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Antiplatelet Medication

NIHR Signal On balance, antiplatelet drugs may be restarted for stroke survivors who have bled into the brain

Published on 15 August 2019

doi: 10.3310/signal-000805

Early research suggests that antiplatelet drugs, such as aspirin, can provide more benefit than harm if restarted at about 2 to 3 months after a brain bleed. The results seem to apply best to those patients with a good prognosis who survive with less disability.

Antiplatelet drugs are of proven benefit to those with a high risk of vascular events; they reduce the risk of heart attacks and strokes because they prevent platelets from clumping together. However, after a type of a stroke caused by a bleed into the brain, an intracerebral haemorrhage, continued use increases the risk of an early further bleed. This risk reduces over time. This has created a dilemma for doctors and patients concerning the balance of benefit and risk leading to uncertainty about if and when to restart these drugs.

Now, a UK trial of 537 adults who were taking antiplatelet drugs before their intracerebral haemorrhage, has found no material difference in the risk of further bleeding or occlusive vascular event if stroke patients are restarted on the drugs when feasible. The results are encouraging and, when combined with the results of two ongoing trials, will help provide more certainty for those faced with this dilemma.

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Why was this study needed?

Intracerebral haemorrhage accounts for up to 15% of all strokes in the UK. In at least a third of cases, the person will have been taking antiplatelet or anticoagulant (such as warfarin) drugs to prevent a heart attack or ischaemic stroke (caused by a blood clot).

Mortality is high – up to 40% in the first month. If a person survives, they will be at increased risk of both blood vessel blockages and further brain bleeds. Yet no randomised trials have been published on whether long-term therapy with antiplatelet or anticoagulant drugs is safe or beneficial.

This trial aimed to assess the effects of antiplatelet drugs on recurrent intracerebral haemorrhage, and whether the risks were outweighed by the benefits of reducing blood clot formation.

What did this study do?

RESTART was a randomised controlled trial of 537 adults from 122 hospitals in the UK. All had been taking either antiplatelet or anticoagulant drugs when they had a bleed in the brain, and then discontinued therapy immediately. They were recruited to the trial on average 76 days after the bleed (range 29 to 146 days). Half were assigned to restart antiplatelet therapy (oral aspirin, dipyridamole or clopidogrel) while the remainder were assigned to avoid them. The average length of follow-up was two years.

The researchers planned to have 720 participants, so the result is less certain than anticipated. Two-thirds of the participants were male.

What did it find?

  • Twelve (4%) people taking antiplatelet drugs had a further intracerebral haemorrhage compared with 23 (9%) people who avoided the drugs, but this difference was not statistically significant (adjusted hazard ratio [aHR] 0.51, 95% confidence interval [CI] 0.25 to 1.03).
  • Major bleeding in the brain or elsewhere also occurred in fewer people on antiplatelet drugs, 18 (7%) compared with 25 (9%) of those avoiding antiplatelet therapy, but again this was not statistically significant (aHR 0.71, 95% CI 0.39 to 1.30).
  • Rates of major clots including heart attacks and ischaemic strokes were similar, 39 (15%) on antiplatelet drugs compared with 38 (14%) of those avoiding them (aHR 1.02, 95% CI 0.65 to 1.60).

What does current guidance say on this issue?

NICE 2019 stroke guidelines do not provide guidance on what to do for people on antiplatelet drugs if they have a haemorrhagic stroke.  

American Heart Association guidelines state that antiplatelet monotherapy might be restarted after an intracerebral haemorrhage, particularly when there are strong indications for these drugs. Lack of evidence has made the European Stroke Association reluctant to make its own recommendations on this topic, although it cites the RESTART trial as a potential means of addressing this dilemma.

What are the implications?

This trial provides some reassurance about the safety of restarting antiplatelet therapy in patients who have experienced an intracerebral haemorrhage, after an interval of a month or more.

The trial recruited fewer patients than planned. More conclusive evidence is expected after the completion of two other trials, when all three can be combined in a meta-analysis.

Nevertheless, it seems that the evidence is improving so that in future, it might better inform the discussion between patients, family and doctors about if and when to resume these drugs.

Citation and Funding

RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet. 2019;393:2613-23.

This study was funded by a special project grant from the British Heart Foundation (number SP/12/2/20422).

Bibliography

Hemphill JC, Greenberg SM, Anderson CS et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015;46(7):2032-60.

NICE. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. National Institute for Health and Care Excellence. London: May 2019.

Steiner T, Salman RA, Beer R et al. European Stroke Association (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke. 2014;9(7):840-55.

Why was this study needed?

Intracerebral haemorrhage accounts for up to 15% of all strokes in the UK. In at least a third of cases, the person will have been taking antiplatelet or anticoagulant (such as warfarin) drugs to prevent a heart attack or ischaemic stroke (caused by a blood clot).

