Enlightenment and Challenges Offered by DAWN Trial (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo)
2017; Lippincott Williams & Wilkins; Volume: 49; Issue: 2 Linguagem: Inglês
10.1161/strokeaha.117.018560
ISSN1524-4628
AutoresGustavo Saposnik, Daniel Strbian,
Tópico(s)Stroke Rehabilitation and Recovery
ResumoHomeStrokeVol. 49, No. 2Enlightenment and Challenges Offered by DAWN Trial (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBEnlightenment and Challenges Offered by DAWN Trial (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) Gustavo Saposnik, MD, MSc, PhDc, FRCPC and Daniel Strbian, MD, PhD, MSc, FESO Gustavo SaposnikGustavo Saposnik From the Division of Neurology, Department of Medicine and Outcomes and Decision Neuroscience Research Unit, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, ON, Canada (G.S.); Laboratory for Social and Neural Systems Research, Department of Economics, University of Zurich, Switzerland (G.S.); and Department of Neurology, Helsinki University Central Hospital, Finland (D.S.). and Daniel StrbianDaniel Strbian From the Division of Neurology, Department of Medicine and Outcomes and Decision Neuroscience Research Unit, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, ON, Canada (G.S.); Laboratory for Social and Neural Systems Research, Department of Economics, University of Zurich, Switzerland (G.S.); and Department of Neurology, Helsinki University Central Hospital, Finland (D.S.). Originally published14 Dec 2017https://doi.org/10.1161/STROKEAHA.117.018560Stroke. 2018;49:498–500is corrected byCorrection to: Enlightenment and Challenges Offered by DAWN Trial (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo)Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2017: Previous Version 1 IntroductionOur greatest weakness lies in giving up. The most certain way to succeed is always to try just one more time (Science: A Collection of Quotes; Sapiens Hub 2017).—Thomas A. Edison (1847–1931)We are in a brand new era of acute stroke care led by 3 monumental achievements: (1) new reperfusion therapies, (2) expansion of the time window when there is still enough brain tissue to save, and (3) better understanding of the role of neuroimaging (eg, diffusion-weighted magnetic resonance imaging or perfusion computed tomographic use for decision-making in reperfusion therapies).The current management of acute ischemic stroke has only very recently dramatically changed with the publication of randomized trials using endovascular thrombectomy (EVT).1–4 Meta-analysis and pooled analysis from these trials consistently revealed an average 2.5×-fold reduction in disability (odds ratio, 2.49; 95% confidence interval, 1.76–3.53; P<0.0001) of EVT (plus SD) in large-vessel occlusions compared with intravenous tPA (tissue-type plasminogen activator) alone.2 The observed benefits comprised different subgroups irrespective of age, sex, stroke severity, location of the occlusion (internal carotid artery versus M1), and time to treatment ( 300 minutes).2,5 As a result, physicians caring for acute stroke patients were given a brand new therapeutic arsenal but might also face more complex decisions (eg, stretching the benefits of EVT trials into real-world practice, subgroups with concomitant—and less investigated—comorbid conditions, time to transfer patients to a tertiary care institution, etc).Recent analysis showed a rapid decay of clinical benefit with EVT after 7.3 hours from the time of last seen well.6 Importantly, we learned about the identification of imaging patterns for patient selection that are associated with higher or lower likelihood of achieving a favorable outcome with reperfusion therapies (eg, collateral flow, infarct volume, tissue susceptibility, mismatch, etc).7–10The DAWN trial (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo)11 combines novel paradigms for a successful treatment of patients with an acute ischemic stroke by pushing the time window to 24 hours from last known well (LKW) and using imaging versus clinical mismatch. The rationale behind expanding the time window to wake-up strokes can be explained by a time×tissue equation describing the final fate of the to be infarcted brain tissue. In other words, the clinical outcomes do not only depend on time of reperfusion but perhaps more importantly, on a function of tissue perfusion (sustained by collateral flow and regional susceptibility to early ischemic changes).12,13DAWN is a multicenter study using a prospective randomized open blinded end-point (PROBE) design that randomized patients with a proven large-vessel occlusion (intracranial internal