Dressings and Topical Agents for Chronic Wounds - NIHR Health ...

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)ReviewSystematic reviews of wound caremanagement: (2) Dressings andtopical agents used in the healingof chronic woundsM BradleyN CullumEA NelsonM PetticrewT SheldonD TorgersonHealth Technology AssessmentNHS R&D HTA ProgrammeHTA

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Systematic reviews of wound caremanagement: (2) Dressings andtopical agents used in the healingof chronic woundsM Bradley 1*N Cullum 2EA Nelson 2M Petticrew 1T Sheldon 3D Torgerson 41 NHS Centre for Reviews and Dissemination, University of York, UK2 Centre for Evidence Based Nursing, University of York, UK3 York Health Policy Group, University of York, UK4 Centre for Health Economics, University of York, UK* Corresponding authorCompeting interests: none declaredPublished December 1999This report should be referenced as follows:Bradley M, Cullum N, Nelson EA, Petticrew M, Sheldon T, Torgerson D. Systematic reviewsof wound care management: (2) Dressings and topical agents used in the healing of chronicwounds. Health Technol Assess 1999;3(17 Pt 2).Health Technology Assessment is indexed in Index Medicus/MEDLINE and Excerpta Medica/EMBASE. Copies of the Executive Summaries are available from the NCCHTA web site(see overleaf).

NHS R&D HTA ProgrammeThe overall aim of the NHS R&D Health Technology Assessment (HTA) programme is toensure that high-quality research information on the costs, effectiveness and broader impactof health technologies is produced in the most efficient way for those who use, manage and workin the NHS. Research is undertaken in those areas where the evidence will lead to the greatestbenefits to patients, either through improved patient outcomes or the most efficient use ofNHS resources.The Standing Group on Health Technology advises on national priorities for health technologyassessment. Six advisory panels assist the Standing Group in identifying and prioritising projects.These priorities are then considered by the HTA Commissioning Board supported by theNational Coordinating Centre for HTA (NCCHTA).This report is one of a series covering acute care, diagnostics and imaging, methodology,pharmaceuticals, population screening, and primary and community care. It was identifiedas a priority by the Pharmaceutical Panel and funded as project number 93/29/01.The views expressed in this publication are those of the authors and not necessarily those of theStanding Group, the Commissioning Board, the Panel members or the Department of Health.The editors wish to emphasise that funding and publication of this research by the NHS shouldnot be taken as implicit support for the recommendations for policy contained herein. Inparticular, policy options in the area of screening will be considered by the National ScreeningCommittee. This Committee, chaired by the Chief Medical Officer, will take into account theviews expressed here, further available evidence and other relevant considerations.Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search,appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permitthe replication of the review by others.Series Editors: Andrew Stevens, Ruairidh Milne and Ken SteinMonograph Editorial Manager: Melanie CorrisThe editors have tried to ensure the accuracy of this report but cannot accept responsibility forany errors or omissions. They would like to thank the referees for their constructive commentson the draft document.ISSN 1366-5278© Crown copyright 1999Enquiries relating to copyright should be addressed to the NCCHTA (see address given below).Published by Core Research, Alton, on behalf of the NCCHTA.Printed on acid-free paper in the UK by The Basingstoke Press, Basingstoke.Copies of this report can be obtained from:The National Coordinating Centre for Health Technology Assessment,Mailpoint 728, Boldrewood,University of Southampton,Southampton, SO16 7PX, UK.Fax: +44 (0) 23 8059 5639 Email: hta@soton.ac.ukhttp://www.hta.nhsweb.nhs.uk

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)List of abbreviationsABPI ankle brachial pressure index *b-FGF basic fibroblast growth factorC comparator *CI confidence intervalCRD Centre for Reviews and Disseminationdf degree of freedomDMSO dimethyl sulfoxideES effect sizeI intervention *ITT intention-to-treatM/F male/female *OR odds ratioPMN polymorphonuclearRCT randomised controlled trialr-PDGH-BB recombinant platelet-derived growth factorSD standard deviationSEM standard error of the mean*Used only in tables and figuresi

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Executive summaryBackgroundWound dressings are designed to keep thewound clean and free from contamination andalso to promote wound healing, particularly inchronic wounds where there may be significanttissue loss.ObjectivesThis review evaluates the evidence foreffectiveness and cost-effectiveness of dressingsand topical preparations in pressure sores,leg ulcers and surgical wounds healing bysecondary intention.MethodsNineteen electronic databases, includingMEDLINE, EMBASE, CINAHL and the CochraneWounds Group’s specialised trials register andwound care journals were searched until October1997. Organisations, manufacturers, researchersand healthcare professionals concerned withwound care were contacted for additional trials.The reference sections of obtained studies werealso searched for further trials.Inclusion criteriaRandomised controlled trials (RCTs), publishedor unpublished, which assessed the effectivenessof a dressing or topical agent in the treatmentof pressure sores, leg ulcers, sinuses and surgicalwounds healing by secondary intention wereincluded in the review. Where a particulardressing was not evaluated by an RCT, prospectivecontrolled trials were included. Studies wereonly included if they reported either theproportion of wounds healed within a timeperiod or the percentage or absolute changein wound area.Data extraction and synthesisTrial data were extracted by one researcher andchecked by a second. The results from each studywere calculated as odds ratios and/or effect sizesand where appropriate, similar studies have beenpooled in a meta-analysis.ResultsSurgical wounds healing bysecondary intentionOnly five studies met the inclusion criteria. All thestudies were of poor quality and had small samplesize. One study found a statistical benefit for wetto-drydressings compared with topical applicationsof aloe vera. However, neither of these products iscommonly used in the UK.Pressure soresTwenty-eight trials evaluated 31 comparisonsof treatments for the healing of pressure sores.The majority of trials were of poor quality. Asingle report suggested that the topical applicationof insulin was of significant benefit forwound healing when compared with standardnursing care. A meta-analysis of five reportscomparing a hydrocolloid dressing with atraditional treatment suggested that treatmentwith the hydrocolloid resulted in a statisticallysignificant improvement in the rate of pressuresore healing.Leg ulcersSixty studies were included that had evaluateddressings or topical agents in arterial andvenous ulcers. Both mononuclear culturedcells in culture medium and topical ketanserinsignificantly increased healing rates comparedwith a control preparation in one trial of arterialleg ulcers. Collagen sponges appeared to beeffective in two trials of leg ulcers but there wereinsufficient data to determine the significanceof these results.Nine trials compared hydrocolloids withtraditional dressings for venous ulcers but metaanalysisdemonstrated no significant differencein the proportion of ulcers healed over the trialperiod. Two trials compared semi-permeablefilms with traditional dressings; one found alarger reduction in wound area under the filmdressing but the other found no significantdifference in healing rates. Two trials comparedfoam dressings and traditional or control therapies;one favoured the foam dressing but the otherfound no difference between treatments. Wovenzinc oxide paste bandage was more effectiveiii

Executive summarythan either an alginate dressing or a zinc oxideimpregnatedstockinette in one trial.In two trials comparing different hydrocolloids, nosignificant difference in healing rates was found.Comparisons of hydrocolloids with foam dressingsfound no difference in effectiveness.In trials of topical agents, allopurinol anddimethyl sulfoxide improved healing in onetrial compared with inert powder. Of two trialscomparing hyaluronic acid with control, one founda difference in daily healing rate and the otherfound no difference in proportion of ulcershealed over the trial period.Four trials compared biological dressings withtraditional therapies. None found statisticallysignificant differences in results.Two trials compared dressings with topicalpreparations. There was no difference in theproportion of ulcers healed between patientstreated with cryopreserved cultured allograftsor a hydrocolloid, though the former-treatedulcers had a higher rate of epithelialisation.A collagen dressing was more effective thantreatment with daily antiseptic.A comparison of buffered acidifying ointment andointment reported there was no difference in theproportion of ulcers healed, but there was a higherrate of epithelialisation with the buffered ointmentgroup. In another, trial there were higher healingrates when two amino acid solutions were comparedwith two groups treated in saline soaks.Publication biasA funnel plot of all trials showed no evidence ofpublication bias. However, publication bias wasindicated in a comparison of traditional andhydrocolloid dressings.Cost-effectiveness analysisNine trials provided data on costs of dressingmaterials and nursing visits. Six evaluated costeffectivenessin pressure sore treatments andthree papers reported cost-effectiveness datain leg ulcer trials.ConclusionsImplication for practiceThere is little evidence to indicate which dressingsor topical agents are the most effective in the treatmentof chronic wounds. However, there is evidencethat hydrocolloid dressings are better thanwet-to-dry dressings for the treatment of pressuresores. In the treatment of venous ulcers, lowadherent dressings are as effective as hydrocolloiddressings beneath compression bandaging.Recommendations for researchResearch methodology could be significantlyimproved and commissioning groups may wish toconsider the following aspects for future research.• The number of patients in a trial should bebased on an a priori sample size calculation.• A truly objective outcome measure should beused or wound healing should be expressed asboth percentage and absolute change in area.• For each patient a single reference woundshould be selected.• Experimental groups should be comparableat baseline.• Head-to-head comparisons of contemporarydressings are required and should use agents thatare recommended for wounds of a similar nature.• A complete and thorough description ofconcurrent treatments, including secondarydressings, should be given in trial reports.• Assessment of outcomes should ideally be blindto treatment, or completely objective.• Survival rate analysis should be adopted for allstudies that assess wound healing.• Studies to determine the biological mechanismsinvolved in wound healing are needed.• Future trials should include cost-effectivenessand quality of life assessments, as well asobjective measures of dressing performance.• Economic evaluations should be incorporatedwithin trials that are sufficiently large to detectappropriate economic and clinical outcomes.• To prevent publication bias and ensure theinclusion of unpublished trials in systematicreviews, those involved in primary researchshould make their data available to thoseundertaking systematic reviews.iv

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Chapter 1IntroductionThis review is the second in a series of systematicreviews of wound care management. The research wascommissioned by the NHS R&D Health TechnologyAssessment (HTA) Programme under the project number93/29/01. To expediate dissemination, some reports willbe published as separate HTA monographs. The completeseries will include the following topics.• The debridement of chronic wounds (HealthTechnol Assess 1999;3(17 Pt 1)).• Dressings and topical agents used in the healing ofchronic wounds (Health Technol Assess 1999;3(17 Pt 2)).• Pressure relief (in preparation).• Compression for venous leg ulcers (in preparation).• Diabetic foot ulcers (in preparation).• Antimicrobial agents (in preparation).• Physical therapies (in preparation).The EditorsThe earliest documentation concerningwound management is found in the PapyrusEbers, which dates from around BC 1500. Thisdocument indicates that crude treatments basedon oiled frog skins, honey, lint and animal greasewere commonly used by the Egyptians as woundcoverings. An early Hindu document, the SusrutuSanhita reported skin grafts being used as early asBC 700. 1 Jeter and Tintle 2 report that spiders webs,new-born puppies boiled in oil of white lilies, andred-hot pokers to cauterise wounds have been usedat various times throughout history. George 3 statesthat the Sumerians were the first to fashion occlusivedressings, which are capable of maintaininga moist environment, using clay.In the 19th century, Pasteur advocated thatwounds should be covered and kept dry becausehe believed this would keep them ‘germ’ free. Thedressings developed at this time, made from cloth,cotton and gauze, have dominated wound managementin recent history and in some countries theycontinue to be the main products used. 3The first manufactured dressings were probablyGamgee wadding and tulle gras. Gamgee 4 discoveredthat degreased cotton wrapped in bleached lintwould absorb fluids, and he introduced his firstdressing in the 19th century. During the 1914–18war, Lumiere in France developed a cotton gauzethat was impregnated with paraffin to prevent thedressing sticking to the wound. Wound managementtechnology did not progress significantlybeyond these early developments until the 1960s,when comparisons were made of wound healingin dry and moist environments. 5,6 Although initialattempts were made to only alter the moistureat the surface of a wound, researchers are nowinvestigating the whole wound healing process inorder to establish what factors impede woundhealing and what characteristics of the environmentcould be manipulated to accelerate healing.A description of the process of wound healing willprovide the rationale for the majority of the woundproducts evaluated within this review.The physiology of wound healingWhen the skin is wounded, a complex series ofcellular and chemical events are initiated whichact on the damaged tissues – blood vessels, dermis,and epidermis.Wounds that result in limited tissue loss, such assurgical wounds, have a tendency to heal rapidlyon the surface as opposing edges of the woundare in close proximity for cellular and structuralrepair. The wound is healed in about a week, butwill continue to mature for a year or more. Duringthis time the structural architecture of the woundchanges, the scar usually flattens, and the skinregains most of its pre-wound tensile strength.In wounds where significant tissue loss occursthe damaged edges are usually unsuitable forprimary closure. In this case, the tissue defectmust be made up before the wound can heal.To facilitate healing, dressings are applied to try toprotect the wound from contamination and keepthe wound surface moist to maintain the integrityof the cells present in the defect. In a dry woundenvironment, dividing cells at the wound edgesare unable to migrate into those areas occupiedby dry scab material.Where healing is protracted as a result ofsignificant tissue loss (e.g. as in deep pressure1

Introduction2sores) or due to underlying pathology (e.g. venousleg ulcers) chronic wounds occur. Although notinitially chronic in nature, both surgical woundsand pilonidal sinuses can develop into chronicwounds if they fail to heal by primary intention.Chronic wounds are those most commonly seenby health professionals and estimates suggestthat the cost of treating leg ulcers alone in theUK is more than £300 million per annum. 7The wound healing processThe biological mechanism associated with woundhealing is complex and still not well understood.Although there is much to learn about the detailof the processes involved, some of the generalconcepts of healing are understood.Chronic open wounds, such as leg ulcers andpressure sores, heal by secondary intention orgranulation, rather than primary intention (themeans by which a surgical incision heals). Plateletaggregation during haemostasis liberates a numberof soluble mediators, including platelet-derivedgrowth factor, which initiate the healing process.Haemostasis is followed by an early inflammatoryphase that is characterised by vasodilatation,increased capillary permeability, complementactivation and polymorphonuclear (PMN) andmacrophage migration into the wound. 8PMNs predominate during the first days of postwoundoccurrence, with the macrophage becomingthe predominant inflammatory cell within 3 days.Macrophages are large, mobile and actively phagocytic,engulfing bacteria and devitalised tissue andacting effectively as the body’s own debridementsystem. Additionally, macrophages are consideredto play a key role in regulating subsequent eventsin the healing process. This is achieved by secretionof a number of factors that regulate their own andother cell functions. These factors are responsiblefor the chemotactic attraction of more macrophagesand the migration and induction of proliferationby fibroblasts and endothelial cells. Theincreasing number of fibroblasts and endothelialcells forming granulation tissue around the fifthday post-injury heralds the ‘proliferative phase’. 9Fibroblasts are the ‘factory cells’ of the woundhealing module. They are rich in mitochondria,endoplasmic reticulum, and Golgi apparatusessential for protein synthesis. Fibroblasts synthesisecollagen and ground substance (proteoglycansand fibronectin), which support new cells, andthe fragile capillary buds, which appear aroundthis time (angiogenesis). The endothelial budsbecome canalised, and are thus able to increasethe vascularity and hence oxygen tension of thenew tissue, so responding to the large metabolicdemand of tissue repair. Epithelialisation requiresthe migration of epithelial cells across the granulationtissue, to close the epidermal defect.Collagen synthesis continues for many months afterwound closure, but also undergoes continual lysis, soa delicate balance exists between the two processes.This final remodelling phase, accompanied by increasingtensile strength of the wound, and a decreasingcellularity, may continue for up to a year.Little research has been carried out to investigatethe differences between acute and chronic wounds,though this comparison is now becoming thefocus of recent work. Most studies of the woundhealing process have been undertaken on acutewounds, usually in experimental animals. Howclosely the healing of a chronic wound followsthe healing pattern of an acute wound is notclear. The question of what makes a chronicwound ‘chronic’ has yet to be answered. 10The healing process is considered to be regulatedby cytokines and growth factors, and recent studieshave demonstrated that the cytokine environmentin a healing chronic wound is different from that ina non-healing wound. 11 However, the precise natureof the defect(s) leading to non-healing remain tobe defined.Moisture and wound healingIn 1962, Winter 5 published his seminal text on theeffect of occlusion on wound healing. Winter madeexperimental wounds in Large-White pigs, andcovered half with occlusive film and left the otherhalf exposed to the air. The occluded, and hencemoist wounds, had an epithelialisation rate twicethat of those left to form a scab.Experimental, acute wounds in humans andanimals appear to heal more rapidly in a moistenvironment. The relevance of this to chronic,pathological wounds is unclear.The role of oxygen inwound healingOxygen is essential for cell metabolism, anddemand is increased by synthetic processes suchas those occurring during wound healing. Shortly

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)after injury, the oxygen tension in a wound falls, sothat by day 3, the pO 2 in the dead space of a woundis below 10 mmHg. 12 This fall in oxygen tension isaccompanied by an increase in the concentrationof carbon dioxide, and a fall in pH. A low pO 2provides optimal conditions for fibroblast regeneration,possibly stimulating the process and increasingthe rate of advance of granulation tissue. 13 Theconcept that hypoxia stimulates healing was furthersupported by Knighton and co-workers 14 whodemonstrated a positive relationship between asteep oxygen gradient between capillaries andhypoxic tissue, and angiogenesis.pH and wound healingFew studies have examined the effect of pH onwound healing. In 1973, Leveen 15 demonstratedthat the acidification of wound surfaces increasedhealing. Varghese and co-workers 16 found woundfluid to be more acidic under a Granuflex ® dressing(ConvaTec Ltd) than under an Opsite ® dressing(Smith & Nephew Healthcare Ltd), the more acidicpH being compatible with in vitro antibacterialactivity. However, there are no high-quality randomisedcontrolled trials (RCTs) examining theeffects of wound pH on ulcer healing.Micro-organisms and ulcer healingThe effect of micro-organisms on ulcer healingremains an area of intense debate. That chronicwounds are usually colonised by bacteria is accepted,and an important distinction should be madebetween colonisation and infection. Infection ischaracterised by the stigmata of pain, inflammation,purulent exudate and heat, and by the moreobjective measures of a PMN response and tissueconcentrations of organisms in excess of 10 5 /g. 17The effect of occlusive dressings on infectionrates is controversial. A review of the impactof antiseptics and antibiotics is currentlyin preparation.Chronic woundsWounds come in a variety of shapes and sizes andmay be classified in terms of aetiology, duration,and degree or depth of tissue loss. Wounds withlittle tissue loss include surgical incisions, minorabrasions, scalds and minor bites. Those withsignificant tissue loss include leg ulcers, pressuresores, and fistulae (all chronic) and severelacerations, gunshot wounds, burns and stabwounds (acute wounds).George 3 estimates that the worldwide prevalenceof wounds is:• surgical: 40–50 million• leg ulcers: 8–10 million• pressure sores: 7–8 million• burns: 7–10 million.In the UK it has been estimated that 0.15–0.18%of the adult population has an open leg ulcerat any one time. 18 This would mean that about60,000 people in the UK are currently beingtreated for a leg ulcer. The prevalence of pressuresores may vary widely according to setting andwhether grade 1 sores, where the tissue isdamaged but the skin remains unbroken, arecounted. Barbenel and co-workres 19 found amean pressure sore prevalence of 8.8% inpatients cared for in hospitals and the community.More recently, a study by O’Dea, 20 found theprevalence in hospitalised patients (excludingobstetric and psychiatric patients) to be 18.6%,including grade 1 sores, and 10.1% excludingthem. In high-risk groups, such as elderly patientswith fractured neck or femur, 66% of hospitalisedpatients will develop a pressure sore. 21 Theimportance of preventing and treating pressuresores has recently been acknowledged inGovernment policy. 22Management of thewound patientThe chronic, non-healing, wounds discussedwithin this review frequently occur through acombination of precipitating (often extrinsic) andperpetuating (often intrinsic) factors. Pressuresores may be precipitated by the patient havingbeen seated for a number of hours but this isunlikely if the patient is conscious, able to shiftposition and in good health. The more likelyreason for pressure sore occurrence is througha combination of localised, sustained, high tissuepressure with other factors, such as severe concurrentillness. Treatment, therefore, generallyfocuses on the local ‘symptom’ of poor tissueperfusion (the wound) and also the contributoryfactors of interface pressure and poor health.This review will only consider the contributionof dressings and local applications used for woundhealing. Other interventions commonly used inthe treatment of pressure and leg ulcers, where3

Introduction4healing rates are low if the underlying pathologyis not addressed, have been reviewed previously. 23,24It is strongly recommended that decisions ontreatment choice should be made in light of allthe available information.Local wound managementTraditional wound dressings are regarded aspassive devices that protect the wound from furtherinjury, while wound healing takes place naturallybeneath. Examples of traditional dressings aregauze, gauze soaked in saline, knitted viscosedressings, and tulle dressings all of which areconsidered in this review. Winter, 5 however,introduced the concept of interactive dressings,which can alter the local wound environment.These interactive dressings have a range ofproperties and are currently the subjectof intense research.The vast majority of these ‘modern’ dressingsare described as occlusive or semi-occlusive.They prevent or reduce the rate of moisturevapour transmission from the wound surface.Completely occlusive dressings (e.g. polythenebags) produce a very moist wound environmentand lead to maceration of the surrounding skin.Semi-occlusive dressings have a range of moisturevapour transmission rates, which permit a lowervolume of moisture to pass to the surface than isproduced by the wound. The result is an accumulationof water vapour at the surface which helpsto maintain a moist wound environment.Interactive dressings may also insulate the woundsurface from excessive heat loss, which is thoughtto inhibit fibroblast activity. The interactive dressingsthat are considered in this review includealginates, collagen, films, foams, hyaluronic acidproducts, hydrocolloids and hydrogels.Despite treatment with passive and interactivedressings, which provide optimal conditions forhealing, many wounds still persist. In a moreaggressive approach active dressings have beendeveloped, which have various properties thatare believed to have a direct role in changing thechemical and cellular make-up of the wound.Examples of active dressings include skin grafts,growth factors and cellular suspensions.A number of characteristics of the ‘ideal dressing’have been described by pharmacists and manymanufacturers refer to these characteristics whenmarketing their products. These are out-lined inBOX 1 The functions of an “ideal” dressing 25• Allow excess exudate to be removed from thewound surface• Provide a moist micro-environment• Be sterile/contaminant free• Do not shed dressing material in the wound• Reduce wound pain• Easy to remove and apply• Do not cause allergic reactions• Act as a semi-permeable membrane• Cause no trauma when removed• Be impermeable to micro-organisms• Provide thermal insulationBox 1. However, as this is an ideal list, none of thedressings in current use fulfil all of the criteria.To bring order to the vast range of productsavailable to a practitioner, the British NationalFormulary 26 has developed a classification systembased on a products’ properties and modeof action.• Wound dressing pads This group of traditionaldressings include knitted viscose dressings andgauze dressings. They are usually in the form ofwoven cotton pads that are applied directly to thewound surface. Some have a perforated film layerto reduce adherence to the wound surface (e.g.Tricotex ® , Smith & Nephew Healthcare Ltd).• Tulle gras dressings Made from cotton or cottonand viscose woven fabric, which has been impregnatedwith white soft paraffin. The dressing isused as a primary wound contact layer and theparaffin is present to reduce the adherence of theproduct to the surface of a granulating wound.Antimicrobial substances may also be included(e.g. povidone iodine or chlorhexidine) (e.g.Paratulle ® , Seton Scholl Healthcare Ltd).• Semi-permeable film dressings This is atransparent film dressing. A thin layer of acrylicadhesive keeps it adherent to the skin but notthe wound surface. These dressings are semipermeableand allow some gaseous exchangebut they are impervious to bacteria 27 (e.g.Tegaderm ® , 3M Ltd).• Hydrocolloid dressings These occlusivedressings contain a hydrocolloid matrix (e.g.gelatin, pectin and carboxymethylcellulose)with elastomeric and adhesive substancesattached to a polymer base. 27 On contactwith wound exudate the hydrocolloid matrix

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)absorbs water, swells and liquefies to forma moist gel (e.g. Granuflex).• Hydrogels These consist of a starch polymer,such as polyethylene oxide or carboxymethylcellulosepolymer and up to 80% water. Theyhave the ability to absorb wound exudate orrehydrate a wound depending on whether thewound is exuding heavily or dry and necrotic(e.g. Intrasite ® , Smith & Nephew HealthcareLtd). These dressings have been evaluated ina systematic review of debriding agents. 28• Alginate dressings These are made fromseaweed, prepared as a salt of alginic acid.When in contact with serum, wound exudate orsolutions containing sodium ions, the insolublecalcium alginate is partially converted to thesoluble sodium salt, and a hydrophilic gel isproduced 27 (e.g. Kaltostat ® , ConvaTec Ltd).• Bead dressings These consist of sterile,dextranomer beads, 0.1–0.3 mm in diameter.When introduced into an exuding wound, thebeads will absorb up to four times their weightof exudate. Bacteria and cellular debris presentin the wound are taken up by capillary actionand become trapped in the spaces betweenthe beads. When the dressing is changed, thisdebris is washed away. They require a secondarydressing to maintain their position in the wound(e.g. Debrisan ® , Pharmacia & Upjohn). Thesedressings have been evaluated in a systematicreview of debriding agents. 28• Foam dressings These consist of either a hydrophobic,polyurethane foam sheet or a liquid thatexpands to fill the wound cavity. They absorbliquid by capillary action (e.g. Lyofoam ® , SetonScholl Healthcare Ltd).Topical preparationsTopical preparations covered in the presentreview include growth factors, oxygen freeradical scavengers, zinc oxide paste, tripeptidecopper complex, and silver sulphadiazinecream. Topical antiseptics and antibioticsare not covered here but are currentlyunder review.Several of these preparations are applied tothe wound to compensate for a deficiency ina particular element considered necessary forwound healing. An example of such a topicalagent is zinc oxide; zinc deficiency has beenassociated with poor wound healing. Otherpreparations are thought to modify the woundenvironment by removing harmful bacteria(e.g. silver sulphadiazine).The use of oxygen free radicals is thought tomediate tissue destruction following prolongedvenous hypertension caused by venous insufficiency.Coleridge-Smith and co-workers 29 proposedthat venous hypertension reduces flow inthe capillaries to such a level that the white cellsare effectively trapped, which causes the release oftoxic oxygen metabolites and proteolytic enzymes.DL-cysteine, DL-methionine-methyl sulphoniumchloride, allopurinol and dimethyl sulfoxide(DMSO) all bind the oxygen free radicals andso are intended to protect the ulcer fromfurther damage.Iloprost has also been applied topically becauseof its action on the micro-vasculature. It reducesplatelet aggregation and has profibrinolytic effectsthat may facilitate the removal of fibrin cuffsaround capillaries in the skin of patients withvenous insufficiency. In patients with peripheralarterial disease it is used systemically, but in thisreview it has only been evaluated as a topicalpreparation.Sucralfate is applied topically because of its abilityto bind to, and protect, angiogenic growth factors,such as basic fibroblast growth factor to increaseits angiogenic activity in the wound.5

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Chapter 2MethodsAsystematic review of primary research wasundertaken using the NHS Centre for Reviewsand Dissemination (CRD) structured guidelines. 30Literature searchNineteen electronic research databases weresearched using a sensitive search strategy designedin collaboration with an information specialist(appendix 1). The electronic search was supplementedby a handsearch of five specialist woundcare journals, 12 conference proceedings, and asearch of systematic reviews held on the NHS CRDDatabase of Abstracts of Reviews of Effectiveness(DARE). The bibliographies of all retrieved andrelevant publications were searched for furtherstudies. Companies with an interest in wound careproducts were approached for unreported trials.An advisory panel of experts in wound management,established to comment on the review asit progressed, were also asked to identify anyadditional trials (appendix 2). Relevant economicevaluations were identified by adding economicrelatedsearch terms to those used in the searchfor clinical trials. Authors of trials published after1985 were contacted and asked to provide detailsof any associated economic evaluations.Study selection anddata extractionRetrieved studies were assessed for relevance bya single reviewer and decisions on final inclusionchecked by a second reviewer; disagreements wereresolved by discussion with a third reviewer. Trials,irrespective of date, language and publication status,were included if they were human-based RCTs thatevaluated the efficacy of a dressing or topical agentin relation to wound healing and had an outcomemeasure that was considered an objective measureof healing. Where study details were lacking, theauthors were invited to provide further information.Retrieved trials that did not meet the inclusioncriteria are recorded in appendix 3.Data from included trials were extracted by asingle reviewer into data extraction tables and thenchecked independently by a second reviewer.Assessing the presence ofpublication biasWhen trials evaluating an intervention aregrouped and reviewed there is a potential formisleading interpretations and inappropriatetreatment choices if all the available informationis not represented. A systematic review attemptsto reduce the influence of this bias by undertakingan extensive search for all published trials,but it is inevitable that information not readilyavailable in the public domain may be overlooked.Studies with negative results frequently remainunpublished, and therefore there is a potentialfor over-reporting of positive results in reviewarticles. The results of a systematic review cantherefore be susceptible to publication bias.It is desirable then for systematic reviews todemonstrate that where a difference is indicatedbetween two treatments it is not as a result ofpublication bias.The presence of publication bias can bedemonstrated by a funnel plot where theestimate of the trial effect is plotted against thesample size. This is a visual tool that relies on therelationship between sample size and precisionof the treatment effect. Small studies show a widevariation in the reported treatment effect andso scatter widely at the bottom of the plot,larger studies show less variation and so tend toaggregate together towards the top of the plot.When publication bias is absent the visual effectis that of an inverted symmetrical funnel, whilein the presence of bias the plot is frequentlyskewed and asymmetrical. 31Although a funnel plot is a useful indication ofpublication bias, it remains a relatively insensitivetechnique relying on visual assessment. Itsvalidity is dependent on there being a sufficientnumber of studies from which to assess thespread of data. In this review only comparisonsbetween traditional and modern dressings providedsufficient numbers of trials to allow theconstruction of a funnel plot. In addition thelarge number of trials that compared a hydrocolloiddressing with a traditional treatmentallowed a separate funnel plot tobe constructed.7

Methods8Assessment of outcome measuresA single standard outcome measure for woundhealing does not exist. Both objective and subjectivemeasures are widely used by researchers,but little effort has been made to determine thevalidity of many of these measurements.Comfort, ease of application, ease of removal,exudate, handling and cosmesis are frequentlyused measures of dressing performance, butthey are not validated outcomes on which tobase decisions of effectiveness. In this reviewthe most commonly validated outcome measuresencountered were based on wound healing. Theunambiguity of complete healing and its importanceto clinicians and patients alike (because of itspotential impact on quality of life and burden ofcare), make it the preferred outcome measure withwhich to compare studies of clinical effectiveness.In accordance with the peer-reviewed protocol,subjective outcome measures such as visual assessmentsof oedema, erythema, granulation and pusand debris were not included unless the authorsassessed their validity. We were unable to find anystudy that validated the subjective outcomemeasures reported.Objective measures of healing are usually based onwound area. Planimetry, often aided by computeranalysis, is the most frequently used method ofcalculating wound area, though other methods,such as the measurement of wound diameter orweight of a tracing drawn around the area of thewound, are also used.Measurements of wound volume are infrequentlyreported in the literature; these methods areoften cumbersome and their accuracy has not beenproven. 32 Computerised image analysis may in thefuture, as the equipment becomes more affordableand portable, prove to be a useful technique forthe assessment of wound volume.Even though objective measures reduce oreliminate subjective biases and reduce randommeasurement errors, they have certain inherentbiases if the patients being compared havewounds with different baseline size.A change in wound area is often expressed as thepercentage change, which unlike the absolutechange in area, takes into account the initial sizeof the wound. For two wounds healing at the samelinear rate (as measured by diameter reduction)percentage area calculations will show a largerchange for a small wound than for a big wound. Theconverse is true when the absolute change in areais measured, as for any unit reduction in woundradius, a bigger area reduction will occur for a largewound. This has important consequences for thevalidity of trial results where there is poor comparabilityin initial wound size at baseline between thetreatment groups. This is illustrated in Table 1.In large trials, randomised allocation shouldensure that the mean wound size and variancein each group is similar. In a small trial randomallocation is unlikely to result in an even distributionof wound sizes. This problem will persistin small trials, even when the average wound sizeappears to be comparable between groups, becausethe distribution of wound sizes about the mean islikely to differ. This is illustrated in Table 2.In a trial where there is poor comparabilitybetween groups for wound size at baseline, andTABLE 1 Percentage and absolute measures of wound healingcan give different results for relative effectivenessGroup AGroup BBaseline mean area (cm 2 ) 50 60Follow-up mean area (cm 2 ) 35 43Mean of % reduction in area 30 28Mean absolute reduction inarea (cm 2 ) 15 17Using % change, wounds in group A appear to have healedmore rapidly than those in group B. The converse is true whenthe outcome is expressed as absolute change in wound areaTABLE 2 Groups with similar means may have differentdistributionsGroup CGroup DWound size at baseline (cm 2 ) 10,10,30,30 4,4,4,70Mean area (cm 2 ) 20 20.5Standard deviation (SD) 11.5 33Groups C and D have approximately the same meanarea. If both groups of wounds heal at the same rate (thetreatments are equally effective) it could be expected that thethree small wounds in group D will heal before those in groupC.Therefore measuring outcome based on the number ofwounds healed within a certain time period will be biased.Similarly, the percentage change in area will appear greaterin group D, while the absolute change in area will appeargreater in group C

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)the outcome is based on the change in area, theresult can only be considered valid if it is obtainedeither against the anticipated direction of the biasfor wound size, or where percentage area changeand absolute area change are in the same direction.If baseline data are not given then it is not possibleto determine the direction of bias and the validityof the result cannot be determined.Despite the potential for objective outcomes to bebiased by differences in wound size at baseline, theyremain the most reliable assessment of wound healingas, unlike subjective measures, they reduce thebiases of the assessor which cannot be estimated.Valid and reliable condition-specific outcomemeasures for patients with chronic wounds arelacking. Such measures would encapsulate thoseaspects of quality of life on which wounds mostimpact, from a patients perspective; they wouldbe sensitive to meaningful changes in qualityof life generated by a change in the wound,including post-healing of the wound. We haveonly identified one such measure, the HylandLeg Ulcer Specific Quality of Life Measure. 33However this tool ceases to be applicable whena wound has healed, thus making it impossible todetermine changes in leg-ulcer-related qualityof life with ulcer healing.9

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Chapter 3ResultsPresentation of resultsThe plots used in this systematic review combinethe results of individual RCTs. Outcomes can eitherbe dichotomous or continuous. Dichotomousoutcomes (e.g. healing or recurrence) are usuallycompared statistically by odds ratios (ORs) orrisk ratios. Continuous outcomes (e.g. rate ofhealing) are measured on a continuous scale.Continuous outcomes are compared statisticallyby mean differences.Forest plotsThe results of both the ORs and mean differencesin healing rates are presented in forest plots toallow a quick comparison to be made with theresults from other studies. Guidance on how tointerpret these figures can be found in appendix 4.Summary tables of all the studies included in thereview are presented in appendices 5–10.Quality assessment of studiesTrials that evaluated surgical wounds healingby secondary intention and pressure sores areconsidered together for the purpose of qualityassessment, as they are small in number andsuffer from similar methodological flaws.Thirty-five studies were identified for inclusion:29 reports, describing 28 trials, were evaluationsof pressure sores, while an further six examinedsurgical wounds healing by secondary intention.The majority of trials had methodologicalweaknesses (appendix 5, Tables 4 and 5). Fewerthan 6% of studies reported an a priori estimateof the number of participants required to havesufficient power to detect a clinical effect asstatistically significant, the median number ofwounds recruited to a trial was 50 (range, 14–168).Blinding of investigators at outcome assessmentwas reported in fewer than 18% of trials. Oneor more patient characteristics were recorded bytreatment group in 80% of studies, but wound sizeat baseline was reported in only 60%. Withdrawalsoccurred in most trials and were recorded bygroup and cause in 88% of trials where it wasappropriate, but only 13% analysed the resultson an intention-to-treat (ITT) basis. Seventy-sixper cent of trials described inclusion criteria, butinformation that indicated whether participantshad been truly randomised to alternativetreatments was given in only 20%.Treatments for surgical woundshealing by secondary intentionThree trials compared a dressing with a recognisedtraditional treatment, one trial compared differentdressings and one trial compared a topical agentwith standard care.Dressing versus traditional treatmentThree trials compared a silicone foam cavitydressing with a traditional gauze dressing. 34–36In each case the gauze had been impregnatedwith a different cleansing agent and thereforepooling the results was inappropriate (Figure 1;appendix 6, Table 7). There was no statisticallysignificant effect in favour of either treatmentfor an outcome measure of time tocomplete healing.Dressing versus dressingComparisons between dressings for the treatmentof surgical wounds healing by secondary intentionare rare; only a single study met the inclusion criteria.In this study 37 a silicone foam cavity dressingwas compared with a polyurethane foam dressing(Figure 2; appendix 6, Table 8). No statisticallysignificant difference was found betweenthe treatments.Topical agents versus traditionaltreatmentIn a comparison between topical applicationof the plant extract aloe vera and standard wetto-drydressings (popular in the USA), the lattertreatment appeared to be more or equally effectivedepending on the nature of the surgical woundunder evaluation 38 (Figure 1; appendix 6, Table 9 ).Wet-to-dry dressings significantly reduced thehealing time for vertical incisions, but there wasno statistical difference between the treatmentsfor transverse incisions. When all wounds whereincluded in the analysis the overall estimate wassignificantly in favour of wet-to-dry dressings.11

ResultsMacfie & McMahon, 1980 34Comparison: Traditional vs. Silicone foam(Silastic Foam ® )Mean baseline area (cm 2 ): 61.5 (5.3 SEM) 55.5 (4.5 SEM)Sample size (N): 25 25Mean time to healing (days): 69.5 (7.3 SEM) 60.3 (3.0 SEM) 9.2 (–6.67, 25.01)Traditional therapy: Gauze dressing soaked in mercuric chlorideWound type: Surgical woundsFollow-up time: Until all wounds had healedWilliams et al., 1981 35Comparison: Traditional vs. Silicone foam(Silastic Foam)Mean baseline area (cm 2 ): 64 (74.5 SD) 59 (57.7 SDSample size (N): 36 44Mean time to healing (days): 57.7 (19.6 SD) 66.2 (26.1 SD) –8.5 (–18.97, 1.97)Traditional therapy: Gauze dressing soaked in chlorhexidine (Hibitane ® )Wound type: Pilonidal sinusesFollow-up time: Until all wounds had healedWalker et al., 1991 36Comparison: Traditional vs. Silicone foam(Silastic Foam)Mean baseline area (cm 2 ): Not stated Not statedSample size (N): 41 34Pilonidal sinus 21 17Abscess 20 17Mean time to healing (days):Pilonidal sinus 33 (range, 20–46) 30 (range, 21–39) 3.0Abscess 39.6 (range, 27–53) 39.8 (range, 26–54) –0.2Traditional therapy: Gauze dressing soaked in EusolWound type: Surgical wounds (pilonidal sinus and abscess)Follow-up time: Until all wounds had healedSchmidt & Greenspoon, 1991 38Comparison: Traditional vs. Aloe veraMean baseline area (cm 2 ): Not stated Not statedSample size (N): 8 13Vertical incisions 5 8Transverse incisions 3 5Mean time to healing (days): 53 (24 SD) 83 (28 SD) –30 (–55.01, –4.99)Vertical incisions 47 (18 SD) 84 (27 SD) –37 (–67.26, –6.74)Transverse incisions 53 (24 SD) 83 (35 SD) –30 (–86.76, 26.76)Traditional therapy: Wet-to-dry dressingsWound type: Surgical woundsFollow-up time: Until all wounds had healedSilastic Foam ® , Calmic Medical Division,Wellcome FoundationHibitane ® , Zeneca–40 –20 0 20 40–4 –2 0 2 4Favours traditionalFavours treatmentOR(95% CI)ES(95% CI)12FIGURE 1 Dressings and topical agents compared with traditional treatments for healing surgical wounds. Study resultsare presented as OR and/or effect size (ES) enclosed by their 95% CI. A single arrow by a trial indicates that the results werebiased by poor comparability between groups for wound size at baseline; the direction of the arrow suggests which interventionwas favoured by the bias. Convergent arrows suggest that the groups were reasonably comparable for wound size, whiledivergent arrows indicate that the bias could not be determined from the data presented

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Butterworth et al., 1992 37Comparison: Polyurethane vs. Silicone foamfoam dressing (Silastic Foam)(Allevyn ® )Mean baseline area (cm 2 ): 12.60 11.78Mean baseline volume (cm 3 ): 32.76 31.81Sample size (N): 40 40Pilonidal sinus 30 32Abdominal wounds 10 8No. of wounds healed (n/N):Pilonidal sinus 29/30 (97%) 29/32 (91%) 0.33 (0.033, 3.40)Abdominal wounds 8/10 (80%) 8/8 (100%) 5.00 (0.21, 120.54)Mean time to healing (days):Pilonidal sinus 51.4 (20.9 SD) 61.9 (26.1 SD) –10.5 (–22.94, 1.94)Abdominal wounds 51.9 (20.5 SD) 56.6 (37.6 SD) –4.70 (–37.18, 27.78)Wound type: Surgical wounds (pinonidal sinus and abdominal)Follow-up time: Until all wounds had healedAllevyn ® , Smith & Nephew Healthcare Ltd0.01 0.1 1 10 100–40 –20 0 20 40Favours AllevynFavours Silastic FoamOR(95% CI)ES(95% CI)FIGURE 2 Various dressings for healing pilonidal sinusesTreatments for pressure soresA single trial compared a topical agent with nodirect treatment, six studies compared a topicalagent with a placebo, three studies directly compareddifferent topical agents and five trialscompared a topical agent with a dressing. Inaddition nine studies (11 reports) that compareda dressing with a traditional treatment wereincluded, and a further seven trials were headto-headcomparisons between dressings.Topical agents versus no treatmentThe incremental benefit of topical insulin inaddition to routine supportive nursing care wasassessed in a single trial 39 (appendix 7, Table 10 ).The routine care given to patients included:position changes, increased fluid intake, a highprotein diet and local massage. The statisticalanalysis presented indicates that the addition ofinsulin resulted in a significant improvement inboth the healing rate and the number of days thattreatment was required. However, this trial wassmall and the primary data were not presented.Topical agents versus placeboSix studies compared a topical agent with aplacebo: one assessed an active cream, onlyreferred to as F14001 40 (formulation not stated butcontains a barley plant extract), another assessedketanserin 41 (Figure 3; appendix 7, Table 11 ), andfour evaluated biologically active agents, which withthe exception of one trial, 42 were growth factors 43–45(Figure 4; appendix 7, Table 11).A statistically significant improvement in outcomewas observed only when active cream F14001 wascompared with placebo; the active cream showeda significantly faster healing rate than placebo. 40The other studies were too small to detect astatistically significant difference.Topical agent versus topical agentAll three trials included in this category comparedbiologically active topical agents; two were comparisonsof growth factors given at differentconcentrations, 43,45 while the third compareddifferent doses of the cytokine interleukin1-beta 42 (Figure 5; appendix 7, Table 11 ).Recombinant platelet-derived growth factor(r-PDGF-BB) given at 100 µg/ml resulted ina statistically significant reduction in woundvolume when compared with a concentrationof 10 µg/ml, but not when compared with1 µg/ml. 45 There was no statistically significantdifference between treatment with concentrationsof 10 µg/ml and 1 µg/ml. 46 These inconsistentresults may be due to random variation reflectingthe small sample size, which never exceeded13

ResultsLe Vasseur & Helme, 1991 40Comparison: Placebo vs. Active cream F14001Mean baseline area (cm 2 ): 9.0 (2.0 SD) 9.6 (3.9 SD)Sample size (N): 13 8Mean time to healing (days): 29.1 (3.6 SD) 18.4 (4.4 SD) 10.7 (7.02, 14.38)Placebo therapy: Placebo creamWound type: Pressure sores (grade II)Follow-up time: 6 weeksTytgat & Van Asch, 1988 41Comparison: Placebo vs. KetanserinMean baseline area (cm 2 ): 8.6 11.5Sample size (N): 8 8% reduction in wound area: 16 81 65Placebo:Placebo ointmentWound type: Pressure sores (grade II or III)Follow-up time: 8 weeks–70 –35 0 35 70ES(95% CI)Favours placeboFavours topical agentFIGURE 3 Topical agents compared with placebo formulations for healing pressure sores14more than five patients in each arm. A further trialfound no statistically significant difference betweenconcentrations of 300 µg/ml and 100 µg/ml of thesame growth factor. 43No statistically significant difference in healingrate was found between comparisons of interleukin1-beta given at different concentrations. 42Topical agents versus dressingsFive trials that met the inclusion criteria compareda topical agent with a dressing. 46–50 Threetrials compared a hydrocolloid with a hydrogel 46–48(Figure 6; appendix 7, Table 12), and two studiescompared polysaccharide beads with eithera calcium alginate dressing 49 or a collagensponge dressing 50 (Figure 7; appendix 7,Table 12 ).One hydrogel resulted in more pressure soresbeing completely healed when compared witha hydrocolloid dressing. 47 However, a smaller,more recent trial, which compared a hydrogelwith a modified version of the previous hydrocolloid,found no statistically significant differencein healing rate between the two groups. 48A further comparison of a hydrogel with thesame modified hydrocolloid, reported insufficientdata to estimate 95% confidence intervals (CIs)and statistical analysis was therefore not possible. 46As these trials either provided insufficientdata or used different outcome measures (i.e.proportion healed and healing rate), it wasnot possible to pool them.In both comparisons between a polysaccharidedressing and an alternative dressing, the ORsindicated a benefit for the alternative treatment.However, this only reached statistical significancein the comparison with calcium alginatedressings. 49Dressings versus traditional treatmentFive trials (six reports) meeting the inclusioncriteria compared a hydrocolloid with a traditionaltreatment (Figure 8; appendix 7, Table 13). In fourof the trials (five reports), the traditional treatmentcomprised saline soaked gauze, 51–55 while in thefifth, wet-to-dry dressings and Dakin’s solutionwere employed. 56Three of the trials found that treatment with thehydrocolloid dressing resulted in a statisticallysignificant increase in the number of woundshealed, 51,54,56 while two found no statisticallysignificant difference between treatments. 52,53,55Pooling the five trials (χ 2 = 5.76, df = 4) indicatedthat the hydrocolloid dressings increased the oddsof healing by three-fold (OR, 2.57; 95% CI,1.58–4.18).

