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Background Magnetic resonance imaging localises cancer in the prostate, allowing for a targeted biopsy with or without transrectal ultrasound-guided systematic biopsy. Targeted biopsy methods include cognitive fusion, where prostate lesions suspicious on magnetic resonance imaging are targeted visually during live ultrasound, and software fusion, where computer software overlays the magnetic resonance imaging image onto the ultrasound in real time. The effectiveness and cost-effectiveness of software fusion technologies compared with cognitive fusion biopsy are uncertain. Objectives To assess the clinical and cost-effectiveness of software fusion biopsy technologies in people with suspected localised and locally advanced prostate cancer. A systematic review was conducted to evaluate the diagnostic accuracy, clinical efficacy and practical implementation of nine software fusion devices compared to cognitive fusion biopsies, and with each other, in people with suspected prostate cancer. Comprehensive searches including MEDLINE, and Embase were conducted up to August 2022 to identify studies which compared software fusion and cognitive fusion biopsies in people with suspected prostate cancer. Risk of bias was assessed with quality assessment of diagnostic accuracy studies-comparative tool. A network meta-analysis comparing software and cognitive fusion with or without concomitant systematic biopsy, and systematic biopsy alone was conducted. Additional outcomes, including safety and usability, were synthesised narratively. A de novo decision model was developed to estimate the cost-effectiveness of targeted software fusion biopsy relative to cognitive fusion biopsy with or without concomitant systematic biopsy for prostate cancer identification in biopsy-naive people. Scenario analyses were undertaken to explore the robustness of the results to variation in the model data sources and alternative assumptions. Results Twenty-three studies (3773 patients with software fusion, 2154 cognitive fusion) were included, of which 13 informed the main meta-analyses. Evidence was available for seven of the nine fusion devices specified in the protocol and at high risk of bias. The meta-analyses show that patients undergoing software fusion biopsy may have: (1) a lower probability of being classified as not having cancer, (2) similar probability of being classified as having non-clinically significant cancer (International Society of Urological Pathology grade 1) and (3) higher probability of being classified at higher International Society of Urological Pathology grades, particularly International Society of Urological Pathology 2. Similar results were obtained when comparing between same biopsy methods where both were combined with systematic biopsy. Evidence was insufficient to conclude whether any individual devices were superior to cognitive fusion, or whether some software fusion technologies were superior to others. Uncertainty in the relative diagnostic accuracy of software fusion versus cognitive fusion reduce the strength of any statements on its cost-effectiveness. The economic analysis suggests incremental cost-effectiveness ratios for software fusion biopsy versus cognitive fusion are within the bounds of cost-effectiveness (£1826 and £5623 per additional quality-adjusted life-year with or with concomitant systematic biopsy, respectively), but this finding needs cautious interpretation. Limitations There was insufficient evidence to explore the impact of effect modifiers. Conclusions Software fusion biopsies may be associated with increased cancer detection in relation to cognitive fusion biopsies, but the evidence is at high risk of bias. Sufficiently powered, high-quality studies are required. Cost-effectiveness results should be interpreted with caution given the limitations of the diagnostic accuracy evidence. Study registration This trial is registered as PROSPERO CRD42022329259. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: 135477) and is published in full in Health Technology Assessment; Vol. 28, No. 61. See the NIHR Funding and Awards website for further information. Plain language summary Men with an magnetic resonance imaging scan that shows possible prostate cancer (PCa) are offered prostate biopsies, where samples of the prostate tissue are collected with a needle, to confirm the presence and severity of cancer. Different biopsy methods exist. In a cognitive fusion biopsy, clinicians will target abnormal looking parts of the prostate by looking at the magnetic resonance imaging scan alongside ‘live’ ultrasound images. During a software fusion (SF) biopsy, a computer software is used to overlay the magnetic resonance imaging scan onto the ultrasound image. This study evaluated whether SF is better at detecting cancer compared with cognitive fusion biopsy, and whether it represents value for money for the National Health Service. We did a comprehensive review of the literature. We combined and re-analysed the evidence, and assessed its quality. We investigated whether SF biopsies are sufficient value for money. Compared with cognitive fusion, patients receiving