Post-trial monitoring of a randomised controlled trial of intensive glycaemic control in type 2 diabetes extended from 10 years to 24 years (UKPDS 91).

BACKGROUND: The 20-year UK Prospective Diabetes Study showed major clinical benefits for people with newly diagnosed type 2 diabetes randomly allocated to intensive glycaemic control with sulfonylurea or insulin therapy or metformin therapy, compared with conventional glycaemic control. 10-year post-trial follow-up identified enduring and emerging glycaemic and metformin legacy treatment effects. We aimed to determine whether these effects would wane by extending follow-up for another 14 years. METHODS: 5102 patients enrolled between 1977 and 1991, of whom 4209 (82·5%) participants were originally randomly allocated to receive either intensive glycaemic control (sulfonylurea or insulin, or if overweight, metformin) or conventional glycaemic control (primarily diet). At the end of the 20-year interventional trial, 3277 surviving participants entered a 10-year post-trial monitoring period, which ran until Sept 30, 2007. Eligible participants for this study were all surviving participants at the end of the 10-year post-trial monitoring period. An extended follow-up of these participants was done by linking them to their routinely collected National Health Service (NHS) data for another 14 years. Clinical outcomes were derived from records of deaths, hospital admissions, outpatient visits, and accident and emergency unit attendances. We examined seven prespecified aggregate clinical outcomes (ie, any diabetes-related endpoint, diabetes-related death, death from any cause, myocardial infarction, stroke, peripheral vascular disease, and microvascular disease) by the randomised glycaemic control strategy on an intention-to-treat basis using Kaplan-Meier time-to-event and log-rank analyses. This study is registered with the ISRCTN registry, number ISRCTN75451837. FINDINGS: Between Oct 1, 2007, and Sept 30, 2021, 1489 (97·6%) of 1525 participants could be linked to routinely collected NHS administrative data. Their mean age at baseline was 50·2 years (SD 8·0), and 41·3% were female. The mean age of those still alive as of Sept 30, 2021, was 79·9 years (SD 8·0). Individual follow-up from baseline ranged from 0 to 42 years, median 17·5 years (IQR 12·3-26·8). Overall follow-up increased by 21%, from 66 972 to 80 724 person-years. For up to 24 years after trial end, the glycaemic and metformin legacy effects showed no sign of waning. Early intensive glycaemic control with sulfonylurea or insulin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 10% (95% CI 2-17; p=0·015) for death from any cause, 17% (6-26; p=0·002) for myocardial infarction, and 26% (14-36; p<0·0001) for microvascular disease. Corresponding absolute risk reductions were 2·7%, 3·3%, and 3·5%, respectively. Early intensive glycaemic control with metformin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 20% (95% CI 5-32; p=0·010) for death from any cause and 31% (12-46; p=0·003) for myocardial infarction. Corresponding absolute risk reductions were 4·9% and 6·2%, respectively. No significant risk reductions during or after the trial for stroke or peripheral vascular disease were observed for both intensive glycaemic control groups, and no significant risk reduction for microvascular disease was observed for metformin therapy. INTERPRETATION: Early intensive glycaemic control with sulfonylurea or insulin, or with metformin, compared with conventional glycaemic control, appears to confer a near-lifelong reduced risk of death and myocardial infarction. Achieving near normoglycaemia immediately following diagnosis might be essential to minimise the lifetime risk of diabetes-related complications to the greatest extent possible. FUNDING: University of Oxford Nuffield Department of Population Health Pump Priming.

Legacy benefits of blood pressure treatment on cardiovascular events are primarily mediated by improved blood pressure variability: the ASCOT trial.

BACKGROUND AND AIMS: Visit-to-visit systolic blood pressure variability (BPV) is an important predictor of cardiovascular (CV) outcomes. The long-term effect of a period of blood pressure (BP) control, but with differential BPV, is uncertain. Morbidity and mortality follow-up of UK participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm has been extended for up to 21 years to determine the CV impact of mean systolic blood pressure (SBP) control and BPV during the trial, and amongst those allocated to amlodipine- and atenolol-based treatment. METHODS: Eight thousand five hundred and eighty hypertensive participants (4305 assigned to amlodipine ± perindopril-based and 4275 to atenolol ± diuretic-based treatment during the in-trial period (median 5.5 years) were followed for up to 21 years (median 17.4 years), using linked hospital and mortality records. A subgroup of participants (n = 2156) was followed up 6 years after the trial closure with a self-administered questionnaire and a clinic visit. In-trial mean SBP and standard deviation of visit-to-visit SBP as a measure of BPV, were measured using >100 000 BP measurements. Cox proportional hazard models were used to estimate the risk [hazard ratios (HRs)], associated with (i) mean with SBP and BPV during the in-trial period, for the CV endpoints occurring after the end of the trial and (ii) randomly assigned treatment to events following randomization, for the first occurrence of pre-specified CV outcomes. RESULTS: Using BP data from the in-trial period, in the post-trial period, although mean SBP was a predictor of CV outcomes {HR per 10 mmHg, 1.14 [95% confidence interval (CI) 1.10-1.17], P < .001}, systolic BPV independent of mean SBP was a strong predictor of CV events [HR per 5 mmHg 1.22 (95% CI 1.18-1.26), P < .001] and predicted events even in participants with well-controlled BP. During 21-year follow-up, those on amlodipine-based compared with atenolol-based in-trial treatment had significantly reduced risk of stroke [HR 0.82 (95% CI 0.72-0.93), P = .003], total CV events [HR 0.93 (95% CI 0.88-0.98), P = .008], total coronary events [HR 0.92 (95% CI 0.86-0.99), P = .024], and atrial fibrillation [HR 0.91 (95% CI 0.83-0.99), P = .030], with weaker evidence of a difference in CV mortality [HR 0.91 (95% CI 0.82-1.01), P = .073]. There was no significant difference in the incidence of non-fatal myocardial infarction and fatal coronary heart disease, heart failure, and all-cause mortality. CONCLUSIONS: Systolic BPV is a strong predictor of CV outcome, even in those with controlled SBP. The long-term benefits of amlodipine-based treatment compared with atenolol-based treatment in reducing CV events appear to be primarily mediated by an effect on systolic BPV during the trial period.

Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear. METHODS: We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history. RESULTS: Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses. CONCLUSIONS: High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.

New Insights into Stroke from Continuous Passively Collected Temperature and Sleep Data Using Wrist-Worn Wearables.

Actigraphy may provide new insights into clinical outcomes and symptom management of patients through passive, continuous data collection. We used the GENEActiv smartwatch to passively collect actigraphy, wrist temperature, and ambient light data from 27 participants after stroke or probable brain transient ischemic attack (TIA) over 42 periods of device wear. We computed 323 features using established algorithms and proposed 25 novel features to characterize sleep and temperature. We investigated statistical associations between the extracted features and clinical outcomes evaluated using clinically validated questionnaires to gain insight into post-stroke recovery. We subsequently fitted logistic regression models to replicate clinical diagnosis (stroke or TIA) and disability due to stroke. The model generalization performance was assessed using a leave-one-subject-out cross validation method with the selected feature subsets, reporting the area under the curve (AUC). We found that several novel features were strongly correlated (|r|>0.3) with stroke symptoms and mental health measures. Using selected novel features, we obtained an AUC of 0.766 to estimate diagnosis and an AUC of 0.749 to estimate whether disability due to stroke was present. Collectively, these findings suggest that features extracted from the temperature smartwatch sensor may reveal additional clinically useful information over and above existing actigraphy-based features.

Clinical Diagnosis and Magnetic Resonance Imaging in Patients With Transient and Minor Neurological Symptoms: A Prospective Cohort Study.

BACKGROUND: The utility of magnetic resonance imaging (MRI) brain in patients with transient or minor neurological symptoms is uncertain. We sought to determine the proportion of participants with transient or minor neurological symptoms who had MRI evidence of acute ischemia at different clinical probabilities of transient ischemic attack (TIA) or minor stroke. METHODS: Cohort of participants with transient or minor neurological symptoms from emergency and outpatient settings. Clinicians at different levels of training gave each participant a diagnostic probability (probable when TIA/stroke was the most likely differential diagnosis; possible when TIA/stroke was not the most likely differential diagnosis; or uncertain when diagnostic probability could not be given) before 1.5 or 3T brain MRI ≤5 days from onset. Post hoc, each clinical syndrome was defined blind to MRI findings as National Institute of Neurological Disorders and Stroke criteria TIA/stroke; International Headache Society criteria migraine aura; non-TIA focal symptoms; or nonfocal symptoms. MRI evidence of acute ischemia was defined by 2 reads of MRI. Stroke was ascertained for at least 90 days and up to 18 months after recruitment. RESULTS: Two hundred seventy-two participated (47% female, mean age 60, SD 14), 58% with MRI ≤2 days of onset. Most (92%) reported focal symptoms. MR evidence of acute ischemia was found, for stroke/TIA clinical probabilities of probable 23 out of 75 (31% [95% CI, 21%-42%]); possible 26 out of 151 (17% [12%-24%]); and uncertain 9 out of 43, (20% [10%-36%]). MRI evidence of acute ischemia was found in National Institute of Neurological Disorders and Stroke criteria TIA/stroke 40 out of 95 (42% [32%-53%]); migraine aura 4 out of 38 (11% [3%-25%]); non-TIA focal symptoms 16 out of 99 (16% [10%-25%]); and no focal features 1 out of 29 (3% [0%-18%]). After MRI, a further 14 (5% [95% CI, 3-8]) would be treated with an antiplatelet drug compared with treatment plan before MRI. By 18 months, a new ischemic stroke occurred in 9 out of 61 (18%) patients with MRI evidence of acute ischemia and 2 out of 211 (1%) without (age-adjusted hazard ratio, 13 [95% CI, 3-62]; P<0.0001). CONCLUSIONS: MRI evidence of acute brain ischemia was found in about 1 in 6 transient or minor neurological symptoms patients with a nonstroke/TIA initial diagnosis or uncertain diagnosis. Methods to determine the clinical and cost-effectiveness of MRI are needed in this population.

