Health Technology Assessment

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Health Technology Assessment, Volume 26, pp 1-152; https://doi.org/10.3310/khha0861

Abstract:
Background: There are few effective interventions for dementia. Aim: To determine the clinical effectiveness and cost-effectiveness of an intervention to promote self-management, independence and self-efficacy in people with early-stage dementia. Objectives: To undertake a randomised controlled trial of the Journeying through Dementia intervention compared with usual care, conduct an internal pilot testing feasibility, assess intervention delivery fidelity and undertake a qualitative exploration of participants’ experiences. Design: A pragmatic two-arm individually randomised trial analysed by intention to treat. Participants: A total of 480 people diagnosed with mild dementia, with capacity to make informed decisions, living in the community and not participating in other studies, and 350 supporters whom they identified, from 13 locations in England, took part. Intervention: Those randomised to the Journeying through Dementia intervention (n = 241) were invited to take part in 12 weekly facilitated groups and four one-to-one sessions delivered in the community by secondary care staff, in addition to their usual care. The control group (n = 239) received usual care. Usual care included drug treatment, needs assessment and referral to appropriate services. Usual care at each site was recorded. Main outcome measures: The primary outcome was Dementia-Related Quality of Life score at 8 months post randomisation, with higher scores representing higher quality of life. Secondary outcomes included resource use, psychological well-being, self-management, instrumental activities of daily living and health-related quality of life. Randomisation and blinding: Participants were randomised in a 1 : 1 ratio. Staff conducting outcome assessments were blinded. Data sources: Outcome measures were administered in participants’ homes at baseline and at 8 and 12 months post randomisation. Interviews were conducted with participants, participating carers and interventionalists. Results: The mean Dementia-Related Quality of Life score at 8 months was 93.3 (standard deviation 13.0) in the intervention arm (n = 191) and 91.9 (standard deviation 14.6) in the control arm (n = 197), with a difference in means of 0.9 (95% confidence interval –1.2 to 3.0; p = 0.380) after adjustment for covariates. This effect size (0.9) was less than the 4 points defined as clinically meaningful. For other outcomes, a difference was found only for Diener’s Flourishing Scale (adjusted mean difference 1.2, 95% confidence interval 0.1 to 2.3), in favour of the intervention (i.e. in a positive direction). The Journeying through Dementia intervention cost £608 more than usual care (95% confidence interval £105 to £1179) and had negligible difference in quality-adjusted life-years (–0.003, 95% confidence interval –0.044 to 0.038). Therefore, the Journeying through Dementia intervention had a mean incremental cost per quality-adjusted life-year of –£202,857 (95% confidence interval –£534,733 to £483,739); however, there is considerable uncertainty around this. Assessed fidelity was good. Interviewed participants described receiving some benefit and a minority benefited greatly. However, negative aspects were also raised by a minority. Seventeen per cent of participants in the intervention arm and 15% of participants in the control arm experienced at least one serious adverse event. None of the serious adverse events were classified as related to the intervention. Limitations: Study limitations include recruitment of an active population, delivery challenges and limitations of existing outcome measures. Conclusions: The Journeying through Dementia programme is not clinically effective, is unlikely to be cost-effective and cannot be recommended in its existing format. Future work: Research should focus on the creation of new outcome measures to assess well-being in dementia and on using elements of the intervention, such as enabling enactment in the community. Trial registration: This trial is registered as ISRCTN17993825. 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. 24. See the NIHR Journals Library website for further project information.
, Thomas Chadwick, , , Helen Mossop, Sonya Carnell, Will King, Alaa Abouhajar, , , et al.
