Thrombolytic Therapy With Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke: Where Do We Go From Here? A Cumulative Meta-Analysis

Background and Purpose— Recombinant tissue plasminogen activator (rtPA; Actilyse) is not as widely used in clinical practice as it could be. Have new data since 1995 strengthened the evidence sufficiently to justify more widespread use of rtPA? Methods— We performed a sequential year-to-year cumulative meta-analysis of randomized controlled trials of rtPA in acute ischemic stroke. Results— Although the amount of data has doubled since 1995, effect estimates for key outcomes remain imprecise, and significant between-trial heterogeneity persists. In the most recent analysis, rtPA up to 6 hours after stroke yielded 55 fewer dead or dependent people per 1000 treated (95% CI, 18 to 92) despite some risk (nonsignificant excess of 19 deaths per 1000 patients treated; 95% CI, 6 fewer to 48 more). Severity of stroke, patient age, and aspirin use were possible sources of heterogeneity. Conclusions— Despite doubling of the data since 1995, the magnitude of risks and benefits with rtPA remains imprecise. This gap in knowledge may be hindering clinical use of rtPA and can be filled only by new trials designed to address these specific issues.

[1]  J. Broderick,et al.  Pilot randomized trial of tissue plasminogen activator in acute ischemic stroke. The TPA Bridging Study Group. , 1993, Stroke.

[2]  J. Grotta,et al.  Guidelines for Thrombolytic Therapy for Acute Stroke: a Supplement to the Guidelines for the Management of Patients with Acute Ischemic Stroke. A statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. , 1996, Stroke.

[3]  C. Fry,et al.  Science of urinary incontinence Report of a Meeting of Physicians and Scientists, University College London , 1994, The Lancet.

[4]  P. King,et al.  Cavitary lung disease. , 2001, Chest.

[5]  F. Mosteller,et al.  A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. Treatments for myocardial infarction. , 1992, JAMA.

[6]  Gruppo Italiano per lo Studio della Soprawivenza nell'Inf Miocardico.,et al.  EFFECTIVENESS OF INTRAVENOUS THROMBOLYTIC TREATMENT IN ACUTE MYOCARDIAL INFARCTION , 1986, The Lancet.

[7]  P. Toutouzas,et al.  Percutaneous implantation of autologous vein graft stent for treatment of coronary artery disease , 1995, The Lancet.

[8]  S. Cramer,et al.  Treatment With Tissue Plasminogen Activator and Inpatient Mortality Rates for Patients With Ischemic Stroke Treated in Community Hospitals , 2001, Stroke.

[9]  G. Tognoni,et al.  The GISSI Study: further analysis. Italian Group for the Study of Streptokinase in Myocardial Infarction (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico, GISSI). , 1987, Circulation.

[10]  Sarah Parish,et al.  Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. , 1988, Journal of the American College of Cardiology.

[11]  J A Paris,et al.  Royal College of Physicians of London , 1848, Provincial medical & surgical journal.

[12]  W. Hacke,et al.  Thrombolytic Therapy in Acute Ischemic Stroke II , 1993, Springer Berlin Heidelberg.

[13]  G. Albers,et al.  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. , 1999, JAMA.

[14]  T. Hayakawa,et al.  Intravenous Tissue Plasminogen Activator in Acute Thromboembolic Stroke: A Placebo-Controlled, Double-Blind Trial , 1993 .

[15]  Johan Herlitz,et al.  Indications for fibrinolytic therapy in suspected acute myocardial infarction : collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients , 1994 .

[16]  Y. Ohtsuki,et al.  ISOLATION OF HTLV-I FROM CEREBROSPINAL FLUID OF A PATIENT WITH MYELOPATHY , 1986, The Lancet.

[17]  J. Grotta,et al.  Intravenous tissue plasminogen activator for acute ischemic stroke: feasibility, safety, and efficacy in the first year of clinical practice. , 1998, Stroke.

[18]  M. Dennis,et al.  A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS. , 2002, Health technology assessment.

[19]  Thrombolytic therapy for acute ischemic stroke - Tissue plasminogen activator for acute ischemic stroke: Is the CAEP Position Statement too negative? , 2001, CJEM.

[20]  E. Veys,et al.  HL-A AND INFECTIVE SACROILEITIS , 1974 .

[21]  Fibrinolytictherapytrialistsf.  Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients , 1994 .

[22]  A. Furlan,et al.  Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. , 2000, JAMA.

