R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 15.

In this latest update we discuss real-world evidence (RWE) guidance from the leading oncology professional societies, the American Society of Clinical Oncology and the European Society for Medical Oncology, and the PRINCIPLED practical guide on the design and analysis of causal RWE studies.

R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 14.

In this latest update we highlight: a publication from the US FDA regarding the definitions of real-world data (RWD) and real-world evidence (RWE); a publication from academic researchers on a demonstration project for target trial emulation; a publication from the National Institute of Health and Care Excellence (NICE) on the 1 year anniversary of their RWE framework; and a publication from NICE and Flatiron Health on the utility of US RWD for initial UK health technology assessment decision making.

The impact of the COVID-19 pandemic on cardiovascular disease prevention and corresponding geographical inequalities in England: interrupted time series analysis.

BACKGROUND: There has been disruption to the detection and management of those with hypertension and atrial fibrillation (AF) during the COVID-19 pandemic. This is likely to vary geographically and could have implications for future mortality and morbidity. We aimed to estimate the change in diagnosed prevalence, treatment and prescription indicators for AF and hypertension and assess corresponding geographical inequalities. METHODS: Using the Quality and Outcomes Framework (2016/17 to 2021/22) and the English Prescribing Datasets (2018 to 2022), we described age standardised prevalence, treatment and prescription item rates for hypertension and AF by geography and over time. Using an interrupted time-series (ITS) analysis, we estimated the impact of the pandemic (from April 2020) on missed diagnoses and on the percentage change in medicines prescribed for these conditions. Finally, we described changes in treatment indicators against Public Health England 2029 cardiovascular risk targets. RESULTS: We observed 143,822 fewer (-143,822, 95%CI:-226,144, -61,500, p = 0.001) diagnoses of hypertension, 60,330 fewer (-60,330, 95%CI: -83,216, -37,444, p = 0.001) diagnoses of AF and 1.79% fewer (-1.79%, 95%CI: -2.37%, -1.22%), p < 0.0001) prescriptions for these conditions over the COVID-19 impact period. There was substantial variation across geography in England in terms of the indirect impact of the COVID-19 pandemic on the diagnosis, prescription, and treatment rates of hypertension and AF. 20% of Sub Integrated Care Boards account for approximately 62% of all missed diagnoses of hypertension. The percentage of individuals who had their hypertension controlled fell from 75.8% in 2019/20 to 64.1% in 2021/22 and the percentage of individuals with AF who were risk assessed fell from 97.2% to 90.7%. CONCLUSIONS: Hypertension and AF detection and management were disrupted during the COVID-19 pandemic. The disruption varied considerably across diseases and geography. This highlights the utility of administrative and geographically granular datasets to inform targeted efforts to mitigate the indirect impacts of the pandemic through applied secondary prevention measures.

Developing and externally validating a machine learning risk prediction model for 30-day mortality after stroke using national stroke registers in the UK and Sweden.

OBJECTIVES: We aimed to develop and externally validate a generalisable risk prediction model for 30-day stroke mortality suitable for supporting quality improvement analytics in stroke care using large nationwide stroke registers in the UK and Sweden. DESIGN: Registry-based cohort study. SETTING: Stroke registries including the Sentinel Stroke National Audit Programme (SSNAP) in England, Wales and Northern Ireland (2013-2019) and the national Swedish stroke register (Riksstroke 2015-2020). PARTICIPANTS AND METHODS: Data from SSNAP were used for developing and temporally validating the model, and data from Riksstroke were used for external validation. Models were developed with the variables available in both registries using logistic regression (LR), LR with elastic net and interaction terms and eXtreme Gradient Boosting (XGBoost). Performances were evaluated with discrimination, calibration and decision curves. OUTCOME MEASURES: The primary outcome was all-cause 30-day in-hospital mortality after stroke. RESULTS: In total, 488 497 patients who had a stroke with 12.4% 30-day in-hospital mortality were used for developing and temporally validating the model in the UK. A total of 128 360 patients who had a stroke with 10.8% 30-day in-hospital mortality and 13.1% all mortality were used for external validation in Sweden. In the SSNAP temporal validation set, the final XGBoost model achieved the highest area under the receiver operating characteristic curve (AUC) (0.852 (95% CI 0.848 to 0.855)) and was well calibrated. The performances on the external validation in Riksstroke were as good and achieved AUC at 0.861 (95% CI 0.858 to 0.865) for in-hospital mortality. For Riksstroke, the models slightly overestimated the risk for in-hospital mortality, while they were better calibrated at the risk for all mortality. CONCLUSION: The risk prediction model was accurate and externally validated using high quality registry data. This is potentially suitable to be deployed as part of quality improvement analytics in stroke care to enable the fair comparison of stroke mortality outcomes across hospitals and health systems across countries.

