Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Association between heavy alcohol consumption and cryptogenic ischaemic stroke in young adults: a case-control study.

BACKGROUND: The underlying risk factors for young-onset cryptogenic ischaemic stroke (CIS) remain unclear. This multicentre study aimed to explore the association between heavy alcohol consumption and CIS with subgroup analyses stratified by sex and age. METHODS: Altogether, 540 patients aged 18-49 years (median age 41; 47.2% women) with a recent CIS and 540 sex-matched and age-matched stroke-free controls were included. Heavy alcohol consumption was defined as >7 (women) and >14 (men) units per week or at least an average of two times per month ≥5 (women) and ≥7 (men) units per instance (binge drinking). A conditional logistic regression adjusting for age, sex, education, hypertension, cardiovascular diseases, diabetes, hypercholesterolaemia, current smoking, obesity, diet and physical inactivity was used to assess the independent association between alcohol consumption and CIS. RESULTS: Patients were twice as more often heavy alcohol users compared with controls (13.7% vs 6.7%, p<0.001), were more likely to have hypertension and they were more often current smokers, overweight and physically inactive. In the entire study population, heavy alcohol consumption was independently associated with CIS (adjusted OR 2.11; 95% CI 1.22 to 3.63). In sex-specific analysis, heavy alcohol consumption was associated with CIS in men (2.72; 95% CI 1.25 to 5.92), but not in women (1.56; 95% CI 0.71 to 3.41). When exploring the association with binge drinking alone, a significant association was shown in the entire cohort (2.43; 95% CI 1.31 to 4.53) and in men (3.36; 95% CI 1.44 to 7.84), but not in women. CONCLUSIONS: Heavy alcohol consumption, particularly binge drinking, appears to be an independent risk factor in young men with CIS.

Neuroprotective Effects of Inhaled Xenon Gas on Brain Structural Gray Matter Changes After Out-of-Hospital Cardiac Arrest Evaluated by Morphometric Analysis: A Substudy of the Randomized Xe-Hypotheca Trial.

BACKGROUND: We have earlier reported that inhaled xenon combined with hypothermia attenuates brain white matter injury in comatose survivors of out-of-hospital cardiac arrest (OHCA). A predefined secondary objective was to assess the effect of inhaled xenon on the structural changes in gray matter in comatose survivors after OHCA. METHODS: Patients were randomly assigned to receive either inhaled xenon combined with target temperature management (33 °C) for 24 h (n = 55, xenon group) or target temperature management alone (n = 55, control group). A change of brain gray matter volume was assessed with a voxel-based morphometry evaluation of high-resolution structural brain magnetic resonance imaging (MRI) data with Statistical Parametric Mapping. Patients were scheduled to undergo the first MRI between 36 and 52 h and a second MRI 10 days after OHCA. RESULTS: Of the 110 randomly assigned patients in the Xe-Hypotheca trial, 66 patients completed both MRI scans. After all imaging-based exclusions, 21 patients in the control group and 24 patients in the xenon group had both scan 1 and scan 2 available for analyses with scans that fulfilled the quality criteria. Compared with the xenon group, the control group had a significant decrease in brain gray matter volume in several clusters in the second scan compared with the first. In a between-group analysis, significant reductions were found in the right amygdala/entorhinal cortex (p = 0.025), left amygdala (p = 0.043), left middle temporal gyrus (p = 0.042), left inferior temporal gyrus (p = 0.008), left parahippocampal gyrus (p = 0.042), left temporal pole (p = 0.042), and left cerebellar cortex (p = 0.005). In the remaining gray matter areas, there were no significant changes between the groups. CONCLUSIONS: In comatose survivors of OHCA, inhaled xenon combined with targeted temperature management preserved gray matter better than hypothermia alone. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00879892.

Comparison of the prognostic value of early-phase proton magnetic resonance spectroscopy and diffusion tensor imaging with serum neuron-specific enolase at 72 h in comatose survivors of out-of-hospital cardiac arrest-a substudy of the XeHypotheca trial.

