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Background and ObjectivesIn the past decade, there have been major improvements in the control of risk factors, acute stroke therapies, and rehabilitation after the availability of high-quality evidence and guidelines on best practices in the acute phase. In this changing landscape, we aimed to investigate the stroke admission rates, time trends, risk factors, and outcomes during the period of 2014–2019 using German nationwide data.MethodsWe obtained data of all acute stroke hospitalizations by the Federal Statistical Office. All hospitalized cases of adults (age 18 years or older) with acute stroke from the years 2014–2019 were analyzed regarding time trends, risk factors, treatments, morbidity, and in-hospital mortality according to stroke subtype (all-cause/ischemic/hemorrhagic).ResultsBetween 2014 and 2019, overall stroke hospitalizations in adults (median age = 76 years, [IQR: 65–83 years]) initially increased from 306,425 in 2014 to peak at 318,849 in 2017 before falling to again to 312,692 in 2019, whereas percentage stroke hospitalizations that resulted in death remained stable during this period at 8.5% in 2014 and 8.6% in 2019. In a multivariate model of 1,882,930 cases, the strongest predictors of in-hospital stroke mortality were hemorrhagic subtype (adjusted OR [aOR] = 3.06, 95% CI 3.02–3.10;p< 0.001), cancer (aOR = 2.11, 2.06–2.16;p< 0.001), congestive heart failure (aOR = 1.70, 1.67–1.73;p< 0.001), and lower extremity arterial disease (aOR = 1.76, 1.67–1.84;p< 0.001).DiscussionDespite recent advances in acute stroke care over the past decade, the percentage of stroke hospitalizations resulting in death remained unchanged. Further research is needed to determine how best to optimize stroke care pathways for multimorbid patients.

Patients who have had a transient ischaemic attack or minor stroke have an increased risk of cardiovascular events for the following 5 years. We aimed to assess 5-year functional outcomes in patients with transient ischaemic attack or minor ischaemic stroke and to determine the factors associated with long-term disability.We analysed data from patients in TIAregistry.org, an international, prospective, observational registry of patients with transient ischaemic attack or minor ischaemic stroke from 61 specialised centres in 21 countries. Patients aged 18 years or older who had a transient ischaemic attack or minor stroke within the previous 7 days between May 30, 2009, and Dec 30, 2011, with a baseline modified Rankin scale (mRS) score of 0-1, and who had been followed up for 5 years, were eligible for inclusion in this study. We evaluated whether existing comorbidities and stroke recurrence, categorised as disabling (mRS score of1, including death) or non-disabling (mRS score of 0-1), at 5 years after baseline, were associated with poor functional outcome (defined as an mRS score of1). We used multivariable generalised equation models for factors associated with poor functional outcome at 5 years and multivariable cause-specific Cox hazard regression models in case of stroke recurrence.Between May 30, 2009, and Dec 30, 2011, 3847 eligible patients were included in the study, 3105 (80·7%) of whom had an mRS evaluation at 5 years of follow-up. Median follow-up duration was 5·00 years (IQR 4·78-5·00). 710 (22·9%) of 3105 patients had an mRS score greater than 1 at 5 years. Factors associated with poor functional outcome at 5 years were older age (per 10-year increase, odds ratio [OR] 2·18, 95% CI 1·93-2·46; p0·0001), diabetes of any type (1·45, 1·18-1·78; p=0·0001), history of stroke or transient ischaemic attack before the qualifying event (1·74, 1·37-2·22; p0·0001), hypertension (1·38, 1·00-1·92; p=0·050), atrial fibrillation or flutter (1·52, 1·04-1·94; p=0·030), congestive heart failure (1·73, 1·22-2·46; p=0·0024), valvular disease (2·47, 1·70-3·58; p0·0001), stroke as qualifying event (1·31, 1·09-1·57; p=0·0037), history of peripheral artery disease (1·98, 1·28-3·07; p=0·0023), history of coronary artery disease (1·32, 1·00-1·74; p=0·049), intracranial haemorrhage during follow up (4·94, 1·91-12·78; p=0·0013), and living alone (1·32, 1·10-1·59; p=0·0031). Regular physical activity before the index event was associated with reduced risk of poor functional outcome (OR 0·52, 95% CI 0·42-0·66; p0·0001). 345 recurrent strokes had occurred at 5 years of follow-up, 141 (40·9%) of which were disabling or fatal. Stroke recurrence increased the risk of having a disability at 5 years (OR 3·52, 95% CI 2·37-5·22; p0·0001). Recurrent disabling or fatal strokes were independently associated with older age (per 10-year increase, hazard ratio [HR] 1·61, 95% CI 1·35-1·92; p0·0001), diabetes of any type (2·23, 1·56-3·17; p0·0001), National Institutes of Health Stroke Scale score of greater than 5 at discharge (5·11, 2·15-12·13; p=0·0013), history of coronary artery disease (1·76, 1·17-2·65; p=0·0063), history of stroke or transient ischaemic attack before the qualifying event (1·54, 1·03-2·29; p=0·035), congestive heart failure (1·86, 1·01-3·47; p=0·044), stroke as qualifying event (1·73, 1·22-2·45; p=0·0024), mRS score of greater than 1 at discharge (2·48, 1·27-4·87; p=0·0083), and intracranial haemorrhage during follow-up (17·15, 9·95-27·43; p0·0001). Regular physical activity before the index event was associated with reduced risk of recurrent disabling stroke at 5 years (HR 0·56, 95% CI 0·31-0·99; p=0·046), and 5-year disability without recurrent stroke (0·61, 0·47-0·79; p=0·0001).We found a substantial burden of disability (mRS score of1) at 5 years after transient ischaemic attack or minor ischemic stroke, and most predictors of this disability were modifiable risk factors. Patients who did regular physical exercise before the index event had a significantly reduced risk of disability at 5 years compared with patients who did no exercise.AstraZeneca, Sanofi, Bristol Myers Squibb, SOS Attaque Cérébrale Association.

