Highlights
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Intraluminal thrombus in the setting of acutely symptomatic carotid artery stenosis increases physician enthusiasm for anticoagulation.
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There remains equipoise in the management of intraluminal thrombus in acutely symptomatic carotid artery stenosis.
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Further work is needed to determine the natural history of carotid intraluminal thrombus before conducting trials in the area.
Introduction
Acutely symptomatic carotid stenosis, often referred to as a “hot carotid,” Reference Ganesh, Beland and Jewett1,Reference Ganesh, Wong and Menon2 describes the situation where a patient presents within hours to days of a new stroke or Transient ischemic attack (TIA) related to carotid artery stenosis (≥50% stenosis). Reference Ganesh, Beland and Jewett1,Reference Ganesh, Wong and Menon2 This etiology of stroke represents a high risk of recurrent events Reference Lovett, Coull and Rothwell3–Reference Karlsson, Kangefjärd and Hermansson7 and is a condition with much equipoise in terms of management. Reference Ganesh, Beland and Jewett1,Reference Ganesh, Wong and Menon2 The hot carotid is further complicated by an intraluminal thrombus (ILT) in as many as 3.1% of cases, the majority of which are due to atherosclerotic plaque rupture. Reference Menon, Singh, Al-Khataami, Demchuk and Goyal8–Reference Dowlatshahi, Lum and Menon11 Carotid ILT, also referred to as a carotid free-floating thrombus, Reference Bhatti, Leon and Labropoulos9,Reference Fridman, Lownie and Mandzia12 is generally defined as a thrombus arising from the carotid arterial wall with circumferential blood flow at its distal aspect. Reference Menon, Singh, Al-Khataami, Demchuk and Goyal8,Reference Bhatti, Leon and Labropoulos9,Reference Fridman, Lownie and Mandzia12
The presence of an ILT in the hot carotid is thought to increase the risk of short-term recurrent ischemia while on medical therapy Reference Bhatti, Leon and Labropoulos9,Reference Vellimana, Kadkhodayan and Rich10,Reference Fridman, Lownie and Mandzia12 though there is an absence of high-quality evidence to support this claim. In addition to concern regarding medical therapy of ILT in the hot carotid, observational studies and post hoc analysis from the NASCET trial have suggested that the presence of an ILT increases the risk of periprocedural stroke and mortality with carotid revascularization. Reference Buchan, Gates, Pelz and Barnett13,Reference Ferguson, Eliasziw and Barr14 These studies however are outdated, do not reflect current procedural techniques, were done before the widespread use of dual antiplatelets in stroke and did not consistently report preoperative anticoagulation in the presence of ILT. Reference Chaturvedi15 We suspect that significant equipoise exists regarding the management of ILT in the hot carotid. In this study, we sought to better understand how physicians navigate this uncertainty, specifically as it relates to anti-thrombotic management and the timing of carotid revascularization as well as exploring considerations regarding future study in the area.
The objective of this study was to use mixed methods to (1) map the varying practice patterns of international experts in carotid ILT management, (2) explore the experiences and practical considerations that inform their management and uncertainties encountered in the process and (3) understand clinician perspectives regarding future trials in patients with carotid ILT. The results of this study will encourage critical reflection of individual and institutional practice patterns as well as informing the development and design of future trials on carotid ILT.
Methods
This was a mixed-methods study of physician approaches to the management of the hot carotid using survey and interview-based methods. The quantitative data included here are from a worldwide (English language) case-based survey of physicians conducted through the “Practice Current” section of Neurology: Clinical Practice, and the methodology has been previously reported. Reference Ganesh, Bartolini and Singh16 This survey was part of a larger study of acutely symptomatic carotid stenosis (hot carotid), and descriptive results have been previously published. Reference Ganesh, Bartolini and Singh16
The questions in the survey were based on a representative case (included in Supplement 1) and were oriented around medical management and revascularization decisions in acutely symptomatic carotid stenosis with and without an associated ILT. The survey was open between September 6, 2018, and November 10, 2019. Demographic questions in the survey included years in practice and practice location (country). Additionally, the preferred method of carotid revascularization in hot carotid cases (endarterectomy or stenting) was asked though not specifically in the context of ILT.
