By Matthew E. Fink, MD

Louis and Gertrude Feil Professor and Chair, Department of Neurology, Associate Dean for Clinical Affairs, New York Presbyterian/Weill Cornell Medical College

Dr. Fink reports no financial relationships relevant to this field of study.

SOURCE: Amerenco P, Denison H, Evans SR, et al. Ticagrelor added to aspirin in acute nonsevere ischemic stroke or transient ischemic attack of atherosclerotic origin. Stroke 2020;51:3504-3513.

Ticagrelor is an antiplatelet agent that works by reversibly binding to P2Y12 adenosine diphosphate receptors on platelets, similar to the mechanism of action of clopidogrel. However, it is a direct-acting drug, and not a pro-drug, and does not need to be enzymatically converted to be active, like clopidogrel. Therefore, it is expected to be effective across a wider population than clopidogrel.

In this double-blind study in patients with non-cardioembolic, non-severe ischemic stroke or transient ischemic attack (TIA), patients were randomized to receive ticagrelor with aspirin or placebo plus aspirin. In the ticagrelor group, patients received 180-mg loading dose on the first day followed by 90 mg twice daily for 30 days. The initial dose of aspirin was 300 mg to 325 mg on day 1 followed by 75 mg to 100 mg per day for 30 days. Treatment was started within 24 hours of symptom onset. The prespecified analysis evaluated stroke recurrence or death within 30 days. The groups were divided into those who had atherosclerosis of the appropriate carotid artery of at least 30% and those who had no significant atherosclerosis.

A total of 11,016 patients were randomized, and 21.3% of them had ipsilateral atherosclerotic stenosis. After 30 days, the primary endpoint of stroke or death occurred in 8.1% of patients with ipsilateral stenosis randomized to ticagrelor, and in 10.9% randomized to placebo (hazard ratio [HR], 0.73; P = 0.023).

In patients without ipsilateral stenosis, the primary event rate was 4.8% with ticagrelor and 5.4% with placebo, a nonsignificant difference. Severe bleeding occurred in 0.4% of patients with atherosclerosis treated with ticagrelor and 0.2% of patients with atherosclerosis treated with placebo. However, in the nonatherosclerotic patients, severe bleeding occurred in 0.5% of the ticagrelor patients and in 0.1% of the control group, a significant difference (HR, 5.87; P = 0.001).

In patients with ipsilateral atherosclerosis and non-severe stroke or TIA, the combination of ticagrelor with aspirin appears to result in a lower rate of recurrent stroke or death at 30 days, compared to patients treated with aspirin alone.

However, this is viewed as an exploratory analysis, and a larger Phase III trial is necessary for confirmation. A head-to-head trial with aspirin/clopidogrel would be informative as well. There is a significantly increased risk of severe bleeding with the use of ticagrelor and aspirin in combination.