Background
Most 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 and improve recovery after stroke in some people. Thrombolytic drugs, however, can also cause serious bleeding in the brain, which can be fatal. One drug, recombinant tissue plasminogen activator (rt-PA), is licensed for use in selected patients within 4.5 hours of stroke in Europe and within three hours in the USA. There is an upper age limit of 80 years in some countries, and a limitation to mainly non-severe stroke in others. Forty per cent more data are available since this review was last updated in 2009.

Objectives
To determine whether, and in what circumstances, thrombolytic therapy might be an effective and safe treatment for acute ischaemic stroke.

Search methods
We searched the Cochrane Stroke Group Trials Register (last searched November 2013), MEDLINE (1966 to November 2013) and EMBASE (1980 to November 2013). We also handsearched conference proceedings and journals, searched reference lists and contacted pharmaceutical companies and trialists.

Selection criteria
Randomised trials of any thrombolytic agent compared with control in people with definite ischaemic stroke.

Data collection and analysis
Two review authors applied the inclusion criteria, extracted data and assessed trial quality. We verified the extracted data with investigators of all major trials, obtaining additional unpublished data if available.

Main results
We included 27 trials, involving 10,187 participants, testing urokinase, streptokinase, rt-PA, recombinant pro-urokinase or desmoteplase. Four trials used intra-arterial administration, while the rest used the intravenous route. Most data come from trials that started treatment up to six hours after stroke. About 44% of the trials (about 70% of the participants) were testing intravenous rt-PA. In earlier studies very few of the participants (0.5%) were aged over 80 years; in this update, 16% of participants are over 80 years of age due to the inclusion of IST-3 (53% of participants in this trial were aged over 80 years). Trials published more recently utilised computerised randomisation, so there are less likely to be baseline imbalances than in previous versions of the review. More than 50% of trials fulfilled criteria for high-grade concealment; there were few losses to follow-up for the main outcomes.

Thrombolytic therapy, mostly administered up to six hours after ischaemic stroke, significantly reduced the proportion of participants who were dead or dependent (modified Rankin 3 to 6) at three to six months after stroke (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.78 to 0.93). Thrombolytic therapy increased the risk of symptomatic intracranial haemorrhage (OR 3.75, 95% CI 3.11 to 4.51), early death (OR 1.69, 95% CI 1.44 to 1.98; 13 trials, 7458 participants) and death by three to six months after stroke (OR 1.18, 95% CI 1.06 to 1.30). Early death after thrombolysis was mostly attributable to intracranial haemorrhage. Treatment within three hours of stroke was more effective in reducing death or dependency (OR 0.66, 95% CI 0.56 to 0.79) without any increase in death (OR 0.99, 95% CI 0.82 to 1.21; 11 trials, 2187 participants). There was heterogeneity between the trials. Contemporaneous antithrombotic drugs increased the risk of death. Trials testing rt-PA showed a significant reduction in death or dependency with treatment up to six hours (OR 0.84, 95% CI 0.77 to 0.93, P = 0.0006; 8 trials, 6729 participants) with significant heterogeneity; treatment within three hours was more beneficial (OR 0.65, 95% CI 0.54 to 0.80, P < 0.0001; 6 trials, 1779 participants) without heterogeneity. Participants aged over 80 years benefited equally to those aged under 80 years, particularly if treated within three hours of stroke.

Authors' conclusions
Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice.

Thrombolysis for acute ischaemic stroke

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(97)03022-5.pdf

Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke

Objective: Hemorrhagic transformation of cerebral infarction (HTI) occurs spontaneously but its frequency and risk factors are uncertain with mixed results in previous studies. We aimed to determine the overall frequency of and risk factors for HTI. Methods: We performed a systematic review according to Cochrane Collaboration methods of published reports of HTI with reliable, systematic follow-up with computed tomography or magnetic resonance imaging. Results: In all, 28 observational studies and 19 randomized controlled trials in stroke were identified that included follow-up imaging data. Problems with inconsistent definitions or small and biased patient populations limited detailed interpretation. The overall frequency of any HTI in untreated patients was 8.5% (95% confidence interval 7%-10%). Severe HTI (i.e., HTI accompanied by neurologic deterioration or parenchymal hematoma formation) occurred in 1.5% (95% confidence interval 0.8%-2.2%). The frequency of HTI increased markedly with increasing use of antithrombotic or thrombolytic drugs. Magnetic resonance imaging detected more HTI than did computed tomography. The published data were generally inadequate to undertake more detailed analysis of risk factors. However, in the 8 studies that did provide the information, HTI was associated with large infarcts, mass effect, hypodensity observed early after the stroke, and age older than 70 years, but not hypertension or cardioembolic stroke. Conclusions: Severe HTI is uncommon in patients not receiving antithrombotic or thrombolytic agents. The methods used to assess the frequency of and risk factors for HTI, particularly a standard of definitions in future prospective studies, could be improved.

Frequency and risk factors for spontaneous hemorrhagic transformation of cerebral infarction.

