The effectiveness and cost-effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) for trauma patients with uncontrolled torso haemorrhage: study protocol for a randomised clinical trial (the UK-REBOA trial).

BACKGROUND: Haemorrhage is the most common cause of preventable death after injury. REBOA is a novel technique whereby a percutaneously inserted balloon is deployed in the aorta, providing a relatively quick means of temporarily controlling haemorrhage and augmenting cerebral and coronary perfusion, until definitive control of haemorrhage can be attained. The aim of the UK-REBOA trial is to establish the clinical and cost-effectiveness of a policy of standard major trauma centre treatment plus REBOA, as compared with standard major trauma centre treatment alone, for the management of uncontrolled torso haemorrhage caused by injury. METHODS: Pragmatic, Bayesian, group-sequential, randomised controlled trial, performed in 16 major trauma centres in England. We aim to randomise 120 injured patients with suspected exsanguinating haemorrhage to either standard major trauma centre care plus REBOA or standard major trauma centre care alone. The primary clinical outcome is 90-day mortality. Secondary clinical outcomes include 3-h, 6-h, and 24-h mortality; in-hospital mortality; 6-month mortality; length of stay (in hospital and intensive care unit); 24-h blood product use; need for haemorrhage control procedure (operation or angioembolisation); and time to commencement of haemorrhage control procedure (REBOA, operation, or angioembolisation). The primary economic outcome is lifetime incremental cost per QALY gained, from a health and personal social services perspective. DISCUSSION: This study, which is the first to randomly allocate patients to treatment with REBOA or standard care, will contribute high-level evidence on the clinical and cost-effectiveness of REBOA in the management of trauma patients with exsanguinating haemorrhage and will provide important data on the feasibility of implementation of REBOA into mainstream clinical practice. TRIAL REGISTRATION: ISRCTN16184981.

Equity of access to critical care services in Scotland: A Bayesian spatial analysis.

BACKGROUND: There is increasing evidence that access to critical care services is not equitable. We aimed to investigate whether location of residence in Scotland impacts on the risk of admission to an Intensive Care Unit and on outcomes. METHODS: This was a population-based Bayesian spatial analysis of adult patients admitted to Intensive Care Units in Scotland between January 2011 and December 2015. We used a Besag-York-Mollié model that allows us to make direct probabilistic comparisons between areas regarding risk of admission to Intensive Care Units and on outcomes. RESULTS: A total of 17,596 patients were included. The five-year age- and sex-standardised admission rate was 352 per 100,000 residents. There was a cluster of Council Areas in the North-East of the country which had lower adjusted admission rates than the Scottish average. Midlothian, in South East Scotland had higher spatially adjusted admission rates than the Scottish average. There was no evidence of geographical variation in mortality. CONCLUSION: Access to critical care services in Scotland varies with location of residence. Possible reasons include differential co-morbidity burden, service provision and access to critical care services. In contrast, the probability of surviving an Intensive Care Unit admission, if admitted, does not show geographical variation.

Total versus partial knee replacement in patients with medial compartment knee osteoarthritis: the TOPKAT RCT.

BACKGROUND: Late-stage medial compartment knee osteoarthritis can be treated using total knee replacement or partial (unicompartmental) knee replacement. There is high variation in treatment choice and insufficient evidence to guide selection. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of partial knee replacement compared with total knee replacement in patients with medial compartment knee osteoarthritis. The findings are intended to guide surgical decision-making for patients, surgeons and health-care providers. DESIGN: This was a randomised, multicentre, pragmatic comparative effectiveness trial that included an expertise component. The target sample size was 500 patients. A web-based randomisation system was used to allocate treatments. SETTING: Twenty-seven NHS hospitals (68 surgeons). PARTICIPANTS: Patients with medial compartment knee osteoarthritis. INTERVENTIONS: The trial compared the overall management strategy of partial knee replacement treatment with total knee replacement treatment. No specified brand or subtype of implant was investigated. MAIN OUTCOME MEASURES: The Oxford Knee Score at 5 years was the primary end point. Secondary outcomes included activity scores, global health measures, transition items, patient satisfaction (Lund Score) and complications (including reoperation, revision and composite 'failure' - defined by minimal Oxford Knee Score improvement and/or reoperation). Cost-effectiveness was also assessed. RESULTS: A total of 528 patients were randomised (partial knee replacement, n = 264; total knee replacement, n = 264). The follow-up primary outcome response rate at 5 years was 88% and both operations had good outcomes. There was no significant difference between groups in mean Oxford Knee Score at 5 years (difference 1.04, 95% confidence interval -0.42 to 2.50). An area under the curve analysis of the Oxford Knee Score at 5 years showed benefit in favour of partial knee replacement over total knee replacement, but the difference was within the minimal clinically important difference [mean 36.6 (standard deviation 8.3) (n = 233), mean 35.1 (standard deviation 9.1) (n = 231), respectively]. Secondary outcome measures showed consistent patterns of benefit in the direction of partial knee replacement compared with total knee replacement although most differences were small and non-significant. Patient-reported improvement (transition) and reflection (would you have the operation again?) showed statistically significant superiority for partial knee replacement only, but both of these variables could be influenced by the lack of blinding. The frequency of reoperation (including revision) by treatment received was similar for both groups: 22 out of 245 for partial knee replacement and 28 out of 269 for total knee replacement patients. Revision rates at 5 years were 10 out of 245 for partial knee replacement and 8 out of 269 for total knee replacement. There were 28 'failures' of partial knee replacement and 38 'failures' of total knee replacement (as defined by composite outcome). Beyond 1 year, partial knee replacement was cost-effective compared with total knee replacement, being associated with greater health benefits (measured using quality-adjusted life-years) and lower health-care costs, reflecting lower costs of the index surgery and subsequent health-care use. LIMITATIONS: It was not possible to blind patients in this study and there was some non-compliance with the allocated treatment interventions. Surgeons providing partial knee replacement were relatively experienced with the procedure. CONCLUSIONS: Both total knee replacement and partial knee replacement are effective, offer similar clinical outcomes and have similar reoperation and complication rates. Some patient-reported measures of treatment approval were significantly higher for partial knee replacement than for total knee replacement. Partial knee replacement was more cost-effective (more effective and cost saving) than total knee replacement at 5 years. FUTURE WORK: Further (10-year) follow-up is in progress to assess the longer-term stability of these findings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03013488 and ClinicalTrials.gov NCT01352247. 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. 24, No. 20. See the NIHR Journals Library website for further project information.

