Pushing the needle: tPA for wake up strokes, or beyond 4.5 hours after ischemic stroke symptom onset, may improve function at 90 days

EBM Focus - Volume 14, Issue 11

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Reference: N Engl J Med 2019 May 9;380(19):1795 (level 2 [mid-level] evidence)

As many as 1 in 4 adults will experience a stroke, which can result in death or disability. Timing for administration of tissue plasminogen activator (tPA) is critical, with previous studies demonstrating reduced disability if given within 3 hours of symptom onset. For tPA between 3 and 4.5 hours, the data has not consistently supported a benefit and professional societies vary in their recommendations for use of tPA in this time period. This leaves nearly 1 in 5 patients with stroke ineligible for tPA administration because they present with symptoms of stroke after waking up, with last known normal well beyond 4.5 hours before presenting to care. The WAKE-UP trial found that tPA may reduce disability among patients with unknown last known normal but imaging findings suggestive of stroke within the last 4.5 hours.

The EXTEND trial is a multicenter randomized trial which enrolled 255 patients with last known normal 4.5-9 hours prior or symptom onset during sleep, with maximum time to randomization of 9 hours from the midpoint of sleep. All patients had mismatch on MRI or CT indicating an area of salvageable tissue and a smaller area of ischemic tissue. Patients considered for endovascular treatment were excluded from the trial. Patients had an average age of 73.7 years in the tPA group compared to 71.0 years in the placebo group, most had large-vessel occlusion on imaging (69% in tPA group vs. 72.3% in placebo group), NIH Stroke Scale average of 12 in the tPA group compared to 10 in the placebo group,and nearly two-thirds with a wake-up stroke. Having enrolled 255 of the anticipated 310 participants, this trial was stopped early after publication of the WAKE-UP trial. The tPA group had a significantly higher rate of excellent functional outcome at 90 days (modified Rankin score of 0 or 1) compared to the placebo group (35.4% vs. 29.5%, adjusted relative risk 1.44, 95% CI 1.01-2.06, NNT = 17). Symptomatic intracranial hemorrhage occurred in 6.2% of participants in the tPA group compared to 0.9% in the placebo group (adjusted relative risk 7.22, 95% CI 0.97-53.54). The 90-day mortality in the tPA group was 11.5% compared to 8.9% in the placebo group, but this difference was not statistically significant (adjusted relative risk 1.17, 95% CI 0.57-2.4).

This trial suggests that tPA may provide benefit for patients with wake-up strokes or with symptom onset 4.5-9 hours before presentation. As both the WAKE-UP trial and this trial were stopped early, it is difficult to draw absolute conclusions from the data. The tPA group in the WAKE-UP trial had a higher rate of mortality compared to placebo (4.1% vs. 1.2%), but this difference was not statistically significant when the trial was stopped due to loss of funding. Several other caveats are worth noting. Not all institutions have the technology available to quantify salvageable tissue, which affects the generalizability of the results. This trial combined patients with wake up strokes and patients with symptoms 4.5-9 hours after symptom onset and this may obscure where any benefit truly lies. Extending tPA administration to wake up strokes and those with longer time from symptom onset may improve 90-day disability, but remember, Time is Brain and getting patients treated as soon as possible remains the key to better outcomes.

For more information, see the topic Thrombolytics for acute stroke in DynaMed Plus. DynaMed users click here.

DynaMed Plus EBM Focus Editorial Team
This EBM Focus was written by Carina Brown, MD, Faculty Development and Information Mastery Fellow and Clinical Instructor at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed Plus and Associate Professor in Family Medicine at the University of Massachusetts Medical School and Katharine DeGeorge, MD, MS, Assistant Professor in Family Medicine at the University of Virginia and Clinical Editor at DynaMed Plus.