Blood pressure variability in acute stroke: Risk factors and association with functional outcomes at 1 month.

BACKGROUND AND PURPOSE: Blood pressure variability, in acute stroke, may be an important modifiable determinant of functional outcome after stroke. In a large international cohort of participants with acute stroke, it was sought to determine the association of blood pressure variability (in the early period of admission) and functional outcomes, and to explore risk factors for increased blood pressure variability. PATIENTS AND METHODS: INTERSTROKE is an international case-control study of risk factors for first acute stroke. Blood pressure was recorded at the time of admission, the morning after admission and the time of interview in cases (median time from admission 36.7 h). Multivariable ordinal regression analysis was employed to determine the association of blood pressure variability (standard deviation [SD] and coefficient of variance) with modified Rankin score at 1-month follow-up, and logistic regression was used to identify risk factors for blood pressure variability. RESULTS: Amongst 13,206 participants, the mean age was 62.19 ± 13.58 years. When measured by SD, both systolic blood pressure variability (odds ratio 1.13; 95% confidence interval 1.03-1.24 for SD ≥20 mmHg) and diastolic blood pressure variability (odds ratio 1.15; 95% confidence interval 1.04-1.26 for SD ≥10 mmHg) were associated with a significant increase in the odds of poor functional outcome. The highest coefficient of variance category was not associated with a significant increase in risk of higher modified Rankin score at 1 month. Increasing age, female sex, high body mass index, history of hypertension, alcohol use, and high urinary potassium and low urinary sodium excretion were associated with increased blood pressure variability. CONCLUSION: Increased blood pressure variability in acute stroke, measured by SD, is associated with an increased risk of poor functional outcome at 1 month. Potentially modifiable risk factors for increased blood pressure variability include low urinary sodium excretion.

Circadian Temperature in Moderate to Severe Acute Stroke Patients.

Background: Stroke patients often present circadian disruption due to multiple causes e.g., primary disease, comorbidities, medication, immobilization, reduced daylight entrainment and sleep disturbances. Objective: To investigate the circadian rhythm of temperature in forehead skin in patients with moderate to severe stroke admitted for rehabilitation. Methods: A physiologic study in form of a secondary analysis of a former randomized study. In total 27 patients with moderate to severe stroke were included between May 1st 2014, and June 1st 2015. Circadian temperature was collected approx. seven days after admission at the acute stroke unit by a skin surface temperature probe as part of a Polysomnography (PSG) measurement. Results: Temperature variations show no circadian rhythm (Type 3 tests of fixed effects by SAS, p = 0.1610). The median temperature variance did fluctuate, but not significantly, and the small changes in circadian temperature variance did not follow the normal temperature variance. Conclusion: Patients with moderate to severe stroke show an abrogated circadian rhythm of temperature. There is an unmet need to understand the mechanisms for this, significance for stroke outcome and treatment.

Processes of Care and Associated Factors in Patients With Stroke by Immigration Status.

BACKGROUND: Receiving evidence-based stroke care processes is associated with good clinical outcome. However, data on early stroke care among immigrants are scarce. OBJECTIVE: We investigated whether guideline-recommended acute stroke care and associated factors differ between immigrants and Danish-born residents. DESIGN: Patients admitted with ischemic and hemorrhagic stroke diagnoses (n=129,724) between 2005 and 2018 were identified from the Danish Stroke Registry. RESULTS: We included 123,928 Danish-born residents and 5796 immigrants with stroke. Compared with Danish-born residents, immigrants were less likely to be admitted to a stroke unit within 24 hours after stroke onset (81.5% vs. 83.9%, P <0.001) and had lower odds of early stroke care including dysphagia screening, physiotherapy, occupational therapy, and nutritional assessment. After adjustment for age, sex, clinical, and sociodemographic factors, immigrants had lower odds of early stroke unit admission (odds ratio [OR]: 0.97; 95% CI, 0.94-0.99), early dysphagia screening (OR: 0.96; 95% CI, 0.93-0.98), early physiotherapy (OR: 0.96; 95% CI, 0.94-0.99), and early occupational therapy (OR: 0.96; 95% CI, 0.93-0.98) than Danish-born residents. Small absolute differences in overall quality of stroke care were found when comparing immigrants and Danish-born residents. Significant factors associated with greater likelihood of stroke care included high income, high education, and cohabitation. CONCLUSIONS: Immigrants had lower chances of early stroke unit admission and received fewer individual early stroke care processes such as dysphagia screening, physiotherapy and occupational therapy than Danish-born residents. However, the absolute disparities were in general minor and largely influenced by socioeconomic status and cohabitation.