PURPOSE: We compared the predictive accuracy of early-phase brain diffusion tensor imaging (DTI), proton magnetic resonance spectroscopy (1H-MRS), and serum neuron-specific enolase (NSE) against the motor score and epileptic seizures (ES) for poor neurological outcome after out-of-hospital cardiac arrest (OHCA). METHODS: The predictive accuracy of DTI, 1H-MRS, and NSE along with motor score at 72 h and ES for the poor neurological outcome (modified Rankin Scale, mRS, 3 - 6) in 92 comatose OHCA patients at 6 months was assessed by area under the receiver operating characteristic curve (AUROC). Combined models of the variables were included as exploratory. RESULTS: The predictive accuracy of fractional anisotropy (FA) of DTI (AUROC 0.73, 95% CI 0.62-0.84), total N-acetyl aspartate/total creatine (tNAA/tCr) of 1H-MRS (0.78 (0.68 - 0.88)), or NSE at 72 h (0.85 (0.76 - 0.93)) was not significantly better than motor score at 72 h (0.88 (95% CI 0.80-0.96)). The addition of FA and tNAA/tCr to a combination of NSE, motor score, and ES provided a small but statistically significant improvement in predictive accuracy (AUROC 0.92 (0.85-0.98) vs 0.98 (0.96-1.00), p = 0.037). CONCLUSION: None of the variables (FA, tNAA/tCr, ES, NSE at 72 h, and motor score at 72 h) differed significantly in predicting poor outcomes in this patient group. Early-phase quantitative neuroimaging provided a statistically significant improvement for the predictive value when combined with ES and motor score with or without NSE. However, in clinical practice, the additional value is small, and considering the costs and challenges of imaging in this patient group, early-phase DTI/MRS cannot be recommended for routine use. TRIAL REGISTRATION: ClinicalTrials.gov NCT00879892, April 13, 2009.

Atrial fibrillation after closure of patent foramen ovale in the REDUCE clinical study.

OBJECTIVES: To describe the occurrence of postprocedural atrial fibrillation (AF) among patients with cryptogenic stroke undergoing patent foramen ovale (PFO) closure in the REDUCE clinical study and analyze for potential risk factors for the development of postprocedural AF. BACKGROUND: AF is an adverse event that might potentially counterbalance the stroke prevention benefit from PFO closure. Data on AF after transcatheter PFO closure are sparse. METHODS: We evaluated data from patients having PFO closure (Gore HELEX or Gore Cardioform Septal Occluder) in the REDUCE clinical trial (n = 408) in at post hoc explorative analysis. Median follow-up was 5.0 years. RESULTS: AF occurred in 30 patients (7.4%) after PFO closure with a total of 34 AF events. Most were reported as non-serious (68%), detected within 45 days post-procedure (79%), and resolved within 2 weeks of onset (63%). One subject with AF had recurrent stroke. Postprocedural AF occurred more frequently among subjects with higher age and large device sizes. Male sex was the only independent predictor of postprocedural AF. We found no association between the type of occluder (HELEX or Gore Cardioform Septal Occluder) or PFO anatomical characteristics and post-procedural AF. CONCLUSION: In the REDUCE clinical study, postprocedural atrial fibrillation was mostly early onset, transient and with no later recurrence. Postprocedural AF occurred more frequently among patients with higher age and larger devices. Male sex was the only independent predictor of postprocedural AF.

Obesity and the Risk of Cryptogenic Ischemic Stroke in Young Adults.

OBJECTIVES: We examined the association between obesity and early-onset cryptogenic ischemic stroke (CIS) and whether fat distribution or sex altered this association. MATERIALS AND METHODS: This prospective, multi-center, case-control study included 345 patients, aged 18-49 years, with first-ever, acute CIS. The control group included 345 age- and sex-matched stroke-free individuals. We measured height, weight, waist circumference, and hip circumference. Obesity metrics analyzed included body mass index (BMI), waist-to-hip ratio (WHR), waist-to-stature ratio (WSR), and a body shape index (ABSI). Models were adjusted for age, level of education, vascular risk factors, and migraine with aura. RESULTS: After adjusting for demographics, vascular risk factors, and migraine with aura, the highest tertile of WHR was associated with CIS (OR for highest versus lowest WHR tertile 2.81, 95%CI 1.43-5.51; P=0.003). In sex-specific analyses, WHR tertiles were not associated with CIS. However, using WHO WHR cutoff values (>0.85 for women, >0.90 for men), abdominally obese women were at increased risk of CIS (OR 2.09, 95%CI 1.02-4.27; P=0.045). After adjusting for confounders, WC, BMI, WSR, or ABSI were not associated with CIS. CONCLUSIONS: Abdominal obesity measured with WHR was an independent risk factor for CIS in young adults after rigorous adjustment for concomitant risk factors.

