection 36. A number of other potential contraindications to its use have been listed elsewhere 37. Given the relative complexity of this technique and its risks, it requires skills and organization. There are two distinct types of wounds in which NPWT has been studied in the management of ulcers of the foot in diabetes, the post-surgical and the chronic non-surgical wound. In earlier systematic reviews, we reported on two large RCTs and a small RCT that suggested in post-operative wounds a significant benefit of NPWT in both the time to healing and the proportion of wounds healed 38-40. However, there were methodological issues in these studies, rendering them subject to bias. One small study was reviewed in the latest review, which compared the use of NPWT on the success of split skin grafting 41. Although apparently improving the number of split skin grafts which took successfully when compared with usual care, the study was of poor methodological quality. A small randomized but single blind study has shown that the qualitative but not quantitative assessment of the graft take improved when NPWT was used in addition to split skin grafting 42, but this was not undertaken in diabetic foot ulcers. Three small RCTs and one cohort study have been identified on the use of NPWT in chronic Diabetic foot ulcers (DFUs) from all three systematic reviews 43-46. All had methodological flaws but showed NPWT was associated with decreased wound volume and depth 43, and decreased time to ulcer healing 44, but these studies were subject to bias, and there is, in addition, considerable publication bias in this area 35. It is not possible to make a recommendation on the use of NPWT in non-surgical wounds because of the lack of available evidence. Four studies of collagen/oxidized regenerated cellulose dressing were identified in the three systematic reviews 47-50. The largest of these failed to show an effect on healing 49. Small, poor-quality studies have reported the use of an acellular dermal regenerative matrix and an acellular bioproduct from pig intestine, but they provided no good data to support the use of these products in routine care 51-53. The latest search also identified a single study of perilesional injections of polydeoxyribonucleotide 54. Although a high-scoring RCT, there are concerns about the poor healing rate in the control arm, the lack of detail concerning offloading and lack of health economic data. Earlier reports have suggested promise of some other agents (acellular bioproduct derived from the porcine small intestinal submucosa, acellular dermal regenerative tissue matrix, talactoferrin and chrysalin) that alter wound biochemistry and cell biology. The studies identified have provided no firm evidence to justify the use of any intervention listed. Platelet concentrates and platelet-derived growth factors have been of interest as a therapeutic target for a number of years. The earliest study identified was of autologous platelet factor 55 but was limited by being undertaken in both leg and foot ulcers, and not all patients had diabetes. A later study on platelet concentrate 56 reported an apparent improvement in wound healing but was marred by a high number of dropouts and the use of per protocol analysis. The problem of the volume of blood required for the preparation of autologous platelet gel or fluid was overcome in a later RCT by the use of blood bank-derived platelets 57. Although the study reported positive results, few details were provided on study inclusion criteria. As this product was used in uninfected, non-ischemic, non-necrotic wounds, this represents a minority of patients with foot ulcers. In addition, the use of non-autologous platelets is potentially associated with adverse effects such as infection. The use of recombinant platelet-derived growth factor has also been assessed. Six RCTs were identified 58-63 that either showed no improvement in healing between intervention and control groups or were marred by significant methodological problems. Given the cost of the product, firm data are required for both its effectiveness and its cost-effectiveness before it is considered for use in routine care. Other recombinant growth factors have also been the subject of studies, and these include basic fibroblast growth factor, epidermal growth factor (EGF) and vascular endothelial growth factor. Two studies of basic fibroblast growth factor 64, 65 do not support the use of this agent in clinical practice. Despite the widespread use of EGF in some countries, only three moderate to high-scoring RCTs have been identified, with conflicting results 66-68. Hence, no clear outcomes in terms of healing or area reduction have been demonstrated. One study of intramuscular injections of a plasmid containing the gene for vascular endothelial growth factor 69 has shown some promising results on reduction in wound area but needs confirmation before this therapy could be recommended in clinical practice. There is currently little evidence to suggest that any single growth factor should be considered for adoption in the management of foot ulcers that fail to heal with standard good care. Several