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Yasir Alrawi - One of the best experts on this subject based on the ideXlab platform.
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refinement of the magnetic resonance diffusion perfusion mismatch concept for thrombolytic patient selection insights from the Desmoteplase in acute stroke trials
Stroke, 2012Co-Authors: Steven Warach, Yasir Alrawi, Anthony J Furlan, Jochen B Fiebach, Salvador Pedraza, Max Wintermark, Annika Lindsten, Jamal Smyej, David B Bharucha, Howard A RowleyAbstract:Background and Purpose—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=...
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vascular occlusion enables selecting acute ischemic stroke patients for treatment with Desmoteplase
Stroke, 2012Co-Authors: Jochen B Fiebach, Yasir Alrawi, Anthony J Furlan, Max Wintermark, Howard A Rowley, Annika Lindsten, Jamal Smyej, Paul Eng, Steven Warach, Salvador PedrazaAbstract:Background and Purpose— 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: . Unique identifiers: [NCT00638781][1], [NCT00638248][2], [NCT00111852][3]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00638781&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00638248&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00111852&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom
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abstract 2595 vascular occlusion as an imaging biomarker for selecting acute ischemic stroke patients for treatment with Desmoteplase
Stroke, 2012Co-Authors: Jochen B Fiebach, Yasir Alrawi, Anthony J Furlan, Max Wintermark, Howard A Rowley, Annika Lindsten, Jamal Smyej, Paul Eng, Steven Warach, Salvador PedrazaAbstract: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.
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abstract 2600 refinement of the mr diffusion perfusion mismatch concept for thrombolytic patient selection insights from the Desmoteplase in acute stroke trials
Stroke, 2012Co-Authors: Steven Warach, Yasir Alrawi, Anthony J Furlan, Jochen B Fiebach, Salvador Pedraza, Max Wintermark, Annika Lindsten, Jamal Smyej, David B Bharucha, Howard A RowleyAbstract: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 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.
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Desmoteplase in acute massive pulmonary thromboembolism
Thrombosis and Haemostasis, 2009Co-Authors: U Tebbe, Peter Bramlage, Andreas Graf, Peter Lechleitner, Christoph Bode, Friedrichchristian Riess, Norbert Clemens, Yasir Alrawi, Stavros Konstantinides, Samuel Z GoldhaberAbstract:Alteplase is standard therapy for patients with acute, massive pulmonary embolism. The novel plasminogen activator Desmoteplase displays high fibrin specificity and selectivity for fibrinbound plasminogen. In a preclinical model Desmoteplase was twice as potent with a shorter lysis time and lower reocclusion rate. We conducted a phase II study comparing 125, 180, and 250 microg/kg bodyweight Desmoteplase with 100 mg alteplase. Efficacy criteria were total pulmonary resistance (TPR), mean pulmonary artery pressure (mPAP), and Miller Index. Intention to treat analysis of 34 patients. The reduction of TPR after 24 hours was comparable between Desmoteplase 180 microg/kg and alteplase (-48.0 +/- 22.4 vs. -50.4 +/- 16.3%; p = n.s. vs. alteplase; p = 0.0002 and p<0.0001 vs. baseline). The greatest effect was achieved with Desmoteplase 250 microg/kg (-56.0 +/- 29.4%; p = n.s. vs. alteplase, p = 0.0055 vs. baseline). Two hours after treatment PAP was reduced by 27.9 (p = 0.0004 vs. baseline) and 30.4% (p = 0.015 vs. baseline) with the higher doses of Desmoteplase and 29.6% with alteplase (p = 0.0006 vs. baseline). Further PAP reduction after 6 hours was most pronounced in the Desmoteplase 250 microg/kg group (-40.1 +/- 18.0%; p = 0.0028 vs. baseline). The reduction of the Miller Index was greatest using Desmoteplase 250 microg/kg (-35.0 +/- 21.7%; p = 0.011 vs. baseline), and alteplase (-41.6 +/- 27.2%; p = 0.0003 vs. baseline). Safety did not differ among the 4 groups. The study results suggest that Desmoteplase at doses of 180 and 250 microg/kg had similar or greater efficacy compared to alteplase 100 mg. Onset of action was faster, safety was comparable.
