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Treat fast but abandon time from ischemic stroke onset as a criterion for treatment: The DAWN and DEFUSE-3 trials

Time from stroke onset is the dominant paradigm for thinking about acute ischemic stroke treatment. Driven by the positive results of NINDS tPA Stroke Trial, the 3-h ‘‘time window’’ is part of the regulated label of indications for alteplase treatment in North America; the ECASS-3 trial convinced European regulators to allow the label to change in Europe to a 4.5-h ‘‘timewindow,’’ but not in North America. The IST-3 trial used a 6-h ‘‘time-window’’ and the combined individual-patient meta-analysis of alteplase stroke trials suggest that average benefit exists to later times. Recent endovascular treatment studies have demonstrated that average benefit can be shown up to 7.3 h from stroke onset. The ESCAPE trial used a 12-h ‘‘time window.’’ The DAWN trial enrolled patients within a 24-h window from stroke onset, principally those with unwitnessed stroke onset, yet showed a dramatic clinical benefit to reperfusion treatment with EVT. The DEFUSE-3 study, which looked at a similar population from 6 to 16 h from onset, has shown similar results. Unknown onset studies, such as MR-WITNESS assessed and successfully thrombolyzed patients with stroke-on-awakening and was supported by other small case series. The larger WAKE-UP trial, assessing a similar population based upon MR imaging, is due to report later this year. How do we synthesize and avoid getting confused by these various time windows of 3, 4.5, 6, 7.3, 12, 16, and 24 h from onset? The answer is both surprisingly simple and complex: we should abandon and substantially deemphasize onset-to-treatment time as the major criterion for deciding whether to offer treatment for acute ischemic stroke. If we are honest, we will explicitly recognize that in many instances, we do not know the true stroke onset time anyway. Stroke onset time is subject to substantial error of measurement. Patients lose their sense of time or cannot identify the time of onset due to the stroke itself. Bystanders are variable witnesses and time anchors may not be present. This was just as true in the randomized trials of stroke thrombolysis as it is for the current EVT trials. Finally, the last-seen-well time is certainly a very conservative estimate of the true stroke onset time because some patients will have suffered their stroke much closer to the time of discovery. Thus, we commonly estimate and use circumstantial evidence to determine the stroke onset time. While time is an important surrogate for the progression of infarction, there is massive variance in that progression within the individual patient. Variation in collaterals and tissue susceptibility result in widely varying temporal trajectories of irreversible infarction. Time gives us a group average only. In the ESCAPE trial, which excluded patients with well-established infarction on qualifying imaging, onset-to-reperfusion time in the EVT group did not predict outcome. When dissected into onset-to-imaging time and imaging-to-reperfusion time, onset-to-imaging time similarly does not predict outcome. However, imaging-to-reperfusion time is highly predictive of outcome, with both reduced variance and a steep declining benefit with time (Figure 1(a) to (c)). In all of these figures, we observe from the scatterplot that there is substantial variance at the individual patient level. We are evolving to an ischemic stroke triage and treatment process that has three stages. First, target patients with disabling stroke without major premorbid medical contraindications (e.g. severe dementia) must be identified. This is the sampling frame. Second, these patients must invoke an acute stroke