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.

Predictors of long-term intraocular pressure control after lens extraction in primary angle closure glaucoma: results from the EAGLE trial.

BACKGROUND/AIMS: To assess baseline ocular parameters in the prediction of long-term intraocular pressure (IOP) control after clear lens extraction (CLE) or laser peripheral iridotomy (LPI) in patients with primary angle closure (PAC) disease using data from the Effectiveness of Early Lens Extraction for the treatment of primary angle-closure glaucoma (EAGLE) tria. METHODS: This study is a secondary analysis of EAGLE data where we define the primary outcome of 'good responders' as those with IOP<21 mm Hg without requiring additional surgery and 'optimal responders' as those who in addition were medication free, at 36-month follow-up. Primary analysis was conducted using a multivariate logistic regression model to assess how randomised interventions and ocular parameters predict treatment response. RESULTS: A total of 369 patients (182 in CLE arm and 187 in LPI arm) completed the 36-month follow-up examination. After CLE, 90% met our predefined 'good response' criterion compared with 67% in the LPI arm, and 66% met 'optimal response' criterion compared with 18% in the LPI arm, with significantly longer drops/surgery-free survival time (p<0.05 for all). Patients randomised to CLE (OR=10.1 (6.1 to 16.8)), Chinese (OR=2.3 (1.3 to 3.9)), and those who had not previously used glaucoma drops (OR=2.8 (1.6 to 4.8)) were more likely to maintain long-term optimal IOP response over 36 months. CONCLUSION: Patients with primary angle closure glaucoma/PAC are 10 times more likely to maintain drop-free good IOP control with initial CLE surgery than LPI. Non-Chinese ethnicity, higher baseline IOP and using glaucoma drops prior to randomisation are predictors of worse long-term IOP response.

Urinary incontinence in men after formal one-to-one pelvic-floor muscle training following radical prostatectomy or transurethral resection of the prostate (MAPS): two parallel randomised controlled trials.

BACKGROUND: Urinary incontinence is common immediately after prostate surgery. Men are often advised to do pelvic-floor exercises, but evidence to support this is inconclusive. Our aim was to establish if formal one-to-one pelvic floor muscle training reduces incontinence. METHODS: We undertook two randomised trials in men in the UK who were incontinent 6 weeks after radical prostatectomy (trial 1) or transurethral resection of the prostate (TURP; trial 2) to compare four sessions with a therapist over 3 months with standard care and lifestyle advice only. Randomisation was by remote computer allocation. Our primary endpoints, collected via postal questionnaires, were participants' reports of urinary incontinence and incremental cost per quality-adjusted life year (QALY) after 12 months. Group assignment was masked from outcome assessors, but this masking was not possible for participants or caregivers. We used intention-to-treat analyses to compare the primary outcome at 12 months. This study is registered, number ISRCTN87696430. FINDINGS: In the intervention group in trial 1, the rate of urinary incontinence at 12 months (148 [76%] of 196) was not significantly different from the control group (151 [77%] of 195; absolute risk difference [RD] -1·9%, 95% CI -10 to 6). In trial 2, the difference in the rate of urinary incontinence at 12 months (126 [65%] of 194) from the control group was not significant (125 [62%] of 203; RD 3·4%, 95% CI -6 to 13). Adjusting for minimisation factors or doing treatment-received analyses did not change these results in either trial. No adverse effects were reported. In both trials, the intervention resulted in higher mean costs per patient (£180 and £209 respectively) but we did not identify evidence of an economically important difference in QALYs (0·002 [95% CI -0·027 to 0·023] and -0·00003 [-0·026 to 0·026]). INTERPRETATION: In settings where information about pelvic-floor exercise is widely available, one-to-one conservative physical therapy for men who are incontinent after prostate surgery is unlikely to be effective or cost effective. The high rates of persisting incontinence after 12 months suggest a substantial unrecognised and unmet need for management in these men. FUNDING: National Institute of Health Research, Health Technology Assessment (NIHR HTA) Programme.

Behavioural optimisation to address trial conduct challenges: case study in the UK-REBOA trial.

