OBJECTIVE:Launched in August 2024, the ACT-GLOBAL (a multifactorial, multiarm, multistage, randomized, global adaptive platform) trial is the first multinational adaptive platform trial for acute stroke. Because it proposes to enroll participants by deferral of consent, the ACT-GLOBAL trial seeks to publish an explicit justification for this practice. METHODS:Following a standardized protocol for establishing whether it is justified to use deferral of consent, all active domains of the ACT-GLOBAL platform adaptive trial were considered according to six questions: (1) Is there evidence-based uncertainty about the research question?; (2) is the standard of care treatment included in the trial, meaning that patients are unlikely to be disadvantaged by their participation?; (3) is the trial of sufficient methodological rigor that it can result in a change of practice?; (4) Are patients eligible for enrollment in the trial likely to be incapable of providing their own consent?; (5) Will seeking to obtain consent from a surrogate decision-maker meaningfully delay treatment and impact outcomes?; and (6) Are steps taken to mitigate the compromise to individual autonomy? RESULTS:The leadership of the ACT-GLOBAL trial is able to answer affirmatively the six questions outlined above in relation to each of the trial's current domains. The results of this analysis suggest that the use of deferral of consent in the ACT-GLOBAL trial is ethically justified, where permitted by law. CONCLUSION:This exercise demonstrates the utility of following an accepted protocol for determining whether alterations to standard consent practices such as deferral of consent are ethically justified in acute stroke research.

Abstract Background and aims In recent years, stroke trials in many jurisdictions have moved towards a system of deferred consent, in which the participant is enrolled as quickly as possible and consent is sought thereafter. We studied the use of various consent strategies in the ESCAPE Next trial, an international acute stroke trial assessing the neuroprotectant nerinetide. Methods We analyzed door-to-randomization times, method of consent (deferral, legally-authorized representative and subject), and rates of participant withdrawal across all 9 participating countries (Australia, Canada, Germany, Italy, the Netherlands, Norway, Singapore, Switzerland, the USA). Results The ESCAPE NEXT trial enrolled 850 subjects, 456 (54%) through deferred or 2 physician consent, 318 through LAR consent (37%), and 76 through subject consent (9%). The median door to randomization time was 50 minutes, which was shortest in the Netherlands (31 minutes) and longest in Singapore (62 minutes). Median door to randomization was shortest in participants enrolled by deferred or 2 physician consent (48 minutes) and longest in those enrolled by LAR consent (54 minutes), though there was significant heterogeneity based on protocol. Overall, 11 participants (1.2%) withdrew consent; though the rate was higher among participants enrolled by deferred consent (1.8%) than by LAR consent (0.63%), this was not statistically significant. Conclusions In the ESCAPE NEXT trial, the majority of participants were enrolled by deferred consent, which was associated with faster door-to-randomization times without a significant increase in the rate of participant withdrawal. These results support the benefits and acceptability of deferral of consent for acute stroke trials. Conflict of interest Nothing to disclose.

Abstract Background and aims Obtaining informed consent is challenging for acute stroke trials. We sought to assess the feasibility of a novel approach: advance consent, in which a person at risk of stroke provides consent to a trial in advance of experiencing an acute stroke. Methods Patients assessed in the Stroke Prevention Clinic at The Ottawa Hospital (Ottawa, Canada) were screened for diagnoses associated with a risk of acute stroke. Eligible patients completed an initial questionnaire and a follow-up questionnaire at 1 year. Participants who responded favourably to the idea of advance consent were invited to provide informed consent for 2 active acute stroke trials. Participants were followed for 1 year with regards to subsequent acute stroke and trial enrollment. Results From July 2023 to July 2024, we screened 1,547 patients; 431 met eligibility criteria, and 157 completed the initial questionnaire. Respondents overwhelmingly approved of advance consent in the initial questionnaire (96%) and at follow-up (92%). Based on their responses, 110 respondents were invited to provide advance consent; 48 participants (43%) did so, with 1 person withdrawing consent. Only 3 participants (2%) experienced any stroke, with none in the advance consent group, and no participants were enrolled into an acute stroke trial. Conclusions In this feasibility study, advance consent was strongly endorsed by participants, though ultimately this did not translate into improved trial enrollment. Conflict of interest Michel Shamy: Nothing to disclose; Ubong Udoh: Nothing to disclose; Brian Dewar: Nothing to disclose; Dar Dowlatshahi: Nothing to disclose

