Emergency Department Resuscitative Endovascular Balloon Occlusion of the Aorta in Trauma Patients With Exsanguinating Hemorrhage: The UK-REBOA Randomized Clinical Trial.

Importance: Bleeding is the most common cause of preventable death after trauma. Objective: To determine the effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) when used in the emergency department along with standard care vs standard care alone on mortality in trauma patients with exsanguinating hemorrhage. Design, Setting, and Participants: Pragmatic, bayesian, randomized clinical trial conducted at 16 major trauma centers in the UK. Patients aged 16 years or older with exsanguinating hemorrhage were enrolled between October 2017 and March 2022 and followed up for 90 days. Intervention: Patients were randomly assigned (1:1 allocation) to a strategy that included REBOA and standard care (n = 46) or standard care alone (n = 44). Main Outcomes and Measures: The primary outcome was all-cause mortality at 90 days. Ten secondary outcomes included mortality at 6 months, while in the hospital, and within 24 hours, 6 hours, or 3 hours; the need for definitive hemorrhage control procedures; time to commencement of definitive hemorrhage control procedures; complications; length of stay; blood product use; and cause of death. Results: Of the 90 patients (median age, 41 years [IQR, 31-59 years]; 62 [69%] were male; and the median Injury Severity Score was 41 [IQR, 29-50]) randomized, 89 were included in the primary outcome analysis because 1 patient in the standard care alone group declined to provide consent for continued participation and data collection 4 days after enrollment. At 90 days, 25 of 46 patients (54%) had experienced all-cause mortality in the REBOA and standard care group vs 18 of 43 patients (42%) in the standard care alone group (odds ratio [OR], 1.58 [95% credible interval, 0.72-3.52]; posterior probability of an OR >1 [indicating increased odds of death with REBOA], 86.9%). Among the 10 secondary outcomes, the ORs for mortality and the posterior probabilities of an OR greater than 1 for 6-month, in-hospital, and 24-, 6-, or 3-hour mortality were all increased in the REBOA and standard care group, and the ORs were increased with earlier mortality end points. There were more deaths due to bleeding in the REBOA and standard care group (8 of 25 patients [32%]) than in standard care alone group (3 of 18 patients [17%]), and most occurred within 24 hours. Conclusions and Relevance: In trauma patients with exsanguinating hemorrhage, a strategy of REBOA and standard care in the emergency department does not reduce, and may increase, mortality compared with standard care alone. Trial Registration: isrctn.org Identifier: ISRCTN16184981.

Laparoscopic supracervical hysterectomy versus endometrial ablation for women with heavy menstrual bleeding (HEALTH): a parallel-group, open-label, randomised controlled trial.

BACKGROUND: Heavy menstrual bleeding affects 25% of women in the UK, many of whom require surgery to treat it. Hysterectomy is effective but has more complications than endometrial ablation, which is less invasive but ultimately leads to hysterectomy in 20% of women. We compared laparoscopic supracervical hysterectomy with endometrial ablation in women seeking surgical treatment for heavy menstrual bleeding. METHODS: In this parallel-group, multicentre, open-label, randomised controlled trial in 31 hospitals in the UK, women younger than 50 years who were referred to a gynaecologist for surgical treatment of heavy menstrual bleeding and who were eligible for endometrial ablation were randomly allocated (1:1) to either laparoscopic supracervical hysterectomy or second generation endometrial ablation. Women were randomly assigned by either an interactive voice response telephone system or an internet-based application with a minimisation algorithm based on centre and age group (<40 years vs ≥40 years). Laparoscopic supracervical hysterectomy involves laparoscopic (keyhole) surgery to remove the upper part of the uterus (the body) containing the endometrium. Endometrial ablation aims to treat heavy menstrual bleeding by destroying the endometrium, which is responsible for heavy periods. The co-primary clinical outcomes were patient satisfaction and condition-specific quality of life, measured with the menorrhagia multi-attribute quality of life scale (MMAS), assessed at 15 months after randomisation. Our analysis was based on the intention-to-treat principle. The trial was registered with the ISRCTN registry, number ISRCTN49013893. FINDINGS: Between May 21, 2014, and March 28, 2017, we enrolled and randomly assigned 660 women (330 in each group). 616 (93%) of 660 women were operated on within the study period, 588 (95%) of whom received the allocated procedure and 28 (5%) of whom had an alternative surgery. At 15 months after randomisation, more women allocated to laparoscopic supracervical hysterectomy were satisfied with their operation compared with those in the endometrial ablation group (270 [97%] of 278 women vs 244 [87%] of 280 women; adjusted percentage difference 9·8, 95% CI 5·1-14·5; adjusted odds ratio [OR] 2·53, 95% CI 1·83-3·48; p<0·0001). Women randomly assigned to laparoscopic supracervical hysterectomy were also more likely to have the best possible MMAS score of 100 than women assigned to endometrial ablation (180 [69%] of 262 women vs 146 [54%] of 268 women; adjusted percentage difference 13·3, 95% CI 3·8-22·8; adjusted OR 1·87, 95% CI 1·31-2·67; p=0·00058). 14 (5%) of 309 women in the laparoscopic supracervical hysterectomy group and 11 (4%) of 307 women in the endometrial ablation group had at least one serious adverse event (adjusted OR 1·30, 95% CI 0·56-3·02; p=0·54). INTERPRETATION: Laparoscopic supracervical hysterectomy is superior to endometrial ablation in terms of clinical effectiveness and has a similar proportion of complications, but takes longer to perform and is associated with a longer recovery. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

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.).