IBM SPSS Statistics (Version 26) was used to analyze the data. Univariable analysis of the use of anticoagulation, dual antiplatelet therapy (DAPT) or single antiplatelet therapy (SAPT) between the ILT and non-ILT cases was done via a Fisher exact test, and the cutoff for significance was p < 0.05. Multivariable logistic regressions were also completed to adjust for confounding factors (region of practice, years in practice and preferred revascularization procedure (CEA or CAS). The preferred revascularization technique was controlled for as it is possible that procedural nuances and differences in timing between techniques may influence the selection of antithrombotic regimens; however, as a sensitivity analysis, we also examined the regression results when not controlling for this variable. Results were expressed as adjusted odds ratios and 95% confidence intervals were determined.
The interview-based component of the study used a qualitative descriptive methodology Reference Sandelowski17 to explore the decision-making approaches, opinions and attitudes of physicians regarding the management of patients with acutely symptomatic carotid stenosis. The methods of this study as well as the results of these interviews regarding general imaging, medical management and revascularization in acutely symptomatic carotid stenosis without ILT have been reported elsewhere. Reference Ganesh, Beland and Jewett1,Reference Ganesh, Beland and Jewett18 The interview and qualitative methodology are outlined in brief below and further details can be found in previous publications related to this study. Reference Ganesh, Beland and Jewett1,Reference Ganesh, Beland and Jewett18 Interviews were conducted entirely in English and took place between May 2018 and June 2021.
Participants were recruited using a snowball sampling strategy with purposive sampling. Reference Parker, Scott and Geddes19–Reference Naderifar, Goli and Ghaljaie21 Participants were sought to ensure sampling of different specialties (neurology and/or internal medicine/geriatrics [for the United Kingdom alone where internists/geriatricians frequently lead stroke teams], neurovascular surgery, interventional neuroradiology) and geographic region (United States of America [USA]/Canada, Latin America or Caribbean, Europe, Africa, Asia and Oceania).
Interviews were conducted until saturation of themes was reached. Reference Sandelowski17,Reference Campbell, Greenwood and Prior22–Reference Malterud, Siersma and Guassora25 Snowball sampling was used to recruit interview participants. Reference Naderifar, Goli and Ghaljaie21 Semi-structured interviews were conducted by neurology residents/fellows with an interest in stroke neurology. Interviewers (A.G., G.J. and R.J.S.) were trained in qualitative interviewing by D.J.T.C. (MD/PhD with extensive qualitative methodology experience), and a topic-specific interview guide was used to ensure consistency of interview style and structure. Interview guides were developed based on principles of “grounded theory” Reference Chapman, Hadfield and Chapman26,Reference Chun Tie, Birks and Francis27 and were intended to encourage interviewees to think about their approaches, the challenges they experience and factors they consider in decision-making when caring for a patient with a hot carotid. The guide was pilot tested before use in the study (included in Supplement 1).
Interviews were digitally recorded and transcribed verbatim by research assistants. Transcripts were imported into NVivo 12 Plus Qualitative Data Analysis software to facilitate analysis and thematic coding by two reviewers (A.G. and B.B.). Opinions relating to ILT in the hot carotid were identified and categorized based on conventional qualitative analysis methods. Reference Hsieh and Shannon28 All interviews were coded by two reviewers, and the team met to review coding and coding strategy and sought to achieve consensus in coding. To synthesize themes from a large number of codes, authors A.G. and B.B. employed the concept of “Grounded Theory” and conventional qualitative content analysis, both of which are recognized methods in qualitative research used to construct theory from systematically gathered qualitative data. Reference Chun Tie, Birks and Francis27–Reference Noble and Mitchell29
The results of the qualitative portion of this study are reported in accordance with the consolidated criteria for reporting qualitative research checklist (Supplement 2). Reference Tong, Sainsbury and Craig30
Results
Quantitative data
Responses from 668 unique participants were recorded over the course of the survey, of which 561 (84.0%) completed the survey in full, though completion of all survey questions was not required. Demographic characteristics of the survey have been previously published Reference Ganesh, Beland and Jewett1 and are included in Supplement 3 (Table 1).
Table 1. Survey respondents’ choice of antithrombotic management with and without associated ILT. Chi-squared test using Fisher’s exact methods reported as P-values
ILT = intraluminal thrombus; SAPT = single antiplatelet therapy; DAPT = dual antiplatelet therapy.
In the case presented in the survey of a hot carotid without ILT, 311 of 621 (50.1%) participants indicated they would use SAPT, 238 of 621 (38.3%) would use DAPT and only 72 of 621 (11.6%) would use anticoagulation (Table 1). In the context of ILT, 399 of 611 (66.0%) would use anticoagulation, and only 97 of 612 (15.0%) and 120 of 612 (19.1%) would use DAPT or SAPT, respectively (Table 1). The presence of ILT significantly reduced the likelihood of participants using SAPT or DAPT for their patient (p < 0.001) and significantly increased the likelihood of using a regimen containing anticoagulation agents (p < 0.001) (Table 1).
