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Clot-dissolving drugs for treating ischaemic stroke in the early stages

Wardlaw JM, Murray V, Berge E, del Zoppo GJ
Published Online: 
29 July 2014

Question

We wanted to compare the safety and efficacy of clot-dissolving (thrombolytic) drugs versus placebo or no treatment in the early stages of ischaemic stroke to see if clot-dissolving drugs improve outcome after stroke.

Background

Most strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with clot-dissolving (thrombolytic) drugs can restore blood flow before major brain damage has occurred and could mean that people are more likely to make a good recovery from their stroke. Thrombolytic drugs can also, however, cause serious bleeding in the brain, which can be fatal. Thrombolytic therapy has now been evaluated in many randomised trials in acute ischaemic stroke. The thrombolytic drug alteplase has been licensed for use within three hours of stroke in the USA and Canada, and within 4.5 hours in most European countries. The numbers of people receiving this treatment successively are increasing.

Study characteristics

We identified 27 trials with a total of 10,187 participants in searches conducted up to November 2013. Most data come from trials testing one drug (recombinant tissue Plasminogen Activator, rt-PA) given into a vein up to six hours after acute ischaemic stroke, but several other drugs were also tested and at different times to treatment after stroke and given into an artery in the brain rather than into a vein in the arm. All trials compared a clot-dissolving drug with a placebo (control) group. Most trials included participants with moderate to severe stroke. All trials took place in hospitals that were used to treating people with stroke. Differences between trials mean that not all trials contribute information to all outcomes, but we have used all available data. Most trials included participants after a computed tomography (CT) brain scan had excluded a brain haemorrhage as the cause of symptoms (a few trials used magnetic resonance brain scanning instead).

Key results

There is general agreement between the earlier trials and the one recent trial added in this update (IST-3) for all main outcomes, and between the 12 trials that tested rt-PA and the 15 trials that tested other clot-dissolving drugs. The main difference between IST-3 and earlier trials was that IST-3 had many participants above 80 years. Clot-dissolving treatment can reduce the risk of long-term dependency on others for daily activities, in spite of there being an increased risk of bleeding in the brain which also increased the risk of early death. Once the early bleeding risk had passed, at three or six months after stroke, people given clot-dissolving drugs were more likely to have recovered from their stroke and to be independent, especially if they had been treated within the first three hours after stroke. Older people benefited as much as younger people. Giving aspirin at the same time as clot-busting drugs increased the risk of bleeding and should be avoided. Further analyses of individual patient data factors such as findings on brain scanning before treatment, and of different ways of giving the treatment, may give more information than the summary data that we used here. Meantime, people who think that they are experiencing a stroke should get to hospital quickly, be assessed by a stroke doctor, have a brain scan and receive clot-dissolving treatment as fast as possible. They should not hesitate by thinking that they will be 'too old' for treatment. The treatment is very effective if started within three hours of stroke and definitely improves outcome if given up to 4.5 hours after stroke, but later than that the effects are less clear and are still being tested in trials. More information is needed from trials in people with mild stroke to see if the benefit of clot-dissolving drugs outweighs the risk of haemorrhage.

Quality of the evidence

The evidence comes mostly from well-conducted randomised trials run by stroke experts. Some trials (8/27) were run by companies that make the clot-dissolving drugs, but most trials (19/27, including most participants) were funded by Government or charity sources independently of drug companies. These results apply to a wide range of people with a wide range of severities of stroke and other medical conditions.