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  • Pedraza, Salvador  (7)
  • 2010-2014  (7)
  • 1
    Online Resource
    Online Resource
    Abstract 2600: Refinement of the MR Diffusion-perfusion Mismatch Concept for Thrombolytic Patient Selection: Insights from the Desmoteplase In Acute Stroke Trials
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Stroke Vol. 43, No. suppl_1 ( 2012-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. suppl_1 ( 2012-02)
    Abstract: The DIAS-2 study was the only large, randomized intravenous thrombolytic trial that selected patients based on the presence of ischemic penumbra. However, DIAS-2 did not confirm the positive findings of the smaller DEDAS and DIAS trials, which also used penumbral selection. Therefore a reevaluation of the penumbra selection strategy is warranted. In post-hoc analyses we assessed the relationships of MRI-measured lesion volumes to clinical measures in DIAS-2, and the relationships of the presence and size of the diffusion-perfusion mismatch to the clinical effect of desmoteplase in DIAS-2 (MRI-selected patients) and in pooled data from MRI-selected 90- and 125-μg/kg dose groups in DIAS, DEDAS, and DIAS-2. In DIAS-2, lesion volumes correlated with NIHSS at both baseline and final time points (P 〈 0·0001), and lesion growth was inversely related to good clinical outcome (P=0.004). In the pooled analysis, treatment was associated with 47% clinical response rate in desmoteplase (n=143) versus 34% in placebo (n=73; P=0.08). For both the pooled sample and for DIAS-2, increasing the minimum baseline mismatch volume (MMV) for inclusion increased the desmoteplase effect size, preferentially decreasing the placebo-response rate. There was a trend of statistically significant differences in effect size in ≤60 mL versus 〉 60 mL baseline mismatch subgroups (P=0.083). The odds ratio for good clinical response between desmoteplase and placebo treatment was 2.83 (95% CI, 1.16-6.94, P=0.023) for a MMV 〉 60 mL. Increasing the minimum NIHSS for inclusion did not affect treatment effect size. Pooled across all desmoteplase trials, penumbral selection by MRI diffusion-perfusion mismatch favored desmoteplase clinical benefit, especially for larger MMV. Based on these results, a three-fold reduction in future trial sample size requirements would be achieved using a criterion of baseline MMV 〉 60 mL over any visible mismatch. These results support a modified diffusion-perfusion mismatch hypothesis for patient selection in later-time-window thrombolytic trials.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.43.suppl_1.A2600
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1467823-8
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Refinement of the Magnetic Resonance Diffusion-Perfusion Mismatch Concept for Thrombolytic Patient Selection : Insights From the Desmoteplase in Acute Stroke Trials
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Stroke Vol. 43, No. 9 ( 2012-09), p. 2313-2318
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. 9 ( 2012-09), p. 2313-2318
    Abstract: The DIAS-2 study was the only large, randomized, intravenous, thrombolytic trial that selected patients based on the presence of ischemic penumbra. However, DIAS-2 did not confirm the positive findings of the smaller DEDAS and DIAS trials, which also used penumbral selection. Therefore, a reevaluation of the penumbra selection strategy is warranted. Methods— In post hoc analyses we assessed the relationships of magnetic resonance imaging–measured lesion volumes with clinical measures in DIAS-2, and the relationships of the presence and size of the diffusion-perfusion mismatch with the clinical effect of desmoteplase in DIAS-2 and in pooled data from DIAS, DEDAS, and DIAS-2. Results— In DIAS-2, lesion volumes correlated with National Institutes of Health Stroke Scale (NIHSS) at both baseline and final time points ( P 〈 0.0001), and lesion growth was inversely related to good clinical outcome ( P =0.004). In the pooled analysis, desmoteplase was associated with 47% clinical response rate (n=143) vs 34% in placebo (n=73; P =0.08). For both the pooled sample and for DIAS-2, increasing the minimum baseline mismatch volume (MMV) for inclusion increased the desmoteplase effect size. The odds ratio for good clinical response between desmoteplase and placebo treatment was 2.83 (95% confidence interval, 1.16–6.94; P =0.023) for MMV 〉 60 mL. Increasing the minimum NIHSS score for inclusion did not affect treatment effect size. Conclusions— Pooled across all desmoteplase trials, desmoteplase appears beneficial in patients with large MMV and ineffective in patients with small MMV. These results support a modified diffusion-perfusion mismatch hypothesis for patient selection in later time-window thrombolytic trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique Identifiers: NCT00638781, NCT00638248, NCT00111852.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.111.642348
