Ticagrelor was not found to be superior to aspirin in patients with acute ischemic stroke or transient ischemic attack (TIA), in terms of reducing rates of stroke, myocardial infarction (MI), or death at 90 days, according to results from the SOCRATES trial.
SOCRATES (Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes) was an international double-blind controlled trial conducted in 33 countries. A total of 13 199 patients were randomly assigned to receive either ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2 through 90).
The primary end point was time to stroke occurrence, MI, or death within 90 days. The secondary end point was the time to ischemic stroke, to be tested in a hierarchical testing sequence if the primary end point difference between treatment groups was significant. Finally, safety end points included time to first major bleeding event, as determined by the PLATO bleeding definition, time to treatment discontinuation, incidence of intracranial hemorrhage, incidence of fatal bleeding, and incidence of serious and selected nonserious adverse events.
A total of 844 primary end-point events were required to detect a hazard ratio (HR) of 0.80 with a final 2-sided significance level of 4.98% and 88.7% power. “On the basis of the pooled observed event rate, the sample size was recalculated during the trial from 9600 to 13 200 patients to accrue the target number of primary events,” the investigators wrote.
Patients included had acute ischemic stroke with a National Institutes of Health Stroke Scale score of 5 or lower or high-risk TIA (ABCD2 [age, blood pressure, clinical features, duration of TIA, and presence or absence of diabetes] stroke risk score of ≥4) or symptomatic intracranial or extracranial arterial stenosis. All patients had undergone a computed tomographic or magnetic resonance imaging scan to rule out intracranial bleeding or other conditions that could affect study treatment.
Within 4.5 hours of symptom onset, 494 patients (3.7%) presented with ischemic stroke—128 of whom had an NIHSS score higher than 3. In the ticagrelor group, 442 of 6589 patients experienced a primary composite end point event whereas in the aspirin group, 497 of 6610 patients did so (HR: 0.89; 95% confidence interval [CI]: 0.78-1.01; P=.07).
Researchers noted that based on the hierarchical testing plan, all secondary end point analyses were considered exploratory and were not used to make conclusions regarding significance.
Ischemic stroke, the main secondary end point, occurred in 385 patients in the ticagrelor group and 441 patients in the aspirin group (HR: 0.87; 95% CI: 0.76-1.00; nominal P=.046).
In addition, major bleeding as defined by PLATO criteria, occurred in 31 patients in the ticagrelor group and 38 patients in the aspirin group (HR: 0.83; 95% CI: 0.52-1.34), and intracranial hemorrhage occurred in 12 and 18 patients, respectively. Patients in the ticagrelor group experienced more dyspnea compared with the aspirin group (6.2% vs 1.4%), but dyspnea is a well-known adverse effect of ticagrelor. In general, there were no significant differences in major safety outcomes.
Finally, a net clinical outcome defined as a composite of stroke, MI, death, or life-threatening bleeding occurred in 6.9% of the ticagrelor group and 7.7% of the aspirin group (HR: 0.90; 95% CI: 0.79-1.02).
“The primary end point event rates in the group with TIA were lower than expected, which raises the possibility that we enrolled some patients with nonischemic conditions mimicking a TIA, in whom antiplatelet therapy is unlikely to be efficacious,” researchers pointed out.
“Subgroup analysis did not reveal a significant interaction indicating a benefit of ticagrelor in patients who were taking aspirin at baseline, but further study of the combination of ticagrelor and aspirin may be warranted,” they concluded, “given the possibility that the rates of ischemic stroke were lower in association with ticagrelor in this group of patients.”
Disclosures: This study was funded by Astra Zeneca.
Johnston SC, Amarenco P, Albers GW, et al; for the SOCRATES Steering Committee and Investigators. N Engl J Med. 2016. doi: 10.1056/NEJMoa1603060.