a SF biopsy may have: (1) a lower probability of having a ‘no cancer’ result, (2) similar probability of having a benign, non-clinically significant (CS) cancer result and (3) higher probability of detecting CS cancer. However, it is uncertain to what extent SF is more accurate than cognitive fusion, because of concerns about the quality of the evidence. We found no evidence that any SF devices were superior to others. Using additional, random biopsies alongside software or cognitive fusion would increase the detection of PCa. We also looked for evidence on the value for money of the SF biopsies to detect PCa and found no relevant studies. We weighed the costs and the benefits of SF biopsy compared to cognitive fusion to determine whether it could be a good use of National Health Service money. The poor quality of information makes the value of the technologies largely unknown. Scientific summary Background Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the UK. In the NHS people with suspected PCa are offered multiparametric magnetic resonance imaging (mpMRI). People with suspected PCa, according to MRI, are offered a biopsy procedure to confirm the presence and severity of cancer. Traditionally patients were offered a systematic transrectal, ultrasound-guided prostate biopsy (or systematic biopsy). Since the introduction of mpMRI, specific areas of abnormal tissue can be targeted, by combining (or fusing) the results of mpMRI and ultrasound imaging. Several methods for fusing MRI and ultrasound images exist, including cognitive fusion (CF), in which a region of interest is identified prior to biopsy and the biopsy operator estimates where it might be on an ultrasound image, and software fusion (SF), where regions of interest on magnetic resonace images are identified and contoured before biopsy and overlayed with the prostate contours on ultrasound images during the biopsy. Systematic biopsy may be used in addition to targeted biopsy. A number of SF technologies are available. However, the effectiveness and cost-effectiveness of SF compared with CF is uncertain. Objectives This study aimed to assess the clinical and cost-effectiveness of SF biopsy systems in people with suspected localised and locally advanced PCa. Methods Systematic review A systematic review of the diagnostic accuracy, clinical effectiveness, safety and practical implementation of nine SF systems compared with CF and with each other, in people suspected PCa according to MRI was conducted. Comprehensive bibliographic searches, including MEDLINE and EMBASE and supplementary sources, were conducted up to 2 August 2022 for published and unpublished literature. Studies of people with suspected PCa who have had a MRI scan that indicates a significant lesion [Likert or prostate imaging – reporting and data system (PI-RADS) score of 3 or more], including biopsy-naive and repeat biopsy patients with a previous negative prostate biopsy, and comparing SF with CF or with another SF device, were included. The following SF technologies were included: ARTEMIS (InnoMedicus ARTEMIS), BioJet (Healthcare Supply Solutions Ltd), BiopSee (Medcom), bkFusion (BK Medical UK Ltd and MIM Software Inc.), Fusion Bx 2.0 (Focal Healthcare), FusionVu (Exact Imaging), iSR’obot Mona LisaTM (Biobot iSR’obot), KOELIS Trinity (KOELIS and Kebomed) and UroNav Fusion Biopsy System (Phillips). Previous versions were also eligible. In-bore (or in-gantry) biopsies were excluded. Prospective, randomised and non-randomised comparative studies were included, and retrospective evidence where no prospective evidence could be found for an eligible SF device. To provide sufficient evidence for a network meta-analysis (NMA), within-patient comparisons or randomised controlled trials (RCTs) between SF and systematic biopsy, and between CF and systematic biopsy, were also eligible to inform indirect comparisons of diagnostic accuracy. Two researchers independently screened the titles and abstracts of all reports identified by the bibliographic searches and of all full-text papers subsequently obtained. Data extraction and quality assessment were conducted by at least one researcher and checked by a second. Risk of bias of diagnostic accuracy studies was assessed using quality assessment of diagnostic accuracy studies-comparative (QUADAS-C). For diagnostic accuracy outcomes, studies reporting sufficient data were included in network meta-analyses comparing SF and CF with or without concomitant systematic biopsy, and systematic biopsy alone, where odds of being categorised in each of different cancer grades were allowed to vary by biopsy type. Results were reported as odds ratios with 95% credible intervals (CrIs). Additional diagnostic accuracy results that could not be pooled in a meta-analysis and clinical effectiveness, safety and implementation outcomes were synthesised narratively. Economic analysis Cost-effectiveness evidence comparing SF biopsy systems with CF for targeted prostate biopsy in men with suspected PCa was identified by the previously mentioned searches, with evidence narratively summarised and tabulated. Studies were appraised for their quality, generalisability and appropriateness