Anthony J Furlan - One of the best experts on this subject based on the ideXlab platform.
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refinement of the magnetic resonance diffusion perfusion mismatch concept for thrombolytic patient selection insights from the Desmoteplase in acute stroke trials
Stroke, 2012Co-Authors: Steven Warach, Yasir Alrawi, Anthony J Furlan, Jochen B Fiebach, Salvador Pedraza, Max Wintermark, Annika Lindsten, Jamal Smyej, David B Bharucha, Howard A RowleyAbstract:Background and Purpose—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=...
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vascular occlusion enables selecting acute ischemic stroke patients for treatment with Desmoteplase
Stroke, 2012Co-Authors: Jochen B Fiebach, Yasir Alrawi, Anthony J Furlan, Max Wintermark, Howard A Rowley, Annika Lindsten, Jamal Smyej, Paul Eng, Steven Warach, Salvador PedrazaAbstract:Background and Purpose— 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: . Unique identifiers: [NCT00638781][1], [NCT00638248][2], [NCT00111852][3]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00638781&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00638248&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00111852&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom
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abstract 2595 vascular occlusion as an imaging biomarker for selecting acute ischemic stroke patients for treatment with Desmoteplase
Stroke, 2012Co-Authors: Jochen B Fiebach, Yasir Alrawi, Anthony J Furlan, Max Wintermark, Howard A Rowley, Annika Lindsten, Jamal Smyej, Paul Eng, Steven Warach, Salvador PedrazaAbstract: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.
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abstract 2600 refinement of the mr diffusion perfusion mismatch concept for thrombolytic patient selection insights from the Desmoteplase in acute stroke trials
Stroke, 2012Co-Authors: Steven Warach, Yasir Alrawi, Anthony J Furlan, Jochen B Fiebach, Salvador Pedraza, Max Wintermark, Annika Lindsten, Jamal Smyej, David B Bharucha, Howard A RowleyAbstract: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 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.
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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
Lancet Neurology, 2009Co-Authors: Werner Hacke, Yasir Alrawi, Anthony J Furlan, Antoni Davalos, Jochen B Fiebach, Franz Gruber, Markku Kaste, Leslie J Lipka, Salvador Pedraza, Peter A RinglebAbstract:Summary Background 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). Methods 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 μg/kg Desmoteplase, 125 μg/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. Findings Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 μg/kg Desmoteplase; 66 received 125 μg/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 μg/kg Desmoteplase, 36% (24 of 66) for 125 μg/kg Desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 μg/kg Desmoteplase 14·0% (0·5 cm 3 ); 125 μg/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 μg/kg Desmoteplase, 4·5% (3 of 66) for 125 μg/kg Desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 μg/kg Desmoteplase; 21% [14 of 66] for 125 μg/kg Desmoteplase; and 6% [4 of 63] for placebo). Interpretation 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. Funding PAION Deutschland GmbH; Forest Laboratories.
Robert L Medcalf - One of the best experts on this subject based on the ideXlab platform.
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t pa but not Desmoteplase induces plasmin dependent opening of a blood brain barrier model under normoxic and ischaemic conditions
Brain Research, 2014Co-Authors: Roxann Freeman, Beeri Niego, David R Croucher, Lars Pedersen, Robert L MedcalfAbstract:Abstract Tissue-type plasminogen activator (t-PA) is the only thrombolytic treatment available for patients with acute ischaemic stroke. However, t-PA can increase permeability of the blood-brain barrier (BBB). Desmoteplase is a plasminogen activator derived from the common vampire bat, currently under clinical development for ischaemic stroke. We compared how t-PA and Desmoteplase influenced BBB permeability using a human in vitro model where primary brain endothelial cells (BEC) and astrocytes are co-cultured on the opposite sides of a porous membrane. Permeability changes were evaluated 6 or 24 h post-stimulation by passage of fluorescent albumin across the membrane. Under normoxic conditions, t-PA, but not Desmoteplase, increased BBB permeability. Surprisingly, the ability of t-PA to affect the barrier was lost under conditions of oxygen-glucose deprivation (OGD). Addition of plasminogen re-sensitised the BBB to the action of t-PA under both normoxia and OGD, but did not affect the inert behaviour of Desmoteplase, even when digested fibrinogen was added to ensure optimal plasmin generation. These observations coincided with plasmin-dependent changes in astrocyte and BEC morphology and disruption of tight junction proteins in BECs, specifically initiated by t-PA but not by Desmoteplase. Finally, inhibition of plasmin post-stimulation with t-PA and plasminogen, especially within 2 h, protected the BBB against t-PA-mediated barrier opening. Hence t-PA, but not Desmoteplase, increases BBB permeability under both normoxic and OGD conditions in a reversible, plasmin-dependent process. The inability of Desmoteplase to increase permeability despite its capacity to generate plasmin provides further support for its use as thrombolytic in patients with ischaemic stroke.
