A prospective randomised controlled trial and economic modelling of antimicrobial silver dressings versus non-adherent control dressings for venous leg ulcers: The VULCAN trial

Article history

The research reported in this issue of the journal was commissioned by the HTA programme as project number 02/10/02. The contractual start date was in July 2004. The draft report began editorial review in August 2008 and was accepted for publication in April 2009. As the funder, by devising a commissioning brief, the HTA programme specified the research question and study design. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

None

Copyright statement

© 2009 Queen’s Printer and Controller of HMSO. This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2009 Queen’s Printer and Controller of HMSO

Background

Venous leg ulcers and quality of life

It is well recognised that venous leg ulcers can cause considerable morbidity and reduced quality of life (QoL). 23,24 However, the main focus of research in the area of venous ulceration has been around the effectiveness of dressings and has not tended to incorporate the impact of ulcers on QoL. 25 Studies that have examined QoL have used a number of different methodological techniques including qualitative and both generic and disease-specific QoL questionnaires. A systematic review by Herber et al. 26 found 24 articles that examined the impact of leg ulcers on QoL, but highlighted the problem that many of the studies did not differentiate participants by ulcer aetiology, i.e. they did not specifically examine venous ulcers.

Treatment of venous leg ulcers

The majority of leg ulcer treatment in the UK takes place in dedicated leg ulcer clinics, but it can also be given by community nurses attending patients’ own homes. 57 Multilayer compression bandaging has been identified as the gold standard in the treatment of venous leg ulcers. 58,59 It has been used in one form or another for over 300 years. 21 The compression is applied in a graduated fashion with the pressure decreasing from the toe to the knee. 60 The mode of action is not clearly understood but it is postulated that the application of external pressure to the calf muscle raises the interstitial tissue pressure, decreases the superficial venous pressure and improves venous return. 58 In order to reduce the venous hypertension, sub-bandage pressures of 40 mmHg at the ankle reducing to 20 mmHg at the knee are recommended. 61 The reduction of the venous pressure and oedema allow healing of the ulcer to occur. The healing rate can vary depending on initial ulcer size and duration. 6 A mean 12-week healing rate of 70% has been reported for small ulcers in specialist leg ulcer clinics,6 while a randomised controlled trial (RCT) that included ulcers of mixed sizes and durations reported a healing rate of 34%. 57

There are two main methods of achieving compression on the leg – compression bandaging and graduated compression hosiery. An alternative that is occasionally used is intermittent pneumatic compression, which involves a system of inflatable boots to apply compression.

Before the application of any of type of compression patients need assessment of the arterial supply to their lower limbs including measurement of ankle brachial pressure index (ABPI), in order to exclude any arterial insufficiency. 6 This kind of arterial assessment is necessary to avoid the risk of tissue damage, including skin necrosis and even limb loss, as a result of applying compression to an ischaemic extremity. 16

The wound infection continuum

Chronic wounds are almost always contaminated with micro-organisms and in small numbers they do not necessarily delay healing. 77,78 Where infection occurs it is most commonly caused by bacteria. Other organisms such as fungi and protozoa (such as Leishmania) are rare causes, while viruses do not generally cause skin infections. The bacteria that infect leg ulcers are often commensals and their impact can be variable, depending on the numbers and type of bacteria present. The criteria used to describe bacterial loading have been loosely defined by the European Wound Management Association79 as follows:

• Contamination is the presence of bacteria with no multiplication.

• Colonisation describes multiplication of bacteria with no host response.

• Infection is said to be present when there is invasion of healthy tissues with a host response.

Another descriptor of the continuum of wound infection is often referred to as critical colonisation or subclinical infection. 80 A state of bacterial colonisation is said to exist which verges on infection. This state has been used to justify the application of antimicrobial dressings in order to reduce the bacterial count and so to aid healing. 81,82 However, the significance of the quantity and type of bacteria in a chronic wound is still the subject of much debate, and there is also confusion about and a lack of understanding of the effect bacteria have on wounds of different aetiologies. 83

A possible factor in the persistence of bacteria in leg ulcers is the formation of biofilms. These have been recognised as a problem in the food industry for many years, but have recently been identified as relevant to infection in humans. 79 They are composed of a complex community of micro-organisms (several different bacterial species) that attach to a surface and are encased in a sticky extracellular polymer membrane which gives protection against many antimicrobial agents (including antibiotics). They have only recently been described in connection with wounds, but are of concern as the bacteria within them can be difficult to eradicate, and therefore a persistent source of infection. 84

Diagnosis of wound infection is not an exact science and recognition of clinical infection may be difficult. It can often be challenging to ascertain from a wound swab whether or not a wound is infected. 85,86 This can be especially difficult with leg ulcers as large numbers of different bacteria are often present – some of which are pathogens and others commensals. 87 Bacteriological investigations are helpful only insofar as they identify which organisms are present, and their sensitivities to particular antibiotics. However, the culture may not identify all the bacteria potentially causing a problem. 88 Health-care professionals need to be able to recognise clinical indicators of infection and the significance (or lack of significance) of the presence of bacteria. 89

Clinical indicators of wound infection in the chronic wound

The classic signs commonly used by health-care professionals to diagnose infection – pain, heat, redness and swelling, with the associated purulent discharge90 – can be difficult to apply to venous leg ulcers. 91,92 Leg ulcer-specific criteria that may indicate infection include:

• Delayed healing. This may be the only sign of an infection. If there are no signs of healing within a 4-week period increased bacterial burden or infection should be considered. 93

• Unexpected pain and tenderness. 94

• Abnormal odour. This can be a sign of the presence of Gram-negative bacilli, Pseudomonas species or anaerobic bacteria. 91

• ‘Pocketing’. This describes the appearance of small deep lesions at the base of the wound caused by a lack of granulation tissue. 94

• Discolouration. Granulation tissue which appears ‘unusually’ dark red in colour may indicate an angiogenic response to pathogens, while black discolouration may be caused by anaerobic bacteria. 92

• Friable granulation tissue (granulation tissue that bleeds easily). 93

• Devitalised tissue. Loose yellow debris and areas of necrosis at the base of a previously healing wound may represent localised infection. 95

These features may be present in varying combinations and degrees. This can lead to real difficulty in assessing whether a wound is ‘infected’ and in need of specific antimicrobial treatment. The lack of a clear definition of infection, and lack of clarity about the significance of bacteria found on microscopy and culture, underpin the uncertainties and use of topical antimicrobials in the treatment of leg ulcers.

Antimicrobials and chronic wounds

Antimicrobials are agents that either kill or inhibit the growth and division of micro-organisms. 79 They include antiseptics, disinfectants and antibiotics.

Historically, the main method of attempting to reduce or eliminate bacteria from a wound was by routine cleansing using an antiseptic. 83 Antiseptics are substances that inhibit the growth and development of micro-organisms and may be bacteriostatic (stop the bacteria multiplying) or bactericidal (kill the bacterial cell). Antiseptics that have been used in wounds include sodium hypochlorite, hydrogen peroxide, chlorhexidine, iodine compounds and silver nitrate solutions. 96 The use of such agents has declined owing to studies that have shown that these solutions did little to rid wounds of harmful bacteria. 96–98 Chlorhexidine and iodine used within a wound are rapidly inactivated in the presence of the wound fluid. 99,100

In recent years there have been concerns regarding the development of bacterial resistance and so the routine use of topical and systemic antibiotics in the treatment of leg ulcers has been discouraged. 101,102 One possible consequence of this has been the increasing use of dressings that are described as antimicrobial. Another is the recognition that such dressings can disrupt bacterial biofilms found on the surface of chronic wounds. 103

Cost-effectiveness of treatments for venous ulceration

There is a lack of rigorous studies examining the economics of treatments for venous leg ulcers. The existing economic costings have been described as unsophisticated, consisting of merely summing the monetary cost of the dressings. 2 With respect to cost-effectiveness, there has been very little work in the area of leg ulcer treatment. A non-systematic review of the literature revealed just two applications of cost-effectiveness in this area. One study109 investigated the potential impact of honey-impregnated dressings, while the other study116 examined silver-releasing dressings.

The first of these studies109 compared the costs and outcomes of treating venous leg ulcers using dressings impregnated with Manuka honey versus usual care. Their randomised trial of 386 participants showed no difference between the groups in terms of healing rates. The honey treatment was more costly and associated with more adverse events.

The second study116 examined the relative cost-effectiveness of four antimicrobial dressings for leg ulcers using a Markov model validated by ‘a group of wound care specialists’, based on wound healing at 4 weeks. These dressings were: Contreet Foam; Aquacel Ag; Actisorb Silver; and Iodoflex. Cost-effectiveness was assessed using a short-term 4-week model and a longer-term Markov model. Contreet Foam was found to be the most cost-effective treatment, with a cost per percentage reduction in wound area of £9.50 compared with between £16.50 and £17.50 for the other treatment options. The Markov analysis of complete healing supported these results. The authors suggested that using Contreet Foam instead of the other dressings could save the UK National Health Service (NHS) between £2.2 million and £4.4 million per year.

The cost-effectiveness of antimicrobial dressings in the treatment of venous leg ulcers is clearly an under-researched area, so the cost-effectiveness analysis undertaken in this study provides a timely contribution to a limited evidence base. The estimation of incremental cost per quality-adjusted life-years (QALYs) gained represents a significant improvement on existing work.

Conclusion

Delayed healing and difficulties in both recognising and determining the clinical significance of infection are major problems in the management of venous leg ulcers. Following clinical assessment, decisions need to be made about what kind of dressing to use. Antimicrobial dressings containing iodine, honey and silver have been promoted for treatment for venous ulcers. Iodine-based dressings have declined in use because of concerns about the possible toxic effects on the body from use of iodine and the limited timescale for which they can be in contact with the wound. Honey dressings have been evaluated in a large RCT, the HALT trial,109 which showed no significant advantage over ‘usual care’.

The range of antimicrobial dressings which contain silver has increased in the last 5 years,112 and they have become the most commonly used type of dressing among nurses caring for leg ulcers in the UK. 114 Dressing manufacturers are continuing to produce new silver products or silver versions of existing dressings as a way to ‘meet demand’. The increasing use of these dressings has cost implications for the health service as they are significantly more expensive than non-silver dressings. Sophisticated marketing of silver products makes the decision for nurses regarding which dressing to use difficult and sometimes confusing.

Evidence on the use of antimicrobial dressings for venous leg ulcers is currently limited and equivocal. 4,113 In 2006, Palfreyman et al. 117 published a Cochrane review that assessed the evidence on dressings (of all kinds) for venous leg ulcers, looking at 44 studies which showed no significant difference in terms of healing between any of the dressing types. This absence of data complicates the selection of an appropriate product. Anecdotal evidence and increasing concerns regarding infection have led to a ‘just in case’ approach, whereby nurses often choose a silver dressing in case infection is playing a part and in the hope of enhancing healing, but without any good evidence base. Antimicrobial use needs to be selective, appropriate and proportionate,110 based on clinical need and not used as a matter of rote or routine. 118

There is currently no good evidence on the cost-effectiveness of using of antimicrobial dressings for venous leg ulcers and specifically with respect to silver dressings. The VULCAN trial sought to address this by evaluating the cost-effectiveness of silver-donating dressings compared with low-adherent dressings for venous leg ulcers.

Introduction

In order to set the planned study in context and to inform its design, two surveys were undertaken:

• an informal survey of nurses attending a national vascular meeting, about the dressings they used (survey 1)

• a comprehensive survey of all areas of the UK about the existence and nature of dedicated services for venous ulcers, including their use of antimicrobial dressings (survey 2).

A further survey was undertaken during the trial to provide further information about the knowledge base and rationale for the use of antimicrobial dressings (survey 3).

Survey 1: informal survey of nurses attending a national vascular meeting

An informal, opportunistic survey was conducted in order to gather data on the range of antimicrobial dressings in use, to inform subsequent surveys and to guide the choice of antimicrobial dressing for the trial. This was carried out by one of the authors (WBC) in November 2003 at a meeting of the Society of Vascular Nurses. Nurses were approached opportunistically between sessions of the meeting – individually or in groups. They were asked two questions related to the types and frequency of antimicrobial dressings used for venous leg ulcers in their local setting. Thirty-eight nurses (who worked in a total of 40 hospital or community Trusts) were questioned and all responded.

Question 1. How often were antimicrobial dressings used in their hospitals or community Trusts in the treatment of venous ulcers?

The responses are shown in Table 1 (percentages were based on the 38 nurses questioned as the denominator).

Question 2. Which dressings or antimicrobial agents were used in their hospital or community Trusts in the treatment of venous ulcers? (If more than one, they were asked to rank, but few described the use of more than one type.)

The responses are shown in Table 2.

Survey 2: comprehensive survey of venous ulcer services throughout the UK

Survey 3: the use of silver and other antimicrobial dressing products

Discussion

From the point of view of planning the randomised trial, the primary aim of the first two surveys was to obtain information about the types of antimicrobial dressings in use in the UK, and the secondary aim was to find out about the existence and organisation of venous ulcer services. None of this information was available from any other source at the time the trial was being planned, and at the time of writing (May 2008) the postal survey remained the most comprehensive source of data about UK venous ulcer services. 114 With regard to the prospect of information for the future about numbers of patients treated and types of treatment used, the postal survey showed that less than half of the services had databases for collection of data and audit: this is disappointing.

The information gained about antimicrobial dressings was of great importance to the purpose and planning of the trial for two reasons. First, the rationale for this research had been an impression that antimicrobial dressings were being widely used in the treatment of venous leg ulcers (in the absence of good evidence of benefit). The first two surveys both confirmed that impression. The initial opportunistic survey suggested that they were used in over 50% of ulcers treatments, in some 42% of areas. Although their use was said to be ‘rare’ by 47% of the nurses questioned, they were reported as never being used by only 11%.

With regard to the specific types of antimicrobial dressings, the surveys prior to recruitment for VULCAN concurred in their finding that silver-based dressings were marginally the most commonly used. In addition, it was our impression (and nurses from around the UK had repeatedly told us) that silver-based dressings were being very actively promoted by manufacturers, and they were being used increasingly. They were claimed to represent the gold standard in modern antimicrobial dressings. Their cost was greater than other types of dressings (see Chapter 5 for a detailed breakdown of costs). For all these reasons silver-based dressings were considered to be the most appropriate type to select for the trial.

The surveys also provided interesting general information about leg ulcer services, showing that these were present in the majority of areas in the UK. The varying organisation and supervision of services almost certainly reflected local circumstances and different approaches to the difficulties of setting up dedicated services which operate across the funding boundaries of acute Trusts and PCTs. The drive by senior clinicians (primarily vascular surgeons and dermatologists) to establish leg ulcer services usually comes from within acute Trusts, but services are widely thought to be best delivered in the community, close to patients’ homes – not least because many patients are elderly and immobile.

The role of nurses in the treatment of venous ulcers is fundamental. They need to be competent in assessment of the arterial circulation before the use of compression and skilled in the application of compression bandaging. The results suggested that there was sufficient ‘in house’ expertise to train nurses in about half of the clinics, but that a similar number attended courses to learn these skills. It is important to note that nurses were in overall charge of about one-third of venous leg ulcer clinics.

The third survey questionnaire took place at the end of the recruitment period for the trial. It was distributed at a time of particular instability and change within the community health-care setting as a result of the reorganisation of the PCTs that took place in 2006/2007. The merger of the four Sheffield PCTs certainly reflected the concerns that were expressed prior to the reorganisation that it would cause distraction, loss of focus and unhappy staff. 120 Community nurses were particularly affected as there were delays in appointing community matrons and merging of community nurse teams, and district nurses had to reapply for their current posts. 121 The poor response rate of 15% (9/59) compared with practice nurses (31%; 29/94) in Sheffield is likely to be a reflection of these difficulties.

There were differences between the two centres in terms of their knowledge of the dressings that contained silver. These mirrored differences in the types of dressings that were used in each centre for the randomised part of the VULCAN trial. During the trial, Urgotul was more widely used in Sheffield and Acticoat in Exeter.

The main sources of evidence on antimicrobial dressings were non-published figures, including information from colleagues, conferences and company representatives. Reliance on those easily accessible sources, rather than peer-reviewed research literature, has been highlighted previously. 122 The lack of high quality research evidence may be another reason that nurses seem to more readily use the more prolific and easier to access evidence available from company representatives and colleagues. A potential concern about company representatives as one of the main sources of evidence and training is that they are likely to have a vested interest in promoting a particular product or brand. 115,123

The respondents to the survey seemed to have a lack of understanding about the clinical indications for the use of silver dressings and about the fact that these dressings are suitable for all types of wound. It was also interesting to note that the respondents cited the non-adherent nature of dressings as being of more importance than the antimicrobial properties of the dressing.

Conclusion

The surveys showed that the most commonly used first- and second-choice antimicrobial dressings were the silver-containing dressings, and they provided details of the specific types of silver dressings in use. This information underpinned decision and selection of dressings for the randomised trial. In addition, the surveys found that dedicated leg ulcer services were operating in most areas of the UK, although their organisation and management varied. Fewer than half of the areas had databases for auditing their activity.

The final survey that was undertaken after the VULCAN trial had been in progress for 3 years found deficiencies in the knowledge about silver dressings and the indications for their use. Sources of knowledge varied: information from commercial companies and ‘hearsay’ from colleagues were more frequently used than studies published in journals. It may be that tissue viability services should increase their educational role, especially in the light of the emergence of new wound care products year upon year.

Introduction

The brief for the proposal was to assess the place of antimicrobial agents in the management of venous leg ulcers. The initial questionnaire survey and expert opinion described in Chapter 2 suggested that during the planning stages of the trial there had been a considerable shift from other types of antimicrobial dressings towards the use of silver-containing dressings. This seemed to be the result of commercial pressure relating to the launch of several new silver-containing dressings.

Since silver-donating dressings had become the most popular kind of antimicrobial dressing, the clinical trial was designed to be a randomised study comparing these with non-adherent dressings without any antimicrobial agent. Different local preferences for the various silver-donating dressings available led to an agreement that this would be a pragmatic trial in which the clinical staff treating the patient could choose their preferred silver-donating dressing from an approved list. The list was compiled by the Trial Steering Committee after seeking information on all the available dressings. The criterion for inclusion was that there was evidence of silver donation to the wound: dressings that contained silver, but did not ‘donate’ silver to the wound were excluded. The list was kept under review by the Steering Committee and new silver-donating dressings that were released onto the market during the trial were added to the approved list as appropriate.

Methods of the clinical trial

Methods of economic analysis

The economic analysis was in two parts. The first was a relatively straightforward analysis of cost-effectiveness using trial data, while the second used cost-effectiveness modelling to extrapolate beyond the trial. In addition to extending beyond the trial time horizon, the modelling complements the trial evaluation by facilitating an analysis of alternative scenarios and subgroups and the rigorous investigation of uncertainty surrounding parameter estimates. The modelling results are arguably more generalisable than those of the trial evaluation and consequently the two may differ.