R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 13.

In this latest update we highlight a report from the European Medicines Agency on their use of real-world evidence (RWE) in decision making, RWE reporting guidance from the Canadian Agency for Drugs and Technologies in Health and highlight some new data demonstrating the value medicines for spinal muscular atrophy have brought patients.

Are Differences in Dysphagia Assessment, Oral Care Provision, or Nasogastric Tube Insertion Associated with Stroke-Associated Pneumonia? A Nationwide Survey Linked to National Stroke Registry Data.

INTRODUCTION: Stroke-associated pneumonia (SAP) is a common complication associated with poor outcomes. Early dysphagia screening and specialist assessment is associated with a reduced risk of SAP. Evidence about oral care and nasogastric tube (NGT) placement is equivocal. This study aimed to expose variations in dysphagia management practices and explore their associations with SAP. PARTICIPANTS AND METHODS: Speech pathologists from 166 stroke units in England and Wales were surveyed about dysphagia assessment and management, oral care, and NGT placement. Survey data were then linked to the Sentinel Stroke National Audit Programme (SSNAP), the national register of stroke. Univariable and multivariable linear regression models were fitted to estimate the association between dysphagia management practices and SAP incidence. RESULTS: 113 hospitals completed the survey (68%). Variation was evident in dysphagia screening protocols (DSPs), oral care, and NGT practice while specialist swallow assessment data patterns were more consistent. Multivariable analysis showed no evidence of an association in incidence of SAP when using a water-only hospital DSP compared to a multiconsistency DSP (B -0.688, 95% CI: -2.912 to 1.536), when using written swallow assessment guidelines compared to not using written guidelines (B 0.671, 95% CI: -1.567 to 2.908), when teams inserted NGTs overnight compared to teams which did not (B -0.505, 95% CI: -2.759 to 1.749), and when teams had a written oral care protocol compared to those which did not (B -1.339, 95% CI: -3.551 to 0.873). DISCUSSION AND CONCLUSION: Variation exists in dysphagia screening and management, but there was no evidence of an association between clinical practice patterns and incidence of SAP. Further research with larger sample sizes is needed to examine association with SAP.

Stroke Care in the United Kingdom During the COVID-19 Pandemic.

BACKGROUND AND PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has potentially caused indirect harm to patients with other conditions via reduced access to health care services. We aimed to describe the impact of the initial wave of the pandemic on admissions, care quality, and outcomes in patients with acute stroke in the United Kingdom. METHODS: Registry-based cohort study of patients with acute stroke admitted to hospital in England, Wales, and Northern Ireland between October 1, 2019, and April 30, 2020, and equivalent periods in the 3 prior years. RESULTS: One hundred fourteen hospitals provided data for a study cohort of 184 017 patients. During the lockdown period (March 23 to April 30), there was a 12% reduction (6923 versus 7902) in the number of admissions compared with the same period in the 3 previous years. Admissions fell more for ischemic than hemorrhagic stroke, for older patients, and for patients with less severe strokes. Quality of care was preserved for all measures and in some domains improved during lockdown (direct access to stroke unit care, 1-hour brain imaging, and swallow screening). Although there was no change in the proportion of patients discharged with good outcome (modified Rankin Scale score, ≤2; 48% versus 48%), 7-day inpatient case fatality increased from 6.9% to 9.4% (P<0.001) and was 22.0% in patients with confirmed or suspected COVID-19 (adjusted rate ratio, 1.41 [1.11-1.80]). CONCLUSIONS: Assuming that the true incidence of acute stroke did not change markedly during the pandemic, hospital avoidance may have created a cohort of untreated stroke patients at risk of poorer outcomes or recurrent events. Unanticipated improvements in stroke care quality should be used as an opportunity for quality improvement and to learn about how to develop resilient health care systems.