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Desmoteplase discovery insights and opportunities for ischaemic stroke
British Journal of Pharmacology, 2012Co-Authors: Robert L MedcalfAbstract:Nature has provided a vast array of bioactive compounds that have been exploited for either diagnostic or therapeutic use. The field of thrombosis and haemostasis in particular has enjoyed much benefit from compounds derived from nature, notably from snakes and blood-feeding animals. Indeed, the likelihood that blood-feeding animals would harbour reagents with relevant pharmacology and with potential pharmaceutical benefit in haemostasis was not too far-fetched. Blood-feeding animals including leeches and ticks have evolved a means to keep blood from clotting or to at least maintain the liquid state, and some of these have been the subject of clinical development. A more recent example of this has been the saliva of the common vampire bat Desmodus rotundus, which has proven to harbour a veritable treasure trove of novel regulatory molecules. Among the bioactive compounds present is a fibrinolytic compound that was shown over 40 years ago to be a potent plasminogen activator. Studies of this vampire bat-derived plasminogen activator, more recently referred to as Desmoteplase, revealed that this protease shared a number of structural and functional similarities to the human fibrinolytic protease, tissue-type plasminogen activator (t-PA) yet harboured critically important differences that have rendered this molecule attractive for clinical development for patients with ischaemic stroke.
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Desmoteplase mediated plasminogen activation and clot lysis are inhibited by the lysine analogue tranexamic acid
Blood Coagulation & Fibrinolysis, 2008Co-Authors: Beeri Niego, Michael K Pugsley, Anita J Horvath, Paul Bernard Coughlin, Robert L MedcalfAbstract:Tranexamic acid (trans-4-aminoethylcyclohexane-1carboxylic acid; t-AMCA) (TA) is a synthetic lysine analogue with potent antifibrinolytic properties. TA saturates lysine binding sites on kringle domains of plasminogen and prevents them from interacting with the fibrin surface, thereby disrupting plasminogen activation and fibrinolysis [1,2]. TA is used clinically to minimize blood loss in a range of haemorrhagic conditions, mainly during cardiac surgeries or in the treatment of chronic bleeding disorders (e.g. menorrhagia) [2]. TA is also considered in bleeding associated with thrombolytic therapy [3]. Control of systemic fibrinolysis in humans requires a therapeutic plasma TA concentration of 10–15mg/ml (63–95mmol/l) [4,5].
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vampire bat salivary plasminogen activator Desmoteplase inhibits tissue type plasminogen activator induced potentiation of excitotoxic injury
Stroke, 2005Co-Authors: Courtney Reddrop, Randal X Moldrich, Philip M Beart, Mark C Farso, Gabriel T Liberatore, David W Howells, Karluwe Petersen, Robert L MedcalfAbstract:Background and Purpose— In contrast to tissue-type plasminogen activator (tPA), vampire bat (Desmodus rotundus) salivary plasminogen activator (Desmoteplase [DSPA]) does not promote excitotoxic injury when injected directly into the brain. We have compared the excitotoxic effects of intravenously delivered tPA and DSPA and determined whether DSPA can antagonize the neurotoxic and calcium enhancing effects of tPA. Methods— The brain striatal region of wild-type c57 Black 6 mice was stereotaxically injected with N-methyl-d-Aspartate (NMDA); 24 hour later, mice received an intravenous injection of tPA or DSPA (10 mg/kg) and lesion size was assessed after 24 hours. Cell death and calcium mobilization studies were performed using cultures of primary murine cortical neurons. Results— NMDA-mediated injury was increased after intravenous administration of tPA, whereas no additional toxicity was seen after administration of DSPA. Unlike DSPA, tPA enhanced NMDA-induced cell death and the NMDA-mediated increase in i...