In view of the primary outcome of the trial being the numbers of patients healed at 12 weeks, this analysis was carried out using data from the first 3 months of the trial. Data beyond this point were used in the cost-effectiveness modelling, which adopts a lifetime perspective.

Assessment of cost-effectiveness

In order to assess the relative cost-effectiveness of the alternative types of dressing at 3 months, data on cost and outcome were brought together to estimate incremental cost-effectiveness ratios (ICERs), specifically the incremental cost per QALY gained of silver-donating antimicrobial dressings relative to the control non-adherent dressings.

The ICER for silver dressings can be located on the cost-effectiveness plane (Figure 1), which is a two-dimensional space in which the origin represents the comparator intervention – in this case the non-adherent dressings. The x-axis represents the average difference in effectiveness per patient between the antimicrobial dressings and the control dressings, while the y-axis represents the average difference in cost per patient between the dressings. The four quadrants are conventionally referred to as points on the compass, namely north-west (NW), north-east (NE), south-west (SW) and south-east (SE). The ICERs can be plotted as points on this plane, with the slope of the line from the origin to the ICER representing the value of the ICER. Treatments with ICERs located in the NW quadrant (more costly, less effective) are said to be dominated by the comparator treatment, while treatments with ICERs located in the SE quadrant (less costly, more effective) are said to dominate the comparator treatment. In practice most new treatments are located in the NE quadrant where increased effectiveness is achieved at increased cost. In this instance the decision to adopt the new treatment will depend upon whether the ICER lies below the acceptable ceiling ratio of the decision maker. If the decision maker’s willingness to pay for a unit of effectiveness (λ) is greater than the ICER, then on efficiency grounds the treatment should be recommended for adoption.

FIGURE 1.

The cost-effectiveness plane.

The point estimates of the ICERs are subject to uncertainty and it is therefore important that this uncertainty is taken into account. Because of the problems associated with estimating confidence intervals (CIs) for ratio statistics, the approach of non-parametric bootstrapping is adopted to represent the uncertainty surrounding the ICER estimates. 128 Cost-effectiveness acceptability curves (CEACs), which summarise the evidence in support of the silver dressings being cost-effective for a range of values of λ, are also presented. 129 A full probabilistic sensitivity analysis was undertaken as part of the modelling. 130

The probabilistic interpretation of the CEAC was from a Bayesian perspective. In effect the CEAC provides information to decision makers on the level of uncertainty associated with a potential decision to recommend the use of a new or additional intervention. For example, a 0.82 probability of an intervention being cost-effective at a ceiling ratio of £30,000 per QALY, say, implies an error probability (i.e. the probability of making a wrong decision) of 0.18 (1 – 0.82). In making a decision regarding the potential recommendation of a new intervention, the decision maker must weigh up these probabilities against one another. Alternatively, instead of deciding whether or not to recommend the new intervention on the basis of the currently available evidence, the decision maker may demand an expected value of perfect information analysis to compare the expected cost of the uncertainty with the value of conducting further research to reduce the uncertainty.

Recruitment

Between March 2005 and November 2007 a total of 304 patients were recruited to the clinical trial. A total of 213 were recruited to the RCT [107 randomised to receive silver dressings and 106 non-adherent dressings – see the Consolidated Standards of Reporting Trials (CONSORT) diagram, Figure 2] and 91 were recruited to the observational study. An additional six patients were initially recruited to the observational arm of the study but were subsequently randomised when they became eligible for the RCT; their outcomes were analysed within the RCT and are not included in the results for the observational arm of the study.

FIGURE 2.

CONSORT diagram showing recruitment to RCT. ITT, intention to treat.

The original protocol estimated a sample size of 150 patients in each group but over the first year of the trial it became evident that recruitment was falling below the expected number. A particular reason for this was the change in structure of the PCTs and reconfiguration of community services, which coincided with the trial. The disruption and uncertainty generated by the merger of the PCTs was widely recognised. 120,121 Recruitment depended upon patients being identified by nurses in the community: they reported that the disruption caused by the reorganisation had a considerable impact on their inclination and ability to recruit. In the Sheffield area there was a complete reorganisation and restructuring with a large number of voluntary redundancies among nurses, district nurse bases being merged and staff having to reapply for their current posts. These changes had a profound effect on morale in the community nursing services and made it difficult to persuade district nurses to take on the additional work required to identify and recruit patients.

As a result of the restructuring it became more difficult to gain access to the nurses dealing with venous leg ulcers. There was increasing management of leg ulcer patients by practice nurses within general practices, who often had a very small caseload of patients with ulcers. Financial restraints also meant that it was difficult for community nursing staff to attend educational meetings, which would have provided more opportunities to publicise the trial and encourage recruitment.

An interim review of recruitment in mid-2006 showed that although total recruitment levels were lower than expected the follow-up to the primary end point was more complete than had been predicted when the sample size estimations were carried out. As a result of this, the overall recruitment target was reduced and the recruitment period was extended to the end of November 2007.

Demographics

Among the 304 patients recruited (213 into the RCT and 91 into the observation study), 172 (57%) were female and the average age was 69.3 years. One hundred and forty-five (48%) were recruited in Sheffield and 159 (52%) in Exeter. The patients recruited in Sheffield had a slightly lower average age and a higher proportion of males compared with Exeter. More details are given in Table 10.

In the RCT 107 patients were allocated to the antimicrobial silver dressing arm and 106 to the control arm. These patients were evenly matched for demographic features (Table 11). The patients in the RCT were stratified by ulcer size and recruitment centre. At initial recruitment, 30 patients in each group (28%) had been stratified in the larger size category having a maximum ulcer diameter of 3 cm or more.

All analysis of the RCT is carried out on an intention to treat basis.

Follow-up

Data were available on complete ulcer healing at the primary end point of 12 weeks on all but five of the 213 patients in the RCT, giving a total follow-up to the primary end point of 97.7%. One patient was lost after moving away from the area, one underwent surgical treatment for varicose veins and withdrew from the trial, and three other patients withdrew from the trial (no further information available).

A summary of the allocation and follow-up of patients is given in the CONSORT diagram in Figure 2 and a CONSORT statement131 (see Appendix 1).

There were no deaths within the first 12 weeks following recruitment. A total of 11 patients died during the first year following recruitment, four in each arm of the RCT and three in the observational study. None of these deaths was directly related to leg problems (ischaemic heart disease = 4, cancer = 4, chest infection = 2, cerebrovascular disease = 1).

Dressings and breaches of protocol

Of the 213 randomised patients, seven (3.3%) did not receive their allocated treatment. Three patients who had been allocated to the control group were treated with silver dressings, one at the request of the patient and two through choice of the nursing staff carrying out the dressings. Four patients allocated to antimicrobial dressings were not treated with silver dressings. In one case lack of availability of the silver dressing was given as the reason and the ulcer healed before the dressing was available, while in the other three the breach of protocol was unexplained.

One patient was started on a silver-donating dressing which was subsequently changed after 4 weeks when it was noted that there was a reaction to the dressing. This was not reported to the research team by the community nurse until after the weekly assessments had been submitted, by which time the reaction had settled and the ulcer had healed. Two patients were started on Silvercel dressings (Johnson & Johnson Wound Management, Ascot). Silvercel had been considered by the Trial Steering Committee for addition to the list of approved dressings, but was never formally added because responses to some questions from the Steering Committee were not received from the manufacturer.

A list of the dressings approved for the trial is given in Table 8. The most common antimicrobial dressing used was Urgotul Ag (39.6%) followed by Acticoat 7 (27.5%) and Aquacel Ag (16.1%). Most patients (96%) remained on the same dressing throughout the 12-week treatment period or until the ulcer had healed. The type of silver-donating dressing was changed in three patients during the period of the trial owing to the unavailability of a particular dressing or nurse preference. Most patients in the control group (87/106; 82%) were treated with low adherence knitted viscose non-adherent dressings throughout the initial 12-week treatment period. The other non-antimicrobial dressings used for some or all of the treatment period in the other cases were Urgotul (non-silver-containing version), Biatain™ (Coloplast), Atrauman™ (Paul Hartmann Ltd, Heywood) and Allevyn™ (Smith & Nephew).

There were geographical differences in preferences for particular types of silver dressings: Urgotul was more commonly used in Sheffield, and Acticoat 7 or Aquacel Ag were more commonly used in Exeter (Table 12).

Patient characteristics

There was a high incidence of pre-existing disease and comorbidity in this group of patients (Table 13). The proportions of participants with a number of specific comorbidities were different between the treatment arms. For example, 45.8% of participants had a previous history of hypertension in the silver-donating antimicrobial group compared with 34% in the control group. However, there were no statistically significant differences between the arms of the randomised trial with respect to these factors.

TABLE 13 - Incidence of comorbidities, smoking history and selected drug history in RCT arms and observational trial

	Antimicrobial, n (%)	Control, n (%)	Total, n (%)
Number of patients	107	106	213
Comorbidity
Hypertension	49 (45.8)	36 (34.0)	85 (39.9)
Osteoarthritis	35 (32.7)	29 (27.4)	64 (30.0)
History of myocardial infarction or cardiac failure	16 (15.0)	14 (13.2)	30 (14.1)
Anaemia	12 (11.2)	6 (5.7)	18 (8.5)
Rheumatoid arthritis	14 (13.1)	20 (18.9)	34 (16.0)
History of stroke or transient cerebral ischaemia	10 (9.3)	7 (6.6)	17 (8.0)
Smoking history
Smoker	18 (16.8)	21 (19.8)	39 (18.3)
Ex-smoker	31 (29.0)	24 (22.6)	55 (25.8)
Current drugs
Aspirin	13 (12.1)	10 (9.4)	23 (10.8)
Diuretics	15 (14.0)	10 (9.4)	25 (11.7)
Warfarin	3 (2.8)	10 (9.4)	13 (6.1)
Atenolol	10 (9.3)	10 (9.4)	20 (9.4)

Overall, 56.3% of patients reported previous episodes of leg ulceration (49.7% in the index limb). A history of venous problems in the legs was common, with 21.1% of patients having had deep vein thrombosis (16.0% in the index limb). A total of 54.5% reported a history of having varicose veins and 22.5% had previously undergone treatment for varicose veins; 21.1% had suffered previous episodes of phlebitis; and 18.3% of patients reported a family history of leg ulceration. More details of these figures are given in Table 14.

TABLE 14 - Ulcer history and aetiological factors for patients in RCT

DVT, deep vein thrombosis; VV, varicose veins.

	Antimicrobial, n (%)	Control, n (%)	Total, n (%)
Number of patients	107	106	213
History of venous problems
Ulcer in index leg	56 (52.3)	44 (41.5)	100 (46.9)
Ulcer (either leg)	61 (57.0)	52 (49.1)	113 (53.1)
VV (index leg)	51 (47.7)	54 (50.9)	105 (49.3)
VV (either leg)	58 (54.2)	58 (54.7)	116 (54.5)
Previous DVT (index leg)	15 (14.0)	19 (17.9)	34 (16.0)
Previous DVT (either leg)	21 (19.6)	24 (22.6)	45 (21.1)
VV surgery (index leg)	20 (18.7)	18 (17.0)	38 (17.8)
VV surgery (either leg)	23 (21.5)	25 (23.6)	48 (22.5)
Previous phlebitis (index leg)	20 (18.7)	17 (16.0)	37 (17.4)
Previous phlebitis (either leg)	25 (23.4)	20 (18.9)	45 (21.1)
Risk factors
Fixed ankle (index leg)	15 (14.0)	18 (17.0)	33 (15.5)
Fixed ankle (either leg)	17 (15.9)	18 (17.0)	35 (16.4)
Fixed hip (index leg)	15 (14.0)	11 (10.4)	26 (12.2)
Fixed hip (either leg)	15 (14.0)	11 (10.4)	26 (12.2)
Ulcer present over 12 weeks	39 (36.4)	43 (40.6)	82 (38.5)
Family history of ulcer	21 (19.6)	18 (17.0)	39 (18.3)
Leg symptoms
Swelling (index leg)	45 (42.1)	53 (50.0)	98 (46.0)
Swelling (either leg)	50 (46.7)	57 (53.8)	107 (50.2)
Claudication (index leg)	5 (4.7)	6 (5.7)	11 (5.2)
Claudication (either leg)	5 (4.7)	7 (6.6)	12 (5.6)
Aching (index leg)	29 (27.1)	35 (33.0)	64 (30.0)
Aching (either leg)	29 (27.1)	35 (33.0)	64 (30.0)
Pain (index leg)	21 (19.6)	24 (22.6)	45 (21.1)
Pain (either leg)	20 (18.7)	23 (21.7)	43 (20.2)

At the time of recruitment the ulcer had been present for more than 12 weeks in 39.1% of patients.

Examination of the ulcer showed the presence of slough in 62.9% and necrosis in 6.1% of all the ulcers in the trial. Granulation tissue was observed in 62% and epithelialisation in 29.6% of ulcers. Exudation of fluid from the ulcer was troublesome for 74.6% patients and 13.1% reported that odour was a problem. A detailed breakdown of the findings on examination is given in Table 15.

TABLE 15 - Ulcer characteristics for patients in RCT

VV, varicose veins.

	Antimicrobial, n (%)	Control, n (%)	Total, n (%)
Number of patients	107	106	213
On examination
Slough	70 (65.4)	64 (60.4)	134 (62.9)
Necrosis	6 (5.6)	7 (6.6)	13 (6.1)
Granulation	68 (63.6)	64 (60.4)	132 (62.0)
Epithelialisation	26 (24.3)	37 (34.9)	63 (29.6)
Problems reported by patients
Exudate	79 (73.8)	80 (75.5)	159 (74.6)
Odour	16 (15.0)	12 (11.3)	28 (13.1)
Leg signs
Visible VV (index leg)	73 (68.2)	78 (73.6)	151 (70.9)
Visible VV (either leg)	79 (73.8)	81 (76.4)	160 (75.1)
Oedema (index leg)	62 (57.9)	67 (63.2)	129 (60.6)
Oedema (either leg)	66 (61.7)	73 (68.9)	139 (65.3)
Eczema (index leg)	37 (34.6)	20 (18.9)	57 (26.8)
Eczema (either leg)	38 (35.5)	23 (21.7)	61 (28.6)
Staining (index leg)	71 (66.4)	66 (62.3)	137 (64.3)
Staining (either leg)	74 (69.2)	75 (70.8)	149 (70.0)
Induration (index leg)	25 (23.4)	18 (17.0)	43 (20.2)
Induration (either leg)	29 (27.1)	18 (17.0)	47 (22.1)
Atrophy/blanching (index leg)	29 (27.1)	29 (27.4)	58 (27.2)
Atrophy/blanching (either leg)	31 (29.0)	31 (29.2)	62 (29.1)
Ankle flares (index leg)	71 (66.4)	69 (65.1)	140 (65.7)
Ankle flares (either leg)	76 (71.0)	72 (67.9)	148 (69.5)

The distribution of ulcer sizes, measured at the time of recruitment both as the maximum diameter and as the area measured using the Visitrak, are shown in Figure 3. There was no significant difference in ulcer size distribution between the two arms of the trial.

FIGURE 3.

Initial ulcer size for patients in RCT arms. Box and whisker plots showing median (central line), 25th and 75th centiles (box), 10th and 90th centiles (whiskers) and outliers. (a) Maximum measured diameter at recruitment (cm). (b) Measured area based upon first Visitrak tracing.

Ulcer healing

Table 16 shows the proportion of ulcers healed in the two arms of the RCT at the primary end point of 12 weeks and the secondary end points of 6 months and 1 year.

The overall proportions healed were 59.6% versus 57.3% for the antimicrobial dressing group versus the control group at 12 weeks, 85.3% versus 78% at 6 months and 96.0% versus 95.7% at 12 months. The relative risk (RR) of healing for the silver dressings versus the control dressings was 1.06 (95% CI 0.80 to 1.40) at 12 weeks. The RRs of healing at 6 months and 1 year were 1.34 (95% CI 0.88 to 2.03) and 1.03 (95% CI 0.51 to 2.08) respectively. None of the differences was statistically significant.

Overall median time to healing was not significantly different between the two groups (p = 0.408 Cox proportional hazard) at 67 days (95% CI 54 to 80) for antimicrobial dressings and 58 days (95% CI 43 to 73) for the control group. The hazard ratio for silver versus control dressings was 1.13 (95% CI 0.85 to 1.51). Large ulcers healed significantly more slowly than small ulcers (p = 0.05 Cox proportional hazard), with a median of 101 days (95% CI 43 to 73) versus 52 days (95% CI 46 to 57) respectively for those above and below 3 cm in initial diameter. The hazard ratio for large versus small ulcers was 1.55 (95% CI 1.15 to 2.10).

In order to investigate predictors of healing at 12 weeks, a binary logistic regression was performed with ‘healed at 12 weeks’ as the dependent variable, with the selection of covariates being based on clinical judgement. Table 17 shows the variables that were included in the regression and their definitions, while Table 18 shows the results.

The non-significant chi-squared statistic in the Hosmer–Lemeshow goodness of fit test indicate that the data fit the regression model well. Significant predictors of healing at 12 weeks were location, gender and ulcer size. The odds ratios for these variables indicated that: the odds of the ulcer healing within 12 weeks were decreased by 0.509 in Sheffield compared with Exeter; they were increased by a factor of 2.156 for females compared with males; and decreased by a factor of 0.425 for large compared with small initial ulcer size (greater or less than 3 cm initial diameter). Further development of modelling relating to the factors affecting healing is presented in Chapter 7. The proportion of ulcers healing over time is shown by allocated treatment, size of ulcer and gender in Figure 4.

FIGURE 4.

Kaplan–Meier survival plots showing proportion of ulcers healed over time.(a) Antimicrobial dressings versus control dressings. (b) Large versus small ulcers. (c) Male versus female participants in the RCT.

Modelling of time to ulcer healing

The analysis was undertaken by pooling all data points from patients consenting to randomisation in order to provide maximal data. The location of the centre (either Sheffield or Exeter) was included within the survival model in order to capture any population demographics that were not explicitly contained within the questionnaire. All data analyses were conducted in stata version 10 (© STATACorp LP, College Station, Texas, USA).

A preliminary analysis investigated the change in hazard rate across time to determine the most appropriate survival model. The change in hazard can be seen in Figure 5.

FIGURE 5.

Change in hazard (i.e. rate of healing) in relationship to analysis time (smoothed hazard estimate).

There were few patients (1.4% of the total) where the follow-up time was greater than 500 days and thus data after this period should be treated with caution. Excluding these data, there was a clear trend for a decreasing hazard, i.e. as the time with an ulcer increased, the probability of healing in the next time unit decreased.