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Mustoe et al., 1994 43Comparison: Placebo vs. r-PDGF-BB, 100 µg/mlMean baseline volume (cm 3 ): 10.8 (13.2 SD) 5.5 (6.1 SD)Sample size (N): 14 15No. of wounds healed (n/N): 3/14 (21%) 2/15 (13%) 0.56 (0.08, 4.01)% reduction in wound volume: 20 71 51Comparison: Placebo vs. r-PDGF-BB, 300 µg/mlMean baseline volume (cm 3 ): 10.8 (13.2 SD) 7.1 (8.8 SD)Sample size (N): 14 12No. of wounds healed (n/N): 3/14 (21%) 0/12 (0%) 0.13 (0.006, 2.83)% reduction in wound volume: 20 60 40Placebo therapy: Not statedWound type: Pressure sores (grade III or IV)Follow-up time: 4 weeksRobson et al., 1992 45Comparison: Placebo vs. r-PDGF-BB, 100 µg/mlMean baseline volume (cm 3 ): 12.9 (3.8 SEM) 11.6 (5.5 SEM)Sample size (N): 7 5% reduction in wound volume: 78.2 (5.6 SEM) 93.5 (4.0 SEM) 15.3 (–1.39, 31.99)Comparison: Placebo vs. r-PDGF-BB, 10 µg/mlMean baseline volume (cm 3 ): 12.9 (3.8 SEM) 15.8 (4.0 SEM)Sample size (N): 7 4% reduction in wound volume: 78.2 (5.6 SEM) 55 (15.0 SEM) –23.2 (–53.15, 6.75)Comparison: Placebo vs. r-PDGF-BB, 1 µg/mlMean baseline volume (cm 3 ): 12.9 (3.8 SEM) 13.8 (4.8 SEM)Sample size (N): 7 4% reduction in wound volume: 78.2 (5.6 SEM) 63 (15.0 SEM) –15.2 (–45.15, 14.75)Placebo therapy: Not statedWound type: Pressure sores (grade III or IV)Follow-up time: 4 weeksRobson et al., 1992 44Comparison: Placebo vs. r-bFGF, 100, 500, 1000 µg/mlMean baseline volume (cm 3 ): Not stated Not statedSample size (N): 14 35No. of wound reduced by ≥ 70% (n/N): 4/14 (29%) 21/35 (60%) 3.75 (0.98, 14.36)% reduction in wound volume: 59 69 10Placebo therapy: Not statedWound type: Pressure sores (grade III or IV)Follow-up time: 22 daysRobson et al., 1994 42Comparison: Placebo vs. Interleukin 1-beta, 1 µg/cm 2Mean baseline volume (cm 3 ): Not stated Not statedSample size (N): 6 6% reduction in wound volume: 75 58 –17Comparison: Placebo vs. Interleukin 1-beta, 0.1 µg/cm 2Mean baseline volume (cm 3 ): Not stated Not statedSample size (N): 6 6% reduction in wound volume: 75 75 0Comparison: Placebo vs. Interleukin 1-beta, 0.01 µg/cm 2Mean baseline volume (cm 3 ): Not stated Not statedSample size (N): 6 6% reduction in wound volume: 75 68 7Placebo therapy: Not statedWound type: Pressure sores (grade III or IV)Follow-up time: 4 weeks0.01 0.1 1 10 100–60 –30 0 30 60Favours placeboFavours treatmentOR(95% CI)ES(95% CI)FIGURE 4 Biologically active dressings compared with placebo formulations for the healing of pressure sores15

ResultsMustoe et al., 1994 43Comparison: r-PDGF-BB, vs. r-PDGF-BB,100 µg/ml 300 µg/mlMean baseline volume (cm 3 ): 5.5 (6.1 SD) 7.1 (8.8 SD)Sample size (N): 15 12No. of wounds healed (n/N): 2/15 0/12 0.22 (0.01, 4.95)% reduction in wound volume: 71 60 11Wound type: Pressure sores (grade III or IV)Follow-up time: 4 weeksRobson et al., 1992 45Comparison: r-PDGF-BB, vs. r-PDGF-BB,10 µg/ml 100 µg/mlMean baseline volume (cm 3 ): 15.8 (4.0 SEM) 11.6 (5.5 SEM)Sample size (N): 4 5% reduction in wound volume: 55 (15 SEM) 93.5 (4.0 SEM) 38.5 (5.55, 71.45)Comparison: r-PDGF-BB, vs. r-PDGF-BB,1 µg/ml 100 µg/mlMean baseline volume (cm 3 ): 13.8 (4.8 SEM) 11.6 (5.5 SEM)Sample size (N): 4 5% reduction in wound volume: 63 (15 SEM) 93.5 (4.0 SEM) 30.5 (–2.45, 63.45)Comparison: r-PDGF-BB, vs. r-PDGF-BB,1 µg/ml 10 µg/mlMean baseline volume (cm 3 ): 13.8 (4.8 SEM) 15.8 (4.0 SEM)Sample size (N): 4 4% reduction in wound volume: 63 (15 SEM) 55 (15.0 SEM) 8.0 (–43.91, 59.91)Wound type: Pressure sores (grade III or IV)Follow-up time: 4 weeksRobson et al., 1994 42Comparison: Interleukin vs. Interleukin1-beta,1-beta,0.1 µg/cm 2 1 µg/cm 2Mean baseline volume (cm 3 ): N/A N/ASample size (N): 6 6% reduction in wound volume: 75 58 –17Comparison: Interleukin vs. Interleukin1-beta,1-beta,0.01 µg/cm 2 1 µg/cm 2Mean baseline volume (cm 3 ): N/A N/ASample size (N): 6 6% reduction in wound volume: 68 58 –10Comparison: Interleukin vs. Interleukin1-beta,1-beta,0.1 µg/cm 2 0.1 µg/cm 2Mean baseline volume (cm 3 ): N/A N/ASample size (N): 6 6% reduction in wound volume: 68 75 –7Wound type: Pressure sores (grade III or IV)Follow-up time: 4 weeks0.01 0.1 1 10 100–40 –20 0 20 40Favours lower doseFavours higher doseOR(95% CI)ES(95% CI)16FIGURE 5 Comparisons of biologically active agents for healing pressure sores

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Brown-Etris et al., 1996 46Comparison: Hydrogel vs. Hydrocolloid(Transorbent ® ) (Granuflex ® CGF)Mean baseline area (cm 2 ): Not stated Not statedSample size (N): 77 63No. of wounds healed (n/N): 39/77 (51%) 37/63 (59%) 1.39 (0.71, 2.72)Absolute reduction in woundarea (cm 2 ):Grade II (2–30 cm 2 ) 3.6 2.3 –1.3Grade III (2–30 cm 2 ) 6.3 5.2 –1.1Grade III (31–80 cm 2 ) 24.5 4.3 –20.2Wound type: Pressure sores (grade II or III)Follow-up time: 10 weeksDarkovich et al., 1990 47Comparison: Hydrogel vs. Hydrocolloid(Biofilm ® )(Granuflex standard)Mean baseline area (cm 2 ): 11.0 (range, 0.2–100) 9.2 (range, 0.4–64)Sample size (N): 60 63No. of wounds healed (n/N): 27/60 (45%) 14/63 (22%) 0.41 (0.19, 0.89)% reduction in wound area (cm 2 ): 68 40 –28Absolute reduction in woundarea (cm 2 ): 7.5 3.7 –3.8Wound type: Pressure soresFollow-up time: 60 daysMulder et al., 1993 48Comparison: Hydrogel vs. Hydrocolloid(Clearsite ® ) (Granuflex CGF)Mean baseline area (cm 2 ): Not stated Not statedSample size (N): 20 20Mean % reduction in woundarea/week (cm 2 ): 8 (14.8 SD) 3.3 (32.7 SD) –4.7 (–20.95, 11.5)Median % reduction in woundarea/week (cm 2 ): 5.6 7.4 1.8Wound type: Pressure soresFollow-up time: 8 weeksTransorbent ® , Braun MedicalGranuflex ® CGF, ConvaTec LtdBiofilm ® , Biotrol, distributed by Clini Med LtdClearsite ® , New Dimension in Medicine0.01 0.1 1 10 100 OR(95% CI)ES–40 –20 0 20 40–10 –5 0 5 10Favours hydrogelFavours Granuflex(95% CI)ES(95% CI)FIGURE 6 Granuflex dressings compared with hydrogels for healing pressure soresA further four trials (five reports) were includedthat compared a dressing with a traditional formof treatment. 57–61 Only one of the trials found astatistically significant difference between treatments(Figure 9; appendix 7, Table 13). This trialshowed that absorption dressings resulted in aquicker reduction in wound depth, but not inwound length when compared with treatmentwith povidone iodine. 60Dressings versus dressingsFour trials compared the same hydrocolloidwith a polyurethane dressing. 62–65 No statisticallysignificant difference was found between thesetreatments either when considered individuallyor pooled (Figure 10 ; appendix 7, Table 14).In addition, no statistically significant differencewas observed between hydrocolloid dressings17

ResultsSayag et al., 1996 49Comparison: Dextranomer vs. Calcium alginate(Debrisan) (Algoseril ® )Mean baseline area (cm 2 ): 16.1 (12.5 SD) 20.1 (12.9 SD)Sample size (N): 45 47No. of wounds reduced by40–100% in area: 19 35 4.00 (1.65, 9.65)No. of wounds reduced by> 75% in area: 6 15 3.05 (1.06, 8.76)Wound type:Follow-up time:Pressure soresUntil the wound reached 40% of its originalsize or on completion of 8 weeks’ treatmentPalmieri, 1992 50Comparison: Dextranomer vs. Collagen sponge(Debrisan)Mean baseline area (cm 2 ): Not stated Not statedSample size (N): 12 12Mean time to healing (days): 47 20 27Wound type: Pressure soresFollow-up time: Until all wound had healedAlgosteril ® , Les Laboratories Brothier0.01 0.1 1 10 100 OR(95% CI)ES–40 –20 0 20 40 (95% CI)Favours dextranomer Favours alternative dressingFIGURE 7 Calcium alginate and collagen sponge dressings compared with topical dextranomer for the healing of pressure sores18(Granuflex and Comfeel) and either a polyhydroxyethylmethacrylate, 66 or an amino acidcopolymer membrane, 67 (Figure 11; appendix 7,Table 14). Similarly there was no statistical differencebetween a semipermeable adhesive dressingand a polyurethane foam dressing 68 (Figure 10;appendix 7, Table 14 ).Treatments for leg ulcersThree trials evaluated primary dressings ortopical agents in the treatment of arterial legulcers: hydrocolloid dressing versus a lowadherent dressing, 69 mononuclear culturedcells versus placebo, 70 and ketanserin versusvehicle alone. 71Twelve trials studied patients with ulcers ofdiverse aetiologies without presenting the resultsaccording to the leg ulcer aetiology. Three trials(seven reports) compared a ‘modern’ dressingwith a traditional dressing, five trials (six reports)compared topical agents with a placebo or traditionaltreatments, three trials were head-to-headcomparisons of dressings, and one trial compareda topical agent with a dressing.Fifty-one trials of dressings and topical agents forvenous leg ulcers were identified. Eighteen trialscompared dressings with traditional treatments(normally gauze-type dressings). Ten trials comparedtwo or more dressings, and seventeen compareda topical preparation with a control. Threetrials compared dressings with topical preparationsand three reported head-to-head comparisons oftopical agents.The majority of trials had methodological weaknesses(appendix 5, Table 6). Fewer than 9% ofstudies reported an a priori estimate of the numberof participants required for the trial to have sufficientpower to detect a clinical difference as statisticallysignificant. The median number of woundsrecruited to a trial was 48.5 (range, 9–233). Blindingof investigators at outcome assessment was reportedin fewer than 7% of trials. One or more patientcharacteristics were recorded by treatment groupin 36 out of 48 (75%) studies, but wound size atbaseline (by group) was reported in only 30 of the48 (62%) studies. Withdrawals occurred in mosttrials and the number and cause were recorded bygroup in 46% of trials where it was appropriate,but only 18% performed an ITT analysis. Sixty-twoper cent described relevant inclusion criteria, but

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Alm et al., 1989 51Comparison: Traditional vs. Hydrocolloid (Comfeel ® )Mean baseline area (cm 2 ): 2.44 2.02Sample size (N): 31 25No. of wounds healed (n/N): 5/31 (16%) 11/25 (44%) 4.09 (1.18, 14.14)Median absolute reductionin wound area (cm 2 ): 1.8 2.0 0.2% reduction in wound area: 68 100 32Traditional therapy: Saline gauzeWound type: Pressure soresFollow-up time: 6 weeksBarrois, 1993; 52 Huchon, 1992 53Comparison: Traditional vs. Hydrocolloid(Granuflexstandard)Mean baseline area (cm 2 ): Not stated Not statedSample size (N): 38 38No. of wounds healed (n/N): 9/38 (24%) 10/38 (26%) 1.15 (0.41, 3.26)% reduction in wound area/week: 7 10 3.00Traditional therapy: Tulle gauze impregnated with povidone-iodineWound type: Pressure soresFollow-up time: 8 weeksColwell et al., 1993 54Comparison: Traditional vs. Hydrocolloid (Granuflex)Mean baseline volume (cm 3 ): 2.4 2.3Sample size (N): 49 48No. of wounds healed (n/N): 1/49 (3%) 11/48 (23%) 14.27 (1.76, 115.56)Traditional therapy: Saline-soaked gauzeWound type: Pressure sores (grade II or III)Follow-up time: 8 weeksGorse & Messner, 1987 56Comparison: Traditional vs. HydrocolloidMean baseline area (cm 2 ): Not stated Not statedSample size (N): 52 (25 patients) 76 (27 patients)No. of wounds healed (n/N): 26/52 (50%) 54/76 (71%) 2.46 (1.18, 5.12)Mean time to healing (days): 10 8.7 1.30Traditional therapy: Wet-to-dry dressings and Dakin’s solutionWound type: Pressure sores (grade II, III or IV)Follow-up time: 75 daysXakellis & Chrischilles, 1992 55Comparison: Traditional vs. HydrocolloidMedian baseline area (cm 2 ): 0.38 0.66Sample size (N): 21 18No. of wounds healed (n/N): 18/21 (86%) 16/18 (89%) 1.33 (0.20, 9.02)Median time to healing (days): 11 9 2Traditional therapy: Saline gauzeWound type: Pressure sores (grade II or III)Follow-up time: 75 daysPooled estimate (fixed-effects model)Comparison: Traditional vs. HydrocolloidTotal no. of wounds healed (n/N): 59/191 (31%) 102/205 (50%) 2.57 (1.58, 4.18)χ 2 = 5.76; df = 4; z = 3.87; p = 0.2180.01 0.1 1 10 100 OR(95% CI)ES–4 –2 0 2 4 (95% CI)–40 –20 0 20 40ES(95% CI)Comfeel ® , Coloplast LtdFavours traditionalFavours hydrocolloidFIGURE 8 Hydrocolloid dressings compared with traditional treatments for the healing of pressure sores19

ResultsOleske et al., 1986 57Comparison: Traditional vs. Polyurethane dressing (Opsite)Mean baseline area (cm 2 ): 12.67 (11.28 SD) 3.9 (0.73 SD)Sample size (N): 6 (6 patients) 7 (5 patients)% reduction in wound area: 26.67 (44.3 SD) 49 (37.31 SD) 22.3 (–27.43, 72.09)Absolute reduction in woundarea (cm 2 ): 2.5 (5.54 SD) 1.8 (1.30 SD) –0.7 (–5.42, 4.02)Traditional therapy:Wound type:Follow-up time:Saline-soaked gauzePressure sores (grade II)10 daysSebern, 1986; 58 1989 59Comparison: Traditional vs. Polyurethane dressing(vapour permeable)Median baseline area (cm 2 ):Grade II 3.4 1.9Grade III 4.5 6.1Sample size (N):Grade II 30 59Grade III 70 41Median % reduction in wound area:Grade II 52 100 48Grade III 44 67 23Traditional therapy:Wound type:Follow-up time:Saline gauzePressure sores (grade II or III)8 weeksSaydak, 1990 60Comparison: Traditional vs. Absorption dressingMean baseline depth (cm): 1.23 (1.05 SD) 1.27 (1.16 SD)Mean baseline length (cm): 5.7 (4.6 SD) 7.5 (4.95 SD)Sample size (N): 11 11% reduction in wound depth: 5.5 (68 SD) 54.2 (26.5 SD) 48.7 (2.8, 94.60)% reduction in wound length: 4.9 (21.1 SD) 13.5 (22.9 SD) 8.6 (–10.98, 28.18)Traditional therapy:Wound type:Follow-up time:Providone-iodinePressure sores8 weeksKraft et al., 1993 61Comparison: Traditional vs. Foam dressing (Epi-Lock ® )Mean baseline area (cm 2 ): Not stated Not statedSample size (N): 14 24No. of wounds healed (n/N): 3/14 (21%) 10/24 (42%) 2.62 (0.58, 11.89)Traditional therapy:Wound type:Follow-up time:Saline-soaked gauzePressure sores (grade II or III)12 weeksEpi-Lock ® ,0.01 0.1 1 10 100 OR(95% CI)ES–60 –30 0 30 60 (95% CI)Favours traditionalFavours treatment20FIGURE 9 Dressings compared with traditional treatments for healing pressure sores

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Bale et al., 1995 63Comparison: Polyurethane vs. Hydrocolloiddressing (Granuflex E ® )(Allevyn)Mean baseline area (cm 2 ): Not stated Not statedSample size (N): 17 15No. of wounds healed (n/N): 10/17 (59%) 4/15 (27%) 0.25 (0.06, 1.14)Wound type: Pressure soresFollow-up time: 8 weeksBanks et al., 1994 64Comparison: Polyurethane vs. Hydrocolloiddressing (Granuflex E)(Spyrosorb ® )Mean baseline area (cm 2 ): 1.47 1.51Sample size (N): 20 20No. of wounds healed (n/N): 12/20 10/20 0.67 (0.19, 2.33)Wound type: Pressure sores (grade II or III)Follow-up time: 6 weeksBanks et al., 1994 63Comparison: Polyurethane vs. Hydrocolloiddressing (Granuflex E)(Spyrosorb)Mean baseline area (cm 2 ): 1.4 2.4Sample size (N): 13 16No. of wounds healed (n/N): 10/13 (77%) 11/16 (69%) 0.70 (0.12, 3.50)Mean time to healing (days): 13.4 12.7 –0.7Wound type: Pressure sores (grade II or III)Follow-up time: 6 weeksBanks et al., 1996 65Comparison: Polyurethane vs. Hydrocolloiddressing (Granuflex E)(Tielle ® )Mean baseline area (cm 2 ): 2.63 2.86Sample size (N): 49 49No. of wounds healed (n/N): 12/50 (24%) 15/49 (31%) 1.32 (0.54, 3.21)% reduction in wound area: 115.4 105 10.4Wound type: Pressure sores (grade II or III)Follow-up time: 6 weeksPooled estimate (fixed-effects model)Comparison: Polyurethane vs. Hydrocolloiddressing (Granuflex E)Total no. of wounds healed (n/N): 40/100 (40%) 44/100 (44%) 0.80 (0.44, 1.44)χ 2 = 3.89; df = 3; z = 0.76; p = 0.274Banks et al., 1994 68Comparison: Polyurethane vs. Semi-permeable dressingdressing(Tegaderm)(Lyofoam)Baseline area (cm 2 ) * :< 1 cm 11 12> 1 cm, < 2.5 cm 2 2> 2.5 cm 6 1Sample size (N): 26 24No. of wounds healed (n/N): 19/26 (73%) 15/24 (63%) 0.61 (0.19, 2.03)Wound type: Pressure sores (grade II or III)Follow-up time: 12 weeks* Date only available for patients completing the trial0.01 0.1 1 10 100 OR(95% CI)ES–4 –2 0 2 4 (95% CI)ESGranuflex E ® , ConvaTec Ltd–20 –10 0 10 20 (95% CI)Spyrosorb ® , C.V. Laboratories LtdTielle ® , Johnson & Johnson Medical LtdFavours polyurethanedressingFavours Granuflex/Tegaderm dressingFIGURE 10 Dressings compared with polyurethane dressings for healing pressure sores21

ResultsBrod et al., 1990 66Comparison: Poly-hema vs. Hydrocolloid(Granuflex standard)Mean baseline area (cm 2 ): 2.5 1.9Sample size (N): 27 16No. of wounds healed (n/N): 14/27 (52%) 9/16 (56%) 1.20 (0.34, 4.14)Median time to healing (days): 32 42 –10Absolute healing rate (cm 2 /week): 0.18 0.1 –0.08Poly-hema:Polyhydroxyethyl methacrylateWound type: Pressure sores (grade II or III)Follow-up time: Until all wounds had healedHondé et al., 1994 67Comparison: Amino acid vs. Hydrocolloidcopolymer(Comfeel)(Inerpan ® )Mean baseline area (cm 2 ): 8.99 6.85Sample size (N): 80 88No. of wounds healed (n/N): 31/80 (39%) 23/88 (26%) 0.56 (0.29, 1.08)Mean time to healing (days): 32 42 –6Inerpan:Amino acid copolymer membraneWound type: Pressure sores (grade II, III or IV)Follow-up time: 8 weeksInerpan ® , Synthelabo0.01 0.1 1 10 100 OR(95% CI)ES–40 –20 0 20 40 (95% CI)ES–0.2 –0.1 0 0.1 0.2 (95% CI)Favours alternativeFavours hydrocolloidFIGURE 11 Hydrocolloid dressings compared with alternative treatments for healing pressure sores22information which indicated that participants hadbeen randomised with allocation concealment wasgiven in only 10% of trials.Arterial leg ulcersDressing versus traditional or controlGibson and co-workers 69 compared a hydrocolloiddressing with a knitted viscose dressing. There wasno difference in healing rates but patients withdrewearlier from the knitted viscose dressing group thanthe hydrocolloid group due to pain (9/9 patientswithdrew in a mean of 19 days in the knitted viscosegroup compared with 4/5 withdrawals due to painand maceration in the hydrocolloid group (meantime to withdrawal, 104 days) (appendix 8, Table 15).Topical agents versus placeboHolzinger and co-workers 70 compared mononuclearcultured cells in a culture medium withthe culture medium alone. There was astatistically significant improvement in theproportion of arterial ulcers healing duringthe trial period in the group treated with thecultured monocytes (appendix 8, Table 16).Janssen 71 compared topical ketanserin with aplacebo. There was a significantly higher rateof epithelialisation in the ketanserin group,but insufficient data on baseline size were givento allow any bias to be assessed. There wereno data on the number of ulcers completelyhealed in the trial period (appendix 8,Table 16).Undifferentiated leg ulcersThirteen trials studied patients with ulcers ofdiverse aetiologies without presenting the resultsaccording to the leg ulcer aetiology.

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Dressing versus controlThree trials (seven reports) compared an interactivedressing with a traditional dressing. 72–78 Inthe one trial 72–75 comparing a hydrocolloid withsaline gauze, a higher proportion of ulcers healedbeneath the hydrocolloid (47% versus 13%), butthis was not statistically significant (OR for healing,5.7; 95% CI, 0.94–34.4). Mian and co-workers 76,77reported a larger reduction in the wound areaunder collagen sponges but there were insufficientdata to determine the significance of this result.Another comparison between a film and a salinegauze dressing found no significant effect ofdressings on healing 78 (appendix 9, Table 17).Dressing versus dressingFour trials were head-to-head comparisonsbetween dressings. Brandrup and co-workers 79reported a larger percentage reduction inwound area under adhesive zinc oxide tape in acomparison with hydrocolloid dressings, but therewere insufficient data to determine the significanceof this result. A comparison between alginate andhydrocolloid fibrous dressings found no difference.80 Palmieri 50 compared a collagen spongedressing with dextranomer and found no differencein healing rates. There was no differencein healing rates between a hydrocellular foamand a hydrocolloid 62 (appendix 9, Table 18).Topical agents versus control/traditional treatmentsFour trials compared topical agents with aplacebo, or traditional treatment. Platelet-derivedwound healing factor, 81,82 zinc oxide paste 83 andhyaluronic acid 84 were all found to heal a significantlygreater proportion of ulcers over the trialperiod, but in each case the wound size bias atbaseline favoured the experimental treatmentgroup. No differences were detected in healingrates in a comparison between various treatments(including low adherent dressings and hydrocolloids)and fibrin glue 85 (appendix 9,Table 19).Topical agents versus dressingsA single comparison of a growth hormone anda hydrocolloid dressing versus a hydrocolloiddressing alone found no difference in healingrates 86 (appendix 9, Table 20).Venous leg ulcersForty-eight trials were identified: 21 trials reported32 unique comparisons and 25 trials reportedreplicated comparisons.Modern dressing versus traditionaltreatmentEighteen trials compared dressings with traditionaltreatments (usually gauze-type dressings). Three trialsreported the results of five ‘unique’ comparisons:• activated charcoal and silver versus gauze 87• alginate dressing versus knitted viscose dressing 88• alginate versus zinc oxide stockinette 89• alginate versus zinc oxide cottongauze bandage 89• zinc oxide stockinette versus zinc oxidecotton gauze bandage. 89The comparisons between alginate versus knittedviscose dressing, 88 activated charcoal and silverdressing, 87 and alginate against stockinette impregnatedwith zinc oxide paste 89 found no differencein proportion of ulcers healed over the trial period.However, Stacey and co-workers 89 did report thata cotton bandage impregnated with zinc oxidepaste healed a higher proportion of ulcers overthe trial period than either an alginate dressing ora zinc oxide-impregnated stockinette (Figure 12;appendix 10, Table 21).Two trials compared foam dressings withtraditional or control therapies. 90–92 One trial 91,92found a reduction in wound area with a polyurethanefoam dressing, which contrasted with anet increase in mean wound size under a sterilegauze compress. In the other trial 90 there was nosignificant difference in the proportion of ulcershealed using a hydrocellular foam compared witha knitted viscose dressing during the trial period(Figure 13; appendix 10, Table 21).Two papers report comparisons between semipermeablefilm dressings and traditional orcontrol therapies. 93,94 One trial 93 found a significantlygreater reduction in wound area under afilm dressing compared with treatment with anUnna’s Boot (zinc oxide, calamine and gelatinpaste) bandage. The other trial 94 found nosignificant difference in the proportion of ulcershealed either with a film dressing or paraffinimpregnatedtulle (Figure 13; appendix 10,Table 21).Nine trials compared hydrocolloid dressingswith traditional or control dressings. 95–104 Of thesenine trials, only one found a statistically significantincrease in the proportion of ulcers healed overthe trial period; this was for a comparison betweena hydrocolloid dressing and paraffin-impregnatedtulle. The groups in this trial, however, were notcomparable at baseline, with larger ulcers being23

ResultsMoffatt et al., 1992 88Comparison: Traditional vs. Alginate dressing (Tegagel ® )Median baseline area (cm 2 ): 6.4 3.6(range, 1.1–9.9) (range, 0.9–9.8)Sample size (N): 30 30No. of wounds healed (n/N): 24/30 26/30 1.62 (0.4, 6.5)Traditional dressing: Knitted viscose dressing (N-A ® )Wound type: Venous leg ulcersFollow-up time: 12 weeksWunderlich & Orfanos, 1991 87Comparison: Traditional vs. Activated charcoal andsilver dressing (Actisorb ® )Mean baseline area (cm 2 ): 2 3Sample size (N): 19 19 3.9 (0.67, 22.7)No. of wounds healed (n/N): 2/19 6/19 10% reduction in wound area: 65 75Traditional dressing:Wound type:Follow-up time:Paraffin gauzeVenous leg ulcers6 weeksStacey et al., 1992 89Comparison: Zinc bandage vs. Zinc stockinetteMean baseline area (cm 2 ): 10.8 9.9(range, 1.5–57.5) (range, 3.6–61.3)Sample size (N): 43 44 1.83 (0.78, 4.28)No. of wounds healed (n/N): 25/43 19/44Wound type:Follow-up time:Venous leg ulcers9 monthsComparison: Zinc bandage vs. AlginateMean baseline area (cm 2 ): 10.8 10.7(range, 1.5–57.5) (range, 2.4–75.4)Sample size (N): 43 46 2.6 (1.1, 6.14)No. of wounds healed (n/N): 25/43 16/46Wound type:Follow-up time:Venous leg ulcers9 monthsComparison: Zinc vs. AlginatestockinetteMean baseline area (cm 2 ): 9.9 10.7(range, 3.6–61.3) (range, 2.4–75.4)Sample size (N): 44 46 1.42 (0.61, 3.34)No. of wounds healed (n/N): 19/44 16/46Wound type:Follow-up time:Venous leg ulcers9 monthsTegagel ® , 3M LtdN-A ® , Johnson & Johnson Medical LtdActisorb ® , Johnson & Johnson Medical Ltd0.01 0.1 1 10 100 OR(95% CI)ES–40 –20 0 20 40 (95% CI)Favours traditional dressingFavours modern dressing24FIGURE 12 Modern compared with traditional dressings for venous leg ulcers

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Pessenhoffer & Stangl, 1989; 91 1992 92Comparison: Traditional vs. Foam (Lyomousse ® )Median baseline area (cm 2 ): 11.7 (24.24 SD) 10.8 (17.4 SD)Sample size (N): 23 25Mean % change in woundarea (no. of wounds remaining): +78.3 (17) –65.6 (24) 144 (48.8, 239)Traditional dressing: Sterile gauze compressWound type: Venous leg ulcersFollow-up time: Up to 281 daysCallam et al., 1992 90Comparison: Traditional vs. Foam (Allevyn)Mean baseline area (cm 2 ): 8.35 10.87Sample size (N): 66 66No. of wounds healed: 23/66 (35%) 31/66 (47%) 1.67 (0.8, 3.3)Traditional therapy: Knitted viscose dressingWound type: Venous leg ulcersFollow-up time: 12 weeksDavis et al., 1992 93Comparison: Traditional vs. Film (Tegaderm/Bioclusive ® )Mean baseline area (cm 2 ): Not stated Not statedSample size (N): 6 patients 5 patientsMean % reduction in wound area: 7.1 (n = 7) 39.26 (n = 5) 32.15 (10.18, 54.12)Traditional dressing: Unna’s BootWound type: Venous leg ulcersFollow-up time: 6 monthsBanerjee et al., 1990 94Comparison: Traditional vs. Film (Synthaderm ® )Mean baseline area (cm 2 ): Not stated Not statedSample size (N): 35 36No. of wounds healed (n/N): 8/35 11/36 1.48 (0.5, 4.3)Traditional dressing: Saline-soaked gauzeWound type: Venous leg ulcersFollow-up time: 17 weeksLyomousse ® , (not distributed in the UK)Bioclusive ® , Johnson & Johnson Medical LtdSynthaderm ® , (not currently distributed)0.01 0.1 1 10 100 OR(95% CI)ES–400 –200 0 200 400 (95% CI)Favours traditionaldressingFavours semi-occlusivedressingFIGURE 13 Foam or film compared with control for venous leg ulcersallocated to the control group. The eight studiesthat provided data on the proportion of ulcerscompletely healed during the trial period werepooled using a random effects model. Therewas no significant difference in the proportionof ulcers healed at follow-up (pooled OR, 1.4;95% CI, 0.83–2.34) (Figure 14; appendix 10,Table 21). A random effects model was used toestimate the overall ES, as it assumes that variationin the meta-analysis is a combination of randomerror within studies and variation between studies.Random effects models are more conservativethan fixed effects models, giving estimates withwider CIs. As there was significant statisticalheterogeneity in this meta-analysis (χ 2 forheterogeneity, 16.72; df = 7; p = 0.019),a random effects model is appropriate.Sensitivity analysis was undertaken by furthermeta-analyses to explore what influence certainstudies had on the overall analysis. Excluding thetrial by Moffatt and co-workers, 97 in which theulcers were more chronic (inclusion criteriaincluded failure to heal with a four-layer regimenafter 24 weeks, or failure to reduce ulcer size bya minimum of 20% in 12 weeks), yielded an OR25

ResultsArnold et al., 1994 99Comparison: Hydrocolloid vs. TraditionalMean baseline area (cm 2 ): 21 (6.85 SEM) 19.83 (6.59 SEM)Sample size (N): 35 35% reduction in wound area: 7.1 (4.3 SD) 43 (7.1 SD) 28Time to healing (weeks): 7.1 (0.2 SEM) 8.2 (0.4 SEM) 1.1No. of wounds healed (n/N): 11/35 (31%) 14/35 (40%) 0.69 (0.26, 1.84)Traditional dressing: Paraffin gauze (USA);povidone-iodine-impregnated gauze (UK)Wound type: Venous leg ulcersFollow-up time: 8 weeksBackhouse et al., 1987 98Comparison: Hydrocolloid vs. Traditional(Granuflex)Median baseline area (cm 2 ): 3.4 (0.4 SD) 3.1 (0.4 SD)Sample size (N): 30 30No. of wounds healed (n/N): 21/30 (70%) 22/30 (73%) 0.85 (0.28, 2.61)Traditional dressing: Knitted viscose dressing (N-A)Wound type: Venous leg ulcersFollow-up time: 12 weeksMeredith & Gray, 1988 100Comparison: Hydrocolloid vs. Traditional(Granuflex)Mean baseline area (cm 2 ): 1.1 4.7Sample size (N): 25 24No. of wounds healed (n/N): 19/25 (76%) 6/24 (25%) 9.5 (2.58, 34.94)Traditional dressing: Paraffin-impregnated gauze (Jelonet)Wound type: Venous leg ulcersFollow-up time: 6 weeksNelson et al., 1995 96Comparison: Hydrocolloid vs. Traditional(Granuflex)Baseline area (cm 2 ): 9.14 11.24Sample size (N): 102 98No. of wounds healed (n/N): 49/102 (48%) 44/98 (45%) 1.13 (0.65, 1.98)Traditional dressing: Knitted viscose dressing (N-A)Wound type: Venous leg ulcersFollow-up time: 24 weeksSmith et al., 1992 95Comparison: Hydrocolloid vs. Traditional(Biofilm)Median baseline area (cm 2 ):Small ulcer (2–4 cm) 3.1 2.6Large ulcer (> 4 cm) 13.3 17.6Sample size (N): 99 101No. of wounds healed (n/N): 50/99 (51%) 47/101 (46%) 1.17 (0.67, 2.04)Traditional dressing: Povidone-iodine-impregnated tulleWound type: Venous leg ulcersFollow-up time: 12 weeks0.01 0.1 1 10 100 OR(95% CI)ES–40 –20 0 20 40 (95% CI)–4 –2 0 2 4ES(95% CI)Favours traditionalFavours hydrocolloid26FIGURE 14 Hydrocolloid compared with traditional dressing for venous leg ulcers

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Mansson, 1996 101Comparison: Hydrocolloid vs. Traditional(Granuflex)Mean baseline area (cm 2 ): 10 (19.1 SD) 7.8 (8.6 SD)Sample size (N): 48 49No. of wounds healed (n/N): 5/48 (10%) 7/49 (14%) 0.7 (0.21, 2.34)% reduction in wound area: 41 24 17Traditional dressing: Povidone-iodine-impregnated tulleWound type: Venous leg ulcersFollow-up time: 12 weeksMilward, 1991 102Comparison: Hydrocolloid vs. Traditional(Comfeel)Mean baseline area (cm 2 ): Not stated Not statedSample size (N): 19 19No. of wounds healed (n/N): 3/19 (16%) 0/19 (0%) 8.28 (0.81, 84.88)Traditional dressing: Not statedWound type: Venous leg ulcersFollow-up time: 12 weeksPooled estimate (random-effects model)Comparison: Hydrocolloid vs. TraditionalTotal no. of wounds healed (n/N): 158/358 (44%) 140/356 (39%) 1.45 (0.83, 2.54)χ 2 = 13.69; df = 6; z = 1.33; p = 0.033Moffatt et al., 1992 97Comparison: Hydrocolloid vs. Traditional(Comfeel)Median baseline area (cm 2 ): 7.3 6.7Sample size (N): 30 30No. of wounds healed (n/N): 13/30 (43%) 7/30 (23%) 2.42 (0.84, 7.03)Traditional dressing: Knitted viscose dressing (N-A)Wound type: Venous leg ulcersFollow-up time: 12 weeksN-A ® , Johnson & Johnson Medical Ltd0.01 0.1 1 10 100 OR(95% CI)ES–40 –20 0 20 40 (95% CI)–4 –2 0 2 4ES(95% CI)Favours traditionalFavours hydrocolloidFIGURE 14 contd Hydrocolloid compared with traditional dressing for venous leg ulcersfor healing of 1.45 (95% CI, 0.83–2.54). Includingthe trial by Lindholm and co-workers, 72–75 in whichboth venous and mixed arterio/venous ulcerswere assessed, produced an overall OR of 1.53(95% CI, 0.91–2.57). Thus, the result of nosignificant difference is robust to the inclusion/exclusion of certain studies and we can reliablyconclude that there is no evidence for a differencein venous ulcer healing beneath hydrocolloiddressings compared with traditional (tulle,knitted viscose or gauze-type) dressings.Dressing versus dressingEleven trials were head-to-head comparisons ofdressings. A significantly shorter healing time wasreported with a collagen sponge dressing whencompared with dextranomer beads. 50 There wasno significant difference in the number of ulcers27

Results28healed under a lyophilised collagen dressingcompared with a hydrocolloid dressing. 105 Therewas a larger reduction in wound area with thehydrocolloid, but insufficient data were given toallow this to be tested for statistical significance,and baseline ulcer size was not given (Figure 15;appendix 10, Table 22).In a trial between a hydropolymer dressing andhydrocolloid dressing, similar numbers of legulcers were healed in both treatment groups. 65The wounds in the hydropolymer dressing grouphad a greater reduction in actual wound area,but this was potentially confounded by the largerulcer area at baseline in this group (the outcomeas reported by the authors in terms of percentagereduction in wound area favoured the hydrocolloid).Similarly, Smith 106 found no differencein either the proportion of ulcers healing orchange in ulcer size in a comparison of anunnamed alginate and a hydrocolloid dressing(Figure 15; appendix 10, Table 22).A further six trials (eight reports) were identifiedwhich had head-to-head comparisons of dressingsfor venous leg ulcers. 107–114 Four trials comparedhydrocolloid dressings. One trial found nosignificant difference in the proportion of ulcershealed in a comparison between a newer formulationhydrocolloid and a hydrocolloid incorporatingcalcium. 107 In a comparison between threehydrocolloid dressings (an original formulation,Granuflex; a newer formulation, Granuflex E;and a third hydrocolloid, Comfeel) sufficientdata were not available to test the statisticalsignificance of the reported results that indicateda greater reduction in wound area occurredwith the improved hydrocolloid. 108–110 The meanreduction in ulcer area per day was highest withthe Granuflex E dressing and lowest with theComfeel dressing. However, data were notprovided on baseline ulcer size, suggesting thatconfounding of the results by poor comparabilityof the groups for wound size at baseline cannot beruled out (appendix 10, Table 22). A further twotrials compared a hydrocolloid dressing (DuoDermCGF ® , ConvaTec Ltd, equivalent to Granuflex E)with alternative hydrocolloid dressings (Tegasorb ® ,3M Ltd and Comfeel Plus ® , Coloplast Ltd). 111,112They found no significant difference in healingrates between the different products.Two trials compared the same hydrocolloiddressing with foam dressings 113,114 and neitherfound a statistically significant difference inproportion of ulcers healed over the trial period.Pooling the data from the two trials again showedno difference in healing rates with either product(OR for healing, 1.0; 95% CI, 0.48–2.07)(Figure 16; appendix 10, Table 22).Topical agents versus traditional/control dressingsTwo trials reported comparisons betweenhyaluronic acid and control dressings. 115,116One reported a significant difference in the dailyhealing rate, which favoured the hyaluronic acid, 115and the other found no significant differencebetween the two treatments in proportion ofulcers healed 116 (Figure 17; appendix 10, Table 23).Five papers reported comparisons betweenbiological dressings (cellular suspensions, porcinedermis or amnion) and traditional therapies. 70,117–119Of these, two reported shorter median healingtimes with the biological dressing (porcine dermisand a tissue engineered product made from humanskin) when compared with a paste bandage or anon-adherent dressing, 117,118 but there were insufficientdata to calculate the statistical significanceof these results. The other three trials found nodifference in the proportion of ulcers healedin a comparison between autologous activatedmononuclear cells and tissue culture medium, 70keratinocyte allografts with paraffin gauze soakedin culture medium, 119 or amnion applied beneathsaline gauze 70,119 (Figure 18; appendix 10, Table 23).Six trials compared topical preparations withcontrols. The comparisons were:• iloprost versus control 120,121• sucralfate versus control 122• allopurinol versus control 123• DMSO versus control 123• DL-cysteine versus control 124• DL-methionine-methyl sulphonium chloride 124• copper ointment versus silver versus cream 125(Figure 19 ; appendix 10, Table 23).Salim 124 compared DL-cysteine powder,DL-methionine-methyl sulphonium chlorideand a placebo (inert powder). There was nosignificant difference in the proportion ofulcers healed with either treatment over thetrial period. In a similar study Salim 123 reporteda higher proportion of ulcers that healed withallopurinol (inert powder) and with DMSOpowder compared with placebo. In both of thesestudies the healing rates were higher than thosereported in any of the other trials (58–85%healed in 12 weeks when analysed on an ITTbasis), and the patients were younger (meanage, 56–59 years). This may have consequences

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Caprio et al., 1995 105Comparison: Hydrocolloid vs. CollagenMean baseline area (cm 2 ): Not stated Not statedSample size (N) * : Not stated Not statedAbsolute reduction in woundarea (cm 2 ): 12.22 8.29 3.86No. of wounds healed (n/N): 25 20Wound type:Follow-up time:Venous leg ulcers8 weeks* 93 patients with 98 ulcersBanks et al., 1996 65Comparison: Hydrocolloid vs. Hydropolymer(Comfeel)(Tielle)Median baseline area (cm 2 ): 3.35 4.31Sample size (N): 50 50No. of wounds healed (n/N): 19/50 18/50 1.09 (0.5, 2.4)Mean absolute reduction inwoundarea (cm 2 ): 17.7 19.3 –16% reduction in wound area: 53 45 8Wound type:Follow-up time:Venous leg ulcers13 weeksSmith, 1994 106Comparison: Hydrocolloid vs. AlginateMean baseline area (cm 2 ): 12.74 22.17Sample size (N): 22 18No. of wounds healed (n/N): 4/22 2/18 1.78 (0.28, 11.1)% reduction in wound area: 57.1 34.9 23.8Wound type:Follow-up time:Venous leg ulcers6 weeksPalmieri, 1992 50Comparison: Dextranomer vs. Collagen spongeBaseline area (cm 2 ): Not stated Not statedSample size (N): 24 24Mean time to healing (days): 60 36 24Wound type:Follow-up time:Venous leg ulcersUnclear0.01 0.1 1 10 100 OR(95% CI)ES–40 –20 0 20 40 (95% CI)–4 –2 0 2 4ES(95% CI)Favours comparison Favours hydrocolloid/dextranomerFIGURE 15 Comparison of modern dressings for venous leg ulcer29

ResultsZuccarelli, 1993 113Comparison: Foam (Allevyn) vs. Hydrocolloid (Granuflex)Mean baseline area (cm 2 ): 9.8 6.9Sample size (N): 19 19No. of wounds healed (n/N): 9/19 9/19 1.0 (0.28, 3.58)% of wounds healed: 47 47Wound type: Venous leg ulcersFollow-up time: 12 weeksBowszyc et al., 1993 114Comparison: Foam vs. Hydrocolloid(Lyofoam)(Comfeel)Median baseline area (cm 2 ): 3.01 3.05Sample size (N): 40 40No. of wounds healed (n/N): 24/40 24/40 1.0 (0.4, 2.4)% of wounds healed: 60 60Wound type: Venous leg ulcersFollow-up time: 16 weeksPooled estimate (fixed-effects model)Comparison: Foam vs. HydrocolloidTotal no. of wounds healed (n/N): 33/59 (56%) 33/59 (56%) 1.00 (0.48, 2.08)χ 2 = 0.00; df = 1; z = 0.00; p = 10.01 0.1 1 10 100 OR(95% CI)Favours foamFavours hydrocolloidFIGURE 16 Hydrocolloid compared with foam dressing for venous leg ulcer30for the generalisability of the results to all leg ulcerpatients treated in the UK.Tsakayannis and co-workers 122 compared sucralfateointment (a substance capable of binding basicfibroblast growth factor, and hence preventingits breakdown), with the cream vehicle aloneand found no difference in the proportion ofulcers healed.Werner-Schlenka and co-workers 120,121 reportedtwo trials that evaluated topical iloprost. Onetrial 121 compared two solutions of iloprost (0.0005%and 0.002%), and in the other 120 patients receivedeither 10 µg/ml (0.001%) for the first 3 days,increasing to 40 µg/ml (0.004%) for the restof the study period, or placebo. There was nosignificant difference in either the proportion ofulcers healed or the reduction in ulcer area overthe trial period (Figure 20; appendix 10, Table 23).Bishop and co-workers 125 compared a tripeptidecopper complex cream with silver sulphadiazineand a control of vehicle cream alone. He foundno difference in the reduction in wound areawith the copper cream but there was a reductionin wound area with the silver sulphadiazinecompared with both the control and thecopper complex (appendix 10, Table 23).Topical agents versus placeboThree trials (five reports) reported comparisonsbetween growth factors and a placebo. 126–130None found a significant difference for eitherthe reduction in ulcer area or proportion ofulcers healed during the trial period. The trialsby Freak and co-workers 127,128 and Rasmussenand co-workers 126,129 were similar in that they bothcompared three dose regimens of biosynthetichuman growth hormone and placebo. Pooling theresults from these two trials (using a fixed effectmodel) for the concentrations used (0.17 IU/mlversus placebo, 1.0 IU/ml versus placebo, and11.2 IU/ml versus placebo) found no significantbenefit for using the growth hormone at any concentration.The study by Falanga and co-workers 130

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Passarini et al., 1982 115Comparison: Traditional vs. Hyaluronic acidMean baseline area (cm 2 ): Not stated Not statedSample size (N): 25 23Mean % reduction in wound area: 44 78 34Traditional therapy: Various treatmentsWound type: Venous leg ulcersFollow-up time: 20 daysGalasso et al., 1978 116Comparison: Traditional vs. Hyaluronic acidMedian baseline area (cm 2 ): Not stated Not statedSample size (N): 35 27No. of wounds healed (n/N): 29/35 (83%) 21/27 (78%) 0.72 (0.2, 2.56)Traditional therapy: GauzeWound type: Venous leg ulcersFollow-up time: Unclear0.01 0.1 1 10 100 OR(95% CI)–40 –20 0 20 40 ES(95% CI)Favours traditionalFavours hyaluronic acidFIGURE 17 Hyaluronic acid compared with traditional dressings for venous leg ulcerscompared one dose of human recombinantepidermal growth factor with placebo (Figure 21;appendix 10, Table 24).Topical agents versus dressingsThree trials compared dressings withtopical preparations for venous ulcers.The comparisons were:• cryopreserved cultured allografts versushydrocolloid dressing 131• daily antiseptic versus collagen 132• magnesium sulphate paste versushydrocolloid. 133Teepe and co-workers 131 compared a hydrocolloiddressing with cryopreserved cultured allografts.There was no difference in the proportion ofulcers healed, but cryopreserved cultured allograftswere associated with a greater reduction in thepercentage area of wound healed (Figure 22;appendix 10, Table 25).A collagen dressing healed a higher proportionof ulcers than treatment with a daily applicationof antiseptic. 132 There was no significant differencein the proportion of ulcers healed in acomparison between magnesium sulphatepaste and a hydrocolloid. 133 The rate of ulcerhealing expressed as area epithelialised per daywas reported as significantly higher with thehydrocolloid dressing, but baseline comparabilityfor ulcer size at randomisation could not beestimated and the presence of underlying biascannot therefore be excluded (Figure 22;appendix 10, Table 25).Topical agent versus topical agentOnly three trials reported head-to-headcomparisons of topical agents. Thecomparisons were:• buffered acidifying ointment versus ointment 134• amino acid solution (two concentrations)versus saline (two concentrations) 135,136• copper versus silver. 125Wilson and co-workers 134 compared a bufferedacidifying ointment with emulsifying ointmentand found no difference in the numbers ofulcers healed. There was a higher healing rate(expressed as percentage area healed per day)in the buffered ointment group, but this wasconfounded by the inequalities in baseline ulcerarea, which was biased towards the bufferedointment (appendix 10, Table 26).31