The rationale for thrombolysis, the most promising pharmacological approach in acute ischaemic stroke, is centred on the principal cause of most ischaemic strokes: the thrombus that occludes the cerebral artery, and renders part of the brain ischaemic. The occluding thrombus is bound together within fibrin. Fibrinolysis acts by activation of plasminogen to plasmin; plasmin splits fibrinogen and fibrin and lyses the clot, which then allows reperfusion of the ischaemic brain. Thrombolytic agents include streptokinase (SK) and recombinant tissue-type plasminogen activator (rt-PA) amongst others under test or development. SK is nonfibrin-specific, has a longer half-life than tissue-type plasminogen activator (t-PA), prevents re-occlusion and is degraded enzymatically in the circulation. rt-PA is more fibrin-specific and clot-dissolving, and is metabolized during the first passage in the liver. In animal models of ischaemic stroke, the effects of rt-PA are remarkably consistent with the effects seen in human clinical trials. For clinical application, some outcome data from the Cochrane Database of Systematic Reviews which includes all randomized evidence available on thrombolysis in man were used. Trials included tested urokinase, SK, rt-PA, pro-urokinase, or desmoteplase. The chief immediate hazard of thrombolytic therapy is fatal intracranial bleeding. However, despite the risk, the human trial data suggest the immediate hazards and the apparent substantial scope for net benefit of thrombolytic therapy given up to 6 h of acute ischaemic stroke. So far the fibrin-specific rt-PA is the only agent to be approved for use in stroke. This may be due to its short half-life and its absence of any specific amount of circulating fibrinogen degradation products, thereby leaving platelet function intact. The short half-life does not leave rt-PA without danger for haemorrhage after the infusion. Due to its fibrin-specificity, it can persist within a fibrin-rich clot for one or more days. The molecular mechanisms with regards to fibrin-specificity in thrombolytic agents should, if further studied, be addressed in within-trial comparisons. rt-PA has antigenic properties and although their long-term clinical relevance is unclear there should be surveillance for allergic reactions in relation to treatment. Although rt-PA is approved for use in selected patients, there is scope for benefit in a much wider variety of patients. A number of trials are underway to assess which additional patients - beyond the age and time limits of the current approval - might benefit, and how best to identify them.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2009.02205.x

The molecular basis of thrombolysis and its clinical application in stroke

The Cochrane Database of Systematic Reviews summarizes all the existing randomized evidence of all treatments for all diseases, so that doctors can quickly access the most up-to-date information. The trials for the Cochrane systematic review of thrombolytic therapy in acute ischemic stroke were identified from extensive searching of the literature and contact with trial investigators. Data on several prespecified outcomes (death and symptomatic intracranial hemorrhages within the first 7 to 10 days after treatment, and death and poor functional outcome at long-term follow-up) were sought in each identified randomized, controlled trial. There have thus far been 17 completed randomized, controlled trials of thrombolytic therapy versus control in 5,216 patients (including the provisional data from the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke [ATLANTIS] A and B and Recombinant Prourokinase in Acute Cerebral Thromboembolism [PROACT] II trials). Of these, eight trials tested recombinant tissue plasminogen activator (rt-PA) in 2,889 patients (56% of all data). Overall, there was an increase in the odds of death within the first 10 days (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.48 to 2.32) and symptomatic intracranial hemorrhage (OR 3.53, 95% CI 2.79 to 4.45) with thrombolysis (slightly less with rt-PA). The odds of death at the end of follow-up were also slightly increased with thrombolysis (OR 1.31, 95% CI 1.13 to 1.52), although this increase was not significant in patients receiving rt-PA. Despite this, overall there was a significant reduction in the number of patients with a poor functional outcome (combined death or dependency) at the end of follow-up (OR 0.83, 95% CI 0.73 to 0.94), which was slightly better in patients receiving rt-PA. Most of the data came from trials testing thrombolysis up to 6 hours after stroke, but the subgroup of patients treated within 3 hours showed a greater reduction in poor functional outcome with thrombolysis (OR 0.58, 95% CI 0.46 to 0.74) with a less adverse effect on death. The available data do not allow much further subgroup analysis, although there is reasonable evidence to indicate that aspirin or heparin given within 24 hours of thrombolytic therapy causes a significant increase in intracranial hemorrhage and death. It is hoped that a meta-analysis using individual patient data may be able to address the effect of thrombolysis in further specific subgroups and examine the interaction between the severity of stroke and the effect of thrombolysis.

Overview of Cochrane thrombolysis meta-analysis.

We evaluated intravenous streptokinase in the treatment of cerebral infarction. Following neurological assessment and cerebral computed tomography (CT), patients aged 40–80 years with symptoms of anterior circulation acute ischaemic stroke were given 1.5 M units streptokinase or saline placebo in a double-blind randomized study. Twenty patients (10 streptokinase, 10 placebo), 11 males, 9 females, aged 57–79 years, were treated out of 512 consecutive admissions to the acute stroke unit over a 2-year period. Initial CT was normal in 11 (6 placebo, 5 streptokinase) and showed early signs of cerebral infarction in nine (4 placebo, 5 streptokinase). Median times from symptom onset to treatment were 5.2 h (placebo) and 5.8 h (streptokinase). Streptokinase treatment was associated with symptomatic symptomatic hypotension in one patient. Repeat CT at 72 h demonstrated intracerebral haematoma in two patients and haemorrhagic infarction in one patient in the streptokinase group; the two cases of haematoma formation were associated with neurological deterioration and death. One patient in the placebo group had evidence of haemorrhagic infarction at 72 h. There were three deaths in each treatment group, all within the first 14 days. Patients with acute stroke can be evaluated with CT and treated with streptokinase within 6 h, but the opportunity for treatment is currently limited to few patients. Streptokinase treatment is not without risk, but potential clinical benefit justifies ongoing multicentre randomized trials.

A pilot study of streptokinase for acute cerebral infarction

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A pilot study of streptokinase for acute cerebral infarction