Thrombolytic therapy for wake-up stroke: A systematic review and meta-analysis
Brian Mac Grory
Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA
Contribution: Conceptualization (lead), Data curation (lead), Formal analysis (lead), Investigation (lead), Methodology (lead), Validation (lead), Writing - original draft (lead), Writing - review & editing (equal)
Search for more papers by this authorIan J. Saldanha
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Brown University School of Public Health, Providence, Rhode Island, USA
Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, USA
Contribution: Data curation (equal), Formal analysis (lead), Methodology (equal), Writing - review & editing (equal)
Search for more papers by this authorEva A. Mistry
Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorChristoph Stretz
Department of Neurology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorSven Poli
Department of Neurology With Focus on Neurovascular Diseases, University Hospital Tübingen, Tübingen, Germany
Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany
Contribution: Conceptualization (supporting), Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorMarek Sykora
Department of Neurology, St. John’s Hospital, Medical Faculty, Sigmund Freud University, Vienna, Austria
Contribution: Conceptualization (supporting), Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorLars Kellert
Department of Neurology, Ludwig Maximilians University, Munich, Germany
Contribution: Conceptualization (supporting), Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorKatharina Feil
Department of Neurology, Ludwig Maximilians University, Munich, Germany
Contribution: Data curation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorShreyansh Shah
Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorRyan McTaggart
Department of Neurology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Department of Neurosurgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Department of Radiology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Contribution: Conceptualization (equal), Writing - review & editing (equal)
Search for more papers by this authorDerek Riebau
Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorShadi Yaghi
Department of Neurology, New York University School of Medicine, New York, New York, USA
Contribution: Conceptualization (supporting), Investigation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorKenneth Gaines
Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorYing Xian
Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA
Contribution: Writing - review & editing (supporting)
Search for more papers by this authorWuwei Feng
Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA
Contribution: Conceptualization (supporting), Supervision (supporting), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Matthew Schrag
Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Correspondence
Matthew Schrag, Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Email: [email protected]
Contribution: Conceptualization (lead), Data curation (equal), Formal analysis (supporting), Supervision (lead), Writing - original draft (supporting), Writing - review & editing (lead)
Search for more papers by this authorBrian Mac Grory
Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA
Contribution: Conceptualization (lead), Data curation (lead), Formal analysis (lead), Investigation (lead), Methodology (lead), Validation (lead), Writing - original draft (lead), Writing - review & editing (equal)
Search for more papers by this authorIan J. Saldanha
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Brown University School of Public Health, Providence, Rhode Island, USA
Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, USA
Contribution: Data curation (equal), Formal analysis (lead), Methodology (equal), Writing - review & editing (equal)
Search for more papers by this authorEva A. Mistry
Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorChristoph Stretz
Department of Neurology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorSven Poli
Department of Neurology With Focus on Neurovascular Diseases, University Hospital Tübingen, Tübingen, Germany
Hertie Institute for Clinical Brain Research, University Hospital Tübingen, Tübingen, Germany
Contribution: Conceptualization (supporting), Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorMarek Sykora
Department of Neurology, St. John’s Hospital, Medical Faculty, Sigmund Freud University, Vienna, Austria
Contribution: Conceptualization (supporting), Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorLars Kellert
Department of Neurology, Ludwig Maximilians University, Munich, Germany
Contribution: Conceptualization (supporting), Data curation (equal), Writing - review & editing (supporting)
Search for more papers by this authorKatharina Feil
Department of Neurology, Ludwig Maximilians University, Munich, Germany
Contribution: Data curation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorShreyansh Shah
Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorRyan McTaggart
Department of Neurology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Department of Neurosurgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Department of Radiology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Contribution: Conceptualization (equal), Writing - review & editing (equal)
Search for more papers by this authorDerek Riebau
Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorShadi Yaghi
Department of Neurology, New York University School of Medicine, New York, New York, USA
Contribution: Conceptualization (supporting), Investigation (supporting), Writing - review & editing (supporting)
Search for more papers by this authorKenneth Gaines
Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Contribution: Conceptualization (supporting), Writing - review & editing (supporting)
Search for more papers by this authorYing Xian
Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA
Contribution: Writing - review & editing (supporting)
Search for more papers by this authorWuwei Feng
Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA
Contribution: Conceptualization (supporting), Supervision (supporting), Writing - review & editing (supporting)
Search for more papers by this authorCorresponding Author
Matthew Schrag
Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Correspondence
Matthew Schrag, Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Email: [email protected]
Contribution: Conceptualization (lead), Data curation (equal), Formal analysis (supporting), Supervision (lead), Writing - original draft (supporting), Writing - review & editing (lead)
Search for more papers by this authorRegistration: This systematic review was prospectively registered through PROSPERO (Registration number: CRD42020151552).