ResultsHolzinger et al., 1994 70Comparison: Placebo vs. Autologous activatedmononuclear cellsMean baseline area (cm 2 ): 5.26 (2.9 SD) 5.14 (2.7 SD)Sample size (N) (venous): 30 (10) 33 (12)No. of wounds healed (n/N):Venous 7/10 (70%) 11/12 (92%) 4.7 (0.4, 54.9)Arterial 10/20 (50%) 18/21 (86%) 6.0 (1.3, 27.0)Placebo:Wound type:Follow-up time:Tissue culture mediumArterial and venous leg ulcersMaximum of 75 daysDuhra et al., 1992 119Comparison: Placebo vs. Keratinocyte allograftsMedian baseline area (cm 2 ): 10.7 (1.7 SEM) 9.1 (1.6 SEM)Sample size (N): 15 (11 patients) 15 (11 patients)No. of wounds healed (n/N): 1/15 (7%) 0/15 (0%) 0.3 (0.01, 8.3)Reduction in mean absolutewound area (cm 2 ): 3.3 2.7 –0.6Placebo:Wound type:Follow-up time:Paraffin gauze soaked in culture mediumVenous leg ulcers6 weeksRundle et al., 1981 117Comparison: Paste bandage vs. Porcine dermisMedian baseline area (cm 2 ): 3.0 2.0(range, 0.5–45.0) (range, 0.2–47.8)Sample size (N): 19 23Median time to healing (weeks): 9 (range, 3–63) 6 (range, 1–16) 21 daysWound type:Follow-up time:Venous leg ulcersNot statedSabolinski et al., 1996 118Comparison: Non-adherent vs. Living skin equivalentdressingMean baseline area (cm 2 ): Not stated Not statedSample size (N) * : Not stated Not statedMedian time to healing (days): 181 57 124 daysWound type:Follow-up time:Venous leg ulcersNot stated* 233 patients0.01 0.1 1 10 100 OR(95% CI)–100 –50 0 50ES100 (95% CI)ES–4 –2 0 2 4 (95% CI)Favours placebo Favours biological dressing32FIGURE 18 Biologically active agents compared with placebo or traditional dressings for venous and arterial leg ulcers

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Calabro et al., 1995 85Comparison: Traditional vs. Topical (fibrin glue)Mean baseline area (cm 2 ): Not stated Not statedSample size (N): 54 26No. of wounds healed (n/N): 48/54 (89%) 20/26 (77%) 0.41 (0.12, 1.45)Traditional therapy: Paraffin or betadine gauzeWound type: Venous leg ulcersFollow-up time: UnclearTsakayannis et al., 1994 122Comparison: Control vs. SucralfateMean baseline area (cm 2 ): Not stated Not statedSample size (patients/wounds): 5/5 4/5No. of wounds healed (n/N): 0/5 (0%) 2/5 (40%) 11.0 (0.37, 324)Traditional therapy: Vehicle aloneWound type: Venous leg ulcersFollow-up time: 8 weeksSalim, 1991 123Comparison: Placebo vs. DMSOBaseline area (cm 2 ): 4.1 (0.2 SEM) 4.6 (0.7 SEM)Sample size (N): 52 50No. of wounds healed (n/N): 31/52 (60%) 42/50 (84%) 3.28 (1.39, 7.71)Reduction in wound area (cm 2 ): 2.8 4.6 1.6Comparison: Placebo vs. AllopurinolBaseline area (cm 2 ): 4.1 (0.2 SEM) 4.4 (0.5 SEM)Sample size (N): 52 51No. of wounds healed (n/N): 31/52 (60%) 42/51 (82%) 2.98 (1.28, 6.94)Reduction in wound area (cm 2 ): 2.8 4.4 1.3Placebo:Inert powderWound type: Venous leg ulcersFollow-up time: 12 weeksSalim, 1992 124Comparison: Placebo vs. DL-cysteineBaseline area (cm 2 ): 4.6 (0.2 SEM) 5.3 (0.3 SEM)Sample size (N): 55 57No. of wounds healed (n/N): 32/55 (58%) 43/57 (75%) 2.17 (0.99, 4.75)Reduction in wound area (cm 2 ): 3.5 4.9 1.4Comparison: Placebo vs. Methionine-methylsulphonium chlorideBaseline area (cm 2 ): 4.6 (0.2 SEM) 4.4 (0.5 SEM)Sample size (N): 55 56No. of wounds healed (n/N): 32/55 (58%) 42/51 (82%) 1.33 (0.20, 9.02)Reduction in wound area (cm 2 ): 3.5 5.0 1.5Placebo:Inert powderWound type: Venous leg ulcersFollow-up time: 12 weeks0.01 0.1 1 10 100 OR(95% CI)ES–4 –2 0 2 4 (95% CI)Favours control/placeboFavours topical agentFIGURE 19 Topical dressings compared with placebo/traditional dressings for venous leg ulcers33

ResultsWerner-Schlenzka & Kuhlmann, 1994 121Comparison: Placebo vs. Iloprost 0.0005%Mean baseline area (cm 2 ): 35.1 25.8Sample size (N): 50 49No. of wounds healed (n/N): 2/50 (4%) 2/49 (4%) 1.02 (0.19, 7.56)Mean % reduction in wound area: 14.6 15.9 1.3Comparison: Placebo vs. Iloprost 0.002%Mean baseline area (cm 2 ): 35.1 26.5Sample size (N): 50 49No. of wounds healed (n/N): 2/50 (4%) 2/49 (4%) 2.73 (0.5, 14.79)Mean % reduction in wound area: 14.6 32.9 18.3Placebo:Not statedWound type: Venous leg ulcersFollow-up time: 8 weeksWerner-Schlenzka & Lehnert, 1994 120Comparison: Placebo vs. Iloprost 0.001%Mean baseline area (cm 2 ): 16.2 26.6Sample size (N): 34 65No. of wounds healed (n/N): 3/34 (9%) 4/65 (6%) 0.677 (0.143, 3.22)Mean % reduction in wound area: 43 44 1Mean absolute reduction inwound area (cm 2 ): 6 9.4 3.4Placebo:HydrogelWound type: Venous leg ulcersFollow-up time: 8 weeks0.01 0.1 1 10 100 OR(95% CI)ES–40 –20 0 20 40 (95% CI)–4 –2 0 2 4ES(95% CI)Favours placeboFavours iloprostFIGURE 20 Iloprost compared with placebo for venous leg ulcers34Bulstrode and co-workers 135,136 compared twosaline soaks (0.9% saline (150 mosmol/l), 5%saline (850 mosmol/l)) with two amino-acidsoaks (150 mosmol/l and 850 mosmol/l) inhospitalised patients. Treatment with the aminoacid soaks resulted in a significantly higher healingrate than with saline soaks, but the smaller meanulcer size in the amino acid group may haveintroduced bias favouring the amino acid group(appendix 10, Table 26). There was no differencein the numbers of ulcers healing between theamino acid group or the saline-treated group.Publication biasStudies with ‘positive’ findings (i.e. those whichshow that a new treatment is more effective thana traditional treatment), may be more likely to getpublished than studies that have ‘negative’ results(i.e. traditional treatment is better) or ‘null’ results(i.e. no difference between new and traditionaltreatment). The published results, therefore, maynot accurately reflect the results of all the trialsthat have been undertaken, and this potentiallyintroduces bias into a summary of results. Publicationbias is more likely to occur for small, singlecentretrials, than large multicentre trials.The presence of publication bias can beassessed by using a funnel plot, which graphicallysummarises the ORs and sample sizes of trials.Publication bias is thought unlikely when the ORsof small trials are equally distributed about the ORsof large trials. Asymmetry, however, indicates thatthere may be some trials missing from the set of

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Falanga et al., 1992 130Comparison: Placebo vs. r-h-EGFMean baseline area (cm 2 ): 19.2 12.8Sample size (N): 22 23No. of wounds healed (n/N): 2/18 (11%) 6/17 (35%) 3.53 (0.63, 19.8)Mean % reduction in wound area: 13 48 35%Placebo:Diluent used to reconstitute r-h-EGFWound type: Venous leg ulcersFollow-up time: 10 weeksFeak et al., 1993 128Comparison: Placebo vs. B-HGH, 0.17 IU/mlMean baseline area (cm 2 ): 10.58 10.24Sample size (N): 7 7% reduction in wound area/week: 22.5 (6.8 SEM) 33 (11 SEM) 11 (–15, 36)Comparison: Placebo vs. B-HGH, 1.0 IU/mlMean baseline area (cm 2 ): 10.58 9.83Sample size (N): 7 6% reduction in wound area/week: 22.5 (6.8 SEM) 25 (14.0 SEM) 3 (–28, 33)Comparison: Placebo vs. B-HGH, 11.2 IU/mlMean baseline area (cm 2 ): 10.58 7.9Sample size (N): 7 6% reduction in wound area/week: 22.5 (6.8 SEM) 11 (3.3 SEM) –11 (–26.3. 3.3)Placebo:PlaceboWound type: Venous leg ulcersFollow-up time: 6–12 weeksRasmussen et al., 1991 129Comparison: Placebo vs. B-HGH, 0.17 IU/mlMean baseline area (cm 2 ): 12 (26 SEM) 14 (26 SEM)Sample size (N): 22 20No. of wounds healed (n/N): 3/22 (14%) 3/20 (15%) 1.15 (0.2, 6.3)% reduction in wound area/week: 7.9 (4.0 SEM) 17.9 (13.0 SEM) 10 (–16.6, 36.6)Comparison: Placebo vs. B-HGH, 1.0 IU/mlMean baseline area (cm 2 ): 12 (26 SEM) 11 (27 SEM)Sample size (N): 22 22No. of wounds healed (n/N): 3/22 (14%) 2/22 (9%) 0.63 (0.1, 4.2)% reduction in wound area/week: 7.9 (4.0 SEM) 7.6 (5.5 SEM) –0.3 (–13.6, 13.0)Comparison: Placebo vs. B-HGH, 11.2 IU/mlMean baseline area (cm 2 ): 12 (26 SEM) 12 (30 SEM)Sample size (N): 22 23No. of wounds healed (n/N): 3/22 (14%) 2/23 (9%) 0.67 (0.1, 4.0)% reduction in wound area/week: 7.9 (4.0 SEM) 9.6 (4.5 SEM) 1.7 (–10, 13.5)Placebo:SalineWound type: Venous leg ulcerFollow-up time: 6 weeksPooled estimate (mean difference; random-effects model)Comparison: Placebo vs. B-HGH, 0.17 IU/mlRandom-effects model 10.3 (–8.1, 28.6)χ 2 = 0.00; df = 1.0; z = 1.10Comparison: Placebo vs. B-HGH, 1.0 IU/mlRandom-effects model 0.15 (–12.1, 12.4)χ 2 = 0.03; df = 1.0; z = 0.02Comparison: Placebo vs. B-HGH, 11.2 IU/mlRandom-effects model –3.4 (12.7. 5.8)χ 2 = 1.87; df = 1.0; z = 0.730.01 0.1 1 10 100 OR(95% CI)ES–40 –20 0 20 40 (95% CI)Favours placeboFavours growth factorsFIGURE 21 Growth factors compared with placebo for venous leg ulcer35

ResultsTosti & Veronesi, 1983 132Comparison: Topical vs. Collagen dressingMean baseline area (cm 2 ): 19.7 19.6Sample size (N): 11 11No. of wounds healed (n/N): 1/11 (9%) 8/11 (73%) 26.6 (2.3, 308)Topical treatment: Daily antisepticWound type: Venous leg ulcerFollow-up time: 26 daysGreguric et al., 1994 133Comparison: Topical vs. Hydrocolloid(Varihesive E ® )Median baseline area (cm 2 ): Not stated Not statedSample size (N): 55 55No. of wounds healed (n/N): 0/55 (0%) 3/55 (5%) 7.4 (0.37, 146.8)Median absolute reduction inwound area/day (mm 2 ): 21 32Topical treatment: Magnesium sulphate pasteWound type: Venous leg ulcerFollow-up time: 10 dressing changesTeepe et al., 1993 131Comparison: Topical vs. Hydrocolloid (Granuflex)Baseline area (cm 2 ): Not stated Not statedSample size (N): 24 23No. of wounds healed (n/N): 6/24 (25%) 5/23 (22%) 0.83 (0.21, 3.2)Mean time to healing (days): 10 8.7 1.3Topical treatment: Cryopreserved cultured allograftsWound type: Venous leg ulcerFollow-up time: 6 weeksVarihesive E ® , Granuflex E, ConvaTec Ltd0.01 0.1 1 10 100 OR(95% CI)ES–4 –2 0 2 4 (95% CI)Favours topical agentFavours dressingFIGURE 22 Topical agents compared with dressings for venous leg ulcer36published trials. The overall funnel plot of allstudies that compared a traditional treatment witha modern therapy showed little evidence of asymmetry(Figure 23). However, for the subgroup oftrials that compared a hydrocolloid dressing witha traditional treatment asymmetry was clearlyevident (Figures 23 and 24). Publication bias forstudies favouring hydrocolloid treatment maybe responsible for this result.Cost-effectivenessThe unit cost of dressings and topical agents aremany times the cost of the traditional comparatorssuch as gauze. The newer agents, however, requireless-frequent dressing changes, for example everyfew days instead of twice daily, and hence requireless nursing time. In addition, the cost of treatinga wound for a long period with an inexpensivedressing may exceed that of treating the samewounds with a dressing that has a higher unit cost,but which is only required for a short period as aresult of its effectiveness. These arguments haveled to speculation that ‘modern’ dressings may bemore cost-effective than gauze-type comparators.Nine trials provided sufficient data on costs oftreatment to allow cost-effectiveness analysis(appendix 11).

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)200Sample size1501005000.01 0.1 1 10 100ORFIGURE 23 A funnel plot for traditional treatments compared with modern dressings or topical agents for the treatment of legulcers and pressure sores.The plotted points indicate the ORs for wound healing for each trial included in the review. In the absence ofpublication bias the points should take the form of an upturned funnel; in the presence of publication bias, the points will be skewed inthe direction of the bias ( ,Traditional vs. dressing/topical agent other than hydrocolloid; , traditional vs. hydrocolloid dressing only)200Sample size95,96150561001015450999852,5355881005172 10200.01 0.1 1 10 100ORFIGURE 24 A funnel plot for traditional treatments compared with hydrocolloid dressings for the treatment of leg ulcers andpressure sores37

ResultsSix trials evaluated cost-effectiveness in pressuresore treatments. These were saline gauze versushydrocolloid (two comparisons), vapour-permeabledressing versus gauze, and foam dressing versussaline gauze. 54,55,58,59,61,62,72 One trial reported thatthe hydrocolloid was significantly cheaper thangauze. 72 Analysis of median costs in one study 55demonstrated that hydrocolloids were cheaper,but that this was dependent upon price assumptionsof nurse time. Another trial found that themoisture vapour-permeable dressing was morecost-effective than gauze for grade II pressuresores, but that there was no difference in outcomefor grade III sores and in these patients gauzewas more cost-effective, though due to the smallsample size there is a possibility of a type 2 error(i.e. concluding that no difference in effectivenessexists when there is one). 58,59 In the third comparisonthe foam dressing was more effective butthe cost-effectiveness was not tested for statisticalsignificance even though the data were stochasticand therefore evaluable. 61Bale and co-workers 62 compared a hydrocolloidwith a hydrocellular foam in 100 patients withpressure sores, leg ulcers or other chronic wounds.There was no evidence that the costs were differentbetween the two groups. CIs on cost data overlapped,thus the incremental cost difference wasnot statistically significant.Colwell and co-workers 54 compared a hydrocolloidwith a moist gauze dressing. Costs of the dressingmaterials were higher in the hydrocolloid group,but fewer dressing changes were required. It wouldhave been appropriate to statistically analyse thecost-effectiveness but this was not done.Three papers reported cost-effectiveness data inleg ulcer trials. These were comparisons of:• gauze versus hydrocolloid 102• paraffin-impregnated tulle versus hydrocolloid 100• alginate versus hydrocolloid. 106In the first two comparisons, the materialcosts were higher for patients treated with thetraditional dressing. This may be due to theincreased frequency of dressing changes in thisgroup (five per week compared with two perweek in Milward’s 102 study). Given the currentemphasis on applying compression bandagesthat are capable of remaining in place for upto 7 days it is unclear whether these results arerelevant to current practice.The comparison between a hydrocolloid dressingand foam dressing did not include anysignificance testing.Overall a comparison between cost-effectiveness ofhydrocolloid and gauze for venous leg ulcers andpressure sores was made using five trials. 54,55,72,100,102The number of dressing changes required waslower for the hydrocolloid group than the gauzegroup. Estimates of incremental variable costs perpatient of hydrocolloid versus gauze ranged from£14–19 cheaper than hydrocolloid dressing (invenous leg ulcers) to US$0.65–12 (£0.14–7.50)more expensive for pressure sores.38

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Chapter 4DiscussionQuality of the studiesQuality assessment suggests that methodologicalflaws are an issue affecting the validity of moststudies in chronic wound care. In general, thestudies were too small to ensure that wounds ofdifferent sizes (and other prognostic variables)were evenly distributed across trial arms, resultingin a bias at baseline in most trials. The majority ofstudies also had a short follow-up and did notanalyse the data by survival analysis, which wouldaccount for both whether and when a woundhealed and which would be a more efficientmethod for estimating the rate of healing.If future trials perpetuate many of themethodological flaws highlighted in thisreview, they are unlikely to provide the necessaryevidence to determine an effective woundmanagement strategy. The variability betweenwounds at baseline for prognostic variablesincluding size, indicates that recruitmentnumbers need to be large and that trials shouldprobably be multicentred. If small single-centredtrials are to be continued they could be improvedby the use of matched or stratified randomisationto ensure a similar distribution of wound sizesbetween treatment groups at baseline, and thedata should be analysed by matched pairs analysiswhere appropriate. However, even with thisimproved design a trial still needs to be largeenough to ensure comparability for bothunknown and known confounding factors.Pressure sores and surgicalwounds healing by secondaryintentionOverall, the number of studies meeting theinclusion criteria is surprisingly small consideringthe relatively open inclusion criteria. To haveapplied more rigorous criteria that addressedspecific methodological issues would have reducedthis small number even further, reflecting again thepoor methodology in many of the trials. The smallnumber of eligible trials, the lack of replication ofcomparisons, and the high variability in quality hasprevented a detailed evaluation of many productsin this review.The focus for the majority of trials were pressuresores, while a smaller number assessed surgicalwounds healing by secondary intention. Resultsfrom this latter group of studies were generallyinconclusive and of poor quality suggestingthat to date this type of wound has been poorlystudied and that more research is required beforedecisions on effective treatments can be made. Atpresent the only study to find a significant benefitfor an intervention in the treatment of granulatingsurgical wounds suggests that wet-to-dry dressings,which are not commonly used in the UK, are moreeffective for healing than the topical applicationof aloe vera. 38 This trial is however, of little relevancein the UK where neither treatment iscommonly used.Studies that compare treatment with no treatmentare very rare in the wound care literature becauseof concern over ethical issues associated with withholdingtreatment from a patient. In this review asingle trial was included that assessed the incrementalbenefit of topical insulin when given inaddition to routine supportive care (not includingdirect management of the wound) for the treatmentof pressure sores. 39 This trial suggested thatapplication of topical insulin did have a statisticallysignificant benefit on wound healing. However,the results were of borderline statistical significance(p = 0.05) and this effect requires furtherexploration and replication.The alternative to withholding treatment froma patient is to employ a placebo. In wound caretrials such placebo treatments are unlikely tobe inert as the application of the placebo orvehicle is likely to change the local environmentof the wound, thereby modifying the biologicalprocesses associated with healing. A placebo istherefore not a substitute for withholding treatmentin studies to determine the rationale foractive treatment. The possible interaction betweenthe vehicle and the healing process together withsmall sample size, may provide some explanationfor why so few of the trials showed a statisticallysignificant difference between an active treatmentand a placebo. Another explanation for the lackof benefit with topical agents is that, providedthe wound environment is conducive to healing,little can be gained from topical applications.39

Discussion40Several trials evaluated a hydrocolloid dressingwith a traditional form of care for the treatmentof pressure sores. 51–56 The combined OR showedthat there was a statistically significant increasein the number of wounds healed when treatedwith the hydrocolloid dressing. However, thetraditional treatments were poor comparators andare unlikely to be used with any frequency withinthe UK, thus the relevance for modern practice isunclear. The finding does however support currentnursing practice, which has eschewed gauze-baseddressings for the management of pressure sores.Studies directly comparing topical agents for thetreatment of pressure sores focused primarily onbiologically active agents. Most of these trials weretoo small to provide conclusive results and theirheterogeneity prevented pooling. At present theresults are highly inconsistent both within andbetween trials, and further, better-designedstudies with larger numbers are required.Trials comparing hydrocolloids with hydrogels,which also absorb exudate and maintain a moistwound surface, are equivocal. 46,47Although several trials have comparedalternative dressings with one another, nonehas shown a statistically significant differencebetween treatments.Leg ulcersThere were insufficient trials evaluating arterial legulcers to recommend any particular dressing forgeneral use. It is interesting to note that the trialby Gibson and co-workers 69 was abandoned due torapid withdrawal from the trial in patients allocatedto a knitted viscose dressing, though there was nodifference in the proportion of ulcers healed. 69Both mononuclear cultured cells 70 and ketanserin 71appeared to increase healing and these topicalagents may be worthy of further study.Only two trials in which the outcome was notreported by ulcer aetiology demonstrated a differencein healing rates. These trials suggested thattreatment with a growth factor, 81,82 or hyaluronicacid 84 were beneficial treatments, but furtherevaluations of these preparations in venous ulcersalone showed no difference in healing rates.Several trials evaluated a hydrocolloid dressing witha traditional dressing, usually paraffin-impregnatedor knitted viscose gauze, in venous leg ulcers.Combining these studies in a meta-analysis usinga random effects model showed that there wasno difference between the treatments for the proportionof ulcers healed. The two largest trials inthis analysis had ORs of 0.92 and 0.88 (odds ofhealing in the control). The smaller trials were,in general, more favourable for the hydrocolloid,suggesting that publication bias may be present.These results conflict with the evidence forpressure sore treatment where the trials suggestedthat hydrocolloid dressings are more effective thantraditional treatments. This apparent disparitybetween wound types may be related to methodof application used for the traditional treatment.A dry dressing, such as a knitted viscose dressing,will produce a moist wound environment whenused under a compression bandage, but may notwhen used over a pressure sore, depending on thesecondary dressings used. Wu and co-workers 137evaluated the moisture loss through compressionbandage(s) and dressings. They found that a drydressing covered with a multi-layer bandage stillhad a vastly reduced water vapour transmissionrate compared with the ulcer surface or thedressing alone. Hence the sum total of materialsapplied over a wound may influence the conditionsfor healing at the wound surface. Many of thetrials do not indicate whether secondary dressingswere used, and as secondary dressings influencethe interface conditions (e.g. temperature andmoisture), then they may well influencehealing rates.There is currently insufficient evidence for eitherfoam or film dressings having a beneficial effecton leg ulcer healing.The one trial of a traditional zinc paste bandagewith a modern (alginate) dressing found the zincpaste to be more effective. However, this may havebeen confounded by the greater magnitude ofcompression beneath the paste (effectively amulti-layer bandage system). 138Comparisons between modern dressings(hydrocolloid dressing, lyophilised collagen,collagen sponge, dextranomer, hydropolymerdressing, alginate dressing, hydrocellular foam,or polyurethane foam) did not indicate thatany of the modern products was more effectivethan another.Comparisons between topical agents and controltreatments revealed only two preparations thatproduced a statistically significant difference inhealing rates. These were DMSO and allopurinol,

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)both of which are oxygen free radical scavengersand were evaluated in the same trial. This trialneeds to be replicated as the possibility that thecomparator (an inert powder) may have had adetrimental effect on healing cannot be ruled out.DMSO has also been found to be effective in thetreatment of diabetic foot ulcers and is worthy offurther investigation. 139Biologically active topical agents, cells ormembranes, were not found to be more effectivethan control dressings, such as paraffin gauze orculture medium. Similarly, growth factors were notdemonstrated to be more effective than the tissueculture medium alone. This is in contrast withevaluations in the treatment of diabetic foot ulcerswhere they have been shown to be effective. 139There may be two explanations for this.• There may be differences in microcirculatorypathology between diabetic and venous ulcers;the former being amenable to treatment bygrowth factor.• Growth factors are effective in the treatment ofvenous leg ulcers but the method of applicationand/or the power of the studies has resultedin a type 2 error. One striking difference in theapplication of growth factors to the two differentwound types is the amount of debridementperformed. During the treatment of diabeticfoot ulcers, the skin and wound are frequentlydebrided to remove dead tissue. 139 A bleedingwound bed may be prepared prior to the applicationof the growth factors. Sharp debridementis rarely performed on venous leg ulcers andthere was no pretreatment debridement in thetrials reported here. 127–130Comparisons between dressings and topical agentsindicated that a collagen dressing was preferableto the daily application of an antiseptic, while ahydrocolloid dressing healed more ulcers thanmagnesium paste. However, neither magnesiumpaste nor topical antiseptic are widely used todayin the UK suggesting that the generalisability ofthese results is limited.Publication biasFunnel plots indicated that publication bias may bepresent for trials that compared hydrocolloids withtraditional treatments. Asymmetry of the funnelplot can result from: 140• publication bias• language bias• multiple publication bias• poor methodological design amongstsmaller studies• true heterogeneity (i.e. ES differs accordingto study size due to intensity of intervention)• chance.It is inevitable that despite searching forunpublished studies this review relies heavilyon published trials. There is at present nostandardised method to ensure a comprehensivesearch for unpublished data. Careful screeningof all included studies was undertaken to reducethe potential for multiple studies and the searchstrategy was designed to improve sensitivity fornon-English publications. True heterogeneity isunlikely to have influenced publication bias asthe largest studies did not employ interventionsthat differed from the smaller ones. The almostuniform direction of the bias suggests that itwas not purely a chance result. Poor methodologicaldesign of the smaller studies could beresponsible for skewing the funnel plot; thesmaller effect size demonstrated in the larger,more rigorous studies may indicate this.However, publication bias remains the mostlikely cause of asymmetry. 140 This type of biasmay result from restrictive practices that preventall the evaluative research entering the publicdomain. There are several reasons why publicationbias could skew the data, two of the mostcommon causes are:• pharmaceutical companies are unlikely tofavour the publication of sponsored trialswhere a result favoured the standard, genericalternative. Such suppression of publicationis more likely for small, under-poweredstudies than for large, multicentre trials• journal editors or researchers may notfavour publication of small studies with‘null’ (i.e. non-significant) results, particularlyif they have been preceded by largerstudies that indicated a positive benefit foran intervention. This does not appear tobe the case here as the majority of trialswere non-significant.Analysis of the funnel plot by date of publicationsuggests there is little evidence that the year ofpublication was related to the outcome reported.In other words, commercial considerations maybe the causative factor of asymmetry (Figure 24).Hydrocolloid dressings were amongst the firstmodern dressings to be intensively marketed andcompanies would be unlikely to publish researchwith negative results. A similar publication bias41

Discussionmay also exist for other commercially importantdressings or topical agents other than hydrocolloiddressings, but the absence of multiple trialsprevents an assessment by funnel plot.Prospective registration of trials would helpprevent this kind of publication bias and ensurethe inclusion of unpublished trials in systematicreviews should become mandatory. Furthermore,those involved in primary research should maketheir data available to those undertakingsystematic reviews.Cost-effectiveness analysisIn appendix 11, Table 27, the results of studiesthat undertook a contemporaneous economicevaluation are summarised. Costs were consideredin two ways. First, the variable cost of treatmentwas estimated. The variable cost is essentially thecost of the dressings used. Second, the differencesin semi-fixed cost, in this instance nurse time, wereestimated for each type of dressing. The rationalefor considering these two costs separately is thatchanging to a dressing type that has a higher orlower purchase cost has immediate effects on thehealthcare budget. In contrast, changing to a formof dressing that decreases or increases nurse timemay not lead to budgetary changes, at least not inthe short term. Thus, it is not always clear that thesaving of a few minutes per patient, allows eitherbudgetary saving or the nursing time to be reallocated.Similarly, increases in dressing timeof a similar magnitude may not lead to increasesin healthcare budgets.The economic studies identified in the reviewtended to be of poor quality.• The studies were all small, which did not allowmodest differences in costs to be identified.• Statistical testing was not always carried outwhen it should have been.• When statistical testing was undertaken,inappropriate tests were used.• Average cost-effectiveness ratios were reportedrather than incremental cost-effectiveness ratios.The results of studies in both leg ulcers andpressure sores indicate that hydrocolloid dressingslead to fewer dressing changes compared with drygauze. The differences in daily dressing changesbetween gauze and hydrocolloid are summarisedin appendix 11, Table 28. On average the studiesusing hydrocolloids changed the dressing onceevery 2 days, while dry gauze was changed at leasttwice a day. In addition, the two UK trials invenous ulcers, in contrast to the non-UK study(appendix 11, Table 29), both indicated thathydrocolloid dressings were less expensive indressing costs than the alternatives (i.e. dry gauzeand paraffin gauze). Given that for pressure soresthe least-expensive dressings (hydrocolloid) alsoappeared to be more effective, this is the mostcost-effective treatment. For venous leg ulcershydrocolloid dressings appeared more costeffectiveas fewer dressing changes occurred inthe studies (five compared with two). However,this may not reflect current UK practice, wheredressing frequency is in part determined by theneed to renew compression bandages. These areusually changed once or twice weekly.42

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Chapter 5ConclusionsThere is insufficient evidence of effectivenessof any particular dressing or topical agent forsurgical wounds healing by secondary intention;the few studies there are, are small and ofpoor quality.There is good evidence to suggest that hydrocolloiddressings are preferential to traditional therapies(i.e. saline gauze and antiseptics) for the treatmentof pressure sores, but there may be publicationbias, which has resulted from more trials withpositive results being published than those withmore negative results. Where topical agents havebeen compared with a placebo for the treatmentof pressure sores there is no evidence to suggestthat the active treatment has a pronounced effecton healing. Comparisons between topical agentsand dressings for the treatment of pressure soressuggest that the application of a topical hydrogelpromotes the healing above that experiencedwith an early hydrocolloid dressing but not forcomparisons with the improved formulation ofthe dressing. Conversely topical polysaccharidebeads were less effective than calcium alginatedressings. Comparisons between dressings wereunable to show any statistically significantdifference in healing rates.Evidence for the effectiveness of dressings ortopical agents in the healing of venous and arterialleg ulcers is also lacking. Meta-analysis of thestudies comparing hydrocolloid and traditionaldressings found no difference. In addition, othercomparisons of modern products and traditionaldressings found no significant differences.Topical agents were, on the whole, not foundto expedite the healing of venous leg ulcers.Only two preparations showed any evidence ofeffectiveness and may be worthy of further study,allopurinol and DMSO.Of the two trials of the treatment of arterial legulcers, only the study evaluating a biologicaldressing was demonstrated to have an influenceon healing. This single study needs replicating.Poor methodological quality may not be the onlyreason the included studies failed to generateconclusive evidence for effectiveness. Anotherexplanation is that given that certain environmentalrequirements are met (e.g. moisture andoxygen), further topical application makes littledifference. Furthermore, significant local andpatient factors that influence wound healing arenot well understood and this lack of understandingmay results in the wrong hypotheses/interventionsbeing tested.Implication for practiceThere is little evidence to indicate whichdressings or topical agents are the most effectivein the treatment of chronic wounds. However,there is evidence to suggest that wet-to-drydressings and saline soaks are not suitable forthe treatment of pressure sores, and that hydrocolloidsare more effective for this indication.Recommendations for researchThis review has highlighted several ways in whichresearch methodology could be improved and hasidentified specific areas which commissioninggroups may wish to consider prioritising forfuture research.Improving study methodologyMuch of the research concerning wounddressings and topical agents is of poor quality.In those trials reviewed, sample sizes were rarelysufficient to detect clinically important effects,and poor baseline comparability of the groupsintroduced bias. Several important messagescan be identified for future studies.• Recruitment numbers should be based on ana priori sample size calculation. In most trialsthe sample size is too small to find a statisticallysignificant difference between treatment groups.Multicentre trials should be considered in orderto recruit sufficient patient numbers. These largetrials have been undertaken in other areas ofhealth care, and although the field of woundcare presents its own difficulties, there is noreason why such trials should not be successful.If these trials are to be commissioned they willrequire a strong infrastructure to provide43

Conclusionssupport, promote collaboration and establish acommon knowledge base.• A truly objective outcome measure should beused, for example time to complete healingof the wound, or wound healing should beexpressed as both percentage and absolutechange in area.• For each patient a single reference woundshould be selected. Multiple wounds on a patientshould not be included in the analysis as they arenot independent unless specialised statisticalanalysis is performed to separate out the effectsof the intervention, (i.e. matched-pairs analysis).• Experimental groups should be comparableat baseline. In small RCTs, randomisation alonewill not achieve comparability; in such situationspatients should be paired by prognosticallyimportant baseline characteristics and thenthe individuals of each pair randomised totreatment. Such randomisation is particularlyimportant if ulcers of different aetiologiesare to be assessed in the same trial.• Head-to-head comparisons of modern wounddressings are required and should use agentsthat are recommended for wounds of asimilar nature.• A complete and thorough description ofconcurrent treatments including secondarydressings should be given in trial reports.• Assessment of outcomes should be blindto treatment.• Survival rate analysis should be adopted for allstudies that assess wound healing.• Studies to determine the biological mechanismsinvolved in wound healing are needed. A betterunderstanding of the healing process maylead to the development of validatedoutcome measures.• All trials should be published where possible.Those involved in primary research shouldmake their data available to those undertakingsystematic reviews.• Future trials should include cost-effectivenessand quality of life assessments, as well asobjective measures of dressing performance.These measures would encapsulate thoseaspects of patient quality of life on whichwounds most impact and would be sensitive tomeaningful changes in quality of life generatedby a change in the wound, including posthealingof the wound.• Economic evaluations should be incorporatedwithin trials that are sufficiently large to detectappropriate economic and clinical outcomes.• Economic evaluations should be plannedcarefully to include appropriate outcomemeasures (e.g. incremental cost-effectivenessratio). Consultation with health economistswould be advantageous.Prioritising future researchThe following questions have not been addressedby the trials conducted to date and are worthconsidering when prioritising primary researchin the future.• The development of valid and reliable conditionspecificoutcome measures for patients withchronic wounds, which would encapsulate thoseaspects of quality of life on which wounds mostimpact.• Trials of hydrocolloid dressings versuscontemporary comparators (rather than salinegauze) for the treatment of pressure sores.• Trials evaluating the cost-effectiveness ofhydrocolloid dressings versus traditionaldressings in the treatment of recalcitrant,large or painful venous leg ulcers.• Trials comparing modern with traditionaldressings in the treatment of surgical woundshealing by secondary intention (includingpilonidal sinuses).• Trials of growth factors in the treatment ofpressure sores and leg ulcers in which there issharp debridement prior to treatment (as thistherapy has shown some benefit in the treatmentof diabetic ulcers).44

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)AcknowledgementsThis review was commissioned by the NHSR&D HTA programme. The authors areindebted to Julie Glanville and Alison Fletcherfor assistance with the search, location andcollection of literature. We are also gratefulto our expert panel (appendix 2) for theirhelpful comments on the review protocoland draft report. The report also benefitedgreatly from comments received from theHTA referees.45

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References122. Tsakayannis D, Li WW, Razvi S, Spirito N. Sucralfateand chronic venous stasis ulcers [letter]. Lancet1994;343(8894):424–5.123. Salim AS. The role of oxygen-derived free radicalsin the management of venous (varicose) ulceration:a new approach. World J Surg 1991;15(2):264–9.124. Salim AS. Role of sulphydryl-containing agents inthe management of venous (varicose) ulceration.A new approach, venous (varicose) ulcers. Clin ExpDermatol 1992;76:427–32.125. Bishop JB, Phillips LG, Mustoe TA, Vander Zee AJ,Wiersema L, Roach DE, et al. A prospective randomizedevaluator-blinded trial of two potential woundhealing agents for the treatment of venous stasisulcers. J Vasc Surg 1992;2:251–7.126. Rasmussen LH, Avnstorp C, Karlsmark T, Peters K,Hørslev-Petersen K. Dose-response study of humangrowth hormone in venous ulcers: influence onhealing and synethesis of collagen types I and III.Phlebology 1994;9:2–98.127. Freak L, Simon D, Edwards AT, Herrick SE,Ferguson M, McCollum CN. The use of topicalhuman growth hormone on chronic venousulcers. J Wound Care 1994;3(2):68–70.128. Freak L, Simon D, Edwards AT, Herrick SE,Ferguson M, McCollum CN. A study of topicalhuman growth hormone on the healing of chronicvenous ulcers. In: Harding KG, Cherry G, Dealey C,Turner TD, editors. Proceedings of the 2ndEuropean Conference on Advances in WoundManagement; 1992, Oct 20–23; Harrogate, UK.London: Macmillan Magazines, 1993:173–5.129. Rasmussen LH, Karlsmark T, Avnstorp C, Peters K,Jørgensen M, Jensen LT. Topical human growthhormone treatment of chronic leg ulcers.Phlebology 1991;6:23–30.130. Falanga V, Eaglstein WH, Bucalo B, Katz MH,Harris B, Carson P. Topical use of humanrecombinant epidermal growth factor (h-EGF)in venous ulcers. J Dermatol Surg Oncol1992;187:604–6.131. Teepe RG, Koch R, Haeseker B. Randomized trialcomparing cryopreserved cultured epidermalallografts with tulle-gras in the treatment of splitthickness skin graft donor sites. J Trauma1993;35(6):850–4.132. Tosti A, Veronesi S. Treatment employing collagenin ulcers. [Ruolo del collagene nel processo diriparazione delle ferite.] G Ital Derm Venereol1983;118(5):289–92.133. Greguric S, Budimcic D, Soldo-Belic A, Tudoric M,Baricevic B, Cajkovac V, et al. Hydrocolloid dressingversus a conventional dressing using magnesiumsulphate paste in the management of venous legulcers. Acta Dermato Venerol Croat 1994;22:65–71.134. Wilson IA, Henry M, Quill RD, Byrne PJ. The pHof varicose ulcer surfaces and its relationship tohealing. Vasa 1979;8(4):339–42.135. Bulstrode CJ, Goode AW, Scott PJ. A prospectivecontrolled trial of topical irrigation in the treatmentof delayed cutaneous healing in human leg ulcers.Clin Sci 1988;7(56):637–40.136. Bulstrode C. The use of stereophotogrammetryto measure the rate of healing in skin defects[thesis]. University of Oxford 1987:121–30.137. Wu P, Nelson EA, Reid WH, Ruckley CV, Gaylor JD.Water vapour transmission rates in burns andchronic leg ulcers: influence of wound dressingsand comparison with in vitro evaluation.Biomaterials 1996;17:1373–7.138. Dale JJ, Callam MJ, Ruckley CV. How efficientis a compression bandage? Nurs Times 1983;Nov 16:49–51.139. Majid M, Cullum N, Fletcher A, O’Meara,Sheldon T. Systematic review of interventionsfor the prevention and treatment of diabeticfoot ulceration. University of York: NHS Centrefor Reviews and Dissemination.140. Kennedy E, Song F, Hunter R, Gilbody S.Risperidone versus ‘conventional’ antipsychoticmedication for schizophrenia. In: CochraneLibrary, 1998;3. Oxford. Update Software.52

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Appendix 1Search strategiesMEDLINE search strategyMEDLINE was searched for RCTs from 1966 toOctober 1997 using a mixture of free text termsand the following subject headings:Wound infectionPilonidal cystWounds and injuriesWound healingLeg ulcerVaricose ulcerSkin ulcerDecubitusThe MEDLINE search strategy used was as follows:1. decubitus ulcer/ or foot ulcer/2. leg ulcer/ or varicose ulcer/3. pilonidal cyst/4. skin ulcer/5. diabetic foot/6. ((plantar or diabetic or heel or venous or stasisor arterial) adj ulcer$).tw.7. ((decubitus or foot or diabetic or ischaemic orpressure) adj ulcer$).tw.8. ((pressure or bed) adj sore$).tw.9. ((pilonidal adj cyst) or (pilonidal adj sinus) orbedsore$).tw.10. ((diabetic adj foot) or (cavity adj wound)).tw.11. ((varicose or leg or skin) adj ulcer$).tw.12. (decubitus or (chronic adj wound$)).tw.13. ((sinus adj wound$) or (cavity adj wound$)).tw.14. or/1–1315. debridement/ or biological dressings/ orbandages/16. occlusive dressings/ or clothing/ or woundhealing/17. antibiotics/ or growth substances/ or plateletderivedgrowth factor/18. fibroblast growth factor/ or electricalstimulation therapy.ti,ab,sh.19. lasers/ or nutrition/ or surgery/ or surgery,plastic/20. surgical flaps/ or skin transplantations/ orhomeopathy/ or homeopathic/21. acupuncture therapy/ or acupuncture/ oralternative medicine/22. alternative medicine/ or massage/ or iloprost/or alginates/23. zinc/ or zinc oxide/ or ointments/ or antiinfectiveagents/24. dermatologic agents/ or colloids/ or cushions/or wheelchairs/25. beds/ or wound dressings/26. (debridement or dressing$ or compress$ orcream$ or (growth adj factor$)).tw.27. (pressure-relie$ or (recombinant adj protein$)or bandag$ or stocking$).tw.28. (antibiotic$ or (electric adj therapy) or laser$or nutrition$ or surg$).tw.29. (homeopath$ or acupunture or massage orreflexology or ultrasound).tw.30. (iloprost or alginate$ or zinc or paste$ orointment$ or hydrocolloid$).tw.31. ((compression adj therapy) or (compressionadj bandag$) or wrap$).tw.32. (bed$ or mattress$ or wheelchair$ or (wheeladj chair) or cushion$).tw.33. ((wound adj dressing$) or vitamin$ or bind$or gauze$ or heals or healing).tw.34. (diet or lotion$ or infect$ or reduc$ or(wound adj healing)).tw.35. (treat$ or prevent$ or epidemiol$ or aetiol$or etiol$ or therap$ or prevalence orincidence).tw.36. or/15–3537. 14 and 3638. random allocation/ or randomizedcontrolled trials/39. controlled clinical trials/ or clinical trials phaseI/ or clinical trials phase II/40. clinical trials phase III/ or clinical trials phaseIV/ or clinical trials overviews/41. single-blind method/ or double-blind method/42. publication bias/ or review/ or review,academic/43. review tutorial/ or meta-analysis/ orsystematic review/44. ((random$ adj controlled adj trial$) or(prospective adj random$)).tw.45. ((random adj allocation) or random$ or(clinical adj trial$) or control$).tw.46. ((standard adj treatment) or compar$ orsingle-blind$ or double-blind$).tw.47. (blind$ or placebo$ or systematic$ or(systematic adj review)).tw.48. (randomized controlled trial or clinicaltrial).pt. or comparative study.sh.49. or/38–4853

Appendix 15450. 37 and 4951. limit 50 to human52. burns/ or wounds, gunshot/ or corneal ulcer/or exp dentistry/53. peptic ulcer/ or duodenal ulcer/ or stomachulcer/54. ((peptic adj ulcer) or (duodenal adj ulcer) ortraum$).tw.55. ((aortocaval adj fistula) or (arteriovenous adjfistula)).tw.56. (bite adj wound$).tw.57. or/52-5658. 51 not 57CINAHL search strategyThe Cumulative Index of Nursing and AlliedHealth Literature (CINAHL) search strategywas as follows:1. pressure ulcer/ or foot ulcer/ or leg ulcer/or skin ulcer/2. diabetic foot/ or diabetic neuropathies/3. diabetic angiopathies/ or diabetes mellitus/co4. pilonidal cyst/ or surgical wound infection/5. ((plantar or diabetic or heel or venous or stasisor arterial) adj ulcer$).tw.6. ((decubitus or foot or diabetic or ischaemicor pressure) adj ulcer$).tw.7. ((pressure or bed) adj sore$).tw.8. ((pilonidal adj cyst) or (pilonidal adj sinus)or bedsore).tw.9. ((diabetic adj foot) or (cavity adj wound)).tw.10. ((varicose or leg or skin) adj ulcer$).tw.11. (decubitus or (chronic adj wound$)).tw.12. ((sinus adj wound$) or (cavity adj wound$)).tw.13. or/1–1214. debridement/ or biological dressings/ orocclusive dressings/15. (bandages.ti,sh,ab,it. and “Bandages andDressings”/) or16. compression garments/ or antibiotics/17. electric stimulation/ or Laser Surgery/ orlasers/th lasers/ or Nutrition Care (SabaHHCC)/ or diet therapy/ or NutritionTherapy (Iowa NIC)/18. surgery, reconstructive/ or surgery, plastic/ orsurgical flaps/19. surgical stapling/ or skin transplantation/ oralternative therapies/20. acupuncture/ or massage/ or zinc/or ointments/21. antiinfective agents, local/ or antibiotics/ ordermatologic agents/22. dermatology nursing/ or colloids/ or bedsand mattresses/23. flotation beds/ or wheelchairs/ orpositioning:wheelchair/ orpositioning:therapy/24. patient positioning/ or positioning/ or woundcare/ or wound healing/25. (debridement or dressing$ or compress$ orcream$).tw.26. ((growth adj factor$) or pressure relie$ or(recombinant adj protein$) or bandag$).tw.27. (stocking$ or antibiotic$ or (electric adjtherapy) or laser$ or nutrition$ or surg$).tw.28. (iloprost or alginate$ or zinc or paste$ orointment$ or hydrocolloid$).tw.29. ((compression adj therapy) or (compressionadj bandag$) or wrap$).tw.30. (bed$ or mattress$ or wheelchair$ or (wheeladj chair) or cushion$).tw.31. ((wound adj dressing$) or vitamin$ or bind$ orgauze$ or heals or healing).tw.32. (diet or lotion$ or infect$ or reduc$ or etiol$or (wound adj healing)).tw.33. (treat$ or prevent$ or epidemiol$ or aetiol$ ortherap$ or prevalence or incidence).tw.34. “Bandages and Dressings”/ or skintransplantation/ or homeopathy/ orointments/ or “beds and mattresses”/35. or/14–3436. 13 and 3537. clinical trials/ or single-blind studies/ ordouble-blind studies/38. control group/ or placebos/ or meta analysis/39. ((random$ adj clinical adj trial$) or(prospective adj random$)).tw.40. ((random adj allocation) or random$ orcontrolled clinical trial$ or control).tw.41. (comparison group$ or (standard adjtreatment) or compar$).tw.42. (single-blind$ or (single adj blind) or doubleblindor (double adj blind)).tw.43. (blind$ or placebo$ or systematic or(systematic adj review)).tw.44. (meta analysis or meta-analysis).tw. or(trials or trial or prospective).tw.45. (clinical trials).sh. or (comparativestudies).sh.46. or/37–4547. 36 and 4648. burns/ or wounds, gunshot/ or cornealulcer/ or exp dentistry/49. peptic ulcer/ or duodenal ulcer/50. ((peptic adj ulcer) or (duodenal adj ulcer)or trauma).tw.51. (burn$ or (gunshot adj wound$) or(corneal adj ulcer) or dentist$ or (bite adjwound)).tw.52. or/48-5153. 47 not 52

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Additional databases searchedISI Science Citation Index (on BIDS)BIOSIS (on Silver Platter)British Diabetic Association DatabaseCISCOM, the database of the Research Councilfor Complementary MedicineCochrane Database of Systematic Reviews (CDSR)Cochrane Wounds Group register of trialsCurrent Research in Britain (CRIB)Database of Abstract of Reviews of Effectiveness(DARE)Dissertation AbstractsDHData (on Datastar, The Dialog Corporation)EconLitEMBASE (on Datastar, The Dialog Corporation)Index to Scientific and Technical Proceedings(searched on BIDS)National Research Register (to locate ongoingresearch in NHS)NHS Economic Evaluation Database (NHS CRD)Royal College of Nursing Database (CD-ROM)System for Information on Grey Literature inEurope (SIGLE, on Blaise Line)55

