Late Window Paradox
2018; Lippincott Williams & Wilkins; Volume: 49; Issue: 3 Linguagem: Inglês
10.1161/strokeaha.117.020200
ISSN1524-4628
Autores Tópico(s)Acute Ischemic Stroke Management
ResumoHomeStrokeVol. 49, No. 3Late Window Paradox Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBLate Window Paradox Gregory W. Albers, MD Gregory W. AlbersGregory W. Albers From the Department of Neurology, Stanford University, Palo Alto, CA. Originally published24 Jan 2018https://doi.org/10.1161/STROKEAHA.117.020200Stroke. 2018;49:768–771The mantra of acute stroke therapy, time is brain is a call to arms that motivates both the public and medical practitioners to treat stroke as a time-critical emergency. Countless articles have documented inexorable declines in favorable clinical outcomes associated with delayed administration of thrombolytic or endovascular therapies. Therefore, one would naturally anticipate that the benefits of endovascular therapy would be markedly more modest if treatment is delayed many hours beyond the guideline-recommended 6-hour therapeutic window. How then do we explain the remarkably robust results of DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) and DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo), 2 recently published trials of endovascular therapy initiated up to 16 to 24 hours after patients were last known well?Larger Benefits With Later TreatmentDAWN randomized patients at a median of 12.5 hours from onset and documented the largest absolute increase in functional independence ever reported in any acute stroke treatment trial, 35.5%.1 DEFUSE 3 randomized patients at a median of 11 hours after onset and documented a 28% increase in functional independence and an additional 20% absolute reduction in death or severe disability, which represents the largest reduction in mortality/severe disability ever achieved.2 By comparison, the pooled analysis of 5 modern early window thrombectomy trials (HERMES [Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials]) revealed an absolute increase in functional independence of 19.5% and a reduction in mortality/severe disability of 11%3 (Figure 1). Both early and late window studies included patients of similar ages, baseline National Institutes of Health Stroke Scale scores, and vessel occlusion sites. Patients were treated with the same modern thrombectomy devices and reperfusion was achieved in similar proportions of patients in the endovascular arms of the early and late window studies. So why was the treatment effect larger in the late window trials?Download figureDownload PowerPointFigure 1. Favorable outcome rates in early vs late window thrombectomy trials. Note that good outcome rates in the late window vs early window trials are similar in the endovascular groups, but the outcomes are less favorable in the control groups of the late window trials. Therefore, the treatment effect is larger in the late window studies (absolute increase in modified Rankin Scale score of 0–2, 19% early window vs 32% late window, P=0.006, Breslow–Day test). The HERMES study3 pooled the results of 5 early window endovascular trials. DAWN indicates DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo; DEFUSE 3, Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3; and HERMES, Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials.Explaining the Paradox by Understanding Stroke EvolutionAn understanding of the evolution of ischemic core lesions and the imaging-based selection criteria used in these studies offers an explanation for the apparent paradox. Several studies have performed magnetic resonance imaging scans on stroke patients with large artery occlusions at various time points after symptom onset. These studies have consistently documented that the growth of early diffusion-weighted imaging (DWI) lesions (which provides a reliable estimate of the ischemic core) varies substantially between patients.4 Some patients, typically individuals with very poor collaterals, develop very large DWI lesions within 2 to 3 hours, whereas other patients have little or no DWI lesion growth for 12 hours or longer. Although some fortunate patients never develop a large infarct despite a persistent large artery occlusion, the vast majority of the slow growers with large vessel occlusions will eventually develop an extensive infarction. However, it typically takes 3 days for the maximum DWI volume to be achieved in nonreperfused patients.4,5The DEFUSE 2 study (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study 2) assessed DWI growth rates in patients with middle cerebral artery or internal carotid artery occlusion.4 Remarkably, ≈50% of these patients had very slow early growth rates, with DWI volumes 50 mL/h, substantial infarct growth would be expected over that 2-hour period between imaging and reperfusion. Some of these patients likely had already achieved their final infarct volume by the time they were randomized. Others likely completed their infarct between the time of initial imaging and when reperfusion was achieved. In either case, no treatment benefit would be anticipated for these patients with completed infarcts, even if they are successfully reperfused. For patients in the medium growth category, infarct growth between baseline imaging and reperfusion would be anticipated to be modest which likely would lead to a favorable response to reperfusion. For patients in the favorable green category, expected growth between imaging and reperfusion would be minimal and very favorable outcomes anticipated after reperfusion, even if the procedure is challenging and reperfusion is significantly delayed. In the medical therapy arm, patients with large intracranial occlusions who do not reperfuse generally do poorly, especially the red patients with poor collaterals who rapidly develop very large infarctions. Among patients in the medical therapy arms who achieve early reperfusion after tPA (tissue-type plasminogen activator) therapy, outcomes comparable to the thrombectomy group would be expected. The considerations summarized above likely explain the relatively modest absolute benefits documented in THRACE (absolute increase in the rate of achieving an modified Rankin Scale score of 0–2 of 11%) and MR CLEAN (14%).Early Window Trials With Small Infarct Cores and Salvageable TissueNow let us consider the early window trials that restricted enrollment to patients with smaller ischemic core lesions (<50 mL in SWIFT PRIME [Solitaire™ With the Intention for Thrombectomy as Primary Endovascular Treatment Trial] and 50 mL were excluded in SWIFT PRIME and >70 mL excluded in EXTEND-IA). *Data for SWIFT PRIME12 includes only patients with the target mismatch profile. EXTEND-IA indicates Extending the Time for Thrombolysis in Emergency Neurological Deficits—Intra-Arterial; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; and SWIFT PRIME, Solitaire™ With the Intention for Thrombectomy as Primary Endovascular Treatment Trial.Late Window TrialsFinally, let us look at the late window trials, DAWN and DEFUSE 3. DAWN enrolled patients based on a clinical-core mismatch with maximum infarct core volumes of 20, 30, or 50 mL, depending on patients' age and National Institutes of Health Stroke Scale score.1 DEFUSE 3 used a hypoperfusion-core mismatch and allowed core volumes up to 70 mL as long as there was a substantial volume of salvageable tissue evident on perfusion imaging.2 Similar to EXTEND-IA and SWIFT PRIME, both studies used automated software (RAPID, iSchemaView, Menlo Park) to determine the ischemic core, and in DEFUSE 3, the penumbra volumes.13 Either computed tomography (CT) perfusion or magnetic resonance imaging diffusion/perfusion were allowed based on recent data showing that with the use of appropriate thresholds and analysis techniques, CT perfusion is able estimate the ischemic core with accuracy that is comparable to magnetic resonance imaging.14,15 Because of the requirement for small core volumes in extended time windows, the vast majority of patients enrolled in both DAWN and DEFUSE 3 were in the green slow growing core category. In fact, the majority of patients in these trials were enrolled at >10 hours and had core volumes of ≤10 mL—these patients had early growth rates of ≤1/mL hour before enrollment! For these patients, even a 2- to 3-hour delay between imaging and reperfusion would not be anticipated to lead to any consequential infarct growth. Because these patients had proximal middle cerebral artery or internal carotid artery occlusions, a very large volume of penumbral salvage would be anticipated if substantial or complete reperfusion is obtained. However, for the medical arm patients in these late window trials, very poor outcomes would be anticipated for 2 key reasons. (1) No intravenous tPA therapy was administered in >90% of these patients—therefore the ≈35% to 40% reperfusion rate seen in patients with favorable imaging profiles who are treated with tPA9,10 did not occur, and patients who achieved early spontaneous reperfusion were excluded. (2) Eventually, the collateral circulation fails and infarcts evolve into the region of critical hypoperfusion.4 Based on perfusion imaging, the volume of tissue at risk is typically substantial in patients with middle cerebral artery or internal carotid artery occlusions, even if good collaterals are present. Only a minority (probably <10%) of these patients have collaterals that are adequate to assure a favorable outcome in the absence of reperfusion. The bottom line is that the medical therapy arms patients in the late window trials had extremely low rates of good outcome, whereas the endovascular arms had favorable outcome rates that were comparable to the early window trials. Therefore, the absolute benefit was larger in the late window studies.Paradox DecipheredIn summary, the critical factors that explain the paradox are (1) a substantial percentage of patients with large vessel intracranial occlusions have very slow growth of the ischemic core for up to 12 hours or longer; (2) the favorable collateral circulation that is responsible for keeping the ischemic core size small eventually fails in most patients and infarct volumes ultimately increase; and (3) clinical outcomes in the control groups of the randomized trials are strongly influenced by whether or not tPA was administered. Therefore, late arriving patients with large vessel occlusions and small infarct core volumes can have extremely robust treatment effects.Clinical ImplicationsThe "time is brain" concept requires a 2018 revision that is more generous than the original and provides a reprieve for the fortunate patients who have favorable collaterals and slow infarct growth. However, because it is not possible to immediately determine the growth rate of the ischemic core, it remains critical to evaluate all stroke patients as urgently as possible. For those who arrive early with a large ischemic core lesion, randomized trials are needed to clarify whether thrombectomy is beneficial. Further research is also needed to clarify whether patients who are transferred within 6 hours of onset to comprehensive centers, with a CT angiography-documented large vessel occlusion and an eligible noncontrast CT, require repeat imaging at the thrombectomy site. The advantage of repeat imaging is that patients who have developed a very large infarct core, suffered hemorrhagic transformation, or experienced reperfusion while in transit, can be spared a resource-intensive invasive procedure. The disadvantage is that for patients with rapid growth rates, the additional time required for imaging may result in less salvageable tissue. Stroke patients in whom thrombectomy can be initiated within 6 to 24 hours should be screened with advanced imaging to determine whether they meet DEFUSE 3 or DAWN criteria for late window thrombectomy. Both late window studies required CT perfusion or DWI to assess the size of the ischemic core and, in DEFUSE 3, CT or magnetic resonance perfusion imaging to estimate the volume of penumbral tissue. Therefore, because access to acute magnetic resonance imaging remains limited, CT perfusion will be required to select late window stroke patients for thrombectomy at most hospitals. As more primary stroke centers begin to perform advanced imaging, these data should be rapidly shared with the comprehensive center to help optimize triage decisions.DisclosuresDr Albers has an equity interest in iSchemaView and is a consultant for iSchemaView and Medtronic.Sources of FundingDEFUSE 3 was funded by the National Institutes of Health (grants U10NS086487 and U01NS092076), Principal Investigator, Dr Albers.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Gregory W. Albers, MD, Department of Neurology, Stanford University, 780 Welch Rd, Suite 350 Palo Alto, CA 94035. E-mail [email protected]References1. Nogueira RG, Jadhav AP, Haussen DC, et al. 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