Combining Early Ischemic Change and Collateral Extent for Functional Outcomes After Endovascular Therapy: An Analysis From AcT Trial.

BACKGROUND: Early ischemic change and collateral extent are colinear with ischemic core volume (ICV). We investigated the relationship between a combined score using the Alberta Stroke Program Early Computed Tomography Score and multiphase computed tomography angiography (mCTA) collateral extent, named mCTA-ACE score, on functional outcomes in endovascular therapy-treated patients. METHODS: We performed a post hoc analysis of a subset of endovascular therapy-treated patients from the Alteplase Compared to Tenecteplase trial which was conducted between December 2019 and January 2022 at 22 centers across Canada. Ten-point mCTA collateral corresponding to M2 to M6 regions of the Alberta Stroke Program Early Computed Tomography Score grid was evaluated as 0 (poor), 1 (moderate), or 2 (normal) and additively combined with the 10-point Alberta Stroke Program Early Computed Tomography Score to produce a 20-point mCTA-ACE score. We investigated the association of mCTA-ACE score with modified Rankin Scale score ≤2 and return to prestroke level of function at 90 to 120 days using mixed-effects logistic regression. In the subset of patients who underwent baseline computed tomography perfusion imaging, we compared the mCTA-ACE score and ICV for outcome prediction. RESULTS: Among 1577 intention-to-treat population in the trial, 368 (23%; 179 men; median age, 73 years) were included, with Alberta Stroke Program Early Computed Tomography Score, mCTA collateral, and combination of both (mCTA-ACE score: median [interquartile range], 8 [7-10], 9 [8-10], and 17 [16-19], respectively). The probability of modified Rankin Scale score ≤2 and return to prestroke level of function increased for each 1-point increase in mCTA-ACE score (odds ratio, 1.16 [95% CI, 1.06-1.28] and 1.22 [95% CI, 1.06-1.40], respectively). Among 173 patients in whom computed tomography perfusion data was assessable, the mCTA-ACE score was inversely correlated with ICV (ρ=-0.46; P<0.01). The mCTA-ACE score was comparable to ICV to predict a modified Rankin Scale score ≤2 and return to prestroke level of function (C statistics 0.71 versus 0.69 and 0.68 versus 0.64, respectively). CONCLUSIONS: The mCTA-ACE score had a significant positive association with functional outcomes after endovascular therapy and had a similar predictive performance as ICV.

Sex-Based Analysis of Workflow and Outcomes in Acute Ischemic Stroke Patients Treated With Alteplase Versus Tenecteplase.

BACKGROUND: Understanding sex differences in stroke care is important in reducing potential disparities. Our objective was to explore sex differences in workflow efficiency, treatment efficacy, and safety in the AcT trial (Alteplase Compared to Tenecteplase). METHODS: AcT was a multicenter, registry-linked randomized noninferiority trial comparing tenecteplase (0.25 mg/kg) with alteplase (0.9 mg/kg) in acute ischemic stroke within 4.5 hours of onset. In this post hoc analysis, baseline characteristics, workflow times, successful reperfusion (extended Thrombolysis in Cerebral Infarction score ≥2b), symptomatic intracerebral hemorrhage, 90-day functional independence (modified Rankin Scale score, 0-1), and 90-day mortality were compared by sex. Mixed-effects regression analysis was used adjusting for age, stroke severity, and occlusion site for outcomes. RESULTS: Of 1577 patients treated with intravenous thrombolysis (2019-2022), 755 (47.9%) were women. Women were older (median, 77 [68-86] years in women versus 70 [59-79] years in men) and had a higher proportion of severe strokes (National Institutes of Health Stroke Scale score >15; 32.4% versus 24.9%) and large vessel occlusions (28.7% versus 21.5%) compared with men. All workflow times were comparable between sexes. Women were less likely to achieve functional independence (31.7% versus 39.8%; unadjusted relative risk, 0.80 [95% CI, 0.70-0.91]) and had higher mortality (17.7% versus 13.3%; unadjusted relative risk, 1.33 [95% CI, 1.06-1.69]). Adjusted analysis showed no difference in outcomes between sexes. CONCLUSIONS: Differences in prognostic factors of age, stroke severity, and occlusion site largely accounted for higher functional dependence and mortality in women. No sex disparities were apparent in workflow quality indicators. Given the integration of the AcT trial into clinical practice, these results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Canadian centers. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Advance Consent in Acute Stroke Trials: Survey of Canadian Stroke Physicians.

