NIHR DC Discover

NIHR Signal Adding a third antiplatelet drug after a stroke doesn’t reduce the risk of another stroke

Published on 27 March 2018

doi: 10.3310/signal-00578

A combination of aspirin, clopidogrel and dipyridamole does not reduce the incidence or severity of recurrent stroke in people who have had a stroke or transient ischaemic attack (TIA).

This NIHR-funded trial compared the triple treatment to current guideline-based antiplatelet therapy for preventing further stroke or TIA (brief loss of blood supply to the brain). UK guidance recommends aspirin initially followed by clopidogrel alone as for most people this gives the best balance of effectiveness and bleeding risk. Dual therapy with aspirin and clopidogrel may be used for the first three months following ischaemic stroke or TIA in certain groups.

The trial of 3,096 adults, mainly in the UK, shows that combining all three drugs does not add benefits. Although the risk of bleeding is low with both treatments it is greater with triple therapy. This suggests that triple antiplatelet therapy should not be used in routine clinical practice.

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Why was this study needed?

Stroke costs the NHS in England approximately £2.8 billion per year. About 110,000 people in England have a first or recurrent stroke each year. Another 20,000 people have a TIA. The risk of having a second or recurrent stroke is highest immediately after a stroke or TIA, so guidelines recommend starting antiplatelet drugs within 48 hours.

Antiplatelet treatment reduces the formation of blood clots, and so lowers the chance of a further stroke in people whose stroke was caused by blood clots (ischaemic stroke). Recent research has shown that combining two different antiplatelet drugs may be more effective than treating with just one. This study aimed to discover whether combining three drugs would be even more effective at reducing the risk of recurrent stroke.

What did this study do?

TARDIS was a randomised controlled trial carried out in 106 hospitals across the UK, Denmark, Georgia and New Zealand. It recruited 3,096 adults admitted to hospital with a TIA or ischaemic stroke not due to a clot coming from the heart who were and at risk of a recurrent ischaemic stroke.

Participants were randomly assigned within 48 hours of symptom onset. The triple therapy group received aspirin (50-150mg daily), clopidogrel (75mg daily) and dipyridamole (300-400mg daily) for 30 days. The control group received similar doses of either combined aspirin and dipyridamole, or clopidogrel alone. After 30 days both groups were given therapy according to guideline recommendations. Follow-up was for 90 days.

As the trial was open-label, patients and clinicians were aware of which treatment they received, but most outcomes were objective, so the bias is unlikely to have affected the results.

What did it find?

  • Overall occurrence of serious adverse events was similar in each group, 22% in the triple therapy group compared with 21% in the control group (adjusted odds ratio [OR] 1.02 95% confidence interval [CI] 0.86 to 1.22).
  • There was no difference in the number of people with a recurrent stroke or TIA between the groups. Either occurred in 6% (93/1,540) of the triple therapy group, versus 7% (105/1,530) of the control group (adjusted common odds ratio [cOR] 0.90, 95% confidence interval [CI] 0.67 to 1.20).
  • Recurrent stroke occurred in 4% of each group, with similar ranges of severity.
  • More severe types of bleeding were more than twice as common in the triple therapy group (adjusted cOR 2.54, 95% CI 2.05 to 3.16). Fatal or major bleeding occurred by day 90 in 3% (39/1,540) of the triple therapy group compared with 1% (17/1,540) of the control group.
  • There was no difference between the groups at 90 days regarding disability, mood, cognition or quality of life.
  • The trial was stopped early on the recommendation of the data monitoring committee.

What does current guidance say on this issue?

The Royal College of Physicians’ 2016 national stroke guideline recommends clopidogrel alone to prevent recurrence for people who have had an ischaemic stroke or TIA. If this cannot be taken or tolerated, they recommend modified-release dipyridamole in combination with aspirin.

For people who also have other conditions such as a stent in the heart vessels or severe narrowing of the vessels in the brain, they recommend clopidogrel plus aspirin. They do not recommend all three drugs to be taken at the same time.

What are the implications?

Triple antiplatelet therapy can’t be recommended in usual clinical practice to reduce the risk of recurrent stroke after stroke or TIA. The three drugs in combination did not reduce the incidence and severity of recurrent stroke or TIA but did increase the risk of major bleeding.

This trial was carried out predominantly in the UK (2,995 of the participants), with wide inclusion criteria, so is likely to apply to the UK population.

Citation and Funding

Bath PM, Woodhouse LJ, Appleton JP, et al; TARDIS Investigators. Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. Lancet. 2017;391:850-59.

This project was funded by the National Institute for Health Research Health Technology Assessment (HTA) programme (project number 10/104/24/) and the British Heart Foundation (grant PG/08/083/25779).

Bibliography

NHS Choices. Stroke. London: Department of Health; 2017.

NICE. Stroke Pathway. London: National Institute for Health and Care Excellence; 2017.

NICE. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events. TA210. London: National Institute for Health and Care Excellence; 2010.

RCP. National clinical guideline for stroke. London: Royal College of Physicians; 2016.

Why was this study needed?

Stroke costs the NHS in England approximately £2.8 billion per year. About 110,000 people in England have a first or recurrent stroke each year. Another 20,000 people have a TIA. The risk of having a second or recurrent stroke is highest immediately after a stroke or TIA, so guidelines recommend starting antiplatelet drugs within 48 hours.

