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Clopidogrel and aspirin lower risk of major stroke after TIA

StrokeAfter a minor stroke or a transient ischaemic attack (TIA), taking the clot-preventing drug clopidogrel along with aspirin may lower risk of having a major stroke within the next 90 days by 25%, according to a large international study. However, there was also a small increase in the risk of haemorrhage.

An international study of 4,881 adults in 10 countries who either had a minor stroke or a TIA showed that people who took clopidogrel plus aspirin had a 25% lower risk of a major stroke, heart attack or death from blood clots within the three months after the first incident, compared with those who took aspirin alone.

"The study gives us solid evidence that we can use this drug combination to prevent strokes in the highest-risk people, but not without some risk of bleeding," said lead author Dr Clay Johnston, dean and professor of neurology at Dell Medical School at The University of Texas at Austin.

Both minor stroke and TIA are warning signs that a person has a 3% to 15% chance of having a more severe stroke within the next three months. Minor stroke is one that results in mild, non-disabling symptoms. TIA, often called a warning stroke or mini-stroke, is caused by a temporary blockage in a blood vessel to the brain that often dissolves or dislodges on its own to stop symptoms. More than a third of US adults have had TIA symptoms, according to the American Stroke Association.

The study also showed a small increase in the risk of haemorrhage in the clopidogrel-aspirin group compared with the aspirin alone group. For every 1,000 patients treated with the combination, an extra five major bleeds would be expected but with 15 fewer strokes and other major ischemic events. Because the bleeding events are generally reversible, the overall benefit outweighs the risk for most patients, Johnston said.

"Of the 33 major haemorrhages that occurred in these 4,881 patients, more than half involved the gastrointestinal tract, and none of them was fatal. These largely preventable or treatable bleeding complications of the treatment have to be balanced against the benefit of avoiding disabling strokes," said co-author Dr J Donald Easton, professor of neurology at the University of California – San Francisco School of Medicine. One previous trial in this area showed that clopidogrel plus aspirin was effective in lowering risks but did not find the risk of haemorrhage.

"The results of this large international trial, when added to the results of previous research, provide evidence to support the use of clopidogrel plus aspirin for 90 days among patients with minor ischemic stroke and high-risk TIA treated within 12 hours," said Dr Ralph Sacco, professor of neurology at Miller School of Medicine at the University of Miami. "This trial is likely to change practice since most clinicians and patients are usually willing to accept the increased risk of haemorrhage to offset the disabling impact of a stroke."

The research was part of the Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT) trial – a randomised, double-blind, placebo-controlled trial conducted between May 2010 and December 2017. It included patient information from 269 sites in 10 countries throughout North America, Europe and Australia. Patients were included if they had a minor stroke or a transient ischemic stroke and were at high risk of having a major stroke.

"It's likely we will see more patients who have had a TIA or a minor stroke receiving the combination of clopidogrel and aspirin in the future," Johnston said. "If you've suffered from a minor stroke or TIA, it's important to see a physician immediately, even in the emergency room, to ensure you're taking steps to avoid a potentially debilitating stroke later on," he said. "There are several tests that need to be done right away to determine the cause of the event and to make sure the best treatments are started as soon as possible."

Clopidogrel, known by the brand name Plavix, is a platelet inhibitor commonly prescribed to people who have peripheral artery disease or who have had a recent heart attack or stroke to prevent future cardiac or stroke events.

Abstract
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.

Authors
S Claiborne Johnston, J Donald Easton, Mary Farrant, William Barsan, Robin A Conwit, Jordan J Elm, Anthony S Kim, Anne S Lindblad, Yuko Y Palesch

[link url="https://news.utexas.edu/2018/05/16/dell-med-research-stroke-prevention-combo-shows-promise"]University of Texas at Austin material[/link]
[link url="https://www.nejm.org/doi/10.1056/NEJMoa1800410"]New England Journal of Medicine abstract[/link]

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