Advance consent presents a potential solution to the challenge of obtaining informed consent for participation in acute stroke trials. Clinicians in stroke prevention clinics are uniquely positioned to identify and seek consent from potential stroke trial participants. To assess the acceptability of advance consent to Canadian stroke clinic physicians, we performed an online survey. We obtained 58 respondents (response rate 35%): the vast majority (82%) expressed comfort with obtaining advance consent and 92% felt that doing so would not be a significant disruption to clinic workflow. These results support further study of advance consent for acute stroke trials.

Advance Consent in Acute Stroke Trials: Survey of Canadian Research Ethics Board Chairs.

Advance consent could allow individuals at high risk of stroke to provide consent before they might become eligible for enrollment in acute stroke trials. This survey explores the acceptability of this novel technique to Canadian Research Ethics Board (REB) chairs that review acute stroke trials. Responses from 15 REB chairs showed that majority of respondents expressed comfort approving studies that adopt advance consent. There was no clear preference for advance consent over deferral of consent, although respondents expressed significant concern with broad rather than trial-specific advance consent. These findings shed light on the acceptability of advance consent to Canadian ethics regulators.

Previous Ischemic Stroke Significantly Alters Stroke Risk in Newly Diagnosed Cancer Patients.

BACKGROUND: Previous ischemic stroke (IS) is a risk factor for subsequent IS in the general population; it is unclear if this relationship remains true in patients with cancer. Our objective was to examine the association between previous IS and risk for future IS in individuals newly diagnosed with cancer. METHODS: We conducted a retrospective population-based matched cohort study of newly diagnosed adult cancer patients (excluding nonmelanoma skin cancers and primary central nervous system tumors) in Ontario, Canada from 2010 to 2020; those with prior IS were matched (1:4) by age, sex, year of cancer diagnosis, cancer stage, and cancer site to those without a history of stroke. Cumulative incidence function curves were created to estimate the incidence of IS. Subdistribution adjusted hazard ratios (aHRs) and 95% CIs were calculated, where death was treated as a competing event. Multivariable analysis was adjusted for imbalanced baseline characteristics. RESULTS: We examined 65 525 individuals with cancer, including 13 070 with a history of IS. The median follow-up duration was 743 days (interquartile range, 177-1729 days). The incidence of IS following cancer diagnosis was 261.3/10 000 person-years in the cohort with prior IS and 75.3/10 000 person-years in those without prior IS. Individuals with prior IS had an increased risk for IS after cancer diagnosis compared with those without a history (aHR, 2.68 [95% CI, 2.41-2.98]); they also had more prevalent cardiovascular risk factors. The highest risk for stroke compared with those without a history of IS was observed in the gynecologic cancer (aHR, 3.84 [95% CI, 2.15-6.85]) and lung cancer (aHR, 3.18 [95% CI, 2.52-4.02]) subgroups. The risk of IS was inversely correlated with lag time of previous stroke; those with IS 1 year before their cancer diagnosis had the highest risk (aHR, 3.68 [95% CI, 3.22-4.22]). CONCLUSIONS: Among individuals with newly diagnosed cancer, those with IS history were almost 3× more likely to experience a stroke after cancer diagnosis, especially if the prediagnosis stroke occurred within 1 year preceding cancer diagnosis.

Effect of Time to Thrombolysis on Clinical Outcomes in Patients With Acute Ischemic Stroke Treated With Tenecteplase Compared to Alteplase: Analysis From the AcT Randomized Controlled Trial.

