NIHR DC Discover

NIHR Signal Early aspirin reduces stroke recurrence following warning symptoms

Published on 7 July 2016

doi: 10.3310/signal-000264

Aspirin taken as soon as possible after a stroke or symptoms of a stroke reduces the risk of further stroke within the next six weeks by about 60%. This is much better than the 13% reduction previously estimated. People with warning strokes, where symptoms resolve within 24 hours, stand to benefit by self-administering aspirin even before a scan can be organised. 

This analysis of 12 large randomised controlled trials compared outcomes for adults taking aspirin, other drugs that prevent blood clots and no treatment. Aspirin importantly and significantly reduced the risk of early recurrent stroke in people with warning strokes and strokes perceived as less severe. 

The results support current recommendations that aspirin should be given immediately after a warning stroke known as a transient ischaemic attack. The recommendation that imaging is required to see if a stroke is due to a bleed in the brain, or not, might be revised to allow early self-administration. 

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Why was this study needed?

There are 152,000 strokes each year in the UK and it is the fourth commonest cause of death. Stroke survivors often require long-term rehabilitation which costs the economy £9 billion per year. Recurrence is common, 3 in 10 will have a repeated stroke or symptoms of stroke that resolve within 24 hours, a warning stroke known as a transient ischaemic attack. 

Early recognition and treatment improve outcomes. The public health campaign, Act FAST, encourages people to seek urgent medical attention when experiencing stroke symptoms. However, a population-based survey from 2013 found that half of the people who went on to have a stroke in the days after a warning had not yet sought medical attention. 

This analysis focuses on the impact of aspirin taken early to reduce the short-term recurrence of stroke, particularly in those who have had a warning. 

What did this study do?

This systematic review pooled data on outcomes for 15,778 participants in 12 randomised trials also looking at the length of time to these outcomes.

The studies compared the risk of having a second stroke after taking aspirin with or without another anti-clot forming drug, dipyridamole compared to placebo.

The effects of aspirin and dipyridamole on the prevention of a second stroke were measured at the following times after the first event: within six weeks, 12 weeks and after 12 weeks.

Large similar studies were included and individual patient data was available which increases the reliability of their pooled results. However, many of the studies were carried out in the 1980s and 1990s, when the medical treatment available was different to now and this may affect the extent of the benefit.

What did it find?

Aspirin reduced the risk of a stroke occurring within 12 weeks of an original stroke or warning stroke.

  • Among 11 trials, with 9,635 participants, aspirin reduced the risk of recurrent stroke within six weeks by about 60% (hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.30 to 0.56) and this risk was similar for 12 weeks (HR 0.46, 95% CI 0.35 to 0.60).
  • Aspirin reduced the risk of a major recurrent stroke – one that causes death or severe disability – up to six weeks after the initial event by about 70% (HR 0.29, 95% CI 0.19-0.46)
  • There was no significant difference between patients given aspirin only and patients not given aspirin in reducing the risk of recurrent stroke after 12 weeks (odds ratio [OR] 0.97, 95% CI 0.84 to 1.12).
  • Adding data from three of the trials where aspirin plus dipyridamole were compared to aspirin showed no difference in the result up to 12 weeks, indicating that dipyridamole has no effect on the short term prevention of recurrent stroke (OR 0.90, 95% CI 0.65 to 1.25).
  • Adding dipyridamole to aspirin significantly reduced the risk of recurrent stroke after 12 weeks (OR 0.76, 95% CI 0.63 to 0.92), despite it having little effect before this time.

What does current guidance say on this issue?

NICE guidance from 2008 on the initial management of stroke and TIA recommends giving patients aspirin early. This news study reinforces this guidance with more recent evidence.

It recommends giving 300mg aspirin within 24 hours of a diagnosis of an ischaemic stroke or warning stroke. If a warning stroke is suspected, aspirin should be given immediately. For acute stroke, aspirin should be given as soon as a bleed has been ruled out by brain imaging. It is recommended that aspirin be continued for two weeks, at which point long-term drug options should be decided.

