What is the Efficacy and Safety of Intravenous Thrombolysis and Thrombectomy Among Patients With a Wake-Up Stroke?

Take-Home MessageAmong patients with a stroke occurring during sleep (wake-up stroke), endovascular therapy increases the likelihood of having a good functional outcome. Intravenous thrombolytic therapy may improve the likelihood of a good functional outcome, but the potential for an increased risk of symptomatic intracranial hemorrhage cannot be ruled out.MethodsData SourcesCochrane Central Register of Controlled Trials, MEDLINE, and Embase were searched from inception to May 24, 2021 for relevant studies. In addition, the US National Institutes of Health Ongoing Trials Register, World Health Organization International Clinical Trials Registry, and Stroke Trials Registry were searched for ongoing trials. There were no language restrictions. The authors also screened reference lists of relevant trials, contacted principal investigators of the identified studies, performed forward tracking of relevant references using the Science Citation Index Cited Reference search, and contacted manufacturers of relevant equipment and devices.Study SelectionTwo authors independently screened articles for inclusion, with any discrepancies resolved by a third reviewer. Eligible studies compared all types of thrombolytic drugs given in any dose by the intravenous route or all types of intra-arterial treatments to standard medical care or placebo for patients with wake-up acute ischemic strokes (with neuroimaging demonstrating no intracranial hemorrhage before randomization). In articles that included trials with both wake-up strokes and strokes occurring among awake patients, only the data for wake-up strokes were included.Data Extraction and SynthesisTwo review authors independently extracted data for each trial. The primary outcome was participants who had a good functional outcome (defined by a modified Rankin Scale score of ≤2) at the end of the follow-up period. The secondary outcomes included death from all causes within 7 to 14 days and at the end of follow-up, symptomatic intracranial hemorrhage at the end of follow-up, quality of life at the end of follow-up, and neurologic status at 7 to 14 days and at the end of follow-up. The risk of bias was determined using the Cochrane Handbook for Systematic Reviews of Interventions.1Higgins JP, Thomas J, Chandler J, et al, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021). Cochrane; 2021. Accessed March 10, 2022. Available at: https://training.cochrane.org/handbookGoogle Scholar For dichotomous outcomes, the authors reported risk ratios with 95% confidence intervals. Heterogeneity was measured using the I2 statistic. Pooled data were evaluated using a fixed-effects model. The authors used the GRADE approach to determine the certainty of evidence. Publication bias was not performed due to the limited number of studies. Tabled 1Comparison of treatments for wake-up stroke.OutcomeNo. of Studies (No. of Participants)Total Events/Total Participants (%)Intervention GroupTotal Events/Total Participants (%)Control GroupRR (95% CI)Heterogeneity (I2) (%)Intravenous ThrombolyticsIndependent functional outcome (mRS ≤ 2)5 (763)258/390 (66.2%)218/373 (58.4%)1.13 (1.01-1.26)0%Symptomatic intracranial hemorrhage4 (754)10/386 (2.6%)2/368 (0.5%)3.47 (0.98-12.26)0%Mortality5 (763)28/390 (7.2%)37/373 (9.9%)0.68 (0.43-1.07)87%Endovascular ThrombectomyIndependent functional outcome (mRS score ≤ 2)2 (205)54/116 (46.6%)8/89 (9.0%)5.12 (2.57-10.17)0%Mortality2 (205)26/116 (22.4%)29/89 (32.6%)0.68 (0.43-1.07)0%CI, Confidence interval; mRS, modified Rankin Scale; RR, risk ratio. Open table in a new tab CI, Confidence interval; mRS, modified Rankin Scale; RR, risk ratio. The initial search yielded 1,709 unique records, of which 7 trials (n = 980 participants) were used in the meta-analysis. Five of the trials examined intravenous thrombolytic treatment versus control and 2 examined endovascular thrombectomy versus control. The trials were published between 2012 and 2020. All 5 of the thrombolytic studies used alteplase as the thrombolytic, and all but 1 of these studies used a 0.9 mg/kg dose (exception using 0.6 mg/kg dose). Two studies used magnetic resonance imaging (MRI) DWI/FLAIR mismatch criteria for selection, 1 study used MRI or computed tomography perfusion core/penumbra mismatch criteria, 1 study used only MRI perfusion core/penumbra