Ticagrelor May Best Aspirin in Stroke of Atherosclerotic Origin

Nancy A. Melville

February 24, 2017

HOUSTON, Texas — Although primary results of a randomized trial showed no difference overall between the approaches, a new subgroup analysis suggests that treatment with the antiplatelet agent ticagrelor (Brilinta, AstraZeneca) shows stronger efficacy than aspirin in the prevention of recurrent acute stroke or transient ischemic attack (TIA) specifically related to ipsilateral atherosclerotic stenosis.

The findings, presented here at the International Stroke Conference (ISC) 2017 and published online February 20 in Lancet Neurology, are from a subanalysis of the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial, which was published in July in the New England Journal of Medicine. SOCRATES was sponsored by AstraZeneca.

"Our findings strengthen the case for targeting patients with documented atherosclerotic origin as the potential cause of the TIA/stroke, in that, in these patients, ticagrelor is far better than aspirin in preventing early recurrence," senior author, Pierre Amarenco, MD, professor and chairman of University Paris Diderot, Paris, France, told Medscape Medical News.

That multicenter trial, conducted in 33 countries, showed that overall, ticagrelor was not superior to aspirin in the prevention of stroke recurrence, myocardial infarction, or death among patients with transient ischemic attack and minor stroke after 90 days of treatment.

Dr Amarenco noted, however, that ticagrelor has shown strong efficacy as an antiplatelet therapy in patients with coronary atherosclerotic disease and is therefore speculated to show greater benefit in patients with acute ischemia specifically of atherosclerotic origin.

The researchers therefore identified 3081 patients (23%) among the 13,199 patients in the SOCRATES trial who were randomly assigned in the ticagrelor treatment group and who had potentially symptomatic ipsilateral atherosclerotic stenosis.

Ticagrelor treatment consisted of a 180-mg loading dose on day 1 within 24 hours of symptom onset, followed by 90 mg twice daily for days 2 to 90, given orally. Participants in the aspirin group (n = 6610) received 300 mg on day 1 within 24 hours of symptom onset, followed by 100 mg daily for days 2 to 90, also given orally.

The results of the subanalysis showed a strong treatment–by–atherosclerotic stenosis interaction (P = .017).

The rate of stroke, myocardial infarction, or death within 90 days was significantly lower in the group with ipsilateral stenosis treated with ticagrelor (6.7%; 103 patients) than in patients with ipsilateral stenosis in the aspirin group (9.6%; 147 patients; P = .003).

The differences in rates of stroke, myocardial infarction, or death within 90 days among 10,119 patients with no ipsilateral stenosis were meanwhile not significant in the ticagrelor group compared with those in the aspirin group who also had no ipsilateral stenosis (6.7% vs 6.9%; P = .72).

Rates of life-threatening bleeding or major or minor bleeding were meanwhile also not significantly different among patients with ipsilateral stenosis in the ticagrelor vs aspirin group.

The reasons why patients with atherosclerotic stroke show a better response to ticagrelor treatment may have to do with the specific mechanisms that the drug targets, Dr Amarenco explained.

"Antiplatelet agents target thromboses formed or superimposed on an ulcerated atherosclerotic plaque in a high flow regimen, while in other causes of stroke the thromboses have different mechanisms," he said.

"[For instance], with atrial thrombosis in the case of atrial fibrillation or deep-vein thrombosis with a low-flow regimen, we know that anticoagulants, vitamin K antagonists, or novel oral anticoagulants are far better than aspirin in preventing thrombosis and recurrence."

Dr Amarenco noted that the findings underscore the need to consider the many unique stroke mechanisms when exploring and refining approaches for stroke recurrence prevention treatments.

The argument follows the ongoing debate between the "lumpers" and the "splitters," Dr Amarenco said.

"There has been debate among vascular neurologists during the last 30 years involving the 'lumpers' — lumping together all ischemic stroke subtypes, including atherosclerotic disease, small vessel disease, and unknown cause of stroke — and the 'splitters,' favoring trials targeting the cause of stroke, for instance atherosclerotic disease, or small vessel disease, or stroke of unknown cause.

"Until now, including in the SOCRATES trial, the lumpers almost always won up until now, and we only had trials lumping together all ischemic stroke patients.

"Now, with the current results, we may be opening an era where we will see more trials targeting patients with a certain cause of stroke.

"I [have been] a 'splitter' for a very long time and strongly advocated to perform the SOCRATES trial only in patients with atherosclerotic stenosis."

While a potential obstacle in looking at subgroups is always having enough numbers for a well-powered analysis, the study nevertheless offers some important insights, Daniel Lackland, PhD, a professor in the Department of Neurosciences, Stroke Neurology Division, Stroke Epidemiology, at the Medical University of South Carolina, Charleston, told Medscape Medical News.

"It can be important to take the 'splitter' approach, and as research evolves, this approach may become more valuable to us," he said.

"Sometimes there just aren't the numbers to support the claims of a subgroup analysis, but if there are adequate numbers, then I do think it can help us move towards a better therapy."

The study was funded by AstraZeneca. Dr Amarenco is a consultant for AstraZeneca. Dr Lackland has disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2017. Abstract LB9. Presented February 23, 2017.

Lancet Neurol. Published online February 20, 2017. Abstract

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