Kevin S. Attenhofer, MD
Embolic stroke of undetermined source is a sub-classification of cryptogenic stroke which describes non-lacunar stroke without an identified cardio embolic source or occlusive atherosclerosis. While multiple pathologies may be at the heart of ESUS, it is thought that the undiagnosed embolic phenomenon driving the ischemia could be treated with anticoagulation. Multiple ongoing and recent trials seek to determine the optimal secondary stroke prevention in patients with ESUS by comparing aspirin to various direct oral anticoagulants (RESPECT-ESUS, NAVIGATE-ESUS, ARCADIA, ATTICUS). Considering the possibility that these studies may be neutral or negative, Amarenco et al. examined the use of antiplatelet agents for ESUS. The authors used data from the Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial to retrospectively compare ticagrelor and aspirin for ESUS. Their hypothesis was that all or some patients with ESUS would show greater benefit from ticagrelor than aspirin.
Why ticagrelor? Current guidelines recommend aspirin therapy; however, the rate of recurrent stroke on aspirin is still 10–15% within the first 90 days after index event. As a result, it is believed that more intense antiplatelet therapy may provide additional benefit in terms of prevention of recurrent ischemic events. Enter ticagrelor — an antiplatelet agent which has been shown to be superior to clopidogrel in recent cardiac literature. The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18,624 patients with ACS to ticagrelor or clopidogrel, in addition to standard care. At 12 months, the ticagrelor group had lower rates of CV death, MI, or stroke than clopidogrel (9.8% vs. 11.7%). Following these results, the SOCRATES trial was designed to investigate the comparative efficacy of ticagrelor versus aspirin in reducing a composite endpoint of recurrent stroke, MI, or death at 90 days in patients presenting with acute neurologic ischemia. In this study, ticagrelor was not clearly superior to aspirin.
In their post hoc analysis, Amarenco et al. reviewed data from the SOCRATES trial. Enrolled patients were ≥40 years old and were randomized for trial entry within 24 hours of symptom onset of a non-severe (NIHSS ≤5) ischemic stroke. While TIA patients were included in SOCRATES, they did not meet the authors’ criteria for ESUS as described above and were excluded from this analysis. At the time of enrollment/randomization into SOCRATES, the ASCOD grading system was used in all patients to characterize main ischemic stroke subtypes (Atherosclerosis, Small vessel disease, Cardiac pathology, Other causes, Dissection). Based on this ASCOD assessment, the authors were able to apply ESUS criteria retroactively and analyzed this subgroup with an intention to treat analysis. Their primary endpoint was the same as in SOCRATES: composite of stroke, MI, and death evaluated at 90 days post-randomization.
Of 13,199 patients randomized in SOCRATES, 4329 were determined to have ESUS. 2126 of these patients were treated with ticagrelor and the remaining 2203 with aspirin. The primary endpoint occurred in 126/2126 (5.9%) ESUS patients on ticagrelor and in 150/2203 (6.8%) patients on aspirin (p=0.24). While this was not statistically significant, a further subgroup analysis of patients with an ipsilateral atherosclerotic stenosis of extra- or intracranial artery of less than 50% or severe aortic arch plaques was more compelling. In these populations, the primary end point occurred in 3.7% in the ticagrelor group and 7.0% in the aspirin group (p=0.02).
In general, these findings are consistent with the overall results of the SOCRATES trial. Ticagrelor is not superior to aspirin in reducing the risk of recurrent stroke in ESUS patients. As noted in previous subgroup analyses, there is a suggestion that ticagrelor may be superior to aspirin in the setting of ipsilateral stenosis < 50% or aortic arch atherosclerosis. It must be noted, however, that this is a subgroup analysis with a relatively low event rate and may not be powered to make such a statement. The authors are also limited by the limitations of the SOCRATES trial. Specifically, their exclusion of high-risk patients (high-grade carotid or severe intracranial stenosis) and 90-day endpoints (the PLATO trial used a 12-month endpoint).
While ticagrelor may not appear to be the answer for ESUS patients, ongoing work is needed. Prospective follow-up data focused on patients with ipsilateral stenosis < 50% and aortic arch atherosclerosis may yield statistically significant findings.