3 Committee discussion
The medical technologies advisory committee considered evidence on antimicrobial agents in topical antimicrobial dressings for locally infected leg ulcers. Evidence was taken from several sources and used to determine whether price variation between agents could be justified by differences in their clinical and cost effectiveness or in non-clinical outcomes important to users. Full details are available in the project documents for this guidance.
The condition
3.1
The National Wound Care Strategy Programme defines a leg ulcer as an ulcer between the knee and ankle that has not healed within 2 weeks. Most leg ulcers are caused by venous insufficiency, although they can also be caused by peripheral vascular disease, reduced mobility, cardiac failure, diabetes or sickle cell disease. Prevalence estimates for leg ulcers vary across the literature. For example, estimates for venous leg ulcers range from a point prevalence of 0.03% (Urwin et al. 2022) to an estimated annual prevalence of 1.08% (Guest et al. 2020). The focus of this assessment is the subset of leg ulcers with a local infection. The prevalence of infection in both leg ulcers of any cause and venous leg ulcers was reported to be 18% (Vowden and Vowden 2009) and 41% (Guest et al. 2020) respectively. Ulcers heal slower when they are infected. Leg ulcers can show signs and symptoms of local infection. The International Wound Infection Institute defines these as either covert or overt. Covert signs and symptoms include:
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hypergranulation
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bleeding or friable granulation
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epithelial bridging and pocketing in granulation tissue
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increasing exudate and
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delayed wound healing beyond expectations.
Overt signs and symptoms include:
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erythema
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local warmth
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swelling
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purulent discharge
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wound breakdown and enlargement
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new or increasing pain and
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increasing malodour.
Leg ulcers can also show signs and symptoms of spreading and systemic infection. People with leg ulcers with a spreading or systemic infection are outside the scope of this late-stage assessment.
Current practice
3.2
The management of infected leg ulcers is described in the NICE guideline on leg ulcer infection: antimicrobial prescribing. This recommends that an antibiotic is offered when there are symptoms or signs of infection (for example, redness or swelling spreading beyond the ulcer, localised warmth, increased pain or fever). In clinical practice, antimicrobial dressings can be used to treat leg ulcers that have signs and symptoms of local infection. The choice of dressing is informed by the wound presentation and the person's individual needs. So, dressing choice often changes throughout the duration of a wound. In general, a dressing should be used for no more than 2 weeks before the wound and dressing are reassessed. Subsequent dressings may be of the same type or there could be a step down to a nonantimicrobial dressing or step up to a second-line option. If there is still evidence of local infection after 2 weeks, further escalation for advice from the tissue viability team may be necessary, depending on local guidance. There is no national guidance on using topical antimicrobial dressings to treat locally infected leg ulcers. This has led to the development of local guidance within formularies (where these exist), and a wide variation in practice and available dressings across the NHS. Other measures aimed at treating locally infected leg ulcers include compression, systemic antimicrobial therapy, wound bed preparation and debridement. The committee discussed shared care and heard from clinical experts. They noted that decisions on shared care are always situation-specific and should be made collaboratively between the healthcare professional and the person with the locally infected leg ulcer.
Lived experience
3.3
A survey of people with locally infected leg ulcers showed that most respondents (10 out of 12) reported that they were not involved in the decision making process to select an antimicrobial dressing. The committee heard from a patient expert how using an antimicrobial dressing for an infected chronic surgical wound had impacted their life. They explained that the dressing caused discomfort and embarrassment, and that there was sometimes a smell from the infected wound. Using the dressing had also had a negative impact on their mental health and their relationships. They also described the lack of shared decision making when being prescribed an antimicrobial dressing. The committee acknowledged that the patient expert had used antimicrobial dressings for an infected surgical wound and not an infected leg ulcer. But, it agreed that a wound infection could have a significant impact on a person's health and quality of life. Clinical experts told the committee that the themes of the lived experience testimony align with their experience of treating leg ulcers. But, the clinical experts acknowledged that there may be different considerations for people with chronic, as opposed to nonchronic, leg ulcers. The committee concluded that a shared decision should always be made, and that the impact of the dressing selection should be considered when deciding which antimicrobial dressing to use.
Healthcare professional preferences
3.4
The committee considered evidence from a user preference assessment completed by healthcare professionals. The assessment aimed to explore which criteria are most important to healthcare professionals when choosing an antimicrobial dressing for a locally infected leg ulcer. This included all aspects of an antimicrobial dressing and not just the antimicrobial agent. Healthcare professionals were selected for the user preference assessment because, although shared decision making is promoted and patient preference is considered, the choice of dressing is ultimately made by the healthcare professional. The group comprised 15 healthcare professionals who had experience of prescribing antimicrobial dressings. The group developed 2 sets of criteria for selecting a dressing. These were criteria based on clinical presentation, which included a holistic assessment of the person's clinical and social needs, and criteria that are independent of clinical presentation.