to inform the decision problem as defined by the National Institute for Health and Care Excellence Diagnostics Assessment Report (NICE DAR) scope. A targeted search was conducted to identify evidence to support the development of a de novo decision model. The searches aimed to identify cost-effectiveness evidence of diagnostic strategies at the point of biopsy to support the model conceptualisation. Evidence was reviewed to (1) identify value components of the biopsy approaches, (2) characterise alternative mechanisms of evidence linkage from disease prevalence, diagnostic accuracy, choice of treatment to final outcomes, and (3) identify any UK-relevant sources of evidence. A de novo decision analytic model was developed to estimate the cost-effectiveness of SF compared to CF. The model evaluated two strategies for two alternative comparisons: (1) targeted SF biopsy versus targeted cognitive biopsy and (2) combined (targeted and systematic) SF biopsy versus combined cognitive biopsy. The four strategies could not be incrementally compared due to the mechanism of evidence generation for the diagnostic accuracy, which relied on separate evidence networks. The de novo model consisted of two components: (1) a decision tree, which captured biopsy adverse events (AEs), repeated biopsies and classified individuals according to their biopsy results and underlying true disease status, and (2) long-term model to link classification to clinical management decisions and this to longer-term costs and consequences (e.g. disease progression and PCa mortality) so that differences in costs, life-year gains and quality-adjusted life-years (QALYs) were quantified over a lifetime horizon. The model required the development of (1) an extension to the evidence synthesis to allow quantifying the extension of test misclassification in the diagnostic model with SF biopsy and CF biopsy, and (2) an inference model to derive unobservable transition probabilities for the long-term model. Results The systematic review of clinical evidence included a total of 3733 patients who received SF and 2154 individuals with CF from 23 studies. Evidence was included for all devices specified in the protocol, except for Fusion Bx 2.0 and FusionVu. Overall, the evidence for all devices was at high risk of bias. Overall, biopsy-naive patients were under-represented. Fourteen studies were included in the meta-analyses. Diagnostic accuracy Across all analyses results must be interpreted with caution due to the high risk of bias in the evidence base and wide uncertainty over the results. The meta-analyses show that patients undergoing SF biopsy may have: (1) a lower probability of being classified as not having cancer, (2) similar probability of being classified as having non-clinically significant cancer [International Society of Urological Pathology (ISUP) grade 1], and (3) higher probability of being classified at higher ISUP grades, particularly ISUP 2. Similar results were obtained where both biopsy methods were combined with systematic biopsy. Additional meta-analyses of cancer detection rates suggest that, compared with CF biopsy, SF may identify more PCa (any grade) (OR 1.30; 95% CrI 1.06, 1.61). Adding systematic biopsy to cognitive or SF may increase the detection of all PCa and of clinically significant (CS) cancer, and from this evidence there is no suggestion that SF with concomitant systematic biopsy is superior to CF with systematic biopsy. Meta-analyses of cancer detection rates, by individual device, showed that compared with CF biopsy, BioJet and Urostation are associated with a higher detection of PCa overall. There was no evidence that any of the SF devices increased detection of CS cancer (except for BioJet, although this is based on one low-quality study), and overall, the evidence was insufficient to conclude whether any individual devices were superior to CF, or whether some SF technologies are more accurate than others. Clinical effectiveness There is no evidence that biopsy positivity rates and safety outcomes differ significantly between SF and CF, or between SF devices. There was some evidence that systems with rigid registration (BioJet or UroNav) are easier and faster to use than elastic registration (KOELIS Trinity), although this is informed by a single, small study and is not conclusive. Cost-effectiveness One full cost-effectiveness study of SF compared targeted SF to targeted CF. However, the findings of the study were not considered generalisable to the decision problem under assessment. Sixteen studies were identified of which nine were selected to inform the conceptualisation and parameterisation of the de novo decision model. The base-case cost-effectiveness analysis suggests for the targeted biopsy and the combined biopsy comparisons, that SF strategy is on average costlier and yields greater QALYs than the CF strategy, resulting in a probabilistic incremental cost-effectiveness ratio (ICER) of £6197 and £2199 per additional QALY for each comparison, respectively. These ICERs are below the lower bound of the cost-effectiveness threshold range recommended by NICE, suggesting that SF may be cost-effective compared to CFs in