Evaluating the effect of inequalities in oral anti-coagulant prescribing on outcomes in people with atrial fibrillation.

Aims: Whilst anti-coagulation is typically recommended for thromboprophylaxis in atrial fibrillation (AF), it is often never prescribed or prematurely discontinued. The aim of this study was to evaluate the effect of inequalities in anti-coagulant prescribing by assessing stroke/systemic embolism (SSE) and bleeding risk in people with AF who continue anti-coagulation compared with those who stop transiently, permanently, or never start. Methods and results: This retrospective cohort study utilized linked Scottish healthcare data to identify adults diagnosed with AF between January 2010 and April 2016, with a CHA2DS2-VASC score of ≥2. They were sub-categorized based on anti-coagulant exposure: never started, continuous, discontinuous, and cessation. Inverse probability of treatment weighting-adjusted Cox regression and competing risk regression was utilized to compare SSE and bleeding risks between cohorts during 5-year follow-up. Of an overall cohort of 47 427 people, 26 277 (55.41%) were never anti-coagulated, 7934 (16.72%) received continuous anti-coagulation, 9107 (19.2%) temporarily discontinued, and 4109 (8.66%) permanently discontinued. Lower socio-economic status, elevated frailty score, and age ≥ 75 were associated with a reduced likelihood of initiation and continuation of anti-coagulation. Stroke/systemic embolism risk was significantly greater in those with discontinuous anti-coagulation, compared with continuous [subhazard ratio (SHR): 2.65; 2.39-2.94]. In the context of a major bleeding event, there was no significant difference in bleeding risk between the cessation and continuous cohorts (SHR 0.94; 0.42-2.14). Conclusion: Our data suggest significant inequalities in anti-coagulation prescribing, with substantial opportunity to improve initiation and continuation. Decision-making should be patient-centred and must recognize that discontinuation or cessation is associated with considerable thromboembolic risk not offset by mitigated bleeding risk.

Health financing challenges in Southeast Asian countries for universal health coverage: a systematic review.

BACKGROUND: Universal Health Coverage (UHC) has received much attention and many countries are striving to achieve it. The Southeast Asian region, in particular, comprises many developing countries with limited resources, exacerbating challenges around attaining UHC. This paper aims to specifically explore the health financing challenges these countries face in achieving UHC via a systematic review approach and formulate recommendations that will be useful for policymakers. METHODS: The systematic review followed the guidelines as recommended by PRISMA. The narrative synthesis approach was used for data synthesis, followed by identifying common themes. RESULTS: The initial search returned 160 articles, and 32 articles were included after the screening process. The identified challenges in health financing towards achieving UHC in the Southeast Asian region are categorised into six main themes, namely (1) Unsustainability of revenue-raising methods, (2) Fragmented health insurance schemes, (3) Incongruity between insurance benefits and people's needs, (4) Political and legislative indifference, (5) Intractable and rapidly rising healthcare cost, (6) Morally reprehensible behaviours. CONCLUSIONS: The challenges identified are diverse and therefore require a multifaceted approach. Regional collaborative efforts between countries will play an essential role in the progress towards UHC and in narrowing the inequity gap. At the national level, individual countries must work towards sustainable health financing strategies by leveraging innovative digital technologies and constantly adapting to dynamic health trends. REGISTRATION: This study is registered with PROSPERO, under registration number CRD42022336624.

Stroke resource utilisation and all-cause mortality in Thailand 2017-2020: A retrospective, cross-sectional study.