Health Technology Assessment, Volume 26, pp 1-172; https://doi.org/10.3310/qoiz6538

Abstract:
Background: Daily, low-dose antibiotic prophylaxis is the current standard care for women with recurrent urinary tract infection. Emerging antimicrobial resistance is a global health concern, prompting research interest in non-antibiotic agents such as methenamine hippurate, but comparative data on their efficacy and safety are lacking. Objective: To assess the clinical effectiveness and cost-effectiveness of methenamine hippurate (Hiprex®; Mylan NV, Canonsburg, PA, USA) compared with current standard care (antibiotic prophylaxis) for recurrent urinary tract infection prevention in adult women. Design: Multicentre, pragmatic, open-label, randomised, non-inferiority trial of 12 months’ treatment with the allocated intervention, including an early, embedded qualitative study and a 6-month post-treatment observation phase. The predefined non-inferiority margin was one urinary tract infection per person-year. Setting: Eight UK NHS secondary care sites. Participants: A total of 240 adult women with recurrent urinary tract infection requiring preventative treatment participated in the trial. Interventions: A central randomisation system allocated participants 1 : 1 to the experimental (methenamine hippurate: 1 g twice daily) or control (once-daily low-dose antibiotics: 50/100 mg of nitrofurantoin, 100 mg of trimethoprim or 250 mg of cefalexin) arm. Crossover between treatment arms was permitted. Main outcome measures: The primary clinical outcome was incidence of symptomatic antibiotic-treated urinary tract infection during the 12-month treatment period. Cost-effectiveness was assessed by incremental cost per quality-adjusted life-year gained, extrapolated over the patient’s expected lifetime using a Markov cohort model. Secondary outcomes included post-treatment urinary tract infections, total antibiotic use, microbiologically proven urinary tract infections, antimicrobial resistance, bacteriuria, hospitalisations and treatment satisfaction. Results: Primary modified intention-to-treat analysis comprised 205 (85%) randomised participants [102/120 (85%) participants in the antibiotics arm and 103/120 (86%) participants in the methenamine hippurate arm] with at least 6 months’ data available. During treatment, the incidence rate of symptomatic, antibiotic-treated urinary tract infections decreased substantially in both arms to 1.38 episodes per person-year (95% confidence interval 1.05 to 1.72 episodes per person-year) for methenamine hippurate and 0.89 episodes per person year (95% confidence interval 0.65 to 1.12 episodes per person-year) for antibiotics (absolute difference 0.49; 90% confidence interval 0.15 to 0.84). This absolute difference did not exceed the predefined, strict, non-inferiority limit of one urinary tract infection per person-year. On average, methenamine hippurate was less costly and more effective than antibiotics in terms of quality-adjusted life-years gained; however, this finding was not consistent over the longer term. The urinary tract infection incidence rate 6 months after treatment completion was 1.72 episodes per year in the methenamine hippurate arm and 1.19 in the antibiotics arm. During treatment, 52% of urine samples taken during symptomatic urinary tract infections were microbiologically confirmed and higher proportions of participants taking daily antibiotics (46/64; 72%) demonstrated antibiotic resistance in Escherichia coli cultured from perineal swabs than participants in the methenamine hippurate arm (39/70; 56%) (p-value = 0.05). Urine cultures revealed that during treatment higher proportions of participants and samples from the antibiotic arm grew E. coli resistant to trimethoprim/co-trimoxazole and cephalosporins, respectively. Conversely, post treatment, higher proportions of participants in the methenamine hippurate arm (9/45; 20%) demonstrated multidrug resistance in E. coli isolated from perineal swabs than participants in the antibiotic arm (2/39; 5%) (p = 0.06). All other secondary outcomes and adverse events were similar in both arms. Limitations: This trial could not define whether or not one particular antibiotic was more beneficial, and progressive data loss hampered economic evaluation. Conclusions: This large, randomised, pragmatic trial in a routine NHS setting has clearly shown that methenamine hippurate is not inferior to current standard care (daily low-dose antibiotics) in preventing recurrent urinary tract infections in women. The results suggest that antimicrobial resistance is proportionally higher in women taking prophylactic antibiotics. Recommendations for research: Future research should include evaluation of other non-antibiotic preventative treatments in well-defined homogeneous patient groups, preferably with the comparator of daily antibiotics. Trial registration: This trial is registered as ISRCTN70219762 and EudraCT 2015-003487-36. 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. 23. See the NIHR Journals Library website for further project information.
Health Technology Assessment, Volume 26, pp 1-158; https://doi.org/10.3310/vhoh9034

Abstract:
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.
, Lee J Middleton, Versha Cheed, William McKinnon, , Fusun Sirkeci, Isaac Manyonda, Anna-Maria Belli, Mary Ann Lumsden, , et al.
