Genetic-Guided Pharmacotherapy for Atrial Fibrillation: A Systematic and Critical Review of Economic Evaluations.

OBJECTIVES: This study aimed to examine the extent and quality of evidence from economic evaluations (EEs) of genetic-guided pharmacotherapy (PGx) for atrial fibrillation (AF) and to identify variables influential in changing base-case conclusions. METHODS: From systematic searches, we included EEs of existing PGx testing to guide pharmacotherapy for AF, without restrictions on population characteristics or language. Articles excluded were genetic tests used to guide device-based therapy or focused on animals. RESULTS: We found 18 EEs (46 comparisons), all model-based cost-utility analysis with or without cost-effectiveness analysis mostly from health system's perspectives, of PGx testing to determine coumadin/direct-acting anticoagulant (DOAC) dosing (14 of 18), to stratify patients into coumadin/DOACs (3 of 18), or to increase patients' adherence to coumadin (1 of 18) versus non-PGx. Most PGx to determine coumadin dosing found PGx more costly and more effective than standard or clinical coumadin dosing (19 of 24 comparisons) but less costly and less effective than standard DOAC dosing (14 of 14 comparisons). The remaining comparisons were too few to observe any trend. Of 61 variables influential in changing base-case conclusions, effectiveness of PGx testing was the most common (37%), accounted for in the models using time-based or medication-based approaches or relative risk. The cost of PGx testing has decreased and plateaued over time. CONCLUSIONS: EEs to date only partially inform decisions on selecting optimal PGx testing for AF, because most evidence focuses on PGx testing to determine coumadin dosing, but less on other purposes. Future EE may refer to the list of influential variables and the approaches used to account for the effect of PGx testing to inform data collection and study design.

Risk prediction of 30-day mortality after stroke using machine learning: a nationwide registry-based cohort study.

BACKGROUNDS: We aimed to develop and validate machine learning (ML) models for 30-day stroke mortality for mortality risk stratification and as benchmarking models for quality improvement in stroke care. METHODS: Data from the UK Sentinel Stroke National Audit Program between 2013 to 2019 were used. Models were developed using XGBoost, Logistic Regression (LR), LR with elastic net with/without interaction terms using 80% randomly selected admissions from 2013 to 2018, validated on the 20% remaining admissions, and temporally validated on 2019 admissions. The models were developed with 30 variables. A reference model was developed using LR and 4 variables. Performances of all models was evaluated in terms of discrimination, calibration, reclassification, Brier scores and Decision-curves. RESULTS: In total, 488,497 stroke patients with a 12.3% 30-day mortality rate were included in the analysis. In 2019 temporal validation set, XGBoost model obtained the lowest Brier score (0.069 (95% CI: 0.068-0.071)) and the highest area under the ROC curve (AUC) (0.895 (95% CI: 0.891-0.900)) which outperformed LR reference model by 0.04 AUC (p < 0.001) and LR with elastic net and interaction term model by 0.003 AUC (p < 0.001). All models were perfectly calibrated for low (< 5%) and moderate risk groups (5-15%) and ≈1% underestimation for high-risk groups (> 15%). The XGBoost model reclassified 1648 (8.1%) low-risk cases by the LR reference model as being moderate or high-risk and gained the most net benefit in decision curve analysis. CONCLUSIONS: All models with 30 variables are potentially useful as benchmarking models in stroke-care quality improvement with ML slightly outperforming others.

Real-world effectiveness of steroids in severe COVID-19: a retrospective cohort study.