OBJECTIVE: To determine resource utilisation, costs and all-cause mortality related to stroke in Thailand. DESIGN: Retrospective, cross-sectional study. SETTING AND PARTICIPANTS: Patients with first-ever stroke in the Thai national claims database between 2017 and 2020 were included for analysis. No individuals were involved. METHODS: We estimated annual treatment costs using two-part models. Survival analysis for all-cause mortality was performed. RESULTS: We identified 386 484 patients with incident stroke of which 56% were men. Mean age was 65 years and ischaemic stroke was the most common subtype. Mean annual cost per patient was 37 179 Thai Baht (95% CI: 36 988 to 37 370). Haemorrhagic stroke was predominantly observed in the youngest age groups with the highest estimated mean annual cost. Patients with haemorrhagic stroke also had a longer length of stay (LOS) in hospital and an increased risk of mortality. Key cost drivers were identified to be age, LOS, comorbidity and thrombolysis. Costs were lower in patients who received rehabilitation; however, only 32% of patients received rehabilitation services. The 4-year survival rate of all stroke types was 66.5% (95% CI: 64.3% to 66.7%). Older age, high comorbidity score, long LOS and being treated outside the Bangkok area were factors associated with significantly increased mortality risk, while receiving thrombolysis or rehabilitation was associated with a decreased risk of death. CONCLUSION: The highest mean cost per patient was found in patients with haemorrhagic stroke. Receiving rehabilitation was associated with lower cost and mortality risk. Rehabilitation and disability outcomes should be improved to ensure an enhancement of health outcomes and efficient use of resources.

Understanding Pathways into Care homes using Data (UnPiCD study): a retrospective cohort study using national linked health and social care data.

BACKGROUND: Pathways into care are poorly understood but important life events for individuals and their families. UK policy is to avoid moving-in to care homes from acute hospital settings. This assumes that moves from secondary care represent a system failure. However, those moving to care homes from community and hospital settings may be fundamentally different groups, each requiring differing care approaches. OBJECTIVE: To characterise individuals who move-in to a care home from hospital and compare with those moving-in from the community. DESIGN AND SETTING: A retrospective cohort study using cross-sectoral data linkage of care home data. METHODS: We included adults moving-in to care homes between 1/4/13 and 31/3/16, recorded in the Scottish Care Home Census. Care home data were linked to general and psychiatric hospital admissions, community prescribing and mortality records to ascertain comorbidities, significant diagnoses, hospital resource use, polypharmacy and frailty. Multivariate logistic regression identified predictors of moving-in from hospital compared to from community. RESULTS: We included 23,892 individuals moving-in to a care home, 13,564 (56.8%) from hospital and 10,328 (43.2%) from the community. High frailty risk adjusted Odds Ratio (aOR) 5.11 (95% Confidence Interval (CI): 4.60-5.68), hospital discharge with diagnosis of fracture aOR 3.91 (95%CI: 3.41-4.47) or stroke aOR 8.42 (95%CI: 6.90-10.29) were associated with moving-in from hospital. Discharge from in-patient psychiatry was also a highly significant predictor aOR 19.12 (95%CI: 16.26-22.48). CONCLUSIONS: Individuals moving-in to care homes directly from hospital are clinically distinct from those from the community. Linkage of cross-sectoral data can allow exploration of pathways into care at scale.

Availability of stroke services and hospital facilities at different hospital levels in Thailand: a cross-sectional survey study.

BACKGROUND: Stroke has one of the biggest burden of disease in Thailand and all health regions have been tasked to develop their service delivery to achieve the national key performance indicators set out by the Thai service plan strategy 2018-2022. Our aim was to characterise stroke services and hospital facilities by investigating differences in facilities across different hospital levels in Thailand. METHODS: Self-complete questionnaires were distributed to 119 hospitals in 12 health regions between November-December 2019. Participants were health professionals whose main responsibilities are related to stroke service provision in their hospital. Descriptive statistics were used to report differences of stroke service provision between advanced-level, standard-level and mid-level referral hospitals. RESULTS: Thirty-eight (32% response rate) completed questionnaires were returned. All advanced-level, standard-level (100%) and 55% of mid-level referral hospitals provided stroke units. Neurologists were available in advanced-level (100%) and standard-level referral hospitals (50%). Standard-level and mid-level referral hospitals only had a quarter of rehabilitation physicians compared to advanced-level referral hospital. Home-based rehabilitation was provided at 100% in mid-level but only at 16% and 50% in advanced-level and standard-level referral hospitals. CONCLUSIONS: Setting up a stroke unit, as a national goal that was set out in the service plan strategy 2018-2022, was achieved fully (100%) in advanced-level and standard-level referral hospitals including key essential supportive components. However, capacity in hospitals was found to be limited and stroke service delivery needs to be improved especially at mid-level referral hospitals. This should include regular organisational surveys and the use of electronic records to facilitate monitoring of clinical/health outcomes of patients.