Health Technology Assessment, Volume 26, pp 1-74; https://doi.org/10.3310/zdeg6110

Abstract:
Background: Uterine fibroids are the most common tumour in women of reproductive age and are associated with heavy menstrual bleeding, abdominal discomfort, subfertility and reduced quality of life. For women wishing to retain their uterus and who do not respond to medical treatment, myomectomy and uterine artery embolisation are therapeutic options. Objectives: We examined the clinical effectiveness and cost-effectiveness of uterine artery embolisation compared with myomectomy in the treatment of symptomatic fibroids. Design: A multicentre, open, randomised trial with a parallel economic evaluation. Setting: Twenty-nine UK hospitals. Participants: Premenopausal women who had symptomatic uterine fibroids amenable to myomectomy or uterine artery embolisation were recruited. Women were excluded if they had significant adenomyosis, any malignancy or pelvic inflammatory disease or if they had already had a previous open myomectomy or uterine artery embolisation. Interventions: Participants were randomised to myomectomy or embolisation in a 1 : 1 ratio using a minimisation algorithm. Myomectomy could be open abdominal, laparoscopic or hysteroscopic. Embolisation of the uterine arteries was performed under fluoroscopic guidance. Main outcome measures: The primary outcome was the Uterine Fibroid Symptom Quality of Life questionnaire (with scores ranging from 0 to 100 and a higher score indicating better quality of life) at 2 years, adjusted for baseline score. The economic evaluation estimated quality-adjusted life-years (derived from EuroQol-5 Dimensions, three-level version, and costs from the NHS perspective). Results: A total of 254 women were randomised – 127 to myomectomy (105 underwent myomectomy) and 127 to uterine artery embolisation (98 underwent embolisation). Information on the primary outcome at 2 years was available for 81% (n = 206) of women. Primary outcome scores at 2 years were 84.6 (standard deviation 21.5) in the myomectomy group and 80.0 (standard deviation 22.0) in the uterine artery embolisation group (intention-to-treat complete-case analysis mean adjusted difference 8.0, 95% confidence interval 1.8 to 14.1, p = 0.01; mean adjusted difference using multiple imputation for missing responses 6.5, 95% confidence interval 1.1 to 11.9). The mean difference in the primary outcome at the 4-year follow-up time point was 5.0 (95% CI –1.4 to 11.5; p = 0.13) in favour of myomectomy. Perioperative and postoperative complications from all initial procedures occurred in similar percentages of women in both groups (29% in the myomectomy group vs. 24% in the UAE group). Twelve women in the uterine embolisation group and six women in the myomectomy group reported pregnancies over 4 years, resulting in seven and five live births, respectively (hazard ratio 0.48, 95% confidence interval 0.18 to 1.28). Over a 2-year time horizon, uterine artery embolisation was associated with higher costs than myomectomy (mean cost £7958, 95% confidence interval £6304 to £9612, vs. mean cost £7314, 95% confidence interval £5854 to £8773), but with fewer quality-adjusted life-years gained (0.74, 95% confidence interval 0.70 to 0.78, vs. 0.83, 95% confidence interval 0.79 to 0.87). The differences in costs (difference £645, 95% confidence interval –£1381 to £2580) and quality-adjusted life-years (difference –0.09, 95% confidence interval –0.11 to –0.04) were small. Similar results were observed over the 4-year time horizon. At a threshold of willingness to pay for a gain of 1 QALY of £20,000, the probability of myomectomy being cost-effective is 98% at 2 years and 96% at 4 years. Limitations: There were a substantial number of women who were not recruited because of their preference for a particular treatment option. Conclusions: Among women with symptomatic uterine fibroids, myomectomy resulted in greater improvement in quality of life than did uterine artery embolisation. The differences in costs and quality-adjusted life-years are very small. Future research should involve women who are desiring pregnancy. Trial registration: This trial is registered as ISRCTN70772394. Funding: This study 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. 22. See the NIHR Journals Library website for further project information.
, Sarah Cameron, Lorna Aucott, , , Thomas Bl Lam, Ruth Thomas, , Alison McDonald, Ken Anson, et al.