INTRODUCTION: Randomised controlled trials have shown that steroids reduce the risk of dying in patients with severe Coronavirus disease 2019 (COVID-19), whilst many real-world studies have failed to replicate this result. We aim to investigate real-world effectiveness of steroids in severe COVID-19. METHODS: Clinical, demographic, and viral genome data extracted from electronic patient record (EPR) was analysed from all SARS-CoV-2 RNA positive patients admitted with severe COVID-19, defined by hypoxia at presentation, between March 13th 2020 and May 27th 2021. Steroid treatment was measured by the number of prescription-days with dexamethasone, hydrocortisone, prednisolone or methylprednisolone. The association between steroid > 3 days treatment and disease outcome was explored using multivariable cox proportional hazards models with adjustment for confounders (including age, gender, ethnicity, co-morbidities and SARS-CoV-2 variant). The outcome was in-hospital mortality. RESULTS: 1100 severe COVID-19 cases were identified having crude hospital mortality of 15.3%. 793/1100 (72.1%) individuals were treated with steroids and 513/1100 (46.6%) received steroid ≤ 3 days. From the multivariate model, steroid > 3 days was associated with decreased hazard of in-hospital mortality (HR: 0.47 (95% CI: 0.31-0.72)). CONCLUSION: The protective effect of steroid treatment for severe COVID-19 reported in randomised clinical trials was replicated in this retrospective study of a large real-world cohort.

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.

Genetic-guided pharmacotherapy for venous thromboembolism: a systematic and critical review of economic evaluations.

Despite the known contributions of genes, genetic-guided pharmacotherapy has not been routinely implemented for venous thromboembolism (VTE). To examine evidence on cost-effectiveness of genetic-guided pharmacotherapy for VTE, we searched six databases, websites of four HTA agencies and citations, with independent double-reviewers in screening, data extraction, and quality rating. The ten eligible studies, all model-based, examined heterogeneous interventions and comparators. Findings varied widely; testing was cost-saving in two base-cases, cost-effective in four, not cost-effective in three, dominated in one. Of 22 model variables that changed decisions about cost-effectiveness, effectiveness/relative effectiveness of the intervention was the most frequent, albeit of poor quality. Studies consistently lacked details on the provision of interventions and comparators as well as on model development and validation. Besides improving the reporting of interventions, comparators, and methodological details, future economic evaluations should examine strategies recommended in guidelines and testing key model variables for decision uncertainty, to advise clinical implementations.

Diabetes As an Independent Risk Factor for Stroke Recurrence in Ischemic Stroke Patients: An Updated Meta-Analysis.

INTRODUCTION: Stroke and its recurrence and diabetes will increase in incidence as the population ages globally. This study explores the relationship between diabetes and stroke recurrence to understand if diabetes is an independent predictor for stroke recurrence in ischemic stroke (IS) patients. METHODS: We conducted a systematic review and meta-analysis of studies on the effect of diabetes on stroke recurrence among patients with IS. We searched population-based studies published before 15th February 2021 in PubMed and EMBASE following PRISMA guidelines. Random-effects estimates of the pooled hazard ratio (HR) and 95% confidence intervals (CIs) of each study were generated. A funnel plot and an Egger test were performed to evaluate publication bias. All statistical analyses were conducted in the R software 4.0.1 and Stata 16.0. RESULTS: The search identified 3,121 citations, of which 27 studies met inclusion criteria. Diabetes was associated with a significant risk of stroke recurrence in all IS patients (pooled HR, 1.50; 95% CI: 1.36-1.65; I2 = 61.0%). Similar results were found in lacunar stroke patients with diabetes (pooled HR, 1.65; 95% CI: 1.41-1.92; I2 = 22.0%). Moreover, we found that the risk of recurrent IS among patients of IS with diabetes was higher than that in those without diabetes (pooled HR, 1.53; 95% CI: 1.30-1.81; I2 = 74.0%). CONCLUSION: Diabetes is an independent risk factor for stroke recurrence among patients with IS.

Risk Prediction of Cognitive Decline after Stroke.

