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Ischemic stroke
Original research
Clot composition and recanalization outcomes in mechanical thrombectomy
  1. Raul G Nogueira1,
  2. Agostinho Pinheiro2,
  3. Waleed Brinjikji3,
  4. Mehdi Abbasi3,
  5. Alhamza R Al-Bayati2,
  6. Mahmoud H Mohammaden4,
  7. Lorena Souza Viana5,
  8. Felipe Ferreira5,
  9. Hend Abdelhamid5,
  10. Nirav R Bhatt1,
  11. Peter Kvamme6,
  12. Kennith F Layton7,
  13. Josser E Delgado Almandoz8,
  14. Ricardo A Hanel9,
  15. Vitor Mendes Pereira10,
  16. Mohammed A Almekhlafi11,
  17. Albert J Yoo12,
  18. Babak S Jahromi13,
  19. Matthew J Gounis14,
  20. Biraj Patel15,16,
  21. Jorge L Arturo Larco17,
  22. Sean Fitzgerald3,
  23. Oana Madalina Mereuta3,18,
  24. Karen Doyle19,
  25. Luis E Savastano17,
  26. Harry J Cloft3,
  27. Ike C Thacker7,
  28. Yasha Kayan8,
  29. Alexander Copelan20,
  30. Amin Aghaebrahim21,
  31. Eric Sauvageau22,
  32. Andrew M Demchuk23,24,
  33. Parita Bhuva25,
  34. Jazba Soomro12,
  35. Pouya Nazari13,26,
  36. Donald Robert Cantrell27,
  37. Ajit S Puri28,
  38. John Entwistle16,
  39. Eric C Polley3,
  40. Michael R Frankel4,29,
  41. David F Kallmes3,
  42. Diogo C Haussen30
  1. 1 UPMC Stroke Institute, Pittsburgh, Pennsylvania, USA
  2. 2 Neurology, UPMC Stroke Institute, Pittsburgh, Pennsylvania, USA
  3. 3 Radiology, Mayo Clinic, Rochester, Minnesota, USA
  4. 4 Department of Neurology, Emory University Atlanta, Atlanta, Georgia, USA
  5. 5 Neurology, Emory University, Atlanta, Georgia, USA
  6. 6 Radiology, University of Tennessee Medical Center, Knoxville, Tennessee, USA
  7. 7 NeuroInterventional Radiology, Baylor University Medical Center, Dallas, Texas, USA
  8. 8 Interventional Neuroradiology, Abbot Northwestern Hospital, 55435, Minnesota, USA
  9. 9 Neurosurgery, Baptist Medical Center Jacksonville, Jacksonville, Florida, USA
  10. 10 Division of Neuroradiology, Department of Medical Imaging and Division of Neurosurgery, Department of Surgery, University Health Network - Toronto Western Hospital, Toronto, Ontario, Canada
  11. 11 Clinical Neurosciences, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
  12. 12 Neurointervention, Texas Stroke Institute, Plano, Texas, USA
  13. 13 Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  14. 14 New England Center for Stroke Research, Department of Radiology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
  15. 15 Radiology, Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA
  16. 16 Radiology, Neurosurgery, Carilion Clinic, Roanoke, Virginia, USA
  17. 17 Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA
  18. 18 CÚRAM–SFI Research Centre for Medical Devices and Physiology Department, National University of Ireland Galway, Galway, Ireland
  19. 19 Physiology, CURAM, National University of Ireland Galway, Galway, Ireland
  20. 20 NeuroInterventional Radiology, Abbott Northwestern Hospital, Minneapolis, Minnesota, USA
  21. 21 Lyerly Neurosurgery, Baptist Health System, Jacksonville, Florida, USA
  22. 22 Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, Florida, USA
  23. 23 Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
  24. 24 University of Calgary, Calgary, Alberta, Canada
  25. 25 Neuroendovascular Surgery, Texas Stroke Institute, Plano, Texas, USA
  26. 26 Neurosurgery and Radiology, Northwestern University, Chicago, Illinois, USA
  27. 27 Radiology, Northwestern University, Chicago, Illinois, USA
  28. 28 Radiology, University of Massachusetts, Worcester, Massachusetts, USA
  29. 29 Marcus Stroke and Neuroscience Center, Grady Memorial Hospital, Atlanta, Georgia, USA
  30. 30 Neurology and Radiology, Emory University School of Medicine, Atlanta, Georgia, USA
  1. Correspondence to Dr Raul G Nogueira, UPMC Stroke Institute, Pittsburgh, Pennsylvania 15213, USA; raul.g.nogueira{at}icloud.com

Abstract

Background Mechanical thrombectomy (MT) has become standard for large vessel occlusions, but rates of complete recanalization are suboptimal. Previous reports correlated radiographic signs with clot composition and a better response to specific techniques. Therefore, understanding clot composition may allow improved outcomes.