carotid artery, M1 segment of the MCA, or both) to receiving EVT (TREVO stent retriever catheter) plus medical treatment (MT) versus MT alone. An eligible participant had LKW (wake-up stroke, unwitnessed and witnessed strokes) within 6 to 24 hours at the time of randomization and a National Institutes of Health Stroke Scale (NIHSS) score of ≥10 (or 20) and prespecified size of infarct volumes (see below 3 patient categories), which could not involve more than one third of the territory of the MCA at baseline. The primary outcome included a weighted modified Rankin Scale (mRS) to optimize capturing health states transitions and the classic dichotomized mRS score of 0 to 2 versus 3 to 6. The authors also defined an enrichment criterion to characterize the clinical benefits based on the core infarct size. Stopping rules included the enrichment criterion and the probability of a treatment effect ≥0.986 if the intervention was deemed efficacious. DAWN was originally planned to include 500 participants, but the Data and Safety Monitoring Board recommended to stop the trial after an interim analysis, by the time of which 206 participants (107 TREVO+MT versus 99 MT) were recruited.What Were the Main Findings?Although age and NIHSS were nicely balanced between the groups (median age was 72 years [interquartile range], and the median NIHSS was 17), there were several imbalances, too. The median interval between time that patient was last known to be well and randomization was 12.2 and 13.3 hours in the active and control groups, respectively. Further, the median time from first symptoms observation to randomization was 4.8 and 5.6 hours, respectively, and participants in the control group had a slightly higher size of infarct volume (median 8.9 versus 7.6 mL), had more frequently >80 years of age (29% versus 23%), less commonly history of atrial fibrillation (24% versus 40%), and more often history of diabetes mellitus (31% versus 24%). Overall, recanalization was observed in 77% of the active group and 39% of controls; 84% of participants in the active arm achieved an modified Treatment in Cerebral Infarction ≥2B (anterograde reperfusion of more than half of previously occluded target artery). Participants randomized to the active arm were 2-fold more likely to have an improvement in their neurological status (odds ratio, 2.1; 95% confidence interval, 1.20–3.12) and more likely to achieve independence at 90 days (odds ratio, 36%; 95% confidence interval, 24%–47%). The authors identified an amazing number needed to treat of 2 for any lower disability at that prespecified time. There was no difference in mortality between groups, but this is not surprising given the relatively small numbers and 3-month follow-up. In as much as 21% of the participants, in-person assessment of the mRS was not possible and was performed as telephone interview with patients, caregivers, or both. The benefits in favor of EVT and medical management remained consistent when compared participants LKW within and beyond 12 hours. There was a reduction in the median size of the core infarct in the active arm compared with controls (8 versus 22 mL; P≤0.001).What Have We Learned From the DAWN Trial?EVT compared with MT is associated with an improvement in clinical outcomes (>70% relative reduction in disability) and higher likelihood of achieving independency for eligible patients with a confirmed large vascular occlusion treated within 24 hours from LKW.A clinical-core mismatch as defined by the DAWN trials seems a relevant selection criterion independent of the time of presentation, which was previously shown in recanalization treatment of another large-vessel occlusion: the basilar artery occlusion.14 This approach represents a paradigm shift in acute stroke care.Patients classified as wake-up stroke would benefit from reperfusion therapies as defined in DAWN trial. For example, participants randomized to thrombectomy arm of the trial plus medical management were more likely to have a wake-up stroke than those in the control group (63% versus 47%) and less frequently unwitnessed stroke (27% versus 38%). This imbalance is of utmost importance and has practical implications for clinicians: last time seen well should be differentiated from the first time seen unwell. We have to realize that most patients randomized in DAWN trials were wake-up strokes (more commonly in the intervention group) with an average time since last seen well of 13 hours, but 5 hours from the time of first observation of stroke symptoms.Generalizability of results: readers may want to bear in mind that a smaller proportion of stroke patients