Review of the clinical RCT evidence and cost-effectiveness data of a sustained-release silver foam dressing in the healing of critically colonised wounds

Presented at a symposium at the 2nd World Union of the Wound Healing Societies, Paris, France, 2004

Keywords: Sustained-release silver foam dressing; evidence-based medicine; critically colonised wounds; cost-effectiveness.

Abstract

This paper presents clinical evidence on a sustained-release silver foam dressing in chronic wounds with regard to efficacy, efficiency and effectiveness of evidence-based medicine. The results are derived from a randomised, controlled, clinical trial (efficacy), a real-life, randomised comparative study from everyday practice (efficiency), and a health-economic evaluation (effectiveness). The results indicate that this sustained-release silver foam dressing provides particular benefit for the treatment of critically colonised wounds. It is suggested that the use of the evidence-based medicine model may be a benchmark for a new level of clinical evidence in wound management.

Introduction

Over the past few years there has been increased use of dressings containing silver, although there is only limited clinical and investigational evidence supporting specific treatment procedures. It has been suggested that silver dressings may be of particular benefit when used for the treatment of critically colonised wounds. This paper discusses the evidence base for a sustained-release silver foam dressing (Contreet Foam), focusing on three areas:

• Clinical research - efficacy (clinical studies)

• Outcomes research - efficiency (everyday practice)

• Health-economic analyses - effectiveness (cost-effectiveness).

The results from a randomised, controlled clinical study including 109 patients are reviewed, as well as a comparative study from everyday practice involving more than 600 patients, and a health-economic analysis.

Evidenced-based medicine and wound care

The highest level of evidence is required in order to practise evidence-based medicine[1]. This is particularly challenging in the field of wound care. Sackett (2000) defined evidence-based wound management as the integration of best research evidence with clinical expertise and patient values[2]. In practice, healthcare practitioners must review the best research evidence, and interpret and compare the research with the current methods of practice[1].

An assessment of the whole patient, the underlying cause, and any patient-centered concerns must be considered before examining the wound itself[3][4]. The concept of wound bed preparation includes debridement, control of bacteria and exudate management[3]. Wound bed preparation provides a framework to facilitate accurate diagnosis and treatment of patients with chronic wounds utilising holistic care and a team approach. The algorithm in Figure 1 identifies the components that should be considered in order to achieve the maximum benefit when using advanced wound care products [3][4]. In evidence-based medicine, efficacy, effectiveness and efficiency are three key concepts (see Box 1) [5]. These principles of evidence-based medicine are incorporated into this algorithm, emphasising that these issues should be integral to modern wound management.

Identifying infection

All chronic wounds contain bacteria and the presence of bacteria obtained from a surface swab does not mean a wound is infected. The diagnosis of infection should be made clinically based on signs and symptoms of the local wound bed, the deeper structures and the surrounding skin. While clinicians have traditionally correlated bacteria number with outcomes, other factors are at play, including virulence and host resistance, as outlined in the equation [6]:

Host resistance is the ability of the host to resist bacterial invasion and the establishment of an increased bacterial burden or infection. There are systemic and local factors that can decrease host resistance. An increase in organism number and virulence of organisms causes the superficial wound bed to produce friable bright red granulation tissue, with an increased amount of slough on the surface, as well as increased discharge and odour. Decreased host resistance allows further bacterial proliferation and invasion of the organisms into deeper tissue.

Bacterial presence in a chronic wound can be described as a continuum starting with contamination or colonisation (bacterial balance) and ending with critical colonisation or infection (bacterial imbalance) as outlined in Figure 2.

Some signs of critical colonisation in a wound are listed in Tables 1 and 2 . Chronic wounds change with time in a dynamic process and must be continuously re-evaluated and re-classified.

Table 1: Clinical signs of critically colonised wounds

A delay in the healing process Increased serous or purulent exudate Foul odour (usually due to anaerobes and Gram-negative organisms) Small areas of yellow to brown slough may be present on the surface of the wound Exuberant granulation builds up on the surface. Bacterial interference results in a poor quality of collagen matrix that will not support re-epithelialisation and healing. The granulation is often a bright red colour and may bleed easily especially on dressing removal (increased blood vessels and poor quality collagen support).

The signs described in Table 1 are localised in the superficial wound bed and are potentially treatable with topical agents, including ionised silver [7][8][9][10].

When host resistance is compromised, bacterial damage can extend beyond the local wound bed. More extensive bacterial damage results in a deeper and surrounding skin compartment infection that usually requires systemic antimicrobial treatment. The presence of surrounding skin pain, warmth and swelling with erythema and possible increase in wound size or new areas of satellite breakdown should alert the clinician to the possibility of a co-existing soft-tissue infection (cellulitis).