Methods Clinical, imaging, and clot data from patients enrolled in the STRIP Registry from September 2016 to September 2020 were analyzed. Samples were fixed in 10% phosphate-buffered formalin and stained with hematoxylin-eosin and Martius Scarlett Blue. Percent composition, richness, and gross appearance were evaluated. Outcome measures included the rate of first-pass effect (FPE, modified Thrombolysis in Cerebral Infarction 2c/3) and the number of passes.

Results A total of 1430 patients of mean±SD age 68.4±13.5 years (median (IQR) baseline National Institutes of Health Stroke Scale score 17.2 (10.5–23), IV-tPA use 36%, stent-retrievers (SR) 27%, contact aspiration (CA) 27%, combined SR+CA 43%) were included. The median (IQR) number of passes was 1 (1–2). FPE was achieved in 39.3% of the cases. There was no association between percent histological composition or clot richness and FPE in the overall population. However, the combined technique resulted in lower FPE rates for red blood cell (RBC)-rich (P<0.0001), platelet-rich (P=0.003), and mixed (P<0.0001) clots. Fibrin-rich and platelet-rich clots required a higher number of passes than RBC-rich and mixed clots (median 2 and 1.5 vs 1, respectively; P=0.02). CA showed a trend towards a higher number of passes with fibrin-rich clots (2 vs 1; P=0.12). By gross appearance, mixed/heterogeneous clots had lower FPE rates than red and white clots.

Conclusions Despite the lack of correlation between clot histology and FPE, our study adds to the growing evidence supporting the notion that clot composition influences recanalization treatment strategy outcomes.

  • Stroke
  • Thrombectomy
  • Device

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/jnis-2023-020117

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Previous reports correlated radiographic signs with clot composition as well as a better response to specific techniques. Therefore, we hypothesized that understanding clot composition may improve mechanical thrombectomy (MT) outcomes.

    WHAT THIS STUDY ADDS

    • This study represents the most comprehensive clot analysis in MT. Despite its large sample size, the study failed to demonstrate any significant association between MT efficacy and clot composition in the overall study population.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Our study provides an extensive and comprehensive histology analysis, adding Martius Scarlett Blue stain to the classic use of hematoxylin and eosin. Despite the lack of correlation between clot histology and FPE in the overall population, our study adds to the growing body of evidence supporting the notion that clot composition influences recanalization outcomes. Additional studies are needed to confirm whether information about clot composition should influence the technique and device selection.

    Introduction

    Mechanical thrombectomy (MT) has become the standard of care for the treatment of large vessel occlusion strokes (LVOS). However, improvements in angiographic outcomes are still to be attained as many patients fail to achieve complete recanalization or do so in a delayed manner. Indeed, the rates of first-pass full recanalization effect (FPE), a key metric to assess MT efficiency, remain suboptimal, ranging from 25.2% to 37.8% in previous reports.1–4 Therefore, improving recanalization speediness and completeness represents a unique opportunity to enhance clinical outcomes.

    Previous studies have reported that the hyperdense-vessel sign (HDVS) on CT and susceptibility vessel sign (SVS) on MRI are associated with red blood cell (RBC)-rich clots.5 6 In addition, it has also been reported that HDVS on CT and SVS on MRI are associated with both better recanalization rates during MT5 7 8 and better response to stent-retrievers (SR) as first-line modality.7 9 In this context, understanding clot composition may allow for better technique selection and consequently improved outcomes.

    The primary purpose of this study was to evaluate histopathological clot composition and its correlation with recanalization outcomes in patients undergoing MT. In addition, we sought to assess the impact of clot composition on recanalization outcomes across the different MT technical modalities.

    Methods

    Patient population

    Consecutive patients enrolled in the STRIP Registry from September 2016 to September 2020 were included. The study was approved by the institutional review board and a waiver of consent was granted. Patients were included if they were ≥18 years of age, had undergone MT treatment for acute ischemic stroke, and clot material was retrieved during the procedure. There was no standardization of the endovascular treatment. Specifically, the choice of devices and techniques was based on the preference of the operators.