Genetic associations of adult height with risk of cardioembolic and other subtypes of ischemic stroke: A mendelian randomization study in multiple ancestries.

BACKGROUND: Taller adult height is associated with lower risks of ischemic heart disease in mendelian randomization (MR) studies, but little is known about the causal relevance of height for different subtypes of ischemic stroke. The present study examined the causal relevance of height for different subtypes of ischemic stroke. METHODS AND FINDINGS: Height-associated genetic variants (up to 2,337) from previous genome-wide association studies (GWASs) were used to construct genetic instruments in different ancestral populations. Two-sample MR approaches were used to examine the associations of genetically determined height with ischemic stroke and its subtypes (cardioembolic stroke, large-artery stroke, and small-vessel stroke) in multiple ancestries (the MEGASTROKE consortium, which included genome-wide studies of stroke and stroke subtypes: 60,341 ischemic stroke cases) supported by additional cases in individuals of white British ancestry (UK Biobank [UKB]: 4,055 cases) and Chinese ancestry (China Kadoorie Biobank [CKB]: 10,297 cases). The associations of genetically determined height with established cardiovascular and other risk factors were examined in 336,750 participants from UKB and 58,277 participants from CKB. In MEGASTROKE, genetically determined height was associated with a 4% lower risk (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.94, 0.99; p = 0.007) of ischemic stroke per 1 standard deviation (SD) taller height, but this masked a much stronger positive association of height with cardioembolic stroke (13% higher risk, OR 1.13 [95% CI 1.07, 1.19], p < 0.001) and stronger inverse associations with large-artery stroke (11% lower risk, OR 0.89 [0.84, 0.95], p < 0.001) and small-vessel stroke (13% lower risk, OR 0.87 [0.83, 0.92], p < 0.001). The findings in both UKB and CKB were directionally concordant with those observed in MEGASTROKE, but did not reach statistical significance: For presumed cardioembolic stroke, the ORs were 1.08 (95% CI 0.86, 1.35; p = 0.53) in UKB and 1.20 (0.77, 1.85; p = 0.43) in CKB; for other subtypes of ischemic stroke in UKB, the OR was 0.97 (95% CI 0.90, 1.05; p = 0.49); and for other nonlacunar stroke and lacunar stroke in CKB, the ORs were 0.89 (0.80, 1.00; p = 0.06) and 0.99 (0.88, 1.12; p = 0.85), respectively. In addition, genetically determined height was also positively associated with atrial fibrillation (available only in UKB), and with lean body mass and lung function, and inversely associated with low-density lipoprotein (LDL) cholesterol in both British and Chinese ancestries. Limitations of this study include potential bias from assortative mating or pleiotropic effects of genetic variants and incomplete generalizability of genetic instruments to different populations. CONCLUSIONS: The findings provide support for a causal association of taller adult height with higher risk of cardioembolic stroke and lower risk of other ischemic stroke subtypes in diverse ancestries. Further research is needed to understand the shared biological and physical pathways underlying the associations between height and stroke risks, which could identify potential targets for treatments to prevent stroke.

Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events: A population-based cohort study of 46 million adults in England.