early studies of cultured dermal fibroblasts, keratinocytes or fibroblast/keratinocyte co-culture were marred either by methodological problems or by low healing rates in the control groups 70-74. Only one well-designed RCT later reported a significant improvement in healing in a group of patients who were otherwise well managed 75, but the trial was stopped prematurely and the result is that the effectiveness and cost-effectiveness of this type of therapy remain to be confirmed. One promising study of co-cultured keratinocytes in combination with fibroblasts followed by epidermal tissue-engineered autograft 76 requires confirmation. There are several concerns related to these products such as the complex application process, costs and suboptimal quality of the skin after healing and the potential of slow-virus. For this reason, we feel that higher level of evidence is needed to justify its routine use. Split skin grafting is widely used for various kinds of non-infected, non-ischemic, non-necrotic wounds, including diabetic foot ulcers. Surprisingly, only one study of split skin grafting 77 has been identified, which for methodological reasons, does not provide support for the use of split skin grafting to improve healing of diabetic foot ulcers. The evidence to justify the use of the various products available has been well reviewed in the three earlier IWGDF reviews, as published earlier, and the evidence to justify the use of any is inconclusive. It is for this reason that the routine use of any such product is not currently recommended. Studies on the use of electrical stimulation 78-80, ultrasound 81, normothermic therapy 82, magnetism 83 and laser therapy 84 have reported no convincing evidence of benefit. Reports of apparent superiority of shockwave therapy over hyperbaric oxygen treatment are marred by the use of per protocol analysis and other methodological problems 85, 86. There is no evidence to justify the recommendation for the adoption of any reported physical therapies in routine practice. Trials of low molecular weight heparin 87, iloprost infusion 88 and of herbal preparations (administered orally in two studies and intravenously in one) 89-91 were of poor quality, and none showed any major improvement in outcome. One recent study of the use of oral vildagliptin 92 reported apparent improvement in healing at 12 weeks in one recent study, but the very low incidence of healing in the control group casts doubt on the likely clinical benefit of this product if used in addition to good clinical care. There is no evidence to justify the recommendation for the adoption of any other systemic therapy to enhance the healing of DFUs in routine practice. Our recommendations are derived from critical systematic review of all relevant publications, but this process has its limitations, and these must be borne in mind. The first is that the reviews sought evidence specifically that an intervention may improve healing (and only of foot ulcers complicating diabetes – and not of other wounds, whether acute or chronic). As, however, the process of healing is a highly complex one, involving the interaction of many different cell types and signalling pathways, it is likely that the benefit of the majority of specific interventions is limited to a particular type of wound and to a particular phase in the healing process. As the process tends to last for weeks or months, this means that the impact of any beneficial effect of a therapy may not be apparent. It is also important to consider whether the benefit of a therapy has been demonstrated in people who are also receiving usual best care, including adequate offloading in those with ulcers on weight-bearing areas of the foot. If, however, studies are of insufficient duration to assess complete healing of an ulcer as an outcome measure, it may be possible to use a surrogate measure – such as percentage reduction in wound area over 4 weeks, which has been shown to correlate with, and to be predictive of, the incidence of eventual healing 93. The adoption of such a surrogate measure will reduce the chance of a short-term response to an intervention being obscured by the complexity of the overall healing process. Demonstration of benefit in such short-duration studies could then be used as the foundation for further work designed to determine the specific population and circumstances in which the use of the intervention is likely to be beneficial. Ultimately, however, the clinical endpoint of care is to accelerate complete healing of chronic ulcers of the foot in diabetes, and this must be demonstrated if any treatment is to be generally recommended. Hitherto, such recommendation has not been possible because of the limitations both in extent and, in many cases, in quality of reported studies. Even though there are a small number of studies suggesting efficacy of particular interventions, there are very few studies confirming effectiveness (and, thereby, of cost-effectiveness) of any particular intervention in routine care. FG, JA, AH, RH, ML, PP, WJ: None declared relating to the interventions reviewed. CA: Consultant: Acelity, Integra and Smith and Nephew.