mismatch criteria, and 1 study selected patients with signs of ischemic tissue at risk of infarction on perfusion computed tomography. The 2 thrombectomy studies selected patients with occlusion of the internal carotid artery or proximal middle cerebral artery. Overall, endovascular therapy and intravenous thrombolytic therapy were associated with a statistically significant difference in rates of independent functional outcome (Table). There was no statistically significant difference in mortality or intracranial hemorrhage. All outcomes were deemed high certainty as per the GRADE criteria. All 7 studies were assessed as low risk of selection bias, blinding bias, and reporting bias. Two studies were deemed to have an unclear risk of attrition bias; the other studies were assessed as low risk. There was an unclear risk of other biases in 6 of the studies. Acute ischemic stroke is a major cause of death and disability both in the United States and worldwide.2Centers for Disease Control and PreventionUnderlying Cause of Death, 1999–2018. CDC WONDER Online Database. Centers for Disease Control and Prevention, Atlanta, GA2018Google Scholar,3Lozano R. Naghavi M. Foreman K. et al.Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2095-2128Abstract Full Text Full Text PDF PubMed Scopus (9757) Google Scholar Intravenous thrombolytic therapy and mechanical thrombectomy are commonly recommended for eligible patients who are within the treatment period.4Powers W.J. Rabinstein A.A. Ackerson T. et al.Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2019; 50: e344-e418Crossref PubMed Scopus (2266) Google Scholar However, approximately one-fifth of strokes occur during sleep (referred to as “wake-up strokes”).5Bassetti C. Aldrich M. Night time versus daytime transient ischaemic attack and ischaemic stroke: a prospective study of 110 patients.J Neurol Neurosurg Psychiatry. 1999; 67: 463-467Crossref PubMed Scopus (55) Google Scholar Among patients with wake-up strokes, the time of onset is often unknown and the benefits of these interventions are less clear. This systematic review and meta-analysis found an improved functional outcome among patients with wake-up stroke who were treated with endovascular therapy.6Roaldsen M.B. Lindekleiv H. Mathiesen E.B. Intravenous thrombolytic treatment and endovascular thrombectomy for ischaemic wake-up stroke.Cochrane Database Syst Rev. 2021; 12CD010995PubMed Google Scholar The authors also reported a small statistically significant benefit for intravenous thrombolytics. However, it is important to consider several limitations with respect to the present review. There were only a limited number of studies, and the sample sizes were small. As such, the review may have been underpowered for some clinically important outcomes (eg, symptomatic intracranial hemorrhage). Of note, 6 of the trials were prematurely terminated, which can be a potential source of bias. There were also different types of advanced imaging techniques used between studies. Moreover, patients in the intravenous thrombolysis group received advanced imaging assessments for evidence of threatened tissue or an ischemia penumbra. Consequently, this may not reflect all patients with ischemic wake-up stroke. Finally, although there was a moderate effect seen for endovascular therapy, the benefit for thrombolysis was much smaller, with the 95% confidence interval barely exceeding 1. Based on the present data, we believe that endovascular therapy should be considered in appropriately selected patients with a wake-up stroke. This would be consistent with recommendations from awake large vessel occlusion stroke trials.7Goyal M. Demchuk A.M. Menon B.K. et al.Randomized assessment of rapid endovascular treatment of ischemic stroke.N Engl J Med. 2015; 372: 1019-1030Crossref PubMed Scopus (4049) Google Scholar, 8Campbell B.C. Mitchell P.J. Kleinig T.J. et al.Endovascular therapy for ischemic stroke with perfusion-imaging selection.N Engl J Med. 2015; 372: 1009-1018Crossref PubMed Scopus (3816) Google Scholar, 9Jovin T.G. Chamorro A. Cobo E. et al.Thrombectomy within 8 hours after symptom onset in ischemic stroke.N Engl J Med. 2015; 372: 2296-2306Crossref PubMed Scopus (3266) Google Scholar Intravenous thrombolytics may be considered in appropriately selected patients, but clinicians must weigh the potential risks of intracranial hemorrhage with the potential benefits to the neurologic outcome.