Thrombolytic therapy for wake-up stroke: A systematic review and meta-analysis

Brian Mac Grory, Ian J. Saldanha, Eva A. Mistry, Christoph Stretz, Sven Poli, Marek Sykora, Lars Kellert, Katharina Feil, Shreyansh Shah, Ryan McTaggart, Derek Riebau, Shadi Yaghi, Kenneth Gaines, Ying Xian, Wuwei Feng, Matthew Schrag

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Background and purpose: According to evidence-based clinical practice guidelines, patients presenting with disabling stroke symptoms should be treated with intravenous tissue plasminogen activator (IV tPA) within 4.5 h of time last known well. However, 25% of strokes are detected upon awakening (i.e., wake-up stroke [WUS]), which renders patients ineligible for IV tPA administered via time-based treatment algorithms, because it is impossible to establish a reliable time of symptom onset. We performed a systematic review and meta-analysis of the efficacy and safety of IV tPA compared with normal saline, placebo, or no treatment in patients with WUS using imaging-based treatment algorithms. Methods: We searched MEDLINE, Web of Science, and Scopus between January 1, 2006 and April 30, 2020. We included controlled trials (randomized or nonrandomized), observational cohort studies (prospective or retrospective), and single-arm studies in which adults with WUS were administered IV tPA after magnetic resonance imaging (MRI)- or computed tomography (CT)-based imaging. Our primary outcome was recovery at 90 days (defined as a modified Rankin Scale [mRS] score of 0–2), and our secondary outcomes were symptomatic intracranial hemorrhage (sICH) within 36 h, mortality, and other adverse effects. Results: We included 16 studies that enrolled a total of 14,017 patients. Most studies were conducted in Europe (37.5%) or North America (37.5%), and 1757 patients (12.5%) received IV tPA. All studies used MRI-based (five studies) or CT-based (10 studies) imaging selection, and one study used a combination of modalities. Sixty-one percent of patients receiving IV tPA achieved an mRS score of 0 to 2 at 90 days (95% confidence interval [CI]: 51%–70%, 12 studies), with a relative risk (RR) of 1.21 compared with patients not receiving IV tPA (95% CI: 1.01–1.46, four studies). Three percent of patients receiving IV tPA experienced sICH within 36 h (95% CI: 2.5%–4.1%; 16 studies), which is an RR of 4.00 compared with patients not receiving IV tPA (95% CI: 2.85–5.61, seven studies). Conclusions: This systematic review and meta-analysis suggests that IV tPA is associated with a better functional outcome at 90 days despite the increased but acceptable risk of sICH. Based on these results, IV tPA should be offered as a treatment for WUS patients with favorable neuroimaging findings.

Original languageEnglish (US)
Pages (from-to)2006-2016
Number of pages11
JournalEuropean Journal of Neurology
Issue number6
StatePublished - Jun 2021
Externally publishedYes


  • ischemic stroke
  • perfusion-based imaging
  • tPA
  • thrombolysis
  • wake-up-stroke

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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