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In 2010/2011, regional commissioners withdrew payment for the fixed-dose combination Combivir, forcing a switch to component drugs. This was deemed clinically acceptable and annual savings of £44 k expected. We estimated the true costs of switching and examined patient outcomes. Information for 46 patients using Combivir was extracted from case notes for each clinical contact in the 12 months pre- and post-switch (clinician seen, tests, antiretrovirals). Post-switch care costs £93/patient more annually versus pre-switch (95% CI £424 to £609), yielding £4278/year more post-switch for all patients. Drug and pathology costs were more expensive post-switch and extra clinical visits required. None of these results were statistically significant. Forty-two per cent of patients switched directly or in the subsequent year to an alternative fixed-dose combination rather than generics. Costs in this group were significantly higher post-switch driven by drug cost. Six patients (13%) reported problems with the switch including confusion around dosing and new side effects. As less-expensive generic antiretroviral drugs become available, it may appear cheaper to switch from fixed-dose combinations to component drugs. However, the additional clinical costs involved may outweigh the initial cost savings of the drugs and switching may cause confusion for some patients, risking loss of adherence. [ABSTRACT FROM AUTHOR]

Background: High flow nasal cannula therapy (HFNC) and continuous positive airway pressure (CPAP) are two widely used modes of non-invasive respiratory support in paediatric critical care units. The FIRST-ABC randomised controlled trials (RCTs) evaluated the clinical and cost-effectiveness of HFNC compared with CPAP in two distinct critical care populations: acutely ill children ('step-up' RCT) and extubated children ('step-down' RCT). Clinical effectiveness findings (time to liberation from all forms of respiratory support) showed that HFNC was non-inferior to CPAP in the step-up RCT, but failed to meet non-inferiority criteria in the step-down RCT. This study evaluates the cost-effectiveness of HFNC versus CPAP., Methods: All-cause mortality, health-related Quality of Life (HrQoL), and costs up to six months were reported using FIRST-ABC RCTs data. HrQoL was measured with the age-appropriate Paediatric Quality of Life Generic Core Scales questionnaire and mapped onto the Child Health Utility 9D index score at six months. Quality-Adjusted Life Years (QALYs) were estimated by combining HrQoL with mortality. Costs at six months were calculated by measuring and valuing healthcare resources used in paediatric critical care units, general medical wards and wider health service. The cost-effectiveness analysis used regression methods to report the cost-effectiveness of HFNC versus CPAP at six months and summarised the uncertainties around the incremental cost-effectiveness results., Results: In both RCTs, the incremental QALYs at six months were similar between the randomised groups. The estimated incremental cost at six months was - £4565 (95% CI - £11,499 to £2368) and - £5702 (95% CI - £11,328 to - £75) for step-down and step-up RCT, respectively. The incremental net benefits of HFNC versus CPAP in step-down RCT and step-up RCT were £4388 (95% CI - £2551 to £11,327) and £5628 (95% CI - £8 to £11,264) respectively. The cost-effectiveness results were surrounded by considerable uncertainties. The results were similar across most pre-specified subgroups, and the base case results were robust to alternative assumptions., Conclusions: HFNC compared to CPAP as non-invasive respiratory support for critically-ill children in paediatric critical care units reduces mean costs and is relatively cost-effective overall and for key subgroups, although there is considerable statistical uncertainty surrounding this result., Competing Interests: Declarations. Ethical approval and consent to participate: The FIRST-ABC master protocol was approved by the East of England–Cambridge South Research Ethics Committee (19/EE/0185) and the UK Health Research Authority (IRAS 260536). The trial was registered with the International Standard Randomised Controlled Trial Number (ISRCTN) Registry (ISRCTN60048867). Written informed consent was obtained from parents/legal guardians of each trial participant. Consent for publication: Not applicable. Competing interests: The authors report funding from the National Institute for Health and Social Care Research (NIHR) Health Technology Assessment Programme to their institutions for the work presented in the manuscript. KR is Director of the NIHR Health and Social Care Delivery Research Programme., (© 2024. The Author(s).)