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Appendix 2Expert advisory panelDr Mary Bliss, *Department of Medicine for the Elderly,Homerton Hospital, LondonProfessor Andrew Boulton,Department of Medicine,Manchester Royal Infirmary, ManchesterProfessor Nick Bosanquet,Department of General Medicine,Imperial College School of Medicine, LondonDr Richard Bull,Department of Dermatology, Homerton Hospital,LondonMr Michael Callam, *Department of Vascular Surgery, Bedford Hospital,BedfordMrs Carol Dealey, *Moseley Hall Hospital, BirminghamProfessor Peter Friedman, *Department of Dermatology, Royal LiverpoolUniversity Hospital, LiverpoolMr Brian Gilchrist,Department of Nursing Studies, King’s College,LondonDr Keith Harding, *Wound Healing Research Unit,University of Wales College of Medicine,University Department of Surgery, CardiffMrs Deborah Hofman,Department of Dermatology, Churchill Hospital,OxfordMrs Vanessa Jones,Wound Healing Research Unit,University of Wales College of Medicine,University Department of Surgery, CardiffDr Christina Lindholm, SwedenDr Raj Mani,Department of Medical Physics,Southampton University Hospital, SouthamptonMs Andrea Nelson,Department of Nursing, University of Liverpool,LiverpoolDr Steve Thomas,Surgical Materials Testing Laboratory, BridgendGeneral Hospital, Mid GlamorganDr Ewan Wilkinson,Buckinghamshire Health Authority, Aylesbury* Also commented on a draft of this review andprovided helpful comments.In addition, Dr Keith Moore, Wound HealingResearch Unit, University of Wales College ofMedicine, University Department of Surgery,Cardiff, commented on parts of this review.57

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Appendix 3Excluded studiesTABLE 3 Studies excluded from the review and reasons for exclusionReference Comparison Reason for exclusionAnzai T, Shiratori A, Ohtomo E, Honda S,Yamamoto T, Nishikawa T, et al. N1-009 vs. base For considerationEvaluation of clinical utility of N1-009 on various cutaneous ulcers.in review ofComparative study with base. 1989:133–4.antimicrobialsAtri SC, Misra J, Bisht D, Misra K. Use of homologous platelet factors Homologous platelet Non-comparative trialin achieving total healing of recalcitrant skin ulcers.factors HPDWHF silverSurgery 1989;108(3):508–12.sulfadiazine dressingAttwood AI. Calcium alginate dressing accelerates split skin graft donor Calcium alginate Not an RCT. Donorsite healing. Br J Plast Surg 1989;42(4):373–9. dressing sites not consideredBarnes J, Burns K. Management of pressure sores: a comparison of Hydrocolloid Not possible toGranuflex hydrocolloid dressing and Granuflex E hydrocolloid dressing.determine theGoing into the ‘90’s:The Pharmacist and Wound Care. Eurosciencesnumber of ulcersCommunication, 1992:19–21.improved or healedBarnett AH, Odugbesan O. Seaweed-based dressings in the management Alginate fibre Review paperof leg ulcers and other wounds. Intensive Ther Clin Monit 1988;9:70–6.Beaconsfield T, Genbacev O,Taylor RS.The treatment of long-standing Placental cream No data on proportionvenous ulcers with an extract of early placenta – pilot study.healed in control groupPhlebology 1991;6:153–8.Berry DP, Bale S, Harding KG. Dressings for treating cavity wounds. Polyurethane foam Subjective outcomeJ Wound Care 1996;5(1):10–13. vs. alginate measureBlair SD,Wright DD, Backhouse CM, Riddle E, McCollum CN. Four-layer bandage Considered forSustained compression and healing of chronic venous ulcers.bandage reviewBMJ 1988;297(6657):1159–61.Brady SM. Management of pressure sores with occlusive dressings in Duoderm or Opsite Did not measurea select population. Nurs Manag 1987;18:47–50. vs. traditional dressing healing rateBucknall T. Experimental and clinical studies on abdominal wound Monofilament nylon Evaluates sutures ratherinfection [unpulished PhD thesis]. London, UK: London University; sutures vs. polyglycolic than wound or topical1981:196–252. acid sutures application dressingButler CM,Topp SM, Coleridge-Smith PD. A comparative randomized Comfeel Plus vs. No data providedstudy on the performance of Comfeel Plus ulcer dressing and Granuflex Granuflex on healing ratesin the healing of leg ulcers. In: Cherry GW, Gottrup F, Lawrence JC,Moffatt CJ,Turner TD, editors. Proceedings of the 5th EuropeanConference on Advances in Wound Management; 1995 Nov 21–24;Harrogate, UK. London: Macmillan Magazines, 1996:274–5.Callaghan DP. Assessment of the effectiveness of Debrisan in healing Debrisan vs. disdaine No data on healingulceration on pressure areas of diabetic patients’ feet. In: Harding KG, dressings in one groupCherry G, Dealey C,Turner TD, editors. Proceedings of the 2nd EuropeanConference on Advances in Wound Management; 1992, Oct 20–23;Harrogate, UK. London: Macmillan Magazines, 1993:82.Chaloner DM, Milward PA, Skitt PJ. A community-based clinical trial of Activated charcoal and Outcome not healingthree dressings in the treatment of leg ulceration. Proceedings of the 1st silver dressing vs.European Conference on Advances in Wound Management; 1991 Sep paraffin gauze4–6; Cardiff, UK. London: Macmillan Magazines, 1992:148–9.continued59

Appendix 3TABLE 3 contd Studies excluded from the review and reasons for exclusionReference Comparison Reason for exclusionCheneworth CC, Hagglund KH,Valmassoi B, Brannon C. Portrait of Foam boot Pressure sorepractice: healing heel ulcers. Adv Wound Care 1994;7(2):44–8.preventionCherry GW, Powell SM, Ryan T. The efficacy of mupirocin in the Antibiotics – topical Considered in themanagement of venous leg ulcers. In: Harding KG, Cherry G, Dealey C,review of antimicrobialsTurner TD, editors. Proceedings of the 2nd European Conference onAdvances in Wound Management; 1992 Oct 20–23; Harrogate, UK.London: Macmillan Magazines, 1993:214.Collier J. A moist, odour-free environment. A multicentred trial of a Hydrocolloid vs. No data on healing –foamed gel and a hydrocolloid dressing. Professional Nurse 1992; foamed gel mentions ‘improved’7(12):804–8.Cony M, Donatien PH, Beylot C, Geniaux M, Maleville J, Bezian JH,et al. Treatment of leg ulcers with an allogenic cultured-keratinocytecollagendressing. Clin Exp Dermatol 1990;15:410–14.Cooper R, Bale S, Harding KG. An improved cleansing regime fora modified foam cavity dressing. In: Harding KG, Dealey C, Cherry G,Gottrup F, editors. Proceedings of the 3rd European Conference onAdvances in Wound Management; 1993 Oct 19–22, Harrogate, UK.London: Macmillan Magazines, 1994.Cultured keratinocytes No control groupComparison of methodsof cleaning dressingCordts PR, Lawrence M, Hanrahan LM, Augustin A, Rodriguez AA, Unna’s Boot vs. Considered inWoodson J, et al. A prospective, randomized trial of Unna’s boot hydrocolloid compression reviewversus Duoderm CGF hydroactive dressing plus compression in themanagement of venous leg ulcers. J Vasc Surg 1992;15(3):480–6.Creese AL, Bale S, Harding KG, Hughes LE. Management of open Silastic foam dressing No outcome of healinggranulating wounds. Physician 1986;February:637–9.vs. gauze dressingDale JJ, Ruckley CV, Harper DR, Gibson B, Nelson EA, Prescott RJ. Oxpentifylline Trial of oral treatmentA randomised, double-blind placebo controlled trial of oxpentifyllinenot dressingin the treatment of venous leg ulcers. In: Negus D, editor. Phlebology‘95. Phlebology 1995;(Suppl 1):917–18.Danielson L, Madsen SM,Westh H. Rates of infection of chronic leg Hydrocolloids Outcome not healingulcers dressed with a hydrocolloid dressing or given an alternativetreatment. In: Harding KG, Cherry G, Dealey C,Turner TD, editors.Proceedings of the 2nd European Conference on Advances in WoundManagement; 1992 Oct 20–23; Harrogate, UK. London: MacmillanMagazines, 1993:97.Degreef H.Treatment of four arteriolar ulcers with topical 2% Ketanserin No comparison groupKetanserin. Curr Ther Res 1988;44(1):100–4.Diem E. [Clinical trial of a new occlusive dressing in the management Hydrocolloid Not an RCTof venous stasis ulceration]. Aktuel Dermatol 1987;13(6):269–72.Eriksson G. Bacterial growth in venous leg ulcers – its clinical significance Bacterial growthin the healing process. In: Ryan TJ, editor. An environment for healing:the role of occlusion. J R Soc Med 1984:44–9.Outcome bacterialgrowthFish FS, Katz I, Hien N, Briden ME, Johnson JA, Patt LM. Evaluation of Glycyl-histidyl– Mohs surgeryglycyl-histidyl-L-lysine copper complex in acute wound healing.L–lysine vs. copperWounds 1991;3:171–7.complex vs. PC1020Fowler EM. New, once-daily pressure sore dressing speeds healing. Bard absorption No outcome dataRegistered Nurse 1983;46(4):56–7.dressing vs. wet-todrydressing60continued

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 3 contd Studies excluded from the review and reasons for exclusionReference Comparison Reason for exclusionFreak L, Simon D, Kinsella A, McCollum C,Walsh J, Lane C. Leg ulcer Leg ulcer costs Not a trial of effectivecare:an audit of cost-effectiveness. Health Trends 1995;27:133–6.ness of dressingsFriedman SJ, Su WP. Management of leg ulcers with hydrocolloid Hydrocolloid Not an RCTocclusive dressing. Arch Dermatol 1984;120(10):1329–36.Genster HG, Oram V. [Arterial insufficiency in the lower extremities Testosterone vs. Not randomised.treated with drugs]. Ugeskr Laeger 1971;133(6):244–6. steroids vs. callicreine Results of ulcer healingvs. depot-padutin not presented separatelyfrom gangreneGibson B. A cost effectiveness comparison of two gels in the treatment Hydrogels vs. Intrasite Included inof sloughy leg ulcers. Advanced Wound Care Symposium; 1995, April;debridement reviewSan Diego.Wayne, PA: Health Management Publications, 1995.Gupta R, Foster ME, Miller E. Calcium alginate in the management of Alginates vs. proflavine Outcome measureacute surgical wounds and abcesses. J Tissue Viability 1991;1(4):115–16.not healingHalbert AR, Stacey MC, Rohr JB, Jopp McKay A.The effect of bacterial Calcium alginate vs. Not a trial ofcolonization on venous ulcer healing. J Dermatol 1992;33(2):75–80. bandages vs. viscopaste effectivenessvs. acobandof dressingsHall P. Prophylactic use of Op-Site on pressure sores. Pressure sore Not an RCTNurs Focus 1983;Jan/Feb:148.prevention vs. OpsiteHunyadi J, Farkas B, Bertenyi C, Olah J, Dobozy A. Keratinocyte Keratinocyte grafting No appropriategrafting: a new means of transplantation for full-thickness wounds.outcome measuresJ Dermatol Surg Oncol 1988;14(1):75–8.Johnson A. Dressings for deep wounds.Allevyn cavity wound dressing. Allevyn cavity wound No data on effective-Nurs Times 1992;88(4):58. dressing vs. Granuflex ness (area of woundspasteor % healed)Klostermann GF, Jakob H. [Comparative testing of a new cream-base Topical applications Crossover trial withagainst unguentum diachylon in ulcus cruris]. Munchener Medizinischeno data on healing atWochenschrift 1974;116(23):1169–70.crossover pointLa Grenade L,Thomas PW, Serjeant GR. A randomized controlled trial DuoDerm vs. Sickle-cell ulcersof solcoseryl and duoderm in chronic sickle-cell ulcers. West Indian solcoserylMed J 1993;42(3):121–3.Leaper DJ, Cameron S, Hewitt H,Winter A, Lucarotti ME. A community- Comfeel vs. jelonet Crossover trial withand hospital-based comparative evaluation of Comfeel Ulcer Dressingsno data on healing atfor chronic leg ulcers. J Dermatol Treat 1991;2:103–6.crossover pointLees V, Ilyas S, Reid CD. A comparison of the use of polythene sheet Polythene sheet vs. Outcome painand Jelonet as temporary dressings for excised wounds. Br J Plast Surg jelonet not healing1991;44(8):612–4.Limova M, Mauro T. Treatment of leg ulcers with cultured epithelial Cultured epithelial No control groupautografts: clinical study and case reports. Ostomy Wound Manag autografts applications1995;41(8):48–50. 52:54–60.Lookingbill DP, Miller SH, Knowles RC. Bacteriology of chronic leg Benzoyl peroxide For consideration inulcers. Arch Dermatol 1978;114:1765–8.review of antimicrobialsMangete EDO,West KS, Blankson CD. Hypertonic saline solution: Hypertonic saline No data givenan effective wound dressing. East African Med J 1993;70(2):104–6. solution on healingMånsson T. Double bandage with ointment stocking as therapy for Compression Not an RCTvenous leg ulcers. elastic roller vs double bandage. J Dermatol Treat bandages1994;5(3):123–6.continued61

Appendix 3TABLE 3 contd Studies excluded from the review and reasons for exclusionReference Comparison Reason for exclusionMilward P, Siddle H, Johnson M, Bridgewater A. A user evaluation on the Triple-care cleanser Evaluation of a skinTriple Care cleanser and cream system examining impact on pressure ulcertreatment rather thanincidence in a long term care centre. Poster presented at the 5th Europeanwound dressingConference on Advances in Wound Management; 1995 Nov 21–24;Harrogate, UK.Mulder G, Jones R, Cederholm-Williams S, Cherry G, Ryan T. Fibrin cuff Hydrocolloid No data on healinglysis in chronic venous ulcers treated with a hydrocolloid dressing.Int J Dermatol 1993;32(4):304–6.Müller K, Matzen E, Gottrup F. Treatment of incisional wound defects Hydrocolloids No data onfollowing laparotomy, in relation to treatment effect, time consumptionhealing outcomesand economy. A methodological description. Proceedings of the 3rdEuropean Conference on Advances in Wound Management. 1994:30–2.Myers SA,Takiguchi S, Slavish S, Rose CL. Consistent wound care and Consistant wound care Not an evaluation ofnutritional support in treatment. Decubitus 1990;3(3):16–28. (cleansing povidone dressings or topicaliodine solution, saline preparationsrinse, Opsite dressing)vs. controlled nutritionalsupport vs. consistantwound care + nutritionalsupport vs. standardhospital treatment(various dressings andsupport surfaces)Nowak A, Bowszyc P, Blaszczyk M. A randomised, controlled, parallel Lyofoam extra dressing No data on healinggroup clinical trial of a new polyurethane foam dressings versus calcium vs. Sorbsanalginate dressing in the treatment of moderately to heavily exuding venousulcers. Lyofoam Extra dressing vs Sorbsan. Poster presented at the 5thEuropean Conference on Advances in Wound Management. 1995 Nov.Petres et al. Alginates versus hydrocolloids in the treatment of venous leg Kaltostat vs. Granuflex Outcome measureulcers. In: Harding KG, Dealey C, Cherry E, Gottrup F, editors. Proceeding‘complete or partialof the 3rd European Conference on Advances in Wound Management;healing’ with no1993 Oct 19–22, Harrogate, UK. London: Macmillan Magazines, 1994:165. breakdown or definitionPierce GF,Tarpley JE, Allman RM, Goode PS, Serdar CM, Morris B, et al. r-PDGF-BB 100 µg/ml Outcome electronTissue repair processes in healing chronic pressure ulcers treated with x r-PDGF-BB microscopyrecombinant platelet-derived growth factor BB. RPDGF-BB 100 µg/ml 300 µg/ml x placebox rPDGF-BB 300 µg/ml x placebo. Am J Pathol 1994;145(6):1399–410.PittÌ G, Milnes M, McMackin S, Boughey F, Fako W. A multi-phase, open Comfeel Plus dressing Conflicting results.label, randomized, parallel comparative study of two hydrocolloid vs. DuoDerm CGF Coloplast contacted fordressings on patients with stage II and stage III exudating pressure ulcers.clarification – no replyComfeel Plus dressing vs Duoderm CGF. Poster presented at theWound Ostomy and Continence Nurses annual conference.Polous et al. [Local-action preparations in treating trophic ulcers in Chonsurid, solcoseryl, Not an RCT.patients with vascular failure]. Vrach Delo 1985;1(10):57–9. lyzozyme Preparations usedpreoperativelyPoole M, Milward P. A randomised prospective crossover trial to investi- Melolin vs. carbonet No data on healinggate the use of an odour-absorbing dressing with a four-layer bandagesystem. Principles, Progress and Practice in Wound Care; 1994 Nov15–17; Harrogate, UK. London: Macmillan Magazines, 1995.Resl V Jr. [Use of ion exchange in therapy of ulcer cruris]. Ion exchange Not an RCTDermatologische Monatsschrift 1973;159(3):249–57.62continued

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 3 contd Studies excluded from the review and reasons for exclusionReference Comparison Reason for exclusionSashchikova VG, Vasil’ev MP, Pukhova ZI. [Use of a fibrous soluble Collagen Not an RCTcollagen preparation in treating trophic ulcers of the lowerextremities]. Vestn Khir 1980;124(1):131–2.Shutler S, Stock J, Bale S, Harding KG, Squires D,Wilson I, et al. A Allevyn adhesive vs. No data on healingmulti-centre comparison of a hydrocellular adhesive dressingGranuflex hydro-(Allevyn Adhesive) and a hydrocolloid dressing (Granuflex) in the colloid dressingmanagement of stage 2 and 3 pressure sores. Allevyn Adhesive vsGranuflex hydrocolloid dressing. Poster presented at the 5th EuropeanConference on Advances in Wound Management; 1995 Nov 21–24;Harrogate, UK.Sironi G, Losa S, DiLuca G, Pezzoni F. Treatment of venous leg ulcers Allevyn, Intrasite No data on healingwith Intrasite gel. OpSite Flexigrid, Allevyn hydrocellular dressing and and Opsite or ulcer areaFlexobande (elastic compression bandage) in vascular surgery. Aprotocol for clinical evaluations. In: Harding KG, Dealey C, Cherry G,Gottrup F, editors. Proceedings of the 3rd European Conference onAdvances in Wound Management; 1993 Oct 19–22; Harrogate, UK.London: Macmillan Magazines, 1994:164.Stahl KW, Chastang C. Promotion healing of arterial and venous ulcers Tetrachlorideca- No objective measureby TCDO. Insight in mechanisms of tissue repair.Tetrachloridecaoxygen oxygen anion of healinganion complex (TCDO). Fortschr Med 1988;106(1):44–6.complexTarvainen K. Cadexomer iodine (Iodosorb) compared with Cadexomer iodine Included indextranomer (Debrisan) in the treatment of chronic leg ulcers. vs. dextranomer debridement reviewActa Chir Scand Suppl 1988;544:57–9.Van-Den-Hoogenband HM.Treatment of leg ulcers with split-thickness Silver sulfadiazine Historical controlskin grafts. Silver sulfadiazine pre-operatively + split thickness skin grafts preoperatively + splitvs split thickness skin grafts only. J Dermatol Surg Oncol 1984;10(8):605–8. thickness skin graftsvs. split thicknessskin grafts onlyVande Berg JS, Robson MC, Mikhail RJ. Extension of the life span of RhuI1-1beta Outcome basedpressure ulcer fibroblasts with recombinant human interleukin-1β. 0.01 µg/cm/day vs. on histologyRhuI1-1β 0.01µg/cm 2 /day vs 0.1µg/cm 2 /day vs 1µg/cm 2 /day vs placebo. 1 µg/cm/day vs.Am J Pathol 1995;146(5):1273–82.placeboWard DJ, Bennett JP, Burgos H, Fabre J.The healing of chronic venous Tissue-culture- Compares fourleg ulcers with prepared human amnion.Tissue-culture-maintained human maintained human methods of preparingamnion vs frozen human amnion vs fresh human amnion vs lyophilised amnion vs. frozen amnion. No controlhuman amnion. Br J Plast Surg 1989;42(4):463–7. human amnion vs. group, thereforefresh human amnion effectiveness of amnionvs. lyophilised human not assessedamnionWatts C, Lee S. Comparison of Allevyn Cavity Wound Dressing to Allevyn cavity wound No data on healingsaline-moistened gauze. In: Harding KG, Dealey C, Cherry G, Gottrup dressing vs. saline-F, editors. Proceedings of the 3rd European Conference on Advances moistened gauzein Wound Management; 1993 Oct 19–22; Harrogate, UK. London:Macmillan Magazines, 1994.Wethers DL, Ramirez GM, Koshy M, Steinberg MH, Phillips G Jr, Siegel RGD peptide matrix Sickle-cell ulcersRS, et al. Accelerated healing of chronic sickle-cell leg ulcers treated vs. saline placebowith RGD peptide matrix. RGD Study Group. RGD peptide matrixvs saline placebo. Blood 1994;84(6):1775–9.continued63

Appendix 3TABLE 3 contd Studies excluded from the review and reasons for exclusionReference Comparison Reason for exclusionWinter A, Hewitt H.Testing a hydrocolloid. Comfeel dressing vs paraffin Comfeel dressing Crossover design withgauze. Nurs Times 1990; 86; (50):59–62. vs. paraffin gauze no report of outcomeat point of crossoverWyszynska Z, Blonska B, Czaplicki J. [Trial use of embryonal and early- Growth factors Not an RCTfetal thymus extractsin the treatment of non-healing skin defects. II.Crural ulcers in humans.] Przegl Dermatol 1987;74:309–15.Zeegelaar JE, Mekkes JR,Westerhof W. Evaluation of clinical wound Iodosorb vs. No data on healinghealing trials using a CIA system. Iodosorb vs DuoDERM E vs Jelonet DuoDerm E vs.gauze. In: Cherry GW, Leaper DJ, Lawrence JC, Milward P, editors. jelonet gauzeProceedings of the 4th European Conference on Advances in WoundManagement; 1994 Sep 6–9; Copenhagen, Denmark. London: MacmillanMagazines, 1995:200.64

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Appendix 4Interpretation of forest plotsThe figure below shows a forest plot as usedin this review. The diagram represents acomparison between hydrocolloid dressings andfoam dressings for the treatment of venous legulcers. For each individual trial the OR result isplotted as a single black square. The lines eitherside of the OR represent the 95% CI for thatresult. The ORs from the two trials have beencombined in a meta-analysis, the result of whichis represented by the black diamond towardsthe bottom of the figure. The horizontal widthof this diamond represents the CI for themeta-analysis.The horizontal axis at the bottom of the figureshows the numerical value of each OR and thevertical line in the centre represents the ‘lineof no effect’, where the OR is 1 (i.e. treatmentand control show equal benefit).In order to extract useful information from a forestplot it is necessary to establish the following:• the nature of the intervention underinvestigation (given in title)• the outcomes being measured (stated in thestudy details on the left side of the figure)• whether each outcome is good/positive(of benefit) or bad/negative (of harm)• whether the OR (or mean difference for themeta-analysis) falls to the left or right of theline of no effectZuccarelli, 1993 113Comparison: Foam (Allevyn) vs. Hydrocolloid (Granuflex)Mean baseline area (cm 2 ): 9.8 6.9Sample size (N): 19 19No. of wounds healed (n/N): 9/19 9/19 1.0 (0.28, 3.58)% of wounds healed: 47 47Wound type: Venous leg ulcersFollow-up time: 12 weeksBowszyc et al., 1993 114Comparison: Foam vs. Hydrocolloid(Lyofoam)(Comfeel)Median baseline area (cm 2 ): 3.01 3.05Sample size (N): 40 40No. of wounds healed (n/N): 24/40 24/40 1.0 (0.4, 2.4)% of wounds healed: 60 60Wound type: Venous leg ulcersFollow-up time: 16 weeksPooled estimate (fixed-effects model)Comparison: Foam vs. HydrocolloidTotal no. of wounds healed (n/N): 33/59 (56%) 33/59 (56%) 1.00 (0.48, 2.08)χ 2 = 0.00; df = 1; z = 0.00; p = 10.01 0.1 1 10 100 OR(95% CI)Favours foamFavours hydrocolloidFIGURE 16 Hydrocolloid compared with foam dressing for venous leg ulcer65

Appendix 4• whether the CIs cross the line of no effect• whether the meta-analysis result ‘looks’ to be afair representation of the individual trial results.If a bad/negative outcome, such as recurrence ofdisease, is measured for a given intervention, thena beneficial result will be one in which the OR isless than one or to the left of the line of no effect(i.e. the intervention results in less of the outcomeand the OR approximates to the proportion of thetreatment group that experience the outcomecompared with the control group). Similarlybeneficial results for good/positive outcomeshave ORs greater than one.If the horizontal CI line crosses the vertical line ofno effect then the result (shown by the OR squareor diamond) does not show a clear or conclusiveeffect. In this systematic review we have used 95%CIs. The CI represents the range in which we are95% confident that the true result of the study lieswhen the result from the individual trial or metaanalysis is extrapolated to the whole of the populationthat was originally sampled in the study.Put another way, this means that, in theory, in95 out of 100 trials we can be confident that theresult will lie somewhere along the horizontal CIline. If the CI crosses the line of no effect then,because we can only be 95% certain that theresult is somewhere along that line, it is possiblethat a result which looks beneficial may in factbe harmful or vice versa. In this situation, theresult would be recorded as inconclusive orof uncertain benefit.The visual appreciation of the results of a reviewwould be the first step in using the review to guidea healthcare decision.The plots used in this systematic review also showthe difference in healing rates when expressed asa percentage or actual reduction in area, bothof which are continuous variables. The differencebetween these values is described as the effect size(ES). With continuous variables the line of noeffect falls at zero instead of 1 as when ORs areused. However, interpretation of the results isidentical to that for OR results (e.g. a result lyingto the left (less than zero) of the line of no effectmeans that the rate of ulcer healing in theintervention group is lower in the treatmentgroup than in the control group).66

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Appendix 5Quality assessment of RCTsTABLE 4 Quality assessment of RCTs of dressings and topical applications for surgical woundsStudy Inclusion and Overall A priori Randomisation Appropriate Blinded Withdrawals ITTexclusion sample sample procedure baseline outcome stated † analysisciteria size size stated characteristics assessmentstated [arms] calculation? reported * reportedSchmidt & ✔ 40 patients + (but fewer ✔ ✔ ✗ ✔b ✗Greenspoon, 1991 38 [2] patients usedthan theanalysissuggested)Butterworth et al., ✔ 80 [2] ✗ ✗ ✔c ✗ ✗ ✗1992 37Williams et al., 1981 35 ✗ 80 [2] ✗ ✗ ✔c ✗ ✗ ✗Macfie & McMahon, ✔ 50 [2] ✗ ✗ ✔c ✗ ✔a ✗1980 34Walker et al., 1991 36 ✗ 75 [2] ✗ ✗ ✔ ✗ N/A N/A✔ = Yes; ✗ = No; N/A = not appropriate (no withdrawals)*Baseline characteristics: ✔ = one or more appropriate characteristics stated (but not initial wound size); ✔c = initial wound size stated†Withdrawals: ✔a = reported by group and with reason; ✔b = withdrawals but not reported by group or reason not given; ✗ = withdrawals not reported67

Appendix 5TABLE 5 Quality assessment of RCTs of dressings and topical applications for pressure soresStudy Inclusion and Overall A priori Randomisation Appropriate Blinded Withdrawals ITTexclusion sample sample procedure baseline outcome stated † analysisciteria size size stated characteristics assessmentstated [arms] calculation? reported * reportedBrod et al., 1990 66 ✔ 43 [2] ✗ ✗ ✔c ✗ ✔a ✗Colwell et al., 1993 54 ✔ 70 [2] ✗ ✗ ✔c ✗ ✔a ✗Barrois, 1993; 52 ✔ 76 [2] ✗ ✗ ✔c ✗ ✔a ✗Huchon, 1992 53Bale et al., 1995 62 ✗ 100 [2] ✗ ✗ ✔ ✗ ✔a ✗Banks et al., 1996 65 ✔ 98 [2] ✗ ✗ ✔c ✗ N/A N/ABrown-Etris et al., ✔ 121 [2] ✗ ✗ ✔ ✔ ✔b ✗1996 46Alm et al., 1989 51 ✗ 50 [2] ✗ ✗ ✔c ✔ ✔b ✗Hondé et al., 1994 67 ✔ 168 [2] ✗ ✔ ✔c ✗ ✔a ✗Banks et al., 1994 64 ✔ 40 [2] ✗ ✔ ✔c ✗ ✔a ✗Banks et al., 1994 63 ✔ 29 [2] ✗ ✗ ✔c ✗ ✔a ✗Banks et al., 1994 68 ✔ 50 [2] ✗ ✔ ✔c ✗ ✔b ✗Kraft et al., 1993 61 ✔ 38 [2] ✗ ✗ ✔ ✗ ✔a ✔Xakellis & ✔ 39 [2] ✗ ✗ ✔c ✗ ✔a ✔Chrischilles, 1992 55Oleske et al., 1986 57 ✔ 15 [2] ✗ ✗ ✔c ✗ ✔b ✗Sebern, 1986; 58 ✔ 200 [2] ✗ ✔ ✔c ✗ ✔b ✗1989 59Van Ort & Gerber, ✔ 14 [2] ✗ ✔ ✔ ✗ N/A N/A1976 39Mustoe et al., 1994 43 ✔ 41 [3] ✗ ✗ ✔c ✔ ✔a ✗Robson et al., 1992 45 ✔ 20 [4] ✗ ✗ ✔c ✔ N/A N/ARobson et al., 1992 44 ✔ 50 [3] ✗ ✗ ✔c ✔ ✔a ✗Robson et al., 1994 42 ✔ 26 [4] ✗ ✗ ✗ ✗ ✔b ✗Saydak, 1990 60 ✔ 16 lesions ✗ ✗ ✔c ✗ N/A N/A[2]LeVasseur & Helme, ✗ 21 [2] ✗ ✗ ✔c ✗ N/A N/A1991 40Tytgat & Van Asch, ✗ 16 [2] ✗ ✗ ✔c ✔ N/A N/A1988 41Gorse & Messner, ✔ 52 [2] ✗ ✗ ✔ ✗ N/A N/A1987 56Palmieri, 1992 50 ✔ 48 [2] ✗ ✗ ✔ ✗ N/A N/ADarkovich et al., ✔ 90 patients ✗ ✗ ✔c ✗ ✔a ✗1990 47 129 wounds[2]Mulder et al., 1993 48 ✔ 67 [3] ✗ ✔ ✔ ✗ ✔b ✗Sayag et al., 1996 49 ✔ 92 [2] ✔ ✔ ✔c ✗ ✔a ✔68✔ = Yes; ✗ = No; N/A = not appropriate (no withdrawals)*Baseline characteristics: ✔ = one or more appropriate characteristics stated (but not initial wound size); ✔c = initial wound size stated†Withdrawals: ✔a = reported by group and with reason; ✔b = withdrawals but not reported by group or reason not given; ✗ = withdrawals not reported

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 6 Quality assessment of RCTs of dressings and topical agents for leg ulcersStudy Inclusion and Overall A priori Randomisation Appropriate Blinded Withdrawals ITTexclusion sample sample procedure baseline outcome stated † analysisciteria size size stated characteristics assessmentstated [arms] calculation? reported * reportedAcosta et al., 1992 86 ✔ 12 [2] ✗ ✔ ✗ ✗ ✗ ✗Armstrong et al., ✔ 44 [2] ✗ ✔ ✗ ✗ ✔b ✗1996 80Arnold et al., 1994 99 ✔ 70 patients [2] ✗ ✗ ✔c ✗ ✔a ✗90 ulcersBackhouse et al., ✔ 56 [2] ✗ ✗ ✔c ✗ ✗ ✗1987; 98 Blair et al.,1988 104Bale et al., 1995 62 ✗ 30 [2] ✗ ✗ ✗ ✗ ✔a ✗Bandrup et al., 1990 79 ✔ 43 [2] ✗ ✗ ✔ c ✗ ✗ ✔Banerjee et al., 1990 94 ✗ 71 [2] ✗ ✗ ✔c ✗ ✔b ✗Banks et al., 1996 65 ✔ 100 [2] ✗ ✔ ✔c ✗ ✗ ✗Bishop et al., 1992 125 68 [3]Bowszyc et al., ✔ 80 patients, ✗ ✔ ✔c ✗ ✗ ✔1994 114 82 legs [2]Bulstrode et al., ✔ 48 [4] ✗ ✔ ✔c ✗ ✗ N/A1988 135Burgess & Robinson, ✔ 121 [3] ✗ ✗ ✗ ✗ ✗ ✗1993; 108 Robinson,1993; 109 Burgess,1993 110Calabro et al., 1995 85 ✗ 80 [2] ✗ ✗ ✗ ✗ ✗ ✗Callam et al., 1992 90 ✔ 132 [2] ✗ ✗ ✔c ✗ ✔a ✔Caprio et al., 1995 105 ✗ 93 [2] ✗ ✗ ✗ ✗ ✔b ✗Davis et al., 1992 93 ✗ 11 patients [2] ✗ ✗ ✗ ✗ ✗ ✗12 ulcersDuhra et al., 1992 119 ✔ 22 patients [2] ✗ ✗ ✔c ✗ ✔a ✔30 ulcersFalanga et al., 1992 130 ✔ 45 [2] ✗ ✗ ✔c ✔ ✔b ✗Freak et al., 1994; 127 ✔ 26 [4] ✗ ✗ ✔c ✔ ✗ ✔1993 128Galasso et al., 1978 116 ✗ 62 [2] ✗ ✗ ✔c ✗ ✔b ✔Gibson et al., 1986 69 ✗ 22 [2] ✗ ✔ ✔c ✗ ✔a ✗Greguric et al., 1994 133 ✔ 110 [2] ✗ ✔ ✗ ✗ ✗ ✗Groenewald, 1984 103 ✗ 72 [2] ✗ ✗ ✗ ✔ ✔a ✗Holzinger et al., ✗ 63 [2] ✗ ✗ ✔ ✗ ✗ ✗1994 70✔ = Yes; ✗ = No; N/A = not appropriate (no withdrawals)*Baseline characteristics: ✔ = one or more appropriate characteristics stated (but not initial wound size); ✔c = initial wound size stated†Withdrawals: ✔a = reported by group and with reason; ✔b = withdrawals but not reported by group or reason not given; ✗ = withdrawals not reportedcontinued69

Appendix 5TABLE 6 contd Quality assessment of RCTs of dressings and topical agents for leg ulcersStudy Inclusion and Overall A priori Randomisation Appropriate Blinded Withdrawals ITTexclusion sample sample procedure baseline outcome stated † analysisciteria size size stated characteristics assessmentstated [arms] calculation? reported * reportedKnighton et al., ✔ 32 [2] ✗ ✔ ✔c ✗ ✔a ✗1988 82Limova et al., 1996 111 ✗ 20 [2] ✗ ✗ ✗ ✗ ✗ ✗Lindholm et al., ✗ 28 [2] ✗ ✗ ✗ ✗ ✗ ✗1993; 73 Lindholm,1995; 74 Lindholm,1994; 75 Ohlssonet al., 1994 72Mansson, 1996 101 ✗ 153 [3] ✗ ✗ ✔c ✗ ✔a ✔Meredith & Gray, ✗ 49 [2] ✗ ✔ ✔c ✗ ✔a ✗1988 100Mian et al., 1991; 76 ✗ 50 [2] ✗ ✗ ✔c ✗ ✗ ✗1992 77Milward, 1991 102 ✗ 38 [2] ✗ ✗ ✗ ✗ ✗ ✗Moffatt et al., 1992 88 ✔ 60 [2] ✗ ✗ ✔c ✗ ✗ ✗Moffatt et al., 1992 97 ✔ 60 [2] ✔ ✔ ✔c ✗ ✔b ✗Nelson et al., 1995 96 ✔ 200 [2] ✔ ✔ ✔c ✗ ✗ ✔Nyfors et al., 1982 78 ✔ 34 [2] ✗ ✗ ✗ ✗ ✗ ✗Palmieri, 1992 50 ✗ 48 [2] ✗ ✗ ✗ ✗ ✗ N/APassarini et al., ✗ 48 [2] ✗ ✗ ✗ ✗ ✗ ✗1982 115Pessenhoffer & ✗ 48 [2] ✗ ✗ ✔c ✗ ✔b ✗Stangl, 1989; 911992 92Rasmussen et al., ✔ 102 [4] ✔ ✗ ✔c ✗ ✔ ✔1991; 129 1994 126Rundle et al., ✗ 26 patients [2] ✗ ✗ ✔c ✗ ✔ ✗1981 117 48 ulcersSabolinski et al., ✗ 233 [2] ✗ ✗ ✗ ✗ ✗ ✗1996 118Salim, 1991 123 ✔ 153 [3] ✔ ✔ ✔c ✗ ✔a ✔Salim, 1992 124 ✔ 168 [3] ✔ ✔ ✔c ✗ ✔a ✔Smith, 1994 106 ✔ 40 [2] ✗ ✗ ✔c ✗ ✔a ✗Smith et al., 1992 95 ✔ 200 [2] ✗ ✔ ✔c ✗ ✔a ✗Stacey et al., ✔ 113 patients [3] ✗ ✗ ✔c ✗ ✔a ✗1992; 89 1997 133 limbsStromberg et al., ✔ 37 [2] N/A ✔ ✔c ✔ ✔b ✗1984 83✔ = Yes; ✗ = No; N/A = not appropriate (no withdrawals)*Baseline characteristics: ✔ = one or more appropriate characteristics stated (but not initial wound size); ✔c = initial wound size stated†Withdrawals: ✔a = reported by group and with reason; ✔b = withdrawals but not reported by group or reason not given; ✗ = withdrawals not reported70continued

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 6 contd Quality assessment of RCTs of dressings and topical agents for leg ulcersStudy Inclusion and Overall A priori Randomisation Appropriate Blinded Withdrawals ITTexclusion sample sample procedure baseline outcome stated † analysisciteria size size stated characteristics assessmentstated [arms] calculation? reported * reportedTeepe et al., 1993 131 ✔ 43 patients [2] ✔ ✗ ✔c ✗ ✔ ✗47 ulcersTorregrossa & ✗ 43 [2] ✗ ✗ ✔ ✗ ✗ ✔Caroti, 1983 84Tosti & Veronesi, ✗ 22 [2] ✗ ✗ ✔c ✗ ✔ ✗1983 132Tsakayannis et al., ✔ 9 patients [2] ✗ ✗ ✗ ✗ ✗ ✗1994 122 10 woundsVeraart et al., ✔ 38 [2] ✗ ✔ ✗ ✗ ✔a ✗1994 107Werner-Schlenzka ✔ 148 [3] ✗ ✗ ✔c ✗ ✗ ✗& Kuhlmann, 1994 121Werner-Schlenzka ✔ 99 [2] ✗ ✗ ✔c ✗ ✔a ✔& Lehnert, 1994 120Whipps Cross, 112 ✗ 29 [2] ✗ ✗ ✔c ✗ ✔b ✗Wilson et al., ✗ 36 [2] ✗ ✗ ✗ ✗ ✔a ✗1979 134Wunderlich & ✔ 40 [2] ✗ ✗ ✔c ✗ ✗ ✗Orfanos, 1991 87Zuccarelli, 1993 113 ✔ 40 [2] ✗ ✗ ✔c ✗ ✔b ✗✔ = Yes; ✗ = No; N/A = not appropriate (no withdrawals)*Baseline characteristics: ✔ = one or more appropriate characteristics stated (but not initial wound size); ✔c = initial wound size stated†Withdrawals: ✔a = reported by group and with reason; ✔b = withdrawals but not reported by group or reason not given; ✗ = withdrawals not reported71

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Appendix 6Studies of treating non-healing surgical woundsTABLE 7 Dressings compared with traditional treatments for the management of surgical wounds healing by secondary intentionStudy Inclusion/ Intervention Baseline Results Withdrawals Commentsand design exclusion details characteristicscriteriaMacfie &McMahon, 1980 34UKWound type:Perineal wounds(surgery).Method ofrandomisation:Not stated.Objectiveoutcome:Time to healing.Setting and lengthof treatment:Community-basedtrial with assessmentundertakenat an outpatientclinic.Treatmentcontinued untilall wounds hadhealed.Inclusion criteria:Patients who hadundergone eitherproctocolectomyor rectalexcisions.Exclusion criteria:No exclusion.Treatment:I: Silicone foam cavitydressing (Silastic Foam ® )applied to the woundcavity by a syringe.Afterexpansion and setting itwas removed, reshapedand then replaced.Thefoam was covered witha dry dressing. Patientsremoved the foam twicea day and took a salt bath.The foam was washed inwater and soaked incetrimide before dryingand replacing, n = 30.C: A gauze dressing soakedin mercuric chloride wasloosely packed into thewound.The pack wasremoved at least once aday and patients took asalt bath while the packwas out, n = 30.Patients were allowed tochange and dress theirown wounds if they feltcomfortable doing so.Otherwise dressingchanges were managedby a visiting nurse.Mean wound volume (cm 3 ):I: 55.5 (4.5 SEM)C: 61.5 (5.3 SEM)Other characteristics:I CMean age (years): 54 59M:F 1:1.3 1:1.8Reason for surgery:Ulcerative colitis 8 6Crohn’s disease 5 3Carcinoma rectum 10 13Villous papilloma 1 0Irradiation colitis 1 1Colloid carcinoma 0 1Diverticulitis 0 1Data are only given for those50 patients, 25 per group,completing the trial.Complete healing:I: 20/25 (80%)C: 20/25 (80%)Mean time to healing(days) for all wounds:I: 60.3 (3.0 SEM)C: 69.5 (7.3 SEM)(p > 0.05, NS;Student’s t-test)I:Three deaths;two patientsfailed to heal forreasons relatedto the natureof their illness.C:Threedeaths; twopatients failedto heal forreasons relatedto the natureof their illness.Withdrawalswere notincluded inthe baselinedata or results.Less analgesiaand fewerdistrict nursevisits appearednecessary forpatients treatedwith SilasticFoam (I).Walker et al.,1991 36UKWound type:Surgical(pilonidal sinusand abscesses).Method ofrandomisation:Not stated.Objectiveoutcome:Time to healing.Assessments weremade twiceweekly by thesurgical team.Setting and lengthof treatment:Outpatientstreated in hospitaland later in thecommunity.Treatment wascontinued untilthe wound healed.A maximumtreatment timewas not specified.Inclusion criteria:Patients withpilonidal sinusesor abscesses.Exclusion criteria:Not stated.Treatment:I: Silicone foam cavitydressing (Silastic Foam).The foam was constructedin the wound and thenremoved. Patients wereinstructed on how toremove and replace thedressing. Dressing wereremoved and washedtwice daily. A new spongewas made when theoriginal no longer fittedthe cavity, n = 34.C: Eusol-soaked gauze athalf strength.The dressingwas laid in the cavity twicedaily and then once dailywhen considered cleanenough by nursing staff,n = 41.After surgery, and priorto randomisation, allwounds were dressedwith ribbon gauze soakedin half strength Eusol.This dressing wasremoved after 48 hoursand patients randomisedto a treatment group.Wound size:Not stated.Other characteristics:All groupsMale patients:Sample size 72Mean age (years) 25Female patients:Sample size 3Mean age (years) 19I CWound type:Pilonidal sinus 17 21Abscess 17 20Mean time to healingfor pilonidal sinuses(days):I: 30 (range, 21–39)C: 33 (range, 20–46)Mean time to healingfor abscesses (days):I: 39.8 (range, 26–54)C: 39.6 (range, 27–53)No withdrawals.Patientsreceiving Itreatmentrequired onlytwo or threevisits torefashion thedressing, whilethose treatedwith C requireddaily visits.I, intervention; C, comparator; SEM, standard error of the mean; SD, standard deviation; M, male; F, femalecontinued73

Appendix 6TABLE 7 contd Dressings compared with traditional treatments for the management of surgical wounds healing by secondary intentionStudy Inclusion/ Intervention Baseline Results Withdrawals Commentsand design exclusion details characteristicscriteriaWilliams, et al.,1981 35UKWound type:Surgical(pilonidal sinus).Method ofrandomisation:Not stated.Objective outcome:Time to healing,defined as whenthe wound surfacewas completelyepithelialised.Assessments weremade weekly.Setting and lengthof treatment:A multicentre trialof outpatientstreated in the community.Treatmentwas continued untilthe wound healed.Inclusion criteria:Patients with apilonidal sinus.Exclusion criteria:Not stated.Treatment:I: Silicone foam cavitydressing (Silastic Foam).The dressing wasrefashioned at weeklyintervals, n = 44.C: Gauze soaked in0.5% aqueous solution ofchlorhexidine (Hibitane).The dressing was changeddaily, n = 36.Mean wound volume (ml):I: 59 (57.7 SD)C: 64 (74.5 SD)Other characteristics:Not stated.Mean time tohealing (days):I: 66.2 (26.1 SD)C: 57.7 (19.6 SD)Not stated.The foamdressing (I) wasassociated withfewer nursevisits per patient(I: 4.6 visits;C: 35.1 visits).Changing thefoam dressing(I) caused milddiscomfort,while the gauzedressing (C)was associatedwith moderateto-severediscomfort.Length ofhospital stayand time lostfrom workwere similar inboth groups.I, intervention; C, comparator; SEM, standard error of the mean; SD, standard deviation; M, male; F, femaleTABLE 8 Comparison of dressings for the treatment of surgical wounds healing by secondary intentionStudy Inclusion/ Intervention Baseline Results Withdrawals Commentsand design exclusion details characteristicscriteria74Butterworth et al.,1992 37UKWound type:Surgical(pilonidal sinus).Method ofrandomisation:Not stated.Objectiveoutcome:Time to healing.Length, widthand depth weremeasured and thewound photographedat weeklyassessments.Setting and lengthof treatment:Outpatientstreated in thecommunity.Treatment wascontinued untilthe wound healed.A maximumtreatment timewas not specified.Inclusion criteria:Patients with acavity wound thathad resulted fromeither pilonidalsinus excisionor abdominalsurgery.Exclusion criteria:Clinical woundinfection; immunosuppression;pregnancy;receiving cytotoxictherapy orradiotherapy.Treatment:I: Polyurethane foamdressing (Allevyn).Thedressing was applieddirectly to the cavity.Where the wound wasdeep more than one dressingwas used as appropriate.Thedressings werechanged when saturatedor at least every 3 days.At dressing changes thewound was washed forat least 20 seconds in tapwater before applying thefresh dressing and securingwith surgical tape, n = 40.C: Silicone foam cavitydressing (Silastic Foam).The foam mixture waspoured into the woundand allowed to set for3 minutes before thedressing was removed.Dressings were cleansedand sterilised twice daily(method of sterilisationnot stated). Dressings wereheld in place by surgicaltape and covered with anabsorbent pad, n = 40.Patients were responsiblefor changing their owndressings.Wound size (mm (range)):I CLength: 63 62(23–148) (25–160)Width: 20 (0–59) 19 (0–51)Depth: 26 (8–82) 27 (5–65)Other characteristics:I CMean age (years): 30.4 28.2Wound type:Pilonidal sinus 30 32Abdominal 10 8Number of pilonidalwounds healed(days to healing):I: 29/30 (51.4; 20.9 SD)C: 29/32 (61.9; 26.1 SD)Number of abdominalwounds healed(days to healing):I: 8/10 (51.9; 20.5 SD)C: 8/8 (56.6; 37.6 SD)Not stated.90% ofpatients fromboth groupsreported thatthe dressingswere painless.

