Usual care and a self-management support programme versus usual care and a relaxation programme for people living with chronic headache disorders: a randomised controlled trial protocol (CHESS).

INTRODUCTION: Chronic headaches are poorly diagnosed and managed and can be exacerbated by medication overuse. There is insufficient evidence on the non-pharmacological approaches to helping people living with chronic headaches. METHODS AND ANALYSIS: Chronic Headache Education and Self-management Study is a pragmatic randomised controlled trial to test the effectiveness and cost-effectiveness of a self-management education support programme on top of usual care for patients with chronic headaches against a control of usual care and relaxation. The intervention is a 2-day group course based on education, personal reflection and a cognitive behavioural approach, plus a nurse-led one-to-one consultation and follow-up over 8 weeks. We aim to recruit 689 participants (356 to the intervention arm and 333 to the control) from primary care and self-referral in London and the Midlands. The trial is powered to show a difference of 2.0 points on the Headache Impact Test, a patient-reported outcome measure at 12 months post randomisation. Secondary outcomes include health related quality of life, self-efficacy, social activation and engagement, anxiety and depression and healthcare utilisation. Outcomes are being measured at 4, 8 and 12 months. Cost-effectiveness will be expressed in terms of incremental cost per quality-adjusted life year gained. ETHICS AND DISSEMINATION: This trial will provide data on effectiveness and cost-effectiveness of a self-management support programme for chronic headaches. The results will inform commissioning of services and clinical practice. North West - Greater Manchester East Research Ethics Committee have approved the trial. The current protocol version is 3.6 date 7 March 2019. TRIAL REGISTRATION NUMBER: ISRCTN79708100.

Treatment of cancer-associated venous thromboembolism: 12-month outcomes of the placebo versus rivaroxaban randomization of the SELECT-D Trial (SELECT-D: 12m).

BACKGROUND: The Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT-D) trial demonstrated reduction in recurrent venous thromboembolism (VTE) but increased bleeding with rivaroxaban compared with dalteparin for treatment of acute VTE in cancer patients, at 6 months. Uncertainty remains around optimal duration of anticoagulation. OBJECTIVES: To assess VTE recurrence and bleeding, with anticoagulation or not, beyond 6 months. PATIENTS/METHODS: In SELECT-D, after 6 months of trial treatment for VTE, patients with active cancer and residual deep vein thrombosis (RDVT) or index pulmonary embolism (PE) were eligible for randomization to a further 6 months of rivaroxaban or placebo. Patients with no RDVT stopped anticoagulation. Primary outcome was VTE recurrence at 12 months. The second randomization closed prematurely because of low recruitment when 92 of the planned 300 patients were recruited. RESULTS: Ninety-two of 136 eligible patients were randomized to rivaroxaban or placebo. The cumulative VTE recurrence after 6 months from the second randomization was 14% with placebo and 4% with rivaroxaban (hazard ratio, 0.32; 95% confidence interval [CI], 0.06-1.58). The major and clinically relevant non-major bleeding rates were 0% and 0% with placebo; and 5% (95% CI, 1-18) and 4% (95% CI, 1-17) with rivaroxaban. In an exploratory analysis, 7 (15%) of 46 placebo patients with RDVT or an index PE experienced recurrent VTE compared to none in the 35 patients in the RDVT-negative cohort (P = .03). CONCLUSION: The SELECT-D trial was underpowered to detect a statistically significant reduction in recurrent VTE with extended anticoagulation. The absence of RDVT and/or index PE, defined a population at low risk of recurrence.

Protocolised non-invasive compared with invasive weaning from mechanical ventilation for adults in intensive care: the Breathe RCT.

