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Semin Neurol 2021; 41(01): 016-027
DOI: 10.1055/s-0040-1722720
Review Article

Alteplase and Adjuvant Therapies for Acute Ischemic Stroke

Adam L. Gottula
1   Department of Emergency Medicine, University of Cincinnati, Cincinnati, Ohio
,
Andrew D. Barreto
2   Department of Neurology, University of Texas Houston, Houston, Texas
,
Opeolu Adeoye
3   Department of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri
› Author Affiliations
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Abstract

Acute ischemic stroke (AIS) is a time sensitive medical emergency and a leading cause of morbidity and mortality worldwide. Intravenous (IV) recombinant tissue plasminogen activator (IV alteplase) is currently the only proven effective medication for the treatment of AIS with promising adjuvant medications currently under investigation. Recent advances in endovascular thrombectomy have broadened therapeutic options in specific patient populations, with modern treatment strategies utilizing advanced imaging modalities to extend the window for treatment. In all cases, rapid treatment remains a priority. The future of IV alteplase and the changing standard for treatment of AIS remain unwritten with the increasing evidence for imaging selection for both endovascular thrombectomy and IV alteplase, while novel adjuncts are under investigation. In this article, we review the history of IV alteplase investigations for stroke, evidence for thrombectomy as an adjunct to IV alteplase, and the potential of novel adjuvant therapeutics currently under investigation.