WHAT WAS THE QUESTION?: Two types of knee replacement are available for patients with arthritis of the inner part of their knee: a partial knee replacement or a total knee replacement. It is not known which replacement offers most benefit for the patient or for the health-care system. WHAT DID WE DO?: We performed a large study involving 528 patients at 27 hospitals with 68 experienced surgeons, in which half of the patients underwent partial knee replacement and the other half underwent total knee replacement. We took yearly scores and measures, including pain, function, whether or not the operation was successful, and the costs of each patient for 5 years. Comparison between treatments was assessed at 5 years post operation. WHAT DID WE FIND?: Good outcomes and relatively few complications were observed after both operations. The measurements taken to assess the clinical benefit were largely very similar between the two groups. Where differences did occur at 5 years, there were only small differences between the two knee replacements and partial knee replacement was generally favoured. Some measurements, however, did show a larger difference between the two groups, including whether or not the operation addressed the patients' problems and whether or not the patient would have the operation again. These measurements were also in favour of partial knee replacement, but caution is required not to overstate importance, as patients in the study knew which device they had had implanted. The number of patients requiring further operations or revision surgery was similar in the two groups. This last finding contrasts with information from previously obtained, mainly non-randomised, studies and is of high relevance. The cost of each operation in relation to the benefit obtained was clearly in favour of partial knee replacement. WHAT DOES THIS MEAN?: Both operations are effective for use in the NHS. There appear to be some modest clinical advantages for patients to undergo partial knee replacement over total knee replacement but, importantly, the study casts doubt over previous concerns on high reoperation rates for partial knee replacement. The study has shown that reoperation rates recorded from different sources (cohort or trials) can be conflicting.

Five-Year Outcomes of a Randomized Trial of Treatments for Varicose Veins.

BACKGROUND: Endovenous laser ablation and ultrasound-guided foam sclerotherapy are recommended alternatives to surgery for the treatment of primary varicose veins, but their long-term comparative effectiveness remains uncertain. METHODS: In a randomized, controlled trial involving 798 participants with primary varicose veins at 11 centers in the United Kingdom, we compared the outcomes of laser ablation, foam sclerotherapy, and surgery. Primary outcomes at 5 years were disease-specific quality of life and generic quality of life, as well as cost-effectiveness based on models of expected costs and quality-adjusted life-years (QALYs) gained that used data on participants' treatment costs and scores on the EuroQol EQ-5D questionnaire. RESULTS: Quality-of-life questionnaires were completed by 595 (75%) of the 798 trial participants. After adjustment for baseline scores and other covariates, scores on the Aberdeen Varicose Vein Questionnaire (on which scores range from 0 to 100, with lower scores indicating a better quality of life) were lower among patients who underwent laser ablation or surgery than among those who underwent foam sclerotherapy (effect size [adjusted differences between groups] for laser ablation vs. foam sclerotherapy, -2.86; 95% confidence interval [CI], -4.49 to -1.22; P<0.001; and for surgery vs. foam sclerotherapy, -2.60; 95% CI, -3.99 to -1.22; P<0.001). Generic quality-of-life measures did not differ among treatment groups. At a threshold willingness-to-pay ratio of £20,000 ($28,433 in U.S. dollars) per QALY, 77.2% of the cost-effectiveness model iterations favored laser ablation. In a two-way comparison between foam sclerotherapy and surgery, 54.5% of the model iterations favored surgery. CONCLUSIONS: In a randomized trial of treatments for varicose veins, disease-specific quality of life 5 years after treatment was better after laser ablation or surgery than after foam sclerotherapy. The majority of the probabilistic cost-effectiveness model iterations favored laser ablation at a willingness-to-pay ratio of £20,000 ($28,433) per QALY. (Funded by the National Institute for Health Research; CLASS Current Controlled Trials number, ISRCTN51995477.).

The clinical and cost-effectiveness of total versus partial knee replacement in patients with medial compartment osteoarthritis (TOPKAT): 5-year outcomes of a randomised controlled trial.

