Synthetic data in cancer and cerebrovascular disease research: A novel approach to big data.

OBJECTIVES: Synthetic datasets are artificially manufactured based on real health systems data but do not contain real patient information. We sought to validate the use of synthetic data in stroke and cancer research by conducting a comparison study of cancer patients with ischemic stroke to non-cancer patients with ischemic stroke. DESIGN: retrospective cohort study. SETTING: We used synthetic data generated by MDClone and compared it to its original source data (i.e. real patient data from the Ottawa Hospital Data Warehouse). OUTCOME MEASURES: We compared key differences in demographics, treatment characteristics, length of stay, and costs between cancer patients with ischemic stroke and non-cancer patients with ischemic stroke. We used a binary, multivariable logistic regression model to identify risk factors for recurrent stroke in the cancer population. RESULTS: Using synthetic data, we found cancer patients with ischemic stroke had a lower prevalence of hypertension (52.0% in the cancer cohort vs 57.7% in the non-cancer cohort, p<0.0001), and a higher prevalence of chronic obstructive pulmonary disease (COPD: 8.5% vs 4.7%, p<0.0001), prior ischemic stroke (1.7% vs 0.1%, p<0.001), and prior venous thromboembolism (VTE: 8.2% vs 1.5%, p<0.0001). They also had a longer length of stay (8 days [IQR 3-16] vs 6 days [IQR 3-13], p = 0.011), and higher costs associated with their stroke encounters: $11,498 (IQR $4,440 -$20,668) in the cancer cohort vs $8,084 (IQR $3,947 -$16,706) in the non-cancer cohort (p = 0.0061). A multivariable logistic regression model identified 5 predictors for recurrent ischemic stroke in the cancer cohort using synthetic data; 3 of the same predictors identified using real patient data with similar effect measures. Summary statistics between synthetic and original datasets did not significantly differ, other than slight differences in the distributions of frequencies for numeric data. CONCLUSION: We demonstrated the utility of synthetic data in stroke and cancer research and provided key differences between cancer and non-cancer patients with ischemic stroke. Synthetic data is a powerful tool that can allow researchers to easily explore hypothesis generation, enable data sharing without privacy breaches, and ensure broad access to big data in a rapid, safe, and reliable fashion.

The Canadian Study of Arterial Inflammation in Patients with Diabetes and Recent Vascular Events, Evaluation of Colchicine Effectiveness (CADENCE): protocol for a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Inflammation is a key mediator in the development and progression of the atherosclerotic disease process as well as its resultant complications, like myocardial infarction (MI), stroke and cardiovascular (CV) death, and is emerging as a novel treatment target. Trials involving anti-inflammatory medications have demonstrated outcome benefit in patients with known CV disease. In this regard, colchicine appears to hold great promise. However, there are potential drawbacks to colchicine use, as some studies have identified an increased risk of infection, and a non-significant trend for increased all-cause mortality. Thus, a more thorough understanding of the underlying mechanism of action of colchicine is needed to enable a better patient selection for this novel CV therapy. OBJECTIVE: The primary objective of the Canadian Study of Arterial Inflammation in Patients with Diabetes and Recent Vascular Events, Evaluation of Colchicine Effectiveness (CADENCE) trial is to assess the effect of colchicine on vascular inflammation in the carotid arteries and ascending aorta measured with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in patients with type 2 diabetes mellitus (T2DM) or pre-diabetes who have experienced a recent vascular event (acute coronary syndrome (ACS)/MI, transient ischaemic attack (TIA) or stroke). Secondary objectives include determining colchicine's effect on inflammatory biomarkers (high-sensitivity C reactive protein (hs-CRP) and interleukin-6 (IL-6)). Additionally, we will assess if baseline inflammation imaging or biomarkers are associated with a treatment response to colchicine determined by imaging. Exploratory objectives will look at: (1) the difference in the inflammatory response to colchicine in patients with coronary events compared with patients with cerebral events; (2) the difference in the inflammatory response to colchicine in different vascular beds; (3) the relationship of FDG-PET imaging markers with serum biomarkers and (4) assessment of quality-of-life changes. METHODS AND DESIGN: CADENCE is a multicentre, prospective, randomised, double-blinded, placebo-controlled study to determine the effect of colchicine on arterial inflammation as assessed with imaging and circulatory biomarkers, specifically carotid arteries and aortic FDG uptake as well as hs-CRP and IL-6 among others. Patients with T2DM or pre-diabetes who have recently experienced a CV event (within 30-120 days after an ACS (ie, ST-elevation MI (STEMI) or non-STEMI)) or TIA/stroke with documented large vessel atherosclerotic disease will be randomised to treatment with either colchicine 0.6 mg oral daily or placebo. Participants will undergo baseline clinical evaluation including EQ5D assessment, blood work for inflammatory markers and FDG PET/CT scan of the ascending aorta and left and right carotid arteries. Patients will undergo treatment for 6 months and have repeat clinical evaluation including EQ5D assessment, blood work for inflammatory markers and FDG PET/CT scan at the conclusion of the study. The primary outcome will be the change in the maximum target to background ratio (TBRmax) in the ascending aorta (or carotid arteries) from baseline to follow-up on FDG PET/CT imaging. DISCUSSION: Colchicine is an exciting potential new therapy for CV risk reduction. However, its use is associated with side effects and greater understanding of its underlying mechanism of action is needed. Importantly, the current study will determine whether its anti-inflammatory action is an indirect systemic effect, or a more local plaque action that decreases inflammation. The results will also help identify patients who will benefit most from such therapy. TRIAL REGISTRATION NUMBER: NCT04181996.

