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Study Summary

The THALES trial was an international, randomized, double-blind, placebo-controlled trial involving patients who had had a mild-to-moderate acute non-cardioembolic ischemic stroke or transient ischemic attack (TIA) and who were not undergoing thrombolysis or thrombectomy. A total of 11,016 patients were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive either ticagrelor (180 mg loading dose followed by 90 mg twice daily) plus aspirin (300-325 mg on the first day followed by 75-100 mg daily) or matching placebo plus aspirin for 30 days. The combination of ticagrelor plus aspirin resulted in significant lower risk of death or stroke within 30 days (the primary efficacy outcome; 5.5% versus 6.6%; HR 0.83, 95% CI 0.71-0.96; P = 0.02), but a higher incidence of severe bleeding (primary safety outcome; 0.5% versus 0.1%, HR 3.99, 95% CI 1.74-9.14; P = 0.001) compared with aspirin alone. In a pre-specified analysis of patients with or without ipsilateral atherosclerotic stenosis of the cervico-cranial vasculature, although the investigators found no treatment by ipsilateral atherosclerosis stenosis subgroup interaction (P = 0.25), patients with ipsilateral stenosis (≥30% vascular stenosis; N = 2351 of 11,016 randomized patients) had greater absolute benefit from ticagrelor plus aspirin compared with aspirin alone (8.1% versus 10.9%; HR 0.73, 95% CI, 0.56–0.96, P = 0.023; see accompanying Hurst’s Central Illustration).

Commentary

Study Strengths: The THALES trial itself was a large, international, multicenter, placebo-controlled trial powered for hard clinical end points. Patients enrolled in the study were receiving appropriate guideline-recommended therapy and only 0.1% of all randomized patients were lost to follow-up. However, this was an exploratory analysis in patients with or without ipsilateral, potentially causal, ≥30% atherosclerotic stenosis of cervico-cranial vasculature.

Study Limitations: The overall THALES trial had several important exclusion criteria that limit the generalizability of the current findings. Patients who had more severe strokes (NIHSS score >5), had a cardioembolic stroke, had initiation of treatment more than 24 hours after symptom onset, or who underwent or planned to undergo thrombolysis or thrombectomy were excluded; therefore, the results of the present trial do not apply to these patients. In addition, more than 90% of the patients enrolled in the trial had an ischemic stroke as a qualifying event; therefore, the treatment effect of the combination of ticagrelor and aspirin in lower risk patients with a TIA is less applicable. This prespecified analysis of patients with or without ipsilateral atherosclerotic stenosis of the cervico-cranial vasculature is limited by this analysis not having been selected as a secondary analysis in the first place; as the authors acknowledge in their manuscript, the results are only hypothesis-generating. In the overall THALES trial, only 21.3% of patients had ipsilateral atherosclerotic stenosis.

Next Steps/Clinical Perspective: Patients with an acute ischemic stroke or TIA are at high risk of recurrent cerebrovascular events in the first few months following their index event. Although ticagrelor in combination with aspirin is commonly used for the prevention of coronary thrombotic events, the effect of the combination of ticagrelor and aspirin in this population has not been well studied. Based on the THALES trial, the combination of ticagrelor plus aspirin is superior, in reducing stroke or death at 30 days, to a regimen of aspirin monotherapy after a minor stroke or TIA. Of note, the effects in absolute terms of this regimen appeared to be greater among patients with ipsilateral atherosclerotic stenosis of the cervico-cranial vasculature. However, while clopidogrel plus aspirin has previously been shown to be more effective than aspirin alone after a minor stroke or TIA, and aspirin plus ticagrelor has been shown to be more effective than aspirin plus clopidogrel in reducing the incidence of major adverse cardiac events after an acute coronary syndrome, their comparative effectiveness remains unknown after a minor stroke or TIA. Notably, clopidogrel is associated with a better safety profile than ticagrelor in terms of major bleeding events; therefore, the benefit-risk ratio of a regimen of clopidogrel plus aspirin may be more favorable than a regimen of ticagrelor plus aspirin in this patient population. The ongoing CHANCE-2 trial will elucidate the comparative efficacy and safety of a regimen of ticagrelor plus aspirin versus clopidogrel plus aspirin after a minor stroke or TIA.

Trial References

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Johnston  SC, Amarenco  P, Denison  H,  et al. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl J Med. 2020; 383: 207–17.
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Amarenco  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.

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