The prevalence of non-contrast CT imaging abnormalities in reversible cerebral vasoconstriction syndrome: A systematic review and meta-analysis.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is a syndrome of recurrent thunderclap headaches and reversible vasoconstriction of the cerebral arteries on neuroimaging within 3 months of onset. Initial non-contrast computed tomography (CT) can reveal abnormalities such as ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage (SAH) can be present in patients with RCVS and may delay diagnosis. AIMS: We conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines. We aimed to estimate the prevalence of imaging abnormalities on initial non-contrast CT head in adult patients with RCVS. DATA SOURCES & ELIGIBILITY CRITERIA: We searched electronic databases including MEDLINE, EMBASE, and the Cochrane Register of Clinical Trials from inception to August 2, 2022. Eligible studies included articles reporting the prevalence of non-contrast CT abnormalities on initial neuroimaging in patients with RCVS, aged 18 and older. Case series, observational studies and clinical trials were included. Data was extracted directly from included papers using a standardized data charting form. RESULTS: The search yielded 722 titles with duplicates removed. Twenty studies that included 379 patients with RCVS met inclusion criteria. We classified non-contrast CT abnormalities as either ischemic stroke, ICH, or SAH. We pooled prevalence data using a random effects model with the inverse-variance weighted method. The most common imaging finding was SAH with a pooled prevalence of 24% (95% CI:17%-33%), followed by ICH at 14% (95% CI:8%-22%), and ischemic stroke at 10% (95% CI:7%-14%). The pooled prevalence of any of these imaging abnormalities on initial non-contrast CT was 31% (95% CI:23%-40%). Risk of bias was moderate to very-high-risk for case-series and low-risk for observational studies. CONCLUSION: Our review demonstrates that one-third of patients with RCVS will have an abnormality on initial non-contrast CT head, including either an ischemic stroke, ICH, or SAH. These findings highlight the diagnostic challenges of RCVS imaging and contribute to our understanding of this disease.

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.

Recurrence of cervical artery dissection: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Cervical artery dissection (CAD) involving the carotid or vertebral arteries is an important cause of stroke in younger patients. The purpose of this systematic review is to assess the risk of recurrent CAD. METHODS: A systematic review and meta-analysis was conducted on studies in which patients experienced radiographically confirmed dissections involving an extracranial segment of the carotid or vertebral artery and in whom CAD recurrence rates were reported. RESULTS: Data were extracted from 29 eligible studies (n = 5898 patients). Analysis of outcomes was performed by pooling incidence rates with random effects models weighting by inverse of variance. The incidence of recurrent CAD was 4% overall (95% confidence interval (CI) = 3-7%), 2% at 1 month (95% CI = 1-5%), and 7% at 1 year in studies with sufficient follow-up (95% CI = 4-13%). The incidence of recurrence associated with ischemic events was 2% (95% CI = 1-3%). CONCLUSIONS: We found low rates of recurrent CAD and even lower rates of recurrence associated with ischemia. Further patient-level data and clinical subgroup analyses would improve the ability to provide patient-level risk stratification.

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.

Network meta-analysis can inform the ethical evaluation of trials that randomise away from standard of care: The case of symptomatic carotid stenosis.

OBJECTIVE: Little guidance exists on the conduct of randomised clinical trials (RCT) that seek to randomise patients away from standard of care. We sought to test the technique of network meta-analysis (NMA) to ascertain best available evidence for the purposes of informing the ethical evaluation of RCTs under these circumstances. We used the example of RCTs for patients with symptomatic, moderate to severe carotid stenosis that seek to compare surgical intervention plus medical therapy (standard of care) versus medical therapy (less than standard of care). STUDY DESIGN AND SETTING: Network meta-analysis of RCTs of adults with symptomatic carotid artery stenosis of 50%-99% who were treated with carotid endarterectomy (CEA), carotid artery stenting (CAS), or medical therapy (MT). The primary outcome was any stroke or death until end of follow-up, and secondary outcome was 30-day risk of ipsilateral stroke/death. RESULTS: We analysed eight studies, with 7187 subjects with symptomatic moderate/severe stenosis (50%-99%). CEA was more efficacious than MT (HR = 0.82, 95% credible intervals [95% CrI] = 0.73-0.92) and CAS (HR 0.73, 95% CrI = 0.62-0.85) for the prevention of any stroke/death. At 30 days, the odds of experiencing an ipsilateral stroke/death were significantly lower in the CEA group compared to both MT (OR = 0.58, 95% CrI = 0.47-0.72) and CAS (OR = 0.68, 95% CrI = 0.55-0.83). CONCLUSION: Our results support the feasibility of using NMA to assess best available evidence to inform the ethical evaluation of RCTs seeking to randomise patients away from standard of care. Our results suggest that a strong argument is required to ethically justify the conduct of RCTs that seek to randomise patients away from standard of care in the setting of symptomatic moderate to severe carotid stenosis.

