Acute treatment of stroke (except thrombectomy)

Purpose of Review: The management of patients with acute stroke has been revolutionized in recent years with the advent of new effective treatments. In this rapidly evolving field, we provide an update on the management of acute stroke excluding thrombectomy, looking to recent, ongoing, and future trials.Recent Findings: Large definitive trials have provided insight into acute stroke care including broadening the therapeutic window for thrombolysis, alternatives to standard dose alteplase, the use of dual antiplatelet therapy early after minor ischemic stroke, and treating elevated blood pressure in intracerebral hemorrhage. Further ongoing and future trials are eagerly awaited in this ever-expanding area.Summary: Although definitive trials have led to improvements in acute stroke care, there remains a need for further research to improve our understanding of pathophysiological mechanisms underlying different stroke types with the potential for treatments to be tailored to the individual

INTEnsive care bundle with blood pressure reduction in acute cerebral hemorrhage trial (INTERACT3): study protocol for a pragmatic stepped-wedge cluster-randomized controlled trial

Background: Early intensive blood pressure (BP) lowering remains the most promising treatment for acute intracerebral hemorrhage (ICH), despite discordant results between clinical trials and potential variation in the treatment effects by approach to control BP. As the third in a series of clinical trials on this topic, the INTEnsive care bundle with blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT3) aims to determine the effectiveness of a goal-directed care bundle protocol of early physiological control (intensive BP lowering, glycemic control, and pyrexia treatment) and reversal of anticoagulation, in acute ICH. Methods: INTERACT3 is a pragmatic, international, multicenter, stepped-wedge (4 phases/3 steps), cluster-randomized controlled trial to determine the effectiveness of a multifaceted care package in adult (age ≥ 18 years) patients (target 8360) with acute ICH (< 6 h of onset) recruited from 110 hospitals (average of 19 consecutive patients per phase) in low- and middle-income countries. After a control phase, each hospital implements the intervention (intensive BP lowering, target systolic < 140 mmHg; glucose control, target 6.1–7.8 mmol/L and 7.8–10.0 mmol/L in those without and with diabetes mellitus, respectively; anti-pyrexia treatment to target body temperature ≤ 37.5 °C; and reversal of anticoagulation, target international normalized ratio < 1.5 within 1 h). Information will be obtained on demographic and baseline clinical characteristics, in-hospital management, and 7-day outcomes. Central trained blinded assessors will conduct telephone interviews to assess physical function and health-related quality of life at 6 months. The primary outcome is the modified Rankin scale (mRS) at 6 months analyzed using ordinal logistic regression. The sample size of 8360 subjects provides 90% power (α = 0.05) to detect a 5.6% absolute improvement (shift) in the primary outcome of the intervention versus control standard care, with various assumptions. Discussion: As the largest clinical trial in acute ICH, INTERACT3 is on schedule to provide an assessment of the effectiveness of a widely applicable goal-directed care bundle for a serious condition in which a clearly proven treatment has yet to be established. Trial registration: ClinicalTrials.gov NCT03209258. Registered on 1 July 2017. Chinese Trial Registry ChiCTR-IOC-17011787. Registered on 28 June 201

Head Position in Stroke Trial (HeadPoST)- sitting-up vs lying-flat positioning of patients with acute stroke: study protocol for a cluster randomised controlled trial

