Background:Traumatic acute subdural haematomas often require surgical evacuation via craniotomy or decompressive craniectomy. Decompressive craniectomy may prevent intracranial hypertension; however, it is unclear whether it is associated with better outcomes. Objective:Multicentre, pragmatic, parallel-group randomised trial to compare the clinical and cost-effectiveness of decompressive craniectomy versus craniotomy for evacuation of acute subdural haematomas. Design:International, multicentre, pragmatic, parallel-group randomised trial with additional observational arm. Setting:Hospitals with neurosurgical services in the UK and internationally. Participants:Patients aged ≥ 16 years, with a diagnosis of acute subdural haematomas on a computed tomography scan that required evacuation with a large bone flap either by craniotomy or decompressive craniectomy according to the opinion of the admitting neurosurgeon. Interventions:The enrolled patients underwent acute subdural haematoma evacuation in the operating room under general anaesthesia. A large bone flap ipsilateral to the haematoma was raised, the dura opened and the haematoma evacuated. Other haematomas, such as contusions, were evacuated at the discretion of the surgeon. If clinically appropriate randomisation occurred, the bone flap was either replaced (craniotomy) or not replaced (decompressive craniectomy). Patients who could not be randomised were followed up in the observational arm. Main outcome measures:Primary outcome measure was the extended Glasgow Outcome Scale assessed 12 months post injury. An economic evaluation (based on UK participants) was undertaken to estimate the cost-effectiveness of craniotomy compared to decompressive craniectomy. Results:Four hundred and fifty patients were randomised: 228 to craniotomy and 222 to craniectomy - with the common odds ratio for the differences across the Glasgow Outcome Scale scores of 0.85 [95% confidence interval (0.6 to 1.18; p = 0.324)]. The results were similar at 6 months. At 12 months, death occurred in 30.2% of the craniotomy group versus 32.2% of the decompressive craniectomy group, vegetative state occurred in 2.3% versus 2.8%, and good recovery occurred in 25.6% and 19.9%, respectively. In the observed cohort, those who had a decompressive craniectomy had significantly worse outcomes at 6 and 12 months, but their baseline characteristics were different. Limitations:Clinicians were not blinded to the trial groups. Decompressive craniectomy was performed in 8.8% of patients allocated to the craniotomy group, and 5.4% of patients allocated to the decompressive craniectomy group underwent craniotomy. Intraoperative non-adherence with allocation did not influence the primary analysis, which was based on the intention-to-treat principle. Conclusions:Among patients undergoing evacuation of acute subdural haematomas, the outcomes were similar in both groups. Additional surgery was required in a higher proportion of patients in the craniotomy group, but more wound complications occurred in the decompressive craniectomy group. Future work:Long-term outcomes of patients following decompressive craniectomy, timing and impact of cranial reconstruction on a patient's rehabilitation. Trial registration:This trial is registered as ISRCTN87370545. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/35/57) and is published in full in Health Technology Assessment; Vol. 30, No. 66. See the NIHR Funding and Awards website for further award information.
Background:The optimal monitoring strategy for adults with inflammatory conditions established on immune-suppressing treatment is unknown. Objectives:To ascertain the optimum strategy of monitoring blood tests for patients established on immune-suppressing drugs. The objectives were to: investigate the association between different strategies of monitoring and detection of pre-specified haematological, hepatic or renal side effects identify prognostic factors associated with pre-specified haematological, hepatic or renal side effects develop prediction models for pre-specified haematological, hepatic or renal side effects evaluate cost-effectiveness of testing strategies, and explore patients' and clinicians' experiences of current testing strategies, and acceptability of recommended strategies. Design:The study undertook systematic review, prognostic modelling, health economic modelling of alternate monitoring intervals, and qualitative study. Setting:Primary and secondary care. Participants:Data from the UK's Clinical Practice Research Datalink and British Association of Dermatologists Biologics Register were used for prediction modelling. Patients with inflammatory conditions treated with immune-suppressing drugs and health professionals were interviewed. Results:There were differences in testing strategies used, outcome definitions and follow-up precluding evidence synthesis. However, clinically significant pre-specified side effects were found to be uncommon or very uncommon during long-term treatment. There was high-quality evidence for elevated liver enzymes and folate non-supplementation being prognostic for methotrexate hepatotoxicity, mercaptopurine being prognostic for thiopurine hepatotoxicity and myelotoxicity; poor thiopurine metabolizer being prognostic for cytopenia; and elevated liver enzymes being prognostic for hepatotoxicity due to anti-tumour necrosis factor-alpha. Five prediction models were developed and validated. They had excellent performance characteristics. The calibration slope (95% confidence interval) in validation cohort was 0.94 (0.85 to 1.02) for methotrexate, 1.10 (0.84 to 1.36) for thiopurines, 0.91 (0.74 to 1.07) for leflunomide, 1.19 (0.96 to 1.43) for sulfasalazine, and 0.90 (0.61 to 1.19) for 5-aminosalicylates. Prediction modelling could not be undertaken for anti-tumour necrosis factor-alpha and mycophenolate due to few outcomes. Health economic modelling found it was cost-effective to increase the interval between monitoring blood tests except in very high-risk scenarios for some drugs (e.g. biennial testing in leflunomide). Eighteen patients from a range of risk profiles, and 13 health professionals were interviewed remotely. They found it acceptable to increase the interval between monitoring blood tests from 3-monthly to 6-monthly or annually depending on their risk profiles. Limitations:It was not possible to synthesise the association between different strategies of testing and detection of pre-specified side effects. A meta-analysis of prognostic factors was not possible. Conclusions:Clinically significant myelotoxicity, hepatotoxicity and nephrotoxicity are uncommon during long-term immune-suppressing drug treatment and were predicted using readily available information. Extending the intervals between monitoring blood tests was more cost-effective than the current practice. It was acceptable to patients and health professionals to increase the interval between monitoring blood tests. Future work:Test clinical effectiveness, undertake knowledge mobilisation, validate in non-UK populations. Research on other biologics. Study registration:The study is registered as PROSPERO CRD42020208042, CRD42020208042 and the interview studies were registered on ClinicalTrials.gov NCT05458531. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR130580) and is published in full in Health Technology Assessment; Vol. 30, No. 64. See the NIHR Funding and Awards website for further award information.
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.