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1467823-8
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Abstract 2595: Vascular Occlusion as an Imaging Biomarker for Selecting Acute Ischemic Stroke Patients for Treatment with Desmoteplase
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Stroke Vol. 43, No. suppl_1 ( 2012-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. suppl_1 ( 2012-02)
    Abstract: Desmoteplase is a novel, highly fibrin-specific and non-neurotoxic thrombolytic agent. Evidence of safety and efficacy was obtained in two phase II trials (DIAS and DEDAS). The DIAS-2 phase III trial did not replicate the positive phase II efficacy findings. Post-hoc analyses were performed with the aim of predicting treatment responders based on CT and MR angiography. The predictive value of infarct volume and TIMI grade at baseline with respect to drug response measured by clinical outcome at Day 90 was investigated using DIAS-2 data. Patients were grouped according to vessel status (TIMI grade) for logistic regression of clinical response, applying the data from DIAS-2 as well as the pooled data from DIAS, DEDAS, and DIAS-2. In DIAS-2, a substantial number of mismatch-selected patients (126/179, 70%) presented with a normal flow/low-grade stenosis (TIMI 2-3) at screening, the majority having a favorable outcome at Day 90. In contrast, favorable outcome rates in patients with vessel occlusion/high-grade stenosis (TIMI 0-1) were 18% with placebo versus 36% and 27% with desmoteplase 90 and 125 μg/kg, respectively. The clinical effect size based on the pooled data from DIAS, DEDAS, and DIAS-2 was borderline statistically significantly different (P=0.05) in the TIMI 0-1 and TIMI 2-3 subgroups. It was favorable for desmoteplase-treated patients presenting with TIMI 0-1 at baseline (odds ratio, 4.144; 95% CI, 1.40-12.23; P=0.010), while there was no desmoteplase treatment benefit in patients presenting with TIMI 2-3 (odds ratio, 1.109). In this sample of patients diagnosed with a mismatch, proximal vessel occlusion or severe stenosis was associated with clinically beneficial treatment effects of desmoteplase. Selecting patients using CT or MR angiography in clinical trials of thrombolytic therapy is justifiable.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.43.suppl_1.A2595
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1467823-8
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Visual and Region of Interest–Based Inter-Rater Agreement in the Assessment of the Diffusion-Weighted Imaging– Fluid-Attenuated Inversion Recovery Mismatch
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Stroke Vol. 45, No. 4 ( 2014-04), p. 1170-1172
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. 4 ( 2014-04), p. 1170-1172
    Abstract: WAKE-UP is a randomized, placebo-controlled MRI-based trial of thrombolysis in wake-up stroke using the mismatch between a lesion’s visibility in diffusion-weighted imaging and fluid-attenuated inversion recovery (FLAIR) sequences as its main imaging inclusion criterion. Visual judgment of lesion conspicuity on FLAIR is however methodically limited by moderate inter-rater agreement. We therefore sought to improve rating homogeneity by incorporating quantitative signal intensity measurements. Methods— One hundred forty-three data sets of patients with acute ischemic stroke were visually rated by 8 raters with respect to WAKE-UP study inclusion and exclusion criteria, and inter-rater agreement was calculated. A subanalysis was performed on 45 cases to determine a threshold value of relative signal intensity (rSI) between the ischemic lesion and contralateral healthy tissue which best corresponded to a visually established verdict of FLAIR positivity. The usefulness of this threshold in improving inter-rater agreement was evaluated in an additional sample of 50 patients. Results— Inter-rater agreement for inclusion into the WAKE-UP trial was 73% with a free-marginal κ of 0.46. A threshold of rSI which best correlated with the visual rating of lesions as FLAIR positive was 1.20. The addition of rSI measurements to visual evaluation did not change the inter-rater agreement. Conclusions— Introducing a semiquantitative measure for FLAIR rSI did not improve the agreement between individual raters. However, enhancing visual assessment with rSI measurements can provide reassurance to local investigators in cases of uncertainty.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.113.002661
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1467823-8
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  • 5
    Online Resource
    Online Resource
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Test Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-up Stroke (WAKE-UP)
    SAGE Publications ; 2014
    In:  International Journal of Stroke Vol. 9, No. 6 ( 2014-08), p. 829-836
    Details