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Vampire bat salivary plasminogen activator (Desmoteplase) inhibits tissue-type plasminogen activator-induced potentiation of excitotoxic injury
'Ovid Technologies (Wolters Kluwer Health)', 2005Co-Authors: Reddrop C, Randal X Moldrich, Pm Beart, Farso M, Gt Liberatore, Dw Howells, Ku Petersen, Wd Schleuning, Robert L MedcalfAbstract:Background and Purpose - In contrast to tissue-type plasminogen activator (tPA), vampire bat ( Desmodus rotundus) salivary plasminogen activator ( Desmoteplase [ DSPA]) does not promote excitotoxic injury when injected directly into the brain. We have compared the excitotoxic effects of intravenously delivered tPA and DSPA and determined whether DSPA can antagonize the neurotoxic and calcium enhancing effects of tPA. Methods - The brain striatal region of wild-type c57 Black 6 mice was stereotaxically injected with N-methyl-D-Aspartate ( NMDA); 24 hour later, mice received an intravenous injection of tPA or DSPA ( 10 mg/kg) and lesion size was assessed after 24 hours. Cell death and calcium mobilization studies were performed using cultures of primary murine cortical neurons. Results - NMDA-mediated injury was increased after intravenous administration of tPA, whereas no additional toxicity was seen after administration of DSPA. Unlike DSPA, tPA enhanced NMDA-induced cell death and the NMDA-mediated increase in intracellular calcium levels in vitro. Moreover, the enhancing effects of tPA were blocked by DSPA. Conclusions - Intravenous administration of tPA promotes excitotoxic injury, raising the possibility that leakage of tPA from the vasculature into the parenchyma contributes to brain damage. The lack of such toxicity by DSPA further encourages its use as a thrombolytic agent in the treatment of ischemic stroke
Howard A Rowley - One of the best experts on this subject based on the ideXlab platform.
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refinement of the magnetic resonance diffusion perfusion mismatch concept for thrombolytic patient selection insights from the Desmoteplase in acute stroke trials
Stroke, 2012Co-Authors: Steven Warach, Yasir Alrawi, Anthony J Furlan, Jochen B Fiebach, Salvador Pedraza, Max Wintermark, Annika Lindsten, Jamal Smyej, David B Bharucha, Howard A RowleyAbstract:Background and Purpose—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=...
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vascular occlusion enables selecting acute ischemic stroke patients for treatment with Desmoteplase
Stroke, 2012Co-Authors: Jochen B Fiebach, Yasir Alrawi, Anthony J Furlan, Max Wintermark, Howard A Rowley, Annika Lindsten, Jamal Smyej, Paul Eng, Steven Warach, Salvador PedrazaAbstract:Background and Purpose— 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: . Unique identifiers: [NCT00638781][1], [NCT00638248][2], [NCT00111852][3]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00638781&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00638248&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00111852&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom
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abstract 2595 vascular occlusion as an imaging biomarker for selecting acute ischemic stroke patients for treatment with Desmoteplase
Stroke, 2012Co-Authors: Jochen B Fiebach, Yasir Alrawi, Anthony J Furlan, Max Wintermark, Howard A Rowley, Annika Lindsten, Jamal Smyej, Paul Eng, Steven Warach, Salvador PedrazaAbstract: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.
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abstract 2600 refinement of the mr diffusion perfusion mismatch concept for thrombolytic patient selection insights from the Desmoteplase in acute stroke trials
Stroke, 2012Co-Authors: Steven Warach, Yasir Alrawi, Anthony J Furlan, Jochen B Fiebach, Salvador Pedraza, Max Wintermark, Annika Lindsten, Jamal Smyej, David B Bharucha, Howard A RowleyAbstract: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 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.