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 PCC on Thrombin Generation among Patients on Factor Xa Inhibitors with Major Bleeding or Needing Urgent Surgery (GAUGE): Design and Rationale.

Background Direct factor Xa inhibitors (FXaIs) account for most oral anticoagulant use and FXaI-associated bleeding events are common. Clinicians have variable national and regional access to specific FXaI reversal agents such as andexanet alfa. Many centers have adopted the use of prothrombin complex concentrates (PCCs) as hemostatic therapy for FXaI-associated major bleeding events. PCC does not impact circulating FXaI levels and its mechanism of action to achieve hemostasis in FXaI-associated bleeding is uncertain. While PCC increases quantitative thrombin generation assay (TGA) parameters, it does not correct FXaI-altered thrombin generation kinetics, nor does it normalize thrombin generation. Clinical data supporting the use of PCC are based on cohort studies reporting clinical hemostatic efficacy, which is difficult to measure. The benefits of PCC for FXaI-associated bleeding beyond supportive care are uncertain. Objective GAUGE is a prospective observational study designed to measure the effects of four-factor PCC administration (Octaplex) on TGA parameters among patients with FXaI-associated bleeding or needing urgent surgery. Methods Laboratory outcomes will include the mean paired change in TGA parameters from pre- to post-PCC administration and the proportion of participants whose post-PCC TGA values fall within a defined reference range. Clinical outcomes will include hemostatic efficacy, thromboembolic complications, and all-cause death at 30 days post-PCC. Conclusion Development of a viable and universally accessible FXaI bleed management strategy is crucial. GAUGE will provide in vivo data on the effects of PCC among patients with FXaI-associated bleeding.

Effect modification of age and hypertension on cancer and prevalence of self-reported stroke - A cross-sectional study.

The objective of this study was to examine the effect modification of age on the relationship between cancer and prevalence of self-reported stroke. We used cross-sectional data from the 2015-2016 iteration of the Canadian Community Health Survey. A multivariable logistic regression model was used to assess the association between cancer and self-reported stroke. Covariates were assessed for effect modification using the maximum likelihood estimation method. We analyzed 86,809 subjects; the prevalence of self-reported stroke was 1.11%. The odds ratio for the association between cancer and self-reported stroke was 1.26 (95% CI 0.98-1.61) after adjusting for age, sex, dyslipidemia, hypertension, diabetes, heart disease, education, and household income. Age and hypertension were found to be effect modifiers, and the association between cancer and self-reported stroke was stronger in younger adults and in those without hypertension. These results suggest that cancer-associated strokes may have unique underlying mechanisms compared to conventional strokes.

Aetiology of extracranial carotid free-floating thrombus in a prospective multicentre cohort.

