Clinical Question

In patients with acute non-severe ischemic stroke or high-risk transient ischemic attack, is ticagrelor superior to aspirin in preventing recurrent stroke and cardiovascular events?

Bottom Line

In patients with acute ischemic stroke or transient ischemic attack, ticagrelor is not superior to aspirin in reducing the risk of stroke, myocardial infarction, or death within 90 days.

Major Points

Ticagrelor, a potent P2Y12 receptor antagonist acting on platelets, was investigated as a potential alternative to aspirin as initial therapy after an acute non-cardioembolic ischemic stroke or high-risk transient ischemic attack. The SOCRATES trial found that ticagrelor did not significantly reduce the rate of subsequent stroke, myocardial infarction, or death compared to aspirin.

Guidelines

As of the knowledge cutoff date, guidelines have not been established that reflect the results of this trial.

Design

- Multicenter, double-blind, randomized, controlled trial - N=13,199 - Ticagrelor: n=6,589 (180 mg loading dose, then 90 mg twice daily days 2-90) - Aspirin: n=6,610 (300 mg on day 1, then 100 mg daily days 2-90) - Setting: 674 centers in 33 countries - Enrollment: January 7, 2014 to October 29, 2015 - Mean follow-up: 90 days - Analysis: Intention-to-treat - Primary outcome: Stroke (ischemic or hemorrhagic), myocardial infarction, or death within 90 days

Population

- Inclusion criteria: Nonsevere ischemic stroke (NIHSS score ≤5) or high-risk TIA (ABCD2 score ≥4 or symptomatic arterial stenosis), ability to start treatment within 24 hours of symptom onset, age ≥40 years, CT or MRI exclusion of intracranial bleeding - Exclusion criteria: Need for specific antiplatelet or anticoagulation therapy, planned revascularization within 7 days, history of atrial fibrillation or suspicion of cardioembolic cause, thrombolysis or mechanical thrombectomy within 24 hours before randomization, severe liver disease, renal failure requiring dialysis, pregnancy, or lactation, among others. - Baseline characteristics: Median age 65 years, 66.7% male

Interventions

- Ticagrelor: 180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90 - Aspirin: 300 mg loading dose on day 1 followed by 100 mg daily for days 2 through 90

Outcomes

- Primary outcome occurrence: Ticagrelor, 6.7% (442 patients); Aspirin, 7.5% (497 patients); hazard ratio 0.89; 95% CI, 0.78 to 1.01; P=0.07. - Ischemic stroke occurrence: Ticagrelor, 5.8% (385 patients); Aspirin, 6.7% (441 patients); hazard ratio 0.87; 95% CI, 0.76 to 1.00; nominal P=0.046. - Safety outcomes: Major bleeding in 0.5% Ticagrelor and 0.6% Aspirin, intracranial hemorrhage in 0.2% Ticagrelor and 0.3% Aspirin, fatal bleeding in 0.1% for both groups.

Criticisms

- No ticagrelor benefit in a significant proportion of patients already on aspirin at the time of the qualifying event. - Subgroup analysis did not show a significant benefit of ticagrelor over aspirin. - Exclusion of patients with a high risk of stroke such as those with carotid or severe intracranial stenosis. - Thrombolytic therapy patients were excluded, thus not generalizable to this population.

Funding

Funded by AstraZeneca.

SOCRATES