Background: Contemporary data on stroke epidemiology and the availability of national stroke clinical registries are important for providing evidence to improve practice and support policy decisions. Aims: To update the most current incidence, case-fatality, and mortality rates on stroke and identify national stroke clinical registries worldwide. Methods: We searched multiple databases (based on our existing search strategy) to identify new original papers, published between 1 November 2018 and 15 December 2021, that met ideal criteria for data on stroke incidence and case-fatality, and added these to the studies reported in our last review. To identify national stroke clinical registries, we updated our last search, using PubMed, from 6 February 2015 until 6 January 2022. We also screened reference lists of review papers, citation history of papers, and the gray literature. Mortality codes for International Classification of Diseases (ICD)-9 and ICD-10 were extracted from the World Health Organization (WHO) for each country providing these data. Population denominators were obtained from the United Nations (UN) or WHO (when data were unavailable in the UN database). Crude and adjusted stroke mortality rates were calculated using country-specific population denominators, and the most recent years of mortality data available for each country. Results: Since our last report in 2020, there were two countries (Chile and France) with new incidence studies meeting criteria for ideal population-based studies. New data on case-fatality were found for Chile and Kenya. The most current mortality data were available for the year 2014 (1 country), 2015 (2 countries), 2016 (11 countries), 2017 (10 countries), 2018 (19 countries), 2019 (36 countries), and 2020 (29 countries). Four countries (Libya, Solomon Islands, United Arab Emirates, and Lebanon) reported mortality data for the first time. Since our last report on registries in 2017, we identified seven more national stroke clinical registries, predominantly in high-income countries. These newly identified registries yielded limited information. Conclusions: Up-to-date data on stroke incidence, case-fatality, and mortality continue to provide evidence of disparities and the scale of burden in low- and middle-income countries. Although more national stroke clinical registries were identified, information from these newly identified registries was limited. Highlighting data scarcity or even where a country is ranked might help facilitate more research or greater policy attention in this field.

Background: Patients who had a cryptogenic stroke (CS) suspected to be causally related to a patent foramen ovale (PFO) are candidates for percutaneous PFO closure. In such patients, it is important to screen for atrial fibrillation (AF). Limited guidance is available regarding AF monitoring strategies in CS patients with PFO addressing optimal monitoring technology and duration. Aim: To provide a narrative review of cardiac rhythm monitoring in CS patients considered for PFO closure, including current practices, stroke recurrences after CS, findings from monitoring studies in CS patients, and predictors for AF detection published in the literature. To propose a personalized strategy for cardiac monitoring in CS patients, accounting for aspects predicting AF detection. Summary of review: AF detection in CS patients is predicted by age, left atrial enlargement, prolonged PR interval, frequent premature atrial contractions, interatrial conduction block, diabetes, prior brain infarctions, leukoaraiosis, elevated B-type natriuretic peptide (BNP)/N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and a family history of AF, as well as composed scores (e.g. CHA2DS2-VASc, atrial fibrillation in embolic stroke of undetermined source (AF-ESUS)). The causal role of the PFO may be accounted for by the risk of paradoxical embolism (RoPE) score and/or the PFO-Associated Stroke Causal Likelihood (PASCAL) classification. Conclusion: A personalized approach to AF detection in CS patients is proposed, accounting for the likelihood of AF detection and aimed at obtaining sufficient confidence regarding the absence of AF in patients considered for PFO closure. In addition, the impact of high-risk PFO features on the monitoring strategy is discussed.

Background: GLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk. Methods: SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) were randomized cardiovascular outcome trials of subcutaneous and oral semaglutide in people with type 2 diabetes at high cardiovascular risk, respectively. Time to first stroke and stroke subtypes were analyzed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction P values. Risk of major adverse cardiovascular event was analyzed according to prior stroke. Results: A total of 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46–1.00]; P =0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29–0.89]; P =0.017). Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37–0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47–1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation ( P interaction =0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of major adverse cardiovascular event and prior stroke ( P interaction >0.05 for all). Conclusions: Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with type 2 diabetes at high cardiovascular risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01720446 and NCT02692716.

Reducing blood pressure (BP) is a highly effective strategy for long-term stroke prevention. Despite overwhelmingly clear evidence from randomized trials that antihypertensive therapy substantially reduces the risk of stroke in primary prevention, uncertainty still surrounds the issue of BP lowering after cerebrovascular events, and the risk of recurrent stroke, coronary events, and vascular death remains significant. Important questions in a secondary prevention setting include should everyone be treated regardless of their poststroke BP, how soon after a stroke should BP-lowering treatment be commenced, how intensively should BP be lowered, what drugs are best, and how should long-term BP control be optimized and monitored. We review the evidence on BP control after a transient ischemic attack or stroke to address these unanswered questions and draw attention to some recent developments that hold promise to improve management of BP in current practice.

