Advances in stroke medicine

Bruce CV Campbell
Med J Aust 2019; 210 (8): . || doi: 10.5694/mja2.50137
Published online: 6 May 2019


  • In recent years, reperfusion therapies such as intravenous thrombolysis and endovascular thrombectomy for ischaemic stroke have dramatically reduced disability and revolutionised stroke management.
  • Thrombolysis with alteplase is effective when administered to patients with potentially disabling stroke, who are not at high risk of bleeding, within 4.5 hours of the time the patient was last known to be well. Emerging evidence suggests that other thrombolytics such as tenecteplase may be even more effective. Treatment may be possible beyond 4.5 hours in patients selected using brain imaging.
  • Endovascular thrombectomy (via angiography) effectively reduces risk of death or dependency in patients with large vessel occlusion (internal carotid, proximal middle cerebral and basilar arteries) if applied within 6 hours of the time they were last known to be well.
  • Endovascular thrombectomy is also beneficial 6–24 hours from the last known well time in selected patients with favourable brain imaging. Thus, some patients with wake‐up stroke are now treatable, and protocols for stroke need to include computed tomography (CT) perfusion scan and CT angiography as routine, in addition to the non‐contrast CT brain scan.
  • Optimised pre‐hospital and emergency department systems (eg, code stroke response teams, pre‐notification by ambulance, direct transport from triage to CT scanner) are essential to maximise the benefit of these strongly time‐dependent therapies. Telemedicine is increasingly providing specialist guidance for these more complex treatment decisions in rural areas.
  • Important developments in secondary stroke prevention include the use of direct oral anticoagulants or left atrial appendage occlusion for atrial fibrillation, and endovascular closure of patent foramen ovale.

  • Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC


Competing interests:

Bruce Campbell has received research support from the National Health and Medical Research Council (GNT1043242, GNT1035688), the Royal Australasian College of Physicians, the Royal Melbourne Hospital Foundation, the National Heart Foundation and the Stroke Foundation. He has received unrestricted grant funding for the EXTEND‐IA trial to the Florey Institute of Neuroscience and Mental Health from Medtronic. He co‐chaired the 2017 Australian Stroke Guidelines content working party.