BACKGROUND: Invasive mechanical ventilation (IMV) is a life-saving intervention. Following resolution of the condition that necessitated IMV, a spontaneous breathing trial (SBT) is used to determine patient readiness for IMV discontinuation. In patients who fail one or more SBTs, there is uncertainty as to the optimum management strategy. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of using non-invasive ventilation (NIV) as an intermediate step in the protocolised weaning of patients from IMV. DESIGN: Pragmatic, open-label, parallel-group randomised controlled trial, with cost-effectiveness analysis. SETTING: A total of 51 critical care units across the UK. PARTICIPANTS: Adult intensive care patients who had received IMV for at least 48 hours, who were categorised as ready to wean from ventilation, and who failed a SBT. INTERVENTIONS: Control group (invasive weaning): patients continued to receive IMV with daily SBTs. A weaning protocol was used to wean pressure support based on the patient's condition. Intervention group (non-invasive weaning): patients were extubated to NIV. A weaning protocol was used to wean inspiratory positive airway pressure, based on the patient's condition. MAIN OUTCOME MEASURES: The primary outcome measure was time to liberation from ventilation. Secondary outcome measures included mortality, duration of IMV, proportion of patients receiving antibiotics for a presumed respiratory infection and health-related quality of life. RESULTS: A total of 364 patients (invasive weaning, n = 182; non-invasive weaning, n = 182) were randomised. Groups were well matched at baseline. There was no difference between the invasive weaning and non-invasive weaning groups in median time to liberation from ventilation {invasive weaning 108 hours [interquartile range (IQR) 57-351 hours] vs. non-invasive weaning 104.3 hours [IQR 34.5-297 hours]; hazard ratio 1.1, 95% confidence interval [CI] 0.89 to 1.39; p = 0.352}. There was also no difference in mortality between groups at any time point. Patients in the non-invasive weaning group had fewer IMV days [invasive weaning 4 days (IQR 2-11 days) vs. non-invasive weaning 1 day (IQR 0-7 days); adjusted mean difference -3.1 days, 95% CI -5.75 to -0.51 days]. In addition, fewer non-invasive weaning patients required antibiotics for a respiratory infection [odds ratio (OR) 0.60, 95% CI 0.41 to 1.00; p = 0.048]. A higher proportion of non-invasive weaning patients required reintubation than those in the invasive weaning group (OR 2.00, 95% CI 1.27 to 3.24). The within-trial economic evaluation showed that NIV was associated with a lower net cost and a higher net effect, and was dominant in health economic terms. The probability that NIV was cost-effective was estimated at 0.58 at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year. CONCLUSIONS: A protocolised non-invasive weaning strategy did not reduce time to liberation from ventilation. However, patients who underwent non-invasive weaning had fewer days requiring IMV and required fewer antibiotics for respiratory infections. FUTURE WORK: In patients who fail a SBT, which factors predict an adverse outcome (reintubation, tracheostomy, death) if extubated and weaned using NIV? TRIAL REGISTRATION: Current Controlled Trials ISRCTN15635197. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 48. See the NIHR Journals Library website for further project information.

Patients who become very unwell may require help from a breathing machine. This requires the patient to be given drugs to put them to sleep (sedation) and have a tube placed through their mouth directly into the windpipe (tube ventilation). This can be life-saving, but may cause harm if used for long periods of time. Non-invasive ventilation (mask ventilation) provides breathing support through a mask that covers the face. Mask ventilation has several advantages over tube ventilation, such as less need for sedation, and it enables the patient to cough and communicate. In previous studies, switching patients from tube to mask ventilation when they start to get better seemed to improve survival rates and reduce complications. The Breathe trial tested if using a protocol to remove tube ventilation and replace it with mask ventilation is better than continuing with tube ventilation until the patient no longer needs breathing machine support. The trial recruited 364 patients. Half of these patients were randomly selected to have the tube removed and replaced with mask ventilation and half were randomly selected to continue with tube ventilation until they no longer needed breathing machine support. The mask group spent 3 fewer days receiving tube ventilation, although the overall time needing breathing machine help (mask and tube) did not change. Fewer patients in the mask group needed antibiotics for chest infections. After removing the tube, twice as many patients needed the tube again in the mask group as in the tube group. There were no differences between the groups in the number of adverse (harm) events or the number of patients who survived to leave hospital. Mask ventilation was no more expensive than tube ventilation. In conclusion, mask ventilation may be an effective alternative to continued tube ventilation when patients start to get better in intensive care.

Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D).

