Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.

BACKGROUND: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. METHODS: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants. FINDINGS: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. INTERPRETATION: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895).

Multimodality local consolidative treatment versus conventional care of advanced lung cancer after first-line systemic anti-cancer treatment: study protocol for the RAMON multicentre randomised controlled trial with an internal pilot.

INTRODUCTION: Lung cancer is the most common cause of cancer death worldwide and most patients present with extensive disease. One-year survival is improving but remains low (37%) despite novel systemic anti-cancer treatments forming the current standard of care. Although new therapies improve survival, most patients have residual disease after treatment, and little is known on how best to manage it. Therefore, residual disease management varies across the UK, with some patients receiving only maintenance systemic anti-cancer treatment while others receive local consolidative treatment (LCT), alongside maintenance systemic anti-cancer treatment. LCT can be a combination of surgery, radiotherapy and/or ablation to remove all remaining cancer within the lung and throughout the body. This is intensive, expensive and impacts quality of life, but we do not know if it results in better survival, nor the extent of impact on quality of life and what the cost might be for healthcare providers. The RAMON study (RAdical Management Of Advanced Non-small cell lung cancer) will evaluate the acceptability, effectiveness and cost-effectiveness of LCT versus no LCT after first-line systemic treatment for advanced lung cancer. METHODS AND ANALYSIS: RAMON is a pragmatic open multicentre, parallel group, superiority randomised controlled trial. We aim to recruit 244 patients aged 18 years and over with advanced non-small-cell lung cancer from 40 UK NHS hospitals. Participants will be randomised in a 1:1 ratio to receive LCT alongside maintenance treatment, or maintenance treatment alone. LCT will be tailored to each patient's specific disease sites. Participants will be followed up for a minimum of 2 years. The primary outcome is overall survival from randomisation. ETHICS AND DISSEMINATION: The West of Scotland Research Ethics Committee (22/WS/0121) gave ethical approval in August 2022 and the Health Research Authority in September 2022. Participants will provide written informed consent before participating in the study. Findings will be presented at international meetings, in peer-reviewed publications, through patient organisations and notifications to patients. TRIAL REGISTRATION NUMBER: ISRCTN11613852.

Impact of video-assisted thoracoscopic lobectomy versus open lobectomy for lung cancer on recovery assessed using self-reported physical function: VIOLET RCT.

BACKGROUND: Lung cancer is the leading cause of cancer death. Surgery remains the main method of managing early-stage disease. Minimal-access video-assisted thoracoscopic surgery results in less tissue trauma than open surgery; however, it is not known if it improves patient outcomes. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of video-assisted thoracoscopic surgery lobectomy with open surgery for the treatment of lung cancer. DESIGN, SETTING AND PARTICIPANTS: A multicentre, superiority, parallel-group, randomised controlled trial with blinding of participants (until hospital discharge) and outcome assessors conducted in nine NHS hospitals. Adults referred for lung resection for known or suspected lung cancer, with disease suitable for both surgeries, were eligible. Participants were followed up for 1 year. INTERVENTIONS: Participants were randomised 1 : 1 to video-assisted thoracoscopic surgery lobectomy or open surgery. Video-assisted thoracoscopic surgery used one to four keyhole incisions without rib spreading. Open surgery used a single incision with rib spreading, with or without rib resection. MAIN OUTCOME MEASURES: The primary outcome was self-reported physical function (using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) at 5 weeks. Secondary outcomes included upstaging to pathologic node stage 2 disease, time from surgery to hospital discharge, pain in the first 2 days, prolonged pain requiring analgesia at > 5 weeks, adverse health events, uptake of adjuvant treatment, overall and disease-free survival, quality of life (Quality of Life Questionnaire Core 30, Quality of Life Questionnaire Lung Cancer 13 and EQ-5D) at 2 and 5 weeks and 3, 6 and 12 months, and cost-effectiveness. RESULTS: A total of 503 patients were randomised between July 2015 and February 2019 (video-assisted thoracoscopic surgery, n = 247; open surgery, n = 256). One participant withdrew before surgery. The mean age of patients was 69 years; 249 (49.5%) patients were men and 242 (48.1%) did not have a confirmed diagnosis. Lobectomy was performed in 453 of 502 (90.2%) participants and complete resection was achieved in 429 of 439 (97.7%) participants. Quality of Life Questionnaire Core 30 physical function was better in the video-assisted thoracoscopic surgery group than in the open-surgery group at 5 weeks (video-assisted thoracoscopic surgery, n = 247; open surgery, n = 255; mean difference 4.65, 95% confidence interval 1.69 to 7.61; p = 0.0089). Upstaging from clinical node stage 0 to pathologic node stage 1 and from clinical node stage 0 or 1 to pathologic node stage 2 was similar (p ≥ 0.50). Pain scores were similar on day 1, but lower in the video-assisted thoracoscopic surgery group on day 2 (mean difference -0.54, 95% confidence interval -0.99 to -0.09; p = 0.018). Analgesic consumption was 10% lower (95% CI -20% to 1%) and the median hospital stay was less (4 vs. 5 days, hazard ratio 1.34, 95% confidence interval 1.09, 1.65; p = 0.006) in the video-assisted thoracoscopic surgery group than in the open-surgery group. Prolonged pain was also less (relative risk 0.82, 95% confidence interval 0.72 to 0.94; p = 0.003). Time to uptake of adjuvant treatment, overall survival and progression-free survival were similar (p ≥ 0.28). Fewer participants in the video-assisted thoracoscopic surgery group than in the open-surgery group experienced complications before and after discharge from hospital (relative risk 0.74, 95% confidence interval 0.66 to 0.84; p < 0.001 and relative risk 0.81, 95% confidence interval 0.66 to 1.00; p = 0.053, respectively). Quality of life to 1 year was better across several domains in the video-assisted thoracoscopic surgery group than in the open-surgery group. The probability that video-assisted thoracoscopic surgery is cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year is 1. LIMITATIONS: Ethnic minorities were under-represented compared with the UK population (< 5%), but the cohort reflected the lung cancer population. CONCLUSIONS: Video-assisted thoracoscopic surgery lobectomy was associated with less pain, fewer complications and better quality of life without any compromise to oncologic outcome. Use of video-assisted thoracoscopic surgery is highly likely to be cost-effective for the NHS. FUTURE WORK: Evaluation of the efficacy of video-assisted thoracoscopic surgery with robotic assistance, which is being offered in many hospitals. TRIAL REGISTRATION: This trial is registered as ISRCTN13472721. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 48. See the NIHR Journals Library website for further project information.