BACKGROUND: Carotid free-floating thrombi (FFT) in patients with acute transient ischaemic attack (TIA)/stroke have a high risk of early recurrent stroke. Management depends on aetiology, which can include local plaque rupture, dissection, coagulopathy, malignancy and cardioembolism. Our objectives were to classify the underlying aetiology of FFT and to estimate the proportion of patients with underlying stenosis requiring revascularisation. METHODS: We prospectively enrolled consecutive patients presenting to three comprehensive stroke centres with acute TIA/stroke and ipsilateral internal carotid artery FFT. The aetiology of FFT was classified as: carotid atherosclerotic disease, carotid dissection, cardioembolism, both carotid atherosclerosis and cardioembolism, or embolic stroke of uncertain source (ESUS). Patients with carotid atherosclerosis were further subclassified as having ≥50% or <50% stenosis. RESULTS: We enrolled 83 patients with confirmed FFT. Aetiological assessments revealed 66/83 (79.5%) had carotid atherosclerotic plaque, 4/83 (4.8%) had a carotid dissection, 10/83 (12%) had both atrial fibrillation and carotid atherosclerotic plaque and 3/83 (3.6%) were classified as ESUS. Of the 76 patients with atherosclerotic plaque (including those with atrial fibrillation), 40 (52.6%) had ≥50% ipsilateral stenosis. CONCLUSIONS: The majority of symptomatic carotid artery FFT are likely caused by local plaque rupture, more than half of which are associated with moderate to severe carotid stenosis requiring revascularisation. However, a significant number of FFTs are caused by non-atherosclerotic mechanisms warranting additional investigations.

Incidence of stroke in the first year after diagnosis of cancer-A systematic review and meta-analysis.

Background: Patients newly diagnosed with cancer represent a population at highest risk for stroke. The objective of this systematic review and meta-analysis was to estimate the incidence of stroke in the first year following a new diagnosis of cancer. Methods: We searched MEDLINE and EMBASE from January 1980 to June 2021 for observational studies that enrolled adults with a new diagnosis of all cancers excluding non-melanoma skin cancer, and that reported the incidence of stroke at 1 year. PRISMA guidelines for meta-analyses were followed. Two reviewers independently extracted data and appraised risk of bias. We used the Dersimonian and Laird random effects method to pool cumulative incidences after logit transformation, and reported pooled proportions as percentages. Statistical heterogeneity was assessed using the I 2 statistic. Results: A total of 12,083 studies were screened; 41 studies were included for analysis. Data from 2,552,121 subjects with cancer were analyzed. The cumulative incidence of total stroke at 1 year was 1.4% (95% CI 0.9-2.2%), while the pooled incidence of ischemic stroke was 1.3% (95% CI 1.0-1.8%) and 0.3% (95% CI 0.1-0.9%) for spontaneous intracerebral hemorrhage (ICH), with consistently high statistical heterogeneity (>99% I 2). Conclusion: The estimated incidence of stroke during the first year after a new diagnosis of cancer is 1.4%, with a higher risk for ischemic stroke than ICH. Cancer patients should be educated on the risk of stroke at the time of diagnosis. Future studies should evaluate optimal primary prevention strategies in this high-risk group of patients. Systematic review registration: https://osf.io/ucwy9/.

Cancer and stroke: What do we know and where do we go?

Cancer is an increasingly recognized cause for ischemic stroke, with recent acknowledgement of cancer-related stroke as an emerging stroke subtype with unique pathophysiologic mechanisms. In addition, cancer-related stroke may differ from stroke in the general population as cancer patients may not receive guideline-recommended stroke care, and the occurrence of stroke may also preclude patients from receiving optimal cancer treatments. Due to the high degree of morbidity and mortality associated with both conditions, understanding the relationship between stroke and cancer is crucial. In this narrative review, we discuss the association between cancer and stroke, the unique pathophysiologic mechanisms underlying this phenomenon, treatment options including acute reperfusion therapies and secondary prevention strategies, compare outcomes between cancer-related stroke and stroke in the general population, and review new and emerging evidence in this field.

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.

Canadian Stroke Best Practice Recommendations: Secondary Prevention of Stroke Update 2020.