Implications of ACC/AHA Versus ESC/EAS LDL-C Recommendations for Residual Risk Reduction in ASCVD: A Simulation Study From DA VINCI.

PURPOSE: Low-density lipoprotein cholesterol (LDL-C) recommendations differ between the 2018 American College of Cardiology/American Heart Association (ACC/AHA) and 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) (< 70 vs. < 55 mg/dl, respectively). In the DA VINCI study, residual cardiovascular risk was predicted in ASCVD patients. The extent to which relative and absolute risk might be lowered by achieving ACC/AHA versus ESC/EAS LDL-C recommended approaches was simulated. METHODS: DA VINCI was a cross-sectional observational study of patients prescribed lipid-lowering therapy (LLT) across 18 European countries. Ten-year cardiovascular risk (CVR) was predicted among ASCVD patients receiving stabilized LLT. For patients with LDL-C ≥ 70 mg/dl, the absolute LDL-C reduction required to achieve an LDL-C of < 70 or < 55 mg/dl (LDL-C of 69 or 54 mg/dl, respectively) was calculated. Relative and absolute risk reductions (RRRs and ARRs) were simulated. RESULTS: Of the 2039 patients, 61% did not achieve LDL-C < 70 mg/dl. For patients with LDL-C ≥ 70 mg/dl, median (interquartile range) baseline LDL-C and 10-year CVR were 93 (81-115) mg/dl and 32% (25-43%), respectively. Median LDL-C reductions of 24 (12-46) and 39 (27-91) mg/dl were needed to achieve an LDL-C of 69 and 54 mg/dl, respectively. Attaining ACC/AHA or ESC/EAS goals resulted in simulated RRRs of 14% (7-25%) and 22% (15-32%), respectively, and ARRs of 4% (2-7%) and 6% (4-9%), respectively. CONCLUSION: In ASCVD patients, achieving ESC/EAS LDL-C goals could result in a 2% additional ARR over 10 years versus the ACC/AHA approach.

High-intensity training in patients with lacunar stroke: A one-year follow-up.

OBJECTIVES: Physical inactivity is a major risk factor for stroke. It is a challenge for patients to initiate and adhere to regular exercise post-stroke. Early initiation of home-based high-intensity interval training (HIIT) may engage patients in physical activity, improve cardiorespiratory fitness, and reduce risk of recurrent stroke. MATERIALS AND METHODS: Post-intervention follow-up of patients with lacunar stroke, randomized to three-months HIIT including weekly motivational calls, or usual care. At follow-up (six- and 12-months post-stroke), we investigated changes in cardiorespiratory fitness, physical activity, fatigue, depression, mental well-being, stress, cognition, cardiovascular function, and recurrent stroke. RESULTS: We included 71 patients of whom 59 patients (mean age: 63.9 ± 8.8 years) completed six- and 12-month follow-up. No change was detected in cardiorespiratory fitness between groups from baseline to 12-months follow-up. At six months, vigorous-intensity activity (median hours/week [interquartile range]) was maintained in the intervention group (baseline, 0[0;2]; post-intervention, 2[0;3]; six-month, 2[0;4]) and increased in the usual care group (baseline, 0[0;1]; post-intervention, 1[0;2]; six-month, 1[0;3]), with no difference between groups. Vigorous-intensity activity declined to baseline levels at 12-months in both groups. Secondary outcomes improved from baseline to 12-months with no significant differences between groups. Similar rate of recurrent stroke (n=3) occurred in each group with a three-month delay in the intervention group. CONCLUSIONS: Early initiated HIIT did not increase long-term cardiorespiratory fitness, but increased time spent doing vigorous-intensity activities post-stroke. Decline to baseline activity level at 12 months warrants identification of motivators to initiate and sustain physical activity post-stroke.

Role of Proxy Respondents in International Stroke Research: Experience of the INTERSTROKE Study.