Criteria based on clinical presentation
3.5
The group identified 5 main criteria related to clinical presentation:
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wound presentation
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medical history and patient characteristics
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previous dressing regimes and efficacy
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mode of action of agent or dressing
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cytotoxicity of antimicrobial agent.
Criteria independent of clinical presentation
3.6
The group also identified 5 criteria that are independent of clinical presentation. Ranked in order of importance, they were:
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conformability
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ease of removal
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application directions
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cost
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sustainability.
Conformability was defined by the group as how conformable the dressing is to the shape of the leg (anatomical landscape) and how well it stays fixed to the site after it has been placed. None of these criteria are specific features of individual branded dressings or antimicrobial agents, but are generic and relate to general dressing performance. The committee noted that apart from cost and, to a lesser extent, ease of removal, these preferences are not captured by the evidence. The committee concluded that future evidence collection should evaluate the performance of dressings in these criteria.
Equality considerations
3.7
Many different groups can be affected by locally infected leg ulcers. Some of these groups have protected characteristics. The committee heard that older people are more likely to have a leg ulcer. Also, people from lower socioeconomic groups can have longer healing times with a higher chance of the ulcer recurring. The committee was made aware that the chance of having a leg ulcer is higher in people who are seriously ill, have a neurological condition, impaired mobility, impaired nutrition or obesity. The risk of infection is also higher in people with conditions such as anaemia, cardiac disease, respiratory disease, peripheral arterial disease, diabetes, renal impairment or rheumatoid arthritis. The committee also heard that people from certain ethnic minority backgrounds (South Asian, Chinese, Black African and Black Caribbean) have an increased risk of diabetes, which increases the risk of infection. Leg ulcers are also more common in people with haemoglobinopathies such as sickle cell disease and thalassaemia. Signs of infection may also be less visible on darker skin. The committee also heard that some conditions, such as diabetes, can make the signs and symptoms of infection less obvious. The committee was made aware that smoking, dependence on alcohol, drug use and nutritional deficiencies can be contributing factors to delayed wound healing. When people are less adherent to their treatment plan, they can be at a higher risk of developing an infection. The committee heard that this may be a risk for people with mental health conditions and learning disabilities. When discussing access to services, the committee heard that people with no fixed address may experience difficulties if they need frequent dressing changes. The committee was made aware that while some of the antimicrobial agents in scope contained animal products, some do not and can be used by people in all faith groups and by vegans. The committee also heard that some dressings and agents may not be suitable during pregnancy or while breastfeeding (some nonactive agents may be suitable), or for people with thyroid dysfunction. The committee understood that people who have locally infected leg ulcers will have individual needs and that these should be considered when selecting an antimicrobial dressing.
Clinical effectiveness
Key evidence is limited
3.8
The evidence for antimicrobial dressings to treat locally infected leg ulcers is heterogeneous and limited in quality. The evidence base is predominantly in adults. The EAG could not determine the relative efficacy of the different antimicrobial agents, despite there being an indication of some benefits in treating infection and wound healing. It identified 35 studies for inclusion in the review. But not all of these were in people with locally infected leg ulcers. If there was no evidence for an antimicrobial agent in people with locally infected leg ulcers, the EAG included studies in people with infected wounds elsewhere on the body. If there was still no evidence for the agent, the EAG included studies in people with leg ulcers that were not infected or where the infection status was unclear. This allowed the EAG to evaluate all but 1 of the agents (no evidence was identified for chlorhexidine) but meant that some evidence was less generalisable to people with infected leg ulcers. Of the 35 studies, 22 were in people with infected leg ulcers. Of these, 19 evaluated silver, 2 iodine, 1 octenidine, 1 dialkylcarbamoyl chloride (DACC) and 2 honey (some studies evaluated more than 1 agent). There were 8 studies in people with infected wounds that were not leg ulcers. Of these, 1 evaluated DACC, 2 honey, 3 enzyme alginogel and 2 chitosan. There were 5 studies in people with leg ulcers that were not infected or where the infection status was unclear. Of these, 2 evaluated polyhexamethylene biguanide (PHMB) and 3 evaluated copper. There was evidence in:
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2 of the 3 subagents of honey (Manuka and monofloral)
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1 of the 2 subagents of iodine (cadexomer iodine)
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the following 7 of the 8 subagents of silver:
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the subagent of copper (cupric oxide).
No evidence was available for polyfloral honey, povidone iodine or nanoparticulate silver. There was no evidence available for any population subgroups such as type of leg ulcer or wound presentation.
