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Background: In young patients, up to 40% of ischemic strokes remain cryptogenic despite modern-day diagnostic work-up. There are limited data on blood pressure (BP) behavior in these patients. Thus, we aimed to compare ambulatory blood pressure (ABP) profiles between young patients with a recent cryptogenic ischemic stroke (CIS) and stroke-free controls., Patients and Methods: In this substudy of the international multicenter case-control study SECRETO (NCT01934725), 24-hour ambulatory blood pressure monitoring (ABPM) was performed in consecutive 18-49-year-old CIS patients and stroke-free controls. The inclusion criteria were met by 132 patients (median age, 41.9 years; 56.1% males) and 106 controls (41.9 years; 56.6% males). We assessed not only 24-hour, daytime, and nighttime ABP but also hypertension phenotypes and nocturnal dipping status., Results: 24-hour and daytime ABP were higher among controls. After adjusting for relevant confounders, a non-dipping pattern of diastolic blood pressure (DBP) was associated with CIS in the entire sample (odds ratio, 3.85; 95% confidence interval, 1.20-12.42), in participants without antihypertensives (4.86; 1.07-22.02), and in participants without a patent foramen ovale (PFO) (7.37; 1.47-36.81). After excluding patients in the first tertile of the delay between the stroke and ABPM, a non-dipping pattern of DBP was not associated with CIS, but a non-dipping pattern of both systolic BP and DBP was (4.85; 1.37-17.10). In participants with a PFO and in those without hypertension by any definition, no associations between non-dipping patterns of BP and CIS emerged., Conclusions: Non-dipping patterns of BP were associated with CIS in the absence of a PFO but not in the absence of hypertension. This may reflect differing pathophysiology underlying CIS in patients with versus without a PFO. Due to limitations of the study, results regarding absolute ABP levels should be interpreted with caution.Key MessagesNocturnal non-dipping patterns of blood pressure were associated with cryptogenic ischemic stroke except in participants with a patent foramen ovale and in those without hypertension by any definition, which may indicate differing pathophysiology underlying cryptogenic ischemic stroke in patients with and without a patent foramen ovale.It might be reasonable to include ambulatory blood pressure monitoring in the diagnostic work-up for young patients with ischemic stroke to detect not only the absolute ambulatory blood pressure levels but also their blood pressure behavior.

