Background and Purpose—: Repeated episodes of limb ischemia and reperfusion (remote ischemic conditioning [RIC]) may improve outcome after acute stroke. Methods—: We performed a pilot blinded placebo-controlled trial in patients with acute ischemic stroke, randomized 1:1 to receive 4 cycles of RIC within 24 hours of ictus. The primary outcome was tolerability and feasibility. Secondary outcomes included safety, clinical efficacy (day 90), putative biomarkers (pre- and post-intervention, day 4), and exploratory hemodynamic measures. Results—: Twenty-six patients (13 RIC and 13 sham) were recruited 15.8 hours (SD 6.2) post-onset, age 76.2 years (SD 10.5), blood pressure 159/83 mm Hg (SD 25/11), and National Institutes of Health Stroke Scale (NIHSS) score 5 (interquartile range, 3.75–9.25). RIC was well tolerated with 49 out of 52 cycles completed in full. Three patients experienced vascular events in the sham group: 2 ischemic strokes and 2 myocardial infarcts versus none in the RIC group ( P =0.076, log-rank test). Compared with sham, there was a significant decrease in day 90 NIHSS score in the RIC group, median NIHSS score 1 (interquartile range, 0.5–5) versus 3 (interquartile range, 2–9.5; P =0.04); RIC augmented plasma HSP27 (heat shock protein 27; P <0.05, repeated 2-way ANOVA) and phosphorylated HSP27 ( P <0.001) but not plasma S100-β, matrix metalloproteinase-9, endocannabinoids, or arterial compliance. Conclusions—: RIC after acute stroke is well tolerated and appears safe and feasible. RIC may improve neurological outcome, and protective mechanisms may be mediated through HSP27. A larger trial is warranted. Clinical Trial Registration—: URL: http://www.isrctn.com . Unique identifier: ISRCTN86672015.

Cannabinoids (CBs) show promise as neuroprotectants with some agents already licensed in humans for other conditions. We systematically reviewed CBs in preclinical stroke to guide further experimental protocols. We selected controlled studies assessing acute administration of CBs for experimental stroke, identified through systematic searches. Data were extracted on lesion volume, outcome and quality, and analyzed using random effect models. Results are expressed as standardized mean difference (SMD) with 95% confidence intervals (CIs). In all, 144 experiments (34 publications) assessed CBs on infarct volume in 1,473 animals. Cannabinoids reduced infarct volume in transient (SMD −1.41 (95% CI −1.71), −1.11) P<0.00001) and permanent (−1.67 (−2.08, −1.27), P<0.00001) ischemia and in all subclasses: endocannabinoids (−1.72 (−2.62, −0.82), P=0.0002), CB₁/CB₂ ligands (−1.75 (−2.19, −1.31), P<0.00001), CB₂ ligands (−1.65 (−2.09, −1.22), P<0.00001), cannabidiol (−1.20 (−1.63, −0.77), P<0.00001), Δ⁹-tetrahydrocannabinol (−1.43 (−2.01, −0.86), P<0.00001), and HU-211 (−2.90 (−4.24, −1.56), P<0.0001). Early and late neuroscores significantly improved with CB use (−1.27 (−1.58, −0.95), P<0.00001; −1.63 (−2.64, −0.62), P<0.002 respectively) and there was no effect on survival. Statistical heterogeneity and publication bias was present, median study quality was 4 (range 1 to 6/8). Overall, CBs significantly reduced infarct volume and improve functional outcome in experimental stroke. Further studies in aged, female and larger animals, with other co-morbidities are required.