Patent Foramen Ovale Closure Decreases the Incidence but Not the Size of New Brain Infarction on Magnetic Resonance Imaging: An Analysis of the REDUCE Trial.

Background and Purpose: Randomized patent foramen ovale closure trials have used open-label end point ascertainment which increases the risk of bias and undermines confidence in the conclusions. The Gore REDUCE trial prospectively performed baseline and follow-up magnetic resonance imaging (MRIs) for all subjects providing an objective measure of the effectiveness of closure. Methods: We performed blinded evaluations of the presence, location, and volume of new infarct on diffusion-weighted imaging of recurrent clinical stroke or new infarct (>3 mm) on T2/fluid attenuated inversion recovery from baseline to follow-up MRI at 2 years, comparing closure to medical therapy alone. We also examined the effect of shunt size and the development of atrial fibrillation on infarct burden at follow-up. Results: At follow-up, new clinical stroke or silent MRI infarct occurred in 18/383 (4.7%) patients who underwent closure and 19/177 (10.7%) medication-only patients (relative risk, 0.44 [95% CI, 0.24­0.81], P=0.02). Clinical strokes were less common in closure patients compared with medically treated patients, 5 (1.3%) versus 12 (6.8%), P=0.001, while silent MRI infarcts were similar, 13 (3.4%) versus 7 (4.0%), P=0.81. There were no differences in number, volumes, and distribution of new infarct comparing closure patients to those treated with medication alone. There were also no differences of number, volumes, and distribution comparing silent infarcts to clinical strokes. Infarct burden was also similar for patients who developed atrial fibrillation and for those with large shunts. Conclusions: The REDUCE trial demonstrates that patent foramen ovale closure prevents recurrent brain infarction based on the objective outcome of new infarcts on MRI. Only clinical strokes were reduced by closure while silent infarctions were similar between study arms, and there were no differences in infarct volume or location comparing silent infarcts to clinical strokes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00738894.

Atrial Cardiopathy and Nonstenosing Large Artery Plaque in Patients With Embolic Stroke of Undetermined Source.

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.

Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke.

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 .).

Comparison of Antiplatelet Therapies for Prevention of Patent Foramen Ovale-Associated Stroke.

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.

Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.

IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892.

Oral Levosimendan Increases Cerebral Blood Flow Velocities in Patients with a History of Stroke or Transient Ischemic Attack: A Pilot Safety Study.

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.

Safety of intravenous thrombolysis for ischemic stroke in patients treated with warfarin.

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.

[Investments of research and treatment of brain diseases will pay of time]. / Aivosairaudet ovat kalleimmat kansantautimme.

In 2010, a quarter of direct healthcare cost in Europe were spent on brain diseases. The importance of preventing and treating brain diseases and maintaining of functional capacity of the brain will increase in our society with ageing population and with increasing cognitive requirements of modern working life. Public funding of basic and clinical neuroscience has, however, frozen to levels achieved years ago, clinical research of brain diseases being at a particular risk. Research projects directed to prevention, treatment, and rehabilitation of brain diseases will pay off, also when assessed by economic measures.

A metabolic profile of xenon and metabolite associations with 6-month mortality after out-of-hospital cardiac arrest: A post-hoc study of the randomised Xe-Hypotheca trial.

