Incidence of first stroke and ethnic differences in stroke pattern in Bradford, UK: Bradford Stroke Study

Background: Information on ethnic disparities in stroke between White and Pakistani population in Europe is scarce. Bradford District has the largest proportion of Pakistani people in England; this provides a unique opportunity to study the difference in stroke between the two major ethnic groups. Aim: To determine the first-ever-stroke incidence and examine the disparities in stroke patterns between Whites and Pakistanis in Bradford. Methods: Prospective 12 months study consisting of 273,327 adults (≥18 years) residents. Stroke cases were identified by multiple overlapping approaches. Results: In the study period, 541 first-ever-strokes were recorded. The crude incidence rate was 198 per 100,000 person-years. Age adjusted-standardized rate to the World Health Organization world population of first-ever-stroke is 155 and 101 per 100,000 person-years in Pakistanis and Whites respectively. Four hundred and thirty-eight patients (81%) were Whites, 83 (15.3%) were Pakistanis, 11 (2%) were Indian and Bangladeshis, and 9 (1.7%) were of other ethnic origin. Pakistanis were significantly younger and had more obesity (p = 0.049), and diabetes mellitus (DM) (p = <0.001). They were less likely to suffer from atrial fibrillation (p = <0.001), be ex- or current smokers (p = <0.001), and drink alcohol above the recommended level (p = 0.007) compared with Whites. In comparison with Whites, higher rates of age-adjusted stroke (1.5-fold), lacunar infarction (threefold), and ischemic infarction due to large artery disease (twofold) were found in the Pakistanis. Conclusions: The incidence of first-ever-stroke is higher in the Pakistanis compared with the Whites in Bradford, UK. Etiology and vascular risk factors vary between the ethnic groups. This information should be considered when investigating stroke etiology, and when planning prevention and care provision to improve outcomes after stroke

Genetically determined blood pressure, antihypertensive drug classes and risk of stroke subtypes

Objective: We employed Mendelian Randomization to explore whether the effects of blood pressure (BP) and BP lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from a GWAS on 757,601 individuals. Applying two-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of WMH. Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not beta blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for CCBs showed particularly strong associations with small vessel stroke and the related radiological phenotype of WMH. Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease

Effects of Antiplatelet Therapy After Stroke Caused by Intracerebral Hemorrhage Extended Follow-up of the RESTART Randomized Clinical Trial

Importance: The Restart or Stop Antithrombotics Randomized Trial (RESTART) found that antiplatelet therapy appeared to be safe up to 5 years after intracerebral hemorrhage (ICH) that had occurred during antithrombotic (antiplatelet or anticoagulant) therapy. Objectives: To monitor adherence, increase duration of follow-up, and improve precision of estimates of the effects of antiplatelet therapy on recurrent ICH and major vascular events. Design, Setting and Participants: From May 22, 2013, through May 31, 2018, this prospective, open, blinded end point, parallel-group randomized clinical trial studied 537 participants at 122 hospitals in the UK. Participants were individuals 18 years or older who had taken antithrombotic therapy for the prevention of occlusive vascular disease when they developed ICH, discontinued antithrombotic therapy, and survived for 24 hours. After initial follow-up ended on November 30, 2018, annual follow-up was extended until November 30, 2020, for a median of 3.0 years (interquartile range [IQR], 2.0-5.0 years) for the trial cohort. Interventions: Computerized randomization that incorporated minimization allocated participants (1:1) to start or avoid antiplatelet therapy. Main Outcomes and Measures: Participants were followed up for the primary outcome (recurrent symptomatic ICH) and secondary outcomes (all major vascular events) for up to 7 years. Data from all randomized participants were analyzed using Cox proportional hazards regression, adjusted for minimization covariates. Results: A total of 537 patients (median age, 76.0 years; IQR, 69.0-82.0 years; 360 [67.0%] male; median time after ICH onset, 76.0 days; IQR, 29.0-146.0 days) were randomly allocated to start (n = 268) or avoid (n = 269 [1 withdrew]) antiplatelet therapy. The primary outcome of recurrent ICH affected 22 of 268 participants (8.2%) allocated to antiplatelet therapy compared with 25 of 268 participants (9.3%) allocated to avoid antiplatelet therapy (adjusted hazard ratio, 0.87; 95% CI, 0.49-1.55; P = .64). A major vascular event affected 72 participants (26.8%) allocated to antiplatelet therapy compared with 87 participants (32.5%) allocated to avoid antiplatelet therapy (hazard ratio, 0.79; 95% CI, 0.58-1.08; P = .14). Conclusions and Relevance: Among patients with ICH who had previously taken antithrombotic therapy, this study found no statistically significant effect of antiplatelet therapy on recurrent ICH or all major vascular events. These findings provide physicians with some reassurance about the use of antiplatelet therapy after ICH if indicated for secondary prevention of major vascular events

Identifying dementia outcomes in UK Biobank: a validation study of primary care, hospital admissions and mortality data