Abstract Background and aims Advance consent, where a patient at risk of incapacitation provides consent before meeting the eligibility criteria for a trial, is an innovative approach that could address the challenges of obtaining informed consent in acute stroke trials. We conducted a feasibility study assessing advance consent as a means of enrolling people at risk of stroke into acute stroke trials. Here we report qualitative outcomes of the study. Methods Patients assessed in the Stroke Prevention Clinic at The Ottawa Hospital (Ottawa, Canada) were screened for diagnoses associated with a risk of acute stroke. Eligible patients completed an initial questionnaire and a follow-up questionnaire at 1 year. In both instances, participants were invited to provide free-text comments about advance consent. Qualitative data gathered from free-text responses were analysed using inductive thematic analysis. Results Of the 157 participants who entered the study, 142 provided free-text comments. In the initial questionnaire, four main themes were identified in favour of advance consent: altruism, agency, personal impact, and trust in the health care team. At one year, respondents identified three more themes: enhancing autonomy, involving family, and ease of use of advance consent. No major concerns or objections were raised. Conclusions These qualitative findings support the acceptability of advance consent for participation in acute stroke trials, both at initial assessment and one year later. Conflict of interest Michel Shamy: Nothing to disclose; Ubong Udoh: Nothing to disclose; Brian Dewar: Nothing to disclose; Dar Dowlatshahi: Nothing to disclose

Abstract Background and aims Obtaining informed consent can be challenging for acute stroke trials. Informed consent forms (ICFs) are highly variable across jurisdictions. We examined the ICFs used in the ESCAPE NEXT trial, an international acute stroke trial assessing the neuroprotectant nerinetide. Methods We analyzed ICFs from each of the 9 countries that participated in ESCAPE NEXT (Australia, Canada, Germany, Italy, the Netherlands, Norway, Singapore, Switzerland, the USA) for length, content, complexity, and use of substitute or deferred consent. A template consent form in English was drafted for each country as part of study start-up, which served as the basis for local versions. Results All countries allowed surrogates to provide consent for an incapacitated patient and all countries except the United States allowed some form of deferral of consent. There was a high degree of consistency regarding content. The mean length of the English ICFs was 14 pages, with the shortest being Singapore at 10 pages and the longest being Italy at 17 pages. The mean length of local language ICFs was 13 pages. Using the Flesh-Kincaid readability assessment, the highest grade level for English ICFs was Australia at 11.8, with the lowest being Norway and Canada, at 7.3. Conclusions Despite homogeneity in content, ICFs used in the ESCAPE NEXT trial varied meaningfully in length and complexity. These results suggest that the information essential to informed consent could likely be communicated in shorter and simpler ICFs than are used in many jurisdictions. Conflict of interest Nothing to disclose.

