Plus Sutures for preventing surgical site infection

Evidence-based recommendations on Plus Sutures for preventing surgical site infection.

# Recommendations
Evidence supports the case for adopting Plus Sutures as part of a bundle of care for preventing surgical site infection in the NHS for people who need wound closure after a surgical procedure when absorbable sutures are an appropriate option.
Cost modelling shows that Plus Sutures is cost saving compared with non-triclosan absorbable sutures by an average of 13.62 per patient. These savings are from reduced surgical site infections. Cost savings will vary by surgery type and baseline risk of surgical site infection. For more information on the cost impact to the NHS please see the NICE resource impact summary report.
Why the committee made these recommendations
Plus Sutures is a range of synthetic, absorbable sutures with triclosan (Irgacare MP), a purified medical grade antimicrobial.
Clinical evidence shows that using Plus Sutures instead of standard absorbable sutures reduces the chance of a surgical site infection.
Even though Plus Sutures is more expensive than standard sutures, cost analyses show that it still leads to cost savings because of the reduction in surgical site infections.# The technology

# Technology
Plus Sutures (Ethicon, Johnson & Johnson Medical) is a range of synthetic, absorbable sutures that are either impregnated with or coated with triclosan (Irgacare MP), a purified medical grade antimicrobial, depending on the suture type. Absorbable sutures are absorbed by tissue over a period of time and do not need removing. The 3 sutures considered in this evaluation are indicated for general soft tissue approximation and ligation. Each has different physical properties and absorption rates, which affects which tissue types it is best suited to:
Coated VICRYL Plus Antibacterial (polyglactin 910) Suture is a multifilament suture (multiple braided threads). VICRYL Plus retains 75% of its original tensile strength at 2 weeks after implantation; 40% to 50% at 3 weeks and 25% at 4 weeks. Complete absorption happens between 57 days and 70 days.
MONOCRYL Plus Antibacterial (poliglecaprone 25) Suture is a monofilament suture (solid and smooth thread). MONOCRYL Plus retains 50% to 60% of its original tensile strength at 1 week and 20% to 30% at 2 weeks. Complete absorption happens between 91 days and 119 days. This suture is also available in a barbed design for knotless suturing (STRATAFIX Plus) but this version of the technology was not included in the evaluation.
PDS Plus Antibacterial (polydioxanone) Suture is a monofilament suture (solid and smooth thread). PDS Plus Antibacterial retains 60% to 80% of its original tensile strength at 2 weeks, 40% to 70% at 4 weeks, and 35% to 60% at 6 weeks. Complete absorption happens between 182 days and 238 days. This suture is also available in a barbed design for knotless suturing (STRATAFIX Plus) but this version of the technology was not included in the evaluation.PDS Plus and MONOCRYL Plus contain no more than 2,360 micrograms/metre triclosan. VICRYL Plus has a coating of copolymer and calcium stearate as well as up to 472 micrograms/metre triclosan. The absorption rates and handling properties are the same as non-triclosan sutures.

# Innovative aspects
Plus Sutures is innovative because sutures are coated or impregnated with triclosan (Irgacare MP). Triclosan is a broad-spectrum antibacterial agent. It helps reduce biofilm formation and bacterial colonisation, preventing the growth of most common organisms associated with surgical site infection for at least 7 days. Plus Sutures is already used in the NHS.

# Intended use
Plus Sutures would replace using non-triclosan absorbable sutures for wound closure in people that have had a surgical procedure, when absorbable sutures are an appropriate option. Plus Sutures should be used as part of a locally agreed bundle of care to reduce surgical site infections. Clinical experts reported that the handling properties of Plus Sutures were identical to non-triclosan sutures. Adopting Plus Sutures would not alter the current care pathway or need any additional training. The technology is already used extensively within the NHS.

# Costs
The cost of Plus Sutures is around 4.25 per suture, based on average prices of the 3 suture types.For more details, see the Johnson & Johnson webpage on Plus Sutures.# 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 are in the project documents on the NICE website.

# Clinical evidence

## The clinical evidence comprises 31 randomised controlled trials
The evidence assessed by the EAC included 31 randomised controlled trials including over 14,000 people. For full details of the clinical evidence, see section 3 of the assessment report in the supporting documentation on the NICE website.