We found no guidance on the self-administration of aspirin.

What are the implications?

This meta-analysis strengthens previous evidence that aspirin prevents recurrent strokes and suggests that the benefits of aspirin to stroke survivors and people with warning strokes have previously been under estimated.

Aspirin is an accessible, cost-effective and low cost drug that is currently advised for self-administration for symptoms of a heart attack. This study highlights the need to reduce delays in patients seeking medical attention for warning symptoms of stroke. It is likely that consideration to promoting self-administration immediately after warning transient symptoms will be reviewed. This is particularly important in remote settings where access to emergency services might be delayed.

These authors point out that bleeding in the brain is rare in patients with warning stroke symptoms lasting under 24 hours and accounts for less than 5% of less disabling full strokes. The trials of anti-thrombotic drugs that have included patients with acute intracranial haemorrhage have not shown any increase in risk of death or of recurrent haemorrhage.

Citation and Funding

Rothwell P, Algra A, Chen Z et al. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials. Lancet. 2016 May 18. [Epub ahead of print].

This study was funded by the National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford and the Wellcome Trust.

Bibliography

NHS Choices. Stroke. London: Department of Health; 2014.

NHS Choices. Stroke – act F.A.S.T. London: Department of Health; undated.

NICE. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. CG68. London: National Institute for Health and Care Excellence; 2008.

The Stroke Association. What is stroke? London: The Stroke Association; 2015.

The Stroke Association. State of the Nation: stroke statistics. London: The Stroke Association; 2016.

Why was this study needed?

There are 152,000 strokes each year in the UK and it is the fourth commonest cause of death. Stroke survivors often require long-term rehabilitation which costs the economy £9 billion per year. Recurrence is common, 3 in 10 will have a repeated stroke or symptoms of stroke that resolve within 24 hours, a warning stroke known as a transient ischaemic attack. 

Early recognition and treatment improve outcomes. The public health campaign, Act FAST, encourages people to seek urgent medical attention when experiencing stroke symptoms. However, a population-based survey from 2013 found that half of the people who went on to have a stroke in the days after a warning had not yet sought medical attention. 

This analysis focuses on the impact of aspirin taken early to reduce the short-term recurrence of stroke, particularly in those who have had a warning. 

What did this study do?

This systematic review pooled data on outcomes for 15,778 participants in 12 randomised trials also looking at the length of time to these outcomes.

The studies compared the risk of having a second stroke after taking aspirin with or without another anti-clot forming drug, dipyridamole compared to placebo.

The effects of aspirin and dipyridamole on the prevention of a second stroke were measured at the following times after the first event: within six weeks, 12 weeks and after 12 weeks.

Large similar studies were included and individual patient data was available which increases the reliability of their pooled results. However, many of the studies were carried out in the 1980s and 1990s, when the medical treatment available was different to now and this may affect the extent of the benefit.

What did it find?

Aspirin reduced the risk of a stroke occurring within 12 weeks of an original stroke or warning stroke.

  • Among 11 trials, with 9,635 participants, aspirin reduced the risk of recurrent stroke within six weeks by about 60% (hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.30 to 0.56) and this risk was similar for 12 weeks (HR 0.46, 95% CI 0.35 to 0.60).
  • Aspirin reduced the risk of a major recurrent stroke – one that causes death or severe disability – up to six weeks after the initial event by about 70% (HR 0.29, 95% CI 0.19-0.46)
  • There was no significant difference between patients given aspirin only and patients not given aspirin in reducing the risk of recurrent stroke after 12 weeks (odds ratio [OR] 0.97, 95% CI 0.84 to 1.12).
  • Adding data from three of the trials where aspirin plus dipyridamole were compared to aspirin showed no difference in the result up to 12 weeks, indicating that dipyridamole has no effect on the short term prevention of recurrent stroke (OR 0.90, 95% CI 0.65 to 1.25).
  • Adding dipyridamole to aspirin significantly reduced the risk of recurrent stroke after 12 weeks (OR 0.76, 95% CI 0.63 to 0.92), despite it having little effect before this time.

