Time window stroke

However, several important studies have shown that intravenous thrombolysis may be beneficial more than 3 hours after stroke onset, provided that only patients with a significant diffusion-perfusion mismatch are treated. In one such smdy, Ribo et al. found that patients with a significant diffusion-perfusion mismatch could be treated safely and effectively in the 3-6-hour time period. In phase II of the desmo-teplase in acute stroke (DIAS) trial, patients with diffusion-perfusion mismatch were treated with desmoteplase up to 9 hours after stroke onset, and showed better outcomes than patients given placebo, with only a minimal incidence of symptomatic hemorrhage. Similar success was achieved in the same time window by the dose escalation study of desmoteplase in acute ischemic stroke (DEDAS). ... 

These studies raise the possibility that, one day, imaging-based treatment protocols may allow for intravenous thrombolysis in patients well outside of the now-accepted 3-hour window, provided they demonstrate substantial diffusion-perfusion mismatch. Such protocols could allow for treatment of a vastly larger number of patients than are currently treated. It has been estimated that only 1-7% of acute stroke patients currently receive thrombolytic medication, and that, in up to 95% of cases, they are ineligible because they present outside of the 3-hour time window. As many as 80% of patients who present 6 hours after stroke onset may demonstrate a significant diffusion-perfusion mismatch. "... 

This section will review the phase III clinical trials of IV thrombolytic agents for acute ischemic stroke, organized by the type of agent and the time window from stroke onset to study drug delivery (Table 3.1). The 1995 National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial is presented first because it showed that IV rt-PA, given within 3 hours of stroke onset, reduced stroke-related disability. This trial was the basis for the United States Food and Drug Administration (FDA) approval for rt-PA for use in acute ischemic stroke. 

The most common reason for lack of rt-PA use in otherwise eligible patients remains, however, delay in presentation to the hospital. The California Acute Stroke Pilot Registry (CASPR) investigators examined the effect of various hypothetical interventions on the rate of rt-PA use. Their data suggested that if all patients with a known time of onset presented to medical attention immediately, the expected overall rate of thrombolytic treatment within 3 hours would have increased from 4.3% to 28.6%. By comparison, the expected rate of treatment that would result from instantaneous prehospital response was 5.5%, from perfect hospital care was 11.5%, and from extension of time window to 6 hours was 8.3%. 

Combination GP Ilb/IIIa and rt-PA Therapy for Acute Stroke The combination of antiplatelet and thrombolytic drugs has proven efficacy in the setting of myocardial ischemia where an additive effect is seen. In acute stroke thrombolysis with a very narrow time window and less than 50% optimal reperfusion rates,adjunctive therapy with antiplatelets may be a promising approach. However, MAST-I concluded that the group of patients receiving streptokinase plus aspirin had a marked increase in 10-day mortality. 

Another important aspect of this study was that the time window for starting the treatment was extended to 1 week after stroke, demonstrating that anti-Nogo therapy is effective even beyond the time of acute brain damage. These findings open the possibility of treatment options for those suffering from chronic brain or spinal cord injuries. 

Of great relevance to the potential use of multimodal MRI in extending the time window for thrombolysis have been the observations that perfusion-diffusion mismatch was present for up to 24 h after symptom onset (Table 3.2). Whilst the presence and volume of mismatch decreases over time, at least 50% of patients still have significant tissue at risk 24 h after stroke onset (Fig. 3.4). This correlates well with positron emission tomography studies that show penumbral tissue persists up to 48 h after symptom onset, and that spontaneous survival of this tissue results in clinical improvement (Markus et al. 2003 Read et al. 2000). There is mounting evidence that the time window for salvage of the penumbra is well beyond 3 h and multimodal MRI can identify such patients. 

In the last fewyears, many unsuccessful acute stroke trials have been reported. Trials of intravenous tPA initiated up to 6 h from symptom onset have failed to demonstrate efficacy in patients without imaging confirmation of the diagnosis or pathophysiologic features most amenable to treatment (Albers and Clark 1999 Hacke et al. 1995, 1998). To demonstrate efficacy in stroke trials with a treatment time window greater than 3 h (including neuroprotective agents), trial design needs to be improved (Davis and Donnan 2002). 

Donnan GA, Howells DW, Markus R, Toni D, Davis SM (2003) Can the time window for administration of thrombolytics in stroke be increased CNS Drugs 17 995-1011 Ernst R, Pancioli A, Tomsick T, Kissela B, Woo D, Kanter D, Jauch E, Carrozzella J, Spilker J, Broderick J (2000) Combined intravenous and intra-arterial recombinant tissue plasminogen activator in acute ischemic stroke. Stroke 31 2552-2557... 

A critical factor in developing a therapeutic strategy against stroke is the time window available. In focal cerebral ischemia, delaying the... 

Schellinger PD, Jansen O, Fiebach JB et al (1999). A standardized MRI stroke protocol comparison with CT in hyperacute intracerebral hemorrhage. Stroke 30 765-768 Schellinger PD, Thomalla G, Fiehler J et al (2007). MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows an analysis of 1210 patients. 

In view of the uncertainties surrounding thrombolysis even within the 0-3 hour time window, the ongoing Third International Stroke Trial (IST-3 www.ist3.com) is randomizing patients to alteplase (rt-PA) in the first six hours after stroke. This trial has no upper age limit in contrast to previous thrombolysis trials and aims to establish the risk-benefit ratio for thrombolysis in a broader selection of patients. 

Even though a large number of different compounds have been proven to reduce the size of brain infarct in animal studies, these drugs caused disappointing results in stroke patients. The reasons for the unsuccessful clinical trials have been either the toxic side effects, which have overridden the neuroprotective potential of the compounds demonstrated in animals, or a limited time window for human therapy. Compounds with no or tolerable side effects combined with a protective potential when administered several hours after ischemic insult are under heavy research [2,6,7],... 

Rowley HA (2005) Extending the time window for thrombolysis Evidence from acute stroke trials. Neuroimaging Chn N Am 15 575-587. 

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