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Commentary
SELECTion criteria for large core trials: dogma or data?
  1. Amrou Sarraj1,
  2. Bruce Campbell2,
  3. Marc Ribo3,
  4. Muhammad Shazam Hussain4,
  5. Michael Chen5,
  6. Michael G Abraham6,
  7. Maarten G Lansberg7,
  8. Vitor Mendes Pereira8,
  9. Spiros Blackburn9,
  10. Clark W Sitton10,
  11. Ronald F Budzik11,
  12. Natalia Pérez de la Ossa12,
  13. Juan F Arenillas13,
  14. Teddy Wu14,
  15. Jordi Blasco15,
  16. Michael Mullen16,
  17. Joanna Schaafsma17,
  18. Jenny P Tsai18,
  19. Navdeep Sangha19,
  20. Osman Kozak20,
  21. Daniel Gibson21,
  22. Steven Warach22,
  23. Dennis Cordato23,
  24. Nathan W Manning23,
  25. Timothy J Kleinig24,
  26. Jean-Marc Olivot25,
  27. Lucas Elijovich26,
  28. Georgios Tsivgoulis26,27,
  29. Andrei Alexandrov26,
  30. Pascal Jabbour28,
  31. Bernard Yan2,
  32. Scott E Kasner16,
  33. Adam S Arthur29,
  34. Mark Parsons23,
  35. James C Grotta30,
  36. Ameer E Hassan31,
  37. Gregory W Albers7
  38. On behalf of SELECT2 Investigators and SELECT2 Steering Committee
  1. 1 Neurology, University of Texas McGovern Medical School, Houston, Texas, USA
  2. 2 The Royal Melbourne Hospital, Melbourne, Victoria, Australia
  3. 3 Neurology, Hospital Vall d'Hebron, Barcelona, Spain
  4. 4 Neurology, Cleveland Clinic, Cleveland, Ohio, USA
  5. 5 Neurology, Rush University Medical Center, Chicago, Illinois, USA
  6. 6 Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA
  7. 7 Neurology & Neurological Sciences, Stanford University, Stanford, California, USA
  8. 8 Surgery, Division of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada
  9. 9 Neurosurgery, University of Texas McGovern Medical School, Houston, Texas, USA
  10. 10 Neuroradiology, University of Texas McGovern Medical School, Houston, Texas, USA
  11. 11 Neurology, Riverside Methodist Hospital, Columbus, Ohio, USA
  12. 12 Stroke Unit, Department of Neurology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  13. 13 Stroke Unit, Neurology Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
  14. 14 Neurology, Christchurch Hospital, Christchurch, New Zealand
  15. 15 Interventional Neuroradiology, Hospital Clinic de Barcelona, Barcelona, Spain
  16. 16 Neurology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  17. 17 Medicine, Division of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada
  18. 18 Department of Neurological Surgery, Spectrum Health Medical Group, Grand Rapids, Michigan, USA
  19. 19 Kaiser Permanente Southern California, Los Angeles, California, USA
  20. 20 Neurosurgery, Jefferson Health - Abington, Abington, Pennsylvania, USA
  21. 21 Ascension Wisconsin, Milwaukee, Wisconsin, USA
  22. 22 Neurology, University of Texas at Austin Dell Seton Medical Center, Austin, Texas, USA
  23. 23 Neurology, Liverpool Hospital, Liverpool, New South Wales, Australia
  24. 24 Neurology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
  25. 25 Stroke Unit, University Hospital Centre Toulouse, Toulouse, France
  26. 26 Neurology, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
  27. 27 Second Department of Neurology, “Attikon” Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
  28. 28 Neurological Surgery, Thomas Jefferson University Hospitals, Wayne, Pennsylvania, USA
  29. 29 Neurosurgery, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
  30. 30 Neurology, Memorial Hermann Hospital - Texas Medical Center, Houston, Texas, USA
  31. 31 Department of Neurology, University of Texas Rio Grande Valley, Harlingen, Texas, USA
  1. Correspondence to Dr Amrou Sarraj, Neurology, University of Texas McGovern Medical School, Houston, TX 77030, USA; Amrou.Sarraj{at}uth.tmc.edu

https://doi.org/10.1136/neurintsurg-2021-017498

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    We thank the Editors of JNIS for alerting us in advance to the concerns about SELECT2 raised by Jadhav1 and colleagues and appreciate the opportunity to explain the rationale for the study design and clarify the benefits of including perfusion imaging-based selection criteria. We are confident that SELECT2 will provide high-level, reliable data regarding the safety and efficacy of endovascular thrombectomy (EVT) for large core patients.

