Background: The majority of strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred. Successful treatment could mean that the patient is more likely to make a good recovery from their stroke. Thrombolytic drugs however, can also cause serious bleeding in the brain which can be fatal. Thrombolytic therapy has now been evaluated in several randomised trials in acute ischaemic stroke.
Objectives: The objective of this review was to assess the safety and efficacy of thrombolytic agents in patients with acute ischaemic stroke.
Search strategy: We searched the Cochrane Stroke Group Trials Register (last searched January 2003), MEDLINE (1966- January 2003) and EMBASE (1980-January 2003). In addition we contacted researchers and pharmaceutical companies, attended relevant conferences and handsearched four Japanese journals.
Selection criteria: Randomised trials of any thrombolytic agent compared with control in patients with definite ischaemic stroke.
Data collection and analysis: 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. Thus published and unpublished data were obtained where available.
Main results: Eighteen trials including 5727 patients were included, but not all trials contributed data to each outcome examined in this review. Sixteen 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 (patients and trials) come from trials testing intravenous tissue plasminogen activator. There are few data from patients aged over 80 years. Much of the data comes from trials conducted in the first half of the 1990s when, in an effort to reduce delays to trial drug administration, on site randomisation methods were used that, in consequence, limited the ability to stratify randomisation on key prognostic variables. Several trials, because of the biological effects of thrombolysis combined with the follow-up methods used, did not have complete blinding of outcome assessment. 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 at three to six months (OR 0.84, 95% CI 0.75 to 0.95). This was in spite of a significant increase in : the odds of death within the first ten days (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.46 to 2.24), the main cause of which was fatal intracranial haemorrhage (OR 4.34, 95% CI 3.14 to 5.99). Symptomatic intracranial haemorrhage was increased following thrombolysis (OR 3.37, 95% CI 2.68 to 4.22). Thrombolytic therapy also increased the odds of death at the end of follow-up at three to six months (OR 1.33, 95% CI 1.15 to 1.53). For patients treated within three hours of stroke, thrombolytic therapy appeared more effective in reducing death or dependency (OR 0.66, 95% CI 0.53 to 0.83) with no statistically significant adverse effect on death (OR 1.13, 95% CI 0.86 to 1.48). There was heterogeneity between the trials that could have been due to many trial features including : thrombolytic drug used, variation in the use of aspirin and heparin, severity of the stroke (both between trials and between treatment groups within trials), and time to treatment. Trials testing intravenous recombinant tissue plasminogen activator suggested that it may be associated with slightly less hazard and more benefit than other drugs when given up to six hours after stroke but these are non-random comparisons - death within the first ten days OR 1.24, 95% CI 0.85 to 1.81, death at the end of follow-up OR 1.17, 95% CI 0.95 to 1.45, dead or dependent at the end of follow-up OR 0.80, 95% CI 0.69 to 0.93. However, no trial has directly comparedup OR 0.80, 95% CI 0.69 to 0.93. However, no trial has directly compared rt-PA with any other thrombolytic agent. There is some evidence that antithrombotic drugs given soon after thrombolysis may increase the risk of death.
Reviewer's conclusions: Overall, thrombolytic therapy appears to result in a significant net reduction in the proportion of patients dead or dependent in activities of daily living. However, this appears to be net of an increase in deaths within the first seven to ten days, symptomatic intracranial haemorrhage, and deaths at follow-up at three to six months. The data from trials using intravenous recombinant tissue plasminogen activator, from which there are 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 for some outcomes and the optimum criteria to identify the patients most likely to benefit and least likely to be harmed, the latest time window, the agent, dose, and route of administration, are not clear. The data are promising and may justify the use of thrombolytic therapy with intravenous recombinant tissue plasminogen activator in experienced centres in highly selected patients where a licence exists. However, the data do not support the widespread use of thrombolytic therapy in routine clinical practice at this time, but suggest that further trials are needed to identify which patients are most likely to benefit from treatment and the environment in which it may best be given. To avoid the problem of data missing from some trials for some key outcomes encountered in this review to date, and to assist future metaanalyses, future trialists should try to collect data in such a way as to be compatible with the basic outcome assessments reviewed here (eg early death, fatal intracranial haemorrhage, poor functional outcome).