If the deep portion of the ulcer probes to bone, osteomyelitis is a possibility, especially if the patient is diabetic with neurotrophic foot ulceration [11]. With infection of the surrounding or deeper structures the wound often increases in size and there may be satellite areas of breakdown Table 2. At this stage, a bacterial swab can be used as a guide to treatment. It is necessary to make treatment decisions before the swab results are available. In general, wounds of less than one month's duration require treatment for Gram-positive organisms; however, if the wound has been present for more than one month, coverage for Gram-positive, Gram-negative and anaerobic organisms will be needed [12].

Table 2: Signs of critical colonisation and infection [13]

Superficial Topical therapy, for example silver dressings	Non-healing Exuberant granulation Bright red colour Increased exudate New slough within bed Odour
Deep and surrounding skin Systemic therapy	Pain Probes to bone Surrounding erythema or oedema > 2cm Surrounding warmth, tenderness Increasing size Satellite areas of breakdown

Sustained-release silver foam dressing

The sustained-release silver foam dressing (Contreet Foam) comprises a soft hydrophilic polyurethane foam containing silver as an integral part of the dressing matrix [14]. The foam component provides a partial fluid lock to help prevent maceration of the surrounding wound margin by the absorbed wound fluid. Silver ions are present in a form that is readily hydro-activated in the presence of fluid or wound exudate [14]. The sustained-release silver foam dressing is active against a variety of micro-organisms including Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa and vancomycin-resistant enterococci (VRE). The sustained release of silver from this dressing has been demonstrated for up to seven days [15] [16].

The potential advantage of a foam and silver dressing combination is that surface bacterial counts can be reduced while removing excess exudate from the wound surface.

Clinical research - management of bacteria and exudate

Efficacy

A clinical study reported elsewhere[17][18][19] was conducted comparing a sustained-release silver foam dressing with a foam dressing without silver (Allevyn Hydrocellular) in patients with venous or mixed venous/arterial leg ulcers and signs of stalled or delayed healing caused by suspected critical colonisation [9][20][21] . The primary aim of this study was to evaluate the relative reduction of ulcer size. The secondary aim was to assess wound-bed preparation. Bacterial balance was measured indirectly through a decrease in wound odour and the presence of healthy granulation tissue. Exudate management was measured through exudate leakage from the dressing and the absorption capacity of the dressing. The degree of maceration was also evaluated.

The study had a block randomisation, multi-centre comparative design. It was conducted in 15 centres predominantly in Europe, with two North American sites in Canada and the USA. There were 109 evaluable patients with chronic non-healing venous and mixed arterial and venous ulcers entered into the study. Fifty-two patients were randomised to the sustained-release silver foam dressing group and 57 patients to the foam dressing without silver group. The study was conducted for four weeks or until complete wound closure. The inclusion criteria comprised: an ankle/brachial index of 0.65 or higher, moderately to highly exudating wounds, delayed healing and treatment with compression therapy for four weeks prior to the study. Ulcers had to show signs of increased bacterial load characterised by one or more of the following: increased exudate, increased pain, discoloration of the granulation tissue and/or foul odour. Exclusion criteria included: the presence of clinical infection (deep or surrounding skin symptoms and signs) that required treatment with systemic antibiotics, and treatment with antibiotics or antiseptics for one week prior to inclusion.

All patients were treated with appropriate compression therapy. After four weeks, the median relative reduction in ulcer area was 45% with the sustained-release silver foam dressing and 25% with the foam dressing without silver as shown in Figure 3 (p=0.0344, Wilcoxon two-sample test). There was a statistically significant difference in the reduction of wound odour in favour of the sustained-release silver foam dressing after one and four weeks (p=0.0013 and 0.0301, respectively, using the Wilcoxon two-sample test), while both groups demonstrated an increase in the presence of healthy granulation tissue.

At one week fluid leakage was noted in 27% of the sustained-release silver foam dressing changes compared with 44% of the foam alone group (p=0.06, Wilcoxon two-sample test). At the end of the study, there were significantly fewer dressing changes associated with exudate leakage in the sustained-release silver foam dressing group (19%) compared with the foam dressing without silver group (49%; p=0.002, Wilcoxon two-sample test). The sustained-release silver foam dressing had a significantly better absorption capacity compared with the foam dressing as evaluated on a five-point scale by study personnel at the end of treatment (p=0.04, Wilcoxon two-sample test).

Outcomes research - the CONTOP study

Efficiency

The sustained-release silver foam dressing has also been evaluated in an effectiveness study in real-life settings. The Contreet Outcome Program (CONTOP) study, was conducted at more than 80 wound care centres in ten countries and has more than 600 patients enrolled. An interim analysis is reported on the first 352 patients with complete data available [22]. The endpoints in this study are the reduction in wound area, wound progress, exudate management, and patient-related outcomes. This study included a number of venous leg ulcers in addition to other aetiologies as shown in Table 3. Patients were randomised to receive either the sustained-release silver foam dressing or treatment in accordance with local best practice, that is the usual treatment provided by the clinic (see Table 4). The study duration was four weeks.