On this evidence an exponential model, where the hazard remains constant across time, was rejected. A Weibull model (which incorporates a parameter to increase or decrease the failure rate in relation with time) was therefore selected as the most appropriate mode as this distribution was also assumed to be clinically plausible. The Weibull model produced a good fit (p < 0.000) and had additional advantages (compared with a flexible baseline hazard) of being less influenced by small patient numbers in later time periods and of being already included within modelling packages.

Two survival analysis scenarios were formally evaluated and these are detailed below.

Recurrence

Among those patients whose ulcers had healed within the first year of the randomised trial (n = 185 patients) a total of 24 had recurrent ulceration, with no significant difference in rates between the antimicrobial dressing and control groups (Table 22).

In an exploratory analysis there were no factors relating to history, comorbidities, symptoms, ulcer features or treatment that significantly predicted the risk of recurrence.

Quality of life and utility valuation

A TTO valuation of health states related to venous ulceration was undertaken by a sample of a 160 members of the general population. However, when analysing the results the study did not integrate with the other data collected during the study and added little additional information. The data were not thought to be suitable for inclusion in the modelling. A decision was therefore made not to include the results from the TTO study in the final report.

Table 23 shows the mean EQ-5D health-state values and the difference between the means at baseline, 1, 3, 6 and 12 months for patients in the non-adherent and antimicrobial groups. Regression analysis of covariance indicated that there was no significant difference between the groups with respect to mean follow-up EQ-5D values after adjusting for baseline values.

Table 24 shows the mean SF-6D health-state values and the difference between the means at baseline, 1, 3, 6 and 12 months for patients in the non-adherent and antimicrobial groups. As with the EQ-5D data, regression analysis of covariance indicated that there was no significant difference between the groups with respect to mean follow-up SF-6D values after adjusting for baseline values.

Table 25 shows the mean EQ-5D health-state values at baseline, 1, 3, 6 and 12 months for patients who had healed at 12 weeks and those who had not healed. Regression analysis of covariance indicated that there was no significant difference between the groups with respect to mean follow-up EQ-5D values after adjusting for baseline values.

The mean difference between the EQ-5D values at baseline and 3 months was 0.0436 for those who had healed (n = 93) and 0.0311 for those who had not healed (n = 52), giving a mean difference of 0.00251.

Table 26 shows the mean SF-6D health-state values at baseline, 1, 3, 6 and 12 months for patients who had healed at 12 weeks and those who had not healed. Regression analysis of covariance indicated that the coefficient on the covariate ‘healed at 12 weeks’ was positive and significant (coefficient = 0.041; p = 0.002). This means that patients whose ulcer had healed at 12 weeks had a significantly better mean SF-6D score at follow-up after adjusting for baseline values.

Table 27 shows the mean scores for the eight dimensions of the SF-36 at baseline, 1, 3, 6 and 12 months for the control and antimicrobial dressing groups. Regression analysis of covariance indicated that there was no significant difference between the groups with respect to any of the dimensions’ mean follow-up scores after adjusting for baseline values.

Observational study

Ninety-one patients were recruited to the observational study. Compared with patients in the RCT there were no significant differences in age or gender; but patients were more likely to be from Exeter, a lower proportion of ulcers were on the left side, and there was a greater proportion of large ulcers (Table 28).

Information was available about the types of dressings used on 82 patients: 43 with antimicrobial silver-donating dressings, 37 with control dressings and two with iodine dressings.

The incidence of comorbidities, smoking history and medication was similar to that in the RCT (Table 29) with the exception of diabetes, which was present in 11/91 (12%) of observational patients, this being an exclusion criterion for randomisation. Other risk factors and ulcer history were similar to those in the RCT (Table 30), as were clinical features (Table 31).

Healing was slower in the observational group than in the RCT – 87% compared with 95.9% respectively being healed by 1 year, although the difference did not reach statistical significance (Table 32).

EQ-5D data

This analysis is based on 141 patients in the RCT arm of the trial who provided EQ-5D responses at baseline and 3 months, of whom 74 were in the antimicrobial dressing group and 67 were in the control dressing group. These 141 patients comprise a self-selected group on the basis that they completed and returned their questionnaires. Tests of differences between these patients and those who did not return their questionnaires revealed that the self-selected group had a higher proportion of patients whose ulcer had healed at 12 weeks (χ² = 6.14; p = 0.013) and a higher proportion of patients from Exeter (χ² = 12.30; p < 0.001).

Table 33 shows the average number of ulcer clinic visits, community nurse home visits, GP contacts and chiropody contacts per patient for the control and antimicrobial dressing groups. The numbers of clinic/home visits was used as a surrogate for the numbers of dressings and bandages used, as these were both changed at each visit.

The only statistically significant difference was in relation to mean number of ulcer clinic visits per patient, with antimicrobial patients having more visits than control patients (8.00 versus 5.61 respectively).

With respect to numbers of prescriptions for hosiery, antibiotics and other medicines, 41 control patients were prescribed hosiery compared with 42 antimicrobial patients, 12 control patients were prescribed antibiotics compared with 21 antimicrobial patients, and seven control patients were prescribed other drugs compared with five antimicrobial patients. Chi-squared tests revealed that none of these differences was significant.

Table 34 shows the average cost per patient of each item of resource use and the average total cost per patient for the control and antimicrobial dressing groups.

The biggest contributor to total costs for both groups was the cost of attending the ulcer clinics, accounting for between 61% and 66% of total costs. Ulcer clinic costs were significantly higher in the antimicrobial dressings group, as were dressing costs. The mean total cost per patient is also significantly higher for the antimicrobial group.

Table 35 shows the point estimate of the ICER for antimicrobial dressings relative to control dressings.

Antimicrobial silver dressings were associated with an incremental cost of £97.85 and an incremental QALY gain of 0.0002 compared with control dressings. When combined, these data gave an ICER for antimicrobial dressings of £489,250 per QALY gained.

Bootstrapping the point estimate of the ICER for antimicrobial dressings resulted in 30% of the replications being located in the NE quadrant of the cost-effectiveness plane (more costly, more effective), 11% being located in the SE quadrant (less costly, more effective), and 13% being located in the SW quadrant (less costly, less effective). The largest proportion of the replications (46%) is located in the NW quadrant, where antimicrobial dressings are more costly and less effective and therefore dominated by control dressings.

Figure 6 shows the CEAC for antimicrobial dressings relative to control dressings. The probabilities that antimicrobial dressings are cost-effective at ceiling ratios of £10,000, £30,000 and £50,000 per QALY are 0.37, 0.40 and 0.40 respectively.

FIGURE 6.

Cost-effectiveness acceptability curve for antimicrobial dressings relative to control dressings (EQ-5D data). QALY, quality-adjusted life-year.

Repeating the above analysis using the more precise estimates of the QALYs enjoyed by patients up to 3 months has little impact on the results. Consequently, this analysis is not reported.

The imputation of missing EQ-5D values had little impact on the results, with the probability that antimicrobial dressings are cost-effective at a ceiling ratio of £30,000 per QALY being the same as that in the initial analysis, i.e. 0.40.

SF-6D data

This analysis was based on 118 patients who provided SF-6D responses at baseline and 3 months, of whom 63 were in the antimicrobial dressing group and 55 were in the control dressing group. As with the EQ-5D data, these 118 patients comprise a self-selected group. Tests of differences between the selected and non-selected patients revealed that the patients in the self-selected group had a higher mean age (72.7 years versus 67.7 years; p = 0.023) and that the self-selected group had a higher proportion of patients from Exeter (χ² = 7.01; p = 0.008).

Table 36 shows the average number of ulcer clinic visits, nurse home visits, GP contacts and chiropody contacts per patient for the control and antimicrobial dressing groups. For the same reasons as outlined above regarding the EQ-5D data, use of bandages and dressings is not reported separately.

As with the EQ-5D data, the only statistically significant difference was in relation to mean number of ulcer clinic visits per patient, with antimicrobial dressing patients having more visits than control patients (8.68 versus 5.60 respectively).

With respect to numbers of prescriptions for hosiery, antibiotics and other medicines, 33 control patients were prescribed hosiery compared with 35 antimicrobial patients, seven control patients were prescribed antibiotics compared with 15 antimicrobial patients, and four control patients were prescribed other drugs compared with two antimicrobial patients. Chi-squared tests revealed that none of these differences was significant. Table 37 shows the average cost per patient of each item of resource use and the average total cost per patient for the control and antimicrobial dressing groups.

As with the EQ-5D data, the biggest contributor to total costs for both groups was the cost of attending the ulcer clinics, accounting for between 61% and 70% of total costs. As before, ulcer clinic costs were significantly higher in the antimicrobial dressing group, as were dressing costs. Once again, the mean total cost per patient was also significantly higher for the antimicrobial group. Table 38 shows the point estimate of the ICER for antimicrobial dressings relative to control dressings.

Compared with control dressings, antimicrobial dressings were associated with an incremental cost of £109.70 and an incremental QALY loss of –0.0069. Thus, antimicrobial dressings were dominated by control dressings.

Bootstrapping the point estimate of the ICER for antimicrobial dressings resulted in 28% of the replications being located in the NE quadrant of the cost-effectiveness plane (more costly, more effective), 12% being located in the SE quadrant (less costly, more effective), and 11% being located in the SW quadrant (less costly, less effective). As was the case with the EQ-5D data, the largest proportion of the replications (49%) is located in the NW quadrant, where antimicrobial dressings are more costly and less effective and therefore dominated by control dressings.

Figure 7 shows the CEAC for antimicrobial dressings relative to control dressings. The probabilities that antimicrobial dressings are cost-effective at ceiling ratios of £10,000, £30,000 and £50,000 per QALY are 0.24, 0.36 and 0.38 respectively.

FIGURE 7.

Cost-effectiveness acceptability curve for antimicrobial dressings relative to control dressings (SF-6D data). QALY, quality-adjusted life-year.

As was the case with the EQ-5D analysis, repeating the above analysis using the more precise estimates of the QALYs enjoyed by patients up to 3 months has little impact on the results. Consequently, this analysis is not reported.

The imputation of missing SF-6D values also had little impact on the results, with the probability that antimicrobial dressings are cost-effective at a ceiling ratio of £30,000 per QALY being 0.34, which is slightly lower than the 0.36 in the initial analysis.

The structure of the model

Model assumptions

A cohort of hypothetical patients were simulated, as later described, and duplicated, with one assumed to receive antimicrobial silver dressings and one assumed to receive a control dressing. For each patient, in each cohort, the time to ulcer healing was predicted using the distributions estimated from the trials, which were detailed in Chapter 4. For simplicity, the time to healing has been rounded to the nearest week (with a minimum of 1 week). For computational efficiency, a discrete simulation methodology was employed.

During the healing process it has been assumed that both costs and utility losses are incurred because of the ulcer – both costs and benefits were discounted at 1.035 per annum,132 which equates to a discount rate of 1.00066 per week. Total costs and QALYs were calculated for the hypothetical cohort who received antimicrobial dressings and those who received the control dressings. The incremental costs and QALYs of silver dressings compared with the control dressings were used to calculate the cost–utility. A schematic of the model is depicted in Figure 8.

FIGURE 8.

A schematic of the model.

The model assumed that patients will not die without the ulcer healing – on the basis that this was unlikely to affect the results, as only a small percentage of ulcers remain unhealed at 5 years. From UK life tables,133 it can be seen that only patients aged 86 and older have an expected survival duration of less than 5 years. Applied to the study cohort this represents a minority of patients (24% in Exeter and 9% in Sheffield). This again suggests that the assumption that people do not die with an unhealed ulcer is unlikely to affect these results.

The assumption of ulcer healing based on the average values for each of the patient characteristics resulted in a predicted 99.8% of ulcers healing in patients presenting in Sheffield and virtually all of those presenting in Exeter. Note that these values cannot be directly compared with those observed in the trials, as these patients did not all have average values for each variable considered.

We have further assumed that ulcers do not recur within the model. This assumption was based on a small number of patients having a recurrent ulcer within the RCT which would result in large uncertainty in constructing distributions to predict the time of recurrence. In the real world, where patients do recur it is recommended that they be assumed to be a new presentation and be treated in accordance with the strategy deemed to be cost-effective.

Finally, the utilities used to populate the model were those derived from the analysis of the responses to the EQ-5D, using the UK tariffs. 124 The decision to exclude the utilities derived from the SF-6D was made on the basis that EQ-5D tariffs are preferred by the National Institute for Clinical Excellence (NICE). 134

Population of the model

Simulating the characteristics of patients presenting with a leg ulcer

The results of the RCT showed that centre, either Exeter or Sheffield, was a significant predictor of time to healing as a consequence of the different demographic characteristics of the sample. In order to allow for this, the model was run separately for both the Exeter and Sheffield centres. The patients presenting to each centre were simulated from the individual centre data, with a statistical distribution assumed to approximate the size of ulcer.

For patients presenting in Exeter the distribution of ulcer size was approximated by 1 plus a lognormal distribution with a normal distribution of the logarithm having a mean of 0.325 and a standard deviation of 0.757. The goodness of the fit is shown in Figure 9.

FIGURE 9.

Statistical distribution fitted to ulcer size for patients presenting in Exeter.

The same methodology was applied for patients presenting in Sheffield. The distribution of ulcer size was approximated by 1 plus a lognormal distribution. The distribution of the logarithm was normal with a mean of 0.500 and a standard deviation of 0.767. The fit is shown in Figure 10.

FIGURE 10.

Statistical distribution fitted to ulcer size for patients presenting in Sheffield.

Excluding ulcer size, all the remaining variables were binary in distribution, as the values took either 1 or zero. Data were taken from each centre and fitted to a beta distribution where alpha represents the number of successes (defined as a 1) and beta the number of failures defined as a zero. The beta distributions fitted to each predictive variable are shown in Table 39. These were used in the probabilistic sensitivity analyses. These variables were not strongly correlated, as shown in Table 21, and therefore could be sampled independently for each patient.

TABLE 39 - Distributions of patient characteristics that were predictive of time to healing.

DVT, deep vein thrombosis; TIA, transient ischaemic attack; VV, varicose veins.

0 = right; 1 = left.

0 = male; 1 = female.

Significantly higher rate in Exeter (p < 0.05).

Significantly higher rate in Sheffield (p < 0.05).

The mean is defined as alpha/(alpha + beta).

	Exeter		Sheffield
	Mean	Alpha, beta	Mean	Alpha, beta
Leg affecteda	0.576	57, 42	0.518	59, 55
Genderb,c	0.626	62, 37	0.465	53, 61
Osteoarthritis	0.313	31, 68	0.289	33, 81
Stroke or TIA	0.091	9, 90	0.070	8, 106
DVTd	0.131	13, 86	0.281	32, 82
VV surgery	0.232	23, 76	0.132	15, 99
Ached	0.232	23, 76	0.360	41, 73
Eczemac	0.333	33, 66	0.211	24, 90
Ankle flare	0.697	69, 30	0.623	71, 43
Fixed ankled	0.061	6, 93	0.237	27, 87

Estimating the number of individual patients that needed to be simulated in order to provide robust answers

The analyses combined the individual time to healing from a cohort of individual patients. In the model a balance needed to be struck between too few patients and too many patients. If there were insufficient patients in the model this could result in the outcome measures being dependent on the random numbers selected and so be potentially inaccurate. Alternatively, too many patients would mean additional computational time that would provide no discernible benefit.

To investigate the likely number of patients required, an exploratory analysis examined the relationship between the modelled average time to healing for patients presenting in Exeter and the number of patients simulated. Midpoint values were used for the model where dressing type was forced into the model as a predictive variable. The results are shown in Figure 11.

FIGURE 11.

The relationship between modelled average time to healing and number of patients simulated.

It can be seen that the results begin to stabilise when 60,000 patients are simulated. To ensure that we were confident sufficient patients were generated we opted to simulate 100,000 patients per simulation run.

The scenarios modelled

A total of three scenarios were explicitly modelled, the base case plus two additional scenarios. These are detailed in Table 40.

Methodology for calculating the results

The results of the modelling are presented in a variety of formats. Initially, the deterministic cost per QALY is presented, which was calculated using the mid-point values for each parameter. Probabilistic sensitivity analyses130 were then conducted both to determine a more accurate estimate of the cost per QALY and to provide a quantification of the uncertainty in the model. These are shown using CEACs129 and plot the probability that an algorithm will be the most cost-effective at each value for willingness to pay, from zero to £200,000 per QALY. One thousand configurations were used for the probabilistic sensitivity analyses which sampled values for the influence of each predictive variable on the time to healing in addition to the underlying Weibull distribution; these samples were undertaken using multivariate normal distribution techniques in order that the correlation between parameters was preserved within each configuration. Cost and disutility data were additionally sampled for each configuration. Provisional statistical analyses, using a willingness to pay of £20,000, showed that this number of configurations was adequate to ensure that the uncertainty in the mean cost per QALY value was not so large as to affect the decision on cost-effectiveness of the intervention.

Model results

Scenario 1

Deterministic and stochastic results for scenario 1 are provided in Table 41. It can be seen that the mean cost per QALY was high at more than £600,000 per QALY for the antimicrobial dressings. Cost-effectiveness acceptability curves are provided in Figures 12 and 13. It can be seen that the probabilities of silver dressings having a cost per QALY below either £20,000 or £30,000 are low – 27% and 32% respectively.

TABLE 41 - Incremental costs and QALYs of silver dressings compared with non-adhesive dressings (per patient treated)

QALY, quality-adjusted life-year.

To the nearest thousand.

		Incremental costs of antimicrobial dressings compared with control dressings (£)	Incremental QALYs of antimicrobial dressings compared with control dressings	Cost per QALY of antimicrobial dressings compared with control dressings (£)a
Exeter	Deterministic	39	5.9 × 10–5	653,000
	Stochastic	41	6.2 × 10–5	662,000
Sheffield	Deterministic	63	9.7 × 10–5	646,000
	Stochastic	66	1.0 × 10–4	665,000

FIGURE 12.

Cost-effectiveness acceptability curve for Exeter demographic (scenario 1). QALY, quality-adjusted life-year.

FIGURE 13.

Cost-effectiveness acceptability curve for Sheffield demographic (scenario 1). QALY, quality-adjusted life-year.

Scenario 2

Deterministic and stochastic results for scenario 2 are shown in Table 42. It can be seen that the cost per QALY was much reduced and was consistently below £20,000. Cost-effectiveness acceptability curves are provided in Figures 14 and 15. It can be seen that the probabilities of the antimicrobial silver dressings having a cost per QALY below either £20,000 or £30,000 were 53% and 62% respectively.

TABLE 42 - Incremental costs and QALYs of silver dressings compared with non-adhesive dressings (per patient treated)

QALY, quality-adjusted life-year.

