Ticagrelor May Be Useful After Stroke, TIA if Event Related to Atherosclerosis

HOUSTON, TX—It might be worth testing ticagrelor versus aspirin for preventing recurrent events in patients with nonsevere acute ischemic strokes or high-risk TIAs that are related to atherosclerotic disease, a prespecified secondary analysis of the neutral SOCRATES trial suggests.

The main trial results published last year showed that the two antiplatelets provided similar risks of stroke, MI, or death through 90 days of treatment in the overall patient population. But in a presentation at the International Stroke Conference held here last week, Pierre Amarenco, MD (Bichat University Hospital, Paris, France), reported that ticagrelor was superior in the roughly a quarter of patients who had ipsilateral stenosis (6.7% vs 9.4%; HR 0.68; 95% CI 0.53-0.88).

There was no hint of benefit in patients without ipsilateral stenosis.

“The interaction that we found suggests . . . an understanding of stroke mechanisms and causes is important to deliver safe and efficacious treatment for early stroke prevention,” Amarenco said during his talk, noting that the findings are consistent with prior evidence showing that atherosclerotic strokes carry higher risks compared with other stroke subtypes.

Thus, he concluded, “targeting patients with atherosclerotic stenosis could be a valuable hypothesis to confirm in future antiplatelet trials.”

Net Clinical Benefit in Patients With Ipsilateral Stenosis

SOCRATES enrolled 13,199 patients at 674 hospitals in 33 countries. For this prespecified exploratory analysis, which was published simultaneously online in the Lancet Neurology, researchers classified patients into atherosclerotic or nonatherosclerotic groups using the ASCOD phenotyping system. About 23% of patients in both the ticagrelor and aspirin groups were deemed to have had an event of atherosclerotic origin, defined as:

• Ipsilateral extra- or intracranial stenosis ≥ 50% or mobile thrombus in the aortic arch
• Ipsilateral extra- or intracranial stenosis <  50% or plaque ≥ 4 mm in the aortic arch

There was a significant interaction between the presence of ipsilateral stenosis and the effect of ticagrelor on the primary endpoint (P = 0.017), with a benefit seen only in patients with atherosclerotic index events.

A suggestion of benefit with ticagrelor in patients with ipsilateral stenosis was seen for the secondary endpoints of ischemic stroke, all strokes, and disabling strokes as well, but the interactions were not significant.

Ticagrelor and aspirin provided similar risks of death and major bleeding, regardless of the presence of atherosclerosis.

When looking at net clinical benefit combining stroke, MI, death, and life-threatening bleeding, ticagrelor again demonstrated superiority to aspirin only in patients with ipsilateral stenosis (7.2% vs 9.5%; HR 0.72; 95% CI 0.57-0.93). The interaction was significant (P = 0.0464).

Take It With a Grain of Salt

Commenting for TCTMD, Larry Goldstein, MD (University of Kentucky, Lexington), said that secondary analyses like this one should be taken with a grain of salt, and in particular are “a little methodologically shaky” when the main outcome of the trial is neutral.

“Having said that,” he added, “the hypothesis is a reasonable one, that the drug would be more efficacious in patients who have evidence of large-vessel atherosclerotic disease that could have been responsible for the stroke or TIA.”

Goldstein said it would be reasonable to do a second prospective trial targeting patients with initial events tied to atherosclerotic disease, noting that that population accounted for a substantial number strokes and TIAs in SOCRATES.

Until such a trial can be performed, clinicians are not likely to start using ticagrelor in this setting, he said, pointing out that the drug is not approved for this indication.

“You generally don’t make treatment decisions based on exploratory analyses, especially if the study was neutral for its primary endpoint,” Goldstein said.