Background Positioning a patient lying-flat in the acute phase of ischaemic stroke may improve recovery and reduce disability, but such a possibility has not been formally tested in a randomised trial. We therefore initiated the Head Position in Stroke Trial (HeadPoST) to determine the effects of lying-flat (0°) compared with sitting-up (≥30°) head positioning in the first 24 hours of hospital admission for patients with acute stroke. Methods/Design We plan to conduct an international, cluster randomised, crossover, open, blinded outcome-assessed clinical trial involving 140 study hospitals (clusters) with established acute stroke care programs. Each hospital will be randomly assigned to sequential policies of lying-flat (0°) or sitting-up (≥30°) head position as a ‘business as usual’ stroke care policy during the first 24 hours of admittance. Each hospital is required to recruit 60 consecutive patients with acute ischaemic stroke (AIS), and all patients with acute intracerebral haemorrhage (ICH) (an estimated average of 10), in the first randomised head position policy before crossing over to the second head position policy with a similar recruitment target. After collection of in-hospital clinical and management data and 7-day outcomes, central trained blinded assessors will conduct a telephone disability assessment with the modified Rankin Scale at 90 days. The primary outcome for analysis is a shift (defined as improvement) in death or disability on this scale. For a cluster size of 60 patients with AIS per intervention and with various assumptions including an intracluster correlation coefficient of 0.03, a sample size of 16,800 patients at 140 centres will provide 90 % power (α 0.05) to detect at least a 16 % relative improvement (shift) in an ordinal logistic regression analysis of the primary outcome. The treatment effect will also be assessed in all patients with ICH who are recruited during each treatment study period. Discussion HeadPoST is a large international clinical trial in which we will rigorously evaluate the effects of different head positioning in patients with acute stroke. Trial registration ClinicalTrials.gov identifier: NCT02162017 (date of registration: 27 April 2014); ANZCTR identifier: ACTRN12614000483651 (date of registration: 9 May 2014). Protocol version and date: version 2.2, 19 June 2014

Beam Charge Asymmetries for Deeply Virtual Compton Scattering on the Proton at CLAS12

The parameterization of the nucleon structure through Generalized Parton Distributions (GPDs) shed a new light on the nucleon internal dynamics. For its direct interpretation, Deeply Virtual Compton Scattering (DVCS) is the golden channel for GPDs investigation. The DVCS process interferes with the Bethe-Heitler (BH) mechanism to constitute the leading order amplitude of the $eN \to eN\gamma$ process. The study of the $ep\gamma$ reaction with polarized positron and electron beams gives a complete set of unique observables to unravel the different contributions to the $ep \gamma$ cross section. This separates the different reaction amplitudes, providing a direct access to their real and imaginary parts which procures crucial constraints on the model dependences and associated systematic uncertainties on GPDs extraction. The real part of the BH-DVCS interference amplitude is particularly sensitive to the $D$-term which parameterizes the Gravitational Form Factors of the nucleon. The separation of the imaginary parts of the interference and DVCS amplitudes provides insights on possible higher-twist effects. We propose to measure the unpolarized and polarized Beam Charge Asymmetries (BCAs) of the $\vec{e}^{\pm}p \to e^{\pm}p \gamma$ process on an unpolarized hydrogen target with {\tt CLAS12}, using polarized positron and electron beams at 10.6~GeV. The azimuthal and $t$-dependences of the unpolarized and polarized BCAs will be measured over a large $(x_B,Q^2)$ phase space using a 100 day run with a luminosity of 0.66$\times 10^{35}$cm$^{-2}\cdot$s$^{-1}$.Comment: Proposal to the Jefferson Lab Program Advisory Committee (PAC51

Impact of evidence-based stroke care on patient outcomes: a multilevel analysis of an international study

Background The uptake of proven stroke treatments varies widely. We aimed to determine the association of evidence‐based processes of care for acute ischemic stroke (AIS) and clinical outcome of patients who participated in the HEADPOST (Head Positioning in Acute Stroke Trial), a multicenter cluster crossover trial of lying flat versus sitting up, head positioning in acute stroke. Methods and Results Use of 8 AIS processes of care were considered: reperfusion therapy in eligible patients; acute stroke unit care; antihypertensive, antiplatelet, statin, and anticoagulation for atrial fibrillation; dysphagia assessment; and physiotherapist review. Hierarchical, mixed, logistic regression models were performed to determine associations with good outcome (modified Rankin Scale scores 0–2) at 90 days, adjusted for patient and hospital variables. Among 9485 patients with AIS, implementation of all processes of care in eligible patients, or “defect‐free” care, was associated with improved outcome (odds ratio, 1.40; 95% CI, 1.18–1.65) and better survival (odds ratio, 2.23; 95% CI, 1.62–3.09). Defect‐free stroke care was also significantly associated with excellent outcome (modified Rankin Scale score 0–1) (odds ratio, 1.22; 95% CI, 1.04–1.43). No hospital characteristic was independently predictive of outcome. Only 1445 (15%) of eligible patients with AIS received all processes of care, with significant regional variations in overall and individual rates. Conclusions Use of evidence‐based care is associated with improved clinical outcome in AIS. Strategies are required to address regional variation in the use of proven AIS treatments

