Peter Sandercock

Background: Obtaining informed consent in people with acute stroke is complex since many, as a direct result of their stroke, lose capacity to make important decisions. Furthermore, reperfusion interventions are time dependent necessitating rapid consent. We developed four different consent approaches to facilitate recruitment of a broad range of patients in the Third International Stroke Trial (IST-3). Aims: To describe the clinical characteristics of patients recruited by different consent methods and the association between these methods and time from stroke onset to randomization. Methods: IST-3 was a randomized controlled trial of thrombolysis for acute ischemic stroke. Clinicians could use one of four consent procedures: written consent, witnessed consent, assent, or a waiver of consent. We analyzed the relationship between consent procedure and baseline variables. The effect of consent procedure on delay time from onset to randomization was determined using analysis of variance to adjust for confounding effects. Results: Of the 3035 patients recruited, the method of consent was known for 3034 (99.9%), and it was written in 985 subjects (32.5%), witnessed verbal consent in 280 (9.2%), assent by relative in 1727 (56.9%), and waiver of consent in 42 subjects (1.4%). Assent was required in 63.4% for those presenting 0–3 h from stroke onset (written consent in 25.3%). Patients with more severe neurological deficits (or with a non-lacunar hemispheric stroke syndrome) were less likely to give written consent. Mean delay between onset and randomization varied significantly between consent types (one-way analysis of variance: F = 15.7 on 3 df, p < 0.0001) (longest at 4.06 h for signed consent and 3.46 h for waiver of consent). Conclusions: Acute stroke trials requiring written informed consent would result in substantial selection bias. Flexible consent methods will ensure a broad range of patients are recruited, enabling trial results to be widely generalizable. Registration: This study’s registered number is ISRCTN25765518.

Background: Inflammation contributes to unstable atherosclerotic plaque and stroke. In randomised trials in patients with coronary disease, canukinumab (an interleukin-1B antagonist) and colchicine (a tubulin inhibitor with pleiotropic anti-inflammatory effects) reduced recurrent vascular events. Hypothesis: Anti-inflammatory therapy with low-dose colchicine plus usual care will reduce recurrent vascular events in patients with non-severe, non-cardioembolic stroke and TIA compared with usual care alone. Design: CONVINCE is a multi-centre international (in 17 countries) Prospective, Randomised Open-label, Blinded-Endpoint assessment (PROBE) controlled Phase 3 clinical trial in 3154 participants. The intervention is colchicine 0.5 mg/day and usual care versus usual care alone (antiplatelet, lipid-lowering, antihypertensive treatment, lifestyle advice). Included patients are at least 40 years, with non-severe ischaemic stroke (modified Rankin score ≤3) or high-risk TIA (ABCD2 > 3, or positive DWI, or cranio-cervical artery stenosis) within 72 hours-28 days of randomisation, with qualifying stroke/TIA most likely caused by large artery stenosis, lacunar disease, or cryptogenic embolism. Exclusions are stroke/TIA caused by cardio-embolism or other defined cause (e.g. dissection), contra-indication to colchicine (including potential drug interactions), or incapacity for participation in a clinical trial. The anticipated median follow-up will be 36 months. The primary analysis will be by intention-to-treat. Outcome: The primary outcome is time to first recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation with unstable angina (non-fatal or fatal). Summary: CONVINCE will provide high-quality randomised data on the efficacy and safety of anti-inflammatory therapy with colchicine for secondary prevention after stroke. Schedule: First-patient first-visit was December 2016. Recruitment to complete in 2021, follow-up to complete in 2023.

Background Alteplase improves functional outcomes of patients with acute ischaemic stroke, but its effects on symptomatic infarct swelling, an adverse complication of stroke and the influence of CT hyperdense artery sign (HAS) are unclear. This substudy of the Third International Stroke Trial aimed to investigate the association between HAS and symptomatic infarct swelling and effect of intravenous alteplase on this association. Methods We included stroke patients whose prerandomisation scan was non-contrast CT. Raters, masked to clinical information, assessed baseline (prerandomisation) and follow-up (24–48 hours postrandomisation) CT scans for HAS, defined as an intracranial artery appearing denser than contralateral arteries. Symptomatic infarct swelling was defined as clinically significant neurological deterioration ≤7 days after stroke with radiological evidence of midline shift, effacement of basal cisterns or uncal herniation. Results Among 2961 patients, HAS presence at baseline was associated with higher risk of symptomatic infarct swelling (OR 2.21; 95% CI 1.42 to 3.44). Alteplase increased the risk of swelling (OR 1.69; 95% CI 1.11 to 2.57), with no difference between patients with and those without baseline HAS (p=0.49). In patients with baseline HAS, alteplase reduced the proportion with HAS at follow-up (OR 0.67; 95% CI 0.50 to 0.91), where HAS disappearance was associated with reduced risk of swelling (OR 0.25, 95% CI 0.14 to 0.47). Conclusion Although alteplase was associated with increased risk of symptomatic infarct swelling in patients with or without baseline HAS, it was also associated with accelerated clearance of HAS, which in return reduced swelling, providing further mechanistic insights to underpin the benefits of alteplase.