BACKGROUND: Lung cancer is a common cause of cancer death worldwide. If the disease is caught early, the part of the lung containing the tumour can be removed in an operation called a lobectomy. The operation can be carried out through a large cut so that the surgeon has a full view of the lung, which is called open surgery, or using several small cuts and a camera, which is called video-assisted thoracoscopic (keyhole) surgery. It is thought that, as keyhole surgery is less invasive, patients recover quicker. However, to the best of our knowledge, there are no high-quality research studies that are applicable to UK practice to support this. This study was conducted so that it could be determined, based on high-quality evidence, which operation provides the best treatment and recovery for patients. WHO PARTICIPATED?: Five hundred and three adults referred for lobectomy for known or suspected lung cancer from nine hospitals in the UK. WHAT WAS INVOLVED?: Participants were randomly allocated to either receive keyhole or open surgery. Participants were followed up for 12 months. We collected information on further treatment, hospital visits, safety information and disease progression over this period. Participants were also asked to complete questionnaires about their health and recovery. WHAT DID THE TRIAL FIND?: For patients with early-stage lung cancer who underwent a lobectomy, keyhole surgery led to less pain, less time in hospital and better quality of life than open surgery, without having a detrimental effect on cancer progression or survival. Keyhole surgery was found to be cost-effective and to provide excellent value for money for the NHS.

Quality-adjusted life years for digital cognitive behavioural therapy for insomnia (Sleepio): a secondary analysis.

BACKGROUND: Insomnia is common, and difficulty with daytime functioning is a core symptom. Studies show cognitive behavioural therapy (CBT) improves functioning, but evidence is needed on its value for money. Quality-adjusted life years (QALYs), capturing length and quality of life, provide a standard metric by which to judge whether a treatment is worth its cost. Studies have found QALY gains with therapist-delivered and therapist-guided CBT, but most have not reached statistical significance. Estimates of QALY gains with fully automated digital CBT (dCBT) for insomnia are lacking. AIM: To assess whether dCBT (Sleepio) for insomnia is associated with gains in QALYs compared with a sleep hygiene education control. DESIGN & SETTING: A secondary analysis of a large effectiveness trial of 1711 participants from the UK, US, and Australia. METHOD: EQ-5D scores, the National Institute for Health and Care Excellence's (NICE's) preferred measure of health-related quality of life (HRQoL), were predicted (mapped) from the 10-item Patient-Reported Outcomes Measurement Information System (PROMIS-10) Global Health scores and used to determine QALYs from baseline to 24 weeks (controlled), and to 48 weeks (uncontrolled). RESULTS: At week 24, QALYs were significantly higher for the dCBT group, with mean QALYs 0.375 and 0.362 in the dCBT and control groups, respectively. The mean difference was 0.014 (95% confidence interval [CI] = 0.008 to 0.019), and this difference was maintained over the 48-week study period (0.026, 95% CI = 0.016 to 0.036). The difference of 0.026 QALYs is equivalent to 9.5 days in perfect health. CONCLUSION: Sleepio is associated with statistically significant gains in QALYs over time compared with control. Findings may be used to power future studies and inform cost-effectiveness analyses of automated dCBT for insomnia scaled to a population level.

Supraglottic airway device versus tracheal intubation in the initial airway management of out-of-hospital cardiac arrest: the AIRWAYS-2 cluster RCT.