BACKGROUND: Late-stage isolated medial knee osteoarthritis can be treated with total knee replacement (TKR) or partial knee replacement (PKR). There is high variation in treatment choice and little robust evidence to guide selection. The Total or Partial Knee Arthroplasty Trial (TOPKAT) therefore aims to assess the clinical effectiveness and cost-effectiveness of TKR versus PKR in patients with medial compartment osteoarthritis of the knee, and this represents an analysis of the main endpoints at 5 years. METHODS: Our multicentre, pragmatic randomised controlled trial was done at 27 UK sites. We used a combined expertise-based and equipoise-based approach, in which patients with isolated osteoarthritis of the medial compartment of the knee and who satisfied general requirements for a medial PKR were randomly assigned (1:1) to receive PKR or TKR by surgeons who were either expert in and willing to perform both surgeries or by a surgeon with particular expertise in the allocated procedure. The primary endpoint was the Oxford Knee Score (OKS) 5 years after randomisation in all patients assigned to groups. Health-care costs (in UK 2017 prices) and cost-effectiveness were also assessed. This trial is registered with ISRCTN (ISRCTN03013488) and ClinicalTrials.gov (NCT01352247). FINDINGS: Between Jan 18, 2010, and Sept 30, 2013, we assessed 962 patients for their eligibility, of whom 431 (45%) patients were excluded (121 [13%] patients did not meet the inclusion criteria and 310 [32%] patients declined to participate) and 528 (55%) patients were randomly assigned to groups. 94% of participants responded to the follow-up survey 5 years after their operation. At the 5-year follow-up, we found no difference in OKS between groups (mean difference 1·04, 95% CI -0·42 to 2·50; p=0·159). In our within-trial cost-effectiveness analysis, we found that PKR was more effective (0·240 additional quality-adjusted life-years, 95% CI 0·046 to 0·434) and less expensive (-£910, 95% CI -1503 to -317) than TKR during the 5 years of follow-up. This finding was a result of slightly better outcomes, lower costs of surgery, and lower follow-up health-care costs with PKR than TKR. INTERPRETATION: Both TKR and PKR are effective, offer similar clinical outcomes, and result in a similar incidence of re-operations and complications. Based on our clinical findings, and results regarding the lower costs and better cost-effectiveness with PKR during the 5-year study period, we suggest that PKR should be considered the first choice for patients with late-stage isolated medial compartment osteoarthritis. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Exploring the role and function of trial steering committees: results of an expert panel meeting.

BACKGROUND: The independent oversight of clinical trials, which is recommended by the Medical Research Council (MRC) Guidelines for Good Clinical Practice, is typically provided by an independent advisory Data Monitoring Committee (DMC) and an independent executive committee, to whom the DMC makes recommendations. The detailed roles and function of this executive committee, known as the Trial Steering Committee (TSC), have not previously been studied or reviewed since those originally proposed by the MRC in 1998. METHODS: An expert panel (n = 7) was convened comprising statisticians, clinicians and trial methodologists with prior TSC experience. Twelve questions about the role and responsibilities of the TSC were discussed by the panel at two full-day meetings. Each meeting was transcribed in full and the discussions were summarised. RESULTS: The expert panel reached agreement on the role of the TSC, to which it was accountable, the membership, the definition of independence, and the experience and training needed. The management of ethical issues, difficult/complex situations and issues the TSC should not ask the DMC to make recommendations on were more difficult to discuss without specific examples, but support existed for further work to help share issues and to provide appropriate training for TSC members. Additional topics discussed, which had not been identified by previous work relating to the DMCs but were pertinent to the role of the TSC, included the following: review of data sharing requests, indemnity, lifespan of the TSC, general TSC administration, and the roles of both the Funder and the Sponsor. CONCLUSIONS: This paper presents recommendations that will contribute to the revision and update of the MRC TSC terms of reference. Uncertainty remains in some areas due to the absence of real-life examples; future guidance on these issues would benefit from a repository of case studies. Notably, the role of a patient and public involvement (PPI) contributor was not discussed, and further work is warranted to explore the role of a PPI contributor in independent trial oversight.

Perspectives on financial incentives to health service providers for increasing breast feeding and smoking quit rates during pregnancy: a mixed methods study.

OBJECTIVE: To explore the acceptability, mechanisms and consequences of provider incentives for smoking cessation and breast feeding as part of the Benefits of Incentives for Breastfeeding and Smoking cessation in pregnancy (BIBS) study. DESIGN: Cross-sectional survey and qualitative interviews. SETTING: Scotland and North West England. PARTICIPANTS: Early years professionals: 497 survey respondents included 156 doctors; 197 health visitors/maternity staff; 144 other health staff. Qualitative interviews or focus groups were conducted with 68 pregnant/postnatal women/family members; 32 service providers; 22 experts/decision-makers; 63 conference attendees. METHODS: Early years professionals were surveyed via email about the acceptability of payments to local health services for reaching smoking cessation in pregnancy and breastfeeding targets. Agreement was measured on a 5-point scale using multivariable ordered logit models. A framework approach was used to analyse free-text survey responses and qualitative data. RESULTS: Health professional net agreement for provider incentives for smoking cessation targets was 52.9% (263/497); net disagreement was 28.6% (142/497). Health visitors/maternity staff were more likely than doctors to agree: OR 2.35 (95% CI 1.51 to 3.64; p<0.001). Net agreement for provider incentives for breastfeeding targets was 44.1% (219/497) and net disagreement was 38.6% (192/497). Agreement was more likely for women (compared with men): OR 1.81 (1.09 to 3.00; p=0.023) and health visitors/maternity staff (compared with doctors): OR 2.54 (95% CI 1.65 to 3.91; p<0.001). Key emergent themes were 'moral tensions around acceptability', 'need for incentives', 'goals', 'collective or divisive action' and 'monitoring and proof'. While provider incentives can focus action and resources, tensions around the impact on relationships raised concerns. Pressure, burden of proof, gaming, box-ticking bureaucracies and health inequalities were counterbalances to potential benefits. CONCLUSIONS: Provider incentives are favoured by non-medical staff. Solutions which increase trust and collaboration towards shared goals, without negatively impacting on relationships or increasing bureaucracy are required.

Clinical effectiveness and cost-effectiveness of open and arthroscopic rotator cuff repair [the UK Rotator Cuff Surgery (UKUFF) randomised trial].