BACKGROUND AND PURPOSE: Cognitive decline is one of the major outcomes after stroke. We have developed and evaluated a risk predictive tool of post-stroke cognitive decline and assessed its clinical utility. METHODS: In this population-based cohort, 4,783 patients with first-ever stroke from the South London Stroke Register (1995-2010) were included in developing the model. Cognitive impairment was measured using the Mini Mental State Examination (cut off 24/30) and the Abbreviated Mental Test (cut off 8/10) at 3-months and yearly thereafter. A penalised mixed-effects linear model was developed and temporal-validated in a new cohort consisted of 1,718 stroke register participants recruited from (2011-2018). Prediction errors on discrimination and calibration were assessed. The clinical utility of the model was evaluated using prognostic accuracy measurements and decision curve analysis. RESULTS: The overall predictive model showed good accuracy, with root mean squared error of 0.12 and R2 of 73%. Good prognostic accuracy for predicting severe cognitive decline was observed AUC: (88%, 95% CI [85-90]), (89.6%, 95% CI [86-92]), (87%, 95% CI [85-91]) at 3 months, one and 5 years respectively. Average predicted recovery patterns were analysed by age, stroke subtype, Glasgow-coma scale, and left-stroke and showed variability. DECISION: curve analysis showed an increased clinical benefit, particularly at threshold probabilities of above 15% for predictive risk of cognitive impairment. CONCLUSIONS: The derived prognostic model seems to accurately screen the risk of post-stroke cognitive decline. Such prediction could support the development of more tailored management evaluations and identify groups for further study and future trials.

Risk and Secondary Prevention of Stroke Recurrence: A Population-Base Cohort Study.

BACKGROUND AND PURPOSE: With recent advances in secondary prevention management, stroke recurrence rates may have changed substantially. We aim to estimate risks and trends of stroke recurrence over the past 2 decades in a population-based cohort of patients with stroke. METHODS: Patients with a first-ever stroke between 1995 and 2018 in South London, United Kingdom (n=6052) were collected and analyzed. Rates of recurrent stroke with 95% CIs were stratified by 5-year period of index stroke and etiologic TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtype. Cumulative incidences were estimated and multivariate Cox models applied to examine associations of recurrence and recurrence-free survival. RESULTS: The rate of stroke recurrence at 5 years reduced from 18% (95% CI, 15%-21%) in those who had their stroke in 1995 to 1999 to 12% (10%-15%) in 2000 to 2005, and no improvement since. Recurrence-free survival has improved (35%, 1995-1999; 67%, 2010-2015). Risk of recurrence or death is lowest for small-vessel occlusion strokes and other ischemic causes (36% and 27% at 5 years, respectively). For cardioembolic and hemorrhagic index strokes around half of first recurrences are of the same type (54% and 51%, respectively). Over the whole study period a 54% increased risk of recurrence was observed among those who had atrial fibrillation before the index stroke (hazard ratio, 1.54 [1.09-2.17]). CONCLUSIONS: The rate of recurrence reduced until mid-2000s but has not changed over the last decade. The majority of cardioembolic or hemorrhagic strokes that have a recurrence are stroke of the same type indicating that the implementation of effective preventive strategies is still suboptimal in these stroke subtypes.

Burden of Stroke in Europe: Thirty-Year Projections of Incidence, Prevalence, Deaths, and Disability-Adjusted Life Years.

BACKGROUND AND PURPOSE: Prediction of stroke impact provides essential information for healthcare planning and priority setting. We aim to estimate 30-year projections of stroke epidemiology in the European Union using multiple modeling approaches. METHODS: Data on stroke incidence, prevalence, deaths, and disability-adjusted life years in the European Union between 1990 and 2017 were obtained from the global burden of disease study. Their trends over time were modeled using 3 modeling strategies: linear, Poisson, and exponential regressions-adjusted for the gross domestic product per capita, which reflects the impact of economic development on health status. We used the Akaike information criterion for model selection. The 30-year projections up to 2047 were estimated using the best fitting models, with inputs on population projections from the United Nations and gross domestic product per capita prospects from the World Bank. The technique was applied separately by age-sex-country groups for each stroke measure. RESULTS: In 2017, there were 1.12 million incident strokes in the European Union, 9.53 million stroke survivors, 0.46 million deaths, and 7.06 million disability-adjusted life years lost because of stroke. By 2047, we estimated an additional 40 000 incident strokes (+3%) and 2.58 million prevalent cases (+27%). Conversely, 80 000 fewer deaths (-17%) and 2.31 million fewer disability-adjusted life years lost (-33%) are projected. The largest increase in the age-adjusted incidence and prevalence rates are expected in Lithuania (average annual percentage change, 0.48% and 0.7% respectively), and the greatest reductions in Portugal (-1.57% and -1.3%). Average annual percentage change in mortality rates will range from -2.86% (Estonia) to -0.08% (Lithuania), and disability-adjusted life years' from -2.77% (Estonia) to -0.23% (Romania). CONCLUSIONS: The number of people living with stroke is estimated to increase by 27% between 2017 and 2047 in the European Union, mainly because of population ageing and improved survival rates. Variations are expected to persist between countries showing opportunities for improvements in prevention and case management particularly in Eastern Europe.

