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

Eur J Neurol. 2021 Jun;28(6):2006-2016. doi: 10.1111/ene.14839. Epub 2021 Apr 15.


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.

Keywords: ischemic stroke; perfusion-based imaging; tPA; thrombolysis; wake-up-stroke.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Adult
  • Fibrinolytic Agents / adverse effects
  • Humans
  • Ischemic Stroke*
  • Prospective Studies
  • Retrospective Studies
  • Risk Factors
  • Stroke* / diagnostic imaging
  • Stroke* / drug therapy
  • Thrombolytic Therapy
  • Tissue Plasminogen Activator / adverse effects
  • Treatment Outcome


  • Fibrinolytic Agents
  • Tissue Plasminogen Activator