Background: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines. Methods: We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from individual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis. Results: During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9–17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4–14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10–1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05–1.32]), per unit increase log e IL-6. Similar associations were observed for hsCRP (MACE RR, 1.19 [95% CI, 1.09–1.29]; recurrent stroke RR, 1.12 [95% CI, 1.04–1.21], per unit increase log e hsCRP). After adjustment for vascular risk factors and treatment, independent associations remained with MACE (IL-6, RR, 1.12 [95% CI, 1.04–1.21]; hsCRP, RR, 1.09 [95% CI, 1.04–1.15]) and recurrent stroke (IL-6, RR, 1.09 [95% CI, 1.00–1.19]; hsCRP, RR, 1.05 [95% CI, 1.00–1.11]). Comparing the top with the bottom quarters (Q4 versus Q1), IL-6 (RR, 1.35 [95% CI, 1.09–1.67]) and hsCRP (RR, 1.31 [95% CI, 1.07–1.61]) were associated with MACE after adjustment. Similar results were observed for recurrent stroke for IL-6 (RR, 1.33 [95% CI, 1.08–1.65]) but not hsCRP (RR, 1.16 [95% CI, 0.93–1.43]). Conclusions: Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.

Background and ObjectivesIndividuals with chronic kidney disease (CKD) appear to be at increased risk of cognitive impairment, with both vascular and neurodegenerative mechanisms postulated. To explore the vascular hypothesis, we studied the association between CKD and dementia before and after TIA and stroke.MethodsIn a prospective, population-based cohort study of TIA and stroke (Oxford Vascular Study; 2002–2012), pre-event and new postevent dementia were ascertained through direct patient assessment and follow-up for 5 years, supplemented by review of hospital/primary care records. Associations between pre-event dementia and CKD (defined as an estimated glomerular filtration rate [eGFR] 2) were examined using logistic regression and between postevent dementia and CKD using Cox and competing risk regression models, adjusted for age, sex, education, stroke severity, prior stroke, white matter disease, diabetes mellitus, and dysphasia.ResultsAmong 2,305 patients with TIA/stroke (median [interquartile range] age, 77 [67–84] years, 1,133 [49%] male, 688 [30%] TIA), 1,174 (50.9%) had CKD. CKD was associated with both pre-event (odds ratio [OR] 2.04 [95% confidence interval (CI) 1.52–2.72]; p < 0.001) and postevent dementia (hazard ratio [HR] 2.01 [95% CI 1.65–2.44]; p < 0.001), but these associations attenuated after adjustment for covariates (OR 0.92 [0.65–1.31]; p = 0.65 and HR 1.09 [0.85–1.39]; p = 0.50). The results were similar when a competing risk model was used (subdistribution HR [SHR] 1.74 [1.43–2.12]; p < 0.001, attenuating to 1.01 [0.78–1.33]; p = 0.92 with adjustment). CKD was more strongly associated with late (>1 year) postevent dementia (SHR 2.32 [1.70–3.17]; p < 0.001), particularly after TIA and minor stroke (SHR 3.08 [2.05–4.64]; p < 0.001), but not significantly so after adjustment (SHR 1.53 [0.90–2.60]; p = 0.12).DiscussionIn patients with TIA and stroke, CKD was not independently associated with either pre- or postevent dementia, suggesting that renal-specific mechanisms are unlikely to play an important role in aetiology.

Introduction: TIA and stroke cause cognitive impairment with a typical “vascular” pattern, including prominent frontal/executive deficits. Cognitive impairment is associated with increased delirium risk and the few available data suggest that executive dysfunction is important. We therefore determined the predictive value of both severity and pattern of cognitive deficits for delirium on long-term follow-up after TIA/stroke. Methods: Surviving TIA/stroke participants on October 1, 2013, in the Oxford Vascular Study (OXVASC) were assessed prospectively for delirium during all hospitalizations over the subsequent 6 months. Associations between OXVASC pre-admission mini-mental state examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores, and delirium during hospitalizations on follow-up were determined using logistic regression adjusted for covariates, including demographic factors, history of depression, baseline stroke severity, and admission illness severity. Results: Among 1,565 TIA/stroke survivors, 158 patients (mean/SD age = 79.2/11.5 years) had ≥1 admission and 59 (37%) had ≥1 delirium episode. Mean/SD time between baseline TIA/stroke and admission was 4.7/3.6 years and between most recent OXVASC cognitive testing and admission was 1.7/1.8 years. MMSE and MoCA scores were associated with delirium: odds ratio (OR) = 1.16 (95% CI 1.07–1.27, p < 0.0001 per point decrease in MMSE) and OR = 1.20 (1.11–1.30, p < 0.0001 MoCA) and associations were robust to adjustment for all covariates, including stroke severity: OR = 1.11 (1.01–1.22, p = 0.03, MMSE) and OR = 1.15 (1.05–1.25, p = 0.003, MoCA). All 10 subtests on the MoCA and 4/11 on the MMSE were significantly associated with delirium with highest predictive value for frontal/executive and recall domains. Conclusions: Cognitive impairment of increasing severity after TIA/stroke predisposed to delirium particularly deficits in frontal/executive domains and recall. Long-term risk of delirium should be considered as part of the overall cerebrovascular disease burden.

