Endovascular Stroke Therapy in the Late Time Window
2018; Lippincott Williams & Wilkins; Volume: 49; Issue: 10 Linguagem: Inglês
10.1161/strokeaha.118.021003
ISSN1524-4628
AutoresPeter D. Schellinger, Bart M. Demaerschalk,
Tópico(s)Cerebrovascular and Carotid Artery Diseases
ResumoHomeStrokeVol. 49, No. 10Endovascular Stroke Therapy in the Late Time Window Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBEndovascular Stroke Therapy in the Late Time Window Peter D. Schellinger, MD, PhD, FESO and Bart M. Demaerschalk, MD, MSc, FRCP(C) Peter D. SchellingerPeter D. Schellinger Correspondence to Peter D. Schellinger, MD, PhD, FESO, Departments of Neurology and Neurogeriatry, Johannes Wesling Medical Center Minden, University Clinic RUB, Hans-Nolte-Str. 1, D-32429 Minden, Germany. Email E-mail Address: [email protected] From the Johannes Wesling Medical Center Minden, UK RUB, Germany (P.D.S.) and Bart M. DemaerschalkBart M. Demaerschalk Mayo Clinic College of Medicine and Science, Rochester, MN (B.M.D.). Originally published18 Sep 2018https://doi.org/10.1161/STROKEAHA.118.021003Stroke. 2018;49:2559–2561Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: September 18, 2018: Ahead of Print Time is on my side, yes it is. Now you all were saying that you want to be free, But you'll come runnin' back (I said you would baby), You'll come runnin' back (like I told you so many times before)—The Rolling Stones from the albums "12 x 5," 1964 and "The Rolling Stones No. 2," 1965Everything comes at the right time, but if the right time is too late to be patient, go earlier before it becomes too late.—Michael Bassey JohnsonFollowing the publication of the practice-changing trials DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) and DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke),1,2 several editorials and practice commentaries—all worthwhile reading—have addressed various aspects and implications of endovascular therapy in the late time window.3–5 This has led to a change in the most recent American Heart Association6 and European Stroke Organization guidelines (presented at the European Stroke Organization Conference 2018, Gothenburg) for the management of acute ischemic stroke. While the overpowering effect of thrombectomy versus standard treatment beyond 6 hours with a number needed to treat of approximately 2 for an improved clinical outcome in both trials is a breakthrough result in acute ischemic stroke therapy, a closer inspection with regard to the time window itself and also to the proposed imaging-based selection process is warranted. Naturally, the total numbers of intravenous thrombolysis (IVT)-treated patients and M2-branch occlusions was negligible in both trials, the former being a significant factor with regard to the large late time window outcome effect.5Time WindowDAWN and DEFUSE-3 are not the only trials which included patients in a time window later than 6 hours from symptom onset to groin puncture. REVASCAT (Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours)7 recruited subjects up to 8 hours, and ESCAPE (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke)8 recruited subjects up to 12 hours, the results of a further trial (POSITIVE [Perfusion Imaging Selection of Ischemic Stroke Patients for Endovascular Therapy]), which was halted after publication of the DAWN and DEFUSE-3 studies are not yet published. A joint analysis (AURORA [Analysis of Pooled Data From Randomized Studies of Thrombectomy More Than 6 Hours After Last Known Well]) of patients from 4 of the 5 trials (excluding POSITIVE) was recently presented at the European Stroke Organization Conference (Jovin et al, European Stroke Organization Conference 2018) in Gothenburg, (publication is pending), whereas results of the late subgroup of ESCAPE were published last year9 and did not show a heterogeneity of treatment effect between early and late time window patients. In brief, AURORA demonstrated a significant treatment benefit of endovascular therapy versus standard treatment increasing the odds for an improved outcome at day 90 by 2.77 (95% CI, 1.95–3.94; number needed to treat, 2.5), which was a similar result to that published by the Hermes collaboration consisting mostly of within 6 hours patients in 2016.10 There was no difference in the subgroups defined by age, or Alberta Stroke Program Early CT Scores, however, the treatment effect was stronger from 12 to 24 hours than from 6 to 12 hours. It should be mentioned that these results are not surprising as most of the patients in AURORA come from the DAWN and DEFUSE-3 trials. Also, in this whole setting, it should be noted that another trial (WAKE UP [Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke]) for IVT in wake up patients with diffusion-weighted imaging (DWI)/fluid attenuated inversion recovery mismatch within a maximum time of 4.5 hours after wake up was positive.11On the one hand, this illustrates that in keeping with the times and actual