How do multiple long-term conditions impact on the cost-of-illness in early rheumatoid arthritis?

OBJECTIVE: Multiple long-term conditions (MLTCs) are prevalent in rheumatoid arthritis (RA) and associated with worse outcomes and greater economic burden. However, little is known about the impact of MLTCs on the cost-of-illness (COI) in early RA, including direct and indirect costs. The objective of this study was to quantify this impact on COI. METHODS: The Scottish Early Rheumatoid Arthritis study is a national cohort of adults with new-onset RA. Direct costs were estimated applying relevant unit costs to health resource utilisation; indirect costs were measured by productivity loss due to health conditions. Two-part models were used, adjusting for age, gender, baseline functional disability and health-related quality of life. The Charlson Comorbidity Index score was calculated using ICD-10 diagnoses. Individuals were defined as 'RA alone', 'RA plus LTC' and 'RA plus MLTCs' according to the number of coexisting LTCs. RESULTS: Data were available for 818 participants. Average annualised direct costs incurred by people with early RA plus MLTCs (£4444; 95% CI £3100 to £6371) were twice as, and almost five times higher than, those with a single LTC (£2184; 95% CI £1596 to £2997) and those without LTC (£919; 95% CI £694 to £1218), respectively. Indirect costs incurred by RA plus MLTCs (£842; 95% CI £377to £1521) were 3.1 times higher than RA alone (£530; 95% CI £273to £854). The relative proportion of direct costs increased with LTC category, ranging from 77.2% to 84.1%. In addition to increased costs with LTCs, costs also increased with age and were higher for men regardless of LTC category. CONCLUSIONS: MLTCs impact on COI early in the course of RA. The presence of LTCs is associated with significant increases in both direct and indirect costs among people with early RA.

Propensity score methods for comparative-effectiveness analysis: A case study of direct oral anticoagulants in the atrial fibrillation population.

OBJECTIVE: To explore methodological challenges when using real-world evidence (RWE) to estimate comparative-effectiveness in the context of Health Technology Assessment of direct oral anticoagulants (DOACs) in Scotland. METHODS: We used linkage data from the Prescribing Information System (PIS), Scottish Morbidity Records (SMR) and mortality records for newly anticoagulated patients to explore methodological challenges in the use of Propensity score (PS) matching, Inverse Probability Weighting (IPW) and covariate adjustment with PS. Model performance was assessed by standardised difference. Clinical outcomes (stroke and major bleeding) and mortality were compared for all DOACs (including apixaban, dabigatran and rivaroxaban) versus warfarin. Patients were followed for 2 years from first oral anticoagulant prescription to first clinical event or death. Censoring was applied for treatment switching or discontinuation. RESULTS: Overall, a good balance of patients' covariates was obtained with every PS model tested. IPW was found to be the best performing method in assessing covariate balance when applied to subgroups with relatively large sample sizes (combined-DOACs versus warfarin). With the IPTW-IPCW approach, the treatment effect tends to be larger, but still in line with the treatment effect estimated using other PS methods. Covariate adjustment with PS in the outcome model performed well when applied to subgroups with smaller sample sizes (dabigatran versus warfarin), as this method does not require further reduction of sample size, and trimming or truncation of extreme weights. CONCLUSION: The choice of adequate PS methods may vary according to the characteristics of the data. If assumptions of unobserved confounding hold, multiple approaches should be identified and tested. PS based methods can be implemented using routinely collected linked data, thus supporting Health Technology decision-making.

Evaluating stroke early supported discharge using cost-consequence analysis.

