Abstract: Falls and fractures are a major problem. Objectives To investigate the clinical effectiveness and cost-effectiveness of alternative falls prevention interventions. Design Three-arm, pragmatic, cluster randomised controlled trial with parallel economic analysis. The unit of randomisation was the general practice. Setting Primary care. Participants People aged ≥ 70 years. Interventions All practices posted an advice leaflet to each participant. Practices randomised to active intervention arms (exercise and multifactorial falls prevention) screened participants for falls risk using a postal questionnaire. Active treatments were delivered to participants at higher risk of falling. Main outcome measures The primary outcome was fracture rate over 18 months, captured from Hospital Episode Statistics, general practice records and self-report. Secondary outcomes were falls rate, health-related quality of life, mortality, frailty and health service resource use. Economic evaluation was expressed in terms of incremental cost per quality-adjusted life-year and incremental net monetary benefit. Results Between 2011 and 2014, we randomised 63 general practices (9803 participants): 21 practices (3223 participants) to advice only, 21 practices (3279 participants) to exercise and 21 practices (3301 participants) to multifactorial falls prevention. In the active intervention arms, 5779 out of 6580 (87.8%) participants responded to the postal fall risk screener, of whom 2153 (37.3%) were classed as being at higher risk of falling and invited for treatment. The rate of intervention uptake was 65% (697 out of 1079) in the exercise arm and 71% (762 out of 1074) in the multifactorial falls prevention arm. Overall, 379 out of 9803 (3.9%) participants sustained a fracture. There was no difference in the fracture rate between the advice and exercise arms (rate ratio 1.20, 95% confidence interval 0.91 to 1.59) or between the advice and multifactorial falls prevention arms (rate ratio 1.30, 95% confidence interval 0.99 to 1.71). There was no difference in falls rate over 18 months (exercise arm: rate ratio 0.99, 95% confidence interval 0.86 to 1.14; multifactorial falls prevention arm: rate ratio 1.13, 95% confidence interval 0.98 to 1.30). A lower rate of falls was observed in the exercise arm at 8 months (rate ratio 0.78, 95% confidence interval 0.64 to 0.96), but not at other time points. There were 289 (2.9%) deaths, with no differences by treatment arm. There was no evidence of effects in prespecified subgroup comparisons, nor in nested intention-to-treat analyses that considered only those at higher risk of falling. Exercise provided the highest expected quality-adjusted life-years (1.120), followed by advice and multifactorial falls prevention, with 1.106 and 1.114 quality-adjusted life-years, respectively. NHS costs associated with exercise (£3720) were lower than the costs of advice (£3737) or of multifactorial falls prevention (£3941). Although incremental differences between treatment arms were small, exercise dominated advice, which in turn dominated multifactorial falls prevention. The incremental net monetary benefit of exercise relative to treatment valued at £30,000 per quality-adjusted life-year is modest, at £191, and for multifactorial falls prevention is £613. Exercise is the most cost-effective treatment. No serious adverse events were reported. Limitations The rate of fractures was lower than anticipated. Conclusions Screen-and-treat falls prevention strategies in primary care did not reduce fractures. Exercise resulted in a short-term reduction in falls and was cost-effective. Future work Exercise is the most promising intervention for primary care. Work is needed to ensure adequate uptake and sustained effects. Trial registration Current Controlled Trials ISRCTN71002650. 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. 25, No. 34. See the NIHR Journals Library website for further project information.