data we have now, time from symptom onset can no longer serve as the strongest sole emergency treatment criterion (for decision making over whether to deliver IVT and even more so endovascular therapy for acute ischemic stroke). Time, alone, can most definitely not serve as a lone exclusion criterion for reperfusion therapy, at least within the first 24 hours of last seen normal.3 On the other hand, the idiom "time is brain" should not be abandoned. It remains essential that once the patient suspected of an acute stroke syndrome enters the prehospital, hospital, interhospital, and intrahospital pathways and once the diagnosis of acute ischemic stroke is established, the diagnostic workup, the treatment decision making, and the actual treatment itself must be performed as fast as possible. This obligatory triage includes the definition of a neurovascular imaging pathway that guides practitioners on precisely which kind of imaging is necessary in a given patient with given characteristics in a given time window.ImagingBesides the time windows, an especially narrow and complex set of imaging inclusion and exclusion criteria varied substantially between the 2 trials. DAWN used a stratification by age and National Institutes of Health Stroke Scale score leading to differing maximum infarct core cutoff volumes measured by a specific imaging software in an automated fashion (>80 years core up to 20 mL, <80 years and National Institutes of Health Stroke Scale 10–19 core up to 30 mL, 1.8 (ratio) and 15 mL (penumbra volume), again measured by a specific imaging software in an automated fashion. The median infarct core volume was 8 and 10 mL in DAWN and DEFUSE 3, respectively. More than half of all the trial subjects presented with wake up strokes in both trials. As elaborated by Albers, varying the selection of imaging is a major explanatory factor for varying outcome effect sizes in all the recent trials and especially in the late time window, coining this the "late time window paradox".5 On the other hand, this imaging-based selection approach for late time window patients using MRI and MRI or computed tomography perfusion imaging techniques places high demands on imaging capabilities and capacities at hospital stroke centers, both in regards to availability and presence of the necessary hardware. On top of this, both trials employed a postprocessing software that is not widely available and comes at an additional cost. It is anticipated that in the near future several vendors will render these services, however, in the interim this impacts negatively broad implementation and generalizability. Ultimately, the definition of what constitutes a stroke alert, the criteria on which it is activated, and the response(s) that it generates will be dependent on the characteristics, expertise, and resources available within a regional stroke system of care. One must also consider that the total number of those patients that receive standard IVT (up to 25% of all acute stroke patients) and early time window endovascular therapy (maximum of 10% with significant overlap to IVT) is probably low. According to recent publications the proportion of potential stroke patients for whom DEFUSE-3 and DAWN criteria apply is ≈2.7%.12 We, therefore, believe that imaging selection criteria need to be qualified, for example, applying ESCAPE criteria with computed tomography and computed tomography multiphase angiography and volumetry of computed tomographic angiography-based lesion core as a substitute for DWI13,14 to the DAWN selection process. Alternatively, the ESCAPE approach could be used out to 12 hours. Given the WAKE UP trial,11 one could use simple DWI volumetry on a reduced MRI protocol to still fulfill DAWN criteria; however, a reliable vascular imaging modality would still have to be added, for example, high-quality magnetic resonance angiography. This would allow hospitals with interventional capacity as well as those that drip and ship to select patients without the need to implement high-end MRI and perfusion imaging capacities with the required hardware and postprocessing software specifications. Accordingly, further research is needed on the equivalence of more simplified imaging solutions to select patients within the late time window.ConclusionsFor acute stroke patients, the late and the unknown time window of up to 24 hours after last seen normal is now open for treatment with intravenous as well as with endovascular reperfusion therapies. This applies to patients with witnessed onset of symptoms within 6 to 24 hours and wake up stroke, according to secondary analyses to a lesser extend also to unwitnessed stroke, because they have a comparable benefit. The change to a physiological (imaging-based) approach using various, indirectly implied (DWI / clinical mismatch, DWI / fluid attenuated inversion recovery mismatch, collateral status), as well as more directly (perfusion imaging of core and tissue at risk of