Keywords

stroke - ischemic - alteplase - thrombectomy - argatroban - eptifibatide


Publication History

Article published online:
20 January 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Mackey J, Kleindorfer D, Sucharew H. et al. Population-based study of wake-up strokes. Neurology 2011; 76 (19) 1662-1667
    CrossrefPubMedGoogle Scholar
  • 2 Saver JL. Time is brain-quantified. Stroke 2006; 37 (01) 263-266
    CrossrefPubMedGoogle Scholar
  • 3 Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 2007; 38 (03) 967-973
    CrossrefPubMedGoogle Scholar
  • 4 Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology 2002; 59 (06) 862-867
    CrossrefPubMedGoogle Scholar
  • 5 Nakagawara J, Minematsu K, Okada Y. et al; J-MARS Investigators. Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice: the Japan post-Marketing Alteplase Registration Study (J-MARS). Stroke 2010; 41 (09) 1984-1989
    CrossrefPubMedGoogle Scholar
  • 6 Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2014; (07) CD000213
    PubMedGoogle Scholar
  • 7 Hacke W, Donnan G, Fieschi C. et al; ATLANTIS Trials Investigators, ECASS Trials Investigators, NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363 (9411): 768-774
    CrossrefPubMedGoogle Scholar
  • 8 Hacke W, Kaste M, Bluhmki E. et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359 (13) 1317-1329
    CrossrefPubMedGoogle Scholar
  • 9 Tong D, Reeves MJ, Hernandez AF. et al. Times from symptom onset to hospital arrival in the get with the guidelines—Stroke Program 2002 to 2009: temporal trends and implications. Stroke 2012; 43 (07) 1912-1917
    CrossrefPubMedGoogle Scholar
  • 10 Rymer MM, Thrutchley DE. Stroke Team at the Mid America Brain and Stroke Institute. Organizing regional networks to increase acute stroke intervention. Neurol Res 2005; 27 (Suppl. 01) S9-S16
    CrossrefPubMedGoogle Scholar
  • 11 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 (24) 1581-1587
    CrossrefPubMedGoogle Scholar
  • 12 Hacke W, Kaste M, Fieschi C. et al; Second European-Australasian Acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998; 352 (9136): 1245-1251
    CrossrefPubMedGoogle Scholar
  • 13 Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999; 282 (21) 2019-2026
    CrossrefPubMedGoogle Scholar
  • 14 Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators. Stroke 2000; 31 (04) 811-816
    CrossrefPubMedGoogle Scholar
  • 15 Thomalla G, Simonsen CZ, Boutitie F. et al; WAKE-UP Investigators. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med 2018; 379 (07) 611-622
    CrossrefPubMedGoogle Scholar
  • 16 Ma H, Campbell BCV, Parsons MW. et al; EXTEND Investigators. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med 2019; 380 (19) 1795-1803
    CrossrefPubMedGoogle Scholar
  • 17 Yamaguchi T, Mori E, Minematsu K. et al; Japan Alteplase Clinical Trial (J-ACT) Group. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT). Stroke 2006; 37 (07) 1810-1815
    CrossrefPubMedGoogle Scholar
  • 18 Anderson CS, Robinson T, Lindley RI. et al; ENCHANTED Investigators and Coordinators. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N Engl J Med 2016; 374 (24) 2313-2323
    CrossrefPubMedGoogle Scholar
  • 19 Hacke W, Kaste M, Fieschi C. et al; The European Cooperative Acute Stroke Study (ECASS). Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995; 274 (13) 1017-1025
    CrossrefPubMedGoogle Scholar
  • 20 Sandercock P, Wardlaw JM, Lindley RI. et al; IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012; 379 (9834): 2352-2363
    CrossrefPubMedGoogle Scholar
  • 21 Wolpert SM, Bruckmann H, Greenlee R, Wechsler L, Pessin MS, del Zoppo GJ. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. The rt-PA Acute Stroke Study Group. AJNR Am J Neuroradiol 1993; 14 (01) 3-13
    Google Scholar
  • 22 Rubiera M, Alvarez-Sabín J, Ribo M. et al. Predictors of early arterial reocclusion after tissue plasminogen activator-induced recanalization in acute ischemic stroke. Stroke 2005; 36 (07) 1452-1456
    CrossrefPubMedGoogle Scholar
  • 23 Muchada M, Rodriguez-Luna D, Pagola J. et al. Impact of time to treatment on tissue-type plasminogen activator-induced recanalization in acute ischemic stroke. Stroke 2014; 45 (09) 2734-2738
    CrossrefPubMedGoogle Scholar
  • 24 Yeo LL, Paliwal P, Teoh HL. et al. Timing of recanalization after intravenous thrombolysis and functional outcomes after acute ischemic stroke. JAMA Neurol 2013; 70 (03) 353-358
    CrossrefPubMedGoogle Scholar
  • 25 Mori E, Minematsu K, Nakagawara J, Yamaguchi T, Sasaki M, Hirano T. Japan Alteplase Clinical Trial II Group. Effects of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in middle cerebral artery occlusion: Japan Alteplase Clinical Trial II (J-ACT II). Stroke 2010; 41 (03) 461-465
    CrossrefPubMedGoogle Scholar
  • 26 Berkhemer OA, Fransen PS, Beumer D. et al; MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372 (01) 11-20