Objectives: To investigate heterogeneity in the cost-effectiveness of high-flow nasal cannula (HFNC) therapy compared with continuous positive airway pressure (CPAP) for acutely ill children requiring noninvasive respiratory support., Methods: Using data from the First-line Support for Assistance in Breathing in Children trial, we explore heterogeneity at the patient and subgroup levels using 2 causal forest approaches and a seemingly unrelated regression approach for comparison. First-line Support for Assistance in Breathing in Children is a noninferiority randomized controlled trial (ISRCTN60048867) involving 24 UK pediatric intensive care units. The Step-up trial focuses on acutely ill children aged 0 to 15 years, requiring noninvasive respiratory support. A total of 600 children were randomly assigned to HFNC and CPAP groups in a 1:1 allocation ratio, with 94 patients excluded because of data unavailability., Results: The primary outcome is the incremental net monetary benefit (INB) of HFNC compared with CPAP, using a willingness-to-pay threshold of £20 000 per quality-adjusted life year gain. INB is derived from total costs and quality-adjusted life years at 6 months. Subgroup analysis showed that some subgroups, such as male children, those aged less than 12 months, and those without severe respiratory distress at randomization, had more favorable INB results. Patient-level analysis revealed heterogeneity in INB estimates, particularly driven by the cost component, with greater uncertainty for those with higher INBs., Conclusions: The estimated overall INB of HFNC is significantly larger for specific patient subgroups, suggesting that the cost-effectiveness of HFNC can be heterogeneous, which highlights the importance of considering patient characteristics in evaluating the cost-effectiveness of HFNC., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Objective: The aim of this study was to explore heterogeneity in the cost-effectiveness of high-flow nasal cannula (HFNC) therapy compared with continuous positive airway pressure (CPAP) in children following extubation., Design: Using data from the FIRST-line support for Assistance in Breathing in Children (FIRST-ABC) trial, we explore heterogeneity at the individual and subgroup levels using a causal forest approach, alongside a seemingly unrelated regression (SUR) approach for comparison., Settings: FIRST-ABC is a noninferiority randomized controlled trial (ISRCTN60048867) including children in UK paediatric intensive care units, which compared HFNC with CPAP as the first-line mode of noninvasive respiratory support., Patients: In the step-down FIRST-ABC, 600 children clinically assessed to require noninvasive respiratory support were randomly assigned to HFNC and CPAP groups with 1:1 treatment allocation ratio. In this analysis, 118 patients were excluded because they did not consent to accessing their medical records, did not consent to follow-up questionnaire or did not receive respiratory support., Measurements and Main Results: The primary outcome of this study is the incremental net monetary benefit (INB) of HFNC compared with CPAP using a willingness-to-pay threshold of £20,000 per QALY gain. INB is calculated based on total costs and quality adjusted life years (QALYs) at 6 months. The findings suggest modest heterogeneity in cost-effectiveness of HFNC compared with CPAP at the subgroup level, while greater heterogeneity is detected at the individual level., Conclusions: The estimated overall INB of HFNC is smaller than the INB for patients with better baseline status suggesting that HFNC can be more cost-effective among less severely ill patients., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Management of hypotension is a fundamental part of pediatric critical care, with cardiovascular support in the form of fluids or vasoactive drugs offered to every hypotensive child. However, optimal blood pressure (BP) targets are unknown. The PRotocolised Evaluation of PermiSSive BP Targets Versus Usual CaRE (PRESSURE) trial aims to evaluate the clinical and cost-effectiveness of a permissive mean arterial pressure (MAP) target of greater than a fifth centile for age compared with usual care., Design: Pragmatic, open, multicenter, parallel-group randomized control trial (RCT) with integrated economic evaluation., Setting: Eighteen PICUs across the United Kingdom., Patients: Infants and children older than 37 weeks corrected gestational age to 16 years accepted to a participating PICU, on mechanical ventilation and receiving vasoactive drugs for hypotension., Interventions: Adjustment of hemodynamic support to achieve a permissive MAP target greater than fifth centile for age during invasive mechanical ventilation., Measurements and Main Results: Randomization is 1:1 to a permissive MAP target or usual care, stratified by site and age group. Due to the emergency nature of the treatment, approaching patients for written informed consent will be deferred until after randomization. The primary clinical outcome is a composite of death and days of ventilatory support at 30 days. Baseline demographics and clinical status will be recorded as well as daily measures of BP and organ support, and discharge outcomes. This RCT received Health Research Authority approval (reference 289545), and a favorable ethical opinion from the East of England-Cambridge South Research Ethics Committee on May 10, 2021 (reference number 21/EE/0084). The trial is registered and has an International Standard RCT Number (reference 20609635)., Conclusions: Trial findings will be disseminated in U.K. national and international conferences and in peer-reviewed journals., Competing Interests: Drs. Harrison, Ramnarayan, and Inwald’s institutions received funding from the National Institute for Health and Care Research (NIHR). Drs. Peters and Mouncey’s institutes received funding from the U.K. National Institute of Health Research (U.K. NIHR) Health Technology Assessment Agency (HTA). Dr. Peters received support for article research from the U.K. NIHR HTA. Dr. Ray’s and Prof. Peters' institute received funding from the National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre; they both received funding from the Engineering and Physical Sciences Research Council. Dr. Ray has received funding from La Roche Ltd for consultancy work. Drs. Sadique and Inwald received support for article research from the NIHR. Dr. Rowan’s institution received funding from the U.K. NIHR; she received support for article research from the U.K. NIHR. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: In the United Kingdom, around 184,000 adults are admitted to an intensive care unit (ICU) each year with over 30% receiving mechanical ventilation. Oxygen is the commonest therapeutic intervention provided to these patients but it is unclear how much oxygen should be administered for the best clinical outcomes., Methods: The UK-ROX trial will evaluate the clinical and cost-effectiveness of conservative oxygen therapy (the minimum oxygen concentration required to maintain an oxygen saturation of 90% ± 2%) versus usual oxygen therapy in critically ill adults receiving supplemental oxygen when invasively mechanically ventilated in ICUs in England, Wales and Northern Ireland. The trial will recruit 16,500 patients from approximately 100 UK adult ICUs. Using a deferred consent model, enrolled participants will be randomly allocated (1:1) to conservative or usual oxygen therapy until ICU discharge or 90 days after randomisation., Objectives: The primary clinical outcome is all cause mortality at 90 days following randomisation., Discussion: The UK-ROX trial has received ethical approval from the South Central - Oxford C Research Ethics Committee (Reference: 20/SC/0423) and the Confidentiality Advisory Group (Reference: 22/CAG/0154). The trial commenced in May 2021 and, at the time of publication, 95 sites had opened to recruitment., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Intensive Care Society 2024.)