Ethical evaluation in acute stroke decision-making.

RATIONALE: The evidentiary standards and epistemic models of clinical care, especially those of evidence-based medicine, are dissimilar to those used in philosophy and examination of how the two systems intersect may help clinicians make more informed treatment decisions. AIMS AND OBJECTIVES: This paper examines the use of ethical frameworks in routine clinical decision-making, using the example of acute stroke treatment decisions to demonstrate that ethical evaluation is integral to clinical practice. METHOD: Utilising acute stroke care as a lens through which to examine the phenomenon of ethical evaluation in medical practice, we offer a philosophical analysis of the presence of ethical evaluation in medicine. RESULTS AND CONCLUSION: We find that the medical establishment should embrace ethical evaluation as intrinsic to medical practice and that medical training and treatment guidelines should reflect this reality. Patients deserve clarity and transparency about how physicians make determinations about their treatment, and physicians should be prepared to offer explanations for those decisions.

Study of Rivaroxaban for Cerebral Venous Thrombosis: A Randomized Controlled Feasibility Trial Comparing Anticoagulation With Rivaroxaban to Standard-of-Care in Symptomatic Cerebral Venous Thrombosis.

BACKGROUND: Emerging data suggest that direct oral anticoagulants may be a suitable choice for anticoagulation for cerebral venous thrombosis (CVT). However, conducting high-quality trials in CVT is challenging as it is a rare disease with low rates of adverse outcomes such as major bleeding and functional dependence. To facilitate the design of future CVT trials, SECRET (Study of Rivaroxaban for Cerebral Venous Thrombosis) assessed (1) the feasibility of recruitment, (2) the safety of rivaroxaban compared with standard-of-care anticoagulation, and (3) patient-centered functional outcomes. METHODS: This was a phase II, prospective, open-label blinded-end point 1:1 randomized trial conducted at 12 Canadian centers. Participants were aged ≥18 years, within 14 days of a new diagnosis of symptomatic CVT, and suitable for oral anticoagulation; they were randomized to receive rivaroxaban 20 mg daily, or standard-of-care anticoagulation (warfarin, target international normalized ratio, 2.0-3.0, or low-molecular-weight heparin) for 180 days, with optional extension up to 365 days. Primary outcomes were annual rate of recruitment (feasibility); and a composite of symptomatic intracranial hemorrhage, major extracranial hemorrhage, or mortality at 180 days (safety). Secondary outcomes included recurrent venous thromboembolism, recanalization, clinically relevant nonmajor bleeding, and functional and patient-reported outcomes (modified Rankin Scale, quality of life, headache, mood, fatigue, and cognition) at days 180 and 365. RESULTS: Fifty-five participants were randomized. The rate of recruitment was 21.3 participants/year; 57% of eligible candidates consented. Median age was 48.0 years (interquartile range, 38.5-73.2); 66% were female. There was 1 primary event (symptomatic intracranial hemorrhage), 2 clinically relevant nonmajor bleeding events, and 1 recurrent CVT by day 180, all in the rivaroxaban group. All participants in both arms had at least partial recanalization by day 180. At enrollment, both groups on average reported reduced quality of life, low mood, fatigue, and headache with impaired cognitive performance. All metrics improved markedly by day 180. CONCLUSIONS: Recruitment targets were reached, but many eligible participants declined randomization. There were numerically more bleeding events in patients taking rivaroxaban compared with control, but rates of bleeding and recurrent venous thromboembolism were low overall and in keeping with previous studies. Participants had symptoms affecting their well-being at enrollment but improved over time. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03178864.

