Background:Multiple sclerosis is an immune-mediated inflammatory disease, causing long-term disability in young adults. Most cases begin as relapsing-remitting multiple sclerosis. Some people have a form of relapsing-remitting multiple sclerosis known as highly active relapsing-remitting multiple sclerosis, defined as multiple sclerosis with unchanged or increased disease activity despite prior treatment with at least one disease-modifying therapy. Objectives:To appraise the clinical and cost-effectiveness of natalizumab [Tysabri® (Biogen, Cambridge, MA, USA)] and natalizumab biosimilar [Tyruko® (Sandoz)] for treating highly active relapsing-remitting multiple sclerosis compared to other disease-modifying therapy. Design:Systematic review with network meta-analysis and economic model. Searches last updated in April 2024. Results:We included 42 studies (22,409 participants): 40 in people with relapsing-remitting multiple sclerosis and 2 in highly active relapsing-remitting multiple sclerosis. Six studies also reported data separately for highly active relapsing-remitting multiple sclerosis. Only four studies evaluated natalizumab or natalizumab biosimilar; none provided data on those with highly active relapsing-remitting multiple sclerosis. Follow-up ranged from 4 to 36 (median 24) months. Most interventions reduced relapses (39 studies, 17 interventions) and magnetic resonance imaging lesions (19 studies, 11 interventions for gadolinium enhancing lesions and 17 studies, 12 interventions for T2-weighted lesions) compared to placebo. Alemtuzumab, ocrelizumab, cladribine, natalizumab, fingolimod and peginterferon beta-1a reduced disease progression compared to placebo (15 studies, 12 interventions). There were no differences in any adverse events (24 studies, 16 interventions), serious adverse events (31 studies, 15 interventions) or treatment-related adverse events (8 studies, no network meta-analysis) for any intervention compared to placebo. Fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b and peginterferon beta-1a were associated with an increased treatment discontinuation (29 studies, 13 interventions). There was little evidence for a difference in quality of life. There was no evidence of a difference between natalizumab and natalizumab biosimilar for relapse rates [rate ratio 0.65 (95% credible interval 0.33 to 1.23], gadolinium enhancing lesions [hazard ratio 1.29 (0.69 to 2.37)], T2-weighted lesions [hazard ratio 1.07 (0.73 to 1.57)], any adverse events [hazard ratio 1.06 (0.77 to 1.46)] or treatment discontinuation [hazard ratio 0.48 (0.13 to 1.76)]. Data in highly active relapsing-remitting multiple sclerosis were available for fingolimod, ocrelizumab, alemtuzumab, cladribine, interferon beta, autologous haematopoietic stem cell treatment and placebo. We also included one study on natalizumab conducted in a population that was close to our definition of highly active relapsing-remitting multiple sclerosis. All interventions except interferon beta-1a were associated with reduced relapse risk compared to placebo (six studies; seven interventions). Compared with natalizumab-intravenous, natalizumab biosimilar-intravenous and natalizumab subcutaneous, all treatments had greater net benefit at £20,000-30,000/quality-adjusted life-year, with the only exception being ocrelizumab, which had lower net benefits. Costs were generally higher on natalizumab than other treatments, though there was no difference in quality-adjusted life-years with 95% credible interval completely overlapping. The results and conclusions were unchanged under all sensitivities. VOI analysis found that the greatest contributor to decision uncertainty was the effectiveness of treatments. Conclusions:There is no direct evidence on the effectiveness of natalizumab or its biosimilar in patients with highly active relapsing-remitting multiple sclerosis. Limited data suggest similar effectiveness in patients with relapsing-remitting multiple sclerosis. The economic model found that natalizumab and natalizumab biosimilar were not cost-effective compared to any of the included comparators in highly active relapsing-remitting multiple sclerosis, with similar quality-adjusted life-years but higher costs, with the only exception being ocrelizumab. Future work:There is need for studies of natalizumab and natalizumab biosimilar in people with highly active relapsing-remitting multiple sclerosis. Study registration:The study is registered as PROSPERO CRD42024556838. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR165943) and is published in full in Health Technology Assessment; Vol. 30, No. 60. See the NIHR Funding and Awards website for further award information.
Background:Our aim was to develop and evaluate the electronic frailty index+, a prognostic tool, including four integrated prognostic-decision models, to stratify older people into subgroups for targeting key interventions. Methods:Prognostic model development, internal validation and external validation using large data sets and longitudinal cohort study data, with decision curve and health economic analysis. Population:Patients aged 65+ years. Key outcomes:The 12-month outcomes for prognostic models: new home care package care home admission emergency department attendance/hospitalisation with fall/fracture all-cause mortality. Statistical methods:We developed and internally validated models for our key outcomes in one large data set. We used internal-external cross-validation for the home care model and full external validation for the remaining three models in a second large data set. We used CARE75+ to investigate additional predictive value of clinical measures practical for primary care. Decision curve analysis:We translated the prognostic models into a framework to support clinical decision-making. Health economic evaluation:We integrated the falls prediction models with effect size estimates from network meta-analysis to examine potential cost savings. Results:We used data from 660,417 patients in SAIL, 88,947 in Connected Bradford and 252 CARE75+ participants. Model performance was promising in internal-external cross-validation, with average calibration slope 1.00 (95% confidence interval 0.99 to 1.01), average calibration-in-the-large -0.01 (95% confidence interval -0.02 to 0.01), average observed/expected ratio 0.99 (95% confidence interval 0.98 to 1.01) and average C-statistic 0.81 (95% confidence interval 0.81 to 0.81). Emergency department attendance/hospitalisation with fall/fracture:Model performance was promising on internal and external validation, although with some evidence for overprediction of falls risk, with calibration slope 1.25 (95% confidence interval 1.24 to 1.27), calibration-in-the-large -0.931 (95% confidence interval -0.938 to -0.920), observed/expected ratio 0.43 (95% confidence interval 0.42 to 0.44), C-statistic 0.83 (0.82 to 0.83). Care home admission:Model performance was promising on internal validation, but it showed some miscalibration on external validation, with calibration slope 0.75 (95% CI 0.74 to 0.76), calibration-in-the-large -1.60 (-1.62 to -1.58) and observed/expected ratio 0.25 (95% CI 0.24 to 0.25), C-statistic of 0.86 (95% CI 0.86 to 0.86). All-cause mortality:The model showed excellent performance across the full range of predicted risks on external validation, with average calibration slope 1.00 (0.98 to 1.01), average calibration-in-the-large -0.23 (-0.27 to -0.19), average observed/expected ratio 0.77 (0.75 to 0.79) and average C-statistic 0.83 (0.82 to 0.83). Economic modelling:Modelling indicated that provision of multifactorial assessment and treatment for people with an annual falls risk of ≥ 40% has the largest cost reduction per targeted person (£1025). Discussion:All four prediction models have promising predictive performance, although some had evidence of overprediction of risk (miscalibration). Decision curve analysis indicates potential clinical utility, and economic modelling provides novel information for policy-makers and commissioners. Future work:Future research should include model impact studies to evaluate use of the models in routine care. Limitations:We were unable to complete external validation of the home care prediction model. Study registration:This study is registered as ClinicalTrials.gov ID NCT04113174. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 127905) and is published in full in Health Technology Assessment; Vol. 30, No. 61. See the NIHR Funding and Awards website for further award information.