Can clinical audits be enhanced by pathway simulation and machine learning? An example from the acute stroke pathway.

OBJECTIVE: To evaluate the application of clinical pathway simulation in machine learning, using clinical audit data, in order to identify key drivers for improving use and speed of thrombolysis at individual hospitals. DESIGN: Computer simulation modelling and machine learning. SETTING: Seven acute stroke units. PARTICIPANTS: Anonymised clinical audit data for 7864 patients. RESULTS: Three factors were pivotal in governing thrombolysis use: (1) the proportion of patients with a known stroke onset time (range 44%-73%), (2) pathway speed (for patients arriving within 4 hours of onset: per-hospital median arrival-to-scan ranged from 11 to 56 min; median scan-to-thrombolysis ranged from 21 to 44 min) and (3) predisposition to use thrombolysis (thrombolysis use ranged from 31% to 52% for patients with stroke scanned with 30 min left to administer thrombolysis). A pathway simulation model could predict the potential benefit of improving individual stages of the clinical pathway speed, whereas a machine learning model could predict the benefit of 'exporting' clinical decision making from one hospital to another, while allowing for differences in patient population between hospitals. By applying pathway simulation and machine learning together, we found a realistic ceiling of 15%-25% use of thrombolysis across different hospitals and, in the seven hospitals studied, a realistic opportunity to double the number of patients with no significant disability that may be attributed to thrombolysis. CONCLUSIONS: National clinical audit may be enhanced by a combination of pathway simulation and machine learning, which best allows for an understanding of key levers for improvement in hyperacute stroke pathways, allowing for differences between local patient populations. These models, based on standard clinical audit data, may be applied at scale while providing results at individual hospital level. The models facilitate understanding of variation and levers for improvement in stroke pathways, and help set realistic targets tailored to local populations.

Diurnal variations in the quality of stroke care in Sweden.

OBJECTIVES: A recent study of acute stroke patients in England and Wales revealed several patterns of temporal variation in quality of care. We hypothesized that similar patterns would be present in Sweden and aimed to describe these patterns. Additionally, we aimed to investigate whether hospital type conferred resilience against temporal variation. MATERIALS AND METHODS: We conducted this nationwide registry-based study using data from the Swedish Stroke Register (Riksstroke) including all adult patients registered with acute stroke between 2011 and 2015. Outcomes included process measures and survival. We modeled time of presentation as on/off-hours, shifts, day of week, 4-hour, and 12-hour time blocks. We studied hospital resilience by comparing outcomes across hospital types. RESULTS: A total of 113 862 stroke events in 72 hospitals were included. The process indicators and survival all showed significant temporal variation. Door-to-needle (DTN) time within 30 minutes was less likely during nighttime than daytime (OR 0.50; 95% CI 0.41-0.60). Patients admitted during off-hours had lower odds of direct stroke unit (SU) admission (OR 0.72; 95% CI 0.70-0.75). 30-day survival was lower in nighttime vs daytime presentations (OR 0.90, 95% CI 0.84-0.96). The effects of temporal variation differed significantly between hospital types for DTN time within 30 minutes and direct SU admission where university hospitals were more resilient than specialized non-university hospitals. CONCLUSIONS: Our study shows that variation in quality of care and survival is present throughout the whole week. We also found that university hospitals were more resilient to temporal variation than specialized non-university hospitals.

Applicability of ENCHANTED trial results to current acute ischemic stroke patients eligible for intravenous thrombolysis in England and Wales: Comparison with the Sentinel Stroke National Audit Programme registry.