To the nearest hundred.

		Incremental costs of silver dressings compared with non-adhesive dressings (£)	Incremental QALYs of silver dressings compared with non-adhesive dressings	Cost per QALY of silver dressings compared with non-adhesive dressings (£)a
Exeter	Deterministic	39	0.0025	15,500
	Stochastic	41	0.0025	16,100
Sheffield	Deterministic	63	0.0041	15,300
	Stochastic	66	0.0041	16,200

FIGURE 14.

Cost-effectiveness acceptability curve for Exeter demographic (scenario 2). QALY, quality-adjusted life-year.

FIGURE 15.

Cost-effectiveness acceptability curve for Sheffield demographic (scenario 2). QALY, quality-adjusted life-year.

The results of the cost-effectiveness modelling showed that antimicrobial dressings in the baseline scenario, where only those variables that were predictive of ulcer healing were included, were not cost-effective. This was also the case in scenario 1, where the mean utility decrement of 0.00251 was used. However, scenario 2, which used the alternative method of calculating the mean utility decrement (i.e. 0.10576) and where dressing type was forced into the model, showed that antimicrobial dressings were potentially cost-effective.

Quality of life

This study demonstrated some of the difficulties in measuring QoL in patients with venous leg ulceration. While it is clear that patients put considerable value on obtaining healing of their ulcers, the conventional generic QoL measures appear to be quite insensitive to the effects of ulcer healing. 48,144 This may reflect the fact that in this elderly group with significant comorbidities the disutility largely depends upon the underlying condition rather than the presence of ulceration. The development of a disease-specific measure for QoL, particularly for patients with leg ulcers, might provide greater sensitivity to assess significant differences in outcome in this group of patients.

The study demonstrated a difference in utility, as measured by the EuroQol tariff, between the healed and unhealed patients at the end of 3 months of approximately 0.1. This is in keeping with values that have been found in previous studies using generic scales144 and similar values have been used in previous cost-effectiveness studies. 145 However, the comparisons of utility between healed and unhealed patients within such studies may reflect confounding due to the poorer healing among those with multiple comorbidities, rather than real differences due to the healing of the ulcer.

One way to try to eliminate this effect is to restrict analysis to paired data considering differences in the change in utility between those who do or do not heal. This results in a much smaller utility difference that does not reach statistical significance. It is likely that these calculations are an oversimplification because changes in QoL related to leg ulcer healing are not a sudden stepwise change at the point of healing, but are likely to be related to the ulcer symptoms and may improve gradually during the healing process.

The evidence from the generic HRQoL scores, particularly the SF-36, is inconclusive in that there was no strong evidence for particular dimensions that are affected by leg ulceration, that distinguished between those treated with antimicrobial or inert dressings or that correlated with the healing of leg ulcers. Previous evidence of QoL estimates in patients with leg ulceration has been of poor quality26 and the previous use of generic questionnaires suggests that they are not sensitive to the healing of leg ulcers. 48 One explanation may be because the utility associated with leg ulceration is relatively small compared with the other comorbidities that are experienced by this group of patients. However, it may also be that the questionnaires are insensitive to factors that determine QoL in patients with leg ulcers. Such factors may not be included in the items addressed by these health status measures, which have been developed largely on the basis of medical opinion rather than on patient preference studies. 146

With the clinical outcomes showing no evidence of significant benefit in either healing rate or QoL, and the cost analysis showing the incremental cost of nearly £100 associated with the use of antimicrobial dressings, the economic analysis alongside the clinical trial shows a low probability that the intervention is cost-effective. The analysis of the data collected clearly showed that, compared with non-adherent dressings, antimicrobial dressings resulted in a significant increase in costs and a non-significant change in QALYs.

Cost-effectiveness modelling

The modelling was carried out to allow a more detailed examination of the determinants of cost-effectiveness and the exploration of areas where there was significant uncertainty in the evidence that would benefit from further research. As with the economic analysis alongside the clinical trial, the base case of the modelling showed the antimicrobial dressings to be dominated by inert dressings, with there being no difference in clinical outcomes and a higher cost associated with the antimicrobial dressings.

In a sensitivity analysis, the dressing type was included in the model, even though it was not a statistically significant predictor of healing, and a small benefit in utility was assumed to occur at the point of healing, based upon the differences in changes of EQ-5D generated utilities. Although this resulted in a small average incremental benefit for the antimicrobial dressings, it was not sufficient to justify the additional cost and there remained a high probability that the treatment was not cost-effective.

It was only when further scenarios were examined which used maximum estimates of utility benefit from ulcer healing, based upon differences in utility that did not allow for the confounding effects of comorbidities, that some estimates of incremental cost-effectiveness were obtained that were within a generally accepted range of cost-effectiveness.

Conclusions

This analysis demonstrates some of the difficulties that arise in appraising technologies for the treatment of venous leg ulcers. The overall cost-effectiveness of a new technology that is aimed to improve the healing of leg ulcers depends upon four main drivers:

• the incremental cost of the new technology

• the incremental benefit in terms of earlier healing

• the improvement in utility associated with healing of the ulcer

• any differences in utility during the treatment period that are associated with the different treatments.

In this particular study there was no evidence of earlier healing or differences in utility between the groups in the treatment period. Both this study and earlier work57 have failed to demonstrate clear evidence of a utility benefit associated with ulcer healing. While this study and previous work144 have used generic measures to estimate a benefit of approximately 0.1 in utility for ulcer healing, there is considerable doubt about the validity of the scales used in assessing this utility and the methodology has not provided correction for possible confounding due to comorbidities. These issues may affect the estimate in opposite directions and further work is required to provide more valid estimates of the changing utility that can be used for future modelling.

If the alteration in utility were in the order of 0.1 and the net benefits of earlier healing in financial and health terms are added together, then even small alterations in time to healing may justify the cost of new treatments if the costs are a relatively small proportion of the overall cost of leg ulcer management. Under these circumstances a trial that was adequately powered to detect a difference in healing rate that might prove cost-effective would require a very large sample size that would be difficult to achieve. Before undertaking further large and expensive clinical studies in this area it would be beneficial to carry out utility studies to quantify the benefits of ulcer healing and guide the design and sample size estimation for such trials. Such work may require the development of new generic or disease-specific measures that have a better face validity in assessing the health impact of leg ulceration.

Antimicrobial dressings have been widely adopted without positive clinical evidence and our survey suggests that silver-donating antimicrobial dressings are currently used in approximately 40% of cases. If this reflects national practice, then the implication is that the NHS could be spending several million pounds on dressings each year with no evidence of clinical benefit.

While it is not possible to generalise the results of this particular study to all antimicrobial agents or other wound aetiologies, its findings are in tune with other evidence that shows no benefit from antimicrobials in the healing of ulcers. Two recent systematic literature reviews have failed to demonstrate any evidence to suggest that any particular class of antimicrobial agent has a significant benefit. 2,113 In addition, a recent major randomised study of another group of antimicrobial dressings, honey-impregnated dressings, has also shown no significant improvement in venous ulcer healing from the use of antimicrobial dressings. 109

In the light of all this evidence there is little to support the use of antimicrobial dressings in the treatment of venous leg ulcers. It would therefore seem logical to use the least expensive, inert dressings beneath compression therapy as standard care.

Implications for health care

1. Based on the results of this trial, there is no indication for the regular use of silver-donating dressings beneath compression in the treatment of venous ulcers: the evidence has shown no advantages over less expensive non-adherent dressings.

2. The trial supports the use of compression bandaging for the healing of venous ulcers, with application of non-adherent dressings (without any antimicrobial component) to the ulcerated areas.

3. Viewed in the light of trial data on other antimicrobial dressings, the results suggest that there is no indication for the regular use of antimicrobial dressings in general in promoting the healing of venous ulcers.

4. The finding of very widespread use of silver-donating dressings, shown by this trial not to be cost-effective, should stimulate the NHS to encourage and to facilitate recruitment of patients to large, well-designed studies of new technologies before they disseminate in an uncontrolled way.

5. This trial has demonstrated a number of the bureaucratic, organisational and cultural obstacles to research, which need to be addressed centrally for improved development of cost-effective services in the long term. In particular, effective mechanisms for engaging frontline clinical staff with the NHS research agenda are urgently required.

Recommendations for future research

1. The differences in healing rates between the two geographical areas of this study have implications for future research. They emphasise the need for very clear descriptions of epidemiology, treatment methods and the experience of staff engaged in compression bandaging; and they suggest an advantage to multicentre studies in different geographical areas, to produce results which can reasonably be generalised to the population as a whole.

2. It is recommended that research into new treatments for leg ulcers includes mathematical modelling to establish the potential value of further clinical trials, and to assist in appropriate trial design prior to undertaking large and expensive clinical trials.

3. This study has not addressed the problems of ulcers that fail to heal after 12 weeks of compression, or the problem of patients who are unable to tolerate compression. It is uncertain whether antimicrobial dressings might have any advantages in either of those situations. Uncertainty also remains about the diagnosis of ‘infection’ in leg ulcers which might be relevant to the use of antimicrobials. These are complex areas for research, but more information would be useful to guide clinical practice.

4. Further work is required in order to identify and validate QoL measures for use in the venous ulcer population. The development of a disease-specific QoL measure for venous ulcer patients that can be used in economic evaluation may be an area for future studies. The currently available generic measures seem insufficiently sensitive to the impact on QoL associated with venous ulceration.

5. The choice of dressing applied within the silver-donating and control groups showed geographical variation even though there are comprehensive national and local guidelines available. Further studies are needed on how clinicians make decisions regarding dressing type and, in particular, the influence of sales representatives as sources of evidence and guidance.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Health Technology Assessment reports published to date

1. Home parenteral nutrition: a systematic review.

   By Richards DM, Deeks JJ, Sheldon TA, Shaffer JL.

2. Diagnosis, management and screening of early localised prostate cancer.

   A review by Selley S, Donovan J, Faulkner A, Coast J, Gillatt D.

3. The diagnosis, management, treatment and costs of prostate cancer in England and Wales.

   A review by Chamberlain J, Melia J, Moss S, Brown J.

4. Screening for fragile X syndrome.

   A review by Murray J, Cuckle H, Taylor G, Hewison J.

5. A review of near patient testing in primary care.

   By Hobbs FDR, Delaney BC, Fitzmaurice DA, Wilson S, Hyde CJ, Thorpe GH, et al.

6. Systematic review of outpatient services for chronic pain control.

   By McQuay HJ, Moore RA, Eccleston C, Morley S, de C Williams AC.

7. Neonatal screening for inborn errors of metabolism: cost, yield and outcome.

   A review by Pollitt RJ, Green A, McCabe CJ, Booth A, Cooper NJ, Leonard JV, et al.

8. Preschool vision screening.

   A review by Snowdon SK, Stewart-Brown SL.

9. Implications of socio-cultural contexts for the ethics of clinical trials.

   A review by Ashcroft RE, Chadwick DW, Clark SRL, Edwards RHT, Frith L, Hutton JL.

10. A critical review of the role of neonatal hearing screening in the detection of congenital hearing impairment.

    By Davis A, Bamford J, Wilson I, Ramkalawan T, Forshaw M, Wright S.

11. Newborn screening for inborn errors of metabolism: a systematic review.

    By Seymour CA, Thomason MJ, Chalmers RA, Addison GM, Bain MD, Cockburn F, et al.

12. Routine preoperative testing: a systematic review of the evidence.

    By Munro J, Booth A, Nicholl J.

13. Systematic review of the effectiveness of laxatives in the elderly.

    By Petticrew M, Watt I, Sheldon T.

14. When and how to assess fast-changing technologies: a comparative study of medical applications of four generic technologies.

    A review by Mowatt G, Bower DJ, Brebner JA, Cairns JA, Grant AM, McKee L.

1. Antenatal screening for Down’s syndrome.

   A review by Wald NJ, Kennard A, Hackshaw A, McGuire A.

2. Screening for ovarian cancer: a systematic review.

   By Bell R, Petticrew M, Luengo S, Sheldon TA.

3. Consensus development methods, and their use in clinical guideline development.

   A review by Murphy MK, Black NA, Lamping DL, McKee CM, Sanderson CFB, Askham J, et al.

4. A cost–utility analysis of interferon beta for multiple sclerosis.

   By Parkin D, McNamee P, Jacoby A, Miller P, Thomas S, Bates D.

5. Effectiveness and efficiency of methods of dialysis therapy for end-stage renal disease: systematic reviews.

   By MacLeod A, Grant A, Donaldson C, Khan I, Campbell M, Daly C, et al.

6. Effectiveness of hip prostheses in primary total hip replacement: a critical review of evidence and an economic model.

   By Faulkner A, Kennedy LG, Baxter K, Donovan J, Wilkinson M, Bevan G.

7. Antimicrobial prophylaxis in colorectal surgery: a systematic review of randomised controlled trials.

   By Song F, Glenny AM.

8. Bone marrow and peripheral blood stem cell transplantation for malignancy.

   A review by Johnson PWM, Simnett SJ, Sweetenham JW, Morgan GJ, Stewart LA.

9. Screening for speech and language delay: a systematic review of the literature.

   By Law J, Boyle J, Harris F, Harkness A, Nye C.

10. Resource allocation for chronic stable angina: a systematic review of effectiveness, costs and cost-effectiveness of alternative interventions.

    By Sculpher MJ, Petticrew M, Kelland JL, Elliott RA, Holdright DR, Buxton MJ.

11. Detection, adherence and control of hypertension for the prevention of stroke: a systematic review.

    By Ebrahim S.

12. Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review.

    By McQuay HJ, Moore RA.

13. Choosing between randomised and nonrandomised studies: a systematic review.

    By Britton A, McKee M, Black N, McPherson K, Sanderson C, Bain C.

14. Evaluating patient-based outcome measures for use in clinical trials.

    A review by Fitzpatrick R, Davey C, Buxton MJ, Jones DR.

15. Ethical issues in the design and conduct of randomised controlled trials.

    A review by Edwards SJL, Lilford RJ, Braunholtz DA, Jackson JC, Hewison J, Thornton J.

16. Qualitative research methods in health technology assessment: a review of the literature.

    By Murphy E, Dingwall R, Greatbatch D, Parker S, Watson P.

17. The costs and benefits of paramedic skills in pre-hospital trauma care.

    By Nicholl J, Hughes S, Dixon S, Turner J, Yates D.

18. Systematic review of endoscopic ultrasound in gastro-oesophageal cancer.

    By Harris KM, Kelly S, Berry E, Hutton J, Roderick P, Cullingworth J, et al.

19. Systematic reviews of trials and other studies.

    By Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F.

20. Primary total hip replacement surgery: a systematic review of outcomes and modelling of cost-effectiveness associated with different prostheses.

    A review by Fitzpatrick R, Shortall E, Sculpher M, Murray D, Morris R, Lodge M, et al.

1. Informed decision making: an annotated bibliography and systematic review.

   By Bekker H, Thornton JG, Airey CM, Connelly JB, Hewison J, Robinson MB, et al.

2. Handling uncertainty when performing economic evaluation of healthcare interventions.

   A review by Briggs AH, Gray AM.

3. The role of expectancies in the placebo effect and their use in the delivery of health care: a systematic review.

   By Crow R, Gage H, Hampson S, Hart J, Kimber A, Thomas H.

4. A randomised controlled trial of different approaches to universal antenatal HIV testing: uptake and acceptability. Annex: Antenatal HIV testing – assessment of a routine voluntary approach.

   By Simpson WM, Johnstone FD, Boyd FM, Goldberg DJ, Hart GJ, Gormley SM, et al.

5. Methods for evaluating area-wide and organisation-based interventions in health and health care: a systematic review.

   By Ukoumunne OC, Gulliford MC, Chinn S, Sterne JAC, Burney PGJ.

6. Assessing the costs of healthcare technologies in clinical trials.

   A review by Johnston K, Buxton MJ, Jones DR, Fitzpatrick R.

7. Cooperatives and their primary care emergency centres: organisation and impact.

   By Hallam L, Henthorne K.

8. Screening for cystic fibrosis.

   A review by Murray J, Cuckle H, Taylor G, Littlewood J, Hewison J.

9. A review of the use of health status measures in economic evaluation.

   By Brazier J, Deverill M, Green C, Harper R, Booth A.

10. Methods for the analysis of quality-of-life and survival data in health technology assessment.

    A review by Billingham LJ, Abrams KR, Jones DR.

11. Antenatal and neonatal haemoglobinopathy screening in the UK: review and economic analysis.

    By Zeuner D, Ades AE, Karnon J, Brown J, Dezateux C, Anionwu EN.

12. Assessing the quality of reports of randomised trials: implications for the conduct of meta-analyses.

    A review by Moher D, Cook DJ, Jadad AR, Tugwell P, Moher M, Jones A, et al.

13. ‘Early warning systems’ for identifying new healthcare technologies.

    By Robert G, Stevens A, Gabbay J.

14. A systematic review of the role of human papillomavirus testing within a cervical screening programme.

    By Cuzick J, Sasieni P, Davies P, Adams J, Normand C, Frater A, et al.

15. Near patient testing in diabetes clinics: appraising the costs and outcomes.

    By Grieve R, Beech R, Vincent J, Mazurkiewicz J.

16. Positron emission tomography: establishing priorities for health technology assessment.

    A review by Robert G, Milne R.

17. The debridement of chronic wounds: a systematic review.

    By Bradley M, Cullum N, Sheldon T.

18. Systematic reviews of wound care management: (2) Dressings and topical agents used in the healing of chronic wounds.

    By Bradley M, Cullum N, Nelson EA, Petticrew M, Sheldon T, Torgerson D.

19. A systematic literature review of spiral and electron beam computed tomography: with particular reference to clinical applications in hepatic lesions, pulmonary embolus and coronary artery disease.

    By Berry E, Kelly S, Hutton J, Harris KM, Roderick P, Boyce JC, et al.

20. What role for statins? A review and economic model.

    By Ebrahim S, Davey Smith G, McCabe C, Payne N, Pickin M, Sheldon TA, et al.

21. Factors that limit the quality, number and progress of randomised controlled trials.

    A review by Prescott RJ, Counsell CE, Gillespie WJ, Grant AM, Russell IT, Kiauka S, et al.

22. Antimicrobial prophylaxis in total hip replacement: a systematic review.

    By Glenny AM, Song F.

23. Health promoting schools and health promotion in schools: two systematic reviews.

    By Lister-Sharp D, Chapman S, Stewart-Brown S, Sowden A.

24. Economic evaluation of a primary care-based education programme for patients with osteoarthritis of the knee.

    A review by Lord J, Victor C, Littlejohns P, Ross FM, Axford JS.

1. The estimation of marginal time preference in a UK-wide sample (TEMPUS) project.

   A review by Cairns JA, van der Pol MM.