BACKGROUND:There are limited data regarding the association between cancer and ischemic stroke, particularly among individuals with previous stroke. OBJECTIVE:Our objective was to measure and compare the risk of ischemic stroke in individuals with and without cancer. METHODS:Population-based matched cohort study in Ontario, Canada. Participants aged ≥18 years with a new diagnosis of cancer were matched (1:1) to cancer-free controls by age and sex in 2 separate matched cohorts based on the absence (matched cohort 1) or presence (matched cohort 2) of prior ischemic stroke. The primary outcome was the incidence of ischemic stroke. We calculated subdistribution adjusted hazard ratios (aHR) and 95% CIs for ischemic stroke (death as a competing event). RESULTS:In matched cohort 1, the rate and risk of ischemic stroke were higher among 620,647 patients with cancer versus 620,647 controls at 1.5 years (4.6/1000 person-years [95% CI, 4.5-4.7] vs 3.5/1000 person-years [95% CI, 3.4-3.6]; aHR, 1.40; 95% CI, 1.34-1.47). In matched cohort 2, the rate and risk of ischemic stroke were similar among 13,924 patients with cancer and 13,924 controls at 1.5 years (26.9/1000 person-years [95%CI 25.1-28.9] vs 22.0 /1000 person-years [95% CI, 20.7-23.4]; aHR, 1.00; 95% CI, 0.88-1.14). In both cohorts, the risk of ischemic stroke was lower in patients with cancer versus controls from 1.5 to 5 years (aHR, 0.72; 95% CI, 0.69-0.74 and aHR, 0.53; 95% CI, 0.46-0.62). CONCLUSIONS:Compared with cancer-free controls, the rate and risk of ischemic stroke were higher 1.5 years after cancer diagnosis in individuals without prior stroke and varied according to cancer site and stage.

Background: Vasospasm is an important complication of subarachnoid hemorrhage (SAH). Attempts to identify patients at highest risk of vasospasm have not led to practice change. We sought to identify patients at lowest risk of vasospasm by testing the prognostic utility of novel low risk criteria: mean MCA velocities on TCD that peaked and remained below 120 cm/s by the 7th day. Methods: Retrospective observational study of TCD values in patients admitted to The Ottawa Hospital with SAH 2018-2023. The primary outcome was presence of moderate to severe vasospasm (MCA mean velocity >160 cm/s) by day 21. Results: Data were collected on 211 patients, of whom 197 fulfilled inclusion criteria. Only 2 of 104 patients (2%) meeting our low-risk criteria developed the primary outcome, compared to 48 of 93 patients (52%) who did not meet criteria (RR 27). The Negative Predictive Value (NPV) for vasospasm in our low-risk group was 98%. Conclusions: Our low-risk criteria based on TCD patterns in the first 7 days after SAH can identify patients at very low risk of vasospasm with great accuracy. This could inform a future prospective study.

BACKGROUND AND AIMS:Achieving a first pass recanalization (FPR) improves clinical outcomes in patients with basilar artery strokes, but its association with initial infarct burden is unknown. We aimed to study the benefits of FPR for basilar artery strokes by initial infarct burden using the Posterior Circulation Alberta Stroke Program Early CT score (pc-ASPECTS). METHODS:We retrospectively analyzed the prospective multicentric Endovascular Treatment of Ischemic Stroke registry and included 194 patients diagnosed with an acute basilar artery occlusion who were treated with thrombectomy. Our primary outcome was a modified Rankin Scale (mRS) of 0-3 at 90 days, and our secondary outcomes were an mRS of 4-6 and mortality. We compared the 90-day clinical outcomes of achieving an FPR versus multiple thrombectomy passes based on patients' initial infarct size on pretreatment MRI: small (pc-ASPECTS = 9-10), medium (pc-ASPECTS = 6-8) and large (pc-ASPECTS <6). RESULTS:Patients with a medium or large infarct size had significantly better outcomes (mRS 0-3 at 3 months) if FPR was achieved than if multiple passes were required (RR = 1.61, 95% CI: 1.16, 2.24; p-value = 0.005; and RR = 3.41, 95% CI: 1.54-7.57; p-value = 0.003, respectively). No similar difference was seen among patients with small infarcts. Achieving an FPR was also associated with a significantly lower mortality risk among patients with a moderate infarct size (RR = 0.36, 95% CI: 0.17-0.79; p-value = 0.010) but not with those with small or large infarcts. CONCLUSIONS:Achieving an FPR significantly improves clinical outcomes in acute stroke patients with basilar artery occlusions undergoing thrombectomy when their infarcts are medium or large. Ongoing research to develop surgical techniques to achieve FPR is crucial to improving patients' prognoses.

