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In patients presenting to hospital with a recent acute ischaemic stroke (that is, one caused by a blockage of one of the brain arteries), the drug alteplase can dissolve (or ‘lyse’) the clot responsible. Randomized trials have previously shown that, if given within about 4.5 hours of the onset of symptoms, alteplase increases the proportion of patients who are free of disability by 3 months, with larger benefits the earlier that alteplase restores the brain’s blood supply (ie, ‘time is brain’).

In a small proportion of patients, however, alteplase causes bleeding into the brain (cerebral haemorrhage), which usually results in serious disability or death.

New research reported in Lancet Neurology today looks closely at the pros and cons of treatment with alteplase, and its findings will help doctors deal with the difficult decision-making as the critical moments tick by.

The study provides better information about the risks of cerebral haemorrhage in patients given alteplase after acute stroke and will help provide additional confidence to doctors who advise patients and carers of patients in the important first few hours after stroke.

The work was undertaken by the Medical Research Council study team at the University of Oxford, led by Professor Colin Baigent and will have an important impact at the cutting edge of emergency treatment, when decisions have to be made swiftly.

“When a person arrives in hospital after a stroke, lost time is lost brain, with alteplase treatment less able to protect the brain the longer it is delayed,” said Professor Baigent. “In treating critically ill patients, doctors need to be able to predict rapidly both the expected reduction in disability from alteplase and the risk of cerebral haemorrhage. They then need to discuss with patients and their families or carers whether the treatment is appropriate. It is a challenging task.

“Doctors need to understand the subtleties of treatments like alteplase, and also have confidence in what they say and do. Our results will help guide best practice based on good quality evidence from research.”

The study was possible because researchers responsible for randomized trials of alteplase in acute stroke combined detailed data from all their trials, thereby allowing all of the available evidence to be analysed together.

Associate Professor Jonathan Emberson, the statistician who supervised the new analyses, said: “Overall in the study, among patients who were given alteplase within 4.5 hours of stroke, 7% more patients were free of disability by 3 months after the stroke. By comparison, alteplase increased the risk of dying from an intracerebral haemorrhage by about 2%, but reduced the risk of dying from other causes by 1%, so the overall excess risk of death was increased by about 1%.”

Dr William Whiteley, consultant clinical neurologist and Medical Research Council Clinician Scientist at the University of Edinburgh, who collaborated with the Oxford team, said:

”Although on average the benefits of alteplase exceeded its risks, our research showed that the precise balance of benefit and risk for a particular patient was dependent not only on how quickly they were treated but also on the severity of the stroke, since the risks of cerebral haemorrhage were larger in more severe strokes.”

The new research helps to address public concerns about the safety of alteplase. In 2014 the UK Medicines and Healthcare products Regulatory Authority announced a review of the evidence by an Expert Working Group, which reported its findings in 2015. It found that alteplase is safe and effective when used within the terms of the product licence.1

Dr Dale Webb, Director of Research and Information at the Stroke Association, said: "We welcome this new analysis which adds to the body of evidence suggesting that the benefits of thrombolysis treatment outweigh the risks when given within 4.5 hours of stroke, and which form the basis of current clinical guidelines. The authors further argue that early treatment is especially important for those patients with severe strokes who are at higher risk of a fatal bleed as a result of thrombolysis treatment.” 

"These findings underline the fact that stroke is a medical emergency which requires urgent medical assessment and treatment. If someone thinks they are having a stroke they should call 999 immediately. At the same time, hospitals need to have the best care pathway in place to ensure eligible patients receive thrombolysis treatment as soon as possible.”

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