- Share - [](https://www.facebook.com/sharer.php?u=https://about.ebsco.com/markdownify/node/31546) - []() - []() - []() # EBM Focus: Pushing the needle — Benefit of Thrombolytics for Stroke beyond Four and a Half Hours A new trial adds to the evidence for a benefit of thrombolytics for stroke beyond four and a half hours. ![covid ten things you need to know blog image ](/sites/default/files/acquiadam-assets/covid-19-ten-things-you-need-to-know-blog-image-780.jpg) [Carina Brown, MD](/health-notes/bio/carina-brown-md) 18 June 2019 *EBM Focus provides concise summaries of clinical trials most likely to inform clinical practice, curated by the DynaMed® editorial team.* As many as one in four 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 three hours of symptom onset. For tPA between three and four and a half 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 one in five patients with stroke ineligible for tPA administration because they present with symptoms of stroke after waking up, with last known normal well beyond four and a half hours before presenting to care. The [WAKE-UP trial](https://www.ncbi.nlm.nih.gov/pubmed/29766770?dopt=Abstract) found that tPA may reduce disability among patients with unknown last known normal but imaging findings suggestive of stroke within the last four and half hours. The [EXTEND trial](https://www.ncbi.nlm.nih.gov/pubmed/31067369?dopt=Abstract) is a multicenter randomized trial which enrolled 255 patients with last known normal four and a half to nine hours previous or symptom onset during sleep, with maximum time to randomization of nine 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 percent in tPA group vs. 72.3 percent 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 zero or one) compared to the placebo group (35.4 percent vs. 29.5 percent, adjusted relative risk 1.44, 95 percent CI 1.01-2.06, NNT = 17). Symptomatic intracranial hemorrhage occurred in 6.2 percent of participants in the tPA group compared to 0.9 percent in the placebo group (adjusted relative risk 7.22, 95 percent CI 0.97-53.54). The 90-day mortality in the tPA group was 11.5 percent compared to 8.9 percent in the placebo group, but this difference was not statistically significant (adjusted relative risk 1.17, 95 percent CI 0.57-2.4). This trial suggests that tPA may provide benefit for patients with wake-up strokes or with symptom onset four and a half to nine 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 percent vs. 1.2 percent), 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 four and a half to nine 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. Earn [CME/CE](https://dynamed.antidotecme.com/) credit for reading this EBM Focus article. [ Sign Up for EBM Focus ](https://www.dynamed.com/home/editorial/ebm-journal/ebm-focus) Category: [Clinical Practice Perspectives ](/blogs/health-notes/category/clinical-practice-perspectives) Tags: [EBMFocus](/blogs/health-notes/tag/ebmfocus) [Evidence–based medicine](/blogs/health-notes/tag/evidence–based-medicine) - Share - [](https://www.facebook.com/sharer.php?u=https://about.ebsco.com/markdownify/node/31546) - []() - []() - []() ## Related Posts [ ![EBM Focus Targeting the Brain blog image ](/sites/default/files/acquiadam-assets/EBM-Focus-Targeting-the-Brain_blog-image-780.png) ](/blogs/health-notes/ebm-focus-targeting-brain-lower-blood-pressure-targets-may-not-reduce-dementia) [EBM Focus: Targeting the Brain − Lower Blood Pressure Targets May Not Reduce Dementia](/blogs/health-notes/ebm-focus-targeting-brain-lower-blood-pressure-targets-may-not-reduce-dementia) 25 March 2019 [ ![five things palliative care blog image ](/sites/default/files/acquiadam-assets/five-things-palliative-care-blog-image-780.jpg) ](/blogs/health-notes/five-things-palliative-care-physician-wishes-all-physicians-knew-about-end-life) [Five Things a Palliative Care Physician Wishes All Physicians Knew about End-of-Life Care](/blogs/health-notes/five-things-palliative-care-physician-wishes-all-physicians-knew-about-end-life) 12 November 2018 [ ![expert opinion low quality evidence blog image ](/sites/default/files/acquiadam-assets/expert-opinion-low-quality-evidence-blog-image-780.jpg) ](/blogs/health-notes/ebm-focus-expert-opinion-and-low-quality-evidence-still-drive-strong) [EBM Focus: Expert Opinion and Low-quality Evidence Still Drive Strong Recommendations in Cardiology](/blogs/health-notes/ebm-focus-expert-opinion-and-low-quality-evidence-still-drive-strong) 10 June 2019