Table 3: Frequency of ulcer types included in the CONTOP study

Ulcer types	Frequency of ulcers
	Sustained-release silver foam dressing	Local best practice
Venous leg ulcers	43%	48%
Mixed venous/arterial leg ulcers	24%	20%
Pressure ulcers	7%	7%
Diabetic foot ulcers	9%	5%
Other	17%	20%

Table 4: Frequency of selected dressing types in the local best practice control group in the CONTOP study

Dressing type	Frequency
Foam/alginates	45%
Hydrocolloid dressings/films	15%
Gauze	4%
Antibiotic/antimicrobial Silver dressings Other	30% 14% (48%) 16% (52%)
Other	6%

The silver foam dressing decreased wound size by 50%, with the comparators reducing wound size by 30% (p=0.006, Wilcoxon two-sample test). There was also a statistically significant increase in the presence of normal granulation tissue in 68% of the sustained-release silver foam-treated patients and 50% of the local best practice group (p=0.002, Wilcoxon two-sample test). Exudate management was evaluated by dressing wear time: the sustained-release silver foam dressing group averaged 3.8 days, which was significantly longer than the local best practice group average of 2.3 days (p=0.0001, Wilcoxon two-sample test). The study also revealed that the sustained-release silver foam dressing showed statistically significant advantages in odour reduction and pain relief as well as the clinical ease of use of the dressing [22].

Health-economic analysis

Effectiveness

Traditionally the consideration of treatment costs in wound care has been limited to dressing costs alone. However, to properly evaluate the financial impact of a treatment strategy on a healthcare system, outcomes also need to be considered. In an analysis of the cost-effectiveness of using the sustained-release silver foam dressing the outcomes considered were average dressing wear-time, the healing time of the ulcers, cost of medical and nursing time for assessment and treatment, and the cost and frequency of complicating infections. A spreadsheet Figure 4 and a Markov model Figure 5[23][24] were designed to perform these health-economic analyses. The two health-economic models were based on methods and procedures from published cost-effectiveness models [23][24]. The analyses were performed with a societal perspective in a UK and German context. The model design and data were validated by a UK and German panel consisting of wound care experts. Following advice from the expert panels, the models were then adjusted and re-analysed and relevant sensitivity analyses were performed to assess the robustness of the models.

The analyses compared four different wound-care dressings used in the treatment of delayed healing venous leg ulcers. A four-week limit was applied in the main models for UK and Germany Figure 4. The Markov model assured that this four-week model had a realistic link to cost-effectiveness of complete wound closure. Figure 5 [25].

The costs of the dressings - and secondary dressings where needed - were determined and the weekly cost per dressing change was calculated using the data from Table 5 and Table 6 [25] [26]. The costs associated with materials including dressings, dressing change frequency, clinician time, and infection were compiled from relevant local sources [25] [26]. Costs specifically related to dressings are outlined in Table 6.

Table 5: Overview of clinical studies of antimicrobial wound dressings included in the analysis

	Reduction in wound area per week (%)	Dressing changes per week	References
Sustained-release silver foam dressing (Contreet Foam)	12.6	2.2	(Karlsmark et al 2003; Sibbald et al 2004) [14] [17] *
Sodium carboxymethylcellulose dressing containing silver (Aquacel Ag)	6.0	1.9	(Vanscheidt et al 2003) [27])
Activated charcoal cloth with silver dressing (Actisorb Silver 220)	11.2	3.6	(Tebbe and Orfanos 1996) [28]
Cadexomer iodine paste (Iodoflex)	9.0	2.7	(Hansson et al 1998) [29]

* data pooled from two different studies.

Table 6: Cost data for the four dressing alternatives in UK and Germany

	Cost per dressing (euro)
	United Kingdom			Germany
	Primary	Secondary	Total	Primary	Secondary	Total
Sustained-release silver foam dressing (Contreet Foam)	10.43	Not necessary*	10.43	11.5	Not necessary*	11.5
Sodium carboxymethyl-cellulose dressing containing silver (Aquacel Ag)	5.93	2.91 (non-adhesive, absorbent: CombiDERM-N)	8.84	7.26	14.2 (self-adhesive, carboxymethoyl-cellulose island dressing:Versiva)	21.46
Activated charcoal cloth with silver dressing (Actisorb Silver 220)	3.53	4.32 (non-adhesive, hydropolymer foam dressing: Tielle Plus Borderless)	7.85	5.46	10.33 (non-adhesive, hydropolymer foam dressing: Tielle Plus Bordeless)	15.79
Cadexomer iodine paste (Iodoflex)**	14.04	0.48 (knitted viscose, silicone impregnated non-adherent dressing: N-A Dressing)	14.52	N/A	N/A	N/A