Background: Asundexian (Bayer AG, Leverkusen, Germany), an oral small molecule factor XIa (FXIa) inhibitor, might prevent thrombosis without increasing bleeding. Asundexian's effect for secondary prevention of recurrent stroke is unknown., Methods: In this randomised, double-blind, placebo-controlled, phase 2b dose-finding trial (PACIFIC-Stroke), patients with acute (within 48 h) non-cardioembolic ischaemic stroke were recruited from 196 hospitals in 23 countries. Patients were eligible if they were aged 45 years or older, to be treated with antiplatelet therapy, and able to have a baseline MRI (either before or within 72 h of randomisation). Eligible participants were randomly assigned (1:1:1:1), using an interactive web-based response system and stratified according to anticipated antiplatelet therapy (single vs dual), to once daily oral asundexian (BAY 2433334) 10 mg, 20 mg, or 50 mg, or placebo in addition to usual antiplatelet therapy, and were followed up during treatment for 26-52 weeks. Brain MRIs were obtained at study entry and at 26 weeks or as soon as possible after treatment discontinuation. The primary efficacy outcome was the dose-response effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after randomisation. The primary safety outcome was major or clinically relevant non-major bleeding as defined by International Society on Thrombosis and Haemostasis criteria. The efficacy outcome was assessed in all participants assigned to treatment, and the safety outcome was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04304508, and is now complete., Findings: Between June 15, 2020, and July 22, 2021, 1880 patients were screened and 1808 participants were randomly assigned to asundexian 10 mg (n=455), 20 mg (n=450), or 50 mg (n=447), or placebo (n=456). Mean age was 67 years (SD 10) and 615 (34%) participants were women, 1193 (66%) were men, 1505 (83%) were White, and 268 (15%) were Asian. The mean time from index stroke to randomisation was 36 h (SD 10) and median baseline National Institutes of Health Stroke Scale score was 2·0 (IQR 1·0-4·0). 783 (43%) participants received dual antiplatelet treatment for a mean duration of 70·1 days (SD 113·4) after randomisation. At 26 weeks, the primary efficacy outcome was observed in 87 (19%) of 456 participants in the placebo group versus 86 (19%) of 455 in the asundexian 10 mg group (crude incidence ratio 0·99 [90% CI 0·79-1·24]), 99 (22%) of 450 in the asundexian 20 mg group (1·15 [0·93-1·43]), and 90 (20%) of 447 in the asundexian 50 mg group (1·06 [0·85-1·32]; t statistic -0·68; p=0·80). The primary safety outcome was observed in 11 (2%) of 452 participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1·57 [90% CI 0·91-2·71])., Interpretation: In this phase 2b trial, FXIa inhibition with asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not increase the composite of major or clinically relevant non-major bleeding compared with placebo in patients with acute, non-cardioembolic ischaemic stroke., Funding: Bayer AG., Competing Interests: Declaration of interests All coauthors or their institutions received financial support from Bayer for participation in the PACIFIC-Stroke trial except HM, PC, BK, and CN who are employees of Bayer. HM, PC, BK, and CN do not hold any stock or stock options with Bayer., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aims: The REDUCE study demonstrated a reduction in the risk of recurrent stroke with patent foramen ovale closure and antiplatelet therapy compared to antiplatelet therapy alone. The clinicians were allowed to choose among aspirin, clopidogrel, or aspirin/dipyridamole with the expectation that all antiplatelet therapies would have similar efficacy in this population. We tested that presumption by comparing recurrent stroke rates among antiplatelet agents within the control arm of the trial., Methods: We evaluated patients in REDUCE study who were randomized to the medical arm. The primary endpoint for this analysis was freedom from clinical ischemic stroke through at least 2 years of follow-up, to a maximum of 5 years. In the primary analysis, antiplatelet treatment was defined as the agent during the week prior to a recurrent stroke or last known contact., Results: Of 223 patients in the medical treatment arm, the initial agent was aspirin 52%, clopidogrel 30%, and aspirin/dipyridamole 12%. Patients treated with aspirin were similar to those treated with alternatives, but were more likely to be enrolled in the United States. The last reported agent was aspirin alone in 55%, clopidogrel alone in 31%, aspirin/dipyridamole in 7%, and other/nothing/missing in 7%. Recurrent stroke rates were similar for all 3 antiplatelet regimens in unadjusted and adjusted analyses, with no overall difference among agents (P= .17)., Conclusions: Among patients with patent foramen ovale-associated stroke who were managed medically, there were no differences among antiplatelet agents in the risk of recurrent stroke, though confidence intervals were wide., Competing Interests: Declaration of Competing Interest Drs. Kasner, Andersen, Iversen, Roine, Sjostrand, Rhodes, and Sondergaard received grant funding from WL Gore and Associates. Bryan Randall is an employee of WL Gore and Associates., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose- Atrial cardiopathy and atherosclerotic plaque are two potential mechanisms underlying embolic strokes of undetermined source (ESUS). The relationship between these two mechanisms among ESUS patients remains unclear. A better understanding of their association may inform targeted secondary prevention strategies. Methods- We examined the association between atrial cardiopathy and atherosclerotic plaque in the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), which enrolled 7213 patients with recent ESUS during 2014 to 2017. For this analysis, we included patients with data on left atrial dimension, location of brain infarction, and cervical large artery plaque. The variables of primary interest were left atrial diameter and cervical plaque ipsilateral to brain infarction. Secondary markers of atrial cardiopathy were premature atrial contractions on Holter monitoring and newly diagnosed atrial fibrillation. For descriptive purposes, left atrial enlargement was defined as ≥4.7 cm. Multivariable logistic regression was used to examine the association between atrial cardiopathy markers and ipsilateral plaque after adjustment for age, sex, body mass index, hypertension, diabetes mellitus, current smoking, and hyperlipidemia. Results- Among 3983 eligible patients, 235 (5.9%) had left atrial enlargement, 939 (23.6%) had ipsilateral plaque, and 94 (2.4%) had both. Shared risk factors for left atrial enlargement and ipsilateral plaque were male sex, white race, hypertension, tobacco use, and coronary artery disease. Despite shared risk factors, increasing left atrial dimension was not associated with ipsilateral plaque after adjustment for covariates (odds ratio per cm, 1.1 [95% CI, 1.0-1.2]; P =0.08). We found no consistent associations between secondary markers of atrial cardiopathy and ipsilateral plaque. Conclusions- In a large population of patients with ESUS, we did not observe a notable association between atrial cardiopathy and atherosclerotic plaque, and few patients had both conditions. These findings suggest that atrial cardiopathy and atherosclerotic plaque may be distinct, nonoverlapping risk factors for stroke among ESUS patients.

Background: The efficacy of closure of a patent foramen ovale (PFO) in the prevention of recurrent stroke after cryptogenic stroke is uncertain. We investigated the effect of PFO closure combined with antiplatelet therapy versus antiplatelet therapy alone on the risks of recurrent stroke and new brain infarctions., Methods: In this multinational trial involving patients with a PFO who had had a cryptogenic stroke, we randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet-only group). Imaging of the brain was performed at the baseline screening and at 24 months. The coprimary end points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24-month incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected on imaging., Results: We enrolled 664 patients (mean age, 45.2 years), of whom 81% had moderate or large interatrial shunts. During a median follow-up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23; 95% confidence interval [CI], 0.09 to 0.62; P=0.002). The incidence of new brain infarctions was significantly lower in the PFO closure group than in the antiplatelet-only group (22 patients [5.7%] vs. 20 patients [11.3%]; relative risk, 0.51; 95% CI, 0.29 to 0.91; P=0.04), but the incidence of silent brain infarction did not differ significantly between the study groups (P=0.97). Serious adverse events occurred in 23.1% of the patients in the PFO closure group and in 27.8% of the patients in the antiplatelet-only group (P=0.22). Serious device-related adverse events occurred in 6 patients (1.4%) in the PFO closure group, and atrial fibrillation occurred in 29 patients (6.6%) after PFO closure., Conclusions: Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation. (Funded by W.L. Gore and Associates; Gore REDUCE ClinicalTrials.gov number, NCT00738894 .).