Background: The impact on clinical outcomes of patient selection using perfusion imaging for endovascular thrombectomy (EVT) in patients with acute ischemic stroke presenting beyond 6 hours from onset remains undetermined in routine clinical practice. Methods: Patients from a national stroke registry that underwent EVT selected with or without perfusion imaging (noncontrast computed tomography/computed tomography angiography) in the early (<6 hours) and late (6–24 hours) time windows, between October 2015 and March 2020, were compared. The primary outcome was the ordinal shift in the modified Rankin Scale score at hospital discharge. Other outcomes included functional independence (modified Rankin Scale score ≤2) and in-hospital mortality, symptomatic intracerebral hemorrhage, successful reperfusion (Thrombolysis in Cerebral Infarction score 2b–3), early neurological deterioration, futile recanalization (modified Rankin Scale score 4–6 despite successful reperfusion) and procedural time metrics. Multivariable analyses were performed, adjusted for age, sex, baseline stroke severity, prestroke disability, intravenous thrombolysis, mode of anesthesia (Model 1) and including EVT technique, balloon guide catheter, and center (Model 2). Results: We included 4249 patients, 3203 in the early window (593 with perfusion versus 2610 without perfusion) and 1046 in the late window (378 with perfusion versus 668 without perfusion). Within the late window, patients with perfusion imaging had a shift towards better functional outcome at discharge compared with those without perfusion imaging (adjusted common odds ratio [OR], 1.45 [95% CI, 1.16–1.83]; P =0.001). There was no significant difference in functional independence (29.3% with perfusion versus 24.8% without; P =0.210) or in the safety outcome measures of symptomatic intracerebral hemorrhage ( P =0.53) and in-hospital mortality (10.6% with perfusion versus 14.3% without; P =0.053). In the early time window, patients with perfusion imaging had significantly improved odds of functional outcome (adjusted common OR, 1.51 [95% CI, 1.28–1.78]; P =0.0001) and functional independence (41.6% versus 33.6%, adjusted OR, 1.31 [95% CI, 1.08–1.59]; P =0.006). Perfusion imaging was associated with lower odds of futile recanalization in both time windows (late: adjusted OR, 0.70 [95% CI, 0.50–0.97]; P =0.034; early: adjusted OR, 0.80 [95% CI, 0.65–0.99]; P =0.047). Conclusions: In this real-world study, acquisition of perfusion imaging for EVT was associated with improvement in functional disability in the early and late time windows compared with nonperfusion neuroimaging. These indirect comparisons should be interpreted with caution while awaiting confirmatory data from prospective randomized trials.

Background: Direct mechanical thrombectomy may result in similar outcomes compared to a bridging approach with intravenous thrombolysis (IVT + MT) in acute ischemic stroke. Recent randomized controlled trials have varied in their design and noninferiority margin. Aim: We sought to meta-analyze accumulated trial data to assess the difference and non-inferiority in clinical and procedural outcomes between direct mechanical thrombectomy and bridging therapy. Summary of review: We conducted a systematic review of electronic databases following the preferred reporting items for systematic reviews and meta-analyses guidelines. Random effects meta-analyses were conducted for the pooled data. The primary outcome was good functional outcome at 90 days (modified Rankin scale (mRS) ≤ 2). Secondary outcomes included excellent functional outcome (mRS ≤ 1), mortality, any intracranial hemorrhage, symptomatic intracranial hemorrhage, successful reperfusion (thrombolysis in cerebral infarction ≥ 2 b), and procedure-related complications. Four randomized controlled trials comprising 1633 patients (817 direct mechanical thrombectomy, 816 bridging therapy) were included. There were no statistical differences for the 90-day good functional outcome (OR = 1.02, 95% CI 0.84–1.25, p = 0.54, I²= 0%), and the absolute risk difference was 1% (95% CI: −4% to 5%). The lower 95% CI falls within the strictest noninferiority margin of −10% among included randomized control trials. Direct mechanical thrombectomy reduced the odds of successful reperfusion (OR = 0.76, 95% CI: 0.60–0.97, p = 0.03, I²= 0%) and any intracranial hemorrhage (OR = 0.65, 95% CI: 0.49–0.86, p = 0.003, I²= 38%). There was no difference in the remaining secondary outcomes. The risk of bias for all studies was low. Conclusion: The combined trial data assessing direct mechanical thrombectomy versus bridging therapy showed no difference in improving good functional outcome. The wide noninferiority thresholds set by individual trials are in contrast with the clinical consensus on minimally important differences. However, our pooled analysis indicates noninferiority of direct mechanical thrombectomy with a 4% margin of confidence. The application of these findings is limited to patients presenting directly to mechanical thrombectomy-capable centers and real-world workflow times may differ against those achieved in a trial setting.

