Vital window for stroke drug
Taking the clot-busting drug alteplase within 90 minutes of a stroke “gives patients more than double the chance of full recovery”, said the Daily Mail.
This news is based on well-conducted research that analysed data on the drug, which is injected to break up blood clots. Although it is already known that quicker treatment leads to better outcomes, the study determined that the drug still showed benefits if used within four and a half hours of a stroke. After this time, however, the risks of side effects may outweigh the benefits. Alteplase is not suitable for everyone and, as recommended by NICE, it can only be given for strokes caused by clots, and be given by experienced staff with appropriate scanning equipment.
With all cases of stroke, rapid assessment and treatment is essential to achieve the best outcome. See Stroke: Act F.A.S.T. to learn the important warning signs that could save vital minutes.
Where did the story come from?
The study was carried out by researchers from the University of Glasgow, and collaborators from various academic institutions. The research was undertaken without outside funding.
The study was published in the peer-reviewed medical journal The Lancet.
This research was generally covered well by the Daily Mail and Daily Telegraph. The newspapers highlighted that treatment given within 90 minutes was the most effective. Even though alteplase treatment is more effective when given quickly, it is
important to emphasise that it is still effective up to four and a half hours after the onset of stroke. A particularly good inclusion in the Daily Mail article was a clear explanation of the symptoms of stroke. It is very important that people are familiar with these signs so that they can call an ambulance if they suspect that someone is having a stoke.
What kind of research was this?
Strokes that are caused by blood clots (ischaemic stroke) can be treated with a drug called alteplase, which breaks up the clot. This allows blood flow to be restored, enabling the tissue to receive oxygen and limiting further damage. Doctors usually aim to give this treatment as soon as possible after the onset of stroke symptoms to limit the time that the brain is starved of oxygen. The current study looked at pooled data from clinical trials for this drug to determine when is the best time to treat patients following a stroke. This analysis included two new trials that had not been included in previous analyses.
All of the trials included in the pooled analysis were randomised controlled trials, the best design for looking at the effect of a drug. However, an inherent problem with pooled analysis is that each study may differ in terms of the study participants’ characteristics or the treatments they received. The researchers therefore have to assess whether the data from various trials are in fact comparable. This research was not a formal systematic review, so it should not be assumed that it includes all relevant trials of the use of alteplase in stroke treatment.
What did the research involve?
The researchers re-analysed the data from eight randomised placebo controlled trials looking at the use of alteplase for stroke. The patients were included if it was clear what time they had their stroke and received a CT scan (or MRI scan) to rule out a haemorrhagic stroke (a stroke caused by a bleed in the brain rather than a blockage). The researchers could then measure the time from stroke onset to the time of treatment.
A number of the trials differed in which patients they considered to be eligible participants. Some trials excluded people who were at a higher risk of bleeding, or already had a large degree of brain damage according to the CT scan. Also, different trials focused on strokes of varying severity.
The patients were given a dose of the drug through an intravenous injection over one hour. In seven of the trials, the patients were given a dose of 0.9 mg per kilo of bodyweight, while in one trial patients were given 1.1 mg/kg.
The patient’s post-stroke disability was measured using three disability assessment scales, which were given up to three months after their stroke. The researchers also recorded how many people had died and how many people had experienced a brain bleed (which is a possible side effect of this treatment).
What were the basic results?
The researchers analysed the data from 3,670 patients. The average age of the patients was 68, and the average onset-to-treatment time was 240 minutes (interquartile range 180 to 284).
If patients received alteplase within 90 minutes, their chance of having no disability was 2.55 times greater than those given a placebo (odds ratio [OR] 2.55, 95% CI 1.44 to 4.52).
With increased time, the benefits of the drug treatment were lower. If they received alteplase between one and a half to three hours after their stroke there was a 64% increased chance of having no disability compared to those who received placebo (OR 1.64, 95% CI 1.12 to 2.40).
The researchers performed a statistical analysis to look for characteristics in the patients that may have contributed to how well they would respond to treatment. They found that how well the patient responded to alteplase (in terms of subsequent disability) depended on the onset-to-treatment time, the person’s age, the degree of the patient’s impairment when they arrived at hospital, blood pressure and previous high blood pressure.
They then devised a statistical model that adjusted for all of these factors. Using this model, they found that the benefit of treatment with alteplase decreased as onset-to-treatment time increased. There was no benefit from the drug if treatment commenced after around 270 minutes.
There was no difference in the number of patients who had received placebo or alteplase who died following their stroke (11.8% of patients who received placebo and 13.6% of patients who received alteplase treated within six hours). However, when the researchers compared the onset-to-treatment time, patients who received alteplase after 270 minutes had an increased risk of death compared to patients who had received the drug earlier after their stroke.
They found that 5.2% of patients who received alteplase had a subsequent brain bleed compared to 1% of the control patients. This corresponded to a five-fold increased risk in the alteplase group (odds ratio 5.37, 95% CI 3.22 to 8.95, p<0.0001).
How did the researchers interpret the results?
The researchers said that by including data from recent clinical trials, they had more data to analyse how a delay in receiving alteplase affected the outcome of patients with stroke. This allowed them to look at not only the benefits but also the risks in relation to treatment delay. They say that “this updated pooled analysis shows that treatment with thrombolysis until 4.5 hours from stroke onset enhances the chance of favourable outcome”.
“Serious haemorrhage rates are independent of onset to time of treatment, but mortality increases with onset to time of treatment longer than 4.5 hours. However, across the time window studied, our analysis showed that the greatest benefit comes from earlier treatment, since net benefit is diminishing and is undetectable in our sample beyond 4.5 hours,” the researchers added.
Conclusion
This study used a pooled analysis of randomised controlled trials to look at how a delay in treatment with alteplase can affect the outcome and risk of death following stroke. As they had pooled data from randomised controlled trials, the quality of the data is likely to be good. Where there were differences between some of the trials (i.e. patient and stroke characteristics) the researchers appear to have considered these differences adequately.
Alteplase is not suitable for all people and, as outlined by NICE guidance, can only be administered by experienced staff to people who have definite non-haemorrhagic stroke, have no increased bleeding risk, and where immediate and repeat brain imaging is readily available.
With all cases of stroke, rapid assessment and treatment is essential to achieve the best outcome.
This study highlights the need for a rapid medical response if someone has a stroke. It is important to recognise the signs that someone is having a stroke:
- Face. The face may have fallen on one side, the person may not be able to smile, or their mouth or eye may have drooped.
- Arms. The person with suspected stroke may not be able to raise both arms and keep them there because of arm weakness or numbness.
- Speech. There may be slurred speech.
These symptoms may vary from person to person, but they usually begin suddenly. If you suspect that you or someone else is having a stroke, you must phone 999 immediately and ask for an ambulance.