Purpose Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer. Patient and Methods In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ± 4.5%, assuming a VTE recurrence rate at 6 months of 10%. Results A total of 203 patients were randomly assigned to each group, 58% of whom had metastases. Twenty-six patients experienced recurrent VTE (dalteparin, n = 18; rivaroxaban, n = 8). The 6-month cumulative VTE recurrence rate was 11% (95% CI, 7% to 16%) with dalteparin and 4% (95% CI, 2% to 9%) with rivaroxaban (hazard ratio [HR], 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate of major bleeding was 4% (95% CI, 2% to 8%) for dalteparin and 6% (95% CI, 3% to 11%) for rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). Corresponding rates of CRNMB were 4% (95% CI, 2% to 9%) and 13% (95% CI, 9% to 19%), respectively (HR, 3.76; 95% CI, 1.63 to 8.69). Conclusion Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin.

Economic evaluation of nebulized magnesium sulphate in acute severe asthma in children.

OBJECTIVES: The aim of this study was to estimate the cost-effectiveness of nebulized magnesium sulphate (MgSO4) in acute asthma in children from the perspective of the UK National Health Service and personal social services. METHODS: An economic evaluation was conducted based on evidence from a randomized placebo controlled multi-center trial of nebulized MgSO4 in severe acute asthma in children. Participants comprised 508 children aged 2-16 years presenting to an emergency department or a children's assessment unit with severe acute asthma across thirty hospitals in the United Kingdom. Children were randomly allocated to receive nebulized salbutamol and ipratropium bromide mixed with either 2.5 ml of isotonic MgSO4 or 2.5 ml of isotonic saline on three occasions at 20-min intervals. Cost-effectiveness outcomes were constructed around the Yung Asthma Severity Score (ASS) after 60 min of treatment; whilst cost-utility outcomes were constructed around the quality-adjusted life-year (QALY) metric. The nonparametric bootstrap method was used to present cost-effectiveness acceptability curves at alternative cost-effectiveness thresholds for either: (i) a unit reduction in ASS; or (ii) an additional QALY. RESULTS: MgSO4 had a 75.1 percent probability of being cost-effective at a GBP 1,000 (EUR 1,148) per unit decrement in ASS threshold, an 88.0 percent probability of being more effective (in terms of reducing the ASS) and a 36.6 percent probability of being less costly. MgSO4 also had a 67.6 percent probability of being cost-effective at a GBP 20,000 (EUR 22,957) per QALY gained threshold, an 8.5 percent probability of being more effective (in terms of generating increased QALYs) and a 69.1 percent probability of being less costly. Sensitivity analyses showed that the results of the economic evaluation were particularly sensitive to the methods used for QALY estimation. CONCLUSIONS: The probability of cost-effectiveness of nebulized isotonic MgSO4, given as an adjuvant to standard treatment of severe acute asthma in children, is less than 70 percent across accepted cost-effectiveness thresholds for an additional QALY.

Methodological and applied concerns surrounding age-related weighting within health economic evaluation.

Economic evaluations that measure the benefits of health interventions in terms of units of health gain inevitably require decision-makers to make judgments about the 'value for money' of those health gains. Decision-making bodies have also commonly returned to the position that a unit of health gain, such as an additional quality-adjusted life year, is of equal value regardless of the characteristics of the recipient. This paper focuses on whether and how health gains in economic evaluation should be differentially weighted by age of recipient. The paper presents a structured overview of evidence from the revealed preference and stated preference literature in this area. It discusses a number of methodological issues raised by differential weighting of health gains by age of recipient. These include identifying appropriate samples for the derivation of age-related weights, methodological issues surrounding the application of the quality-adjusted life year measure, the relative merits of alternative valuation techniques for weighting exercises, the impact of context and design effects on derived values and operational concerns surrounding the application of age-related weights within economic evaluation. The paper ends with pointers for potential future research in this area.

Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial.