The 2020 update of the Canadian Stroke Best Practice Recommendations (CSBPR) for the Secondary Prevention of Stroke includes current evidence-based recommendations and expert opinions intended for use by clinicians across a broad range of settings. They provide guidance for the prevention of ischemic stroke recurrence through the identification and management of modifiable vascular risk factors. Recommendations address triage, diagnostic testing, lifestyle behaviors, vaping, hypertension, hyperlipidemia, diabetes, atrial fibrillation, other cardiac conditions, antiplatelet and anticoagulant therapies, and carotid and vertebral artery disease. This update of the previous 2017 guideline contains several new or revised recommendations. Recommendations regarding triage and initial assessment of acute transient ischemic attack (TIA) and minor stroke have been simplified, and selected aspects of the etiological stroke workup are revised. Updated treatment recommendations based on new evidence have been made for dual antiplatelet therapy for TIA and minor stroke; anticoagulant therapy for atrial fibrillation; embolic strokes of undetermined source; low-density lipoprotein lowering; hypertriglyceridemia; diabetes treatment; and patent foramen ovale management. A new section has been added to provide practical guidance regarding temporary interruption of antithrombotic therapy for surgical procedures. Cancer-associated ischemic stroke is addressed. A section on virtual care delivery of secondary stroke prevention services in included to highlight a shifting paradigm of care delivery made more urgent by the global pandemic. In addition, where appropriate, sex differences as they pertain to treatments have been addressed. The CSBPR include supporting materials such as implementation resources to facilitate the adoption of evidence into practice and performance measures to enable monitoring of uptake and effectiveness of recommendations.

Incidence of stroke in the first year after diagnosis of cancer-A protocol for systematic review and meta-analysis.

INTRODUCTION: There is an increased risk of stroke in patients with cancer-this risk is particularly heightened around the time of cancer diagnosis, although no studies have systematically quantified this risk in the literature. Patients newly diagnosed with cancer without prior stroke represent a highly susceptible population in whom there is a window of opportunity to study and implement primary prevention strategies. Therefore, the objective of this systematic review and meta-analysis is to identify the cumulative incidence of ischemic and hemorrhagic strokes during the first year after a diagnosis of cancer. METHODS AND ANALYSIS: MEDLINE, EMBASE, and PubMed will be searched with the assistance from a medical information specialist, from 1980 until present. Eligible studies will include observational studies that have enrolled adult patients newly diagnosed with cancer and report outcomes of stroke during the first year of cancer diagnosis. We will exclude all randomized and non-randomized interventional studies. Data on participant characteristics, study design, baseline characteristics, and outcome characteristics will be extracted. Study quality will be assessed using the Newcastle-Ottawa Scale for cohort studies, and heterogeneity will be assessed using the I2 statistic. Pooled cumulative incidence will be calculated for ischemic and hemorrhagic strokes separately using a random-effects model. ETHICS AND DISSEMINATION: No formal research ethics approval is necessary as primary data collection will not be done. We will disseminate our findings through scientific conference presentations, peer-reviewed publications, and social media/the press. The findings from this review will inform clinicians and patients regarding the risk of stroke in patients newly diagnosed with cancer by quantifying the cumulative incidence of each subtype of stroke during the first year after a diagnosis of cancer. This represents a window of opportunity to implement prevention strategies in a susceptible population. REGISTRATION ID WITH OPEN SCIENCE FRAMEWORK: osf.io/ucwy9.

Neuroimaging of Acute Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) accounts for 10% to 20% of all strokes worldwide and is associated with high morbidity and mortality. Neuroimaging is clinically important for the rapid diagnosis of ICH and underlying etiologies, but also for identification of ICH expansion, often as-sociated with an increased risk for poor outcome. In this context, rapid assessment of early hema-toma expansion risk is both an opportunity for therapeutic intervention and a potential hazard for hematoma evacuation surgery. In this review, we provide an overview of the current literature surrounding the use of multimodal neuroimaging of ICH for etiological diagnosis, prediction of early hematoma expansion, and prognostication of neurological outcome. Specifically, we discuss standard imaging using computed tomography, the value of different vascular imaging modalities to identify underlying causes and present recent advances in magnetic resonance imaging and computed tomography perfusion.

Clinical Utility and Cost of Inpatient Transthoracic Echocardiography Following Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: It is unclear whether it is clinically necessary or cost-effective to routinely obtain a transthoracic echocardiogram (TTE) during inpatient admission for ischemic stroke. METHODS: We assessed consecutive patients presenting with acute ischemic stroke at a comprehensive stroke center from 2015 to 2017 who underwent TTE. We assessed for findings on TTE that would warrant urgent intervention including cardiac thrombus, atrial myxoma, mitral stenosis, valve vegetation, valve dysfunction requiring surgery, and low ejection fraction. Subsequent changes in management included changes in anticoagulation, antibiotics, or valve surgery. We calculated in-hospital resource utilization and associated costs for inpatient TTE using individual direct cost details within a case-costing system. RESULTS: Of 695 patients admitted with acute ischemic stroke, 516 (74%) had a TTE and were included in our analysis. TTE findings were potentially clinically significant in 30 patients (5.8%) and changed management in 17 patients (3.3%). Inpatient admission was prolonged to expedite TTE in 24 patients, while TTE occurred after discharge in 76 patients. After correcting for the cost of TTE, the mean difference in cost to prolong an admission for TTE was $555.52 (USD), or $16 832 per change in management. CONCLUSIONS: Given the low clinical utility of inpatient TTE after acute ischemic stroke and the costs associated with prolonging admission, discharge from hospital should not be delayed solely to obtain TTE.