Resource allocation decisions under pandemic conditions: A cross-sectional survey of Ontario physicians.

The COVID-19 pandemic has forced physicians to confront difficult choices regarding the allocation of scarce resources, such as ventilators and critical care beds. Developing policies to guide the allocation of such resources has proven challenging. An understanding of physicians' attitudes and beliefs surrounding resource allocation could help inform policymaking. As a replication and extension of a survey of Ottawa physicians conducted in 2020, we surveyed physicians across Ontario, Canada in April 2021. This survey examined physicians' sense of preparedness to allocate critical care resources during the pandemic, attitudes concerning resource allocation policy, and approaches to resource allocation decision-making. Of the 253 responses included for analysis, the majority (67%) of respondents indicated feeling "somewhat" or "a little prepared" to make resource allocation decisions, while 20% indicated feeling "not at all prepared." Most respondents (86%) agreed that a policy to guide resource allocation in the event of scarcity should exist. Physicians overwhelmingly agreed that important factors to consider when making resource allocation decisions included the patient likelihood of survival, frailty index, comorbidities, and cognitive status. Responses from the province-wide survey conducted in 2021 resemble the results of an analogous survey of Ottawa physicians conducted in 2020. Physicians generally felt underprepared to make resource allocation decisions and agreed that official policies should guide such decisions. Identification of factors relevant to resource allocation was remarkably consistent across this sample and that taken in 2020.

What do we talk about when we talk about "equipoise"? Stakeholder interviews assessing the use of equipoise in clinical research ethics.

INTRODUCTION: Equipoise, generally defined as uncertainty about the relative effects of the treatments being compared in a trial, is frequently referenced as an ethical standard for the conduct of randomized clinical trials. However, it seems to be defined in several different ways and may be used differently by different individuals. We explored how clinical researchers, chairs of research ethics boards, and philosophers of science define and reason with this term. METHODS: We completed semi-structured interviews about clinical trial ethics with 15 clinical researchers, 15 research ethics board chairs, and 15 philosophers of science/bioethicists. Each participant was asked a standardized set of 10 questions, 4 of which were specifically about equipoise. All interviews were conducted telephonically and transcribed. Responses were grouped and analysed via a modified grounded theory method. RESULTS: Forty-three respondents defined equipoise in 7 logically distinct ways, and 2 respondents could not explicitly define it. The most common definition, offered by 14 respondents (31%), defined "equipoise" as a disagreement at the level of a community of physicians. There was significant variability in definitions offered between and within groups. When asked how they would "operationalize" equipoise - i.e. check or test for its presence - respondents provided 7 alternatives, the most common being in relation to a literature review (15/45, 33%). The vast majority of respondents (35/45, 78%) felt the concept was helpful, though many acknowledged that the lack of a clear definition or operationalization was problematic. CONCLUSION: There is significant variation in definitions of equipoise offered by respondents, suggesting that parties within groups and between groups may be referring to different concepts when they reference "equipoise". This non-uniformity may impact fairness and transparency and opens the door to potential ethical problems in the evaluation of clinical trials - for instance, a patient may understand equipoise very differently than the researchers enrolling her in a trial, which could cause her agreement to participate to be based upon false premises.

Prevalence of spontaneous recanalisation of complete internal carotid occlusion: protocol for a systematic scoping review.