INTRODUCTION: Measuring patient-reported information in stroke research is challenging. To overcome this, use of proxy respondents is often a necessary strategy. In this study, we report on use and effect of proxy respondents on patient case-mix in a large international epidemiologic stroke study (INTERSTROKE). METHODS: This was a cross-sectional study of 13,458 cases of acute first stroke in 32 countries. A standardized study questionnaire recording behavioural cardiovascular risk factors was administered to the patient, and if unable to communicate adequately, a valid proxy, or both. We used logistic regression to evaluate the association of age, sex, education, occupation, stroke severity, and region with need for proxy respondent, and report odds ratio (OR) with 95% confidence interval (CI). RESULTS: Among 13,458 participants with acute stroke, questionnaires were completed by patients alone in 41.4% (n = 5,573), combination of patient and proxy together in 21.7% (n = 2,918), and proxy alone in 36.9% (n = 4,967). Use of proxy alone was greater in participants with severe stroke (4.7% with modified-Rankin score of 0 vs. 80.5% in those with score 5; OR 187.13; 95% CI: 119.61-308.22), older persons (43.8% of those aged 80 years and over vs. 33.2% of those aged less than 40 years; age per decade OR 1.09; 95% CI: 1.06-1.12), women (40.7% vs. 34.3% of men; OR 1.32 95% CI: 1.22-1.43), and those less educated (58.9% of those never educated vs. 25.7% of those who attended third level education; OR 7.84; 95% CI: 6.78-9.08). CONCLUSION: Use of proxy respondents enhances the generalizability of international research studies of stroke, by increasing representation of women, patients with severe stroke, older age, and lower education.

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.

Use of reperfusion therapy and time delay in patients with ischaemic stroke by immigration status: A register-based cohort study in Denmark.

BACKGROUND AND PURPOSE: Reperfusion therapy is the mainstay of treatment for acute ischaemic stroke (AIS); however, little is known about the use of reperfusion therapy and time delay amongst immigrants. METHODS: This is a Danish nationwide register-based cohort study of patients with AIS aged ≥18 years (n = 49,817) recruited from 2009 to 2018. Use of reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy) and time delay between immigrants and Danish-born residents were compared using multivariable logistics and quantile regression. RESULTS: Overall, 10,649 (39.8%) Danish-born residents and 452 (39.0%) immigrants with AIS were treated with reperfusion therapy in patients arriving <4.5 h following stroke onset. Compared with Danish-born residents, immigrants had lower odds of receiving reperfusion therapy after adjustment for prehospital delay, age, sex, stroke severity, sociodemographic factors and comorbidities (adjusted odds ratio 0.67; 95% confidence interval 0.49-0.92, p = 0.01). The lowest odds were observed amongst immigrants originating from Poland and non-Western countries. Similarly, immigrants had a longer prehospital delay than Danish-born residents in the fully adjusted model in patients arriving <4.5 h after stroke onset (15 min; 95% confidence interval 4-26 min, p = 0.03). No evidence was found that system delay and clinical outcome differed between immigrants and Danish-born residents in patients eligible for reperfusion therapy after adjustment for sociodemographic factors and comorbidities. CONCLUSION: Immigration status was significantly associated with lower chances of receiving reperfusion therapy and there may be differences in patient delay between immigrants and Danish-born residents in patients arriving to a stroke unit <4.5 h after stroke onset.

Sleep-disordered breathing and cerebral small vessel disease-acute and 6 months after ischemic stroke.

PURPOSE: Sleep-disordered breathing (SDB) occurs frequently after stroke and is associated with poor functional outcome and increased mortality. The purpose of this study was to detect changes in SDB over time after acute ischemic stroke and investigate relationships between SDB and stroke etiologies with focus on cerebral small vessel disease. METHODS: From May 2015 to August 2016, we conducted an observational study of 99 patients with mild to moderate stroke (median age: 68 years, range 36-88; 56% men). Polysomnography was performed within 7 days of stroke onset (n = 91) and after 6 months (n = 52). The strokes were classified using the etiological TOAST classification. Total small vessel disease (SVD) scores were calculated based on MRIs. RESULTS: SDB, defined as an apnea-hypopnea index (AHI) ≥ 15, was found in 56% of patients in the acute state and in 44% at follow-up. AHI decreased over time (median change 4.7, 95% confidence interval [95% CI] 0.5-8.9; p = 0.03). Patients with AHI ≥ 15 in both the acute state and at follow-up had higher SVD score at follow-up (p = 0.003). AHI was not associated with ischemic stroke subgroups according to the TOAST classification. DISCUSSION: In conclusion, 6 months after stroke, AHI decreased, but 44% still had AHI ≥ 15. Persistent SDB in both the acute state and at follow-up was associated with a higher SVD score, but not to the TOAST subgroups. SDB evaluation should be offered to stroke patients, and the effect of SDB on cerebral small vessel disease needs to be further investigated using the well-defined SVD score. TRIAL REGISTRATION: clinicaltrials.gov NCT02111408, April 11, 2014.