2. Geriatric rehabilitation following fractures in older people: a systematic review.

   By Cameron I, Crotty M, Currie C, Finnegan T, Gillespie L, Gillespie W, et al.

3. Screening for sickle cell disease and thalassaemia: a systematic review with supplementary research.

   By Davies SC, Cronin E, Gill M, Greengross P, Hickman M, Normand C.

4. Community provision of hearing aids and related audiology services.

   A review by Reeves DJ, Alborz A, Hickson FS, Bamford JM.

5. False-negative results in screening programmes: systematic review of impact and implications.

   By Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K.

6. Costs and benefits of community postnatal support workers: a randomised controlled trial.

   By Morrell CJ, Spiby H, Stewart P, Walters S, Morgan A.

7. Implantable contraceptives (subdermal implants and hormonally impregnated intrauterine systems) versus other forms of reversible contraceptives: two systematic reviews to assess relative effectiveness, acceptability, tolerability and cost-effectiveness.

   By French RS, Cowan FM, Mansour DJA, Morris S, Procter T, Hughes D, et al.

8. An introduction to statistical methods for health technology assessment.

   A review by White SJ, Ashby D, Brown PJ.

9. Disease-modifying drugs for multiple sclerosis: a rapid and systematic review.

   By Clegg A, Bryant J, Milne R.

10. Publication and related biases.

    A review by Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ.

11. Cost and outcome implications of the organisation of vascular services.

    By Michaels J, Brazier J, Palfreyman S, Shackley P, Slack R.

12. Monitoring blood glucose control in diabetes mellitus: a systematic review.

    By Coster S, Gulliford MC, Seed PT, Powrie JK, Swaminathan R.

13. The effectiveness of domiciliary health visiting: a systematic review of international studies and a selective review of the British literature.

    By Elkan R, Kendrick D, Hewitt M, Robinson JJA, Tolley K, Blair M, et al.

14. The determinants of screening uptake and interventions for increasing uptake: a systematic review.

    By Jepson R, Clegg A, Forbes C, Lewis R, Sowden A, Kleijnen J.

15. The effectiveness and cost-effectiveness of prophylactic removal of wisdom teeth.

    A rapid review by Song F, O’Meara S, Wilson P, Golder S, Kleijnen J.

16. Ultrasound screening in pregnancy: a systematic review of the clinical effectiveness, cost-effectiveness and women’s views.

    By Bricker L, Garcia J, Henderson J, Mugford M, Neilson J, Roberts T, et al.

17. A rapid and systematic review of the effectiveness and cost-effectiveness of the taxanes used in the treatment of advanced breast and ovarian cancer.

    By Lister-Sharp D, McDonagh MS, Khan KS, Kleijnen J.

18. Liquid-based cytology in cervical screening: a rapid and systematic review.

    By Payne N, Chilcott J, McGoogan E.

19. Randomised controlled trial of non-directive counselling, cognitive–behaviour therapy and usual general practitioner care in the management of depression as well as mixed anxiety and depression in primary care.

    By King M, Sibbald B, Ward E, Bower P, Lloyd M, Gabbay M, et al.

20. Routine referral for radiography of patients presenting with low back pain: is patients’ outcome influenced by GPs’ referral for plain radiography?

    By Kerry S, Hilton S, Patel S, Dundas D, Rink E, Lord J.

21. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration.

    By O’Meara S, Cullum N, Majid M, Sheldon T.

22. Using routine data to complement and enhance the results of randomised controlled trials.

    By Lewsey JD, Leyland AH, Murray GD, Boddy FA.

23. Coronary artery stents in the treatment of ischaemic heart disease: a rapid and systematic review.

    By Meads C, Cummins C, Jolly K, Stevens A, Burls A, Hyde C.

24. Outcome measures for adult critical care: a systematic review.

    By Hayes JA, Black NA, Jenkinson C, Young JD, Rowan KM, Daly K, et al.

25. A systematic review to evaluate the effectiveness of interventions to promote the initiation of breastfeeding.

    By Fairbank L, O’Meara S, Renfrew MJ, Woolridge M, Sowden AJ, Lister-Sharp D.

26. Implantable cardioverter defibrillators: arrhythmias. A rapid and systematic review.

    By Parkes J, Bryant J, Milne R.

27. Treatments for fatigue in multiple sclerosis: a rapid and systematic review.

    By Brañas P, Jordan R, Fry-Smith A, Burls A, Hyde C.

28. Early asthma prophylaxis, natural history, skeletal development and economy (EASE): a pilot randomised controlled trial.

    By Baxter-Jones ADG, Helms PJ, Russell G, Grant A, Ross S, Cairns JA, et al.

29. Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis.

    By Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HAW.

30. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists in the medical management of unstable angina.

    By McDonagh MS, Bachmann LM, Golder S, Kleijnen J, ter Riet G.

31. A randomised controlled trial of prehospital intravenous fluid replacement therapy in serious trauma.

    By Turner J, Nicholl J, Webber L, Cox H, Dixon S, Yates D.

32. Intrathecal pumps for giving opioids in chronic pain: a systematic review.

    By Williams JE, Louw G, Towlerton G.

33. Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review.

    By Shepherd J, Waugh N, Hewitson P.

34. A systematic review of comparisons of effect sizes derived from randomised and non-randomised studies.

    By MacLehose RR, Reeves BC, Harvey IM, Sheldon TA, Russell IT, Black AMS.

35. Intravascular ultrasound-guided interventions in coronary artery disease: a systematic literature review, with decision-analytic modelling, of outcomes and cost-effectiveness.

    By Berry E, Kelly S, Hutton J, Lindsay HSJ, Blaxill JM, Evans JA, et al.

36. A randomised controlled trial to evaluate the effectiveness and cost-effectiveness of counselling patients with chronic depression.

    By Simpson S, Corney R, Fitzgerald P, Beecham J.

37. Systematic review of treatments for atopic eczema.

    By Hoare C, Li Wan Po A, Williams H.

38. Bayesian methods in health technology assessment: a review.

    By Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR.

39. The management of dyspepsia: a systematic review.

    By Delaney B, Moayyedi P, Deeks J, Innes M, Soo S, Barton P, et al.

40. A systematic review of treatments for severe psoriasis.

    By Griffiths CEM, Clark CM, Chalmers RJG, Li Wan Po A, Williams HC.

1. Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer’s disease: a rapid and systematic review.

   By Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K, et al.

2. The clinical effectiveness and cost-effectiveness of riluzole for motor neurone disease: a rapid and systematic review.

   By Stewart A, Sandercock J, Bryan S, Hyde C, Barton PM, Fry-Smith A, et al.

3. Equity and the economic evaluation of healthcare.

   By Sassi F, Archard L, Le Grand J.

4. Quality-of-life measures in chronic diseases of childhood.

   By Eiser C, Morse R.

5. Eliciting public preferences for healthcare: a systematic review of techniques.

   By Ryan M, Scott DA, Reeves C, Bate A, van Teijlingen ER, Russell EM, et al.

6. General health status measures for people with cognitive impairment: learning disability and acquired brain injury.

   By Riemsma RP, Forbes CA, Glanville JM, Eastwood AJ, Kleijnen J.

7. An assessment of screening strategies for fragile X syndrome in the UK.

   By Pembrey ME, Barnicoat AJ, Carmichael B, Bobrow M, Turner G.

8. Issues in methodological research: perspectives from researchers and commissioners.

   By Lilford RJ, Richardson A, Stevens A, Fitzpatrick R, Edwards S, Rock F, et al.

9. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy.

   By Cullum N, Nelson EA, Flemming K, Sheldon T.

10. Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review.

    By Hampson SE, Skinner TC, Hart J, Storey L, Gage H, Foxcroft D, et al.

11. Effectiveness of autologous chondrocyte transplantation for hyaline cartilage defects in knees: a rapid and systematic review.

    By Jobanputra P, Parry D, Fry-Smith A, Burls A.

12. Statistical assessment of the learning curves of health technologies.

    By Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF, Russell IT.

13. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma: a rapid and systematic review.

    By Dinnes J, Cave C, Huang S, Major K, Milne R.

14. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of debriding agents in treating surgical wounds healing by secondary intention.

    By Lewis R, Whiting P, ter Riet G, O’Meara S, Glanville J.

15. Home treatment for mental health problems: a systematic review.

    By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

16. How to develop cost-conscious guidelines.

    By Eccles M, Mason J.

17. The role of specialist nurses in multiple sclerosis: a rapid and systematic review.

    By De Broe S, Christopher F, Waugh N.

18. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity.

    By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

19. The clinical effectiveness and cost-effectiveness of pioglitazone for type 2 diabetes mellitus: a rapid and systematic review.

    By Chilcott J, Wight J, Lloyd Jones M, Tappenden P.

20. Extended scope of nursing practice: a multicentre randomised controlled trial of appropriately trained nurses and preregistration house officers in preoperative assessment in elective general surgery.

    By Kinley H, Czoski-Murray C, George S, McCabe C, Primrose J, Reilly C, et al.

21. Systematic reviews of the effectiveness of day care for people with severe mental disorders: (1) Acute day hospital versus admission; (2) Vocational rehabilitation; (3) Day hospital versus outpatient care.

    By Marshall M, Crowther R, Almaraz- Serrano A, Creed F, Sledge W, Kluiter H, et al.

22. The measurement and monitoring of surgical adverse events.

    By Bruce J, Russell EM, Mollison J, Krukowski ZH.

23. Action research: a systematic review and guidance for assessment.

    By Waterman H, Tillen D, Dickson R, de Koning K.

24. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of gemcitabine for the treatment of pancreatic cancer.

    By Ward S, Morris E, Bansback N, Calvert N, Crellin A, Forman D, et al.

25. A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.

    By Lloyd Jones M, Hummel S, Bansback N, Orr B, Seymour M.

26. Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature.

    By Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, et al.

27. The cost-effectiveness of magnetic resonance imaging for investigation of the knee joint.

    By Bryan S, Weatherburn G, Bungay H, Hatrick C, Salas C, Parry D, et al.

28. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of topotecan for ovarian cancer.

    By Forbes C, Shirran L, Bagnall A-M, Duffy S, ter Riet G.

29. Superseded by a report published in a later volume.

30. The role of radiography in primary care patients with low back pain of at least 6 weeks duration: a randomised (unblinded) controlled trial.

    By Kendrick D, Fielding K, Bentley E, Miller P, Kerslake R, Pringle M.

31. Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients.

    By McColl E, Jacoby A, Thomas L, Soutter J, Bamford C, Steen N, et al.

32. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.

    By Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N.

33. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.

    By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G.

34. Depot antipsychotic medication in the treatment of patients with schizophrenia: (1) Meta-review; (2) Patient and nurse attitudes.

    By David AS, Adams C.

35. A systematic review of controlled trials of the effectiveness and cost-effectiveness of brief psychological treatments for depression.

    By Churchill R, Hunot V, Corney R, Knapp M, McGuire H, Tylee A, et al.

36. Cost analysis of child health surveillance.

    By Sanderson D, Wright D, Acton C, Duree D.

1. A study of the methods used to select review criteria for clinical audit.

   By Hearnshaw H, Harker R, Cheater F, Baker R, Grimshaw G.

2. Fludarabine as second-line therapy for B cell chronic lymphocytic leukaemia: a technology assessment.

   By Hyde C, Wake B, Bryan S, Barton P, Fry-Smith A, Davenport C, et al.

3. Rituximab as third-line treatment for refractory or recurrent Stage III or IV follicular non-Hodgkin’s lymphoma: a systematic review and economic evaluation.

   By Wake B, Hyde C, Bryan S, Barton P, Song F, Fry-Smith A, et al.

4. A systematic review of discharge arrangements for older people.

   By Parker SG, Peet SM, McPherson A, Cannaby AM, Baker R, Wilson A, et al.

5. The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: a systematic review and economic evaluation.

   By Peters J, Stevenson M, Beverley C, Lim J, Smith S.

6. The clinical effectiveness and cost-effectiveness of sibutramine in the management of obesity: a technology assessment.

   By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

7. The cost-effectiveness of magnetic resonance angiography for carotid artery stenosis and peripheral vascular disease: a systematic review.

   By Berry E, Kelly S, Westwood ME, Davies LM, Gough MJ, Bamford JM, et al.

8. Promoting physical activity in South Asian Muslim women through ‘exercise on prescription’.

   By Carroll B, Ali N, Azam N.

9. Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation.

   By Burls A, Clark W, Stewart T, Preston C, Bryan S, Jefferson T, et al.

10. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models.

    By Richards RG, Sampson FC, Beard SM, Tappenden P.

11. Screening for gestational diabetes: a systematic review and economic evaluation.

    By Scott DA, Loveman E, McIntyre L, Waugh N.

12. The clinical effectiveness and cost-effectiveness of surgery for people with morbid obesity: a systematic review and economic evaluation.

    By Clegg AJ, Colquitt J, Sidhu MK, Royle P, Loveman E, Walker A.

13. The clinical effectiveness of trastuzumab for breast cancer: a systematic review.

    By Lewis R, Bagnall A-M, Forbes C, Shirran E, Duffy S, Kleijnen J, et al.

14. The clinical effectiveness and cost-effectiveness of vinorelbine for breast cancer: a systematic review and economic evaluation.

    By Lewis R, Bagnall A-M, King S, Woolacott N, Forbes C, Shirran L, et al.

15. A systematic review of the effectiveness and cost-effectiveness of metal-on-metal hip resurfacing arthroplasty for treatment of hip disease.

    By Vale L, Wyness L, McCormack K, McKenzie L, Brazzelli M, Stearns SC.

16. The clinical effectiveness and cost-effectiveness of bupropion and nicotine replacement therapy for smoking cessation: a systematic review and economic evaluation.

    By Woolacott NF, Jones L, Forbes CA, Mather LC, Sowden AJ, Song FJ, et al.

17. A systematic review of effectiveness and economic evaluation of new drug treatments for juvenile idiopathic arthritis: etanercept.

    By Cummins C, Connock M, Fry-Smith A, Burls A.

18. Clinical effectiveness and cost-effectiveness of growth hormone in children: a systematic review and economic evaluation.

    By Bryant J, Cave C, Mihaylova B, Chase D, McIntyre L, Gerard K, et al.

19. Clinical effectiveness and cost-effectiveness of growth hormone in adults in relation to impact on quality of life: a systematic review and economic evaluation.

    By Bryant J, Loveman E, Chase D, Mihaylova B, Cave C, Gerard K, et al.

20. Clinical medication review by a pharmacist of patients on repeat prescriptions in general practice: a randomised controlled trial.

    By Zermansky AG, Petty DR, Raynor DK, Lowe CJ, Freementle N, Vail A.

21. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation.

    By Jobanputra P, Barton P, Bryan S, Burls A.

22. A systematic review and economic evaluation of computerised cognitive behaviour therapy for depression and anxiety.

    By Kaltenthaler E, Shackley P, Stevens K, Beverley C, Parry G, Chilcott J.

23. A systematic review and economic evaluation of pegylated liposomal doxorubicin hydrochloride for ovarian cancer.

    By Forbes C, Wilby J, Richardson G, Sculpher M, Mather L, Reimsma R.

24. A systematic review of the effectiveness of interventions based on a stages-of-change approach to promote individual behaviour change.

    By Riemsma RP, Pattenden J, Bridle C, Sowden AJ, Mather L, Watt IS, et al.

25. A systematic review update of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists.

    By Robinson M, Ginnelly L, Sculpher M, Jones L, Riemsma R, Palmer S, et al.

26. A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS.

    By Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan J, et al.

27. A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in a bronchiectasis clinic.

    By Caine N, Sharples LD, Hollingworth W, French J, Keogan M, Exley A, et al.

28. Clinical effectiveness and cost – consequences of selective serotonin reuptake inhibitors in the treatment of sex offenders.

    By Adi Y, Ashcroft D, Browne K, Beech A, Fry-Smith A, Hyde C.

29. Treatment of established osteoporosis: a systematic review and cost–utility analysis.

    By Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd Jones M.

30. Which anaesthetic agents are cost-effective in day surgery? Literature review, national survey of practice and randomised controlled trial.

    By Elliott RA Payne K, Moore JK, Davies LM, Harper NJN, St Leger AS, et al.

31. Screening for hepatitis C among injecting drug users and in genitourinary medicine clinics: systematic reviews of effectiveness, modelling study and national survey of current practice.

    By Stein K, Dalziel K, Walker A, McIntyre L, Jenkins B, Horne J, et al.

32. The measurement of satisfaction with healthcare: implications for practice from a systematic review of the literature.

    By Crow R, Gage H, Hampson S, Hart J, Kimber A, Storey L, et al.

33. The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review.

    By Garside R, Round A, Dalziel K, Stein K, Royle R.

34. A comparative study of hypertonic saline, daily and alternate-day rhDNase in children with cystic fibrosis.

    By Suri R, Wallis C, Bush A, Thompson S, Normand C, Flather M, et al.

35. A systematic review of the costs and effectiveness of different models of paediatric home care.

    By Parker G, Bhakta P, Lovett CA, Paisley S, Olsen R, Turner D, et al.

1. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study.

   By Egger M, Jüni P, Bartlett C, Holenstein F, Sterne J.

2. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of home versus hospital or satellite unit haemodialysis for people with end-stage renal failure.

   By Mowatt G, Vale L, Perez J, Wyness L, Fraser C, MacLeod A, et al.

3. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn’s disease.

   By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

4. A review of the clinical effectiveness and cost-effectiveness of routine anti-D prophylaxis for pregnant women who are rhesus negative.

   By Chilcott J, Lloyd Jones M, Wight J, Forman K, Wray J, Beverley C, et al.

5. Systematic review and evaluation of the use of tumour markers in paediatric oncology: Ewing’s sarcoma and neuroblastoma.

   By Riley RD, Burchill SA, Abrams KR, Heney D, Lambert PC, Jones DR, et al.

6. The cost-effectiveness of screening for Helicobacter pylori to reduce mortality and morbidity from gastric cancer and peptic ulcer disease: a discrete-event simulation model.

   By Roderick P, Davies R, Raftery J, Crabbe D, Pearce R, Bhandari P, et al.

7. The clinical effectiveness and cost-effectiveness of routine dental checks: a systematic review and economic evaluation.

   By Davenport C, Elley K, Salas C, Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

8. A multicentre randomised controlled trial assessing the costs and benefits of using structured information and analysis of women’s preferences in the management of menorrhagia.

   By Kennedy ADM, Sculpher MJ, Coulter A, Dwyer N, Rees M, Horsley S, et al.

9. Clinical effectiveness and cost–utility of photodynamic therapy for wet age-related macular degeneration: a systematic review and economic evaluation.

   By Meads C, Salas C, Roberts T, Moore D, Fry-Smith A, Hyde C.

10. Evaluation of molecular tests for prenatal diagnosis of chromosome abnormalities.

    By Grimshaw GM, Szczepura A, Hultén M, MacDonald F, Nevin NC, Sutton F, et al.

11. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).

    By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM.

12. The effectiveness and cost-effectiveness of ultrasound locating devices for central venous access: a systematic review and economic evaluation.

    By Calvert N, Hind D, McWilliams RG, Thomas SM, Beverley C, Davidson A.

13. A systematic review of atypical antipsychotics in schizophrenia.

    By Bagnall A-M, Jones L, Lewis R, Ginnelly L, Glanville J, Torgerson D, et al.

14. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study.

    By Donovan J, Hamdy F, Neal D, Peters T, Oliver S, Brindle L, et al.

15. Early thrombolysis for the treatment of acute myocardial infarction: a systematic review and economic evaluation.

    By Boland A, Dundar Y, Bagust A, Haycox A, Hill R, Mujica Mota R, et al.

16. Screening for fragile X syndrome: a literature review and modelling.

    By Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A.

17. Systematic review of endoscopic sinus surgery for nasal polyps.

    By Dalziel K, Stein K, Round A, Garside R, Royle P.

18. Towards efficient guidelines: how to monitor guideline use in primary care.

    By Hutchinson A, McIntosh A, Cox S, Gilbert C.

19. Effectiveness and cost-effectiveness of acute hospital-based spinal cord injuries services: systematic review.

    By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

20. Prioritisation of health technology assessment. The PATHS model: methods and case studies.

    By Townsend J, Buxton M, Harper G.

21. Systematic review of the clinical effectiveness and cost-effectiveness of tension-free vaginal tape for treatment of urinary stress incontinence.

    By Cody J, Wyness L, Wallace S, Glazener C, Kilonzo M, Stearns S, et al.

22. The clinical and cost-effectiveness of patient education models for diabetes: a systematic review and economic evaluation.

    By Loveman E, Cave C, Green C, Royle P, Dunn N, Waugh N.

23. The role of modelling in prioritising and planning clinical trials.

    By Chilcott J, Brennan A, Booth A, Karnon J, Tappenden P.

24. Cost–benefit evaluation of routine influenza immunisation in people 65–74 years of age.

    By Allsup S, Gosney M, Haycox A, Regan M.

25. The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors.

    By Wight J, Chilcott J, Holmes M, Brewer N.

26. Can randomised trials rely on existing electronic data? A feasibility study to explore the value of routine data in health technology assessment.

    By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

27. Evaluating non-randomised intervention studies.

    By Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al.

28. A randomised controlled trial to assess the impact of a package comprising a patient-orientated, evidence-based self- help guidebook and patient-centred consultations on disease management and satisfaction in inflammatory bowel disease.

    By Kennedy A, Nelson E, Reeves D, Richardson G, Roberts C, Robinson A, et al.

29. The effectiveness of diagnostic tests for the assessment of shoulder pain due to soft tissue disorders: a systematic review.

    By Dinnes J, Loveman E, McIntyre L, Waugh N.

30. The value of digital imaging in diabetic retinopathy.

    By Sharp PF, Olson J, Strachan F, Hipwell J, Ludbrook A, O’Donnell M, et al.

31. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy.

    By Law M, Wald N, Morris J.

32. Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

    By Ward S, Kaltenthaler E, Cowan J, Brewer N.

33. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: a systematic review.

    By Hummel S, Paisley S, Morgan A, Currie E, Brewer N.

34. Literature searching for clinical and cost-effectiveness studies used in health technology assessment reports carried out for the National Institute for Clinical Excellence appraisal system.

    By Royle P, Waugh N.

35. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B.

    By Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K.

36. A randomised controlled trial to evaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients by nurses.

    By Boland A, Haycox A, Bagust A, Fitzsimmons L.

37. Redesigning postnatal care: a randomised controlled trial of protocol-based midwifery-led care focused on individual women’s physical and psychological health needs.

    By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ, Knowles H, et al.

38. Estimating implied rates of discount in healthcare decision-making.

    By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.

39. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: a review of the literature with epidemiological and economic modelling.

    By Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Medley GF, et al.

40. Treatments for spasticity and pain in multiple sclerosis: a systematic review.

    By Beard S, Hunn A, Wight J.

41. The inclusion of reports of randomised trials published in languages other than English in systematic reviews.

    By Moher D, Pham B, Lawson ML, Klassen TP.

42. The impact of screening on future health-promoting behaviours and health beliefs: a systematic review.

    By Bankhead CR, Brett J, Bukach C, Webster P, Stewart-Brown S, Munafo M, et al.

1. What is the best imaging strategy for acute stroke?

   By Wardlaw JM, Keir SL, Seymour J, Lewis S, Sandercock PAG, Dennis MS, et al.

2. Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care.

   By Mant J, McManus RJ, Oakes RAL, Delaney BC, Barton PM, Deeks JJ, et al.

3. The effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation for heavy menstrual bleeding: a systematic review and economic modelling.

   By Garside R, Stein K, Wyatt K, Round A, Price A.

4. A systematic review of the role of bisphosphonates in metastatic disease.

   By Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al.

5. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda^®) for locally advanced and/or metastatic breast cancer.

   By Jones L, Hawkins N, Westwood M, Wright K, Richardson G, Riemsma R.

6. Effectiveness and efficiency of guideline dissemination and implementation strategies.

   By Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CR, Vale L, et al.

7. Clinical effectiveness and costs of the Sugarbaker procedure for the treatment of pseudomyxoma peritonei.

   By Bryant J, Clegg AJ, Sidhu MK, Brodin H, Royle P, Davidson P.

8. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use.

   By Morgan K, Dixon S, Mathers N, Thompson J, Tomeny M.

9. Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome.

   By Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ.

10. A systematic review and economic evaluation of magnetic resonance cholangiopancreatography compared with diagnostic endoscopic retrograde cholangiopancreatography.

    By Kaltenthaler E, Bravo Vergel Y, Chilcott J, Thomas S, Blakeborough T, Walters SJ, et al.

11. The use of modelling to evaluate new drugs for patients with a chronic condition: the case of antibodies against tumour necrosis factor in rheumatoid arthritis.

    By Barton P, Jobanputra P, Wilson J, Bryan S, Burls A.

12. Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review.

    By Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S.

13. Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

    By Czoski-Murray C, Warren E, Chilcott J, Beverley C, Psyllaki MA, Cowan J.

14. Routine examination of the newborn: the EMREN study. Evaluation of an extension of the midwife role including a randomised controlled trial of appropriately trained midwives and paediatric senior house officers.

    By Townsend J, Wolke D, Hayes J, Davé S, Rogers C, Bloomfield L, et al.

15. Involving consumers in research and development agenda setting for the NHS: developing an evidence-based approach.

    By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

16. A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

    By Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al.

17. Does early magnetic resonance imaging influence management or improve outcome in patients referred to secondary care with low back pain? A pragmatic randomised controlled trial.

    By Gilbert FJ, Grant AM, Gillan MGC, Vale L, Scott NW, Campbell MK, et al.

18. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis.

    By Clark W, Jobanputra P, Barton P, Burls A.

19. A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

    By Bridle C, Palmer S, Bagnall A-M, Darba J, Duffy S, Sculpher M, et al.

20. Liquid-based cytology in cervical screening: an updated rapid and systematic review and economic analysis.

    By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

21. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.

    By Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, et al.

22. Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

    By Dretzke J, Cummins C, Sandercock J, Fry-Smith A, Barrett T, Burls A.

23. Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids in trauma patients.

    By Dretzke J, Sandercock J, Bayliss S, Burls A.

24. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.

    By Dündar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, et al.

25. Development and validation of methods for assessing the quality of diagnostic accuracy studies.

    By Whiting P, Rutjes AWS, Dinnes J, Reitsma JB, Bossuyt PMM, Kleijnen J.

26. EVALUATE hysterectomy trial: a multicentre randomised trial comparing abdominal, vaginal and laparoscopic methods of hysterectomy.

    By Garry R, Fountain J, Brown J, Manca A, Mason S, Sculpher M, et al.

27. Methods for expected value of information analysis in complex health economic models: developments on the health economics of interferon-β and glatiramer acetate for multiple sclerosis.

    By Tappenden P, Chilcott JB, Eggington S, Oakley J, McCabe C.

28. Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis.

    By Dalziel K, Round A, Stein K, Garside R, Price A.

29. VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.

    By Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, on behalf of the VenUS Team.

30. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.

    By Mowatt G, Vale L, Brazzelli M, Hernandez R, Murray A, Scott N, et al.

31. A pilot study on the use of decision theory and value of information analysis as part of the NHS Health Technology Assessment programme.

    By Claxton K, Ginnelly L, Sculpher M, Philips Z, Palmer S.

32. The Social Support and Family Health Study: a randomised controlled trial and economic evaluation of two alternative forms of postnatal support for mothers living in disadvantaged inner-city areas.

    By Wiggins M, Oakley A, Roberts I, Turner H, Rajan L, Austerberry H, et al.

33. Psychosocial aspects of genetic screening of pregnant women and newborns: a systematic review.

    By Green JM, Hewison J, Bekker HL, Bryant, Cuckle HS.

34. Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

    By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

35. Coronary artery stents: a rapid systematic review and economic evaluation.

    By Hill R, Bagust A, Bakhai A, Dickson R, Dündar Y, Haycox A, et al.

36. Review of guidelines for good practice in decision-analytic modelling in health technology assessment.

    By Philips Z, Ginnelly L, Sculpher M, Claxton K, Golder S, Riemsma R, et al.

37. Rituximab (MabThera^®) for aggressive non-Hodgkin’s lymphoma: systematic review and economic evaluation.

    By Knight C, Hind D, Brewer N, Abbott V.

38. Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.

    By Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, et al.

39. Pegylated interferon α-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J.

40. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment- elevation acute coronary syndromes: a systematic review and economic evaluation.

    By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

41. Provision, uptake and cost of cardiac rehabilitation programmes: improving services to under-represented groups.

    By Beswick AD, Rees K, Griebsch I, Taylor FC, Burke M, West RR, et al.

42. Involving South Asian patients in clinical trials.

    By Hussain-Gambles M, Leese B, Atkin K, Brown J, Mason S, Tovey P.

43. Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.

    By Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N.

44. Identification and assessment of ongoing trials in health technology assessment reviews.

    By Song FJ, Fry-Smith A, Davenport C, Bayliss S, Adi Y, Wilson JS, et al.

45. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine

    By Warren E, Weatherley-Jones E, Chilcott J, Beverley C.

46. Supplementation of a home-based exercise programme with a class-based programme for people with osteoarthritis of the knees: a randomised controlled trial and health economic analysis.

    By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N, Roberts CR, et al.

47. Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation.

    By Green C, Colquitt JL, Kirby J, Davidson P, Payne E.

48. Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis.

    By Vickers AJ, Rees RW, Zollman CE, McCarney R, Smith CM, Ellis N, et al.

49. Generalisability in economic evaluation studies in healthcare: a review and case studies.

    By Sculpher MJ, Pang FS, Manca A, Drummond MF, Golder S, Urdahl H, et al.

50. Virtual outreach: a randomised controlled trial and economic evaluation of joint teleconferenced medical consultations.

    By Wallace P, Barber J, Clayton W, Currell R, Fleming K, Garner P, et al.

1. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne.

   By Ozolins M, Eady EA, Avery A, Cunliffe WJ, O’Neill C, Simpson NB, et al.

2. Do the findings of case series studies vary significantly according to methodological characteristics?

   By Dalziel K, Round A, Stein K, Garside R, Castelnuovo E, Payne L.

3. Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

   By Wilson BJ, Torrance N, Mollison J, Wordsworth S, Gray JR, Haites NE, et al.

4. Randomised evaluation of alternative electrosurgical modalities to treat bladder outflow obstruction in men with benign prostatic hyperplasia.

   By Fowler C, McAllister W, Plail R, Karim O, Yang Q.

5. A pragmatic randomised controlled trial of the cost-effectiveness of palliative therapies for patients with inoperable oesophageal cancer.

   By Shenfine J, McNamee P, Steen N, Bond J, Griffin SM.

6. Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography.

   By Taylor P, Champness J, Given- Wilson R, Johnston K, Potts H.

7. Issues in data monitoring and interim analysis of trials.

   By Grant AM, Altman DG, Babiker AB, Campbell MK, Clemens FJ, Darbyshire JH, et al.

8. Lay public’s understanding of equipoise and randomisation in randomised controlled trials.

   By Robinson EJ, Kerr CEP, Stevens AJ, Lilford RJ, Braunholtz DA, Edwards SJ, et al.

9. Clinical and cost-effectiveness of electroconvulsive therapy for depressive illness, schizophrenia, catatonia and mania: systematic reviews and economic modelling studies.

   By Greenhalgh J, Knight C, Hind D, Beverley C, Walters S.

10. Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology.

    By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

11. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris^®) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

    By Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, et al.

12. A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy.

    By Dinnes J, Deeks J, Kirby J, Roderick P.

13. Cervical screening programmes: can automation help? Evidence from systematic reviews, an economic analysis and a simulation modelling exercise applied to the UK.

    By Willis BH, Barton P, Pearmain P, Bryan S, Hyde C.

14. Laparoscopic surgery for inguinal hernia repair: systematic review of effectiveness and economic evaluation.

    By McCormack K, Wake B, Perez J, Fraser C, Cook J, McIntosh E, et al.

15. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation.

    By Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al.

16. A randomised controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine.

    By Peveler R, Kendrick T, Buxton M, Longworth L, Baldwin D, Moore M, et al.

17. Clinical effectiveness and cost-effectiveness of immediate angioplasty for acute myocardial infarction: systematic review and economic evaluation.

    By Hartwell D, Colquitt J, Loveman E, Clegg AJ, Brodin H, Waugh N, et al.

18. A randomised controlled comparison of alternative strategies in stroke care.

    By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

19. The investigation and analysis of critical incidents and adverse events in healthcare.

    By Woloshynowych M, Rogers S, Taylor-Adams S, Vincent C.

20. Potential use of routine databases in health technology assessment.

    By Raftery J, Roderick P, Stevens A.

21. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study.

    By Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al.

22. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis.

    By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

23. A systematic review to examine the impact of psycho-educational interventions on health outcomes and costs in adults and children with difficult asthma.

    By Smith JR, Mugford M, Holland R, Candy B, Noble MJ, Harrison BDW, et al.

24. An evaluation of the costs, effectiveness and quality of renal replacement therapy provision in renal satellite units in England and Wales.

    By Roderick P, Nicholson T, Armitage A, Mehta R, Mullee M, Gerard K, et al.

25. Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation.

    By Wilson J, Connock M, Song F, Yao G, Fry-Smith A, Raftery J, et al.

26. Indirect comparisons of competing interventions.

    By Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R, et al.

27. Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.

    By Robinson M, Palmer S, Sculpher M, Philips Z, Ginnelly L, Bowens A, et al.

28. Outcomes of electrically stimulated gracilis neosphincter surgery.

    By Tillin T, Chambers M, Feldman R.

29. The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

    By Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, et al.

30. Systematic review on urine albumin testing for early detection of diabetic complications.

    By Newman DJ, Mattock MB, Dawnay ABS, Kerry S, McGuire A, Yaqoob M, et al.

31. Randomised controlled trial of the cost-effectiveness of water-based therapy for lower limb osteoarthritis.

    By Cochrane T, Davey RC, Matthes Edwards SM.

32. Longer term clinical and economic benefits of offering acupuncture care to patients with chronic low back pain.

    By Thomas KJ, MacPherson H, Ratcliffe J, Thorpe L, Brazier J, Campbell M, et al.

33. Cost-effectiveness and safety of epidural steroids in the management of sciatica.

    By Price C, Arden N, Coglan L, Rogers P.

34. The British Rheumatoid Outcome Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis.

    By Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL.

35. Conceptual framework and systematic review of the effects of participants’ and professionals’ preferences in randomised controlled trials.

    By King M, Nazareth I, Lampe F, Bower P, Chandler M, Morou M, et al.

36. The clinical and cost-effectiveness of implantable cardioverter defibrillators: a systematic review.

    By Bryant J, Brodin H, Loveman E, Payne E, Clegg A.

37. A trial of problem-solving by community mental health nurses for anxiety, depression and life difficulties among general practice patients. The CPN-GP study.

    By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J, Pickering R, et al.

38. The causes and effects of socio-demographic exclusions from clinical trials.

    By Bartlett C, Doyal L, Ebrahim S, Davey P, Bachmann M, Egger M, et al.

39. Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis.

    By Epps H, Ginnelly L, Utley M, Southwood T, Gallivan S, Sculpher M, et al.

40. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study.

    By Hobbs FDR, Fitzmaurice DA, Mant J, Murray E, Jowett S, Bryan S, et al.

41. Displaced intracapsular hip fractures in fit, older people: a randomised comparison of reduction and fixation, bipolar hemiarthroplasty and total hip arthroplasty.

    By Keating JF, Grant A, Masson M, Scott NW, Forbes JF.

42. Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland.

    By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR, Major KA, et al.

43. The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.

    By Castelnuovo E, Stein K, Pitt M, Garside R, Payne E.

44. Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

    By Knowles R, Griebsch I, Dezateux C, Brown J, Bull C, Wren C.

45. The clinical and cost-effectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation.

    By Clegg AJ, Scott DA, Loveman E, Colquitt J, Hutchinson J, Royle P, et al.

46. The effectiveness of the Heidelberg Retina Tomograph and laser diagnostic glaucoma scanning system (GDx) in detecting and monitoring glaucoma.

    By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

47. Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.

    By Clar C, Cummins E, McIntyre L, Thomas S, Lamb J, Bain L, et al.

48. Systematic review of effectiveness of different treatments for childhood retinoblastoma.

    By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K, Riemsma R.

49. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis.

    By Roderick P, Ferris G, Wilson K, Halls H, Jackson D, Collins R, et al.

50. The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

    By Dretzke J, Frew E, Davenport C, Barlow J, Stewart-Brown S, Sandercock J, et al.

1. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease.

   By Loveman E, Green C, Kirby J, Takeda A, Picot J, Payne E, et al.

2. FOOD: a multicentre randomised trial evaluating feeding policies in patients admitted to hospital with a recent stroke.

   By Dennis M, Lewis S, Cranswick G, Forbes J.

3. The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer: systematic reviews.

   By Black C, Bagust A, Boland A, Walker S, McLeod C, De Verteuil R, et al.

4. A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise the seizure focus in people with refractory epilepsy being considered for surgery.

   By Whiting P, Gupta R, Burch J, Mujica Mota RE, Wright K, Marson A, et al.

5. Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies.

   By Dundar Y, Dodd S, Dickson R, Walley T, Haycox A, Williamson PR.

6. Systematic review and evaluation of methods of assessing urinary incontinence.

   By Martin JL, Williams KS, Abrams KR, Turner DA, Sutton AJ, Chapple C, et al.