Rationale: Cooling reduced infarct size and improved neurological outcomes in animal studies modeling ischemic stroke, and also improved outcome in randomized clinical trials in patients with hypoxic-ischemic brain injury after cardiac arrest. Cooling awake patients with ischemic stroke has been shown feasible in phase II clinical trials., Primary Aim: To determine whether systemic cooling to a target body temperature between 34·0 and 35·0°C, started within six-hours of symptom onset and maintained for 24 h, improves functional outcome at three-months in patients with acute ischemic stroke., Design: International, multicenter, phase III, randomized, open-label clinical trial with blinded outcome assessment in 1500 patients aged 18 years or older with acute ischemic stroke and a National Institutes of Health Stroke Scale score of 6 up to and including 18. In patients randomized to hypothermia, cooling to a target body temperature of 34-35°C will be started within six-hours after symptom onset with rapid intravenous infusion of refrigerated normal saline or a surface cooling technique and maintained for 24 h with a surface or endovascular technique. Patients randomized to hypothermia will receive pethidine and buspirone to prevent shivering and discomfort., Primary Outcome: Score on the modified Rankin Scale at 91 days, as analyzed with ordinal logistic regression and expressed as a common odds ratio., Discussion: With 750 patients per intervention group, this trial has 90% power to detect 7% absolute improvement at the 5% significance level. The full trial protocol is available at http://www.eurohyp1.eu. ClinicalTrials.gov Identifier: NCT01833312., (© 2014 World Stroke Organization.)

Objective: Controversy surrounds the safety of intravenous (IV) tissue plasminogen activator (tPA) in ischemic stroke patients treated with warfarin. The European tPA license precludes its use in anticoagulated patients altogether. American guidelines accept IV tPA use with an international normalized ratio (INR) ≤ 1.7. The influence of warfarin on symptomatic intracerebral hemorrhage (SICH), arterial recanalization, and long-term functional outcome in stroke thrombolysis remains unclear., Methods: We analyzed data from 45,074 patients treated with IV tPA enrolled in the Safe Implementation of Thrombolysis in Stroke (SITS) International Stroke Thrombolysis Register. A total of 768 patients had baseline warfarin treatment with INR ≤ 1.7. Outcome measures were SICH, arterial recanalization, mortality, and functional independence at 3 months., Results: Patients on warfarin with INR ≤ 1.7 were older, had more comorbidities, and had more severe strokes compared to patients without warfarin. There were no significant differences between patients with and without warfarin in SICH rates (adjusted odds ratio [aOR] = 1.23, 95% confidence interval [CI] = 0.72-2.11 per SITS-MOST; aOR = 1.26, 95% CI = 0.82-1.70 per European Cooperative Acute Stroke Study II) after adjustment for age, stroke severity, and comorbidities. Neither did warfarin independently influence mortality (aOR = 1.05, 95% CI = 0.83-1.35) or functional independence at 3 months (aOR = 1.01, 95% CI = 0.81-1.24). Arterial recanalization by computed tomography/magnetic resonance angiography trended higher in warfarin patients (62% [37 of 59] vs 55% [776/1,475], p = 0.066). Recanalization approximated by disappearance at 22 to 36 hours of a baseline hyperdense middle cerebral artery sign was increased (63% [124 of 196] vs 55% [3,901 of 7,099], p = 0.022)., Interpretation: Warfarin treatment with INR ≤ 1.7 did not increase the risk for SICH or death, and had no impact on long-term functional outcome in patients treated with IV tPA for acute ischemic stroke., (© 2013 American Neurological Association.)

Background: In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA)., Methods: In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2·0-3·0). Patients and investigators were masked to treatment allocation. Between Dec 18, 2006, and June 17, 2009, 14 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767., Findings: 7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2·79% rivaroxaban vs 2·96% warfarin; hazard ratio [HR] 0·94, 95% CI 0·77-1·16) and those without (1·44%vs 1·88%; 0·77, 0·58-1·01; interaction p=0·23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13·31% rivaroxaban vs 13·87% warfarin; HR 0·96, 95% CI 0·87-1·07) and those without (16·69%vs 15·19%; 1·10, 0·99-1·21; interaction p=0·08)., Interpretation: There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF., Funding: Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background and Purpose: Treatment of stroke consumes a significant portion of all healthcare expenditure. We developed a system for monitoring costs from individual patient data on a national level in Finland., Methods: Multiple national administrative registers were linked to gain episode-of-care data on all hospital-treated patients with incident stroke over the years 1999 to 2007 (n = 94,316). Inpatient and specialist outpatient costs were evaluated with a cost database, long-term care costs with fixed prices, and medication costs with true retail prices., Results: For the patients of Year 2007, the mean 1-year costs after an ischemic stroke were $29 580, after an intracerebral hemorrhage $36,220, and after a subarachnoid hemorrhage $42,570, valued in Year 2008 U.S. dollars. Only part of these costs are attributable to stroke, because the annual costs prior to stroke were significant, $8900 before ischemic stroke, $7600 before intracerebral hemorrhage, and $4200 before subarachnoid hemorrhage. Older patients with ischemic stroke, and, among patients with ischemic stroke and subarachnoid hemorrhage, women, incurred higher costs. The mean estimated lifetime costs were $130,000 after ischemic stroke or intracerebral hemorrhage and $80,000 after subarachnoid hemorrhage. Annually $1.6 billion is spent in the care of Finnish patients with stroke, which equals to 7% of the national healthcare expenditure, or 0.6% of the gross domestic product. Costs of patients with stroke are increasing with prolonged survival and the aging population., Conclusions: Treatment of patients with stroke is a large national investment. Setting up a nationwide system for continuous monitoring of stroke costs is feasible. Cost data should optimally be evaluated in conjunction with effectiveness and performance indicators.