BACKGROUND: Clinical trials comprise multiple processes at various stages of the trial lifecycle. These processes often involve complex behaviours such as recruiting vulnerable patient populations and clinicians having to deliver complex trial interventions successfully. Few studies have utilised a behavioural framework to assess challenges and develop strategies for effective trial recruitment and delivery of trial interventions. This study reports the application of an innovative methodological approach to understand core trial processes, namely recruitment and intervention delivery, using a behavioural science approach to develop strategies designed to mitigate trial process problems. METHODS: The UK-REBOA trial aims to evaluate the clinical and cost-effectiveness of resuscitative endovascular balloon occlusion of the aorta (a novel intervention) in injured patients with exsanguinating haemorrhage. A behavioural investigation ('diagnosis') was conducted using theory-informed (Theoretical Domains Framework, TDF) semi-structured interviews with site staff from the UK-REBOA trial to examine trial processes which could be improved in relation to trial recruitment and delivery of the intervention. Interviews were analysed using the TDF to identify influences on behaviour, which were then mapped to techniques for behaviour change and developed into potential solutions. RESULTS: The behavioural diagnosis of the challenges experienced during trial processes highlighted factors relevant to a range of TDF domains: Skills, Environmental context and resources, Beliefs about capabilities, Beliefs about consequences, Social influences, and Memory, attention, and decision-making processes. Within the solution development phase, we identified 24 suitable behaviour change techniques that were developed into proposed solutions to target reported process problems with the aim of changing behaviour to improve recruitment and/or intervention delivery. Proposed solutions included targeted changes to trial training content, suggestions to restructure the environment (e.g. reinforced the purpose of the trial with information about the social and environmental consequences) and other strategies to reduce barriers to recruitment and intervention delivery. CONCLUSIONS: This study demonstrates the feasibility of applying a behavioural approach to investigate ('diagnose') behavioural trial process problems and subsequently develop and implement targeted solutions ('treatment') in an active trauma trial. Understanding the factors that affected behaviour, attitudes and beliefs in this trauma trial allowed us to implement theoretically informed, evidence-based solutions designed to enhance trial practices. TRIAL REGISTRATION: ISRCTN 16,184,981.

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.

After-effects reported by women following colposcopy, cervical biopsies and LLETZ: results from the TOMBOLA trial.

OBJECTIVE: Few studies have investigated physical after-effects of colposcopy. We compared post-colposcopy self-reported pain, bleeding, discharge and menstrual changes in women who underwent: colposcopic examination only; cervical punch biopsies; and large loop excision of the transformation zone (LLETZ). DESIGN: Observational study nested within a randomised controlled trial. SETTING: Grampian, Tayside and Nottingham. POPULATION: Nine hundred-and-twenty-nine women, aged 20-59, with low-grade cytology, who had completed their initial colposcopic management. METHODS: Women completed questionnaires on after-effects at approximately 6-weeks, and on menstruation at 4-months, post-colposcopy. MAIN OUTCOME MEASURES: Frequency of pain, bleeding, discharge; changes to first menstrual period post-colposcopy. RESULTS: Seven hundred-and-fifty-one women (80%) completed the 6-week questionnaire. Of women who had only a colposcopic examination, 14-18% reported pain, bleeding or discharge. Around half of women who had biopsies only and two-thirds treated by LLETZ reported pain or discharge (biopsies: 53% pain, 46% discharge; LLETZ: 67% pain, 63% discharge). The frequency of bleeding was similar in the biopsy (79%) and LLETZ groups (87%). Women treated by LLETZ reported bleeding and discharge of significantly longer duration than other women. The duration of pain was similar across management groups. Forty-three percent of women managed by biopsies and 71% managed by LLETZ reported some change to their first period post-colposcopy, as did 29% who only had a colposcopic examination. CONCLUSIONS: Cervical punch biopsies and, especially, LLETZ carry a substantial risk of after-effects. After-effects are also reported by women managed solely by colposcopic examination. Ensuring that women are fully informed about after-effects may help to alleviate anxiety and provide reassurance, thereby minimising the harms of screening.