BACKGROUND: The AcT (Alteplase Compared to Tenecteplase) randomized controlled trial showed that tenecteplase is noninferior to alteplase in treating patients with acute ischemic stroke within 4.5 hours of symptom onset. The effect of time to treatment on clinical outcomes with alteplase is well known; however, the nature of this relationship is yet to be described with tenecteplase. We assessed whether the association of time to thrombolysis treatment with clinical outcomes in patients with acute ischemic stroke differs by whether they receive intravenous tenecteplase versus alteplase. METHODS: Patients included were from AcT, a pragmatic, registry-linked, phase 3 randomized controlled trial comparing intravenous tenecteplase to alteplase in patients with acute ischemic stroke. Eligible patients were >18 years old, with disabling neurological deficits, presenting within 4.5 hours of symptom onset, and eligible for thrombolysis. Primary outcome was modified Rankin Scale score 0 to 1 at 90 days. Safety outcomes included 24-hour symptomatic intracerebral hemorrhage and 90-day mortality rates. Mixed-effects logistic regression was used to assess the following: (a) the association of stroke symptom onset to needle time; (b) door (hospital arrival) to needle time with outcomes; and (c) if these associations were modified by type of thrombolytic administered (tenecteplase versus alteplase), after adjusting for age, sex, baseline stroke severity, and site of intracranial occlusion. RESULTS: Of the 1538 patients included in this analysis, 1146 (74.5%; 591 tenecteplase and 555 alteplase) presented within 3 hours versus 392 (25.5%; 196: TNK and 196 alteplase) who presented within 3 to 4.5 hours of symptom onset. Baseline patient characteristics in the 0 to 3 hours versus 3- to 4.5-hour time window were similar, except patients in the 3- to 4.5-hour window had lower median baseline National Institutes of Health Stroke Severity Scale (10 versus 7, respectively) and lower proportion of patients with large vessel occlusion on baseline CT angiography (26.9% versus 18.7%, respectively). Type of thrombolytic agent (tenecteplase versus alteplase) did not modify the association between continuous onset to needle time (Pinteraction=0.161) or door-to-needle time (Pinteraction=0.972) and primary clinical outcome. Irrespective of the thrombolytic agent used, each 30-minute reduction in onset to needle time was associated with a 1.8% increase while every 10 minutes reduction in door-to-needle time was associated with a 0.2% increase in the probability of achieving 90-day modified Rankin Scale score 0 to 1, respectively. CONCLUSIONS: The effect of time to tenecteplase administration on clinical outcomes is like that of alteplase, with faster administration resulting in better clinical outcomes. REGISTRATION: URL: https://classic. CLINICALTRIALS: gov; Unique identifier: NCT03889249.

Ethical Justification for Deferral of Consent in the AcT Trial for Acute Ischemic Stroke.

The AcT trial (Alteplase Compared to Tenecteplase) compares alteplase or tenecteplase for patients with acute ischemic stroke. All eligible patients are enrolled by deferral of consent. Although the use of deferral of consent in the AcT trial meets the requirements of Canadian policy, we sought to provide a more explicit and rigorous approach to the justification of deferral of consent organized around 3 questions. Ultimately, the approach we outline here could become the foundation for a general justification for deferral of consent.

"Everything has been tried and his heart can't recover ": A Descriptive Review of "Do Everything!" in the Archive of Ontario Consent and Capacity Board.