BACKGROUND: Uncertainty exists regarding the best management of patients with degenerative tears of the rotator cuff. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of arthroscopic and open rotator cuff repair in patients aged ≥ 50 years with degenerative rotator cuff tendon tears. DESIGN: Two parallel-group randomised controlled trial. SETTING: Nineteen teaching and district general hospitals in the UK. PARTICIPANTS: Patients (n = 273) aged ≥ 50 years with degenerative rotator cuff tendon tears. INTERVENTIONS: Arthroscopic surgery and open rotator cuff repair, with surgeons using their usual and preferred method of arthroscopic or open repair. Follow-up was by telephone questionnaire at 2 and 8 weeks after surgery and by postal questionnaire at 8, 12 and 24 months after randomisation. MAIN OUTCOME MEASURES: The Oxford Shoulder Score (OSS) at 24 months was the primary outcome measure. Magnetic resonance imaging evaluation of the shoulder was made at 12 months after surgery to assess the integrity of the repair. RESULTS: The mean OSS improved from 26.3 [standard deviation (SD) 8.2] at baseline to 41.7 (SD 7.9) at 24 months for arthroscopic surgery and from 25.0 (SD 8.0) at baseline to 41.5 (SD 7.9) at 24 months for open surgery. When effect sizes are shown for the intervention, a negative sign indicates that an open procedure is favoured. For the intention-to-treat analysis, there was no statistical difference between the groups, the difference in OSS score at 24 months was -0.76 [95% confidence interval (CI) -2.75 to 1.22; p = 0.452] and the CI excluded the predetermined clinically important difference in the OSS of 3 points. There was also no statistical difference when the groups were compared per protocol (difference in OSS score -0.46, 95% CI -5.30 to 4.39; p = 0.854). The questionnaire response rate was > 86%. At 8 months, 77% of participants reported that shoulder problems were much or slightly better, and at 24 months this increased to 85%. There were no significant differences in mean cost between the arthroscopic group and the open repair group for any of the component resource-use categories, nor for the total follow-up costs at 24 months. The overall treatment cost at 2 years was £2567 (SD £176) for arthroscopic surgery and £2699 (SD £149) for open surgery, according to intention-to-treat analysis. For the per-protocol analysis there was a significant difference in total initial procedure-related costs between the arthroscopic group and the open repair group, with arthroscopic repair being more costly by £371 (95% CI £135 to £607). Total quality-adjusted life-years accrued at 24 months averaged 1.34 (SD 0.05) in the arthroscopic repair group and 1.35 (SD 0.05) in the open repair group, a non-significant difference of 0.01 (95% CI -0.11 to 0.10). The rate of re-tear was not significantly different across the randomised groups (46.4% and 38.6% for arthroscopic and open surgery, respectively). The participants with tears that were impossible to repair had the lowest OSSs, the participants with re-tears had slightly higher OSSs and the participants with healed repairs had the most improved OSSs. These findings were the same when analysed per protocol. CONCLUSION: In patients aged > 50 years with a degenerative rotator cuff tear there is no difference in clinical effectiveness or cost-effectiveness between open repair and arthroscopic repair at 2 years for the primary outcome (OSS) and all other prespecified secondary outcomes. Future work should explore new methods to improve tendon healing and reduce the high rate of re-tears observed in this trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN97804283. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 80. See the NIHR Journals Library website for further project information.

Access to specialist care: Optimizing the geographic configuration of trauma systems.

BACKGROUND: The optimal geographic configuration of health care systems is key to maximizing accessibility while promoting the efficient use of resources. This article reports the use of a novel approach to inform the optimal configuration of a national trauma system. METHODS: This is a prospective cohort study of all trauma patients, 15 years and older, attended to by the Scottish Ambulance Service, between July 1, 2013, and June 30, 2014. Patients underwent notional triage to one of three levels of care (major trauma center [MTC], trauma unit, or local emergency hospital). We used geographic information systems software to calculate access times, by road and air, from all incident locations to all candidate hospitals. We then modeled the performance of all mathematically possible network configurations and used multiobjective optimization to determine geospatially optimized configurations. RESULTS: A total of 80,391 casualties were included. A network with only high- or moderate-volume MTCs (admitting at least 650 or 400 severely injured patients per year, respectively) would be optimally configured with a single MTC. A network accepting lower-volume MTCs (at least 240 severely injured patients per year) would be optimally configured with two MTCs. Both configurations would necessitate an increase in the number of helicopter retrievals. CONCLUSION: This study has shown that a novel combination of notional triage, network analysis, and mathematical optimization can be used to inform the planning of a national clinical network. Scotland's trauma system could be optimized with one or two MTCs. LEVEL OF EVIDENCE: Care management study, level IV.

Clinical effectiveness and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the Comparison of LAser, Surgery and foam Sclerotherapy (CLASS) randomised controlled trial.