The diagnostic accuracy of OCT angiography in naive and treated neovascular age-related macular degeneration: a review.

Optical coherence tomography angiography (OCTA) is a non-invasive retinal imaging innovation that has been gaining popularity for the evaluation of the retinal vasculature. Of clinical importance is its current use either as an alternative or in conjunction with conventional dye-based angiography in neovascular age-related macular degeneration. OCTA is not without limitations and these include image artefact, a relatively small field of view and failure of the segmentation algorithms, which can confound the interpretation of findings. While there are numerous publications on OCTA in neovascular AMD, few have examined the diagnostic accuracy of this new technology compared with the accepted gold standard of fundus fluorescein angiography (FFA). In this review, we summarise the literature on the clinical application of OCTA in nAMD. In particular, we have reviewed the published articles that have reported the sensitivity and specificity of OCTA in the diagnosis of nAMD, and those that have described and or correlated the morphological findings and compared them to dye-based angiography.

Early lens extraction with intraocular lens implantation for the treatment of primary angle closure glaucoma: an economic evaluation based on data from the EAGLE trial.

OBJECTIVE: To investigate the cost-effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle closure glaucoma (PACG) compared to standard care. DESIGN: Cost-effectiveness analysis alongside a multicentre pragmatic two-arm randomised controlled trial. Patients were followed-up for 36 months, and data on health service usage and health state utility were collected and analysed within the trial time horizon. A Markov model was developed to extrapolate the results over a 5-year and 10-year time horizon. SETTING: 22 hospital eye services in the UK. POPULATION: Males and females aged 50 years or over with newly diagnosed PACG or primary angle closure (PAC). INTERVENTIONS: Lens extraction compared to standard care (ie, laser iridotomy followed by medical therapy and glaucoma surgery). OUTCOME MEASURES: Costs of primary and secondary healthcare usage (UK NHS perspective), quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) for lens extraction versus standard care. RESULTS: The mean age of participants was 67.5 (8.42), 57.5% were women, 44.6% had both eyes eligible, 1.4% were of Asian ethnicity and 35.4% had PAC. The mean health service costs were higher in patients randomised to lens extraction: £2467 vs £1486. The mean adjusted QALYs were also higher with early lens extraction: 2.602 vs 2.533. The ICER for lens extraction versus standard care was £14 284 per QALY gained at three years. Modelling suggests that the ICER may drop to £7090 per QALY gained by 5 years and that lens extraction may be cost saving by 10 years. Our results are generally robust to changes in the key input parameters and assumptions. CONCLUSIONS: We find that lens extraction has a 67-89% chance of being cost-effective at 3 years and that it may be cost saving by 10 years. TRIAL REGISTRATION NUMBER: ISRCTN44464607; Results.

Enclosing a pen with a postal questionnaire can significantly increase the response rate.

BACKGROUND AND OBJECTIVES: It is important to maximize response rates to postal questionnaires. We compared the impact of three low-cost interventions on response rates. METHODS: A 2 x 2 x 2 factorial trial was conducted, nested within TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears). Three interventions were evaluated: (1) enclosing a TOMBOLA-branded pen with the questionnaire (as opposed to no pen); (2) sending the questionnaires by first class post (as opposed to second class); and (3) enclosing a preaddressed return envelope on which there was a second class postage stamp (rather than a freepost business-reply envelope). Nine hundred thirty women, aged 20-59 years, due to receive a TOMBOLA psychosocial questionnaire by post during June-August 2003 were randomized. RESULTS: Enclosing a pen resulted in a statistically significant 7.0% increase in the cumulative proportion of questionnaires returned (from 61.5 to 68.5%; P = .002). The adjusted odds of response was significantly raised (odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.04-1.82). Neither first class post nor providing a stamped envelope had a significant impact on response. There were no interactions between the interventions. CONCLUSIONS: Enclosing a pen with a questionnaire can significantly increase response. This low-cost strategy was effective against a background of "good practice" with regard to the administration of postal questionnaires.

After-effects reported by women having follow-up cervical cytology tests in primary care: a cohort study within the TOMBOLA trial.

