Elena Zapata-Arriaza, MD

Johnston SC, Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson M, Ladenvall P, Molina CA, Wang Y, for the THALES Investigators. Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. N Engl J Med. 2020;383:207-217.

Without urgent treatment, the risk of major stroke in the week after a transient ischemic attack (TIA) or minor stroke can be as high as 10%. Some studies have shown that the combination of aspirin (ASA) plus Clopidogrel reduces the risk of stroke and other major ischemic events. Given the limitations in Clopidogrel due to hepatic conversion and the high resistance rates, Ticagrelor emerges as an interesting alternative, not dependent on metabolic activation.

With the aim of testing the effect of Ticagrelor and aspirin combination on stroke prevention, Johnston et al performed this randomized, placebo-controlled, double-blind trial involving patients who had had a mild-to-moderate acute noncardioembolic ischemic stroke, with a NIHSS≤5 or TIA, and who were not undergoing thrombolysis or thrombectomy. The patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive a 30-day regimen of either Ticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily) or matching placebo plus aspirin. The primary outcome was a composite of stroke or death within 30 days. Secondary outcomes were first subsequent ischemic stroke and the incidence of disability within 30 days. The primary safety outcome was severe bleeding.

The main results are shown in the following table, which compares THALES main outcomes with previous similar trials. Regarding functional outcomes, the incidence of disability did not differ significantly between the two groups.

The main results are shown in the following table, which compares THALES main outcomes with previous similar trials.

Ticagrelor is a direct-acting antiplatelet agent, not dependent on metabolic activation, widely employed in coronary thrombotic events prevention, but its use is less established for secondary prevention after TIA or wtroke. From this trial, the authors conclude that among patients with mild-to-moderate ischemic stroke or high-risk TIA who received a combination of Ticagrelor and aspirin, the risk of stroke or death was lower than that among patients who received aspirin alone. Double antiplatelet therapy has demonstrated lower risk of cerebrovascular events and death in previous trials (POINT, CHANCE, among others). However, in the mentioned trials, the comparator was aspirin+Clopidogrel. It is relevant to highlight that differences in  patient populations and outcomes definitions prevent comparisons between trials.

In addition, further studies are ongoing now to compare Clopidogrel+aspirin vs Ticagrelor+aspirin in high-risk patients (CHANCE-II). But given growing evidence, the question is what antiplatelet should we choose if we want to employ double antiplatelet therapy, Clopidogrel or Ticagrelor? Despite study differences, it seems that trials favor marginally Clopidogrel use, due to the relative reduction in the risk of recurrent ischemic stroke with ASA+Clopidogrel tend to be higher than Ticagrelor+ASA use. Regarding bleeding risk, this was higher in patients under Ticagrelor+ASA compared to Clopidogrel+ASA.

Finally, the aforementioned trials have been displayed in high-risk patients, according to ABCD2 score, so its application cannot be generalized to all TIA. It seems that Clopidogrel is slightly more effective and safe when compared to Ticagrelor use. However, this does not mean that Ticagrelor’s path in secondary stroke prevention will be short. In fact, Ticagrelor could be very useful in those patients resistant to Clopidogrel, and its usefulness in patients with atherosclerotic stenosis, in whom Ticagrelor has shown greater effectiveness than aspirin, remains to be seen. Ticagrelor guarantees a correct antiplatelet treatment for the patient; however, the bleeding risk exceeds that previously published and could limit the benefit it provides.