Background About 25% of patients with acute ischemic stroke have lacunar infarct on follow‐up imaging. In this secondary analysis from the AcT (Alteplase Compared With Tenecteplase) trial, we assessed if there is variation in safety or efficacy of intravenous thrombolysis by infarct type in patients with no visible occlusion. We also determined if this effect differed between tenecteplase and alteplase. Methods and Results This is a secondary analysis from the AcT trial. Lacunar infarct was defined as single, ≤15 mm, and in regions supplied by perforating arterioles on 24‐hour imaging. Outcomes included symptomatic intracerebral hemorrhage at 24 hours, any hemorrhage on imaging, and 90‐day modified Rankin Scale score. Mixed‐effects regression models adjusted for age, sex, stroke severity, thrombolytic type, and onset‐to‐needle time were used. Of 1577 patients, 456/29.9% had no visible occlusion and interpretable follow‐up imaging (magnetic resonance imaging: 41.2%). Of these 93 (20.4%) (magnetic resonance imaging: 62.3%) had lacunar infarct, 171 (37.5%) (magnetic resonance imaging: 67.4%) had nonlacunar infarct, and 192 (42.1%) (magnetic resonance imaging: 7.3%) had no visible infarct. Four patients (2.3%) in the group with nonlacunar infarct and none in the groups with lacunar infarct and no visible infarct developed symptomatic intracerebral hemorrhage. Any intracranial hemorrhage was highest (21; 12.4%) in the group with nonlacunar infarct. There was no significant interaction between thrombolytic type and treatment outcomes. Conclusions In the AcT trial, safety of intravenous thrombolysis was similar across all infarct types in patients with no visible occlusion but functional outcomes were worst in patients with nonlacunar infarct. Safety and functional outcomes after intravenous thrombolysis were better in the groups with lacunar infarct and no visible infarct as compared with the overall trial population.

OBJECTIVES:This study seeks to propose a novel framework for the ethical justification of randomized controlled trials (RCTs). STUDY DESIGN AND SETTING:This paper develops a novel framework for the ethical evaluation of RCTs, explored through the example of trials on endovascular thrombectomy for acute ischemic stroke. We propose that RCTs can be categorized into four quadrants, where justification in each quadrant relates to different thresholds for permissibility (the ethical defensibility of the trial) and necessity (the social and scientific importance of conducting the trial). RESULTS:Trials can be situated within four quadrants based on the interventions being compared: standard vs standard treatment in the alpha quadrant, standard vs novel treatment in the beta quadrant, standard vs no treatment in the gamma quadrant, and no treatment vs novel treatment in the delta quadrant. In each quadrant, the thresholds to establish permissibility and necessity will differ. The controversies that surrounded trials of thrombectomy for acute stroke can be understood as representing differing points of view about whether those trials should have been situated in the beta or delta quadrant. These differing conclusions highlight the importance of using a quadrant-based analysis in assessing the ethical permissibility and necessity of RCTs. CONCLUSION:The proposed four quadrants framework provides a comprehensive and precise approach to assessing the ethical justification of RCTs. Implementing this framework could improve regulatory evaluations of RCTs and reduce unnecessary harm to trial participants, while balancing the objectives of scientific advancement. PLAIN LANGUAGE SUMMARY:In medical research, randomized controlled trials (RCTs) are used to test how well treatments work. However, RCTs can place patients at risk, so they should be ethically justified. This paper introduces a "four quadrants" framework to help determine when trials are ethically justified. The method proposed in this paper divides RCTs into four categories, or quadrants, based on their epistemic circumstances, or what is known about the treatments being compared. First is the alpha quadrant, in which trials compare two standard treatments. Second is the beta quadrant, in which trials compare a standard treatment with a standard plus a new treatment. Third, the gamma quadrant includes trials that compare a standard treatment with no treatment. Fourth, the delta quadrant includes trials that compare a new treatment with no treatment. The trials matter because the strength of the case to conduct a trial in any one of these quadrants will be different based on the strength of the argument necessary to prove that it is both permissible (one could do it) and necessary (one should do it). Using this methodology, we analyzed the case of endovascular thrombectomy trials for acute ischemic stroke conducted in the 2010s. We show that analysis using the four quadrants approach helps to understand the ethical controversy that beset these trials and offers a way forward in terms of resolving future potential conflicts.