Background: Hypertension is the leading modifiable risk factor for cerebral small vessel diseases (SVDs). Yet, it is unknown whether antihypertensive drug classes differentially affect microvascular function in SVDs. Aims: To test whether amlodipine has a beneficial effect on microvascular function when compared to either losartan or atenolol, and whether losartan has a beneficial effect when compared to atenolol in patients with symptomatic SVDs. Design: TREAT-SVDs is an investigator-led, prospective, open-label, randomised crossover trial with blinded endpoint assessment (PROBE design) conducted at five study sites across Europe. Patients aged 18 years or older with symptomatic SVD who have an indication for antihypertensive treatment and are suffering from either sporadic SVD and a history of lacunar stroke or vascular cognitive impairment (group A) or CADASIL (group B) are randomly allocated 1:1:1 to one of three sequences of antihypertensive treatment. Patients stop their regular antihypertensive medication for a 2-week run-in period followed by 4-week periods of monotherapy with amlodipine, losartan and atenolol in random order as open-label medication in standard dose. Outcomes: The primary outcome measure is cerebrovascular reactivity (CVR) as determined by blood oxygen level dependent brain MRI signal response to hypercapnic challenge with change in CVR in normal appearing white matter as primary endpoint. Secondary outcome measures are mean systolic blood pressure (BP) and BP variability (BPv). Discussion: TREAT-SVDs will provide insights into the effects of different antihypertensive drugs on CVR, BP, and BPv in patients with symptomatic sporadic and hereditary SVDs. Funding: European Union’s Horizon 2020 programme. Trial registration: NCT03082014.

Introduction There is limited knowledge of the effects of blood pressure (BP) lowering on cerebral haemodynamics after transient ischaemic attack (TIA) and non-disabling stroke, particularly at older ages. We aimed to evaluate changes in transcranial Doppler (TCD) haemodynamic indices in patients undergoing early blood pressure lowering after TIA/non-disabling stroke, irrespective of age. Patients and methods Among consecutive eligible patients attending a rapid-access clinic with suspected TIA/non-disabling stroke and no evidence of extra/intracranial stenosis, hypertensive ones underwent intensive BP-lowering guided by daily home telemetric blood pressure monitoring (HBPM). Clinic-based BP, HBPM, End-tidal CO2 and bilateral middle cerebral artery (MCA) velocity on TCD were compared in the acute setting versus one-month follow-up; changes were stratified by baseline hypertension (clinic-BP≥140/90) and by age (Results In 697 patients with repeated TCD measures, mean/SD baseline systolic-BP (145.0/21.3 mmHg) was reduced by an average of 11.3/19.9 mmHg ( p < 0.0001) at one-month (133.7/17.4 mmHg), driven by patients hypertensive at baseline (systolic-BP change = −19.0/19.2 mmHg, p < 0.001; vs −0.5/15.4, p = 0.62 in normotensives). Compared with baseline, a significant change was observed at one-month only in mean/SD MCA end diastolic velocity (EDV) (0.77/7.26 cm/s, p = 0.005) and in resistance index (RI) (−0.005/0.051, p = 0.016), driven by hypertensive patients (mean/SD EDV change: 1.145/6.96 cm/s p = 0.001, RI change −0.007/0.06, p = 0.014). Findings were similar at all ages (EDV change – ptrend=0.357; RI change – ptrend=0.225), including 117 patients aged ≥80. EDV and RI changes were largest in 100 patients with clinic systolic-BP decrease ≥30 mmHg (mean/SD EDV change = 2.49/7.47 cm/s, p = 0.001; RI change −0.024/0.063, p < 0.0001). Conclusion There was no evidence of worsening of TCD haemodynamic indices associated with BP-lowering soon after TIA/non-disabling stroke, irrespective of age and degree of BP reduction. In fact, EDV increase and RI decrease observed after treatment of hypertensive patients suggest a decrease in distal vascular resistance.

Supplemental Digital Content is available in the text., Background and Purpose: Urgent assessment aimed at reducing stroke risk after transient ischemic attack or minor stroke is cost-effective over the short-term. However, it is unclear if the short-term impact is lost on long-term follow-up, with recurrent events being delayed rather than prevented. By 10-year follow-up of the EXPRESS study (Early Use of Existing Preventive Strategies for Stroke), previously showing urgent assessment reduced 90-day stroke risk by 80%, we determined whether that early benefit was still evident long-term for stroke risk, disability, and costs. Methods: EXPRESS was a prospective population-based before (phase 1: April 2002–September 2004; n=310) versus after (phase 2: October 2004–March 2007; n=281) study of the effect of early assessment and treatment of transient ischemic attack/minor stroke on early recurrent stroke risk, with an external control. This report assesses the effect on 10-year recurrent stroke risk, functional outcomes, quality-of-life, and costs. Results: A reduction in stroke risk in phase 2 was still evident at 10 years (55/23.3% versus 82/31.6%; hazard ratio=0.68 [95% CI, 0.48–0.95]; P=0.024), as was the impact on risk of disabling or fatal stroke (17/7.7% versus 32/13.1%; hazard ratio=0.54 [0.30–0.97]; P=0.036). These effects were due to maintenance of the early reduction in stroke risk, with neither additional benefit nor rebound catch-up after 90 days (post-90 days hazard ratio=0.88 [0.65–1.44], P=0.88; and hazard ratio=0.83 [0.42–1.65], P=0.59, respectively). Disability-free life expectancy was 0.59 (0.03–1.15; P=0.043) years higher in patients in phase 2, as was quality-adjusted life expectancy (0.49 [0.03–0.95]; P=0.036). Overall, 10-year costs were nonsignificantly higher in patients attending the phase 2 clinic ($1022 [-3865–5907]; P=0.66). The additional cost per quality-adjusted life year gained in phase 2 versus phase 1 was $2103, well below current cost-effectiveness thresholds. Conclusions: Urgent assessment and treatment of patients with transient ischemic attack or minor stroke resulted in a long-term reduction in recurrent strokes and improved outcomes, with little atrophy of the early benefit over time, representing good value for money even with a 10-year time horizon. Our results suggest that other effective acute treatments in transient ischemic attack/minor stroke in the short-term will also have the potential to have long-term benefit.