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 9 Topical agents compared with traditional treatments for the management of surgical wounds healing by secondary intentionStudy Inclusion/ Intervention Baseline Results Withdrawals Commentsand design exclusion details characteristicscriteriaSchmidt &Greenspoon,1991 38USAWound type:SurgicalMethod ofrandomisation:Stratifiedrandomisationby computerallocation.Objectiveoutcome:Time to healing.Method ofassessmentnot stated.Setting and lengthof treatment:Outpatientstreated in thecommunity.Patients weretreated untilthe wound wascompletelyepithelialised.Inclusion criteria:Outpatients withsurgical woundsrequiring healingby secondaryintention aftereither Caesareandelivery orlaparotomy forgynaecologicalsurgery. Allwounds hadopened spontaneouslyor hadbeen drained totreat a seroma,haematoma, orwound abscessbefore referral.Exclusion criteria:Diabetes mellitus;cancer; use ofglucocorticoidsor immunosuppressivedrugs; historyof abdominalirradiation; achronic debilitatingdisease.At commencementno patienthad cellulitis atthe wound siteor requiredantibiotic therapy.Treatment:I: Aloe vera gel.Traditionaltreatment was supplementedby the additionof aloe vera (CarringtonDermal wound gel formulation)to the granulatingarea, n = 20.C: Traditional treatment.The wound was debridedwith either a gauze pad ora scalpel as required andirrigated with high-volume,high pressure irrigations.A wet-to-dry dressingwas applied.This wasrepeated every 8 hoursuntil the commencementof granulation, after whichtreatment was repeatedevery 12 hours, n = 20.A visiting home nurseperformed all thetreatment changesfor both groups.Wound size:Not stated.Other characteristics:All groupsMean age (years): 28.3M:FAll femaleEthnic origin: HispanicWeight (kg): 73.7I CAbdominalwound types:Vertical incision 10 11Transverse incision 10 9Note: the mean surface areaof transverse incisions wasstatistically larger in the Igroup at baseline.This willinvalidate comparisonsbetween the two groups.Mean time to healingfor vertical incisiononly (days):I: 84 (± 27; n = 8)C: 47 (± 18; n = 5)(p < 0.05; NS)Mean time to healingfor transverse incisiononly (days):I: 83 (± 35; n = 5)C: 53 (± 24; n = 3) (NS)Mean time to healingall wound types (days):I: 83 (± 28; n = 13)C: 53 (± 24; n = 8)(p < 0.03)(Student’s t-testwas used for normallydistributed data whilethe Wilcoxon nonpairedrank sumwas used to comparenon-normallydistributed data).I: Two with avertical incisionand five with atransverseincision.C: Six with avertical incisionand six with atransverseincision.No adverseeffects wererecorded ineither group.75

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Appendix 7Studies of healing pressure soresTABLE 10 Topical agents compared with no direct wound managementStudy Inclusion/ Intervention Baseline Results Withdrawals Commentsand design exclusion details characteristicscriteriaVan Ort &Gerber, 1976 39UKMethod ofrandomisation:Random numberlist.Objective outcome:Rate of healing ofwound, definedas decrease indiameter perday assessed byphotograph.Setting and lengthof treatment:Nursing home.Treatment continuedfor 15 days.Inclusion criteria:Decubitus ulcers;skin break due topressure, evidenceby epidermalinjury involvingerythema, pallor,cyanosis andsuperficial erosion.Size of sorebetween 1.0 cmand 7.0 cm.Skin breakdown inexistence 14 daysor less prior toadmission to study.Exclusion criteria:Not stated.I:Topical application often units of U-40 regularinsulin (USP) twice a dayfor 5 days. Insulin wasdropped from a syringeand exposed to the airto dry. No dressing wasapplied, n = 6.C:All participants receivedroutine supportive nursingcare including positionchanges, increased fluidintake, high protein diet,and local massage. Onlypatients in the treatmentgroup received insulintherapy, n = 8.Area of wound:Not stated.Other characteristics:I CMean age(years): 72.5 (all groups)M:F 1:5 1:7Authors state no statisticallysignificant differences on arange of other variables,including body build, bloodglucose, fluid and proteinintake, number and location ofulcers, mobility, incontinence,diabetes mellitus, endocrine,circulatory, digestive, genitourinaryor musculoskeletaldisease, use of antibiotics,anticoagulants, parenteralinsulin, oral hypoglycaernic,steroids or vitamins.Healing rate:Statistical analysisbetween the healingrate of the two groupsfavoured treatmentwith I.t = 7.71 (p = 0.05)Student’s t-test.Number of days oftreatment required:Statistical analysisbetween the two groupsagain favouredtreatment with I.t = 2.65 (p = 0.05).Note: Primary datawere not available inthis study.None.Time to healingappeared todepend on age,number ofpressure sores,respiratory,nervous systemand musculoskeletaldiseaseand mentaldisorder, andantibiotictherapy, butthe results ofsignificancetests are notpresented.77

Appendix 7TABLE 11 Topical agents (including concentration comparisons) compared with placebo formulationsStudy Inclusion/ Intervention Baseline Results Withdrawals Commentsand design exclusion details characteristicscriteriaLe Vasseur &Helme, 1991 40AustraliaMethod ofrandomisation:Not randomised.Objective outcome:Ulcer area assessedby weekly photography.Timetohealing.Setting and lengthof treatment:Hospital andnursing homepatients.Treatmentcontinued for6 weeks.Inclusion criteria:Grade I and IIpressure ulcers.Exclusion criteria:Not stated.Treatment:I: Active cream F14001(extract of barley plantat 1% concentration incetomacrogol creambase), n = 8.C: Placebo cream(not stated), n = 13.Ulcer size (cm 2 ):I: 9.6 (3.9 SD)C: 9.0 (2.0 SD)Other characteristics:I CAge (years): 82.5 81.5Norton score: 10.9 12.9Duration(months): 7.6 3.5Wound size:No significant maineffect found by ANOVAfor treatment, thoughpatients in the activegroup showed asignificantly greaterreduction in size atweek 4, but not week 6.Healing time (days):I: 18.4 (4.4 SD)C: 29.1 (3.6 SD)None.Mustoe et al.,1994 43USAMethod ofrandomisation:Not stated.Objective outcome:Wound volume andarea assessed byalginate mouldingand planimetry;time to healingSetting and lengthof treatment:Nursing homesor hospitals.Treatment for28 days, follow-upof 5 months.Inclusion criteria:Clinical confirmationof grade IIIor IV pressuresore in adult, withtotal surface areabetween 4 and100 cm 2 and noevidence of surroundingcellulitisor malignant neoplasmsin the areaof the ulcer orelsewhere.Exclusion criteria:Venous or arterialulcer implicated inthe cause of theulcer; existence ofsignificant endocrinedisease ormalignant neoplasmsin past5 years; use ofimmunotherapy,cytotoxic chemotherapyor aninvestigationaldrug or drugs.Treatment:I1: r-PDGF-BB, 100 mg/ml,n = 15.I2: r-PDGF-BB, 300 mg/ml,n = 12.C1: Placebo, n = 14.Treatments applied daily asa topical spray, at a volumeof 10 ml/cm 2 . All woundsdressed daily with moistsaline gauze dressingsand mechanically debridedas necessary during treatmentperiod. Intermittentpressure relief wasobtained through turningregimens according tonursing home and hospitalroutines. Pressure-reducingmattresses were not used.Mean wound volume (cm 3 ):C1: 10.8 ± 13.2I1: 5.5 ± 6.1I2: 7.1 ± 8.8Other characteristics:C1 I1 I2Mean age: 73.4 73.5 67.5M:F 1:1.8 1:2.8 1:1.4Duration(months): 2 5.2 3.9% of patients at grade:III 21.4 26.7 25IV 78.6 73.3 75Location (%):Ischium 29 20 17Sacrum 43 33 42Trochanter21 27 17Other 7 20 25Groups were also comparableon baseline laboratory valuese.g. blood albumin, haemoglobinand protein.Complete healingat 28 days:C1: 3I1: 2I2: 0% reduction in sorevolume at 28 days:C1: 20I1: 71I2: 60No significant differencesafter adjustmentfor differences in initialvolume using ANCOVA(p = 0.06). For the twotreatment groupscombined mean volumewas less than withplacebo (p = 0.009).Reduction in woundarea at 28 days:After ANCOVAadjustment for initialarea, no significantgroup differences(p = 0.08).Time to achieve50% healing:No significantdifferences (p = 0.22)5-month follow-up:majority of ulcersremained unhealed,suggesting thattreatment effectswere transient.None reported.After 5 monthsfollow-up, themajority ofulcers remainedunhealed andstatic in size.ANOVA, analysis of variance; ANCOVA, analysis of covariancecontinued78

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 11 contd Topical agents (including concentration comparisons) compared with placebo formulationsStudy Inclusion/ Intervention Baseline Results Withdrawals Commentsand design exclusion details characteristicscriteriaRobson et al.,1992 45USAMethod ofrandomisation:Not stated.Objective outcome:% change in wounddepth and volumeusing wound gauge,mould weight.Setting and lengthof treatment:Inpatient setting.Treatment continuedfor 28 days;follow-up for upto 5 months.Inclusion criteria:Sores between25 and 95 cm 2 withfull-thickness skinloss (grade III orIV) or penetratingto bony prominence(grade IV),with no past orpresent evidenceof malignancy, withmechanicaldebridement ofnecrotic tissue atleast 2 days prior,and normal orclinically insignificantresults on pretreatmentbloodcount, and coagulation,chemistryand urinalysis.Exclusion criteria:Arterial or venousdisorder resultingin ulceratedwounds; clinicallysignificant disease;significant malnutrition;recentuse of steroidaltherapy; immunotherapyor cytotoxicchemotherapy;diabetes.Treatment:r-PDGF-BB at threeconcentrations:I1: 1 µg/ml, n = 4I2: 10 µg/ml, n = 4I3: 100 µg/ml, n = 5.Treatment given dailyfor 4 weeks at a doseof 0.01 ml/cm 2 of soresurface.After treatmentthe wound was left opento allow absorption. Eachsore was packed withsterile gauze and closedwith Biobrane.C1: Placebo (not stated),n = 7.Mean wound depth (cm):C1: 2.8 ± 0.4 (range, 1.5–5.2)I1: 1.7 ± 0.5 (range, 0.5–2.7)I2: 1.6 ± 0.6 (range, 0.8–3.5)I3: 2.8 ± 1.0 (range, 1.6–6.8)(Comparison of means byANOVA: NS.)Mean wound volume (cm 3 ):C1: 12.9 ± 3.8 (range, 5–33)I1: 13.8 ± 4.8 (range, 5–26)I2: 15.8 ± 4.0 (range, 9–28)I3: 11.6 ± 5.5 (range, 4–33)(Comparison of means byANOVA: NS.)Wound duration (months):C1: 14.2 ± 6.2 (range, 1–37)I1: 11.6 ± 5.5 (range, 3–27)I2: 16 ± 7.1 (range, 4–36)I3: 17.3 ± 12.4 (range, 4–67)(Comparison of means byANOVA: NS.)Other characteristics:Age (years):C1: 27 ± 2 (range, 22–35)I1: 40 ± 8 (range, 21–56)I2: 43 ± 5 (range, 32–54)I3: 29 ± 4 (range, 21–45)(Comparison of means byANOVA: NS.)% reduction in woundvolume at 28 days:C1: 78.2% (5.6 SEM)I1: 63% (15 SEM)I2: 55% (15 SEM)I3: 93.5% (4 SEM)No clinically significantdifferences betweenpatients treated with 1or 10 µg of r-PDGF-BB.None reported.Histologicalevaluation of thetissue biopsiesfound notreatmentrelatedgroupdifferences incellular influx orextracellularmatrixdeposition.The 100 µg/ml“tended to havegreater fibroblasticandendothelial cellinflux”, but nodata presented.Robson et al.,1992 44USAMethod ofrandomisation:Not stated.Objective outcome:Change in diameterand volume ofwound, measuredby planimetry andalginate moulding.Setting and lengthof treatment:Multicentre trialof hospitalisedpatients.Treatmentcontinued for22 days.Inclusion criteria:Hospitalisedpatients aged18–65 years,grade III or IVpressure soresbetween 10 and200 cm 2 extendingfrom bone tosubcutaneoustissue. Mechanicaldebridement> 24 hours beforetreatment. Normalor clinicallyinsignificant abnormalitiesin completeblood count,coagulation, bloodchemistry, andurinalysis.Exclusion criteria:Arterial or venousdisorder, or wounddue to vasculitis;clinically significantsystemic diseaseor malnutrition;recent steroidaltherapy; penicillinallergy.r-bFGF at threeconcentrations:I1: 100 µg/ml, n = 11I2: 500 µg/ml, n = 11I3: 1000 µg/ml, n = 12.Treatments given atdifferent applicationschedules, at a dose volumeof 1.01 ml/cm 2 .Woundpacked with salinemoistenedsterile gauzechanged after 12 hours.(note: 35 patients enteredthis arm of the trial, butdata were only providedfor 34).C1: Placebo (not stated),n = 14.All patients weredenervated in the areaof ulceration because ofcongenital or acquiredspinal cord pathology.Standard pressurerelievingdevices wereused as appropriate.Baseline data are only presentfor all r-bFGF groupscombined (I1, I2, I3)Initial ulcer size:Not stated, but reported thatthere were no significantgroup differences.Other characteristics:I1, I2, I3 C1Age (years): 37.8 37.9Duration(months): 17.7 25.9M:F 3.9:1(all groups)No statistically significantdifferences were foundbetween baseline characteristics(Wilcoxon test).No group differences inethnicity.Number of patientsachieving 70% volumereduction:I1, I2, I3: 21/35 (60%)C1: 4/14 (29%)(p = 0.047)% reduction inwound volume:I1, I2, I3: 69%C1: 59%One patient inplacebo groupremoved fromtrial becauseof possibleneoplasm.Blindedobserversreportedsignificantdifferences invisual improvementof overallhealing, favouringr-bFGF (I1, I2,I3). No statisticaltests reported.Fibroblast andcapillary countsappear from ahistogram tofavour r-bFGFbut the differencesappearsmall and nostatistical testsare reported.continued79

Appendix 7TABLE 11 contd Topical agents (including concentration comparisons) compared with placebo formulationsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaRobson et al.,1994 42USAMethod ofrandomisation:Not stated.Objective outcome:% decrease inwound volumefrom baseline.Setting and lengthof treatment:Inpatients.Treatment untilhealing or maximumof 28 days.Inclusion criteria:Pressure soresextending from thebone to the subcutaneoustissue(grade III/IV sores).Exclusion criteria:Significant renal,hepatic, cardiac,endocrine or haematologicdisease,or neoplasticdisease producingulcerated wounds;arterial or venousdisorders resultingin ulceratedwounds; systemicsepsis from thepressure ulcer; lackof cooperation;‘unsuitability’,inability to provideinformed consent;whirlpool therapyrequirements; HIV+;use of investigationaldrugs within1 month beforestudy entry; ortreatment of thetarget ulcer withcytokines within3 months of entry.Treatment:Interleukin 1-beta, acytokine given in a singletreatment per day at threedifferent concentrations:I1: 0.01 µg/cm 2I2: 0.1 µg/cm 2I3: 1.0 µg/cm 2 .0.01 ml/cm 2 was deliveredby spray after saline cleansing.Woundswere thenair-dried and dressed withsaline-moistened dressing,changed 12 hours later.Treatment applied at threedifferent dosages of 0.01,0.1 and 1.0 to six patientsper group (total n = 18).C1: Placebo (not stated),n = 6.All patients weredenervated in the areaof ulceration because ofcongenital or acquiredspinal cord pathology.Pressure-relieving deviceswere used as appropriate.Patients on non-air-fluidisedbeds re-positioned every2 hours.No statistically significantdifferences were reportedbetween groups in race,gender, tobacco use, ulcerlocation, age, height, weight, orulcer stage or size at baseline.No data are presented.All pressure sores werelocated on the sacrum,ischium or trochanter.% reduction inwound volume:I1: 68%I2: 75%I3: 58%C1: 25%I1: 1I2: 0I3: 1C1: 0Of the twowithdrawals,one left hospitalbefore completionof studyand one waswithdrawnbecause ofosteomyelitisat base of ulcer.These werereplaced;unclear howthis was done.Effect oftreatmenton fibroblastsassessed butnot reportedin detail.Tytgat & Van Asch,1988 41BelgiumMethod ofallocation:Not randomised.Objective outcome:Wound area.Setting and lengthof treatment:Setting not stated.Treatment wascontinued for3 weeks.Inclusion criteria:Multiple sclerosispatients withdecubitus ulcers.No otherinformation.Exclusion criteria:Not stated.Treatment:I1: 2% Ketanserinointment, n = 8C1: Placebo ointment(not stated), n = 8Each was applied twicedaily for 3 weeks.Median wound area (mm 2 ):I: 1150C: 860Other characteristics:I1 C1Mean age(years): 58 60M: F 1:1 (all groups)Duration(weeks): 17 24Diabetes: 1 0% reduction in woundarea at 3 weeks:I1: 81%C1: 16%(p < 0.05,Wilcoxonmatched-pairs signedranks test).None reported.No side-effectsin either group.80

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 12 Topical agents compared with dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaBrown-Etris et al.,1996 46USAMethod ofrandomisation:Method notstated; stratificationoccurred accordingto surface areaand stage.Objective outcome:Area reductionassessed by gravimetricplanimetrywith wound tracingonto plastic filmand photography.Independentanalysis by biostatisticalanalysisfirm. Change inlevel of woundmargin underminingassessed.Setting and lengthof treatment:Hospital, longtermcare, homeor outpatients.Medical centres(no other details).Trial participationwas until 10 weeks,or treatmentchange wasindicated or thewound healed,whichevercame first.Inclusion criteria:Patients > 18 yearswith one or morepressure ulcers.Grade II, III or IVonly. Wound sizebetween 2 and80 cm 2 and < 1 cmdeep, clinically noninfected,escharfree,with ≥ 75%granulation basewith fixed woundmargins. Adequatenutritional intakeby mouth tube orhyperalimentation.Exclusion criteria:Grade I ulcers orgrade IV ulcerswith exposedtendon or bone;wound size < 2 cm 2or > 80 cm 2 , or> 1 cm deep;wounds coveredwith necroticeschar or necroticwound basecontaining > 25%slough; diagnosisor suspicion ofosteomyelitis atstudy wound site;carcinomatosis, orsigns or symptomsof wound clinicalinfection; inadequatenutritional intake;sinus tract, tunnellingor > 0.5 cm ofwound marginundermining.Treatment:I1:Topical hydrogel(Transorbent), n = 66.I2: Hydrocolloid dressing(Duoderm CGF, GranuflexCGF), n = 55.Evaluation took placeweekly, dressing changesoccurred every 7 days ormore frequently.Mean surface area of wound:Not stated.Other characteristics:All groupsMean age (years): 70M:F 1:1I1 I2Duration (months):< 1 23% 31%1–3 38% 49%4–6 10% 14%7–12 13% 2%> 12 16% 4%Location:Sacrum 33% 37%Trochanter 17% 26%Heel 16% 18%Ischium 16% 13%Malleolus 10% 4%Spine 6% 2%Knee 2% 0%Surface area reductionat 10 weeks (cm 2 ):Grade II ulcers(2–30 cm 2 ):I1: 3.6, n = 12I2: 2.3, n = 12 (NS)Grade III ulcers(2–30 cm 2 ):I1: 6.3, n = 42I2: 5.2, n = 36 (NS)Grade III ulcers(31–80 cm 2 ):I1: 24.5, n = 3I2: 4.3, n = 2 (NS)Insufficient data wereavailable for analysisof the followingsubgroupings:Grade II (31–80 cm 2 )Grade IV (2–30 cm 2 )Grade IV (31–80 cm 2 )19 randomisedpatients werenot included inthe analysis asthey did notcomplete thefirst 3 weeks ofthe study, ormissed two ormore sequentialweekly visits.No significantdifferences inclinical woundinfection, odour,or dressingchanges/week.Darkovich et al.,1990 47USAMethod ofrandomisation:Not stated.Objective outcome:Perimeter of ulcertraced and insome cases photographedto determinethe size ofthe ulcer. Numberof ulcers healed.Setting and lengthof treatment:Maximum 60 daytrial unless woundhealed, patientdischarged orwithdrawn byclinician. Measurementstaken ateach dressingchange or at leastweekly intervals.Inclusion criteria:Patients in acutecare facilities andnursing homeswith grade I or IIpressure soresulcers (size> 2 cm 2 ).Exclusion criteria:Receiving radiationtherapy; infection,sinus tracts orfistulae in thewound; a bloodsugar level> 180 mg/dl;no improvednutritional status.Treatment:I1: Hydrogel (Biofilm),n = 62.I2: Hydrocolloid(DuoDerm; Granuflex),n = 67.All wounds were initiallycleansed with hydrogenperoxide and saline.Patients with an oily skinwere degreased to allowfor a 1.25 inch adhesionbelt around the wound.Although this was notmaintained where thewound was > 20 cm 2 ,instead utilising4 x 4 inch dressings.Dressings were usuallychanged every 3–4 daysand washed in salinebefore reapplication. Allpatients lay on pressurereducingmattresses.Mean area of wound (cm 2 ):Biofilm: 11.0 (range, 0.2–100)DuoDerm: 9.2 (range, 0.4–64)Other characteristics:All groupsMean age (years): 75M:F 1:1.6I1 I2Ratio of gradeI:II ulcers: 1:1.3 1:1.6Serum albumin(g/dl): 2.8 2.7No. of grade Iwounds: 27 31No. of grade IIwounds: 35 67There was a significantdifference between the ageof patients in the acute caresetting (69) and the extendedcare facilities (83).Mean area of pressuresore at 60 days (cm 2 ):I1: 3.5C1: 5.5Mean reduction(absolute and relative)in pressure sore areaat 60 days (cm 2 ):I1: 7.5 (68%)I2: 3.7 (40%)Complete healingat 60 days:I1: 26/60 (43%)I2: 15/24 (24%)Mean treatment days:I1: 12I2: 11.3Six extremeresults wereexempt fromthe analysis tomake it moremeaningful.Three patientsin the I1 groupand one in theI2 group hadwounds thatenlarged by> 10% per day.One patientin each groupwas excludedbecause theirwoundsdecreasedby more than25% per day.Hydrogels suchas Biofilm (I1)offered theability to absorbexcess fluidwithout degradationand maintaina moistenvironment.Patientsappeared toprefer I1 toobecause of thelack of odour,cushioning andlightness.The gel layer inI2 was found todegrade easily,which necessitatedmechanicalcleansing of thewound, whichdamaged thehealing tissuelayers.continued81

Appendix 7TABLE 12 contd Topical agents compared with dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaMulder et al.,1993 48USAMethod ofrandomisation:Computerallocation.Objectiveoutcomes:Perimeter of ulcertraced on to atransparency andarea determined bycomputer. Largestlength, width anddepth of the woundwas measured anda photograph wastaken at eachassessment.Setting and lengthof treatment:A multicentre trial(three independentsites).Assessmentsof ulcer size madeweekly for 8 weeksor until the ulcerwas healed.Wherepossible, eachpatient evaluatedby same investigatorthroughoutthe trial.Inclusion criteria:Grade II and IIIpressure sores≥ 1.5 cm x 0.5 cm,but ≤ 10 cm x10 cm. All patientshad to be >18 yearsand have a lifeexpectancy of atleast 2 months.Exclusion criteria:Grade IV woundsor those withtendon, bone,capsule, or fasciaexposure; pregnancy;chemoherapy;priorwound infection;extensive underminingof the ulcer(> 1 cm); AIDS;patients receiving> 10 mg ofcorticosteroids.Treatment:I1: Hydrogel (Clearsite),changed twice a week,n = 23.I2: Hydrocolloid dressing(DuoDerm, Granuflex)changed twice a week,n = 20.C1: Saline solution andmoistened gauze, changedthree times a day, n = 21.Dressings were changedeither by the patient or thecare giver, after they hadreceived appropriateinstructions.67 patients wereenrolled in to the trial –data analysed for only64 patients.Area of wound (cm 2 ):Not stated.Other characteristics:I1 I2 C1Mean age(years): 56.7 63.1 57.2M:F 1:3.6 1:5.6 1:9.5Ulcer stage:Grade II 8 9 5Grade III 14 13 18Race (patients):Black 4 3 6White 17 16 14Hispanic 1 1 0No statistically significantdifferences between thethree groups.Mean % reduction inwound area per week:I1: 8 (14.8 SD)I2: 3.3 (32.7 SD)C1: 5.1 (14.8 SD)(p > 0.05; nonparametrictest)Median % reduction inwound area per week:I1: 5.6I2: 7.4C1: 7.0(p > 0.05; nonparametrictest)I1:Three patientswere omittedfrom the finalanalysis. Noreasons aregiven for thesewithdrawals.I2: 0C1: 0Three patientswere not evaluableand theirdata are notpresented inthe baselinecharacteristics.One patienttreated withI2 had mild irritation,anothershowed minorsensitivity.One case ofinflammationoccurred in theI1 group, andanother patienthad excoriation,which waspossibly relatedto I1 treatment.There wereno adversereactions toC1 treatment.Palmieri, 1992 50ItalyMethod ofallocation:Not stated.Objective outcome:Time to healing.Setting and lengthof treatment:Wound clinic.Treatment wascontinued untilall woundshad healed.Inclusion criteria:Venous leg ulcers;pressure sores;diabetic gangrene;pressure sores;post-traumaticwounds; burnsand radioactiveulcers. Note: Dataare only given herefor leg ulcers andpressure sores.Exclusion criteria:Additional treatmentswith drugs(with the exceptionof digitalis).Treatment:I1: Collagen spongeapplied directly to thewound after saline nebulisation.Thedressing waschecked every day and ifthe collagen sponge wasswollen or partiallyreabsorbed more spongewas applied withoutremoving the previousone. Greasy sponge andregular non-allergenictape completed thedressing, n = 24.Polysaccharide beads(Debrisan) were applieddirectly to the woundbead and replaceddaily, n = 24.All wounds were sharpdebrided prior to randomisation.In addition allwounds were treated toensure negative bacterialcultures at baseline.Wound area:Not stated.Other characteristics:All groupsAge range (years): 58–75M:F 1: 0.6Wound type:Leg ulcers 12Diabetic gangrene 12Pressure sores 12Post traumatic 12Mean time tohealing (days):Leg ulcers:I1: 36I2: 60(p < 0.005;Student’s t-test)Pressure sores:I1: 20I2: 47(p < 0.001;Student’s t-test)No withdrawals.continued82

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 12 contd Topical agents compared with dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaSayag et al., 1996 49FranceMethod ofrandomisation:Sealed envelopes.Objective outcome:Area of ulcermeasured byplanimetry, digitisedtwice and the areacalculated bycomputer.Themean of the twovalues was usedto determineindividual ulcerarea. A photographwas taken of eachwound at everyevaluation.Setting and lengthof treatment:A multicentre trialbased at 20 centres(17 specialising inthe care of elderlypeople and threein dermatology).Assessments weremade on a weeklybasis by the same.Inclusion criteria:Patients aged≥ 60 yearshospitalised for≥ 8 weeks, witha pressure soregraded III or IVand surface areafrom 5–100 cm 2 .Sores werelocated on thesacrum, ischium,trochantersand heels.Exclusion criteria:More than half thetotal ulcer area hadgranulating tissue;ulcer covered bynecrotic plaque;active infectionrequiring local orsystemic antibiotictherapy; severerenal failure.Treatment:I1: Polysaccharide beads(Debrisan paste) applied toa depth of 3 mm over thewound surface, n = 45.I2: Calcium alginate dressings(Algosteril) applieddirectly on to wound tocover the entire area,n = 47.In both groups a sterilegauze was applied as asecondary dressing. Noother local treatmentswere used except for salinesolution the use of whichwas not restricted. Dressingswere inspected andchanged daily or at leastevery 4 days dependingon the degree of exudate.Mean area of wound (cm 2 ):I1: 16.1 ± 12.5 SDI2: 20.1 ± 12.9 SDOther characteristics:I1 I2Mean age(years): 80.4 (9.1) 81.9 (8.9)M:F 1:2.8 1:2.9Mean (SD)duration(months): 3.0 (3.2) 3.5 (3.8)Wound grade:III 30 33IV 15 14No significant differencebetween the two groups.Where patients had multiplewounds only one was selectedfor study.Mean wound areareduction perweek (cm 2 ):I1: 0.27 ± 3.21 SDI2: 2.39 ± 3.54 SD(p = 0.0001;Student’s t-test)Mean wound areareduction per weekusing the data fromonly those patientsreaching ≥ 40% (cm 2 ):I1: 2.15 ± 3.60 SDI2: 3.55 ± 2.18 SD(p = 0.0004;Student’s t-test)Number of woundswith > 75% reductionin area:I1: 6 (13%)I2: 15 (32%)Number of pressuresores with > 40%reduction in area:I1: 19 (42%)I2: 35 (74%)(p = 0.002 exact)I1: 22I2: 10All withdrawalswere included inthe analysis andfew were consideredto haveimproved at thelast evaluation.End pointdata were notavailable for onepatient in theI2 group due toadmission to aspecial care unit.Reasons forwithdrawals:I1: death (6);adverse event(1); deteriorationor stagnationof ulcer after4 week (15).I2: death (5);transfer (2);deteriorationof health (1);deteriorationor stagnationof ulcer after4 week (2).On averagethe number ofdressing changesper week wassimilar: 4.28(1.49 SD) forI2 and 4.52(1.42 SD) for I1.8% of I2and 33%of I1 patientsexperiencedadverse effects.83

Appendix 7TABLE 13 Dressings compared with traditional therapyStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaAlm et al., 1989 51SwedenMethod ofrandomisation:Method not stated.Stratification used.Randomisation ofsores, not patients,took place.Objective outcome:Weekly photographyof ulcer,evaluated bydermatologistblinded totreatment.Setting and lengthof treatment:Long-stay wards(multicentre).Treatment wasinitially for 6 weeks;if healing not complete,treatmentcontinued for3–6 weeks.Inclusion criteria:Patients on longtermwards withpressure sores.Exclusion criteria:Patients with aNorton score< 7.Treatment:I1: Hydrocolloid dressings(Comfeel) changed whennecessary.This includedComfeel Ulcus sheet,paste and powder. Sheet:sodium carboxymethylcelluloseparticlesembedded in an adhesiveelastic mass. Paste: sodiumcarboxymethylcellulose,guar cellulose and xanthancellulose (25 ulcers).C1: Wet saline gauzechanged routinely twicedaily (31 ulcers). 50 patientswith 56 pressure soreswere randomised.Wound size:I1 C1Median depth (mm): 1.75 2.00Median area (cm 2 ): 2.02 2.44Other characteristicsI1 C1Mean age (years): 84 83M:F approx. 1:3 (all groups)Duration (months): 4.6 4.8Norton score: 12 13Body weight (kg): 50 50About one-third of sores wereon the heel, and one third onthe sacral region.Complete healingat 6 weeks:I1: 11/25 (44%)C2: 5/31 (16%)Median reductionin wound area at6 weeks (cm 2 ):I1: 2 (100% reduction)C1: 1.8 (70% reduction)(p = 0.006)Wound depth:Median depth onlysignificant at week 4(p = 0.047)Detailed analysis ofresults for granulatedtissue not reported, butstated that hydrocolloiddressing filled withgranulation tissuemore quickly.I1: 2C1: 3Drop-outsoccurred becauseof deathfor reasonsunrelated totreatment, orviolation ofprotocol orunknownreasons. Onepatient waslost becausedata wereincomplete.Patients in thehydrocolloid(I1) group werereported to havethe most favourablehealingdistributionfunction, thoughthe overalldifference wasnon-significant.No difference inpain at dressingchanges.Barrois, 1992; 52Huchon, 1992 53FranceMethod ofrandomisation:Not stated.Objective outcome:Sores improved(totally or partiallyhealed). Decreasein surface area/week.Tracing tookplace every 7 days,with photograph atdays 0, 28, 56.Setting and lengthof treatment:56 days or earlierif sore healed.Inclusion criteria:Patients with opennecrotic pressuresores or ulceration.Exclusion criteria:Not stated.Treatment:I1: Hydrocolloid dressing(Granuflex standard),n = 38.C1: Standard dressing(Tulle gauze) impregnatedwith povidone-iodineantiseptic, n = 38.Cleansing was carried outwith saline, and debridementwith forceps ifnecessary.Mean surface area of wound:15 cm 2 (all patients). Surfacearea of sores reported ascomparable betweentreatment groups, nodetails presented.No other baseline detailsof patients.Complete healingat 8 weeks:I1: 10/38 (26%)C1: 9/38 (24%)(p = 0.16)(partial healing:22 vs. 18)Overall improvementat 8 weeks:Granuflex: 32 (84%)Standard: 27 (71%)Reduction in area:I1: 10%/weekC1: 7%/weekI1:Two patientsdue to deteriorationinpressure sore.C1: Five patientsdue to deteriorationin pressuresore.No adverseeffects observed,but no data arereported.Mean dressingsused:Granuflex:2.4/weekStandard:5.1/week(p < 0.0001).continued84

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 13 contd Dressings compared with traditional therapyStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaColwell et al.,1993 54USAMethod ofrandomisation:Not stated.Objective outcome:Decrease in woundsize and area, measuredby tracingevery 4th day onacetate film andmeasuring withelectronic planimeter.Width andlength recorded. %of pressure ulcerscompletely healedcalculated.Setting and lengthof treatment:Academic tertiarycarecentre.Averagelength of timein study = 17 days,range 6–56 days.Inclusion criteria:Patients withpressure sores.Exclusion criteria:Underlying conditionor treatmentlikely to affecthealing. Clinicallyinfected sores,grade I or IVpressure sores, orpressure ulcer thatcould not beaccurately graded.Patients wereexcluded if theydid not remain inthe study for≥ 8 days, or werereceiving othersore therapy likelyto confound results(e.g. hydrotherapy).Treatment:I1: Hydrocolloid dressing(DuoDerm; Granuflex)extending at least 2.5 cmbeyond sore margins,changed every 4 daysor as needed, n = 33.C1: Moist gauze dressingswith 0.9% sodium chloridesolution, loosely appliedand covered with steriledry gauze dressing anda secondary dressing tokeep inner dressing moist,secured with hypoallergenictape. Changed every6 hours, or as needed,n = 37.All patients were placedon pressure-reducingsurface (foam overlay orlow air-loss bed), and inboth groups ulcers andsurrounding skin werecleansed with warm tapwater and dried.C1 I1No. of ulcers: 48 49(49%) (51%)Sore location:Sacrum/coccyx 29 27(60%) (55%)Other 19 22(40%) (45%)Duration of sore:< 1 month 25 27(60%) (59%)1–3 months 21 19(45%) (41%)Ulcer grade:II 33 21(69%) (44%)III 15 28(31%) (56%)Initial ulcerLength (cm): 1–21 1–12Width (cm): 0.4–10 1–10Area (cm): 2.3 2.4Total : 70 patients with97 pressure ulcersOther characteristics:C1 I1Mean age (years): 68 68M:F1:1.1 (all groups)No significant differences incontinence or general health;typical patient had poor health,nutritional status, and wasconfused and debilitated.Significantly more grade II ulcersin I1 group, hence groups werestratified by ulcer grade foranalysis. Significantly fewer I1patients with diabetes.Complete healingat 8 weeks:I1: 11/49 (22%)C1: 1/18 (2%) (p = 0.04)No statisticallysignificant groupdifference in total soresurface area at end ofstudy, controlling forinitial surface area, stageof sore, and length oftime in study (F = 2.03,p > 0.05).No significant groupdifferences in change insore length or width,either between orwithin groups.Of 94 patientsinitially enrolled,24 did not complete8 days oftreatment forreasons notgiven, five weredischarged priorto completionof 8 days oftreatment, 12died of unrelatedcauses, five werelost to follow-up.Two droppedout because ofcolonisationwith methicillinresistantStaphylococcusaureus,one becauseulcer progressedto grade IV.No other outcomesreported,though a majorfocus of thepaper was costeffectiveness.Total cost percase was muchlower with I1than C1.Gorse & Messner,1987 56USAMethod ofrandomisation:Not randomised.One treatmentused on each oftwo wards; patientswere allocated towards to give abalance of surgicaland medicalpatients.Objective outcome:% of sores improved;decreasein ulcer area.Setting and lengthof treatment:Hospital. Maximumof 75 daysfollow-up.Inclusion criteria:Pressure sores ofgrade II, III or IVpressure sores.Exclusion criteria:Adjacent osteomyelitisor extensionof pressuresore into fascia,bone and/or jointspace; venousstasis and ischaemiculcers of theextremities;rapidly fatalunderlying disease;and plannedhospital dischargewithin 7 days oftreatment initiation.Treatment:I1: Dakin’s solution(wet-to-dry dressing)changed every 48 hours,n = 25 patients with52 pressure sores.I2: Hydrocolloid dressingchanged every 4 days ormore frequently if contaminatedor if systematicinfection developed,n = 27 patients with76 pressure sores.Mean area of wound:Not stated.Other characteristics:I1 I2Mean age (years): 72 68.4% of sores amongpatients > 65 years: 75% 56%Distribution of underlyingdisease, distribution of pressuresores by site, proportion ofgrade II sores, and nutritionalstatus all reported to be similarin the two groups. A greater %of pressure sores was presentin the ambulatory wet-to-drygroup, and a greater % of soresin this group were infected(p = 0.021).Complete healingat 75 days:I1: 26/52 (50%)I2: 54/76 (71%)Rate of decrease inwound area (cm 2 /day):I1: 0.55I2: 0.72 (NS)Mean days to healing:I1: 8.7I2: 10.0 (NS).Results based on thosewounds that did heal.None.continued85

Appendix 7TABLE 13 contd Dressings compared with traditional therapyStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaKraft et al., 1993 61USAMethod ofrandomisation:Not stated.Objective outcome:Number of pressuresores at weeks3, 6, 12, and 24.Setting and lengthof treatment:Tertiary careveteran’s hospital.Patients treated for24 weeks.Inclusion criteria:Patients withpressure soresExclusions criteria:Grade I and IVpressure sores;infected ulcers;patients on specialbeds; unstableinsulin-dependentdiabetes; serumalbumin < 2 g;haemoglobin< 12 g; Class IVcongestive heartfailure; chronicrenal failure; severeperipheral vasculardisease; severechronic obstructivepulmonary disease.Treatment:I1: Non-adherent semiocclusivefoam wounddressing with an adhesivecover (Epi-Lock), n = 24.C1: Saline-moistenedgauze, changed onceevery 8 hours, n = 14.Standardised dressingprocedures applied inboth groups.Wound area:Not stated.Other characteristics:Mean age: 56 years (all groups)Geriatric but mainly spinal cordinjured patients.Duration of sores: ranged fromnew to 5 years. Ulcers inexistence 2 months or less in53% of subjects. Previoushospitalisation for pressure ulcertreatment (usually saline)reported in 53% of patients.Grade II sores were present on22 patients and grade III werefound on 16 patients.Number of patientshealed by week 12:I1: 10/24 (42%)C1: 2/14 (14%) (p = 0.1)Number of patientshealed by week 12:I1: 10/24 (42%)C1: 3/14 (21%)(p = 0.26)I1: 11 (five wherestaff requestedremoval, andfour because ofreactions totreatment)C1: Six (twodeaths, onereaction tosaline, threeother reasons).Grade II ulcersshowed mosthealing by6 weeks.Grade III ulcershealed moreslowly.Epi-lock (I1)dressingrequired fewerdressings perweek and lessnursing time, sothat the overallweekly dressingcost for Epi-lockwas US$21 vs.US$75 for saline.Oleske et al., 1986 57USAMethod ofrandomisation:Quasiexperimental,random assignmentof treatmentprotocol andrandom assignmentof patients.Objective outcome:Reduction inwound area.Setting and lengthof treatment:University hospital.Treatment wascontinued for10 days.Inclusion criteria:> 21 years, afebrile,confined to bed,wheelchair or chairand expected to beso for at least2 weeks, expectedto be hospitalisedfor at least 2 weeks,patient or next ofkin English speaking.Ulcer with skinbreak not expendingto muscle (gradeI or II only), in anarea not currentlybeing irradiatedwith no evidenceof infection. Haemoglobinlevel at least10 g/dl.Exclusion criteria:Patients with skinbreakdown due tonon-pressurerelated causes;ulcer too small forreliable measurement(< 2 cm).Treatment:I1: Self-adhesivepolyurethane dressing(Opsite) applied forapproximately 2 daysotherwise changedonly if dislodged fromthe sore, n = 7.C1: Normal salinemoistenedgauze cutto size and coveredwith a plastic pad heldin place by paper tape.Dressing changed every4 hours around the clockduring study period, ormore frequently if soiled,n = 6.Pretreatment in bothgroups consisted of rinsingwith normal saline beforeapplication of dressing.Mean area of wound (cm 2 ):I1: 3.9 (0.73 SD)C1: 12.67 (11.28 SD) (NS)Mean longest axis (cm):I1: 3.1C1: 3.1 (NS)Other characteristics:Mean age: 69 years (all groups).Sex ratio not reported, butgroups reported not to bedifferent. All sores treated werein gluteal or coccyx areas.Mean decrease inwound surface areaat 10 days (cm 2 ):I1: 1.8 (1.30 SD)C1: 2.5 (5.54 SD)% reduction in woundarea at 10 days:I1: 49 (37.31 SD)C1: 26.67 (44.3 SD)One patienttransferred to anursing home.No details onwhich groupthey belongedto.No otheroutcomes.Saydak, 1990 60USAMethod ofrandomisation:Not randomised.Alternate allocationof wounds wasused.Objective outcome:Length of greatestaxis and depth,measured withsterile calipers.Setting and lengthof treatment:Veterans medicalcentre.Treatmentfor 2–8 weeksdepending onlength of stay.Inclusion:Patients with atleast two pressuresores of comparablelength and depth.Exclusion:Known sensitivityto povidone-iodine.Treatment:I1:Absorption dressing.The dressing waschanged daily.C1: Povidone-iodinesolution (1%) with normalsaline rinse.Total of 11 patientsincluded in study, witheach patient acting ashis own control.Wound size:Mean depth (cm):I1: 1.27 (1.16 SD)C1: 1.23 (1.05 SD) (NS)Mean length (cm):I1: 7.5 (4.95 SD)C1: 5.7 (4.6 SD) (NS)Other characteristics:All subjects were male, meanage 64 years.Ten had someneurological disorder; nine wereconfined to bed; six were on awater mattress; four on an airfluidisedbed or mattress; onewas on an eggcrate mattress.Location of sores:Five patients had soreson their hip, three had hipand sacral sores.Mean % reduction indepth of wound:I1: 54.2 (26.5 SD)C1: 5.5 (68 SD) (NS)Mean % reduction inlength of wound:I1: 13.5 (22.9 SD)C1: 4.9 (21.1 SD) (NS)None.Odour controlimproved morewith absorptiondressing.86continued

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 13 contd Dressings compared with traditional therapyStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaSebern, 1986; 581989 59USAMethod ofrandomisation:Random numberlist used to assignulcers totreatments.Objective outcome:Healing status; finalgrade of pressuresore; decrease inwound area.Setting and lengthof treatment:Home care setting.Treatment continuedfor 8 weeks.Inclusion criteria:Patients withgrade II or grade IIIpressure ulcersreceiving visits fromnursing service.Exclusion criteria:Wound containingeschar, grade I or IVulcer, patient hadterminal illness,white cell count< 4000, or patienthad three or moreexisting ulcers;necrotic ulcers;pressure ulcers> 50 cm 2 .Treatment:I1: Polyurethane steriledressing (moisture vapourpermeable). Changed dailyto three times a weekdepending on adherenceof dressing, n = 100 sores.C1:Wet-to-dry gauzedressing, with saline onthe contact layer, coveredwith dry gauze and pad.Changed every 24 hours,with saline used to loosendressing, and irrigation withhalf-strength hydrogenperoxide and saline. Ifwound was contaminated,povidone iodine wasapplied for 2 minutes andrinsed away with saline,n = 100 sores.Study protocol includeda turning schedule andwheelchair push-ups.Wheelchair-dependentpatients were given asilicone gel pad or densefoam cushion, or analternating pressure padfor patients in bed.Thesame protocol for pressurerelief and wound irrigationwas used in both groups.Median area of wound (cm 2 ):Grade II:I1: 1.9C1: 3.4Grade III:I1: 6.1C1: 4.5Other characteristics:I1 C1Mean age (years): 76.3 72.4Grade II: 59% 30%Grade III: 41% 70%No statistically significant groupdifferences in height, weight andPULSES score.All participants had a chronicillness, and according toPULSES score were veryseverely disabled. All patientshad chronic illness (mostlyfocal cerebral disorders, spinalcord disorders, neurologicaldisorders, and miscellaneouschronic conditions, e.g. cardiaccauses) and poor nutrition.5–9% of ulcers were onthe foot.Median decrease inwound area at 8 weeks:Grade II ulcers:I1: 100%C1: 52% (p < 0.01)Grade III ulcers:I1: 67%C1: 44% (p = 0.15) (NS)Healing statusat 8 weeks:(Four-point scale:healed, progress, nochange, deteriorated/discontinued)Grade II ulcers: noneof the gauze-treatedgroup healed vs. 64%of MVP-treated ulcers.Chi-squared test:(p < 0.01).Grade III ulcers: nosignificant groupdifferences.Final grade:I1 dressing had lowerfinal grade (p < 0.01,chi-square).23 drop-outsin less than3 weeks; mostfrequentlydue to death,hospitalisation,and inability tocomply with thestudy protocolfor pressurerelief.No differencesin supply costs,but costs oftreatment(includingnursing visits)for grade IIulcers significantlylowerwith I1(p < 0.05).Less pain withI1, though nodata presented.Xakellis &Chrischilles, 1992 55USAMethod ofrandomisation:Not stated.Objective outcome:Number of woundshealed (i.e. withepithelial coveringby inspection andabsence of moistsurface by palpation).Timetohealing.Setting and lengthof treatment:Intermediate-levellong-term carefacility.Treatmentperiod 6 monthsmaximum.Inclusion criteria:Patients with skinbreak over a bonyprominence.Exclusion criteria:Grade I or IVpressure sores;rapidly fatal disease,or anticipateddischarge withinone week; skinulcers from causeother than pressure,e.g. venousstasis ulcers.Treatment:I1: Hydrocolloid dressingrimmed with tape, changedif non-occlusive andchanged twice weekly toallow wound assessment.Cleaned with normal salineat this time, n = 18.C1: Saline gauze (nonsterile8-ply 4 x 4-inchgauze dressing moistenedwith saline covered withtwo non-sterile gauzedressing rimmed withtape), n = 21.Routine care to all participantsincluded repositioningevery 2 hours andcleaning of incontinencewith warm water asrequired. Necrotic tissuewas debrided using sharpdebridement at enrolmentand during treatment asnecessary. All patientswere placed on an airmattress and an air-filledwheelchair cushion.Median wound surfacearea (cm 2 ):I1: 0.66C1: 0.38 (NS)Other characteristics:I1 C1Age (years): 77 84M:F 1:12 (all groups)Norton score: 11 13No statistically significantgroup differences in otherbaseline measures, includingcomorbidities (diabetes, stroke,cancer, dementia, urinary tractinfection, Foley catheterisation,other mobility limiting condition),incontinence, nutritionalstatus, % with exudate,erythema, necrotic tissue,maceration, sore grade IIor III, location of ulcer, orhistory of ulcer at same site.Complete healingat 6 months:I1: 16/18 (89%)C1: 18/21 (86%) (NS)Median time tohealing (days):I1: 9C1: 11 (p = 0.12)75% of I1 group healedwithin 14 days vs.26 days in C1.Healing rate wassignificantly reducedwhen exudate waspresent at baseline,and after adjustmentfor this variable, healingrates did not differsignificantly betweenthe two groups.I1:TwowithdrawalsC1:Threedeaths.Median nursingcost (includingcost of nursingtime) wassignificantlylower for thehydrocolloidgroup (I1),though totalnursing costsusing local nursingwages werenot significantlydifferent, thoughat national wagerates hydrocolloidtreatmentwascheaper.PULSES score, a measure of severity of illness; MVP, moisture vapour permeable87