Background:Paramedics frequently administer analgesic medications for pain following trauma. Morphine is the most commonly administered strong analgesic. However, it may not be the best option as it may lower blood pressure, depress respiration and there is a risk of dependency. Ketamine might be a better option. We sought to compare clinical and cost-effectiveness of paramedic administered ketamine and morphine in patients with severe pain following trauma. Methods:PACKMaN was a double-blinded, randomised controlled, superiority trial. Eligible patients were 16 years of age or over, had an acute injury, and articulated a pain score of 7 or greater on a 0-10 numeric rating score. We excluded pregnant patients, prisoners, those unable to articulate a pain score and anyone lacking capacity. The maximum dose of morphine was 20 mg while the maximum dose of ketamine was 30 mg. The trial drug was titrated to effect. The primary outcome was the Sum of Pain Intensity Difference score. Results:We randomised 449 participants: 219 (49%) received ketamine and 230 (51%) received morphine. The Sum of Pain Intensity Difference score was 3.5 (standard deviation 2.8) for ketamine and 3.4 (standard deviation 3.0) for morphine. We found no significant difference in efficacy between drugs (adjusted mean difference 0.1, 95% confidence interval -0.4 to 0.6; p = 0.7). Ketamine was more likely to achieve 'very much improvement' (odds ratio 1.58, 95% confidence interval 1.08 to 2.31; p = 0.019) and to do so more rapidly than morphine (hazard ratio 1.42, 95% confidence interval 1.09 to 1.84; p = 0.009). However, morphine was likely to last longer than ketamine (hazard ratio 1.28, 95% confidence interval 1.05 to 1.56; p = 0.013). There was no evidence of a significant difference in serious adverse events. Conclusion:Ketamine does not provide superior analgesia than morphine when treating acute severe trauma pain. Ketamine is a suitable alternative that is safe for use by paramedics. Limitations:Patients were required to provide verbal assent to participate, consequently we were only able to recruit patients who had capacity to understand what was being asked of them. It is also therefore probable that we were unable to recruit the most severely injured patients. These factors may limit generalisability of our results. Furthermore, we were unable to complete a planned sensitivity analysis to determine if there was a difference in treatment response between patients with more minor injuries and those who were more severely injured. Finally, we experienced a loss to follow-up at 3 and 6 months, so our findings for long term outcomes may have been underpowered. Future work:Future research should focus on identification of the optimal drug (or combination of drugs), dosing and drug route to achieve rapid control of pain. In addition, it would be valuable to explore the relationship between paramedic analgesia and the development of chronic pain. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR128086.
Background:Most mechanically ventilated intensive care unit patients require sedation and analgesia for comfort. Current usual care is propofol-based sedation plus an opioid analgesic. The alpha2 agonists dexmedetomidine and clonidine are potential alternative sedatives, but their clinical and cost-effectiveness are uncertain. Objective(s):To evaluate the clinical and cost-effectiveness and safety of alpha2 agonists (dexmedetomidine and clonidine) compared with propofol for sedating adult intensive care unit patients. Design and methods:Pragmatic open-label three-arm trial. Embedded process and economic evaluation. Setting and participants:Forty-one intensive care units in the UK. Recruitment from December 2018 to October 2023. Participants were 1437 adults within 48 hours of starting mechanical ventilation expected to require ≥ 48 hours of mechanical ventilation [analysis population: propofol (N = 471), dexmedetomidine (N = 457), and clonidine-based (N = 476) sedation]. Median time from intubation to randomisation was 21.0 (first, third quartile: 13.2, 31.3) hours. Interventions:In all groups, bedside algorithms targeted a Richmond Agitation Sedation Scale of -2 to + 1 unless clinicians requested deeper sedation. Intervention groups' algorithms supported alpha2-agonist up-titration and propofol down-titration followed by sedation primarily with allocated alpha2 agonist. Supplemental propofol was permitted if required. Outcomes:Primary outcome was time to successful extubation, analysed allowing for death as a competing risk. Secondary outcomes included mortality, sedation quality, rates of delirium and cardiovascular adverse events. Long-term outcomes included: experience of intensive care unit care; anxiety, depression and post-traumatic stress; cognitive function; health-related quality of life. Results:Mean (standard deviation) patient age was 59.2 (14.9) years; 901 (65%) male. The sub-distribution hazard ratio for time to successful extubation for dexmedetomidine versus propofol was 1.09 (95% confidence interval 0.96 to 1.25; p = 0.20) and for clonidine versus propofol was 1.05 (0.95 to 1.17; p = 0.34), with hazard ratio > 1 favouring alpha2 agonist. Median (95% confidence interval) hours from randomisation to successful extubation was: propofol 162 (136 to 170); dexmedetomidine 136 (117 to 150); and clonidine 146 (124 to 168). There was no effect interaction with age, sepsis status, median Sequential Organ Failure Assessment Score, or median Prediction of Delirium in intensive care unit patients' delirium risk score. Delirium rates were similar, but agitation occurred at higher rate than propofol with both alpha2 agonists [dexmedetomidine vs. propofol risk ratio (95% confidence intervals) 1.54 (1.21 to 1.97); clonidine vs. propofol 1.55 (1.22 to 1.97)]. Rates of severe bradycardia (rate < 50/minute) were higher with both alpha2 agonists compared with propofol [dexmedetomidine vs. propofol rate ratio (95% confidence interval) 1.62 (1.36 to 1.93); clonidine vs. propofol 1.58 (1.33 to 1.88)]. Mortality was similar over 180 days follow-up [dexmedetomidine vs. propofol hazard ratio (95% confidence interval) 0.98 (0.77 to 1.24); clonidine vs. propofol 1.04 (0.82 to 1.31)]. Process evaluation indicated a range of contextual factors at intensive care unit and individual level that influenced intervention delivery, including: intensive care unit culture, prior clinician opinions/beliefs, staffing pressures (exacerbated by the COVID-19 pandemic), clinician experience and concerns about alpha2-agonist side effects. There was no difference in cost-effectiveness between the groups. Limitations:This was a pragmatic unblinded trial, with associated risk of performance and ascertainment bias. Future work:Future trials should explore the effectiveness of alpha2 agonists as sedatives in other populations, for example paediatric critical care and acute brain injury. Conclusions:In mechanically ventilated critically ill patients, neither dexmedetomidine- nor clonidine-based sedation was superior for major clinical outcomes or more cost-effective compared with propofol-based sedation. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/93/01.
Background The integration of artificial intelligence in medical image classification for screening has the potential to enhance efficiency, diagnostic accuracy and accessibility. However, ethical concerns such as accountability, bias, transparency and the impact on healthcare professionals remain critical. This review synthesises qualitative evidence on the ethical considerations surrounding artificial intelligence adoption in screening programmes. Methods A systematic search of qualitative studies, from June 2020 to September 2024, was conducted across multiple databases: MEDLINE, EMBASE, PsycInfo ® (American Psychological Association, Washington, DC, USA) and Cumulative Index to Nursing and Allied Health Literature. Primary qualitative studies exploring healthcare professionals’, patients’ and other stakeholders’ perspectives on artificial intelligence in screening were included. Thematic analysis was performed, and findings were assessed using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative Research approach to evaluate confidence in the evidence. Results Fourteen qualitative studies were included, covering perspectives from clinicians, radiologists, artificial intelligence developers, policy-makers and patients. Key ethical concerns identified included: (1) the necessity of human oversight to ensure that artificial intelligences diagnostic recommendations are appropriate; (2) challenges in assigning liability when artificial intelligence errors occur; (3) risks of algorithmic bias due to discrepancies between training data sets and real-world populations; (4) concerns over data privacy, cybersecurity and informed consent in artificial intelligence-driven decision-making; (5) the need for transparency in artificial intelligence decision-making processes to build trust and (6) potential deskilling of healthcare professionals and shifts in professional responsibilities. While artificial intelligence was seen as a valuable tool to augment clinical decision-making, stakeholders emphasised that ethical frameworks must guide its implementation to maintain public trust and patient safety. Conclusion This review highlights the critical considerations that must be addressed to ensure the responsible integration of artificial intelligence in medical screening. Policy-makers, healthcare institutions and developers should prioritise human oversight, robust regulatory frameworks and strategies to mitigate bias and ensure transparency. Future research should focus on disease-specific artificial intelligence applications and long-term ethical implications. Study registration The protocol for this study is registered on PROSPERO as CRD42024599536. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR172233) and is published in full in Health Technology Assessment ; Vol. 30, No. 51. See the NIHR Funding and Awards website for further award information.