  • 1. Deloittte Access Economics. The economic impact of stroke in Australia. Deloittte Access Economics, 2013. (viewed Aug 2018).
  • 2. Stroke Unit Trialists’ Collaboration. Collaborative systematic review of the randomised trials of organised inpatient (stroke unit) care after stroke. BMJ 1997; 314: 1151–1159.
  • 3. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo‐controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349: 1641–1649.
  • 4. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569–1581.
  • 5. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 2007; 6: 215–222.
  • 6. The 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.
  • 7. Thomalla 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.
  • 8. Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis up to 9 hours after stroke onset guided by perfusion imaging. N Engl J Med 2019. In press.
  • 9. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372: 11–20.
  • 10. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion‐imaging selection. N Engl J Med 2015; 372: 1009–1018.
  • 11. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372: 1019–1030.
  • 12. Saver JL, Goyal M, Bonafe A, et al. Stent‐retriever thrombectomy after intravenous t‐PA vs. t‐PA alone in stroke. N Engl J Med 2015; 372: 2285–2295.
  • 13. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015; 372: 2296–2306.
  • 14. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018; 378: 11–21.
  • 15. Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018; 378: 708–718.
  • 16. Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta‐analysis of individual patient data from randomised trials. Lancet 2014; 384: 1929–1935.
  • 17. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large‐vessel ischaemic stroke: a meta‐analysis of individual patient data from five randomised trials. Lancet 2016; 387: 1723–1731.
  • 18. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40 000 randomized patients from the Chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 2000; 31: 1240–1249.
  • 19. Anderson CS, Heeley E, Huang Y, et al. Rapid blood‐pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013; 368: 2355–2365.
  • 20. Hacke 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.
  • 21. Stroke Foundation. Clinical guidelines for stroke management 2017 [website]. (viewed Aug 2018).
  • 22. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2018; 49: e46–e110.
  • 23. Casaubon LK, Boulanger JM, Blacquiere D, et al. Canadian stroke best practice recommendations: hyperacute stroke care guidelines, update 2015. Int J Stroke 2015; 10: 924–940.
  • 24. Ringleb P, Schellinger PD, Hacke W, Europaischen S. European Stroke Organisation 2008 guidelines for managing acute cerebral infarction or transient ischemic attack. Part 1 [German]. Nervenarzt 2008; 79: 936–957.
  • 25. Stroke Foundation. National stroke audit acute services 2017 [website]. (viewed Aug 2018).
  • 26. Lees 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.
  • 27. Wahlgren N, Ahmed N, Davalos 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.
  • 28. Myslimi F, Caparros F, Dequatre‐Ponchelle N, et al. Orolingual angioedema during or after thrombolysis for cerebral ischemia. Stroke 2016; 47: 1825–1830.
  • 29. Cheong E, Dodd L, Smith W, Kleinig T. Icatibant as a potential treatment of life‐threatening alteplase‐induced angioedema. J Stroke Cerebrovasc Dis 2018; 27: e36–e37.
  • 30. Smith EE, Abdullah AR, Petkovska I, et al. Poor outcomes in patients who do not receive intravenous tissue plasminogen activator because of mild or improving ischemic stroke. Stroke 2005; 36: 2497–2499.
  • 31. Khatri P, Kleindorfer DO, Devlin T, et al. Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits: the PRISMS randomized clinical trial. JAMA 2018; 320: 156–166.
  • 32. Coutts SB, Modi J, Patel SK, et al. CT/CT angiography and MRI findings predict recurrent stroke after transient ischemic attack and minor stroke: results of the prospective CATCH study. Stroke 2012; 43: 1013–1017.
  • 33. Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med 2012; 366: 1099–1107.
  • 34. Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med 2018; 378: 1573–1582.
  • 35. Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open‐label, blinded endpoint study. Lancet Neurol 2015; 14: 368–376.
  • 36. Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR‐TEST): a phase 3, randomised, open‐label, blinded endpoint trial. Lancet Neurol 2017; 16: 781–788.
  • 37. Mair G, von Kummer R, Adami A, et al. Arterial obstruction on computed tomographic or magnetic resonance angiography and response to intravenous thrombolytics in ischemic stroke. Stroke 2017; 48: 353–360.
  • 38. Furlan A, Higashida R, Wechsler L, et al. Intra‐arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999; 282: 2003–2011.
  • 39. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t‐PA versus t‐PA alone for stroke. N Engl J Med 2013; 368: 893–903.
  • 40. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; 368: 904–913.
