Thrombolysis for acute ischaemic stroke.
BACKGROUND
The majority of strokes are due to blockage of an artery in the brain by a blood clot. Clot dissolving (or thrombolytic) drugs may reduce brain damage from the stroke, but may also cause serious bleeding in the brain. Thrombolytic therapy has now been evaluated in several randomised trials in acute ischaemic stroke.


OBJECTIVE
The objective of this review was to assess the safety and efficacy of thrombolytic agents in patients with acute ischaemic stroke.


METHODS
Cochrane Stroke Review Group search strategy plus ongoing contact with researchers and pharmaceutical companies. Last search conducted March 1999.


METHODS
Randomised trials of any thrombolytic agent compared with control in patients with definite ischaemic stroke.


METHODS
One reviewer applied the inclusion criteria and extracted the data. Trial quality was assessed. The extracted data were verified by the principal investigators of all major trials.


RESULTS
Seventeen trials including 5216 patients were included. Fifteen trials were double-blind. The trials tested urokinase, streptokinase, recombinant tissue plasminogen activator or recombinant pro-urokinase. Two trials used intra-arterial administration but the rest used the intravenous route. About 50% of the data come from trials testing intravenous tissue Plasminogen Activator. Thrombolytic therapy significantly increased the odds of death within the first ten days (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.48 to 2.32). The main cause of the increase in deaths was fatal intracranial haemorrhage following thrombolysis (OR 4.15, 95% CI 2.96 to 5.84). Symptomatic intracranial haemorrhage is also increased following thrombolysis (OR 3.53, 95% CI 2.79 to 4.45). Thrombolytic therapy also increased the odds of death at the end of follow-up (OR 1.31, 95% CI 1.13 to 1. 52). Despite this, thrombolytic therapy, administered up to six hours after ischaemic stroke, significantly reduced the proportion of patients who were dead or dependent (modified Rankin 3 to 6) at the end of follow-up (OR 0.83, 95% CI 0.73 to 0.94). For patients treated within three hours of stroke, thrombolytic therapy appeared more effective in reducing death or dependency (OR 0.58, 95% CI 0.46 to 0.74) with less adverse effect on death (OR 1.11, 95% CI 0.84 to 1.47). There was heterogeneity between the trials that could have been due to : thrombolytic drug used, variation in the concomitant use of aspirin and heparin, severity of the stroke, and time to treatment. Trials testing intravenous recombinant tissue Plasminogen Activator suggest that it may be associated with slightly less hazard and more benefit when given up to six hours after stroke - death within the first ten days OR 1.24, 95% CI 0.85 to 1.81, death at the end of follow-up OR 1.16, 95% CI 0.94 to 1.44, dead or dependent at the end of follow-up OR 0.79, 95% CI 0.68 to 0.92. One trial that tested thrombolysis plus aspirin showed an increase in deaths of patients given both drugs in combination compared with thrombolysis alone.


CONCLUSIONS
Thrombolytic therapy increases deaths within the first seven to ten days, and deaths at final follow-up. Thrombolytic therapy also significantly increases symptomatic and fatal intracranial haemorrhage. These risks are offset by a reduction in disability in survivors, so that there is, overall, a significant net reduction in the proportion of patients dead or dependent in activities of daily living. The data from trials using intravenous recombinant tissue Plasminogen Activator, from which there is the most evidence on thrombolytic therapy so far, suggest that it may be associated with less hazard and more benefit. There was heterogeneity between the trials and the optimum criteria to identify the patients most likely to benefit and least likely to be harmed, the agent, dose, and route of administration, are not clear. (ABSTRACT TRUNCATED)
Wardlaw
J M
JM
Neurosciences Trials Unit, Department of Clinical Neurosciences, Western General Hospital, Crewe Road, Edinburgh, UK, EH4 2XU. jmw@skull.dcn.ed.ac.uk
del Zoppo
G
G
Yamaguchi
T
T
D002545:Brain Ischemia / Q000188:drug therapy; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D020521:Stroke / Q000188:drug therapy*; D015912:Thrombolytic Therapy
D005343:Fibrinolytic Agents