Laparoscopic cholecystectomy versus conservative management for adults with uncomplicated symptomatic gallstones: the C-GALL RCT.

Background: Gallstone disease is a common gastrointestinal disorder in industrialised societies. The prevalence of gallstones in the adult population is estimated to be approximately 10-15%, and around 80% remain asymptomatic. At present, cholecystectomy is the default option for people with symptomatic gallstone disease. Objectives: To assess the clinical and cost-effectiveness of observation/conservative management compared with laparoscopic cholecystectomy for preventing recurrent symptoms and complications in adults presenting with uncomplicated symptomatic gallstones in secondary care. Design: Parallel group, multicentre patient randomised superiority pragmatic trial with up to 24 months follow-up and embedded qualitative research. Within-trial cost-utility and 10-year Markov model analyses. Development of a core outcome set for uncomplicated symptomatic gallstone disease. Setting: Secondary care elective settings. Participants: Adults with symptomatic uncomplicated gallstone disease referred to a secondary care setting were considered for inclusion. Interventions: Participants were randomised 1: 1 at clinic to receive either laparoscopic cholecystectomy or observation/conservative management. Main outcome measures: The primary outcome was quality of life measured by area under the curve over 18 months using the Short Form-36 bodily pain domain. Secondary outcomes included the Otago gallstones' condition-specific questionnaire, Short Form-36 domains (excluding bodily pain), area under the curve over 24 months for Short Form-36 bodily pain domain, persistent symptoms, complications and need for further treatment. No outcomes were blinded to allocation. Results: Between August 2016 and November 2019, 434 participants were randomised (217 in each group) from 20 United Kingdom centres. By 24 months, 64 (29.5%) in the observation/conservative management group and 153 (70.5%) in the laparoscopic cholecystectomy group had received surgery, median time to surgery of 9.0 months (interquartile range, 5.6-15.0) and 4.7 months (interquartile range 2.6-7.9), respectively. At 18 months, the mean Short Form-36 norm-based bodily pain score was 49.4 (standard deviation 11.7) in the observation/conservative management group and 50.4 (standard deviation 11.6) in the laparoscopic cholecystectomy group. The mean area under the curve over 18 months was 46.8 for both groups with no difference: mean difference -0.0, 95% confidence interval (-1.7 to 1.7); p-value 0.996; n = 203 observation/conservative, n = 205 cholecystectomy. There was no evidence of differences in quality of life, complications or need for further treatment at up to 24 months follow-up. Condition-specific quality of life at 24 months favoured cholecystectomy: mean difference 9.0, 95% confidence interval (4.1 to 14.0), p < 0.001 with a similar pattern for the persistent symptoms score. Within-trial cost-utility analysis found observation/conservative management over 24 months was less costly than cholecystectomy (mean difference -£1033). A non-significant quality-adjusted life-year difference of -0.019 favouring cholecystectomy resulted in an incremental cost-effectiveness ratio of £55,235. The Markov model continued to favour observation/conservative management, but some scenarios reversed the findings due to uncertainties in longer-term quality of life. The core outcome set included 11 critically important outcomes from both patients and healthcare professionals. Conclusions: The results suggested that in the short term (up to 24 months) observation/conservative management may be a cost-effective use of National Health Service resources in selected patients, but subsequent surgeries in the randomised groups and differences in quality of life beyond 24 months could reverse this finding. Future research should focus on longer-term follow-up data and identification of the cohort of patients that should be routinely offered surgery. Trial registration: This trial is registered as ISRCTN55215960. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/71) and is published in full in Health Technology Assessment; Vol. 28, No. 26. See the NIHR Funding and Awards website for further award information.

The C-GALL study assessed the benefits, in terms of symptoms, quality of life and costs, of cholecystectomy versus observation (conservative management: by the patient and general practitioner that might include dietary advice and pain management and surgery if needed). Four hundred and thirty-four patients with symptomatic gallstones were randomly allocated surgery or conservative management. The main symptom of ongoing bodily pain and some other quality-of-life measures were assessed over the next 2 years using postal questionnaires. After 2 years, 70% of those allocated to surgery had been operated on and 37% of the observation group either had an operation or were waiting for one. There was no difference in bodily pain or overall quality of life between the groups. However, participants in the surgery group reported fewer ongoing problems related to their gallstone disease or after surgery than those in the conservative management group. Surgery was, however, more costly than conservative management. The C-GALL study has shown that for some patients, a conservative management approach may be a sufficient and less costly way of managing their gallstone symptoms rather than going straight on the waiting list for surgery. More research is needed to identify which patients benefit most from surgery.

The UK resuscitative endovascular balloon occlusion of the aorta in trauma patients with life-threatening torso haemorrhage: the (UK-REBOA) multicentre RCT.