Antiplatelet treatment reduces the formation of blood clots, and so lowers the chance of a further stroke in people whose stroke was caused by blood clots (ischaemic stroke). Recent research has shown that combining two different antiplatelet drugs may be more effective than treating with just one. This study aimed to discover whether combining three drugs would be even more effective at reducing the risk of recurrent stroke.

What did this study do?

TARDIS was a randomised controlled trial carried out in 106 hospitals across the UK, Denmark, Georgia and New Zealand. It recruited 3,096 adults admitted to hospital with a TIA or ischaemic stroke not due to a clot coming from the heart who were and at risk of a recurrent ischaemic stroke.

Participants were randomly assigned within 48 hours of symptom onset. The triple therapy group received aspirin (50-150mg daily), clopidogrel (75mg daily) and dipyridamole (300-400mg daily) for 30 days. The control group received similar doses of either combined aspirin and dipyridamole, or clopidogrel alone. After 30 days both groups were given therapy according to guideline recommendations. Follow-up was for 90 days.

As the trial was open-label, patients and clinicians were aware of which treatment they received, but most outcomes were objective, so the bias is unlikely to have affected the results.

What did it find?

  • Overall occurrence of serious adverse events was similar in each group, 22% in the triple therapy group compared with 21% in the control group (adjusted odds ratio [OR] 1.02 95% confidence interval [CI] 0.86 to 1.22).
  • There was no difference in the number of people with a recurrent stroke or TIA between the groups. Either occurred in 6% (93/1,540) of the triple therapy group, versus 7% (105/1,530) of the control group (adjusted common odds ratio [cOR] 0.90, 95% confidence interval [CI] 0.67 to 1.20).
  • Recurrent stroke occurred in 4% of each group, with similar ranges of severity.
  • More severe types of bleeding were more than twice as common in the triple therapy group (adjusted cOR 2.54, 95% CI 2.05 to 3.16). Fatal or major bleeding occurred by day 90 in 3% (39/1,540) of the triple therapy group compared with 1% (17/1,540) of the control group.
  • There was no difference between the groups at 90 days regarding disability, mood, cognition or quality of life.
  • The trial was stopped early on the recommendation of the data monitoring committee.

What does current guidance say on this issue?

The Royal College of Physicians’ 2016 national stroke guideline recommends clopidogrel alone to prevent recurrence for people who have had an ischaemic stroke or TIA. If this cannot be taken or tolerated, they recommend modified-release dipyridamole in combination with aspirin.

For people who also have other conditions such as a stent in the heart vessels or severe narrowing of the vessels in the brain, they recommend clopidogrel plus aspirin. They do not recommend all three drugs to be taken at the same time.

What are the implications?

Triple antiplatelet therapy can’t be recommended in usual clinical practice to reduce the risk of recurrent stroke after stroke or TIA. The three drugs in combination did not reduce the incidence and severity of recurrent stroke or TIA but did increase the risk of major bleeding.

This trial was carried out predominantly in the UK (2,995 of the participants), with wide inclusion criteria, so is likely to apply to the UK population.

Citation and Funding

Bath PM, Woodhouse LJ, Appleton JP, et al; TARDIS Investigators. Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. Lancet. 2017;391:850-59.

This project was funded by the National Institute for Health Research Health Technology Assessment (HTA) programme (project number 10/104/24/) and the British Heart Foundation (grant PG/08/083/25779).

Bibliography

NHS Choices. Stroke. London: Department of Health; 2017.

NICE. Stroke Pathway. London: National Institute for Health and Care Excellence; 2017.

NICE. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events. TA210. London: National Institute for Health and Care Excellence; 2010.

RCP. National clinical guideline for stroke. London: Royal College of Physicians; 2016.

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Published on 25 December 2017

Bath, P. M.,Woodhouse, L. J.,Appleton, J. P.,Beridze, M.,Christensen, H.,Dineen, R. A.,Duley, L.,England, T. J.,Flaherty, K.,Havard, D.,Heptinstall, S.,James, M.,Krishnan, K.,Markus, H. S.,Montgomery, A. A.,Pocock, S. J.,Randall, M.,Ranta, A.,Robinson, T. G.,Scutt, P.,Venables, G. S.,Sprigg, N.

Lancet , 2017

BACKGROUND: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. METHODS: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. FINDINGS: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0.90, 95% CI 0.67-1.20, p=0.47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2.54, 95% CI 2.05-3.16, p<0.0001). INTERPRETATION: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. FUNDING: National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

Expert commentary

Even with rapid implementation of secondary prevention the risk of recurrent ischaemic stroke is high with the greatest risk being in the first 30 days. The temptation is to treat patients more aggressively by adding additional antiplatelet agents. This study shows what a delicate balance there is between risk and benefit, with triple therapy resulting in no additional benefit but significantly increased haemorrhage.

While there are hints in the data that small strokes and TIAs may benefit from triple therapy clinicians should not be tempted to go beyond current guideline recommendations.

Professor Anthony Rudd, Consultant Stroke Physician, Guys and St Thomas' Hospital NHS Trust