BACKGROUND: When a cardiac arrest occurs, cardiopulmonary resuscitation should be started immediately. However, there is limited evidence about the best approach to airway management during cardiac arrest. OBJECTIVE: The objective was to determine whether or not the i-gel® (Intersurgical Ltd, Wokingham, UK) supraglottic airway is superior to tracheal intubation as the initial advanced airway management strategy in adults with non-traumatic out-of-hospital cardiac arrest. DESIGN: This was a pragmatic, open, parallel, two-group, multicentre, cluster randomised controlled trial. A cost-effectiveness analysis accompanied the trial. SETTING: The setting was four ambulance services in England. PARTICIPANTS: Patients aged ≥ 18 years who had a non-traumatic out-of-hospital cardiac arrest and were attended by a participating paramedic were enrolled automatically under a waiver of consent between June 2015 and August 2017. Follow-up ended in February 2018. INTERVENTION: Paramedics were randomised 1 : 1 to use tracheal intubation (764 paramedics) or i-gel (759 paramedics) for their initial advanced airway management and were unblinded. MAIN OUTCOME MEASURES: The primary outcome was modified Rankin Scale score at hospital discharge or 30 days after out-of-hospital cardiac arrest, whichever occurred earlier, collected by assessors blinded to allocation. The modified Rankin Scale, a measure of neurological disability, was dichotomised: a score of 0-3 (good outcome) or 4-6 (poor outcome/death). The primary outcome for the economic evaluation was quality-adjusted life-years, estimated using the EuroQol-5 Dimensions, five-level version. RESULTS: A total of 9296 patients (supraglottic airway group, 4886; tracheal intubation group, 4410) were enrolled [median age 73 years; 3373 (36.3%) women]; modified Rankin Scale score was known for 9289 patients. Characteristics were similar between groups. A total of 6.4% (311/4882) of patients in the supraglottic airway group and 6.8% (300/4407) of patients in the tracheal intubation group had a good outcome (adjusted difference in proportions of patients experiencing a good outcome: -0.6%, 95% confidence interval -1.6% to 0.4%). The supraglottic airway group had a higher initial ventilation success rate than the tracheal intubation group [87.4% (4255/4868) vs. 79.0% (3473/4397), respectively; adjusted difference in proportions of patients: 8.3%, 95% confidence interval 6.3% to 10.2%]; however, patients in the tracheal intubation group were less likely to receive advanced airway management than patients in the supraglottic airway group [77.6% (3419/4404) vs. 85.2% (4161/4883), respectively]. Regurgitation rate was similar between the groups [supraglottic airway group, 26.1% (1268/4865); tracheal intubation group, 24.5% (1072/4372); adjusted difference in proportions of patients: 1.4%, 95% confidence interval -0.6% to 3.4%], as was aspiration rate [supraglottic airway group, 15.1% (729/4824); tracheal intubation group, 14.9% (647/4337); adjusted difference in proportions of patients: 0.1%, 95% confidence interval -1.5% to 1.8%]. The longer-term outcomes were also similar between the groups (modified Rankin Scale: at 3 months, odds ratio 0.89, 95% confidence interval 0.69 to 1.14; at 6 months, odds ratio 0.91, 95% confidence interval 0.71 to 1.16). Sensitivity analyses did not alter the overall findings. There were no unexpected serious adverse events. Mean quality-adjusted life-years to 6 months were 0.03 in both groups (supraglottic airway group minus tracheal intubation group difference -0.0015, 95% confidence interval -0.0059 to 0.0028), and total costs were £157 (95% confidence interval -£270 to £583) lower in the tracheal intubation group. Although the point estimate of the incremental cost-effectiveness ratio suggested that tracheal intubation may be cost-effective, the huge uncertainty around this result indicates no evidence of a difference between groups. LIMITATIONS: Limitations included imbalance in the number of patients in each group, caused by unequal distribution of high-enrolling paramedics; crossover between groups; and the fact that participating paramedics, who were volunteers, might not be representative of all paramedics in the UK. Findings may not be applicable to other countries. CONCLUSION: Among patients with out-of-hospital cardiac arrest, randomisation to the supraglottic airway group compared with the tracheal intubation group did not result in a difference in outcome at 30 days. There were no notable differences in costs, outcomes and overall cost-effectiveness between the groups. FUTURE WORK: Future work could compare alternative supraglottic airway types with tracheal intubation; include a randomised trial of bag mask ventilation versus supraglottic airways; and involve other patient populations, including children, people with trauma and people in hospital. TRIAL REGISTRATION: This trial is registered as ISRCTN08256118. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and supported by the NIHR Comprehensive Research Networks and will be published in full in Health Technology Assessment; Vol. 26, No. 21. See the NIHR Journals Library website for further project information.

BACKGROUND: Cardiac arrest is a serious medical emergency in which the heartbeat and breathing stop suddenly. Every year in the UK, a large number of patients (around 123 per 100,000) suffer a cardiac arrest outside hospital. Only 7­9% of these patients survive to leave hospital. The best initial treatment in cardiac arrest is cardiopulmonary resuscitation (commonly known as CPR), during which it is vital to give chest compressions and maintain a clear airway. Two main techniques are used to keep the airway clear: tracheal intubation (inserting a breathing tube into the windpipe) and a supraglottic airway device (a newer device that is inserted less deeply and sits just above the voicebox). Both techniques are used routinely by paramedics in the UK when treating a cardiac arrest, but there is no evidence about which technique is best. The AIRWAYS-2 trial aimed to find out whether or not a supraglottic airway device is better than tracheal intubation. WHO PARTICIPATED AND WHAT WAS INVOLVED?: Paramedics from four UK ambulance services were put into one of two groups at random. One group was randomly chosen to use tracheal intubation and the other group was randomly chosen to use a supraglottic airway device at all adult cardiac arrests they attended for approximately 2 years. Paramedics were able to apply their clinical judgement and use a different device if they felt that this would be best for the patient. A total of 1523 paramedics took part and enrolled 9296 patients. Following cardiac arrest, a patient's recovery was assessed as good or poor (including patients who did not survive). WHAT DID THE TRIAL FIND?: A similar percentage of patients in both groups had a good recovery. There was no evidence to suggest that the supraglottic airway device was any better than tracheal intubation for treating a cardiac arrest.

Video-Assisted Thoracoscopic or Open Lobectomy in Early-Stage Lung Cancer.

BACKGROUND: There is limited randomized evidence on the comparative outcomes of early-stage lung cancer resection by video-assisted thoracoscopic surgery (VATS) versus open resection. METHODS: We conducted a parallel-group multicenter randomized trial that recruited participants with known or suspected early-stage lung cancer and randomly assigned them to open or VATS resection of their lesions. The primary outcome was physical function at 5 weeks as a measure of recovery using the European Organisation for Research and Treatment of Cancer core health-related quality of life questionnaire (QLQ-C30) (scores range from 0 to 100, with higher scores indicating better function; the clinical minimally important difference for improvement is 5 points). We followed the patients for an additional 47 weeks for other outcomes. RESULTS: A total of 503 participants were randomly assigned (247 to VATS and 256 to open lobectomy). At 5 weeks, median physical function was 73 in the VATS group and 67 in the open surgery group, with a mean difference of 4.65 points (95% confidence interval, 1.69 to 7.61). Of the participants allocated to VATS, 30.7% had serious adverse events after discharge compared with 37.8% of those allocated to open surgery (risk ratio, 0.81 [95% confidence interval, 0.66 to 1.00]). At 52 weeks, there were no differences in cancer progression-free survival (hazard ratio, 0.74 [0.43 to 1.27]) or overall survival (hazard ratio, 0.67 [0.32 to 1.40]). CONCLUSIONS: VATS lobectomy for lung cancer is associated with a better recovery of physical function in the 5 weeks after random assignment compared with open surgery. Long-term oncologic outcomes will require continued follow-up to assess. (Funded by the National Institute for Health Research Health Technology Assessment programme [reference number 13/04/03]; ISRCTN number, ISRCTN13472721.)