PURPOSE: To evaluate different stroke early supported discharge (ESD) services in different geographical settings using cost-consequence analysis (CCA), which presents information about costs and outcomes in the form of a balance sheet. ESD is a multidisciplinary service intervention that facilitates discharge from hospital and includes delivery of stroke specialist rehabilitation at home. MATERIALS AND METHODS: Data were collected from six purposively sampled services across the Midlands, East and North of England. All services, rural and urban, provided stroke rehabilitation to patients in their own homes. Cost data included direct and overhead costs of service provision and staff travel. Consequence data included service level adherence to an expert consensus regarding the specification of ESD service provision. RESULTS: We observed that the most rural services had the highest service cost per patient. The main costs associated with running each ESD service were staff costs. In terms of the consequences, there was a positive association between service costs per patient and greater adherence to meeting the evidence-based ESD service specification agreed by an expert panel. CONCLUSIONS: This study found that rural services were associated with higher costs per patient, which in turn were associated with greater adherence to the expert consensus regarding ESD service specification. We suggest additional resources and costs are required in order for rural services to meet evidence-based criteria.Implications for rehabilitationThe main costs of an early supported discharge (ESD) service for stroke survivors were staff costs and these were positively associated with greater levels of rurality.Greater costs were associated with greater adherence to ESD core components, which has been previously found to enhance the effectiveness of ESD service provision.The cost-consequence analysis provides a descriptive summary for decision-makers about the costs of delivering ESD, suggesting additional resources and costs are required in order for rural services to meet evidence-based criteria.

Healthcare Costs for Metastatic Castration-Resistant Prostate Cancer Patients Treated with Abiraterone or Enzalutamide.

OBJECTIVE: The aim was to assess the real-world healthcare resource use and direct medical costs for metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide, in whom chemotherapy is not yet indicated (pre-chemotherapy) or who had previously received docetaxel-based chemotherapy (post-chemotherapy), before commencing these medicines. METHODS: A retrospective cost analysis of mCRPC patients who commenced abiraterone or enzalutamide between 2012 and 2015 was conducted. Routinely collected datasets from the largest health board in Scotland and the UK, Greater Glasgow and Clyde, were linked. They contained information on patient demographics, diagnosis, outpatient consultations, hospital admissions, treatments (abiraterone and enzalutamide), and supportive medicines. Unit costs were obtained from the Scottish Health Service Costs, Personal Social Services Research Unit, and British National Formulary. Generalised linear model-based regression was used to estimate total mean direct costs, and two-part models were used to estimate separate cost components. All models were adjusted for propensity score and key variables. Sensitivity analysis was conducted to explore the impact of hypothetical patient access scheme discounts. RESULTS: Estimated total mean direct medical costs of treating mCRPC patients were similar, albeit with wide and overlapping confidence intervals. Across both treatments, patients who received abiraterone or enzalutamide in a pre-chemotherapy setting incurred the highest total mean direct medical costs. However, post-chemotherapy patients were associated with higher outpatient clinic visits, inpatient hospital admissions, and supportive medicines. Regarding relative contribution to the total mean direct medical cost, the treatment costs were the main contributor, followed by inpatient admissions, outpatient clinic visits, and supportive medicines. CONCLUSION: The total mean direct medical costs were similar for abiraterone and enzalutamide patients. The costs were not driven by the choice of treatment regimen, but treatment setting (pre-chemotherapy or post-chemotherapy indications) and related healthcare resource utilisation. Future studies should focus on economic evaluations, such as cost-effectiveness analyses, using real-world data.

Following the science? Comparison of methodological and reporting quality of covid-19 and other research from the first wave of the pandemic.

BACKGROUND: Following the initial identification of the 2019 coronavirus disease (covid-19), the subsequent months saw substantial increases in published biomedical research. Concerns have been raised in both scientific and lay press around the quality of some of this research. We assessed clinical research from major clinical journals, comparing methodological and reporting quality of covid-19 papers published in the first wave (here defined as December 2019 to May 2020 inclusive) of the viral pandemic with non-covid papers published at the same time. METHODS: We reviewed research publications (print and online) from The BMJ, Journal of the American Medical Association (JAMA), The Lancet, and New England Journal of Medicine, from first publication of a covid-19 research paper (February 2020) to May 2020 inclusive. Paired reviewers were randomly allocated to extract data on methodological quality (risk of bias) and reporting quality (adherence to reporting guidance) from each paper using validated assessment tools. A random 10% of papers were assessed by a third, independent rater. Overall methodological quality for each paper was rated high, low or unclear. Reporting quality was described as percentage of total items reported. RESULTS: From 168 research papers, 165 were eligible, including 54 (33%) papers with a covid-19 focus. For methodological quality, 18 (33%) covid-19 papers and 83 (73%) non-covid papers were rated as low risk of bias, OR 6.32 (95%CI 2.85 to 14.00). The difference in quality was maintained after adjusting for publication date, results, funding, study design, journal and raters (OR 6.09 (95%CI 2.09 to 17.72)). For reporting quality, adherence to reporting guidelines was poorer for covid-19 papers, mean percentage of total items reported 72% (95%CI:66 to 77) for covid-19 papers and 84% (95%CI:81 to 87) for non-covid. CONCLUSIONS: Across various measures, we have demonstrated that covid-19 research from the first wave of the pandemic was potentially of lower quality than contemporaneous non-covid research. While some differences may be an inevitable consequence of conducting research during a viral pandemic, poor reporting should not be accepted.