BACKGROUND: Randomized controlled trials provide high-level evidence, but the necessity to include selected patients may limit the generalisability of their results. METHODS: Comparisons were made of baseline and outcome data between patients with acute ischemic stroke (AIS) recruited into the alteplase-dose arm of the international, multi-center, Enhanced Control of Hypertension and Thrombolysis Stroke study (ENCHANTED) in the United Kingdom (UK), and alteplase-treated AIS patients registered in the UK Sentinel Stroke National Audit Programme (SSNAP) registry, over the study period June 2012 to October 2015. RESULTS: There were 770 AIS patients (41.2% female; mean age 72 years) included in ENCHANTED at sites in England and Wales, which was 19.5% of alteplase-treated AIS patients registered in the SSNAP registry. Trial participants were significantly older, had lower baseline neurological severity, less likely Asian, and had more premorbid symptoms, hypertension and atrial fibrillation. Although ENCHANTED participants had higher rates of symptomatic intracerebral hemorrhage than those in SSNAP, there were no differences in onset-to-treatment time, levels of disability (assessed by the modified Rankin scale) at hospital discharge, and mortality over 90 days between groups. CONCLUSIONS: Despite the high level of participation, equipoise over the dose of alteplase among UK clinician investigators favored the inclusion of older, frailer, milder AIS patients in the ENCHANTED trial. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.clinicaltrials.gov . Unique identifier: NCT01422616.

Associations Between 30-Day Mortality, Specialist Nursing, and Daily Physician Ward Rounds in a National Stroke Registry.

Background and Purpose- Well-organized stroke care is associated with better patient outcomes, but the most important organizational factors are unknown. Methods- Data were extracted from the Sentinel Stroke National Audit Programme of adults with acute stroke treated in stroke hospitals in England and Wales between April 2013 and March 2015. Multilevel models with random intercepts for hospitals were used to estimate the association of each variable with 30-day mortality to estimate the impact of admission to differently organized hospitals. Results- Of the 143 578 patients with acute stroke admitted to 154 hospitals, 14.4% died within 30 days of admission. In adjusted analyses, admission to hospitals with higher ratios of nurses trained in swallow screening was associated with reduced odds of death ( P=0.004), and admission to hospitals with daily physician ward rounds was associated with 10% lower odds of mortality compared with less-frequent ward rounds (95% CI, 0.82-0.98; P=0.013). Number of stroke admissions and overall ratio of registered nurses on duty at weekends were not found to be independently associated with mortality after adjustment for other factors. Conclusions- If these associations are causal, an extra 1332 deaths annually in England and Wales could be saved by hospitals providing care associated with a ratio of nurses trained in swallow screening of at least 3 per 10 beds and daily stroke physician ward rounds.

Impact of Dysphagia Assessment and Management on Risk of Stroke-Associated Pneumonia: A Systematic Review.

BACKGROUND: Patients with dysphagia are at an increased risk of stroke-associated pneumonia. There is wide variation in the way patients are screened and assessed during the acute phase. The aim of this review was to identify the methods of assessment and management in acute stroke that influence the risk of stroke-associated pneumonia. Studies of stroke patients that reported dysphagia screening, assessment or management and occurrence of pneumonia during acute phase stroke were screened for inclusion after electronic searches of multiple databases from inception to November 2016. The primary outcome was association with stroke-associated pneumonia. SUMMARY: Twelve studies of 87,824 patients were included. The type of dysphagia screening protocol varied widely across and within studies. There was limited information on what comprised a specialist swallow assessment and alternative feeding was the only management strategy, which was reported for association with stroke-associated pneumonia. Use of a formal screening protocol and early dysphagia screening (EDS) and assessment by a speech and language pathologist (SLP) were associated with a reduced risk of stroke-associated pneumonia. There was marked heterogeneity between the included studies, which precluded meta-analysis. Key Messages: There is variation in the assessment and management of dysphagia in acute stroke. There is increasing evidence that EDS and specialist swallow assessment by an SLP may reduce the odds of stroke-associated pneumonia. There is the potential for other factors to influence the incidence of stroke-associated pneumonia during the acute phase.

The economic burden of stroke care in England, Wales and Northern Ireland: Using a national stroke register to estimate and report patient-level health economic outcomes in stroke.