both the targeted and the combined comparisons. However, these results should be interpreted cautiously given the uncertainties in the relative diagnostic accuracy evidence which informs the model. The probabilistic analysis suggests a higher probability of cost-effectiveness for SF versus CF at the range of cost-effectiveness thresholds recommended by NICE (0.64 and 0.68 at £20,000 and £30,000 per additional QALY for targeted SF biopsy). Discussion This assessment includes a broad, comprehensive literature search for software and CF technologies and has been conducted following recognised guidelines to ensure high quality. The review identified evidence on the diagnostic accuracy of nine SF technologies, and is the first systematic review to formally compare the relative accuracy of SF and CF, with and without systematic biopsy, as well as different SF devices, using both direct and indirect evidence in a NMA. Unlike recent systematic review evidence, our review found that SF increased detection of clinically insignificant cancer compared with CF. Our review has a number of limitations. The evidence included in the systematic review is at high risk of bias overall. There was variation in patient and study characteristics. Biopsy-naive patients, who form the large majority of patients eligible for targeted biopsy, were under-represented, although there was insufficient evidence to evaluate whether the relative accuracy of software and CF differed between biopsy-naive and repeat biopsy patients. There was insufficient evidence to explore the impact of a number of other potential effect modifiers, including lesion location, operator experience, biopsy routes and anaesthesia methods. There were few studies per comparison, not all studies reported outcomes by all cancer grades, and most estimates from the meta-analyses were imprecise, particularly at higher cancer grades where data were most sparse. The network meta-analyses relied on the assumption that CF was equivalent across different centres, which is uncertain. No evidence was found for most of this assessment’s prespecified outcomes: biopsy sample suitability/quality, number of repeat biopsies performed, procedure completion rates, software failure rate, time to diagnosis, length of hospital stay, time taken for MR image preparation, subsequent PCa management, re-biopsy rate, hospitalisation, overall survival, progression-free survival (PFS), patient- and carer- reported outcomes [including tolerability and health-related quality of life (HRQoL)], barriers and facilitators to implementations. The cost-effectiveness results are driven by the modelled differences in diagnostic accuracy between software and CF, particularly the increased correct detection of Cambridge Prognostic Group 1 (CPG 1) (resulting in net losses for SF) and CPG 2 (resulting in net gains for SF). The External Assessment Group (EAG)’s NMA and its extension underpinned the economic model, so its limitations apply to the cost-effectiveness estimates. The magnitude of value realised for SF, compared with CF, depends on the balance between different degrees of misclassification and correct classification with the two technologies and on the prevalence of disease at each cancer grade. The value of SF is thus driven by comparative diagnostic accuracy (compared to ‘gold standard’) derived where evidence is particularly sparse (cancer grades above 2), and by prevalence, which is also affected by evidence sparsity. Therefore, the estimates of cost-effectiveness are affected by unquantified uncertainty and should be interpreted with caution. Conclusions Compared to CF biopsy, patients undergoing SF biopsy may show a lower probability of being classified as not having cancer, similar probability of being classified as having non-CS cancer, and a higher probability of being classified at higher ISUPs, particularly ISUP 2. Both SF and CF biopsy can miss CS cancer lesions, and the addition of standard-systematic biopsy increases the detection of all PCa and CS cancer for both fusion methods. There is insufficient evidence to conclude on the relative accuracy and clinical effectiveness of different software devices. Cost-effectiveness estimates comparing software to CF were generally favourable to SF, except where the technologies were assumed to have the same diagnostic accuracy. The drivers of economic value of SF, comparative diagnostic accuracy and prevalence, are affected by unquantified uncertainty. Judgements on the economic value of SF require integration of the uncertainties over the clinical evidence with the overall cost-effectiveness. Recommendations for further research High-quality, sufficiently powered RCT evidence comparing SF biopsy with CF biopsy is required to address limitations from the existing evidence. Improved reporting of diagnostic accuracy outcomes would enable future syntheses to make use of a larger body of evidence. Study registration This trial is registered as PROSPERO CRD42022329259. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: 135477) and is published in full in Health Technology Assessment; Vol. 28, No. 61. See the NIHR Funding and Awards website for further information.