Background and Purpose: Blood pressure variability (BPV) from beat to beat is associated with an increased risk of cardiovascular events and enables rapid assessment of BPV, but the underlying causes of elevated BPV are unclear. Methods: In consecutive patients within 4 to 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), continuous noninvasive blood pressure was measured beat to beat over 5 minutes (Finometer). Arterial stiffness was measured by carotid-femoral pulse wave velocity (Sphygmocor). After automated and manual data cleaning, associations between BPV (residual coefficient of variation), demographic factors, and arterial stiffness were determined for both systolic and diastolic blood pressure, by ANOVA and linear models. Relationships between demographic factors and arterial stiffness were determined by interaction terms and mediation. Results: Among 1013 patients, 54 (5.3%) were in AF, and 51 (5%) had low-quality recordings. In a general linear model including the remaining 908 participants, systolic BPV (SBPV) was most strongly associated with age ( P =0.00003), body mass index (BMI; P =0.003), and arterial stiffness ( P =0.008), with weaker independent associations with current smoking ( P =0.01) and a low diastolic blood pressure ( P =0.046). However, while there was a linear increase in SBPV with BMI in men, in women, SBPV was lowest for a BMI in the normal range but was greater below 20 or above 30 (ANOVA, P =0.012; BMI-sex interaction, P =0.03). Although BMI and pulse wave velocity were partially independent, increased pulse wave velocity mediated ≈32% of the relationship between increased BMI and SBPV ( P Conclusions: Vascular aging, manifest as arterial stiffness, was a strong determinant of increased SBPV and partially mediated the effect of increased BMI. However, although high BMI was independently associated with SBPV in both sexes, a low BMI was associated with increased SBPV only in women. SBPV may partially mediate the relationship between BMI and cardiovascular events, while obesity may provide a modifiable target to reduce SBPV and cardiovascular events.

Background and Purpose: Prestroke dementia prevalence is high and impacts outcome. Although the IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly) is being used to assess prestroke cognition, data on its validity for prestroke dementia are lacking. We studied the accuracy of the short-form (16-item) IQCODE for pre-event dementia in a population-based study of all transient ischemic attack (TIA)/stroke. Methods: All patients with TIA/stroke in a defined population of ≈92 720 (Oxford Vascular Study, 2002–2017) with IQCODE were included. IQCODE questionnaires were given to participants at baseline interview with instructions to pass to an informant for completion and return by post. Diagnosis of pre-event dementia was defined as prior diagnosis of dementia, or dementia by the Diagnostic and Statistical Manual of Mental Disorders-IV criteria on study interview and hand-searching of the entire medical record blinded to IQCODE. Reliability of the IQCODE for dementia was determined by the area under the receiver operating characteristic curve, sensitivity and specificity, stratified by age, event severity, and first-ever stroke. Results: Among 2059 interviewed survivors, IQCODE were returned in 1068 (mean age/SD=72.9/12.3, 47% TIA, 52.3% male, 68 [6.4%] pre-event dementia). Area under the receiver operating characteristic curve for IQCODE for pre-event dementia was 0.94 (95% CI, 0.90–0.97, P 3.48 (sensitivity=89.7%; specificity=84.2%) but was nonsignificantly higher for major stroke (National Institutes of Health Stroke Scale score ≥3) than minor stroke/TIA (>3.85 versus >3.47). Performance was similar in patients with first-ever stroke (area under the receiver operating characteristic curve, 0.92 [0.88–0.97]; sensitivity=85.7%; specificity=84.8% for cutoff >3.48). All 16-IQCODE questions discriminated between dementia and no dementia (all P Conclusions: IQCODE has excellent accuracy for detecting preexisting dementia in TIA and stroke with the pattern of deficits suggesting prominent executive dysfunction.

Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Background Diagnosis of transient ischaemic attacks (TIAs) can be difficult. There is consensus on classic symptoms (eg, motor weakness, dysphasia, hemianopia, monocular visual loss) but no consensus on several monosymptomatic events with sudden-onset, non-progressive, focal negative symptoms (eg, isolated diplopia, dysarthria, vertigo, ataxia, sensory loss, and bilateral visual disturbance), with much variation in investigation and treatment. Methods We prospectively ascertained and investigated all strokes and sudden onset transient neurological symptoms in a population of 92 728 people (no age restrictions) from Oxfordshire, UK, who sought medical attention at nine primary care practices or at the John Radcliffe Hospital, Oxford, UK (Oxford Vascular Study). Patients classified at baseline with minor ischaemic stroke (National Institutes of Health Stroke Score Findings Between April 1, 2002, and March 31, 2018, 2878 patients were identified with minor ischaemic stroke (n=1287), classic TIA (n=1021), or non-consensus TIA (n=570). Follow-up was to Oct 1, 2018 (median 5·2 [IQR 2·6–9·2] years). 577 first recurrent strokes after the index event occurred during 17 009 person-years of follow-up. 90-day stroke risk from time of the index event after a non-consensus TIA was similar to that after classic TIA (10·6% [95% CI 7·8–12·9] vs 11·6% [95% CI 9·6–13·6]; hazard ratio 0·87, 95% CI 0·64–1·19; p=0·43), and higher than after amaurosis fugax (4·3% [95% CI 0·6–8·0]; p=0·042). However, patients with non-consensus TIA were less likely to seek medical attention on the day of the event than were those with classic TIA (336 of 570 [59%] vs 768 of 1021 [75%]; odds ratio [OR] 0·47, 95% CI 0·38–0·59; p Interpretation Patients with non-consensus TIA are at high early and long-term risk of stroke and have cardiovascular pathological findings on investigation similar to those of classic TIA. Designation of non-consensus TIAs as definite cerebrovascular events will increase overall TIA diagnoses by about 50%. Funding Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, Wolfson Foundation, Masonic Charitable Foundation, and British Heart Foundation.

