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SOCRATES: Ticagrelor no better than aspirin at improving outcomes after ischemic stroke, TIA
Ticagrelor was not superior to aspirin at reducing stroke, MI or death at 90 days after acute ischemic stroke or transient ischemic attack, according to the results of the SOCRATES trial.
The results were presented at the European Stroke Organisation Conference and published in The New England Journal of Medicine.
Researchers enrolled 13,199 patients (mean age, 66 years; 41% women) at 674 sites in 33 countries in the SOCRATES study. All patients had nonsevere acute ischemic stroke or TIA deemed high risk; none had received IV or intra-arterial thrombolysis, nor were they determined to have had cardioembolic stroke.
Within 24 hours of symptom onset, patients were randomly assigned a 180-mg loading dose of ticagrelor (Brilinta, AstraZeneca) on day 1 followed by 90 mg twice daily from day 2 to day 90 or a 300-mg dose of aspirin on day 1 followed by 100 mg/day from day 2 to day 90.
The primary endpoint was time to occurrence of death, stroke or MI at 90 days.
S. Claiborne Johnston, MD, PhD, dean of the Dell Medical School at the University of Texas, Austin, and colleagues determined that 6.7% of those assigned ticagrelor had a primary endpoint event vs. 7.5% of those assigned aspirin (HR = 0.89; 95% CI, 0.78-1.01).
S. Claiborne Johnston
Because the primary endpoint did not achieve statistical significance, secondary endpoints were considered exploratory. The main secondary endpoint of ischemic stroke occurred in 5.8% of patients in the ticagrelor group vs. 6.7% in the aspirin group (HR = 0.87; 95% CI, 0.76-1).
The ticagrelor group had a lower rate of any stroke than the aspirin group (6% vs. 6.8%; HR = 0.86; 95% CI, 0.75-0.99), but none of the other secondary endpoints achieved statistical significance.
Major bleeding at 90 days did not differ between the groups (ticagrelor, 0.5%; aspirin, 0.6%; HR = 0.83; 95% CI, 0.52-1.34), and the other safety endpoints also did not reach statistical significance, according to the researchers.
Discontinuation of the study drug was more frequent in the ticagrelor group (17.5% vs. 14.7%), most commonly because of dyspnea (1.4% vs. 0.3%); overall, the rates of dyspnea were 6.2% in the ticagrelor group and 1.4% in the aspirin group, the researchers found.
“Although some studies have suggested that the risk of stroke after [TIA] has decreased in recent years, our trial confirms previous studies that have shown a high risk in the first 2 weeks, with particularly high event rates in the first 2 days,” Johnston and colleagues wrote in The New England Journal of Medicine. – by Erik Swain
References:
Johnston SC, et al. Official Welcome and Large Clinical Trials. Presented at: European Stroke Organisation Conference; May 10-12, 2016; Barcelona, Spain.
Johnston SC, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1603060.
Disclosure: The study was funded by AstraZeneca. Johnston reports receiving grant support from AstraZeneca and nonfinancial support from Sanofi. Please see the full study for a list of the other researchers’ relevant financial disclosures.
Perspective
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In a large recurrent stroke prevention study of patients who were largely from Europe (approximately 57%) or Asia or Australia (approximately 30%) and who had TIA or milder ischemic stroke events, rapid treatment with ticagrelor was not found to be superior to aspirin for the prevention of stroke, MI or death within 90 days.
One might expect that a direct acting and potent platelet inhibitor of the P2Y12 category would be superior to aspirin. However, certain factors may be in play whereby the likelihood of a superiority claim for ticagrelor could be diminished. For example, a high representation of lacunar stroke or TIA patients in the study might dilute out a potential beneficial effect of ticagrelor over aspirin, as the ideal stroke subtype target for a P2Y12 platelet inhibitor might be an unstable atherosclerotic plaque. Furthermore, if aggressive medical management is achieved successfully with high-potency lipid-lowering agents and BP-lowering therapies, a ceiling may be reached whereby antiplatelet therapy might only be able to provide a more limited benefit for recurrent stroke prevention, especially if a ruptured or unstable atherosclerotic plaque is not the major underlying stroke mechanism.
Currently, the American Heart Association/American Stroke Association 2014 guidelines recommend that we consider a combination of aspirin and clopidogrel for administration within 24 hours of a minor stroke or TIA, to be continued for 90 days. A similar recommendation is considered reasonable for dual antiplatelet therapy when there is high-grade symptomatic intracranial occlusive disease. After 90 days, the clinician may choose to administer monotherapy with aspirin, aspirin plus extended-release dipyridamole, or clopidogrel. When there is a compelling cardiac indication, aspirin plus clopidogrel combination therapy may be recommended.