Abstract
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.
CONFLICT OF INTERESTS
None of the authors declare conflicts of interest related to these data. The corresponding author had access to all data and takes responsibility for the accuracy of this article. All coauthors have reviewed the final draft and approved the submission.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
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| ene14839-sup-0001-AppendixS1.docxWord document, 1.1 MB |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Powers WJ, Rabinstein AA, 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-e418.
- 2Moradiya Y, Janjua N. Presentation and outcomes of "Wake-up strokes" In a large randomized stroke trial: Analysis of data from the international stroke trial. J Stroke Cerebrovasc Dis. 2013; 22: e286-292.
- 3Koton S, Tanne D, Bornstein NM, NASIS Investigators. Ischemic stroke on awakening: patients’ characteristics, outcomes and potential for reperfusion therapy. Neuroepidemiology. 2012; 39: 149-153.
- 4Thomalla G, Simonsen CZ, Boutitie F, et al. Mri-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018; 379: 611-622.
- 5Koga M, Yamamoto H, Inoue M, et al. Thrombolysis with alteplase at 0.6 mg/kg for stroke with unknown time of onset: a randomized controlled trial. Stroke. 2020; 51: 1530-1538.
- 6Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: An updated pooled analysis of ecass, atlantis, ninds, and epithet trials. Lancet. 2010; 375: 1695-1703.
- 7Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis. Stroke. 1998; 29: 992-996.
- 8Casetta I, Granieri E, Fallica E, la Cecilia O, Paolino E, Manfredini R. Patient demographic and clinical features and circadian variation in onset of ischemic stroke. Arch Neurol. 2002; 59: 48-53.
- 9Lago A, Geffner D, Tembl J, Landete L, Valero C, Baquero M. Circadian variation in acute ischemic stroke: a hospital-based study. Stroke. 1998; 29: 1873-1875.
- 10Marler JR, Price TR, Clark GL, et al. Morning increase in onset of ischemic stroke. Stroke. 1989; 20: 473-476.
- 11Tsivgoulis G, Katsanos AH, Malhotra K, et al. Thrombolysis for acute ischemic stroke in the unwitnessed or extended therapeutic time window. Neurology. 2020; 94: e1241-e1248.
- 12Thomalla G, Boutitie F, Ma H, et al. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: Systematic review and meta-analysis of individual patient data. Lancet. 2020; 396: 1574-1584.
- 13Fink JN, Kumar S, Horkan C, et al. The stroke patient who woke up: Clinical and radiological features, including diffusion and perfusion MRI. Stroke. 2002; 33: 988-993.
- 14Huisa BN, Raman R, Ernstrom K, et al. Alberta stroke program early ct score (aspects) in patients with wake-up stroke. J Stroke Cerebrovasc Dis. 2010; 19: 475-479.
- 15Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type plasminogen activator use for ischemic stroke in the united states: A doubling of treatment rates over the course of 5 years. Stroke. 2011; 42: 1952-1955.
- 16Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008; 359: 1317-1329.
- 17Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the safe implementation of thrombolysis in stroke-monitoring study (sits-most): An observational study. Lancet. 2007; 369: 275-282.
- 18Sterne JAC, Savović J, Page MJ, et al. Rob 2: A revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366: l4898.
- 19Sterne JA, Hernán MA, Reeves BC, et al. Robins-i: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016; 355: i4919.
- 20von Hippel PT. The heterogeneity statistic i(2) can be biased in small meta-analyses. BMC Med Res Methodol. 2015; 15: 35.
- 21Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21: 1539-1558.
- 22Barreto AD, Martin-Schild S, Hallevi H, et al. Thrombolytic therapy for patients who wake-up with stroke. Stroke. 2009; 40: 827-832.
- 23Hill MD, Kenney C, Dzialowski I, et al. Tissue window in stroke thrombolysis study (twist): a safety study. Can J Neurol Sci. 2013; 40: 17-20.
- 24Manawadu D, Bodla S, Keep J, Jarosz J, Kalra L. An observational study of thrombolysis outcomes in wake-up ischemic stroke patients. Stroke. 2013; 44: 427-431.
- 25Anaissie JE, Monlezun DJ, Siegler JE, et al. Intravenous tissue plasminogen activator for wake-up stroke: a propensity score-matched analysis. J Stroke Cerebrovasc Dis. 2016; 25: 2603-2609.