* Contreet Foam does not need a secondary dressing. ** Iodoflex is not part of the German models, as it is not available in Germany. The weekly cost per dressing change was calculated as: Weekly dressing change cost = (Primary and secondary dressing cost + Nursing time + Travel cost + Gloves + Wound cleansing + Compression bandages) x Dressing changes per week x The cost of risk of infection. The choice of secondary dressings was based on manufacturers' instructions for use and the expert panels' advice. The size of the secondary dressing was selected so it could fully cover the primary dressing. For the sensitivity analysis, cheaper alternatives were selected, again based on the expert panels' advice.

The results from the weekly cost per dressing change were used to calculate the cost per percentage reduction in wound area as shown in Table 7[25][26].

Table 7: Frequency of ulcer types included in the CONTOP study

	Cost per percentage relative reduction in wound area (euro)
	United Kingdom	Germany
Sustained-release silver foam dressing (Contreet Foam)	14.18	4.18
Sodium carboxymethyl-cellulose dressing containing silver (Aquacel Ag)	26.37	11.10
Activated charcoal cloth with silver dressing (Actisorb Silver 220)	24.81	8.90
Cadexomer iodine paste (Iodoflex)	25.43	NA

The differences in costs between UK and German results are primarily due to different cost structures for nursing salaries in the two countries. [25][26].

Sensitivity analyses were performed to assess the robustness of the results. Both the cost and efficacy data were altered up and down by 20%. These calculations also included replacing the secondary dressings with less costly alternative dressings where appropriate. The link between cost of relative reduction in wound area and the cost per healed wound was ensured through the use of the Markov model. The results from this Markov model confirmed the results from the four-week model [25]. The sensitivity analyses showed that the models were robust and that the sustained-release silver foam dressing was the most cost-effective choice in regard to cost per relative reduction in wound area as well as cost per healed wound [25].

Discussion

The importance of the bacterial load, the appearance of the superficial wound bed including wound exudate, the host resistance, and the most appropriate course of treatment for patients with critically colonised and infected wounds are subject to debate and disagreement. The importance of evidence-based studies to support optimal decision making for wound treatment cannot, therefore, be overstated.

This review article summarises the use of a sustained-release silver foam dressing in the treatment of non-healing chronic wounds. Roma-Moore stated that 'only controlled clinical evaluations ideally support final decisions about the best treatments to use in achieving wound care outcomes'[30]. The evidence-based medicine approach combined with the principles of wound bed preparation led to the design of the first RCT of a moist wound healing silver dressing for chronic wound care.

In this RCT, a sustained-release silver foam dressing significantly decreased odour and exudate faster than the non-active foam dressing. The results showed a 45% reduction in ulcer size from baseline for the sustained-release silver foam dressing compared with 25% for the foam dressing without silver. In a recent study by Vanscheidt et al evaluating a sodium carboxymethylcellulose dressing containing silver (Aquacel Ag) the mean ulcer area was reduced by 23.9% over the same period of time (four weeks) [27]. According to Flanagan (2003) a percentage area reduction of less than 20-40% over the initial two to four weeks of treatment is a reliable indicator that the wound is not responding well to the treatment [31].

Randomised, controlled trials are often criticised because they do not represent the full spectrum of patients in real-life settings. The CONTOP study was designed to address the issues of everyday practice and has produced comparable results to the randomised, controlled trial of the benefits of the sustained-release silver foam dressing compared with local best practice. The results showed a 50% reduction in ulcer size for the sustained-release silver foam dressing compared with 30% for local best practice. In addition, the dressings were changed less frequently in patients treated with the sustained-release silver foam dressing.

New products will not become part of everyday practice if they add additional costs to the healthcare system. By calculating the total healthcare costs based on evidence and expert opinion as developed in the models outlined in this paper, the sustained-release silver foam dressing was demonstrated to provide cost-effective treatment of wounds both in terms of cost per percentage relative reduction in wound area and cost per healed wound. This is a preliminary estimate of real clinical costing of the components that are included in cost-effectiveness analyses. This concept needs to be prospectively tested in practice and, depending on the clinical expertise, the healthcare system obstacles and the cost of the product, these figures can change and need to be critically evaluated for each healthcare delivery model.

Conclusion

The results of this analysis indicate that the sustained-release silver foam dressing (Contreet Foam) is of particular benefit for the treatment of critically colonised wounds. The use of an evidence-based medicine model provides a framework for future analysis of the efficacy, efficiency and effectiveness of new technologies in wound care. This model adds rigour and sets a benchmark for a new level of clinical evidence. This is of particular importance in areas of wound management where there is only limited clinical and investigational evidence to support specific treatment procedures.

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