Health Technology Assessment, Volume 26, pp 1-70; https://doi.org/10.3310/wuzw9042

Abstract:
Background: Urinary stone disease affects 2–3% of the general population. Ureteric stones are associated with severe pain and can have a significant impact on a patient’s quality of life. Most ureteric stones are expected to pass spontaneously with supportive care; however, between one-fifth and one-third of patients require an active intervention. The two standard interventions are shockwave lithotripsy and ureteroscopic stone treatment. Both treatments are effective, but they differ in terms of invasiveness, anaesthetic requirement, treatment setting, number of procedures, complications, patient-reported outcomes and cost. There is uncertainty around which is the more clinically effective and cost-effective treatment. Objectives: To determine if shockwave lithotripsy is clinically effective and cost-effective compared with ureteroscopic stone treatment in adults with ureteric stones who are judged to require active intervention. Design: A pragmatic, multicentre, non-inferiority, randomised controlled trial of shockwave lithotripsy as a first-line treatment option compared with primary ureteroscopic stone treatment for ureteric stones. Setting: Urology departments in 25 NHS hospitals in the UK. Participants: Adults aged ≥ 16 years presenting with a single ureteric stone in any segment of the ureter, confirmed by computerised tomography, who were able to undergo either shockwave lithotripsy or ureteroscopic stone treatment and to complete trial procedures. Intervention: Eligible participants were randomised 1 : 1 to shockwave lithotripsy (up to two sessions) or ureteroscopic stone treatment. Main outcome measures: The primary clinical outcome measure was resolution of the stone episode (stone clearance), which was operationally defined as ‘no further intervention required to facilitate stone clearance’ up to 6 months from randomisation. This was determined from 8-week and 6-month case report forms and any additional hospital visit case report form that was completed by research staff. The primary economic outcome measure was the incremental cost per quality-adjusted life-year gained at 6 months from randomisation. We estimated costs from NHS resources and calculated quality-adjusted life-years from participant completion of the EuroQol-5 Dimensions, three-level version, at baseline, pre intervention, 1 week post intervention and 8 weeks and 6 months post randomisation. Results: In the shockwave lithotripsy arm, 67 out of 302 (22.2%) participants needed further treatment. In the ureteroscopic stone treatment arm, 31 out of 302 (10.3%) participants needed further treatment. The absolute risk difference was 11.4% (95% confidence interval 5.0% to 17.8%); the upper bound of the 95% confidence interval ruled out the prespecified margin of non-inferiority (which was 20%). The mean quality-adjusted life-year difference (shockwave lithotripsy vs. ureteroscopic stone treatment) was –0.021 (95% confidence interval 0.033 to –0.010) and the mean cost difference was –£809 (95% confidence interval –£1061 to –£551). The probability that shockwave lithotripsy is cost-effective is 79% at a threshold of society’s willingness to pay for a quality-adjusted life-year of £30,000. The CEAC is derived from the joint distribution of incremental costs and incremental effects. Most of the results fall in the south-west quadrant of the cost effectiveness plane as SWL always costs less but is less effective. Limitations: A limitation of the trial was low return and completion rates of patient questionnaires. The study was initially powered for 500 patients in each arm; however, the total number of patients recruited was only 307 and 306 patients in the ureteroscopic stone treatment and shockwave lithotripsy arms, respectively. Conclusions: Patients receiving shockwave lithotripsy needed more further interventions than those receiving primary ureteroscopic retrieval, although the overall costs for those receiving the shockwave treatment were lower. The absolute risk difference between the two clinical pathways (11.4%) was lower than expected and at a level that is acceptable to clinicians and patients. The shockwave lithotripsy pathway is more cost-effective in an NHS setting, but results in lower quality of life. Future work: (1) The generic health-related quality-of-life tools used in this study do not fully capture the impact of the various treatment pathways on patients. A condition-specific health-related quality-of-life tool should be developed. (2) Reporting of ureteric stone trials would benefit from agreement on a core outcome set that would ensure that future trials are easier to compare. Trial registration: This trial is registered as ISRCTN92289221. 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. 26, No. 19. See the NIHR Journals Library website for further project information.
, Scott Harris, Kenneth A Miles, , Nagmi R Qureshi, , , , Donald Sinclair, Andrew Shah, et al.