The most common antithrombotic regimen selected by respondents in the case of ILT was heparin monotherapy (27.8%), followed by low-molecular-weight heparin monotherapy (16.1%) (Figure 1, Table 2). To control for confounding factors, a multivariable logistic regression was performed examining factors associated with preference for anticoagulation or SAPT in the case of ILT. When controlling for years in practice and preferred method of revascularization, we found that respondents practicing in Europe (aOR 0.44 [95% CI 0.27–0.71]) or Central/South America (aOR 0.34 [95% CI 0.19–0.60]) were less likely to choose a regimen containing anticoagulation for a patient with ILT (Table 3). In the multivariable regression, we also found that respondents from Europe (aOR 3.04 [95% CI 1.68–5.50]) or Central/South America (aOR 2.44 [95% CI 1.22–4.88]) were more likely to use SAPT in the context of hot carotid with ILT (Table 4). Results were similar on sensitivity analyses that did not adjust for the preferred revascularization technique.
Figure 1. Survey respondents’ choice of antithrombotic management with and without associated intraluminal thrombus (ILT). Error bars represent 95% confidence intervals. SAPT = single antiplatelet therapy; DAPT = dual antiplatelet therapy.
Table 2. Antithrombotic regimens selected by survey respondents in the case of hot carotid with intraluminal thrombus (ILT). Regimens with less than 10 total responses not included here
Table 3. Factors associated with choosing a regimen containing anticoagulation for a patient with acutely symptomatic carotid stenosis awaiting revascularization, when told that there was an associated intraluminal thrombus. Significant P-values are indicated with an asterisk
Table 4. Factors associated with choosing SAPT (*single antiplatelet therapy) for a patient with acutely symptomatic carotid stenosis awaiting revascularization, when told that there was an associated intraluminal thrombus. Significant P-values are indicated with an asterisk
Qualitative data
We interviewed 22 physicians between May 2018 and June 2021 (24 approached, 2 refused due to other commitments). The demographic characteristics have been previously reported and are included in Supplement 3 (Table 2). Interviews lasted 30–60 minutes. Relevant quotes from the interviews are organized thematically and included in Table 5. A coding matrix of interview codes used to develop the themes below is included in Supplement 3 (Figure 3).
Table 5. Summary of key themes from interviews with representative quotes
Therapeutic uncertainty regarding anticoagulation
The debate about using DAPT versus anticoagulation in the acute management of ILT in the hot carotid emerged as a theme in this study, with no clear consensus or preference among participants Supplement 3 (Figure 1). The decision to favor the use of DAPT or anticoagulation did not display any regional or specialty variation. In terms of decision-making regarding the use of DAPT or anticoagulation, a theme emerged regarding the size of the stroke as being a factor that may dissuade participants from anticoagulating patients. Here participants were weighing the risks of recurrent stroke against the risk of hemorrhagic transformation when choosing an optimal antithrombotic therapy. Participants expressed uncertainty regarding the appropriate management choice in this setting Supplement 3 (Figure 2), noting the absence of high-quality natural history data for this condition with current strategies.
Some people anticoagulate these patients. I still tend to give them dual antiplatelets. (Europe, Neurologist 1)
I might be inclined to give heparin depending on the size of the stroke. If it is a large stroke with risk of hemorrhage I would avoid heparin but I would tend to give heparin and aspirin, even both, if the stroke is smaller or a TIA. (North America, Neurologist 4)
Decision to reimage
There was a preference for reimaging patients in 3–7 days after initiating treatment to look for complete or partial clot resolution in patients being considered for revascularization (i.e., suspected stenosis greater than ≥50%). In patients with mild to moderate stenosis, who were not being considered for revascularization, participants favored a longer interval of follow-up imaging, up to 6 weeks after initiating therapy.