    Clot processing and histological characterization

    Each thrombus was immediately fixed in 10% phosphate-buffered formalin. Emboli were shipped to a central core laboratory for standard tissue processing and embedded in paraffin. Gross photographs were obtained for each clot type. The chief histopathologist for the study assessed each gross specimen and categorized gross clot color as red, white, or heterogeneous. Then, formalin-fixed paraffin-embedded clot material was cut into 3–5 µm sections. Representative slides from each clot were stained with hematoxylin and eosin and Martius Scarlett Blue.

    Representative Martius Scarlett Blue-stained slides were sent for whole slide scanning (Aperio ScansScope AT-Turbo, Leica Biosystems). Histological quantification was performed using Orbit Image Analysis Software (www.Orbit.bio) as per the standard operating procedure. Details of the methodology for Orbit image analysis have been previously described.10

    Data collection

    Data regarding clinical presentation, stroke pathogenesis, imaging findings, treatment strategies, and outcomes were collected using a data abstraction form. For treatment strategies, we collected data on the revascularization technique used (SR vs contact aspiration (CA) vs combined techniques). For revascularization outcomes, we collected the final modified Thrombolysis in Cerebral Infarction (mTICI), number of passes, and first-pass mTICI 2c/3.

    Statistical analysis

    For the purpose of statistical analysis, the primary outcome was first-pass mTICI 2c/3, as reported by the operating site. Clots were categorized based on both gross and microscopic appearance. Thus, we performed analyses of clot color (ie, red, white, and heterogeneous) and clot composition (ie, percent of RBCs, fibrin, and platelets), and revascularization outcomes. The purpose of the gross color analysis was to account for the overall structure of the clot in addition to the standard microscopic analyses. Clots were defined as platelet-rich, fibrin-rich, or RBC-rich if they had >50% of any of these components. If a clot did not have >50% of any component, it was considered heterogeneous. A secondary analysis was performed to study the correlation between histological and gross composition with the number of passes performed. Categorical variables were compared using the χ2 test. Continuous variables were compared using the Wilcoxon test because of the non-normal distribution. All statistical correlations were assessed using JMP 14.0 (www.jmp.com, Cary, North Carolina, USA).

    Results

    Patient population and baseline characteristics

    A total of 1430 patients were included in the study. The mean±SD age was 68.4±13.5 years. The median (IQR) baseline National Institutes of Health Stroke Scale score was 17.2 (10.5–23). A total of 517 (36%) patients received IV tissue plasminogen activator (tPA). SR were used in 390 cases (27%), CA in 381 patients (27%), and combined SR+CA in 616 patients (43%). The median number of passes was 1 (IQR 1–2).

    The two most common locations for occlusions were the M1 segment of the middle cerebral artery (689 patients, 55%) and the internal carotid artery (307 patients, 22%). There was no difference in the distribution of occlusion location by technique (p=0.21). The median (IQR) RBC percentage was 43% (26–62%), the median (IQR) platelet percentage was 21% (12–36%), and the median (IQR) fibrin percentage was 24% (15–35%). Macroscopically, 24% of clots were predominantly red, 9% were predominantly white, and 66% were heterogeneous/mixed. Histologically, 41% of clots were RBC-rich, 10% were fibrin-rich, 13% were platelet-rich, and 37% were heterogeneous (table 1).

    View this table:
    Table 1

    Summary of baseline characteristics

    Revascularization rates by histological composition

    Overall, there was no association between percent histological composition and FPE as the median percent RBC, fibrin, and platelet composition in the FPE group versus non-FPE groups were 43% vs 42% (P=0.96), 23% vs 25% (P=0.07), and 21% vs 20% (P=0.48), respectively. The same was true when assessing each individual technique (ie, SR vs CA vs combined SR+CA technique). These data are summarized in table 2. When examining the relationship between the number of passes and percent composition, we found no correlation between percent RBC (P=0.18) or percent platelets (P=0.26) and the number of passes. There was a weak direct correlation between percent fibrin and the number of passes (P=0.0002, R2=0.1). This occurred in both the CA (P=0.04, R2=0.12) and the combined SR+CA technique (P=0.003, R2=0.14) groups.