Abstract: Adrenaline has been used as a treatment for cardiac arrest for many years, despite uncertainty about its effects on long-term outcomes and concerns that it may cause worse neurological outcomes. Objectives The objectives were to evaluate the effects of adrenaline on survival and neurological outcomes, and to assess the cost-effectiveness of adrenaline use. Design This was a pragmatic, randomised, allocation-concealed, placebo-controlled, parallel-group superiority trial and economic evaluation. Costs are expressed in Great British pounds and reported in 2016/17 prices. Setting This trial was set in five NHS ambulance services in England and Wales. Participants Adults treated for an out-of-hospital cardiac arrest were included. Patients were ineligible if they were pregnant, if they were aged 〈  16 years, if the cardiac arrest had been caused by anaphylaxis or life-threatening asthma, or if adrenaline had already been given. Interventions Participants were randomised to either adrenaline (1 mg) or placebo in a 1 : 1 allocation ratio by the opening of allocation-concealed treatment packs. Main outcome measures The primary outcome was survival to 30 days. The secondary outcomes were survival to hospital admission, survival to hospital discharge, survival at 3, 6 and 12 months, neurological outcomes and health-related quality of life through to 6 months. The economic evaluation assessed the incremental cost per quality-adjusted life-year gained from the perspective of the NHS and Personal Social Services. Participants, clinical teams and those assessing patient outcomes were masked to the treatment allocation. Results From December 2014 to October 2017, 8014 participants were assigned to the adrenaline ( n  = 4015) or to the placebo ( n  = 3999) arm. At 30 days, 130 out of 4012 participants (3.2%) in the adrenaline arm and 94 out of 3995 (2.4%) in the placebo arm were alive (adjusted odds ratio for survival 1.47, 95% confidence interval 1.09 to 1.97). For secondary outcomes, survival to hospital admission was higher for those receiving adrenaline than for those receiving placebo (23.6% vs. 8.0%; adjusted odds ratio 3.83, 95% confidence interval 3.30 to 4.43). The rate of favourable neurological outcome at hospital discharge was not significantly different between the arms (2.2% vs. 1.9%; adjusted odds ratio 1.19, 95% confidence interval 0.85 to 1.68). The pattern of improved survival but no significant improvement in neurological outcomes continued through to 6 months. By 12 months, survival in the adrenaline arm was 2.7%, compared with 2.0% in the placebo arm (adjusted odds ratio 1.38, 95% confidence interval 1.00 to 1.92). An adjusted subgroup analysis did not identify significant interactions. The incremental cost-effectiveness ratio for adrenaline was estimated at £1,693,003 per quality-adjusted life-year gained over the first 6 months after the cardiac arrest event and £81,070 per quality-adjusted life-year gained over the lifetime of survivors. Additional economic analyses estimated incremental cost-effectiveness ratios for adrenaline at £982,880 per percentage point increase in overall survival and £377,232 per percentage point increase in neurological outcomes over the first 6 months after the cardiac arrest. Limitations The estimate for survival with a favourable neurological outcome is imprecise because of the small numbers of patients surviving with a good outcome. Conclusions Adrenaline improved long-term survival, but there was no evidence that it significantly improved neurological outcomes. The incremental cost-effectiveness ratio per quality-adjusted life-year exceeds the threshold of £20,000–30,000 per quality-adjusted life-year usually supported by the NHS. Future work Further research is required to better understand patients’ preferences in relation to survival and neurological outcomes after out-of-hospital cardiac arrest and to aid interpretation of the trial findings from a patient and public perspective. Trial registration Current Controlled Trials ISRCTN73485024 and EudraCT 2014-000792-11. 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. 25, No. 25. See the NIHR Journals Library website for further project information.