Long-term trends in death and dependence after ischaemic strokes: A retrospective cohort study using the South London Stroke Register (SLSR).

BACKGROUND: There have been reductions in stroke mortality over recent decades, but estimates by aetiological subtypes are limited. This study estimates time trends in mortality and functional dependence by ischaemic stroke (IS) aetiological subtype over a 16-year period. METHODS AND FINDINGS: The study population was 357,308 in 2011; 50.4% were males, 56% were white, and 25% were of black ethnic backgrounds. Population-based case ascertainment of stroke was conducted, and all participants who had their first-ever IS between 2000 and 2015 were identified. Further classification was concluded according to the underlying mechanism into large-artery atherosclerosis (LAA), cardio-embolism (CE), small-vessel occlusion (SVO), other determined aetiologies (OTH), and undetermined aetiologies (UND). Temporal trends in survival rates were examined using proportional-hazards survival modelling, adjusted for demography, prestroke risk factors, case mix variables, and processes of care. We carried out additional regression analyses to explore patterns in case-fatality rates (CFRs) at 30 days and 1 year and to explore whether these trends occurred at the expense of greater functional dependence (Barthel Index [BI] < 15) among survivors. A total of 3,128 patients with first-ever ISs were registered. The median age was 70.7 years; 50.9% were males; and 66.2% were white, 25.5% were black, and 8.3% were of other ethnic groups. Between 2000-2003 and 2012-2015, the adjusted overall mortality decreased by 24% (hazard ratio [HR] per year 0.976; 95% confidence interval [CI] 0.959-0.993). Mortality reductions were equally noted in both sexes and in the white and black populations but were only significant in CE strokes (HR per year 0.972; 95% CI 0.945‒0.998) and in patients aged ≥55 years (HR per year 0.975; 95% CI 0.959‒0.992). CFRs within 30 days and 1 year after an IS declined by 38% (rate ratio [RR] per year 0.962; 95% CI 0.941‒0.984) and 37% (RR per year 0.963; 95% CI 0.949‒0.976), respectively. Recent IS was independently associated with a 23% reduced risk of functional dependence at 3 months after onset (RR per year 0.983; 95% CI 0.968-0.998; p = 0.002 for trend). The study is limited by small number of events in certain subgroups (e.g., LAA), which could have led to insufficient power to detect significant trends. CONCLUSIONS: Both mortality and 3-month functional dependence after IS decreased by an annual average of around 2.4% and 1.7%, respectively, during 2000‒2015. Such reductions were particularly evident in strokes of CE origins and in those aged ≥55 years.

Trends in prevalence of acute stroke impairments: A population-based cohort study using the South London Stroke Register.