Additional limitations of the evidence
3.9
There is limited evidence comparing the effectiveness of the different agents in the relevant outcomes. Most outcomes were not well reported or were measured using different tools across studies, making it difficult to draw conclusions from the data. Key outcomes with the most evidence were infection status, complete or partial wound healing and change in size or area of ulcer or wound. Minimal quality-of-life data was found. The included studies varied in design and healthcare setting. Only 8 of the studies were done at least partially in the UK, so the evidence is less generalisable to the NHS. The studies also lack statistical power and agents were not compared in similar types of dressing. The EAG found most studies in people with infected leg ulcers have a moderate to high risk of bias. The committee concluded that there was not enough evidence to make conclusions on the relative performance of the different agents and subagents in all outcomes.
Cost effectiveness
Model structure
3.10
The EAG developed a Markov model that included 4 health states:
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infected, unhealed wound
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noninfected, unhealed wound
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healed wound
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death.
The EAG compared 6 agents with each other in a fully incremental analysis and a pairwise analysis between agents. These were iodine, copper, chitosan, silver, honey and PHMB. There was not enough evidence available to include chlorhexidine, enzyme alginogel, octenidine or DACC in the analysis. Subanalyses were done using the same methods to compare relevant subagents with each other. The results of the main and subanalyses were presented as total costs and associated quality-adjusted life years (QALYs). The EAG used a 1‑year time horizon with a 1‑week cycle length.
Model limitations and scenario analyses
3.13
The committee felt that there were several limitations in the model. These were caused by the uncertainty in, or the lack of, available data to inform the parameters and the assumptions that the EAG had to make. So the results from the economic evaluation should be interpreted with caution. The EAG did several additional scenario analyses to explore these uncertainties. They included:
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varying the weighted cost of the antimicrobial dressing per agent to the maximum and minimum possible
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linking healthcare professional visits and associated resource costs to the frequency of dressing changes
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varying the frequency of dressing changes
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aligning the cost of iodine to cadexomer iodine (the base case used povidone iodine cost and cadexomer iodine efficacy)
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varying the resource requirements, costs and utilities of different health states
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assuming clinical equivalence between agents
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applying different rates of infection.
There was not enough evidence to do analysis of any of the subgroups, including:
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type of leg ulcer
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wound presentation
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location of ulcer or
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complexities that may impact the treatment of leg ulcer infections.
Results of the economic evaluation
3.14
Because of the uncertainty in the evidence used to inform it, the results from the economic model are highly uncertain. The difference in costs and QALYs are small and the 95% confidence intervals overlapped for all agents in both costs and QALYs. So the EAG could not conclude whether there are clinically meaningful differences between the agents. The high level of uncertainty remained for all of the EAG's scenario analyses. It also remained for the analysis of subagents, which compared 2 honey subagents with each other and the 3 subgroups of silver subagents with each other. The cost of a dressing and the effectiveness of a dressing to clear an infection were 2 of the main drivers of cost effectiveness in the model. Prescription duration and the frequency of dressing changes were also drivers of cost effectiveness. Because of the high uncertainty and lack of data, the committee concluded that more evidence was needed to determine if one antimicrobial agent offered more value than another to the NHS. The committee also noted that because of the uncertainty in the clinical evidence informing the economic evaluation, altering the model structure would be unlikely to produce more certain conclusions.
Resource impact assessment
3.15
There is not enough evidence to determine if price variations between agents are justified. Resource impact analysis showed that using clinically appropriate but less expensive options could make savings for the NHS. The analysis is based on the assumptions used in the EAG's economic model and acknowledges the limitations discussed in the external assessment report. The conclusions of the resource impact analysis are that savings would depend on local current practice, prices being paid, and the considerations for choosing the least expensive option (see recommendations 1.3 and 1.4).
Justification for price variation
3.16
The committee discussed the clinical and economic evidence, the user preference assessment and the patient expert's lived experience. It concluded that it was not possible to determine if the price variation between antimicrobial agents was justified by differences in clinical or cost effectiveness. The committee emphasised that an appropriate range of antimicrobial dressings should be available for healthcare professionals to meet the needs of people with locally infected leg ulcers.
Evidence needed to show additional value
3.17
The committee concluded that more evidence is needed to justify the price variation between antimicrobial agents used in antimicrobial dressings to treat locally infected leg. It noted that it was not possible to determine the value of individual antimicrobial agents because the available evidence lacked head-to-head comparisons of similar dressings. The committee asked for more evidence using clinical and cost outcomes that can inform a health economic evaluation. It also asked that evidence be collected to evaluate the performance of dressings in the criteria identified in the user preference assessment.