## The evidence for reducing surgical site infection incidence is of good quality
The evidence base for Plus Sutures is extensive, of relatively high quality and is generalisable to the UK NHS. The EAC used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology for appraising the quality of evidence for each outcome and said that the quality of evidence for surgical site infection incidence was high. This was considered the most important outcome and was reported by nearly all the included studies, with most of them using the same definition. None of the other outcomes listed in the scope had sufficiently robust empirical evidence to show Plus Sutures was statistically superior to standard sutures. However, some other outcomes can be inferred or extrapolated from the established reduction in incidence of surgical site infection, such as a shorter hospital stay, and lower readmission rates and healthcare costs. The EAC concluded that Plus Sutures use is associated with a causative reduction in the incidence of surgical site infection.

## Device-related adverse events reported in the evidence suggest using Plus Sutures is safe
To assess device-related adverse events, the EAC reviewed the randomised controlled trial data included in the assessment and also did a dedicated literature review to assess the nature of adverse events after using Plus Sutures. Studies that reported adverse events included 18 of the randomised controlled trials that were included in the assessment and an additional 17 randomised and non-randomised studies. Triclosan allergy was noted in a published case report that referenced a retrospective analysis of 113,162 patients who had been patch tested with triclosan 2% petroleum. A positive reaction was seen in only 363 patients (0.32%) but 54% of positive reactions were considered clinically relevant. The EAC concluded that there is no discernible safety signal from using Plus Sutures. The EAC noted that this conclusion was supported by information from the company (on the very low amounts of triclosan used in the sutures and on the rapid metabolism of triclosan) and by the clinical experts, who had not seen any cases of triclosan reactions. For full details of the adverse events, see section 6 of the assessment report in the supporting documentation on the NICE website.

## Results of company meta-analyses show that Plus Sutures is associated with a 30% reduction in the risk of surgical site infection
The company did 6 de novo meta-analyses to establish the overall pooled effect size associated with Plus Sutures on the incidence of surgical site infections. The primary outcome was the relative risk of developing a surgical site infection between Plus Sutures and control groups. The 6 separate meta-analyses were done using:
all studies that provided enough data (base case, 28 studies)
a subset of studies in adults (25 studies)
a subset of studies in children (2 studies)
a subset of studies in patients with clean wounds (15 studies)
a subset of studies in patients with non-clean wounds (12 studies)
all studies of Plus Sutures including STRATAFIX Plus that provided enough data, as a sensitivity analysis (31 studies).The results of the meta-analyses showed that Plus Sutures is associated with a nearly 30% reduction in the risk of surgical site infection in the base case and all results were considered statistically significant (with a 95% confidence interval of 0.59 to 0.85). The EAC noted that the company meta-analyses are of a high quality and at a low risk of bias. The methodology and results are transparent and clearly reported.

## The EAC did additional meta-analyses
The EAC validated the company's meta-analyses by replicating the analysis, and did 3 additional analyses. The EAC noted that because of heterogeneity the studies were not similar enough for fixed effects analysis, and the analysis should primarily be reported using a random effects model. However, this variation had minimal effects on the results. The additional analyses included stratifying the evidence by study quality, sample size and location. The results of the additional analyses indicated that Plus Sutures reduced the risk of surgical site infection, but the size of the effect appeared to be related to study quality and sample size. When only high-quality studies were included in the analysis the difference was not statistically significant. However, the EAC advised that this should be interpreted with caution because the smaller sample sizes and varied event rates will affect the precision and impact of the analysis.

## The company submitted additional analyses suggesting sustainability benefits
Based on the Sustainable Care Pathways Guidance, the company provided an analysis of the environmental impact of surgical site infections to NHS England. Environmental impact is presented in the guidance document in terms of 3 main environmental metrics: greenhouse gas emissions, fresh water use and waste generation. The report indicates that by preventing surgical site infections, using Plus Sutures results in potential environmental benefits to the NHS in England.

# Cost evidence

## The company identified 8 economic studies
The company identified 8 studies that were relevant to the economic submission. The EAC concluded that the literature search was satisfactory and agreed that the 8 studies were relevant to the evaluation. The company said that all of the studies reporting on introduction of Plus Sutures resulted in cost savings but that none of the parameters in the company's de novo model were informed by the economic literature. For full details of the cost evidence, see section 9.1.2 of the assessment report in the supporting documentation on the NICE website.