Appendix 7TABLE 14 Comparisons of modern dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaBale et al., 1995 62UKMethod ofrandomisation:Not stated.Objective outcome:Total healing ratesand % reduction inwound area.Setting and lengthof treatment:Community-basedtrial with patientsfollowed untilwound healedup to maximumof 8 weeks.Inclusion criteria:Pressure sores, legulcers and otherwounds wereincluded. No otherinclusion/exclusioncriteria given.Exclusion criteria:Not stated.Treatment:I1: Hydrocellular dressing(Allevyn), n = 51; 17 withpressure sores.I2:‘Improved formulation’hydrocolloid dressing,Trade name not stated(ConvaTec), n = 49;15 with pressure sores.Mean surface area of wound:Not stated.Other characteristics:I1 I2Mean age (years): 76 78M:F1:3.3 (all groups)Complete healingat 8 weeks:Pressure sores:I1: 10/17 (59%)I2: 4/15 (27%); p = 0.07Leg ulcers:I1: 2/16 (13%)I2: 1/14 (7%)Other wounds:I1: 11/17 (65%)I2: 10/17 (59%)All wounds:I1: 23/50 (46%)I2: 15/46 (33%)No stratified resultsfor reduction inwound area.14 patientswithdrawn dueto adverseincidents, ofwhich seven(maceration,overgranulationand pain), wererelated todressings. Fourpatients excludedfromanalysis: onedue to lost casereport forms,two patientsspent < 7 days instudy, so insufficientdata; andone protocolviolation.Patient-assessedcomfort ofdressings wasalso analysed.Hydrocellulardressings (I1)were morecomfortable,but results notstratified bywound type.Banks et al., 1994 64UKMethod ofrandomisation:Computergeneratedrandom order.Objective outcome:Healing.Setting and lengthof treatment:Patients resident inthe communitytreated for 6 weeksunless the pressuresore had healed.Inclusion criteria:Aged > 16 years,with shallow, moistsores of grade II orIII that could becovered adequatelywith a single 10 cmx 10 cm dressing,who could bemanaged to preventfurther lesionsdeveloping.Exclusion criteria:Patients with lesionsinvolving tissuesother than skin andsubcutaneous fat,grade I, IV or Vpressure sores, dryor necrotic lesions(included oncedebrided); patientstaking systemiccorticosteroids;patients whosesores had beendressedwith either of thetreatments in theprevious 2 weeks,or who hadpreviously reactedto either dressing;infected pressuresores; patientsincapable of givingan opinion aboutthe dressing;patients incontinentof urine or faeceswith sacral pressuresores or site likelyto be soiled.Treatment:I1: Hydrocolloid dressing(Granuflex E), n = 20.I2: Polyurethane dressing(Spyrosorb), n = 20.Patients in both groupswere provided withpressure-relievingmattresses and cushions.Dressings were changedwhen the area discolouredby exudate was < 1 cmfrom edge. Cleansingwith warmed saline wasundertaken if necessary.No topical applicationswere allowed.Mean wound area (cm 2 ):I1: 1.51I2: 1.47Other characteristicsI1 I2Median age (years): 73 71M:F1.1:1 (all groups)Median duration(days): 21 56Wound location:Buttock 45% 50%Sacrum 5% 20%Other 50% 30%Complete healingat 6 weeks:I1: 10/20 (50%)I2: 12/20 (60%) (NS)I2:Twowithdrawals forreasonsunrelated towoundI1:Two forwound deterioration;two forovergranulation;two for discomfort;fourfor reasonsunrelated tothe wound.Spyrosorb (I2)reported to beeasier to remove(p < 0.005).No significantdifferences inreported painon removal, orcomfort, ormean numberof days whichdressingremained inplace.continued88

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 14 contd Comparisons of modern dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaBanks et al., 1994 63UKMethod ofrandomisation:Not stated.Objective outcome:Healing withinstudy period.Time to healing.Setting and lengthof treatment:Hospital based.Final assessmentwas after 6 weeksof treatment orsooner if woundhealed.Inclusion criteria:Aged > 16 years,with shallow, moistsores of grade II orIII that could becovered adequatelywith a single 10 cmx 10 cm dressing,who could bemanaged to preventfurther lesionsdeveloping.Exclusion criteria:Patients with lesionsinvolving tissuesother than skin andsubcutaneous fat;dry or necroticlesions (includedonce debrided);patients takingsystemic corticosteroids;patientswhose sores hadbeen dressed witheither treatment inpast 2 weeks, orwho had previouslyshown sensitivityto either dressing;infected sores;patients incapableof giving an opinionabout the dressing;patients incontinentof urine or faeceswith sacral pressuresores or site likelyto be soiled.Treatment:I1: Hydrocolloid dressing(Granuflex E), n = 16.I2: Polyurethane dressing(Spyrosorb), n = 13.Mean wound area (cm 2 ):I1: 2.4I2: 1.4Other characteristics:I1 I2Median age (years): 74 73M:F1.1:6 (all groups)Median duration(days): 6.5 7Wound location:Buttock 56% 62%Sacrum 38% 31%Other 6% 8%Complete healingat 6 weeks:I1: 11/16 (69%)I2: 10/13 (77%) (NS)Median time to healing(days):I1: 12.7 (n = 12)I2: 13.4 (n = 10) (NS)I1: Four all dueto wound- ordressing-relatedproblems.I2:Threewithdrawals(two due towound- ordressing-relatedproblems).No differencesin comfort, orlength of timedressingsremained in situ.Spyrosorb significantlyeasier toremove andassociatedwith significantlyless pain atdressing changes(p < 0.005).No differencein appearanceor odour.Banks et al., 1994 68UKMethod ofrandomisation:Independently, bysealed envelope.Objective outcome:Healing rate andtime to healing.Setting and lengthof treatment:Hospital andcommunity.12 weeks, or untilwound healed.Inclusion criteria:Grade II or IIIpressure sores.Exclusion criteria:Terminal illness,necrotic or infectedsores, sores> 6–7 cm in anydirection, orpatient unavailablefor full 12 weeks.Treatment:I1: Polyurethane foamdressing (Lyofoam A),n = 26.I2: Low-adherence dressing(N-A) secured with vapourpermeablefilm (Tegaderm),n = 24.Dressing changed whennecessary. Patients alsohad access to pressurerelievingequipment.Mean area of wound(no. of patients):I1I2< 1 cm 2 : 11 12> 1 cm 2 ,< 2.5 cm 2 : 2 2> 2.5 cm 2 : 6 1Other characteristics:68% of patients aged> 75 yearsM:F 1:1.836% had body mass index< 19 kg/m 2 .Most common wound wassacral site (53%) followed bybuttocks (32%), trochanterand foot, not heels (both 6%),and heels (3%).Duration of sore not knownfor 28% of patients. Notreported by group.Complete healingat 12 weeks:I1: 19/26 (73%)I2: 15/24 (63%) (NS)I1: 7I2: 912 withdrawals(no otherinformation)and fourpatients died.No significantgroup differencesin painon removalor comfort,or nurseassessedeaseof applicationor removal.continued89

Appendix 7TABLE 14 contd Comparisons of modern dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaBanks et al., 1996 65UKMethod ofrandomisation:Not stated.Objective outcome:Relative changein wound area.Number of ulcershealed. Improvementin woundcondition.Setting and lengthof treatment:Community setting.Up to 13 weeks(leg ulcers).4–6 weeks(pressure sores).Inclusion criteria:Patients with gradeII and III pressuresores, or venousleg ulcers.Exclusion criteria:Not stated.Treatment:I1: Hydrocolloid dressing(Granuflex improvedformulation) leg ulcers,n = 50; pressure sores,n = 49.I2: Hydropolymer dressing(Tielle), leg ulcers, n = 50;pressure sores, n = 50.Dressings were changedevery 7th day.Mean surface area ofwound (mm 2 ):Leg ulcers:I1: 334.7I2: 431.3Pressure sores:I1: 286.24.7I2: 263.6Other characteristics:I1I2Leg ulcers:Mean age 75.3 73.4M:F 1:2.5 (all groups)Pressure sores:Mean age 78.6 80.1M:F 1:2.2 (all groups)No significant differences inulcer duration, wound area,visual appearance, exudate,odour, or pain at baseline. Forpressure sores there was alsono difference in baseline gradedistribution.Approximately half of thepressure sores in each groupwere on the heels.Both wound types were freeof clinical infection, and had amaximum dimension of 8 cm.Number of ulcershealed at 6 weeks:Leg ulcers:I1: 19/50 (38%)I2: 18/50 (36%)(p = 0.84)Pressure sores:I1: 15/49 (31%)I2: 12/49 ( 24%)(p = 0.5)Relative change in meanwound area at 6 weeks:Leg ulcers:I1: 31.5%I2: 49.3% (p = 0.6)Pressure sores:I1: 115.4%I2: 105% (p = 0.9)I1: 4I2: 4No differencein comfort orease of removalbetween thetwo treatmentsBrod et al., 1990 66USAMethod ofrandomisation:Stratified by lesiongrade andrandomised,method not stated.Patients wererandomised in theratio 60:40 to twotreatments.Objective outcome:% with completehealing; time tocomplete healing;absolute healingrate (area/week).Setting and lengthof treatment:Academic skillednursing facilitycaring for theelderly.Treatmentcontinued tocomplete ulcerhealing (maximumtreatment lengthapprox. 100 days)Inclusion criteria:Grade II or IIIpressure soresas assessed byinspection, andestimated lifeexpectancy of≥ 6 months.Normal marrow,hepatic and renalfunctioning.Exclusion criteria:Not stated.Treatment:I1: Polyhydroxyethylmethacrylate (Poly-hema)dissolved in polyethyleneglycol, applied as a pastewhich solidified to a flexibledressing, n = 27.I2: Hydrocolloid dressing(DuoDerm, Granuflex)applied as a sheet withadhesive backing, n = 16.Surgical debridement tookplace before randomisationin three patients. Dressingwere changed routinelytwice weekly, with additionaldressings if dressingcame off or becamecontaminated ordisrupted.Median area of wound (cm 2 ):I1: 2.5I2: 1.9 (p = 0.09)Other characteristics:All groupsMean age (years): 84.5M:FNot statedWound duration(months): Not statedComplete healing atfinal assessment:I1: 52%I2: 62% (p = 0.54)Median time to healing(days):I1: 32I2: 42 (p = 0.56)Absolute healing rate toweek 6 (cm 2 /week):I1: 0.18I2: 0.1 (p = 0.005)I1:Two deaths.I2: One death(due to concurrentillness);two patients(7.4%) discontinuedtreatmentbecauseof adverseeffects orpoor response.DuoDerm easierto apply, being apaste.Complicationswere uncommon,but no datapresented.continued90

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 14 contd Comparisons of modern dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaHondé et al., 1994 67FranceMethod ofrandomisation:Randomisationlist prepared bybiometry groupusing SAS software.Objective outcome:Number of patientshealed; medianhealing time.Setting and lengthof treatment:Hospital, multicentre.Either8 weeks or untilulcer healing,whicheveroccurred first.Inclusion criteria:Hospitalisedpatients > 65 yearsold, with grade II toIV pressure sore< 10 cm diameter.Exclusion criteria:Signs and symptomsof clinical infection(treated beforeentry); necroticpressure soreswith black crust(removed beforeentry); pressuresores on irradiatedskin; sores requiringsurgery; deep ulcersextending to bonewith risk of osteitiscomplications;patients on airfluidisedbeds.Treatment:I1:Amino acid copolymermembrane (Inerpan),n = 80.I2: Standard hydrocolloiddressing (Comfeel),n = 88.Mean surface area (cm 2 ):I1: 8.99I2: 6.85 (NS)Other characteristics:I1 I2Age (years): 80 84M:F 1:2.6 (all groups)Grade distribution:Grade II 64% 54%Grade III 30% 40%Grade IV 6% 6%No significant differences inweight, height, systolic ordiastolic blood pressure,Norton score or range ofplasma measures assessingnutritional status.Complete healingat 8 weeks:I1: 31/80 (39%)I2: 23/88 (26%)(p = 0.089)Median healing timeat 8 weeks (days):I1: 32I2: 38Analysis adjusted forinitial wound depthfound difference infavour of Inerpan(p = 0.044).% change in area frombaseline: Reported tobe higher with Inerpan(p = 0.09) but nodata presented.38 withdrawals.I1: Four foremergentreasons (mainlynecrosis); tenfor reasonsunrelated totreatment(mainly death,transfer ordischarge).I2: Six foremergentreasons (mainlynecrosis); 18for reasonsunrelated totreatment(mainly death,transfer ordischarge).Investigators’unblindedassessment atcompletion ofstudy favouredInerpan. Unclearwhat this assessmentwas basedon. Ease of caresimilar in eachgroup.Trial sponsoredby companyproducingInerpan.91

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Appendix 8Studies of healing arterial leg ulcersTABLE 15 Dressings compared with control/traditional treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaGibson et al.,1995 69UKWound type:Arterial ulcersMethod ofrandomisation:Sequentiallynumbered, sealed,opaque envelopes.Objective outcome:Ulcer area determinedby tracingulcer outline ontoacetate and subsequentplanimetryby operator blindto treatment.22 patients witharterial leg ulcersor diabetes.Inclusion criteria:ABPI < 0.8 ordiabetic ulcer> 2 months’duration.Ulcer > 10 mmin length.Exclusion criteria:Severe concurrentdisease; steroidtherapy; warfarin;vasoactive drugs;infected leg ulcer.Treatment:I1: Knitted viscose dressing(N-A), n = 10.I2: Hydrocolloid dressing(Granuflex), n = 12.Concurrent treatment:Orthopaedic woolbandage and crepe bandage.Patients also randomisedto oxpentifylline(Trental ® ) or placebo.Mean age (years):I1: 72.5 (range, 58–83)I2: 73.1 (range, 61–81)Mean ulcer duration (months):I1: 10.8I2: 13.3Mean ulcer size (mm 2 ):I1: 1489.4 (range, 89–7440)I2: 1005.1 (range, 193–2038)Number healed in trial:I1: 0I2: 3I1: Nine dueto dressing.I2: Five (four dueto dressing).Mean time towithdrawal:I1: 18.8 daysI2: 104 daysSponsored byConvaTec Ltd.Setting and lengthof treatment:Multicentred, multifactorialtrial inoutpatient leg ulcerclinics. 6 months.ABPI, ankle brachial pressure index93

Appendix 8TABLE 16 Topical preparations compared with control/traditional treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaJanssen et al.,1989 71BelgiumWound type:Arterial andarteriolar ulcers.Method ofrandomisation:Not reported.Objective outcome:Wound surfacearea measured byplanimetry. Also‘scored’ on basis ofgranulation tissue.Setting and lengthof treatment:Multicentre trial.2–8 weeks.299 patients withdecubitus ulcers,venous insufficiency,inoperable arterialinsufficiency,arteriolar insufficiency,and chroniculcers in diabeticswere recruited.40 patients hadarterial orarteriolar ulcers.Exclusion criteria:Life expectancy of< 6 weeks.Treatment:I1: 2% Formulation ofketanserin base microfinein polyethylene glycol,n = 19.I2: Polyethylene glycol,n = 21.Both were appliedtwice daily.Concurrent interventions:Surgical or mechanicaldebridement plus cleansingwith antiseptics.Mean wound area:No data.Number completelyhealed at 8 weeks:No data.Final wound area as% of initial at 5 weeks:I1: 11%I2: 62%Stated that woundarea was less in treatedgroup (Mann-WhitneyU test, p < 0.05).Holzinger et al.,1994 70AustriaWound type:Leg ulcers (arterialand venous).Method ofrandomisation:Not stated.Objective outcome:Time to healing.Setting and lengthof treatment:Setting not stated.Patients weretreated until healingor for a maximumof 75 days.Patients with legulcers arising fromchronic arterialocculsive disease(CAOD) or venouspost-thromboticsyndrome (PTS).All patients hadpreviously beenunsuccessfullytreated withalternativetherapies.Exclusion criteria:Not stated.Treatment:I1: Autologous activatedmononuclear cells insuspension were applied tothe wound by drippingfrom a syringe and allowedto dry. After 20 minutesthe wound was coveredwith a paraffin dressing.Prior to treatment woundswere cleansed with sterilesaline. Dressings and topicalagents were changed twicea week, n = 33.I2: Placebo of tissue culturemedium alone.Treatmentwas otherwise as statedfor I1, n = 30.Mean wound area (cm 2 ):I1: 5.14 (2.7 SD)I2: 5.26 (2.9 SD)Other characteristics:I1 I2Mean age (years): 65.3 63.6M:F 1:0.6 1:0.5Pretreatment(months): 9.2 9.4CAOD 21 20PTS 12 10Diabetes 9 5Mean time to healingat 75 days (weeks) forall wounds:I1: 4.7 (1.9 SD)I2: 8.1 (1.2 SD)(p < 0.01, Student’st-test)3.4% (2.34, 4.56)Mean time to healing at75 days (weeks) forCAOD wounds:I1: 5.0 (2.0 SD) n = 18I2: 8.4 (2.1 SD) n = 10(p < 0.01, Student’st-test)3.4% (1.75, 5.05)Mean time to healingat 75 days (weeks) forPTS wounds:I1: 3.9 (1.4 SD) n = 11I2: 7.7 (3.5 SD) n = 7(p < 0.01, Student’st-test)3.8 (1.328, 6.272)All the above resultsdo not include thenon-responders after75 days.Number of woundshealed at 60 days:I1: 30I2: 16OR = 8.75(2.186, 35.027)No withdrawals,but threepatients in thetreatment groupand 14 in theplacebo groupwere classed asnon-respondersat 75 days andnot included inthe time tohealing analysis.94

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Appendix 9Studies of healing arterial leg ulcers notdifferentiated by aetiologyTABLE 17 Dressings compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaMian et al., 1991; 761992 77ItalyWound type:Mixed leg ulcers.Method ofrandomisation:Not apparentlyrandomised.Objective outcome:Area of ulcer; nodetails on method.Patients withangiodermatitisof the lower limb(n = 30), chronicdisepithelialisation(n = 5) or a homogeneousseries whoacted as controls(n = 15).Exclusion criteria:No information.Treatment:I1: Lyophilised collagensponges applied to foci ofexuding wounds, n = 35.I2: Standard pressuredressing, n = 15.Mean wound area (mm 2 ):I1: 5675 (814 SD)I2: 5510 (630 SD)Other characteristics:Age (years):I1: 72.8 (12.5)I2: 69.0 (11.7)Wound area at end oftrial: (mm 2 ):I1: 3434 (416)I2: 4180 (240)% reduction in area atend of trial:I1: 39.5%I2: 24.1%No datapresented.Also presentsresults as aregenerationindex. Noinformation ontime of trial,randomisation,concurrenttherapies,setting.Setting and lengthof treatment:No information.Nyfors et al., 1982 78Wound type:Leg ulcers –mixed aetiology.Method ofrandomisation:Not stated.Objective outcome:Ulcer areaestimation usingplanimetry.Setting and lengthof treatment:Policlinic(outpatient clinic).31 patients withvenous, arterioscleroticor mixedulcer aetiology.22 women and ninemen, age 35–89years. 20 varicoseulcers, seven postthromboticorvaricose, two mixedaetiology (arterialand venous) andtwo arterial ulcers.Three patients hadulcers on bothlimbs. 34 ulcers –17 in each group.Exclusion criteria:Ulcer infection;erysipelas.Treatment:I1: Film dressing(Synthaderm),n = 17 ulcersI2: Saline gauze (5%),n = 17 ulcers.Concurrent treatments:Elastic compressionbandage.Mean wound area (cm 2 ):All groups: 0.5–78Number completelyhealedat 8 weeks:I1: 8/17 (47%)I2: 9/17 (53%)No data.continued95

Appendix 9TABLE 17 contd Dressings compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaOhlsson et al.,1994; 72Lindholm et al.,1993; 73Lindholm, 1994; 751995 74SwedenWound type:Leg ulcers ofvenous or arteriovenousaetiology.Method ofrandomisation:‘Randomlyallocated totreatment’.Objective outcome:Photograph ofulcer with fixedscale frame.No. of patientshealing ulcer.Setting and lengthof treatment:Community setting.6 weeks.30 consecutivepatients withvenous or arterialand venous legulcers.Exclusion criteria:None stated.Treatment:I1: Saline-soaked gauzechanged twice a day, n = 15.I2: Hydrocolloid dressingchanged once a week orsooner if exudate leakage,n = 15.Concurrent treatments:Ulcers cleansed with soapand tap water. Low stretchcompression bandageapplied to all limbs.Mean wound area (mm 2 ):I1: 857 (range, 80–3808)I2: 1387 (range, 25–6795)Other characteristics:Venous:mixed aetiology:I1: 12:2I2: 10:4Age (median):I1: 73.5I2: 77.6Number completelyhealed at 6 weeks:I1: 2/15 (13%)I2: 7/15 (47%)Wound area after6 weeks (mm 2 ):I1: 696I2: 678Mean % area change:I1: 19%I2: 51%(p < 0.13,Wilcoxon test)Mean treatmentcosts (SEK):Dressing materials only:I1: 608 (range, 169–2423)I2: 653 (range, 53–2423)Mean staff costs (SEK):I1: 3518I2: 1565Total treatmentcosts (SEK):I1: 4126 (range, 341–13,156)I2: 1565 (range, 102–6196)Statistical analysis ofhealing, costs and painby Wilcoxon’s test.I1: One patientwithdrew due toerysipelas.I2: One patientwithdrew forsocial reasons.Pain alsoassessed usinga visual analoguescale.Patients inhydrocolloidgroup reportedless pain atdressing changes.96

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 18 Comparisons of dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaArmstrong et al.,1996 80UK and FranceWound type:Leg ulcers.Method ofrandomisation:Randomised bynumbered, sealedenvelopes. Stratifiedaccording to woundexudate; moderateor high. Moderateexudate defined asrequiring a change ofdressing every 24–48 hours with a conventionaldressing,or 48–72 days with amodern absorbentdressing. Heavyexudate defined as:requiring changesevery 24 hours orless with a conventionaldressingsor every 48 hourswith a modernabsorbent dressing.Objective outcome:Ulcer area assessedby measurementand photography atbaseline, at days 14,28 42.Setting and lengthof treatment:Multicentre trial,Scotland, France andEngland. 6 weeksfollow-up.44 patients withleg ulcers describedas moderately orheavily exuding.Inclusion criteria:Moderately orheavily exudingulcer. Age> 18 years.< 7.5 cm in anyone dimension.Treatment:I1:Aquacel ® , a hydrocolloidfibrous dressing, n = 21I2: Kaltostat ® , an alginate,fibrous dressing, n = 23.Concurrent treatments:Secondary dressing was athin hydrocolloid. A bandagingregimen appropriatefor the ulcer aetiology wasapplied. Dressings changedas required.Limited mobility orwere immobile:I1: 62%I2: 52%Median percentagechange in ulcer area:I1: 30.5%I2: 28.1%(NS)Complete healing:I1: 6/21 (29%)I2: 2/23 (9%)Mean wear time (days):I1: 4.11I2: 3.05 difference = 1.03(95% CI, 0.385–1.672)Pain at dressing change:I1 I2None 144 186Mild 38 29Moderate 6 8Severe 2 0Excruciating 0 0No analysis of pain.I1: 5I2: 7Sponsored byConvaTec Ltd.Bandrup et al.,1990 79DenmarkWound type:Leg ulcers (venousand arterial).Method of randomisation:Patientswere matched inpairs before randomisationto avoidtime associatedvariables and theinfluence of ulcertype. Sealed envelopeswere used forrandomisation.Objective outcome:Ulcer size tracedon to plastic foiland area measuredby planimetry.Setting and lengthof treatment:Outpatients treatedat a wound clinicby a district nurse.Patients treatedfor 8 weeks withassessment at 2, 4and 8 weeks.Outpatients withvenous and arterialleg ulcers between1 and 100 cm 2 .Multiple ulcerswere included butonly the largestwas monitored.Exclusion criteria:Chemotherapy;glucocorticosteriods;antibiotics;positive patch teststo the dressings.Treatment:I1: DuoDerm applied tothe ulcer and 5 cm ofsurrounding skin, n = 21.I2: Mezinc ® applied tothe ulcer and 0.5 cm ofsurrounding skin, n = 22.Prior to dressing all ulcerswere debrided and cleanedwith 0.9% sodium chloride.This was repeated at eachdressing change.Absorbent materialwas applied on top ofthe dressings and a compressionbandage wasallowed for venous ulcers.Dressings were changedonce a day for the first14 days and thereafterevery third day.Mean wound area (cm 2 ):I1: 11.1 (9.1 SD)I2: 13.7 (15.9 SD)Other characteristics:I1 I2Mean age (years): 77 73M:F 1:6.5 1:2.2Median duration(months): 5 8Wound type:Venous/arterial 14/1 14/2Baseline results are onlyavailable for the 31 patientscompleting the trial.Mean % reduction inulcer area at 8 weeks:I1: 48%I2: 64%Number of ulcershealed at 8 weeks:I1: 4I2: 4% reduction in size(I1 vs. I2): 16%OR healed (I1 vs. I2):1:059 (95% CI, 0.228;4.922)I1: Two due toskin irritation;one developederysipelas; threedue to ulcerdeterioration.I2: Two due topositive patchtest; one due torecurring erysipelas;one dueto pain; twowere lost tofollow-up (onedeath, onetransferred).Spearmancorrelationcoefficientsuggested thatulcer healingwas related tosystolic bloodpressure(r = 0.63), butnot patient age,ulcer durationor initial ulcerarea.Aquacel ® , Kaltostat ® , ConvaTec Ltd; Mezinc ® , Molnlycke Healthcarecontinued97

Appendix 9TABLE 18 contd Comparisons of dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaPalmieri, 1992 50ItalyWound type:Leg ulcers, diabeticulcers, pressuresores, posttraumaticulcers.Method ofrandomisation:Not stated.Objective outcome:Time to healing.Setting and lengthof treatment:Wound clinic basedtrial.Treatment wascontinued until allwounds wereconsidered healed.Patients withvenous leg ulcers;pressure sores;burns and radioactiveulcers. Datawill only be givenfor leg ulcers.Exclusion criteria:Additional treatmentwith drugs(with the exceptionof digitalis).Treatment:I1: Collagen spongeapplied directly to thewound after salinenebulisation.The dressingwas checked every day andif the collagen was swollenor partially reabsorbed bycollagenases or lysosomalenzymes more of theproduct was added withoutremoving the previous one.Greasy sponge and regularnon-allergenic tape completedthe dressing, n = 6.I2: Dextranomer beadsapplied directly to thewound bed and replaceddaily, n = 6.Prior to randomisation allwounds underwent sharpdebridement to remove allnecrotic tissue. In additionall wounds were treated toensure negative bacterialcultures at baseline.Mean area of wounds:Not stated.Other characteristics:All groupsAge range (years): 58–75M:F 1:0.6Wound type:Leg ulcers 12Diabetic gangrene 12Pressure sores 12Post-traumatic 12Mean time tohealing (days):I1: 36I2: 60( * p < 0.005, Student’st-test).ES:I1 vs. I2 leg ulcers = 24No withdrawals.98

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 19 Topical preparations compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaStromberg & Agren,1984 83SwedenWound type:Venous ulcers andarterial ulcers.Method ofrandomisation:Not stated butpatients matchedfor ulcer type andtime of admissionbefore allocation.Objective outcome:Ulcer tracings atweekly intervals –then planimetry.(Trial period 8weeks). Outcomewas assessed blindto treatment.Setting and lengthof treatment:Community trial –patients attendedclinic.37 patientsattending ahospital clinic,18 with venousleg ulcers, 19 witharterial leg ulcers.24 females,13 males.Inclusion criteria:Ulcer area0.5–100 cm 2 .Exclusion criteria:Symptoms indicatedmore than onecause of the ulcer.Systemic zinc orantibiotic therapy.Diagnostic criteria:Venous ulcers:ABPI ≥ 0.9 or0.5–0.9 plus clinicalsigns.Arterialulcers: ABPI ≤ 0.5or 0.5–0.9 plusclinical signs.Treatment:I1: Sterile dry cottoncompress with zinc oxide(400 µg/cm 2 ), n = 18.I2: Sterile dry cottoncompress, n = 18.Concurrent treatments:Wound cleansing withsterile normal saline.Dressed once a day.Patients with venous legulcers had compression.Antibiotics given asrequired.Median ulcer area (cm 2 ):I1: 3.6 (range, 0.5–14.4)I2: 4.2 (range, 1.4–85.4)Ulcer sizes not evenlydistributed between groups:two largest ulcers to theplacebo group, (range, 1.4–85.4 cm 2 ); three smallest to thezinc group (range, 0.5–14.4).Other characteristics:I1 I2Median age 78 (66–95)(years):(all groups)M:F 1:1.1 1:3.5Diabetes: 3 5Ulcer type:Venous 4 8Arterial 4 7Ulcers healed in8 weeks:I1: 6I2: 4Ulcers healed in12 weeks:I1: 11I2: 4Ulcer area at end of8 weeks mean (cm 2 ):I1: 0.4 (range, 0–17.1)I2: 2.7 (range, 0–65.0)Number of paincomplaints:I1: 1I2: 2No data on healing ofulcers by aetiology.Sequential analysis wasused ‘to demonstratethat the treatment wassuperior (p < 0.05)’.I1: Patientdeveloped anulcer infectionduring treatment.Another patientappears to havebeen withdrawndue to ulcerenlargingI2: Six developedulcer infectionsand were withdrawn;onediscontinuedtreatment asdressing adheredto wound.Also measuredserum zinc levelsat end of trial:median values(µmol/l):I1: 10.6 (range,5.9–14.8)I2: 10.1 (range,7.7–12.3)Torregrossa &Caroti, 1983 84ItalyWound type:Mixed aetiologies,post-traumaticand vascularinsufficiency ulcers.Method ofrandomisation:Not clear ifrandom.Objectiveoutcome:Ulcer area astraced onto atransparent sheetand digitised usinga computer.Setting and lengthof treatment:30 days.Patients withvenous, arterial,pressure or traumaticleg ulcers.Exclusion criteria:Cellulitis ornecrotic ischaemia.Treatment:I1:Twice-daily applicationof gauze impregnated withhyaluronic acid, n = 27.I2: Control group withvarious treatment, n = 16.Concurrent treatments:Antibiotics.Mean wound area (mm 2 ):I1: 417I2: 568Other characteristics:I1 I2Ulcers:Venous 20 9Arterial 1 1Traumatic 6 5Pressure 0 1Duration of ulcer (months):I1: 3.7I2: 3.1Mean age (years):I1: 69I2: 69Healed in 30 days:I1: 9/27 (33%)I2: 0/16 (0%)No data.continued99

Appendix 9TABLE 19 contd Topical preparations compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaCalabro et al., 1995 85ItalyWound type:Venous, traumatic,arterial anddiabetic leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Ulcer area as tracedonto a transparentsheet and digitisedusing a computer.Setting and lengthof treatment:Outpatient clinic.80 patients withulcers of mixedaetiologies;59 women and21 men.Exclusion criteria:None stated.Treatment:I1: Fibrin glue appliedweekly.I2:‘Traditional’ treatments(paraffin gauze, povidoneiodine gauze, Duoderm,Biofilm, Cutinova ® ).Concurrent treatments:All non-arterial ulcers hadelastic compression.Mean wound area:No data.Ulcer aetiology:69 venous disease, three trauma,two arterial, six diabetic.Other characteristics:Age: 35–80 years.Healed in trial:I1: 20/26 (77%)I2: 48/54 (89%)Time to heal:I1: 15 days–3 monthsI2: 3–9 months.No data.Knighton et al.,1990; 81 1988 82USAWound type:Leg ulcers due tovenous disease,diabetes, peripheralvascular diseaseand vasculitis.Method ofrandomisation:Blinded cardselection process.Objective outcome:Not stated.Setting and lengthof treatment:Wound-healingclinic of hospital;outpatients visitedclinic every2–3 weeks.32 patients witha chronicallynon-healing, fullthickness,cutaneousulcer of a lowerextremity of at least8 weeks’ duration.Normal peripheralblood platelet.Exclusion criteria:Failure to followprotocol instructionson two ormore visits;amputation of theextremity beforecompletion of thetrial; any extensivesurgical interventionafter randomisation.Treatment:I1: Platelet-derived woundhealing formula added toplatelet buffer solution andmicrocrytstalline collagen,n =16 patients.I2: Platelet buffer solutionand microcrytstallinecollagen, n = 16 patients.Concurrent treatments:sharply debrided in theclinic to remove all fibrin,infected, foreign ornecrotic tissue.Mean wound area (cm 2 ):I1: 11.6 (24.5 SD)I2: 22.0 (19.2 SD)Other characteristics:Wound duration (weeks):I1: 119 (114 SD)I2: 47 (63 SD)Diagnosis (I1:I2):Diabetes 5:4Peripheral vascular disease 1:3Venous stasis 6:4Vasculitis 1:0Age (years):I1: 64 (8 SD)I2: 62 (10 SD)Number completelyhealed at 8 weeks:I1: 17/21 (81%)I2: 2/13 (15%)At termination13 patients with 21wounds remained in I1,while 11 patients with13 wounds remainedin group I2:I1:Three: one fornon-compliance;one due toamputation; oneincomplete data.I2: Five: two noncompliance;twoamputation; oneincomplete dataanalysis.TABLE 20 Topical preparations compared with dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaAcosta et al., 1992 86SpainWound type:Chronic leg ulcers(arterial andvenous).Method ofrandomisation:Not stated.Objective outcome:Ulcer area astraced onto atransparent sheetand digitised usinga computer.12 patients withvenous or arterialleg ulcers: eightwomen andfour men.Nine venous ulcers,two arterial ulcersand one neuropathiculcer.Exclusion criteria:Cellulitis ornecrotic ischaemia.Treatment:I1: Growth hormone mixedwith paraffin, covered witha hydrocolloid dressing(Comfeel).I2: Hydrocolloid dressing.(Comfeel).Concurrent treatments:Swabs were taken formicrobiological culture andsensitivity. If the result waspositive, antibiotics werecommenced. No mentionof compression for venousleg ulcers.Mean wound area:No data.Other characteristics:No data.Percentage reduction inwound area:I1: 82%I2: 77%Not significantlydifferent (MANOVA).No data.Setting and lengthof treatment:Appear to be inoutpatients department,4 weeks.100MANOVA, multiple analysis of variance

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Appendix 10Studies of healing venous leg ulcersTABLE 21 Dressings compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaArnold et al.,1994 99UK and USAWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Ulcer healing andulcer area.Setting and lengthof treatment:Outpatient, hospitalclinic, multicentrestudy; 10 weeks.70 patients with90 venous ulcersattending clinic.Exclusion criteria:Arterial insufficiency;vasculitis;rheumatoidarthritis; deepdermal involvement;exposure of tendon;muscle or bone.Treatment:I1: Hydrocolloid dressing,n = 35.I2: Conventional dressing(paraffin gauze in USA,povidone iodine gauzein UK), n = 35.Compression:Unna’s Boot.Mean wound area (mm 2 ):I1: 2100 (685 SEM)I2: 1983 (659 SEM)Mean wound duration (weeks):I1: 46.2I2: 47.8Number completelyhealed at 8 weeks:I1: 11/35 (31%)I2: 14/35 (40%)Reduction inwound area:I1: 71% (4.3 SD)I2: 43% (7.1 SD)Time to healing (weeks):I1: 7.1 (0.2 SEM)I2: 8.2 (0.4 SEM)I1:Nine:twoinfection; onediscomfort; sixunrelated todressing.I2: Seven: threepain/discomfort;one cellulitis;one infection;two unrelatedto dressing.Backhouse et al.,1987 98UKMethod ofrandomisation:‘Randomised’.Outcome measure:Ulcer traced oncellophane, this wastransferred ontocard and the areaderived from theweight of the card.Setting and lengthof treatment:Venous ulcer clinic.Follow-up 12 week.56 patients withchronic venous legulcers smaller than10 cm 2 .Exclusion criteria:Arterial diseaseas indicated byDoppler assessment.I1: Hydrocolloid(Granuflex), n = 30.I2: Non-adherent dressing(N-A), n = 30.Concurrent treatments:All ulcers were washedwith saline and had allloose slough removed.All patients receivedcompression bandaging(four-layer). Antibacterialspermitted only for spreadingcellulitis. Dressedweekly unless exudewas excessive.Mean ulcer area (cm 2 ):I1: 3.4 (0.4)I2: 3.1 (0.4)Mean age (years):I1: 69.9I2: 67.5Median duration of presentulcer (months):I1: 22I2: 21Number healed at12 weeks:I1: 21/30 (70%)I2: 22/30 (73%)Not stated.Sponsored byJohnson &Johnson, 3M,Sigvaris, Zyma,and Squibb.Streptococcalcellulitis wasseen in sevencases:I1: 4I2: 3.Banerjee et al.,1990 94Wound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Ulcer area: tracingsof ulcer outline andphotographs takenat weeks 0, 4, 8, 12and 17.Setting and lengthof treatment:Inpatients orattending a dayhospital for theelderly; 17 weeks.71 elderly patientswith venous legulcers.Exclusion criteria:Significant peripheralvasculardisease (assessedusing Dopplerultrasound).Ulcers wereassessed anddressed byone person.Treatment:I1: Polyurethane film(Synthaderm), n = 36.I2: Paraffin-impregnatedtulle (Paratulle ® ), n = 35.Concurrent treatments:Cleansed by pouring warmsaline over ulcers.Treatmentapplied, then a padplaced on top. Supportbandage (K-band ® ) appliedfrom toes to knee.Median wound area (cm 2 ):I1: 12.2 (range, 1.1–138)I2: 11.4 (range, 1.3–134)Other characteristics:Mean age (years):I1: 75.9 (7.7 SD)I2: 81.2 (7.3 SD)Ulcer duration (years):I1: 2I2: 2Number of recurrent ulcers:I1: 14I2: 14Number treated by adistrict nurse:I1: 30I2: 26Locomotor problems:I1: 26I2: 30All groups:50% of patients lived alone.1/3 were on diuretics.Number completelyhealed at 17 weeks:I1: 11/36 (30%)I2: 8/35 (23%) (NS)I1: Eight: onewithdrawn;seven deaths.I2: 11: eightwithdrawn;three deaths.Paratulle ® , Seton Scholl Healthcare Ltdcontinued101

Appendix 10TABLE 21 contd Dressings compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaCallam et al., 1992 90UKWound type:Venous leg ulcers.Method ofrandomisation:‘Randomlyallocated’.Objective outcome:Complete ulcerhealing, change inulcer area.Setting and lengthof treatment:Multicentre trial.Outpatients –treatment providedby experiencedresearch nurses.Factorial designof trial with compressionalso compared;12 weeks.132 patients withvenous leg ulcersattending trial legulcer clinics.Exclusion criteria:Diabetes mellitus;rheumatoidarthritis;ABPI < 0.8.Treatment:I1: Knitted viscose dressing(Tricotex ® ), n = 66.I2: Polyurethane foam(Allevyn), n = 66.Concurrent treatments:Compression applied bymultilayer compression,either long-stretch orshort stretch.The dressings andbandages had separateeffects (interaction test:p = 0.87) and thereforecomparisons could bemade between dressings.Treatment provided byspecialist nurses.Mean wound area (cm 2 ):I1: 8.35I2: 10.87Other characteristics:I1 I2Duration of ulcer:< 6 months 31 336–11 months 18 181–2 years 11 143+ years 6 1Mean durationof ulcer (months): 11.2 11.7Mean age (years): 63 64M:F 30:36 29:37Number completelyhealed at 12 weeks:I1: 23I2: 31 (NS; p = 0.08,stepwise Cox model)Primary outcome ofcomplete ulcer healingwas assessed usingCox survival analysis.Secondary outcomemeasure of change inulcer area was examinedusing a stratified twosampleWilcoxon test(the four strata havingbeen chosen on thebasis of pre-specifiedlevels of initial ulcersize). Forward stepwiseselection of baselinecovariate ensured thatany potentially influentialimbalances in baselinecharacteristics weretaken into account.Patients withdrawnfrom treatment wereconsidered failures oftreatment rather thanlost to follow-up.I1: 15 after amean of 5.5weeks: twosensitivity; sixexudate; 12deterioration;one socialreasons; sixother (includingbandageslippage).I2: 13 after amean of 4.6weeks: eightsensitivity; sevenexudate; 12deterioration;one social reasons;four other(including bandageslippage).Note: Morethan one reasoncould be givenfor each patient.Funded by Smith& Nephew(manufactureboth dressings).Also assesseddressing influenceon pain.Davis et al., 1992 93USAWound type:Venous leg ulcers.Method ofrandomisation:‘Randomlyassigned’.Objective outcome:Ulcer traced.Setting and lengthof treatment:6 months.11 patients with12 ulcerated legs;ulcers diagnosed asbeing secondary tovenous insufficiency.Exclusion criteria:Arterial pathology.Treatment:I1: Polyurethane film andUnna’s Boot (n = 5 legs);(Tegaderm or Bioclusiveaccording to availability).I2: Unna’s Boot alone(Unna’s Boot = wide meshgauze impregnated withzinc oxide, calamine andgelatine, all covered withan elastic bandage to keepin place and apply compression),n = 7.Concurrent treatments:Cleansed by scrubbinglower leg with a washcloth,mild soap and water.Wound was then irrigatedwith saline. All patientsreceived 1 hour ofintermittent pneumaticcompression therapy.Ulcers redressedtwice weekly.Mean wound area:No data, but ‘larger woundswere placed in theexperimental group’.Other characteristics:No details.Number completelyhealed at 6 months:No data.Reduction in woundarea (cm 2 /day):I1: 0.30 (five ulcers)I2: 0.12 (seven ulcers)(Excluding bilateralulcerated leg:I1: 0.27 (n = 4)I2: 0.13 (n = 6))Mean reduction inwound area (cm 2 ):I1: 39.26 (25.56 SD)I2: 7.11 (6.11 SD)None stated.Unit of randomisationwaspatient butresults arepresented asper ulcer.Tricotex ® , Smith & Nephew Healthcare Ltdcontinued102

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 21 contd Dressings compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaGroenewald,1984 103South AfricaWound type:Venous ulceration.Method ofrandomisation:Randomised butmethod not stated.Objective outcome:Reduction in ulcersize – ulcer outlinetraced onto acetate(area measurementby person notinvolved in trial).Average of threearea tracings wasused.Setting and lengthof treatment:Setting unclear;8 weeks.72 patientssuffering fromvenous leg ulcers,the majority wereof > 6 monthsduration.Treatment:I1: Conventional treatment,n = 36.I2: Hydrocolloid dressing,n = 36.Concurrent treatments:I1: Ulcer and surroundingskin washed with a softbrush and solution ofpovidone iodine. Povidoneiodine placed onto ulcer.Foam pad, zinc pastebandage and an elasticcompression bandage.I2: Skin cleansed with softbrush and povidone iodinesolution.No data on ulcer size ordistribution of sizes intwo groups.All groupsM:F approx. 1:3Reduction inulcer size:I1: 22.62%I2: 67.64%p < 0.0001, pooledSEM 3.51.I1: Six: overwhelmingsepsisand increase inulcer size.I2: Seven: twonon-compliant;five treatmentshad to bestopped (twopain and irritation,threeoverwhelmingsepsis).Appears asthough thecontrol grouphad compressionwhereas the trialgroup did not.Withoutbaseline datait is not possibleto determine thesignificance ofthe results.Mansson, 1996 101Sweden, Denmark,The Netherlandsand UKWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Ulcer area –method ofmeasurementnot stated.Setting and lengthof treatment:Multicentre trial;12 weeks.153 patients withvenous leg ulcersattending trialcentres.Inclusion criteria:None.Exclusion criteria:None.Treatment:I1: Cadexomer iodine(Iodosorb), n = 56.I2: Hydrocolloid (DuodermE, Granuflex E), n = 48.I3. Paraffin-impregnatedgauze (Jelonet), n = 49.Concurrent treatment:Compression bandages(Comprilan ® ).Mean duration of ulcer (years):I1: 8.4 (14.4 SD)I2: 3.9 (8.4 SD)I3. 7.8 (12.8 SD)Mean initial ulcer area (median):I1: 9.6 (5.1) (13.4 SD)I2: 10.0 (5.8) (19.1 SD)I3. 7.8 (5.1) (8.6 SD)Other characteristics:I1 I2 I3M:F 15:41 15:33 18:31Mean age (years):I1: 74(13.6 SD)I2: 74 (12.7 SD)I3. 72 (12.8 SD)Number healed in12 weeks:I1: 8/56 (14%)I2: 5/48 (10%)I3. 7/49 (14%)Number with woundinfection:I1: 1I2: 5I3. 4Mean reduction inwound area (%):I1: 62I2: 41I3. 24Mean ulcer area at12 weeks (cm 2 ):I1: 5.2 (8.6 SD), n = 56I2: 6.0 (9.8 SD), n = 46I3. 6.1 (9.6 SD), n = 49ITT analysis:Median ulcer areaat 12 weeks:I1: 1.8 (range, 0–46.6)I2: 1.9 (range, 0–53.2)I3. 3.2 (range, 0–48.4)I1: Seven: onewound infection;six pain.I2: 13: threeincreases inulcer size; fivewound infections;fivedermatitis onperi-ulcer skin.I3.Ten: sixincrease inulcer area;four woundinfection.Sponsoredby PerstorpPharma.Pain graduallydecreased infrequencythroughoutthe trial,except for theDuoderm Egroup at 8 and12 weeks.There wasno differencebetween thegroups in theuse of analgesics(no datapresented).Comprilan ® , Beiersdorfcontinued103