BACKGROUND: Little evidence is available for the effect of nebulised magnesium sulphate (MgSO(4)) in acute asthma in children. We assessed the effect of MgSO(4) treatment in children with severe acute asthma. METHODS: In this randomised placebo-controlled, multi-centre, parallel trial, we enrolled children (aged 2-16 years) with severe acute asthma who did not respond to standard inhaled treatment from 30 hospitals in the UK. Children were randomly allocated (1:1) to receive nebulised salbutamol and ipratropium bromide with either 2·5 mL of isotonic MgSO(4) (250 mmol/L; 151 mg per dose; MgSO(4) group) or 2·5 mL of isotonic saline (placebo group) on three occasions at 20-min intervals. Randomisation was done with a computer-generated randomisation sequence, with random block sizes of two to four. Both patients and researchers were masked to treatment allocation. The primary outcome measure was the Yung Asthma Severity Score (ASS) at 60 min post-randomisation. We used a statistical significance level of p<0·05 for a between-group difference, but regarded a between-group difference in ASS of 0·5 as the minimal clinically significant treatment effect. Analysis was done by intention to treat. This trial is registered with controlled-trials.com, number ISRCTN81456894. FINDINGS: Between Jan 3, 2009, and March 20, 2011, we recruited and randomly assigned 508 children to treatment: 252 to MgSO(4) and 256 to placebo. Mean ASS at 60 min was lower in the MgSO(4) group (4·72 [SD 1·37]) than it was in the placebo group (4·95 [SD 1·40]; adjusted difference -0·25, 95% CI -0·48 to -0·02; p=0·03). This difference, however, was not clinically significant. The clinical effect was larger in children with more severe asthma exacerbation (p=0·03) and those with symptoms present for less than 6 h (p=0·049). We detected no difference in the occurrence of adverse events between groups. INTERPRETATION: Overall, nebulised isotonic MgSO(4), given as an adjuvant to standard treatment, did not show a clinically significant improvement in mean ASS in children with acute severe asthma. However, the greatest clinical response was seen in children with more severe attacks (SaO(2)<92%) at presentation and those with preceding symptoms lasting less than 6 h. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Perinatal and maternal outcomes by planned place of birth for healthy women with low risk pregnancies: the Birthplace in England national prospective cohort study.

OBJECTIVE: To compare perinatal outcomes, maternal outcomes, and interventions in labour by planned place of birth at the start of care in labour for women with low risk pregnancies. DESIGN: Prospective cohort study. SETTING: England: all NHS trusts providing intrapartum care at home, all freestanding midwifery units, all alongside midwifery units (midwife led units on a hospital site with an obstetric unit), and a stratified random sample of obstetric units. PARTICIPANTS: 64,538 eligible women with a singleton, term (≥37 weeks gestation), and "booked" pregnancy who gave birth between April 2008 and April 2010. Planned caesarean sections and caesarean sections before the onset of labour and unplanned home births were excluded. MAIN OUTCOME MEASURE: A composite primary outcome of perinatal mortality and intrapartum related neonatal morbidities (stillbirth after start of care in labour, early neonatal death, neonatal encephalopathy, meconium aspiration syndrome, brachial plexus injury, fractured humerus, or fractured clavicle) was used to compare outcomes by planned place of birth at the start of care in labour (at home, freestanding midwifery units, alongside midwifery units, and obstetric units). RESULTS: There were 250 primary outcome events and an overall weighted incidence of 4.3 per 1000 births (95% CI 3.3 to 5.5). Overall, there were no significant differences in the adjusted odds of the primary outcome for any of the non-obstetric unit settings compared with obstetric units. For nulliparous women, the odds of the primary outcome were higher for planned home births (adjusted odds ratio 1.75, 95% CI 1.07 to 2.86) but not for either midwifery unit setting. For multiparous women, there were no significant differences in the incidence of the primary outcome by planned place of birth. Interventions during labour were substantially lower in all non-obstetric unit settings. Transfers from non-obstetric unit settings were more frequent for nulliparous women (36% to 45%) than for multiparous women (9% to 13%). CONCLUSIONS: The results support a policy of offering healthy women with low risk pregnancies a choice of birth setting. Women planning birth in a midwifery unit and multiparous women planning birth at home experience fewer interventions than those planning birth in an obstetric unit with no impact on perinatal outcomes. For nulliparous women, planned home births also have fewer interventions but have poorer perinatal outcomes.

Cost-utility analysis of topical intranasal steroids for otitis media with effusion based on evidence from the GNOME trial.