Cost impact of introducing a treatment escalation/limitation plan during patients' last hospital admission before death.

OBJECTIVE: A recent study found that the use of a treatment escalation/limitation plan (TELP) was associated with a significant reduction in non-beneficial interventions (NBIs) and harms in patients admitted acutely who subsequently died. We quantify the economic benefit of the use of a TELP. DESIGN: NBIs were micro-costed. Mean costs for patients with a TELP were compared to patients without a TELP using generalized linear model regression, and results were extrapolated to the Scottish population. SETTING: Medical, surgical and intensive care units of district general hospital in Scotland, UK. PARTICIPANTS: Two hundred and eighty-seven consecutive patients who died over 3 months in 2017. Of these, death was 'expected' in 245 (85.4%) using Gold Standards Framework criteria. INTERVENTION: Treatment escalation/limitation plan. MAIN OUTCOME MEASURE: Between-group difference in estimated mean cost of NBIs. RESULTS: The group with a TELP (n = 152) had a mean reduction in hospital costs due to NBIs of GB £220.29 (US $;281.97) compared to those without a TELP (n = 132) (95% confidence intervals GB £323.31 (US $413.84) to GB £117.27 (US $150.11), P = <0.001). Assuming that a TELP could be put in place for all expected deaths in Scottish hospitals, the potential annual saving would be GB £2.4 million (US $3.1 million) from having a TELP in place for all 'expected' deaths in hospital. CONCLUSIONS: The use of a TELP in an acute hospital setting may result in a reduction in costs attributable to NBIs.

Economic burden of rheumatoid arthritis: a systematic review of literature in biologic era.

BACKGROUND: The past decades have seen rapid advances in the treatment of rheumatoid arthritis (RA). In particular, the introduction of biologic and targeted synthetic disease-modifying antirheumatic drugs have improved clinical outcomes and reconfigured traditional RA cost compositions. OBJECTIVES: To map the existing evidence concerning cost of illness of RA, as the treatment pathway evolves in the biologic era, and examine how costs have been measured and estimated, in order to assemble and appropriately interpret available data. METHODS: Systematic review of studies that estimated the costs of patients with RA. Multiple electronic databases were searched to identify studies published between 2000 and 2019. The reported total costs and cost components were evaluated according to the study and population characteristics. The Cochran-Armitage test was used to determine statistically significant trends in increasing or decreasing proportions over time. RESULTS: Overall, 72 studies were included. Drug costs compromised the main component (up to 87%) of direct costs with an increasing trajectory over time, although not statistically significant. The proportion of costs for hospitalisation showed a statistically significant decrease chronologically (p=0.044). Indirect costs, primarily associated with absenteeism and work disability accounted for 39% to 86% of total costs. The reported indirect costs are highly sensitive to the approach to estimation. CONCLUSIONS: A decreasing trend in inpatient costs chronologically suggested a cost shift in other components of direct costs. Indirect costs still contributed a considerable proportion of total costs, with work disability being the main cost component. Economic analyses that do not incorporate or appropriately measure indirect costs will underestimate the full economic impact of RA.

A two-part model to estimate inpatient, outpatient, prescribing and care home costs associated with atrial fibrillation in Scotland.