Association between spontaneous internal carotid artery dissection and perivascular adipose tissue attenuation on computed tomography angiography

OnlinePublBackground: Spontaneous cervical artery dissection (sCAD) is a leading cause of ischemic stroke in young patients. Studies using high-resolution magnetic resonance imaging and positron emission tomography have suggested vessel wall inflammation to be a pathogenic factor in sCAD. Computed tomography (CT) attenuation of perivascular adipose tissue (PVAT) is an established non-invasive imaging biomarker of inflammation in coronary arteries, with higher attenuation values reflecting a greater degree of vascular inflammation. Objectives: We evaluate the CT attenuation of PVAT surrounding the internal carotid artery (PVATcarotid) with and without spontaneous dissection. Methods: Single-center prospective observational study of 56 consecutive patients with CT-verified spontaneous dissection of the internal carotid artery (ICA). Of these patients, six underwent follow-up computed tomography angiography (CTA). Twenty-two patients who underwent CTA for acute neurological symptoms but did not have dissection formed the control group. Using semi-automated research software, PVATcarotid was measured as the mean Hounsfield unit (HU) attenuation of adipose tissue within a defined volume of interest surrounding the ICA. Results: PVATcarotid was significantly higher around dissected ICA compared with non-dissected contralateral ICA in the same patients (−58.7±10.2 vs −68.9±8.1HU, p<0.0001) and ICA of patients without dissection (−58.7±10.2 vs −69.3±9.3HU, p<0.0001). After a median follow-up of 89days, there was a significant reduction in PVATcarotid around dissected ICA (−57.5±13.4 to −74.3±10.5HU, p<0.05), while no change was observed around non-dissected contralateral ICA (−71.0±4.4 to −74.1±4.1HU, p=0.19). ICA dissection was an independent predictor of PVATcarotid following multivariable adjustment for age and the presence of ICA occlusion. Conclusion: PVATcarotid is elevated in the presence of sCAD and may decrease following the acute event.Kevin Cheng, Andrew Lin, Ximena Stecher, Tomas Bernstein, Paulo Zuñiga, Enrico Mazzon, Alejandro Brunser, Violeta Diaz, Gonzalo Martinez, William Cameron, Stephen J Nicholls, Sanjay Patel, Damini Dey, Dennis TL Wong, and Paula Muñoz Venturell

Dysphagia screening and risks of pneumonia and adverse outcomes after acute stroke: An international multicenter study.

BACKGROUND:Dysphagia is associated with aspiration pneumonia after stroke. Data are limited on the influences of dysphagia screen and assessment in clinical practice. AIMS:To determine associations between a "brief" screen and "detailed" assessment of dysphagia on clinical outcomes in acute stroke patients. METHODS:A prospective cohort study analyzed retrospectively using data from a multicenter, cluster cross-over, randomized controlled trial (Head Positioning in Acute Stroke Trial [HeadPoST]) from 114 hospitals in nine countries. HeadPoST included 11,093 acute stroke patients randomized to lying-flat or sitting-up head positioning. Herein, we report predefined secondary analyses of the association of dysphagia screening and assessment and clinical outcomes of pneumonia and death or disability (modified Rankin scale 3-6) at 90 days. RESULTS:Overall, 8784 (79.2%) and 3917 (35.3%) patients were screened and assessed for dysphagia, respectively, but the frequency and timing for each varied widely across regions. Neither use of a screen nor an assessment for dysphagia was associated with the outcomes, but their results were compared to "screen-pass" patients, those who failed had higher risks of pneumonia (adjusted odds ratio [aOR] = 3.00, 95% confidence interval [CI] = 2.18-4.10) and death or disability (aOR = 1.66, 95% CI = 1.41-1.95). Similar results were evidence for the results of an assessment for dysphagia. Subsequent feeding restrictions were related to higher risk of pneumonia in patients failed dysphagia screen or assessment (aOR = 4.06, 95% CI = 1.72-9.54). CONCLUSIONS:Failing a dysphagia screen is associated with increased risks of pneumonia and poor clinical outcome after acute stroke. Further studies concentrate on determining the effective subsequent feeding actions are needed to improve patient outcomes