    The choice of imaging modality for identifying large core in acute ischemic stroke remains an area of considerable debate. Magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI), computed tomography (CT) or MR perfusion imaging and Alberta Stroke Program Early CT Score (ASPECTS) have all been proposed and studied. At present, there is no clear consensus on which imaging modality is best for identifying patients with large core. It is important to recognize that the early window randomized EVT trials used a broad range of imaging selection criteria. The imaging selection criteria for the initial five pivotal trials ranged from allowing patients to be enrolled regardless of the degree of early infarct signs,2 to studies that required a specific ASPECTS score range in addition to other imaging criteria,3–5 to EXTEND IA6 where the ASPECTS score was not considered, and CT perfusion (CTP) mismatch with a maximum estimated core size was required. All five trials were successful but with substantial variability in the treatment effect, leaving uncertainty as to the optimal imaging approach as well as whether there are patient subgroups who do not benefit. In fact, those utilizing perfusion mismatch criteria (EXTEND-IA, SWIFT PRIME) had higher rates of modified Rankin Scale (mRS) scores 0–2 and larger treatment effects, compared with other trials.2–6

    Even if a treatment has a clear benefit in most patients, there can be important subgroups that do not benefit or are harmed. The overall study results with all subgroups included can be positive, but important subgroups who should not be treated may exist. Based on well-established pathophysiology of brain ischemia, we believe that the subgroup of large core patients who are most likely to benefit from EVT are those who continue to have penumbral tissue at the time of the procedure. The subgroup that is least likely to benefit are patients who have competed their infarct and no longer have any penumbral tissue. Multiple studies have suggested that about 15% of early window large vessel occlusion patients may have a completed infarct due to very poor collaterals7–9 and these patients are the most likely to present with a large core. The design of SELECT2 is unique – and in our opinion offers important advantages in that it will allow assessment of the heterogeneity of EVT treatment effects in patients with large core on CT by assessing their ischemic core volumes on perfusion imaging, which has increasingly become part of the diagnostic algorithm for stroke patients on arrival to the hospital.10 This design will allow for a randomized assessment of whether perfusion imaging in large core patients provides additional data that influence the safety and efficacy of thrombectomy.

    Accuracy of CTP

    Concern was raised that CTP does not provide a reliable estimate of the ischemic core, with the particular concern about misidentification of patients who may not actually have a large region of irreversible injury. The accuracy of CTP for estimating the size of the core can vary depending on a number of parameters including the time between stroke onset and imaging and the imaging parameters used to acquire the perfusion imaging and the software chosen to analyze the data. Use of a standardized CTP acquisition at the study sites and the use of a validated software platform (RAPID, iSchemaView) helps to reduce this variability within the SELECT2 study. An independent study from Kiel11 that compared CTP software programs for accuracy showed that the perfusion software included in SELECT2 was more accurate than other programs for estimating ischemic core, with a substantially lower incidence of core overestimation. In addition, multiple studies have shown good performance in core estimation, without significant overestimation, when using the same perfusion software used in SELECT2.4 7 12 13 For example, in SWIFT PRIME, core overestimation was rare and when it occurred the median volume was only 4 mL.14 Furthermore, in a pooled analysis of data from HERMES and EXTEND-IA TNK using the same software as the one used in SELECT2, the median difference between the CTP estimated ischemic core volume and the diffusion lesion volume at 24 hours was 4.4 (IQR 1.2–12.0) mL and “volumetric CTP core overestimation was uncommon”.15 Only one of the studies cited by Jadhav et al suggesting CTP is not accurate for estimating core used the perfusion software we are using in SELECT2 and that study found that only 16% had core overcall of 10 mL or more using follow-up CT (rather than MRI which is more sensitive for estimating infarct volume).16 The authors of this study concluded “CBF <30% may overestimate infarct core volume, especially in patients imaged in the very early time window and with fast complete reperfusion”. We agree that recent evidence has demonstrated that cerebral blood flow (CBF) <30% is not the optimal threshold for estimating core in patients imaged within 90 min of stroke onset17 18 and recently implemented a plan to address this in SELECT2 by using the <20% threshold in patients imaged within 2 hours from last known well (LKW). Additionally, perfusion imaging may be more accurate than an ASPECT score threshold to differentiate patients with salvageable tissue from those with a completed infarct because it estimates not only the core but also the penumbra (mismatch). Multiple studies have demonstrated that patients without a mismatch do not have a favorable clinical response to reperfusion.7 9 13 19 20 Based on these differing positions in the field regarding the benefit of CTP for patient selection, there exists scientific equipoise, and thus the need for a randomized trial such as SELECT2 to help address this question.