    View this table:
    Table 2

    Outcomes with percent composition

    Revascularization rates by clot richness

    Overall, FPE rates were not significantly different based on clot richness (40% for RBC-rich, 39% for fibrin-rich, 42% for platelet-rich, and 38% for mixed, P=0.74). FPE rates were lower for combined SR+CA techniques than for SR and CA techniques for RBC-rich clots (P<0.0001), platelet-rich clots (P=0.003), and mixed clots (P<0.0001). There was a trend towards lower FPE rates in fibrin-rich clots with CA compared with SR (35% vs 49%, P=0.12). There were no differences in revascularization rates between SR and CA for RBC-rich, platelet-rich, and mixed clots. These data are summarized in table 3.

    View this table:
    Table 3

    Outcomes based on richness

    Regarding the median number of passes, fibrin-rich and platelet-rich clots had a higher median number of passes than RBC-rich and mixed clots (2 and 1.5 vs 1, respectively, P=0.02). By technique, combined techniques required a median number of two passes no matter the dominant component of the clot. CA had a trend towards a higher median number of passes for fibrin-rich clots compared with SR (2 vs 1, P=0.12).

    Revascularization rates by gross clot composition

    By gross appearance, mixed/heterogeneous clots had lower FPE rates than red and white clots (38% vs 43% and 48%, respectively, P=0.03). Mixed clots required a median of two passes compared with one pass for red and white clots (P=0.02). Combined techniques had the lowest FPE rates for red, white, and mixed clots and the highest median number of passes. There were no differences in FPE rates between CA and SR for red, white, and mixed clots. These data are summarized in table 4.

    View this table:
    Table 4

    Outcomes based on gross composition

    Discussion

    Our study was based on the premise of a direct correlation between clot histology and MT outcomes. This hypothesis was derived from previous studies suggesting an association between angiographic recanalization with both clot composition11–13 and radiology signs known to reflect clot composition.8 14–16 Despite its large sample size, our study failed to demonstrate any significant association between MT efficacy, using FPE as the key metric, with either clot histologic percent composition or richness in the overall study population. However, the inability of finding more significant associations in our studies might be related to their relatively simple methodology and it remains possible that the use of more advanced techniques including analysis of clot mechanical properties, immunohistochemistry, scanning electron microscopy, and proteomics might yield different results.

    Another important goal of our study was to try to identify clot characteristics that could potentially guide the best choice of MT technique during interventional procedures. After the ASTER-2 trial and other reports17–19 failed to demonstrate a superiority of a combined technique, we postulated that clot composition could potentially aid in the decision-making of device and technique selection. Previous reports linking higher thrombus density, HDVS, and SVS with higher rates of successful recanalization with SR versus CA as the initial treatment modality7 9 15 16 20 provided background to our second hypothesis: RBC-rich clots could be potentially better treated with SR while non-RBC-rich clots would respond better to CA. However, the use of SR (vs CA) to treat RBC-rich clots was not associated with better angiographic outcomes in our study. Notably, a previous analysis of the STRIP Registry, also based on hematoxylin and eosin and Martius Scarlett Blue stains, did not find any consistent or reliable means to differentiate clots from cardioembolic versus large artery atherosclerosis origin.21 However, the inability of finding more significant associations in our studies might be related to their relatively simple methodology and it remains possible that the use of more advanced techniques including analysis of clot mechanical properties, immunohistochemistry, scanning electron microscopy, and proteomics might yield different results. This is at least in part substantiated by the growing literature supporting the associations between clot imaging, clot composition, and choice of treatment modality.5 9