Cost-effectiveness of the i-gel supraglottic airway device compared to tracheal intubation during out-of-hospital cardiac arrest: Findings from the AIRWAYS-2 randomised controlled trial.

AIM: Optimal airway management during out-of-hospital cardiac arrest (OHCA) is uncertain. Complications from tracheal intubation (TI) may be avoided with supraglottic airway (SGA) devices. The AIRWAYS-2 cluster randomised controlled trial (ISRCTN08256118) compared the i-gel SGA with TI as the initial advanced airway management (AAM) strategy by paramedics treating adults with non-traumatic OHCA. This paper reports the trial cost-effectiveness analysis. METHODS: A within-trial cost-effectiveness analysis of the i-gel compared with TI was conducted, with a six-month time horizon, from the perspective of the UK National Health Service (NHS) and personal social services. The primary outcome measure was quality-adjusted life years (QALYs), estimated using the EQ-5D-5L questionnaire. Multilevel linear regression modelling was used to account for clustering by paramedic when combining costs and outcomes. RESULTS: 9296 eligible patients were attended by 1382 trial paramedics and enrolled in the AIRWAYS-2 trial (4410 TI, 4886 i-gel). Mean QALYs to six months were 0.03 in both groups (i-gel minus TI difference -0.0015, 95% CI -0.0059 to 0.0028). Total costs per participant up to six months post-OHCA were £3570 and £3413 in the i-gel and TI groups respectively (mean difference £157, 95% CI -£270 to £583). Based on mean difference point estimates, TI was more effective and less costly than i-gel; however differences were small and there was great uncertainty around these results. CONCLUSION: The small differences between groups in QALYs and costs shows no difference in the cost-effectiveness of the i-gel and TI when used as the initial AAM strategy in adults with non-traumatic OHCA.

Is there a renoprotective value to leukodepletion during heart valve surgery? A randomized controlled trial (ROLO).

BACKGROUND: Acute Kidney Injury (AKI) adversely affects outcomes after cardiac surgery. A major mediator of AKI is the activation of leukocytes through exposure to the cardiopulmonary bypass circuit. We evaluate the use of leukodepletion filters throughout bypass to protect against post-operative AKI by removing activated leukocytes during cardiac surgery. METHODS: This is a single-centre, double-blind, randomized controlled trial comparing the use of leukodepletion versus a standard arterial filter throughout bypass. Elective adult patients undergoing heart valve surgery with or without concomitant procedures were investigated. The primary clinical outcome measured was the development of AKI according to the KDIGO criteria. Secondary measures included biomarkers of renal tubular damage (urinary Retinol Binding Protein and Kidney Injury Molecule-1), glomerular kidney injury (urinary Micro Albumin and serum Cystatin C) and urinary Neutrophil Gelatinase Associated Lipocalin, as well as the length of hospital stay and quality of life measures through EQ-5D-5L questionnaires. RESULTS: The ROLO trial randomized 64 participants with a rate of recruitment higher than anticipated (57% achieved, 40% anticipated). The incidence of AKI was greater in the leukodepletion filter group (44% versus 23%, risk difference 21, 95% CI - 2 to 44%). This clinical finding was supported by biomarker levels especially by a tendency toward glomerular insult at 48 h, demonstrated by a raised serum Cystatin C (mean difference 0.11, 95% CI 0.00 to 0.23, p = 0.068) in the leukodepleted group. There was however no clear association between the incidence or severity of AKI and length of hospital stay. On average, health related quality of life returned to pre-operative levels in both groups within 3 months of surgery. CONCLUSIONS: Leukocyte depletion during cardiopulmonary bypass does not significantly reduce the incidence of AKI after valvular heart surgery. Other methods to ameliorate renal dysfunction after cardiac surgery need to be investigated. TRIAL REGISTRATION: The trial was registered by the International Standard Randomized Controlled Trial Number Registry ISRCTN42121335 . Registered on the 18 February 2014. The trial was run by the Bristol Clinical Trials and Evaluation Unit. This trial was financially supported by the National Institute of Health Research (Research for Patient Benefit), award ID: PB-PG-0711-25,090.

Mesothelioma and Radical Surgery 2 (MARS 2): protocol for a multicentre randomised trial comparing (extended) pleurectomy decortication versus no (extended) pleurectomy decortication for patients with malignant pleural mesothelioma.