BACKGROUND: Foam sclerotherapy (foam) and endovenous laser ablation (EVLA) have emerged as alternative treatments to surgery for patients with varicose veins, but uncertainty exists regarding their effectiveness in the medium to longer term. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of foam, EVLA and surgery for the treatment of varicose veins. DESIGN: A parallel-group randomised controlled trial (RCT) without blinding, and economic modelling evaluation. SETTING: Eleven UK specialist vascular centres. PARTICIPANTS: Seven hundred and ninety-eight patients with primary varicose veins (foam, n = 292; surgery, n = 294; EVLA, n = 212). INTERVENTIONS: Patients were randomised between all three treatment options (eight centres) or between foam and surgery (three centres). PRIMARY OUTCOME MEASURES: Disease-specific [Aberdeen Varicose Vein Questionnaire (AVVQ)] and generic [European Quality of Life-5 Dimensions (EQ-5D), Short Form questionnaire-36 items (SF-36) physical and mental component scores] quality of life (QoL) at 6 months. Cost-effectiveness as cost per quality-adjusted life-year (QALY) gained. SECONDARY OUTCOME MEASURES: Quality of life at 6 weeks; residual varicose veins; Venous Clinical Severity Score (VCSS); complication rates; return to normal activity; truncal vein ablation rates; and costs. RESULTS: The results appear generalisable in that participants' baseline characteristics (apart from a lower-than-expected proportion of females) and post-treatment improvement in outcomes were comparable with those in other RCTs. The health gain achieved in the AVVQ with foam was significantly lower than with surgery at 6 months [effect size -1.74, 95% confidence interval (CI) -2.97 to -0.50; p = 0.006], but was similar to that achieved with EVLA. The health gain in SF-36 mental component score for foam was worse than that for EVLA (effect size 1.54, 95% CI 0.01 to 3.06; p = 0.048) but similar to that for surgery. There were no differences in EQ-5D or SF-36 component scores in the surgery versus foam or surgery versus EVLA comparisons at 6 months. The trial-based cost-effectiveness analysis showed that, at 6 months, foam had the highest probability of being considered cost-effective at a ceiling willingness-to-pay ratio of £20,000 per QALY. EVLA was found to cost £26,107 per QALY gained versus foam, and was less costly and generated slightly more QALYs than surgery. Markov modelling using trial costs and the limited recurrence data available suggested that, at 5 years, EVLA had the highest probability (≈ 79%) of being cost-effective at conventional thresholds, followed by foam (≈ 17%) and surgery (≈ 5%). With regard to secondary outcomes, health gains at 6 weeks (p < 0.005) were greater for EVLA than for foam (EQ-5D, p = 0.004). There were fewer procedural complications in the EVLA group (1%) than after foam (7%) and surgery (8%) (p < 0.001). Participants returned to a wide range of behaviours more quickly following foam or EVLA than following surgery (p < 0.05). There were no differences in VCSS between the three treatments. Truncal ablation rates were higher for surgery (p < 0.001) and EVLA (p < 0.001) than for foam, and were similar for surgery and EVLA. CONCLUSIONS: Considerations of both the 6-month clinical outcomes and the estimated 5-year cost-effectiveness suggest that EVLA should be considered as the treatment of choice for suitable patients. FUTURE WORK: Five-year trial results are currently being evaluated to compare the cost-effectiveness of foam, surgery and EVLA, and to determine the recurrence rates following each treatment. This trial has highlighted the need for long-term outcome data from RCTs on QoL, recurrence rates and costs for foam sclerotherapy and other endovenous techniques compared against each other and against surgery. TRIAL REGISTRATION: Current Controlled Trials ISRCTN51995477. 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. 19, No. 27. See the NIHR Journals Library website for further project information.

Strengthening the ethical assessment of placebo-controlled surgical trials: three proposals.

BACKGROUND: Placebo-controlled surgical trials can provide important information about the efficacy of surgical interventions. However, they are ethically contentious as placebo surgery entails the risk of harms to recipients, such as pain, scarring or anaesthetic misadventure. This has led to claims that placebo-controlled surgical trials are inherently unethical. On the other hand, without placebo-controlled surgical trials, it may be impossible to know whether an apparent benefit from surgery is due to the intervention itself or to the placebo effect. DISCUSSION: In this paper we investigate justifications for placebo-controlled surgical trials and suggest three measures for strengthening their ethical acceptability. We argue that, given the extent, irreversibility and cost of surgical interventions, there is a need for the best possible evidence about their efficacy. In some cases, the strongest evidence will be from placebo-controlled surgical trials, especially where interventions are for outcomes (such as pain) that are likely to elicit a placebo response. In the second part of the paper, we propose three specific measures to increase the ethical acceptability of placebo-controlled surgical trials. The first is structured consultation with the relevant patient community about the risks and benefits of particular placebo-controlled surgical trials. The second seeks to address the therapeutic misconception through the use of educational materials, informed by patient consultation. Finally, we argue for ethical consideration of non-surgeon clinicians who are necessarily involved in the delivery of placebo-surgical interventions. SUMMARY: If there is no appropriate surgical comparator and the risks can be reduced to the absolute minimum (given the type of placebo procedure required), and the research has the support of the relevant patient community, there may be grounds for judging that the potential benefits of specific placebo-controlled surgical trials outweigh the risks. If so justified, the ethical acceptability of placebo-controlled surgical trials can be enhanced through using educational measures to address participant vulnerability, and by recognizing clinicians who are necessary participants in the research.

A randomized trial comparing treatments for varicose veins.

BACKGROUND: Ultrasound-guided foam sclerotherapy and endovenous laser ablation are widely used alternatives to surgery for the treatment of varicose veins, but their comparative effectiveness and safety remain uncertain. METHODS: In a randomized trial involving 798 participants with primary varicose veins at 11 centers in the United Kingdom, we compared the outcomes of foam, laser, and surgical treatments. Primary outcomes at 6 months were disease-specific quality of life and generic quality of life, as measured on several scales. Secondary outcomes included complications and measures of clinical success. RESULTS: After adjustment for baseline scores and other covariates, the mean disease-specific quality of life was slightly worse after treatment with foam than after surgery (P=0.006) but was similar in the laser and surgery groups. There were no significant differences between the surgery group and the foam or the laser group in measures of generic quality of life. The frequency of procedural complications was similar in the foam group (6%) and the surgery group (7%) but was lower in the laser group (1%) than in the surgery group (P<0.001); the frequency of serious adverse events (approximately 3%) was similar among the groups. Measures of clinical success were similar among the groups, but successful ablation of the main trunks of the saphenous vein was less common in the foam group than in the surgery group (P<0.001). CONCLUSIONS: Quality-of-life measures were generally similar among the study groups, with the exception of a slightly worse disease-specific quality of life in the foam group than in the surgery group. All treatments had similar clinical efficacy, but complications were less frequent after laser treatment and ablation rates were lower after foam treatment. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN51995477.).