Statistical analysis plan for the Head Position in Stroke Trial (HeadPoST): an international cluster cross-over randomised trial

Background There is evidence to indicate that the lying flat head position increases cerebral blood flow and oxygenation in patients with acute ischemic stroke, but how these physiological effects translate into clinical outcomes is uncertain. The Head Position in Stroke Trial (HeadPoST) aims to determine the comparative effectiveness of lying flat (0°) compared to sitting up (≥30°) head positioning, initiated within 24 hours of hospital admission for patients with acute stroke. Design An international, pragmatic, cluster randomised, crossover, open, blinded outcome assessed clinical trial. Each hospital with an established acute stroke unit (cluster) site was required to recruit up to 140 consecutive cases of acute stroke (one phase of head positioning before immediately crossing over to the other phase of head positioning), including both acute ischaemic stroke and intracerebral haemorrhage, in each randomised head position as a ‘business as usual’ policy. Objective To outline in detail the predetermined statistical analysis plan (SAP) for the study. Methods All accumulated data will be reviewed and formally assessed. Information regarding baseline characteristics of patients, their process of care and management will be outlined, and for each item, statistically relevant descriptive elements will be described. For the trial outcomes, the most appropriate statistical comparisons are described. Results A SAP was developed that is transparent, verifiable, and predetermined before completion of data collection. Conclusions We developed a predetermined SAP for HeadPoST to avoid analysis bias arising from prior knowledge of the findings, in order to reliably quantify the benefits and harms of lying flat versus sitting up early after the onset of acute stroke. </p

Influence of Including Patients with Premorbid Disability in Acute Stroke Trials: The HeadPoST Experience.

BACKGROUND: Patients with premorbid functional impairment are generally excluded from acute stroke trials. We aimed to determine the impact of including such patients in the Head Positioning in acute Stroke Trial (HeadPoST) and early additional impairment on outcomes. METHODS: Post hoc analyses of HeadPoST, an international, cluster-randomized crossover trial of lying-flat versus sitting-up head positioning in acute stroke. Associations of early additional impairment, defined as change in modified Rankin scale (mRS) scores from premorbid levels (estimated at baseline) to Day 7 ("early ΔmRS"), and poor outcome (mRS score 3-6) at Day 90 were determined with generalized linear mixed model. Heterogeneity of the trial treatment effect was tested according to premorbid mRS scores 0-1 versus 2-5. RESULTS: Of 8,285 patients (38.9% female, mean age 68 ± 13 years) with complete data, there were 1,984 (23.9%) with premorbid functional impairment (mRS 2-5). A significant linear association was evident for early ∆mRS and poor outcome (per 1-point increase in ΔmRS, adjusted odds ratio 1.20, 95% confidence interval 1.14-1.27; p < 0.0001). Patients with greater premorbid functional impairment were less likely to develop additional impairment, but their risk of poor 90-day outcome significantly increased with increasing (worse) premorbid mRS scores (linear trend p < 0.0001). There was no heterogeneity of the trial treatment effect by level of premorbid function. CONCLUSIONS: Early poststroke functional impairment that exceeded premorbid levels was associated with worse 90-day outcome, and this association increased with greater premorbid functional impairment. Yet, including premorbid impaired patients in the HeadPoST did not materially affect the subsequent treatment effect. CLINICAL TRIAL REGISTRATION: HeadPoST is registered at http://www.ClinicalTrials.gov (NCT02162017)