Background: Presence of right-to-left shunt has been proposed as a mechanism of paradoxical embolism in patients with active cancer. Our study thus aims to investigate the role of shunting in stroke occurrence among cancer patients. Methods: This is a retrospective study with our population consisting of patients presenting to the Ottawa Hospital with ischemic stroke between January 01, 2020, and December 31, 2022. Presence of right-to-left shunting is identified in patients with and without cancer diagnosis within one year of ischemic stroke. The prevalence of shunt is assessed using 95% confidence intervals (CI). Results: Among 654 patients, 495 (37% female, median age 53 years) were included in the study, in which 47 (9.5%) had active cancer, with 12 patients (25.5%, 95% CI 14 - 40) diagnosed with a shunt. In contrast, among 448 patients (90.5%) without active cancer, 133 patients (30%, 95% CI 25 - 34) were found to have a shunt. Conclusions: The prevalence of right-to-left shunting tends to be lower in patients with ischemic stroke and active cancer diagnosis. Our results are similar to a recent study indicating a higher rate of shunt among patients without cancer. Our finding does not support the hypothesis that cancer-associated stroke is related to right-to-left shunting.

Importance:The cumulative burden of chronic vascular and neurodegenerative changes contributes to brain frailty, which may reduce the brain's capacity to recover from acute ischemic stroke (AIS). The association between brain frailty markers and poststroke outcomes after thrombolysis is unclear. Objective:To evaluate associations between brain frailty assessed on non-contrast-enhanced computed tomography (NCCT) and magnetic resonance imaging (MRI) and functional outcome in patients with AIS treated with intravenous thrombolysis. Design, Setting, and Participants:This cohort study was a post hoc analysis of the Alteplase compared to Tenecteplase (AcT) trial, an investigator-led, registry-linked, parallel-group, open-label, randomized clinical trial that enrolled patients between December 10, 2019, and January 25, 2022, at 22 primary and comprehensive stroke centers across Canada. Participants included adults 18 years or older diagnosed with ischemic stroke causing disabling neurological deficit, presenting within 4.5 hours of symptom onset, and meeting Canadian guidelines for thrombolysis. Markers of brain frailty (cortical and subcortical atrophy, white matter changes [Fazekas score, grouped as 0, 1-2, and 3-6], lacunes, chronic infarctions, and [on MRI] microbleeds, siderosis, and enlarged perivascular spaces) were retrospectively assessed while reviewers were blinded to outcome variables. Analyses were performed from July 24, 2024, to March 25, 2025. Exposures:Patients underwent baseline NCCT and were randomized to receive intravenous thrombolysis with alteplase (0.9 mg/kg) or tenecteplase (0.25 mg/kg). Some patients also received posttreatment brain MRI. Main Outcomes and Measures:The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score of 0-1) at 90 days. Secondary outcomes included 90-day ordinal mRS score (trichotomized as 0-2, 3-4, and 5-6), symptomatic intracerebral hemorrhage, and mortality. Sensitivity analyses were performed in patients with available MRI scans. Results:Among the 1568 patients (median age, 74 [IQR, 63-83] years; 817 male [52.1%]) with interpretable NCCT findings, after correcting for multiple comparisons, higher total Fazekas score of 3 to 6 compared with 0 was associated with lower odds of a 90-day mRS score of 0 to 1 (adjusted odds ratio [OR], 0.40 [95% CI, 0.24-0.65]). Total Fazekas score (adjusted common OR [ACOR], 2.80 [95% CI, 1.88-4.16]), cortical atrophy (ACOR, 2.65 [95% CI. 1.63-4.32]), and total brain frailty score (ACOR, 3.15 [95% CI, 1.87-5.33]) were each associated with worse ordinal mRS, but were not associated with safety outcomes. Conclusions and Relevance:In this cohort study of patients with AIS treated with intravenous thrombolysis, brain frailty markers-particularly white matter changes, cortical atrophy, and total brain frailty-were associated with worse outcomes. Consideration of these neuroimaging markers may better inform clinicians and patients about treatment expectations from thrombolytic therapy.