Background and Purpose: Early neurological improvement (ENI) after thrombolytic therapy of acute stroke has been linked with recanalization and favorable outcome, although its definition shows considerable variation. We tested the ability of ENI, as defined in previous publications, to predict vessel recanalization and 3-month functional outcome after intravenous thrombolysis recorded in an extensive patient cohort in the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR)., Methods: Of 21,534 patients registered between December 2002 and December 2008, 798 patients (3.7%) had CT- or MR angiography-documented baseline vessel occlusion and also angiography data at 22 to 36 hours post-treatment. ENI definitions assessed at 2 hours and 24 hours post-treatment were (1) National Institutes of Health Stroke Scale (NIHSS) score improvement ≥4 points from baseline; (2) NIHSS 0, 1, or improvement ≥8; (3) NIHSS ≤3 or improvement ≥10; (4) improvement by 20%; (5) 40% from baseline; or (6) NIHSS score 0 to 1. Receiver operating curve analysis and multiple logistic regression were performed to evaluate the association of ENI with vessel recanalization and favorable functional outcome (modified Rankin Scale score 0 to 2 at 3 months)., Results: ENI at 2 hours had fair accuracy to diagnose recanalization as derived from receiver operating curve analysis. Definitions of improvement based on percent of NIHSS score change from baseline demonstrate better accuracy to diagnose recanalization at 2 hours and 24 hours than the definitions based on NIHSS cutoffs (the best performance at 2 hours was area under the curve 0.633, sensitivity 58%, specificity 69%, positive predictive value 68%, and negative predictive value 59% for 20% improvement; and area under the curve 0.692, sensitivity 69%, specificity 70%, positive predictive value 70%, and negative predictive value 62% for 40% improvement at 24 hours). ENI-predicted functional outcome with OR 2.8 to 6.0 independently from recanalization in the angiography cohort (n=695) and with OR of 6.9 to 9.7 in the whole cohort (n=18 181)., Conclusions: Early 20% neurological improvement at 2 hours was the best predictor of 3-month functional outcome and recanalization after thrombolysis, although fairly accurate, and may serve as a surrogate marker of recanalization if only imaging evaluation of vessel status is not available. If recanalization status is required after intravenous thrombolysis, vascular imaging is recommended despite ENI.

Introduction: This article in this supplement issue on the Performance, Effectiveness, and Costs of Treatment episodes (PERFECT) project describes trends in Finnish stroke treatment and outcome., Material and Methods: The PERFECT Stroke study uses multiple national registry linkages at individual patient level to produce a national stroke database with comprehensive follow-up of all hospital-treated stroke patients in Finland., Results: There were 94,316 incident stroke patients treated in Finnish hospitals from 1999 to 2007. Lengths-of-stays decreased after ischemic stroke (IS), and increased after intracerebral (ICH) and subarachnoid (SAH) hemorrhage. Ten-year survival improved in IS (hazard ratio 0.75; 95% CI 0.71-0.79) and ICH patients (0.88; 0.79-0.97), increasing median survival by 2 and 1 life-years respectively. This has translated into more days spent home among IS patients, but not among ICH patients. Treatment by neurologists improved the survival of IS (odds ratio [OR] 1.77; 95% CI 1.70-1.84) and ICH patients (OR 1.55; 95% CI 1.40-1.69), and treatment by neurosurgeons of SAH patients (OR 2.66; 95% CI 2.25-3.16), the effects were further improved by care in specialized stroke centers., Discussion: The survival of Finnish IS and ICH patients has improved. Specialized acute care was associated with improved outcome.