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.

Renal Impairment and Risk of Acute Stroke: The INTERSTROKE Study.

BACKGROUND: Previous studies reported an association of renal impairment with stroke, but there are uncertainties underpinning this association. AIMS: We explored if the association is explained by shared risk factors or is independent and whether there are regional or stroke subtype variations. METHODS: INTERSTROKE is a case-control study and the largest international study of risk factors for first acute stroke, completed in 27 countries. We included individuals with available serum creatinine values and calculated estimated glomerular filtration rate (eGFR). Renal impairment was defined as eGFR <60 mL/min/1.73 m2. Multivariable conditional logistic regression was used to determine the association of renal function with stroke. RESULTS: Of 21,127 participants, 41.0% were female, the mean age was 62.3 ± 13.4 years, and the mean eGFR was 79.9 ± 23.5 mL/min/1.73 m2. The prevalence of renal impairment was higher in cases (22.9% vs. 17.7%, p < 0.001) and differed by region (p < 0.001). After adjustment, lower eGFR was associated with increased odds of stroke. Renal impairment was associated with increased odds of all stroke (OR 1.35; 95% CI: 1.24-1.47), with higher odds for intracerebral hemorrhage (OR 1.60; 95% CI: 1.35-1.89) than ischemic stroke (OR 1.29; 95% CI: 1.17-1.42) (pinteraction 0.12). The largest magnitudes of association were seen in younger participants and those living in Africa, South Asia, or South America (pinteraction < 0.001 for all stroke). Renal impairment was also associated with poorer clinical outcome (RRR 2.97; 95% CI: 2.50-3.54 for death within 1 month). CONCLUSION: Renal impairment is an important risk factor for stroke, particularly in younger patients, and is associated with more severe stroke and worse outcomes.

Assessment of patients with a suspected cardioembolic ischemic stroke. A national consensus statement.

OBJECTIVES: Several cardiovascular, structural, and functional abnormalities have been considered as potential causes of cardioembolic ischemic strokes. Beyond atrial fibrillation, other sources of embolism clearly exist and may warrant urgent action, but they are only a minor part of the many stroke mechanisms and strokes that seem to be of embolic origin remain without a determined source. The associations between stroke and findings like atrial fibrillation, valve calcification, or heart failure are confounded by co-existing risk factors for atherosclerosis and vascular disease. In addition, a patent foramen ovale which is a common abnormality in the general population is mostly an innocent bystander in patients with ischemic stroke. For these reasons, experts from the national Danish societies of cardiology, neurology, stroke, and neuroradiology sought to develop a consensus document to provide national recommendations on how to manage patients with a suspected cardioembolic stroke. Design: Comprehensive literature search and analyses were done by a panel of experts and presented at a consensus meeting. Evidence supporting each subject was vetted by open discussion and statements were adjusted thereafter. Results: The most common sources of embolic stroke were identified, and the statement provides advise on how neurologist can identify cases that need referral, and what is expected by the cardiologist. Conclusions: A primary neurological and neuroradiological assessment is mandatory and neurovascular specialists should manage the initiation of secondary prophylactic treatment. If a cardioembolic stroke is suspected, a dedicated cardiologist experienced in the management of cardioembolism should provide a tailored clinical and echocardiographic assessment.

Workforce Attachment after Ischemic Stroke - The Importance of Time to Thrombolytic Therapy.