Health Technology Assessment, Volume 26, pp 1-180; https://doi.org/10.3310/wcei8321

Abstract:
Background: Current pathways recommend positron emission tomography–computerised tomography for the characterisation of solitary pulmonary nodules. Dynamic contrast-enhanced computerised tomography may be a more cost-effective approach. Objectives: To determine the diagnostic performances of dynamic contrast-enhanced computerised tomography and positron emission tomography–computerised tomography in the NHS for solitary pulmonary nodules. Systematic reviews and a health economic evaluation contributed to the decision-analytic modelling to assess the likely costs and health outcomes resulting from incorporation of dynamic contrast-enhanced computerised tomography into management strategies. Design: Multicentre comparative accuracy trial. Setting: Secondary or tertiary outpatient settings at 16 hospitals in the UK. Participants: Participants with solitary pulmonary nodules of ≥ 8 mm and of ≤ 30 mm in size with no malignancy in the previous 2 years were included. Interventions: Baseline positron emission tomography–computerised tomography and dynamic contrast-enhanced computer tomography with 2 years’ follow-up. Main outcome measures: Primary outcome measures were sensitivity, specificity and diagnostic accuracy for positron emission tomography–computerised tomography and dynamic contrast-enhanced computerised tomography. Incremental cost-effectiveness ratios compared management strategies that used dynamic contrast-enhanced computerised tomography with management strategies that did not use dynamic contrast-enhanced computerised tomography. Results: A total of 380 patients were recruited (median age 69 years). Of 312 patients with matched dynamic contrast-enhanced computer tomography and positron emission tomography–computerised tomography examinations, 191 (61%) were cancer patients. The sensitivity, specificity and diagnostic accuracy for positron emission tomography–computerised tomography and dynamic contrast-enhanced computer tomography were 72.8% (95% confidence interval 66.1% to 78.6%), 81.8% (95% confidence interval 74.0% to 87.7%), 76.3% (95% confidence interval 71.3% to 80.7%) and 95.3% (95% confidence interval 91.3% to 97.5%), 29.8% (95% confidence interval 22.3% to 38.4%) and 69.9% (95% confidence interval 64.6% to 74.7%), respectively. Exploratory modelling showed that maximum standardised uptake values had the best diagnostic accuracy, with an area under the curve of 0.87, which increased to 0.90 if combined with dynamic contrast-enhanced computerised tomography peak enhancement. The economic analysis showed that, over 24 months, dynamic contrast-enhanced computerised tomography was less costly (£3305, 95% confidence interval £2952 to £3746) than positron emission tomography–computerised tomography (£4013, 95% confidence interval £3673 to £4498) or a strategy combining the two tests (£4058, 95% confidence interval £3702 to £4547). Positron emission tomography–computerised tomography led to more patients with malignant nodules being correctly managed, 0.44 on average (95% confidence interval 0.39 to 0.49), compared with 0.40 (95% confidence interval 0.35 to 0.45); using both tests further increased this (0.47, 95% confidence interval 0.42 to 0.51). Limitations: The high prevalence of malignancy in nodules observed in this trial, compared with that observed in nodules identified within screening programmes, limits the generalisation of the current results to nodules identified by screening. Conclusions: Findings from this research indicate that positron emission tomography–computerised tomography is more accurate than dynamic contrast-enhanced computerised tomography for the characterisation of solitary pulmonary nodules. A combination of maximum standardised uptake value and peak enhancement had the highest accuracy with a small increase in costs. Findings from this research also indicate that a combined positron emission tomography–dynamic contrast-enhanced computerised tomography approach with a slightly higher willingness to pay to avoid missing small cancers or to avoid a ‘watch and wait’ policy may be an approach to consider. Future work: Integration of the dynamic contrast-enhanced component into the positron emission tomography–computerised tomography examination and the feasibility of dynamic contrast-enhanced computerised tomography at lung screening for the characterisation of solitary pulmonary nodules should be explored, together with a lower radiation dose protocol. Study registration: This study is registered as PROSPERO CRD42018112215 and CRD42019124299, and the trial is registered as ISRCTN30784948 and ClinicalTrials.gov NCT02013063. 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. 26, No. 17. See the NIHR Journals Library website for further project information.
, Kevin P Morris, Joanne Jordan, Lisa McIlmurray, , Roisin Boyle, , , , , et al.