BACKGROUND: In end-of-life situations, the phrase "do everything" is sometimes invoked by physicians, patients, or substitute decision-makers (SDM), though its meaning is ambiguous. We examined instances of the phrase "do everything" in the archive of the Ontario Consent and Capacity Board (CCB) in Canada, a tribunal with judicial authority to adjudicate physician-patient conflicts in order to explore its potential meanings. METHODS: We systematically searched the CCB's online public archive from its inception to 2018 for any references to "do everything" in the context of critical care medicine and end-of-life care. Two independent assessors reviewed decisions, collected characteristics, and identified key themes. RESULTS: Of 598 cases in the archive, 41 referred to "do everything" in end-of-life situations. The phrase was overwhelmingly invoked by SDMs (38/41, 93%), typically to advocate for life-prolonging measures that contradicted physician advice. Physicians generally related "doing everything" to describe the interventions they had already performed (3/41, 7%), using it to recommend focusing on patients' quality of life. SDMs were generally reluctant to accept death, whereas physicians found prolonging life at all costs to be morally distressing. The CCB did not interpret appeals to "do everything" legally but followed existing laws by deferring to patients' prior wishes whenever known, or to concepts of "best interests" when not. The CCB generally recommended against life-prolonging measures in these cases (26/41, 63%), focusing on patients' "well-being" and "best interests." CONCLUSIONS: In this unique sample of cases involving conflict surrounding resuscitation and end-of-life care, references to "do everything" highlighted conflicts over quantity versus quality of life. These appeals were associated with signs of cognitive distress on the behalf of SDMs who were facing the prospect of a patient's death, whereas physicians identified moral distress related to the prolongation of patients' suffering through their use of life-sustaining interventions. This divergence in perspectives on death versus suffering was consistently the locus of conflict. These findings support the importance of tools such as the Serious Illness Conversation Guide that can be used by physicians to direct conversations on the patients' goals, wishes, trade-offs, and to recommend a treatment plan that may include palliative care. TRIAL REGISTRATION: Not applicable.

Deferral of Consent: Recent Lessons From Canadian Acute Stroke Trials.

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Variability Predictors of Vasospasm in Subarachnoid Hemorrhage: A Feasibility Study.

BACKGROUND: Mean cerebral blood flow velocity (mean-CBFV) obtained from Transcranial Doppler (TCD) poorly predicts cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage (aSAH). Variability descriptors of mean-CBFV obtained during extended TCD recordings may improve this prediction. We assessed the feasibility of generating reliable linear and non-linear descriptors of mean-CBFV variability using extended recordings in aSAH patients and in healthy controls. We also explored which of those metrics might have the ability to discriminate between aSAH patients and healthy controls, and among patients who would go on to develop vasospasm and those who would not. METHODS: Bilateral mean-CBFV, blood pressure, and heart rate were continuously recorded for 40 minutes in aSAH patients (n = 8) within the first 5 days after ictus, in age-matched healthy controls (n = 8) and in additional young controls (n = 8). We obtained linear [standard deviation, coefficient of variations, and the very-low (0.003-0.040 Hz), low (0.040-0.150 Hz), and high-frequency (0.15-0.4 Hz) power spectra] and non-linear (Fractality, deterministic Chaos analyses) variability metrics. RESULTS: We successfully obtained TCD recordings from patients and healthy controls and calculated the desired metrics of mean-CBFV variability. Differences were appreciable between aSAH patients and healthy controls, as well as between aSAH patients who later developed vasospasm and those who did not. CONCLUSIONS: A 40-minute TCD recording provides reliable variability metrics in aSAH patients and healthy controls. Future studies are required to determine if mean-CBFV variability metrics remain stable over time, and whether they may serve to identify patients who are at greatest risk of developing cerebral vasospasm after aSAH.

Decreased Stroke Presentation Rates at a Comprehensive Stroke Center during COVID-19.

We reviewed stroke care delivery during the COVID-19 pandemic at our stroke center and provincial telestroke system. We counted referrals to our prevention clinic, code strokes, thrombolysis, endovascular thrombectomies, and activations of a provincial telestroke system from February to April of 2017-2020. In April 2020, there was 28% reduction in prevention clinic referrals, 32% reduction in code strokes, and 26% reduction in telestroke activations compared to prior years. Thrombolysis and endovascular thrombectomy rates remained constant. Fewer patients received stroke services across the spectrum from prevention, acute care to telestroke care in Ontario, Canada, during the COVID-19 pandemic.

Goods, causes and intentions: problems with applying the doctrine of double effect to palliative sedation.