OBJECTIVES: The ability to remain in employment addresses an important consequence of stroke beyond the usual clinical parameters. However, data on the association between time to intravenous thrombolysis and workforce attachment in patients with acute ischemic stroke are sparse. MATERIALS AND METHODS: In this nationwide cohort study, stroke patients of working age (18-60 years) treated with thrombolysis (2011-2016) who were part of the workforce prior to admission and alive at discharge were identified using the Danish Stroke Registry. The association between time to thrombolysis and workforce attachment one year later was examined with multivariable logistic regression. RESULTS: The study population comprised 1,329 patients (median age 51 years [25th-75th percentile 45-56], 67.3% men). The median National Institutes of Health Stroke Scale score at presentation was 4 (25th-75th percentile 2-8), and the median time from symptom-onset to initiation of thrombolysis was 140min (25th-75th percentile 104-196min). The proportion of patients who were part of the workforce at one-year follow-up was 64.6%, 64.3%, 64.9%, and 60.0% in patients receiving thrombolysis within 90min, between 91-180min, between 181-270min, and after 270min, respectively. In adjusted analysis, time to thrombolysis between 91-180min, 181-270min, and >270min was not significantly associated with workforce attachment compared with thrombolysis received ≤90min of symptom-onset (ORs 0.89 [95%CI 0.60-1.31], 0.93 [0.66-1.31], and 0.80 [0.43-1.52], respectively). CONCLUSIONS: In patients of working age admitted with stroke and treated with thrombolysis, two out of three were part of the workforce one year after discharge. There was no graded relationship between time to thrombolysis and the likelihood of workforce attachment.

Characteristics and Outcomes in Patients With COVID-19 and Acute Ischemic Stroke: The Global COVID-19 Stroke Registry.

Recent case-series of small size implied a pathophysiological association between coronavirus disease 2019 (COVID-19) and severe large-vessel acute ischemic stroke. Given that severe strokes are typically associated with poor prognosis and can be very efficiently treated with recanalization techniques, confirmation of this putative association is urgently warranted in a large representative patient cohort to alert stroke clinicians, and inform pre- and in-hospital acute stroke patient pathways. We pooled all consecutive patients hospitalized with laboratory-confirmed COVID-19 and acute ischemic stroke in 28 sites from 16 countries. To assess whether stroke severity and outcomes (assessed at discharge or at the latest assessment for those patients still hospitalized) in patients with acute ischemic stroke are different between patients with COVID-19 and non-COVID-19, we performed 1:1 propensity score matching analyses of our COVID-19 patients with non-COVID-19 patients registered in the Acute Stroke Registry and Analysis of Lausanne Registry between 2003 and 2019. Between January 27, 2020, and May 19, 2020, 174 patients (median age 71.2 years; 37.9% females) with COVID-19 and acute ischemic stroke were hospitalized (median of 12 patients per site). The median National Institutes of Health Stroke Scale was 10 (interquartile range [IQR], 4-18). In the 1:1 matched sample of 336 patients with COVID-19 and non-COVID-19, the median National Institutes of Health Stroke Scale was higher in patients with COVID-19 (10 [IQR, 4-18] versus 6 [IQR, 3-14]), P=0.03; (odds ratio, 1.69 [95% CI, 1.08-2.65] for higher National Institutes of Health Stroke Scale score). There were 48 (27.6%) deaths, of which 22 were attributed to COVID-19 and 26 to stroke. Among 96 survivors with available information about disability status, 49 (51%) had severe disability at discharge. In the propensity score-matched population (n=330), patients with COVID-19 had higher risk for severe disability (median mRS 4 [IQR, 2-6] versus 2 [IQR, 1-4], P<0.001) and death (odds ratio, 4.3 [95% CI, 2.22-8.30]) compared with patients without COVID-19. Our findings suggest that COVID-19 associated ischemic strokes are more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes.

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.

Multiple Soluble Components of the Glycocalyx Are Increased in Patient Plasma After Ischemic Stroke.

Background and Purpose- The GLX (glycocalyx) is a protein/polysaccharide meshwork at the cellular surface. Consisting largely of glycosaminoglycans and proteoglycans, the GLX can shed in response to stress. In this study, we assay 11 components of the GLX in plasma from patients with ischemic stroke from a longitudinal cohort. Methods- Plasma samples from healthy individuals (N=8), and patients with ischemic stroke day ≥3, day 7, and day 90 (N=9-14) were immunoassayed for diverse components of the GLX. Results- Median stroke severity was mild (National Institutes of Health Stroke Scale 2.0 (range, 0-6) at day ≤3). Three (keratan-chondroitin-heparan-sulfate) of 4 glycosaminoglycans and CD44 (proteoglycan) were increased at day 7 and returned to baseline at day 90. Proteoglycan syndecan (Syn)-3 increased and Syn-2 levels decreased, significantly. Conclusions- Individual GLX components are often assayed as stand-alone biomarkers for endothelial health. This study suggests a full assessment of GLX components is more indicative of the endothelial health of an individual and represents a complex GLX signature that may be valuable as a composite biomarker of disease.