    Benefit of EVT in favorable ASPECTS, large CTP core – not so “indisputable”

    Concern was raised that patients with favorable ASPECTS and a large CTP core have already been proven to benefit from EVT with “indisputable and unequivocal evidence”. We do not agree. Let us review the data here.

    The early window clinical trials typically did not enroll sufficient patients with large core on perfusion imaging. Indeed, the vast majority of the patients in the HERMES meta-analysis had very small cores as shown in figure 1, and very few with an ischemic core >50 mL.13 Thus, the retrospective analyses that have been performed on this limited database are underpowered to evaluate this subgroup and cannot be interpreted as providing a high level of evidence.

    Figure 1
    Figure 1

    Distribution of ischemic core volume using relative cerebral blood flow (rCBF) of <30% threshold in patients included in the HERMES meta-analysis who received computed tomography (CT) perfusion, showing limited number of patients with core volume with >50 mL, and a vast majority of the patients have ischemic core volume <50 mL. Reprinted with permission from Elsevier. All rights reserved.

    In HERMES, of 50/591 (8.4%) patients who had ischemic core of 70 mL or higher on CTP, there were imbalances in baseline ASPECTS (thrombectomy 8 (6–9) vs medical management 5 (4–7), P=0.001) and ischemic core volumes (85 (74–108) mL vs 110 mL (86–137) mL, P=0.12) in favor of EVT, potentially confounding analyses in this subpopulation.13 Furthermore, at least half of the 25 patients who received medical management demonstrated an ASPECTS of 4–5, suggesting a significant concordance between CT and CTP imaging in the early window, which suggests that a large CTP core in ASPECTS 6–10 patients is uncommon. In addition, among the small population of HERMES patients who did not have a perfusion mismatch, “these patients had no functional improvement from endovascular treatment (cOR 0.87 (95% CI 0.20 to 3.81), P=0·85)”.13 These wide confidence intervals suggest that EVT outcomes could be 4–5 times better or worse than medical management.

    SELECT2 was designed based in part on the data from the first SELECT study. Institutional review board approval was obtained from all participating centers in SELECT and all patients or their legally authorized representatives provided informed written consent prior to participation. In SELECT, of 285 patients receiving EVT, 197 presented with ASPECTS 6–10 on non-contrast CT within 6 hours of last known well. Some 173 (88%) of these patients demonstrated an ischemic core of <50 mL on CTP imaging, whereas 24 (12%) had an ischemic core of ≥50 mL. The distribution of the mRS scores at 90 days in these patients is provided in figure 2.

    Figure 2
    Figure 2

    Distribution of functional outcomes as measured by modified Rankin Scale (mRS) scores obtained at 90-day follow-up in SELECT trial patients who presented within 6 hours of last known well with computed tomography (CT) ASPECTS of 6–10, stratified by ischemic core volume (relative cerebral blood flow (rCBF) <30%) on CT perfusion.