Background: There is currently insufficient evidence for the clinical effectiveness and cost-effectiveness of psychological therapies for post-stroke depression.Objective: To evaluate the feasibility of undertaking a definitive trial to evaluate the clinical effectiveness and cost-effectiveness of behavioural activation (BA) compared with usual stroke care for treating post-stroke depression.Design: Parallel-group, feasibility, multicentre, randomised controlled trial with nested qualitative research and a health economic evaluation.Setting: Acute and community stroke services in three sites in England.Participants: Community-dwelling adults 3 months to 5 years post stroke who are depressed, as determined by the Patient Health Questionnaire-9 (PHQ-9) or the Visual Analogue Mood Scales ‘Sad’ item. Exclusions: patients who are blind and/or deaf, have dementia, are unable to communicate in English, do not have mental capacity to consent, are receiving treatment for depression at the time of stroke onset or are currently receiving psychological intervention.Randomisation and blinding: Participants were randomised (1 : 1 ratio) to BA or usual stroke care. Randomisation was conducted using a computer-generated list with random permuted blocks of varying sizes, stratified by site. Participants and therapists were aware of the allocation, but outcome assessors were blind.Interventions: The intervention arm received up to 15 sessions of BA over 4 months. BA aims to improve mood by increasing people’s level of enjoyable or valued activities. The control arm received usual care only.Main outcome measures: Primary feasibility outcomes concerned feasibility of recruitment to the main trial, acceptability of research procedures and measures, appropriateness of baseline and outcome measures, retention of participants and potential value of conducting the definitive trial. Secondary feasibility outcomes concerned the delivery of the intervention. The primary clinical outcome 6 months post randomisation was the PHQ-9. Secondary clinical outcomes were Stroke Aphasic Depression Questionnaire – Hospital version, Nottingham Leisure Questionnaire, Nottingham Extended Activities of Daily Living, Carer Strain Index, EuroQol-5 Dimensions, five-level version and health-care resource use questionnaire.Results: Forty-eight participants were recruited in 27 centre-months of recruitment, at a recruitment rate of 1.8 participants per centre per month. The 25 participants randomised to receive BA attended a mean of 8.5 therapy sessions [standard deviation (SD) 4.4 therapy sessions]; 23 participants were allocated to usual care. Outcome assessments were completed by 39 (81%) participants (BA,n = 18; usual care,n = 21). Mean PHQ-9 scores at 6-month follow-up were 10.1 points (SD 6.9 points) and 14.4 points (SD 5.1 points) in the BA and control groups, respectively, a difference of –3.8 (95% confidence interval –6.9 to –0.6) after adjusting for baseline PHQ-9 score and centre, representing a reduction in depression in the BA arm. Therapy was delivered as intended. BA was acceptable to participants, carers and therapists. Value-of-information analysis indicates that the benefits of conducting a definitive trial would be likely to outweigh the costs. It is estimated that a sample size of between 580 and 623 participants would be needed for a definitive trial.Limitations: Target recruitment was not achieved, although we identified methods to improve recruitment.Conclusions: The Behavioural Activation Therapy for Depression after Stroke trial was feasible with regard to the majority of outcomes. The outstanding issue is whether or not a sufficient number of participants could be recruited within a reasonable time frame for a definitive trial. Future work is required to identify whether or not there are sufficient sites that are able to deliver the services required for a definitive trial.Trial registration: Current Controlled Trials ISRCTN12715175.Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 23, No. 47. See the NIHR Journals Library website for further project information.