INTRODUCTION: Mesothelioma remains a lethal cancer. To date, systemic therapy with pemetrexed and a platinum drug remains the only licensed standard of care. As the median survival for patients with mesothelioma is 12.1 months, surgery is an important consideration to improve survival and/or quality of life. Currently, only two surgical trials have been performed which found that neither extensive (extra-pleural pneumonectomy) or limited (partial pleurectomy) surgery improved survival (although there was some evidence of improved quality of life). Therefore, clinicians are now looking to evaluate pleurectomy decortication, the only radical treatment option left. METHODS AND ANALYSIS: The MARS 2 study is a UK multicentre open parallel group randomised controlled trial comparing the effectiveness and cost-effectiveness of surgery-(extended) pleurectomy decortication-versus no surgery for the treatment of pleural mesothelioma. The study will test the hypothesis that surgery and chemotherapy is superior to chemotherapy alone with respect to overall survival. Secondary outcomes include health-related quality of life, progression-free survival, measures of safety (adverse events) and resource use to 2 years. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment. ETHICS AND DISSEMINATION: Research ethics approval was granted by London - Camberwell St. Giles Research Ethics Committee (reference 13/LO/1481) on 7 November 2013. We will submit the results for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ISRCTN-ISRCTN44351742 and ClinicalTrials.gov-NCT02040272.

Effectiveness, cost-effectiveness and safety of gabapentin versus placebo as an adjunct to multimodal pain regimens in surgical patients: protocol of a placebo controlled randomised controlled trial with blinding (GAP study).

INTRODUCTION: Gabapentin is an antiepileptic drug currently licensed to treat epilepsy and neuropathic pain but has been used off-label to treat acute postoperative pain. The GAP study will compare the effectiveness, cost-effectiveness and safety of gabapentin as an adjunct to standard multimodal analgesia versus placebo for the management of pain after major surgery. METHODS AND ANALYSIS: The GAP study is a multicentre, double-blind, randomised controlled trial in patients aged 18 years and over, undergoing different types of major surgery (cardiac, thoracic or abdominal). Patients will be randomised in a 1:1 ratio to receive either gabapentin (600 mg just before surgery and 600 mg/day for 2 days after surgery) or placebo in addition to usual pain management for each type of surgery. Patients will be followed up daily until hospital discharge and then at 4 weeks and 4 months after surgery. The primary outcome is length of hospital stay following surgery. Secondary outcomes include pain, total opioid use, adverse health events, health related quality of life and costs. ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committee . Findings will be shared with participating hospitals and disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. Patients will be informed of the results through patient organisations and participant newsletters. TRIAL REGISTRATION NUMBER: ISRCTN63614165.

Study protocol for VIdeo assisted thoracoscopic lobectomy versus conventional Open LobEcTomy for lung cancer, a UK multicentre randomised controlled trial with an internal pilot (the VIOLET study).

INTRODUCTION: Lung cancer is a leading cause of cancer deaths worldwide and surgery remains the main treatment for early stage disease. Prior to the introduction of video-assisted thoracoscopic surgery (VATS), lung resection for cancer was undertaken through an open thoracotomy. To date, the evidence base supporting the different surgical approaches is based on non-randomised studies, small randomised trials and is focused mainly on short-term in-hospital outcomes. METHODS AND ANALYSIS: The VIdeo assisted thoracoscopic lobectomy versus conventional Open LobEcTomy for lung cancer study is a UK multicentre parallel group randomised controlled trial (RCT) with blinding of outcome assessors and participants (to hospital discharge) comparing the effectiveness, cost-effectiveness and acceptability of VATS lobectomy versus open lobectomy for treatment of lung cancer. We will test the hypothesis that VATS lobectomy is superior to open lobectomy with respect to self-reported physical function 5 weeks after randomisation (approximately 1 month after surgery). Secondary outcomes include assessment of efficacy (hospital stay, pain, proportion and time to uptake of chemotherapy), measures of safety (adverse health events), oncological outcomes (proportion of patients upstaged to pathologic N2 (pN2) disease and disease-free survival), overall survival and health related quality of life to 1 year. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment. ETHICS AND DISSEMINATION: This trial has been approved by the UK (Dulwich) National Research Ethics Service Committee London. Findings will be written-up as methodology papers for conference presentation, and publication in peer-reviewed journals. Many aspects of the feasibility work will inform surgical RCTs in general and these will be reported at methodology meetings. We will also link with lung cancer clinical studies groups. The patient and public involvement group that works with the Respiratory Biomedical Research Unit at the Brompton Hospital will help identify how we can best publicise the findings. TRIAL REGISTRATION NUMBER: ISRCTN13472721.

Cardiovascular magnetic resonance in emergency patients with multivessel disease or unobstructed coronary arteries: a cost-effectiveness analysis in the UK.

OBJECTIVE: To identify the key drivers of cost-effectiveness for cardiovascular magnetic resonance (CMR) when patients activate the primary percutaneous coronary intervention (PPCI) pathway. DESIGN: Economic decision models for two patient subgroups populated from secondary sources, each with a 1 year time horizon from the perspective of the National Health Service (NHS) and personal social services in the UK. SETTING: Usual care (with or without CMR) in the NHS. PARTICIPANTS: Patients who activated the PPCI pathway, and for Model 1: underwent an emergency coronary angiogram and PPCI, and were found to have multivessel coronary artery disease. For Model 2: underwent an emergency coronary angiogram and were found to have unobstructed coronary arteries. INTERVENTIONS: Model 1 (multivessel disease) compared two different ischaemia testing methods, CMR or fractional flow reserve (FFR), versus stress echocardiography. Model 2 (unobstructed arteries) compared CMR with standard echocardiography versus standard echocardiography alone. MAIN OUTCOME MEASURES: Key drivers of cost-effectiveness for CMR, incremental costs and quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios. RESULTS: In both models, the incremental costs and QALYs between CMR (or FFR, Model 1) versus no CMR (stress echocardiography, Model 1 and standard echocardiography, Model 2) were small (CMR: -£64 (95% CI -£232 to £187)/FFR: £360 (95% CI -£116 to £844) and CMR/FFR: 0.0012 QALYs (95% CI -0.0076 to 0.0093)) and (£98 (95% CI -£199 to £488) and 0.0005 QALYs (95% CI -0.0050 to 0.0077)), respectively. The diagnostic accuracy of the tests was the key driver of cost-effectiveness for both patient groups. CONCLUSIONS: If CMR were introduced for all subgroups of patients who activate the PPCI pathway, it is likely that diagnostic accuracy would be a key determinant of its cost-effectiveness. Further research is needed to definitively answer whether revascularisation guided by CMR or FFR leads to different clinical outcomes in acute coronary syndrome patients with multivessel disease.