What does current guidance say on this issue?

NICE guidance from 2008 on the initial management of stroke and TIA recommends giving patients aspirin early. This news study reinforces this guidance with more recent evidence.

It recommends giving 300mg aspirin within 24 hours of a diagnosis of an ischaemic stroke or warning stroke. If a warning stroke is suspected, aspirin should be given immediately. For acute stroke, aspirin should be given as soon as a bleed has been ruled out by brain imaging. It is recommended that aspirin be continued for two weeks, at which point long-term drug options should be decided.

We found no guidance on the self-administration of aspirin.

What are the implications?

This meta-analysis strengthens previous evidence that aspirin prevents recurrent strokes and suggests that the benefits of aspirin to stroke survivors and people with warning strokes have previously been under estimated.

Aspirin is an accessible, cost-effective and low cost drug that is currently advised for self-administration for symptoms of a heart attack. This study highlights the need to reduce delays in patients seeking medical attention for warning symptoms of stroke. It is likely that consideration to promoting self-administration immediately after warning transient symptoms will be reviewed. This is particularly important in remote settings where access to emergency services might be delayed.

These authors point out that bleeding in the brain is rare in patients with warning stroke symptoms lasting under 24 hours and accounts for less than 5% of less disabling full strokes. The trials of anti-thrombotic drugs that have included patients with acute intracranial haemorrhage have not shown any increase in risk of death or of recurrent haemorrhage.

Citation and Funding

Rothwell P, Algra A, Chen Z et al. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials. Lancet. 2016 May 18. [Epub ahead of print].

This study was funded by the National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford and the Wellcome Trust.

Bibliography

NHS Choices. Stroke. London: Department of Health; 2014.

NHS Choices. Stroke – act F.A.S.T. London: Department of Health; undated.

NICE. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. CG68. London: National Institute for Health and Care Excellence; 2008.

The Stroke Association. What is stroke? London: The Stroke Association; 2015.

The Stroke Association. State of the Nation: stroke statistics. London: The Stroke Association; 2016.

Effects of Centralizing Acute Stroke Services on Stroke Care Provision in Two Large Metropolitan Areas in England

