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Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study.

ABSTRACT: Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI).In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 microg/kg desmoteplase, 125 microg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852.Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 microg/kg desmoteplase; 66 received 125 microg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10.6 cm(3) and 52.5 cm(3), respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 microg/kg desmoteplase, 36% (24 of 66) for 125 microg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 microg/kg desmoteplase 14.0% (0.5 cm(3)); 125 microg/kg desmoteplase 10.8% (0.3 cm(3)); placebo -10.0% (-0.9 cm(3)). The rates of symptomatic intracranial haemorrhage were 3.5% (2 of 57) for 90 microg/kg desmoteplase, 4.5% (3 of 66) for 125 microg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 microg/kg desmoteplase; 21% [14 of 66] for 125 microg/kg desmoteplase; and 6% [4 of 63] for placebo).The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase.PAION Deutschland GmbH; Forest Laboratories.

SUBMITTER: Hacke W

PROVIDER: S-EPMC2730486 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study.

Hacke Werner W Furlan Anthony J AJ Al-Rawi Yasir Y Davalos Antoni A Fiebach Jochen B JB Gruber Franz F Kaste Markku M Lipka Leslie J LJ Pedraza Salvador S Ringleb Peter A PA Rowley Howard A HA Schneider Dietmar D Schwamm Lee H LH Leal Joaquin Serena JS Söhngen Mariola M Teal Phil A PA Wilhelm-Ogunbiyi Karin K Wintermark Max M Warach Steven S

The Lancet. Neurology 20081225 2

<h4>Background</h4>Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI).<h4>Methods</h4>In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT ima ...[more]

PMID: 19097942

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Project description:OBJECTIVES:Diffusion-weighted imaging (DWI) and the introduction of the intravoxel incoherent motion (IVIM) model have provided a unique method for evaluating perfusion and diffusion within a tissue without the need for a contrast agent. Despite its relevance, cardiac DWI has thus far been limited by low b values because of signal loss induced by physiological motion. The goal of this study was to develop a methodology for estimating IVIM parameters of in vivo cardiac magnetic resonance imaging using an efficient DWI acquisition framework. This was achieved by investigating various acquisition strategies (principal component analysis [PCA] filtering and temporal maximum intensity projection [PCATMIP] and single trigger delay [TD]) and fitting methods. MATERIAL AND METHODS:Simulations were performed on a synthetic dataset of diffusion-weighted signal intensity (SI) to determine the fitting method that would yield IVIM parameters with the greatest accuracy. The required number of b values to correctly estimate IVIM parameters was also investigated. Breath-hold DWI scans were performed for 12 volunteers to collect several TD values during diastole. Thirteen b values ranging from 0 to 550 s/mm were used. The IVIM parameters derived using the data from all the acquired TDs (PCATMIP technique) were compared with those derived using a single acquisition performed at an optimized diastolic time point (1TD). RESULTS:The main result of this study was that PCATMIP, when combined with a fitting model that accounted for T1 and T2 relaxation, provided IVIM parameters with less variability. However, an acquisition performed with 1 optimized diastolic TD provided results that were as good as those provided using PCATMIP if the R-R variability during the acquisition was sufficiently low (± 5%). Furthermore, the use of only 9 b values (that could be acquired in 2 breath-holds), instead of 13 b values (requiring 3 breath-holds), was sufficient to determine the IVIM parameters. CONCLUSIONS:This study demonstrates that IVIM is technically feasible in vivo and reports for the first time the perfusion fraction, f, and the diffusion coefficients, D and D*, for the cardiac DWI of healthy volunteers. Motion-induced signal loss, which is the main problem associated with cardiac DWI, could be avoided with the combined use of sliding acquisition during the cardiac cycle and image postprocessing with the PCATMIP algorithm. This study provides new perspectives for perfusion imaging without a contrast agent and demonstrates that IVIM parameters can act as promising tools to further characterize microvascular abnormalities or dysfunction.