Physician preparedness for resource allocation decisions under pandemic conditions: A cross-sectional survey of Canadian physicians, April 2020.

BACKGROUND: Under the pandemic conditions created by the novel coronavirus of 2019 (COVID-19), physicians have faced difficult choices allocating scarce resources, including but not limited to critical care beds and ventilators. Past experiences with severe acute respiratory syndrome (SARS) and current reports suggest that making these decisions carries a heavy emotional toll for physicians around the world. We sought to explore Canadian physicians' preparedness and attitudes regarding resource allocation decisions. METHODS: From April 3 to April 13, 2020, we conducted an 8-question online survey of physicians practicing in the region of Ottawa, Ontario, Canada, organized around 4 themes: physician preparedness for resource rationing, physician preparedness to offer palliative care, attitudes towards resource allocation policy, and approaches to resource allocation decision-making. RESULTS: We collected 219 responses, of which 165 were used for analysis. The majority (78%) of respondents felt "somewhat" or "a little prepared" to make resource allocation decisions, and 13% felt "not at all prepared." A majority of respondents (63%) expected the provision of palliative care to be "very" or "somewhat difficult." Most respondents (83%) either strongly or somewhat agreed that there should be policy to guide resource allocation. Physicians overwhelmingly agreed on certain factors that would be important in resource allocation, including whether patients were likely to survive, and whether they had dementia and other significant comorbidities. Respondents generally did not feel confident that they would have the social support they needed at the time of making resource allocation decisions. INTERPRETATION: This rapidly implemented survey suggests that a sample of Canadian physicians feel underprepared to make resource allocation decisions, and desire both more emotional support and clear, transparent, evidence-based policy.

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.

Activated prothrombin complex concentrates for direct oral anticoagulant-associated bleeding or urgent surgery: Hemostatic and thrombotic outcomes.

INTRODUCTION: Studies evaluating the use of activated prothrombin complex concentrates (aPCCs) for DOAC-associated bleeding are sparse. MATERIALS AND METHODS: We conducted a retrospective study of patients receiving aPCC for DOAC-associated bleeding or for pre-operative optimization of hemostasis prior to urgent surgery. The primary efficacy outcome was hemostatic efficacy, the primary safety outcome was the 30-day thromboembolic complication rate. RESULTS: Eighty-two patients were included in the analysis; 14 patients on dabigatran, 39 patients on rivaroxaban and 29 patients on apixaban. Fifty-four patients received aPCC for major bleeding and 28 patients prior to urgent surgery. Mean aPCC dosing was 2974 IU (SD ± 857 IU). Hemostasis was deemed effective by ISTH criteria in 50% of cases and "Good" or "Moderate" by Sarode criteria in 45.2% and 14.3% of cases, respectively. Surgical hemostasis was rated as "Normal" in 84% of cases pre-operative administration. Median pre-aPCC INR was 1.6 (IQR 0.5) and median post-aPCC INR was 1.2 (IQR 0.2) (p < 0.00001). Median pre-aPCC aPTT was 36 s (IQR 12.8), median post-aPCC aPTT was 29 s (IQR 9.8) (p = 0.0001). The 30-day thromboembolic event rate was 6.1%. CONCLUSION: Further study is needed to characterize the hemostatic effects and thromboembolic risk of aPCC among patients with DOAC-associated bleeding or for attempted normalization of hemostasis prior to urgent surgery.

Early vascular imaging and key system strategies expedite carotid revascularization after transient ischemic attack and stroke.

