Aspirin with ticagrelor lowers the risk of the composite of death or stroke compared to aspirin alone in patients with mild to moderate acute non-cardioembolic ischemic stroke or transient ischemic attack (TIA), according to newly released results from a randomized, double-blind trial.
S. Claiborne Johnston, MD, PhD, of Dell Medical School at the University of Texas at Austin, and colleagues reported the findings of The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial published in the July 16 issue of The New England Journal of Medicine.
Acute ischemic stroke or TIA is accompanied by subsequent ischemic strokes in 5% to 10% of patients. Prior studies have demonstrated a benefit of aspirin and clopidogrel for secondary prevention in these patients. Clopidogrel is a P2Y12 receptor inhibitor, which requires hepatic conversion to its active form. In certain patients, this function is inefficient, limiting its effectiveness.
Ticagrelor is an irreversible, direct-acting P2Y12 receptor inhibitor. Monotherapy with ticagrelor has not been shown to be superior to aspirin alone for preventing cardiovascular events in patients with acute ischemic stroke or TIA. The THALES trial was designed to compare aspirin and ticagrelor to aspirin alone for the prevention death or stroke in patients with acute non-cardioembolic ischemic stroke or TIA.
This multicentered, randomized, double-blinded, placebo-controlled, parallel-group trial enrolled 11,073 patients across 414 sites in 28 countries. Included were 11,016 patients at least 40 years old who had either a mild to moderate acute non-cardioembolic ischemic stroke (as determined by a National Institutes of Health Stroke Scale [NIHSS] score of 5 or less) or a high-risk TIA.
Patients were excluded if they received intravenous or intra-arterial thrombolysis, or if mechanical thrombectomy was planned within 24 hours before randomization. Additional exclusion criteria included patients with atrial fibrillation, ventricular aneurysm, hypersensitivity to aspirin or ticagrelor, bleeding diathesis, coagulopathy, bleeding, or suspected cardioembolic etiology of their event.
Patients had imaging to rule out intracranial hemorrhage and then were randomized within 24 hours of symptoms to receive either ticagrelor and aspirin or a matching placebo with aspirin in a 1:1 fashion for 30 days.
The primary outcome of interest was a composite of stroke or death at 30 days from randomization. The secondary outcome of interest was first subsequent ischemic stroke and disability measured as a score of greater than 1 on the modified Rankin scale. Outcomes were analyzed on an intention-to-treat basis.
Of the 11,016 patients included, 5,523 received aspirin and ticagrelor and 5,493 received aspirin and placebo. Baseline clinical characteristics were similar between both groups. The mean age of the patients was 65 years. Most patients presented with acute ischemic stroke (91%). Only 15 (0.2%) patients had incomplete follow-up.
The primary composite outcome of stroke or death at 30-days occurred less frequently in patients who received aspirin and ticagrelor than in those who received aspirin and placebo (5.5% vs. 6.6%; hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.71-0.96; p=0.02). The secondary outcome of recurrent ischemic stroke occurred less frequently in patients receiving aspirin and ticagrelor than in patients receiving aspirin and placebo (5.0% vs. 6.3%; HR, 0.79; 95% CI, 0.68-0.93; p=0.004). Overall disability did no differ between the two groups (23.8% vs. 24.1%; odds ratio, 0.98; 95% CI, 0.89-1.07; p=0.61).
The safety outcome of severe bleeding occurred more frequently in patients receiving aspirin and ticagrelor than in patients receiving aspirin and placebo (0.5% vs. 0.1%, p=0.001). Intracranial hemorrhage occurred in 0.4% of patients receiving aspirin and ticagrelor and in 0.1% of patients receiving aspirin and placebo (HR, 3.99; 95% CI, 1.74-9.14; p=0.001).
This study was limited by the exclusion of patients with more severe strokes (NIHSS >5); thus, the results of this study are not generalizable to all patients with ischemic stroke.
In contrast to earlier studies demonstrating the benefit of dual antiplatelet therapy for secondary prevention, the THALES trial did demonstrate a significant increase in severe bleeding and intracranial hemorrhage.
Peter M. Rothwell, F.Med.Sci.,of the University of Oxford, U.K., wrote an editorial accompanying the study. He acknowledged the prior data supporting the use of antiplatelet therapy for secondary prevention of stroke. He mentioned two prior dual antiplatelet therapy trials for secondary prevention of ischemic stroke. The POINT trial and the CHANCE trial demonstrated a larger relative risk reduction of recurrent ischemic stroke with aspirin plus clopidogrel in comparison with the data from the THALES trial using aspirin plus ticagrelor. Furthermore, he added, the risk of severe bleeding and in particular, intracranial hemorrhage were higher in the THALES trial than in the POINT and CHANCE trial.
"The bleeding risk associated with ticagrelor and aspirin might exceed the benefit among lower-risk patients who make up the majority in practice, and so the current trial results should not be overgeneralized," he concluded
This trial was funded by AstraZeneca
Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. N Eng J Med 2020;383:207-17. DOI: 10.1056/NEJMoa1916870
Rothwell PM. Antiplatelet Treatment to Prevent Early Recurrent Stroke. N Eng J Med 2020;383:276-8. DOI: 10.1056/NEJMe2018927