Background: Raised blood pressure is common in acute stroke, and is associated with an increased risk of poor outcomes. We aimed to examine whether careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure., Methods: Participants in this randomised, placebo-controlled, double-blind trial were recruited from 146 centres in nine north European countries. Patients older than 18 years with acute stroke (ischaemic or haemorrhagic) and systolic blood pressure of 140 mm Hg or higher were included within 30 h of symptom onset. Patients were randomly allocated to candesartan or placebo (1:1) for 7 days, with doses increasing from 4 mg on day 1 to 16 mg on days 3 to 7. Randomisation was stratified by centre, with blocks of six packs of candesartan or placebo. Patients and investigators were masked to treatment allocation. There were two co-primary effect variables: the composite endpoint of vascular death, myocardial infarction, or stroke during the first 6 months; and functional outcome at 6 months, as measured by the modified Rankin Scale. Analyses were by intention to treat. The study is registered, number NCT00120003 (ClinicalTrials.gov), and ISRCTN13643354., Findings: 2029 patients were randomly allocated to treatment groups (1017 candesartan, 1012 placebo), and data for status at 6 months were available for 2004 patients (99%; 1000 candesartan, 1004 placebo). During the 7-day treatment period, blood pressures were significantly lower in patients allocated candesartan than in those on placebo (mean 147/82 mm Hg [SD 23/14] in the candesartan group on day 7 vs 152/84 mm Hg [22/14] in the placebo group; p<0·0001). During 6 months' follow-up, the risk of the composite vascular endpoint did not differ between treatment groups (candesartan, 120 events, vs placebo, 111 events; adjusted hazard ratio 1·09, 95% CI 0·84-1·41; p=0·52). Analysis of functional outcome suggested a higher risk of poor outcome in the candesartan group (adjusted common odds ratio 1·17, 95% CI 1·00-1·38; p=0·048 [not significant at p≤0·025 level]). The observed effects were similar for all prespecified secondary endpoints (including death from any cause, vascular death, ischaemic stroke, haemorrhagic stroke, myocardial infarction, stroke progression, symptomatic hypotension, and renal failure) and outcomes (Scandinavian Stroke Scale score at 7 days and Barthel index at 6 months), and there was no evidence of a differential effect in any of the prespecified subgroups. During follow-up, nine (1%) patients on candesartan and five (<1%) on placebo had symptomatic hypotension, and renal failure was reported for 18 (2%) patients taking candesartan and 13 (1%) allocated placebo., Interpretation: There was no indication that careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised blood pressure. If anything, the evidence suggested a harmful effect., Funding: South-Eastern Norway Regional Health Authority; Oslo University Hospital Ullevål; AstraZeneca; Takeda., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Elevated blood pressure following acute stroke is common, and yet early antihypertensive treatment is controversial. ACCESS suggested a beneficial effect of the angiotensin receptor blocker candesartan in the acute phase of stroke, but these findings need to be confirmed in new, large trials., Aims and Design: The Scandinavian Candesartan Acute Stroke Trial is an international randomised, placebo-controlled, double-blind trial of candesartan in acute stroke. We plan to recruit 2500 patients presenting within 30 h of stroke (ischaemic or haemorrhagic) and with systolic blood pressure ≥140 mmHg. The recruited patients are randomly assigned to candesartan or placebo for 7-days (doses increasing from 4 to 16 mg once daily). Randomisation is performed centrally via a secure web interface. The follow-up period is 6-months. Patients are included from the following nine North-European countries: Norway, Sweden, Denmark, Belgium, Germany, Poland, Lithuania, Estonia and Finland., Study Outcomes: There are two co-primary effect variables: • Functional status at 6-months, measured by the modified Rankin Scale, and • vascular death, myocardial infarction or stroke during the first 6-months. Secondary outcome variables: Secondary effect variables include • the Barthel index (functional status) • EuroQol (quality of life) and • Mini-mental state examination (cognition) at 6-months • Health economic costs during the first 6-months, Funding: The Scandinavian Candesartan Acute Stroke Trial receives basic funding from Norwegian health authorities. AstraZeneca supplies the trial drugs, and AstraZeneca and Takeda support the trial with limited, unrestricted grants., Summary: The Scandinavian Candesartan Acute Stroke Trial is the first large trial of angiotensin receptor blockers in patients with elevated blood pressure and acute stroke, and aims to answer whether treatment with angiotensin receptor blockers is beneficial for this indication.

Background and Purpose: Stroke databases are established to systematically evaluate both the treatment and outcome of stroke patients and the structure and processes of stroke services. Comprehensive data collection on this common disease is resource-intensive, and national stroke databases often include only patients from selected hospitals. Here we describe an alternative national stroke database., Methods: We established a nationwide stroke database with multiple administrative registry linkages at the individual-patient level. Information on comorbidities; treatments before, during, and after stroke; living status; recurrences; case fatality; and costs were collected for each hospital-treated stroke patient., Results: The current database includes 94 316 patients with incident stroke between January 1999 and December 2007, with follow-up until December 2008. Annually, 10 500 new patients are being added. One-year recurrence was 13% and case fatality was 27% during the study period. In 2007, 86% of patients survived 1 month and 77% were living at home at 3 months, but the proportion treated in stroke centers (62%) or with nationally recommended secondary preventive medication after ischemic stroke (49%) was still suboptimal., Conclusions: In comparison with other national stroke databases, our method enables higher coverage and more thorough follow-up of patients. Information on long-term recurrences, case fatality, or costs is not often included in national stroke databases. Our database has low maintenance costs, but it lacks detailed data on in-hospital processes. Use of national administrative data, where such linkage is possible, saves resources, achieves high rates of long-term follow-up, and allows for comprehensive monitoring of the burden of the disease.

