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; Furlan, Anthony J.; Al-Rawi, Yasir; Dávalos, Antoni; Fiebach, Jochen B.; Gruber, Franz; Kaste, Markku; Lipka, Leslie J.; Pedraza, Salvador; Ringleb, Peter; Rowley, Howard A.; Schneider, Dietmar; Schwamm, Lee H.; Leal, Joaquín Serena; Söhngen, Mariola; Teal, P.; Wilhelm-Ogunbiyi, Karin; Wintermark, Max; Warach, Steven

doi:10.1016/s1474-4422(08)70267-9

Cited by 519 publications

(393 citation statements)

References 18 publications

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“…Moreover, there is ambiguity about the optimal perfusion threshold that can distinguish benign oligemia from 'penumbral' tissue (Dani et al, 2011). Clinical trials using 'mismatch' as a selection criteria for thrombolysis have shown variable success (Davis et al, 2008;Hacke et al, 2005Hacke et al, , 2009). An imaging marker of stunned but potentially salvageable tissue may help to overcome shortcomings of DWI and PWI.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Functional Cerebral Blood Volume Responses to Normobaric Hyperoxia in Acute Ischemic Stroke

Mandeville

et al. 2012

J Cereb Blood Flow Metab

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Studies suggest that neuroprotective effects of normobaric oxygen (NBO) therapy in acute stroke are partly mediated by hemodynamic alterations. We investigated cerebral hemodynamic effects of repeated NBO exposures. Serial magnetic resonance imaging (MRI) was performed in Wistar rats subjected to focal ischemic stroke. Normobaric oxygen-induced functional cerebral blood volume (fCBV) responses were analyzed. All rats had diffusion-weighted MRI (DWI) lesions within larger perfusion deficits, with DWI lesion expansion after 3 hours. Functional cerebral blood volume responses to NBO were spatially and temporally heterogeneous. Contralateral healthy tissue responded consistently with vasoconstriction that increased with time. No significant responses were evident in the acute DWI lesion. In hypoperfused regions surrounding the acute DWI lesion, tissue that remained viable until the end of the experiment showed relative preservation of mean fCBV at early time points, with some rats showing increased fCBV (vasodilation); however, these regions later exhibited significantly decreased fCBV (vasoconstriction). Tissue that became DWI abnormal by study-end initially showed marginal fCBV changes that later became moderate fCBV reductions. Our results suggest that a reverse-steal hemodynamic effect may occur in peripheral ischemic zones during NBO treatment of focal stroke. In addition, CBV responses to NBO challenge may have potential as an imaging marker to distinguish ischemic core from salvageable tissues.

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Section: Discussionmentioning

confidence: 99%

Dynamic Functional Cerebral Blood Volume Responses to Normobaric Hyperoxia in Acute Ischemic Stroke

Mandeville

et al. 2012

J Cereb Blood Flow Metab

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“…A high response rate in the placebo arm can affect the potential of detecting treatment effects in clinical trials 20, 21, 22. In the CHIMES study, almost half in the placebo group achieved functional independence (mRS 0 to 1) at the end of 3 months.…”

Section: Discussionmentioning

confidence: 99%

The value of patient selection in demonstrating treatment effect in stroke recovery trials: lessons from the CHIMES study of MLC601 (NeuroAiD)

Venketasubramanian

Lee

Wong

et al. 2015

Journal of Evidence-Based Medicine

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ObjectiveThe CHIMES Study compared MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. We aimed to verify if patient selection based on two prognostic factors (ie, stroke severity and time to treatment) improves detection of a treatment effect with MLC601.MethodsAnalyses were performed using data from the CHIMES Study, an international, randomized, placebo‐controlled, double‐blind trial comparing MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. Three subgroups, that is, onset to treatment time (OTT) ≥48 hours; baseline National Institute of Health Stroke Scale (NIHSS) ≥10; both OTT ≥48 hours and baseline NIHSS ≥10, were analyzed using modified Rankin Scale (mRS) ≤1 and a composite endpoint of mRS ≤1, Barthel Index ≥95, and NIHSS ≤1 at month 3.ResultsPlacebo response rates were lower (ie, worse natural outcome) among subgroups with prognostic factors. Conversely, MLC601 treatment effects were significantly higher in the subgroups with prognostic factors than for the entire cohort, being highest among patients with both OTT ≥48 hours and baseline NIHSS of 10 to 14: odds ratios of 2.18 (95% CI 1.02 to 4.65) for month 3 mRS ≤1 and 3.88 (95% CI 1.03 to 14.71) for the composite endpoint.Conclusions: Patients who have moderately severe strokes and longer OTT demonstrate better treatment effects with MLC601. These factors can guide patient selection in future trials.

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“…The DIAS-2 (The Desmoteplase in Acute Ischemic Stroke) study, however, did not show any benefit of desmoteplase. 118 The phase III clinical trials of desmoteplase (DIAS-3) showed that desmoteplase is safe, but did not improve functional outcomes when administered to patients after 3-9 h of ischemic stroke. 119 (ix) Staphylokinase (SAK) It is a 15.5 kDa (136 residues) single chain polypeptide that is secreted by certain strains of Staphylococcus aureus.…”

Section: (Iv) Monteplase (E6010)mentioning

confidence: 99%

The evolution of recombinant thrombolytics: Current status and future directions

Adivitiya

Khasa

2016

Bioengineered

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Cardiovascular disorders are on the rise worldwide due to alcohol abuse, obesity, hypertension, raised blood lipids, diabetes and age-related risks. The use of classical antiplatelet and anticoagulant therapies combined with surgical intervention helped to clear blood clots during the inceptive years. However, the discovery of streptokinase and urokinase ushered the way of using these enzymes as thrombolytic agents to degrade the fibrin network with an issue of systemic hemorrhage. The development of second generation plasminogen activators like anistreplase and tissue plasminogen activator partially controlled this problem. The third generation molecules, majorly t-PA variants, showed desirable properties of improved stability, safety and efficacy with enhanced fibrin specificity. Plasmin variants are produced as direct fibrinolytic agents as a futuristic approach with targeted delivery of these drugs using liposome technlogy. The novel molecules from microbial, plant and animal origin present the future of direct thrombolytics due to their safety and ease of administration.

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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

Cited by 519 publications

References 18 publications

Dynamic Functional Cerebral Blood Volume Responses to Normobaric Hyperoxia in Acute Ischemic Stroke

Dynamic Functional Cerebral Blood Volume Responses to Normobaric Hyperoxia in Acute Ischemic Stroke

The value of patient selection in demonstrating treatment effect in stroke recovery trials: lessons from the CHIMES study of MLC601 (NeuroAiD)

The evolution of recombinant thrombolytics: Current status and future directions

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