Background: Risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) are the most effective breast and ovarian cancer preventive interventions. EQ-5D is the recommended tool to assess the quality of life and determine health-related utility scores (HRUSs), yet there are no published EQ-5D HRUSs after these procedures. These are essential for clinicians counselling patients and for health-economic evaluations., Methods: We used aggregate data from our published systematic review and converted SF-36/SF-12 summary scores to EQ-5D HRUSs using a published mapping algorithm. Study control arm or age-matched country-specific reference values provided comparison. Random-effects meta-analysis provided adjusted disutilities and utility scores. Subgroup analyses included long-term vs. short-term follow-up., Results: Four studies (209 patients) reported RRM outcomes using SF-36, and five studies (742 patients) reported RRSO outcomes using SF-12/SF-36. RRM is associated with a long-term (>2 years) disutility of -0.08 (95% CI -0.11, -0.04) (I 2 31.4%) and a utility of 0.92 (95% CI 0.88, 0.95) (I 2 31.4%). RRSO is associated with a long-term (>1 year) disutility of -0.03 (95% CI -0.05, 0.00) (I 2 17.2%) and a utility of 0.97 (95% CI 0.94, 0.99) (I 2 34.0%)., Conclusions: We present the first HRUSs sourced from patients following RRM and RRSO. There is a need for high-quality prospective studies to characterise quality of life at different timepoints.

Background: The optimal target for systemic oxygenation in critically ill children is unknown. Liberal oxygenation is widely practiced, but has been associated with harm in paediatric patients. We aimed to evaluate whether conservative oxygenation would reduce duration of organ support or incidence of death compared to standard care., Methods: Oxy-PICU was a pragmatic, multicentre, open-label, randomised controlled trial in 15 UK paediatric intensive care units (PICUs). Children admitted as an emergency, who were older than 38 weeks corrected gestational age and younger than 16 years receiving invasive ventilation and supplemental oxygen were randomly allocated in a 1:1 ratio via a concealed, central, web-based randomisation system to conservative peripheral oxygen saturations ([SpO 2 ] 88-92%) or liberal (SpO 2 >94%) targets. The primary outcome was the duration of organ support at 30 days following random allocation, a rank-based endpoint with death either on or before day 30 as the worst outcome (a score equating to 31 days of organ support), with survivors assigned a score between 1 and 30 depending on the number of calendar days of organ support received. The primary effect estimate was the probabilistic index, a value greater than 0·5 indicating more than 50% probability that conservative oxygenation is superior to liberal oxygenation for a randomly selected patient. All participants in whom consent was available were included in the intention-to-treat analysis. The completed study was registered with the ISRCTN registry (ISRCTN92103439)., Findings: Between Sept 1, 2020, and May 15, 2022, 2040 children were randomly allocated to conservative or liberal oxygenation groups. Consent was available for 1872 (92%) of 2040 children. The conservative oxygenation group comprised 939 children (528 [57%] of 927 were female and 399 [43%] of 927 were male) and the liberal oxygenation group included 933 children (511 [56%] of 920 were female and 409 [45%] of 920 were male). Duration of organ support or death in the first 30 days was significantly lower in the conservative oxygenation group (probabilistic index 0·53, 95% CI 0·50-0·55; p=0·04 Wilcoxon rank-sum test, adjusted odds ratio 0·84 [95% CI 0·72-0·99]). Prespecified adverse events were reported in 24 (3%) of 939 patients in the conservative oxygenation group and 36 (4%) of 933 patients in the liberal oxygenation group., Interpretation: Among invasively ventilated children who were admitted as an emergency to a PICU receiving supplemental oxygen, a conservative oxygenation target resulted in a small, but significant, greater probability of a better outcome in terms of duration of organ support at 30 days or death when compared with a liberal oxygenation target. Widespread adoption of a conservative oxygenation saturation target (SpO 2 88-92%) could help improve outcomes and reduce costs for the sickest children admitted to PICUs., Funding: UK National Institute for Health and Care Research Health Technology Assessment Programme., Competing Interests: Declaration of interests All authors report funding from the National Institute for Health and Social Care Research (NIHR) Health Technology Assessment Programme to their institutions for the work presented in the manuscript. SR reports funding to their institution from UK Engineering and Physical Science Research Council, and consulting fees, honoraria, and travel fees from Roche and the Malaysian Society of Intensive Care during the study period. KMR is Director of the NIHR Health and Social Care Delivery Research Programme. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Understanding the health care activity and associated hospital costs of caring for people living with HIV is an important component of assessing the cost effectiveness of new technologies and for budget planning., Methods: Data collected between 2010 and 2017 from an English HIV treatment centre were combined with national reference costs to estimate the rate of hospital attendances and costs per quarter year, according to demographic and clinical factors. The final dataset included records for 1763 people living with HIV, which was analysed using negative binomial regression models and general estimating equations., Results: People living with HIV experienced an unadjusted average of 0.028 (standard deviation [SD] 0.20) inpatient episodes per quarter, equivalent to one every 9 years, and 1.85 (SD 2.30) outpatient visits per quarter. The unadjusted mean quarterly cost per person with HIV (excluding antiretroviral drug costs) was £439 (SD 604). Outpatient appointments and inpatient episodes accounted for 88% and 6% of total costs, respectively. In adjusted models, low CD4 count was the strongest predictor of inpatient stays and outpatient visits. Low CD4 count and new patient status (having a first visit at the Trust in the last 6 months) were the factors that most increased estimated costs. Associations were weaker or less consistent for demographic factors (age, sex/sexual orientation/ethnicity). Sensitivity analyses suggest that the findings were generally robust to alternative parameter and modelling assumptions., Conclusion: A number of factors predicted hospital activity and costs, but CD4 cell count and new patient status were the strongest. The study results can be incorporated into future economic evaluations and budget impact assessments of HIV-related technologies., (© 2023 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Importance: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19., Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19., Design, Setting, and Participants: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022)., Interventions: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days., Main Outcomes and Measures: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes., Results: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively)., Conclusions and Relevance: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Purpose: Many intensive care units (ICUs) have transitioned from systemic heparin anticoagulation (SHA) to regional citrate anticoagulation (RCA) for continuous kidney replacement therapy (CKRT). We evaluated the clinical and health economic impacts of ICU transition to RCA., Materials and Methods: We surveyed all adult general ICUs in England and Wales to identify transition dates and conducted a micro-costing study in eight ICUs. We then conducted an interrupted time-series analysis of linked, routinely collected health records., Results: In 69,001 patients who received CKRT (8585 RCA, 60,416 SHA) in 181 ICUs between 2009 and 2017, transition to RCA was not associated with a change in 90-day mortality (adjusted odds ratio 0.98, 95% CI 0.89-1.08) but was associated with step-increases in duration of kidney support (0.53 days, 95% CI 0.28-0.79), advanced cardiovascular support (0.23 days, 95% CI 0.09-0.38) and ICU length of stay (0.86 days, 95% CI 0.24-1.49). The estimated one-year incremental net monetary benefit per patient was £ - 2376 (95% CI £ - 3841-£ - 911), with an estimated likelihood of cost-effectiveness of <0.1%., Conclusions: Transition to RCA was associated with significant increases in healthcare resource use, without corresponding clinical benefit, and is highly unlikely to be cost-effective over a one-year time horizon., Competing Interests: Declaration of Competing Interest MO has received speaker honoraria and research funding from Fresenius Medical, speaker honoraria and research funding from Baxter, and is a member of an advisory board of Fresenius – NxStage. LF has received research funding from Baxter and lecture fees from Baxter and Fresenius. PW was Chief Medical Officer for Sensyne health and holds shares in the company. He declares grants from Wellcome, the National Institute for Health and Care Research, and Sensyne Health during the study period., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Highlights: This article compares the relative preferences from stated preference (SP) questions requiring ordered categorical versus discrete choice responses. The approaches were contrasted for blood donation service characteristics that offer opportunities to donate blood.The estimates of relative preferences for alternative blood donation service characteristics were similar between the 2 forms of SP approach.This study illustrates how SP survey questions can be formulated to provide responses on an ordered categorical scale and to estimate marginal rates of substitution between different attributes, which can be compared with those derived from discrete choice experiment (DCE) choices.The article highlights the potential value of considering alternative choice framings rather than relying solely on DCEs.