    CrossrefPubMedGoogle Scholar
  • 27 Campbell BC, Mitchell PJ, Kleinig TJ. et al; EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372 (11) 1009-1018
    CrossrefPubMedGoogle Scholar
  • 28 Goyal M, Demchuk AM, Menon BK. et al; ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372 (11) 1019-1030
    CrossrefPubMedGoogle Scholar
  • 29 Jovin TG, Chamorro A, Cobo E. et al; REVASCAT Trial Investigators. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015; 372 (24) 2296-2306
    CrossrefPubMedGoogle Scholar
  • 30 Saver JL, Goyal M, Bonafe A. et al; SWIFT PRIME Investigators. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015; 372 (24) 2285-2295
    CrossrefPubMedGoogle Scholar
  • 31 Badhiwala JH, Nassiri F, Alhazzani W. et al. Endovascular thrombectomy for acute ischemic stroke: a meta-analysis. JAMA 2015; 314 (17) 1832-1843
    CrossrefPubMedGoogle Scholar
  • 32 Goyal M, Menon BK, van Zwam WH. et al; HERMES collaborators. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016; 387 (10029): 1723-1731
    CrossrefPubMedGoogle Scholar
  • 33 Adeoye O, Albright KC, Carr BG. et al. Geographic access to acute stroke care in the United States. Stroke 2014; 45 (10) 3019-3024
    CrossrefPubMedGoogle Scholar
  • 34 Bhatia R, Hill MD, Shobha N. et al. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. Stroke 2010; 41 (10) 2254-2258
    CrossrefPubMedGoogle Scholar
  • 35 Wunderlich MT, Goertler M, Postert T. et al; Duplex Sonography in Acute Stroke (DIAS) Study Group, Competence Network Stroke. Recanalization after intravenous thrombolysis: does a recanalization time window exist?. Neurology 2007; 68 (17) 1364-1368
    CrossrefPubMedGoogle Scholar
  • 36 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 (21) 2003-2011
    CrossrefPubMedGoogle Scholar
  • 37 Smith WS, Sung G, Starkman S. et al; MERCI Trial Investigators. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke 2005; 36 (07) 1432-1438
    CrossrefPubMedGoogle Scholar
  • 38 Smith WS, Sung G, Saver J. et al; Multi MERCI Investigators. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke 2008; 39 (04) 1205-1212
    CrossrefPubMedGoogle Scholar
  • 39 Saver JL, Jahan R, Levy EI. et al; SWIFT Trialists. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet 2012; 380 (9849): 1241-1249
    CrossrefPubMedGoogle Scholar
  • 40 Albers GW, Marks MP, Kemp S. et al; DEFUSE 3 Investigators. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018; 378 (08) 708-718
    CrossrefPubMedGoogle Scholar
  • 41 Nogueira RG, Jadhav AP, Haussen DC. et al; DAWN Trial Investigators. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018; 378 (01) 11-21
    CrossrefPubMedGoogle Scholar
  • 42 Bracard S, Ducrocq X, Mas JL. et al; THRACE investigators. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Lancet Neurol 2016; 15 (11) 1138-1147
    CrossrefPubMedGoogle Scholar
  • 43 Mocco J, Zaidat OO, von Kummer R. et al; THERAPY Trial Investigators*. Aspiration thrombectomy after intravenous alteplase versus intravenous alteplase alone. Stroke 2016; 47 (09) 2331-2338
    CrossrefPubMedGoogle Scholar
  • 44 Muir KW, Ford GA, Messow CM. et al; PISTE Investigators. Endovascular therapy for acute ischaemic stroke: the Pragmatic Ischaemic Stroke Thrombectomy Evaluation (PISTE) randomised, controlled trial. J Neurol Neurosurg Psychiatry 2017; 88 (01) 38-44
    CrossrefPubMedGoogle Scholar
  • 45 Khoury NN, Darsaut TE, Ghostine J. et al; EASI trial collaborators. Erratum to “Endovascular thrombectomy and medical therapy versus medical therapy alone in acute stroke: a randomized care trial”. J Neuroradiol 2017; 44 (05) 351
    CrossrefPubMedGoogle Scholar
  • 46 Broderick JP, Palesch YY, Demchuk AM. et al; Interventional Management of Stroke (IMS) III Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013; 368 (10) 893-903
    CrossrefPubMedGoogle Scholar
  • 47 Ciccone A, Valvassori L, Investigators SE. SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013; 368 (25) 2433-2434
    PubMedGoogle Scholar
  • 48 Kidwell CS, Jahan R. Endovascular treatment of acute ischemic stroke. Neurol Clin 2015; 33 (02) 401-420
    CrossrefPubMedGoogle Scholar
  • 49 Kidwell CS, Jahan R, Gornbein J. et al; MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013; 368 (10) 914-923
    CrossrefPubMedGoogle Scholar
  • 50 Khoury NN, Darsaut TE, Ghostine J. et al; EASI trial collaborators. Endovascular thrombectomy and medical therapy versus medical therapy alone in acute stroke: a randomized care trial. J Neuroradiol 2017; 44 (03) 198-202
    CrossrefPubMedGoogle Scholar
  • 51 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359 (09) 938-949
    CrossrefPubMedGoogle Scholar
  • 52 Scarborough RM. Development of eptifibatide. Am Heart J 1999; 138 (6 Pt 1): 1093-1104
    CrossrefPubMedGoogle Scholar
  • 53 Jeske WP, Fareed J, Hoppensteadt DA, Lewis B, Walenga JM. Pharmacology of argatroban. Expert Rev Hematol 2010; 3 (05) 527-539