Abstract: Usual primary care for patients with musculoskeletal pain varies widely and treatment outcomes are suboptimal. Stratified care involves targeting treatments according to patient subgroups, in the hope of maximising treatment benefit and reducing potential harm or unnecessary interventions. This programme developed a new prognostic stratified primary care approach, where treatments are matched to a patient’s risk of future persistent pain and disability based on a prognostic tool, and compared this with usual care. Objectives In four linked work packages, we refined and validated a prognostic tool [the Keele STarT MSK (Subgrouping for Targeted Treatment for Musculoskeletal pain) Tool] to identify risk of poor outcome and defined cut-off scores to distinguish patient risk subgroups (work package 1); defined and agreed new matched treatment options for each risk subgroup and developed a support package for delivery of stratified care (work package 2); tested the feasibility of delivering the stratified approach through a pilot randomised controlled trial and externally validated the prognostic tool (work package 3); and tested the effectiveness of the approach by comparing the clinical effectiveness and cost-effectiveness of stratified primary care with that of usual care through a cluster randomised controlled trial with embedded health economic and qualitative studies (work package 4). Setting General practices and linked musculoskeletal services in the West Midlands of England, UK. Participants Adults registered with participating practices consulting with back, neck, shoulder, knee or multisite musculoskeletal pain, and clinicians involved in managing these patients. Design The programme included the following work packages: work package 1 – a prospective cohort study in 12 practices; work package 2 – an evidence synthesis, consensus group workshops and qualitative studies; work package 3 – a cluster feasibility and pilot trial in eight practices; and work package 4 – a main cluster randomised controlled trial in 24 practices, with health economic analyses and process evaluation. Interventions Stratified care comprised training general practitioners to use the tool and match patients to treatment options depending on their risk subgroup. Usual care comprised usual non-stratified primary care without formal stratification tools. Main outcome measures Cohort primary end points included function (Short Form questionnaire-36 items physical component score) and pain intensity (numerical rating scale). The trial primary end point for patient outcomes was pain intensity (monthly for 6 months) (0–10 numerical rating scale). An audit of primary care electronic medical records evaluated the impact of stratified care on clinical decision-making regarding patient management. Results Work package 1 – the cohort study ( n = 1890 patients) refined and validated a new 10-item tool with which to stratify patients with the five most common musculoskeletal pain presentations. The tool subgroups patients into three strata with different characteristics and prognoses. Work package 2: 17 treatment options were recommended – four for patients at low risk, 10 for patients at medium risk and 15 for patients at high risk. Work package 3: the feasibility and pilot trial included 524 patients, and the learning led to amendments to several tool items and a reduced set of treatments (14 in total). Work package 4: in the main trial, 1211 patients consented to data collection (534 in stratified care, 677 in usual care). Stratified primary care did not lead to statistically significant differences in the primary patient outcome of pain intensity [stratified care mean 4.4 (standard deviation 2.3) vs. usual care mean 4.6 (standard deviation 2.4); adjusted mean difference –0.16, 95% confidence interval –0.65 to 0.34; p = 0.535]. Where differences were observed, these were largely isolated to patients at high risk of poor outcome (the smallest subgroup), in favour of stratified care. Positive differences were, however, observed in general practitioner clinical decision-making, with increased provision of written self-management information and referrals to physiotherapy, plus reductions in prescription medication. The economic evaluation demonstrated that costs of care were similar across trial arms (£6.85, 95% confidence interval –£107.82 to £121.54 more for stratified care), with incremental quality-adjusted life-years of 0.0041 (95% confidence interval –0.0013 to 0.0094), representing a net quality-adjusted life-year gain. Stratified care was associated with an incremental cost-effectiveness ratio of £1670 per additional quality-adjusted life-year gained. At a willingness-to-pay threshold (λ) of £20,000 per quality-adjusted life-year, the incremental net monetary benefit was £132 and the probability of stratified care being cost-effective was approximately 73%. The very small differences suggest caution in the interpretation of this result. The qualitative findings revealed that general practitioners felt stratified care had a positive role in informing clinical decision-making, helped them to give greater attention to psychosocial issues and take a more functional approach, and facilitated negotiations with patients about treatment options such as imaging. Limitations The randomised controlled trial was not powered to detect differences between stratified and usual care for patients in each risk subgroup (low, medium and high) nor with each different musculoskeletal pain presentation. The stratified care electronic medical record template ‘fired’ only once per patient. Conclusions The Keele STarT MSK Tool is a valid instrument with which to discriminate between, and predict outcomes of, primary care patients with musculoskeletal pain. Although the randomised trial showed no significant benefit in patient-reported outcomes compared with usual care, some aspects of clinical decision-making improved and the approach was cost-effective. Future work The Keele STarT MSK Tool has been shared with over 1000 tool license requestees, leading to other work. Trial data sets have also led to other work, developing personalised prognostic models for back and neck pain patients (the European Union-funded Back-UP project). The challenge remains how to improve outcomes for primary care patients with musculoskeletal pain. Trial registration This trial is registered as ISRCTN15366334. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research ; Vol. 11, No. 4. See the NIHR Journals Library website for further project information.