Practice patterns and outcomes after stroke across countries at different economic levels (INTERSTROKE): an international observational study.

BACKGROUND: Stroke disproportionately affects people in low-income and middle-income countries. Although improvements in stroke care and outcomes have been reported in high-income countries, little is known about practice and outcomes in low and middle-income countries. We aimed to compare patterns of care available and their association with patient outcomes across countries at different economic levels. METHODS: We studied the patterns and effect of practice variations (ie, treatments used and access to services) among participants in the INTERSTROKE study, an international observational study that enrolled 13 447 stroke patients from 142 clinical sites in 32 countries between Jan 11, 2007, and Aug 8, 2015. We supplemented patient data with a questionnaire about health-care and stroke service facilities at all participating hospitals. Using univariate and multivariate regression analyses to account for patient casemix and service clustering, we estimated the association between services available, treatments given, and patient outcomes (death or dependency) at 1 month. FINDINGS: We obtained full information for 12 342 (92%) of 13 447 INTERSTROKE patients, from 108 hospitals in 28 countries; 2576 from 38 hospitals in ten high-income countries and 9766 from 70 hospitals in 18 low and middle-income countries. Patients in low-income and middle-income countries more often had severe strokes, intracerebral haemorrhage, poorer access to services, and used fewer investigations and treatments (p<0·0001) than those in high-income countries, although only differences in patient characteristics explained the poorer clinical outcomes in low and middle-income countries. However across all countries, irrespective of economic level, access to a stroke unit was associated with improved use of investigations and treatments, access to other rehabilitation services, and improved survival without severe dependency (odds ratio [OR] 1·29; 95% CI 1·14-1·44; all p<0·0001), which was independent of patient casemix characteristics and other measures of care. Use of acute antiplatelet treatment was associated with improved survival (1·39; 1·12-1·72) irrespective of other patient and service characteristics. INTERPRETATION: Evidence-based treatments, diagnostics, and stroke units were less commonly available or used in low and middle-income countries. Access to stroke units and appropriate use of antiplatelet treatment were associated with improved recovery. Improved care and facilities in low-income and middle-income countries are essential to improve outcomes. FUNDING: Chest, Heart and Stroke Scotland.

The Effects of Naturalistic Light on Diurnal Plasma Melatonin and Serum Cortisol Levels in Stroke Patients during Admission for Rehabilitation: A Randomized Controlled Trial.

Background: Stroke patients admitted for rehabilitation often lack sufficient daytime blue light exposure due to the absence of natural light and are often exposed to light at unnatural time points. We hypothesized that artificial light imitating daylight, termed naturalistic light, would stabilize the circadian rhythm of plasma melatonin and serum cortisol levels among long-term hospitalized stroke patients. Methods: A quasi-randomized controlled trial. Stroke patients in need of rehabilitation were randomized between May 1, 2014, and June 1, 2015 to either a rehabilitation unit equipped entirely with always on naturalistic lighting (IU), or to a rehabilitation unit with standard indoor lighting (CU). At both inclusion and discharge after a hospital stay of at least 2 weeks, plasma melatonin and serum cortisol levels were measured every 4 hours over a 24-hour period. Circadian rhythm was estimated using cosinor analysis, and variance between time-points. Results: A total of 43 were able to participate in the blood collection. Normal diurnal rhythm of melatonin was disrupted at both inclusion and discharge. In the IU group, melatonin plasma levels were increased at discharge compared to inclusion (n = 23; median diff, 2.9; IQR: -1.0 to 9.9, p = 0.030) and rhythmicity evolved (n = 23; p = 0.007). In the CU group, melatonin plasma levels were similar between discharge and inclusion and no rhythmicity evolved. Overall, both patient groups showed normal cortisol diurnal rhythms at both inclusion and discharge. Conclusions: This study is the first to demonstrate elevated melatonin plasma levels and evolved rhythmicity due to stimulation with naturalistic light.