Background: The most common cause of preventable death after injury is haemorrhage. Resuscitative endovascular balloon occlusion of the aorta is intended to provide earlier, temporary haemorrhage control, to facilitate transfer to an operating theatre or interventional radiology suite for definitive haemostasis. Objective: To compare standard care plus resuscitative endovascular balloon occlusion of the aorta versus standard care in patients with exsanguinating haemorrhage in the emergency department. Design: Pragmatic, multicentre, Bayesian, group-sequential, registry-enabled, open-label, parallel-group randomised controlled trial to determine the clinical and cost-effectiveness of standard care plus resuscitative endovascular balloon occlusion of the aorta, compared to standard care alone. Setting: United Kingdom Major Trauma Centres. Participants: Trauma patients aged 16 years or older with confirmed or suspected life-threatening torso haemorrhage deemed amenable to adjunctive treatment with resuscitative endovascular balloon occlusion of the aorta. Interventions: Participants were randomly assigned 1 : 1 to: standard care, as expected in a major trauma centre standard care plus resuscitative endovascular balloon occlusion of the aorta. Main outcome measures: Primary: Mortality at 90 days. Secondary: Mortality at 6 months, while in hospital, and within 24, 6 and 3 hours; need for haemorrhage control procedures, time to commencement of haemorrhage procedure, complications, length of stay (hospital and intensive care unit-free days), blood product use. Health economic: Expected United Kingdom National Health Service perspective costs, life-years and quality-adjusted life-years, modelled over a lifetime horizon. Data sources: Case report forms, Trauma Audit and Research Network registry, NHS Digital (Hospital Episode Statistics and Office of National Statistics data). Results: Ninety patients were enrolled: 46 were randomised to standard care plus resuscitative endovascular balloon occlusion of the aorta and 44 to standard care. Mortality at 90 days was higher in the standard care plus resuscitative endovascular balloon occlusion of the aorta group (54%) compared to the standard care group (42%). The odds ratio was 1.58 (95% credible interval 0.72 to 3.52). The posterior probability of an odds ratio > 1 (indicating increased odds of death with resuscitative endovascular balloon occlusion of the aorta) was 86.9%. The overall effect did not change when an enthusiastic prior was used or when the estimate was adjusted for baseline characteristics. For the secondary outcomes (3, 6 and 24 hours mortality), the posterior probability that standard care plus resuscitative endovascular balloon occlusion of the aorta was harmful was higher than for the primary outcome. Additional analyses to account for intercurrent events did not change the direction of the estimate for mortality at any time point. Death due to haemorrhage was more common in the standard care plus resuscitative endovascular balloon occlusion of the aorta group than in the standard care group. There were no serious adverse device effects. Resuscitative endovascular balloon occlusion of the aorta is less costly (probability 99%), due to the competing mortality risk but also substantially less effective in terms of lifetime quality-adjusted life-years (probability 91%). Limitations: The size of the study reflects the relative infrequency of exsanguinating traumatic haemorrhage in the United Kingdom. There were some baseline imbalances between groups, but adjusted analyses had little effect on the estimates. Conclusions: This is the first randomised trial of the addition of resuscitative endovascular balloon occlusion of the aorta to standard care in the management of exsanguinating haemorrhage. All the analyses suggest that a strategy of standard care plus resuscitative endovascular balloon occlusion of the aorta is potentially harmful. Future work: The role (if any) of resuscitative endovascular balloon occlusion of the aorta in the pre-hospital setting remains unclear. Further research to clarify its potential (or not) may be required. Trial registration: This trial is registered as ISRCTN16184981. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/199/09) and is published in full in Health Technology Assessment; Vol. 28, No. 54. See the NIHR Funding and Awards website for further award information.

Trauma (physical injury) is a major cause of death and disability. The most common cause of preventable death after injury is uncontrolled bleeding. Resuscitative endovascular balloon occlusion of the aorta is a technique whereby a small balloon is inflated in the aorta (main blood vessel) which aims to limit blood loss until an operation can be done to stop the bleeding. In this study, which is the first randomised trial in the world of this technique, we investigated whether adding resuscitative endovascular balloon occlusion of the aorta to the standard care received in a major trauma centre reduced the risk of death in trauma patients who had life-threatening uncontrolled bleeding. The study took place in 16 major trauma centres in the United Kingdom. Ninety adult trauma patients with confirmed or suspected uncontrolled bleeding took part and were randomly divided into two groups: (1) those who received standard care and (2) those who received standard care plus resuscitative endovascular balloon occlusion of the aorta. We followed participants for 6 months using routinely collected data from the National Health Service and from the Trauma Audit Research Network registry. We also contacted surviving patients at 6 months to ask about their quality of life. In the standard care group, 42% of participants died within 90 days of their injury compared to 54% of participants in the standard care plus resuscitative endovascular balloon occlusion of the aorta group. Risk of death was also higher in the standard care plus resuscitative endovascular balloon occlusion of the aorta group at all other time points (3, 6 and 24 hours, in hospital and at 6 months). Overall, the study showed that the use of resuscitative endovascular balloon occlusion of the aorta in hospital increased the risk of death.

Effectiveness of conservative management versus laparoscopic cholecystectomy in the prevention of recurrent symptoms and complications in adults with uncomplicated symptomatic gallstone disease (C-GALL trial): pragmatic, multicentre randomised controlled trial.