    When analyzing clot richness and treatment modality, there were lower FPE rates for the combined technique with RBC-rich, platelet-rich, and mixed clots. This finding adds to the growing controversy surrounding the common belief that maximalist approaches invariably lead to superior angiographic results. Although the rates of successful (eTICI ≥2b: 86.2% vs 72.3%; P<0.001) and near-complete or complete (eTICI ≥2c: 59.6% vs 49.5%; P=0.04) recanalization with the assigned intervention alone were higher with combined therapy than SR in the ASTER-2 randomized clinical trial (n=405), neither the rate of modified FPE (eTICI ≥2b: 53.7% vs 44.6%; P=0.056) nor FPE (eTICI 3: 24.1% vs 17.8%; P=0.10) differed significantly, and 90-day functional outcomes were similar across the groups.9 In a single-center series comprising a total of 420 patients, Mohammaden et al found that first-line SR alone resulted in similar rates of FPE (mTICI ≥2c: 51% vs 53%, P=0.58), modified FPE (mTICI ≥2b: 60.4% vs 63%, P=0.35), final successful recanalization (98% vs 97.6%, P=0.75), and 90-day functional outcomes as first-line combined therapy.18 Likewise, an analysis of the ROSSETTI registry showed that both approaches had a similar FPE rate (52% vs 46.9%, P=0.337) and modified FPE (60.1% vs 54.7%, P=0.308) across the two groups.19 Notably, SR alone resulted in higher rates of final successful (mTICI ≥2b: 86.8% vs 74.2%, P=0.002) and excellent (mTICI ≥2c (76.2% vs 55.5%, P<0.001) recanalization as well as shorter procedural times (median puncture to revascularization: 24 (14–46) min vs 37 (24.5–63.5) min, P<0.001) as combined therapy, but again there was no significant difference in the rates of good functional outcome at 90 days. Conversely, first-line device strategy with combined therapy (as opposed to either SR or CA alone) was independently associated with an increase in the likelihood of FPE (OR 1.58 (95% CI 1.11 to 2.24), P<0.001) in the ETIS Registry (n=1832).22 These contrasting results could be at least partially related to the fact that a balloon guide catheter was used in 100% of the procedures in the Mohammaden et al and ROSSETTI Registry series compared with only in 21.3% of the cases in the ETIS Registry analysis, as the benefit of adding a balloon guide catheter to combined therapy represents another area of controversy.23 24 The results of meta-analysis comparing the rates of FPE across the different techniques (SR alone, CA alone, and combined therapy) have also been conflicting.25 26

    In this context, the concept of treatment modality selection based on individual clot characteristics becomes very appealing, and our findings may direct interventionists to consider avoiding a combined approach in the setting of HDVS on CT or an SVS on MRI as these imaging signs have been associated with RBC-rich and mixed clots.5 6 Another interesting observation from our study was that fibrin-rich and platelet-rich clots were associated with an increased number of passes, trending to an even higher number when approached by CA. Congruently, clot perviousness, a surrogate for residual flow along the thrombus on non-contrast CT and CT angiography, has been associated with higher RBC, lower fibrin, and lower platelet content,27 28 as well as with higher chances of first pass recanalization with CA as the first modality.29 However, there are conflicting data on the relationship between clot perviousness and histological composition, with some studies demonstrating that clot perviousness seems to be actually associated with lower fractions of RBC counts and a higher percentage of fibrin/platelet aggregate content instead.30 31

    Advances in imaging techniques may lead to a better understanding of clot composition and aid in decision making about the ideal treatment strategies. Currently, the use of radiology signs to tailor intervention techniques is being assessed by a trial that compares a first-line strategy combining SR and CA with CA alone in the presence of SVS.32 In the near future, novel technologies such as the incorporation of bioimpedance microsensors to microguidewires designed to detect in situ thrombus composition may potentially serve as a procedural tool to guide choice of the optimal treatment modality.33

    Our study has some important limitations, especially related to the inherent selection bias since histologic analysis was obviously only possible in cases of successful MT, excluding from our study an essential group of patients in whom the interventional procedure could not retrieve a clot. Angiographic assessments were provided by the sites without central core laboratory adjudication. As mentioned above, more advanced techniques including analysis of clot mechanical properties, immunohistochemistry, scanning electron microscopy, and proteomics were not performed and therefore should be considered in the future. There was no testing for inter- and intra-rater reliability of the gross examination of the clots. The lack of standardization of the endovascular treatment may have biased our results as the choice of devices and techniques may have been influenced by different imaging and procedural factors. Furthermore, treatment techniques may vary within the same device or combination of device categories depending on many factors, including the use of a balloon guide catheter, the positioning and degree of interaction between the SR and aspiration catheter during the retrieval process, among others. We did not analyze the data according to the use versus no use of bridging IV thrombolysis. However, there was no interaction between IV tPA administration and clot composition in a previous analysis of the STRIP Registry that included the same 1430 clots, suggesting that bridging IV thrombolysis does not result in any significant changes in clot composition.34 Finally, there is poor standardization around the clot analysis techniques and clot composition definitions, which make the comparison across studies more difficult.

    Conclusion

    As stroke care evolves and the indications for MT continue to expand, optimizing the speediness and completeness of recanalization represents a unique opportunity to enhance clinical outcomes. Although other studies have previously investigated the association between clot histology and procedural parameters,11–13 this is one of the largest studies performed to date. We also provide a more comprehensive histology analysis, adding Martius Scarlett Blue stain to the classic use of hematoxylin and eosin. Despite the lack of correlation between clot histology and FPE in the overall population, our study adds to the growing body of evidence supporting the notion that clot composition influences recanalization outcomes. Additional studies are needed to confirm whether information about clot composition should influence technique and device selection.