[23]  Thompson G. Robinson,et al.  National Clinical Guidelines for Stroke. , 2001 .

[24]  M. Hommel,et al.  Thrombolytic therapy with streptokinase in acute ischemic stroke. , 1996, The New England journal of medicine.

[25]  D. Ketley,et al.  Impact of clinical trials on clinical practice: example of thrombolysis for acute myocardial infarction , 1993, The Lancet.

[26]  J. Grotta,et al.  Neurologists' attitudes regarding rt-PA for acute ischemic stroke , 1998, Neurology.

[27]  P. Lyden.  Further randomized controlled trials of tPA within 3 hours are required-not! , 2001, Stroke.

[28]  W R Clarke,et al.  Baseline NIH Stroke Scale score strongly predicts outcome after stroke , 1999, Neurology.

[29]  R. Collins,et al.  Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side-effects from 33 randomized controlled trials. , 1985, European heart journal.

[30]  L. Bolognese,et al.  RANDOMISED TRIAL OF INTRAVENOUS STREPTOKINASE, ORAL ASPIRIN, BOTH, OR NEITHER AMONG 17 187 CASES OF SUSPECTED ACUTE MYOCARDIAL INFARCTION: ISIS-2 , 1988, The Lancet.

[31]  G. B. Young,et al.  Intravenous tissue plasminogen activator for acute ischemic stroke in patients ≥80 years old: The London, Canada experience , 2001, Stroke.

[32]  Multicentre Acute Stroke Trial—Italy Group.  Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke , 1995, The Lancet.

[33]  W. Sterling Edwards,et al.  Blood Vessels , 1959 .

[34]  G. Hankey,et al.  Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. , 1996, Journal of the American Medical Association (JAMA).

[35]  J. Rankin.  Cerebral Vascular Accidents in Patients over the Age of 60: II. Prognosis , 1957, Scottish medical journal.

[36]  Joseph P. Broderick,et al.  Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. , 1995 .

[37]  M. Kaste,et al.  Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II) , 1998, The Lancet.

[38]  L. Munari,et al.  RANDOMIZED CONTROLLED TRIAL OF STREPTOKINASE, ASPIRIN, AND COMBINATION OF BOTH IN TREATMENT OF ACUTE ISCHEMIC STROKE , 1995 .

[39]  B. J. Sussman,et al.  Thrombolysis with fibrinolysin in cerebral arterial occlusion. , 1958, Journal of the American Medical Association.

[40]  H. Ijichi,et al.  Clinical evaluation for efficacy of tissue caltured urokinase (TCUK) on cerebral thrombosis by means of multi-center double-blind study , 1981 .

[41]  S Hamilton,et al.  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. , 2000, Stroke.

[42]  R. Higashida,et al.  PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. , 1998, Stroke.

[43]  A. Morris,et al.  A pilot study of streptokinase for acute cerebral infarction. , 1995, QJM : monthly journal of the Association of Physicians.

[44]  Walker,et al.  Collaborative overview of randomised trials of antiplatelet therapy Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients , 1994 .

[45]  M. Kaste,et al.  Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS) , 1995, JAMA.

[46]  R. Lindley,et al.  Further randomized controlled trials of tissue plasminogen activator within 3 hours are required. , 2001, Stroke.

[47]  A. Yamadori,et al.  Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke , 1992, Neurology.

[48]  F. Mahoney,et al.  FUNCTIONAL EVALUATION: THE BARTHEL INDEX. , 2018, Maryland state medical journal.

[49]  R. Higashida,et al.  Intra-arterial Prourokinase for Acute Ischemic Stroke: The PROACT II Study: A Randomized Controlled Trial , 1999 .

[50]  Fibrinolytic Therapy Trialists' Collaborative Group.  Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients , 1994, The Lancet.

[51]  P D Lyden,et al.  Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. , 1996, Circulation.

[52]  N. Anderson,et al.  Opinion of New Zealand physicians on management of acute ischaemic stroke: results of a national survey. , 1999, Australian and New Zealand journal of medicine.

[53]  C Weinstein,et al.  The National Clinical Guidelines for Stroke , 2000, Journal of the Royal College of Physicians of London.

[54]  R. Sacco,et al.  Antithrombotic and thrombolytic therapy for ischemic stroke. , 2001, Chest.

[55]  Koroshetz Wj,et al.  Tissue plasminogen activator for acute ischemic stroke. , 1996, The New England journal of medicine.

[56]  R. Grieve.  When will enough be enough? , 1993, Nature.