Published on 18 May 2016

P Rothwell, A Algra, Z Chen, H Diener, B Norrving, Z Mehta

The Lancet , 2016

Background Aspirin is recommended for secondary prevention after transient ischaemic attack (TIA) or ischaemic stroke on the basis of trials showing a 13% reduction in long-term risk of recurrent stroke. However, the risk of major stroke is very high for only the first few days after TIA and minor ischaemic stroke, and observational studies show substantially greater benefits of early medical treatment in the acute phase than do longer-term trials. We hypothesised that the short-term benefits of early aspirin have been underestimated. Methods Pooling the individual patient data from all randomised trials of aspirin versus control in secondary prevention after TIA or ischaemic stroke, we studied the effects of aspirin on the risk and severity of recurrent stroke, stratified by the following time periods: less than 6 weeks, 6–12 weeks, and more than 12 weeks after randomisation. We compared the severity of early recurrent strokes between treatment groups with shift analysis of modified Rankin Scale (mRS) score. To understand possible mechanisms of action, we also studied the time course of the interaction between effects of aspirin and dipyridamole in secondary prevention of stroke. In a further analysis we pooled data from trials of aspirin versus control in which patients were randomised less than 48 h after major acute stroke, stratified by severity of baseline neurological deficit, to establish the very early time course of the effect of aspirin on risk of recurrent ischaemic stroke and how this differs by severity at baseline. Findings We pooled data for 15 778 participants from 12 trials of aspirin versus control in secondary prevention. Aspirin reduced the 6 week risk of recurrent ischaemic stroke by about 60% (84 of 8452 participants in the aspirin group had an ischaemic stroke vs 175 of 7326; hazard ratio [HR] 0·42, 95% CI 0·32–0·55, p<0·0001) and disabling or fatal ischaemic stroke by about 70% (36 of 8452 vs 110 of 7326; 0·29, 0·20–0·42, p<0·0001), with greatest benefit noted in patients presenting with TIA or minor stroke (at 0–2 weeks, two of 6691 participants in the aspirin group with TIA or minor stroke had a disabling or fatal ischaemic stroke vs 23 of 5726 in the control group, HR 0·07, 95% CI 0·02–0·31, p=0·0004; at 0–6 weeks, 14 vs 60 participants, 0·19, 0·11–0·34, p<0·0001). The effect of aspirin on early recurrent ischaemic stroke was due partly to a substantial reduction in severity (mRS shift analysis odds ratio [OR] 0·42, 0·26–0·70, p=0·0007). These effects were independent of dose, patient characteristics, or aetiology of TIA or stroke. Some further reduction in risk of ischaemic stroke accrued for aspirin only versus control from 6–12 weeks, but there was no benefit after 12 weeks (stroke risk OR 0·97, 0·84–1·12, p=0·67; severity mRS shift OR 1·00, 0·77–1·29, p=0·97). By contrast, dipyridamole plus aspirin versus aspirin alone had no effect on risk or severity of recurrent ischaemic stroke within 12 weeks (OR 0·90, 95% CI 0·65–1·25, p=0·53; mRS shift OR 0·90, 0·37–1·72, p=0·99), but dipyridamole did reduce risk thereafter (0·76, 0·63–0·92, p=0·005), particularly of disabling or fatal ischaemic stroke (0·64, 0·49–0·84, p=0·0010). We pooled data for 40 531 participants from three trials of aspirin versus control in major acute stroke. The reduction in risk of recurrent ischaemic stroke at 14 days was most evident in patients with less severe baseline deficits, and was substantial by the second day after starting treatment (2–3 day HR 0·37, 95% CI 0·25–0·57, p<0·0001). Interpretation Our findings confirm that medical treatment substantially reduces the risk of early recurrent stroke after TIA and minor stroke and identify aspirin as the key intervention. The considerable early benefit from aspirin warrants public education about self-administration after possible TIA. The previously unrecognised effect of aspirin on severity of early recurrent stroke, the diminishing benefit with longer-term use, and the contrasting time course of effects of dipyridamole have implications for understanding mechanisms of action. Funding Wellcome Trust, the National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford.

An ischaemic stroke occurs when an artery inside the brain becomes blocked with a blood clot. This causes a lack of oxygen in the body leading to damage to the brain.

A haemorrhagic stroke occurs when there is a loss of blood supply, and therefore oxygen, to the brain because a blood vessel bursts inside the brain. They are usually more life threatening than ischaemic strokes.

Haemorrhagic strokes are less common than ischaemic strokes, and account for about 15% of all strokes.

A transient ischaemic attack is a temporary disruption of the blood supply, and therefore lack of oxygen, to the brain causing symptoms similar to those of a stroke. However, a transient ischaemic attack does not last as a long as a stroke and symptoms resolve within 24 hours.

Expert commentary

This paper is a reminder of the value of prompt aspirin therapy as an effective, safe, simple and low-cost method to reduce the frequency and severity of stroke in people with TIA and stroke. Public education campaigns, such as the Act FAST, now mean that many people recognise the symptoms of stroke and know to seek medical attention promptly. Given the safety of aspirin, even in haemorrhagic stroke, sucking a soluble aspirin while awaiting urgent medical assessment may be sensible advice.

Peter Sandercock, Professor of Medical Neurology and Honorary Consultant Neurologist, University of Edinburgh