PURPOSE: Out-of-hospital cardiac arrest (OHCA) carries a relatively poor prognosis and requires multimodal prognostication to guide clinical decisions. Identification of previously unrecognized metabolic routes associated with patient outcome may contribute to future biomarker discovery. In OHCA, inhaled xenon elicits neuro- and cardioprotection. However, the metabolic effects remain unknown. MATERIALS AND METHODS: In this post-hoc study of the randomised, 2-group, single-blind, phase 2 Xe-Hypotheca trial, 110 OHCA survivors were randomised 1:1 to receive targeted temperature management (TTM) at 33°C with or without inhaled xenon during 24 h. Blood samples for nuclear magnetic resonance spectroscopy metabolic profiling were drawn upon admission, at 24 and 72 h. RESULTS: At 24 h, increased lactate, adjusted hazard-ratio 2.25, 95% CI [1.53; 3.30], p<0.001, and decreased branched-chain amino acids (BCAA) leucine 0.64 [0.5; 0.82], p = 0.007, and valine 0.37 [0.22; 0.63], p = 0.003, associated with 6-month mortality. At 72 h, increased lactate 2.77 [1.76; 4.36], p<0.001, and alanine 2.43 [1.56; 3.78], p = 0.001, and decreased small HDL cholesterol ester content (S-HDL-CE) 0.36 [0.19; 0.68], p = 0.021, associated with mortality. No difference was observed between xenon and control groups. CONCLUSIONS: In OHCA patients receiving TTM with or without xenon, high lactate and alanine and decreased BCAAs and S-HDL-CE associated with increased mortality. It remains to be established whether current observations on BCAAs, and possibly alanine and lactate, could reflect neural damage via their roles in the metabolism of the neurotransmitter glutamate. Xenon did not significantly alter the measured metabolic profile, a potentially beneficial attribute in the context of compromised ICU patients. TRIAL REGISTRATION: Trial Registry number: ClinicalTrials.gov Identifier: NCT00879892.

Feasibility and cardiac safety of inhaled xenon in combination with therapeutic hypothermia following out-of-hospital cardiac arrest.

OBJECTIVES: Preclinical studies reveal the neuroprotective properties of xenon, especially when combined with hypothermia. The purpose of this study was to investigate the feasibility and cardiac safety of inhaled xenon treatment combined with therapeutic hypothermia in out-of-hospital cardiac arrest patients. DESIGN: An open controlled and randomized single-centre clinical drug trial (clinicaltrials.gov NCT00879892). SETTING: A multipurpose ICU in university hospital. PATIENTS: Thirty-six adult out-of-hospital cardiac arrest patients (18-80 years old) with ventricular fibrillation or pulseless ventricular tachycardia as initial cardiac rhythm. INTERVENTIONS: Patients were randomly assigned to receive either mild therapeutic hypothermia treatment with target temperature of 33°C (mild therapeutic hypothermia group, n=18) alone or in combination with xenon by inhalation, to achieve a target concentration of at least 40% (Xenon+mild therapeutic hypothermia group, n=18) for 24 hours. Thirty-three patients were evaluable (mild therapeutic hypothermia group, n=17; Xenon+mild therapeutic hypothermia group, n=16). MEASUREMENTS AND MAIN RESULTS: Patients were treated and monitored according to the Utstein protocol. The release of troponin-T was determined at arrival to hospital and at 24, 48, and 72 hours after out-of-hospital cardiac arrest. The median end-tidal xenon concentration was 47% and duration of the xenon inhalation was 25.5 hours. The frequency of serious adverse events, including inhospital mortality, status epilepticus, and acute kidney injury, was similar in both groups and there were no unexpected serious adverse reactions to xenon during hospital stay. In addition, xenon did not induce significant conduction, repolarization, or rhythm abnormalities. Median dose of norepinephrine during hypothermia was lower in xenon-treated patients (mild therapeutic hypothermia group=5.30 mg vs Xenon+mild therapeutic hypothermia group=2.95 mg, p=0.06). Heart rate was significantly lower in Xenon+mild therapeutic hypothermia patients during hypothermia (p=0.04). Postarrival incremental change in troponin-T at 72 hours was significantly less in the Xenon+mild therapeutic hypothermia group (p=0.04). CONCLUSIONS: Xenon treatment in combination with hypothermia is feasible and has favorable cardiac features in survivors of out-of-hospital cardiac arrest.

24-hour ambulatory blood pressure and cryptogenic ischemic stroke in young adults.

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.

The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial.

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.