    Despite a favorable ASPECTS score, patients who presented within 6 hours with an ischemic core of 50 mL or larger demonstrated significantly less functional independence (26% vs 58%, P=0.003) and greater mortality (48% vs 9%, P<0.001), symptomatic intracerebral hemorrhage (ICH) (17% vs 5%, P=0.038), and neurological worsening (26% vs 8%, P=0.009) when compared with patients who presented with a favorable ASPECTS and smaller ischemic core. Additionally, the functional independence rate of 26% in the favorable ASPECTS/large core on CTP group in SELECT is similar to the functional independence rate of 26.5% in the control group from HERMES, further supporting equipoise in this patient subgroup.

    In addition, there are many examples of studies that randomized a subgroup of uncertain benefit even if that subgroup had been included in a prior randomized study that showed benefit in the total population. For example, the PRISMS study evaluated the efficacy and safety of intravenous thrombolysis in a subgroup of patients who were included in the original NINDS tissue plasminogen activator (tPA) studies.21 Subsequent endarterectomy studies have also identified subgroups that did not benefit, even though they were included in prior positive studies.22

    What is the evidence for benefit in patients with CTP core volumes of 50–70 mL in the late time window?

    Data from DEFUSE 3 were used to argue that we already have definitive evidence that core volumes of 50–70 mL benefit from late window EVT.23 However, only half of the subgroup they cite with core “larger than DAWN” (n=18) had ischemic core of >50 mL. This analysis reported cOR 20.9 (95% CI 1.3 to 337.8) while adjusting only for age and National Institutes of Health Stroke Scale (NIHSS). This evidence is far from precise or sufficient. Additionally, these data are limited to the 6–16 hour window. The DAWN trial inclusion criteria did not allow patients with core volume >50 mL, thus there is no evidence on these patients beyond 16 hours. The limited evidence for EVT efficacy in early window patients with core volumes >50 mL is described above.

    However, we acknowledge that core lesions between 50 and 70 mL are not considered by all to be “large core” and therefore we have prespecified a sensitivity analysis in the statistical analysis plan that assess EVT efficacy and safety with and without this subgroup.

    Data regarding patients with low ASPECTS and favorable CTP core volumes

    Another group of interest are those with poor ASPECTS but moderate core volumes and significant penumbra. These patients have been shown to have substantial treatment effects in high-quality randomized studies, and some of these patients had ASPECT scores <6.6 12 For example, patients enrolled in DEFUSE 3 with an ASPECTS of 5 had a median core size of 30 mL and large penumbral volumes. In the SELECT EVT group, the median CTP core volume for patients with ASPECTS of 5 was 25 (IQR 14–43) mL. For those with ASPECTS of 4 the median CTP core was 59 (IQR 36–80) mL.24

    This subgroup of patients with poor ASPECTS/favorable CTP (that are included in the ongoing ASPECTS-only randomized controlled trials) had higher rates of functional independence and a much better safety profile in SELECT as compared with the good ASPECTS/unfavorable CTP (see figure 3).24

    Figure 3
    Figure 3

    Proportion of functional independence and safety outcomes stratifying by computed tomography (CT) and CT perfusion (CTP) profiles in patients receiving thrombectomy in the SELECT trial. Patients with favorable profiles on both imaging modalities demonstrated the highest functional independence and lowest rates of safety outcomes. Patients with unfavorable CT but favorable CTP demonstrated moderately reduced functional independence with similar safety outcomes to patients with a favorable profile on both imaging modalities. Patients with favorable CT but unfavorable CTP had lower functional independence and high rates of symptomatic intracranial hemorrhage (ICH), neurological worsening, and mortality. Reprinted with permission from John Wiley & Sons, Inc. All rights reserved.

    Additionally, a pooled analysis from SELECT and TREVO registry also demonstrated marked variability in outcomes in patients with ASPECTS of 3–5 with differing baseline ischemic core volumes.25 As core volume increased, functional independence decreased, while symptomatic ICH and mortality substantially increased. These findings highlight the heterogeneity of outcomes in patients with large core on CT ASPECTS based on the core volume assessed by perfusion imaging. This point influenced the design of SELECT2: the availability of both CT-based ASPECTS and CTP-based ischemic core volumes will allow for an assessment of EVT treatment effect heterogeneity which is not possible in the studies that only assess ASPECTS. It is plausible, as has already been shown (SELECT+TREVO results), that thrombectomy outcomes in patients with large core based on ASPECTS vary based on their CTP core volumes.

