NIHR DC Discover

Antiplatelet drugs

NIHR Signal Two antiplatelet drugs may prevent further strokes but increase major bleeds

Published on 2 October 2018

doi: 10.3310/signal-000649

People experiencing a minor stroke or a transient ischaemic attack have a lower risk of further stroke within 90 days if given clopidogrel and aspirin, rather than aspirin alone. However, taking both drugs doubles the risk of bleeding over the same period.

Current UK guidelines recommend using clopidogrel alone.

In this major international trial of nearly 5,000 people, those who took the dual treatment had fewer heart attacks or strokes than those who took aspirin only, particularly in the first 30 days of treatment. Major bleeding risk was fairly constant on combined treatment throughout 90 days, occurring in 0.9% compared with 0.4% on aspirin.

This study provides more evidence on the balance of benefits and risks. Further research into the timing and duration of dual antiplatelet therapy is needed.

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Why was this study needed?

About 136,000 people in England have a first or recurrent ischaemic stroke (due to a clot) each year. Another 20,000 people have a transient ischaemic attack (TIA)  – where a small clot causes a temporary lack of blood supply to an area of the brain, but the neurological symptoms fully resolve within 24 hours. The risk of having a recurrent ischaemic stroke or stroke within 90 days of a TIA is up to 17%.

Antiplatelet treatment such as aspirin reduces the formation of blood clots, and so lowers the chance of a further ischaemic stroke by around 20%.

A previous large trial in China (CHANCE) found that dual therapy with clopidogrel and aspirin for 21 days was more effective than aspirin alone. They did not find an increased bleeding risk, but the trial differed in ethnic mix from the UK.

This study helps build further evidence on safety and effectiveness of dual antiplatelet therapy.

What did this study do?

The POINT randomised trial recruited 4,881 adults (83% in the US) from 269 international sites. Participants were randomly allocated to either dual therapy, or aspirin alone within 12 hours of having a mild ischaemic stroke, or a high-risk TIA.

Dual therapy involved 600mg clopidogrel on day 1, then 75mg/day on days 2 to 90, and aspirin ranging from 50mg to 325mg/day (depending on usual dosage in the trial country). The comparison group took a placebo resembling clopidogrel plus aspirin doses in the same range as the dual therapy group.

The trial was well conducted, but it was underpowered because it was halted before the planned number of participants had been treated. This was due to early findings that the combination caused more bleeding.

What did it find?

  • People taking clopidogrel with aspirin had lower rates of ischaemic events (a combined outcome of ischaemic stroke, heart attack, or death due to blood clots) than those on aspirin alone (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59 to 0.95). Absolute numbers of ischaemic events were 121/2,432 (5%) in the dual therapy group and 160/2,449 (6.5%) in the aspirin only group.
  • Taking dual therapy after a minor stroke reduced the risk of ischaemic events compared with aspirin (HR 0.71, 95% CI 0.53 to 0.95) but there was uncertain benefit after TIA (HR 0.85, 95% CI 0.57 to 1.28).
  • Ischaemic strokes were less common in people on dual therapy (HR 0.72, 95% CI 0.56 to 0.92), as was the combined outcome of all strokes due to clots or bleeding (HR 0.74, 95% CI 0.58 to 0.94).
  • People on dual therapy had a higher risk of major bleeding than those on aspirin alone (HR 2.32, 95% CI 1.10 to 4.87). Absolute numbers of major bleeding events were 23/2,432 (0.9%) in the dual therapy group and 10/2,449 (0.4%) in the aspirin only group.
  • For 1,000 people treated with clopidogrel and aspirin for 90 days, an estimated 15 adverse events due to clotting would be prevented, and an estimated five people would have major bleeding.

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. This guideline recognises that clopidogrel is not licensed for use in people following TIA.

Current NICE guidelines on diagnosis and initial management of stroke and TIA recommend aspirin or clopidogrel. They do not provide recommendations on the use of aspirin and clopidogrel dual therapy.

The NICE guidelines include a research recommendation, calling for studies which examine whether modified-release dipyridamole or clopidogrel with aspirin improves outcomes compared with aspirin alone when administered early after acute ischaemic stroke.

What are the implications?

For people who have had a mild stroke or a high-risk TIA this evidence shows that although dual therapy reduces the risk of further ischaemic events, this is at the expense of increasing the risk of major bleeding.

Given the difference in bleeding rates between this and the CHANCE study, future research may be needed into the dosage and duration of dual therapy to maximise benefits and reduce potential harms. The position remains unclear for people following a moderate or severe stroke or those who are eligible to have the clot dissolved or removed as they were excluded from the study.

Citation and Funding

Johnston SC, Easton JD, Mary Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N England J Med. 2018;379:215-25.

This project was funded by grants from the National Institute of Neurological Disorders and Stroke (U01 NS062835, U01 NS056975, and U01 NS059041). Clopidogrel and placebo were provided by Sanofi for 75% of the patients in the trial.

Bibliography

NHS Digital. Hospital admitted patient care activity, 2016-17: diagnosis. NHS Digital. London: 2017.

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

NICE. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. CG68. London: National Institute for Health and Care Excellence; 2017.

NICE. Transient ischaemic attack. ESUOM 23. London: National Institute for Health and Care Excellence; 2013.

Royal College of Physicians Intercollegiate Stroke Working Party. National clinical guideline for stroke (fifth edition). London: Royal College of Physicians Intercollegiate Stroke Working Party; 2016.

Squizzato  A, Bellesini  M, Takeda  A, et al. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events. Cochrane Database Syst Revs. 2017;12:CD005158.

Why was this study needed?

