Cost-Consequence Analysis of Deprescribing to Optimize Health Outcomes for Frail Older People: A Within-Trial Analysis.

OBJECTIVES: The structured, clinically supervised withdrawal of medicines, known as deprescribing, is one strategy to address inappropriate polypharmacy. This study aimed to evaluate the costs and consequences of deprescribing in frail older people living in residential aged care facilities (RACFs) in Australia. DESIGN: A within-trial cost-consequence analysis of a deprescribing intervention-Opti-Med. The Opti-Med double-blind randomized controlled trial of deprescribing included 3 groups: blinded control, blinded intervention, and an open intervention group. SETTING AND PARTICIPANTS: Seventeen RACFs in Western Australia and New South Wales. Participants were 303 older people living in participating RACFs from March 2014 to February 2019. METHODS: Analysis was conducted from the health sector perspective. Health economic outcomes assessed include cost saved from deprescribed medicines and the incremental quality-adjusted life-years. Costs were presented in 2022 Australian dollars. RESULTS: The total cost of the Opti-Med intervention was $239.13 per participant. The costs saved through deprescribed medicines over 12 months after adjusting for mortality within the trial period was $328.90 per participant in the blinded intervention group and $164.00 per participant in the open intervention group. On average, the cost of the intervention was more than offset by the cost saved from deprescribed medicines. Extrapolating these findings to the Australian population suggests a potential net cost saving of about $1 to $16 million per annum for the health system nationally. The incremental quality-adjusted life-years were very similar across the 3 groups within the trial period. CONCLUSIONS AND IMPLICATIONS: Deprescribing for frail older people living in RACFs can be a cost-saving intervention without reducing the quality of life. Systemwide implementation of deprescribing across RACFs in Australia has the potential to improve health care delivery through the cost savings, which could be reapplied to further optimize care within RACFs.

Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial.

Background: Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130-140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target <180 mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018. Methods: All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24-36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings: There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24-36 h. Mean achieved systolic blood pressures over 1-24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24-36 h (0.3 [IQR 0.0-16.6] in the intensive group and 0.9 [0.0-12.5] in the guideline group; log Δmean -0.17, 95% CI -0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses. Interpretation: Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity. Funding: National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Economic evaluation of digitally enabled aged and neurological rehabilitation care in the Activity and MObility UsiNg Technology (AMOUNT) trial.

OBJECTIVE: To investigate the trial-based cost-effectiveness of the addition of a tailored digitally enabled exercise intervention to usual care shown to be clinically effective in improving mobility in the Activity and MObility UsiNg Technology (AMOUNT) rehabilitation trial compared to usual care alone. DESIGN: Economic evaluation alongside a pragmatic randomized controlled trial. PARTICIPANTS: 300 people receiving inpatient aged and neurological rehabilitation were randomized to the intervention (n = 149) or usual care control group (n = 151). MAIN MEASURES: Incremental cost effectiveness ratios were calculated for the additional costs per additional person demonstrating a meaningful improvement in mobility (3-point in Short Physical Performance Battery) and quality-adjusted life years gained at 6 months (primary analysis). The joint probability distribution of costs and outcomes was examined using bootstrapping. RESULTS: The mean cost saving for the intervention group at 6 months was AU$2286 (95% Bootstrapped cost CI: -$11,190 to $6410) per participant; 68% and 67% of bootstraps showed the intervention to be dominant (i.e. more effective and cost saving) for mobility and quality-adjusted life years, respectively. The probability of the intervention being cost-effective considering a willingness to pay threshold of AU$50,000 per additional person with a meaningful improvement in mobility or quality-adjusted life year gained was 93% and 77%, respectively. CONCLUSIONS: The AMOUNT intervention had a high probability of being cost-effective if decision makers are willing to pay AU$50,000 per meaningful improvement in mobility or per quality-adjusted life year gained, and a moderate probability of being cost-saving and effective considering both outcomes at 6 months post randomization.

The cost of providing a community-based model of care to people with spinal cord injury, and the healthcare costs and economic burden to households of spinal cord injury in Bangladesh.