Objectives:To determine which primary endovascular revascularisation strategy represents the most clinical and cost-effective treatment for patients with chronic limb threatening ischaemia who require an endovascular femoro-popliteal, with or without an infra-popliteal revascularisation. Design:Three-arm open-label pragmatic multicentre randomised phase 3 superiority trial. Setting:Thirty-five UK NHS vascular units. Participants:Patients with chronic limb threatening ischaemia who required an endovascular femoro-popliteal with or without an infra-popliteal revascularisation. Interventions:Participants were randomly assigned (1 : 1 : 1) to either a femoro-popliteal plain balloon angioplasty with or without bare metal stenting (considered as control or reference), or a drug-coated balloon angioplasty with or without bare metal stenting, or a drug-eluting stenting first revascularisation strategy. Methods:The primary outcome was amputation-free survival defined as time to first major amputation or death from any cause. Secondary outcomes included overall survival, limb salvage, major adverse limb events, major adverse cardiac events and other pre-specified clinical and patient reported outcome measures. Serious adverse events were collected up to 30 days following the first revascularisation procedure. Results:Between 29 January 2016 and 31 August 2021, 481 participants [167 (35%) women] of mean age 71.8 years (standard deviation 10.8) were randomised. Major amputation or death occurred in 106 of 160 (66%) participants in the plain balloon angioplasty ± bare metal stenting group, 97 of 161 (60%) participants in the drug-coated balloon angioplasty ± bare metal stenting, and 93 of 159 (58%) participants in the drug-eluting stenting group [adjusted hazard ratios: plain balloon angioplasty ± bare metal stenting vs. drug-coated balloon angioplasty ± bare metal stenting: 0.84 (97.5% confidence interval 0.61 to 1.16), p = 0.22; plain balloon angioplasty ± bare metal stenting vs. drug-eluting stenting: 0.83 (97.5% confidence interval 0.60 to 1.15), p = 0.20]. There were no differences in serious adverse events between the groups. There were no differences in mortality when drug technology arms were pooled versus plain balloon angioplasty ± bare metal stenting. When compared to plain balloon angioplasty, drug-eluting stenting was less costly [-£724 (95% confidence interval -£4975 to £2631)] and resulted in additional 0.048 quality-adjusted life-years (95% confidence interval -0.060 to 0.148). Drug-coated balloon angioplasty was unlikely to be a cost-effective option (probability 52% of being cost-effective at £20,000 per quality-adjusted life-year) while drug-eluting stenting was potentially cost-effective (probability 76% of being cost-effective at £20,000 per quality-adjusted life-year). Conclusions:Neither drug-coated balloon angioplasty ± bare metal stenting, nor drug-eluting stenting, conferred significant clinical benefit over plain balloon angioplasty ± bare metal stenting when used in the femoro-popliteal segment in patients undergoing femoro-popliteal ± infra-popliteal endovascular revascularisation for chronic limb threatening ischaemia. Drug-eluting stenting and drug-coated balloon angioplasty in chronic limb threatening ischaemia patients were found to offer moderate benefits in health economic outcomes particularly when drug-eluting stenting was compared to plain balloon angioplasty. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 13/81/02.
Objectives To systematically review evidence of the clinical effectiveness of psychosocial interventions for adults with substance use disorder that have a co-occurring common mental health disorder or borderline personality disorder. To identify papers that estimate the cost-effectiveness of interventions for patients with substance use disorder and common mental health disorder or borderline personality disorder. Methods An umbrella review (a systematic review of systematic reviews) for clinical effectiveness was conducted. Systematic database searches [MEDLINE, EMBASE, PsycInfo ® (American Psychological Association, Washington, DC, USA), Cochrane Database of Systematic Reviews, and Web of Science] were carried out in February 2024. Inclusion criteria: Adults with substance use disorder and common mental health disorder or borderline personality disorder; psychosocial interventions (with or without pharmacological therapies); comparators psychosocial treatments, treatment as usual, waitlist/no treatment; systematic reviews of randomised controlled trials. Data, including critical appraisal, were extracted into a standardised form by one reviewer, and checked by another. Data were discussed in a narrative review. A literature review of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and EconLit were undertaken to identify cost-effectiveness papers. An illustrative model was constructed to show how cost-effectiveness could be calculated if data were available. Results Of 5420 unique records, 30 systematic reviews were included in the clinical review. The methodological quality of the reviews was generally good. Most of the interventions and many of the active comparators studied resulted in some improvement for patients. Most reviews focused on depression, anxiety or post-traumatic stress disorder; there were some looking at mixed common mental health disorder or borderline personality disorder. There was much heterogeneity both between reviews, and between the randomised controlled trials within the reviews. The results suggested integrated treatment for co-occurring diagnosis patients may be better for common mental health disorder outcomes than treatment as usual of parallel uncoordinated services. One study was identified that met the cost-effectiveness criteria. However, this reported results alongside a clinical study and was not a modelling paper. The illustrative model should aid future researchers. Limitations Heterogeneity made it difficult to reach an overall conclusion about which therapies were best. Most reviews stated the results were not generalisable across all populations or settings. There were few reviews of borderline personality disorder; or of common mental health disorder other than anxiety/depression/post-traumatic stress disorder. Future works Future research comparing integrated with parallel or sequential treatment, with follow-up of 6 months or longer, and sample size large enough to encompass dropout, may be beneficial. Conclusions No implications for current practice could be recommended due to heterogeneity of reviews/randomised controlled trials within reviews. Study registration This study is registered as PROSPERO CRD42024515813. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR166951) and is published in full in Health Technology Assessment ; Vol. 30, No. 49. See the NIHR Funding and Awards website for further award information.
Background:Predicting a diagnosis of pre-eclampsia is based on a combination of clinical assessment of blood pressure, presence of protein in the urine, symptoms and laboratory test abnormalities. Accurately detecting pre-eclampsia is important to avoid false-positive diagnoses which could lead to unnecessary antenatal admissions and/or preterm delivery. Four blood tests that measure the biomarkers of placental growth factor or the ratio of soluble fms-like tyrosine kinase-1 to placental growth factor are available (known as Triage, Elecsys, DELFIA Xpress, and BRAHMS Kryptor tests). Abnormal measurements of these biomarkers can be used as an aid to predict a diagnosis of pre-eclampsia and maternal and fetal outcomes. Objectives:To evaluate the test accuracy, clinical effectiveness and cost-effectiveness of placental growth factor -based tests used in conjunction with standard clinical assessment for predicting pre-eclampsia and maternal and fetal outcomes in pregnant women who are referred to secondary care with suspected pre-eclampsia in weeks 20-37 of pregnancy. Data sources and methods:A systematic review of the diagnostic/prognostic accuracy and clinical effectiveness of placental growth factor-based tests with standard clinical assessment. Database included MEDical Literature Analysis and Retrieval System, Excerpta Medica dataBASE and Cochrane Library. Other sources searched included relevant conference proceedings and websites, grey literature and research in progress. The most recent date of searching was 18 March 2021. An independent economic analysis was conducted using a decision tree model. The model includes short-term costs and quality-adjusted life-years for the management of women, maternal and neonatal outcomes and long-term outcomes for severe neonatal complications. The model compared the use of the test alongside standard clinical assessment to standard clinical assessment only. Two different estimates of standard clinical assessment were included, from the INSPIRE study and from National Institute of Health and Care Excellence Diagnostic Guidance 23. Results:Seventeen studies were included in the systematic review. Two large, randomised trials provided the best available evidence to inform the economic model: The PARROT trial (Triage test) and the INSPIRE trial (Elecsys test). When used as rule-out tests for pre-eclampsia (with neonatal outcomes included), all four tests produced higher quality-adjusted life-years and higher costs than both types of standard clinical assessment. The incremental cost per quality-adjusted life-year ranged from £637 (DELFIA test vs. standard clinical assessment from INSPIRE) to £47,393 (Triage test vs. standard clinical assessment from diagnostics guidance 23) per quality-adjusted life-year. Incremental costs and quality-adjusted life-years were always very small, with incremental costs always less than the cost of the test and incremental quality-adjusted life-years always < 0.006. Limitations:Although the evidence for placental growth factor-based tests is advancing, there remains uncertainty for key parameters, such as diagnostic sensitivity and specificity. This particularly affects the Elecsys test. Conclusions:Despite uncertainties from lack of data, and heterogeneity across studies, the use of placental growth factor-based tests to rule out and rule in pre-eclampsia has the potential to provide improved outcomes at reduced cost when compared with standard clinical assessment. Future work:Future research priorities include more rigorous evaluation of the DELFIA and BRAHMS placental growth factor-based tests, more evidence for Triage and Elecsys as rule-in tests, and greater focus on Black, and Asian and Mixed ethnicity groups. Study registration:This study is registered as PROSPERO CRD42020227085. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR132386) and is published in full in Health Technology Assessment; Vol. 30, No. 54. See the NIHR Funding and Awards website for further award information.