OBJECTIVE: This study aimed to estimate global inpatient, outpatient, prescribing and care home costs for patients with atrial fibrillation using population-based, individual-level linked data. DESIGN: A two-part model was employed to estimate the probability of resource utilisation and costs conditional on positive utilisation using individual-level linked data. SETTINGS: Scotland, 5 years following first hospitalisation for AF between 1997 and 2015. PARTICIPANTS: Patients hospitalised with a known diagnosis of AF or atrial flutter. PRIMARY AND SECONDARY OUTCOME MEASURES: Inpatient, outpatient, prescribing and care home costs. RESULTS: The mean annual cost for a patient with AF was estimated at £3785 (95% CI £3767 to £3804). Inpatient admissions and outpatient visits accounted for 79% and 8% of total costs, respectively; prescriptions and care home stay accounted for 7% and 6% of total costs. Inpatient cost was the main driver across all age groups. While inpatient cost contributions (~80%) were constant between 0 and 84 years, they decreased for patients over 85 years. This is offset by increasing care home cost contributions. Mean annual costs associated with AF increased significantly with increasing number of comorbidities. CONCLUSION: This study used a contemporary and representative cohort, and a comprehensive approach to estimate global costs associated with AF, taking into account resource utilisation beyond hospital care. While overall costs, considerably affected by comorbidity, did not increase with increasing age, care home costs increased proportionally with age. Inpatient admission was the main contributor to the overall financial burden of AF, highlighting the need for improved mechanisms of early diagnosis to prevent hospitalisations.

Cost-effectiveness of treating hepatitis C in Seychelles.

INTRODUCTION: approximately eighty million people around the world are living with hepatitis C, and 700,000 people die every year, due to hepatitis C related complications. In Seychelles, a total of 777 cases of hepatitis C were reported from 2002 to 2016, but up to mid of 2016, the cases were not being treated. Treatment with Harvoni, a combination of sofosbuvir and ledipasvir (SOF/LDV), is now being offered on the condition that the patient does not, or has stopped, injecting drugs. This paper is the first to establish the cost effectiveness of treating all cases of hepatitis C in Seychelles with Harvoni, as compared to no treatment. METHODS: data extracted from literature was used to populate an economic model to calculate cost-effectiveness from Seychelles' government perspective. The model structure was also informed by the systematic review and an accompanying grading of economic models using the Consolidated Health Economic Evaluation Reporting Standard (CHEERS) checklist. A Markov model was developed, employing a lifetime horizon and costs and benefits were analysed from a payer's perspective and combined into incremental cost effectiveness ratios (ICERs). RESULTS: the direct-acting antiviral (DAA), Harvoni, was found to be cost-saving in Seychelles hepatitis C virus (HCV) cohort, as compared to no treatment, with an ICER of € 753.65/QALY. The treatment was also cost-saving when stratified by gender, with the ICER of male and female being € 783.74/QALY and € 635.20/QALY, respectively. Moreover, the results obtained from acceptability curves showed that treating patients with Harvoni is the most cost-effective option, even for low thresholds. CONCLUSION: treating hepatitis C cases in Seychelles is cost-saving. It is worth developing a treatment programme to include all cases of hepatitis C, regardless of status of drug injection.

Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT.