Public acceptability of financial incentives for smoking cessation in pregnancy and breast feeding: a survey of the British public.

OBJECTIVE: To survey public attitudes about incentives for smoking cessation in pregnancy and for breast feeding to inform trial design. DESIGN: Cross-sectional survey. SETTING AND PARTICIPANTS: British general public. METHODS: Seven promising incentive strategies had been identified from evidence syntheses and qualitative interview data from service users and providers. These were shopping vouchers for: (1) validated smoking cessation in pregnancy and (2) after birth; (3) for a smoke-free home; (4) for proven breast feeding; (5) a free breast pump; (6) payments to health services for reaching smoking cessation in pregnancy targets and (7) breastfeeding targets. Ipsos MORI used area quota sampling and home-administered computer-assisted questionnaires, with randomised question order to assess agreement with different incentives (measured on a five-point scale). Demographic data and target behaviour experience were recorded. Analysis used multivariable ordered logit models. RESULTS: Agreement with incentives was mixed (ranging from 34% to 46%) among a representative sample of 1144 British adults. Mean agreement score was highest for a free breast pump, and lowest for incentives for smoking abstinence after birth. More women disagreed with shopping vouchers than men. Those with lower levels of education disagreed more with smoking cessation incentives and a breast pump. Those aged 44 or under agreed more with all incentive strategies compared with those aged 65 and over, particularly provider targets for smoking cessation. Non-white ethnic groups agreed particularly with breastfeeding incentives. Current smokers with previous stop attempts and respondents who had breast fed children agreed with providing vouchers for the respective behaviours. Up to £40/month vouchers for behaviour change were acceptable (>85%). CONCLUSIONS: Women and the less educated were more likely to disagree, but men and women of childbearing age to agree, with incentives designed for their benefit. Trials evaluating reach, impact on health inequalities and ethnic groups are required prior to implementing incentive interventions. TRIAL REGISTRATION NUMBER: CRD42012001980.

Selective decontamination of the digestive tract in critically ill patients treated in intensive care units: a mixed-methods feasibility study (the SuDDICU study).

BACKGROUND: Hospital-acquired infections (HAIs) are a major cause of morbidity and mortality. Critically ill patients in intensive care units (ICUs) are particularly susceptible to these infections. One intervention that has gained much attention in reducing HAIs is selective decontamination of the digestive tract (SDD). SDD involves the application of topical non-absorbable antibiotics to the oropharynx and stomach and a short course of intravenous (i.v.) antibiotics. SDD may reduce infections and improve mortality, but has not been widely adopted in the UK or internationally. Hence, there is a need to identify the reasons for low uptake and whether or not further clinical research is needed before wider implementation would be considered appropriate. OBJECTIVES: The project objectives were to (1) identify and describe the SDD intervention, (2) identify views about the evidence base, (3) identify acceptability of further research and (4) identify feasibility of further randomised controlled trials (RCTs). DESIGN: A four-stage approach involving (1) case studies of two ICUs in which SDD is delivered including observations, interviews and documentary analysis, (2) a three-round Delphi study for in-depth investigation of clinicians' views, including semi-structured interviews and two iterations of questionnaires with structured feedback, (3) a nationwide online survey of consultants in intensive care medicine and clinical microbiology and (4) semistructured interviews with international clinical triallists to identify the feasibility of further research. SETTING: Case studies were set in two UK ICUs. Other stages of this research were conducted by telephone and online with NHS staff working in ICUs. PARTICIPANTS: (1) Staff involved in SDD adoption or delivery in two UK ICUs, (2) ICU experts (intensive care consultants, clinical microbiologists, hospital pharmacists and ICU clinical leads), (3) all intensive care consultants and clinical microbiologists in the UK with responsibility for patients in ICUs were invited and (4) international triallists, selected from their research profiles in intensive care, clinical trials and/or implementation trials. INTERVENTIONS: SDD involves the application of topical non-absorbable antibiotics to the oropharynx and stomach and a short course of i.v. antibiotics. MAIN OUTCOME MEASURES: Levels of support for, or opposition to, SDD in UK ICUs; views about the SDD evidence base and about barriers to implementation; and feasibility of further SDD research (e.g. likely participation rates). RESULTS: (1) The two case studies identified complexity in the interplay of clinical and behavioural components of SDD, involving multiple staff. However, from the perspective of individual staff, delivery of SDD was regarded as simple and straightforward. (2) The Delphi study (n = 42) identified (a) specific barriers to SDD implementation, (b) uncertainty about the evidence base and (c) bimodal distributions for key variables, e.g. support for, or opposition to, SDD. (3) The national survey (n = 468) identified uncertainty about the effect of SDD on antimicrobial resistance, infection rates, mortality and cost-effectiveness. Most participants would participate in further SDD research. (4) The triallist interviews (n = 10) focused largely on the substantial challenges of conducting a large, multinational clinical effectiveness trial. CONCLUSIONS: There was considerable uncertainty about possible benefits and harms of SDD. Further large-scale clinical effectiveness trials of SDD in ICUs may be required to address these uncertainties, especially relating to antimicrobial resistance. There was a general willingness to participate in a future effectiveness RCT of SDD. However, support was not unanimous. Future research should address the barriers to acceptance and participation in any trial. There was some, but a low level of, interest in adoption of SDD, or studies to encourage implementation of SDD into practice. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 25. See the NIHR Journals Library website for further project information.