## The company's model structure and time horizon are appropriate
The company submitted a simple decision tree which models a population of adults and children who need wound closure after a surgical procedure. The model assesses the cost of wound closure plus the cost of treatment for people who develop a surgical site infection. An additional branch of the decision tree modelled the mortality of people with a surgical site infection and was used by the company to calculate a cost per death avoided using cost-effectiveness methodology. The EAC considered the model structure to be appropriate, except for the mortality branch of the decision tree which complicates the model for the purposes of a cost-consequence modelling approach. The time horizon modelled was 1 year. The EAC noted that this aligns with published economic evaluations of Plus Sutures.

## The EAC accepted all assumptions in the company model
The company model made the following assumptions:
Risk of surgical site infection relates only to those detected and treated during the initial inpatient episode or on readmission.
The average surgical site infection episode cost does not include the cost of treating surgical site infections in the community.
The risk of infection with Plus Sutures is calculated by applying the relative risk of surgical site infection associated with using Plus Sutures reported in the meta-analyses to a baseline risk of surgical site infection. The baseline risk of surgical site infection is based on UK data.
Adverse events were not included in the model.The EAC concluded that the model assumptions were appropriate, conservative and supported by the evidence.

## The EAC made some minor changes to the costs of the technology
The company provided an estimate of the cost of Plus Sutures based on a weighted average of sales, including knotless, barbed sutures, and STRATAFIX Plus. The EAC reported that the company's estimation of the cost was not sufficiently transparent or reproducible, and included STRATAFIX Plus, which the EAC did not include in their analysis. The EAC amended the cost of the technology by calculating a mean cost of 3.63 to 4.94 depending on Plus Suture type.

## The EAC's changes to the model have a minimal effect on results
Because there were so few changes to the model parameters the EAC and the company's results were similar. In the EAC's base-case analysis Plus Sutures was found to be cost saving by a mean of 13.62 per person compared with the company's 13.88 per person.

## The company's extensive sensitivity analyses suggest that using Plus Sutures is cost saving
The company reported results of a 1way deterministic sensitivity analysis that showed that the model was most sensitive to changes in the incidence of surgical site infection. However, the model was still cost saving even when the lowest plausible surgical site infection incidence was used (0.5%). Twoway deterministic sensitivity analyses were used to explore the combined effect of surgical site infection incidence and relative risk, and surgical site infection incidence and cost of surgical site infection. The results were cost saving in all cases. This was further supported by threshold analyses that reported the following break-even points (deemed by the company and the EAC to be unlikely or implausible):
a cost of surgical site infection of less than 1,410
incidence of surgical site infection of less than 0.24%
a relative risk of 0.93
at least 21 sutures.The results of the probabilistic sensitivity analysis, reported for the base case only, showed that Plus Sutures was cost saving in 99.8% of iterations (out of 1,000 iterations). The summary result was that Plus Sutures was associated with cost savings of 13.96 (95% credible intervals 4.97 to 22.22) per person.

## Plus Sutures remains cost saving in the EAC's additional sensitivity analyses
The EAC did additional sensitivity analyses that explored the uncertainty in the cost savings associated with each subgroup (adults, children, clean wounds and non-clean wounds) and the effect of different relative risk values reported in the EAC's meta-analyses of the clinical evidence (study quality, sample size and location). Plus Sutures was cost saving in all subgroups investigated. The most uncertainty was in the clean wound subgroup (9.30; 95% credible intervals -2.24 to 19.26; 94.6% probability of cost saving). The meta-analysis showed that the size of the effect of using Plus Sutures (lowering the risk of surgical site infection) diminished when only studies of a high quality, or large sample size, were included in the analysis (see section 3.5). The sensitivity analyses showed that using Plus Sutures remains cost saving when the relative risk from the higher quality studies and studies with larger samples sizes was adopted, but there was more uncertainty in the results.# Committee discussion

# Clinical-effectiveness overview

## The evidence shows that Plus Sutures is effective in reducing the incidence of surgical site infection
The evidence base for Plus Sutures is large, of relatively high quality and is likely to be generalisable to the NHS. Some of the individual studies did not show a significant reduction in surgical site infection incidence for Plus Sutures. However, when all results were combined in the meta-analyses, the effect was significant. Additional analyses done by the external assessment centre (EAC) showed that the size of effect was smaller when studies were stratified by quality or sample size. But it was not possible to determine if this was because of the effect measured in the studies or because of the small number of studies included in the analyses. The committee concluded that, although the effect size may vary depending on population and type of procedure, the evidence showed that Plus Sutures is likely to lead to overall reductions in surgical site infections.