Health Technology Assessment, Volume 26, pp 1-114; https://doi.org/10.3310/tcfx3817

Abstract:
Background: Daily assessment of patient readiness for liberation from invasive mechanical ventilation can reduce the duration of ventilation. However, there is uncertainty about the effectiveness of this in a paediatric population. Objectives: To determine the effect of a ventilation liberation intervention in critically ill children who are anticipated to have a prolonged duration of mechanical ventilation (primary objective) and in all children (secondary objective). Design: A pragmatic, stepped-wedge, cluster randomised trial with economic and process evaluations. Setting: Paediatric intensive care units in the UK. Participants: Invasively mechanically ventilated children (aged < 16 years). Interventions: The intervention incorporated co-ordinated multidisciplinary care, patient-relevant sedation plans linked to sedation assessment, assessment of ventilation parameters with a higher than usual trigger for undertaking an extubation readiness test and a spontaneous breathing trial on low levels of respiratory support to test extubation readiness. The comparator was usual care. Hospital sites were randomised sequentially to transition from control to intervention and were non-blinded. Main outcome measures: The primary outcome measure was the duration of invasive mechanical ventilation until the first successful extubation. The secondary outcome measures were successful extubation, unplanned extubation and reintubation, post-extubation use of non-invasive ventilation, tracheostomy, post-extubation stridor, adverse events, length of intensive care and hospital stay, mortality and cost per respiratory complication avoided at 28 days. Results: The trial included 10,495 patient admissions from 18 paediatric intensive care units from 5 February 2018 to 14 October 2019. In children with anticipated prolonged ventilation (n = 8843 admissions: control, n = 4155; intervention, n = 4688), the intervention resulted in a significantly shorter time to successful extubation [cluster and time-adjusted median difference –6.1 hours (interquartile range –8.2 to –5.3 hours); adjusted hazard ratio 1.11, 95% confidence interval 1.02 to 1.20; p = 0.02] and a higher incidence of successful extubation (adjusted relative risk 1.01, 95% confidence interval 1.00 to 1.02; p = 0.03) and unplanned extubation (adjusted relative risk 1.62, 95% confidence interval 1.05 to 2.51; p = 0.03), but not reintubation (adjusted relative risk 1.10, 95% confidence interval 0.89 to 1.36; p = 0.38). In the intervention period, the use of post-extubation non-invasive ventilation was significantly higher (adjusted relative risk 1.22, 95% confidence interval 1.01 to 1.49; p = 0.04), with no evidence of a difference in intensive care length of stay or other harms, but hospital length of stay was longer (adjusted hazard ratio 0.89, 95% confidence interval 0.81 to 0.97; p = 0.01). Findings for all children were broadly similar. The control period was associated with lower, but not statistically significantly lower, total costs (cost difference, mean £929.05, 95% confidence interval –£516.54 to £2374.64) and significantly fewer respiratory complications avoided (mean difference –0.10, 95% confidence interval –0.16 to –0.03). Limitations: The unblinded intervention assignment may have resulted in performance or detection bias. It was not possible to determine which components were primarily responsible for the observed effect. Treatment effect in a more homogeneous group remains to be determined. Conclusions: The intervention resulted in a statistically significant small reduction in time to first successful extubation; thus, the clinical importance of the effect size is uncertain. Future work: Future work should explore intervention sustainability and effects of the intervention in other paediatric populations. Trial registration: This trial is registered as ISRCTN16998143. 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. 26, No. 18. See the NIHR Journals Library website for further project information.
, Mari Imamura, Corinne Booth, Lorna Aucott, , Paul Manson, Graham Scotland,
Health Technology Assessment, Volume 26, pp 1-76; https://doi.org/10.3310/rsvk2062

Abstract:
Background: Convulsive status epilepticus is defined as ≥ 5 minutes of either continuous seizure activity or repetitive seizures without regaining consciousness. It is regarded as an emergency condition that requires prompt treatment to avoid hospitalisation and to reduce morbidity and mortality. Rapid pre-hospital first-line treatment of convulsive status epilepticus is currently benzodiazepines, administered either by trained caregivers in the community (e.g. buccal midazolam, rectal diazepam) or by trained health professionals via intramuscular or intravenous routes (e.g. midazolam, lorazepam). There is a lack of clarity about the optimal treatment for convulsive status epilepticus in the pre-hospital setting. Objectives: To assess the current evidence on the clinical effectiveness and cost-effectiveness of treatments for adults with convulsive status epilepticus in the pre-hospital setting. Data sources: We searched major electronic databases, including MEDLINE, EMBASE, PsycInfo®, CINAHL, CENTRAL, NHS Economic Evaluation Database, Health Technology Assessment Database, Research Papers in Economics, and the ISPOR Scientific Presentations Database, with no restrictions on publication date or language of publication. Final searches were carried out on 21 July 2020. Review methods: Systematic review of randomised controlled trials assessing adults with convulsive status epilepticus who received treatment before or on arrival at the emergency department. Eligible treatments were any antiepileptic drugs offered as first-line treatments, regardless of their route of administration. Primary outcomes were seizure cessation, seizure recurrence and adverse events. Two reviewers independently screened all citations identified by the search strategy, retrieved full-text articles, extracted data and assessed the risk of bias of the included trials. Results were described narratively. Results: Four trials (1345 randomised participants, of whom 1234 were adults) assessed the intravenous or intramuscular use of benzodiazepines or other antiepileptic drugs for the pre-hospital treatment of convulsive status