BACKGROUND: Palliative sedation and analgesia are employed in patients with refractory and intractable symptoms at the end of life to reduce their suffering by lowering their level of consciousness. The doctrine of double effect, a philosophical principle that justifies doing a "good action" with a potentially "bad effect," is frequently employed to provide an ethical justification for this practice. MAIN TEXT: We argue that palliative sedation and analgesia do not fulfill the conditions required to apply the doctrine of double effect, and therefore its use in this domain is inappropriate. Furthermore, we argue that the frequent application of the doctrine of double effect to palliative sedation and analgesia reflects physicians' discomfort with the complex moral, intentional, and causal aspects of end-of-life care. CONCLUSIONS: We are concerned that this misapplication of the doctrine of double effect can consequently impair physicians' ethical reasoning and relationships with patients at the end of life.

Evaluating Hematoma Expansion Scores in Acute Spontaneous Intracerebral Hemorrhage: A Systematic Scoping Review.

Background and Purpose- In acute spontaneous intracerebral hemorrhage, multiple hematoma expansion scores have been proposed for use in clinical trial environments. We performed a systematic scoping review to identify all existing hematoma expansion scores and describe their development, validation, and relative performance. Methods- Two reviewers searched MEDLINE, PUBMED, EMBASE, and CENTRAL (Cochrane Central Register of Controlled Trials) for studies that derived or validated a hematoma expansion prediction score in adults presenting with spontaneous intracerebral hemorrhage. A descriptive analysis of the extracted data was performed, focusing on score development techniques and predictive capabilities. Results- Of the 14 434 records retrieved, 15 studies met inclusion criteria and 10 prediction scores were identified. Validation analysis using independent samples was performed in 9 studies on 5 scores. All derivation studies reported high performance with C statistics ranging from 0.72 to 0.93. In validation, the C-statistic range was broader with studies reporting 0.62 to 0.77. For every score, the risk of expansion increased with each point increase, although patients with high scores were rare. Conclusions- At present, 10 hematoma expansion scores have been developed, of which 5 have been externally validated. Real-world performance in validation studies was lower than performance in derivation studies. Data from the current literature are insufficient to support a meaningful meta-analysis.

Diagnosis of Transient Ischemic Attack: Sex-Specific Differences From a Retrospective Cohort Study.

BACKGROUND AND PURPOSE: Research suggests that women and men may present with different transient ischemic attack (TIA) and stroke symptoms. We aimed to explore symptoms and features associated with a definite TIA/stroke diagnosis and whether those associations differed by sex. METHODS: We completed a retrospective cohort study of patients referred to The Ottawa Hospital Stroke Prevention Clinic in 2015. Exploratory multinomial logistic regression was used to evaluate candidate variables associated with diagnosis and patient sex. Backwards elimination of the interaction terms with a significance level for staying in the model of 0.25 was used to arrive at a more parsimonious model. RESULTS: Based on 1770 complete patient records, sex-specific differences were noted in TIA/stroke diagnosis based on features such as duration of event, suddenness of symptom onset, unilateral sensory loss, and pain. CONCLUSIONS: This preliminary work identified sex-specific differences in the final diagnosis of TIA/stroke based on common presenting symptoms/features. More research is needed to understand if there are biases or sex-based differences in TIA/stroke manifestations and diagnosis.

Early Dabigatran Treatment After Transient Ischemic Attack and Minor Ischemic Stroke Does Not Result in Hemorrhagic Transformation.

