A Consensus Statement of The Canadian Stroke Consortium*

J.W. Norris, A. Buchan, R. Cote, V. Hachinski, S.J. Phillips, A. Shuaib, F. Silver, D. Simard and P. Teal on behalf of The Canadian Stroke Consortium*

Abstract: Background: The thromobolytic drug, tissue plasminogen activator (tPA) has been approved in the United States for the treatment of acute ischemic stroke amid controversy and concern about the balance of risk and benefit. The Canadian Stroke Consortium (CSC), a national network of neurologists who collaborate on joint projects in stroke medicine, including clinical trials and consensus statements, has developed guidelines for the use of tPA in Canada. Methods and Results: The CSC Board of Directors wrote a preliminary report based on existing publications, including randomized drug trials and the report of a special committee struck by the Stroke Council of the American Heart Association. This draft was circulated to the CSC membership-at-large for suggestions or amendments, to produce this final draft. Conclusions: The present guidelines have been devised to represent a Canadian viewpoint of management. The Health Protection Branch of the Ministry of Health of Canada has not yet produced an evaluation. Further modification of these guidelines may be necessary when more data from clinical trials and experience with the drug become available.

Caution: The following statement should not be considered an endorsement for the general use of t-PA in acute ischemic stroke. When deemed indicated, t-PA should be used solely by physicians experienced in acute stroke management.

Between 1995 - 1996, results of five randomized, placebo controlled trials of intravenous thrombolysis were published, using either streptokinase or recombinant tissue plasminogen activator, t-PA.^1-5 Trials of intra-arterial thrombolytic agents are still in progress and will not be dealt with here.

The FDA approved t-PA for clinical use in June 1996. However, there is concern that the use of t-PA, without proper safeguards, may result in net harm, in acute stroke patients. The Canadian Stroke Consortium has drafted this consensus statement, based on current available evidence and with reference to the Stroke Council of the American Heart Association (AHA) published guidelines.⁶

The role of t-PA for acute ischemic stroke remains controversial^.7 We recommend that its use be restricted to physicians who are experienced in the management of acute stroke and who work in hospitals where the protocol has been approved, for those patients who fall within the strict guidelines we outline and with the understanding that it may confer benefit and that it does carry significant risk. The patient and family need to be fully informed. Modification of these guidelines is likely with the publication of additional trials currently in progress.

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SUMMARIES OF RECENT TRIALS

Streptokinase Trials

There have been three trials of intravenous streptokinase: multicentre acute stroke trials - MAST E (Europe)1 and MAST I (Italy),² and the Australian Streptokinase Trial (ASK).³ All were stopped by the Safety Committees because of increased mortality and increased cerebral hemorrhage. At present, streptokinase cannot be recommended except as part of a clinical trial.

t-PA Trials

There have been two trials, the European Cooperative Acute Stroke Study (ECASS)⁴ and the National Institute of Neurological Disorders and Stroke (NINDS) Study.⁵

In the ECASS study, t-PA was given I.V. at a dose of 1.1 mg/kg up to a total of 100 mg, infusing 10% over 1-2 minutes and the rest over the next hour. There was no significant effect on neurological recovery and a non-significant increase in mortality. Intracranial hemorrhages were three fold more common than in the control group. The time window in this study was 6 hours.

In the NINDS study, t-PA was given at a dose of 0.9 mg/kg up to a total of 90 mg, again infusing over one hour. Although there was no significant difference in mortality at 3 months, there was significantly less disability in the t-PA treated group while symptomatic intracranial hemorrhage was 10 fold more frequent in the t-PA treated group (6.4% vs. 0.6%). The time window was 3 hours.

A recent systematic review of these trials has stated that there is insufficient evidence to recommend the use of thrombolytic drugs to treat acute ischemic stroke at the moment except in the context of further randomized controlled trials.⁸

Guidelines

1) Thrombolytic therapy for acute stroke must be administered in an acute care setting by a physician with expertise in the diagnosis and management of stroke. In most cases t-PA will be given by a neurologist in a tertiary care or major hospital setting. The use of a hospital-approved protocol is recommended. Community hospitals considering the use of t-PA should assess their capability to accurately and safely apply these guidelines.

2) CT scanning must be available on a 24 hour basis with personnel experienced in the detection of early CT signs of significant infarction and intracerebral hemorrhage. CT evidence of cerebral hemorrhage or significant mass effect, as shown by ventricular compression or midline shift, are absolute contra-indications to thrombolytic therapy.