7. The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

   By Connock M, Frew E, Evans B-W, Bryan S, Cummins C, Fry-Smith A, et al.

8. Surveillance of Barrett’s oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

   By Garside R, Pitt M, Somerville M, Stein K, Price A, Gilbert N.

9. Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.

   By Main C, Bojke L, Griffin S, Norman G, Barbieri M, Mather L, et al.

10. Evaluation of molecular techniques in prediction and diagnosis of cytomegalovirus disease in immunocompromised patients.

    By Szczepura A, Westmoreland D, Vinogradova Y, Fox J, Clark M.

11. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.

    By Wu O, Robertson L, Twaddle S, Lowe GDO, Clark P, Greaves M, et al.

12. A series of systematic reviews to inform a decision analysis for sampling and treating infected diabetic foot ulcers.

    By Nelson EA, O’Meara S, Craig D, Iglesias C, Golder S, Dalton J, et al.

13. Randomised clinical trial, observational study and assessment of cost-effectiveness of the treatment of varicose veins (REACTIV trial).

    By Michaels JA, Campbell WB, Brazier JE, MacIntyre JB, Palfreyman SJ, Ratcliffe J, et al.

14. The cost-effectiveness of screening for oral cancer in primary care.

    By Speight PM, Palmer S, Moles DR, Downer MC, Smith DH, Henriksson M, et al.

15. Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

    By Goodacre S, Sampson F, Stevenson M, Wailoo A, Sutton A, Thomas S, et al.

16. Systematic review of the effectiveness and cost-effectiveness of HealOzone^® for the treatment of occlusal pit/fissure caries and root caries.

    By Brazzelli M, McKenzie L, Fielding S, Fraser C, Clarkson J, Kilonzo M, et al.

17. Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment.

    By Lewis SW, Davies L, Jones PB, Barnes TRE, Murray RM, Kerwin R, et al.

18. Diagnostic tests and algorithms used in the investigation of haematuria: systematic reviews and economic evaluation.

    By Rodgers M, Nixon J, Hempel S, Aho T, Kelly J, Neal D, et al.

19. Cognitive behavioural therapy in addition to antispasmodic therapy for irritable bowel syndrome in primary care: randomised controlled trial.

    By Kennedy TM, Chalder T, McCrone P, Darnley S, Knapp M, Jones RH, et al.

20. A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharidosis type 1.

    By Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, et al.

21. Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation.

    By Wright M, Grieve R, Roberts J, Main J, Thomas HC, on behalf of the UK Mild Hepatitis C Trial Investigators.

22. Pressure relieving support surfaces: a randomised evaluation.

    By Nixon J, Nelson EA, Cranny G, Iglesias CP, Hawkins K, Cullum NA, et al.

23. A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.

    By King S, Griffin S, Hodges Z, Weatherly H, Asseburg C, Richardson G, et al.

24. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review.

    By Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al.

25. Effectiveness and cost-effectiveness of salicylic acid and cryotherapy for cutaneous warts. An economic decision model.

    By Thomas KS, Keogh-Brown MR, Chalmers JR, Fordham RJ, Holland RC, Armstrong SJ, et al.

26. A systematic literature review of the effectiveness of non-pharmacological interventions to prevent wandering in dementia and evaluation of the ethical implications and acceptability of their use.

    By Robinson L, Hutchings D, Corner L, Beyer F, Dickinson H, Vanoli A, et al.

27. A review of the evidence on the effects and costs of implantable cardioverter defibrillator therapy in different patient groups, and modelling of cost-effectiveness and cost–utility for these groups in a UK context.

    By Buxton M, Caine N, Chase D, Connelly D, Grace A, Jackson C, et al.

28. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Takeda A, Davidson P, Price A.

29. An evaluation of the clinical and cost-effectiveness of pulmonary artery catheters in patient management in intensive care: a systematic review and a randomised controlled trial.

    By Harvey S, Stevens K, Harrison D, Young D, Brampton W, McCabe C, et al.

30. Accurate, practical and cost-effective assessment of carotid stenosis in the UK.

    By Wardlaw JM, Chappell FM, Stevenson M, De Nigris E, Thomas S, Gillard J, et al.

31. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.

    By Woolacott N, Bravo Vergel Y, Hawkins N, Kainth A, Khadjesari Z, Misso K, et al.

32. The cost-effectiveness of testing for hepatitis C in former injecting drug users.

    By Castelnuovo E, Thompson-Coon J, Pitt M, Cramp M, Siebert U, Price A, et al.

33. Computerised cognitive behaviour therapy for depression and anxiety update: a systematic review and economic evaluation.

    By Kaltenthaler E, Brazier J, De Nigris E, Tumur I, Ferriter M, Beverley C, et al.

34. Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy.

    By Williams C, Brunskill S, Altman D, Briggs A, Campbell H, Clarke M, et al.

35. Psychological therapies including dialectical behaviour therapy for borderline personality disorder: a systematic review and preliminary economic evaluation.

    By Brazier J, Tumur I, Holmes M, Ferriter M, Parry G, Dent-Brown K, et al.

36. Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model.

    By Whiting P, Westwood M, Bojke L, Palmer S, Richardson G, Cooper J, et al.

37. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme.

    By O’Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A.

38. A comparison of the cost-effectiveness of five strategies for the prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling.

    By Brown TJ, Hooper L, Elliott RA, Payne K, Webb R, Roberts C, et al.

39. The effectiveness and cost-effectiveness of computed tomography screening for coronary artery disease: systematic review.

    By Waugh N, Black C, Walker S, McIntyre L, Cummins E, Hillis G.

40. What are the clinical outcome and cost-effectiveness of endoscopy undertaken by nurses when compared with doctors? A Multi-Institution Nurse Endoscopy Trial (MINuET).

    By Williams J, Russell I, Durai D, Cheung W-Y, Farrin A, Bloor K, et al.

41. The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation.

    By Pandor A, Eggington S, Paisley S, Tappenden P, Sutcliffe P.

42. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness.

    By Chen Y-F, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al.

43. Telemedicine in dermatology: a randomised controlled trial.

    By Bowns IR, Collins K, Walters SJ, McDonagh AJG.

44. Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model.

    By Davies L, Brown TJ, Haynes S, Payne K, Elliott RA, McCollum C.

45. Clinical effectiveness and cost-effectiveness of laparoscopic surgery for colorectal cancer: systematic reviews and economic evaluation.

    By Murray A, Lourenco T, de Verteuil R, Hernandez R, Fraser C, McKinley A, et al.

46. Etanercept and efalizumab for the treatment of psoriasis: a systematic review.

    By Woolacott N, Hawkins N, Mason A, Kainth A, Khadjesari Z, Bravo Vergel Y, et al.

47. Systematic reviews of clinical decision tools for acute abdominal pain.

    By Liu JLY, Wyatt JC, Deeks JJ, Clamp S, Keen J, Verde P, et al.

48. Evaluation of the ventricular assist device programme in the UK.

    By Sharples L, Buxton M, Caine N, Cafferty F, Demiris N, Dyer M, et al.

49. A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.

    By Yao G, Albon E, Adi Y, Milford D, Bayliss S, Ready A, et al.

50. Amniocentesis results: investigation of anxiety. The ARIA trial.

    By Hewison J, Nixon J, Fountain J, Cocks K, Jones C, Mason G, et al.

1. Pemetrexed disodium for the treatment of malignant pleural mesothelioma: a systematic review and economic evaluation.

   By Dundar Y, Bagust A, Dickson R, Dodd S, Green J, Haycox A, et al.

2. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of docetaxel in combination with prednisone or prednisolone for the treatment of hormone-refractory metastatic prostate cancer.

   By Collins R, Fenwick E, Trowman R, Perard R, Norman G, Light K, et al.

3. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection.

   By Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, et al.

4. The clinical effectiveness and cost-effectiveness of strontium ranelate for the prevention of osteoporotic fragility fractures in postmenopausal women.

   By Stevenson M, Davis S, Lloyd-Jones M, Beverley C.

5. A systematic review of quantitative and qualitative research on the role and effectiveness of written information available to patients about individual medicines.

   By Raynor DK, Blenkinsopp A, Knapp P, Grime J, Nicolson DJ, Pollock K, et al.

6. Oral naltrexone as a treatment for relapse prevention in formerly opioid-dependent drug users: a systematic review and economic evaluation.

   By Adi Y, Juarez-Garcia A, Wang D, Jowett S, Frew E, Day E, et al.

7. Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.

   By Kanis JA, Stevenson M, McCloskey EV, Davis S, Lloyd-Jones M.

8. Epidemiological, social, diagnostic and economic evaluation of population screening for genital chlamydial infection.

   By Low N, McCarthy A, Macleod J, Salisbury C, Campbell R, Roberts TE, et al.

9. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation.

   By Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, et al.

10. Exercise Evaluation Randomised Trial (EXERT): a randomised trial comparing GP referral for leisure centre-based exercise, community-based walking and advice only.

    By Isaacs AJ, Critchley JA, See Tai S, Buckingham K, Westley D, Harridge SDR, et al.

11. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Hartwell D, Davidson P, Price A, Waugh N.

12. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

    By Tappenden P, Jones R, Paisley S, Carroll C.

13. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment.

    By Wilson J, Yao GL, Raftery J, Bohlius J, Brunskill S, Sandercock J, et al.

14. A systematic review and economic evaluation of statins for the prevention of coronary events.

    By Ward S, Lloyd Jones M, Pandor A, Holmes M, Ara R, Ryan A, et al.

15. A systematic review of the effectiveness and cost-effectiveness of different models of community-based respite care for frail older people and their carers.

    By Mason A, Weatherly H, Spilsbury K, Arksey H, Golder S, Adamson J, et al.

16. Additional therapy for young children with spastic cerebral palsy: a randomised controlled trial.

    By Weindling AM, Cunningham CC, Glenn SM, Edwards RT, Reeves DJ.

17. Screening for type 2 diabetes: literature review and economic modelling.

    By Waugh N, Scotland G, McNamee P, Gillett M, Brennan A, Goyder E, et al.

18. The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Mealing S, Roome C, Snaith A, et al.

19. The clinical effectiveness and cost-effectiveness of gemcitabine for metastatic breast cancer: a systematic review and economic evaluation.

    By Takeda AL, Jones J, Loveman E, Tan SC, Clegg AJ.

20. A systematic review of duplex ultrasound, magnetic resonance angiography and computed tomography angiography for the diagnosis and assessment of symptomatic, lower limb peripheral arterial disease.

    By Collins R, Cranny G, Burch J, Aguiar-Ibáñez R, Craig D, Wright K, et al.

21. The clinical effectiveness and cost-effectiveness of treatments for children with idiopathic steroid-resistant nephrotic syndrome: a systematic review.

    By Colquitt JL, Kirby J, Green C, Cooper K, Trompeter RS.

22. A systematic review of the routine monitoring of growth in children of primary school age to identify growth-related conditions.

    By Fayter D, Nixon J, Hartley S, Rithalia A, Butler G, Rudolf M, et al.

23. Systematic review of the effectiveness of preventing and treating Staphylococcus aureus carriage in reducing peritoneal catheter-related infections.

    By McCormack K, Rabindranath K, Kilonzo M, Vale L, Fraser C, McIntyre L, et al.

24. The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis.

    By McLoughlin DM, Mogg A, Eranti S, Pluck G, Purvis R, Edwards D, et al.

25. A randomised controlled trial and economic evaluation of direct versus indirect and individual versus group modes of speech and language therapy for children with primary language impairment.

    By Boyle J, McCartney E, Forbes J, O’Hare A.

26. Hormonal therapies for early breast cancer: systematic review and economic evaluation.

    By Hind D, Ward S, De Nigris E, Simpson E, Carroll C, Wyld L.

27. Cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review.

    By Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A.

28. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation.

    By McLeod C, Bagust A, Boland A, Dagenais P, Dickson R, Dundar Y, et al.

29. Prenatal screening and treatment strategies to prevent group B streptococcal and other bacterial infections in early infancy: cost-effectiveness and expected value of information analyses.

    By Colbourn T, Asseburg C, Bojke L, Philips Z, Claxton K, Ades AE, et al.

30. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review.

    By Garrison KR, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I, et al.

31. A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial.

    By Prescott RJ, Kunkler IH, Williams LJ, King CC, Jack W, van der Pol M, et al.

32. Current practice, accuracy, effectiveness and cost-effectiveness of the school entry hearing screen.

    By Bamford J, Fortnum H, Bristow K, Smith J, Vamvakas G, Davies L, et al.

33. The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation.

    By Black C, Cummins E, Royle P, Philip S, Waugh N.

34. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis.

    By Thompson Coon J, Rogers G, Hewson P, Wright D, Anderson R, Cramp M, et al.

35. The Birmingham Rehabilitation Uptake Maximisation Study (BRUM). Homebased compared with hospital-based cardiac rehabilitation in a multi-ethnic population: cost-effectiveness and patient adherence.

    By Jolly K, Taylor R, Lip GYH, Greenfield S, Raftery J, Mant J, et al.

36. A systematic review of the clinical, public health and cost-effectiveness of rapid diagnostic tests for the detection and identification of bacterial intestinal pathogens in faeces and food.

    By Abubakar I, Irvine L, Aldus CF, Wyatt GM, Fordham R, Schelenz S, et al.

37. A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

    By Marson AG, Appleton R, Baker GA, Chadwick DW, Doughty J, Eaton B, et al.

38. Clinical effectiveness and cost-effectiveness of different models of managing long-term oral anti-coagulation therapy: a systematic review and economic modelling.

    By Connock M, Stevens C, Fry-Smith A, Jowett S, Fitzmaurice D, Moore D, et al.

39. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder.

    By Soares-Weiser K, Bravo Vergel Y, Beynon S, Dunn G, Barbieri M, Duffy S, et al.

40. Taxanes for the adjuvant treatment of early breast cancer: systematic review and economic evaluation.

    By Ward S, Simpson E, Davis S, Hind D, Rees A, Wilkinson A.

41. The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation.

    By Burr JM, Mowatt G, Hernández R, Siddiqui MAR, Cook J, Lourenco T, et al.

42. Acceptability, benefit and costs of early screening for hearing disability: a study of potential screening tests and models.

    By Davis A, Smith P, Ferguson M, Stephens D, Gianopoulos I.

43. Contamination in trials of educational interventions.

    By Keogh-Brown MR, Bachmann MO, Shepstone L, Hewitt C, Howe A, Ramsay CR, et al.

44. Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers.

    By Facey K, Bradbury I, Laking G, Payne E.

45. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Rogers G, Dyer M, Mealing S, et al.

46. Drug-eluting stents: a systematic review and economic evaluation.

    By Hill RA, Boland A, Dickson R, Dündar Y, Haycox A, McLeod C, et al.

47. The clinical effectiveness and cost-effectiveness of cardiac resynchronisation (biventricular pacing) for heart failure: systematic review and economic model.

    By Fox M, Mealing S, Anderson R, Dean J, Stein K, Price A, et al.

48. Recruitment to randomised trials: strategies for trial enrolment and participation study. The STEPS study.

    By Campbell MK, Snowdon C, Francis D, Elbourne D, McDonald AM, Knight R, et al.

49. Cost-effectiveness of functional cardiac testing in the diagnosis and management of coronary artery disease: a randomised controlled trial. The CECaT trial.

    By Sharples L, Hughes V, Crean A, Dyer M, Buxton M, Goldsmith K, et al.

50. Evaluation of diagnostic tests when there is no gold standard. A review of methods.

    By Rutjes AWS, Reitsma JB, Coomarasamy A, Khan KS, Bossuyt PMM.

51. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding.

    By Leontiadis GI, Sreedharan A, Dorward S, Barton P, Delaney B, Howden CW, et al.

52. A review and critique of modelling in prioritising and designing screening programmes.

    By Karnon J, Goyder E, Tappenden P, McPhie S, Towers I, Brazier J, et al.

53. An assessment of the impact of the NHS Health Technology Assessment Programme.

    By Hanney S, Buxton M, Green C, Coulson D, Raftery J.

1. A systematic review and economic model of switching from nonglycopeptide to glycopeptide antibiotic prophylaxis for surgery.

   By Cranny G, Elliott R, Weatherly H, Chambers D, Hawkins N, Myers L, et al.

2. ‘Cut down to quit’ with nicotine replacement therapies in smoking cessation: a systematic review of effectiveness and economic analysis.

   By Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P, Moore D.

3. A systematic review of the effectiveness of strategies for reducing fracture risk in children with juvenile idiopathic arthritis with additional data on long-term risk of fracture and cost of disease management.

   By Thornton J, Ashcroft D, O’Neill T, Elliott R, Adams J, Roberts C, et al.

4. Does befriending by trained lay workers improve psychological well-being and quality of life for carers of people with dementia, and at what cost? A randomised controlled trial.

   By Charlesworth G, Shepstone L, Wilson E, Thalanany M, Mugford M, Poland F.

5. A multi-centre retrospective cohort study comparing the efficacy, safety and cost-effectiveness of hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids. The HOPEFUL study.

   By Hirst A, Dutton S, Wu O, Briggs A, Edwards C, Waldenmaier L, et al.

6. Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling.

   By Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley L, et al.

7. The use of economic evaluations in NHS decision-making: a review and empirical investigation.

   By Williams I, McIver S, Moore D, Bryan S.

8. Stapled haemorrhoidectomy (haemorrhoidopexy) for the treatment of haemorrhoids: a systematic review and economic evaluation.

   By Burch J, Epstein D, Baba-Akbari A, Weatherly H, Fox D, Golder S, et al.

9. The clinical effectiveness of diabetes education models for Type 2 diabetes: a systematic review.

   By Loveman E, Frampton GK, Clegg AJ.

10. Payment to healthcare professionals for patient recruitment to trials: systematic review and qualitative study.

    By Raftery J, Bryant J, Powell J, Kerr C, Hawker S.

11. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation.

    By Chen Y-F, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, et al.

12. The clinical effectiveness and cost-effectiveness of central venous catheters treated with anti-infective agents in preventing bloodstream infections: a systematic review and economic evaluation.

    By Hockenhull JC, Dwan K, Boland A, Smith G, Bagust A, Dundar Y, et al.

13. Stepped treatment of older adults on laxatives. The STOOL trial.

    By Mihaylov S, Stark C, McColl E, Steen N, Vanoli A, Rubin G, et al.

14. A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

    By Goodyer IM, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, et al.

15. The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: systematic review and economic evaluation.

    By Hind D, Tappenden P, Tumur I, Eggington E, Sutcliffe P, Ryan A.

16. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration: a systematic review and economic evaluation.

    By Colquitt JL, Jones J, Tan SC, Takeda A, Clegg AJ, Price A.

17. Systematic review of the clinical effectiveness and cost-effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of coronary artery disease.