Appendix 10TABLE 21 contd Dressings compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaMeredith et al.,1988 100UKWound type:Venous leg ulcers.Method ofrandomisation:Random numbertable.Objective outcome:Ulcer area determinedby tracingulcer outlineonto acetatefilm, subsequentscanning anddigitisation. Ulcers< 1 cm 2 were alsomeasured by using1 mm 2 graph paper.Setting and lengthof treatment:Leg ulcer clinic;6 weeks.50 patientsattending the legulcer clinics withan ulcer deemed tobe due to venousinsufficiency, irrespectiveof whetherpatients wasdiabetic or not.Exclusion criteria:None stated.Treatment:I1: Hydrocolloid(Granuflex), n = 25.I2: One layer of paraffinimpregnatedparaffin gauze(Jelonet) covered with acotton dressing pad, n = 25.Concurrent treatments:Ulcers cleansed usingnormal saline, or in a fewcases, povidone iodine.Support provided byElastocrepe ® or straightTubigrip ® .Dressings were changedat least weekly or whenrequired due to exudateleakage.Patients in the hydrocolloidgroup were permitted toremove the Tubigrip andbathe or shower. This wasnot permitted for thecontrol group.Mean wound area (cm 2 ):I1: 1.1I2: 4.7(three very large ulcers wereallocated to the I2 group: 29.9,25.5 and 14.7 cm 2 )Other characteristics:Both groupsMean age(years): 70.4 (range, 32–92)Number completelyhealed at 6 weeks:I1: 19/25 (76%)I2: 6/25 (24%)No inferential statisticspresented.Mean reduction inwound area (cm 2 ):I1: 0.84I2: 0.32Cost of dressings (£)(including non-drugtariff items):I1: 436.86I2: 855.87One fromcontrol group– admitted tohospital foran unrelatedcondition.This patient isomitted fromdata presented.No adversereactions toeither dressing.Milward, 1991 102UKWound type:Not stated.Method ofrandomisation:Not stated.Objective outcome:Ulcer healed.Setting and lengthof treatment:Community trial;12 weeks.38 patients withwounds in thecommunity.Exclusion criteria:Treatment:I1:Traditional dressing,n = 19.I2: Hydrocolloid (Comfeel),n = 19.Mean wound area:No data.Number completelyhealed at 12 weeks:I1: 0I2: 3Median decrease inulcer area (%):I1: 7.66I2: 63.3Cost of dressings (£):I1: 2815.35I2: 2541.02Number of visits:I1: 1056I2: 436No data.Moffatt et al.,1992 97UKWound type:Venous leg ulcers.Method ofrandomisation:Assigning sequentialnumbers toeach patient andrelating this to arandomisationgroup.Objective outcome:Ulcer areameasured usingcomputerisedplanimetry.Setting and lengthof treatment:Community legulcer clinics;12 weeks.60 patients formcommunity leg ulcerclinics with nonhealingulcers.Inclusion criteria:Failure to reduceby 20% of originalsize in 12 weeks;or failure to heal in24 weeks of fourlayerbandaging; orABPI ≥ 0.8.Exclusion criteria:Known allergy orcontraindication toone of the trialtreatments.Treatment:I1: Knitted viscose dressing(N-A), n = 30.I2: Hydrocolloid (Comfeel),n = 30.Concurrent treatment:Four-layer compressionbandaging applied.Median ulcer size (cm 2 ):I1: 6.7 (range, 2.6–14.9)I2: 7.3 (range, 1.3–66.3)No data on duration of ulcer.Other characteristics:I1 I2Female: 18 15Median age (years): 71 74Diabetes: 3 0Hypertension: 4 3All groupsAge range (years): 26–89Ulcer size (cm 2 ): 1.3–66.3M:F 27:33Number healed after12 weeks:I1: Seven healed (23%)I2: 13 healed (43%)Cumulative healing ratein the trial:I1: 17%I2: 46%(relative risk = 2.25,95% CI, 0.88, 5.75)Four withdrew:two refused tocontinue; twodied in trialperiod.A priori powercalculation:10% vs. 40%healing in12 weeks(power =80%, at 5%significance).Comparison oflife tables up to12 weeks oftreatment wasmade using thelog-rank method.Comparisonswere made usingthe chi-squareand Mann–Whitney U test.Funded byColoplast(Comfeel).Elastocrepe ® , Smith & Nephew Healthcare Ltd; Tubigrip ® , SSL Ltd104continued

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 21 contd Dressings compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaMoffatt et al.,1992 88UKWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Ulcer area – notstated how thiswas measured.Setting and lengthof treatment:Community clinics;12 week follow-up.60 patients withvenous ulcers fromcommunity legulcer clinics.Inclusion criteria:ABPI ≥ 0.8; surfacearea < 10 cm 2 .Exclusion criteria:Known allergy tothe products inthe trial.Treatment:I1:Tegagel, n = 30.I2: N-A, n = 30.Concurrent treatments:Four-layer compressionbandaging. Cleansed andredressed weekly oraccording to excessiveexudate or infection.Median ulcer size (cm 2 ):I1: 3.6 (range, 0.9–9.8)I2: 6.4 (range, 1.1–9.9)Median ulcer duration (months):I1: 2 (range, 1–192)I2: 3 (range, 1–20)Other characteristics:I1 I2Male: 10 13Hypertension: 8 4Diabetes: 0 0All patientsAge (years): range, 38–88Ulcers healed at12 weeks:I1:Tegagel, 26/30 (87%)I2: N-A, 24/30 (80%)No difference.Analysis by life tablefor time to completehealing.No data.Sponsoredby 3M.Nelson et al.,1995 96UKWound type:Venous leg ulcers(confirmed bypresence of multicentre,factorialstudy of dressing;bandage and drug(oxpentifylline).Method ofrandomisation:Sequentiallynumbered, sealed,opaque envelopes.Objective outcome:Ulcer area determinedby tracingulcer outline ontoacetate. Subjectedto planimetry bysomeone blind totreatment.200 patientsattending leg ulcerclinics with ulcersof minimum8 weeks durationand 1 cm diameter.Inclusion criteria:Age >18 years;consent; clinicalsigns of venousdisease and confirmationof venouspathology by handheldDopplerexamination.Exclusion criteria:ABPI < 0.8; severeconcurrent disease;diabetes; rheumatoidarthritis; takingwarfarin, steroids,or vasoactive drugs.Treatment:I1: Knitted viscose dressing(N-A), n = 98.I2: Hydrocolloid(Granuflex E), n = 102.Concurrent treatments:Also randomised tobandages: four-layeror Granuflex adhesivecompression bandage,and 1200 mg oxpentifyllinedaily or placebo.Ulcer size (mm 2 ):I1: 1124, n = 94I2: 914, n = 98Healed in trial:I1: 44/98 (45%)I2: 49/102 (48%)No data.Sponsored byConvatec UKand HoechstMarion Roussel.Setting and lengthof treatment:Outpatients;24 weeks.Dressings done byexperiencedresearch nurses.continued105

Appendix 10TABLE 21 contd Dressings compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaPessenhoffer &Stangl, 1989; 91 1992 92AustriaWound type:Venous leg ulcers.Method ofrandomisation:‘Allocated by lot’.Objective outcome:Area, circumferenceand maximumdiameter of ulcer.Measured by photographyusing aPolaroid camera andthen digitisation.Setting and lengthof treatment:Outpatients; followupperiod is up to281 days.48 patients withvenous leg ulcers.Inclusion criteria:None.Exclusion criteria:None.Treatment:I1: Polyurethane foam(Lyomousse), n = 25.I2: Sterile gauze compress,n = 23.Concurrent treatments:Cleansing with normalsaline, compression bandageby Fischer method.Fibrolan ® cream (enzymaticwound cleanser) appliedif required.Mean area of ulcers (mm 2 ):I1: 1078.3 (1743.6 SD)I2: 1170.2 (2424.5 SD)Mean circumference ofulcers (mm 2 ):I1: 130.8 (106.2 SD)I2: 121.5 (103.9 SD)Other characteristics:I1 I2M:F 4:21 3:20Mean age (years):I1: 65.7 (12.6 SD)I2: 66.7 (9.3 SD)% change in ulcer area:I1: –65.6 (47.0 SD)I2: +78.3 (215.8 SD)(negative value indicatesa reduction in area).I1: One.I2: Six.Reasons forwithdrawal:patients did notre-attend orwere admittedto hospital forfurthertreatment.Completehealing notreported.Smith et al., 1992 95UKWound type:Venous leg ulcers.Method ofrandomisation:Not stated butstratified by initialmaximum ulcerdiameter, 2–4 cmor > 4 cm.Objective outcome:Ulcer areameasured monthlyby tracing ontoacetate and subsequentplanimetry.Average of threearea measurementswas taken foreach assessment.Pain and comfortmeasured monthlyon a five-pointscale.Setting and lengthof treatment:Patients attendedhospital for initialassessment andmonthly thereafter;the communitynurses carried outall other treatments.Trialperiod4 months.200 patients withvenous leg ulcers,minimum diameter2 cm, attending anoutpatient clinic.Assessed bycontinuous waveultrasound andphotoplethysmography.In thosepatients withbilateral ulcerationdata were recordedfor the right legonly.Exclusion criteria:Diabetes; rheumatoidarthritis;infected ulcers;known intoleranceto iodine; neurologicalimpairment;lymphoedema;intolerance to compression;malignantdisease in ulcer;ABPI < 0.75.Treatment:I1: Biofilm applied witha 2 cm overlap all aroundthe ulcer. In deep ulcersBiofilm powder was usedto fill the cavity and thenthe Biofilm dressing wasapplied over this (n = 64small ulcers, n = 35 largeulcers, 99 in total).I2: Jelonet and Betadine ® ,cut to the shape of theulcer, absorbent padplaced over this (n = 62small ulcers, n = 30 largeulcers, 101 in total).Two patients who wererandomised to Jelonetreceived Biofilm instead;three patients receivedJelonet instead of Biofilm(due to administrativeerror).Fibrolan ® , Parke-Davis; Betadine ® , SSL Ltd;Venosan ® , CredenhillConcurrent interventions:Cleansed with isotonic,sterile saline. Compression(two shaped supportbandages (shaped Tubigrip)or compression stocking -Venosan ® 2002). Dressingsdone by district nurses.Patients in the I1 groupwere allowed to removetheir stocking and batheor shower. Patients in thecontrol group were notable to do this.Age (years):I1: Small ulcer = 74I1: Large ulcer = 76I2: Small ulcer = 72I2: Large ulcer = 73Median ulcer duration (months):I1: Small ulcer = 5I1: Large ulcer = 4I2: Small ulcer = 3I2: Large ulcer = 17Median ulcer area (cm 2 ):I1: Small ulcer = 3.1I1: Large ulcer = 13.3I2: Small ulcer = 2.6I2: Large ulcer = 17.6Analysed by treatment receivedrather than ITT.Median healing ratein 1st month (cm 2 /day)(n = 153):I1: Small 0.056 (n = 50)I1: Large 0.184 (n = 25)I2: Small 0.062 (n = 52)I2: Large 0.017 (n = 26)(p = 0.09 for largeulcers; p = 0.4 forsmall ulcers)Number healed in4 months:I1: Small 38/64 (59%)I1: Large 12/35 (34%)I2: Small 43/62 (69%)I2: Large 4/39 (10%)All ulcers healed in trial:I1: 50/99 (50.5%)I2: 47/101 (46.5%)The association betweenwhether the ulcer healedand the treatmentreceived was examinedusing Fisher’s exact test.Biofilm and controldressings were notsignificantly different inhealing ulcers sized 2–4cm (p = 0.27). In theulcers sized > 4 cm,Biofilm did result in ahigher proportion ofulcers healing (p = 0.02).Relative risks and 95%CI from proportionalhazards model:Ulcer area (cm 2 )(halving initial area) =1.92 (1.58, 2.33)Duration of ulceration(months) (halving this)= 1.35 (1.17, 1.56)Age (years) (10-yeardecrease) = 1.34(1.12, 1.59)Biofilm treatment =1.16 (0.77, 1.77)No deep vein involvement(determined byPPG) = 1.80 (1.19, 2.78).I1: 21: ninerefused; fivewere admittedto hospital; sixhad suspectedallergic reaction;one moved away.I1: Six: threerefused; oneinfection; twoadmitted tohospital.I2: 14: fourrefused; oneinfection; fiveadmitted tohospital; twohad suspectedallergic reaction;two died.I2: 19: sevenrefused; 11infection; onemoved away.Note: None ofthe suspectedallergic reactionswere confirmedby patch testing.Rate of infectionwas significantlyhigher in thelarge ulcer/Betadine group(p = 0.004,Fisher’s exacttest).Pain: in firstmonths for123 patients: lesspain in Biofilmgroup (p = 0.02),no difference forcomfort.Sponsored byClinimed Ltd.106continued

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 21 contd Dressings compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaStacey et al., 1991 89AustraliaWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Ulcer area –method of assessmentnot stated.Setting and lengthof treatment:Outpatient footand leg ulcer clinic.Follow-up period9 months.113 patients with133 ulcerated limbs,suffering fromproven venousulceration.Inclusion criteria:Proven venousulceration (plethysmography);ABPI(cut-off pointnot stated);ulcer diameter0.5–10 cm.Exclusion criteria:Diabetes; rheumatoidarthritis;arterial disease;cellulitis.Treatment:I1: Zinc-impregnatedbandage (Viscopaste ® ) ina spiral fashion, n = 43.I2: Zinc oxide-impregnatedstockinet (Acoband ® ),n = 44.I3: Alginate dressing(Kaltostat), n = 46.Concurrent treatments:Leg and foot washed ina soap and water bath.Standard compressionused over dressing (twoElastocrepe bandages)plus Tubigrip.Dressings changed twiceor three times a week inearly stages of treatment,reducing to weekly oncethe exudate had reduced.Mean ulcer area (cm 2 ):I1: 10.8 (range, 1.5–57.5)I2: 9.9 (range, 3.6–61.3)I3: 10.7 (range, 2.4–75.4)All patientsMedian age 74(years): (range, 31–92)M:F 46:67% totally healedin 3 months:I1: 66%I2: 50%I3: 45%(numerator anddenominator not given).Time to total healingcompared using a logrank analysis: Viscopastewas better than eitherthe zinc-impregnatedstockinette (p < 0.05)or the Kaltostat(p < 0.05).There was no differencein the healing betweenthe alginate and thestockinette group.I1: Five: twoallergy; onepain; twomedical/personal.I2: Six: oneallergy; one pain;one cellulitis;three medical/personal.I3:Ten: oneallergy; threepain; threecellulitis; threemedical/personal.Wunderlich &Orfanos, 1992 87GermanyWound type:Venous leg ulcers.Method ofrandomisation:No details.Objective outcome:Ulcer size – tracingsubjected topplanimetry every2 weeks.Setting and lengthof treatment:6 weeks.40 patients withvenous leg ulcers ofwhom 38 producedevaluable data.Exclusion criteria:Diabetes mellitus,steroid therapy,drugs which affectwound healing.Treatment:I1: 5 days cleaning withmechanical and enzymaticdebridement and thenapplication of a polyamide,activated charcoal dressingwith 0.15% silver.I2: 5 days cleaning withmechanical and enzymaticdebridement then dressingaccording to stage of healingGranulation: paraffin oilor PVI cream; epithelialisation:Fettgaze or oil inwater emulsion.Concurrent treatments:Mechanical debridementat least every 4 days.Mean wound area (mm 2 ):I1: 3I2: 2Other characteristics:I1 I2M:F 7:12 4:15Age (years): 74.3 72.9Duration ofulcer (years): 7.6 7.9Number completelyhealed at 6 weeks:I1: 6/19 (32%)I2: 2/19 (11%)Wound area at endof 6 weeks (change)(mm 2 ):I1: 1 (2)I2: 1 (1)% reduction inulcer size:I1: 75%I2: 65%No data.Viscopaste ® , Smith & Nephew Healthcare Ltd; Acoband ® , Auspharm107

Appendix 10TABLE 22 Comparisons of dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaCaprio et al.,1995 105ItalyWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Tracings and photographsof ulceroutlines made ondays 0, 28 and 56.Setting and lengthof treatment:Five centres,8 weeks.93 patients with98 clean ulcers ofvenous origin.Exclusion criteria:None.Treatment:I1: Hydrocolloid(Granuflex E).I2: Lyophilised collagencovered with gauze andcotton bandage.Mean wound area:No data.Number completelyhealed at 8 weeks:I1: 25I2: 20Unable to calculate %healed as numbers ineach group not given.Reduction in woundarea (mm 2 /week):I1: 152.7I2: 103.66Total mean cost ofdressing materials (lira):I1: 102,607I2: 142,527No data.Product-relatedadverse events:I1: 0I2: 5Palmieri, 1992 50ItalyWound type:Mixed (leg ulcers;diabetic; pressuresores; posttraumatic).Method ofrandomisation:Not stated.Objective outcome:Time to healing.Setting and lengthof treatment:Wound clinicbased trial.Treatment wascontinued untilall wounds wereconsidered healed.48 patientswith venous legulcers (12); pressuresores (12); burns(12) and radioactiveulcers (12). Datawill only be givenfor leg ulcers.Exclusion criteria:Additional treatmentwith drugs(with the exceptionof digitalis).Treatment:I1: Collagen sponge applieddirectly to the wound aftersaline nebulisation.Thedressing was checkedeveryday and if the collagenwas swollen or partiallyreabsorbed by collagenasesor lysosomal enzymesmore of the product wasadded without removingthe previous one. Greasysponge and regular nonallergenic tape completedthe dressing (24).I2: Dextranomer beadsapplied directly to thewound bed and replaceddaily (24).Prior to randomisation allwounds underwent sharpdebridement to remove allnecrotic tissue. In additionall wounds were treated toensure negative bacterialcultures at baseline.Mean area of wounds:Not stated.Other characteristics:All patients(n = 48)Age range (years): 58–75M:F 1:0.6Mean time tohealing (days):I1: 36I2: 60( * p < 0.005: = p < 0.001:Student’s t-test).No withdrawals.Banks et al., 1996 65UKWound type:Leg ulcers andpressure sores.Method ofrandomisation:Not stated.Objective outcome:Not stated.Setting and lengthof treatment:13 weeks. Multicentrestudy inthe community.200 patients:100 with venousleg ulcers and 100with grade II or IIIpressure sores.Inclusion criteria:I1: Pressure sores:grade II or III.I2: Venous legulcers: ABPI > 0.8.Exclusion criteria:Clinical infection.Treatment:Leg ulcers: n = 100.I1: Hydrocolloid(Granuflex), n = 50.I2: Hydropolymer (Tielle),n = 50.Leg ulcers:Median age (years):I1: 80I2: 77Ulcer duration (months):I1 I2< 1 3 21–3 13 9> 3 34 39Ulcer area (mean/median; mm 2 ):I1: 334.7/243.5 (range, 10–2758)I2: 431.3/417.5 (range, 16–1876)Leg ulcers:Ulcers healed in13 weeks:I1: 19/47 (40%)I2: 18/49 (37%)Mean % change inulcer area:I1: 31.5I2: 49.3Change in mean ulcerarea (mm 2 ):I1: 334.7–157.6I2: 431.3–238.3No data.No details of theconcurrenttreatments.continued108

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 22 contd Comparisons of dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaSmith, 1994 106UKWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objectiveoutcome:Ulcer areameasured bytracing ulceroutline ontoacetate sheet andcalculating areausing imageanalyser.40 patients withvenous ulcersgreater than 2.5 cmin diameter.Exclusion criteria:Wound infection;immune deficiency;steroid therapy;malignant disease.Treatment:I1:Alginate (not named),n = 18.I2: Hydrocolloid(Granuflex), n = 22.Concurrent treatments:Wound cleansed withphysiological saline, compressionapplied. N.B.gauze used as a secondarydressing over alginate.Mean baseline ulcer area (cm 2 ):I1: 12.74I2: 22.17Number healedin 6 weeks:I1: 2/18 (11%)I2: 4/22 (18%)% change in ulcer size:I1: 34.9I2: 57.1 (NS)Cost of treatmentmaterials:I1: £364.08I2: £431.73I1: Six: four forpain, two forinfection.I2: Six: one forpain, one forinfection, one forpossible allergy,one dressingleakage, onemisdiagnosis,one subjectdefaulted.Also measuredpain, sleepdisturbance,convenience,ease of applicationandremoval.Pain levels fellduring trial withboth treatments.Setting and lengthof treatment:Dermatologyoutpatients clinic.6 weeks.Veraart et al.,1994 107The NetherlandsWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Tracing of ulceroutline on transparentfoil for latercomputerisedplanimetry.Setting and lengthof treatment:Two centre trial;outpatients;8 weeks. Dressingsdone by hospitalnurses only.38 patients.Inclusion criteria:Signs of venousinsufficiency ABPI> 0.9. Refillingtime by LRR> 25 seconds.Exclusion criteria:Acute skin diseasearound the ulcer;severe concurrentillness (high bloodpressure, diabetes,cardiopulmonarydisease); steroids/immunosuppressants.Treatment:Both hydrocolloids.I1: Comfeel ExtraAbsorbing dressing, n = 19.I2: Granuflex (DuoDerm)CGF, n = 19.Concurrent treatments:Cleansed with normalsaline, short-stretchbandages (Elco Rosidal ® )applied twice weekly forthe first 4 weeks andweekly thereafter.If there was more than oneulcer per patient the largestulcer was monitored.Mean age (years):I1: 70.5 (range, 53–85)I2: 67.5 (range, 42–85)No data on baseline area/duration.Healed in 8 weeks:I1: 12/19 (63%)I2: 10/19 (53%)Numbers healed andtime to healing weresimilar in the twogroups.I1:Three: onepatient didnot want tocontinue/DNA;two worseningof peri-woundeczema.I2: Seven: threedid not want tocontinue/DNA;three injury ofperi-ulcer skin;one extensiveexudate andodour leakage.Also measuredpain and pH.Burgess &Robinson, 1993 108UKWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Traced ontoacetate fortnightly.Setting and lengthof treatment:Multicentre,communitystudy; follow-up13 weeks.79 patients withvenous leg ulcers.Exclusion criteria:ABPI < 0.8.Treatment:I1: Standard Granuflex.I2: Improved formulationGranuflex.Concurrent treatments:Class 2 graduatedcompression hosiery –removed at night if wished.Mean wound area:Not stated.Other characteristics:Not reported.Reduction in woundarea (mm 2 /day):I1: 7I2: 8.17No datapresented.Sponsored byConvaTec. Differencebetweentwo formulationsof Granuflex isthat the improvedformulationdoes notform a liquid gelupon hydration,rather a gelatinousmass isretained withinthe body of thedressing.Thismay make thedressing lessprone toleakage.continued109

Appendix 10TABLE 22 contd Comparisons of dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaRobinson, 1993 109UKWound type:Venous leg ulcers.Method ofrandomisation:‘Randomly assigned’.Objective outcome:Ulcer size recordedby tracing ontoacetate fortnightly,this was digitised.Setting and lengthof treatment:Multicentre,community trial.13 weeks.121 patientsliving at home,with venousleg ulcers.Exclusion criteria:ABPI < 0.8.Treatment:I1: Granuflex.I2: Comfeel.I3: Improved formulationGranuflex.Concurrent treatments:Class 2 graduatedcompression hosiery.Mean wound area:Not stated.Other characteristics:Total ulcer area (mm 2 ):77,923.Reduction in wound area(mm 2 /day):I1: 7.06I2: 6.07I3: 8.17Labour and material costs:I1: Not statedI2: £4.15 per dayI3: £3.39 per dayCost-effectiveness(cost per day/area healedper day):I1: Not statedI2: £0.68 per mm 2 per dayI3: £0.41 per mm 2 per dayMean duration of visit was17 minutes.Not stated.Sponsored byConvaTec.Have requesteda copy of finalreport — notreceived.This is the sametrail as Burgess,referencenumber 108.Zuccarelli, 1993 113FranceWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Wounds assessedweekly and outlinestraced at 0, 4, 8 and12 weeks.Setting and lengthof treatment:12 weeks, settingunclear.40 patients withvenous leg ulcersof at least 4 weeksduration. 38 patientswere evaluable.Inclusion criteria:Age >18 years;duration > 4 weeks;venous insufficiencyconfirmed byDoppler.Exclusion criteria:ABPI < 0.8; pregnancy;myocardialinfarction < 6 monthspreviously; uncontrolledhypertension;unstable diabetes orrheumatoid arthritis;necrotic orinfected ulcers.Treatment:I1: Hydrocellular dressing(Allevyn), n = 19.I2: Hydrocolloid(Granuflex), n = 19.Concurrent treatments:Compression bandages.(Nylex ® and Biflex ® ).Dressings and bandageschanged weekly or moreoften if required due toirritation, excess exudate,or pain. Steroids foreczematous peri-ulcerskin as required.In the case of multipleulcers the largest ulcerwas monitored.Mean ulcer area (cm 2 ):I1: 9.8I2: 6.9Mean ulcer duration (weeks):I1: 48.9I2: 37.4Mean age (years):I1: 70.1I2: 77.3M:FI1: 6:13I2: 2:17Previous ulceration:I1: 14I2: 17Baseline data only available forthose completing the trial.Number healedat 12 weeks:I1: 9 /19 (47%)I2: 9 /19 (47%)I1: None.I2:Two allergicreaction, andone intoleranceof peri-ulcerskin.One patient lostto follow-up andone record booklost.Bowszyc et al.,1993 114PolandWound type:Venous leg ulcers.Method ofrandomisation:Allocated totreatmentaccording to apre-preparedrandomisationlisting.Objective outcome:Area of ulcer measuredat baselineand weekly thereafterby tracingulcer outline ontoa transparent gridand by measurementof the lengthand breadth ofthe ulcer.Setting and lengthof treatment:Dermatology clinic.16 weeks follow-up.80 patients (82affected legs; 27men; 53 women)with venous legulcers attending adermatology clinic.Inclusion criteria:Age > 18 years;ABPI ≥ 0.8.Exclusion criteria:Diabetes; heavilyexuding wound;necrotic ulcer,clinically infected;poor state ofhealth; immunocompromised;corticosteroidtreatment.Treatment:I1: Polyurethane foamdressing (Lyofoam), n = 40.I2: Hydrocolloid dressing(Granuflex), n = 40.Concurrent treatments:Sloughy wounds treatedwith sodium chloridesolution containing0.3–0.4% available chlorinebefore entry to the study.Setopress high compressionbandage applied.Dressings and bandageschanged weekly or accordingto exudate level.Mean area of largest ulcer (cm 2 ):I1: 3.01 (4.88 SD)I2: 3.05 (6.77 SD)Mean pre-trial duration (weeks):I1: 26.2 (37.6 SD)I2: 36.1 (70.9 SD)Mean age (years):I1: 64.2I2: 55.5Other characteristics:11 I2Completelymobile: 28 35Initial numberof ulcers ( – x): 83 12Number of legs whereulcers completelyhealed in 16 weeks:I1: 24 (60%)I2: 24 (60%)I1: Four.I2: Four.Three for personalreasons;two for localisedinfection; onerequired steroidsfor an allergy;one had veryhigh exudatelevels and thedressing wouldnot adhere; onecomplained ofsevere pain inthe leg.Five wereexcludedbecause they hadheavily exudingwounds; unclearif this was prerandomisation.Mean pain scoreon removal:I1: 3.72 (0.55 SD)I2. 3.63 (0.83 SD)(NS)(scale = 1–4;very painful– no pain).110continued

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 22 contd Comparisons of dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaLimova, 1996 111USAWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Ulcer area.Setting and lengthof treatment:8 weeks.20 patients withvenous leg ulcers.Inclusion criteria:Not stated.Exclusion criteria:Not stated.Treatment:I1: DuoDerm CGFhydrocolloid dressing,n = 10.I2:Tegasorb hydrocolloiddressing, n = 10.Concurrent treatments:All had Medicopaste ®and Coban ® bandages,changed weekly.Mean wound area:No data.Number of ulcershealed in trial period:I1: 2/10 (20%)I2: 6/10 (60%)No data.The Tegasorbdressing was‘preferred interms of ease ofapplication toskin, adhesion toskin, conformability,exudateabsorption,barrier properties,transparencyandpatient comfort’.No data presentedfor theseparameters.Whipps Cross 112UKWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Ulcer area.Setting and lengthof treatment:6 weeks.29 outpatients withvenous leg ulcers.Inclusion criteria:Not stated.Exclusion criteria:Not stated.Treatment:I1: DuoDerm CGFhydrocolloid dressing,n = 16.I2: Comfeel Plus, n = 13.Concurrent treatments:Class II (UK) stockings –Venosan.Median wound area (cm 2 ):I1: 4.9 (range, 1.9–10.1)I2: 6.4 (range, 5.5–19.23)Other characteristics:I1 I2M:F 3:13 5:8Mean age (years):I1: 71.4 (16.5 SD)I2: 70.3 (10.75 SD)Median duration of ulcer(months) (interquartile range):I1: 13 (5.5–28.5)I2: 12 (4–18)Reduction in woundarea during trial:I1: 45%I2: 57%Median wear time (days):I1: 7I2: 7Stated that the healingrates in the two groupswere similar whetheranalysed by ulcer areaor perimeter.Two withdrawalsdue to reactionsto dressingbut not clearwhether fromI1 or I2:Dressings werealso assessed interms of conditionof dressingafter 1 week,wear time, easeof removal ofdressing, amountof exudate, andease of applicationof newdressing. Easeof dressingremoval andcomfort scoresaid to be higherfor ComfeelPlus, thoughno analysispresented.111

Appendix 10TABLE 23 Topical preparations compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaPassarini et al.,1982 115ItalyWound type:Venous leg ulcers.Method ofrandomisation:Not stated.Objective outcome:Ulcer area andhealing index(% healed).48 patients withvenous leg ulcers(26 women and22 men).Exclusion criteria:No data.Treatment:I1: Hyaluronic acid ongauze 2 mg in glycerine ona 10 x 10 cm gauze pad;changed daily, n = 23.I2: Control: varioustreatments (e.g. localantibiotics, zinc cream),n = 25.Concurrent treatments:All had surgical orenzymatic cleansing.Mean wound area:No data.Other characteristics:I1 I2M:F 9:14 13:12Age (years): 61 67Reduction in woundarea:I1: 78%I2: 44%No data.Setting and lengthof treatment:Outpatients;20 days.Galasso et al.,1978 116ItalyWound type:Venous ulcer.Method ofrandomisation:Not clear ifrandomly allocated.Objective outcome:Ulcer healed.Setting and lengthof treatment:62 patients withvenous disease.Exclusion criteria:Extending infection< 2 cm.Treatment:I1: Hyaluronic acid ongauze, n = 27.I2: Gauze, n = 35.Ulcers cleaned elasticcompression during dayand elevation at night.Zinc oxide paste bandageused on 12 controlpatients.Ulcer duration (months):I1: 23.1 (33.67 SD)I2: 7.4 (7.0 SD)Ulcer length (cm):I1 I22 5 92–4.9 11 165.0 2 15.1–9.9 3 8≥ 10 6 1Deep:superficial venous disease:I1: 17:10I2: 24:11Deep:superficial ulcer:I1: 11:16I2: 12:23Number healed:I1: 21/27I2: 29/35OR healing:0.72 (0.2, 2.56)I1:Three.I2: Four.Rundle et al.,1981 117UKWound type:Venous leg ulcers.Method ofrandomisation:‘Randomlyallocated’.Objective outcome:Tracing of ulcer onacetate.This tracingwas transferred tocard of knowndensity and thiswas weighed.Hence the areacould be calculated.Setting and lengthof treatment:Two hospitaloutpatient departments;no data ontrial period; appliedby experiencedphysiotherapists.26 ambulatorypatients with48 ulcers. Patientswith multiple ulcersreceived only onetype of therapy.Exclusion criteria:No data.Treatment:I1:Application ofporcine dermis (afterreconstitution in isotonicsaline). Then paste bandageand self-adhesive elasticcompression bandage(15 patients with23 ulcers).I2: Paste bandage andself-adhesive elastic compression(11 patientswith 20 ulcers).Concurrent treatments:Ulcer cleaned with isotonicsaline. Dressings changedtwice weekly as long asthere was frank exudateand thereafter weekly.Mean wound area (cm 2 ):I1: 0.2–47.8 (median, 2.0)I2: 0.5–45.0 (median, 3.0)Other characteristics:Age (years):I1: 45–88 (median, 62)I2: 56–80 (median, 73)Number completelyhealed in trial:Not stated.Median duration ofhealing: (weeks):I1: 6 (range, 1–16)I2: 9 (range, 3–63)Difference = 21 days.I1: Four (fiveulcers): twoadmitted dueto failure toheal; one patient(with twoulcers) failedto attend; onesuffered a sensitivityreactionand wasadmitted tohospital.I2: One patientfailed to heal andwas admitted tohospital.continued112

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 23 contd Topical preparations compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaSabolinski et al.,1996 118USAWound type:Leg ulcers(venous).Method ofrandomisation:Not stated.Objective outcome:Time to healing.Setting and lengthof treatment:Outpatientstreated in thecommunity.Thetrial was continueduntil all ulcers hadhealed.Patients withvenous leg ulcers.Exclusion criteria:Not stated.Treatment:I1: Living Skin Equivalent ®was applied directly to theulcer and dressed with athree-layer wrap composedof a primary non-adherentdressing, a cotton bolster,and a high-stretch compressionbandage.Thedressing was changedweekly.The living skinequivalent was appliedgenerally only twice,subsequent treatment onlyinvolved application of thethree-layer wrap dressing.I2: Graduated, multi-layeredcompression (CMP)therapy entailing weeklyapplications of a four-layerwrap consisting of aprimary non-adherentdressing, a secondarybolster dressing, a zincgelatin-impregnated gauze,and a high-stretchcompression bandage.233 patients were randomisedto one of the twogroups.The number ofpatients in each group isnot stated.Mean wound area (cm 2 ):Not stated.Other characteristics:Not stated.Median time tohealing (days):I1: 57I2: 181ES:I1 vs. I2 124Not stated.I1 costsUS$2601 perpatient, whileI2 costsUS$3257 perpatient.Duhra et al.,1992 119UKWound type:Leg ulcers(venous).Method ofrandomisation:Not stated, butrandomisationwas by ulcernot patient.Objective outcome:Reduction in ulcersize assessed bytracing the woundshape and thentransferring it tograph paper tocalculate the area.A photograph wastaken at eachassessment.Setting and lengthof treatment:Outpatients attendinga leg ulcerclinic.Treatmentwas continued untilthe wound healedor for a maximumof 6 weeks.Assessmentswere madeevery 2 weeksby the sameinvestigator.Patients withvenous ulcers of< 30 cm 2 andpresent for atleast 6 months.Treatment:I1: Keratinocyte allograftsreleased with 0.25%Dispase ® and backed witha non-adherent dressing(Jelonet) several layersof gauze and an absorbentpad.Tubigrip and a compressionbandage. Dressingswere changed every 5 daysby a qualified nurse (11patients with 15 wounds).I2: Placebo of an identicaldressing soaked in culturemedium (11 patients with15 wounds).Concurrent treatments:All ulcers were treatedwith conventional therapyuntil they were suitablefor grafting.Wounds in both groupswere cleansed with sterilesaline before application ofthe dressing. Patients wereinstructed to rest at homewith their feet elevated for48 hours.Mean wound area (cm 2 ):I1: 9.1 (1.6 SEM)I2: 10.7 (1.7 SEM)Other characteristics:I1 I2Mean age (years): 70.6 63.7M:F 1:1.2 1:1.8Mean duration(years): 4.8 4.5OR no healed (I1 vs. I2):0.3118 (0.0117, 8292)ES absolute (I1 vs. I2):0.6.Reduction in mean ulcerarea (cm 2 ) at 6 weeks:I1: 2.7I2: 3.3(p < 0.001 betweenbaseline size: p > 0.05.NS between groups atfinal assessment).Number of woundshealed at 6 weeks:I1: 0I2: 1Three patientswith a total offour ulcers werewithdrawn: threeulcers were inthe allograft (I1)group and one inthe placebo (I2)group. All theseulcers becameclinicallyinfected.There wasno significantdifference in painrelief betweenthe two groupsthroughout thestudy period.Living Skin Equivalent ® , Organogenesis Inc.continued113

Appendix 10TABLE 23 contd Topical preparations compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaTsakayannis et al.,1994 122USAWound type:Venous leg ulcers.Method ofrandomisation:Not clear thatpatients wererandomly allocated.Nine patients withten full-thicknesswounds, open atleast 8 weeks.Exclusion criteria:Infection, surgeryindicated.Treatment:I1: Sucralfate ointment(four patients with fivewounds).I2: Vehicle alone (fivepatients with five wounds).Concurrent interventions:No data.No data.Number completelyhealed in 8 weeks:I1: 2/4 patients healed(= 2/5 ulcers) 50%I2: 0/5 ulcers healed(= 0/5 patients) 0%No withdrawals.Letter to Vasa,very limitedinformation.No adverseevents orwithdrawalsreported.Objective outcome:Ulcers examinedbiweekly for ulcercontraction. Areaquantified usingphotoplanimetry.Setting and lengthof treatment:Setting not stated.8 weeks.Salim, 1992 124IraqWound type:Venous ulcers.Method ofrandomisation:Sealed envelopes.Objective outcome:Not stated.Setting and lengthof treatment:Outpatients.168 patientsin three groups(90 women and78 men).Inclusion criteria:Non-circumferentialulcers; on medialaspect of the leg;< 10 cm 2 area;first ulcer; grossleg oedema.Exclusion criteria:Alcoholism; ulcerinfection; pregnancy;diabetes; hypertension;steroids;non-steroidal antiinflammatorydrugs;regular medicationuse; hepatic or renaldisorders; rheumatoidarthritis;collagen diseases;venous ulcerationconfirmed byhistory, examinationand ABPI.Treatment:I1: DL-cysteine powder,n = 57.I2: DL-methionine-methylsulphonium chloride,n = 56.I3: Placebo powder, n = 55.Concurrent treatments:Ulcer cleansed with normalsaline, skin treated witholive oil. Non-adherentdressing + four-layercompression bandage.Dressed every day for7 days and then weekly.I1 I2 I3M:F 29:28 25:31 24:31Mean age (years):I1: 58 (range, 30–69)I2: 59 (range, 29–71)I3: 56 (range, 28–72)Mean ulcer duration (months):I1: 20I2: 24I3: 22Mean (± SEM) ulcer size (cm 2 ):I1: 5.3 ± 0.3I2: 5.5 ± 0.1I3: 4.6 ± 0.2Ulcer size at 12 weeks(cm 2 ):I1: 0.4 ± 0.1I2: 0.5 ± 0.1I3: 1.1 ± 0.2Number healed at12 weeks (not ITT):I1: 43 (93% of 46)I2: 42 (93% of 45)I3: 32 (70% of 46)ITT analysis:I1: 43/57 (75%)I2: 42/56 (75%)I3: 32/55 (58%)(p = 0.078)I1: 11: threeinfection; threeadverse events;one concomitanttreatment; fournon-compliant.I2: 11: fourinfection; twoadverse events;two concomitanttreatment; threenon-compliant.I3: None: fourinfection; twoadverse events;three noncompliant.When allpatients whowere excludedfrom the studyand the analysisrepeated withall the excludedulcers assumedto be healed orunhealed, thenthe placeboremained significantlyworsethan the othertwo treatments.(p < 0.01).However if theanalysis assumesthat the placeboexclusionshealed, and noneof the otherexclusionshealed, then thedifference is nolonger statisticallysignificant.Calculations notpresented. Diddo an a prioripower calculation(80%power to predictdifference of30% betweentwo groups,p < 0.05).continued114

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 23 contd Topical preparations compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaSalim, 1991 123IraqWound type:Venous ulcers.Method ofrandomisation:Alternatingsequence sealedenvelopes.Objective outcome:Ulcer size determinedby tracingthe ulcer marginonto cellophaneand then transferringthe outlineto card with aknown weight toarea ratio.Setting and lengthof treatment:Outpatients.153 patients inthree groups(n = 51; n = 50;n = 52).Inclusion criteria:Non-circumferentialulcers; on medialside of the leg,< 10 cm 2 area; firstulcer; gross legoedema; no evidenceof surgeryor injection sclerotherapyfor varicoseveins; venous ulcerationconfirmed byhistory; clinical andDoppler examinationand ABPI.Exclusion criteria:Alcoholism; ulcerinfection; pregnancy;diabetes; hypertension;steroids;non-steroidal antiinflammatorydrugs;regular medicationuse; hepatic or renaldisorders; seriousunderlying disease;rheumatoidarthritis; collagendiseases.Treatment:I1: Allopurinol powder,n = 51.I2: DMSO powder(pharmaceutical grade BP),n = 50.I3: Placebo (inert powder),n = 52.Concurrent treatments:Ulcer cleansed withnormal saline, devitalisedskin removed with olive oil.Skin treated with propyleneglycol monostearate. Nonadherentdressing + layered(crepe, Elset ® and Coban)compression bandage.Dressed every day for7 days and then weekly.Presents data only for patients‘fully evaluable’.I1 I2 I3M:F 29:28 25:31 24:31Mean age (years):I1: 56 (range, 31–68), n = 45I2: 57 (range, 29–71), n = 44I3: 58 (range, 28–71), n = 44Mean ulcer duration (months):I1: 24, n = 45I2: 23, n = 44I3: 20, n = 44Mean ulcer size (± SEM; cm 2 ):I1: 4.4 ± 0.5I2: 4.6 ± 0.7I3: 4.1 ± 0.2Ulcer size at 12 weeks(cm 2 ):I1: 0.3 ± 0.1I2: 0.2 ± 0.1I3: 1.3 ± 0.3Reduction in ulcer areain 12 weeks (cm 2 ):I1: 4.1I2: 4.4I3: 2.8Number healed at12 weeks (not ITT):I1: 42 (93% of 45)I2: 42 (95% of 44)I3: 31 (70% of 44)ITT analysis:I1: 42/51 (82%)I2: 42/50 (84%)I3: 31/52 (60%)I1: Six: threeinfection; oneadverse events;one concomitanttreatment; onenon-compliant.I2: Six: twoinfection; twoadverse events;two noncompliant.I3: Eight: fourinfection; oneadverse events;three noncompliant.When allpatients whowere excludedfrom the studyand the analysisrepeated with allthe excludedulcers assumedto be healed orunhealed, thenthe placeboremained significantlyworsethan the othertwo treatments(p < 0.01).However if theanalysis assumesthat the placeboexclusions healed,and none ofthe other exclusionshealed,then the differenceis no longerstatisticallysignificant.Calculationsnot presented.Did do ana priori powercalculation(80% powerto predict differenceof 30%between groups,p < 0.05).Bishop et al.,1992 125USAWound type:Venous ulcer.Method ofrandomisation:Not stated butulcers were stratifiedby lesion size:3–20 cm 2 or21–50 cm 2 .Objective outcome:Ulcer traced andarea determined bydigitised planimetryweekly. Evaluatorwas blind totreatment.Setting and lengthof treatment:Multicentre trial;4 weeks.93 patientsadmitted to theplastic surgeryclinics with lowerextremity ulcerationcaused byvenous insufficiency.Inclusion criteria:Age 21–90 years;ulcer duration≥ 3 months; ulcersurface area3–50 cm 2 .Exclusion criteria:Women of childbearingpotentialwho are, or arelikely to becomepregnant;> 105 bacteria/gof tissue in thewound; systemicsepsis of presenceof bone infection;ABPI < 0.5; hypercupraemia;systemicimmunosuppressiveor cytotoxictherapy; insulindependentdiabetes mellitus.Treatment:I1: 0.4% tripeptide coppercomplex in petrolatumbased cream (Unibase ® ),n = 31 (29).I2: 1% silver sulphadiazinecream, n = 29 (28).I3: Petrolatum-based cream(Unibase), n = 30 (29).Numbers in brackets referto the 86 patients forwhom data are presented.Treatments dispensedby a third party. Patientinstructed on dailyapplication of cream.Concurrent treatments:Ulcers cleansed by rinsingwith normal saline. Afterapplication of cream, a nonadherentdressing andelastic bandage was applied.Mean ulcer area [median] (cm 2 ):I1: 9.9 (8.5 SD) [6.5]I2: 11.9 (11.2 SD) [6.9]I3: 9.6 (8.1 SD) [6.2]Mean ulcer duration [median](months):I1: 57.1 (94.9 SD) [11.0]I2: 44.1 (58.0 SD) [19.0]I3: 38.0 (88.7 SD) [12.0]Number of ulcers > 20 cm 2 :I1: 5I2: 5I3: 4Other characteristics:Mean age (years):I1: 58.2 (14.6 SD)I2: 58.2 (14.5 SD)I3: 51.6 (17.3 SD)M:FI1: 14:15I2: 9:19I3: 20:9Weight (kg):I1: 92.1 (26.1 SD)I2: 92.2 (35.6 SD)I3: 103.2 (34.7 SD)Number completelyhealed at 4 weeks:I1: 0/31 (0%)I2: 6/29 (21%)I3: 1/30 (3%)% reduction in woundarea at week 4:I1: 18.7 (9.07 SEM)I2: 44.0 (8.21 SEM)I3: 22.5 (10.2 SEM)Comparisons (analysedby method of leastsquare means) +Fisher’s exact test:I1 vs. I2, p = 0.03I1 vs. I3, p = 0.82I2 vs. I3, p = 0.05Silver sulphadiazinecream was better thanthe other two preparations.Therewasno difference in efficacybetween the other twopreparations. Comparingreduction in wound areausing Tukey–Kramer,I1 vs. I2, I1 vs. I3 andI2 vs. I3, all havep > 0.05.Immediatewithdrawals:I1: OneI2:Twocontinued115

Appendix 10TABLE 23 contd Topical preparations compared with traditional/control treatmentsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaWerner-Schlenzka& Lehnert, 1994 120GermanyWound type:Leg ulcers(venous).Method ofrandomisation:Not stated.Objective outcome:Ulcer size.Woundswere measuredeach week bytaking a tracing anddetermining thearea by computeraidedplanimetery.A photograph wastaken on the 1st,2nd and 8th weekof treatment.Setting and lengthof treatment:A multicentretrial at 14 sites;treatment wascontinued for8 weeks.Both out- andinpatients with legulcers thought tobe of venous originin the size range3–100 cm 2 .Multiple ulcerswere included butonly the largestwas monitored.Exclusion criteria:Ulcers present forless than 2 months;ABPI < 0.9.Treatment:I1: Iloprost, 10 µg/ml forthe first 3 days and thenat 40 µg/ml for the restof the treatment period iftolerated well, otherwisepatients were returned tothe lower concentration.The Iloprost was incorporatedinto a hydrogel toaid application, n = 65.I2: Placebo: hydrogelonly.The increase intreatment concentrationin the Iloprost group wassimulated in the placebogroup, n = 34.Systemic medicationof concomitant diseasewas continued and documented.Compressionwas obligatory.Mean wound area (cm 2 ):I1: 26.6I2: 16.2Wound dimensions are onlyavailable for valid cases (i.e.those completing the trial).Other characteristics:I1 I2Mean age (years): 64.6 63.4M:F 1:4 1:5.8Ankle index: 1.09 1.14Duration:2–6 months 10 76–12 months 14 41–5 years 17 11> 5 years 24 12Diabetes: 14 5Mean % reductionin ulcer area (cm 2 )at 8 weeks:I1: 44%I2: 43%Absolute reduction inmean ulcer area (cm 2 )at 8 weeks:I1: 9.4I2: 6Difference 3.4(p > 0.05, NS;ANCOVA).Results by ITT analysiswere also insignificant.Number of ulcershealed at 8 weeks:I1: 4I2: 3OR 0.6776 (0.143, 3.22)I1: 12: onerefusal of compression;oneprogression; oneno regular visit;one pain; onefurther treatmentrefused;seven violationsof the studyprotocol.I2: Six: onebleeding fromulcer; one newulcer; two progression;twoviolations of thestudy protocol.Larger numberof diabetics inthe Iloprostgroup may haveinfluenced thehealing rates.83% of Iloprostpatients toleratedthe higherconcentration.88% of patientsin the placebogroup toleratethe simulatedincrease inconcentration.Forty-seven(72%) patientson Iloprostand 21 (62%%)on placebocomplained ofadverse events(i.e. burning,itching, stingingand pain).Werner-Schlenzka& Kuhlmann,1994 121GermanyWound type:Leg ulcers(venous).Method ofrandomisation:Not stated.Objective outcome:Reduction in ulcersize determined bytracing the ulcerand measuring thearea by computeraidedplanimetry.Photographs weretaken at intervalsthroughoutthe study.Setting and lengthof treatment:Clinic-based trial.Treatment wascontinued until thewound healed orfor a maximumof 8 weeks.Patients withulcers thought tobe of venous originand no larger than2 cm 2 . Multipleulcers wereincluded but onlythe largest wasmonitored.Exclusion criteria:ABPI indexmeasured byDoppler ultrasound< 0.9; antibiotics;creams containingantiphogistics orcorticoids.Treatment:I1: Iloprost solution,0.0005%, n = 49.I2: Iloprost solution,0.002%, n = 49.I3: Placebo, n = 50.All treatments wereprepared by an independentperson prior toapplication. 1.5 ml of thetreatment was appliedtwice weekly with a cottonstick to the ulcer edge andulcer surrounding.Treatmentof the ulcer base wascontinued in the usual way.Systemic medicationof concomitant diseasewas continued and documented.Compression wasobligatory with lastobind.Mean ulcer area (cm 2 ):I1: 25.8I2: 26.5I3: 35.1Other characteristics:I1 I2 I3Mean age(years):Male 53.9 59.8 55.4Female 61.4 56.8 60.0M:F 1:3.5 1:3.1 1:1.8ABPI: 1.1 1.1 1.1Duration:< 6 months 12 14 136–12 months 9 8 21–5 years 15 12 22> 5 years 13 12 13Unknown 0 0 0Number of woundshealed after 8 weeks:I1: 2I2: 5I3: 2Mean % reduction inulcer area at 8 weeks:I1: 15.9I2: 32.9I3: 14.6OR healedI1 vs. I2:0.3745 (0.069, 2.031)I1 vs. I3:1.021 (0.138, 7.556)I2 vs. I3:2.727 (0.503, 14.788)% reduction (difference):I1 vs. I2: –17%I1 vs. I3: 1.3%I2 vs. I3: 18.3%Not stated.90% of patientsfor both groupsreported thatthe dressingswere painless.116