    The argument regarding not enrolling patients where treatment benefits have been “proven” in prior studies could equally apply to patients with an ASPECTS of 4 or 5 with small–moderate CTP core volumes and a large mismatch who are eligible for enrollment in studies that the commentary authors are involved with.

    Inter-rater agreement for ASPECTS

    As demonstrated recently by Van Horn et al from the TENSION trial investigators, even after ASPECTS training, one in three readings from study neuroradiologists resulted in misclassification on non-contrast CT based on TENSION eligibility criteria (0–2 vs 3–5 vs 6–8) in 20 illustrative cases.26 The potential consequences of inaccurate ASPECTs readings during the trial may threaten the validity and reproducibility of the study results.

    We have accounted for the potential reliability concerns with ASPECTS in SELECT2 since the trial assesses large core on both CT and perfusion and evaluates the heterogeneity of thrombectomy effects in the different subgroups to allow a comprehensive assessment of the large core population.

    Risk of early stopping for efficacy or futility

    A concern raised was that SELECT2 might be stopped early because the patients with a large CTP core had a substantial benefit, while the large ASPECTS core patients may not show a statistical difference due to lack of power. This hypothetical concern is extremely unlikely to occur. The entire trial will be stopped early only if there is overwhelming efficacy in the entire population. A dominating effect in one subgroup is highly unlikely in SELECT2 given the substantial overlap between large CTP core and large ASPECTS core patients when both modalities are acquired.27 SELECT2 has a prespecified sensitivity analysis that assesses EVT efficacy and safety both with and without the large CTP core/ASPECTS 6–10 subgroup. Additionally, all patients’ data and subgroups of interest are reviewed regularly by our data and safety board (DSMB) of world-renowned experts in the field.

    Similar issues of concern can be raised regarding studies that enroll patients entirely based on ASPECT scores. For example, if the ASPECTS-based studies are negative, we will not know if this is because the penumbral subgroup had benefit and the non-penumbral group did not, since there is no assessment of penumbra. If the studies are marginally positive, it is possible that they could reflect a substantial treatment effect in the penumbral patients and no treatment effect, or even some harm, in the non-penumbral patients. In addition, because inter-rater agreement on ASPECTS is only moderate, it is highly likely that some patients with site-read ASPECTS of <6 will be determined to have a higher ASPECTS on the core laboratory read by expert neuroradiologists.

    Ultimately, the SELECT2 trial and the ASPECTS-based selection trials will all be needed to help evaluate the question of EVT in large core patients.

    Conclusions

    In conclusion, the editorialists, who are involved in complementary large core trials, assume they already know the answer as to whether EVT is beneficial in early window patients with a large CTP core and favorable ASPECTS, but they are relying on limited, low-quality evidence. Since ASPECTS is insensitive to irreversible ischemic changes in the early hours after symptom onset, some patients with very poor collaterals develop large regions of irreversible injury prior to the degree of injury being reflected in a low ASPECT score. As supported by the data presented above, these patients may or may not benefit from EVT and SELECT2 is the only study designed to clarify this issue.

    The importance of the SELECT2 trial in addressing a critical area of therapeutic uncertainty has been supported by 30 institutional review boards, hundreds of investigators, and the United States Food and Drug Administration who have carefully considered the SELECT2 protocol and approved participation in the study. We look forward to the data from SELECT2 and other ongoing large core trials as we are confident that all of these trials will contribute to moving the field forward.

    Data availability statement

    Data are available upon reasonable request from the corresponding author.

