Review of stroke thrombolytics
Andrew Bivard, Longting Lin, Mark W Parsonsb, Andrew Bivard, Longting Lin, Mark W Parsonsb
Abstract
The cornerstone of acute ischemic stroke treatment relies on rapid clearance of an offending thrombus in the cerebrovascular system. There are various drugs and different methods of assessment to select patients more likely to respond to treatment. Current clinical guidelines recommend the administration of intravenous alteplase (following a brain noncontract CT to exclude hemorrhage) within 4.5 hours of stroke onset. Because of the short therapeutic time window, the risk of hemorrhage, and relatively limited efficacy of alteplase for large clot burden, research is ongoing to find more effective and safer reperfusion therapy, as well as focussing on refinement of patient selection for acute reperfusion treatment. Studies using advanced imaging (incorporating perfusion CT or diffusion/perfusion MRI) may allow us to use thrombolytics, or possibly endovascular therapy, in an extended time window. Recent clinical trials have suggested that Tenecteplase, used in conjunction with advanced imaging selection, resulted in more effective reperfusion than alteplase, which translated into increased clinical benefit. Studies using Desmoteplase have suggested its potential benefit in a sub-group of patients with large artery occlusion and salveageable tissue, in an extended time window. Other ways to improve acute reperfusion approaches are being actively explored, including endovascular therapy, and the enhancement of thrombolysis by ultrasound insonation of the clot (sono-thrombolysis).
Keywords: Ischemic stroke; Stroke trials; Thrombolysis.
Figures
References
- Senes S. How we manage stroke in Australia. AIHW cat no CVD 31. Canberra: Australian Institute of Health and Welfare; 2006.
- Rothwell PM. The high cost of not funding stroke research: a comparison with heart disease and cancer. Lancet. 2001;357:1612–1616.
- Baron JC, Bousser MG, Rey A, Guillard A, Comar D, Castaigne P. Reversal of focal 'misery-perfusion syndrome' by extra-intracranial arterial bypass in hemodynamic cerebral ischemia: a case study with 15O positron emission tomography. Stroke. 1981;12:454–459.
- Stoll G, Bendszus M. Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. Stroke. 2006;37:1923–1932.
- Friedman M, Bovenkamp GJV. The pathogenesis of a coronary thrombus. Am J Pathol. 1966;48:19–44.
- Jorgensen L. Experimental platelet and coagulation thrombi: a histological study of arterial and venous thrombi of varying age in untreated and heparinized rabbits. Acta Pathol Microbiol Scand. 1964;62:189–223.
- Marder VJ, Chute DJ, Starkman S, Abolian AM, Kidwell C, Liebeskind D, et al. Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke. Stroke. 2006;37:2086–2093.
- Hirsh J, Fuster V American Heart Association. Guide to anticoagulant therapy. Part 2: Oral anticoagulants. Circulation. 1994;89:1469–1480.
- Colman RW, Rao AK, Rubin RN. Factor XI deficiency and hemostasis. Am J Hematol. 1994;45:73–78.
- Hughes M, Lip GY. Stroke and thrombembolism in atrial fibrillation: a systemic review of stroke risk factors, risk stratification schema and cost effectiveness data. Thromb Haemost. 2008;99:295–304.
- Brenner S. The molecular evolution of genes and proteins: a tale of two serines. Nature. 1988;334:528–530.
- Murray V, Norrving B, Sandercock PA, Terént A, Wardlaw JM, Wester P. The molecular basis of thrombolysis and its clinical application in stroke. J Intern Med. 2010;267:191–208.
- Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ, et al. Streptokinase for acute ischemic stroke with relationship to time of administration. JAMA. 1996;276:961–966.
- The multicenter acute stroke trial - Europe study group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med. 1996;335(3):145–150.
- Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke The PROACT II Study: A Randomized Controlled Trial. JAMA. 1999;282:2003–2011.
- Furlan AJ, Eyding D, Albers GW, Al-Rawi Y, Lees KR, Rowley HA, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke. 2006;37:1227–1231.
- Haley EC, Jr, Levy DE, Brott TG, Sheppard GL, Wong MC, Kongable GL, et al. Urgent therapy for stroke. Part II. Pilot study of tissue plasminogen activator administered 91-180 minutes from onset. Stroke. 1992;23:641–645.
- 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.
- Brott TG, Haley EC, Jr, Levy DE, Barsan W, Broderick J, Sheppard GL, et al. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke. 1992;23:632–640.
- Yamaguchi T, Mori E, Minematsu K, Nakagawara J, Hashi K, Saito I, et al. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT) Stroke. 2006;37:1810–1815.
- Smith WS, Lev MH, English JD, Camargo EC, Chou M, Johnston SC, et al. Significance of large vessel intracranial occlusion causing acute ischemic stroke and TIA. Stroke. 2009;40:3834–3840.
- Nam HS, Kim EY, Kim SH, Kim YD, Kim J, Lee HS, et al. Prediction of thrombus resolution after intravenous thrombolysis assessed by CT-based thrombus imaging. Thromb Haemost. 2012;107:786–794.
- Parsons MW, Christensen S, McElduff P, Levi CR, Butcher KS, De Silva DA, et al. Pretreatment diffusion- and perfusion-mr lesion volumes have a crucial influence on clinical response to stroke thrombolysis. J Cereb Blood Flow Metab. 2010;30:1214–1225.
- Yoo AJ, Verduzco LA, Schaefer PW, Hirsch JA, Rabinov JD, González RG. MRI-based selection for intra-arterial stroke therapy: value of pretreatment diffusion-weighted imaging lesion volume in selecting patients with acute stroke who will benefit from early recanalization. Stroke. 2009;40:2046–2054.