Effect of a Strategy of a Supraglottic Airway Device vs Tracheal Intubation During Out-of-Hospital Cardiac Arrest on Functional Outcome: The AIRWAYS-2 Randomized Clinical Trial.

Importance: The optimal approach to airway management during out-of-hospital cardiac arrest is unknown. Objective: To determine whether a supraglottic airway device (SGA) is superior to tracheal intubation (TI) as the initial advanced airway management strategy in adults with nontraumatic out-of-hospital cardiac arrest. Design, Setting, and Participants: Multicenter, cluster randomized clinical trial of paramedics from 4 ambulance services in England responding to emergencies for approximately 21 million people. Patients aged 18 years or older who had a nontraumatic out-of-hospital cardiac arrest and were treated by a participating paramedic were enrolled automatically under a waiver of consent between June 2015 and August 2017; follow-up ended in February 2018. Interventions: Paramedics were randomized 1:1 to use TI (764 paramedics) or SGA (759 paramedics) as their initial advanced airway management strategy. Main Outcomes and Measures: The primary outcome was modified Rankin Scale score at hospital discharge or 30 days after out-of-hospital cardiac arrest, whichever occurred sooner. Modified Rankin Scale score was divided into 2 ranges: 0-3 (good outcome) or 4-6 (poor outcome; 6 = death). Secondary outcomes included ventilation success, regurgitation, and aspiration. Results: A total of 9296 patients (4886 in the SGA group and 4410 in the TI group) were enrolled (median age, 73 years; 3373 were women [36.3%]), and the modified Rankin Scale score was known for 9289 patients. In the SGA group, 311 of 4882 patients (6.4%) had a good outcome (modified Rankin Scale score range, 0-3) vs 300 of 4407 patients (6.8%) in the TI group (adjusted risk difference [RD], -0.6% [95% CI, -1.6% to 0.4%]). Initial ventilation was successful in 4255 of 4868 patients (87.4%) in the SGA group compared with 3473 of 4397 patients (79.0%) in the TI group (adjusted RD, 8.3% [95% CI, 6.3% to 10.2%]). However, patients randomized to receive TI were less likely to receive advanced airway management (3419 of 4404 patients [77.6%] vs 4161 of 4883 patients [85.2%] in the SGA group). Two of the secondary outcomes (regurgitation and aspiration) were not significantly different between groups (regurgitation: 1268 of 4865 patients [26.1%] in the SGA group vs 1072 of 4372 patients [24.5%] in the TI group; adjusted RD, 1.4% [95% CI, -0.6% to 3.4%]; aspiration: 729 of 4824 patients [15.1%] vs 647 of 4337 patients [14.9%], respectively; adjusted RD, 0.1% [95% CI, -1.5% to 1.8%]). Conclusions and Relevance: Among patients with out-of-hospital cardiac arrest, randomization to a strategy of advanced airway management with a supraglottic airway device compared with tracheal intubation did not result in a favorable functional outcome at 30 days. Trial Registration: ISRCTN Identifier: 08256118.

Accurate costs of blood transfusion: a microcosting of administering blood products in the United Kingdom National Health Service.

BACKGROUND: In an environment of limited health care resources, it is crucial for health care systems which provide blood transfusion to have accurate and comprehensive information on the costs of transfusion, incorporating not only the costs of blood products, but also their administration. Unfortunately, in many countries accurate costs for administering blood are not available. Our study aimed to generate comprehensive estimates of the costs of administering transfusions for the UK National Health Service. STUDY DESIGN AND METHODS: A detailed microcosting study was used to cost two key inputs into transfusion: transfusion laboratory and nursing inputs. For each input, data collection forms were developed to capture staff time, equipment, and consumables associated with each step in the transfusion process. Costing results were combined with costs of blood product wastage to calculate the cost per unit transfused, separately for different blood products. Data were collected in 2014/15 British pounds and converted to US dollars. RESULTS: A total of 438 data collection forms were completed by 74 staff. The cost of administering blood was $71 (£49) per unit for red blood cells, $84 (£58) for platelets, $55 (£38) for fresh-frozen plasma, and $72 (£49) for cryoprecipitate. CONCLUSIONS: Blood administration costs add substantially to the costs of the blood products themselves. These are frequently incurred costs; applying estimates to the blood components supplied to UK hospitals in 2015, the annual cost of blood administration, excluding blood products, exceeds $175 (£120) million. These results provide more accurate estimates of the total costs of transfusion than those previously available.

The use of community pharmacies in North West England: an observational study.

BACKGROUND: There are few studies of community pharmacy footfall and activity in the existing literature, especially by direct observation. OBJECTIVE: To describe the characteristics of counter interactions between pharmacy staff and customers. METHOD: Structured observation of all interactions between pharmacy staff and customers across the weekly opening hours of five pharmacies diverse in location and ownership. KEY FINDINGS: Three-quarters (76%) of observed interactions were associated with prescriptions, but a significant minority accessed cognitive services. CONCLUSIONS: Dispensing was the primary activity across the diverse range of pharmacies. Reasons for visits are diversifying into advice and services, particularly among younger users.

Design and implementation of the AIRWAYS-2 trial: A multi-centre cluster randomised controlled trial of the clinical and cost effectiveness of the i-gel supraglottic airway device versus tracheal intubation in the initial airway management of out of hospital cardiac arrest.

