Acute Stroke or Transient Ischaemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes - SOCRATES

Contribution To Literature:

The SOCRATES trial showed that ticagrelor monotherapy with 90 mg BID was not superior to aspirin 100 mg daily in reducing major cardiovascular events in patients presenting with low-acuity ischemic stroke or high-risk transient ischemic attack (TIA).

Description:

The goal of the trial was to compare the safety and efficacy of ticagrelor compared with aspirin in patients with an acute ischemic stroke.

Study Design

Patients with acute ischemic stroke were randomized in a 1:1 fashion to receive either aspirin 300 mg load + 100 mg/day (n = 6,610) or ticagrelor 180 mg load + 90 mg BID (n = 6,589) within 24 hours of presentation.

  • Total number of enrollees: 13,307
  • Total number randomized: 13,199
  • Duration of follow-up: 90 days
  • Mean patient age: 65.9 years
  • Percentage female: 41.5%

Inclusion criteria:

  • Acute ischemic stroke
  • National Institutes of Health Stroke Scale (NIHSS) score ≤5
  • High-risk TIA
  • Randomization within 24 hours of symptom onset
  • Age ≥40 years
  • No evidence of intracranial bleeding

Exclusion criteria:

  • Planned use of other antiplatelet agents or anticoagulation
  • Plan for carotid, cerebrovascular, or coronary revascularization within 7 days of randomization
  • Hypersensitivity to aspirin or ticagrelor
  • History of atrial fibrillation, ventricular aneurysm, or suspicion for cardioembolic cause of stroke
  • Intravenous or intra-arterial thrombolysis or mechanical thrombectomy within 24 hours
  • Known bleeding diathesis or coagulation disorder
  • History of symptomatic nontraumatic intracranial hemorrhage at any time
  • Gastrointestinal bleeding within 6 months or major surgery within 1 month

Other salient features/characteristics:

  • White race: 66.5%
  • Qualifying event as stroke: 73%
  • NIHSS score ≤3: 67.4%
  • Prior stroke or TIA: 18%

Principal Findings:

The primary outcome, death, myocardial infarction, or stroke, for ticagrelor vs. aspirin: 6.7% vs. 7.5%, hazard ratio 0.89, 95% confidence interval 0.78-1.01, p = 0.07

  • Death: 1.0% vs. 0.9%, p = 0.36, for ticagrelor vs. aspirin, respectively
  • All strokes: 5.9% vs. 6.8%, p = 0.03, for ticagrelor vs. aspirin, respectively
  • Myocardial infarction: 0.4% vs. 0.3%, p = 0.55, for ticagrelor vs. aspirin, respectively

Secondary outcomes  (for ticagrelor vs. aspirin, respectively):

  • Ischemic stroke: 5.8% vs. 6.7%, p = 0.046
  • Cardiovascular death: 0.6% vs. 0.5%, p = 0.48
  • Major bleeding: 0.5% vs. 0.6%, p = 0.45
  • Intracranial hemorrhage: 0.2% vs. 0.3%, p = 0.3
  • Procedural bleeding: 5 vs. 3 patients
  • PLATO major or minor bleeding: 1.6% vs. 1.2%, p = 0.06
  • GUSTO moderate or severe bleeding: 0.5% vs. 0.5%, p = 0.96

Effect in Asian patients (n = 3,858, 29% of total): Asian patients in the SOCRATES trial were younger, were less likely to be women, had lower body mass index, had fewer vascular risk factors, and had a lower proportion taking secondary prevention medications before randomization. Primary event rate was higher overall in Asian patients (10.6% vs. 5.7%, p < 0.001). Effect of ticagrelor vs. aspirin for the primary endpoint: 9.7% vs. 11.6%, p = 0.04, p for interaction = 0.27. First stroke: 9.0% vs. 10.7%, p = 0.04; p for interaction = 0.38. Major bleeding: 0.7% vs. 0.9%, p = 0.47.

Effect in embolic stroke of unknown source (ESUS): ESUS was noted in 32.8% of patients. There was no treatment-by-ESUS category interaction (p = 0.83). HR in ESUS patients was 0.87 (95% CI 0.68-1.10, p = 0.24). In an exploratory analysis, among patients with ESUS and ipsilateral carotid stenosis <50% and/or aortic arch atheroma, the primary endpoint was significantly reduced (3.7% vs. 7.0%, HR 0.51, 95% CI 0.29-0.90, p = 0.021, p for heterogeneity = 0.04).

Interpretation:

The results of this trial indicate that ticagrelor monotherapy with 90 mg BID is not superior to aspirin 100 mg daily in reducing major cardiovascular events in patients presenting with low acuity ischemic stroke (NIHSS ≤5; not receiving thrombolysis or mechanical thrombectomy) or high-risk TIA. The trial was powered for hierarchical testing. Thus, although all strokes and ischemic strokes were lower in the ticagrelor arm, the finding is considered hypothesis generating. Major bleeding was similar between the two arms. It is unknown if a benefit may be observed on longer duration of follow-up, or perhaps in patients with proven ischemic stroke only (since some patients with TIA may not have disease modifiable by antiplatelet agents).

The results in Asian patients are also hypothesis generating, and it is unclear if this represents a true differential biological effect, greater power due to higher event rates, or poor baseline management of risk factors. Similarly, the finding of benefit among patients with ESUS and ipsilateral carotid stenosis <50% and/or aortic arch atheroma is hypothesis generating.

References:

Amarenco P, Albers GW, Denison H, et al., on behalf of the SOCRATES Steering Committee and Investigators. Ticagrelor Versus Aspirin in Acute Embolic Stroke of Undetermined Source. Stroke 2017;48:2480-7.

Easton JD, Aunes M, Albers GW, et al., on behalf of the SOCRATES Steering Committee and Investigators. Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After TIA or Acute Ischemic Stroke in the SOCRATES Study. Circulation 2017;136:907-16.

Wang Y, Minematsu K, Wong KS, et al., on behalf of the SOCRATES Steering Committee and Investigators. Ticagrelor in Acute Stroke or Transient Ischemic Attack in Asian Patients: From the SOCRATES Trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes). Stroke 2017;48:167-73.

Johnston SC, Amarenco P, Albers GW, et al., on behalf of the SOCRATES Steering Committee and Investigators. Ticagrelor Versus Aspirin in Acute Stroke or Transient Ischemic Attack. N Engl J Med 2016;375:35-43.


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