OBJECTIVE: To assess the clinical and cost effectiveness of conservative management compared with laparoscopic cholecystectomy for the prevention of symptoms and complications in adults with uncomplicated symptomatic gallstone disease. DESIGN: Parallel group, pragmatic randomised, superiority trial. SETTING: 20 secondary care centres in the UK. PARTICIPANTS: 434 adults (>18 years) with uncomplicated symptomatic gallstone disease referred to secondary care, assessed for eligibility between August 2016 and November 2019, and randomly assigned (1:1) to receive conservative management or laparoscopic cholecystectomy. INTERVENTIONS: Conservative management or surgical removal of the gallbladder. MAIN OUTCOME MEASURES: The primary patient outcome was quality of life, measured by area under the curve, over 18 months using the short form 36 (SF-36) bodily pain domain, with higher scores (range 0-100) indicating better quality of life. Other outcomes included costs to the NHS, quality adjusted life years (QALYs), and incremental cost effectiveness ratio. RESULTS: Of 2667 patients assessed for eligibility, 434 were randomised: 217 to the conservative management group and 217 to the laparoscopic cholecystectomy group. By 18 months, 54 (25%) participants in the conservative management arm and 146 (67%) in the cholecystectomy arm had received surgery. The mean SF-36 norm based bodily pain score was 49.4 (standard deviation 11.7) in the conservative management arm and 50.4 (11.6) in the cholecystectomy arm. The SF-36 bodily pain area under the curve up to 18 months did not differ (mean difference 0.0, 95% confidence interval -1.7 to 1.7; P=1.00). Conservative management was less costly (mean difference -£1033, (-$1334; -€1205), 95% credible interval -£1413 to -£632) and QALYs did not differ (mean difference -0.019, 95% credible interval -0.06 to 0.02). CONCLUSIONS: In the short term (≤18 months), laparoscopic surgery is no more effective than conservative management for adults with uncomplicated symptomatic gallstone disease, and as such conservative management should be considered as an alternative to surgery. From an NHS perspective, conservative management may be cost effective for uncomplicated symptomatic gallstone disease. As costs, complications, and benefits will continue to be incurred in both groups beyond 18 months, future research should focus on longer term follow-up to establish effectiveness and lifetime cost effectiveness and to identify the cohort of patients who should be routinely offered surgery. TRIAL REGISTRATION: ISRCTN registry ISRCTN55215960.

Medical versus surgical management for gastro-oesophageal reflux disease (GORD) in adults.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is a common condition with up to 20% of patients from Westernised countries experiencing heartburn, reflux or both intermittently. It is unclear whether medical or surgical (laparoscopic fundoplication) management is the most clinically and cost-effective treatment for controlling GORD. OBJECTIVES: To compare the effects of medical management versus laparoscopic fundoplication surgery on health-related and GORD-specific quality of life (QOL) in adults with GORD. SEARCH STRATEGY: We searched CENTRAL (Issue 2, 2009), MEDLINE (1966 to May 2009) and EMBASE (1980 to May 2009). We handsearched conference abstracts and reference lists from published trials to identify further trials. We contacted experts in the field for relevant unpublished material. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing medical management with laparoscopic fundoplication surgery. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from articles identified for inclusion and assessed the methodological quality of eligible trials. Primary outcomes were: health-related and GORD-specific QOL, heartburn, regurgitation and dysphagia. MAIN RESULTS: Four trials were included with a total of 1232 randomised participants. Health-related QOL was reported by four studies although data were combined using fixed-effect models for two studies (Anvari 2006; REFLUX Trial 2008). There were statistically significant improvements in health-related QOL at three months and one year after surgery compared to medical therapy (mean difference (MD) SF36 general health score -5.23, 95% CI -6.83 to -3.62; I(2) = 0%). All four studies reported significant improvements in GORD-specific QOL after surgery compared to medical therapy although data were not combined. There is evidence to suggest that symptoms of heartburn, reflux and bloating are improved after surgery compared to medical therapy, but a small proportion of participants have persistent postoperative dysphagia. Overall rates of postoperative complications were low but surgery is not without risk and postoperative adverse events occurred although they were uncommon. The costs of surgery are considerably higher than the cost of medical management although data are based on the first year of treatment therefore the cost and side effects associated with long-term treatment of chronic GORD need to be considered. AUTHORS' CONCLUSIONS: There is evidence that laparoscopic fundoplication surgery is more effective than medical management for the treatment of GORD at least in the short to medium term. Surgery does carry some risk and whether the benefits of surgery are sustained in the long term remains uncertain. Treatment decisions for GORD should be based on patient and surgeon preference.

How to deal with a temporary suspension and restarting your trial: our experiences and lessons learnt.

Whilst the issues around early termination of randomised controlled trials (RCTs) are well documented in the literature, trials can also be temporarily suspended with the real prospect that they may subsequently restart. There is little guidance in the literature as to how to manage such a temporary suspension. In this paper, we describe the temporary suspension of a trial within our clinical trials unit because of concerns over the safety of transvaginal synthetic mesh implants. We also describe the challenges, considerations, and lessons learnt during the suspension that we are now applying in the current COVID-19 pandemic which has led to activities in many RCTs across the world undergoing a temporary suspension.There were three key phases within the temporary suspension: the decision to suspend, implementation of the suspension, and restarting. Each of these phases presented individual challenges which are discussed within this paper, along with the lessons learnt. There were obvious challenges around recruitment, delivery of the intervention, and follow-up. Additional challenges included communication between stakeholders, evolving risk assessment, updates to trial protocol and associated paperwork, maintaining site engagement, data-analysis, and workload within the trial team and Sponsor organisation.Based on our experience of managing a temporary suspension, we developed an action plan and guidance (see Additional File 1) for managing a significant trial event, such as a temporary suspension. We have used this document to help us manage the suspension of activities within our portfolio of trials during the current COVID-19 pandemic.