    By Mowatt G, Cummins E, Waugh N, Walker S, Cook J, Jia X, et al.

18. Structural neuroimaging in psychosis: a systematic review and economic evaluation.

    By Albon E, Tsourapas A, Frew E, Davenport C, Oyebode F, Bayliss S, et al.

19. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in adults and children aged 12 years and over.

    By Shepherd J, Rogers G, Anderson R, Main C, Thompson-Coon J, Hartwell D, et al.

20. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in children under the age of 12 years.

    By Main C, Shepherd J, Anderson R, Rogers G, Thompson-Coon J, Liu Z, et al.

21. Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation.

    By Ara R, Tumur I, Pandor A, Duenas A, Williams R, Wilkinson A, et al.

22. Topical or oral ibuprofen for chronic knee pain in older people. The TOIB study.

    By Underwood M, Ashby D, Carnes D, Castelnuovo E, Cross P, Harding G, et al.

23. A prospective randomised comparison of minor surgery in primary and secondary care. The MiSTIC trial.

    By George S, Pockney P, Primrose J, Smith H, Little P, Kinley H, et al.

24. A review and critical appraisal of measures of therapist–patient interactions in mental health settings.

    By Cahill J, Barkham M, Hardy G, Gilbody S, Richards D, Bower P, et al.

25. The clinical effectiveness and cost-effectiveness of screening programmes for amblyopia and strabismus in children up to the age of 4–5 years: a systematic review and economic evaluation.

    By Carlton J, Karnon J, Czoski-Murray C, Smith KJ, Marr J.

26. A systematic review of the clinical effectiveness and cost-effectiveness and economic modelling of minimal incision total hip replacement approaches in the management of arthritic disease of the hip.

    By de Verteuil R, Imamura M, Zhu S, Glazener C, Fraser C, Munro N, et al.

27. A preliminary model-based assessment of the cost–utility of a screening programme for early age-related macular degeneration.

    By Karnon J, Czoski-Murray C, Smith K, Brand C, Chakravarthy U, Davis S, et al.

28. Intravenous magnesium sulphate and sotalol for prevention of atrial fibrillation after coronary artery bypass surgery: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Frampton GK, Tanajewski L, Turner D, Price A.

29. Absorbent products for urinary/faecal incontinence: a comparative evaluation of key product categories.

    By Fader M, Cottenden A, Getliffe K, Gage H, Clarke-O’Neill S, Jamieson K, et al.

30. A systematic review of repetitive functional task practice with modelling of resource use, costs and effectiveness.

    By French B, Leathley M, Sutton C, McAdam J, Thomas L, Forster A, et al.

31. The effectiveness and cost-effectivness of minimal access surgery amongst people with gastro-oesophageal reflux disease – a UK collaborative study. The reflux trial.

    By Grant A, Wileman S, Ramsay C, Bojke L, Epstein D, Sculpher M, et al.

32. Time to full publication of studies of anti-cancer medicines for breast cancer and the potential for publication bias: a short systematic review.

    By Takeda A, Loveman E, Harris P, Hartwell D, Welch K.

33. Performance of screening tests for child physical abuse in accident and emergency departments.

    By Woodman J, Pitt M, Wentz R, Taylor B, Hodes D, Gilbert RE.

34. Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation.

    By Rodgers M, McKenna C, Palmer S, Chambers D, Van Hout S, Golder S, et al.

35. Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement.

    By Lourenco T, Armstrong N, N’Dow J, Nabi G, Deverill M, Pickard R, et al.

36. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.

    By Wang D, Cummins C, Bayliss S, Sandercock J, Burls A.

1. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation.

   By McLeod C, Fleeman N, Kirkham J, Bagust A, Boland A, Chu P, et al.

2. Thrombophilia testing in people with venous thromboembolism: systematic review and cost-effectiveness analysis.

   By Simpson EL, Stevenson MD, Rawdin A, Papaioannou D.

3. Surgical procedures and non-surgical devices for the management of non-apnoeic snoring: a systematic review of clinical effects and associated treatment costs.

   By Main C, Liu Z, Welch K, Weiner G, Quentin Jones S, Stein K.

4. Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea–hypopnoea syndrome: a systematic review and economic analysis.

   By McDaid C, Griffin S, Weatherly H, Durée K, van der Burgt M, van Hout S, Akers J, et al.

5. Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review.

   By Sutcliffe P, Hummel S, Simpson E, Young T, Rees A, Wilkinson A, et al.

6. The harmful health effects of recreational ecstasy: a systematic review of observational evidence.

   By Rogers G, Elston J, Garside R, Roome C, Taylor R, Younger P, et al.

7. Systematic review of the clinical effectiveness and cost-effectiveness of oesophageal Doppler monitoring in critically ill and high-risk surgical patients.

   By Mowatt G, Houston G, Hernández R, de Verteuil R, Fraser C, Cuthbertson B, et al.

8. The use of surrogate outcomes in model-based cost-effectiveness analyses: a survey of UK Health Technology Assessment reports.

   By Taylor RS, Elston J.

9. Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) – a randomised controlled trial.

   By Potter J, Mistri A, Brodie F, Chernova J, Wilson E, Jagger C, et al.

10. Routine antenatal anti-D prophylaxis for RhD-negative women: a systematic review and economic evaluation.

    By Pilgrim H, Lloyd-Jones M, Rees A.

11. Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.

    By Tappenden P, Jackson R, Cooper K, Rees A, Simpson E, Read R, et al.

12. Improving the evaluation of therapeutic interventions in multiple sclerosis: the role of new psychometric methods.

    By Hobart J, Cano S.

13. Treatment of severe ankle sprain: a pragmatic randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of three types of mechanical ankle support with tubular bandage. The CAST trial.

    By Cooke MW, Marsh JL, Clark M, Nakash R, Jarvis RM, Hutton JL, et al. , on behalf of the CAST trial group.

14. Non-occupational postexposure prophylaxis for HIV: a systematic review.

    By Bryant J, Baxter L, Hird S.

15. Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial.

    By Farmer AJ, Wade AN, French DP, Simon J, Yudkin P, Gray A, et al.

16. How far does screening women for domestic (partner) violence in different health-care settings meet criteria for a screening programme? Systematic reviews of nine UK National Screening Committee criteria.

    By Feder G, Ramsay J, Dunne D, Rose M, Arsene C, Norman R, et al.

17. Spinal cord stimulation for chronic pain of neuropathic or ischaemic origin: systematic review and economic evaluation.

    By Simpson, EL, Duenas A, Holmes MW, Papaioannou D, Chilcott J.

18. The role of magnetic resonance imaging in the identification of suspected acoustic neuroma: a systematic review of clinical and costeffectiveness and natural history.

    By Fortnum H, O’Neill C, Taylor R, Lenthall R, Nikolopoulos T, Lightfoot G, et al.

19. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study.

    By Little P, Turner S, Rumsby K, Warner G, Moore M, Lowes JA, et al.

20. Systematic review of respite care in the frail elderly.

    By Shaw C, McNamara R, Abrams K, Cannings-John R, Hood K, Longo M, et al.

21. Neuroleptics in the treatment of aggressive challenging behaviour for people with intellectual disabilities: a randomised controlled trial (NACHBID).

    By Tyrer P, Oliver-Africano P, Romeo R, Knapp M, Dickens S, Bouras N, et al.

22. Randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of selective serotonin reuptake inhibitors plus supportive care, versus supportive care alone, for mild to moderate depression with somatic symptoms in primary care: the THREAD (THREshold for AntiDepressant response) study.

    By Kendrick T, Chatwin J, Dowrick C, Tylee A, Morriss R, Peveler R, et al.

23. Diagnostic strategies using DNA testing for hereditary haemochromatosis in at-risk populations: a systematic review and economic evaluation.

    By Bryant J, Cooper K, Picot J, Clegg A, Roderick P, Rosenberg W, et al.

24. Enhanced external counterpulsation for the treatment of stable angina and heart failure: a systematic review and economic analysis.

    By McKenna C, McDaid C, Suekarran S, Hawkins N, Claxton K, Light K, et al.

25. Development of a decision support tool for primary care management of patients with abnormal liver function tests without clinically apparent liver disease: a record-linkage population cohort study and decision analysis (ALFIE).

    By Donnan PT, McLernon D, Dillon JF, Ryder S, Roderick P, Sullivan F, et al.

26. A systematic review of presumed consent systems for deceased organ donation.

    By Rithalia A, McDaid C, Suekarran S, Norman G, Myers L, Sowden A.

27. Paracetamol and ibuprofen for the treatment of fever in children: the PITCH randomised controlled trial.

    By Hay AD, Redmond NM, Costelloe C, Montgomery AA, Fletcher M, Hollinghurst S, et al.

28. A randomised controlled trial to compare minimally invasive glucose monitoring devices with conventional monitoring in the management of insulin-treated diabetes mellitus (MITRE).

    By Newman SP, Cooke D, Casbard A, Walker S, Meredith S, Nunn A, et al.

29. Sensitivity analysis in economic evaluation: an audit of NICE current practice and a review of its use and value in decision-making.

    By Andronis L, Barton P, Bryan S.

30. Trastuzumab for the treatment of primary breast cancer in HER2-positive women: a single technology appraisal.

    By Ward S, Pilgrim H, Hind D.

31. Docetaxel for the adjuvant treatment of early node-positive breast cancer: a single technology appraisal.

    By Chilcott J, Lloyd Jones M, Wilkinson A.

32. The use of paclitaxel in the management of early stage breast cancer.

    By Griffin S, Dunn G, Palmer S, Macfarlane K, Brent S, Dyker A, et al.

33. Rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin’s lymphoma.

    By Dundar Y, Bagust A, Hounsome J, McLeod C, Boland A, Davis H, et al.

34. Bortezomib for the treatment of multiple myeloma patients.

    By Green C, Bryant J, Takeda A, Cooper K, Clegg A, Smith A, et al.

35. Fludarabine phosphate for the firstline treatment of chronic lymphocytic leukaemia.

    By Walker S, Palmer S, Erhorn S, Brent S, Dyker A, Ferrie L, et al.

36. Erlotinib for the treatment of relapsed non-small cell lung cancer.

    By McLeod C, Bagust A, Boland A, Hockenhull J, Dundar Y, Proudlove C, et al.

37. Cetuximab plus radiotherapy for the treatment of locally advanced squamous cell carcinoma of the head and neck.

    By Griffin S, Walker S, Sculpher M, White S, Erhorn S, Brent S, et al.

38. Infliximab for the treatment of adults with psoriasis.

    By Loveman E, Turner D, Hartwell D, Cooper K, Clegg A

39. Psychological interventions for postnatal depression: cluster randomised trial and economic evaluation. The PoNDER trial.

    By Morrell CJ, Warner R, Slade P, Dixon S, Walters S, Paley G, et al.

40. The effect of different treatment durations of clopidogrel in patients with non-ST-segment elevation acute coronary syndromes: a systematic review and value of information analysis.

    By Rogowski R, Burch J, Palmer S, Craigs C, Golder S, Woolacott N.

41. Systematic review and individual patient data meta-analysis of diagnosis of heart failure, with modelling of implications of different diagnostic strategies in primary care.

    By Mant J, Doust J, Roalfe A, Barton P, Cowie MR, Glasziou P, et al.

42. A multicentre randomised controlled trial of the use of continuous positive airway pressure and non-invasive positive pressure ventilation in the early treatment of patients presenting to the emergency department with severe acute cardiogenic pulmonary oedema: the 3CPO trial.

    By Gray AJ, Goodacre S, Newby DE, Masson MA, Sampson F, Dixon S, et al. , on behalf of the 3CPO study investigators.

43. Early high-dose lipid-lowering therapy to avoid cardiac events: a systematic review and economic evaluation.

    By Ara R, Pandor A, Stevens J, Rees A, Rafia R.

44. Adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic hepatitis B: an updated systematic review and economic evaluation.

    By Jones J, Shepherd J, Baxter L, Gospodarevskaya E, Hartwell D, Harris P, et al.

45. Methods to identify postnatal depression in primary care: an integrated evidence synthesis and value of information analysis.

    By Hewitt CE, Gilbody SM, Brealey S, Paulden M, Palmer S, Mann R, et al.

46. A double-blind randomised placebocontrolled trial of topical intranasal corticosteroids in 4- to 11-year-old children with persistent bilateral otitis media with effusion in primary care.

    By Williamson I, Benge S, Barton S, Petrou S, Letley L, Fasey N, et al.

47. The effectiveness and cost-effectiveness of methods of storing donated kidneys from deceased donors: a systematic review and economic model.

    By Bond M, Pitt M, Akoh J, Moxham T, Hoyle M, Anderson R.

48. Rehabilitation of older patients: day hospital compared with rehabilitation at home. A randomised controlled trial.

    By Parker SG, Oliver P, Pennington M, Bond J, Jagger C, Enderby PM, et al.

49. Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis.

    By Renfrew MJ, Craig D, Dyson L, McCormick F, Rice S, King SE, et al.

50. The clinical effectiveness and costeffectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation.

    By Picot J, Jones J, Colquitt JL, Gospodarevskaya E, Loveman E, Baxter L, et al.

51. Rapid testing for group B streptococcus during labour: a test accuracy study with evaluation of acceptability and cost-effectiveness.

    By Daniels J, Gray J, Pattison H, Roberts T, Edwards E, Milner P, et al.

52. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling.

    By Honest H, Forbes CA, Durée KH, Norman G, Duffy SB, Tsourapas A, et al.

53. The effectiveness and cost-effectiveness of cochlear implants for severe to profound deafness in children and adults: a systematic review and economic model.

    By Bond M, Mealing S, Anderson R, Elston J, Weiner G, Taylor RS, et al.

54. Gemcitabine for the treatment of metastatic breast cancer.

    By Jones J, Takeda A, Tan SC, Cooper K, Loveman E, Clegg A.

55. Varenicline in the management of smoking cessation: a single technology appraisal.

    By Hind D, Tappenden P, Peters J, Kenjegalieva K.

56. Alteplase for the treatment of acute ischaemic stroke: a single technology appraisal.

    By Lloyd Jones M, Holmes M.

57. Rituximab for the treatment of rheumatoid arthritis.

    By Bagust A, Boland A, Hockenhull J, Fleeman N, Greenhalgh J, Dundar Y, et al.

58. Omalizumab for the treatment of severe persistent allergic asthma.

    By Jones J, Shepherd J, Hartwell D, Harris P, Cooper K, Takeda A, et al.

59. Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin’s lymphoma.

    By Boland A, Bagust A, Hockenhull J, Davis H, Chu P, Dickson R.

60. Adalimumab for the treatment of psoriasis.

    By Turner D, Picot J, Cooper K, Loveman E.

61. Dabigatran etexilate for the prevention of venous thromboembolism in patients undergoing elective hip and knee surgery: a single technology appraisal.

    By Holmes M, C Carroll C, Papaioannou D.

62. Romiplostim for the treatment of chronic immune or idiopathic thrombocytopenic purpura: a single technology appraisal.

    By Mowatt G, Boachie C, Crowther M, Fraser C, Hernández R, Jia X, et al.

63. Sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer.

    By Bond M, Hoyle M, Moxham T, Napier M, Anderson R.

64. Vitamin K to prevent fractures in older women: systematic review and economic evaluation.

    By Stevenson M, Lloyd-Jones M, Papaioannou D.

65. The effects of biofeedback for the treatment of essential hypertension: a systematic review.

    By Greenhalgh J, Dickson R, Dundar Y.

66. A randomised controlled trial of the use of aciclovir and/or prednisolone for the early treatment of Bell’s palsy: the BELLS study.

    By Sullivan FM, Swan IRC, Donnan PT, Morrison JM, Smith BH, McKinstry B, et al.

67. Lapatinib for the treatment of HER2-overexpressing breast cancer.

    By Jones J, Takeda A, Picot J, von Keyserlingk C, Clegg A.

68. Infliximab for the treatment of ulcerative colitis.

    By Hyde C, Bryan S, Juarez-Garcia A, Andronis L, Fry-Smith A.

69. Rimonabant for the treatment of overweight and obese people.

    By Burch J, McKenna C, Palmer S, Norman G, Glanville J, Sculpher M, et al.

70. Telbivudine for the treatment of chronic hepatitis B infection.

    By Hartwell D, Jones J, Harris P, Cooper K.

71. Entecavir for the treatment of chronic hepatitis B infection.

    By Shepherd J, Gospodarevskaya E, Frampton G, Cooper, K.

72. Febuxostat for the treatment of hyperuricaemia in people with gout: a single technology appraisal.

    By Stevenson M, Pandor A.

73. Rivaroxaban for the prevention of venous thromboembolism: a single technology appraisal.

    By Stevenson M, Scope A, Holmes M, Rees A, Kaltenthaler E.

74. Cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck.

    By Greenhalgh J, Bagust A, Boland A, Fleeman N, McLeod C, Dundar Y, et al.

75. Mifamurtide for the treatment of osteosarcoma: a single technology appraisal.

    By Pandor A, Fitzgerald P, Stevenson M, Papaioannou D.

76. Ustekinumab for the treatment of moderate to severe psoriasis.

    By Gospodarevskaya E, Picot J, Cooper K, Loveman E, Takeda A.

77. Endovascular stents for abdominal aortic aneurysms: a systematic review and economic model.

    By Chambers D, Epstein D, Walker S, Fayter D, Paton F, Wright K, et al.

78. Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: a systematic review and economic evaluation.

    By Chen Y-F, Jowett S, Barton P, Malottki K, Hyde C, Gibbs JSR, et al.

79. Cessation of attention deficit hyperactivity disorder drugs in the young (CADDY) – a pharmacoepidemiological and qualitative study.

    By Wong ICK, Asherson P, Bilbow A, Clifford S, Coghill D, R DeSoysa R, et al.

80. ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening.

    By Kitchener HC, Almonte M, Gilham C, Dowie R, Stoykova B, Sargent A, et al.

81. The clinical effectiveness of glucosamine and chondroitin supplements in slowing or arresting progression of osteoarthritis of the knee: a systematic review and economic evaluation.

    By Black C, Clar C, Henderson R, MacEachern C, McNamee P, Quayyum Z, et al.

82. Randomised preference trial of medical versus surgical termination of pregnancy less than 14 weeks’ gestation (TOPS).

    By Robson SC, Kelly T, Howel D, Deverill M, Hewison J, Lie MLS, et al.

83. Randomised controlled trial of the use of three dressing preparations in the management of chronic ulceration of the foot in diabetes.

    By Jeffcoate WJ, Price PE, Phillips CJ, Game FL, Mudge E, Davies S, et al.

84. VenUS II: a randomised controlled trial of larval therapy in the management of leg ulcers.

    By Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C, et al.

Health Technology Assessment programme

1. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

2. Director, Medical Care Research Unit, University of Sheffield