BACKGROUND: Acute stroke impairments often result in poor long-term outcome for stroke survivors. The aim of this study was to estimate the trends over time in the prevalence of these acute stroke impairments. METHODS AND FINDINGS: All first-ever stroke patients recorded in the South London Stroke Register (SLSR) between 2001 and 2018 were included in this cohort study. Multivariable Poisson regression models with robust error variance were used to estimate the adjusted prevalence of 8 acute impairments, across six 3-year time cohorts. Prevalence ratios comparing impairments over time were also calculated, stratified by age, sex, ethnicity, and aetiological classification (Trial of Org 10172 in Acute Stroke Treatment [TOAST]). A total of 4,683 patients had a stroke between 2001 and 2018. Mean age was 68.9 years, 48% were female, and 64% were White. After adjustment for demographic factors, pre-stroke risk factors, and stroke subtype, the prevalence of 3 out of the 8 acute impairments declined during the 18-year period, including limb motor deficit (from 77% [95% CI 74%-81%] to 62% [56%-68%], p < 0.001), dysphagia (37% [33%-41%] to 15% [12%-20%], p < 0.001), and urinary incontinence (43% [39%-47%) to 29% [24%-35%], p < 0.001). Declines in limb impairment over time were 2 times greater in men than women (prevalence ratio 0.73 [95% CI 0.64-0.84] and 0.87 [95% CI 0.77-0.98], respectively). Declines also tended to be greater in younger patients. Stratified by TOAST classification, the prevalence of all impairments was high for large artery atherosclerosis (LAA), cardioembolism (CE), and stroke of undetermined aetiology. Conversely, small vessel occlusions (SVOs) had low levels of all impairments except for limb motor impairment and dysarthria. While we have assessed 8 key acute stroke impairments, this study is limited by a focus on physical impairments, although cognitive impairments are equally important to understand. In addition, this is an inner-city cohort, which has unique characteristics compared to other populations. CONCLUSIONS: In this study, we found that stroke patients in the SLSR had a complexity of acute impairments, of which limb motor deficit, dysphagia, and incontinence have declined between 2001 and 2018. These reductions have not been uniform across all patient groups, with women and the older population, in particular, seeing fewer reductions.

Inverse problem approach to regularized regression models with application to predicting recovery after stroke.

Regression modelling is a powerful statistical tool often used in biomedical and clinical research. It could be formulated as an inverse problem that measures the discrepancy between the target outcome and the data produced by representation of the modelled predictors. This approach could simultaneously perform variable selection and coefficient estimation. We focus particularly on a linear regression issue, Y ∼ N ( X ß , σ I n ) , where ß ∈ R p is the parameter of interest and its components are the regression coefficients. The inverse problem finds an estimate for the parameter ß , which is mapped by the linear operator ( L : ß âŸ¶ X ß ) to the observed outcome data Y = X ß + ε . This problem could be conveyed by finding a solution in the affine subspace L - 1 ( Y ) . However, in the presence of collinearity, high-dimensional data and high conditioning number of the related covariance matrix, the solution may not be unique, so the introduction of prior information to reduce the subset L - 1 ( Y ) and regularize the inverse problem is needed. Informed by Huber's robust statistics framework, we propose an optimal regularizer to the regression problem. We compare results of the proposed method and other penalized regression regularization methods: ridge, lasso, adaptive-lasso and elastic-net under different strong hypothesis such as high conditioning number of the covariance matrix and high error amplitude, on both simulated and real data from the South London Stroke Register. The proposed approach can be extended to mixed regression models. Our inverse problem framework coupled with robust statistics methodology offer new insights in statistical regression and learning. It could open a new research development for model fitting and learning.

The Impact of Pre- and Post-Stroke Statin Use on Stroke Severity and Long-Term Outcomes: A Population-Based Cohort Study.

BACKGROUND: The benefit of statins on stroke incidence is well known. However, data on the relationship between pre- and post-stroke statin use, recurrence, and survival outcomes are limited. We aim to investigate the short- and long-term relationships between statin prescription, stroke recurrence, and survival in patients with first-ever ischemic stroke. METHODS: Data were collected from the population-based South London Stroke Register for the years 1995-2015. Patients were assessed at the time of first ever stroke, 3 months, and annually thereafter. Data on vascular risk factors, treatments prescribed, sociodemographic characteristics, stroke subtype, survival, and stroke recurrence were collected. Cox proportional hazard analyses were used to assess the relationship of statin prescriptions pre- and post-stroke on stroke severity, long-term recurrence and survival. RESULTS: Patients prescribed statins both pre- and post-stroke showed a 24% reduction in mortality (adjusted Hazard Ratio [aHR] 0.76, 0.60-0.97), those who were prescribed statins pre-stroke and then stopped post-stroke showed greater risk of mortality (aHR 1.85, 1.10-3.12) and stroke recurrence (aHR 3.25, 1.35-7.84) compared to those that were not prescribed statins at any time. No associations were observed between pre-stroke statin and severity of the initial stroke overall, though a protective effect against moderate/severe stroke (Glasgow Coma Scale ≤12) was observed in those aged 75+ years (aOR 0.70, 0.52-0.95). CONCLUSIONS: Statins play a significant role in improving the survival rates after a stroke. Adherence to the National Guidelines that promote statin treatment, primary and secondary prevention of stroke should be monitored and a focus for quality improvement programs.

