Target Ticagrelor to Minor Stroke, TIA Patients With Arterial Stenosis

November 17, 2020

Among patients with minor stroke or transient ischemic attack (TIA), dual antiplatelet therapy with ticagrelor and aspirin has the best risk-benefit ratio for those who also have ipsilateral intracranial or extracranial arterial stenosis, a new subgroup analysis of the THALES trial shows.

The analysis found that patients with ipsilateral atherosclerosis stenosis had a higher absolute risk for stroke or death at 30 days and a greater absolute risk reduction for these outcomes with ticagrelor when added to aspirin compared with patients who did not have ipsilateral atherosclerosis stenosis.

"Our results suggest that this subgroup of patients with ipsilateral atherosclerosis may be the appropriate target for ticagrelor plus aspirin therapy over a 30-day period after the index stroke," lead author Pierre Amarenco, MD, professor of neurology at Bichat University Hospital, Paris, France, told theheart.org | Medscape Cardiology.

The THALES trial randomly assigned patients who were within 24 hours of symptom onset with a noncardioembolic, nonsevere ischemic stroke or high-risk TIA to 1 month of treatment with ticagrelor or placebo. All patients received aspirin. The main results of the trial, reported earlier this year in The New England Journal of Medicine, showed a 17% reduction in the 30-day risk for stroke or death in the ticagrelor group.

Before randomization, patients had undergone CT or MRI of the brain. The present subgroup analysis included patients with symptomatic ipsilateral intracranial or extracranial arterial stenosis (≥30% narrowing in the diameter of the lumen of an artery that could account for the clinical presentation).

The new subgroup analysis was presented at the 2020 American Heart Association (AHA) Scientific Sessions and was simultaneously published online in Stroke.

Results showed that of 11,016 patients in the THALES trial, 2351 patients (21.3%) had an ipsilateral atherosclerotic stenosis. After 30 days, a primary endpoint (stroke or death) occurred in 8.1% of those patients who received ticagrelor and in 10.9% of those who received placebo (hazard ratio, 0.73; P = .023). The number needed to treat to prevent one event was 34.

Among patients without ipsilateral stenosis, the event rate was 4.8% in the ticagrelor group and 5.4% in the placebo group (hazard ratio, 0.89; P = .23). The P value for interaction was nonsignificant, at .245.

Severe bleeding occurred in 0.4% of patients with ipsilateral atherosclerotic stenosis who received ticagrelor, vs 0.2% with placebo, a nonsignificant difference. Among the patients who did not have ipsilateral stenosis, severe bleeding occurred in 0.5% of those who received ticagrelor, vs 0.1% of those who received placebo (hazard ratio = 5.87; P = .001).

"In our study, the absolute risk in patients with ipsilateral atherosclerotic stenosis was twice the risk of patients without. This is consistent with other registries and trials," the THALES researchers report.

"In this subanalysis, we found a greater absolute risk reduction of stroke or death with ticagrelor plus aspirin in the group with atherosclerotic stenosis, with a number needed to treat of 34 and a number needed to harm of 951," Amarenco noted.

In the overall THALES population, the number need to treat was 92, and number needed to harm was 263.

"Our analysis certainly identifies that targeting patients with ipsilateral atherosclerotic disease maximizes the benefit and minimizes the risk of bleeding complications," Amarenco said.

Among patients without ipsilateral stenosis, small-vessel disease was likely highly represented, which may to a large degree account for the excess bleeding. This would explain the difference in bleeding risk between the patients with and those without ipsilateral stenosis, the THALES researchers suggest. "However, the number of safety end points is small, and we should be cautious in interpreting them," they add.

Amarenco pointed out that by atherosclerotic stenosis subgroup interaction, the treatment was not significant; therefore, the overall results of the THALES trial reported in earlier this year also applies to the subgroup with nonatherosclerotic disease.

However, in the Stroke article, the authors conclude: "These patients [with ipsilateral stenosis] form indisputably a group to target with this therapy after a TIA or a minor ischemic stroke."

Amarenco noted that 20% of the patients in the THALES trial had atherosclerotic stenosis, but in real-world clinical practice, they likely make up 40% of patients with minor stroke or high-risk TIA. The difference probably is due to the fact that outside the trial, some investigators treat these patients with clopidogrel plus aspirin.

"These patients are easy to identify with current diagnostic tools such as CT angiography or MR angiography or ultrasound, which are all routinely used at admission in stroke unit and TIA clinic and readily available," he noted.

The THALES researchers point out that this subgroup analysis, although prespecified, was not selected as a secondary analysis and thus should be seen as exploratory and hypothesis generating.

The discussant of the trial at the AHA late-breaking session, Lisa McCullough, MD, chair of neurology at McGovern Medical School, University of Texas, Houston, Texas, said: "It is clear from the overall THALES trial, from other trials (CHANCE and POINT with clopidogrel), that there is a benefit of dual antiplatelet therapy for secondary prevention in minor stroke/TIA patients, especially in the first 30 days. These new results show the benefit was even greater in those with ipsilateral carotid stenosis."

McCullough raised several questions regarding the study, including whether the benefit would be greater in the long term compared to carotid revascularization and whether ticagrelor would be better than clopidogrel.

The THALES trial was sponsored by AstraZeneca. Amarenco received grants and personal fees from AstraZeneca and Bristol-Myers Squibb during the conduct of the study. McCullough has disclosed no relevant financial relationships.

American Heart Association (AHA) Scientific Sessions 2020: Abstract LBS.07. Presented November 16, 2020.

Stroke. Published online November 16, 2020. Abstract

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