OBJECTIVES: To estimate the cost-effectiveness of topical intranasal steroids for the treatment of otitis media with effusion (OME) in primary care from the perspective of the UK National Health Service. METHODS: An economic evaluation was conducted based on evidence from the double-blind, randomized, placebo-controlled GPRF [General Practice Research Framework] Nasal Steroids for Otitis Media with Effusion (GNOME) trial. Participants comprised 217 children aged 4-11 years who had at least one episode of otitis media or related ear problem in the previous 12 months and had tympanometrically confirmed bilateral OME. Children were randomly allocated to receive either mometasone furoate 50 microg or placebo spray once daily into each nostril for 3 months. The main outcome measure was the incremental cost per quality-adjusted life-year (QALY) gained for topical steroids compared with placebo. The nonparametric bootstrap method was used to present cost-effectiveness acceptability curves at alternative willingness to pay thresholds. RESULTS: Children receiving topical steroids accrued nonsignificantly higher costs (incremental cost/child: pound11, 95% confidence interval [CI]: - pound199 to pound222) and nonsignificantly fewer QALYs (incremental QALY gain/child: -0.0166, 95% CI: -0.0652 to 0.0320) than those receiving placebo. Topical steroids had a 24.19% probability of being cost-effective at a pound20,000 per QALY gained threshold, a 23.82% probability of being more effective and a 46.25% probability of being less costly. Sensitivity and subgroup analyses showed incremental costs and benefits to be highly sensitive to the methods used and the patient group considered, although differences between groups did not reach statistical significance in any analysis. CONCLUSIONS: Topical steroids are unlikely to be a cost-effective treatment for OME in general practice.

Home-based care after a shortened hospital stay versus hospital-based care postpartum: an economic evaluation.

OBJECTIVES: To compare the cost effectiveness of early postnatal discharge and home midwifery support with a traditional postnatal hospital stay. DESIGN: Cost minimisation analysis within a pragmatic randomised controlled trial. SETTING: The University Hospital of Geneva and its catchment area. POPULATION: Four hundred and fifty-nine deliveries of a single infant at term following an uncomplicated pregnancy. METHODS: Prospective economic evaluation alongside a randomised controlled trial in which women were allocated to either early postnatal discharge combined with home midwifery support (n= 228) or a traditional postnatal hospital stay (n= 231). MAIN OUTCOME MEASURES: Costs (Swiss francs, 2000 prices) to the health service, social services, patients, carers and society accrued between delivery and 28 days postpartum. RESULTS: Clinical and psychosocial outcomes were similar in the two trial arms. Early postnatal discharge combined with home midwifery support resulted in a significant reduction in postnatal hospital care costs (bootstrap mean difference 1524 francs, 95% confidence interval [CI] 675 to 2403) and a significant increase in community care costs (bootstrap mean difference 295 francs, 95% CI 245 to 343). There were no significant differences in average hospital readmission, hospital outpatient care, direct non-medical and indirect costs between the two trial groups. Overall, early postnatal discharge combined with home midwifery support resulted in a significant cost saving of 1221 francs per mother-infant dyad (bootstrap mean difference 1209 francs, 95% CI 202 to 2155). This finding remained relatively robust following variations in the values of key economic parameters performed as part of a comprehensive sensitivity analysis. CONCLUSIONS: A policy of early postnatal discharge combined with home midwifery support exhibits weak economic dominance over traditional postnatal care, that is, it significantly reduces costs without compromising the health and wellbeing of the mother and infant.

The economic costs of alternative modes of delivery during the first two months postpartum: results from a Scottish observational study.

A study was conducted to estimate the economic costs of alternative modes of delivery during the first two months postpartum. Hospital and community health service utilisation data for 1242 women were extracted from self-completed questionnaires, medical case notes and computerised hospital discharge records. Unit costs (1999-2000 prices) were collected for each item of resource use and combined with resource volumes to obtain a net cost per woman. There were significant differences in initial hospitalisation costs between the three mode of delivery groups (spontaneous vaginal delivery pounds sterling 1431, instrumental vaginal delivery pounds sterling 1970, caesarean section pounds sterling 2924, P < 0.001). There were also significant differences in the cost of hospital readmissions, community midwifery care and general practitioner care between the three mode of delivery groups. However, total post-discharge health care costs did not vary significantly by mode of delivery. Total health care costs were estimated at pounds sterling 1698 for a spontaneous vaginal delivery, pounds sterling 2262 for an instrumental vaginal delivery and pounds sterling 3200 for a caesarean section (P < 0.001). It is imperative that hospital and community health service providers recognise the economic impact of alternative modes of delivery in their service planning.