Our approach in these cases has been to put them on a heparin infusion and then re-image them in 3 days or so to see if the clot has resolved. If there is an associated stenosis, then I won’t stent that until I’ve seen some resolution of the clot. The rationale being that otherwise I might send a piece of the clot flying off during the procedure, if it’s unstable. (North America, Neuroradiologist 2)
Importantly, the rationale for reimaging was not just to ensure the resolution of the clot but also to clarify the true extent of the underlying plaque and its associated degree of stenosis. Participants noted that it can be challenging in the initial imaging to adequately distinguish the boundaries between ILT and the underlying plaque; as such, as the clot resolves in follow-up imaging, it may become evident that the plaque is actually resulting in minimal stenosis – which, for several participants, would dampen their enthusiasm for revascularization.
Sometimes cross-sectional imaging would overestimate [the degree of stenosis in the case of ILT] and on [repeat imaging] you might not see the same [degree of stenosis]. (North America, Neuroradiologist 1)
Revascularization choices
In general, participants favored not doing hyperacute revascularization and waiting for clot resolution or partial resolution with medical therapy before proceeding with revascularization if indicated. This was driven by concern about the high risk for perioperative distal embolization events.
If there is a mobile thrombus [then] no surgery immediately. Vascular surgery and interventional radiology think risk is too high. (Asia Neurologist 1)
In cases where revascularization procedures were performed in the context of ILT, there appeared to be a preference for carotid endarterectomy (CEA). The rationale expressed for this preference was a perceived high risk of clot embolization when passing a filter/catheter by the ILT, which is required in carotid artery stenting (CAS), and therefore, there was a desire to avoid this by performing CEA instead.
If there is a mobile thrombus in artery, we think there is a very high risk of embolization and the risk is higher if we perform an endovascular treatment because you have to pass through the artery with a filter in all the procedures. There is a risk of embolization that we believe is lower if the patients get endarterectomy. (Europe, Neurologist 2)
However, some favored stenting over CEA in the setting of ILT. The argument here was that stenting offered a better means of visualizing residual clots using contrast injections while the procedure was in progress.
Certainly my recommendation in such cases would be to avoid endarterectomy because with that surgery you won’t be able to directly visualize the clot and you have no idea whether you’ve sent it off as an embolus while you’re working on it. On the other hand with stenting, you can keep your eye on any residual clot while you’re working. (North America, Neuroradiologist 2)
Future trial design and anticipated challenges
There was a clear interest in further high-quality studies (i.e., Randomized control trials) on the management of ILT in the hot carotid. Participants identified DAPT as the minimum acceptable therapy and indicated they would be happy to randomize patients to DAPT versus anticoagulation regimens. Experts had an interest in future trials and viewed these as ethical based on the significant equipoise in the area and a lack of high-quality evidence to inform clinical practice.
In the acute setting with hot carotid, I think there is enough equipoise that [physicians] would be willing to randomize to that trial. (North America, Neurologist 3)
In the interviews, multiple experts raised concerns regarding recruitment and achieving an adequate event rate to effectively study ILT management in hot carotid. ILT in the hot carotid might not be encountered frequently enough to achieve rapid enrollment; as such, the experts felt that it was important for trials to have a very inclusive and pragmatic approach to international recruitment in order to avoid further narrowing an already small patient pool. Additionally, there was a desire for future studies to quantify the natural history of ILT to therefore better inform future trial development.
The core challenge, of course, is to recruit the patients. This is not a very frequent condition. (Europe, Neurologist 3)
I am swayed by the pathologists who tell me that every time they look at an acute plaque which has been resected they always find fresh thrombus so that means to me well, that doesn’t mean that fresh thrombus is more or less dangerous. (North America, Neurologist 2)
Discussion
The results of this mixed-methods study provide a description of the current practice patterns of stroke physicians in managing ILT in the hot carotid, particularly in relation to antithrombotic management, revascularization and imaging. This data provides insight into the factors that affect physicians’ decision-making in these cases as well as mapping interest and considerations regarding future trials of ILT in the hot carotid population.
Results of the quantitative analysis suggest that the presence of an ILT significantly alters antithrombotic management choices by increasing the likelihood of using anticoagulation and decreasing the use of SAPT or DAPT. This is consistent with other reports highlighting enthusiasm and institutional preference for anticoagulation in these cases. Reference Vellimana, Kadkhodayan and Rich10,Reference Singh, Chakraborty and Dey31 There does however remain equipoise in antithrombotic strategies, as evident in our survey, where one-third of physicians preferred antiplatelet agents over anticoagulation in cases of ILT, with significant geographic practice variation noted as well, suggesting an unmet need to answer the question of optimal medical therapy in ILT. This equipoise is supported by the thematic analysis of our qualitative interviews. Quantitative analysis of the survey included here suggests that factors that influence decision-making in antithrombotic management may be related to practice region; specifically, when controlling for years in practice and preferred revascularization, physicians from Europe and Central/South America were less likely to use antithrombotic regimens containing anticoagulation in patients with ILT and a hot carotid. Regional variations in practice as we see here have been previously published in other related areas of the stroke literature, for example, geographic variation in thrombolysis rates. Reference Skolarus, Meurer, Shanmugasundaram, Adelman, Scott and Burke32,Reference Suolang, Chen, Wang, Gottesman and Faigle33 No clear regional or specialty variation emerged on the topic of antithrombotic management in the interview thematic analysis; however, stroke size and the associated risk of hemorrhagic transformation were identified as important factors in deciding when to use anticoagulation.