Health outcomes after out of hospital cardiac arrest (OHCA) are extremely poor, with only 7-9% of patients in the United Kingdom (UK) surviving to hospital discharge. Currently emergency medical services (EMS) use either tracheal intubation or newer supraglottic airway devices (SGAs) to provide advanced airway management during OHCA. Equipoise between the two techniques has led to calls for a well-designed randomised controlled trial. The primary objective of the AIRWAYS-2 trial is to assess whether the clinical effectiveness of the i-gel, a second-generation SGA, is superior to tracheal intubation in the initial airway management of OHCA patients in the UK. Paramedics recruited to the AIRWAYS-2 trial are randomised to use either tracheal intubation or i-gel as their first advanced airway intervention. Adults who have had a non-traumatic OHCA and are attended by an AIRWAYS-2 paramedic are retrospectively assessed against eligibility criteria for inclusion. The primary outcome is the modified Rankin Scale score at hospital discharge. Secondary objectives are to: (i) estimate differences between groups in outcome measures relating to airway management, hospital stay and recovery at 3 and 6 months; (ii) estimate the cost effectiveness of the i-gel compared to tracheal intubation. Because OHCA patient needs immediate treatment there are several unusual features and challenges to the design and implementation of this trial; these include level of randomisation, the automatic enrolment model, enrolment of patients that lack capacity and minimisation of bias. Patient enrolment began in June 2015. The trial will enrol 9070 patients over two years. The results are expected to influence future resuscitation guidelines. Trial Registration ISRCTN: 08256118.

A multicentre randomised controlled trial of Transfusion Indication Threshold Reduction on transfusion rates, morbidity and health-care resource use following cardiac surgery (TITRe2).

BACKGROUND: Uncertainty about optimal red blood cell transfusion thresholds in cardiac surgery is reflected in widely varying transfusion rates between surgeons and cardiac centres. OBJECTIVE: To test the hypothesis that a restrictive compared with a liberal threshold for red blood cell transfusion after cardiac surgery reduces post-operative morbidity and health-care costs. DESIGN: Multicentre, parallel randomised controlled trial and within-trial cost-utility analysis from a UK NHS and Personal Social Services perspective. We could not blind health-care staff but tried to blind participants. Random allocations were generated by computer and minimised by centre and operation. SETTING: Seventeen specialist cardiac surgery centres in UK NHS hospitals. PARTICIPANTS: Patients aged > 16 years undergoing non-emergency cardiac surgery with post-operative haemoglobin < 9 g/dl. Exclusion criteria were: unwilling to have transfusion owing to beliefs; platelet, red blood cell or clotting disorder; ongoing or recurrent sepsis; and critical limb ischaemia. INTERVENTIONS: Participants in the liberal group were eligible for transfusion immediately after randomisation (post-operative haemoglobin < 9 g/dl); participants in the restrictive group were eligible for transfusion if their post-operative haemoglobin fell to < 7.5 g/dl during the index hospital stay. MAIN OUTCOME MEASURES: The primary outcome was a composite outcome of any serious infectious (sepsis or wound infection) or ischaemic event (permanent stroke, myocardial infarction, gut infarction or acute kidney injury) during the 3 months after randomisation. Events were verified or adjudicated by blinded personnel. Secondary outcomes included blood products transfused; infectious events; ischaemic events; quality of life (European Quality of Life-5 Dimensions); duration of intensive care or high-dependency unit stay; duration of hospital stay; significant pulmonary morbidity; all-cause mortality; resource use, costs and cost-effectiveness. RESULTS: We randomised 2007 participants between 15 July 2009 and 18 February 2013; four withdrew, leaving 1000 and 1003 in the restrictive and liberal groups, respectively. Transfusion rates after randomisation were 53.4% (534/1000) and 92.2% (925/1003). The primary outcome occurred in 35.1% (331/944) and 33.0% (317/962) of participants in the restrictive and liberal groups [odds ratio (OR) 1.11, 95% confidence interval (CI) 0.91 to 1.34; p = 0.30], respectively. There were no subgroup effects for the primary outcome, although some sensitivity analyses substantially altered the estimated OR. There were no differences for secondary clinical outcomes except for mortality, with more deaths in the restrictive group (4.2%, 42/1000 vs. 2.6%, 26/1003; hazard ratio 1.64, 95% CI 1.00 to 2.67; p = 0.045). Serious post-operative complications excluding primary outcome events occurred in 35.7% (354/991) and 34.2% (339/991) of participants in the restrictive and liberal groups, respectively. The total cost per participant from surgery to 3 months postoperatively differed little by group, just £182 less (standard error £488) in the restrictive group, largely owing to the difference in red blood cells cost. In the base-case cost-effectiveness results, the point estimate suggested that the restrictive threshold was cost-effective; however, this result was very uncertain partly owing to the negligible difference in quality-adjusted life-years gained. CONCLUSIONS: A restrictive transfusion threshold is not superior to a liberal threshold after cardiac surgery. This finding supports restrictive transfusion due to reduced consumption and costs of red blood cells. However, secondary findings create uncertainty about recommending restrictive transfusion and prompt a new hypothesis that liberal transfusion may be superior after cardiac surgery. Reanalyses of existing trial datasets, excluding all participants who did not breach the liberal threshold, followed by a meta-analysis of the reanalysed results are the most obvious research steps to address the new hypothesis about the possible harm of red blood cell transfusion. TRIAL REGISTRATION: Current Controlled Trials ISRCTN70923932. 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. 20, No. 60. See the NIHR Journals Library website for further project information.

Quantifying the healthcare costs of treating severely bleeding major trauma patients: a national study for England.