BACKGROUND: Thromboses in unusual locations after the Coronavirus Disease 2019 (COVID-19) vaccine ChAdOx1-S have been reported, although their frequency with vaccines of different types is uncertain at a population level. The aim of this study was to estimate the population-level risks of hospitalised thrombocytopenia and major arterial and venous thromboses after COVID-19 vaccination. METHODS AND FINDINGS: In this whole-population cohort study, we analysed linked electronic health records from adults living in England, from 8 December 2020 to 18 March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous, and thrombocytopenic outcomes 1 to 28 and >28 days after first vaccination dose for ChAdOx1-S and BNT162b2 vaccines. Analyses were performed separately for ages <70 and ≥70 years and adjusted for age, age2, sex, ethnicity, and deprivation. We also prespecified adjustment for anticoagulant medication, combined oral contraceptive medication, hormone replacement therapy medication, history of pulmonary embolism or deep vein thrombosis, and history of coronavirus infection in analyses of venous thrombosis; and diabetes, hypertension, smoking, antiplatelet medication, blood pressure lowering medication, lipid lowering medication, anticoagulant medication, history of stroke, and history of myocardial infarction in analyses of arterial thromboses. We selected further covariates with backward selection. Of 46 million adults, 23 million (51%) were women; 39 million (84%) were <70; and 3.7 million (8.1%) Asian or Asian British, 1.6 million (3.5%) Black or Black British, 36 million (79%) White, 0.7 million (1.5%) mixed ethnicity, and 1.5 million (3.2%) were of another ethnicity. Approximately 21 million (46%) adults had their first vaccination between 8 December 2020 and 18 March 2021. The crude incidence rates (per 100,000 person-years) of all venous events were as follows: prevaccination, 140 [95% confidence interval (CI): 138 to 142]; ≤28 days post-ChAdOx1-S, 294 (281 to 307); >28 days post-ChAdOx1-S, 359 (338 to 382), ≤28 days post-BNT162b2-S, 241 (229 to 253); >28 days post-BNT162b2-S 277 (263 to 291). The crude incidence rates (per 100,000 person-years) of all arterial events were as follows: prevaccination, 546 (95% CI: 541 to 555); ≤28 days post-ChAdOx1-S, 1,211 (1,185 to 1,237); >28 days post-ChAdOx1-S, 1678 (1,630 to 1,726), ≤28 days post-BNT162b2-S, 1,242 (1,214 to 1,269); >28 days post-BNT162b2-S, 1,539 (1,507 to 1,572). Adjusted HRs (aHRs) 1 to 28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and ≥70 years, respectively, were 0.97 (95% CI: 0.90 to 1.05) and 0.58 (0.53 to 0.63) for venous thromboses, and 0.90 (0.86 to 0.95) and 0.76 (0.73 to 0.79) for arterial thromboses. Corresponding aHRs for BNT162b2 were 0.81 (0.74 to 0.88) and 0.57 (0.53 to 0.62) for venous thromboses, and 0.94 (0.90 to 0.99) and 0.72 (0.70 to 0.75) for arterial thromboses. aHRs for thrombotic events were higher at younger ages for venous thromboses after ChAdOx1-S, and for arterial thromboses after both vaccines. Rates of intracranial venous thrombosis (ICVT) and of thrombocytopenia in adults aged <70 years were higher 1 to 28 days after ChAdOx1-S (aHRs 2.27, 95% CI: 1.33 to 3.88 and 1.71, 1.35 to 2.16, respectively), but not after BNT162b2 (0.59, 0.24 to 1.45 and 1.00, 0.75 to 1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1 to 28 days after ChAdOx1-S were 0.9 to 3 per million, varying by age and sex. The main limitations of the study are as follows: (i) it relies on the accuracy of coded healthcare data to identify exposures, covariates, and outcomes; (ii) the use of primary reason for hospital admission to measure outcome, which improves the positive predictive value but may lead to an underestimation of incidence; and (iii) potential unmeasured confounding. CONCLUSIONS: In this study, we observed increases in rates of ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years that were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults aged <40 years are needed. For people aged ≥70 years, rates of arterial or venous thrombotic events were generally lower after either vaccine compared with unvaccinated, suggesting that either vaccine is suitable in this age group.

Functional Abilities of an International Post-Stroke Population: Standard Assessment of Global Everyday Activities (SAGEA) Scale.

BACKGROUND AND OBJECTIVES: Function is an important outcome after stroke; traditional assessments may not capture functional deficits important to patients. We examined the validity of the Standard Assessment of Global Everyday Activities (SAGEA), a patient-reported outcome that assesses activities important to patients and for use in international clinical trials. METHODS: The NAVIGATE-ESUS trial evaluated rivaroxaban compared to aspirin in preventing recurrent stroke in 7213 participants. The Modified Rankin Scale (mRS), the National Institutes of Health Stroke Scale (NIHSS), and the SAGEA were collected at entry. Chi square tests were used to compare proportions and Spearman rank correlations were used to compare between measures. SAGEA was compared to the Modified Frailty Index (MFI) and the occurrence of infarct to examine criterion validity RESULTS: Participants were 67 years, 2/3 were male, and at baseline 30% had no disability and 58% had slight disability according to mRS scores. SAGEA was weakly correlated with the mRS (r=0.37), the NIHSS (r=0.29) and the MFI (r=0.30). Of the 2154 with an mRS score of 0, 61% reported difficulty on the SAGEA. The largest discrepancies between SAGEA and other measures were because of cognitive functional deficits detected by the SAGEA that were not identified on other assessments. A larger number of MRI identified infarcts (acute and covert) were associated with a higher SAGEA score (p=0.007). CONCLUSIONS: The SAGEA is a simple, globally applicable measure of cognitive and functional abilities that identifies issues that other commonly used assessments of disability and function do not capture.

Rivaroxaban versus aspirin on functional and cognitive outcomes after embolic stroke of undetermined source: NAVIGATE ESUS trial.