BACKGROUND: International guidelines recommend carotid revascularization within 14 days for patients with a symptomatic transient ischemic attack (TIA) or stroke event. However, significant delays in care persist, with only 9% of outpatients and 36% of inpatients in Ontario meeting this target. The study objective was to explore the influence of health system factors on carotid revascularization timelines. METHODS: We conducted a retrospective chart review of all symptomatic TIA/stroke patients undergoing carotid endarterectomy or stenting at The Ottawa Hospital (2015-2016). The primary outcome was time from TIA/stroke to carotid revascularization. Health system variables of interest included location and timing of patient presentation, timelines to vascular imaging, and same-day collaboration between key services such as emergency, neurology, and surgery. Descriptive statistics and univariate analysis were used to determine statistically significant differences between groups. RESULTS: A total of 228 records met the inclusion criteria. The median time from TIA/stroke to carotid revascularization was 10 days, with 58% of patients meeting the 14-day guideline. Prompt patient presentation to emergency demonstrated significantly shorter timelines to surgery (7 days; P < .001). Early vascular imaging was strongly correlated with early revascularization (4-5 days; P < .001). In addition, collaboration from two or more care services enhanced timelines to surgery ranging from 2.0 to 6.5 days (P < .001-.008). CONCLUSIONS: Early/emergency response to stroke symptoms was pivotal in achieving best practice recommendations for rapid carotid revascularization, emphasizing the need for ongoing public awareness. Emergency and ambulatory strategies to facilitate urgent vascular imaging, as well as mechanisms for same-day communication between teams require optimization to promote early revascularization.

What are potential barriers and enablers to patient and physician participation in Canadian cell therapy trials for stroke? A stakeholder interview study.

OBJECTIVES: Early phase cell therapy trials face many barriers to successful, timely completion. To optimise the conduct of a planned clinical trial of mesenchymal stem cell (MSC) therapy for chronic stroke, we sought patient and physician views on possible barriers and enablers that may influence their participation. DESIGN: Semistructured interview study. SETTING: Patients were recruited from three rehabilitation centres in Ontario, Canada; physicians were recruited from across Canada through snowball sampling. PARTICIPANTS: Thirteen chronic stroke patients (patients who had experienced a stroke at least 3 months prior; 10 male, 3 female) and 15 physicians (stroke physiatrists; 9 male, 6 female) participated in our interview study. Data adequacy was reached after 13 patient interviews and 13 physician interviews. METHODS: Interview guides and directed content analysis were based on the Theoretical Domains Framework (TDF). Interviews were coded, and relevant themes were identified. RESULTS: Most patients were optimistic about participating in an MSC therapy clinical trial, and many expressed interest in participating, even if it was a randomised controlled trial with the possibility of being allocated to a placebo group. However, the method of administration of cells (intravascular preferred to intracerebral) and goal of the trial (efficacy preferred to safety) may influence their intention to participate. All physicians expressed interest in screening for the trial, though many stated they were less motivated to contribute to a safety trial. Physicians also identified several time-related barriers and the need for resources to ensure feasibility. CONCLUSIONS: This novel application of the TDF helped identify key potential barriers and enablers prior to conducting a clinical trial of MSC therapy for stroke. This will be used to refine the design and conduct of our trial. A similar approach may be adopted by other investigators considering early phase cell therapy trials.

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

From the Lab to Patients: a Systematic Review and Meta-Analysis of Mesenchymal Stem Cell Therapy for Stroke.

There may be the potential to improve stroke recovery with mesenchymal stem cells (MSCs); however, questions about the efficacy and safety of this treatment remain. To address these issues and inform future studies, we performed a preclinical and clinical systematic review of MSC therapy for subacute and chronic ischemic stroke. MEDLINE, Embase, the Cochrane Register of Controlled Trials, and PubMed were searched. For the clinical review, interventional and observational studies of MSC therapy in ischemic stroke patients were included. For the preclinical review, interventional studies of MSC therapy using in vivo animal models of subacute or chronic stroke were included. Measures of safety and efficacy were assessed. Eleven clinical and 76 preclinical studies were included. Preclinically, MSC therapy was associated with significant benefits for multiple measures of motor and neurological function. Clinically, MSC therapy appeared to be safe, with no increase in adverse events reported (with the exception of self-limited fever immediately following injection). However, the efficacy of treatment was less apparent, with significant heterogeneity in both study design and effect size being observed. Additionally, in the only randomized phase II study to date, efficacy of MSC therapy was not observed. Preclinically, MSC therapy demonstrated considerable efficacy. Although MSC therapy demonstrated safety in the clinical setting, efficacy has yet to be determined. Future studies will need to address the discordance in the continuity of evidence as MSC therapy has been translated from "bench-to-bedside".