INTRODUCTION: Although previously thought to be a rare occurrence, spontaneous recanalisation is not uncommon, with a growing number of reports describing this phenomenon. However, the frequency, time course and mechanism of spontaneous recanalisation remain unknown. A better characterisation of these events is essential to ensuring adequate identification and proper future trial design for treatment. OBJECTIVE: To describe the current body of literature around spontaneous recanalisation following internal carotid occlusion. METHODS AND ANALYSIS: With the assistance of an information specialist, we will search MEDLINE, Embase, Cochrane Central Register for Controlled Trials and Web of Science for studies of adults with spontaneous recanalisation or transient occlusion of the internal carotid artery. Two reviewers will independently collect data on included studies pertaining to publication data, study population information, timepoints of initial presentation, recanalisation and subsequent follow-up. ETHICS AND DISSEMINATION: Primary data will not be collected; therefore, formal ethics is not required. The findings of this study will be disseminated through peer-reviewed publications and presentations at academic conferences.

Advance consent for participation in randomised controlled trials for emergency conditions: a scoping review.

OBJECTIVE: Advance consent is a recognised method of obtaining informed consent for participation in research, whereby a potential participant provides consent for future involvement in a study contingent on qualifying for the study's inclusion criteria on a later date. The goal of this study is to map the existing literature on the use of advance consent for enrolment in randomised controlled trials (RCTs) for emergency conditions. DESIGN: Scoping review designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Extension for Scoping Reviews guidelines. DATA SOURCES: We searched electronic databases including MEDLINE, Embase, Web of Science and the Cochrane Register of Clinical Trials from inception to 10 February 2020. ELIGIBILITY CRITERIA: Eligible studies included articles that discussed or employed the use of advance consent for enrolment in RCTs related to emergency conditions. There were no restrictions on the type of eligible study. Data were extracted directly from included papers using a standardised data charting form. We produced a narrative review including article type and authors' dispositions towards advance consent. RESULTS: Our search yielded 1039 titles with duplicates removed. Six articles met inclusion criteria. Three articles discussed the theoretical use of research advance directives in emergency conditions; one article evaluated stakeholders' perceptions of advance consent; and one article described a method for patients to document their preferences for participation in future research. Only one study employed advance consent to enrol participants into a clinical trial for an emergency condition. CONCLUSION: Our review demonstrates that there has been minimal exploration of advance consent for enrolment in RCTs for emergency conditions. Future studies could aim to assess the acceptability of advance consent to participants, along with the feasibility of enrolling research participants using this method of consent. PROTOCOL: The protocol for this scoping review was published a priori.

Spontaneous Recanalization of Internal Carotid Artery Occlusion: A Case Report.

INTRODUCTION: Spontaneous recanalization of an occluded internal carotid artery (ICA) is thought to be unlikely. However, there has been a growing number of reports describing this phenomenon. Despite this, the frequency, time course, and mechanism of spontaneous recanalization remain unknown. In this paper, we describe a patient with a symptomatic recanalization of an occluded left ICA. CASE REPORT: A 70-year-old woman presented with transient speech arrest and right upper extremity weakness related to an occluded ICA. After 3 days, her weakness and aphasia reappeared and worsened transiently. A repeat computed tomography angiography revealed recanalization of the occluded ICA, as well as new ischemic changes in the previously hypoperfused left insular region. This finding changed the management from medical management to revascularization with a stent, after which the patient was discharged home with acetylsalicylic acid and clopidogrel. CONCLUSIONS: Although previously thought to be a rare occurrence, spontaneous recanalization is not uncommon. Further research into this phenomenon as proper identification and characterization of this phenomenon can influence follow-up and management.

Protocol for Deferral of Consent in Acute Stroke Trials.

The challenges of conducting hyperacute stroke research and obtaining informed consent have been increasingly recognized within the stroke research community in recent years. Deferral of consent, in which a patient is enrolled in a trial and then provides consent at some point thereafter, is increasingly used to enroll patients into hyperacute stroke trials in Canada and Europe, although it is not permitted in the United States. Deferral of consent offers several potential advantages-quicker door-to-randomization, increased enrolment, decreased selection bias-but these must be balanced against the risk of enrolling patients against their wishes. We seek to minimize the attendant risks of deferral of consent by offering practical guidance regarding how to conduct acute stroke trials using deferral of consent. Building on existing guidelines and recent experiences with deferral of consent in acute stroke trials, we have developed a protocol for the use of deferral of consent that aims to maximize patient involvement while minimizing ethical and scientific risks.