Mortality is high – up to 40% in the first month. If a person survives, they will be at increased risk of both blood vessel blockages and further brain bleeds. Yet no randomised trials have been published on whether long-term therapy with antiplatelet or anticoagulant drugs is safe or beneficial.

This trial aimed to assess the effects of antiplatelet drugs on recurrent intracerebral haemorrhage, and whether the risks were outweighed by the benefits of reducing blood clot formation.

What did this study do?

RESTART was a randomised controlled trial of 537 adults from 122 hospitals in the UK. All had been taking either antiplatelet or anticoagulant drugs when they had a bleed in the brain, and then discontinued therapy immediately. They were recruited to the trial on average 76 days after the bleed (range 29 to 146 days). Half were assigned to restart antiplatelet therapy (oral aspirin, dipyridamole or clopidogrel) while the remainder were assigned to avoid them. The average length of follow-up was two years.

The researchers planned to have 720 participants, so the result is less certain than anticipated. Two-thirds of the participants were male.

What did it find?

  • Twelve (4%) people taking antiplatelet drugs had a further intracerebral haemorrhage compared with 23 (9%) people who avoided the drugs, but this difference was not statistically significant (adjusted hazard ratio [aHR] 0.51, 95% confidence interval [CI] 0.25 to 1.03).
  • Major bleeding in the brain or elsewhere also occurred in fewer people on antiplatelet drugs, 18 (7%) compared with 25 (9%) of those avoiding antiplatelet therapy, but again this was not statistically significant (aHR 0.71, 95% CI 0.39 to 1.30).
  • Rates of major clots including heart attacks and ischaemic strokes were similar, 39 (15%) on antiplatelet drugs compared with 38 (14%) of those avoiding them (aHR 1.02, 95% CI 0.65 to 1.60).

What does current guidance say on this issue?

NICE 2019 stroke guidelines do not provide guidance on what to do for people on antiplatelet drugs if they have a haemorrhagic stroke.  

American Heart Association guidelines state that antiplatelet monotherapy might be restarted after an intracerebral haemorrhage, particularly when there are strong indications for these drugs. Lack of evidence has made the European Stroke Association reluctant to make its own recommendations on this topic, although it cites the RESTART trial as a potential means of addressing this dilemma.

What are the implications?

This trial provides some reassurance about the safety of restarting antiplatelet therapy in patients who have experienced an intracerebral haemorrhage, after an interval of a month or more.

The trial recruited fewer patients than planned. More conclusive evidence is expected after the completion of two other trials, when all three can be combined in a meta-analysis.

Nevertheless, it seems that the evidence is improving so that in future, it might better inform the discussion between patients, family and doctors about if and when to resume these drugs.

Citation and Funding

RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet. 2019;393:2613-23.

This study was funded by a special project grant from the British Heart Foundation (number SP/12/2/20422).

Bibliography

Hemphill JC, Greenberg SM, Anderson CS et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015;46(7):2032-60.

NICE. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. National Institute for Health and Care Excellence. London: May 2019.

Steiner T, Salman RA, Beer R et al. European Stroke Association (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke. 2014;9(7):840-55.

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Published on 28 May 2019

RESTART Collaboration

Lancet , 2019

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (>/=18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2.0 years (IQR [1.0- 3.0]; completeness 99.3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0.51 [95% CI 0.25-1.03]; p=0.060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0.71 [0.39-1.30]; p=0.27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1.02 [0.65-1.60]; p=0.92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation.

Expert commentary

Doctors always worry about prescribing medications that increase the risk of bleeding. Traditionally, antiplatelet agents are stopped if there is a brain bleed.

The results of the RESTART study show that these worries are unfounded and that re-starting antiplatelet agents after a haemorrhagic stroke is in fact indicated rather than prohibited.

These results require a change in the mindset of prescribers and may be difficult to implement due to deep-seated anxieties. It is a high-quality study and should lead to changes in national guidance in due course. It will certainly change my practice.

Elizabeth Warburton, Consultant Physician in Stroke Medicine, Addenbrooke’s Hospital, Cambridge; Neurology Unit, University of Cambridge

The commentator declares no conflicting interests

Expert commentary

I did not recruit participants to the RESTART trial as I believed that restarting antiplatelet therapy may increase the risk of a further intracranial haemorrhage. This was a widely held view and may be the reason why the trial did not recruit to target.

Now the results are available I have changed my mind. I feel there may be benefit from restarting antiplatelet therapy, but the evidence is inconclusive, i.e. the results included risks of both benefit and harm. I will not be changing my clinical practice based upon RESTART but eagerly await the results of two ongoing trials and subsequent meta-analysis. However, I am now in equipoise about the risks and benefits and would consider participating in a future trial.

Helen Rodgers, Professor of Stroke Care, Newcastle University

The commentator declares working in the same department as a study author, and also sharing membership of the British Association of Stroke Physicians Executive with a study author.