    Data availability statement

    Data are available upon reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study was approved by the Mayo Clinic IRB under the following ID: Mayo Clinic IRB - 16-00113. The study is based on a registry, not including private or identifiable information. Therefore, consent was waived by the IRB.

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    Footnotes

    • X @agostinhocp, @Mahmoudneuro, @lorena_neuro, @nirav_r_bhatt, @VitorMendesPer1, @AlmekhlafiMa, @PouyaNazari5, @AjitSPuri1, @diogohaussen

    • Contributors RGN, AP, WB, DCH are the gauarantor of this project and contributed to the conception as well as design of the study. RGN, AP, WB, MA, ARA-B, PK, KFL, JEDA, RAH, VMP, MAA, AJY, BSJ, MJG, BP, JLAL, SF, OMM, KD, LES, HJC, ICT, YK, AC, AG, ES, AMD, PB, JS, PN, DRC, ASP, JE, ECP, DFK, DCH contributed to acquisition and analysis of data. RGN, AP, WB, MHM, LSV, FF, HA, NRB contributed to drafting the text or preparing figures.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests RGN reported consulting fees for advisory roles with Anaconda, Biogen, Cerenovus, Genentech, Hybernia, Imperative Care, Medtronic, Phenox, Philips, Prolong Pharmaceuticals, Stryker Neurovascular, Shanghai Wallaby, and Synchron and stock options for advisory roles with Astrocyte, Brainomix, Cerebrotech, Ceretrieve, Corindus Vascular Robotics, Vesalio, Viz-AI, RapidPulse, and Perfuze, and investments in Viz-AI, Perfuze, Cerebrotech, Reist/Q’Apel Medical, Truvic, and Viseon. WB is a consulting medical director for MIVI Neurovascular, consultant for Cerenovus, Microvention, Stryker, Medtronic, Imperative Care and receives research funding from Cerenovus, Brainomix, NIH. ARA-B is a consultant for Stryker Neurovascular. RAH is a consultant for Stryker, Medtronic, Cerenovous, Microvention, Balt, Phenox, Rapid Medical, and Q’Apel. He is on the advisory board for MiVI, eLum, Three Rivers, Shape Medical, and Corindus. AJY receives grants from Medtronic, Cerenovus, Penumbra, Stryker, and Penumbra. He is a consultant for Cerenovus, Penumbra, Vesalio, Zoll, Philips, Rapid Medical, and StrokeNet (MOST trial). AJY also has equity interest in Insera Therapeutics and Nicolab. MJG has been a consultant on a fee-per-hour basis for Alembic LLC, Astrocyte Pharmaceuticals, BendIt Technologies, Cerenovus, Imperative Care, the Jacob’s Institute, Medtronic Neurovascular, Mentice, Mivi Neurosciences, phenox GmbH, Q’Apel, Route 92 Medical, Scientia, Stryker, Wallaby Medical; holds stock in Imperative Care, InNeuroCo, Galaxy Therapeutics and Neurogami; and has received research support from the National Institutes of Health (NIH), the United States – Israel Binational Science Foundation, Anaconda, ApicBio, Arsenal Medical, Axovant, Balt, Cerenovus, Ceretrieve, CereVasc LLC, Cook Medical, Galaxy Therapeutics, Gentuity, Gilbert Foundation, Imperative Care, InNeuroCo, Insera, Jacob’s Institute, Magneto, Microvention, Medtronic Neurovascular, MIVI Neurosciences, Naglreiter MDDO, Neurogami, Philips Healthcare, Progressive Medical, Pulse Medical, Rapid Medical, Route 92 Medical, Scientia, Stryker Neurovascular, Syntheon, ThrombX Medical, Wallaby Medical, the Wyss Institute and Xtract Medical. KD is supported by a grant from Science Foundation Ireland (SFI) and the European Regional Development Fund (ERDF) under grant number 13/RC/2073_P2. ASP is a consultant for Medtronic Neurovascular, Stryker Neurovascular, Balt, Q’Apel Medical, Cerenovus, Microvention, Imperative Care, Agile, Merit, CereVasc and Arsenal Medical and receives research grants from NIH, Microvention. DCH is a consultant for Stryker,Cerenovus and is a member of the Data and Safety Monitoring Board for Vesalio and Jacobs Institute. He also holds stock options of VizAI. The other authors have no competing interests to disclose.

    • Provenance and peer review Not commissioned; externally peer reviewed.