Prontosan for acute and chronic wounds
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3 Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence is in the project documents on the NICE website.
Clinical evidence
The main clinical evidence comprises 18 studies
3.1 The evidence assessed by the EAC included 18 studies. Sixteen were full-text peer-reviewed publications and 2 were unpublished studies. Of the included studies, 9 were comparative studies (7 randomised controlled trials and 2 observational studies) and 9 were non-comparative observational studies. The comparative evidence included a total of 792 people, of which 415 had Prontosan, 281 had saline, 53 had saline or Ringer's solution, 23 had silver sulfadiazine, and 20 had sterile water. For full details of the clinical evidence, see section 4 of the assessment report. Find the assessment report in the supporting documentation file in the project documents on the NICE website.
The randomised controlled trials and the comparative and non-comparative studies were heterogeneous and at high risk of bias
3.2 The EAC considered the strength of the evidence to be limited, with only 1 randomised controlled trial at low risk of bias. The remaining studies were considered to be at high risk of bias. Further limitations of the evidence base included the following points:
Most of the included studies had small sample sizes and some of the larger randomised controlled trials were underpowered (meaning they do not have enough people to answer the research question).
Prontosan was not used consistently across the studies. It was not always used in a way that reflects NHS practice, or in line with the company's instructions for use.
Outcomes were not always clearly reported and similar outcomes were reported differently across different studies. This made it difficult to make comparisons and draw conclusions across the evidence base.
There are 4 comparative studies for venous leg ulcers
3.3 Four studies were included for venous leg ulcers, 3 randomised controlled trials (Borges 2018; Harding 2012, unpublished; Romanelli 2010) and 1 comparative retrospective analysis (Andriessen 2008). All 3 randomised controlled trials had a small sample size and may have been underpowered. The control group in Andriessen 2008 had either saline or Ringer's solution. The clinical experts advised the EAC that Ringer's solution is not routinely used in the NHS to cleanse wounds. However, they explained that there is a dressing that contains Ringer's solution available and this would be used if clinically indicated for debridement (rinsing the wound and removing dead tissue and debris). Reported outcomes included wound healing, wound infection and pain.
There is limited evidence for burn wounds with no NHS comparators
3.4 Only 3 studies were included for burns, 1 randomised controlled trial (Wattanaploy 2017) and 2 non-comparative studies (Ciprandi 2018; Kiefer 2018). The sample size in the randomised controlled trial was small, saline was used in both arms, and the comparator was silver sulfadiazine. This was not considered to be standard care in the NHS so was not included in the scope for this guidance as a comparator for Prontosan. However, the EAC stated that silver sulfadiazine would be an appropriate treatment for burns. Reported outcomes included wound healing, wound infection, pain and treatment satisfaction.
There is limited evidence for surgical site wounds
3.5 Only 1 study, a randomised controlled trial, was included for surgical site wounds (Saleh 2016). This study had a small sample size, and the comparator was sterile water. The EAC included this study because surgical site wounds were considered relevant to the decision problem. The EAC noted that although the study compared Prontosan with sterile-water soaked dressings, only one dressing was applied after surgery. This treatment approach may have limited applicability to the NHS. The study outcomes included wound infection but not wound healing.
The evidence for different types of chronic wounds was varied with 3 comparative studies
3.6 Different types of chronic wounds were included in 10 studies; 2 randomised controlled trials (Bellingeri 2016; Valenzuela 2008), 1 comparative cohort study (Assadian 2018) and 7 non-comparative studies (Atkin 2020; Ricci 2018; Moore 2016; Durante 2014; Moller 2008; Horrocks 2006; Orropallo, unpublished). Bellingeri 2016 was at low risk of bias, but the study was underpowered and at risk of selective reporting. Valenzuela 2008 used the gel only. This may not be applicable to the NHS because the wound would usually be soaked before the gel was used (see section 4.2 of the assessment report). Assadian 2018 had a small sample size and had limited applicability to the NHS because only a single application of Prontosan was used. Reported outcomes included wound healing, wound infection, pain, dressing changes and quality of life.