Verifying participant-reported clinical outcomes: challenges and implications.

BACKGROUND: Researchers often rely on trial participants to self-report clinical outcomes (for example, fractures, re-operations). Little information exists as to the 'accuracy' of participant-reported clinical outcomes, particularly in randomised controlled trials (RCTs). To help address this evidence gap, we report four case studies, nested within different RCTs where participant-reported clinical outcome data were compared with those reported by clinicians or extracted from medical notes. METHODS: Four publicly-funded RCTs with different methods of verifying participant-reported outcomes were identified. In KAT, the participants were asked about hospital admissions for any reason. Where it was thought to be relevant to the trial knee, further information was sought from the lead surgeon at the admitting site to confirm whether or not the admission was relevant to the trial knee. In REFLUX, participants were asked about hospital admissions for any reason. For participants who reported a re-operation, further information was sought from the lead surgeon at the admitting site to confirm this. In RECORD, participants were asked three questions regarding broken bones. Where low-trauma fractures were reported, clinical verification was sought, initially from the research nurse at the site. In CATHETER, participants were asked about urinary tract infections (UTIs), and a prescription of antibiotics was provided for the treatment of UTIs following urethral catheterisation. The GPs of those who reported a UTI were contacted to confirm that an antibiotic prescription had been issued for the suspected UTI. RESULTS: In KAT, 397 of 6882 (6%) participant-reported hospital admissions were confirmed as relevant to the trial knee. In REFLUX, 16 of 19 participants (84%) who appeared to have had a re-operation were confirmed as having had one. In RECORD, 473 of 781 (61%) fractures reported by participants were confirmed as being low-trauma fractures. In CATHETER, 429 of 830 participant-reported UTIs (52%) were confirmed as such by the GPs. CONCLUSIONS: We used different approaches in our verification of participant-reported outcomes in clinical trials, and we believe there is no one optimal solution. Consideration of issues such as what information is sought from participants, the phrasing of questions, whether the medical records are a true 'gold standard' and costs and benefits to the RCT may help determine the appropriate approach.

Laparoscopic supracervical hysterectomy compared with second-generation endometrial ablation for heavy menstrual bleeding: the HEALTH RCT.

BACKGROUND: Heavy menstrual bleeding (HMB) is a common problem that affects many British women. When initial medical treatment is unsuccessful, the National Institute for Health and Care Excellence recommends surgical options such as endometrial ablation (EA) or hysterectomy. Although clinically and economically more effective than EA, total hysterectomy necessitates a longer hospital stay and is associated with slower recovery and a higher risk of complications. Improvements in endoscopic equipment and training have made laparoscopic supracervical hysterectomy (LASH) accessible to most gynaecologists. This operation could preserve the advantages of total hysterectomy and reduce the risk of complications. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of LASH with second-generation EA in women with HMB. DESIGN: A parallel-group, multicentre, randomised controlled trial. Allocation was by remote web-based randomisation (1 : 1 ratio). Surgeons and participants were not blinded to the allocated procedure. SETTING: Thirty-one UK secondary and tertiary hospitals. PARTICIPANTS: Women aged < 50 years with HMB. Exclusion criteria included plans to conceive; endometrial atypia; abnormal cytology; uterine cavity size > 11 cm; any fibroids > 3 cm; contraindications to laparoscopic surgery; previous EA; and inability to give informed consent or complete trial paperwork. INTERVENTIONS: LASH compared with second-generation EA. MAIN OUTCOME MEASURES: Co-primary clinical outcome measures were (1) patient satisfaction and (2) Menorrhagia Multi-Attribute Quality-of-Life Scale (MMAS) score at 15 months post randomisation. The primary economic outcome was incremental cost (NHS perspective) per quality-adjusted life-year (QALY) gained. RESULTS: A total of 330 participants were randomised to each group (total n = 660). Women randomised to LASH were more likely to be satisfied with their treatment than those randomised to EA (97.1% vs. 87.1%) [adjusted difference in proportions 0.10, 95% confidence interval (CI) 0.05 to 0.15; adjusted odds ratio (OR) from ordinal logistic regression (OLR) 2.53, 95% CI 1.83 to 3.48; p < 0.001]. Women randomised to LASH were also more likely to have the best possible MMAS score of 100 (68.7% vs. 54.5%) (adjusted difference in proportions 0.13, 95% CI 0.04 to 0.23; adjusted OR from OLR 1.87, 95% CI 1.31 to 2.67; p = 0.001). Serious adverse event rates were low and similar in both groups (4.5% vs. 3.6%). There was a significant difference in adjusted mean costs between LASH (£2886) and EA (£1282) at 15 months, but no significant difference in QALYs. Based on an extrapolation of expected differences in cost and QALYs out to 10 years, LASH cost an additional £1362 for an average QALY gain of 0.11, equating to an incremental cost-effectiveness ratio of £12,314 per QALY. Probabilities of cost-effectiveness were 53%, 71% and 80% at cost-effectiveness thresholds of £13,000, £20,000 and £30,000 per QALY gained, respectively. LIMITATIONS: Follow-up data beyond 15 months post randomisation are not available to inform cost-effectiveness. CONCLUSION: LASH is superior to EA in terms of clinical effectiveness. EA is less costly in the short term, but expected higher retreatment rates mean that LASH could be considered cost-effective by 10 years post procedure. FUTURE WORK: Retreatment rates, satisfaction and quality-of-life scores at 10-year follow-up will help to inform long-term cost-effectiveness. TRIAI REGISTRATION: Current Controlled Trials ISRCTN49013893. 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. 23, No. 53. See the NIHR Journals Library website for further project information.