  • 41. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013; 368: 914–923.
  • 42. Campbell BCV, van Zwam WH, Goyal M, et al. Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta‐analysis of individual patient data. Lancet Neurol 2018; 17: 47–53.
  • 43. Lowhagen Henden P, Rentzos A, Karlsson JE, et al. General anesthesia versus conscious sedation for endovascular treatment of acute ischemic stroke: the AnStroke trial (Anesthesia During Stroke). Stroke 2017; 48: 1601–1607.
  • 44. Schonenberger S, Uhlmann L, Hacke W, et al. Effect of conscious sedation vs general anesthesia on early neurological improvement among patients with ischemic stroke undergoing endovascular thrombectomy: a randomized clinical trial. JAMA 2016; 316: 1986–1996.
  • 45. Simonsen CZ, Yoo AJ, Sorensen LH, et al. Effect of general anesthesia and conscious sedation during endovascular therapy on infarct growth and clinical outcomes in acute ischemic stroke: a randomized clinical trial. JAMA Neurol 2018; 75: 470–477.
  • 46. Roman LS, Menon BK, Blasco J, et al. Imaging features and safety and efficacy of endovascular stroke treatment: a meta‐analysis of individual patient‐level data. Lancet Neurol 2018; 17: 895–904.
  • 47. Campbell BCV, Majoie C, Albers GW, et al. Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta‐analysis of individual patient‐level data. Lancet Neurol 2018; 18: 46–55.
  • 48. Saver JL, Goyal M, van der Lugt A, et al. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta‐analysis. JAMA 2016; 316: 1279–1288.
  • 49. Mistry EA, Mistry AM, Nakawah MO, et al. Mechanical thrombectomy outcomes with and without intravenous thrombolysis in stroke patients: a meta‐analysis. Stroke 2017; 48: 2450–2456.
  • 50. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST‐elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127: e362–e425.
  • 51. Meretoja A, Strbian D, Mustanoja S, et al. Reducing in‐hospital delay to 20 minutes in stroke thrombolysis. Neurology 2012; 79: 306–313.
  • 52. Meretoja A, Weir L, Ugalde M, et al. Helsinki model cut stroke thrombolysis delays to 25 minutes in Melbourne in only 4 months. Neurology 2013; 81: 1071–1076.
  • 53. Campbell BCV. Stroke imaging: do it right the first time. JAMA Neurol 2017; 74: 1298–1300.
  • 54. Ng FC, Low E, Andrew E, et al. Deconstruction of interhospital transfer workflow in large vessel occlusion: real‐world data in the thrombectomy era. Stroke 2017; 48: 1976–1979.
  • 55. Perez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 2014; 45: 87–91.
  • 56. Zhao H, Pesavento L, Coote S, et al. Ambulance clinical triage for acute stroke treatment: paramedic triage algorithm for large vessel occlusion. Stroke 2018; 49: 945–951.
  • 57. Fassbender K, Grotta JC, Walter S, et al. Mobile stroke units for prehospital thrombolysis, triage, and beyond: benefits and challenges. Lancet Neurol 2017; 16: 227–237.
  • 58. Murray CJ, Vos T, Lozano R, et al. Disability‐adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990‐2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2197–2223.
  • 59. Zhang LF, Yang J, Hong Z, Yuan GG, Zhou BF, Zhao LC, Huang YN, Chen J, Wu YF; Collaborative Group of China Multicenter Study of Cardiovascular Epidemiology. Proportion of different subtypes of stroke in China. Stroke 2003; 34: 2091–2096.
  • 60. Qureshi AI, Palesch YY, Barsan WG, et al. Intensive blood‐pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med 2016; 375: 1033–1043.
  • 61. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014; 370: 2478–2486.
  • 62. Group SR, Wright JT, Jr., Williamson JD, et al. A randomized trial of intensive versus standard blood‐pressure control. N Engl J Med 2015; 373: 2103–2116.
  • 63. Arima H, Chalmers J, Woodward M, et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. J Hypertens 2006; 24: 1201–1208.
  • 64. Amarenco P, Bogousslavsky J, Callahan A, et al. High‐dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549–559.
  • 65. Rothwell PM, Algra A, Chen Z, et al. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time‐course analysis of randomised trials. Lancet 2016; 388: 365–375.
  • 66. Wang Y, Zhao X, Liu L, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369: 11–19.
  • 67. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high‐risk TIA. N Engl J Med 2018; 379: 215–225.
  • 68. Nishimura M, Sab S, Reeves RR, Hsu JC. Percutaneous left atrial appendage occlusion in atrial fibrillation patients with a contraindication to oral anticoagulation: a focused review. Europace 2017; 20: 1412–1419.
  • 69. Hart RG, Sharma M, Mundl H, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med 2018; 378: 2191–2201.
  • 70. Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017; 377: 1011–1021.
  • 71. Sondergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017; 377: 1033–1042.
  • 72. Saver JL, Carroll JD, Thaler DE, et al. Long‐term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017; 377: 1022–1032.


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