A Multicentre, Randomized, Double-Blinded, Placebo-Controlled Phase III Study to Investigate Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND)

Ma, Henry; Parsons, Mark; Christensen, Søren; Campbell, Bruce; Чурилов, Леонид; Connelly, Alan; Yan, Bernard; Bladin, Chris; Phan, Than; Barber, P. Alan; Read, Stephen; Hankey, Graeme J.; Markus, Romesh; Wijeratne, Tissa; Grimley, Rohan; Mahant, Neil; Kleinig, Timothy; Sturm, John; Lee, A.; Blacker, David; Gerraty, Richard; Krause, Martín; Desmond, Patricia; McBride, Simon; Carey, Leanne; Howells, David W.; Hsu, Chung Y.; Davis, Stephen M.; Donnan, Geoffrey A.

doi:10.1111/j.1747-4949.2011.00730.x

Cited by 183 publications

(153 citation statements)

References 23 publications

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“…Infarct core was defined as the region of acute DWI lesion that lay within the coregistered final infarct. Mismatch was defined as a ratio of perfusion lesion volume (threshold T max > 6 seconds) to diffusion lesion volume > 1.2 and absolute difference > 10 mL as employed in the current EXTEND randomized trial of IV thrombolysis in patients 4.5 to 9 hours after the stroke onset (Ma et al, 2011). To analyze the effect of DLR on mismatch classification, mismatch was compared using two definitions of the diffusion lesion volume: (1) the raw diffusion lesion volume and (2) the raw diffusion lesion volume after subtraction of the apparent reversal volume.…”

Section: Methodsmentioning

confidence: 99%

The Infarct Core is Well Represented by the Acute Diffusion Lesion: Sustained Reversal is Infrequent

Campbell

Purushotham

Christensen

et al. 2011

J Cereb Blood Flow Metab

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179

156

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Diffusion-weighted imaging (DWI) is commonly used to assess irreversibly infarcted tissue but its accuracy is challenged by reports of diffusion lesion reversal (DLR). We investigated the frequency and implications for mismatch classification of DLR using imaging from the EPITHET (Echoplanar Imaging Thrombolytic Evaluation Trial) and DEFUSE (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) studies. In 119 patients (83 treated with IV tissue plasminogen activator), follow-up images were coregistered to acute diffusion images and the lesions manually outlined to their maximal visual extent in diffusion space. Diffusion lesion reversal was defined as voxels of acute diffusion lesion that corresponded to normal brain at follow-up (i.e., final infarct, leukoaraiosis, and cerebrospinal fluid (CSF) voxels were excluded from consideration). The appearance of DLR was visually checked for artifacts, the volume calculated, and the impact of adjusting baseline diffusion lesion volume for DLR volume on perfusion-diffusion mismatch analyzed. Median DLR volume reduced from 4.4 to 1.5 mL after excluding CSF/leukoaraiosis. Visual inspection verified 8/119 (6.7%) with true DLR, median volume 2.33 mL. Subtracting DLR from acute diffusion volume altered perfusion-diffusion mismatch (T max > 6 seconds, ratio > 1.2) in 3/119 (2.5%) patients. Diffusion lesion reversal between baseline and 3 to 6 hours DWI was also uncommon (7/65, 11%) and often transient. Clinically relevant DLR is uncommon and rarely alters perfusion-diffusion mismatch. The acute diffusion lesion is generally a reliable signature of the infarct core.

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Section: Methodsmentioning

confidence: 99%

The Infarct Core is Well Represented by the Acute Diffusion Lesion: Sustained Reversal is Infrequent

Campbell

Purushotham

Christensen

et al. 2011

J Cereb Blood Flow Metab

Self Cite

179

156

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“…[1][2][3][4] In both techniques, maps of regional hemodynamic parameters like CBF or CBV are derived from dynamic images that quantify the concentrations of an intravenously injected contrast agent as it passes through the brain. Clinical studies often omit consideration of the postprocessing algorithms that convert concentration measurements to perfusion maps, implicitly accepting their accuracy.…”

mentioning

confidence: 99%

Exposing Hidden Truncation-Related Errors in Acute Stroke Perfusion Imaging

Copen¹,

Deipolyi²,

Schaefer³

et al. 2014

AJNR Am J Neuroradiol

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“…The experience from re-analyses of EPITHET and DEFUSE data has led to refined definitions of mismatch with more restrictive definitions of the perfusion lesion [22,23]. These adapted definitions are used in the ongoing Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) trial [24]. It has already been proposed to extend the concept of perfusion-diffusion mismatch to the identification of wake-up stroke patients that are likely to benefit from thrombolysis [25][26][27].…”

Section: Imaging Approaches To Guide Treatment In Wake-up Strokementioning

confidence: 99%

“…The EXTEND study is a randomized, multicenter, double-blind, placebo-controlled phase III trial of intravenous thrombolysis with rt-PA in ischemic stroke patients [24]. Patients can be enrolled if treatment can be initiated within 3 h (or 4.5 h depending on local practice) up to 9 h of symptom onset or in case of wake-up stroke if the midpoint between sleep onset (or last known to be normal) and time of waking up is at maximum 9 h. Further clinical inclusion criteria include a National Institutes of Health Stroke Scale (NIHSS) score of 4-26.…”

Section: Clinical Trials Of Thrombolysis In Wake-up Strokementioning

confidence: 99%

Treating Wake-Up Stroke Patients

Thomalla

Fiehler

2013

Curr Radiol Rep

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In 20-25 % of stroke patients, stroke occurs during sleep. Due to the missing information on time of symptom onset, these patients with ''wake-up stroke'' are excluded from treatment with intravenous thrombolysis based on licensing criteria. Within the past years, however, new approaches to guide treatment in wake-up stroke patients have been suggested and are currently being tested in clinical trials. This article gives an overview of imaging and clinical characteristics of wake-up stroke patients and recent approaches to guide treatment in these patients. Penumbral imaging using multiparametric MRI including diffusion-weighted imaging (DWI) and perfusion imaging or multiparametric CT including CT perfusion is hypothesized to identify stroke patients with tissue at risk independent from time of symptom onset who might benefit from reperfusion treatment. This approach is currently being tested in the EXTEND trial, which also allows for randomization of wake-up stroke patients. A different approach is the use of multiparametric MRI to estimate lesion age in patients with unknown time of symptom onset based on the characteristic course of signal changes and MR parameter changes. The mismatch between a visible lesion on DWI and normal FLAIR (DWI-FLAIR mismatch) identifies patients that are likely to be within a time window of 4.5 h of symptom onset and thus likely to benefit from intravenous thrombolysis. This concept is used to enroll patients in the European randomized controlled WAKE-UP trial of MRIbased thrombolysis in patients with unknown time of symptom onset. The results of these clinical trials are expected to change clinical practice and to improve the treatment of wake-up stroke patients in the near future.

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A Multicentre, Randomized, Double-Blinded, Placebo-Controlled Phase III Study to Investigate Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND)

Cited by 183 publications

References 23 publications

The Infarct Core is Well Represented by the Acute Diffusion Lesion: Sustained Reversal is Infrequent

The Infarct Core is Well Represented by the Acute Diffusion Lesion: Sustained Reversal is Infrequent

Exposing Hidden Truncation-Related Errors in Acute Stroke Perfusion Imaging

Treating Wake-Up Stroke Patients

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