Background: Most surgical incisions heal by primary intention (i.e. wound edges are apposed with sutures, clips or glue); however, some heal by secondary intention (i.e. the wound is left open and heals by formation of granulation tissue). There is, however, a lack of evidence regarding the epidemiology, management and impact on patients’ quality of life of these surgical wounds healing by secondary intention, resulting in uncertainty regarding effective treatments and difficulty in planning care and research. Objectives: To derive a better understanding of the nature, extent, costs, impact and outcomes of surgical wounds healing by secondary intention, effective treatments, and the value and nature of further research. Design: Cross-sectional survey; inception cohort; cost-effectiveness and value of implementation analyses; qualitative interviews; and pilot, feasibility randomised controlled trial. Setting: Acute and community care settings in Leeds and Hull, Yorkshire, UK. Participants: Adults (or for qualitative interviews, patients or practitioners) with previous experience of a surgical wound healing by secondary intention. Inclusion criteria varied between the individual workstreams. Interventions: The pilot, feasibility randomised controlled trial compared negative-pressure wound therapy – a device applying a controlled vacuum to a wound via a dressing – with usual care (no negative-pressure wound therapy). Results: Survey data estimated that treated surgical wounds healing by secondary intention have a point prevalence of 4.1 per 10,000 population (95% confidence interval 3.5 to 4.7 per 10,000 population). Surgical wounds healing by secondary intention most frequently occurred following colorectal surgery (n = 80, 42.8% cross-sectional survey; n = 136, 39.7% inception cohort) and were often planned before surgery (n = 89, 47.6% cross-sectional survey; n = 236, 60.1% inception cohort). Wound care was frequently delivered in community settings (n = 109, 58.3%) and most patients (n = 184, 98.4%) received active wound treatment. Cohort data identified hydrofibre dressings (n = 259, 65.9%) as the most common treatment, although 29.3% (n = 115) of participants used negative-pressure wound therapy at some time during the study. Surgical wounds healing by secondary intention occurred in 81.4% (n = 320) of participants at a median of 86 days (95% confidence interval 75 to 103 days). Baseline wound area (p ≤ 0.01), surgical wound contamination (determined during surgery; p = 0.04) and wound infection at any time (p ≤ 0.01) (i.e. at baseline or postoperatively) were found to be predictors of prolonged healing. Econometric models, using observational, cohort study data, identified that, with little uncertainty, negative-pressure wound therapy treatment is more costly and less effective than standard dressing treatment for the healing of open surgical wounds. Model A (ordinary least squares with imputation) effectiveness: 73 days longer than those who did not receive negative-pressure wound therapy (95% credible interval 33.8 to 112.8 days longer). Model A cost-effectiveness (associated incremental quality-adjusted life-years): observables –0.012 (standard error 0.005) and unobservables –0.008 (standard error 0.011). Model B (two-stage model, logistic and linear regression) effectiveness: 46 days longer than those who did not receive negative-pressure wound therapy (95% credible interval 19.6 to 72.5 days longer). Model B cost-effectiveness (associated incremental quality-adjusted life-years): observables –0.007 (standard error 0.004) and unobservables –0.027 (standard error 0.017). Patient interviews (n = 20) identified initial reactions to surgical wounds healing by secondary intention of shock and disbelief. Impaired quality of life characterised the long healing process, with particular impact on daily living for patients with families or in paid employment. Patients were willing to try any treatment promising wound healing. Health professionals (n = 12) had variable knowledge of surgical wound healing by secondary intention treatments and, frequently, favoured