    References

    1. ↵
      2. Jadhav AP ,
      3. Hacke W ,
      4. Dippel DWJ , et al
      . Select wisely: the ethical challenge of defining large core with perfusion in the early time window. J Neurointerv Surg 2021;13:499–501.doi:10.1136/neurintsurg-2021-017386 pmid:http://www.ncbi.nlm.nih.gov/pubmed/33875552
      OpenUrlPubMed
    2. ↵
      2. Berkhemer OA ,
      3. Fransen PSS ,
      4. Beumer D , et al
      . A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11–20.doi:10.1056/NEJMoa1411587 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25517348
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      2. Goyal M ,
      3. Demchuk AM ,
      4. Menon BK , et al
      . Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019–30.doi:10.1056/NEJMoa1414905 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25671798
      OpenUrlCrossRefPubMed
    4. ↵
      2. Saver JL ,
      3. Goyal M ,
      4. Bonafe A , et al
      . Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015;372:2285–95.doi:10.1056/NEJMoa1415061 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25882376
      OpenUrlCrossRefPubMed
    5. ↵
      2. Jovin TG ,
      3. Chamorro A ,
      4. Cobo E , et al
      . Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015;372:2296–306.doi:10.1056/NEJMoa1503780 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25882510
      OpenUrlCrossRefPubMed
    6. ↵
      2. Campbell BCV ,
      3. Mitchell PJ ,
      4. Kleinig TJ , et al
      . Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015;372:1009–18.doi:10.1056/NEJMoa1414792 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25671797
      OpenUrlCrossRefPubMed
    7. ↵
      2. Lansberg MG ,
      3. Straka M ,
      4. Kemp S , et al
      . MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study. Lancet Neurol 2012;11:860–7.doi:10.1016/S1474-4422(12)70203-X pmid:http://www.ncbi.nlm.nih.gov/pubmed/22954705
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      2. Albers GW
      . Late window paradox. Stroke 2018;49:768–71.doi:10.1161/STROKEAHA.117.020200 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29367336
      OpenUrlFREE Full Text
    9. ↵
      2. Olivot J-M ,
      3. Albucher J-F ,
      4. Guenego A , et al
      . Mismatch profile influences outcome after mechanical thrombectomy. Stroke 2021;52:232–40.doi:10.1161/STROKEAHA.120.031929 pmid:http://www.ncbi.nlm.nih.gov/pubmed/33349010
      OpenUrlPubMed
    10. ↵
      2. Hassan AE
      . New technology add-on payment (NTAP) for viz LVO: a WIN for stroke care. J Neurointerv Surg 2021;13:406–8.doi:10.1136/neurintsurg-2020-016897 pmid:http://www.ncbi.nlm.nih.gov/pubmed/33234600
      OpenUrlFREE Full Text
    11. ↵
      2. Austein F ,
      3. Riedel C ,
      4. Kerby T , et al
      . Comparison of perfusion CT software to predict the final infarct volume after thrombectomy. Stroke 2016;47:2311–7.doi:10.1161/STROKEAHA.116.013147 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27507864
      OpenUrlAbstract/FREE Full Text
    12. ↵
      2. Albers GW ,
      3. Marks MP ,
      4. Kemp S , et al
      . Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018;378:708–18.doi:10.1056/NEJMoa1713973 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29364767
      OpenUrlCrossRefPubMed
    13. ↵
      2. Campbell BCV ,
      3. Majoie CBLM ,
      4. Albers GW , et al
      . Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data. Lancet Neurol 2019;18:46–55.doi:10.1016/S1474-4422(18)30314-4 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30413385
      OpenUrlCrossRefPubMed
    14. ↵
      2. Albers GW ,
      3. Goyal M ,
      4. Jahan R , et al
      . Ischemic core and hypoperfusion volumes predict infarct size in SWIFT PRIME. Ann Neurol 2016;79:76–89.doi:10.1002/ana.24543 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26476022
      OpenUrlCrossRefPubMed
    15. ↵
      2. Hoving JW ,
      3. Marquering HA ,
      4. Majoie CBLM , et al