- Ogata T, Christensen S, Nagakane Y, Ma H, Campbell BC, Churilov L, et al. The effects of alteplase 3 to 6 hours after stroke in the EPITHET-DEFUSE combined dataset: post hoc case-control study. Stroke. 2013;44:87–93. Epub 2012 Dec 18.
- Ford GA, Ahmed N, Azevedo E, Grond M, Larrue V, Lindsberg PJ, et al. Intravenous alteplase for stroke in those older than 80 years old. Stroke. 2010;41:2568–2574.
- IST-3 collaborative group. Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, et al. 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;379:2352–2363. Epub 2012 May 23.
- Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Van De Werf F, Adgey J, Ardissino D, Armstrong PW, Aylward P, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999;354:716–722.
- Al-Shwafi KA, de Meester A, Pirenne B, Col JJ. Comparative fibrinolytic activity of front-loaded alteplase and the single-bolus mutants tenecteplase and lanoteplase during treatment of acute myocardial infarction. Am Heart J. 2003;145:217–225.
- Haley EC, Jr, Thompson JL, Grotta JC, Lyden PD, Hemmen TG, Brown DL, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke. 2010;41:707–711.
- Parsons MW, Miteff F, Bateman GA, Spratt N, Loiselle A, Attia J, et al. Acute ischemic stroke: imaging-guided tenecteplase treatment in an extended time window. Neurology. 2009;72:915–921.
- Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomized trial of tenecteplase and alteplase for acute ischemic stroke. N Engl J Med. 2012;366:1099–1107.
- Hawkey C. Inhibitor of platelet aggregation present in saliva of the vampire bat Desmodus rotundus. Br J Haematol. 1967;13:1014–1020.
- Schleuning WD. Vampire bat plasminogen activator DSPA-alpha-1 (desmoteplase): a thrombolytic drug optimized by natural selection. Haemostasis. 2001;31:118–122.
- Bringmann P, Gruber D, Liese A, Toschi L, Kratzchmar J, Schleuning WD, et al. Structural features mediating fibrin selectivity of vampire bat plasminogen activators. J Biol Chem. 1995;270:25596–25603.
- Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36:66–73.
- Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, 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.
- del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol. 1992;32:78–86.
- Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology. 2002;59:862–867.
- Tomsick T, Broderick J, Carrozella J, Khatri P, Hill M, Palesch Y, et al. Revascularization results in the Interventional Management of Stroke II trial. AJNR Am J Neuroradiol. 2008;29:582–587.
- Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al. Endovascular therapy after intravenous t-Pa versus t-PA alone for stroke. N Engl J Med. 2013;368:893–903.
- Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368:914–923.
- Saver JL, Jahan R, Levy EI, Jovin TG, Baxter B, Nogueira RG, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet. 2012;380:1241–1249.
- Nogueira RG, Lutsep HL, Gupta R, Jovin TG, Albers GW, Walker GA, et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet. 2012;380:1231–1240.
- Cintas P, Nguyen F, Boneu B, Larrue V. Enhancement of enzymatic fibrinolysis with 2-MHz ultrasound and microbubbles. J Thromb Haemost. 2004;2:1163–1166.
- Everbach EC, Francis CW. Cavitational mechanisms in ultrasound-accelerated thrombolysis at 1 MHz. Ultrasound Med Biol. 2000;26:1153–1160.
- Eggers J, König I, Koch B, Händler G, Seidel G. Sonothrombolysis with transcranial color-coded sonography and recombinant tissue-type plasminogen activator in acute middle cerebral artery main stem occlusion: results from a randomized study. Stroke. 2008;39:1470–1475.
- Cintas P, Le Traon AP, Larrue V. Enhancement of enzymatic fibrinolysis with 2-MHz ultrasound and microbubbles. J Thromb Haemost. 2004;2:1163–1166.
- Eisenberg PR, Sobel BE, Jaffe AS. Activation of prothrombin accompanying thrombolysis with recombinant tissue-type plasminogen activator. J Am Coll Cardiol. 1992;19:1065–1069.
- De Luca G, Suryapranata H, Stone GW, Antoniucci D, Tcheng JE, Neumann FJ, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA. 2005;293:1759–1765.
- Seitz RJ, Meisel S, Moll M, Wittsack HJ, Junghans U, Siebler M. The effect of combined thrombolysis with rtPA and tirofiban on ischemic brain lesions. Neurology. 2004;62:2110–2112.
- Morris DC, Silver B, Mitsias P, Lewandowski C, Patel S, Daley S, et al. Treatment of acute ischemic stroke with recombinant tissue plasminogen activator and abciximab. Acad Emerg Med. 2003;10:1396–1399.
- Korin N, Kanapathipillai M, Matthews BD, Crescente M, Brill A, Mammoto T, et al. Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science. 2012;337:738–742.
- Bivard A, Spratt N, Levi C, Parsons M. Perfusion computer tomography: Imaging and clinical validation in acute ischaemic stroke. Brain. 2011;134:3408–3416.
- Colman R, Marder V, Clowes A, George J, Goldhaber S. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd ed. Philadeplhia: J. B. Lippincott Company; 1994. p. 3.
- Nordt TK, Bode C. Thrombolysis: newer thrombolytic agents and their role in clinical medicine. Heart. 2003;89:1358–1362.
- Baruah DB, Dash RN, Chaudhari MR, Kad-am SS. Plasminogen activators: a comparison. Vascul Pharmacol. 2006;44:1–9.
Source: PubMed