INTRODUCTION: Stroke registries are used in many settings to measure stroke treatment and outcomes, but rarely include data on health economic outcomes. We aimed to extend the Sentinel Stroke National Audit Programme registry of England, Wales and Northern Ireland to derive and report patient-level estimates of the cost of stroke care. METHODS: An individual patient simulation model was built to estimate health and social care costs at one and five years after stroke, and the cost-benefits of thrombolysis and early supported discharge. Costs were stratified according to age, sex, stroke type (ischaemic or primary intracerebral haemorrhage) and stroke severity. The results were illustrated using data on all patients with stroke included in Sentinel Stroke National Audit Programme from April 2015 to March 2016 (n = 84,184). RESULTS: The total cost of health and social care for patients with acute stroke each year in England, Wales and Northern Ireland was £3.60 billion in the first five years after admission (mean per patient cost: £46,039). There was fivefold variation in the magnitude of costs between patients, ranging from £19,101 to £107,336. Costs increased with older age, increasing stroke severity and intracerebral hemorrhage stroke. Increasing the proportion of eligible patients receiving thrombolysis or early supported discharge was estimated to save health and social care costs by five years after stroke. DISCUSSION: The cost of stroke care is large and varies widely between patients. Increasing the proportion of eligible patients receiving thrombolysis or early supported discharge could contribute to reducing the financial burden of stroke. CONCLUSION: Extending stroke registers to report individualised data on costs may enhance their potential to support quality improvement and research.

Socioeconomic disparities in first stroke incidence, quality of care, and survival: a nationwide registry-based cohort study of 44 million adults in England.

BACKGROUND: We aimed to estimate socioeconomic disparities in the incidence of hospitalisation for first-ever stroke, quality of care, and post-stroke survival for the adult population of England. METHODS: In this cohort study, we obtained data collected by a nationwide register on patients aged 18 years or older hospitalised for first-ever acute ischaemic stroke or primary intracerebral haemorrhage in England from July 1, 2013, to March 31, 2016. We classified socioeconomic status at the level of Lower Super Output Areas using the Index of Multiple Deprivation, a neighbourhood measure of deprivation. Multivariable models were fitted to estimate the incidence of hospitalisation for first stroke (negative binomial), quality of care using 12 quality metrics (multilevel logistic), and all-cause 1 year case fatality (Cox proportional hazards). FINDINGS: Of the 43·8 million adults in England, 145 324 were admitted to hospital with their first-ever stroke: 126 640 (87%) with ischaemic stroke, 17 233 (12%) with intracerebral haemorrhage, and 1451 (1%) with undetermined stroke type. We observed a socioeconomic gradient in the incidence of hospitalisation for ischaemic stroke (adjusted incidence rate ratio 2·0, 95% CI 1·7-2·3 for the most vs least deprived deciles) and intracerebral haemorrhage (1·6, 1·3-1·9). Patients from the lowest socioeconomic groups had first stroke a median of 7 years earlier than those from the highest (p<0·0001), and had a higher prevalence of pre-stroke disability and diabetes. Patients from lower socioeconomic groups were less likely to receive five of 12 care processes but were more likely to receive early supported discharge (adjusted odds ratio 1·14, 95% CI 1·07-1·22). Low socioeconomic status was associated with a 26% higher adjusted risk of 1-year mortality (adjusted hazard ratio 1·26, 95% CI 1·20-1·33, for highest vs lowest deprivation decile), but this gradient was largely attenuated after adjustment for the presence of pre-stroke diabetes, hypertension, and atrial fibrillation (1·11, 1·05-1·17). INTERPRETATION: Wide socioeconomic disparities exist in the burden of ischaemic stroke and intracerebral haemorrhage in England, most notably in stroke hospitalisation risk and case fatality and, to a lesser extent, in the quality of health care. Reducing these disparities requires interventions to improve the quality of acute stroke care and address disparities in cardiovascular risk factors present before stroke. FUNDING: NHS England and the Welsh Government.

Outcomes of Nonagenarians with Acute Ischemic Stroke Treated with Intravenous Thrombolytics.