DESIGN: Descriptive. SETTING: Community, Bangladesh. OBJECTIVES: To determine the costs associated with providing a community-based model of care delivered as part of the CIVIC trial to people discharged from hospital with recent spinal cord injury (SCI), and to determine the economic burden to households. METHODS: Records were kept of the costs of providing a community-based model of care to participants of the CIVIC trial. Data were also collected at discharge and 2 years post discharge to capture out-of-pocket healthcare costs over the preceding 2 years, and the number of participants suffering catastrophic health expenditure and illness-induced poverty. RESULTS: The mean cost of providing the community-based model of care to participants assigned to the intervention group (n = 204) was US$237 per participant. The mean out-of-pocket healthcare cost over the first 2 years post discharge was US$472 per participant (n = 410), and US$448 per control participant (n = 206). Median (IQR) equivalent annual household incomes prior to SCI and at 2 years post discharge were US$721 (US$452-1129) and US$464 (US$214-799), respectively. Of the 378 participants alive at 2 years, 324 (86%) had catastrophic health expenditure, and 161 of 212 participants who were not in poverty prior to injury (76%) were pushed into illness-induced poverty within 2 years of injury. CONCLUSION: The cost of providing community-based support to people with SCI for 2 years post discharge in Bangladesh is relatively inexpensive but an overwhelming majority of households rapidly experience financial catastrophe, and most fall into poverty.

Apolipoprotein E and Health in Older Men: The Concord Health and Ageing in Men Project.

APOE genotype has been associated with various age-related outcomes including Alzheimer's disease, frailty, and mortality. In this study, the relationship between health, particularly cognitive function, and APOE was investigated in older men from the Concord Health and Ageing in Men Project (n = 1,616; age 76.9 ± 5.5 years [range 70-97 years]; Australia). Baseline characteristics and survival up to 12 years were determined. Frailty was measured using Cardiovascular Health study (CHS) criteria and Rockwood frailty index, and cognition using Mini-Mental State Examination (MMSE) and Addenbrookes Cognitive Examination. APOE ε4 was less common in the oldest men and those born in Mediterranean countries. APOE ε2 was beneficially associated with cholesterol, creatinine, gamma-glutamyl transaminase, glucose, and HDL cholesterol while APOE ε4 was adversely associated with cholesterol and albumin. APOE ε4 was associated with a clinical diagnosis of Alzheimer's disease when adjusted for age and region of birth (ε4 homozygotes Odds ratio (OR) 7.0; ε4 heterozygotes OR 2.4, p < .05), and APOE ε2 had a small positive association with cognition. On multivariate regression, overall cognitive function in the entire cohort was associated with age, country of birth, education, and frailty (all p < .001). APOE was not associated with frailty or survival. In conclusion, age and region of birth influenced distribution of APOE genotype in older men. Although APOE ε4 was associated with Alzheimer's disease, overall cognitive function in the cohort was associated more strongly with frailty than APOE genotype.

Caregiver-Delivered Stroke Rehabilitation in Rural China.

Background and Purpose- Stroke disability is a major health burden in rural China where rehabilitation services are inadequate. We aimed to determine the effectiveness of a novel nurse-led, caregiver-delivered model of stroke rehabilitation in rural China. Methods- A multicenter prospective, randomized open, blinded outcome assessed, controlled trial was conducted in 3 rural county hospitals in China: Zhangwu, Liaoning Province (Northeast); Qingtongxia, Ningxia Hui Autonomous Region (Northwest); and Dianjiang, Chongqing Municipality (Southwest). Adult patients (age 18-79 years) with residual disability (Barthel Index score ≤80/100) after a recent acute stroke were randomized to a new service model or usual care. The new intervention was multifaceted and was based on a task-shifting / training-the-trainers model, supported by a custom-designed smartphone application, where patients and caregivers received evidence-based in-hospital education and stroke rehabilitation training (focus on mobility, self-care, and toileting), delivered by trained nurses before hospital discharge, and 3 postdischarge support telephone calls. Outcome assessments were undertaken before hospital discharge and at 3 and 6 months. Primary outcome was physical functioning (Barthel Index scores) at 6 months, assessed by research staff blind to treatment allocation, adjusted for baseline covariates in an intention-to-treat analysis. Secondary outcomes included measures of mobility, health-related quality of life, mood, and caregiver burden. The study included a process evaluation that assessed intervention fidelity. Results- From November 2014 to December 2016, 246 stroke patients were randomized to intervention (n=118) or control (n=128) groups. There was no statistically significant difference in adjusted 6-month Barthel Index scores between groups (70.1 versus 74.1, mean difference, -4.0 [95% CI, -10.0 to 2.9]), nor any differences across the other outcome measures. Process evaluation interviews revealed that the intervention was desirable and positively accepted by nurses, caregivers, and patients but was considered too complex despite efforts to simplify materials for the rural context. Key strategies identified for future studies included the use of community health workers, smartphone application enhancement, and simpler and more frequent training for nurses, caregivers, and patients. Conclusions- A novel nurse-led, digital supported, caregiver-delivered stroke rehabilitation program did not improve patient physical functioning after stroke in rural China. Further stroke rehabilitation research suitable for resource-poor settings is required, with several components being suggested through stakeholder interviews in our study. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02247921.

Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial.

BACKGROUND: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. METHODS: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. FINDINGS: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. INTERPRETATION: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. FUNDING: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Protocol for process evaluation of CIVIC randomised controlled trial: Community-based InterVentions to prevent serIous Complications following spinal cord injury in Bangladesh.

INTRODUCTION: People with spinal cord injuries in low-income and middle-income countries are highly vulnerable to life-threatening complications in the period immediately after discharge from hospital. We are conducting a randomised controlled trial in Bangladesh to determine whether all-cause mortality at 2 years can be reduced if health professionals regularly ring and visit participants in their homes following discharge. We will conduct a process evaluation alongside the trial to explain the trial results and determine the feasibility of scaling this intervention up in low-income and middle-income countries if it is found to be effective. METHODS AND ANALYSIS: Our process evaluation is based on the Realist and Reach, Effectiveness, Adoption, Implementation and Maintenance frameworks. We will use a mixed methods approach that uses both qualitative and quantitative data. For example, we will audit a sample of telephone interactions between intervention participants and the healthcare professionals, and we will conduct semistructured interviews with people reflective of various interest groups. Quantitative data will also be collected to determine the number and length of interactions between the healthcare professionals and participants, the types of issues identified during each interaction and the nature of the support and advice provided by the healthcare professionals. All quantitative and qualitative data will be analysed iteratively before the final analysis of the trial results. These data will then be triangulated with the final results of the primary outcome. ETHICS AND DISSEMINATION: Ethics approval was obtained from the institutional ethics committee at the site in Bangladesh and from the University of Sydney, Australia. The study will be conducted in compliance with all stipulations of its protocol, the conditions of ethics committee approval and the relevant regulatory bodies. The results of the trial will be disseminated through publications in peer-reviewed scientific journals and presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ACTRN12615000630516.

Clinical stroke research in resource limited settings: Tips and hints.

Background Most stroke research is conducted in high income countries, yet most stroke occurs in low- and middle-income countries. There is an urgent need to build stroke research capacity in low- and middle-income countries. Aims To review the global health literature on how to improve research capacity in low- and middle-income countries, provide additional data from the recently completed ATTEND Trial and provide examples from our own experience. Summary of review The main themes from our literature review were: manpower and workload, research training, research question and methodology and research funding. The literature and our own experience emphasized the importance of local stakeholders to ensure that the research was appropriate, that there were robust local ethics and regulatory processes, and research was conducted by trained personnel. Research training opportunities can be developed locally, or internationally, with many international schemes available to help support new researchers from low- and middle-income country settings. International collaboration can successfully leverage funding from high income countries that not only generate data for the local country, but also provide new data appropriate to high income countries. Conclusions Building stroke research capacity in low- and middle-income countries will be vital in improving global health given the huge burden of stroke in these countries.

The potential health and economic impact of improving stroke care standards for Australia.

Background Evidence of the burden of suboptimal stroke care should expedite quality improvement. We aimed to estimate the health and economic impact of improving acute stroke management to best practice standards using Australia as a case study. Methods Hospital performance in Australia was estimated using data from the National Stroke Audit of Acute Services 2013. The percentage of patients provided evidence-based therapies in all hospitals was compared to that achieved in the aggregate of top performing benchmark hospitals (that included between them, a minimum contribution of 15% of all cases audited). The number of additional patients who would receive therapies if this performance gap was rectified was applied to a standardized economic simulation model that comprised stroke rates and resource-use estimates from the North East Melbourne Stroke Incidence Study applied to the 2013 Australian population. Results In 2013, 41,398 patients were estimated to have been hospitalized with stroke. If acute care was improved to that of Australian benchmarks, there would be an additional 15,317 patients accessing stroke units; 1960 receiving thrombolysis; and 4007 being treated with antihypertensive medication, 3082 with antiplatelet medication, 2179 with anticoagulant medication, and 3514 with lipid-lowering therapy. Approximately 9329 disability-adjusted life years could be avoided. This additional care provided would be cost effective at AUD 3304 per disability adjusted life year avoided. Conclusion The benefits of reducing evidence-practice gaps in Australia are considerable. Further investment in initiatives to optimize hospital care is justified.

