SOCRATES: Ticagrelor Not Superior to Aspirin for Stroke, TIA

May 11, 2016

BARCELONA — The antiplatelet agent ticagrelor (Brilinta, Astra Zeneca), was not found to be significantly superior to aspirin in reducing stroke, myocardial infarction (MI), or death at 90 days, the primary endpoint, in patients with acute ischemic stroke or transient ischemic attack (TIA), in the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial.

However, predefined exploratory analyses showed indications that ticagrelor may be more effective at 7 days in reducing ischemic stroke and all stroke, as well as in several subgroups, including those taking aspirin at baseline.

The results of the SOCRATES trial were presented here by Clay Johnston, MD, Dell Medical School, University of Texas, Austin, at the European Stroke Organisation Conference (ESOC). They were also simultaneously published online May 10 in the New England Journal of Medicine.

"The trial was negative for its primary endpoint so we can't say ticagrelor is superior to aspirin in this setting, and we can't really recommend ticagrelor for the treatment of stroke or TIA at present," Dr Johnston told Medscape Medical News.

Clay Johnston, MD

"But it was very close (P = .07), and there were subgroups where it may very well be beneficial on its own or in combination with aspirin," he added. "The stroke risk was very high in this group very early on, so we need to be very vigilant and aggressive in this setting."

"Although some studies have suggested that the risk of stroke after transient ischemic attack 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," the authors conclude in their paper.

Treat Earlier and Combine With Aspirin?

On lessons learned for the possibility of a future trial, Dr Johnston said he would recommend earlier treatment — within 12 hours — "as that was one group that saw the most benefit."

"Also, those patients who came in on aspirin did particularly well when ticagrelor was added, so it may make sense to look at the combination of ticagrelor plus aspirin vs aspirin alone in a future trial," he added.

"This was the design of the CHANCE [Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events] trial which showed a benefit of clopidogrel in stroke/TIA and is also the way the ongoing POINT [Platelet-Oriented Inhibition in New TIA and minor ischemic stroke] trial is designed," he said.

He said he hoped future trials would be conducted with ticagrelor or other more potent antiplatelet agents in stroke, but "there's no commitment from AstraZeneca [the company that funded the SOCRATES trial] at this point."

Commenting on the study for Medscape Medical News, Peter Rothwell, MD, Oxford University, United Kingdom, said, "We have to accept there was a trend towards greater benefit with ticagrelor, but if you took out patients who were already on aspirin then there would be no benefit on the rest of the population," Dr Rothwell said. "So overall the trend was really coming from the subgroup taking aspirin at baseline."

As a possible explanation for this, he noted that some evidence suggests that aspirin loses its effect over time, "so if a patient has been on aspirin for years, just continuing aspirin doesn't necessarily make sense."

SOCRATES

The SOCRATES trial, conducted in 674 centers in 33 countries, involved 13,199 patients with a nonsevere ischemic stroke or high-risk TIA who had not received intravenous or intra-arterial thrombolysis and were not considered to have had a cardioembolic stroke.

They were randomly assigned within 24 hours of symptom onset to receive 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 (stroke, MI, or death within 90 days) occurred in 6.7% of the ticagrelor group vs 7.5% of those treated with aspirin (hazard ratio, 0.89; 95% confidence interval [CI], 0.78 - 1.01; P = 0.07).

Ischemic stroke occurred in 5.8% of the ticagrelor group vs 6.7% of the aspirin group (hazard ratio, 0.87; 95% CI, 0.76 - 1.00).

Major bleeding occurred in 0.5% of patients treated with ticagrelor and in 0.6% of patients treated with aspirin; intracranial hemorrhage occurred in 0.2% and 0.3%, respectively, and fatal bleeding in 0.1% and 0.1%.

A net clinical outcome, defined as a composite of stroke, MI, death, or life-threatening bleeding, occurred in 6.9% of patients in the ticagrelor group and 7.7% of patients in the aspirin group (hazard ratio, 0.90; 95% CI, 0.79 - 1.02).

One third of patients were taking aspirin at baseline, and in this group patients randomly assigned to ticagrelor showed a greater benefit, with the primary endpoint occurring in 6.5% vs 8.4% continuing on aspirin (hazard ratio, 0.76; 95% CI, 0.61 - 0.95).

On this observation, the researchers point out that because the antiplatelet effects of aspirin typically last several days, the introduction of ticagrelor represented short-term dual-antiplatelet therapy.

"Subgroup analysis did not reveal a significant interaction indicating a benefit of ticagrelor in patients who were taking aspirin at baseline," they write, "but further study of the combination of ticagrelor and aspirin may be warranted, given the possibility that the rates of ischemic stroke were lower in association with ticagrelor in this group of patients."

The other subgroup that appeared to have shown more benefit of ticagrelor consisted of patients treated within 12 hours of symptom onset, about one third of the total. In this group, the primary endpoint occurred in 6.9% of those given ticagrelor vs 8.5% of those receiving aspirin (hazard ratio, 0.80; 95% CI, 0.65 - 0.98).

The authors point out that there were only limited patients at especially high risk for stroke, such as those with high-grade carotid or severe intracranial stenosis, because these patients may have undergone vascular interventions or may have been treated with the combination of clopidogrel plus aspirin on the basis of the CHANCE trial.

They also note that the primary endpoint event rates in the group with transient ischemic attack were lower than expected, "which raises the possibility that we enrolled some patients with non-ischemic conditions mimicking a transient ischemic attack, in whom antiplatelet therapy is unlikely to be efficacious."

The SOCRATES trial was funded by AstraZeneca. Dr. Johnston reports grant support from AstraZeneca and nonfinancial support from Sanofi during the conduct of the study.

European Stroke Organisation Conference (ESCO) 2016. Presented May 10, 2016.

N Engl J Med. Published online May 10, 2016. Full text

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