OBJECTIVES: The optimal timing of anticoagulation after ischemic stroke in atrial fibrillation (AF) patients is unknown. Our aim was to demonstrate the feasibility and safety of initiating dabigatran therapy within 14 days of transient ischemic attack (TIA) or minor stroke in AF patients. PATIENTS AND METHODS: A prospective, multi-center registry (NCT02415855) in patients with AF treated with dabigatran within 14 days of acute ischemic stroke/TIA (National Institutes of Health Stroke Scale (NIHSS) ≤ 3) onset. Baseline and follow-up computed tomography (CT) scans were assessed for hemorrhagic transformation (HT) and graded by using European Cooperative Acute Stroke Study criteria. RESULTS: One hundred and one patients, with a mean age of 72.4 ± 11.5 years, were enrolled. Median infarct volume was 0 ml. Median time from index event onset to dabigatran initiation was 2 days, and median baseline NIHSS was 1. Pre-treatment HT was present in seven patients. No patients developed symptomatic HT. On the day 7 CT scan, HT was present in six patients (one progressing from baseline hemorrhagic infarction type 1). Infarct volume was a predictor of incident HT (odds ratio = 1.063 [1.020-1.107], p < 0.003). All six (100%) patients with new/progressive HT were functionally independent (modified Rankin Scale (mRS) = 0-2) at 30 days, which was similar to those without HT (90%, p = 0.422). Recurrent ischemic events occurred within 30 days in four patients, two of which were associated with severe disability and death (mRS 5 and 6, respectively). CONCLUSION: Early dabigatran treatment did not precipitate symptomatic HT after minor stroke. Asymptomatic HT was associated with larger baseline infarct volumes. Early recurrent ischemic events may be clinically more important.

Deferral of Consent in Acute Stroke Trials.

Background and Purpose- The ESCAPE trial (The Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times) was a multicentre, randomized controlled trial of endovascular thrombectomy versus standard care for patients with acute ischemic stroke that allowed patients to be enrolled with deferred consent. We investigated the knowledge and opinions of these patients or their authorized third parties about the consent process. Methods- All patients (or their authorized third parties) enrolled with deferral of consent in ESCAPE were invited to complete a 12-question survey within the first 4 days of enrollment and again at 90 days. Questions investigated knowledge of the ESCAPE trial and opinions on deferral of consent. Results- Of 56 patients enrolled with deferred consent, 33 (59%) completed the initial survey, and of these, 27 (81%) completed the 90-day follow-up. Enrollment with deferred consent was not associated with a significant difference in door-to-randomization times (50.5 versus 57 minutes; P=0.29) but allowed these 56 patients to participate in the trial. Only 52% of respondents understood that patients could be randomized to thrombectomy or standard care, although most understood the other basic principles of the trial. At baseline and at 90 days, respondents disagreed or strongly disagreed with deferred consent in acute stroke trials generally (82% and 78%) and in the ESCAPE trial specifically (93% and 91%). Conclusions- Respondents generally disagreed with the use of deferred consent for enrollment in the ESCAPE trial and in stroke trials more generally.

Harnessing the power of placebos in movement disorders: Insights from Parkinson's disease in clinical research and practice.

The placebo effect alongside the detrimental nocebo and lessebo effects associated with the use of placebos are well-recognized phenomena. Research conducted in the last two decades has demonstrated that the placebo effect is a measurable health benefit with well-known neurobiological correlates. In this review, we describe the current knowledge about how to best make use of the placebo effect to improve clinical research and optimize clinical care. We will cover four key topics: (1) setting the stage: historical perspectives on the use of placebos; (2) optimizing the use of placebos in clinical trials; (3) use of placebos in clinical practice; and (4) how can we minimize the ethical risks of using placebos? The adoption of the placebo-controlled trial as a standard in the therapeutic development reduced the placebo effect to background noise in a therapeutic signal. Strategies to minimize the placebo effect in clinical trials have been used to obtain positive efficacy results. In more recent years, new study paradigms encouraged a change in the views on placebos and the placebo effect. Alternative study designs and the development of biomarkers for a placebo response permit a better understanding of the contribution of the placebo effect to the results of interventional studies, without minimizing it. In clinical practice, optimizing the placebo effect (and reducing nocebo effects) has the potential to improve care for our patients, but raises ethical challenges. An enhanced patient-physician relationship would be central to any evidence-based intervention used in clinical care to heighten the placebo effect. © 2018 International Parkinson and Movement Disorder Society.