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Review: Data are insufficient to evaluate the effectiveness of doses and administration routes of thrombolytic agents for acute ischemic stroke

ACP J Club. 1999 May-June;130:62. doi:10.7326/ACPJC-1999-130-3-062

Source Citation

Liu M, Wardlaw J. Thrombolysis in acute ischaemic stroke: direct randomised comparisons of different doses, routes of administration and agents. Cochrane Review, latest version 13 Apr 1998. In: The Cochrane Library. Oxford: Update Software.



Which thrombolytic agents are most effective for acute ischemic stroke? What is the optimal dose of the thrombolytic agents?

Data sources

Studies were identified through MEDLINE (1966 to 1997), Embase/Excerpta Medica (1974 to February 1997), BIOSIS (1969 to 1997), DERWENT Drug File (1983 to 1997), SCISEARCH (1974 to 1997), ADIS, National Research Register, CRISP, and Dissertation Abstracts. 25 journals were hand searched, pharmaceutical companies and trial investigators were contacted, and meeting abstracts were scanned.

Study selection

Randomized controlled trials were selected if the patients were studied within 14 days of onset of acute ischemic stroke; if thrombolytic drugs were compared directly with each other or in different doses or administration routes; and if outcomes of function, death, intracerebral hemorrhage, major extracerebral hemorrhage, or other major extracerebral events were assessed. Any thrombolytic agent was included (urokinase, pro-urokinase, streptokinase, tissue plasminogen activator, or lumbrokinase).

Data extraction

Data were extracted on study quality; patient and study characteristics, including thrombolytic agents, doses, and administration routes; and outcomes.

Main results

8 randomized controlled trials were included (1334 patients); all were done in Japan. 7 trials compared high doses of thrombolytic agents with low doses of the same agents, and 3 compared different agents. More fatal intracerebral hemorrhages occurred in the high-dose groups than in the low-dose groups (Table). No other differences occurred when high-dose and low-dose agents were compared (death or dependence at the end of follow-up, all-cause mortality at 2 wk or study end, major intracerebral hemorrhage during follow-up, and total major extracerebral hemorrhage during follow-up). 3 trials compared different agents, and no differences were shown for any outcome. Data were insufficient to assess the effectiveness of different administration routes.


Data are insufficient to compare doses and administration routes for individual thrombolytic agents and to compare different thrombolytic agents in acute ischemic stroke. Some limited data, however, suggest that high-dose agents carry an increased risk for fatal intracerebral hemorrhage.

Source of funding: U.K. Medical Research Council.

For correspondence: Dr. J. Wardlaw, Reader and Honorary Consultant Neuroradiologist, Neurosciences Trials Unit, Department of Clinical Neurosciences, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK. FAX 44-131-332-5150.

Table. High-dose vs low-dose thrombolytic agents for acute ischemic stroke*

Outcome at 1 mo Weighted rate for low-dose RRI (95% CI) NNH†
Fatal intracerebral hemorrhage 0.3% 251% (8 to 1044) 133

*Abbreviations defined in Glossary; RRI, NNH, and CI calculated from data in article.
†Typical NNH.


Liu and Wardlaw provide a valuable summary of existing trials that directly compares different thrombolytic doses and agents for acute ischemic stroke. The doses and administration routes used, however, are unconventional compared with current practice; no direct randomized comparisons of conventional regimens have been done. The European Cooperative Acute Stroke Study (ECASS I), using recombinant tissue plasminogen activator (rt-PA), 1.1 mg/kg of body weight, reported higher mortality and intracerebral hemorrhage rates for the treated groups than for patients receiving the National Institute of Neurologic Disorders and Stroke (NINDS) trial dose of rt-PA, 0.9 mg/kg (1, 2). These results prompted a second trial, ECASS II, which used the 0.9 mg/kg dose (3). The symptomatic intracerebral hemorrhage rate in this treated population was closer to that in the NINDS trial (8.8% vs 6.4%), suggesting that a lower dose of rt-PA may be safer (2, 3).

Since June 1996, rt-PA in a 0.9 mg/kg dose has been approved by the U. S. Food and Drug Administration for the treatment of acute ischemic stroke. Because of the high rate of intracerebral hemorrhage seen in ECASS I in patients with early signs of infarction on computed tomography, it is recommended that these patients not receive thrombolytics (4). To further minimize the risk for intracerebral hemorrhage, strict adherence to the American Heart Association guidelines for the use of thrombolytics is recommended (4). Debate remains and research is needed on how patients should be screened for thrombolysis, on which thrombolytic to use, and by what route thrombolysis should be delivered.

Judith A. Hinchey, MD
Robert G. Holloway, MD, MPHUniversity of RochesterRochester, New York, USA


1. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study. JAMA. 1995;274:1017-25.

2. 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;333:1581-7.

3. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352:1245-51.

4. Adams HP Jr, Brott TG, Furlan AJ, 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. Stroke. 1996;27:1711-8.