Background:Despite the relative success of immuno-modulatory disease-modifying therapy in relapsing remitting multiple sclerosis, progressive worsening of disability remains a major problem, particularly for those with secondary progressive multiple sclerosis. Various underlying mechanisms are likely to contribute, augmented by comorbidities (such as vascular risk) and ageing. In the phase 2b MS-STAT trial, simvastatin (80 mg) (Sandoz Ltd, Camberley, UK) reduced the mean annualised whole brain atrophy rate by 43% compared to placebo in patients with secondary progressive multiple sclerosis (p = 0.003). We now report the phase 3, MS-STAT2 trial, with confirmed progression of disability as the primary outcome. Methods:A multicentre, phase 3, randomised, double-blind, placebo-controlled clinical trial was conducted at 31 UK neuroscience centres and district general hospitals. Secondary progressive multiple sclerosis participants aged 18-65 years were randomised 1 : 1 to oral simvastatin (80 mg), or matched placebo, based on a minimisation algorithm that incorporated the following factors: sex (male/female); age (< or ≥ 45 years); Expanded Disability Status Scale baseline score (≤ 5.5 or ≥ 6); whether participants were taking newly licensed (2017 onward) disease-modifying treatments for secondary progressive multiple sclerosis; and trial site. An independent and secure online randomisation service was used. All participants, site investigators and the trial co-ordinating team were blinded to treatment allocation. The Expanded Disability Status Scale was measured every 6 months and was compared to baseline scores, with remote data collection used when enforced by the COVID-19 pandemic. The primary outcome was time to Expanded Disability Status Scale-confirmed disability progression. Progression of disability was defined as an increase of at least one point on the Expanded Disability Status Scale if the baseline score was < 6, or an increase of 0.5 point if the baseline score was ≥ 6. The initial disability progression event was finalised as confirmed if the increase in Expanded Disability Status Scale score persisted at the next assessments ≥ 6 months later. Follow-up was for 36 months, or 54 months, for those without confirmed disability progression at 36 months who agreed to enter an optional blinded extension. An intention-to-treat analysis was carried out. Findings:The study was conducted between 10 May 2018 and 26 July 2024. There were 964 participants randomised, with 482 in the placebo group and 482 in the simvastatin group. 173 (35.9%) participants in the placebo group and 192 (39.8%) participants in the simvastatin group experienced Expanded Disability Status Scale-confirmed disability progression (adjusted hazard ratio = 1.13, 95% confidence interval 0.91 to 1.39, p = 0.263). No material differences in the secondary outcomes were observed. No major safety issues were seen. Interpretation:The MS-STAT2 trial did not demonstrate a treatment effect of simvastatin in slowing disability progression in participants with secondary progressive multiple sclerosis. Despite the favourable outcomes of the previous phase 2b trial, simvastatin use in secondary progressive multiple sclerosis should be confined to existing vascular indications. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 15/57/143.
Background:NHS Talking Therapies for anxiety and depression is a service that provides people in England with psychological support. There are several referral routes into the service, digital front door technologies being the most recent addition. Aim:The aim of this National Institute for Health and Care Excellence early value assessment was to map available evidence, assess potential benefits and costs of NHS Talking Therapies referral pathways with and without digital front door technologies, and identify evidence gaps to help direct future data collection and further research. Methods:The External Assessment Group carried out a systematic literature review (December 2024) to gather evidence relating to Limbic Access (Limbic), Wysa Digital Referral Assistant (Wysa), Censeo Digital (Psyomics) and AskFirst (Sensely). Information was collected across four broad outcome categories: accuracy and acceptability, resource and system impact, patient-reported outcomes, and costs. All study types were eligible for inclusion in the systematic literature review, along with evidence provided by the manufacturers of digital front door technologies (via requests for information). In addition, the External Assessment Group interviewed and sent questionnaires to stakeholders, including National Institute for Health and Care Excellence Specialist Committee Members, and carried out exploratory analyses of costs and benefits. Results:Evidence was only available for two digital front door technologies: Limbic Access and Wysa Digital Referral Assistant. Literature meeting the systematic literature review eligibility criteria comprised two published peer-reviewed studies, six unpublished studies and five requests for information responses. The strongest evidence related to accessibility and overall satisfaction with Limbic Access. Results from one peer-reviewed study showed that Limbic Access increased the number of referrals to NHS Talking Therapies versus services that did not implement the technology (odds ratio = 1.10, 95% confidence interval 1.075 to 1.131); this included an increase in access for some minority groups [Asian (odds ratio = 1.29; confidence interval 1.163 to 1.422), Black (odds ratio = 1.35, confidence interval 1.183 to 1.551) and non-binary (odds ratio = 2.95; confidence interval 2.065 to 4.206)]. Overall satisfaction reported by users who completed the Limbic Access referral process was high (≥ 89%). Resource impact evidence was provided by one peer-reviewed study; results showed that Limbic Access reduced clinical assessment duration by 12.7 minutes. No relevant information on quality and accuracy was identified. Interviews and questionnaires:Respondents were positive about digital front door technologies, suggesting that these tools could lead to better quality and more accurate (1) pre-referral practices and (2) initial clinical assessments; however, experts were unable to clearly define quality or accuracy. Cost-effectiveness analyses:The External Assessment Group's exploratory economic analysis results suggested that the amount of clinical assessment time required to notionally offset the Limbic Access or Wysa Digital Referral Assistant licence cost was small (< 3 minutes). Limitations:Most published evidence was non-comparative. The strength of the evidence provided by the technology companies was difficult to assess due to limited detail. Conclusions:Further evidence is required to better understand the benefits and costs of digital front door technologies for NHS Talking Therapies. Future work:Evidence generation should focus on whether digital front door technologies improve the accuracy and quality of clinical assessments and their impact on resources throughout the referral pathway. Study registration:This study is registered as PROSPERO CRD42025634844. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR171847) and is published in full in Health Technology Assessment; Vol. 30, No. 52. See the NIHR Funding and Awards website for further award information.