epilepticus in adults. Three trials at a low risk of bias showed that benzodiazepines were effective in stopping seizures. In particular, intramuscular midazolam was non-inferior to intravenous lorazepam. The addition of levetiracetam to clonazepam did not show clear advantages over clonazepam alone. One trial at a high risk of bias showed that phenobarbital plus optional phenytoin was more effective in terminating seizures than diazepam plus phenytoin. The median time to seizure cessation from drug administration varied from 1.6 minutes to 15 minutes. The proportion of people with recurrence of seizures ranged from 10.4% to 19.1% in two trials reporting this outcome. Across trials, the rates of respiratory depression among participants receiving active treatments were generally low (from 6.4% to 10.6%). The mortality rate ranged from 2% to 7.6% in active treatment groups and from 6.2% to 15.5% in control groups. Only one study based on retrospective observational data met the criteria for economic evaluation; therefore, it was not possible to draw any robust conclusions on cost-effectiveness. Limitations: The limited number of identified trials and their differences in terms of treatment comparisons and outcomes hindered any meaningful pooling of data. None of the included trials was conducted in the UK and none assessed the use of buccal midazolam or rectal diazepam. The review of economic evaluations was hampered by lack of suitable data. Conclusions: Both intravenous lorazepam and intravenous diazepam administered by paramedics are more effective than a placebo in the treatments of adults with convulsive status epilepticus, and intramuscular midazolam is non-inferior to intravenous lorazepam. Large well-designed clinical trials are needed to establish which benzodiazepines are more effective and preferable in the pre-hospital setting. Study registration: This study is registered as PROSPERO CRD42020201953. Funding: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 26, No. 20. See the NIHR Journals Library website for further project information.
Damian R Griffin, Edward J Dickenson, , , Joanna Smith, , , , Rachel Hobson, Jeremy Fry, et al.
Health Technology Assessment, Volume 26, pp 1-236; https://doi.org/10.3310/fxii0508

Abstract:
Background: Femoroacetabular impingement syndrome is an important cause of hip pain in young adults. It can be treated by arthroscopic hip surgery or with physiotherapist-led conservative care. Objective: To compare the clinical effectiveness and cost-effectiveness of hip arthroscopy with best conservative care. Design: The UK FASHIoN (full trial of arthroscopic surgery for hip impingement compared with non-operative care) trial was a pragmatic, multicentre, randomised controlled trial that was carried out at 23 NHS hospitals. Participants: Participants were included if they had femoroacetabular impingement, were aged ≥ 16 years old, had hip pain with radiographic features of cam or pincer morphology (but no osteoarthritis) and were believed to be likely to benefit from hip arthroscopy. Intervention: Participants were randomly allocated (1 : 1) to receive hip arthroscopy followed by postoperative physiotherapy, or personalised hip therapy (i.e. an individualised physiotherapist-led programme of conservative care). Randomisation was stratified by impingement type and recruiting centre using a central telephone randomisation service. Outcome assessment and analysis were masked. Main outcome measure: The primary outcome was hip-related quality of life, measured by the patient-reported International Hip Outcome Tool (iHOT-33) 12 months after randomisation, and analysed by intention to treat. Results: Between July 2012 and July 2016, 648 eligible patients were identified and 348 participants were recruited. In total, 171 participants were allocated to receive hip arthroscopy and 177 participants were allocated to receive personalised hip therapy. Three further patients were excluded from the trial after randomisation because they did not meet the eligibility criteria. Follow-up at the primary outcome assessment was 92% (N = 319; hip arthroscopy, n = 157; personalised hip therapy, n = 162). At 12 months, mean International Hip Outcome Tool (iHOT-33) score had improved from 39.2 (standard deviation 20.9) points to 58.8 (standard deviation 27.2) points for participants in the hip arthroscopy group, and from 35.6 (standard deviation 18.2) points to 49.7 (standard deviation 25.5) points for participants in personalised hip therapy group. In the primary analysis, the mean difference in International Hip Outcome Tool scores, adjusted for impingement type, sex, baseline International Hip Outcome Tool score and centre, was 6.8 (95% confidence interval 1.7 to 12.0) points in favour of hip arthroscopy (p = 0.0093). This estimate of treatment effect exceeded the minimum clinically important difference (6.1 points). Five (83%) of six serious adverse events in the hip arthroscopy group were related to treatment and one serious adverse event in the personalised hip therapy group was not. Thirty-eight (24%) personalised hip therapy patients chose to have hip arthroscopy between 1 and 3 years after randomisation. Nineteen (12%) hip arthroscopy patients had a revision arthroscopy. Eleven (7%) personalised hip therapy patients and three (2%) hip arthroscopy patients had a hip replacement within 3 years. Limitations: Study participants and treating clinicians were not blinded to the intervention arm. Delays were encountered in participants accessing treatment, particularly surgery. Follow-up lasted for 3 years. Conclusion: Hip arthroscopy and personalised hip therapy both improved hip-related quality of life for patients with femoroacetabular impingement syndrome. Hip arthroscopy led to a greater improvement in quality of life than personalised hip therapy, and this difference was clinically significant at 12 months. This study does not demonstrate cost-effectiveness of hip arthroscopy compared with personalised hip therapy within the first 12 months. Further follow-up will reveal whether or not the clinical benefits of hip arthroscopy are maintained and whether or not it is cost-effective in the long term. Trial registration: Current Controlled Trials ISRCTN64081839. 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. 26, No. 16. See the NIHR Journals Library website for further project information.