Project description:BackgroundAn accurate prediction of tissue outcome in acute ischemic stroke patients is of high interest for treatment decision making. To date, various machine learning models have been proposed that combine multi-parametric imaging data for this purpose. However, most of these machine learning models were trained using voxel information extracted from the whole brain, without taking differences in susceptibility to ischemia into account that exist between brain regions. The aim of this study was to develop and evaluate a local tissue outcome prediction approach, which makes predictions using locally trained machine learning models and thus accounts for regional differences.Material and methodsMulti-parametric MRI data from 99 acute ischemic stroke patients were used for the development and evaluation of the local tissue outcome prediction approach. Diffusion (ADC) and perfusion parameter maps (CBF, CBV, MTT, Tmax) and corresponding follow-up lesion masks for each patient were registered to the MNI brain atlas. Logistic regression (LR) and random forest (RF) models were trained employing a local approach, which makes predictions using models individually trained for each specific voxel position using the corresponding local data. A global approach, which uses a single model trained using all voxels of the brain, was used for comparison. Tissue outcome predictions resulting from the global and local RF and LR models, as well as a combined (hybrid) approach were quantitatively evaluated and compared using the area under the receiver operating characteristic curve (ROC AUC), the Dice coefficient, and the sensitivity and specificity metrics.ResultsStatistical analysis revealed the highest ROC AUC and Dice values for the hybrid approach. With 0.872 (ROC AUC; LR) and 0.353 (Dice; RF), these values were significantly higher (p < 0.01) than the values of the two other approaches. In addition, the local approach achieved the highest sensitivity of 0.448 (LR). Overall, the hybrid approach was only outperformed in sensitivity (LR) by the local approach and in specificity by both other approaches. However, in these cases the effect sizes were comparatively small.ConclusionThe results of this study suggest that using locally trained machine learning models can lead to better lesion outcome prediction results compared to a single global machine learning model trained using all voxel information independent of the location in the brain.

Project description:ObjectiveThrombus microfragmentation causing peripheral emboli (PE) during mechanical thrombectomy (MT) may modulate treatment effects, even in cases with successful reperfusion. This study aims to investigate whether intravenous alteplase is of potential benefit in reducing PE after successful MT.MethodsPatients from a prospective study treated at a tertiary care stroke center between 08/2017 and 12/2019 were analyzed. The main inclusion criterion was successful reperfusion after MT (defined as expanded thrombolysis in cerebral infarction (eTICI) scale ≥ 2b50) of large vessel occlusion anterior circulation stroke. All patients received a high-resolution diffusion-weighted imaging (DWI) follow-up 24 h after MT for PE detection. Patients were grouped as "direct MT" (no alteplase) or as MT plus additional intravenous alteplase. The number and volume of ischemic core lesions and PE were then quantified and analyzed.ResultsFifty-six patients were prospectively enrolled. Additional intravenous alteplase was administered in 46.3% (26/56). There were no statistically significant differences of PE compared by groups of direct MT and additional intravenous alteplase administration regarding mean numbers (12.1, 95% CI 8.6-15.5 vs. 11.1, 95% CI 7.0-15.1; p = 0.701), and median volume (0.70 mL, IQR 0.21-1.55 vs. 0.39 mL, IQR 0.10-1.62; p = 0.554). In uni- and multivariable linear regression analysis, higher eTICI scores were significantly associated with reduced PE, while the administration of alteplase was neither associated with numbers nor volume of peripheral emboli. Additional alteplase did not alter reperfusion success.ConclusionsIntravenous alteplase neither affects the number nor volume of sub-angiographic DWI-PE after successful endovascular reperfusion. In the light of currently running randomized trials, further studies are warranted to validate these findings.Key points• Thrombus microfragmentation during endovascular stroke treatment may cause peripheral emboli that are only detectable on diffusion-weighted imaging and may directly compromise treatment effects. • In this prospective study, the application of intravenous alteplase did not influence the occurrence of peripheral emboli detected on high-resolution diffusion-weighted imaging. • A higher degree of recanalization was associated with a reduced number and volume of peripheral emboli and better functional outcome, while contrariwise, peripheral emboli did not modify the effect of recanalization on modified Rankin Scale scores at day 90.

Dataset Information

Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study.

Publications

Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study.

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