BACKGROUND: Nonagenarians are under-represented in thrombolytic trials for acute ischemic stroke (AIS). The effectiveness of intravenous thrombolytics in nonagenarians in terms of safety and outcome is not well established. MATERIALS AND METHODS: We used a multinational registry to identify patients aged 90 years or older with good baseline functional status who presented with AIS. Differences in outcomes-disability level at 90 days, frequency of symptomatic intracerebral hemorrhage (sICH), and mortality-between patients who did and did not receive thrombolytics were assessed using multivariable logistic regression, adjusted for prespecified prognostic factors. Coarsened exact matching (CEM) was utilized before evaluating outcome by balancing both groups in the sensitivity analysis. RESULTS: We identified 227 previously independent nonagenarians with AIS; 122 received intravenous thrombolytics and 105 did not. In the unmatched cohort, ordinal analysis showed a significant treatment effect (adjusted common odds ratio [OR]: .61, 95% confidence interval [CI]: .39-.96). There was an absolute difference of 8.1% in the rate of excellent outcome in favor of thrombolysis (17.4% versus 9.3%; adjusted ratio: .30, 95% CI: .12-.77). Rates of sICH and in-hospital mortality were not different. Similarly, in the matched cohort, CEM analysis showed a shift in the primary outcome distribution in favor of thrombolysis (adjusted common OR: .45, 95% CI: .26-.76). CONCLUSIONS: Nonagenarians treated with thrombolytics showed lower stroke-related disability at 90 days than those not treated, without significant difference in sICH and in-hospital mortality rates. These observations cannot exclude a residual confounding effect, but provide evidence that thrombolytics should not be withheld from nonagenarians because of age alone.

The association between delays in screening for and assessing dysphagia after acute stroke, and the risk of stroke-associated pneumonia.

BACKGROUND: There is no robust evidence that screening patients with acute stroke for dysphagia reduces the risk of stroke-associated pneumonia (SAP), or of how quickly it should be done after admission. We aimed to identify if delays in bedside dysphagia screening and comprehensive dysphagia assessments by a speech and language therapist (SALT) were associated with patients' risk of SAP. METHODS: Nationwide, registry-based, prospective cohort study of patients admitted with acute stroke in England and Wales. Multilevel multivariable logistic regression models were fitted, adjusting for patient variables and stroke severity. The exposures were time from (1) admission to bedside dysphagia screen, and (2) admission to comprehensive dysphagia assessment. RESULTS: Of 63 650 patients admitted with acute stroke, 55 838 (88%) had a dysphagia screen, and 24 542 (39%) a comprehensive dysphagia assessment. Patients with the longest delays in dysphagia screening (4th quartile adjusted OR 1.14, 1.03 to 1.24) and SALT dysphagia assessment (4th quartile adjusted OR 2.01, 1.76 to 2.30) had a higher risk of SAP. The risk of SAP increased in a dose-response manner with delays in SALT dysphagia assessment, with an absolute increase of pneumonia incidence of 1% per day of delay. CONCLUSIONS: Delays in screening for and assessing dysphagia after stroke, are associated with higher risk of SAP. Since SAP is one of the main causes of mortality after acute stroke, early dysphagia assessment may contribute to preventing deaths from acute stroke and could be implemented even in settings without access to high-technology specialist stroke care.

Patient outcomes up to 15†years after stroke: survival, disability, quality of life, cognition and mental health.

BACKGROUND: The global epidemiological shift of disease burden towards long-term conditions means understanding long-term outcomes of cardiovascular disease is increasingly important. More people are surviving stroke to experience its long-term consequences, but outcomes in people living more >10 years after stroke have not been described in detail. METHODS: Data were collected for the population-based South London Stroke Register, with participants followed up annually until death. Outcomes were survival, disability, activity, cognitive impairment, quality of life, depression and anxiety. FINDINGS: Of 2625 people having first-ever stroke, 262 (21%) survived to 15 years. By 15 years, 61% (95% CI 55% to 67%) of the survivors were male, with a median age of stroke onset of 58 years (IQR 48-66). 87% of the 15-year survivors were living at home and 33.8% (26.2% to 42.4%) had mild disability, 14.3% (9.2% to 21.4%) moderate disability and 15.0% (9.9% to 22.3%) severe disability. The prevalence of disability increased with time but 1 in 10 of the 15-year survivors had lived with moderate-severe disability since their stroke. At 15 years, the prevalence of cognitive impairment was 30.0% (19.5% to 43.1%), depression 39.1% (30.9% to 47.9%) and anxiety 34.9% (27.0% to 43.8%), and survivors reported greater loss of physical than mental quality of life. CONCLUSIONS: One in five people live at least 15 years after a stroke and poor functional, cognitive and psychological outcomes affect a substantial proportion of these long-term survivors. As the global population of individuals with cardiovascular long-term conditions grows, research and health services will need to increasingly focus on preventing and managing the long-term consequences of stroke.