- 26Barreto AD, Fanale CV, Alexandrov AV, et al. Prospective, open-label safety study of intravenous recombinant tissue plasminogen activator in wake-up stroke. Ann Neurol. 2016; 80: 211-218.
- 27Urrutia VC, Faigle R, Zeiler SR, et al. Safety of intravenous alteplase within 4.5 hours for patients awakening with stroke symptoms. PLoS One. 2018; 13:e0197714.
- 28Armon C, Wainstein J, Gour A, et al. Ct-guided thrombolytic treatment of patients with wake-up strokes. eNeurologicalSci. 2019; 14: 91-97.
- 29Sykora M, Kellert L, Michel P, et al. Thrombolysis in stroke with unknown onset based on non-contrast computerized tomography (trust ct). J Am Heart Assoc. 2020; 9:e014265.
- 30Morelli N, Rota E, Immovilli P, et al. Computed tomography perfusion-based thrombolysis in wake-up stroke. Intern Emerg Med. 2015; 10: 977-984.
- 31Feil K, Reidler P, Kunz WG, et al. Addressing a real-life problem: Treatment with intravenous thrombolysis and mechanical thrombectomy in acute stroke patients with an extended time window beyond 4.5 h based on computed tomography perfusion imaging. Eur J Neurol. 2020; 27: 168-174.
- 32Bai Q, Zhao Z, Fu P, et al. Clinical outcomes of fast mri-based thrombolysis in wake-up strokes compared to superacute ischemic strokes within 12 hours. Neurol Res. 2013; 35: 492-497.
- 33Schwamm LH, Wu O, Song SS, et al. Intravenous thrombolysis in unwitnessed stroke onset: Mr witness trial results. Ann Neurol. 2018; 83: 980-993.
- 34Zhao J, Zhao H, Li R, et al. Outcome of multimodal mri-guided intravenous thrombolysis in patients with stroke with unknown time of onset. Stroke Vasc Neurol. 2019; 4: 3-7.
- 35Krebs S, Posekany A, Ferrari J, et al. Intravenous thrombolysis in wake-up stroke: Real-world data from the austrian stroke unit registry. Eur J Neurol. 2019; 26: 754-759.
- 36Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med. 2000; 342: 1887-1892.
- 37Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med. 2000; 342: 1878-1886.
- 38Shrier I, Boivin JF, Steele RJ, et al. Should meta-analyses of interventions include observational studies in addition to randomized controlled trials? A critical examination of underlying principles. Am J Epidemiol. 2007; 166: 1203-1209.
- 39Rothwell PM. External validity of randomised controlled trials: "To whom do the results of this trial apply?". Lancet. 2005; 365: 82-93.
- 40 National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581-1587.
- 41Silva GS, Lima FO, Camargo ECS, et al. Wake-up stroke: clinical and neuroimaging characteristics. Cerebrovasc Dis. 2010; 29: 336-342.
- 42Dankbaar JW, Bienfait HP, van den Berg C, et al. Wake-up stroke versus stroke with known onset time: clinical and multimodality ct imaging characteristics. Cerebrovasc Dis. 2018; 45: 236-244.
- 43Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019; 380: 1795-1803.
- 44Psychogios K, Magoufis G, Safouris A, et al. Eligibility for intravenous thrombolysis in acute ischemic stroke patients presenting in the 4.5-9 h window. Neuroradiology. 2020; 62: 733-739.
- 45Moseley ME, Kucharczyk J, Mintorovitch J, et al. Diffusion-weighted mr imaging of acute stroke: Correlation with t2-weighted and magnetic susceptibility-enhanced mr imaging in cats. Am J Neuroradiol. 1990; 11: 423-429.
- 46Hoehn-Berlage M, Eis M, Back T, Kohno K, Yamashita K. Changes of relaxation times (t1, t2) and apparent diffusion coefficient after permanent middle cerebral artery occlusion in the rat: Temporal evolution, regional extent, and comparison with histology. Magn Reson Med. 1995; 34: 824-834.
- 47Venkatesan R, Lin W, Gurleyik K, et al. Absolute measurements of water content using magnetic resonance imaging: preliminary findings in an in vivo focal ischemic rat model. Magn Reson Med. 2000; 43: 146-150.
10.1002/(SICI)1522-2594(200001)43:1<146::AID-MRM18>3.0.CO;2-L CAS PubMed Web of Science® Google Scholar
- 48Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Aspects study group. Alberta stroke programme early ct score. Lancet. 2000; 355: 1670-1674.