Background:Fatigue is common in many long-term medical conditions. Interventions to date have largely been in single conditions. Objective:To conduct a mixed-methods evidence synthesis of the clinical and cost-effectiveness and acceptability of non-pharmacological interventions for fatigue in adults with long-term medical conditions. Methods:Randomised controlled trials, cost-effectiveness studies, or qualitative studies of non-pharmacological interventions for fatigue in long-term medical conditions where fatigue was either a criterion for inclusion, the primary target of the intervention, or the primary or coprimary outcome. Studies of post-infectious, post-traumatic, cancer-related or idiopathic fatigue were excluded. Information sources:Searches used the MEDical Literature Analysis and Retrieval System, Excerpta Medica dataBASE, Cumulative Index to Nursing and Allied Health Literature, and American Psychological Association PsycInfo® (American Psychological Association, Washington, DC, USA) databases. We used systematic CLUSTER searching for qualitative studies and Epistemonikos for systematic reviews. Involvement of patients:We held three rounds of five focus groups involving people with fatigue in long-term conditions to ensure that assumptions in, and reporting of, the research had validity with the patient population. Risk of bias:Risk-of-bias assessment of all studies included in the network meta-analysis was undertaken using an adapted version 2 of the Cochrane risk-of-bias tool for randomised controlled trials. Synthesis of results:Clinical effectiveness evaluation used random effects network meta-analyses at three time points. The cost-effectiveness analysis involved a de novo analysis of interventions identified as clinically effective. The qualitative synthesis involved a thematic synthesis of primary studies of interventions and a mega-synthesis of reviews of patient experience of fatigue across different conditions. Focus groups were analysed by thematic analysis, and findings from all work packages were integrated in a final synthesis by the research team. Results:The clinical effectiveness review included 88 randomised controlled trials, involving 27 interventions, with 6636 participants included at end of treatment, 1849 in the short term and 2322 in the long term. Synthesis of results:Compared to usual care at long-term follow-up, cognitive-behavioural therapy-based interventions and physical activity promotion showed statistically significant reductions in fatigue (standardised mean difference -0.4, 95% credible interval -0.63 to -0.21, 9 studies; and -0.52, -0.86 to -0.18, 2 studies), respectively. Effective interventions provided positive net monetary benefit versus usual care, particularly when delivered in a group format, when valuing a quality-adjusted life-year at £20,000. Individuals vary in their experience of fatigue in ways that are not simply due to their medical condition, indicating that interventions need to be adaptable to individuals' experiences and capabilities. Discussion:The evidence base is relatively small, heterogeneous and includes studies at moderate to high risk of bias. More than half of the included trials were in multiple sclerosis. Interpretation:Interventions for fatigue that support people to increase physical activity or are based on cognitive-behavioural therapy are acceptable and effective in reducing fatigue in people with different long-term medical conditions, with the potential to be cost-effective. Based on the qualitative synthesis, we propose a three-stage component model for interventions. Future work:Future trials should focus on the feasibility and effectiveness of transdiagnostic fatigue services, fatigue interventions in multimorbidity, and investigations of emerging non-invasive stimulation interventions. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR154660.
Background:Severe combined immunodeficiency is an inherited condition arising from mutations in at least 19 known genes. Severe combined immunodeficiency can be identified through screening, family history or clinical presentation. Severe combined immunodeficiency is usually asymptomatic at birth and presents, in infancy, as recurrent and frequently severe infections. Without treatment, severe combined immunodeficiency is usually fatal in the first year of life. Objectives:To summarise the available evidence relevant to newborn screening for severe combined immunodeficiency in the UK NHS newborn blood spot screening programme. Three research questions, concerning the accuracy of screening tests, the efficacy of early treatment and the acceptability of screening, were developed to address this objective. Methods:Eleven bibliographic databases were searched for relevant studies from 2011 to April 2024. Separate inclusion criteria were specified for each research question. Study selection, data extraction and assessment of methodological quality followed standard systematic review methods. A narrative synthesis of results is presented, structured by research question. No meta-analyses were conducted. Results:Most positive predictive values, calculated from reports of newborn blood spot screening programme experience, were between 3.6% and 26%. Screening algorithms incorporating repeat sampling in preterm babies appeared to reduce false positives due to prematurity. However, the large number of other conditions that can give rise to a positive screening result mean that the positive predictive value for severe combined immunodeficiency remains consistently poor. Two small studies reported that early diagnosis of severe combined immunodeficiency, via newborn blood spot screening or family history and following the introduction of newborn blood spot screening, respectively, was associated with non-statistically significant improvements in post-transplant survival. A third study analysed data on n = 902 United States patients with severe combined immunodeficiency collected over a 28-year period and reported the results of multivariable Cox regression analyses, adjusted for demographic disease-related and transplant-related variables found to be significant on univariate analysis, showing that diagnosis of severe combined immunodeficiency via newborn blood spot screening significantly improved survival compared to diagnosis via clinical presentation. Qualitative data from the publications included in this evidence summary were generally indicative of parental support for newborn blood spot screening for severe combined immunodeficiency, but was mainly derived from parents of healthy newborns. Limitations:The systematic review component of this evidence summary was limited by a restriction to full publications in the English language. Conclusions:The current published evidence base alone is not adequate to fully support implementation of newborn blood spot screening for severe combined immunodeficiency. With respect to UK National Screening Committee population screening criteria, criterion 4 was partially met and there was insufficient evidence to adequately assess whether criterion 6 was met. The findings of this evidence summary should be considered alongside findings from the recent in-service evaluation of newborn screening for severe combined immunodeficiency conducted in the NHS in England and the results of cost-effectiveness modelling. Future work:Further work is needed to inform policy on how the identification of non-severe combined immunodeficiency T-cell lymphopenia conditions by screening should be treated. Stakeholder dialogue and patient and public involvement activities may be helpful. In particular, the views of parents who have lived experience of a non-severe combined immunodeficiency (incidental) finding from newborn blood spot screening for severe combined immunodeficiency should be sought. Study registration:This study is registered as PROSPERO CRD42024544200. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR168307) and is published in full in Health Technology Assessment; Vol. 30, No. 45. See the NIHR Funding and Awards website for further award information.
Background:Evidence is required on the relative effectiveness of sulphonylureas, dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter 2 inhibitors added to metformin for people with type 2 diabetes mellitus. Objectives:To assess disparities in the initiation of second-line antidiabetic treatments prescribed among people with type 2 diabetes mellitus in England according to ethnicity and social deprivation. To compare the effectiveness of sulphonylureas, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors added to metformin for people with type 2 diabetes mellitus who require second-line treatment in routine clinical practice. To examine heterogeneity in the comparative short-term (12 months) effectiveness of sulphonylureas versus dipeptidyl peptidase-4 inhibitors combined with metformin on levels of glycated haemoglobin across the entire target population and subpopulations of decision-making relevance. To assess the comparative effectiveness of sulphonylureas, dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter 2 inhibitors added to metformin according to individual risk-factor profiles of multiple long-term conditions. To calibrate the RAPIDS microsimulation model to UK data and then use the resultant RAPIDS-UK model to predict probabilities of long-term complications for people with type 2 diabetes mellitus in England after second-line treatment with sulphonylureas, dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter 2 inhibitors added to metformin. Methods:We included adults with type 2 diabetes mellitus who initiated second-line antidiabetic treatment with sulphonylureas, dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter 2 inhibitors added to metformin monotherapy. We used data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics and the Office of National Statistics. We applied target trial emulation and instrumental variable analyses to reduce the risks of biases, including confounding. The primary outcome was change in mean glycated haemoglobin (mmol/mol) at 1-year follow-up. Secondary outcomes: change in mean body mass index, systolic blood pressure, estimated glomerular filtration rate and time to major adverse kidney event, major adverse cardiovascular event, heart failure hospitalisation, eye disease, amputation and all-cause mortality. We assessed treatment effect heterogeneity according to multiple long-term conditions. We used a microsimulation model to report the impact on long-term complications. Results:After the instrumental variable analysis, the mean 95% confidence interval differences in glycated haemoglobin change between baseline and 1 year were: -2.5 mmol/mol (-3.7 to -1.3) for sodium-glucose cotransporter 2 inhibitors versus sulphonylureas, and -3.2 mmol/mol (-4.6 to -1.8) for sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors. Sodium-glucose cotransporter 2 inhibitors were more effective in reducing body mass index and systolic blood pressure compared to either sulphonylureas or dipeptidyl peptidase-4 inhibitors. Sodium-glucose cotransporter 2 inhibitors were also more effective at reducing mean glycated haemoglobin at 2-year follow-up, at reducing body mass index and systolic blood pressure at 1- and 2-year follow-ups and at reducing the hazards of heart failure hospitalisation (vs. dipeptidyl peptidase-4 inhibitors) and ≥ 40% decline in estimated glomerular filtration rate (vs. sulphonylureas). We did not find evidence of treatment effect heterogeneity by baseline cardiovascular disease status or multiple long-term condition profiles. The microsimulation model found that sodium-glucose cotransporter 2 inhibitors led to lower predicted incidence of end-stage kidney disease, heart failure and eye disease. Public and patient involvement translation workshop participants provided valuable insights on how best to share our findings. Limitations:We could only partially evaluate the main instrumental variable assumptions. Conclusions:We found that sodium-glucose cotransporter 2 inhibitors were better than dipeptidyl peptidase-4 inhibitors and sulphonylureas at improving important risk factors and at reducing the risk of complications among a general population of people with type 2 diabetes mellitus. Future work:Newer antidiabetic treatments should be evaluated. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR128490.