Abstract: To compare the clinical effectiveness of adding a single ultrasound guided intra-articular hip injection of corticosteroid and local anaesthetic to advice and education in adults with hip osteoarthritis. Design Pragmatic, three arm, parallel group, single blind, randomised controlled trial. Setting Two community musculoskeletal services in England. Participants 199 adults aged ≥40 years with hip osteoarthritis and at least moderate pain: 67 were randomly assigned to receive advice and education (best current treatment (BCT)), 66 to BCT plus ultrasound guided injection of triamcinolone and lidocaine, and 66 to BCT plus ultrasound guided injection of lidocaine. Interventions BCT alone, BCT plus ultrasound guided intra-articular hip injection of 40 mg triamcinolone acetonide and 4 mL 1% lidocaine hydrochloride, or BCT plus ultrasound guided intra-articular hip injection of 5 mL 1% lidocaine. Participants in the ultrasound guided arms were masked to the injection they received. Main outcome measures The primary outcome was self-reported current intensity of hip pain (0-10 Numerical Rating Scale) over six months. Outcomes were self-reported at two weeks and at two, four, and six months. Results Mean age of the study sample was 62.8 years (standard deviation 10.0) and 113 (57%) were women. Average weighted follow-up rate across time points was 93%. Greater mean improvement in hip pain intensity over six months was reported with BCT plus ultrasound-triamcinolone-lidocaine compared with BCT: mean difference −1.43 (95% confidence interval −2.15 to −0.72), P 〈 0.001; standardised mean difference −0.55 (−0.82 to −0.27). No difference in hip pain intensity over six months was reported between BCT plus ultrasound-triamcinolone-lidocaine compared with BCT plus ultrasound-lidocaine (−0.52 (−1.21 to 0.18)). The presence of ultrasound confirmed synovitis or effusion was associated with a significant interaction effect favouring BCT plus ultrasound-triamcinolone-lidocaine (−1.70 (−3.10 to −0.30)). One participant in the BCT plus ultrasound-triamcinolone-lidocaine group with a bioprosthetic aortic valve died from subacute bacterial endocarditis four months after the intervention, deemed possibly related to the trial treatment. Conclusions Ultrasound guided intra-articular hip injection of triamcinolone is a treatment option to add to BCT for people with hip osteoarthritis. Trial registration EudraCT 2014-003412-37; ISRCTN50550256 .

Abstract: The ‘Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration In Cardiac Arrest’ (PARAMEDIC2) trial showed that adrenaline improves overall survival, but not neurological outcomes. We sought to determine the within-trial and lifetime health and social care costs and benefits associated with adrenaline, including secondary benefits from organ donation. Methods We estimated the costs, benefits (quality-adjusted life years (QALYs)) and incremental cost-effectiveness ratios (ICERs) associated with adrenaline during the 6-month trial follow-up. Model-based analyses explored how results altered when the time horizon was extended beyond 6 months and the scope extended to include recipients of donated organs. Results The within-trial (6 months) and lifetime horizon economic evaluations focussed on the trial population produced ICERs of £1,693,003 (€1,946,953) and £81,070 (€93,231) per QALY gained in 2017 prices, respectively, reflecting significantly higher mean costs and only marginally higher mean QALYs in the adrenaline group. The probability that adrenaline is cost-effective was less than 1% across a range of cost-effectiveness thresholds. Combined direct economic effects over the lifetimes of survivors and indirect economic effects in organ recipients produced an ICER of £16,086 (€18,499) per QALY gained for adrenaline with the probability that adrenaline is cost-effective increasing to 90% at a £30,000 (€34,500) per QALY cost-effectiveness threshold. Conclusions Adrenaline was not cost-effective when only directly related costs and consequences are considered. However, incorporating the indirect economic effects associated with transplanted organs substantially alters cost-effectiveness, suggesting decision-makers should consider the complexity of direct and indirect economic impacts of adrenaline. Trial registration ISRCTN73485024 . Registered on 13 March 2014.