# Side effects and adverse events

## Using Plus Sutures is safe and allergies to triclosan are very rare
No significant device-related adverse events were identified from the published evidence. The clinical experts noted that triclosan is safe and is used in many consumer products, at much higher concentrations and amounts than in Plus Sutures. None of the clinical experts had encountered anyone who had an allergic reaction to triclosan in Plus Sutures. The committee concluded that using Plus Sutures is safe and that adverse or allergic reactions to triclosan are likely to be very rare. The committee discussed antimicrobial stewardship considerations and concluded that neither the product nor concentration of triclosan raised concerns about resistance.

# Equality considerations

## Surgeons consider a number of factors when choosing the appropriate suture
The committee discussed equality considerations for the use of Plus Sutures in the general population. The instructions for use highlight that 'absorbable sutures, including Plus Sutures may not be appropriate for older people, those who are malnourished, debilitated or have conditions that may prevent wound healing'. The clinical experts explained that a number of factors must be taken into consideration by the surgeon choosing the suture, including comorbidities, surgery type, tissue type and condition. The committee concluded that these were factors that surgeons would consider within the patient assessment for appropriate management plans. It did not consider there to be any equality issues as a result of its recommendations.

# Relevance to the NHS

## Plus Sutures should be used as part of a bundle of care to reduce surgical site infections
The clinical experts noted that, in their experience, Plus Sutures was most effective at reducing infections in deep and superficial tissue layers, rather than deep organ space tissues. However, the experts stated that while using Plus Sutures has been shown to reduce surgical site infection risk, to maximise their effect, they should be used alongside an appropriate care bundle for surgical site infection prevention, including antibiotic use, appropriate hair removal, glycaemic control and normothermia. The clinical experts reported their experience that introducing Plus Sutures to the surgical site infection prevention care bundle had resulted in fewer surgical site infections. The committee concluded that Plus Sutures should be used as part of a bundle of care to reduce surgical site infections.

# NHS considerations overview

## GPs with minor surgery clinics may also benefit from using Plus Sutures
The evidence on Plus Sutures was from hospitals. However, the committee noted that some GP clinics provide minor surgery services and use broadly the same care bundles for infection prevention as used in hospitals. The committee stated that the evidence collected in secondary care is likely to be largely generalisable to primary care settings. The committee concluded that Plus Sutures could be considered in GP minor surgery clinics.

# Training

## No additional training is needed to use Plus Sutures
The clinical experts advised that no further training is needed to use Plus Sutures compared with non-triclosan sutures. The addition of triclosan does not change the absorption profile when identifying the appropriate suture or change the handling of the suture itself. Clinical experts reported that the handling properties of Plus Sutures were identical to non-triclosan sutures and no modification of existing procedures is needed. The committee concluded that adopting Plus Sutures would not need a change to services.

# Cost-modelling overview

## The EAC's changes to the cost model are appropriate
The committee noted that the EAC made minor changes to the cost model, which were appropriate and accepted. The committee concluded that the comprehensive subgroup and sensitivity analyses supported cost savings in all subgroups.

# Main cost drivers

## Reduction in surgical site infection incidence is the main cost driver in the model
The committee discussed the estimated cost of surgical site infections and accepted the use of a UK study, which reported the cost savings associated with surgical site infections in hospitals (Jenks et al. 2014). Reduction in surgical site infection was the main driver for the cost savings. The committee concluded that the cost savings were likely to be realised in practice and were supported by the evidence and experience of the clinical experts.

# Scenario analyses

## Plus Sutures is cost saving in all likely scenarios
The committee discussed the comprehensive scenario analyses completed by the company and EAC, which showed Plus Sutures reduced the risk of surgical site infections in most scenarios. It accepted that results from the subgroups in which statistical significance was reduced should be interpreted with caution because the smaller sample sizes affect the analysis. The committee concluded that Plus Sutures is likely to save costs in most scenarios and that the scenarios at which costs break even are clinically unlikely.

# Cost savings

## The true cost of treating surgical site infections in the community is likely to be underestimated
The committee discussed the potential for further cost savings in the community as a result of fewer hospital-acquired surgical site infections and therefore less need for follow-up care, which was not captured in the economic model. The committee agreed with the company and the EAC that the cost savings in the cost modelling are likely to be conservative.

## Plus Sutures is likely to be cost saving across all groups
The committee was satisfied that the cost-modelling evidence indicates that Plus Sutures is cost saving compared with non-triclosan absorbable sutures by an average of 13.62 per patient. The committee concluded that the sensitivity analyses showed that Plus Sutures remained cost saving across all subgroups.