INTRODUCTION: Severely bleeding trauma patients are a small proportion of the major trauma population but account for 40% of all trauma deaths. Healthcare resource use and costs are likely to be substantial but have not been fully quantified. Knowledge of costs is essential for developing targeted cost reduction strategies, informing health policy, and ensuring the cost-effectiveness of interventions. METHODS: In collaboration with the Trauma Audit Research Network (TARN) detailed patient-level data on in-hospital resource use, extended care at hospital discharge, and readmissions up to 12 months post-injury were collected on 441 consecutive adult major trauma patients with severe bleeding presenting at 22 hospitals (21 in England and one in Wales). Resource use data were costed using national unit costs and mean costs estimated for the cohort and for clinically relevant subgroups. Using nationally available data on trauma presentations in England, patient-level cost estimates were up-scaled to a national level. RESULTS: The mean (95% confidence interval) total cost of initial hospital inpatient care was £19,770 (£18,177 to £21,364) per patient, of which 62% was attributable to ventilation, intensive care, and ward stays, 16% to surgery, and 12% to blood component transfusion. Nursing home and rehabilitation unit care and re-admissions to hospital increased the cost to £20,591 (£18,924 to £22,257). Costs were significantly higher for more severely injured trauma patients (Injury Severity Score ≥15) and those with blunt injuries. Cost estimates for England were £148,300,000, with over a third of this cost attributable to patients aged 65 years and over. CONCLUSIONS: Severely bleeding major trauma patients are a high cost subgroup of all major trauma patients, and the cost burden is projected to rise further as a consequence of an aging population and as evidence continues to emerge on the benefits of early and simultaneous administration of blood products in pre-specified ratios. The findings from this study provide a previously unreported baseline from which the potential impact of changes to service provision and/or treatment practice can begin to be evaluated. Further studies are still required to determine the full costs of post-discharge care requirements, which are also likely to be substantial.

Emergency supply of prescription-only medicines to patients by community pharmacists: a mixed methods evaluation incorporating patient, pharmacist and GP perspectives.

OBJECTIVE: To evaluate and inform emergency supply of prescription-only medicines by community pharmacists (CPs), including how the service could form an integral component of established healthcare provision to maximise adherence. DESIGN: Mixed methods. 4 phases: prospective audit of emergency supply requests for prescribed medicines (October-November 2012 and April 2013); interviews with CPs (February-April 2013); follow-up interviews with patients (April-May 2013); interactive feedback sessions with general practice teams (October-November 2013). SETTING: 22 community pharmacies and 6 general practices in Northwest England. PARTICIPANTS: 27 CPs with experience of dealing with requests for emergency supplies; 25 patients who received an emergency supply of a prescribed medicine; 58 staff at 6 general practices. RESULTS: Clinical audit in 22 pharmacies over two 4-week periods reported that 526 medicines were requested by 450 patients. Requests peaked over a bank holiday and around weekends. A significant number of supplies were made during practice opening hours. Most requests were for older patients and for medicines used in long-term conditions. Difficulty in renewing repeat medication (forgetting to order, or prescription delays) was the major reason for requests. The majority of medicines were 'loaned' in advance of a National Health Service (NHS) prescription. Interviews with CPs and patients indicated that continuous supply had a positive impact on medicines adherence, removing the need to access urgent care. General practice staff were surprised and concerned by the extent of emergency supply episodes. CONCLUSIONS: CPs regularly provide emergency supplies to patients who run out of their repeat medication, including during practice opening hours. This may aid adherence. There is currently no feedback loop, however, to general practice. Patient care and interprofessional communication may be better served by the introduction of a formally structured and funded NHS emergency supply service from community pharmacies, with ongoing optimisation of repeat prescribing.

Liberal or restrictive transfusion after cardiac surgery.

BACKGROUND: Whether a restrictive threshold for hemoglobin level in red-cell transfusions, as compared with a liberal threshold, reduces postoperative morbidity and health care costs after cardiac surgery is uncertain. METHODS: We conducted a multicenter, parallel-group trial in which patients older than 16 years of age who were undergoing nonemergency cardiac surgery were recruited from 17 centers in the United Kingdom. Patients with a postoperative hemoglobin level of less than 9 g per deciliter were randomly assigned to a restrictive transfusion threshold (hemoglobin level <7.5 g per deciliter) or a liberal transfusion threshold (hemoglobin level <9 g per deciliter). The primary outcome was a serious infection (sepsis or wound infection) or an ischemic event (permanent stroke [confirmation on brain imaging and deficit in motor, sensory, or coordination functions], myocardial infarction, infarction of the gut, or acute kidney injury) within 3 months after randomization. Health care costs, excluding the index surgery, were estimated from the day of surgery to 3 months after surgery. RESULTS: A total of 2007 patients underwent randomization; 4 participants withdrew, leaving 1000 in the restrictive-threshold group and 1003 in the liberal-threshold group. Transfusion rates after randomization were 53.4% and 92.2% in the two groups, respectively. The primary outcome occurred in 35.1% of the patients in the restrictive-threshold group and 33.0% of the patients in the liberal-threshold group (odds ratio, 1.11; 95% confidence interval [CI], 0.91 to 1.34; P=0.30); there was no indication of heterogeneity according to subgroup. There were more deaths in the restrictive-threshold group than in the liberal-threshold group (4.2% vs. 2.6%; hazard ratio, 1.64; 95% CI, 1.00 to 2.67; P=0.045). Serious postoperative complications, excluding primary-outcome events, occurred in 35.7% of participants in the restrictive-threshold group and 34.2% of participants in the liberal-threshold group. Total costs did not differ significantly between the groups. CONCLUSIONS: A restrictive transfusion threshold after cardiac surgery was not superior to a liberal threshold with respect to morbidity or health care costs. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN70923932.).