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 24 Topical preparations compared with placeboStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaRasmussen et al.,1991; 129 1994 126DenmarkWound type:Venous leg ulcers.Method ofrandomisation:Randomised inblocks of four.Stratified accordingto initial ulcer area.Objective outcome:Ulcer tracing andarea determined bypoint counting.Setting and lengthof treatment:Multicentre trial;treated at homeby a research unitnurse; 6 weeks,(2 weeks run-inperiod of treatmentwith compressionand ahydrocolloid).102 patients withvenous ulcerationof more than3 months duration;aged > 18 years;ulcer area > 1.5cm 2 ; able to toleratecompression.Exclusion criteria:ABPI < 0.8;diabetes; haemoglobin< 6 mmol/l;systemic corticosteroidor cytotoxictherapy; cellulitisand history of evidenceof peripheralarterial disease.Treatment:I1: Human growthhormone, 0.17 IU/l, n = 20.I2: Human growthhormone, 1.0 IU/l, n = 22.I3: Human growthhormone, 11.2 IU/l, n = 23.I4: Saline solution, n = 22.(all 0.1 ml/cm 2 /day 5 daysa week).Sandwich technique ofadministration was used:one piece of hydrocolloidwas placed around theulcer margins and a secondplaced over this to form afluid tight seal which incorporateda connecting piecethrough which fluids couldbe administered.Concurrent treatment:Ulcers washed in sterilewater through thedressing before treatment,1 ml/cm 2 .Treatment fluidadministered and left for30 minutes. Double layerof compression bandagesapplied, reapplied daily.Dressings changed1–5 times weekly (mean =three times a week).Mean wound area (cm 2 ):I1: 14 (26 SEM)I2: 11 (27 SEM)I3: 12 (30 SEM)I4: 12 (26 SEM)Average duration ofulcer (months):I1: 24 (6 SEM)I2: 56 (19 SEM)I3: 36 (12 SEM)I4: 26 (6 SEM)Other characteristics:I1 I2 I3 I4Age (years): 78 75 78 77(20) (21) (17) (24)M:F 3:21 7:16 8:15 13:9Baseline details are only forpatients completing the trial.Number completelyhealed at 6 weeks:I1: 3/20 (15%)I2: 2/22 (9%)I3: 2/23 (9%)I4: 3/22 (14%)Number completelyhealed at 3 months:Incomplete follow-up:I1: 7/20 (35%)I2: 3/22 (14%)I3: 3/23 (13%)I4: 3/22 (14%)Healing rate %per week:I1: 17.9 (13.0)I2: 7.6 (5.5)I3: 9.6 (4.5)I4: 7.9 (4.0)I1:Threeinfection.I2: One infection.I3: None.I4:Two: oneinfection; onevasculitis.There werea futher ninewithdrawals butall were includedin the analysis.(Nine patientswithdrew duringthe run-in perioddue to reasonsof dressing intolerance,infectiousdisease, inabilityto tolerate compression,andunwillingness toparticipate. Fourpatients wereexcluded fromthe analysesbecause ofcellulitis necessitatingantibiotictreatment, andneed for achange in therapy(three in I1 andone in I2). Onepatient was excludedbecauseof severe peripheralvasculardisease, andanother washospitalisedduring the firstweek of treatmentfor pneumonia.Thisleft87 for analysis ofhealing rates.)Performed ana priori powercalculation.Adversereactions:I1:Threeinfection; oneulcer worsening.I2:Two infection;one noncompliance.I3:Two infection;one ulcerworsening; oneeczema; onevasculitis; onehospitalisation.I4: One infection.continued117

Appendix 10TABLE 24 contd Topical preparations compared with placeboStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaFreak et al., 1993; 1321994 131UKWound type:Chronic venous legulcers.Method ofrandomisation:Stratified accordingto ulcer size (aboveor below 10 cm 2 ).Traced ontoacetate film,computerisedplanimetry.Setting and lengthof treatment:Ulcer clinic atweekly intervals;visited at homeby research nurse5 days a week;treatment for6 weeks initially –if not achieved 50%healing at this pointthen continued fora further 6 weeks.29 Patients with avenous ulcer of atleast three months’duration, ulcersize greater than1.5 cm 2 .Exclusion criteria:ABPI < 0.8; insulindependentdiabetesmellitus; haemoglobin< 9 g/dl;oral or parenteralcorticosteroids orcytotoxic therapywithin the previous6 months; withcellulitis; deep tissueinfection; gangrene;amputation forperipheral vasculardisease; intermittentclaudication; unreliablecontraception.Threepatientswho consented toenter the studyfailed to completethe 2 week run-inperiod so 26received trialmedication.Treatment:I1: Biosynthetic humangrowth hormone,0.17 IU/ml, n = 7.I2: Biosynthetic humangrowth hormone,1.0 IU/ml, n = 6.I3: Biosynthetic humangrowth hormone,11.2 IU/ml, n = 6.I4: Placebo, n = 7.0.1 ml/cm 2 ulcer area.Concurrent treatments:Ulcers cleansed with saline.Sandwich dressing of twolayers of hydrocolloid, thebottom layer covered theperi-ulcer skin only, the toplayer contained a port forthe introduction of the trialfluid. Four-layer compressionbandaging renewedweekly.Mean wound area (cm 2 ):I1: 10.24I2: 9.83I3: 7.90I4: 10.58Other characteristics:Duration of ulcer (months):I1: 44.14I2: 98.33I3: 20.5I4: 54.57Age (years):I1: 73.42I2: 65.33I3: 75.83I4: 70.42Number completelyhealed at 8 weeks:No data.Reduction in woundarea, % per week:I1: 33 (11% SEM)I2: 25 (14% SEM)I3: 11 (3.3% SEM)I4: 22 (6.8% SEM)Comparisons (SEM):I1 vs. I4: +11%I2 vs. I4: +3%I3 vs. I4: –11%.No data.Compliance withthe trial dressingwas poor mainlybecause of thedamage to thesurrounding skin.In these circumstancesa nonadherentdressingwas applied toallow the periulcerto recover.Therefore a largenumber ofpatients did notreceive five dosesper week.Problems withthe surroundingskin were reportedin 104/201visits (maceration,inflammation,and newulcers).Trialabandoned afterrecruitment of 29patients (< 30%of those originallyplanned).Sponsored byColoplast andNovo Nordisk.Falanga et al.,1992 130USAWound type:Venous ulcers.Method ofrandomisation:Objective outcome:Length, width ofulcer; double-blindevaluation.Setting and lengthof treatment:10 weeks.45 patientswith ulcers of< 2 years duration;no recent sign ofre-epithelialisation,or granulationtissue covering< 50% of ulcer area.Exclusion criteria:Atypical locationof ulcer; ulcerinvolving gangrene;tendon; ABPI < 0.8;history of systemicmalignancy; uncontrolleddiabetes;medication knownto interfere withhealing such ascorticosteroids orimmunosuppressiveagents.Treatment:I1: Reconstitutedlyophilised humanrecombinant epidermalgrowth factor (h-EGF),7.5 ml on a non-adherentpad left in place for30 minutes, n = 23.I2: Diluent used toreconstitute h-EGF alone,7.5 ml on a non-adherentpad left in place for30 minutes, n = 22.Concurrent treatments:Legs were dressed witha gauze bandage and acompression bandage.The patient administeredtreatment twice daily. Anew batch was suppliedto the patient weekly.Systemic antibiotics wereallowed if necessary totreat cellulitis.Mean wound area (cm 2 ):I1: 12.8I2: 19.2Other characteristics:All groupsAge (years): 60M:F 20:26Ethnic origin:White 11Black 21Hispanic 12Baseline data omit one patientwho never received thetreatment.Number completelyhealed at 10 weeks:I1: 6/17 (35%)I2: 2/18 (11%)Mean (median)reduction inwound area:I1: 48% (73%)I2: 13% (33%)Difference = 35%,p = 0.32.Adverse events:I1: One severe burningsensation and erythema;one patient with ahistory of epilepsy hadseizures during twoapplication of thetreatment.I2: One moderate painaround the ulcer; twopatients developedcellulitis.Ten in total:four lost tofollow-up;three protocolviolations; twocellulitis; onepatient wasnever treated.(One patientnever receivedthe treatmentand was excludedfromthe analysis.Nine furtherpatients withdrewfrom thetrial and therefore35 patientswere included inthe analysis.)Sponsored byEthicon Inc.118

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 25 Topical preparations compared with dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaTosti & Veronesi,1983 132ItalyWound type:Venous leg ulcers.Method ofrandomisation:Not stated; notclear if randomlyallocated (CCT).Objective outcome:Ulcer area astraced onto atransparent sheetand digitised usinga computer.Setting and lengthof treatment:26 days.22 patients withvenous leg ulcers(11 men and11 women); age65–80 years.Treatment:I1: Collagen dressing atday 2, and day 8 andthereafter weekly,n = 11.I2: Control (local antiseptic)applied daily, n = 11.Mean wound area (cm 2 ):I1: 19.6I2: 19.7Other characteristics:I1 I2Age (years): 71.9 72.5M:F 5:6 6:5Number healed in26 days:I1: 8/11 (73%)I2: 1/11 (9%)I1: None.I2: One lost tofollow-up.Greguric et al.,1994 133CroatiaWound type:Venous leg ulcers.Method ofrandomisation:Consecutivelynumbered, sealedenvelope.Objective outcome:Ulcer traced atenrolment andsubsequentlyarea measuredby computerisedplanimetry.Photograph taken.Setting and lengthof treatment:Multicentre trial.Inpatients andoutpatients; treatmentwas for amaximum of tendressing changes.110 patients withvenous leg ulcers.Exclusion criteria:Ulcer size < 2.5 cmin length or > 5 cm;ABPI < 0.9; rheumatoidarthritis; sicklecelldisease; patientswith sensitivity toany of the interventionsused;malignant ulcers;malignant disease;patients taking antineoplasticdrugs or> 5 mg prednisoloneper day;immune deficiencyor immunosuppressivedrugtherapy; pregnancy;patients withabnormal woundhealing; and thosewho would bebetter treated by analternative regimen.Treatment:I1: 10 x 10 cm piece ofhydrocolloid (Varihesive),n = 55. Compressionapplied by use of twoshaped tubular bandages,changed on average every2 days.I2: Magnesium sulphatepaste (approx. 15 g), appliedto ulcer using a spatula.Bland petroleum jellyapplied to surrounding skinand then approximately sixpieces of sterile gauzeapplied on top. Dressingchanged on average everyday, n = 55. Ulcers cleanedwith normal saline andhydrogen peroxide.Double layer of elasticbandage applied toprovide compression.Mean wound area:Not stated.Other characteristics:Mean age (years):I1: 61 (15 SD)I2: 61 (13 SD)Median ulcer duration (days):I1: 1737 (15,902 * )I2: 1987 (12,218 * )*95% central rangeDeep ulcer:superficial ulcerI1: 11:44I2: 10:45Number completelyhealed at ten dressingchanges:I1: 3/55 (5%)I2: 0/55 (0%)Reduction in woundarea (mm 2 /day):I1: 32I2: 21No data.Adverse events:I1: 12 adverseevents in 11patients (fivethought notrelated todressing). Eventspossibly due todressing werepain in leg (1),itching of periulcerskin (1),erythema ofsurrounding skin(1), bullousreaction (1),erysiplelas cruis(1). Eventsprobably dueto dressing were1 cm 2 erosionof skin underthe dressingVarihesive E =Granuflex E =ImprovedFormulationGranuflex =Duoderm E.I2: No data.Trial durationin two groupsis dissimilar(approx. 21 daysin hydrocolloidand 10 days inconventionaltreatment).continued119

Appendix 10TABLE 25 contd Topical preparations compared with dressingsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaTeepe et al., 1993 131The Netherlandsand BelgiumWound type:Venous leg ulcers.Method ofrandomisation:Not stated. Bothcentres wererandomisedseparately.Objective outcome:Computerisedplanimetric analysisof cellophanetracings takenweekly.Setting and lengthof treatment:Multicentre trial;outpatienttreatment; 6 weeksthen cross-over.43 consecutivepatients with47 unilateral orbilateral ulcers.Inclusion criteria:Ulcer duration atleast 3 months;evidence of venousinsufficiency asdemonstrated byclinical findingsor LRR.Treatment:I1: Hydrocolloid(Granuflex/DuoDerm)(21 patients with23 ulcers).I2: Cryopreserved culturedallografts (22 patients with24 ulcers).Concurrent treatments:Saline dressings anddebridement for 2 weekspre-trial.At each dressingchange, ulcer cleansedwith saline, debrided ifnecessary, and shortstretchcompressionbandage applied (Elko).Mean ulcer area (cm 2 ):I1: 1.4 (0.4 SD)I2: 2.3 (0.95 SD)Median ulcer area (cm 2 ):I1: 6.1 (range, 0.99–21.37)I2: 9.0 (range, 1.09–40.35)Other characteristics:Mean age (years):I1: 69 (range, 39–85)I2: 74 (range, 60–90)Mean ulcer duration (months):I1: 26 (range, 3–360)I2: 25 (range, 3–40)M:FI1: 6:16I2: 5:16Number healedat 6 weeks:I1: 5/25 (20%)I2: 6/24 (25%)Ulcer area after6 weeks; % of initialulcer area (from graph):I1: 38I2: 18 (p = 0.01)Absolute change inulcer area:I1: 0.9I2: 1.4Healing rate in first6 weeks was higherwith I2 (p = 0.03).Cross-over at 6 weeksif not healed.Also measured pain(no difference betweenstudy groups).I1: Four: threedue to woundinfection; onenon-compliance.I2: Five: fourdue to woundinfection; onedue to treatmentfailure.Performed ana priori powercalculation; 90%vs. 50% healing in6 weeks = 20 ineach arm, 80%power, a + 0.05.120

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 26 Comparisons of topical preparationsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaWilson et al.,1979 134EireWound type:Varicose ulcers.Method ofrandomisation:Method not stated– ‘randomlyseparated’.Objective outcome:Ulcer areadetermined byplanimetry.Setting and lengthof treatment:Outpatient clinic.Trial period isunclear.36 patients withvaricose ulcerattending a varicoseulcer clinic.Inclusion criteria:None stated.Exclusion criteria:Diabetes mellitusGroup I1 had largermean ulcer areaat baseline – nodata provided.Treatment:I1: Buffered acidifyingointment (M/15 phosphatebuffer in emulsifyingointment), pH 6, n = 18.I2: Emulsifying ointment,pH 7.3, n = 18.Concurrent treatments:Covered with gauze,crepe bandage and elasticstocking. Dressings donetwice a week.I1 had larger mean ulcer areaat baseline – no data provided.Mean healing rate(cm 2 /day):I1: 22.6 (15.2 SD)I2: 3.3 (7.4 SD)Number healed in trial:I1: 16/16 (16/18)I2: 11/13 (11/18)Figures in bracketsindicate proportionhealing includingwithdrawals.I1:Two: onefound to bediabetic andthereforeexcluded; onepoor responseand withdrawn.I2: Five poorresponse andwithdrawn.Authors selectedseven patientswith equal ulcerareas and comparedthe healingrate (cm 2 /day).The treatmentgroup had ahigher rate(16.3/5.8) comparedwith thecontrol (6.3/3.3),p < 0.005.Bishop et al.,1992 125USAWound type:Venous ulcer.Method ofrandomisation:Not stated butulcers werestratified by lesionsize: 3–20 cm 2 or21–50 cm 2 .Objective outcome:Ulcer traced andarea determined bydigitised planimetryweekly. Evaluatorwas blind totreatment.Setting and lengthof treatment:Multicentre trial;4 weeks.93 patientsadmitted to theplastic surgeryclinics with lowerextremity ulcerationcaused byvenous insufficiency.Inclusion criteria:Age 21–90 years;ulcer duration≥ 3 months; ulcersurface area3–50 cm 2 .Exclusion criteria:Women of childbearingpotentialwho are, or arelikely to becomepregnant;> 105 bacteria/gof tissue in thewound; systemicsepsis of presenceof bone infection;ABPI < 0.5; hypercupraemia;systemicimmunosuppressiveor cytotoxictherapy; insulindependentdiabetes mellitus.Treatment:I1: 0.4% tripeptide coppercomplex in petrolatumbasedcream (Unibase),n = 31 (29).I2: 1% silver sulphadiazinecream, n = 29 (28).I3: Control (petrolatumbasedcream; Unibase),n = 30 (29).Numbers in bracketsrefer to the 86 patients forwhom data are presented.Treatments dispensedby a third party. Patientinstructed on dailyapplication of cream.Concurrent treatments:Ulcers cleansed by rinsingwith normal saline.Afterapplication of cream, a nonadherentdressing andelastic bandage was applied.Mean wound area:Mean ulcer area [median] (cm 2 ):I1: 9.9 (8.5 SD) [6.5]I2: 11.9 (11.2 SD) [6.9]I3: 9.6 (8.1 SD) [6.2]Mean ulcer duration [median](months):I1: 57.1 (94.9 SD) [11.0]I2: 44.1 (58.0 SD) [19.0]I3: 38.0 (88.7 SD) [12.0]Number of ulcers > 20 cm 2 :I1: 5I2: 5I3: 4Other characteristics:Mean age (years):I1: 58.2 (14.5 SD)I2: 58.2 (17.3 SD)I3: 51.6 (14.6 SD)M:FI1: 14:15I2: 9:19I3: 20:9Weight (kg):I1: 92.1 (26.1 SD)I2: 92.2 (35.6 SD)I3: 103.2 (34.7 SD)Number completelyhealed at 4 weeks:I1: 0/31 (0%)I2: 6/29 (21%)I3: 1/30 (3%)% Reduction in woundarea at week 4:I1: 18.7 (9.07 SEM)I2: 44.0 (8.21 SEM)I3: 22.5 (10.2 SEM)Comparisons: (analysedby method of leastsquare means) +Fisher’s exact test.I1 vs. I2, p = 0.03I1 vs. I3, p = 0.82I2 vs. I3, p = 0.05Silver sulphadiazinecream was better thanthe other two preparations.Therewasno difference in efficacybetween the othertwo preparations.Comparing reductionin wound area usingTukey–Kramer, I1 vs. I2,I1 vs. I3 and I2 vs. I3, allhave p > 0.05.Immediatewithdrawals:I1: OneI2:Twocontinued121

Appendix 10TABLE 26 contd Comparisons of topical preparationsStudy and Inclusion/ Intervention details Baseline characteristics Results Withdrawals Commentsdesignexclusion criteriaBulstrode, 1988; 1351987 136UKWound type:Leg ulcers.Method ofrandomisation:Drawing cardsfrom a sealed box.Objective outcome:Time to healing.Ulcer size wasdetermined bydirect computerplanimetry. Aphotograph wastaken weekly.Setting and lengthof treatment:Hospital-basedtrial. Treatmentwas continued untilthe wound healedor for a maximumof 6 weeks.Patients withchronic leg ulcerspresent for morethan 2 years withno major underlyingdisease. Patientshad to agree tobe admitted tohospital for aminimum period of6 weeks’ bed restor until completeulcer healing.Exclusion criteria:Haemoglobin< 10 g; activearthritis; diabetes;cardiac insufficiency:peripheral vascularindex of < 0.9;diastolic bloodpressure> 100 mmHg.Treatment:I1: Saline 0.9% NaC1(osmolarity 150 mosmol/l),n = 12.I2: Electrolyte freeamino acid (osmolarity150 mosmol/l), n = 12.I3: Hypertonic saline 5%NaC1 (osmolarity 850mosmol/l), n = 12.I4: Electrolyte freeamino acid (osmolarity850 mosmol/l), n = 12.On admission to hospitalthe ulcers were cleanedwith Eusol mixed withliquid paraffin until theulcer base consisted ofclean, granulating tissue.Ulcers were dressed dailyafter a bath with a simplesterile gauze into which aflexible polythene tube wastucked.The dressing wascovered with a backing ofwaterproof plaster tape,while the tube was attachedto a syringe loaded withirrigation solution.The rateof irrigation kept the dressingmoist and non-adherentwithout flooding. Bed restwas compulsory and at notime were patients allowedto sit with their legsdependent. Daily physiotherapywas performed.The manufacturersstandard method ofapplication was followedfor both treatments.Mean wound area (mm 2 ):I1: 32.5I2: 31.3I3: 47.8I4: 38.4Other characteristics:Mean age (years):I1: 73I2: 74I3: 72I4: 77M:FI1: 1:11I2: 1:5I3: 0:12I4: 1:5OR healing:I1 vs. I2 0.7 (0.13, 3.79)I1 vs. I3 5.5 (0.51, 59.1)I1 vs. I4 0.167 (0.03, 0.98)I2 vs. I3 7.86 (0.75, 82.18)I2 vs. I4 0.24 (0.042, 1.36)I4 vs. I3 33 (2.91, 374.5)OR combined:I1 + I3 vs. I2 + I40.188 (0.0524, 0.6738)I3 + I4 vs. I1 + I21.19 (0.3738, 3.792)% difference combined:I1 + I3 vs. I2 + I4 49%I3 + I4 vs. I1 + I2 15%Number of woundshealed after 6 weeks:I1: 4I2: 5I3: 1I4: 9I1 and I3 vs. I2 and I4,p > 0.05(saline vs. amino acid)I3 and I4 vs. I1 and I2,p > 0.5(concentrated vs. dilute)(Chi-square test)Mean % reduction inulcer area at 3 weeks:I1: 25I2: 32I3: 0I4: 42Change in area at thethird week has beenstrongly correlated withfinal healing (r > 0.85,p < 0.05) and so wasused by the authors forevaluation purposes.% difference:I1 vs. I2 –7%I1 vs. I3 25%I1 vs. I4 –17%I2 vs. I3 32%I2 vs. I4 –10%I4 vs. I3 42%No withdrawals.Using onlythe 3-week dataweekly healingrates can bedetermined.Thisshows that thereductions are:I1 = 25%I2 = 32%I3 = 0%I4 = 42%Using thesedata I1 and I3vs. I2 and I4 issignificantp < 0.005, butI3 and I4 vs. I1and I2 is notsignificant(p > 0.15).122

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Appendix 11Studies of cost-effectiveness123

Appendix 11124TABLE 27 Summary of cost-effectiveness dataStudy Treatment Variable cost Variable cost Incremental Semi-fixed cost Semi-fixed cost Incremental ICERs Commentof control of intervention variable cost of control (per of intervention difference(per patient) (per patient) (per patient) patient) (units per patient (unitsand price) and price)Milward, 1990 Control: Gauze, £2815 (£148) £2541 (£134) £274 (–£14) 1056 nurse visits 436 nurse visits –620 nurse visits Dominated Data stochastic non = 19 (none healed). (56 visits) (23 visits) (–33 visits) indication of variance andUK pounds sterling I: Hydrocolloid, n = 19 Five per week over 1.9 per week over no significance testing.(three healed). 12 weeks (0.7 per day) 12 weeks (0.27 per day)Ohlsson, 1994 Control: Saline gauze, (SEK 608; (SEK 653; (SEK 45) 1053 dressing changes 181 dressing changes –872 dressing Variable K Statistical testing of totaln = 14 (two healed). range, 169–970) range, 53–2423) (mean, 75; range 21–94) (mean, 13; range 2–33) changes 8 per ulcer; costs indicate hydrocolloidSwedish kronor I: Hydrocolloid, n = 14 12.5 per week over 2.2 per week (–62 per patient) semi-fixed, significantly cheaper than(seven healed). 6 weeks (1.8 per day) 0.31 per day (over 6 weeks) dominated gauze.Meridith, 1988 Control: Paraffin gauze, £856 (£36) £437 (£17) –£419 (–£19) Not possible Not possible Not possible Dominated Data stochastic, no indicationn = 24 (six healed). to estimate to estimate to estimate of variance and no significanceUK pounds sterling I: Hydrocolloid, n = 25 testing.(19 healed).Smith, 1994 Control: Alginate, £364 (£20) £432 (£20) £0 Not possible Not possible Not possible Dominated Data stochastic, no indicationn = 18 (two healed). to estimate to estimate to estimate of variance and no significanceUK pounds sterling I: Hydrocolloid, n = 22 testing.(four healed).Sebern, 1986, 1989 Control: Gauze and (Grade II ulcers (Grade II ulcers (–$2) ($39) (Grade II ulcers (Grade II ulcers (–$502) ($101) II ulcers For grade II ulcers MVP moretape, n = 100. $99; grade III $97; grade III $1260; grade III $758; grade III dominated. cost-effective; no differenceUS dollars (1986) I: Vapour-permeable ulcers $140) ulcers $179) ulcers $1272) ulcers $1373) III ulcers in outcome for grade IIIdressing, n =100. dominated ulcers therefore gauzein other dominates; however, possibledirection type 2 error.Xakellis, 1992 Control: saline gauze, Median $4; Median $13; ($12) 28 dressing changes; 3.5 dressing changes; 25 changes $15 for Study reported mediansn = 21 (18 healed). mean $6; mean $18; 17.8 per week; 2.7 per week; variable which are difficult toUS dollars (1990) I: Hydrocolloid dressing, interquartile interquartile 2.5 per day 0.39 per day Dominated interpret. Data were testedn = 18 (16 healed). range, $3–9) range, $10–26. (over 11 days) (over 9 days) for semi-fixed for statistical significanceusing tests of medians;hydrocolloid significantlycheaper depending on priceassumptions of nurse time.Kraft et al., 1993 Control: Saline gauze, $5.25 per week $12.18 per week $6.93 per week 21 dressing changes 2.5 dressing changes –18.5 dressing $24.75 per Foam dressing higher initialn = 14. per week; 3 per day per week; 0.34 per day changes week for acquisition costs but reducedUS dollars I: Foam dressing, (over 24 weeks) (over 24 weeks) variable used of nursing time and wasn = 24. dominated more effective. Data werefor semi-fixed stochastic but were not subjectto statistical analysis thereforeit is not clear whetherreduction in dressing changesis statistically significant.continued

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)TABLE 27 contd Summary of cost-effectiveness dataStudy Treatment Variable cost Variable cost Incremental Semi-fixed cost Semi-fixed cost Incremental ICERs Commentof control of intervention variable cost of control (per of intervention difference(per patient) (per patient) (per patient) patient) (units per patient (unitsand price) and price)Bale et al., 1995 Control: Hydrocolloid, 8 weeks of 8 weeks of £1 1.7 dressing changes 1.9 dressing changes 0.2 £8 per healed No evidence that costs weren = 46. treatment: treatment: per week (95% CI, 1, 7); per week (95% CI, 1, 15); patient in different statistically betweenUK pound sterling I: Hydrocellular, n = 50. Material costs Material costs 0.24 per day 0.27 per day dressing costs two groups. Paper presented£15; other £29; other (over 8 weeks) (over 8 weeks) average cost-effectivenessdressing costs dressing costs 0.12 dressing ratios (£179 and £130 for£44 (95% CI, £31 (95% CI, visits per hydrocolloid and hydro-£20, £68) (£59 £27, £35) (£60 patient cellular, respectively),per patient) per patient) which underestimates thepotential cost-effectivenessof hydrocellular dressing.Colwell et al., 1993 Control: Moist gauze $1.93 per day $2.58 per day $0.65 4.1 dressing changes 0.42 dressing changes –3.68 $3.25 per Materials cost higher fordressing, n = 49. per day (over 17 days) per day (over 17 days) healed patient hydrocolloid dressings dueUS dollars I: Hydrocolloid, n = 48. Dominated to greater acquisition costs;for semi-fixed however, number of dressingchanges reduced. Nostatistical testing of costdifferences which wouldhave been appropriate.125

Appendix 11TABLE 28 Differences in dressing frequency betweenhydrocolloid and gauze dressingsDressing type Difference Significance(95% CI)Hydrocolloid GauzeAverage no. of 0.43 2.58 2.15 p = 0.01dressing changes (0.93, 3.37)per day aSummary statisticsNumber of studies b 5 5Mean 0.34 2.42Median 0.31 2.5Minimum 0.24 0.7Maximum 0.42 4.1aAfter adjusting for length of studybFive studies not common to both groupsTABLE 29 Incremental variable costs of hydrocolloid dressingscompared with gauzeStudy Incremental variable 1997 £UK acost per patientMilward, 1991 102 –£14 (1990) 17.49Ohlssen, et al., 1994 72 45 SEK (1994) 3.19Meridith & Gray, 1988 100 –£19 (1988) 27.99Xakellis & Chrischilles, $12 (1990) 9.021992 55Colwell, et al., 1993 54 $0.65 (1993) 0.46aConverted using GNP purchasing power parities and inflated using retailprices index126

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Health Technology Assessmentpanel membershipThis report was identified as a priority by the Pharmaceutical Panel.Current membersChair:Professor Francis H CreedUniversity of ManchesterProfessor Clifford BaileyUniversity of LeedsMs Tracy BuryChartered Societyof PhysiotherapyProfessor Collette CliffordUniversity of BirminghamDr Katherine DartonM.I.N.D.Mr John DunningPapworth Hospital, CambridgeMr Jonathan EarnshawGloucester Royal HospitalMr Leonard FenwickFreeman Groupof Hospitals,Newcastle-upon-TyneProfessor David FieldLeicester Royal InfirmaryMs Grace GibbsWest Middlesex UniversityHospital NHS TrustAcute Sector PanelDr Neville GoodmanSouthmead HospitalServices Trust,BristolProfessor Mark HaggardMRC Institute ofHearing Research,University of NottinghamProfessor Robert HawkinsUniversity of ManchesterDr Duncan KeeleyGeneral Practitioner, ThameDr Rajan MadhokEast Riding Health AuthorityDr John PounsfordFrenchay Hospital,BristolDr Mark SculpherUniversity of YorkDr Iqbal SramNHS Executive,North West RegionMrs Joan WebsterConsumer memberPast membersProfessor John Farndon *University of BristolProfessor Senga BondUniversity of Newcastleupon-TyneProfessor Ian CameronSoutheast Thames RegionalHealth AuthorityMs Lynne ClemenceMid-Kent Health Care TrustProfessor Cam DonaldsonUniversity of AberdeenProfessor Richard EllisSt James’s University Hospital,LeedsMr Ian HammondBedford & Shires Health& Care NHS TrustProfessor Adrian HarrisChurchill Hospital, OxfordDr Gwyneth LewisDepartment of HealthMrs Wilma MacPhersonSt Thomas’s & Guy’s Hospitals,LondonDr Chris McCallGeneral Practitioner,DorsetProfessor Alan McGregorSt Thomas’s Hospital,LondonProfessor Jon NichollUniversity of SheffieldProfessor John NormanUniversity of SouthamptonProfessor Michael SheppardQueen Elizabeth Hospital,BirminghamProfessor Gordon StirratSt Michael’s Hospital,BristolDr William Tarnow-MordiUniversity of DundeeProfessor Kenneth TaylorHammersmith Hospital,London*Previous Chaircontinued131

Health Technology Assessment panel membershipcontinuedCurrent membersChair:Professor Mike SmithUniversity of LeedsDr Philip J AyresLeeds Teaching HospitalsNHS TrustDr Paul CollinsonSt George’s Hospital, LondonDr Barry CooksonPublic HealthLaboratory Service, ColindaleDiagnostics and Imaging PanelProfessor David C CumberlandUniversity of SheffieldProfessor Adrian DixonUniversity of CambridgeMr Steve Ebdon-JacksonDepartment of HealthMrs Maggie FitchettAssociation of Cytogeneticists,OxfordDr Peter HowlettPortsmouth Hospitals NHS TrustProfessor Alistair McGuireCity University, LondonDr Andrew MooreEditor, BandolierDr Peter MooreScience Writer, AshteadProfessor Chris PriceLondon HospitalMedical SchoolDr William RosenbergUniversity of SouthamptonMr Tony TesterSouth BedfordshireCommunity Health CouncilDr Gillian VivianRoyal Cornwall Hospitals TrustDr Greg WarnerGeneral Practitioner,HampshirePast membersProfessor Michael Maisey *Guy’s & St Thomas’s Hospitals,LondonProfessor MA Ferguson-SmithUniversity of CambridgeProfessor Donald JeffriesSt Bartholomew’s Hospital,LondonProfessor John StuartUniversity of BirminghamProfessor Andrew AdamGuy’s, King’s & St Thomas’sSchool of Medicine & Dentistry,LondonDr Pat CookeRDRD, Trent RegionalHealth AuthorityDr Mansel HaeneyUniversity of ManchesterProfessor Sean HiltonSt George’s HospitalMedical School, LondonDr Ian ReynoldsNottingham Health AuthorityProfessor Colin RobertsUniversity of Wales Collegeof MedicineDr Ala SzczepuraUniversity of WarwickMr Stephen ThorntonCambridge & HuntingdonHealth CommissionMs Julia DavisonSt Bartholomew’s Hospital,LondonMr John HuttonMEDTAP International Inc.,LondonMiss Annette SergeantChase Farm Hospital, EnfieldDr Jo Walsworth-BellSouth StaffordshireHealth AuthorityCurrent membersMethodology GroupChair:Professor Martin BuxtonHealth EconomicsResearch Group,Brunel UniversityProfessor Doug AltmanICRF/NHS Centre forStatistics in Medicine,University of OxfordDr David ArmstrongGuy’s, King’s & St Thomas’sSchool of Medicine& Dentistry, LondonProfessor Nicholas BlackLondon School of Hygiene& Tropical MedicineProfessor Ann BowlingUniversity College LondonMedical SchoolDr Mike ClarkeUK Cochrane Centre, OxfordProfessor Paul DieppeMRC Health ServicesResearch Collaboration,University of BristolProfessor Mike DrummondCentre for Health Economics,University of YorkDr Vikki EntwistleUniversity of AberdeenProfessor Ewan FerlieImperial College, LondonProfessor Ray FitzpatrickUniversity of OxfordMrs Jenny GriffinDepartment of HealthProfessor Jeremy GrimshawUniversity of AberdeenDr Stephen HarrisonUniversity of LeedsMr John HendersonDepartment of HealthProfessor Richard LilfordR&D, West MidlandsProfessor Theresa MarteauGuy’s, King’s & St Thomas’sSchool of Medicine& Dentistry, LondonDr Henry McQuayUniversity of OxfordDr Nick PayneUniversity of SheffieldProfessor Maggie PearsonNHS Executive North WestDr David SpiegelhalterInstitute of Public Health,CambridgeProfessor Joy TownsendUniversity of HertfordshireMs Caroline WoodroffeStanding Group on Consumersin NHS ResearchPast membersProfessor Anthony Culyer *University of YorkProfessor Michael BaumRoyal Marsden HospitalDr Rory CollinsUniversity of OxfordProfessor George Davey SmithUniversity of BristolProfessor Stephen FrankelUniversity of BristolMr Philip HewitsonLeeds FHSAMr Nick MaysKing’s Fund, LondonProfessor Ian RussellUniversity of YorkProfessor David SackettCentre for EvidenceBased Medicine, OxfordDr Peter SandercockUniversity of EdinburghDr Maurice SlevinSt Bartholomew’s Hospital,LondonProfessor Charles WarlowWestern General Hospital,Edinburgh132*Previous Chair

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Current membersPharmaceutical PanelChair:Professor Tom WalleyUniversity of LiverpoolDr Felicity GabbayTranscrip LtdDr Peter GolightlyDrug Information Services,NHS Executive TrentDr Alastair GrayHealth EconomicsResearch Centre,University of OxfordProfessor Rod GriffithsNHS ExecutiveWest MidlandsMrs Jeanette HoweDepartment of HealthProfessor Trevor JonesABPI, LondonMs Sally KnightLister Hospital, StevenageDr Andrew MortimoreSouthampton & SW HantsHealth AuthorityMr Nigel OffenNHS Executive EasternDr John ReynoldsThe Oxford Radcliffe HospitalMrs Marianne RiggeThe College of Health,LondonMr Simon RobbinsCamden & IslingtonHealth Authority, LondonDr Frances RotblatMedicines Control AgencyDr Eamonn SheridanSt James’s University Hospital,LeedsMrs Katrina SimisterNational Prescribing Centre,LiverpoolDr Ross TaylorUniversity of AberdeenPast membersProfessor Michael Rawlins *University of Newcastleupon-TyneDr Colin BradleyUniversity of BirminghamProfessor AlasdairBreckenridgeRDRD, Northwest RegionalHealth AuthorityMs Christine ClarkHope Hospital, SalfordMrs Julie DentEaling, Hammersmith &Hounslow Health Authority,LondonMr Barrie DowdeswellRoyal Victoria Infirmary,Newcastle-upon-TyneDr Tim ElliottDepartment of HealthDr Desmond FitzgeraldMere, Bucklow Hill, CheshireProfessor Keith GullUniversity of ManchesterDr Keith JonesMedicines Control AgencyDr John PosnettUniversity of YorkDr Tim van ZwanenbergNorthern RegionalHealth AuthorityDr Kent WoodsRDRD, Trent RO,SheffieldCurrent membersPopulation Screening PanelChair:Professor Sir JohnGrimley EvansRadcliffe Infirmary, OxfordMrs Stella BurnsideAltnagelvin Hospitals Trust,LondonderryMr John CairnsUniversity of AberdeenProfessor Howard CuckleUniversity of LeedsDr Carol DezateuxInstitute of Child Health,LondonMrs Anne Dixon-BrownNHS Executive EasternProfessor Dian DonnaiSt Mary’s Hospital,ManchesterDr Tom FaheyUniversity of BristolMrs Gillian FletcherNational Childbirth TrustDr JA Muir GrayNational Screening Committee,NHS Executive OxfordProfessor Alexander MarkhamSt James’s University Hospital,LeedsDr Ann McPhersonGeneral Practitioner,OxfordDr Susan MossInstitute of Cancer ResearchMr John NettletonConsumer memberMrs Julietta PatnickNHS CervicalScreening Programme,SheffieldDr Sarah Stewart-BrownHealth Service Research Unit,University of OxfordPast membersDr Sheila Adam *Department of HealthProfessor George FreemanCharing Cross & WestminsterMedical School, LondonDr Mike GillBrent & HarrowHealth AuthorityDr Anne LudbrookUniversity of AberdeenProfessor Theresa MarteauGuy’s, King’s &St Thomas’s School ofMedicine & Dentistry,LondonProfessor Catherine PeckhamInstitute of Child Health,LondonDr Connie SmithParkside NHS Trust,LondonMs Polly ToynbeeJournalistProfessor Nick WaldUniversity of LondonProfessor Ciaran WoodmanCentre forCancer Epidemiology,Manchester*Previous Chaircontinued133

Health Technology Assessment panel membershipcontinuedCurrent membersPrimary and Community Care PanelChair:Dr John TrippRoyal Devon & ExeterHealthcare NHS TrustMr Kevin BartonEast London & CityHealth AuthorityProfessor John BondUniversity of Newcastleupon-TyneDr John BrazierUniversity of SheffieldMs Judith BrodieCancer BACUPMr Shaun BroganRidgeway Primary Care Group,AylesburyMr Joe CorkillNational Association forPatient ParticipationDr Nicky CullumUniversity of YorkProfessor Pam EnderbyUniversity of SheffieldDr Andrew FarmerInstitute of Health Sciences,OxfordDr Jim FordDepartment of HealthProfessor Richard HobbsUniversity of BirminghamProfessor Allen HutchinsonUniversity of SheffieldDr Aidan MacFarlaneIndependent ConsultantProfessor David MantInstitute of Health Sciences,OxfordDr Chris McCallGeneral Practitioner, DorsetDr Robert PevelerUniversity of SouthamptonProfessor Jennie PopayUniversity of SalfordDr Ken SteinNorth & East DevonHealth AuthorityPast membersProfessor Angela Coulter *King’s Fund, LondonProfessor Martin Roland *University of ManchesterDr Simon AllisonUniversity of NottinghamProfessor Shah EbrahimRoyal Free Hospital, LondonMs Cathy GritznerKing’s Fund, LondonProfessor Andrew HainesRDRD, North ThamesRegional Health AuthorityDr Nicholas HicksOxfordshire Health AuthorityMr Edward JonesRochdale FHSAProfessor Roger JonesGuy’s, King’s & St Thomas’sSchool of Medicine& Dentistry,LondonMr Lionel JoyceChief Executive,Newcastle City HealthNHS TrustProfessor Martin KnappLondon School of Economics& Political ScienceDr Phillip LeechDepartment of HealthProfessor Karen LukerUniversity of LiverpoolDr Fiona MossThames Postgraduate Medical& Dental EducationProfessor Dianne NewhamKing’s College LondonProfessor Gillian ParkerUniversity of LeicesterDr Mary RenfrewUniversity of OxfordMs Hilary ScottTower Hamlets HealthcareNHS Trust, London134*Previous Chair

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2)Current membersNational Coordinating Centre forHealth Technology Assessment, Advisory GroupChair:Professor John GabbayWessex Institute for HealthResearch & DevelopmentDr Sheila AdamDepartment of HealthProfessor Nicholas BlackLondon School of Hygieneand Tropical MedicineProfessor Martin BuxtonHealth EconomicsResearch Group,Brunel UniversityMr Harry CaytonAlzheimer’s Disease SocietyProfessor Angela CoulterThe King’s Fund, LondonProfessor Paul DieppeMRC Health ServicesResearch Collaboration,University of BristolProfessor MikeDrummondCentre for Health Economics,University of YorkProfessor Shah EbrahimMRC Health ServicesResearch Collaboration,University of BristolMs Lynn KerridgeWessex Institute for HealthResearch & DevelopmentProfessor Jos KleijnenNHS Centre for Reviewsand Dissemination,University of YorkDr Ruairidh MilneWessex Institute for HealthResearch & DevelopmentMs Kay PattisonResearch &Development Directorate,NHS ExecutiveProfessor James RafteryHealth Economics Unit,University of BirminghamProfessor Ian RussellDepartment ofHealth Sciences &Clinical Evaluation,University of YorkDr Ken SteinNorth & East DevonHealth AuthorityProfessor Andrew StevensDepartment of PublicHealth & Epidemiology,University of BirminghamProfessor Kent WoodsDepartment of Medicine& Therapeutics,University of LeicesterPast memberDr Paul RoderickWessex Institute for HealthResearch & Development135

HTA Commissioning BoardCurrent membersChair:Professor Shah EbrahimProfessor of Epidemiologyof Ageing, University of BristolProfessor Doug AltmanDirector, ICRF MedicalStatistics Group, Centre forStatistics in Medicine,University of OxfordProfessor John BondDirector, Centre for HealthServices Research, University ofNewcastle-upon-TyneMr Peter BowerGeneral Manager andIndependent Health Advisor,Thames Valley PrimaryCare AgencyMs Christine ClarkHonorary Research Pharmacist,Hope Hospital, SalfordProfessor Martin EcclesProfessor ofClinical Effectiveness,University of Newcastleupon-TyneDr Mike GillRegional Director ofPublic Health,NHS Executive South EastDr Alastair GrayDirector, Health EconomicsResearch Centre,University of OxfordProfessor Mark HaggardDirector, MRC Instituteof Hearing Research,University of NottinghamDr Jenny HewisonSenior Lecturer,Department of Psychology,University of LeedsProfessor Alison KitsonDirector, Royal College ofNursing InstituteDr Donna LampingSenior Lecturer,Department of Public Health,London School of Hygiene &Tropical MedicineProfessor Alan MaynardJoint Director, York HealthPolicy Group, University of YorkProfessor David NealJoint Director, York HealthPolicy Group, University of YorkProfessor Jon NichollDirector, Medical CareResearch Unit,University of SheffieldProfessor Gillian ParkerNuffield Professor ofCommunity Care,University of LeicesterDr Tim PetersReader in Medical Statistics,Department of Social Medicine,University of BristolProfessor Martin SeversProfessor in ElderlyHealth Care,University of PortsmouthDr Sarah Stewart-BrownHealth Service Research Unit,University of OxfordProfessor Ala SzczepuraDirector, Centre forHealth Services Studies,University of WarwickDr Gillian VivianConsultant, Royal CornwallHospitals TrustProfessor Graham WattDepartment of General Practice,University of GlasgowProfessor Kent WoodsProfessor of Therapeutics,University of LeicesterDr Jeremy WyattSenior Fellow,Health KnowledgeManagement Centre,University College LondonPast membersProfessor Ian Russell *Department of HealthSciences & Clinical Evaluation,University of YorkProfessor Charles Florey *Department of Epidemiology& Public Health,Ninewells Hospital& Medical School,University of DundeeProfessor David CohenProfessor of Health Economics,University of GlamorganMr Barrie DowdeswellChief Executive,Royal Victoria Infirmary,Newcastle-upon-TyneDr Michael HorlingtonHead of Corporate Licensing,Smith & Nephew GroupResearch CentreProfessor Sir Miles IrvingProfessor of Surgery,University of Manchester,Hope Hospital,SalfordProfessor Martin KnappDirector,Personal Social ServicesResearch Unit,London School of Economics& Political ScienceProfessor Theresa MarteauDirector, Psychology &Genetics Research Group,Guy’s, King’s & St Thomas’sSchool of Medicine & Dentistry,LondonProfessor Sally McIntyreMRC Medical Sociology Unit,GlasgowProfessor David SackettCentre for Evidence BasedMedicine, OxfordDr David SpiegelhalterMRC Biostatistics Unit,Institute of Public Health,CambridgeProfessor David WilliamsDepartment ofClinical Engineering,University of LiverpoolDr Mark WilliamsPublic Health Physician,Bristol* Previous Chair

Health Technology Assessment 1999; Vol. 3: No. 17 (Pt 2) Dressings and topical agents for chronic woundsCopies of this report can be obtained from:The National Coordinating Centre for Health Technology Assessment,Mailpoint 728, Boldrewood,University of Southampton,Southampton, SO16 7PX, UK.Fax: +44 (0) 23 8059 5639 Email: hta@soton.ac.ukhttp://www.hta.nhsweb.nhs.uk ISSN 1366-5278