BACKGROUND: The effect of interventions on functional impairment is an important outcome in stroke prevention trials and should be considered as an adjunct to counting discrete events. In the NAVIGATE-ESUS trial, 7213 patients with recent embolic strokes of undetermined source were randomized to rivaroxaban (15 mg once daily) or aspirin (100 mg daily). After 11 months there was no effect on the prevention of recurrent stroke. AIMS: To determine the effect of rivaroxaban compared to aspirin on functional and cognitive outcomes. METHODS: Function and cognition were measured at baseline, 1 year, and study end using the Standard Assessment of Global Everyday Activities (SAGEA), a 15-item scale assessing cognitive, instrumental, and basic activities of daily living as well as mobility, and the Montreal Cognitive Assessment (MoCA). Changes in scores were calculated by subtracting either study end or 1-year scores from baseline, and differences in distributions were compared using the Mann-Whitney U test. SAGEA and MoCA scores were also correlated with recurrent stroke. RESULTS: Follow-up SAGEA scores were available in 6378 (88%) participants. There was no difference in change in function for those allocated to rivaroxaban compared to aspirin (Mann-Whitney U test, p = 0.8), with both distributions having a median (25p,75p) change of 0 (-2,1). Overall, more of those who experienced a recurrent stroke (n=247; mostly minor ischemic), reported functional difficulty at study end versus entry, compared with those who did not (51% versus 30%, chi-square test, p< 0.001), and this was consistent across global regions. There was no difference in the change in cognition by treatment group, nor were recurrent strokes associated with a change in cognition. CONCLUSIONS: Rivaroxaban, compared to aspirin, was not associated with changes in functional or cognitive status in patients with recent ESUS. The SAGEA scale detected changes in functional status associated with recurrent strokes in an international stroke population.

Long-Term Incidence of Stroke and Dementia in ASCOT.

Background and Purpose: Management of stroke risk factors might reduce later dementia. In ASCOT (Anglo-Scandinavian Outcome Trial), we determined whether dementia or stroke were associated with different blood pressure (BP)­lowering regimens; atorvastatin or placebo; and mean BP, BP variability, and mean cholesterol levels. Methods: Participants with hypertension and ≥3 cardiovascular disease risk factors were randomly allocated to amlodipine- or atenolol-based BP-lowering regimen targeting BP <140/90 mm Hg for 5.5 years. Participants with total cholesterol ≤6.5 mmol/L were also randomly allocated to atorvastatin 10 mg or placebo for 3.3 years. Mean and LDL (low-density lipoprotein) cholesterol, BP, and SD of BP were calculated from 6 months to end of trial. UK participants were linked to electronic health records to ascertain deaths and hospitalization in general and mental health hospitals. Dementia and stroke were ascertained by validated code lists and within-trial ascertainment. Results: Of 8580 UK participants, 7300 were followed up to 21 years from randomization. Atorvastatin for 3.3 years had no measurable effect on stroke (264 versus 272; adjusted hazard ratio [HR], 0.92 [95% CI, 0.78­1.09]; P=0.341) or dementia (238 versus 227; adjusted HR, 0.98 [95% CI, 0.82­1.18]; P=0.837) compared with placebo. Mean total cholesterol was not associated with later stroke or dementia. An amlodipine-based compared with an atenolol-based regimen for 5.5 years reduced stroke (443 versus 522; adjusted HR, 0.82 [95% CI, 0.72­0.93]; P=0.003) but not dementia (450 versus 465; adjusted HR, 0.94 [95% CI, 0.82­1.07]; P=0.334) over follow-up. BP variability (SD mean BP) was associated with a higher risk of dementia (per 5 mm Hg HR, 1.14 [95% CI, 1.06­1.24]; P<0.001) and stroke (HR, 1.21 [95% CI, 1.12­1.32]; P<0.001) adjusted for mean BP. Conclusions: An amlodipine-based BP regimen reduced the long-term incidence of stroke compared with an atenolol-based regimen but had no measurable effect on dementia. Atorvastatin had no effect on either stroke or dementia. Higher BP variability was associated with a higher incidence of later dementia and stroke.

Role of Blood-Based Biomarkers in Ischemic Stroke Prognosis: A Systematic Review.

BACKGROUND AND PURPOSE: Outcome prognostication in ischemic stroke patients remains challenging due to limited predictive properties of existing models. Blood-based biomarkers might provide additional information to established prognostic factors. We intended to identify the most promising prognostic biomarkers in ischemic stroke, their incremental prognostic value, and whether their predictive value differs among etiologies. METHODS: We searched MEDLINE (Ovid) and Institute for Scientific Information Web of Knowledge for articles reporting the predictive performance of blood-based biomarkers measured up to 7 days after ischemic stroke and reporting functional outcome or death at least 7 days after stroke. This work updates a previous systematic review (up to January 2007), follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and was registered (International Prospective Register of Systematic Reviews PROSPERO 2018; https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42018094671). RESULTS: Two hundred ninety-one articles published between January 2007 and August 2018 comprising 257 different biomarkers met inclusion criteria. Median sample size was 232 (interquartile range, 110-455); 260 (89%) articles reported regression analyses with 78% adjusting for stroke severity, 82% for age, 67% for both, and 9% for none of them; 37% investigated discrimination, 5% calibration, and 11% reclassification. Including publications from a previous systematic review (1960-January 2007), natriuretic peptides, copeptin, procalcitonin, mannose-binding lectin, adipocyte fatty acid-binding protein, and cortisol were the biomarkers most consistently associated with poor outcome in higher-quality studies showing an incremental value over established prognostic factors. Other biomarkers were less consistently associated with poor outcome or were reported in lower quality studies. High heterogeneity among studies precluded the performance of a meta-analysis. CONCLUSIONS: The number of reports on prognostic blood-based biomarkers in ischemic stroke increased 3.5-fold in the period January 2007 to August 2018. Although sample size increased, methodological flaws are still common. Natriuretic peptides and markers of inflammation, atherogenesis, and stress response are the most promising prognostic biomarkers among identified studies.

