SOCRATES - Ticagrelor vs aspirin in minor ischemic stroke or TIA

Johnston SC, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med 2016;online

Clinical Question

In patients with non-cardioembolic transient ischemic attack (TIA) or minor acute ischemic stroke, does ticagrelor reduce the risk of CV events without increasing bleeding events compared to ASA?

Bottom Line

In patients with non-cardioembolic TIA or minor ischemic stroke, ticagrelor did not statistically significantly reduce the risk of stroke or other cardiovascular events at 90 days, though this trial was underpowered to identify a clinically significant reduction in favor of ticagrelor.

Given this statistical uncertainty, some clinicians may elect to use ticagrelor instead of ASA in certain patients. Key considerations in favor of sticking to ASA include a lower risk of drug discontinuation (3% absolute lower risk), minor bleed and dyspnea (5% absolute lower risk), and a much lower cost (~$260 cheaper/3 months).

Design

Allocation-concealed "superiority" RCT with all (patients, clinicians, investigators) blinded, low loss-to-follow-up (1.5%), analyzed using the intention-to-treat population.

Patients and Setting

  • 33 countries, 674 centers
  • January 2014 - October 2015
  • Inclusion criteria:
    1. Men or women 40+ y/o
    2. Stroke or TIA
      • Acute ischemic stroke with NIHSS score 5 or less (/42), or
      • High-risk TIA
        • ABCS^2 score 4+ (/7), or
        • Documented symptomatic intracranial arterial occlusion, or
        • Documented internal carotid artery occlusive disease
    3. <24h of symptom onset
    4. Head CT/MRI to rule out hemorrhage or other pathology (e.g. AVM, tumor, abscess) that could explain symptoms
  • Key exclusion criteria:
    • Suspicion of cardioembolic origin of stroke/TIA
    • Planned revascularization (cerebrovascular, carotid, or coronary) requiring stopping study medications <7 days of randomization 
    • PMHx:
      • Any hx of AF, ventricular aneurysm
      • Hx of symptomatic non-traumatic ICH at any time, GI bleed within 6 months, major surgery within 30 days, bleeding diathesis or coagulation disorder
      • Severe liver disease or renal failure requiring dialysis
    • Concurrent meds:
      • Receipt of any IV or intra-arterial thrombolytic or mechanical thrombectomy <24h prior to randomization
      • Planned use of other antiplatelets or anticoagulants for other indication
      • Patients receiving dual antiplatelet therapy (DAPT)
      • Anticipated use of strong CYP3A4 inhibitor/substrate
      • Anticipated need for NSAIDs >7 days
  • ? screened -> 13,199 randomized
  • Average patient:
    • 65.8 y/o
    • 42% female
    • Race: ~2/3 White, ~1/3 Asian, <5% other
    • Region: Europe 57%, Asia/Australia 30%, North America 7%, Central/South America 5%
    • BMI 26
    • Event: Ischemic stroke ~3/4, TIA ~1/4
    • PMHx
      • Previous ischemic stroke 12%
      • Previous TIA 6%
      • CAD (MI) 9% (4%)
      • HTN 73%
      • Dyslipidemia 38%
      • Diabetes 25%
    • Taking ASA before randomization ~1/3

Intervention and Control

  • Intervention: Ticagrelor
    • Loading dose: 180 mg PO x1
    • Maintenance dose: 90 mg PO BID x90 days
  • Control: ASA
    • Loading dose: 300 mg PO x1
    • Maintenance dose: 100 mg PO once daily x90 days
  • Co-interventions common to both groups:
    • NO thrombolytic or endovascular therapy to treat the event
    • After 1st 90 days, treated at discretion of investigator x30 days & followed at 120 days (this extended follow-up is not reported in this paper)

Outcomes

  • @ 90 days
  • Efficacy: No statistically significant difference in primary outcome, though the lower end of the confidence interval suggests a possible risk reduction with ticagrelor as high as 1.65% (absolute). Additionally, although this trial wasn't designed as a non-inferiority trial, the upper end of the confidence interval (HR 1.01) provides definite evidence that ticagrelor is at least as good as ASA for this outcome in this patient population.
  • Safety: 
    • Bleeding: No significant difference in major or intracranial hemorrhages
    • Dyspnea: As in other studies of ticagrelor (see PLATO and PEGASUS), ticagrelor increased the risk of dyspnea
    • Discontinuation: Patients on ticagrelor were more likely to permanently discontinue the study drug, which was due to a greater risk of dyspnea & any bleeding
  • Subgroup analyses: None of 15 subgroup analyses were significant, including evaluating the impact of aspirin use prior to admission (p for test for interaction = 0.10)

Outcomes in SOCRATES

Key Considerations

Generalizability: This trial enrolled a very specific population of patients with TIA or stroke with low symptom burden, but high risk of recurrence. It's unclear from the study flow diagram how many patients were assessed for eligibility to identify the 13,000+ randomized patients. It's also unclear how the net effect (on both recurrent ischemic CVA and hemorrhagic strokes) in a population of ischemic stroke patients with higher NIHSS score.

Overall balance of considerations for ticagrelor versus ASA

  • Efficacy: Though not statistically significantly different, there is high likelihood that ticagrelor is marginally better than ASA in reducing stroke recurrence in this patient population
  • Safety: No difference in major bleeding, but significantly more dyspnea in the ticagrelor group, which led to study drug discontinuation and may have had unmeasured consequences on patient quality of life
    • Anecdotally, in some cases ticagrelor-related dyspnea leads to excessive and unnecessary testing (e.g. chest CT, pulmonary function tests, sputum cultures) that may result in additional unnecessary treatment
  • Cost of 90-days of treatment (approximate): Ticagrelor $280, aspirin $12
  • Convenience: Ticagrelor needs to be taken twice daily versus once daily for ASA
  • Drug interactions: Ticagrelor has a number of pharmacokinetic drug interactions with CYP3A4 inhibitors that ASA is free from

Unanswered questions

  • How does ticagrelor monotherapy compare to other interventions, including clopidogrel monotherapy, dual antiplatelet therapy with ASA + clopidogrel (CHANCE trial regimen) or ASA + dipyridamole?
  • If patients are event-free in these first 90 days, what regimen should they continue in the long term? If ticagrelor was initially used, would continuing it indefinitely provide additional benefit compared to switching back to ASA?
  • Do patients who have a stroke/TIA on ASA (those who "fail ASA") benefit from switching to a different antiplatelet regimen?

 

Summary author: Ricky Turgeon BSc(Pharm), ACPR, PharmD
Summary date: updated 26 May 2016