About 136,000 people in England have a first or recurrent ischaemic stroke (due to a clot) each year. Another 20,000 people have a transient ischaemic attack (TIA)  – where a small clot causes a temporary lack of blood supply to an area of the brain, but the neurological symptoms fully resolve within 24 hours. The risk of having a recurrent ischaemic stroke or stroke within 90 days of a TIA is up to 17%.

Antiplatelet treatment such as aspirin reduces the formation of blood clots, and so lowers the chance of a further ischaemic stroke by around 20%.

A previous large trial in China (CHANCE) found that dual therapy with clopidogrel and aspirin for 21 days was more effective than aspirin alone. They did not find an increased bleeding risk, but the trial differed in ethnic mix from the UK.

This study helps build further evidence on safety and effectiveness of dual antiplatelet therapy.

What did this study do?

The POINT randomised trial recruited 4,881 adults (83% in the US) from 269 international sites. Participants were randomly allocated to either dual therapy, or aspirin alone within 12 hours of having a mild ischaemic stroke, or a high-risk TIA.

Dual therapy involved 600mg clopidogrel on day 1, then 75mg/day on days 2 to 90, and aspirin ranging from 50mg to 325mg/day (depending on usual dosage in the trial country). The comparison group took a placebo resembling clopidogrel plus aspirin doses in the same range as the dual therapy group.

The trial was well conducted, but it was underpowered because it was halted before the planned number of participants had been treated. This was due to early findings that the combination caused more bleeding.

What did it find?

  • People taking clopidogrel with aspirin had lower rates of ischaemic events (a combined outcome of ischaemic stroke, heart attack, or death due to blood clots) than those on aspirin alone (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59 to 0.95). Absolute numbers of ischaemic events were 121/2,432 (5%) in the dual therapy group and 160/2,449 (6.5%) in the aspirin only group.
  • Taking dual therapy after a minor stroke reduced the risk of ischaemic events compared with aspirin (HR 0.71, 95% CI 0.53 to 0.95) but there was uncertain benefit after TIA (HR 0.85, 95% CI 0.57 to 1.28).
  • Ischaemic strokes were less common in people on dual therapy (HR 0.72, 95% CI 0.56 to 0.92), as was the combined outcome of all strokes due to clots or bleeding (HR 0.74, 95% CI 0.58 to 0.94).
  • People on dual therapy had a higher risk of major bleeding than those on aspirin alone (HR 2.32, 95% CI 1.10 to 4.87). Absolute numbers of major bleeding events were 23/2,432 (0.9%) in the dual therapy group and 10/2,449 (0.4%) in the aspirin only group.
  • For 1,000 people treated with clopidogrel and aspirin for 90 days, an estimated 15 adverse events due to clotting would be prevented, and an estimated five people would have major bleeding.

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. This guideline recognises that clopidogrel is not licensed for use in people following TIA.

Current NICE guidelines on diagnosis and initial management of stroke and TIA recommend aspirin or clopidogrel. They do not provide recommendations on the use of aspirin and clopidogrel dual therapy.

The NICE guidelines include a research recommendation, calling for studies which examine whether modified-release dipyridamole or clopidogrel with aspirin improves outcomes compared with aspirin alone when administered early after acute ischaemic stroke.

What are the implications?

For people who have had a mild stroke or a high-risk TIA this evidence shows that although dual therapy reduces the risk of further ischaemic events, this is at the expense of increasing the risk of major bleeding.

Given the difference in bleeding rates between this and the CHANCE study, future research may be needed into the dosage and duration of dual therapy to maximise benefits and reduce potential harms. The position remains unclear for people following a moderate or severe stroke or those who are eligible to have the clot dissolved or removed as they were excluded from the study.

Citation and Funding

Johnston SC, Easton JD, Mary Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N England J Med. 2018;379:215-25.

This project was funded by grants from the National Institute of Neurological Disorders and Stroke (U01 NS062835, U01 NS056975, and U01 NS059041). Clopidogrel and placebo were provided by Sanofi for 75% of the patients in the trial.

Bibliography

NHS Digital. Hospital admitted patient care activity, 2016-17: diagnosis. NHS Digital. London: 2017.

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

NICE. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. CG68. London: National Institute for Health and Care Excellence; 2017.

NICE. Transient ischaemic attack. ESUOM 23. London: National Institute for Health and Care Excellence; 2013.

Royal College of Physicians Intercollegiate Stroke Working Party. National clinical guideline for stroke (fifth edition). London: Royal College of Physicians Intercollegiate Stroke Working Party; 2016.

Squizzato  A, Bellesini  M, Takeda  A, et al. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events. Cochrane Database Syst Revs. 2017;12:CD005158.

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA

Published on 17 May 2018

Johnston, S. C.,Easton, J. D.,Farrant, M.,Barsan, W.,Conwit, R. A.,Elm, J. J.,Kim, A. S.,Lindblad, A. S.,Palesch, Y. Y.

N Engl J Med , 2018

Background Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. Methods In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. Results A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). Conclusions In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).

Expert commentary

In treating a transient ischaemic attack (TIA) or minor stroke, finding the balance between reducing the risk of recurrent ischaemia and the risk of major haemorrhage is proving challenging.

The POINT trial was stopped early when the pre-specified safety boundary for major haemorrhage, driven by non-intracranial bleeds, was exceeded. However, there was also a significant reduction in major ischaemic events in the dual antiplatelet group, the majority of which occurred in the first 30 days, whereas bleeding rates remained fairly constant over the 90-day treatment period.

Therefore, there may be a place for the use of shorter-term dual anti-platelets immediately after TIA or minor stroke. The Chinese CHANCE trial (aspirin and clopidogrel for 21 days) did not see excess bleeding rates. In both POINT and CHANCE, the comparator was aspirin. The current recommended treatment in the UK, however, is clopidogrel monotherapy.

Tim England, Associate Professor of Stroke Medicine, University of Nottingham and Royal Derby Hospital