Background There is uncertainty around which patients with asymptomatic carotid stenosis should be offered surgical intervention. Although stroke rates were unrelated to the degree of stenosis in the medical-treatment-only groups in previous randomised trials, this could simply reflect recruitment bias and there has been no systematic analysis of a stenosis-risk association in cohort studies. We aimed to establish whether there is any association between the degree of asymptomatic stenosis and ipsilateral stroke risk in patients on contemporary medical treatment. Methods We did a prospective population-based study (Oxford Vascular Study; OxVasc), and a systematic review and meta-analysis. All patients in OxVasc with a recent suspected transient ischaemic attack or stroke, between April 1, 2002, and April 1, 2017, who had asymptomatic carotid stenosis were included in these analyses. We commenced contemporary medical treatment and determined ipsilateral stroke risk in this cohort by face-to-face follow-up (to Oct 1, 2020). We also did a systematic review and meta-analysis of all published studies (from Jan 1, 1980, to Oct 1, 2020) reporting ipsilateral stroke risk in patients with asymptomatic carotid stenosis. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, and included both observational cohort studies and medical treatment groups of randomised controlled trials if the number of patients exceeded 30, ipsilateral stroke rates (or the raw data to calculate these) were provided, and were published in English. Findings Between April 1, 2002, and April 1, 2017, 2354 patients were consecutively enrolled in OxVasc and 2178 patients underwent carotid imaging, of whom 207 had 50–99% asymptomatic stenosis of at least one carotid bifurcation (mean age at imaging: 77·5 years [SD 10·3]; 88 [43%] women). The 5-year ipsilateral stroke risk increased with the degree of stenosis; patients with 70–99% stenosis had a significantly greater 5-year ipsilateral stroke risk than did those with 50–69% stenosis (six [14·6%; 95% CI 3·5–25·7] of 53 patients vs none of 154; p Interpretation Contrary to the assumptions of current guidelines and the findings of subgroup analyses of previous randomised controlled trials, the stroke risk reported in cohort studies was highly dependent on the degree of asymptomatic carotid stenosis, suggesting that the benefit of endarterectomy might be underestimated in patients with severe stenosis. Conversely, the 5-year stroke risk was low for patients with moderate stenosis on contemporary medical treatment, calling into question any benefit from revascularisation. Funding NIHR Oxford Biomedical Research Centre, Wellcome Trust, Wolfson Foundation, and the British Heart Foundation.

Background Intracranial atherosclerotic stenosis is a highly prevalent cause of stroke worldwide with important ethnic disparities. Widely considered to be a common cause of stroke in Asian and Afro-Caribbean populations, relatively less is known about the burden and significance of intracranial atherosclerotic stenosis in Caucasians. Aims We aim to highlight recent insights and advances into the prevalence, prognosis, and treatment of symptomatic and asymptomatic atherosclerotic intracranial atherosclerotic stenosis in Caucasian patients. Summary of review We identified 48 articles studying intracranial atherosclerotic stenosis in Caucasian patients with ischemic stroke or transient ischemic attack. Most studies were on hospital-based cohorts of consecutive patients and half were graded as “fair” quality. There was significant variation between studies in the definition of intracranial atherosclerotic stenosis and in the imaging modalities used to detect intracranial atherosclerotic stenosis. Overall, 12.1% of Caucasian patients were found to have any intracranial atherosclerotic stenosis, 6.4% symptomatic intracranial atherosclerotic stenosis and 11.1% asymptomatic intracranial atherosclerotic stenosis, with higher rates at older ages. In studies reporting prognosis, there were 61 and 10 same-territory ischemic strokes in 1000 person-years in patients with symptomatic and asymptomatic intracranial atherosclerotic stenosis, respectively. Percutaneous stenting and angioplasty have not proven superior to intensive medical management in patients with symptomatic intracranial atherosclerotic stenosis. Conclusions Intracranial atherosclerotic stenosis has previously been neglected as a cause of stroke in Caucasians but is highly prevalent at older ages and frequently discovered with the growing use of noninvasive angiography. Intensive medical therapy is the treatment of choice, but there is a need to develop novel treatments or therapeutic approaches to lower the risk of stroke in higher risk patients.