Background: The CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death. Methods: The CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis. Results: There were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58–0.94). There was no evidence of heterogeneity by severity (p = 0.64) or country income (p = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69–1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83–1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70–0.87) and death within 28 days (RR 0.88, 95% CI 0.82–0.94). Conclusions: Tranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury. Trial registration: ISRCTN15088122, registered on 19 July 2011; NCT01402882, registered on 26 July 2011.

Purpose: CT attenuation of ischemic brain reduces with time after stroke onset. We aimed to quantify this relationship and test the feasibility and accuracy of estimating stroke onset time using only CT attenuation of visible ischemic lesions, the CT-Clock Tool. Methods: We selected CT scans with ischemic lesions representing a range of stroke-onset-to-scan times (elapsed time) from a well-defined stroke trial. We measured the attenuation of ischemic lesions and contralateral normal brain to derive attenuation ratio. We assigned scans to development (75%) or test (25%) datasets. We plotted the relationship between attenuation ratio and elapsed time in the development dataset and derived a best-fit curve. We calculated estimated time in the test dataset using only the attenuation ratio curve. We compared estimated time to elapsed time and derived absolute error for estimated time. We assessed area under the receiver operating characteristic (AUROC) curve for identifying scans ≤ 4.5 h elapsed time. Results: We included 342 scans from 200 patients (41% male, median age 83 years). Elapsed time range: 22 min to 36 days. Estimation errors were least at early elapsed times (r = 0.82, p < 0.0001): median absolute error was 23, 106, 1030 and 1933 min for scans acquired ≤ 3, > 3–9, > 9–30 and > 30 h from stroke onset, respectively. AUROC was high at 0.955. Conclusions: It is feasible to accurately estimate stroke onset time using simple attenuation measures of ischemic brain. Our method was most accurate 0–9 h from onset and may be useful for treatment eligibility assessment, especially where imaging resources are limited.

Professor Eivind Berge, MD, PhD died from cancer on 6 February 2020. He was a highly respected stroke expert, clinical trialist and clinician scientist who made substantial contributions to evidence-based stroke medicine and the work of the European Stroke Organisation.

Background: Our Cochrane review of selective serotonin inhibitors for stroke recovery indicated that fluoxetine may improve functional recovery, but the trials were small and most were at high risk of bias.Objectives: The Fluoxetine Or Control Under Supervision (FOCUS) trial tested the hypothesis that fluoxetine improves recovery after stroke.Design: The FOCUS trial was a pragmatic, multicentre, parallel-group, individually randomised, placebo-controlled trial.Setting: This trial took place in 103 UK hospitals.Participants: Patients were eligible if they were aged ≥ 18 years, had a clinical stroke diagnosis, with focal neurological deficits, between 2 and 15 days after onset.Interventions: Patients were randomly allocated 20 mg of fluoxetine once per day or the matching placebo for 6 months via a web-based system using a minimisation algorithm.Main outcome measures: The primary outcome was the modified Rankin Scale at 6 months. Patients, carers, health-care staff and the trial team were masked to treatment allocation. Outcome was assessed at 6 and 12 months after randomisation. Patients were analysed by their treatment allocation as specified in a published statistical analysis plan.Results: Between 10 September 2012 and 31 March 2017, we recruited 3127 patients, 1564 of whom were allocated fluoxetine and 1563 of whom were allocated placebo. The modified Rankin Scale score at 6 months was available for 1553 out of 1564 (99.3%) of those allocated fluoxetine and 1553 out of 1563 (99.4%) of those allocated placebo. The distribution across modified Rankin Scale categories at 6 months was similar in the two groups (common odds ratio adjusted for minimisation variables 0.951, 95% confidence interval 0.839 to 1.079;p = 0.439). Compared with placebo, patients who were allocated fluoxetine were less likely to develop a new episode of depression by 6 months [210 (13.0%) vs. 269 (16.9%), difference –3.78%, 95% confidence interval –1.26% to –6.30%;p = 0.003], but had more bone fractures [45 (2.9%) vs. 23 (1.5%), difference 1.41%, 95% confidence interval 0.38% to 2.43%;p = 0.007]. There were no statistically significant differences in any other recorded events at 6 or 12 months. Health economic analyses showed no differences between groups in health-related quality of life, hospital bed usage or health-care costs.Limitations: Some non-adherence to trial medication, lack of face-to-face assessment of neurological status at follow-up and lack of formal psychiatric diagnosis during follow-up.Conclusions: 20 mg of fluoxetine daily for 6 months after acute stroke did not improve patients’ functional outcome but decreased the occurrence of depression and increased the risk of fractures. These data inform decisions about using fluoxetine after stroke to improve functional outcome or to prevent or treat mood disorders. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) (Australasia/Vietnam) and Efficacy oF Fluoxetine – a randomisEd Controlled Trial in Stroke (EFFECTS) (Sweden) trials recruited an additional 2780 patients and will report their results in 2020. These three trials have an almost identical protocol, which was collaboratively developed. Our planned individual patient data meta-analysis will provide more precise estimates of the effects of fluoxetine after stroke and indicate whether or not effects vary depending on patients’ characteristics and health-care setting.Trial registration: Current Controlled Trials ISRCTN83290762.Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 22. See the NIHR Journals Library website for further project information. The Stroke Association (reference TSA 2011101) funded the start-up phase.