      . Volumetric and spatial accuracy of computed tomography perfusion estimated ischemic core volume in patients with acute ischemic stroke. Stroke 2018;49:2368–75.doi:10.1161/STROKEAHA.118.020846 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30355095
      OpenUrlPubMed
    16. ↵
      2. Martins N ,
      3. Aires A ,
      4. Mendez B , et al
      . Ghost infarct core and admission computed tomography perfusion: redefining the role of neuroimaging in acute ischemic stroke. Interv Neurol 2018;7:513–21.doi:10.1159/000490117 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30410531
      OpenUrlCrossRefPubMed
    17. ↵
      2. Legault C ,
      3. Lansberg M ,
      4. Heit J , et al
      . Abstract TP66: optimizing CT perfusion thresholds for identification of ischemic core in hyperacute stroke. Stroke 2019;50:ATP66. doi:10.1161/str.50.suppl_1.TP66
    18. ↵
      2. Najm M ,
      3. Al-Ajlan FS ,
      4. Boesen ME , et al
      . Defining CT perfusion thresholds for infarction in the golden hour and with ultra-early reperfusion. Can J Neurol Sci 2018;45:339–42.doi:10.1017/cjn.2017.287 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29455683
      OpenUrlPubMed
    19. ↵
      2. Albers GW ,
      3. Thijs VN ,
      4. Wechsler L , et al
      . Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60:508–17.doi:10.1002/ana.20976 pmid:http://www.ncbi.nlm.nih.gov/pubmed/17066483
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      2. Campbell BCV ,
      3. Ma H ,
      4. Ringleb PA , et al
      . Extending thrombolysis to 4·5-9 H and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data. Lancet 2019;394:139–47.doi:10.1016/S0140-6736(19)31053-0 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31128925
      OpenUrlCrossRefPubMed
    21. ↵
      2. Khatri P ,
      3. Kleindorfer DO ,
      4. Devlin T , et al
      . Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits: the PRISMS randomized clinical trial. JAMA 2018;320:156–66.doi:10.1001/jama.2018.8496 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29998337
      OpenUrlPubMed
    22. ↵
      2. Kernan WN ,
      3. Ovbiagele B ,
      4. Black HR , et al
      . Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:2160–236.doi:10.1161/STR.0000000000000024 pmid:http://www.ncbi.nlm.nih.gov/pubmed/24788967
      OpenUrlAbstract/FREE Full Text
    23. ↵
      2. Leslie-Mazwi TM ,
      3. Hamilton S ,
      4. Mlynash M , et al
      . DEFUSE 3 Non-DAWN patients. Stroke 2019;50:618–25.doi:10.1161/STROKEAHA.118.023310 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30727856
      OpenUrlPubMed
    24. ↵
      2. Sarraj A ,
      3. Hassan AE ,
      4. Grotta J , et al
      . Optimizing patient selection for endovascular treatment in acute ischemic stroke (SELECT): a prospective, multicenter cohort study of imaging selection. Ann Neurol 2020;87:419–33.doi:10.1002/ana.25669 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31916270
      OpenUrlCrossRefPubMed
    25. ↵
      2. Sarraj A ,
      3. Hassan A ,
      4. Grotta J , et al
      . LB8 - Endovascular thrombectomy outcomes in large core on CT are strongly associated with perfusion core volume and time: implications from two large cohorts for future trials, 2019. Available: https://www.abstractsonline.com/pp8/?&_ga=2.182712485.2033359330.1614910857-723606518.1614910857#!/4715/presentation/13354 [Accessed 3 Apr 2021].
    26. ↵
      2. van Horn N ,
      3. Kniep H ,
      4. Broocks G , et al
      . ASPECTS interobserver agreement of 100 investigators from the TENSION study. Clin Neuroradiol 2021. doi:doi:10.1007/s00062-020-00988-x. [Epub ahead of print: 27 Jan 2021].pmid:http://www.ncbi.nlm.nih.gov/pubmed/33502563
    27. ↵
      2. Sarraj A ,
      3. Hassan AE ,
      4. Savitz S , et al
      . Outcomes of endovascular thrombectomy vs medical management alone in patients with large ischemic cores: a secondary analysis of the optimizing patient's selection for endovascular treatment in acute ischemic stroke (SELECT) study. JAMA Neurol 2019;76:1147–56.doi:10.1001/jamaneurol.2019.2109 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31355873
      OpenUrlPubMed