negative-pressure wound therapy, despite the lack of robust evidence. The pilot feasibility randomised controlled trial screened 248 patients for eligibility and subsequently recruited and randomised 40 participants to receive negative-pressure wound therapy or usual care (no negative-pressure wound therapy). Data indicated that it was feasible to complete a full randomised controlled trial to provide definitive evidence for the clinical effectiveness and cost-effectiveness of negative-pressure wound therapy as a treatment for surgical wounds healing by secondary intention. Key elements and recommendations for a larger randomised controlled trial were identified. Limitations: This research programme was conducted in a single geographical area (i.e. Yorkshire and the Humber, UK) and local guidelines and practices may have affected treatment availability, and so may not represent UK-wide treatment choices. A wide range of wound types were included; however, some wound types may be under-represented, meaning that this research may not represent the overall surgical wound healing by secondary intention population. The lack of randomised controlled trial data on the relative effects of negative-pressure wound therapy in surgical wounds healing by secondary intention resulted in much of the economic modelling being based on observational data. Observational data, even with extensive adjustment, do not negate the potential for unresolved confounding to affect the results, which can reduce confidence in conclusions drawn from observational data. Definitive evidence from a randomised controlled trial may be the only way to overcome this lack of confidence. Conclusions: This research has provided new information regarding the nature, extent, costs, impacts and outcomes of surgical wounds healing by secondary intention, treatment effectiveness, and the value and nature of future research, while addressing previous uncertainties regarding the problem of surgical wounds healing by secondary intention. Aspects of our research indicate that negative-pressure wound therapy is more costly and less effective than standard dressing for the healing of open surgical wounds. However, because this conclusion is based solely on observational data, it may be affected by unresolved confounding. Should a future randomised controlled trial be considered necessary, its design should reflect careful consideration of the findings of this programme of research. Future work: This research signals the importance of further research on surgical wound healing by secondary intention. Key research questions raised by this programme of research include (1) which treatments are clinically effective and cost-effective for surgical wound healing by secondary intention for all patients or for particular patient subgroups? (2) Can particular prognostic factors predict time to healing of surgical wound healing by secondary intention? And (3) do psychosocial interventions have the potential to improve quality of life in people with hard-to-heal surgical wound healing by secondary intention? Given that negative-pressure wound therapy has been widely adopted, with relatively little evidence to support its use, the design and outcomes of a randomised controlled trial would need to be carefully considered. We focused in this research on wound healing, and maintain, based on the findings of patient interviews, that this is a key outcome for future research. Impacts of negative-pressure wound therapy on outcomes such as infection and reoperation should also be considered, as should patients’ views of the treatment. The type of patient group recruited and the outcomes of interest will all influence the duration of follow-up of any planned study. The comparator in any future study will also need careful consideration. Trial registration: Current Controlled Trials ISRCTN12761776. Funding: This project was funded by the National Institute for Health Research Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 8, No. 7. See the National Institute for Health Research Journals Library website for further project information.