Long-Term Survival After Intravenous Thrombolysis for Ischemic Stroke: A Propensity Score-Matched Cohort With up to 10-Year Follow-Up.

BACKGROUND AND PURPOSE: Intravenous thrombolysis with alteplase is one of the few approved treatments for acute ischemic stroke; nevertheless, little is known about its long-term effects on survival and recovery because clinical trials follow-up times are limited. METHODS: Patients registered between January 2005 and December 2015, to the population-based South London Stroke Register of first-ever strokes. Propensity score was used to match thrombolyzed and control cases to a 1:2 ratio by demographical and clinical covariates. The primary outcome was survival up to 10 years using Kaplan-Meier estimates, Cox proportional hazards, and restricted mean survival time. Secondary outcomes included stroke recurrence and functional status (Barthel Index and Frenchay Activities Index scores) at 5 years. RESULTS: From 2052 ischemic strokes, 246 treated patients were matched to 492 controls. Median follow-up time 5.45 years (interquartile range, 4.56). Survival was higher in the treatment group (median, 5.72 years) compared with control group (4.98 years, stratified log-rank test <0.001). The number needed to treat to prevent 1 death at 5 years was 12 and 20 at 10 years. After Cox regression analysis, thrombolysis reduced risk of mortality by 37% (hazard ratio, 0.63; 95% confidence interval [CI], 0.48-0.82) at 10 years; however, after introducing a multiplicative interaction term into the model, mortality risk reduction was 42% (hazard ratio, 0.58; 95% CI, 0.40-0.82) at 10 years for those arriving within 3 hours to the hospital. On average, in a 10-year period, treated patients lived 1 year longer than controls. At 5 years, thrombolysis was associated with independence (Barthel Index≥90; odds ratio, 3.76; 95% CI, 1.22-13.34) and increased odds of a higher Frenchay Activities Index (proportional odds ratio, 2.37; 95% CI, 1.16-4.91). There was no difference in stroke recurrence. CONCLUSIONS: Thrombolysis with intravenous alteplase is associated with improved long-term survival and functional status after ischemic stroke.

Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND AND PURPOSE: A variant in the histone deacetylase 9 (HDAC9) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate. METHODS: Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression. RESULTS: A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P=0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3-0.7; P=0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29-0.77; P=0.003). CONCLUSIONS: These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke.

Long-term trends in incidence and risk factors for ischaemic stroke subtypes: Prospective population study of the South London Stroke Register.