Benefits and Risks of Dual Versus Single Antiplatelet Therapy for Secondary Stroke Prevention: A Systematic Review for the 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack.

BACKGROUND: Dual antiplatelet therapy (DAPT) after ischemic stroke or transient ischemic attack may reduce recurrent stroke but also increase severe bleeding compared with single antiplatelet therapy (SAPT). The American Heart Association/American Stroke Association convened an evidence review committee to perform a systematic review and meta-analysis of the benefits and risks of DAPT compared with SAPT for secondary ischemic stroke prevention. METHODS: The Medline, Embase, and Cochrane databases were searched on December 5, 2019, to identify phase III or IV randomized controlled trials (n≥100) from December 1999 to December 2019. We calculated unadjusted relative risks (RRs) and performed meta-analyses of studies based on the duration of treatment (short [≤90 days] versus long [>90 days]). RESULTS: Three short-duration randomized controlled trials were identified that enrolled mostly patients with minor stroke or high risk transient ischemic attack. In these trials, DAPT, compared with SAPT, was associated with a lower 90-day risk of recurrent ischemic stroke (pooled RR, 0.68 [95% CI, 0.55-0.83], I 2=37.1%). There was no significant increase in major bleeding with DAPT in short-duration trials (pooled RR, 1.88 [95% CI, 0.93-3.83], I 2=8.9%). In 2 long-duration treatment randomized controlled trials (mean treatment duration, 18-40 months), DAPT was not associated with a significant reduction in recurrent ischemic stroke (pooled RR, 0.89 [95% CI, 0.79-1.02], I 2=1.4%), but was associated with a higher risk of major bleeding (pooled RR, 2.42 [95% CI, 1.37-4.30], I 2=75.5%). CONCLUSIONS: DAPT was more effective than SAPT for prevention of secondary ischemic stroke when initiated early after the onset of minor stroke/high-risk transient ischemic attack and treatment duration was <90 days. However, when the treatment duration was longer and initiated later after stroke or transient ischemic attack onset, DAPT was not more effective than SAPT for ischemic stroke prevention and it increased the risk of bleeding.

Telemedicine Cognitive Behavioral Therapy for Anxiety After Stroke: Proof-of-Concept Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Disabling anxiety affects a quarter of stroke survivors but access to treatment is poor. We developed a telemedicine model for delivering guided self-help cognitive behavioral therapy (CBT) for anxiety after stroke (TASK-CBT). We aimed to evaluate the feasibility of TASK-CBT in a randomized controlled trial workflow that enabled all trial procedures to be carried out remotely. In addition, we explored the feasibility of wrist-worn actigraphy sensor as a way of measuring objective outcomes in this clinical trial. METHODS: We recruited adult community-based stroke patients (n=27) and randomly allocated them to TASK-CBT (n=14) or relaxation therapy (TASK-Relax), an active comparator (n=13). RESULTS: In our sample (mean age 65 [±10]; 56% men; 63% stroke, 37% transient ischemic attacks), remote self-enrolment, electronic signature, intervention delivery, and automated follow-up were feasible. All participants completed all TASK-CBT sessions (14/14). Lower levels of anxiety were observed in TASK-CBT when compared with TASK-Relax at both weeks 6 and 20. Mean actigraphy sensor wearing-time was 33 days (±15). CONCLUSIONS: Our preliminary feasibility data from the current study support a larger definitive clinical trial and the use of wrist-worn actigraphy sensor in anxious stroke survivors. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03439813.

Are large simple trials for dementia prevention possible?

New trials of dementia prevention are needed to test novel strategies and agents. Large, simple, cardiovascular trials have successfully discovered treatments with moderate but worthwhile effects to prevent heart attack and stroke. The design of these trials may hold lessons for the dementia prevention. Here we outline suitable populations, interventions and outcomes for large simple trials in dementia prevention. We consider what features are needed to maximise efficiency. Populations could be selected by age, clinical or genetic risk factors or clinical presentation. Patients and their families prioritise functional and clinical outcomes over cognitive scores and levels of biomarkers. Loss of particular functions or dementia diagnoses therefore are most meaningful to participants and potential patients and can be measured in large trials. The size of the population and duration of follow-up needed for dementia prevention trials will be a major challenge and will need collaboration between many clinical investigators, funders and patient organisations.

Anxiety After Stroke: The Importance of Subtyping.