Early signs of ischemia including sulcal effacement or parenchymal hypodensity are associated with an increased risk of intracranial bleeding but are not absolute contra-indications to t-PA.

3) t-PA should be administered intravenously in a dose of 0.9 mg/kg to a maximum of 90 mg, with an initial 10% given as a bolus over 1-2 minutes and the remainder of the dose infused over 60 minutes. The drug must be given within 3 hours of stroke onset. It is not recommended if the time of symptom onset is uncertain, for example in aphasic patients without collateral history or in patients who have neurological deficits upon awakening.

4) Exclusions:

i) CT evidence of cerebral hemorrhage or an infarction involving more than one-third of middle cerebral artery territory

ii) Blood pressure > 185/110

iii) Use of anticoagulants in the previous 48 hours and a prolonged PTT or an INR > 1.7 or platelet count < 100,000

iv) Stroke or head injury in the prior 3 months

v) Major surgery within prior 14 days

vi) Blood glucose < 3 or > 22 mmol/L

vii) Seizures at the onset of stroke

viii) Other bleeding (e.g., G.I.) within prior 21 days

ix) Myocardial infarct within 3 weeks

x) Rapidly improving neurological signs or minimal deficit

xi) Other illness that could limit effectiveness or increase risk of bleeding in the judgment of the physician.

5) No aspirin, heparin, warfarin, ticlopidine or other antiplatelet drugs must be given for at least 24 hours after t-PA. Aspirin treatment prior to t-PA infusion is not a contra-indication.

6) Facilities must be readily available on a 24 hour basis to manage hemorrhagic complications. Intracerebral hemorrhage is probable if unexpected neurological deterioration occurs following the use of t-PA. The infusion should be discontinued immediately and an emergency CT scan obtained. The indications for neurosurgical intervention have not been defined for either spontaneous intracerebral hematomas or those associated with t-PA treatment. Management decisions have to be made empirically by the responsible physician with or without consultation with a neurosurgeon.

7) Vital signs should be taken every 15 minutes during the drug infusion, then 30 minutes for the next 2 hours, then hourly for 5 hours. Neurovital signs should be performed hourly for 6 hours, and then according to the patient's condition.

8) If patient is hypertensive (BP > 180/110), labetalol should be infused I.V. 10 mg over 1-2 minutes repeated every 10-20 minutes up to a dose of 150 mg. Monitoring the BP every 15 minutes during and for 24 hours after t-PA has been given.⁶

9) Informed consent should be obtained from the patient and/or family prior to treatment with t-PA in accordance with hospital policies and procedures.

*Canadian Stroke Consortium

The members of the Canadian Stroke Consortium, listed alphabetically are as follows:

Brian Anderson, MD, St. Boniface Hospital, Winnipeg, Manitoba; Rudolf Arts, MD, Royal Victoria Hospital, Barrie, Ontario; Peter Bailey, MD, St John Regional Hospital, St John, New Brunswick; Neville Bayer, MD, St. Michael's Hospital, Toronto, Ontario; Michel Beaudry, MD, Chicoutimi, Québec; Sabbah Bekhor, MD, St. Mary's Hospital, Montreal, Quebec; André Bellavance, MD, and Léo Berger, MD, Hôpital Charles LeMoyne, Montreal; Gilles Bernier, MD, Hôpital Notre-Dame, Montreal; Sandra Black, MD, Sunnybrook Health Science Centre, Toronto; Alastair Buchan, MD, Foothills Hospital, Calgary; Donald Cameron, MD, Lion's Gate Hospital, Vancouver, British Columbia; Joseph Carlton, MD, Jewish General Hospital, Montreal; Jean-Louis Caron, MD, Montreal General Hospital, Montreal; Sharon Cohen, MD, North York General, Toronto;