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dose escalation of Desmoteplase for acute ischemic stroke dedas evidence of safety and efficacy 3 to 9 hours after stroke onset
Stroke, 2006Co-Authors: Anthony J Furlan, Yasir Alrawi, Gregory W Albers, Howard A Rowley, Steven Warach, Dirk Eyding, Kennedy N R Lees, Christian Sachara, Mariola Soehngen, Werner HackeAbstract:Background and Purpose— Desmoteplase is a novel plasminogen activator with favorable features in vitro compared with available agents. This study evaluated safety and efficacy of intravenous (IV) Desmoteplase in patients with perfusion/diffusion mismatch on MRI 3 to 9 hours after onset of acute ischemic stroke. Methods— DEDAS was a placebo-controlled, double-blind, randomized, dose-escalation study investigating doses of 90 μg/kg and 125 μg/kg Desmoteplase. Eligibility criteria included baseline National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch. The safety end point was the rate of symptomatic intracranial hemorrhage. Primary efficacy co-end points were MRI reperfusion 4 to 8 hours after treatment and good clinical outcome at 90 days. The primary analyses were intent-to-treat. Before unblinding, a target population, excluding patients violating specific MRI criteria, was defined. Results— Thirty-seven patients were randomized and received ...
Salvador Pedraza - One of the best experts on this subject based on the ideXlab platform.
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Desmoteplase 3 to 9 hours after major artery occlusion stroke the dias 4 trial efficacy and safety study of Desmoteplase to treat acute ischemic stroke
Stroke, 2016Co-Authors: Rudiger Von Kummer, Jochen B Fiebach, Salvador Pedraza, Etsuro Mori, Thomas Truelsen, Jens Kristian S Jensen, Bjorn A Gronning, Karlolof Lovblad, Javier Romero, Hugues ChabriatAbstract:Background and Purpose— The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of Desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous Desmoteplase for the treatment of ischemic stroke in an extended time window. Methods— Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with Desmoteplase (90 μg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events. Results— In DIAS-4, 52 of 124 (41.9%) Desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P =0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) Desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P =0.096). Treatment with Desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08–2.35; P =0.019). Recanalization was associated with favorable outcomes (mRS 0–2) at day 90 in both the treatment arms. Conclusions— Late treatment with intravenous 90 µg/kg Desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months. Clinical Trial Registration— URL: . Unique identifier: [NCT00856661][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00856661&atom=%2Fstrokeaha%2F47%2F12%2F2880.atom
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refinement of the magnetic resonance diffusion perfusion mismatch concept for thrombolytic patient selection insights from the Desmoteplase in acute stroke trials
Stroke, 2012Co-Authors: Steven Warach, Yasir Alrawi, Anthony J Furlan, Jochen B Fiebach, Salvador Pedraza, Max Wintermark, Annika Lindsten, Jamal Smyej, David B Bharucha, Howard A RowleyAbstract:Background and Purpose—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=...
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vascular occlusion enables selecting acute ischemic stroke patients for treatment with Desmoteplase
Stroke, 2012Co-Authors: Jochen B Fiebach, Yasir Alrawi, Anthony J Furlan, Max Wintermark, Howard A Rowley, Annika Lindsten, Jamal Smyej, Paul Eng, Steven Warach, Salvador PedrazaAbstract:Background and Purpose— 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: . Unique identifiers: [NCT00638781][1], [NCT00638248][2], [NCT00111852][3]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00638781&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00638248&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00111852&atom=%2Fstrokeaha%2F43%2F6%2F1561.atom
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abstract 2595 vascular occlusion as an imaging biomarker for selecting acute ischemic stroke patients for treatment with Desmoteplase
Stroke, 2012Co-Authors: Jochen B Fiebach, Yasir Alrawi, Anthony J Furlan, Max Wintermark, Howard A Rowley, Annika Lindsten, Jamal Smyej, Paul Eng, Steven Warach, Salvador PedrazaAbstract: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.
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abstract 2600 refinement of the mr diffusion perfusion mismatch concept for thrombolytic patient selection insights from the Desmoteplase in acute stroke trials
Stroke, 2012Co-Authors: Steven Warach, Yasir Alrawi, Anthony J Furlan, Jochen B Fiebach, Salvador Pedraza, Max Wintermark, Annika Lindsten, Jamal Smyej, David B Bharucha, Howard A RowleyAbstract: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 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.