BACKGROUND AND PURPOSE: Anxiety after stroke is common and disabling. Stroke trialists have treated anxiety as a homogenous condition, and intervention studies have followed suit, neglecting the different treatment approaches for phobic and generalized anxiety. Using diagnostic psychiatric interviews, we aimed to report the frequency of phobic and generalized anxiety, phobic avoidance, predictors of anxiety, and patient outcomes at 3 months poststroke/transient ischemic attack. METHODS: We followed prospectively a cohort of new diagnosis of stroke/transient ischemic attack at 3 months with a telephone semistructured psychiatric interview, Fear Questionnaire, modified Rankin Scale, EuroQol-5D5L, and Work and Social Adjustment Scale. RESULTS: Anxiety disorder was common (any anxiety disorder, 38 of 175 [22%]). Phobic disorder was the predominant anxiety subtype: phobic disorder only, 18 of 175 (10%); phobic and generalized anxiety disorder, 13 of 175 (7%); and generalized anxiety disorder only, 7 of 175 (4%). Participants with anxiety disorder reported higher level of phobic avoidance across all situations on the Fear Questionnaire. Younger age (per decade increase in odds ratio, 0.64; 95% confidence interval, 0.45-0.91) and having previous anxiety/depression (odds ratio, 4.38; 95% confidence interval, 1.94-9.89) were predictors for anxiety poststroke/transient ischemic attack. Participants with anxiety disorder were more dependent (modified Rankin Scale score 3-5, [anxiety] 55% versus [no anxiety] 29%; P<0.0005), had poorer quality of life on EQ-5D5L, and restricted participation (Work and Social Adjustment Scale: median, interquartile range, [anxiety] 19.5, 10-27 versus [no anxiety] 0, 0-5; P<0.001). CONCLUSIONS: Anxiety after stroke/transient ischemic attack is predominantly phobic and is associated with poorer patient outcomes. Trials of anxiety intervention in stroke should consider the different treatment approaches needed for phobic and generalized anxiety.

Effect of Dysphagia Screening Strategies on Clinical Outcomes After Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke.

INTRODUCTION: Dysphagia screening protocols have been recommended to identify patients at risk for aspiration. The American Heart Association convened an evidence review committee to systematically review evidence for the effectiveness of dysphagia screening protocols to reduce the risk of pneumonia, death, or dependency after stroke. METHODS: The Medline, Embase, and Cochrane databases were searched on November 1, 2016, to identify randomized controlled trials (RCTs) comparing dysphagia screening protocols or quality interventions with increased dysphagia screening rates and reporting outcomes of pneumonia, death, or dependency. RESULTS: Three RCTs were identified. One RCT found that a combined nursing quality improvement intervention targeting fever and glucose management and dysphagia screening reduced death and dependency but without reducing the pneumonia rate. Another RCT failed to find evidence that pneumonia rates were reduced by adding the cough reflex to routine dysphagia screening. A smaller RCT randomly assigned 2 hospital wards to a stroke care pathway including dysphagia screening or regular care and found that patients on the stroke care pathway were less likely to require intubation and mechanical ventilation; however, the study was small and at risk for bias. CONCLUSIONS: There were insufficient RCT data to determine the effect of dysphagia screening protocols on reducing the rates of pneumonia, death, or dependency after stroke. Additional trials are needed to compare the validity, feasibility, and clinical effectiveness of different screening methods for dysphagia.

Accuracy of Prediction Instruments for Diagnosing Large Vessel Occlusion in Individuals With Suspected Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke.

INTRODUCTION: Endovascular thrombectomy is a highly efficacious treatment for large vessel occlusion (LVO). LVO prediction instruments, based on stroke signs and symptoms, have been proposed to identify stroke patients with LVO for rapid transport to endovascular thrombectomy-capable hospitals. This evidence review committee was commissioned by the American Heart Association/American Stroke Association to systematically review evidence for the accuracy of LVO prediction instruments. METHODS: Medline, Embase, and Cochrane databases were searched on October 27, 2016. Study quality was assessed with the Quality Assessment of Diagnostic Accuracy-2 tool. RESULTS: Thirty-six relevant studies were identified. Most studies (21 of 36) recruited patients with ischemic stroke, with few studies in the prehospital setting (4 of 36) and in populations that included hemorrhagic stroke or stroke mimics (12 of 36). The most frequently studied prediction instrument was the National Institutes of Health Stroke Scale. Most studies had either some risk of bias or unclear risk of bias. Reported discrimination of LVO mostly ranged from 0.70 to 0.85, as measured by the C statistic. In meta-analysis, sensitivity was as high as 87% and specificity was as high as 90%, but no threshold on any instruments predicted LVO with both high sensitivity and specificity. With a positive LVO prediction test, the probability of LVO could be 50% to 60% (depending on the LVO prevalence in the population), but the probability of LVO with a negative test could still be ≥10%. CONCLUSIONS: No scale predicted LVO with both high sensitivity and high specificity. Systems that use LVO prediction instruments for triage will miss some patients with LVO and milder stroke. More prospective studies are needed to assess the accuracy of LVO prediction instruments in the prehospital setting in all patients with suspected stroke, including patients with hemorrhagic stroke and stroke mimics.

Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes: A Pooled Analysis of 9 Trials.