A randomised controlled trial of the clinical effectiveness and cost-effectiveness of different knee prostheses: the Knee Arthroplasty Trial (KAT).

BACKGROUND: In the late 1990s, new developments in knee replacement were identified as a priority for research within the NHS. The newer forms of arthroplasty were more expensive and information was needed on their safety and cost-effectiveness. OBJECTIVES: The Knee Arthroplasty Trial examined the clinical effectiveness and cost-effectiveness of four aspects of knee replacement surgery: patellar resurfacing, mobile bearings, all-polyethylene tibial components and unicompartmental replacement. DESIGN: This study comprised a partial factorial, pragmatic, multicentre randomised controlled trial with a trial-based cost-utility analysis which was conducted from the perspective of the NHS and the patients treated. Allocation was computer generated in a 1 : 1 ratio using a central system, stratified by eligible comparisons and surgeon, minimised by participant age, gender and site of disease. Surgeons were not blinded to allocated procedures. Participants were unblinded if they requested to know the prosthesis they received. SETTING: The setting for the trial was UK secondary care. PARTICIPANTS: Patients were eligible for inclusion if a decision had been made for them to have primary knee replacement surgery. Patients were recruited to comparisons for which the surgeon was in equipoise about which type of operation was most suitable. INTERVENTIONS: Patients were randomised to receive a knee replacement with the following: patellar resurfacing or no patellar resurfacing irrespective of the design of the prosthesis used; a mobile bearing between the tibial and femoral components or a bearing fixed to the tibial component; a tibial component made of either only high-density polyethylene ('all polyethylene') or a polyethylene bearing fixed to a metal backing plate with attached stem; or unicompartmental or total knee replacement. MAIN OUTCOME MEASURES: The primary outcome was the Oxford Knee Score (OKS). Other outcomes were Short Form 12; EuroQol 5D; intraoperative and postoperative complications; additional surgery; cost; and cost-effectiveness. Patients were followed up for a median of 10 years; the economic evaluation took a 10-year time horizon, discounting costs and quality-adjusted life-years (QALYs) at 3.5% per annum. RESULTS: A total of 116 surgeons in 34 centres participated and 2352 participants were randomised: 1715 in patellar resurfacing; 539 in mobile bearing; 409 in all-polyethylene tibial component; and 34 in the unicompartmental comparisons. Of those randomised, 345 were randomised to two comparisons. We can be more than 95% confident that patellar resurfacing is cost-effective, despite there being no significant difference in clinical outcomes, because of increased QALYs [0.187; 95% confidence interval (CI) -0.025 to 0.399] and reduced costs (-£104; 95% CI -£630 to £423). We found no definite advantage or disadvantage of mobile bearings in OKS, quality of life, reoperation and revision rates or cost-effectiveness. We found improved functional results for metal-backed tibias: complication, reoperation and revision rates were similar. The metal-backed tibia was cost-effective (particularly in the elderly), costing £35 per QALY gained. CONCLUSIONS: The results provide evidence to support the routine resurfacing of the patella and the use of metal-backed tibial components even in the elderly. Further follow-up is required to assess the stability of these findings over time and to inform the decision between mobile and fixed bearings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45837371. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and the orthopaedic industry. It will be published in full in Health Technology Assessment; Vol. 18, No. 19. See the NIHR Journals Library website for further project information.

A pragmatic multi-centre randomised controlled trial of fluid loading in high-risk surgical patients undergoing major elective surgery--the FOCCUS study.

INTRODUCTION: Fluid strategies may impact on patient outcomes in major elective surgery. We aimed to study the effectiveness and cost-effectiveness of pre-operative fluid loading in high-risk surgical patients undergoing major elective surgery. METHODS: This was a pragmatic, non-blinded, multi-centre, randomised, controlled trial. We sought to recruit 128 consecutive high-risk surgical patients undergoing major abdominal surgery. The patients underwent pre-operative fluid loading with 25 ml/kg of Ringer's solution in the six hours before surgery. The control group had no pre-operative fluid loading. The primary outcome was the number of hospital days after surgery with cost-effectiveness as a secondary outcome. RESULTS: A total of 111 patients were recruited within the study time frame in agreement with the funder. The median pre-operative fluid loading volume was 1,875 ml (IQR 1,375 to 2,025) in the fluid group compared to 0 (IQR 0 to 0) in controls with days in hospital after surgery 12.2 (SD 11.5) days compared to 17.4 (SD 20.0) and an adjusted mean difference of 5.5 days (median 2.2 days; 95% CI -0.44 to 11.44; P = 0.07). There was a reduction in adverse events in the fluid intervention group (P = 0.048) and no increase in fluid based complications. The intervention was less costly and more effective (adjusted average cost saving: £2,047; adjusted average gain in benefit: 0.0431 quality adjusted life year (QALY)) and has a high probability of being cost-effective. CONCLUSIONS: Pre-operative intravenous fluid loading leads to a non-significant reduction in hospital length of stay after high-risk major surgery and is likely to be cost-effective. Confirmatory work is required to determine whether these effects are reproducible, and to confirm whether this simple intervention could allow more cost-effective delivery of care. TRIAL REGISTRATION: Prospective Clinical Trials, ISRCTN32188676.

Developing the clinical components of a complex intervention for a glaucoma screening trial: a mixed methods study.