This observed equipoise is consistent with previous literature Reference Bhatti, Leon and Labropoulos9,Reference Fridman, Lownie and Mandzia12 and is likely related to a general lack of high-quality evidence and conflicting reports on the topic. The most robust evidence for antithrombotic management in ILT is a recent meta-analysis of 525 cases derived from a systematic review of case reports and case series of ILT in the hot carotid, which showed no benefit of anticoagulation in reducing adverse outcomes (stroke, TIA, death). Similar results were reported in a 2007 systematic review as well. Reference Bhatti, Leon and Labropoulos9 The nature of this evidence (meta-analysis of case reports/case series) however is low quality. Additionally, given concerns of ascertainment and information bias in prior studies, the authors underscored the need for large-scale prospective cohort data to better inform practice and ensure the feasibility of future trials – a concern that was echoed in our interviews. Reference Fridman, Lownie and Mandzia12
Results of the qualitative analysis suggest a preference for avoiding hyperacute revascularization and, ideally, waiting for thrombus resolution following antithrombotic therapy before pursuing revascularization, though few participants commented on this consideration. Compared to the issue of antithrombotic management, there appeared to be less equipoise regarding revascularization timing among interview experts. This is perhaps driven by the somewhat outdated though comparatively more methodologically robust evidence regarding risk of CEA in the presence of ILT. Reference Goldstein, McCrory and Landsman34,Reference Barnett, Meldrum and Eliasziw35 For example, a retrospective study of 1160 CEAs performed at 12 sites between 1987 and 1990 found that ILT was associated with a numerically higher frequency of 30-day stroke recurrence 14.3% in ILT versus 5.4% without ILT; however, this was not statistically significant, and there were only 28 patients with ILT included. Reference Goldstein, McCrory and Landsman34 More recently, in the abovementioned meta-analysis (2019), there was no association of early revascularization (within 72 hours) with the composite outcome of TIA, stroke or death when controlling for other variables in regression analysis though as mentioned the generalizability of this finding is limited. Reference Fridman, Lownie and Mandzia12 These reviews however rely on outdated data Reference Fridman, Lownie and Mandzia12,Reference Goldstein, McCrory and Landsman34 and thus do not reflect current procedural techniques and other medical management (e.g., high-intensity statin therapy).
With regard to procedure type, few interviewed experts commented on this consideration. From the results here, however, CEA appears to be the preferred intervention, though equipoise was noted. Specifically, experts were making this decision based on the perceived risk of clot embolization, although contrasting opinions were noted, with some expressing that the risk of embolization in CEA was prohibitively high, while others expressed the same opinion regarding CAS. These results support that there is an absence of literature to inform the decision of CAS versus CEA in ILT cases, and this likely depends on multidisciplinary and context-specific considerations of the treating physician.