    CrossrefPubMedGoogle Scholar
  • 54 Lyden P, Pereira B, Chen B. et al. Direct thrombin inhibitor argatroban reduces stroke damage in 2 different models. Stroke 2014; 45 (03) 896-899
    CrossrefPubMedGoogle Scholar
  • 55 Morris DC, Zhang L, Zhang ZG. et al. Extension of the therapeutic window for recombinant tissue plasminogen activator with argatroban in a rat model of embolic stroke. Stroke 2001; 32 (11) 2635-2640
    CrossrefPubMedGoogle Scholar
  • 56 Kobayashi S, Tazaki Y. Effect of the thrombin inhibitor argatroban in acute cerebral thrombosis. Semin Thromb Hemost 1997; 23 (06) 531-534
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 LaMonte MP, Nash ML, Wang DZ. et al; ARGIS-1 Investigators. Argatroban anticoagulation in patients with acute ischemic stroke (ARGIS-1): a randomized, placebo-controlled safety study. Stroke 2004; 35 (07) 1677-1682
    CrossrefPubMedGoogle Scholar
  • 58 Choudhri TF, Hoh BL, Zerwes HG. et al. Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation. J Clin Invest 1998; 102 (07) 1301-1310
    CrossrefPubMedGoogle Scholar
  • 59 Shuaib A, Yang Y, Nakada MT, Li Q, Yang T. Glycoprotein IIb/IIIa antagonist, murine 7E3 F(ab') 2, and tissue plasminogen activator in focal ischemia: evaluation of efficacy and risk of hemorrhage with combination therapy. J Cereb Blood Flow Metab 2002; 22 (02) 215-222
    CrossrefPubMedGoogle Scholar
  • 60 Ding G, Jiang Q, Zhang L. et al. Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor. J Cereb Blood Flow Metab 2005; 25 (01) 87-97
    CrossrefPubMedGoogle Scholar
  • 61 Ohman EM, Kleiman NS, Gacioch G. et al; IMPACT-AMI Investigators. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction. Results of a randomized, placebo-controlled, dose-ranging trial. Circulation 1997; 95 (04) 846-854
    CrossrefPubMedGoogle Scholar
  • 62 Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339 (07) 436-443
    CrossrefPubMedGoogle Scholar
  • 63 Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Integrilin to minimise platelet aggregation and coronary thrombosis-II. Lancet 1997; 349 (9063): 1422-1428
    CrossrefPubMedGoogle Scholar
  • 64 Barreto AD, Alexandrov AV, Lyden P. et al. The argatroban and tissue-type plasminogen activator stroke study: final results of a pilot safety study. Stroke 2012; 43 (03) 770-775
    CrossrefPubMedGoogle Scholar
  • 65 Tsivgoulis G, Sharma VK, Lao AY, Malkoff MD, Alexandrov AV. Validation of transcranial Doppler with computed tomography angiography in acute cerebral ischemia. Stroke 2007; 38 (04) 1245-1249
    CrossrefPubMedGoogle Scholar
  • 66 Barreto AD, Ford GA, Shen L. et al; ARTSS-2 Investigators. Randomized, multicenter trial of ARTSS-2 (argatroban with recombinant tissue plasminogen activator for acute stroke). Stroke 2017; 48 (06) 1608-1616
    CrossrefPubMedGoogle Scholar
  • 67 Lou M, Safdar A, Mehdiratta M. et al. The HAT score: a simple grading scale for predicting hemorrhage after thrombolysis. Neurology 2008; 71 (18) 1417-1423
    CrossrefPubMedGoogle Scholar
  • 68 Berekashvili K, Soomro J, Shen L. et al. Safety and feasibility of argatroban, recombinant tissue plasminogen activator, and intra-arterial therapy in stroke (ARTSS-IA study). J Stroke Cerebrovasc Dis 2018; 27 (12) 3647-3651
    CrossrefPubMedGoogle Scholar
  • 69 Pancioli AM, Broderick J, Brott T. et al; CLEAR Trial Investigators. The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: the CLEAR stroke trial. Stroke 2008; 39 (12) 3268-3276
    CrossrefPubMedGoogle Scholar
  • 70 Pancioli AM, Adeoye O, Schmit PA. et al; CLEAR-ER Investigators. Combined approach to lysis utilizing eptifibatide and recombinant tissue plasminogen activator in acute ischemic stroke-enhanced regimen stroke trial. Stroke 2013; 44 (09) 2381-2387
    CrossrefPubMedGoogle Scholar
  • 71 Adeoye O, Sucharew H, Khoury J. et al; CLEAR-ER, IMS III, and ALIAS Part 2 Investigators. Recombinant tissue-type plasminogen activator plus eptifibatide versus recombinant tissue-type plasminogen activator alone in acute ischemic stroke: propensity score-matched post hoc analysis. Stroke 2015; 46 (02) 461-464
    CrossrefPubMedGoogle Scholar
  • 72 Saver JL, Yafeh B. Confirmation of tPA treatment effect by baseline severity-adjusted end point reanalysis of the NINDS-tPA stroke trials. Stroke 2007; 38 (02) 414-416
    CrossrefPubMedGoogle Scholar
  • 73 Adeoye O, Sucharew H, Khoury J. et al. Combined approach to lysis utilizing eptifibatide and recombinant tissue-type plasminogen activator in acute ischemic stroke-full dose regimen stroke trial. Stroke 2015; 46 (09) 2529-2533
    CrossrefPubMedGoogle Scholar
  • 74 Adeoye O, Barreto A. Multi-arm Optimization of Stroke Thrombolysis (MOST). U.S. National Library of Medicine. Published 2018. Accessed May 1, 2019 at: https://clinicaltrials.gov/ct2/show/NCT03735979?term=Adeoye&rank=1
    Google Scholar