BACKGROUND: Glaucoma is a leading cause of avoidable blindness worldwide. Open angle glaucoma is the most common type of glaucoma. No randomised controlled trials have been conducted evaluating the effectiveness of glaucoma screening for reducing sight loss. It is unclear what the most appropriate intervention to be evaluated in any glaucoma screening trial would be. The purpose of this study was to develop the clinical components of an intervention for evaluation in a glaucoma (open angle) screening trial that would be feasible and acceptable in a UK eye-care service. METHODS: A mixed-methods study, based on the Medical Research Council (MRC) framework for complex interventions, integrating qualitative (semi-structured interviews with 46 UK eye-care providers, policy makers and health service commissioners), and quantitative (economic modelling) methods. Interview data were synthesised and used to revise the screening interventions compared within an existing economic model. RESULTS: The qualitative data indicated broad based support for a glaucoma screening trial to take place in primary care, using ophthalmic trained technical assistants supported by optometry input. The precise location should be tailored to local circumstances. There was variability in opinion around the choice of screening test and target population. Integrating the interview findings with cost-effectiveness criteria reduced 189 potential components to a two test intervention including either optic nerve photography or screening mode perimetry (a measure of visual field sensitivity) with or without tonometry (a measure of intraocular pressure). It would be more cost-effective, and thus acceptable in a policy context, to target screening for open angle glaucoma to those at highest risk but for both practicality and equity arguments the optimal strategy was screening a general population cohort beginning at age forty. CONCLUSIONS: Interventions for screening for open angle glaucoma that would be feasible from a service delivery perspective were identified. Integration within an economic modelling framework explicitly highlighted the trade-off between cost-effectiveness, feasibility and equity. This study exemplifies the MRC recommendation to integrate qualitative and quantitative methods in developing complex interventions. The next step in the development pathway should encompass the views of service users.

Using a business model approach and marketing techniques for recruitment to clinical trials.

Randomised controlled trials (RCTs) are generally regarded as the gold standard for evaluating health care interventions. The level of uncertainty around a trial's estimate of effect is, however, frequently linked to how successful the trial has been in recruiting and retaining participants. As recruitment is often slower or more difficult than expected, with many trials failing to reach their target sample size within the timescale and funding originally envisaged, the results are often less reliable than they could have been. The high number of trials that require an extension to the recruitment period in order to reach the required sample size potentially delays the introduction of more effective therapies into routine clinical practice. Moreover, it may result in less research being undertaken as resources are redirected to extending existing trials rather than funding additional studies.Poor recruitment to publicly-funded RCTs has been much debated but there remains remarkably little clear evidence as to why many trials fail to recruit well, which recruitment methods work, in which populations and settings and for what type of intervention. One proposed solution to improving recruitment and retention is to adopt methodology from the business world to inform and structure trial management techniques.We review what is known about interventions to improve recruitment to trials. We describe a proposed business approach to trials and discuss the implementation of using a business model, using insights gained from three case studies.

A cost-utility analysis of microwave endometrial ablation versus thermal balloon endometrial ablation.

OBJECTIVE: To evaluate the cost-effectiveness of microwave endometrial ablation (MEA) and thermal balloon endometrial ablation (TBALL) for heavy menstrual bleeding. METHODS: A cost-utility analysis performed alongside a pragmatic RCT in a single hospital within Scotland on women undergoing MEA and TBALL. Resource use data collected from all 314 trial participants were combined with study specific and published unit cost data to estimate a cost per patient. Quality-adjusted life-years (QALYs) were based on EQ-5D responses at baseline, 2 weeks, 6 and 12 months. The incremental cost per QALY of TBALL versus MEA was calculated and bootstrapping was performed to determine the likelihood that a treatment would be cost-effective at different threshold values for society's willingness to pay for a QALY. RESULTS: The mean cost of TBALL (10 years equipment life, 100 uses annually) of reusable equipment was pound181 (95% confidence interval [CI] pound70-434) greater than MEA. There were no statistically significant differences between the total nonhealth costs and health benefits of the two arms. On average, MEA provided more QALYs after adjusting for baseline EQ-5D score (0.017; 95% CI 0.017-0.051). In terms of mean incremental cost per QALY, MEA was, on average, dominant (less costly and at least as effective) and there was over a 90% chance that MEA would be considered cost-effective at a pound20,000 threshold of a cost per QALY. CONCLUSIONS: MEA is likely to be more cost-effective than TBALL at 1 year. Further longer-term follow-up is, however, needed.

A pragmatic multi-centre randomised controlled trial of fluid loading and level of dependency in high-risk surgical patients undergoing major elective surgery: trial protocol.

BACKGROUND: Patients undergoing major elective or urgent surgery are at high risk of death or significant morbidity. Measures to reduce this morbidity and mortality include pre-operative optimisation and use of higher levels of dependency care after surgery. We propose a pragmatic multi-centre randomised controlled trial of level of dependency and pre-operative fluid therapy in high-risk surgical patients undergoing major elective surgery. METHODS/DESIGN: A multi-centre randomised controlled trial with a 2 * 2 factorial design. The first randomisation is to pre-operative fluid therapy or standard regimen and the second randomisation is to routine intensive care versus high dependency care during the early post-operative period. We intend to recruit 204 patients undergoing major elective and urgent abdominal and thoraco-abdominal surgery who fulfil high-risk surgical criteria. The primary outcome for the comparison of level of care is cost-effectiveness at six months and for the comparison of fluid optimisation is the number of hospital days after surgery. DISCUSSION: We believe that the results of this study will be invaluable in determining the future care and clinical resource utilisation for this group of patients and thus will have a major impact on clinical practice. TRIAL REGISTRATION: Trial registration number - ISRCTN32188676.