    In: International Journal of Stroke, SAGE Publications, Vol. 9, No. 6 ( 2014-08), p. 829-836
    Abstract: In about 20% of acute ischemic stroke patients stroke occurs during sleep. These patients are generally excluded from intravenous thrombolysis. MRI can identify patients within the time-window for thrombolysis (≤4·5 h from symptom onset) by a mismatch between the acute ischemic lesion visible on diffusion weighted imaging (DWI) but not visible on fluid-attenuated inversion recovery (FLAIR) imaging. Aims and hypothesis The study aims to test the efficacy and safety of MRI-guided thrombolysis with tissue plasminogen activator (rtPA) in ischemic stroke patients with unknown time of symptom onset, e.g., waking up with stroke symptoms. We hypothesize that stroke patients with unknown time of symptom onset with a DWI-FLAIR-mismatch pattern on MRI will have improved outcome when treated with rtPA compared to placebo. Design WAKE-UP is an investigator initiated, European, multicentre, randomized, double-blind, placebo-controlled clinical trial. Patients with unknown time of symptom onset who fulfil clinical inclusion criteria (disabling neurological deficit, no contraindications against thrombolysis) will be studied by MRI. Patients with MRI findings of a DWI-FLAIR-mismatch will be randomised to either treatment with rtPA or placebo. Study outcome The primary efficacy endpoint will be favourable outcome defined by modified Rankin Scale 0–1 at day 90. The primary safety outcome measures will be mortality and death or dependency defined by modified Rankin Scale 4–6 at 90 days. Discussion If positive, WAKE-UP is expected to change clinical practice making effective and safe treatment available for a large group of acute stroke patients currently excluded from specific acute therapy.
    Type of Medium: Online Resource
    ISSN: 1747-4930 , 1747-4949
    URL: Article
    DOI: 10.1111/ijs.12011
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2014
    detail.hit.zdb_id: 2211666-7
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  • 6
    Online Resource
    Online Resource
    Vascular Occlusion Enables Selecting Acute Ischemic Stroke Patients for Treatment With Desmoteplase
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Stroke Vol. 43, No. 6 ( 2012-06), p. 1561-1566
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. 6 ( 2012-06), p. 1561-1566
    Abstract: Desmoteplase is a novel and highly fibrin-specific thrombolytic agent. Evidence of safety and efficacy was obtained in 2 phase II trials (Desmoteplase In Acute Ischemic Stroke [DIAS] and Desmoteplase for Acute Ischemic Stroke [DEDAS] ). The DIAS-2 phase III trial did not replicate the positive phase II efficacy findings. Post hoc analyses were performed with the aim of predicting treatment responders based on CTA and MRA. Methods— Patients were grouped according to vessel status (Thrombolysis In Myocardial Infarction [TIMI] grade) for logistic regression of clinical response, applying the data from DIAS-2 as well as the pooled data from DIAS, DEDAS, and DIAS-2. Results— In DIAS-2, a substantial number of mismatch-selected patients (126/179; 70%) presented with a normal flow/low-grade stenosis (TIMI 2–3) at screening, with the majority having a favorable outcome at day 90. In contrast, favorable outcome rates in patients with vessel occlusion/high-grade stenosis (TIMI 0–1) were 18% with placebo versus 36% and 27% with desmoteplase 90 and 125 μg/kg, respectively. The clinical effect based on the pooled data from DIAS, DEDAS, and DIAS-2 was favorable for desmoteplase-treated patients presenting with TIMI 0 to 1 at baseline (OR, 4.144; 95% CI, 1.40–12.23; P =0.010). There was no desmoteplase treatment benefit in patients presenting with TIMI 2 to 3 (OR, 1.109). Conclusions— In this sample of patients with a mismatch diagnosed, proximal vessel occlusion or severe stenosis was associated with clinically beneficial treatment effects of desmoteplase. Selecting patients using CTA or MRA in clinical trials of thrombolytic therapy is justifiable. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00638781, NCT00638248, NCT00111852.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.111.642322
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1467823-8
    Location Call Number Limitation Availability
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    Online Resource
  • 7
    Online Resource
    Online Resource
    Acute Stroke Imaging Research Roadmap II
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Stroke Vol. 44, No. 9 ( 2013-09), p. 2628-2639
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. 9 ( 2013-09), p. 2628-2639
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.113.002015
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1467823-8
    Location Call Number Limitation Availability
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    Online Resource
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