The results of the qualitative interviews showed support for future trials examining the management of ILT in the hot carotid. Interviewed experts expressed an interest in a trial that would compare DAPT versus anticoagulation in this group and were agreeable to randomizing these therapies. In preparation for trials, there seems to be a need for high-quality natural history data on patients with ILT in the context of current practices, expanding on the current data that is limited to case series. High-quality data on recurrent stroke outcomes with current practices is needed, and this will help inform estimations of effect size and event rate for powering trials. Preliminary work in this regard has come from a recent prospective cohort study of ILTs (with a range of ILT at different extra and intracranial locations, the majority being carotid ILT), which showed low rates of stroke recurrence (6.6%) and high rates of partial or complete thrombus resolution (74.6%) with medical therapy (heparin plus aspirin). Reference Singh, Chakraborty and Dey31
Limitations
This study does have a few important limitations to acknowledge. The first of which is the sample demographic in both the survey and interview portions of this study. Both the survey and interview were conducted in English, which limited participation from non-English speaking participants. Additionally, there was a significant overrepresentation of North American and European clinicians both in the survey and interviews which could limit the generalizability to other regions. Women were also underrepresented in the interviews. Furthermore, given that the survey analysis here was post hoc, the questions were not optimized for all aspects of ILT management and did not include questions regarding how age and stroke size/location would influence management. Additionally, the survey did not ask patients about practice subspecialty (i.e., general neurology, stroke neurology, neuroradiology/interventionalist), which could influence practice patterns. In terms of methodology for the qualitative portion of the study, snowball sampling does have the potential to introduce bias Reference Kirchherr and Charles36 as participants may be more likely to recommend like-minded colleagues for inclusion in the study. That being said, snowball sampling remains one of the most used and well-studied sampling methods in qualitative research.(Reference Parker, Scott and Geddes19,Reference Kirchherr and Charles36) Finally, it should be acknowledged that there has been a significant gap in time between data collection and publication (data collection completed in June 2021). Despite this, the questions posed in this study remain relevant in today’s context, with very little work being published in the field of carotid ILT in recent years.
Conclusion
The management of ILT in patients with a hot carotid continues to represent a treatment dilemma for physicians. Driven largely by methodologically limited and often outdated data, physicians must determine their management of these cases by weighing the risk of recurrent ischemic events with more conservative therapy against the possible harms of more aggressive therapies such as anticoagulation or hyperacute revascularization. While the results of this study show a preference for anticoagulation and delayed revascularization in patients with ILT and a hot carotid, much equipoise remains. Further study should be conducted to first better understand the natural history of ILT in hot carotid, specifically high-quality prospective cohort studies, followed by pragmatic randomized trials to determine optimal management techniques. Our interviews specifically have helped establish what would be considered top contenders for comparative strategies in future studies (i.e., at least dual antiplatelet vs. anticoagulation). Doing so would provide answers to the management of a condition that continues to be surrounded by much of the same uncertainty as it was in decades past.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/cjn.2024.348.
Author contributions
D.M. was responsible for data analysis, primary manuscript writing and revision of the paper. B.B. analyzed data and helped revise the paper. G.A.E.J. collected data, assisted with analysis and helped revise the paper. L.B. helped develop the quantitative survey and helped revise the paper. D.J.T.C. was involved in the design of the study, analysis of data and revision of the paper. M.V. was involved in data collection, analysis of the data and revision of the paper. R.J.S. was involved in the design of the study, data collection and revision of the paper. J.H.W. was involved in the study design and manuscript revision. B.K.M. supervised the study and was involved in the conception, design, writing, analysis and revision of the paper. A.G. was involved in the conception and design of the study, collected and analyzed the data, co-wrote the first draft and revised the paper.
Funding statement
This study was funded by a Heart and Stroke Foundation Professorship held by Dr Bijoy K. Menon.
Competing interests
None.
Disclosures
Dr Maclean reports no disclosures. Dr Beland reports no disclosures. Dr Jewett reports no disclosures. Dr Bartolini has received consulting fees from Vertex Pharmaceuticals and a stipend as the editor-in-chief of Neurology: Clinical Practice. Dr Campbell has received research support from the Canadian Institutes of Health Research, Alberta Innovates and Diabetes Canada and support for attending meetings from Diabetes Action Canada/MyROAD and has receipt of equipment, materials, drugs, medical writing, gifts or other services from Siemens Healthineers. Dr Varma reports no disclosures. Dr Singh reports no disclosures. Dr Wong reports no disclosures. Dr Menon reports no disclosures. Dr Ganesh reports membership in editorial boards of Neurology, Neurology: Clinical Practice and Stroke; research support from the Canadian Institutes of Health Research, Alberta Innovates, Campus Alberta Neurosciences, Government of Canada – INOVAIT Program, Government of Canada – New Frontiers in Research Fund, Microvention, Alzheimer Society of Canada, Alzheimer Society of Alberta and Northwest Territories, Heart and Stroke Foundation of Canada, Panmure House, Brain Canada, MSI Foundation and the France Canada Research Fund; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alexion, Biogen and Servier Canada; and a patent application (US 17/ 317,771) for a system for delivery of remote ischemic conditioning or other cuff-based therapies and a provisional patent (US 63/326,027) for systems and methods for enhancing the efficiency of initiating, conducting and funding research projects and stock or stock options in SnapDx Inc. and Collavidence Inc. (Let’s Get Proof).