BACKGROUND: Although it is recognised that some women experience pain or bleeding during a cervical cytology test, few studies have quantified physical after-effects of these tests. AIM: To investigate the frequency, severity, and duration of after-effects in women undergoing follow-up cervical cytology tests, and to identify subgroups with higher frequencies in Grampian, Tayside, and Nottingham. DESIGN: Cohort study nested with a multi-centre individually randomised controlled trial. METHOD: The cohort included 1120 women, aged 20-59 years, with low-grade abnormal cervical cytology who completed a baseline sociodemographic questionnaire and had a follow-up cervical cytology test in primary care 6 months later. Six weeks after this test, women completed a postal questionnaire on pain, bleeding, and discharge experienced after the test, including duration and severity. The adjusted prevalence of each after-effect was computed using logistic regression. RESULTS: A total of 884 women (79%) completed the after-effects questionnaire; 30% of women experienced one or more after-effect: 15% reported pain, 16% bleeding, and 7% discharge. The duration of discharge was ≤2 days for 66%, 3-6 days for 22%, and ≥7 days for 11% of women. Pain or bleeding lasted ≤2 days in more than 80% of women. Severe after-effects were reported by <1% of women. The prevalence of pain decreased with increasing age. Bleeding was more frequent among nulliparous women. Discharge was more common among oral contraceptive users. CONCLUSION: Pain, bleeding, and discharge are not uncommon in women having follow-up cervical cytology tests. Informing women about possible after-effects could better prepare them and provide reassurance, thereby minimising potential non-adherence with follow-up or non-participation with screening in the future.

The effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle-closure glaucoma (EAGLE): study protocol for a randomized controlled trial.

BACKGROUND: Glaucoma is the leading cause of irreversible blindness. Although primary open-angle glaucoma is more common, primary angle-closure glaucoma (PACG) is more likely to result in irreversible blindness. By 2020, 5·3 million people worldwide will be blind because of PACG. The current standard care for PACG is a stepped approach of a combination of laser iridotomy surgery (to open the drainage angle) and medical treatment (to reduce intraocular pressure). If these treatments fail, glaucoma surgery (eg, trabeculectomy) is indicated. It has been proposed that, because the lens of the eye plays a major role in the mechanisms leading to PACG, early clear lens extraction will improve glaucoma control by opening the drainage angle. This procedure might reduce the need for drugs and glaucoma surgery, maintain good visual acuity, and improve quality of life compared with standard care.EAGLE aims to evaluate whether early lens extraction improves patient-reported, clinical outcomes, and cost-effectiveness, compared with standard care. METHODS/DESIGN: EAGLE is a multicentre pragmatic randomized trial. All people presenting to the recruitment centres in the UK and east Asia with newly diagnosed PACG and who are at least 50 years old are eligible.The primary outcomes are EQ-5D, intraocular pressure, and incremental cost per quality adjusted life year (QALY) gained. Other outcomes are: vision and glaucoma-specific patient-reported outcomes, visual acuity, visual field, angle closure, number of medications, additional surgery (e.g., trabeculectomy), costs to the health services and patients, and adverse events.A single main analysis will be done at the end of the trial, after three years of follow-up. The analysis will be based on all participants as randomized (intention to treat). 400 participants (200 in each group) will be recruited, to have 90% power at 5% significance level to detect a difference in EQ-5D score between the two groups of 0·05, and a mean difference in intraocular pressure of 1·75 mm Hg. The study will have 80% power to detect a difference of 15% in the glaucoma surgery rate. TRIAL REGISTRATION: ISRCTN44464607.

Developing a pelvic floor muscle training regimen for use in a trial intervention.

This paper explains the rationale behind the intervention used for a large multi-centred randomised controlled trial for men following transurethral resection of prostate or radical prostatectomy. It shows the content of the protocol used and explains why this particular protocol of pelvic floor muscle exercises and urge suppression techniques was chosen for men in the intervention group. The trial will evaluate whether this intervention will be effective for men with urinary incontinence and sexual dysfunction after prostate surgery. ISRCTN number: ISRCTN87696430.