BACKGROUND: As the average life expectancy increases, more people are predicted to have strokes. Recent studies have shown an increasing incidence in certain types of cerebral infarction. We aimed to estimate time trends in incidence, prior risk factors, and use of preventive treatments for ischaemic stroke (IS) aetiological subtypes and to ascertain any demographic disparities. METHODS AND FINDINGS: Population-based data from the South London Stroke Register (SLSR) between 2000 and 2015 were studied. IS was classified, based on the underlying mechanism, into large-artery atherosclerosis (LAA), cardio-embolism (CE), small-vessel occlusion (SVO), other determined aetiologies (OTH), and undetermined aetiologies (UND). After calculation of age-, sex-, and ethnicity-specific incidence rates by subtype for the 16-year period, we analysed trends using Cochran-Armitage tests, Poisson regression models, and locally estimated scatterplot smoothers (loess). A total of 3,088 patients with first IS were registered. Between 2000-2003 and 2012-2015, the age-adjusted incidence of IS decreased by 43% from 137.3 to 78.4/100,000/year (incidence rate ratio [IRR] 0.57, 95% CI 0.5-0.64). Significant declines were observed in all subtypes, particularly in SVO (37.4-18; p < 0.0001) and less in CE (39.3-25; p < 0.0001). Reductions were recorded in males and females, younger (<55 years old) and older (≥55 years old) individuals, and white and black ethnic groups, though not significantly in the latter (144.6-116.2; p = 0.31 for IS). A 4-fold increase in prior-to-stroke use of statins was found (adjusted odds ratio [OR] 4.39, 95% CI 3.29-5.86), and despite the increasing prevalence of hypertension (OR 1.54, 95% CI 1.21-1.96) and atrial fibrillation (OR 1.7, 95% CI 1.22-2.36), preventive use of antihypertensive and antiplatelet drugs was declining. A smaller number of participants in certain subgroup-specific analyses (e.g., black ethnicity and LAA subtype) could have limited the power to identify significant trends. CONCLUSIONS: The incidence of ISs has been declining since 2000 in all age groups but to a lesser extent in the black population. The reported changes in medication use are unlikely to fully explain the reduction in stroke incidence; however, innovative prevention strategies and better management of risk factors may contribute further reduction.

Patient, carer and public involvement in major system change in acute stroke services: The construction of value.

BACKGROUND: Patient and public involvement is required where changes to care provided by the UK National Health Service are proposed. Yet involvement is characterized by ambiguity about its rationales, methods and impact. AIMS: To understand how patients and carers were involved in major system changes (MSCs) to the delivery of acute stroke care in 2 English cities, and what kinds of effects involvement was thought to produce. METHODS: Analysis of documents from both MSC projects, and retrospective in-depth interviews with 45 purposively selected individuals (providers, commissioners, third-sector employees) involved in the MSC. RESULTS: Involvement was enacted through consultation exercises; lay membership of governance structures; and elicitation of patient perspectives. Interviewees' views of involvement in these MSCs varied, reflecting different views of involvement per se, and of implicit quality criteria. The value of involvement lay not in its contribution to acute service redesign but in its facilitation of the changes developed by professionals. We propose 3 conceptual categories-agitation management, verification and substantiation-to identify types of process through which involvement was seen to facilitate system change. DISCUSSION: Involvement was seen to have strategic and intrinsic value. Its strategic value lay in facilitating the implementation of a model of care that aimed to deliver evidence-based care to all; its intrinsic value was in the idea of citizen participation in change processes as an end in its own right. The concept of value, rather than impact, may provide greater traction in analyses of contemporary involvement practices.

Patient experience of centralized acute stroke care pathways.

BACKGROUND: In 2010, Greater Manchester (GM) and London centralized acute stroke care services into a reduced number of hyperacute stroke units, with local stroke units providing on-going care nearer patients' homes. OBJECTIVE: To explore the impact of centralized acute stroke care pathways on the experiences of patients. DESIGN: Qualitative interview study. Thematic analysis was undertaken, using deductive and inductive approaches. Final data analysis explored themes related to five chronological phases of the centralized stroke care pathway. SETTING AND PARTICIPANTS: Recruitment from 3 hospitals in GM (15 stroke patients/8 family members) and 4 in London (21 stroke patients/9 family members). RESULTS: Participants were impressed with emergency services and initial reception at hospital: disquiet about travelling further than a local hospital was allayed by clear explanations. Participants knew who was treating them and were involved in decisions. Difficulties for families visiting hospitals a distance from home were raised. Repatriation to local hospitals was not always timely, but no detrimental effects were reported. Discharge to the community was viewed less positively. DISCUSSION AND CONCLUSIONS: Patients on the centralized acute stroke care pathways reported many positive aspects of care: the centralization of care pathways can offer patients a good experience. Disadvantages of travelling further were perceived to be outweighed by the opportunity to receive the best quality care. This study highlights the necessity for all staff on a centralized care pathway to provide clear and accessible information to patients, in order to maximize their experience of care.

