The effects of alteplase 3 to 6 hours after stroke in the EPITHET-DEFUSE combined dataset: post hoc case-control study

From the Florey Neuroscience Institutes, Austin Health, Melbourne, Australia.
Stroke (Impact Factor: 5.72). 12/2012; 44(1). DOI: 10.1161/STROKEAHA.112.668301
Source: PubMed


Background and purpose:
Two phase 2 studies of alteplase in acute ischemic stroke 3 to 6 hours after onset, Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET; a randomized, controlled, double-blinded trial), and Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study (DEFUSE; open-label, treatment only) using MR imaging-based outcomes have been conducted. We have pooled individual patient data from these to assess the response to alteplase. The primary hypothesis was that alteplase would significantly attenuate infarct growth compared with placebo in mismatch-selected patients using coregistration techniques.

The EPITHET-DEFUSE study datasets were pooled while retaining the original inclusion and exclusion criteria. Significant hypoperfusion was defined as a Tmax delay >6 seconds), and coregistration techniques were used to define MR diffusion-weighted imaging/perfusion-weighted imaging mismatch. Neuroimaging, parameters including reperfusion, recanalization, symptomatic intracerebral hemorrhage, and clinical outcomes were assessed. Alteplase and placebo groups were compared for the primary outcome of infarct growth as well for secondary outcome measures.

From 165 patients with adequate MR scans in the EPITHET-DEFUSE pooled data, 121 patients (73.3%) were found to have mismatch. For the primary outcome analysis, 60 patients received alteplase and 41 placebo. Mismatch patients receiving alteplase had significantly attenuated infarct growth compared with placebo (P=0.025). The reperfusion rate was also increased (62.7% vs 31.7%; P=0.003). Mortality and clinical outcomes were not different between groups.

The data provide further evidence that alteplase significantly attenuates infarct growth and increases reperfusion compared with placebo in the 3- to 6- hour time window in patients selected based on MR penumbral imaging.

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    • "Although the primary outcome was negative (mean geometric infarct growth) all secondary outcomes were positive and confirmed that alteplase attenuated infarct growth in mismatch patients. Other analyses from the EPITHET dataset have shown that the diffusion infarct core is the strongest predictor of response to thrombolysis, with a chance of good outcome dropping if the core >25 mL and there being virtually no benefit >70 mL.23,24 Pooled analysis from EPITHET and another trial of alteplase 3-6 hours after ischemic stroke, the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study (DEFUSE), showed that patients in the 3-6 hours time window with a favourable imaging profile, i.e. a large penumbra, and small infarct core.25 "
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    ABSTRACT: The cornerstone of acute ischemic stroke treatment relies on rapid clearance of an offending thrombus in the cerebrovascular system. There are various drugs and different methods of assessment to select patients more likely to respond to treatment. Current clinical guidelines recommend the administration of intravenous alteplase (following a brain noncontract CT to exclude hemorrhage) within 4.5 hours of stroke onset. Because of the short therapeutic time window, the risk of hemorrhage, and relatively limited efficacy of alteplase for large clot burden, research is ongoing to find more effective and safer reperfusion therapy, as well as focussing on refinement of patient selection for acute reperfusion treatment. Studies using advanced imaging (incorporating perfusion CT or diffusion/perfusion MRI) may allow us to use thrombolytics, or possibly endovascular therapy, in an extended time window. Recent clinical trials have suggested that Tenecteplase, used in conjunction with advanced imaging selection, resulted in more effective reperfusion than alteplase, which translated into increased clinical benefit. Studies using Desmoteplase have suggested its potential benefit in a sub-group of patients with large artery occlusion and salveageable tissue, in an extended time window. Other ways to improve acute reperfusion approaches are being actively explored, including endovascular therapy, and the enhancement of thrombolysis by ultrasound insonation of the clot (sono-thrombolysis).
    Full-text · Article · May 2013
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    Preview · Article · Feb 2012 · Stroke
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    ABSTRACT: Among the many advances in acute ischemic stroke (AIS) management, thrombolysis with intravenous (IV) tissue plasminogen activator (tPA) within 3 hours after symptom onset has been the only approved pharmacological therapy in AIS. However, IV administration of tPA has many limitations in clinical practice, and the proportion of eligible patients remains quite low. Many clinical trials have attempted to overcome this by increasing the therapeutic time window and enhancing the efficacy of reperfusion by the intra-arterial (IA) approach with novel mechanical devices. In addition, the application of new thrombolytic agents and identification of suitable thrombolytic candidates by multimodal brain imaging is another field of active research in thrombolytic therapy. We reviewed AIS management, focusing on thrombolysis with IV therapy, IA therapy, and IV-IA bridging therapy.
    Preview · Article · May 2013 · Journal of the Korean Medical Association
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