Background:National Institute for Health and Care Excellence technology appraisals assess the effectiveness and cost-effectiveness of medicines at a single point in the treatment pathway. However, for some disease areas, such as non-small cell lung cancer, there are many recommendations, making it difficult to use National Institute for Health and Care Excellence guidance. The treatment pathway for metastatic stage 4 non-small cell lung cancer can be divided into decision points (nodes) based on histology (squamous or non-squamous), programmed death-ligand 1 expression, presence of tumour mutations and line of therapy. The National Institute for Health and Care Excellence commissioned this pilot to assess the potential of taking a 'pathways approach' to technology appraisals. The aim was to build a single disease-specific cost-effectiveness model for metastatic stage 4 non-small cell lung cancer patients not eligible for targeted therapies at first line, that can be updated with economic and clinical data as required. Methods:We conducted a systematic review (searches last updated 11 July 2025) and network meta-analysis of treatment efficacy and safety at each decision node in the pathway. We used flexible fractional polynomial models for primary outcome progression-free survival, required for a model of treatment sequences. We built a novel cost-effectiveness model that compared sequences of treatments, and was populated using network meta-analyses for progression-free survival, data on overall survival after last-line therapy, evidence on treatment sequences from an analysis of systemic anticancer therapy data, and quality of life, cost and resource use estimates from previous technology appraisals. Drug list prices were used, but confidential discounts are available. Results:We included 15 randomised controlled trials and 1 single-arm study in the review, judged as some concerns or low risk of bias. Immunotherapies, in combination with doublet platinum chemotherapy, were most effective first-line treatments, although with higher adverse event rates. Immunotherapy monotherapies were most effective at second line, unless patients were suitable for targeted therapies. Sequences starting with atezolizumab + bevacizumab + doublet platinum chemotherapy had similar costs and quality-adjusted life-years to sequences starting with pembrolizumab + doublet platinum chemotherapy. Sequences starting with pemetrexed + platinum chemotherapy had the lowest costs but also the lowest total quality-adjusted life-years. Sequences for non-squamous non-small cell lung cancer, programmed death-ligand 1 ≥ 50%:Sequences starting with pembrolizumab + doublet platinum chemotherapy had highest quality-adjusted life-years, but higher costs compared to other sequences. Sequences starting with pemetrexed + platinum chemotherapy had the lowest cost and the lowest number of quality-adjusted life-years. Sequences for squamous non-small cell lung cancer, programmed death-ligand 1 < 50%:Sequences starting with pembrolizumab + doublet platinum chemotherapy had higher quality-adjusted life-years and higher costs than sequences starting with platinum chemotherapy. Sequences for squamous non-small cell lung cancer, programmed death-ligand 1 ≥ 50%:Sequences starting with atezolizumab had the highest predicted quality-adjusted life-year gains, slightly higher than for sequences starting with pembrolizumab. Sequences starting with platinum chemotherapy had the lowest quality-adjusted life-years, but the lowest total costs. Patients in the systemic anticancer therapy analysis had a shorter time on treatment than those in trials, resulting in lower treatment costs and causing the immunotherapy sequences to appear more cost effective. Conclusions:Our model can be used to estimate either the most cost-effective sequence of treatments or the most cost-effective treatment at a given point in the pathway, although our results are based on drug list prices and these would need to be updated to draw conclusions about the relative cost-effectiveness of different treatment sequences. We were able to use real-world data from systemic anticancer therapy to estimate model parameters and sequences that reflect clinical practice. Our model can readily be updated and used as a reference model for metastatic non-small cell lung cancer. Study registration:The study is registered as PROSPERO CRD42023470119. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR136097) and is published in full in Health Technology Assessment; Vol. 30, No. 46. See the NIHR Funding and Awards website for further award information.
Background Incontinence-associated dermatitis is prevalent in long-term care facilities and homecare settings among adults who are incontinent of urine and/or faeces. Strategies to protect skin integrity are needed. This study aimed to co-design and test the feasibility of a training manual and care guidance (Incontinence-Associated Dermatitis Manual) to prevent and treat incontinence-associated dermatitis in long-term care facilities and homecare settings. Methods This was a three-phase study: (1) evidence synthesis and intervention development, (2) definitive study design (a cluster-randomised controlled trial with an embedded process evaluation) and (3) a 3-month feasibility study. Our Cochrane review was updated following a similar methodology to the original review. The intervention (underpinned by findings from the Cochrane review) was developed with 16 stakeholders. The feasibility study targeted four long-term care facilities and two homecare providers, randomising them (each as a cluster) to intervention or control. Recruitment targeted 288 participants (48 per cluster). Feasibility outcomes included recruitment and retention rates, completeness of data, acceptability of intervention and methods and intervention fidelity. Outcome measures included: Ghent Global incontinence-associated dermatitis categorisation tool, minimum data set and incontinence-associated dermatitis intervention tool. Process evaluation interviews with two care recipients, 11 family carers and 13 care staff implementing the Incontinence-Associated Dermatitis Manual and their managers were conducted. Observations of 22 episodes of care assessed intervention fidelity. Qualitative data were analysed using thematic analysis. Summary feasibility outcome measures using means or proportions, together with 95% confidence intervals, were reported. Results The reviews of interventions for prevention and treatment of incontinence-associated dermatitis included 15 trials with 1089 participants and 19 trials with 1164 participants, respectively. All participants were incontinent of urine, stool or both. Little evidence, of very low to low quality, was found on the effects of interventions for preventing and treating incontinence-associated dermatitis in adults. The proposed cluster-randomised controlled trial was agreed, with one additional outcome measure added, and the co-designed intervention (incontinence-associated dermatitis manual) included training (3 hours face-to-face and online), an online manual and a poster/flow chart to support care decision-making. After a COVID-19-related pause of 7 months, obtaining governance and ethical approvals for the feasibility study was delayed by 27 months. Five sites were recruited from 49 approached. All randomised sites were retained. Seventy-six (16%) of the 477 participants approached were randomised, of which 58 (76%) completed the study. Ghent Global incontinence-associated dermatitis categorisation tool, minimum data set and incontinence-associated dermatitis intervention tool had complete or almost-complete 3-month outcome data in participants, whereas other outcome measures had contrastingly poor data completeness due to participant cognitive impairment. Process evaluation showed few potential participants had capacity to consent, and gaining consultee approval was challenging. Care staff liked the incontinence-associated dermatitis manual, describing it as ‘ helpful ’. Twenty-eight people accessed the incontinence-associated dermatitis manual online, and 15 care staff downloaded a certificate of completion of training. Intervention fidelity was not always observed. Limitations The study was limited by the impact of COVID on both the social care sector and research governance systems and processes. The prevalence of incontinence-associated dermatitis in study sites was lower than expected. Conclusions It was feasible to develop the Incontinence-Associated Dermatitis Manual. The randomised controlled trial was not feasible as designed, with specific challenges regarding site and participant recruitment, governance and intervention fidelity. Future work We plan to revise the methods used in this feasibility study to address limitations, especially issues of recruitment, and develop a protocol for a new trial with nested feasibility study. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR128865.