Africa is the world’s most genetically diverse, second largest, and second most populous continent, with over one billion people distributed across 54 countries. With a 23% lifetime risk of stroke, Africa has some of the highest rates of stroke worldwide and many occur in the prime of life with huge economic losses and grave implications for the individual, family, and the society in terms of mental capital, productivity, and socioeconomic progress. Tackling the escalating burden of stroke in Africa requires prioritized, multipronged, and inter-sectoral strategies tailored to the unique African epidemiological, cultural, socioeconomic, and lifestyle landscape. The African Stroke Organization (ASO) is a new pan-African coalition that brings together stroke researchers, clinicians, and other health-care professionals with participation of national and regional stroke societies and stroke support organizations. With a vision to reduce the rapidly increasing burden of stroke in Africa, the ASO has a four-pronged focus on (1) research, (2) capacity building, (3) development of stroke services, and (4) collaboration with all stakeholders. This will be delivered through advocacy, awareness, and empowerment initiatives to bring about people-focused changes in policy, clinical practice, and public education. In the spirit of the African philosophy of Ubuntu “I am because we are,” the ASO will harness the power of diversity, inclusiveness, togetherness, and team work to build a strong, enduring, and impactful platform for tackling stroke in Africa.

Education in stroke is relevant to stroke survivors, clinicians, care providers, and healthcare system administrators and is of special importance in resource-limited settings. The World Stroke Organization Education Committee undertook a program of work, culminating in a focused workshop, to establish the key educational priorities, and work toward maximizing the WSOs impact on the global burden of stroke. A facilitated workshop took place during the World Stroke Congress in Montreal, Canada in October 2018. The workshop was developed using opinions on priority topics for World Stroke Organization educational activities obtained from web-based surveys of World Stroke Organization Members, supplemented by interviews with international stroke support organizations. The workshop included over 50 international participants, selected to represent a balance of age, gender, geographical region, and different levels of health resources. Participants also included members of the World Stroke Organization Education Committee, the World Stroke Academy, stroke support organizations, and the International Journal of Stroke editorial board. The workshop focused on understanding more about educational needs (at all levels), with emphasis on resource-limited settings. Three broad questions were posed: (1) What are the key educational needs: (a) in your region, (b) from your perspective (e.g. stroke support organization)? (2) Do the current educational activities offered by World Stroke Organization and WSA meet your needs? (3) What could World Stroke Organization/World Stroke Academy offer in your region that would meet your needs? The facilitated discussions were recorded, and the results transcribed and summarized by members of the World Stroke Organization Education Committee. Five key needs were identified: 1. Collaborative interdisciplinary, training in both stroke care and how to advocate for stroke. 2. Educational materials provided in a wider range of formats that could be adapted to local circumstances and clinical practices. 3. Educational activities for healthcare providers and stroke support organizations organized regionally, with the World Stroke Organization providing organizational support, and a pool of experts, therapists, nurses, etc. to deliver locally relevant materials. 4. Clear and authoritative online resources, where it is easy to find key policy and protocol guidance. 5. A range of online interactive education and training resources to help build knowledge and competence in stroke care. The results of the workshop have been presented to the World Stroke Organization Board and will be used to help to guide the educational initiatives of the World Stroke Organization and World Stroke Academy going forward.

Aim: As part of a program of work to develop an educational strategy and implementation plan for the World Stroke Organization, we conducted a survey of World Stroke Organization members (health professionals, laypersons (Stroke Support Organizations)) to identify their potential educational needs. Methods: We developed a questionnaire to identify priority educational needs in consultation with the World Stroke Organization Education Committee. The World Stroke Organization invited all individual members and associated Stroke Support Organizations to complete the questionnaire via a web-based survey. Survey responses were supplemented by questionnaires emailed directly to key persons in Stroke Support Organizations and information from semi-structured telephone interviews, where necessary. The questionnaire asked respondents to prioritize topics in diagnosis, management of acute stroke, stroke care services, stroke rehabilitation, and stroke prevention. Free-text responses were assessed with word cloud. Results: The online survey was completed by 264 respondents from 60 countries; 19.1% were from low- and middle-income countries, 59% were stroke specialist physicians, 28% allied health professionals or nurses, 9% Stroke Support Organizations, 4% general physicians. Fifteen Stroke Support Organizations from 11 countries responded to the emailed survey. Seven Stroke Support Organizations' members were interviewed by telephone; one was interviewed in-person. We highlight the two highest priority topics in each of the five questionnaire domains. Conclusion: The 10 priority topics were all applicable in a low- or middle-income setting: setting up and delivering stroke diagnosis, treatment, rehabilitation and prevention services, and emphasized the most basic elements of care. The survey participants have identified a number of key topics that merit inclusion in stroke teaching materials and courses, especially those aimed at practitioners working in resource-limited settings.