"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.

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.

How are randomized clinical trials ethically justified? A systematic scoping review and thematic analysis of reasons that ethically justify randomized clinical trials.

OBJECTIVES: We set out to identify and count the types of reasons that are used in contemporary scholarship about the ethical permissibility of randomized trials, with the goal of developing a finer grained taxonomy of reasons than what is currently used by most participants in this literature. Because of its central role in justifying normative conclusions about randomized clinical trials (RCTs), we paid particular attention to both uses of the keyword "equipoise" and to the different concepts associated with it. METHODS: We conducted a scoping review to identify articles that included arguments that were likely to express reasons justifying RCTs. Text excerpts that expressed reasoning about the ethical permissibility of RCTs were extracted from relevant papers, and our data were generated by coding these excerpts using a mixed-methods protocol that fused elements of a grounded analysis and thematic coding. In our study, each theme corresponded to a specific type of reason that was contentful and stable when applied to our corpus of text extracts. RESULTS: Our search, screening, and text extraction process yielded 1,335 unique text excerpts, which then formed the basis of our coding. Although we found that 16 themes were sufficient to saturate this corpus, slightly less than 100% of our excerpts were covered by just 10 themes. We also tracked uses of 16 keywords in the text excerpts to explore whether there was any relationship between the keywords and our themes and found that keywords frequently did not cooccur with the presence of our themes. CONCLUSIONS: Our data and analysis support the conclusion that there is significant diversity in the types of reasons offered to justify RCTs; 10 themes effectively captured all the text excerpts we analyzed, and these themes cannot be reduced to the occurrence of relevant keywords. This result highlights how individuals and organizations may use different reasons to consider randomized trials to be justified and even when they use similar language the concepts they are referencing may not be consistent.

Use of evidence in acute stroke decision-making: Implications for evidence-based medicine.

RATIONALE, AIMS AND OBJECTIVES: Evidence-Based Medicine proposes a prescriptive model of physician decision-making in which 'best evidence' is used to guide best practice. And yet, proponents of EBM acknowledge that EBM fails to offer a systematic theory of physician decision-making. METHODS: In this paper, we explore how physicians from the neurology and emergency medicine communities have responded to an evolving body of evidence surrounding the acute treatment of patients with ischemic stroke. Through analysis of this case study, we argue that EBM's vision of evidence-based medical decision-making fails to appreciate a process that we have termed epistemic evaluation. RESULTS AND CONCLUSIONS: Physicians are required to interpret and apply any knowledge-even what EBM would term 'best evidence'-in light of their own knowledge, background and experience. This is consequential for EBM as understanding what physicians do and why they do it would appear to be essential to achieving optimal practice in accordance with best evidence.

Many trials of hydroxychloroquine for SARS-CoV-2 were redundant and potentially unethical: an analysis of the NIH clinical trials registry.

OBJECTIVE: We sought to map the landscape of trials investigating hydroxychloroquine (HCQ) for SARS-CoV-2 in order to draw conclusions about how clinical trials have been conducted in the pandemic environment and offer potential regulatory recommendations. STUDY DESIGN AND SETTING: We identified and captured data related to registered studies using HCQ to treat SARS-CoV-2 registered with the publicly available National Institutes of Health (NIH) Clinical Trials Registry between February and November 2020. RESULTS: Between February and November 2020, 206 studies investigating HCQ in SARS-CoV-2 were registered with the NIH Clinical Trials Registry. As of November 2020, 135 studies were listed as ongoing, 22 have been completed, and 46 are either suspended or have been terminated. Reasons for suspension or termination included difficulties with patient recruitment (n = 9), emerging evidence showing a lack of benefit of HCQ (n = 7), and recommendations by regulatory boards to discontinue (n = 10). CONCLUSION: Many clinical trials of HCQ were launched in the first months of the pandemic, and a significant proportion of them remained active as of November 2020. The medical community appears to have responded very quickly to political interest in HCQ, while responding much more slowly to the evolving medical evidence of its lack of efficacy.

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.