Almost 1.5 million women in England and Wales suffer from heavy periods. Initial treatment involves tablets or a medicated coil inserted within the womb. Sometimes these treatments do not work and many women need an operation, either endometrial ablation (EA) (removing the lining of the womb) or a full hysterectomy (complete removal of the womb). Previous studies have shown that a full hysterectomy is better at relieving symptoms, but the risk of complications during surgery is higher and patients take longer to recover fully. A newer operation, laparoscopic (keyhole) supracervical hysterectomy, or 'LASH', removes only the part of the womb that causes periods and preserves the cervix or neck of the womb. Women who have LASH can expect fewer complications, earlier discharge from hospital and quicker recovery time. In this study, we compared EA with LASH by asking women who had either procedure how they felt about it 1 year after their operation. Regardless of which operation they had, most women were very satisfied and felt that their symptoms were better. However, the results were much better for those who had the LASH operation, although these women stayed in hospital for longer and took more time to recover. There was no difference in complications from either surgery, although nearly 1 in 20 women who had an EA returned within 1 year to have their wombs removed in a second operation. Although LASH led to a greater improvement in symptoms and levels of satisfaction, it was more expensive in terms of costs incurred by both the health service and society. Given that some women who had an EA are likely to need a second operation in the future, LASH surgery may provide better value for money in the long term.

HEALTH: laparoscopic supracervical hysterectomy versus second-generation endometrial ablation for the treatment of heavy menstrual bleeding: study protocol for a randomised controlled trial.

BACKGROUND: Heavy menstrual bleeding (HMB) is a common problem affecting approximately 1.5 million women in England and Wales with a major impact on their physical, emotional, social and material quality of life. It is the fourth most common reason why women attend gynaecology outpatient clinics and accounts for one-fifth of all gynaecology outpatient referrals. Initial treatment in primary care is medical - either by means of oral or injected medication or the levonorgestrel-intrauterine system (Mirena®). If medical treatment fails then surgical treatment can be offered, either endometrial ablation (EA), which destroys the lining of the cavity of the uterus (endometrium), or hysterectomy, i.e. surgical removal of the uterus. While effective, conventional hysterectomy is invasive and carries a risk of complications due to injury to other pelvic structures. The procedure can be simplified and complications minimised by undertaking a 'supracervical' hysterectomy where the cervix is left in situ and only the body of the uterus removed. Recent advances in endoscopic technologies have facilitated increased use of laparoscopic supracervical hysterectomy (LASH) which can be performed as a day-case procedure and is relatively easy for the surgeon to learn. HEALTH (Hysterectomy or Endometrial AbLation Trial for Heavy menstrual bleeding) aims to address the question 'Is LASH superior to second generation EA for the treatment of HMB in terms of clinical and cost effectiveness?' METHODS/DESIGN: Women aged < 50 years, with HMB, in whom medical treatment has failed and who are eligible for EA will be considered for trial entry. We aim to recruit women from approximately 30 active secondary care centres in the UK NHS who carry out both surgical procedures. All women who consent will complete a diary of pain symptoms from day 1 to day 14 after surgery, postal questionnaires at six weeks and six months after surgery and 15 months post randomisation. Healthcare utilisation questions will also be completed at the six-week, six-month and 15-month time-points. DISCUSSION: Measuring the comparative effectiveness of LASH vs EA will provide the robust evidence required to determine whether the new technique should be adopted widely in the NHS. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN49013893 . Registered on 28 January 2014.

Male synthetic sling versus artificial urinary sphincter trial for men with urodynamic stress incontinence after prostate surgery (MASTER): study protocol for a randomised controlled trial.

BACKGROUND: Stress urinary incontinence (SUI) is a frequent adverse effect for men undergoing prostate surgery. A large proportion (around 8% after radical prostatectomy and 2% after transurethral resection of prostate (TURP)) are left with severe disabling incontinence which adversely effects their quality of life and many are reliant on containment measures such as pads (27% and 6% respectively). Surgery is currently the only option for active management of the problem. The overwhelming majority of surgeries for persistent bothersome SUI involve artificial urinary sphincter (AUS) insertion. However, this is expensive, and necessitates manipulation of a pump to enable voiding. More recently, an alternative to AUS has been developed - a synthetic sling for men which elevates the urethra, thus treating SUI. This is thought, by some, to be less invasive, more acceptable and less expensive than AUS but clear evidence for this is lacking. The MASTER trial aims to determine whether the male synthetic sling is non-inferior to implantation of the AUS for men who have SUI after prostate surgery (for cancer or benign disease), judged primarily on clinical effectiveness but also considering relative harms and cost-effectiveness. METHODS/DESIGN: Men with urodynamic stress incontinence (USI) after prostate surgery, for whom surgery is judged appropriate, are the target population. We aim to recruit men from secondary care urological centres in the UK NHS who carry out surgery for post-prostatectomy incontinence. Outcomes will be assessed by participant-completed questionnaires and 3-day urinary bladder diaries at baseline, 6, 12 and 24 months. The 24-h urinary pad test will be used at baseline as an objective assessment of urine loss. Clinical data will be completed at the time of surgery to provide details of the operative procedures, complications and resource use in hospital. At 12 months, men will also have a clinical review to evaluate the results of surgery (including another 24-h pad test) and to identify problems or need for further treatment. DISCUSSION: A robust examination of the comparative effectiveness of the male synthetic sling will provide high-quality evidence to determine whether or not it should be adopted widely in the NHS. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Registry: Number ISRCTN49212975 . Registered on 22 July 2013. First patient randomised on 29 January 2014.