Background: In September, 2008, the European Acute Stroke Study III (ECASS III) randomised trial and the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) observational study reported the efficacy and safety of the extension of the time window for intravenous alteplase treatment from within 3 h to within 4.5 h after stroke onset. We aimed to assess the implementation of the wider time window, its effect on the admission-to-treatment time, and safety and functional outcome in patients recorded in SITS-ISTR., Methods: Patients treated according to the criteria of the European Summary of Product Characteristics, except for the time window, were included. Patients were grouped according to whether they were registered into SITS-ISTR before or after October, 2008. We measured admission-to-treatment time and rates of symptomatic intracerebral haemorrhage, mortality, and functional independence at 3 months., Findings: 23 942 patients were included in SITS-ISTR between December, 2002, and February, 2010, of whom 2376 were treated 3-4.5 h after symptom onset. The proportion of patients treated within 3-4.5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs 67 of 1023 [7%]). The median admission-to-treatment time was 65 min both for patients registered before and after October, 2008 (p=0.94). 352 (2%) of 21 204 patients treated within 3 h and 52 (2%) of 2317 treated within 3-4.5 h of stroke had symptomatic intracerebral haemorrhage at 3 months (adjusted odds ratio [OR] 1.44, 95% CI 1.05-1.97; p=0.02). 2287 (12%) of 18 583 patients who were treated within 3 h and 218 (12%) of 1817 who were treated within 3-4.5 h had died by the 3-month follow-up (adjusted OR 1.26, 95% CI 1.07-1.49; p=0.005); 10 531 (57%) of 18 317 patients treated within 3 h of stroke and 1075 (60%) of 1784 who were treated within 3-4.5 h were functionally independent at 3 months (adjusted OR 0.84, 95% CI 0.75-0.95; p=0.005)., Interpretation: Since October, 2008, thrombolysis within 3-4.5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased. Safety and functional outcomes are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier. Thrombolysis should be initiated within 4.5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset., Funding: Boehringer Ingelheim, Ferrer, the European Union Public Health Executive Authority, and Medical Training and Research (ALF) from Stockholm County Council and Karolinska Institutet., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background and Purpose: Previous studies show better outcomes for patients with stroke receiving care in stroke units, but many different stroke unit criteria have been published. In this study, we explored whether stroke centers fulfilling standardized Brain Attack Coalition criteria produce better patient outcomes than hospitals without stroke centers., Methods: We did an observational register-linkage study of all patients with ischemic stroke treated in Finland between 1999 and 2006. After exclusion of recurrent strokes and nonanalyzable patients, we included 61 685 consecutive patients treated in 333 hospitals classified in national audits either as Comprehensive Stroke Centers, Primary Stroke Centers, or General Hospitals according to Brain Attack Coalition criteria. Primary outcome measures were case-fatality and being in institutional care 1 year after stroke., Results: Care in stroke centers was associated with lower 1-year case-fatality and reduced institutional care compared with General Hospitals. The number-needed-to-treat to prevent 1 death or institutional care at 1 year was 29 for Comprehensive Stroke Centers and 40 for Primary Stroke Centers versus General Hospitals. Patients treated in stroke centers had lower mortality during the entire follow-up of up to 9 years and their median survival was increased by 1 year., Conclusions: This study shows a clear association between the level of acute stroke care and patient outcome and supports use of published criteria for primary and comprehensive stroke centers.

Background and Purpose: The Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST) unadjusted results demonstrated that intravenous alteplase is well tolerated and that the effects were comparable with those seen in randomized, controlled trials (RCTs) when used in routine clinical practice within 3 hours of ischemic stroke onset. We aimed to identify outcome predictors and adjust the outcomes of the SITS-MOST to the baseline characteristics of RCTs., Methods: The study population was SITS-MOST (n=6483) and pooled RCTs (n=464) patients treated with intravenous alteplase within 3 hours of stroke onset. Multivariable, backward stepwise regression analyses (until Por=1 within 7 days with any hemorrhage (RCT definition), mortality, and independency as defined by modified Rankin Score of 0 to 2 at 3 months., Results: The adjusted proportion of symptomatic intracerebral hemorrhage for SITS-MOST was 8.5% (95% CI, 7.9 to 9.0) versus 8.6% (6.3 to 11.6) for pooled RCTs; mortality was 15.5% (14.7 to 16.2) versus 17.3% (14.1 to 21.1); and independency was 50.4% (49.6 to 51.2) versus 50.1% (44.5 to 54.7), respectively. In the multivariable analysis, older age, high blood glucose, high National Institutes of Health Stroke Scale score, and current infarction on imaging scans were related to poor outcome in all parameters. Systolic blood pressure, atrial fibrillation, and weight were additional predictors of symptomatic intracerebral hemorrhage. Current smokers had a lower rate of symptomatic intracerebral hemorrhage. Disability before current stroke (modified Rankin Score 2 to 5), diastolic blood pressure, antiplatelet other than aspirin, congestive heart failure, patients treated in new centers, and male sex were related to high mortality at 3 months., Conclusions: The adjusted outcomes from SITS-MOST were almost identical to those in relevant RCTs and reinforce the conclusion drawn previously in the unadjusted analysis. We identified several important outcome predictors to better identify patients suitable for thrombolysis.