BACKGROUND: Management of bone and joint infection commonly includes 4-6 weeks of intravenous (IV) antibiotics, but there is little evidence to suggest that oral (PO) therapy results in worse outcomes. OBJECTIVE: To determine whether or not PO antibiotics are non-inferior to IV antibiotics in treating bone and joint infection. DESIGN: Parallel-group, randomised (1 : 1), open-label, non-inferiority trial. The non-inferiority margin was 7.5%. SETTING: Twenty-six NHS hospitals. PARTICIPANTS: Adults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least 6 weeks of antibiotics, and who had received ≤ 7 days of IV therapy from definitive surgery (or start of planned curative treatment in patients managed non-operatively). INTERVENTIONS: Participants were centrally computer-randomised to PO or IV antibiotics to complete the first 6 weeks of therapy. Follow-on PO therapy was permitted in either arm. MAIN OUTCOME MEASURE: The primary outcome was the proportion of participants experiencing treatment failure within 1 year. An associated cost-effectiveness evaluation assessed health resource use and quality-of-life data. RESULTS: Out of 1054 participants (527 in each arm), end-point data were available for 1015 (96.30%) participants. Treatment failure was identified in 141 out of 1015 (13.89%) participants: 74 out of 506 (14.62%) and 67 out of 509 (13.16%) of those participants randomised to IV and PO therapy, respectively. In the intention-to-treat analysis, using multiple imputation to include all participants, the imputed risk difference between PO and IV therapy for definitive treatment failure was -1.38% (90% confidence interval -4.94% to 2.19%), thus meeting the non-inferiority criterion. A complete-case analysis, a per-protocol analysis and sensitivity analyses for missing data each confirmed this result. With the exception of IV catheter complications [49/523 (9.37%) in the IV arm vs. 5/523 (0.96%) in the PO arm)], there was no significant difference between the two arms in the incidence of serious adverse events. PO therapy was highly cost-effective, yielding a saving of £2740 per patient without any significant difference in quality-adjusted life-years between the two arms of the trial. LIMITATIONS: The OVIVA (Oral Versus IntraVenous Antibiotics) trial was an open-label trial, but bias was limited by assessing all potential end points by a blinded adjudication committee. The population was heterogenous, which facilitated generalisability but limited the statistical power of subgroup analyses. Participants were only followed up for 1 year so differences in late recurrence cannot be excluded. CONCLUSIONS: PO antibiotic therapy is non-inferior to IV therapy when used during the first 6 weeks in the treatment for bone and joint infection, as assessed by definitive treatment failure within 1 year of randomisation. These findings challenge the current standard of care and provide an opportunity to realise significant benefits for patients, antimicrobial stewardship and the health economy. FUTURE WORK: Further work is required to define the optimal total duration of therapy for bone and joint infection in the context of specific surgical interventions. Currently, wide variation in clinical practice suggests significant redundancy that likely contributes to the excess and unnecessary use of antibiotics. TRIAL REGISTRATION: Current Controlled Trials ISRCTN91566927. 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. 38. See the NIHR Journals Library website for further project information.

Treatment of bone and joint infection usually requires a long course of antibiotics. Doctors usually give these by injection through a vein (intravenously) for the first 4­6 weeks, rather than by mouth (orally). Although intravenous (IV) administration is more expensive and less convenient for patients, most doctors believe that it is more effective. However, there is little evidence to support this. The OVIVA (Oral Versus IntraVenous Antibiotics) trial set out to challenge this assumption. A total of 1054 patients from 26 UK hospitals were randomly allocated to receive the first 6 weeks of antibiotic therapy either intravenously or orally. Irrespective of the route of administration, the choice of antibiotic was left to an infection specialist so as to ensure that the most appropriate antibiotics were given. Patients were followed up for 1 year. Thirty-nine participants were lost to follow-up. Among the remaining 1015 participants, treatment failure occurred in 14.6% of those treated intravenously and 13.2% of those treated with PO antibiotics. This difference could easily have occurred by chance. Even if it was not by chance, the difference does not suggest that PO therapy is associated with worse outcomes than IV therapy and is too small to conclude that PO therapy is better than IV therapy. Participants in the IV group stayed in hospital longer and 10% of them had complications related to the IV line used for administering the antibiotics. In addition, their treatment was, overall, more expensive. We conclude that PO antibiotic therapy has no disadvantages for the early management of bone and joint infection. It is also cheaper and associated with fewer complications.

What is the impact of large-scale implementation of stroke Early Supported Discharge? A mixed methods realist evaluation study protocol.

BACKGROUND: Stroke Early Supported Discharge (ESD) is a service innovation that facilitates discharge from hospital and delivery of specialist rehabilitation in patients' homes. There is currently widespread implementation of ESD services in many countries, driven by robust clinical trial evidence. In England, the type of ESD service patients receive on the ground is variable, and in some regions, ESD is still not offered at all. This protocol presents a study designed to investigate the mechanisms and outcomes of implementing ESD at scale in real-world conditions. This will help to establish which models of ESD are most effective and in what context. METHODS: A realist evaluation approach composed of two interlinking work packages will be adopted to investigate how and why ESD works, for whom and in what circumstances. Work package 1 (WP1) will begin with a rapid evidence synthesis to formulate preliminary realist hypotheses. Quantitative analyses of historical prospective Sentinel Stroke National Audit Programme (SSNAP) data will be performed to evaluate service outcomes based on the degree to which evidence-based ESD has been implemented. Work package 2 (WP2) will involve the qualitative investigation of purposively selected case study sites featuring in WP1 and covering different regions in England. The perspectives of clinicians, managers, commissioners, and service users will be explored qualitatively. Cost implications of ESD models will be examined using a cost-consequence analysis. Cross-case comparisons and triangulation of the data sources from both work packages will be performed to test, revise, and refine initial programme theories and address research aims. DISCUSSION: This study will investigate whether and how current large-scale implementation of ESD is achieving the outcomes suggested by the evidence base. The theory-driven evaluation approach will highlight key mechanisms and contextual conditions necessary to optimise outcomes and allow us to draw transferable lessons to inform the effective implementation and sustainability of ESD in clinical practice. In addition, the methodological framework will progress the theoretical understanding of implementation and evaluation of complex rehabilitation interventions in stroke care. TRIAL REGISTRATION: ISRCTN: 15568163, registration date: 26 October 2018.