, Emily F Dixon, Alicia Gill, Jon Bishop, Maria D’Amico, Khaled Ahmed, , Kostas Tryposkiadis, , , et al.
Health Technology Assessment, Volume 26, pp 1-82; https://doi.org/10.3310/bicf1187

Abstract:
Background: Mother-to-baby transmission of group B Streptococcus (Streptococcus agalactiae) is the main cause of early-onset infection. Objectives: We investigated if intrapartum antibiotic prophylaxis directed by a rapid intrapartum test reduces maternal and neonatal antibiotic use, compared with usual care (i.e. risk factor-directed antibiotics), among women with risk factors for vertical group B Streptococcus transmission, and examined the accuracy and cost-effectiveness of the rapid test. Design: An unblinded cluster randomised controlled trial with a nested test accuracy study, an economic evaluation and a microbiology substudy. Setting: UK maternity units were randomised to either a strategy of rapid test or usual care. Participants: Vaginal and rectal swabs were taken from women with risk factors for vertical group B Streptococcus transmission in established term labour. The accuracy of the GeneXpert® Dx IV GBS rapid testing system (Cepheid, Maurens-Scopont, France) was compared with the standard of selective enrichment culture in diagnosing maternal group B Streptococcus colonisation. Main outcome measures: Primary outcomes were rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection and accuracy estimates of the rapid test. Secondary outcomes were maternal antibiotics for any indication, neonatal antibiotic exposure, maternal antibiotic duration, neonatal group B Streptococcus colonisation, maternal and neonatal antibiotic resistance, neonatal morbidity and mortality, and cost-effectiveness of the strategies. Results: Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units and 906 mothers (951 babies) participated in usual-care units. There were no differences in the rates of intrapartum antibiotic prophylaxis for preventing early-onset group B Streptococcus infection in the rapid test units (41%, 297/716) compared with the usual-care units (36%, 328/906) (risk ratio 1.16, 95% confidence interval 0.83 to 1.64). There were no differences between the groups in intrapartum antibiotic administration for any indication (risk ratio 0.99, 95% confidence interval 0.81 to 1.21). Babies born in the rapid test units were 29% less likely to receive antibiotics (risk ratio 0.71, 95% confidence interval 0.54 to 0.95) than those born in usual-care units. The sensitivity and specificity of the rapid test were 86% (95% confidence interval 81% to 91%) and 89% (95% confidence interval 85% to 92%), respectively. In 14% of women (99/710), the rapid test was invalid or the machine failed to provide a result. In the economic analysis, the rapid test was shown to be both less effective and more costly and, therefore, dominated by usual care. Sensitivity analysis indicated potential lower costs for the rapid test strategy when neonatal costs were included. No serious adverse events were reported. Conclusions: The Group B Streptococcus 2 (GBS2) trial found no evidence that the rapid test reduces the rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection. The rapid test has the potential to reduce neonatal exposure to antibiotics, but economically is dominated by usual care. The accuracy of the test is within acceptable limits. Future work: The role of routine testing for prevention of neonatal infection requires evaluation in a randomised controlled trial. Trial registration: Current Controlled Trials ISRCTN74746075. 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. 26, No. 12. See the NIHR Journals Library website for further project information.
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