Background: Compression is an effective and recommended treatment for venous leg ulcers. Although the four-layer bandage (4LB) is regarded as the gold standard compression system, it is recognised that the amount of compression delivered might be compromised by poor application technique. Also the bulky nature of the bandages might reduce ankle or leg mobility and make the wearing of shoes difficult. Two-layer compression hosiery systems are now available for the treatment of venous leg ulcers. Two-layer hosiery (HH) may be advantageous, as it has reduced bulk, which might enhance ankle or leg mobility and patient adherence. Some patients can also remove and reapply two-layer hosiery, which may encourage self-management and could reduce costs. However, little robust evidence exists about the effectiveness of two-layer hosiery for ulcer healing and no previous trials have compared two-layer hosiery delivering ‘high’ compression with the 4LB. Objectives: Part I To compare the clinical effectiveness and cost-effectiveness of HH and 4LB in terms of time to complete healing of venous leg ulcers. Part II To synthesise the relative effectiveness evidence (for ulcer healing) of high-compression treatments for venous leg ulcers using a mixed-treatment comparison (MTC). Part III To construct a decision-analytic model to assess the cost-effectiveness of high-compression treatments for venous leg ulcers. Design: Part I A multicentred, pragmatic, two-arm, parallel, open randomised controlled trial (RCT) with an economic evaluation. Part II MTC using all relevant RCT data – including Venous leg Ulcer Study IV (VenUS IV). Part III A decision-analytic Markov model. Settings: Part I Community nurse teams or services, general practitioner practices, leg ulcer clinics, tissue viability clinics or services and wound clinics within England and Northern Ireland. Participants: Part I Patients aged ≥ 18 years with a venous leg ulcer, who were willing and able to tolerate high compression. Interventions: Part I Participants in the intervention group received HH. The control group received the 4LB, which was applied according to standard practice. Both treatments are designed to deliver 40 mmHg of compression at the ankle. Part II and III All relevant high-compression treatments including HH, the 4LB and the two-layer bandage (2LB). Main outcome measures: Part I The primary outcome measure was time to healing of the reference ulcer (blinded assessment). Part II Time to ulcer healing. Part III Quality-adjusted life-years (QALYs) and costs. Results: Part I A total of 457 participants were recruited. There was no evidence of a difference in time to healing of the reference ulcer between groups in an adjusted analysis [hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.79 to 1.25; p = 0.96]. Time to ulcer recurrence was significantly shorter in the 4LB group (HR = 0.56, 95% CI 0.33 to 0.94; p = 0.026). In terms of cost-effectiveness, using QALYs as the measure of benefit, HH had a > 95% probability of being the most cost-effective treatment based on the within-trial analysis. Part II The MTC suggests that the 2LB has the highest probability of ulcer healing compared with other high-compression treatments. However, this evidence is categorised as low to very low quality. Part III Results suggested that the 2LB had the highest probability of being the most cost-effective high-compression treatment for venous leg ulcers. Conclusions: Trial data from VenUS IV found no evidence of a difference in venous ulcer healing between HH and the 4LB. HH may reduce ulcer recurrence rates compared with the 4LB and be a cost-effective treatment. When all available high-compression treatments were considered, the 2LB had the highest probability of being clinically effective and cost-effective. However, the underpinning evidence was sparse and more research is needed. Further research should thus focus on establishing, in a high-quality trial, the effectiveness of this compression system in particular. Trial registration: Current Controlled Trials ISRCTN49373072. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 57. See the NIHR Journals Library website for further project information.

Abstract Background Sparse relative effectiveness evidence is a frequent problem in Health Technology Assessment (HTA). Where evidence directly pertaining to the decision problem is sparse, it may be feasible to expand the evidence-base to include studies that relate to the decision problem only indirectly: for instance, when there is no evidence on a comparator, evidence on other treatments of the same molecular class could be used; similarly, a decision on children may borrow-strength from evidence on adults. Usually, in HTA, such indirect evidence is either included by ignoring any differences (‘lumping’) or not included at all (‘splitting’). However, a range of more sophisticated methods exists, primarily in the biostatistics literature. The objective of this study is to identify and classify the breadth of the available information-sharing methods. Methods Forwards and backwards citation-mining techniques were used on a set of seminal papers on the topic of information-sharing. Papers were included if they specified (network) meta-analytic methods for combining information from distinct populations, interventions, outcomes or study-designs. Results Overall, 89 papers were included. A plethora of evidence synthesis methods have been used for information-sharing. Most papers (n=79) described methods that shared information on relative treatment effects. Amongst these, there was a strong emphasis on methods for information-sharing across multiple outcomes (n=42) and treatments (n=25), with fewer papers focusing on study-designs (n=23) or populations (n=8). We categorise and discuss the methods under four ’core’ relationships of information-sharing: functional, exchangeability-based, prior-based and multivariate relationships, and explain the assumptions made within each of these core approaches. Conclusions This study highlights the range of information-sharing methods available. These methods often impose more moderate assumptions than lumping or splitting. Hence, the degree of information-sharing that they impose could potentially be considered more appropriate. Our identification of four ‘core’ methods of information-sharing allows for an improved understanding of the assumptions underpinning the different methods. Further research is required to understand how the methods differ in terms of the strength of sharing they impose and the implications of this for health care decisions.