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

Abstract

Background and purpose: In patients with acute mild-moderate ischemic stroke or high-risk transient ischemic attack, the THALES trial (Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death) demonstrated that when added to aspirin, ticagrelor reduced stroke or death but increased risk of severe hemorrhage compared with placebo. The primary efficacy outcome of THALES included hemorrhagic stroke and death, events also counted in the primary safety outcome. We sought to disentangle risk and benefit, assess their relative impact, and attempt to identify subgroups with disproportionate risk or benefit.

Methods: In a randomized, placebo-controlled, double-blind trial of patients with mild-to-moderate acute noncardioembolic ischemic stroke or high-risk transient ischemic attack, patients were randomized within 24 hours after symptom onset to a 30-day regimen of either ticagrelor plus aspirin or matching placebo plus aspirin. For the present analyses, we defined the efficacy outcome, major ischemic events, as the composite of ischemic stroke or nonhemorrhagic death, and defined the safety outcome, major hemorrhage, as intracranial hemorrhage or hemorrhagic death. Net clinical impact was defined as the combination of these 2 end points.

Results: In 11 016 patients (5523 ticagrelor-aspirin and 5493 aspirin), a major ischemic event occurred in 294 patients (5.3%) in the ticagrelor-aspirin group and in 359 patients (6.5%) in the aspirin group (absolute risk reduction 1.19% [95% CI, 0.31%–2.07%]). Major hemorrhage occurred in 22 patients (0.4%) in the ticagrelor-aspirin group and 6 patients (0.1%) in the aspirin group (absolute risk increase 0.29% [95% CI, 0.10%–0.48%]). Net clinical impact favored ticagrelor-aspirin (absolute risk reduction 0.97% [95% CI, 0.08%–1.87%]). Findings were similar when different thresholds for disability were applied and over a range of predefined subgroups.

Conclusions: In patients with mild-moderate ischemic stroke or high-risk transient ischemic attack, ischemic benefits of 30-day treatment with ticagrelor-aspirin outweigh risks of hemorrhage.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354429.

Keywords: aspirin; benefit-risk assessment; ischemic attack, transient; ischemic stroke; ticagrelor; treatment outcome.

Figure 1.

Absolute risk differences between treatment with ticagrelor-aspirin and aspirin alone for the original outcome measures and for various disentangled measures of irreversible harm from ischemia and hemorrhage. Bars indicate 95% CI. GUSTO indicates Global Utilization of Streptokinase and Tissue-Type Plasminogen Activator for Occluded Coronary Arteries; mRS, modified Rankin Scale; NNH, number needed to harm; and NNT, number needed to treat.

Figure 2.

Absolute risk differences between ticagrelor-aspirin and aspirin alone on net clinical impact (combining major ischemic events and major hemorrhage) in predefined subgroups. Bars indicate 95% CI. No interaction was significant. BMI indicates body mass index; NIHSS, National Institutes of Health; and TIA, transient ischemic attack.

Figure 3.

Absolute risk differences between ticagrelor-aspirin and aspirin alone on major ischemic events (blue) and major hemorrhage (red) in predefined subgroups. Bars indicate 95% CI. No interaction was significant. BMI indicates body mass index; NIHSS, National Institutes of Health; and TIA, transient ischemic attack.