With both an aging population and greater post-stroke survival, multimorbidity is a growing healthcare challenge, affecting over 40% of stroke patients, and rising rapidly and predictably with increasing age. Commonly defined as the co-occurrence of two or more chronic conditions, multimorbidity burden is a strong adverse prognostic factor, associated with greater short- and long-term stroke mortality, worse rehabilitation outcomes, and reduced use of secondary prevention. Chronic kidney disease can be considered as the archetypal comorbidity, being age-dependent and also affecting about 40% of stroke patients. Chronic kidney disease and stroke share very similar traditional cardiovascular risk factor profiles such as hypertension and diabetes, though novel chronic kidney disease-specific risk factors such as inflammation and oxidative stress have also been proposed. Using chronic kidney disease as an exemplar condition, we explore the mechanisms of risk in multimorbidity, implications for management, impact on stroke severity, and downstream consequences such as post-stroke cognitive impairment and dementia.

Background Beat-to-beat blood pressure variability is associated with increased stroke risk but its importance at different ages is unclear. Aims To determine the age-sex distribution of blood pressure variability in patients with transient ischemic stroke or minor stroke. Methods In consecutive patients within six weeks of transient ischemic stroke or non-disabling stroke (Oxford Vascular Study), non-invasive blood pressure was measured beat-to-beat over five minutes (Finometer). The age-sex distribution of blood pressure variability (residual coefficient of variation) was determined for systolic blood pressure and diastolic blood pressure. The risk of top-decile blood pressure variability was estimated (logistic regression), unadjusted, and adjusted for age, sex, and cardiovascular risk factors. Results In 908 of 1013 patients, excluding 54 in atrial fibrillation and 51 with low quality recordings, residual coefficient of variation was positively skewed with a median systolic residual coefficient of variation of 4.2% (IQR 3.2–5.5) and diastolic residual coefficient of variation of 3.9% (3.0–5.5), with 90th centile thresholds of 7.2 and 7.3%. Median systolic residual coefficient of variation was higher in patients under 50 years (4.5 and 3.0–5.3) compared to 60–70 years (4.1 and 3.2–5.2), but rose to 4.5% (3.5–6.9) above 80 years, with an increasingly positive skew. The proportion of patients with markedly elevated blood pressure variability in the top-decile increased significantly per decade (OR 1.72, p Conclusions Median beat-to-beat blood pressure variability fell in midlife, reflecting loss of physiological, organized blood pressure variability. However, rates of markedly elevated blood pressure variability significantly increased with greater age, suggesting that blood pressure variability may be particularly important in older patients.

Cerebral arterial pulsatility is strongly associated with cerebral small vessel disease and lacunar stroke yet its dependence on central versus local haemodynamic processes is unclear. In a population-based study of patients on best medical managment, 4–6 weeks after a TIA or non-disabling stroke, arterial stiffness and aortic systolic, diastolic and pulse pressures were measured (Sphygmocor). Middle cerebral artery peak and trough flow velocities and Gosling’s pulsatility index were measured by transcranial ultrasound. In 981 participants, aortic and cerebral pulsatility rose strongly with age in both sexes, but aortic diastolic pressure fell more with age in men whilst cerebral trough velocity fell more in women. There was no significant association between aortic systolic or diastolic blood pressure with cerebral peak or trough flow velocity but aortic pulse pressure explained 37% of the variance in cerebral arterial pulsatility, before adjustment, whilst 49% of the variance was explained by aortic pulse pressure, arterial stiffness, age, gender and cardiovascular risk factors. Furthermore, arterial stiffness partially mediated the relationship between aortic and cerebral pulsatility. Overall, absolute aortic pressures and cerebral blood flow velocity were poorly correlated but aortic and cerebral pulsatility were strongly related, suggesting a key role for transmission of aortic pulsatility to the brain.

IntroductionUnruptured intracranial aneurysms (UIAs) are common incidental imaging findings, but there are few data in patients with transient ischaemic attack (TIA)/stroke. The frequency of UIA might be higher due to shared risk factors, but rupture risk might be reduced by intensive secondary prevention. We determined the prevalence and prognosis of UIA in patients with suspected TIA/minor stroke.MethodsAll patients referred to the population-based Oxford Vascular Study (2011–2020) with suspected TIA/minor stroke and non-invasive angiography were included. We determined the prevalence of incidental asymptomatic UIA and the risk of subsequent subarachnoid haemorrhage (SAH) by follow-up on intensive medical treatment, with guideline-based monitoring/management. We also did a systematic review of UIA prevalence/prognosis in cohorts with TIA/stroke.FindingsAmong 2013 eligible patients, 95 (4.7%) had 103 previously unknown asymptomatic UIA. Female sex (OR 2.3, 95% CI 1.5 to 3.7), smoking (2.1, 1.2 to 3.6) and hypertension (1.6, 1.0 to 2.5) were independently predictive of UIA, with a prevalence of 11.1% in those with all three risk factors. During mean follow-up of 4.5 years, only one SAH occurred: 2.3 (95% CI 0.3 to 16.6) per 1000 person-years. We identified 19 studies of UIA in TIA/stroke cohorts (n=12 781), all with either symptomatic carotid stenosis or major acute stroke. The pooled mean UIA prevalence in patients with TIA/stroke was 5.1% (95% CI 4.8 to 5.5) and the incidence of SAH was 4.6 (95% CI 1.9 to 11.0) per 1000 person-years.InterpretationThe 5% prevalence of UIA in patients with confirmed TIA/minor stroke is likely higher than that in the general population. However, the risk of SAH on intensive medical treatment and guideline-based management/monitoring is low.