Background: Intravenous alteplase is approved for use within 3 h of ischaemic stroke onset, although a meta-analysis of randomised controlled trials suggests treatment benefit up to 4.5 h. We compared outcome in patients treated between 3 h and 4.5 h versus those treated within 3 h, who were recorded in the in the Safe Implementation of Treatments in Stroke (SITS), a prospective internet-based audit of the International Stroke Thrombolysis Registry (ISTR)., Methods: We compared 664 patients presenting with ischaemic stroke and given intravenous altepase (0.9 mg/kg total dose) between 3 h and 4.5 h with 11 865 patients treated within 3 h. All patients were otherwise compliant with European summary of product characteristics criteria and had been documented in the international stroke treatment registry between Dec 25, 2002, and Nov 15, 2007. Outcome measures were symptomatic intracerebral haemorrhage within 24 h (haemorrhage type 2 associated with National Institutes of Health Stroke Scale [NIHSS] > or = 4 points deterioration), and mortality and independence (modified Rankin scale of 0-2) at 3 months., Findings: In the 3-4.5-h cohort, treatment was started at a median of 55 min later after symptom onset (195 min [IQR 187-210] vs 140 min [115-165], p<0.0001), median age was 3 years younger (65 years [55-73] vs 68 years [58-74], p<0.0001), and stroke severity was lower (NIHSS score 11 [7-16] vs 12 [8-17], p<0.0001) than in the 3-h cohort. We recorded no significant differences between the 3-4.5-h cohort and the within 3-h cohort for any outcome measure--rate of symptomatic intracerebral haemorrhage: 2.2% (14 of 649) versus 1.6% (183 of 11 681) (odds ratio [OR] 1.18 [95% CI 0.89-1.55], p=0.24; adjusted OR 1.32 [1.00-1.75], p=0.052); mortality: 12.7% (70 of 551) versus 12.2% (1263 of 10 368) (OR 1.02 [0.90-1.17]; p=0.72; adjusted OR 1.15 [1.00-1.33]; p=0.053); and independence: 58.0% (314 of 541) versus 56.3% (5756 of 10231) (OR 1.04 [0.95-1.13], p=0.42; adjusted OR 0.93 [0.84-1.03], p=0.18)., Interpretation: Alteplase remains safe when given at 3-4.5 h after ischaemic stroke, offering an opportunity for patients who cannot be treated within the standard 3-h timeframe., Funding: Boehringer-Ingelheim, European Union Public Health Executive Authority.

Background: The aim of the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was to assess the safety and efficacy of intravenous alteplase as thrombolytic therapy within the first 3 h of onset of acute ischaemic stroke. Under European Union regulations, SITS-MOST was required to assess the safety profile of alteplase in clinical practice by comparison with results in randomised controlled trials., Methods: 6483 patients were recruited from 285 centres (50% with little previous experience in stroke thrombolysis) in 14 countries between 2002 and 2006 for this prospective, open, monitored, observational study. Primary outcomes were symptomatic (a deterioration in National Institutes of Health stroke scale score of >or=4) intracerebral haemorrhage type 2 within 24 h and mortality at 3 months. We compared mortality, the proportion of patients with symptomatic intracerebral haemorrhage as per the Cochrane definition, and functional outcome at 3 months with relevant pooled results from randomised controlled trials., Findings: Baseline characteristics of patients in SITS-MOST were much the same as those in the pooled randomised controlled trials. At 24 h, the proportion of patients with symptomatic intracerebral haemorrhage (per the SITS-MOST protocol) was 1.7% (107/6444; 95% CI 1.4-2.0); at 7 days, the proportion with the same condition as per the Cochrane definition was 7.3% (468/6438; 6.7-7.9) compared with 8.6% (40/465; 6.3-11.6) in the pooled randomised controlled trials. The mortality rate at 3 months in SITS-MOST was 11.3% (701/6218; 10.5-12.1) compared with 17.3% (83/479; 14.1-21.1) in the pooled randomised controlled trials., Interpretation: These data confirm that intravenous alteplase is safe and effective in routine clinical use when used within 3 h of stroke onset, even by centres with little previous experience of thrombolytic therapy for acute stroke. The findings should encourage wider use of thrombolytic therapy for suitable patients treated in stroke centres.

Background and Purpose: We sought to determine the recovery of cortical auditory discrimination in aphasic, left-hemisphere-stroke patients by using an electrophysiological response called mismatch negativity (MMN) and speech-comprehension tests., Methods: MMN in 8 left-hemisphere stroke patients was recorded in response to duration and frequency changes in a repetitive, harmonically rich tone 4 and 10 days and again 3 and 6 months after their first unilateral stroke. Eight age-matched, healthy persons served as control subjects., Results: At 4 days after stroke onset, patients' sound discrimination was impaired in their left hemisphere, as suggested by attenuated MMNs, especially to right-ear stimuli. At 3 months after stroke, however, MMN to the right-ear duration change had significantly increased and was of normal size. A significant change for the frequency MMN was found for left-ear stimuli between 3 and 6 months after stroke. During the follow-up period, progressive improvement in speech-comprehension tests was also observed. Furthermore, there was a significant correlation between the change in the duration MMN amplitude and the Boston Diagnostic Aphasia Examination speech-comprehension test from 10 days to 3 months after stroke., Conclusions: These results suggest that the MMN can be used as an index of the recovery of auditory discrimination.