It is not certain if Prontosan has better outcomes than saline
3.7 In total, 6 randomised controlled trials compared Prontosan with saline alone. Wound healing was reported in 1 study (Harding 2012, unpublished), wound size in 2 studies (Romanelli 2010; Valenzuela 2008) and wound condition improvement in 1 study (Bellingeri 2016). Of these 4 studies, there was only 1 study that showed statistical significance in wound improvement (Bellingeri 2016). Infection rate was reported in 1 study (Harding 2012, unpublished), bacterial burden in 2 studies (Assadian 2018; Romanelli 2010), bacterial load in 1 study (Borges 2018), inflammation score in 1 study (Bellingeri 2016), and microbiological cultures in 1 study (Valenzuela 2008). Of these 6 studies, there were only 2 studies that showed statistical significance, a reduction in bacterial burden (Romanelli 2010) and a reduction in inflammation score (Bellingeri 2016). Pain was reported in 3 studies (Bellingeri 2016; Harding 2012, unpublished; Romanelli 2010). Only 1 study found a significant reduction in pain when using Prontosan (Romanelli 2010). The EAC concluded that Prontosan appeared to be effective for some clinical parameters in chronic wounds, but there is not enough good quality comparative evidence with saline.
Prontosan is safe, easy to use and has potential benefits but evidence is limited
3.8 Prontosan is safe, adverse events are rare, the products are easy to use and it has the potential to improve wound pain but the evidence is limited.
Cost evidence
The company's cost modelling finds Prontosan to be cost saving
3.9 The company submitted 2 de novo cost analyses with different model structures. One used a Markov model (wound closure model) that compared costs for Prontosan with saline to treat venous leg ulcers until full wound closure. The time horizon was 1 year. The clinical experts advised the EAC that when using Prontosan wounds healed within a year. The company provided 2 alternative data sets for rate of wound healing for this model (Andriessen 2008 and Harding 2012, unpublished). The other model was a simple cost model (wound bed preparation model) that compared costs for Prontosan with saline to treat chronic wounds (for example, leg ulcers and pressure ulcers) until the wound bed is fully granulated. This means that there are visible signs that the wound is healing. The time horizon used was the time to reach a Bates-Jensen wound assessment tool (BWAT) score of 14. The BWAT score is a clinical tool used for scoring wound healing. The time taken to reach a score of 14 was 4.1 weeks for Prontosan and 11.3 weeks for saline (Bellingeri 2016). The company reported base-case cost savings per person with Prontosan of £1,118.26 and £1,188.47 for the wound closure model (with data from Andriessen 2008 and Harding 2012, unpublished, respectively) and £1,134.40 for the wound bed preparation model. For full details of the cost evidence, see section 9 of the assessment report.
The EAC agrees with the company's cost models but the key limitation is that the clinical evidence is uncertain
3.10 The EAC agreed with the structure of both of the company's models and its assumptions and made minor alterations to the costs and resource use. This had little impact on the cost savings (for full details see section 9 of the assessment report). The EAC noted that the inputs for wound healing and infection rates in the wound closure model were uncertain, as were the inputs for wound bed improvement in the wound bed preparation model. It made the following comments:
Andriessen (2008) is a retrospective comparative case series of 112 patients with venous leg ulcers with a follow-up time of 6 months. The EAC considered that Andriessen 2008 was a suitable data source because of the larger number of patients and longer follow up. However, the study was at high risk of bias because of potential selection and reporting bias.
Harding (2012) is a small, unpublished, UK pilot randomised controlled trial with 34 patients. The shorter follow-up period of 12 weeks meant that there was greater reliance on extrapolation for the calculation of transition probabilities for wound healing. There were some concerns about the randomisation process.
Bellingeri (2016) is a randomised controlled trial of 289 patients with pressure ulcers or vascular leg ulcers at low risk of bias. The follow up was 28 days, and wounds were assessed using the BWAT score. The company used an Excel trendline to extend the graphs to reach a mean BWAT score for both arms. However, there were concerns about the data. The study seemed to use only 8 out of the 13 dimensions of the BWAT. This meant the overall score was not on a scale of 13 to 65, but on a scale of 8 to 40. As a result, the EAC could not be confident that a reported BWAT score of 13 or 14 in Bellingeri (2018) accurately corresponded to a wound approaching healing or one that has healed. However, no improved data source has been identified.
The EAC base case uses the wound closure model with inputs from Andriessen 2008 and estimates a cost saving of £951.01 per person
3.11 The EAC considered that the wound closure model with clinical inputs from Andriessen 2008 was the most appropriate base case. It concluded that Andriessen 2008 was the most suitable data source and provided the most robust estimates for wound improvement, deterioration and recurrence that reflected the clinical reality of treating chronic wounds. This model estimated a cost saving from the use of Prontosan compared with saline of £951.01 per patient over a time horizon of 1 year.
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