infarction) shown subtrates of the ischemic penumbra concept has finally entered the stage. The actual time within a prescribed time window alone is not sufficient to determine eligibility for reperfusion therapy in acute ischemic stroke patients. Still, speed to treatment is invaluable.Treating in the late time window is a major but not the last step into the direction of allowing our stroke patients an access to therapeutic options unheard of fewer than 5 years ago. We concur with Hill and Goyal: identify disabling strokes, image the brain and vessels (quickly) to identify the target patient and then treat fast.3 Although there is justifiable enthusiasm over DAWN and DEFUSE-3 results, the core principles of acute ischemic stroke management have not changed appreciably: waste no time assembling the requisite focused clinical stroke history and examination, waste no time imaging the brain and blood vessels, waste no time synthesizing the clinical and radiological pictures, waste no time declaratively diagnosing, and waste no time offering definitive fast treatment.DisclosuresDr Schellinger received honoraria, travel grants, and consulting fees from Boehringer Ingelheim, Cerevast, and Medtronic (formerly Covidien, EV3) is an expert witness for the German court and is a member of the steering committee for ECASS 4 EXTEND (European Cooperative Stroke Study-4: Extending the Time for Thrombolysis in Emergency Neurological Deficits) and CLOTBUST-ER (Combined Lysis of Thrombus With Ultrasound and Systemic Tissue Plasminogen Activator for Emergent Revascularization in Acute Ischemic Stroke). The other author reports no conflicts.FootnotesCorrespondence to Peter D. Schellinger, MD, PhD, FESO, Departments of Neurology and Neurogeriatry, Johannes Wesling Medical Center Minden, University Clinic RUB, Hans-Nolte-Str. 1, D-32429 Minden, Germany. Email peter.[email protected]deReferences1. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al; DAWN Trial Investigators. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct.N Engl J Med. 2018; 378:11–21. doi: 10.1056/NEJMoa1706442CrossrefMedlineGoogle Scholar2. Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al; DEFUSE 3 Investigators. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging.N Engl J Med. 2018; 378:708–718. doi: 10.1056/NEJMoa1713973CrossrefMedlineGoogle Scholar3. Hill MD, Goyal M. Treat fast but abandon time from ischemic stroke onset as a criterion for treatment: the DAWN and DEFUSE-3 trials.Int J Stroke. 2018; 13:344–347. doi: 10.1177/1747493018769004CrossrefMedlineGoogle Scholar4. Hacke W. A new DAWN for imaging-based selection in the treatment of acute stroke.N Engl J Med. 2018; 378:81–83. doi: 10.1056/NEJMe1713367CrossrefMedlineGoogle Scholar5. Albers GW. Late window paradox.Stroke. 2018; 49:768–771. doi: 10.1161/STROKEAHA.117.020200LinkGoogle Scholar6. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al; American Heart Association Stroke Council. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2018; 49:e46–e110. doi: 10.1161/STR.0000000000000158LinkGoogle Scholar7. Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al; REVASCAT Trial Investigators. 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Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials.Lancet. 2016; 387:1723–1731. doi: 10.1016/S0140-6736(16)00163-XCrossrefMedlineGoogle Scholar11. Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, et al; WAKE-UP Investigators. MRI-guided thrombolysis for stroke with unknown time of onset.N Engl J Med. 2018; 379:611–622. doi: 10.1056/NEJMoa1804355CrossrefMedlineGoogle Scholar12. Jadhav AP, Desai SM, Kenmuir CL, Rocha M, Starr MT, Molyneaux BJ, et al. Eligibility for endovascular trial enrollment in the 6- to 24-hour time window: analysis of a single comprehensive stroke center.Stroke. 2018; 49:1015–1017. doi: 10.1161/STROKEAHA.117.020273LinkGoogle Scholar13. Schramm P, Schellinger PD, Fiebach JB, Heiland S, Jansen O, Knauth M, et al. Comparison of CT and CT angiography source images with diffusion-weighted imaging in patients with acute stroke within 6 hours after onset.Stroke. 2002; 33:2426–2432.LinkGoogle Scholar14. Schramm P, Schellinger PD, Klotz E, Kallenberg K, Fiebach JB, Külkens S, et al. 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Marshall R (2019) Image-Guided Intravenous Alteplase for Stroke — Shattering a Time Window, New England Journal of Medicine, 10.1056/NEJMe1904791, 380:19, (1865-1866), Online publication date: 9-May-2019. October 2018Vol 49, Issue 10 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.118.021003PMID: 30355126 Manuscript receivedJune 11, 2018Manuscript acceptedAugust 9, 2018Originally publishedSeptember 18, 2018Manuscript revisedJuly 30, 2018 Keywordsmagnetic resonance imagingtriagethrombectomyemergency treatmentreperfusionPDF download Advertisement SubjectsAngiographyComputerized Tomography (CT)Magnetic Resonance Imaging (MRI)Treatment
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