Background and Purpose: Thrombolysis with alteplase is used in acute ischemic stroke within 3 hours after symptom onset in many stroke centers, but experience remains limited in Europe., Methods: Using eligibility and management criteria similar to those published by the American Heart Association, we treated 75 consecutive patients aged 21 to 83 years (mean age, 63.6 years; median Scandinavian Stroke Scale score, 32/58) with hemispheric infarction with alteplase in 1998-2001. Their neuroradiological findings (ischemic and hemorrhagic changes) and functional outcome at 3 months were evaluated., Results: Sixty-one percent of the patients had recovered functional independence (Barthel Index 95 to 100) at the 3-month follow-up. On the modified Rankin Scale (mRS), 37% (28/75) of patients had no or minimal symptoms (mRS 0 to 1), while 17% (13/75) remained dependent (mRS 4 to 5) and 5% (4/75) died. Cerebral parenchymal hematomas occurred in 8% (6/75) and hemorrhagic transformation in 8% (6/75) of the patients. Low initial diastolic blood pressure and administration of intravenous antihypertensive medication were associated with unfavorable outcome (mRS 3 to 6)., Conclusions: We conclude that our management protocol for thrombolytic therapy is safe. These rates of functional outcome, case fatality, and hemorrhagic cerebral events compare favorably with those of other published series of stroke thrombolysis with similar time windows and management guidelines. Associations between blood pressure and its treatment during thrombolysis with functional outcome deserve further analysis.

Background and Objectives: Persons with Alzheimer's disease (AD) have been suggested to receive suboptimal treatment. We studied the 30-day mortality after ischemic stroke, hemorrhagic stroke, or myocardial infarction in individuals with or without AD. Methods: An exposure matched cohort of all Finnish community-dwellers diagnosed with clinically verified AD in 2005-2012 (n = 73,005) and 1-4 matched comparison persons/AD-affected person (n = 215,449). Data on 30-day mortality after ischemic stroke (n = 16,419; deaths: n = 2,748), hemorrhagic stroke (n = 3,570; deaths: n = 1,224), and myocardial infarction (n = 15,304; deaths: n = 3,804) were obtained from the National Hospital Discharge register. The main analyses were restricted to first-ever events. Results: Persons with AD had slightly higher 30-day mortality after ischemic stroke (adjusted HR 1.36, 95% Confidence interval (CI) 1.24,1.49), hemorrhagic stroke (adjusted HR 1.11, 95% CI 0.98,1.25), or myocardial infarction (adjusted HR, 1.40, 9% CI 1.30,1.51). The associations were not affected by age, gender, or co-morbidities and remained similar when patients with previous ischemic strokes or infarctions were included. The absolute risk increase in 30-day mortality after ischemic or hemorrhagic stroke and myocardial infarction were 4.9% (95% CI 3.3,6.5), 3.3% (95% CI-1.6,8.2), and 7.5% (95% CI 5.0,10.0), respectively. Conclusions: Although the 30-day mortality was somewhat higher in the AD cohort, the absolute differences were small indicating that acute treatment was not notably inferior in AD patients. The slightly higher mortality was not explained by co-morbidities but may reflect the higher mortality of AD persons in general, or treatment practice of patients with severe cognitive impairment. [ABSTRACT FROM AUTHOR]

Over 2 million people are affected by intracerebral haemorrhage (ICH) worldwide every year, one third of them dying within 1 month, and many survivors being left with permanent disability. Unlike most other stroke types, the incidence, morbidity and mortality of ICH have not declined over time. No standardised diagnostic workup for the detection of the various underlying causes of ICH currently exists, and the evidence for medical or surgical therapeutic interventions remains limited. A dedicated European research programme for ICH is needed to identify ways to reduce the burden of ICH-related death and disability. The European Research Network on Intracerebral Haemorrhage EURONICH is a multidisciplinary academic research collaboration that has been established to define current research priorities and to conduct large clinical studies on all aspects of ICH. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background Intravenous levosimendan is indicated for acute heart failure. The compound has shown promising beneficial effects in ischemic stroke models. Objective We evaluated the efficacy and safety of oral levosimendan in patients with a history of cerebral ischemia. Methods In a randomized, double-blind, placebo-controlled, parallel-group study, 16 patients with a history of ischemic stroke/transient ischemic attack received oral levosimendan in 5 escalating doses from 0.125 to 2.0 mg daily for 18-day intervals of each dose; 5 patients received placebo. Twenty-four-hour ambulatory ECG and cerebral blood flow velocities using transcranial Doppler ultrasound were recorded at baseline and at the end of each dosing period. Vasomotor reactivity was assessed via the breath holding index. In addition, plasma levels of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and the metabolites of levosimendan were determined. Results Levosimendan induced an increase in cerebral blood flow velocities and a decrease in NT-pro-BNP compared with placebo. There was no significant effect on breath holding index. Doses ≥0.5 mg increased heart rate by 5 to 9 beats/min. The dose level of 2.0 mg exceeded the preset safety margin of ventricular extrasystoles per hour (ie, upper 90% CI of the ratio of levosimendan to placebo above 2) with an estimate of 3.10 (90% CI, 0.95–10.07). Conclusions Oral levosimendan increases cerebral blood flow velocities and diminishes NT-pro-BNP levels in patients with earlier ischemic cerebrovascular event. Daily doses up to 1.0 mg were well tolerated, whereas the 2.0 mg dose level induced an increase in ventricular extrasystoles. ClinicalTrials.gov identifier: NCT00698763. [ABSTRACT FROM AUTHOR]