Obtaining consent for participation in acute stroke trials is particularly challenging due to the time pressure of delivering immediate treatment. As a result, patients are often not able to provide informed consent to participate in clinical trials. Modifications to standard consent practices such as deferral of consent , surrogate consent, or 2-physician consent can produce problems including violating patient autonomy, disadvantaging patients through their participation and biasing results. Alternatively, advance consent , in which patients at risk of stroke consent to participate in RCTs before they experience a stroke, could address these challenges. In this study, we assessed the acceptability of advance consent to people at risk of stroke. Methods: We approached patients deemed at risk of stroke in the Stroke Prevention Clinic of the Ottawa Hospital, a tertiary care facility in Ontario, Canada. Eligible patients were invited to complete a questionnaire regarding advance consent. Patients who responded positively to questions about advance consent were offered the opportunity to consent in advance to the EASI-TOC and/or FASTEST clinical trials. Results: We screened 1547 patients over a 1-year period (July 2023 – July 2024), of whom 431 (28%) were eligible to participate. Of the 431 eligible participants, 157 (36%) completed the initial questionnaire. Of these, 96% (151/157) either agreed or strongly agreed that inviting stroke patients to provide advance consent to participate in clinical research trials is appropriate. Further, 95% (149/157) of participants either agreed or strongly agreed that they would provide advance consent to specific acute stroke clinical research trials, and 69% (108/157) either agreed or strongly agreed that they would provide advance consent to all acute stroke research trials, whether or not they were given the details of the trial. Ultimately, 123 respondents were eligible to be offered advance consent, of whom 45 (37%) provided advance consent to participate in at least one ongoing trial. One participant (0.8%) specified in advance that they would not want to participate in these trials. Discussion: Preliminary results of this feasibility study show that patients were open to the idea of providing advance consent to participate in acute stroke research and a sizable portion of patients were willing to provide advance consent for ongoing trials.

INTRODUCTION:The spontaneous recanalization of an occluded extracranial internal carotid artery (ICA) is thought to be an uncommon etiology of ischemic stroke. However, a growing number of reports describe this phenomenon. We sought to perform a scoping review of the literature to assess the prevalence of spontaneous ICA recanalization and its timing in relation to occlusion, and any patterns in imaging and treatment. METHODS:MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Web of Science were searched from inception to March 2024 for studies that included adults with spontaneous recanalization or transient occlusion of the extracranial internal carotid artery. Two investigators independently screened the studies and extracted data around recanalization proportion, timepoints, imaging, and treatment. These results were described qualitatively, and descriptive statistics were calculated where appropriate. RESULTS:Of 2807 studies screened, 53 met inclusion criteria, of which 17 were cohort studies and 36 were case studies, including a total of 818 patients. The proportion of recanalization was reported in 17 cohort studies for a median of 21.2% (IQR 9.2-37.5%). Amongst the studies which reported recanalization, 46.7% of those within the cohort studies recanalized within 6 months, whereas case studies reported that 66.7% of recanalizations occurred in that same timeframe. When reported, antiplatelet treatment was the most common medical treatment pre- and post-recanalization. Doppler imaging was used to identify recanalization in 67.9% of studies, and angiography was used in 54.7%. Twenty-one studies reported a revascularization procedure following spontaneous recanalization. CONCLUSIONS:Spontaneous recanalization of an occluded extracranial carotid artery may occur, and possibly within 6 months after documented occlusion. However, clear data are lacking regarding a standard approach to imaging or treatment of patients with occluded carotid arteries.