Blood pressure–lowering drugs have different blood pressure–lowering profiles. We studied if differences in blood pressure mean and variability can explain the differences in risks of cardiovascular events and death among 15 245 high-risk hypertensive patients randomized to valsartan or amlodipine and followed for 4.2 years in the VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation). We selected patients with ≥3 visits and performed Cox regression analyses, defining mean blood pressure as a time-dependent covariate and visit-to-visit and within-visit blood pressure variability as the SD. Of 14 996 eligible patients, participants in the valsartan group had higher systolic mean blood pressure by 2.2 mm Hg, higher visit-to-visit systolic variability by 1.4 mm Hg, and higher within-visit systolic variability by 0.2 mm Hg ( P values

Supplemental Digital Content is available in the text., Background and Purpose— Population-based studies provide the most reliable data on stroke incidence. A previous systematic review of population-based studies suggested that stroke incidence in high-income countries decreased by 42% between the 1970s and early 2000s. However, it is uncertain whether this trend of steady decline has been maintained in more recent periods. Methods— Data from OCSP (Oxfordshire Community Stroke Project; 1981–1986) and OXVASC (Oxford Vascular Study; 2002–2017) along with other published population-based stroke incidence studies that reported temporal trends of stroke incidence since 1990 in high-income countries were included. Age-standardized relative incidence rate ratios were calculated for each study and then pooled with inverse-variance weighted random-effects meta-analysis. Projection estimates were calculated for the number of incident stroke patients in the United Kingdom from year 2015 to 2045. Results— In Oxfordshire, stroke incidence fell by 32% from OCSP to OXVASC, with a similar trend before or after year 2000. With the projected aging population, if the age-specific stroke incidence continued to decrease at its current rate (6% every 5 years), there would still be a 13% increase of the number of first-ever strokes in the United Kingdom up to year 2045. Incorporating the Oxfordshire data with other 12 population-based studies, stroke incidence declined steadily between the 1990s and 2010s within each study, resulting in a 28% decline over an average period of 16.5 years (pooled incidence rate ratio, 0.72 [95% CI, 0.66–0.79]; P

Background Data on stroke epidemiology and availability of hospital-based stroke services around the world are important for guiding policy decisions and healthcare planning. Aims To provide the most current incidence, mortality and case–fatality data on stroke and describe current availability of stroke units around the world by country. Methods We searched multiple databases (based on our existing search strategy) to identify new original manuscripts and review articles published between 1 June 2016 and 31 October 2018 that met the ideal criteria for data on stroke incidence and case–fatality. For data on the availability of hospital-based stroke services, we searched PubMed for all literature published up until 31 June 2018. We further screened reference lists, citation history of manuscripts and gray literature for this information. Mortality codes for International Classification of Diseases-9 and International Classification of Diseases-10 were extracted from the World Health Organization mortality database for each country providing these data. Population denominators were obtained from the World Health Organization, and when these were unavailable within a two-year period of mortality data, population denominators within a two-year period were obtained from the United Nations. Using country-specific population denominators and the most recent years of mortality data available for each country, we calculated both the crude mortality from stroke and mortality adjusted to the World Health Organization world population. Results Since our last report in 2017, there were two countries with new incidence studies, China ( n = 1) and India ( n = 2) that met the ideal criteria. New data on case–fatality were found for Estonia and India. The most current mortality data were available for the year 2015 (39 countries), 2016 (43 countries), and 2017 (7 countries). No new data on mortality were available for six countries. Availability of stroke units was noted for 63 countries, and the proportion of patients treated in stroke units was reported for 35/63 countries. Conclusion Up-to-date data on stroke incidence, case–fatality, and mortality statistics provide evidence of variation among countries and changing magnitudes of burden among high and low–middle income countries. Reporting of hospital-based stroke units remains limited and should be encouraged.

BackgroundPatients with primary intracerebral haemorrhage (ICH) are at increased long-term risks of recurrent stroke and other comorbidities. However, available estimates come predominantly from hospital-based studies with relatively short follow-up. Moreover, there are also uncertainties about the influence of ICH location on risks of recurrent stroke, disability, dementia and quality of life.MethodsIn a population-based study (Oxford Vascular Study/2002–2018) of patients with a first ICH with follow-up to 10 years, we determined the long-term risks of recurrent stroke, disability, quality of life, dementia and hospital care costs stratified by haematoma location.ResultsOf 255 cases with primary ICH (mean/SD age 75.5/13.1), 109 (42.7%) had lobar ICH, 144 (56.5%) non-lobar ICH and 2 (0.8%) had uncertain location. Annual rates of recurrent ICH were higher after lobar versus non-lobar ICH (lobar=4.0%, 2.7–7.2 vs 1.1%, 0.3–2.8; p=0.02). Moreover, cumulative rate of dementia was also higher for lobar versus non-lobar ICH (n/% lobar=20/36.4% vs 16/20.8%, p=0.047), and there was a higher proportion of disability at 5 years in survivors (15/60.0% vs 9/31.0%, p=0.03). The 10-year quality-adjusted life years (QALYs) were also lower after lobar versus non-lobar ICH (2.9 vs 3.8 for non-lobar, p=0.04). Overall, the mean 10-year censor-adjusted costs were £19 292, with over 80% of costs due to inpatient hospital admission costs, which did not vary by haematoma location (p=0.90).ConclusionCompared with non-lobar ICH, the substantially higher 10-year risks of recurrent stroke, dementia and lower QALYs after lobar ICH highlight the need for more effective prevention for this patient group.