evaluated for reperfusions therapies may be eligible for EVT given that the number of eligible patients could be >15 to 20:1 ratio or less, depending on the method for imaging selection.The authors used a restricted criteria based on the presence of clinical-imaging mismatch defined by age, NIHSS, and infarct core. Participants who qualified based on the RAPID computed tomography perfusion/magnetic resonance imaging criteria had relatively small core infarctions (median infarction volume=8 cc [interquartile range 2–18]). In other words, we have limited understanding on the therapeutic benefits among patients with larger core infarcts (also importantly, patients with ischemia involving more than one third of the MCA at baseline were excluded).What Are Practical Clinical Challenges After DAWN Trial?The translation of DAWN results into our practice requires a more thoughtful process. First, the expansion of time window by including wake-up strokes would change the dynamics of the drip-and-ship and discussions about transfers to tertiary stroke centers. However, some skeptical readers may appreciate the gap between LKW and time from first symptoms observation (≈5 hours) and smaller infarct volumes, both suggesting that the great majority of patients received reperfusion therapies (active and controls) within 6 hours in DAWN trial. This is similar to participants in previous EVT trials, thus limiting the time window expansion.As a result, it is unclear how clinicians would apply the selection criteria used in DAWN into their own clinical practice.Second, not all eligible patients would qualify for EVT under the same paradigm. Participants of DAWN were selected for inclusion and randomization to thrombectomy or control if they had a small infarct core in relation to their age and NIHSS score. For example, patients aged >80 had to have an NIHSS score of >10 and a core volume 10 and a core 20 and a core 5 as in the ESCAPE trial [Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times]),8 but would not qualify as per DAWN criteria. Another consideration is the lack of availability of computed tomographic perfusion imaging/DWI in some host institutions, which would limit the implementation of DAWN trial for wake-up strokes or consideration to transfer to tertiary stroke centers.The authors are to be commended toward applying innovative strategies for patient selection by including participants who would otherwise had no hope with reperfusion therapies before DAWN. In the view of acute stroke management during the past 2 decades, this change truly is from Dusk till DAWN.Paraphrasing Carl Sagan, "our species needs, and deserves, a citizenry with minds wide awake and a basic understanding of how the world works" (Science: A Collection of Quotes; Sapiens Hub 2017). We are in the right direction toward better understanding how to treat large-vessel occlusions and, therefore, ameliorate the effects of stroke.DisclosuresDr Saposnik is supported by the Heart and Stroke Foundation of Canada Career Award following an open and peer-reviewed competition. The other author reports no conflicts.Footnotes*Drs Saposnik and Strbian contributed equally.Correspondence to Gustavo Saposnik, MD, MSc, PhDc, FRCPC, Department of Medicine (Neurology), Stroke Outcomes and Decision Neuroscience Research Unit, St. Michael's Hospital, University of Toronto, 55 Queen St E, Toronto, ON M5C 1R6, Canada. E-mail [email protected]References1. Bush CK, Kurimella D, Cross LJ, Conner KR, Martin-Schild S, He J, et al. Endovascular treatment with stent-retriever devices for acute ischemic stroke: a meta-analysis of Randomized Controlled Trials.PLoS One. 2016; 11:e0147287. doi: 10.1371/journal.pone.0147287.CrossrefMedlineGoogle Scholar2. 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Kim B, Kim H, Jeong H, Yang M, Jung C, Han M, Kim J, Demchuk A and Bae H (2018) Tenacity of Collateral Perfusion in Proximal Cerebral Arterial Occlusions 6–12 h after Onset, Cerebrovascular Diseases, 10.1159/000489894, 45:5-6, (263-269), . Related articlesCorrection to: Enlightenment and Challenges Offered by DAWN Trial (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo)Stroke. 2018;49:e38-e38 February 2018Vol 49, Issue 2 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.117.018560PMID: 29242390 Manuscript receivedNovember 15, 2017Manuscript acceptedNovember 21, 2017Originally publishedDecember 14, 2017Manuscript revisedNovember 20, 2017 Keywordsreperfusiontime windowreviewneuroimagingclinical trialPDF download Advertisement SubjectsIschemic StrokeMortality/Survival
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