BACKGROUND: Thrombolytic therapy with intravenous alteplase within 4.5 hours of ischemic stroke onset increases the overall likelihood of an excellent outcome (no, or nondisabling, symptoms). Any improvement in functional outcome distribution has value, and herein we provide an assessment of the effect of alteplase on the distribution of the functional level by treatment delay, age, and stroke severity. METHODS: Prespecified pooled analysis of 6756 patients from 9 randomized trials comparing alteplase versus placebo/open control. Ordinal logistic regression models assessed treatment differences after adjustment for treatment delay, age, stroke severity, and relevant interaction term(s). RESULTS: Treatment with alteplase was beneficial for a delay in treatment extending to 4.5 hours after stroke onset, with a greater benefit with earlier treatment. Neither age nor stroke severity significantly influenced the slope of the relationship between benefit and time to treatment initiation. For the observed case mix of patients treated within 4.5 hours of stroke onset (mean 3 hours and 20 minutes), the net absolute benefit from alteplase (ie, the difference between those who would do better if given alteplase and those who would do worse) was 55 patients per 1000 treated (95% confidence interval, 13-91; P=0.004). CONCLUSIONS: Treatment with intravenous alteplase initiated within 4.5 hours of stroke onset increases the chance of achieving an improved level of function for all patients across the age spectrum, including the over 80s and across all severities of stroke studied (top versus bottom fifth means: 22 versus 4); the earlier that treatment is initiated, the greater the benefit.

Alteplase for acute ischemic stroke: outcomes by clinically important subgroups in the Third International Stroke Trial.

BACKGROUND AND PURPOSE: Our aim was to identify whether particular subgroups of patients had an unacceptably high risk of symptomatic intracranial hemorrhage or low chance of benefit when treated with alteplase (recombinant tissue-type plasminogen activator). METHODS: Third International Stroke Trial was an international randomized trial of the intravenous (IV) recombinant plasminogen activator alteplase (0.9 mg/kg) versus control in 3035 (1515 versus 1520) patients. We analyzed the effect of recombinant tissue-type plasminogen activator on 6-month functional outcome, early death, and symptomatic intracranial hemorrhage (both ≤7 days). We tested for any differences in treatment effect between subgroups by a test of interaction. Our 13 protocol prespecified subgroups were time to randomization, age, sex, stroke subtype, atrial fibrillation, early ischemic change (clinician and expert panel), prior antiplatelet use, stroke severity, diastolic and systolic blood pressure at randomization, center's thrombolysis experience, and trial phase. Analyses were adjusted for key baseline prognostic factors. RESULTS: There were no significant interactions in the subgroups analyzed that were consistent across all 3 outcomes. Treatment with recombinant tissue-type plasminogen activator increased the odds of symptomatic intracranial hemorrhage by a greater amount in patients taking prior antiplatelets than those who were not (P=0.019 for test of interaction), but had no clear detrimental effect on functional outcome at 6 months in this group (P=0.781 for test of interaction). CONCLUSIONS: Among the types of patient in the Third International Stroke Trial, this secondary analysis did not identify any subgroups for whom treatment should be avoided. Given the limitations of the analysis, we found no clear evidence to avoid treatment in patients with prior ischemic stroke, diabetes mellitus, or hypertension. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN25765518. http://www.controlled-trials.com/ISRCTN25765518.

Effect of alteplase within 6 hours of acute ischemic stroke on all-cause mortality (third International Stroke Trial).

BACKGROUND AND PURPOSE: Prompt thrombolytic therapy with intravenous alteplase reduces disability after acute ischemic stroke. In an exploratory analysis, we examined whether long-term survival varied by baseline characteristics after alteplase. METHODS: In this open-treatment, international, randomized, controlled trial, ischemic stroke patients were randomly allocated <6 hours of onset to intravenous alteplase (0.9 mg/kg) plus standard care (n=1515) or standard care alone (n=1520). We followed patients to death, censoring when last known to be alive. We grouped patients by delay to randomization, and good or poor predicted prognosis (calculated from baseline National Institutes of Health Stroke Scale [NIHSS] score and age). We present absolute mortality differences between treated and control groups at 7 days, 6 months, and 18 months poststroke. RESULTS: Alteplase was not associated with a significant increase in mortality within 18 months (0.6% [95% confidence interval (CI), -2.9% to +4.2] P=0.72] in all patients with complete vital status (99.9%, 3034/3035). In patients randomized <3 hours of stroke, 18-month mortality was lower in the alteplase-treated group than the control group (40.6% [95% CI, 42.6-52.7] versus 47.8% [95% CI, 35.5-45.3]; P=0.0434]. The difference in 18-month mortality between alteplase-treated and control patients was greater in patients who were randomized early (<3 hours) compared with late (3-6 hours; +9% [95% CI, 1-17]; P=0.0317). Alteplase led to a greater improvement in 18-month survival in patients with a poor prognosis than in patients with a good prognosis (+8% [95% CI, 2-14]; P=0.0091). CONCLUSIONS: These exploratory analyses of the third International Stroke Trial (IST-3) trial support improving acute stroke patients' access to earlier alteplase treatment, treatment of patients with poor prognosis, and further randomized controlled trials in minor stroke to replicate these findings. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN25765518.