Dates of birth and seasonal changes in well-being among 4904 subjects completing the seasonal pattern assessment questionnaire.

BACKGROUND: Abnormal distributions of birthdates, suggesting intrauterine aetiological factors, have been found in several psychiatric disorders, including one study of out-patients with Seasonal Affective Disorder (S.A.D.). We investigated birthdate distribution in relation to seasonal changes in well-being among a cohort who had completed the Seasonal Pattern Assessment Questionnaire (SPAQ). METHOD: A sample of 4904 subjects, aged 16 to 64, completed the SPAQ. 476 were cases of S.A.D. on the SPAQ and 580 were cases of sub-syndromal S.A.D. (S-S.A.D.). 92 were interview confirmed cases of S.A.D. Months and dates of birth were compared between S.A.D. cases and all others, between S.A.D. and S-S.A.D. cases combined and all others, and between interview confirmed cases and all others. Seasonality, as measured through seasonal fluctuations in well-being on the Global Seasonality Scores (GSS) of the SPAQ, was compared for all subjects by month and season of birth. RESULTS: There was no evidence of an atypical pattern of birthdates for subjects fulfilling criteria for S.A.D., for the combined S.A.D./S-S.A.D. group or for interview confirmed cases. There was also no relationship between seasonality on the GSS and month or season of birth. LIMITATIONS: Diagnoses of S.A.D. made by SPAQ criteria are likely to be overinclusive. CONCLUSION: Our findings differ from studies of patients with more severe mood disorders, including psychiatric out-patients with S.A.D. The lack of association between seasonality and birthdates in our study adds credence to the view that the aetiology of S.A.D. relates to separable factors predisposing to affective disorders and to seasonality.

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.

Role of L-citrulline transport in nitric oxide synthesis in rat aortic smooth muscle cells activated with LPS and interferon-gamma.

(1) l-citrulline, a coproduct of nitric oxide synthase (NOS)-catalysed metabolism of l-arginine to nitric oxide (NO), is an important intermediate of the urea cycle and a precursor for l-arginine biosynthesis in vascular cells. (2) In the present study, we have examined the characteristics of l-citrulline transport, regulation by lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) and the ability of l-citrulline to sustain NO synthesis in rat cultured aortic smooth muscle cells. (3) l-citrulline transport was saturable with an apparent Km=1.6+/-0.2 mm and Vmax=5.9+/-0.6 pmol microg-1 protein min-1. Transport was pH-insensitive, partially Na+-dependent and markedly inhibited by substrates selective for amino-acid transport systems L and N but not by l-arginine or substrates for systems A, ASC, xc- or XAG. Moreover, transport was not altered in cells treated with LPS (100 microg ml-1) and IFN-gamma (50 U ml-1) for 0-24 h. (4) Unlike l-arginine, l-citrulline could not sustain maximal NO production in cells expressing iNOS. (5) Our findings provide the first evidence in vascular smooth muscle cells that l-citrulline transport is mediated via a low-affinity carrier with characteristics resembling systems L and N. Moreover, in l-arginine-deprived rat aortic smooth muscle cells, l-citrulline cannot sustain maximal NO release via iNOS.

Seasonal affective disorder and social deprivation in Aberdeen.

BACKGROUND: Unlike non-seasonal depression, there is some evidence that seasonal affective disorder (SAD) is more common among more affluent socioeconomic groups. METHODS: In primary care settings in Aberdeen, 4557 subjects had previously completed a Seasonal Pattern Assessment Questionnaire (SPAQ). From the subjects' postcodes they were allocated a Carstairs score which placed them in one of seven categories of socioeconomic deprivation. These categories were compared with regard to seasonal pathology from the SPAQ ratings. RESULTS: Complete postcodes and Carstairs scores were established for 3772 (83%) of the 4557 subjects. No statistically significant relationship between socioeconomic deprivation and SPAQ ratings was detected. LIMITATIONS: The study population was an affluent one relative to Scotland as a whole which may have reduced the likelihood of a positive finding. The study was conducted 7 years after the census on which postcode deprivation scores were calculated, and changes therein may have occurred. CONCLUSIONS: SAD either has no relationship to social deprivation or is associated with affluence and this distinguishes it from non-seasonal depression.

Beliefs about surgery: Development and validation of an instrument to assess cognitive representations about surgery, in the context of a chronic illness.