Community-based InterVentions to prevent serIous Complications (CIVIC) following spinal cord injury in Bangladesh: protocol of a randomised controlled trial.

INTRODUCTION: In low-income and middle-income countries, people with spinal cord injury (SCI) are vulnerable to life-threatening complications after they are discharged from hospital. The aim of this trial is to determine the effectiveness and cost-effectiveness of an inexpensive and sustainable model of community-based care designed to prevent and manage complications in people with SCI in Bangladesh. METHODS AND ANALYSIS: A pragmatic randomised controlled trial will be undertaken. 410 wheelchair-dependent people with recent SCI will be randomised to Intervention and Control groups shortly after discharge from hospital. Participants in the Intervention group will receive regular telephone-based care and three home visits from a health professional over the 2 years after discharge. Participants in the Control group will receive standard care, which does not involve regular contact with health professionals. The primary outcome is all-cause mortality at 2 years. Recruitment started on 12 July 2015 and the trial is expected to take 5 years to complete. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Institutional Ethics Committee at the site in Bangladesh and from the University of Sydney, Australia. The study will be conducted in compliance with all stipulations of its protocol, the conditions of ethics committee approval, the NHMRC National Statement on Ethical Conduct in Human Research (2007), the Note for Guidance on Good Clinical Practice (CPMP/ICH-135/95) and the Bangladesh Guidance on Clinical Trial Inspection (2011). The results of the trial will be disseminated through publications in peer-reviewed scientific journals and presentations at scientific conferences. TRIAL REGISTRATION NUMBERS: ACTRN12615000630516, U1111-1171-1876.

Interobserver agreement for the bedside clinical assessment of suspected stroke.

BACKGROUND AND PURPOSE: Stroke remains primarily a clinical diagnosis, with information obtained from history and examination determining further management. We aimed to measure inter-rater reliability for the clinical assessment of stroke, with emphasis on items of history, timing of symptom onset, and diagnosis of stroke or mimic. We explored reasons for poor reliability. METHODS: The study was based in an urban hospital with an acute stroke unit. Pairs of observers independently assessed suspected stroke patients. Findings from history, neurological examination, and the diagnosis of stroke or mimic, were recorded on a standard form. Reliability was measured by the kappa statistic. We assessed the impact of observer experience and confidence, time of assessment, and patient-related factors of age, confusion, and aphasia on inter-rater reliability. RESULTS: Ninety-eight patients were recruited. Most items of the history and the diagnosis of stroke were found to have moderate to good inter-rater reliability. There was agreement for the hour and minute of symptom onset in only 45% of cases. Observer experience and confidence improved reliability; patient-related factors of confusion and aphasia made the assessment more difficult. There was a trend for worse inter-rater reliability among patients assessed very early and very late after symptom onset. CONCLUSIONS: Clinicians should be aware that inter-rater reliability of the clinical assessment is affected by a variety of factors and is improved by experience and confidence. Our findings have implications for training of doctors who assess patients with suspected stroke and identifies the more reliable components of the clinical assessment.

Thrombolysis for acute ischaemic stroke: consumer involvement in design of new randomised controlled trial.

OBJECTIVES: To determine whether consumer involvement would help to solve some of the ethical problems associated with research into thrombolysis for acute ischaemic stroke, with its inherent risk of fatal intracranial haemorrhage. DESIGN: Quantitative and qualitative research. SETTING AND PARTICIPANTS: CONSULTATION PHASE: three meetings were held to discuss the planned research, and participants completed a questionnaire. QUALITATIVE WORK: focus group meetings explored the issues raised during the consultation phase. Design of information leaflets for patients and relatives: trial materials were drafted during the consultation phase and revised in the light of feedback from the focus group meetings and review by patients and carers on a stroke rehabilitation unit. RESULTS: 54 people attended the consultation meetings. Four (9%) participants considered the risks of thrombolysis too great, but most (89%) were prepared to accept the treatment in a clinical trial. Nearly all would accept treatment if it was shown to be effective. Most (85%) would give their consent to enter the planned trial. The focus group meetings and feedback from patients and carers led to significant changes in the information leaflets. The revised trial materials were considered ethical by a national multicentre research ethics committee. CONCLUSIONS: Consumers generally supported a planned trial, and their involvement helped to refine trial consent procedures and led to an ethically acceptable trial design.