Oral versus Intravenous Antibiotics for Bone and Joint Infection.

BACKGROUND: The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. METHODS: We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. RESULTS: Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of -1.4 percentage points (90% confidence interval [CI], -4.9 to 2.2; 95% CI, -5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). CONCLUSIONS: Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927 .).

Correction to: Real-World Safety of Intravitreal Bevacizumab and Ranibizumab Treatments for Retinal Diseases in Thailand: A Prospective Observational Study.

The Open Access license, which previously read.

A framework for conducting economic evaluations alongside natural experiments.

Internationally, policy makers are increasingly focussed on reducing the detrimental consequences and rising costs associated with unhealthy diets, inactivity, smoking, alcohol and other risk factors on the health of their populations. This has led to an increase in the demand for evidence-based, cost-effective Population Health Interventions (PHIs) to reverse this trend. Given that research designs such as randomised controlled trials (RCTs) are often not suited to the evaluation of PHIs, Natural Experiments (NEs) are now frequently being used as a design to evaluate such complex, preventive PHIs. However, current guidance for economic evaluation focusses on RCT designs and therefore does not address the specific challenges of NE designs. Using such guidance can lead to sub-optimal design, data collection and analysis for NEs, leading to bias in the estimated effectiveness and cost-effectiveness of the PHI. As a consequence, there is a growing recognition of the need to identify a robust methodological framework for the design and conducting of economic evaluations alongside such NEs. This paper outlines the challenges inherent to the design and conduct of economic evaluations of PHIs alongside NEs, providing a comprehensive framework and outlining a research agenda in this area.

Cost-effectiveness of oral versus intravenous antibiotics (OVIVA) in patients with bone and joint infection: evidence from a non-inferiority trial.

Background: Bone and joint infections are becoming increasingly common and are usually treated with surgery and a course of intravenous antibiotics. However, there is no evidence to support the superiority of intravenous therapy and there is a growing body of literature showing that oral therapy is effective in treating these infections.Given this lack of evidence the clinical trial 'Oral Versus Intravenous Antibiotics' (OVIVA) was designed to assess the clinical and cost-effectiveness of intravenous versus oral antibiotics for the treatment of bone and joint infections, using a non-inferiority design. Clinical results from the trial indicate that oral antibiotics are non-inferior to intravenous antibiotics. The aim of this paper is to evaluate the cost-effectiveness of intravenous compared to oral antibiotics for treating bone and joint infections, using data from OVIVA. Methods: A cost-utility analysis was carried out, the main economic outcome measure was the quality adjusted life-year, measured using the EQ-5D-3L questionnaire, combined with costs to estimate cost-effectiveness over 12-months follow-up. Results: Results show that costs were significantly lower in the oral arm compared to the intravenous arm, a difference of £2,740 (95% confidence interval £1,488 to £3,992). Results of four sensitivity analyses were consistent with the base-case results. QALYs were marginally higher in the oral arm, however this difference was not statistically significant; -0.007 (95% confidence interval -0.045 to 0.031). Conclusions: Treating patients with bone and joint infections for the first six weeks of therapy with oral antibiotics is both less costly and does not result in detectable differences in quality of life compared to treatment with intravenous antibiotics. Adopting a practice of treating bone and joint infections with oral antibiotics early in the course of therapy could potentially save the UK National Health Service over £17 million annually.