Background:There is currently wide variation in prehospital major trauma triage across the National Health Service, with regional ambulance services using different triage tools, varying in format, structure and variables. Objectives:To develop a national triage tool that is acceptable, usable, accurate, and optimises under- and over-triage. Design:A three-phase research programme, comprising Phase 1: development of a new triage tool by expert consensus informed by existing evidence, a systematic review of elderly triage, document analysis of current tools, decision-analytic modelling, expert consensus definition of a major trauma reference standard, and a qualitative examination of current triage; Phase 2: case-cohort study validating triage tools identified and developed in Phase 1, with identification of an optimally performing candidate triage tool; Phase 3: evaluation of the candidate triage tool following implementation, including cohort study investigating accuracy of triage decisions, cost-effectiveness analysis, and examination of user experiences. Setting:English regional trauma networks served by the South-Western, West Midlands, Yorkshire and London Ambulance Services. Phase 2 case-cohort study and Phase 3 cohort studies performed between 1 November 2019 and 28 February 2020, and 1 November 2021 and 15 May 2022, respectively. Participants:Injured patients presenting to ambulance services in participating regional trauma networks. Results:In Phase 1, document analysis identified 19 United Kingdom triage tools and 34 published international tools. The systematic review demonstrated limited diagnostic accuracy of triage tools in the elderly, with divergent real-life triage decisions. The reference standard included the need for critical trauma-related interventions, significant individual anatomical injuries, burden of multiple minor injuries and specific patient attributes. Decision-analytic modelling indicated that high-specificity triage tools were favoured. Triage tool simplicity and the option for clinical judgement were valued by stakeholders, but real-world triage was a multifaceted, nonlinear, dynamic and multiagency process. Following review of Phase 1 evidence, a three-step Major Trauma Triage Study candidate triage tool targeting relatively higher specificity was developed through expert consensus. The Phase 2 case-cohort sample included 2757 patients, with a weighted prevalence of major trauma of 3.1% (95% confidence interval 2.3% to 4.0%). The Major Trauma Triage Study tool performed optimally compared to under- and over-triage targets (sensitivity 37.3%, specificity 95.1%). In Phase 3, the newly implemented Major Trauma Triage Study triage tool was received favourably by stakeholders. Prehospital triage decisions using the new tool demonstrated a sensitivity of 55.3% (95% confidence interval 51.8% to 58.7%) and specificity of 94.3% (95% confidence interval 94.1% to 94.6%, n = 38,010, 2.2% prevalence of major trauma). Minimal differences were apparent between the costs (£149) and benefits (0.006 quality-adjusted life-years) of triage decisions, regardless of the triage tool used, reflecting similar real-life triage accuracy. However, the new Major Trauma Triage Study tool appeared cost-effective when theoretical triage tool performance was examined, demonstrating an incremental cost effectiveness ratio of £21,163. Conclusions:The Major Trauma Triage Study triage tool performed optimally, targeted an appropriate under-/over-triage trade-off, and was perceived to perform well by stakeholders. National implementation could ensure evidence-based, standardised and cost-effective triage. Limitations:Significant variation in National Health Service ambulance service and trauma network configurations could limit the generalisability of results. Future work:Paediatric triage, pre-alerting and the benefit of remote clinical support could benefit from future research. Trial registration:This trial is registered as Current Controlled Trials ISRCTN17968752. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/16/04) and is published in full in Health Technology Assessment; Vol. 30, No. 34. See the NIHR Funding and Awards website for further award information.
Background:Ovarian hyperstimulation syndrome is a potentially serious complication of fertility treatments. Standard care often involves monitoring, then hospitalisation for severe cases. Some evidence suggests early outpatient paracentesis may prevent hospitalisation, but adequately powered randomised trials are lacking. Objectives:To establish the clinical and cost-effectiveness, safety and acceptability of early active outpatient management for moderate or severe ovarian hyperstimulation syndrome. Design and methods:A pragmatic, parallel, open-label, multicentre, superiority, adaptive, group sequential randomised controlled trial with an internal pilot was planned. The study included preliminary qualitative work and a post-trial survey. The main trial recruited participants with moderate or severe, early or late ovarian hyperstimulation syndrome from UK fertility clinics. Participants were randomised 1 : 1 to receive either outpatient paracentesis or usual care (conservative management). The primary outcome was ovarian hyperstimulation syndrome-related hospital admission within 28 days. Results:The trial was terminated early due to poor recruitment. Only 8 participants were randomised (5 to conservative management, 3 to outpatient paracentesis) across 3 of 9 opened sites, compared to the planned 224 participants. All eight had moderate ovarian hyperstimulation syndrome at baseline. Two participants were hospitalised for ovarian hyperstimulation syndrome-related reasons (one from each group). Six participants' symptoms resolved during follow-up, while two had unknown outcomes. There were no reported serious adverse events caused by the intervention. The post-trial survey of 16 fertility centres found increased use of preventive measures like freeze-all cycles, antagonist protocols and gonadotropin-releasing hormone trigger, during and after the SARS-CoV-2 (COVID-19) pandemic. Limitations:The small sample size precludes drawing any definitive conclusions about effectiveness, safety or cost-effectiveness. The study was severely impacted by the COVID-19 pandemic, affecting site set-up and recruitment, and changes in clinical practice during the pandemic may have reduced ovarian hyperstimulation syndrome cases. Conclusions:No definitive clinical conclusions can be drawn from this study about the effectiveness of outpatient management compared to conservative management. The pandemic prompted lasting modifications in ovarian hyperstimulation syndrome prevention strategies at many fertility clinics. Future work:Given the observed low incidence rates of ovarian hyperstimulation syndrome and challenges in recruitment, future research may need to consider alternative study designs in observational settings rather than randomised trials that reflect the changing reality of clinical management and prevention of ovarian hyperstimulation syndrome, particularly following the recent COVID pandemic. Additionally, the research community should reflect on strategies to improve trial resilience and adaptability in the face of major disruptions like pandemics. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR128137.
Background:HomeHealth is a home-based, voluntary sector service supporting older people with mild frailty to maintain independence through behaviour change. Support workers discuss the person's priorities and enable setting/achieving goals around mobility, nutrition, socialising and/or psychological well-being. Aims:We tested clinical and cost-effectiveness of HomeHealth for maintaining independence in older people with mild frailty in a randomised controlled trial. Methods:Design: Single-blind, parallel randomised controlled trial open between 18 January 2021 and 4 July 2023, with mixed-methods process evaluation. Setting: Community-dwelling older people aged 65+ years with mild frailty from 27 general practices and community settings in London, Yorkshire and Hertfordshire. Randomisation: Participants were randomised 1 : 1 to receive HomeHealth or treatment as usual. Outcomes: Primary outcome was independence in activities of daily living (modified Barthel Index), analysed using linear mixed models. Secondary outcomes included frailty phenotype score, extended activities of daily living, well-being, psychological distress, loneliness, cognition, falls and mortality. Health economic outcomes included quality of life, capability and service use, including hospital admissions. Cost-effectiveness acceptability curves and cost-effectiveness planes were used to represent the probability of cost-effectiveness compared to treatment as usual. Process evaluation: We conducted semistructured interviews with participants receiving the intervention, HomeHealth workers and other stakeholders supporting service delivery. Interviews were thematically analysed. Fidelity of audio-recorded appointments was assessed by two independent raters. We evaluated potential mechanisms of impact using data from appointments attended, types of goals set and progress towards goals. Findings:We recruited 388 participants, mean age 81.4 years (standard deviation 6.5), 64% female and 94% White British/European. HomeHealth did not improve Barthel Index scores at 12 months (0.250, 95% confidence interval -0.932 to 1.432). At 6 months, we found small significant reductions in psychological distress (-1.237, 95% confidence interval -2.127 to -0.348), and frailty phenotype score (-0.252, 95% confidence interval -0.487 to -0.017). At 12 months, we found significant improvements in well-being (1.449, 95% confidence interval 0.124 to 2.775), reduced unplanned admissions (incidence rate ratio 0.65, 95% confidence interval 0.54 to 0.92) with lower associated costs (-£586/participant, 95% confidence interval -351 to -821). There were no differences in other outcomes. HomeHealth dominates treatment as usual with a negative point estimate for incremental costs (-796, 95% confidence interval -2016 to 424), positive point estimate for incremental quality-adjusted life-years (0.009, -0.021 to 0.039) and high probability of cost-effectiveness. Process evaluation: Sixty-four semistructured interviews were completed, including 49 participants and 15 HomeHealth workers/stakeholders. The service was acceptable and safe, with good fidelity of delivery. Participants made progress on personalised goals, most working on enhancing mobility. They found the service empowering, and received emotional/practical support. Engagement was more challenging when participants identified no need for change, had significant memory impairment or new/declining illness. Flexibility around varying symptoms and incorporating behaviour change into existing routines promoted engagement. Conclusion:HomeHealth did not improve independent functioning for older people with mild frailty. There were small significant improvements in frailty status, psychological distress and well-being and a 35% reduction in unplanned admissions, with high probability of cost-effectiveness. Limitations:We used a pragmatic design with intervention delivery in real-world settings during/after the COVID-19 pandemic, potentially with more variability in delivery. Our findings might not apply to other geographical settings/healthcare systems. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR128334.