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Anthony Costantino, MD, Abbotsford, British Columbia; Robert Côté, MD, L'Hôpital Général de Montréal, Montreal; Terry Curran, MD, Vernon, British Columbia; Nicole Daneault, MD, L'Hôpital St. Luc, Montréal; Martin del Campo, MD, North York Branson, Toronto; Hiren B. Desai, Windsor Health Centre, Windsor, Ontario; Gabrielle deVeber, MD, Oakville, Ontario; Robert Duke, MD, Victoria Medical Centre, Hamilton, Ontario; Liam Durcan, MD, Montreal Neurological Institute, Montreal; George Elleker, MD, Walter Mackenzie Health Science Centre, Edmonton, Alberta; Peter Ender, MD, Hôpital Jean Talon, Montreal; Marek Gawel, MD, Sunnybrook Health Science Centre, Toronto; Vladimir Hachinski, MD, University Hospital, London; Antoine Hakim, MD, Ottawa General Hospital, Ottawa, Ontario; Byrne Harper, MD, Moncton, New Brunswick; Kennely Ho, MD, Kitchener, Ontario; Keith Hoyte, MD, Foothills Hospital, Calgary; David Howse, MD, Queen's University, Kingston, Ontario; Jack Jhamandas, MD, Walter Mackenzie Health Science Centre, Edmonton; Frank Kemble, MD, Victoria, British Columbia; Andrew Kertesz, MD, St. Joseph's Hospital, London; Gary Klein, MD, Rockyview Hospital, Calgary; Edwin Klimek, MD, St. Catharines, Ontario; Louise-Helene Lebrun, MD, L'Hôpital St. Luc, Montréal; Ariane Mackey, MD, Hôpital de l'Enfant-Jesus, Quebec City, Quebec; Richard Magder, MD, Humber River Regional Hospital, Toronto; John Maher, MD, Royal Victoria Hospital, Barrie; Vance Makin, MD, Vancouver; Luc Marchand, MD, Hotel-Dieu de Montreal, Montreal; Jeffrey Minuk, MD, Jewish General Hospital, Montreal; David Morganthau, MD, Humber River Regional, Toronto; John Norris, MD, CSC Chairman, Sunnybrook Health Science Centre, Toronto; David Novak, MD, Penticton, British Columbia; Wieslaw Oczkowski, MD, Victoria Medical Centre, Hamilton; Georges Patry, MD, Hotel-Dieu de Quebec, Quebec City; Andrew Penn, MD, Edmonton; James Perry, MD, Sunnybrook Health Science Centre, Toronto; Marc Petitclerc, MD, Hôtel-Dieu de Lévis, Lévis, Quebec; Stephen Phillips, MD, Queen Elizabeth II Health Sciences Centre, New Halifax Infirmary Site, Halifax, Nova Scotia; William Pryse-Phillips, The General Hospital - Health Sciences Centre, St John's, Newfoundland; Ali Rajput, MD, Royal University Hospital, Saskatoon, Saskatchewan; Donald Rivest, MD, Hotel Dieu de Levis, Levis; T. Peter Seland, MD, Kelowna, British Columbia; Daniel Selchen, MD, Mississauga Hospital, Toronto; Mukul Sharma, MD, Windsor; Ashfaq Shuaib, MD, Walter Mackenzie Health Sciences Centre, Edmonton; Frank Silver, MD, The Toronto Hospital - Western Division, Toronto; David Silverberg, MD, Moncton; Denis Simard, MD, Hôpital de l'Enfant-Jesus, Quebec City; David Spence, Robarts Research Institute, London; Paul Stenerson, MD, Edmonton; Chao Tai, MD, Edmonton; Philip Teal, MD, Vancouver General Hospital, Vancouver; Jeanne Teitelbaum, MD, Maisonneuve-Rosemont Hospital, Montreal; Felix Veloso, MD, Regina, Saskatchewan; Lyle Weston, MD, Moncton; Toni Winder, MD, Lethbridge, Alberta; Michael Winger, MD, Windsor Health Centre, Windsor; Milton Wong, MD, St. Paul's Hospital, Vancouver; Chidambaram Yegappan, MD, The General Hospital - Health Sciences Centre, St John's, Newfoundland.

REFERENCES

1. The Multicenter Acute Stroke Trial - Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996; 335: 145-150.

2. The Multicentre Acute Stroke Trial - Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet. 1995; 346: 1509-1514.

3. Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischaemic stroke with relationship to time of administration. JAMA 1996; 276: 961-966.

4. Hacke W, Kaste M, Fieschi C, et al. for The European Cooperative Acute Stroke Study (ECASS). Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995; 274: 1017-1025.

5. 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.

6. Guidelines for Thrombolytic Therapy for Acute Stroke: A Supplement to the Guidelines for the Management of Patients With Acute Ischemic Stroke. Stroke Council, American Heart Association. Stroke 1996; 27: 1711-1718.

7. European Strategies for Early Intervention in Stroke: A Report of an Ad Hoc Consensus Group Meeting. Cerebrovascular Dis 1996; 6: 315-324.

8. Wardlaw JM, Warlow CP, Counsell C. Systematic review of evidence on thrombolytic therapy for acute ischemic stroke. Lancet 1997; 350: 607-614.

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Received August 22, 1997. Accepted in final form February 10, 1998.

Reprint requests to: Canadian Stroke Consortium, Headquarters Office, Room C408, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5

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