Prospective, population-based studies that recruit participants in mid-life are valuable resources for dementia research. Follow-up in these studies is often through linkage to routinely-collected healthcare datasets. We investigated the accuracy of these datasets for dementia case ascertainment in a validation study using data from UK Biobank—an open access, population-based study of > 500,000 adults aged 40–69 years at recruitment in 2006–2010. From 17,198 UK Biobank participants recruited in Edinburgh, we identified those with ≥ 1 dementia code in their linked primary care, hospital admissions or mortality data and compared their coded diagnoses to clinical expert adjudication of their full-text medical record. We calculated the positive predictive value (PPV, the proportion of cases identified that were true positives) for all-cause dementia, Alzheimer’s disease and vascular dementia for each dataset alone and in combination, and explored algorithmic code combinations to improve PPV. Among 120 participants, PPVs for all-cause dementia were 86.8%, 87.3% and 80.0% for primary care, hospital admissions and mortality data respectively and 82.5% across all datasets. We identified three algorithms that balanced a high PPV with reasonable case ascertainment. For Alzheimer’s disease, PPVs were 74.1% for primary care, 68.2% for hospital admissions, 50.0% for mortality data and 71.4% in combination. PPV for vascular dementia was 43.8% across all sources. UK routinely-collected healthcare data can be used to identify all-cause dementia in prospective studies. PPVs for Alzheimer’s disease and vascular dementia are lower. Further research is required to explore the geographic generalisability of these findings

Incidence and Characteristics of Total Stroke in the United States

BACKGROUND AND PURPOSE: Stroke, increasingly referred to as a "brain attack", is one of the leading causes of death and the leading cause of adult disability in the United States. It has recently been estimated that there were three quarters of a million strokes in the United States in 1995. The aim of this study was to replicate the 1995 estimate and examine if there was an increase from 1995 to 1996 by using a large administrative claims database representative of all 1996 US inpatient discharges. METHODS: We used the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, release 5, which contains ≈ 20 percent of all 1996 US inpatient discharges. We identified stroke patients by using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes from 430 to 438, and we compared the 1996 database with that of 1995. RESULTS: There were 712,000 occurrences of stroke with hospitalization (95% CI 688,000 to 737,000) and an estimated 71,000 occurrences of stroke without hospitalization. This totaled 783,000 occurrences of stroke in 1996, compared to 750,000 in 1995. The overall rate for occurrence of total stroke (first-ever and recurrent) was 269 per 100,000 population (age- and sex-adjusted to 1996 US population). CONCLUSIONS: We estimate that there were 783,000 first-ever or recurrent strokes in the United States during 1996, compared to the figure of 750,000 in 1995. This study replicates and confirms the previous annual estimates of approximately three quarters of a million total strokes. This slight increase is likely due to the aging of the population and the population gain in the US from 1995 to 1996

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy. Methods RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627. Findings Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05). Interpretation Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision

Impact of detecting potentially serious incidental findings during multi-modal imaging [version 3; referees: 2 approved, 1 approved with reservations]

Background: There are limited data on the impact of feedback of incidental findings (IFs) from research imaging. We evaluated the impact of UK Biobank’s protocol for handling potentially serious IFs in a multi-modal imaging study of 100,000 participants (radiographer ‘flagging’ with radiologist confirmation of potentially serious IFs) compared with systematic radiologist review of all images. Methods: Brain, cardiac and body magnetic resonance, and dual-energy x-ray absorptiometry scans from the first 1000 imaged UK Biobank participants were independently assessed for potentially serious IFs using both protocols. We surveyed participants with potentially serious IFs and their GPs up to six months after imaging to determine subsequent clinical assessments, final diagnoses, emotional, financial and work or activity impacts. Results: Compared to systematic radiologist review, radiographer flagging resulted in substantially fewer participants with potentially serious IFs (179/1000 [17.9%] versus 18/1000 [1.8%]) and a higher proportion with serious final diagnoses (21/179 [11.7%] versus 5/18 [27.8%]). Radiographer flagging missed 16/21 serious final diagnoses (i.e., false negatives), while systematic radiologist review generated large numbers o

The Multiple Sclerosis Risk Sharing Scheme Monitoring Study – early results and lessons for the future

Background: Risk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS. Methods: This case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis (MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments. Results: Centres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies. Conclusion: Successful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed

Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls

BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms

Retinal arteriolar geometry is associated with cerebral white matter hyperintensities on MRI

Background. Cerebral small vessel disease (lacunar stroke and cerebral white matter hyperintensities) is caused by vessel abnormalities of unknown aetiology. Retinal vessels show developmental and pathophysiological similarities to cerebral small vessels and microvessel geometry may influence vascular efficiency. Hypothesis. We hypothesized that retinal arteriolar branching angles or co-efficients (the ratio of the sum of the cross sectional areas of the two daughter vessels to the cross sectional area of the parent vessel at an arteriolar bifurcation) may be associated with cerebral small vessel disease. Methods. We performed a cross-sectional observational study in a tertiary referral hospital, United Kingdom. An experienced stroke physician recruited consecutive patients presenting with lacunar ischaemic stroke with a control group consisting of patients with minor cortical ischaemic stroke. We performed brain magnetic resonance imaging to assess the recent infarct and periventricular and deep white matter hyperintensities. We subtyped stroke with clinical and radiological findings. We took digital retinal photography to assess retinal arteriolar branching co-efficients and branching angles using a semi-automated technique. Results. We recruited 205 patients (104 lacunar stroke, 101 cortical stroke), mean age 68 (Standard Deviation 12) years. With multivariate analysis, increased branching coefficient was associated with periventricular white matter hyperintensities (p=0.006) and ischaemic heart disease (p<0.001); decreased branching co-efficient with deep white matter hyperintensities (p=0.003) but not with lacunar stroke subtype (p=0.96). We found no associations with retinal branching angles. Conclusions. Retinal arteriolar geometry differs between cerebral small vessel phenotypes. More research is needed to ascertain the clinical significance of these findings