The potential role of cost-utility analysis in the decision to implement major system change in acute stroke services in metropolitan areas in England.

BACKGROUND: The economic implications of major system change are an important component of the decision to implement health service reconfigurations. Little is known about how best to report the results of economic evaluations of major system change to inform decision-makers. Reconfiguration of acute stroke care in two metropolitan areas in England, namely London and Greater Manchester (GM), was used to analyse the economic implications of two different implementation strategies for major system change. METHODS: A decision analytic model was used to calculate difference-in-differences in costs and outcomes before and after the implementation of two major system change strategies in stroke care in London and GM. Values in the model were based on patient level data from Hospital Episode Statistics, linked mortality data from the Office of National Statistics and data from two national stroke audits. Results were presented as net monetary benefit (NMB) and using Programme Budgeting and Marginal Analysis (PBMA) to assess the costs and benefits of a hypothetical typical region in England with approximately 4000 strokes a year. RESULTS: In London, after 90 days, there were nine fewer deaths per 1000 patients compared to the rest of England (95% CI -24 to 6) at an additional cost of £770,027 per 1000 stroke patients admitted. There were two additional deaths (95% CI -19 to 23) in GM, with a total costs saving of £156,118 per 1000 patients compared to the rest of England. At a £30,000 willingness to pay the NMB was higher in London and GM than the rest of England over the same time period. The results of the PBMA suggest that a GM style reconfiguration could result in a total greater health benefit to a region. Implementation costs were £136 per patient in London and £75 in GM. CONCLUSIONS: The implementation of major system change in acute stroke care may result in a net health benefit to a region, even one functioning within a fixed budget. The choice of what model of stroke reconfiguration to implement may depend on the relative importance of clinical versus cost outcomes.

Weekly variation in health-care quality by day and time of admission: a nationwide, registry-based, prospective cohort study of acute stroke care.

BACKGROUND: Studies in many health systems have shown evidence of poorer quality health care for patients admitted on weekends or overnight than for those admitted during the week (the so-called weekend effect). We postulated that variation in quality was dependent on not only day, but also time, of admission, and aimed to describe the pattern and magnitude of variation in the quality of acute stroke care across the entire week. METHODS: We did this nationwide, registry-based, prospective cohort study using data from the Sentinel Stroke National Audit Programme. We included all adult patients (aged >16 years) admitted to hospital with acute stroke (ischaemic or primary intracerebral haemorrhage) in England and Wales between April 1, 2013, and March 31, 2014. Our outcome measure was 30 day post-admission survival. We estimated adjusted odds ratios for 13 indicators of acute stroke-care quality by fitting multilevel multivariable regression models across 42 4-h time periods per week. FINDINGS: The study cohort comprised 74,307 patients with acute stroke admitted to 199 hospitals. Care quality varied across the entire week, not only between weekends and weekdays, with different quality measures showing different patterns and magnitudes of temporal variation. We identified four patterns of variation: a diurnal pattern (thrombolysis, brain scan within 12 h, brain scan within 1 h, dysphagia screening), a day of the week pattern (stroke physician assessment, nurse assessment, physiotherapy, occupational therapy, and assessment of communication and swallowing by a speech and language therapist), an off-hours pattern (door-to-needle time for thrombolysis), and a flow pattern whereby quality changed sequentially across days (stroke-unit admission within 4 h). The largest magnitude of variation was for door-to-needle time within 60 min (range in quality 35-66% [16/46-232/350]; coefficient of variation 18·2). There was no difference in 30 day survival between weekends and weekdays (adjusted odds ratio 1·03, 95% CI 0·95-1·13), but patients admitted overnight on weekdays had lower odds of survival (0·90, 0·82-0·99). INTERPRETATION: The weekend effect is a simplification, and just one of several patterns of weekly variation occurring in the quality of stroke care. Weekly variation should be further investigated in other health-care settings, and quality improvement should focus on reducing temporal variation in quality and not only the weekend effect. FUNDING: None.