    Footnotes

    • Twitter @amrsarrajMD, @marcriboj, @dr_mchen, @VitorMendesPer1, @DrPatchiz, @PascalJabbourMD, @AdamArthurMD

    • Collaborators SELECT2 Investigators and SELECT2 Steering Committee.

    • Contributors AS designed and drafted the manuscript and provided administrative support. GWA designed and drafted the manuscript and provided critical revisions. BC, MR, MSH, MC, MGA, MGL, VMP, SB, CWS, RFB, NPO, JFA, TW, JB, MM, JS, JPT, NS, OK, DG, SW, DC, NWM, TJK, JMO, LE, GT, AA, PJ, BY, SEK, ASA, MP, JCG, and AEH provided critical revisions to the manuscript.

    • 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 AS reports serving as the Principal Investigator (PI) for SELECT, SELECT2, a site PI for DEFUSE 3, and a speaker bureau and advisory board member in Stryker. MR reports serving as a site PI and steering committee member for SELECT2, and holds consulting agreement for Medtronic, Stryker, Cerenovus, Anaconda Biomed, Apta Targets, Sanofi, and reports serving as a speakers bureau member for: Philips, UCB Pharma, Ischemia View, and reports ownership in Anaconda Biomed, and Methinks. MSH reports receiving fees for consulting for Cerenovus, and reports serving as a member on DSMB for Rapid Medical, and DSMB for Cerenovus, and a steering committee member and a site PI for SELECT2. MGL reports serving as a steering committee member for SELECT2, and PI for DEFUSE 3. BY reports serving as a co-PI for SELECT2 and DIRECTS SAFE. JFA reports having received honoraria as speaker/consultant for the following companies: BI, Pfizer, Daiichi, Bayer, Amgen, and Medtronic; and reports serving as a site PI on SELECT2. The institutions where JFA works have received research funding from Spanish Ministry of Economy, European Comission, and Castilla y León Departments of Health and Education. JMO receives consulting fees from Aptoll, Abbvie, Medtronic, and reports receiving speaker fees from Pfizer, Bristol Myers Squibb. LE reports serving as a site PI on SELECT2 and a sonsultant for Cerenovus, Medtronic, VizAI, Microvention, and Scientia. AA reports serving as a speaker bureau member and consultant for NovaSignal, Longeviti, and Siemens. NW Manning reports serving as a site PI on SELECT2, and a consultant for Balt, Stryker, Microvention and Medtronic. CWS reports serving as an Imaging Core Lab member for SELECT and SELECT2. SEK reports serving as a site PI on SELECT2, and reports receiving consultant fees from Medtronic, receiving grants non-relevant to this work from WL Gore, Medtronic, Bristol-Myers Squibb, and other fees from Bristol-Myers Squibb (consultant), Abbvie (consultant), UpToDate (royalties), and Elsevier (royalties). ASA reports serving as a consultant for Balt, Johnson and Johnson, Medtronic, Microvention, Penumbra, Scientia, Siemens, Stryker, and reports receiving research support from Balt, Medtronic, Microvention, Penumbra, and Siemens, and is a shareholder at Azimuth, Bendit, Cerebrotech, Endostream, Magneto, Marblehead, Mentice, Neurogami, Serenity, Synchron, Triad Medical, and Truvic. MP reports research partnership with Siemens, Apollo Medical Imaging, and Canon; and reports serving as an advisory boards member for Medtronic, Boehringer Ingelheim. AEH reports serving as a consultant/speaker for Medtronic, Microvention, Stryker, Penumbra, Cerenovus, Genentech, GE Healthcare, Scientia, Balt; a site PI on SELECT2 and COMPLETE study – Penumbra, LVO SYNCHRONISE; steering committee/publication committee member for SELECT, DAWN, SELECT2, EXPEDITE II, EMBOLISE, CLEAR; a Proctor for Pipeline, FRED, Wingspan, and Onyx; and is supported by grants from GE Healthcare, Valley Baptist. GWA reports serving as a steering committee member for SELECT2, PI for DEFUSE 3, and reports receiving consulting fees for iSV and Genentech and has equity interest in iSV. BC, MGA, MC, SB, RFB, NPO, TW, JB, MM, JS, JPT, NS, OK, DG, SW, DC, and TJK report serving as site PIs for SELECT2. VMP, GT, PJ, and JCG report no relevant disclosures and no conflicts of interest to this work.

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

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