Background:Adolescents experiencing psychiatric emergencies often require intensive interventions to prevent hospitalisation and support their return to education, employment or training. Intensive Community Care Services aim to provide an alternative to inpatient care. Aims:To evaluate the effectiveness of Intensive Community Care Services compared to treatment as usual in reducing the time to start or return to education, employment or training for young people with psychiatric emergencies. Method:A multicentre, parallel-group, single-blinded, randomised controlled trial, including an internal feasibility phase, across seven NHS trusts in the United Kingdom. Adolescents aged 12-17 were randomised to receive either Intensive Community Care Services or treatment as usual. The primary outcome was the time to start or return to education, employment or training within a 6-month observation period. Secondary outcomes included clinical symptoms, functioning and service satisfaction. Process evaluation used semistructured visual interviews followed by thematic decomposition analysis. The impact of COVID-19 and the importance of continuity of care were explored in a series of cohort studies based in emergency departments. A consensus meeting was held to define the features of Intensive Community Care Services. Results:Of the approximately 977 adolescents screened, 36 were randomised in a 1 : 1 ratio using a web-based randomisation system stratified by the NHS trust using variable block sizes to receive either Intensive Community Care Services or treatment as usual. A key reason for poor recruitment was the absence of an alternative to Intensive Community Care Services. The recruitment rate did not meet pre-specified progression criteria (n = 55 by the first 6 months of recruitment), and conducting a full evaluation trial was deemed not feasible. Thirty participants from the pilot sample (83.3%) returned to education, employment or training during the 6-month follow-up period, with a median time to education, employment or training of 9 days (interquartile range 1-49). The median time to education, employment or training was lower in the Intensive Community Care Services group (6 days) compared to the treatment-as-usual group (12 days), with a hazard ratio of 1.34 (95% confidence interval 0.63 to 2.86). Estimated effect sizes for secondary outcomes were also in the direction of a benefit under Intensive Community Care Services, with higher satisfaction with services and improvements in clinical symptoms and functioning. There was a greater total average cost for the treatment-as-usual group at £15,155 (standard deviation 31,560), compared to £7063 (standard deviation 10,605) for Intensive Community Care Services. Due to the small sample size, no inferences regarding Intensive Community Care Services effectiveness or cost-effectiveness can be drawn. Fourteen young people participated in the process evaluation. Inpatient care received both praise for effective diagnoses and therapeutic interventions and criticism for a sterile approach and inadequate staff attention. Intensive Community Care Services was valued for the personalised approach, exemplified by beneficial home visits. During COVID-19, there was a significant reduction in emergency presentations of young people, followed by a significant increase post pandemic. The follow-up attendance rate increased by more than three times if the follow-up appointment was offered by the same clinician who saw the young person in an emergency room (odds ratio 3.66, 95% confidence interval 1.65 to 8.13). Intensive Community Care Services teams should use the modified Dartmouth Assertive Community Treatment Fidelity Scale to assess their quality. Recruitment to a randomised controlled trial of this kind can be improved if all new Intensive Community Care Services teams are considered to be experimental services and an equipoise between Intensive Community Care Services and existing services acknowledged. Future work:Rigorous post-implementation research is warranted for those areas that choose to implement Intensive Community Care Services. An adequately powered randomised controlled trial is needed to confirm the pilot findings of the IVY study and explore the full potential of Intensive Community Care Services as an alternative to inpatient and other community-based services for young people with severe mental health needs. Clinicians' experience delivering Intensive Community Care Services should be explored in further qualitative studies. Limitations:The most significant limitation of this pilot study is the very small sample size, which was a direct result of recruitment difficulties. As a result, we were unable to draw any inferences about the effectiveness or cost-effectiveness of Intensive Community Care Services relative to treatment as usual. It was not possible to blind participants to the intervention they were receiving. The 6-month follow-up period may have been insufficient to capture important long-term outcomes. Conclusions:No definitive conclusions can be drawn from this study. Preliminary results suggest that Intensive Community Care Services may support a faster return to education, employment or training than treatment as usual. Intensive Community Care Services may be cost-effective compared to treatment as usual. Additional mental health professionals should be deployed to Intensive Community Care Services during future lockdowns. The same Intensive Community Care Services professionals should offer assessments in emergency departments and provide community follow-up. Research with a larger sample is warranted to confirm these findings. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR127408.
Background:The long-term use of strong opioids for chronic non-cancer pain puts people at risk of serious harm. Objectives:To test the effectiveness and cost-effectiveness of a multicomponent intervention targeting opioid use for the treatment of chronic pain. Design:A multicentred randomised controlled trial with embedded process evaluation. Setting:Primary care. Participants:Adults using strong opioids for non-malignant chronic. Interventions:Participants were randomised 1 : 1 (using a minimisation programme stratified by geographical locality, baseline pain intensity score and baseline morphine equivalent dose) to either usual care (an educational booklet and relaxation compact disc) or usual care plus the I-WOTCH intervention; 3 day-long group sessions delivered by a nurse and lay facilitator, plus a one-to-one session and ongoing telephone contact from the nurse to support opioid tapering. Main outcome measures:The two primary outcomes were Patient-Reported Outcomes Measurement Information System Pain Interference Short Form (8A), and proportion using no opioids, at 12 months. Results:We randomised 608 people. At 12 months, there was no between-group difference in Patient-Reported Outcomes Measurement Information System Pain Interference Short Form (8A) scores; mean difference, -0.52 (95% confidence interval -1.94 to 0.89). At 12 months, 65/225 (29%) of people in the intervention group and 15/208 (7%) of people in usual-care group reported using no opioids [odds ratio 5.55 (95% confidence interval 2.80 to 10.99)], absolute difference, 21.7% (95% confidence interval 14.8 to 28.6). Over a lifetime horizon, I-WOTCH is on average associated with an incremental cost of £9277 per person, and provides an additional 0.314 quality-adjusted life-years. The deterministic incremental cost per quality-adjusted life-year gained was £29,543. The I-WOTCH intervention may be cost-effective compared to best usual care. The process evaluation suggested group support and shared experience were important to those trying to taper. Limitations:The opioid use analysis is based solely on participant self-report. The findings only apply to people willing to consider opioid reduction and may not apply to a more complex secondary care population. The results may not be applicable to people using very high opioid doses. Conclusions:The I-WOTCH intervention helps substantially more people stop opioids than best usual care without adversely affecting pain interference. Future work:The I-WOTCH intervention should be tested in different healthcare settings and other populations. Trial registration:This trial is registered as Current Controlled Trials ISRCTN49470934. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/224/04) and is published in full in Health Technology Assessment; Vol. 30, No. 35. See the NIHR Funding and Awards website for further award information.
