Ticagrelor Added to Aspirin in Acute Nonsevere Ischemic Stroke or Transient Ischemic Attack of Atherosclerotic Origin

Abstract

Background and Purpose: Among patients with a transient ischemic attack or minor ischemic strokes, those with ipsilateral atherosclerotic stenosis of cervicocranial vasculature have the highest risk of recurrent vascular events. Methods: In the double-blind THALES (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial, we randomized patients with a noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–30) or placebo added to aspirin (300–325 mg on day 1 followed by 75–100 mg daily for days 2–30) within 24 hours of symptom onset. The present paper reports a prespecified analysis in patients with and without ipsilateral, potentially causal atherosclerotic stenosis ≥30% of cervicocranial vasculature. The primary end point was time to the occurrence of stroke or death within 30 days. Results: Of 11 016 randomized patients, 2351 (21.3%) patients had an ipsilateral atherosclerotic stenosis. After 30 days, a primary end point occurred in 92/1136 (8.1%) patients with ipsilateral stenosis randomized to ticagrelor and in 132/1215 (10.9%) randomized to placebo (hazard ratio 0.73 [95% CI, 0.56–0.96], P =0.023) resulting in a number needed to treat of 34 (95% CI, 19–171). In patients without ipsilateral stenosis, the corresponding event rate was 211/4387 (4.8%) and 230/4278 (5.4%), respectively (hazard ratio, 0.89 [95% CI, 0.74–1.08]; P =0.23, P interaction =0.245). Severe bleeding occurred in 4 (0.4%) and 3 (0.2%) patients with ipsilateral atherosclerotic stenosis on ticagrelor and on placebo, respectively ( P =NS), and in 24 (0.5%) and 4 (0.1%), respectively, in 8665 patients without ipsilateral stenosis (hazard ratio=5.87 [95% CI, 2.04–16.9], P =0.001). Conclusions: In this exploratory analysis comparing ticagrelor added to aspirin to aspirin alone, we found no treatment by ipsilateral atherosclerosis stenosis subgroup interaction but did identify a higher absolute risk and a greater absolute risk reduction of stroke or death at 30 days in patients with ipsilateral atherosclerosis stenosis than in those without. In this easily identified population, ticagrelor added to aspirin provided a clinically meaningful benefit with a number needed to treat of 34 (95% CI, 19–171). Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03354429.

Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack

“…A previous secondary analysis defined an atherosclerotic subgroup as those with ipsilateral cervical or intracranial arterial stenosis ≥30%. 14 While the net clinical impact was numerically greater in those with atherosclerosis (ARR, 2.76% [95% CI, 0.38%–5.13%]) compared with those without (0.40% [95% CI, 0.53%–1.33%]), the interaction was not significant ( P =0.26). Similarly, interactions were not significant for major ischemic events or major hemorrhage.…”

Oral Antiplatelet Therapy for Secondary Prevention of Non-Cardioembolic Ischemic Cerebrovascular Events

“…The primary endpoint of stroke or death at 30 days occurred in 8.1% patients randomized to ticagrelor versus 10.9% in the placebo arm (p = 0.023), with an almost 30% reduction in the risk of stroke recurrence (p = 0.02). Once again, Kaplan-Meier curves revealed the efficacy was greater in the first period from index event, exactly within the first 10 days [32].…”

Ticagrelor Use in Stroke Patients: Past, Present, and Future

“…A sub-group analysis of THALES trial involving stroke patients with ipsilateral stenosis investigated the primary endpoint i.e., time to the occurrence of stroke or death within 30 days. 17 Patients randomized to ticagrelor achieved a lower rate (8.1% v/s 10.9%) of primary endpoint. A few limitations of THALES were: absence of long-term data on the efficacy and safety beyond 30 days and study patient population was limited to Caucasians and Asians, limiting the generalizability of the results.…”