OBJECTIVES: Within a trial of medical and surgical treatments for gastro-esophageal reflux disease (GORD), involving randomised arms and preference arms, we tested the applicability of the Beliefs about Medicines Questionnaire (BMQ) and developed and tested the validity of a new Beliefs about Surgery Questionnaire (BSQ). METHODS: Patients with GORD (N = 43) were interviewed to elicit their beliefs about medical and surgical treatments. These contributed to the development of BSQ items. The BMQ and BSQ were completed by trial participants at baseline (randomised trial: N = 325; preference trial: N = 414). Factor analysis and discriminant function analysis were used to assess validity. RESULTS: Principal components analysis (PCA) largely replicated the four-factor BMQ structure. PCA of the combined BMQ/BSQ yielded six factors explaining 54.5% variance. BSQ items loaded onto distinct factors, demonstrating divergence from BMQ. As predicted, BMQ/BSQ scores enabled correct classification of 78.5% of participants to medication and surgery groups in the preference trial (chi(2)(6) = 205.9, p < 0.001) but only 54.5% (no better than chance) in the randomised trial (chi(2)(6) = 9.4, p = 0.154). CONCLUSIONS: The BSQ is a valid measure of perceptions about surgical treatments for GORD. With the BMQ, it provides information that may guide patients' choices about treatment. This measure may be applicable to other conditions.

Minimal access surgery compared with medical management for chronic gastro-oesophageal reflux disease: UK collaborative randomised trial.

OBJECTIVE: To determine the relative benefits and risks of laparoscopic fundoplication surgery as an alternative to long term drug treatment for chronic gastro-oesophageal reflux disease (GORD). DESIGN: Multicentre, pragmatic randomised trial (with parallel preference groups). SETTING: 21 hospitals in the United Kingdom. PARTICIPANTS: 357 randomised participants (178 surgical, 179 medical) and 453 preference participants (261, 192); mean age 46; 66% men. All participants had documented evidence of GORD and symptoms for >12 months. INTERVENTION: The type of laparoscopic fundoplication used was left to the discretion of the surgeon. Those allocated to medical treatment had their treatment reviewed and adjusted as necessary by a local gastroenterologist, and subsequent clinical management was at the discretion of the clinician responsible for care. MAIN OUTCOME MEASURES: The disease specific REFLUX quality of life score (primary outcome), SF-36, EQ-5D, and medication use, measured at time points equivalent to three and 12 months after surgery, and surgical complications. MAIN RESULTS: Randomised participants had received drugs for GORD for median of 32 months before trial entry. Baseline REFLUX scores were 63.6 (SD 24.1) and 66.8 (SD 24.5) in the surgical and medical randomised groups, respectively. Of those randomised to surgery, 111 (62%) actually had total or partial fundoplication. Surgical complications were uncommon with a conversion rate of 0.6% and no mortality. By 12 months, 38% (59/154) randomised to surgery (14% (14/104) among those who had fundoplication) were taking reflux medication versus 90% (147/164) randomised medical management. The REFLUX score favoured the randomised surgical group (14.0, 95% confidence interval 9.6 to 18.4; P<0.001). Differences of a third to half of 1 SD in other health status measures also favoured the randomised surgical group. Baseline scores in the preference for surgery group were the worst; by 12 months these were better than in the preference for medical treatment group. CONCLUSION: At least up to 12 months after surgery, laparoscopic fundoplication significantly increased measures of health status in patients with GORD. TRIAL REGISTRATION: ISRCTN15517081.

The development of a new measure of quality of life in the management of gastro-oesophageal reflux disease: the Reflux questionnaire.

INTRODUCTION: This paper reports on the development of a new measure of health-related quality of life for use among patients with gastro-oesophageal reflux disease (GORD), funded as part of the REFLUX trial. This is a large UK multi centre trial that aims to compare the clinical and cost effectiveness of minimal access surgery with best medical treatment for patients with GORD within the NHS. METHOD: Potential items were identified via a series of interviews and focus groups carried out with patients who were receiving/had received medical or surgical treatment for GORD. The final measure consisted of 31 items covering 7 categories (Heartburn; Acid reflux; Wind; Eating and swallowing; Bowel movements; Sleep; Work, physical and social activities). The measure produced two outputs: a quality of life score (RQLS) and five Reflux symptom scores. Reliability (internal consistency), criterion validity with the SF-36 and, sensitivity to change in terms of relationship with reported change in prescribed medication were assessed amongst a sample of 794 patients recruited into the trial. RESULTS: The measure was shown to be internally consistent, to show criterion validity with the SF-36 and sensitive to changes in patients use of prescribed medication at baseline and 3 month follow-up. DISCUSSION: The Reflux questionnaire is a new self-administered questionnaire for use amongst patients with GORD. Initial findings suggest that the new measure is valid, reliable, acceptable to respondents and simple to administer in both a clinical and research context.

Use of health care services in seasonal affective disorder.

BACKGROUND: Little is known about the presentation and management of seasonal affective disorder (SAD) in primary care. AIMS: To determine the use of health care services by people suffering from SAD. METHOD: Following a screening of patients consulting in primary care, 123 were identified as suffering from SAD. Each was age- and gender-matched with two primary care consulters with minimal seasonal morbidity, yielding 246 non-seasonal controls. From primary care records, health care usage over a 5-year period was established. RESULTS: Patients with SAD consulted in primary care significantly more often than controls and presented with a wider variety of symptoms. They received more prescriptions, underwent more investigations and had more referrals to secondary care. CONCLUSIONS: Patients with SAD are heavy users of health care services. This may reflect the condition itself, its comorbidity or factors related to the personality or help-seeking behaviour of sufferers.