Elsevier

The Lancet Neurology

Volume 16, Issue 4, April 2017, Pages 301-310
The Lancet Neurology

Articles
Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial

https://doi.org/10.1016/S1474-4422(17)30038-8Get rights and content

Summary

Background

Ticagrelor is an effective antiplatelet therapy for patients with coronary atherosclerotic disease and might be more effective than aspirin in preventing recurrent stroke and cardiovascular events in patients with acute cerebral ischaemia of atherosclerotic origin. Our aim was to test for a treatment-by-ipsilateral atherosclerotic stenosis interaction in a subgroup analysis of patients in the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial.

Methods

SOCRATES was a randomised, double-blind, controlled trial of ticagrelor versus aspirin in patients aged 40 years or older with a non-cardioembolic, non-severe acute ischaemic stroke, or high-risk transient ischaemic attack from 674 hospitals in 33 countries. We randomly allocated patients (1:1) to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–90, given orally) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2–90, given orally) within 24 h of symptom onset. Investigators classified all patients into atherosclerotic and non-atherosclerotic groups for the prespecified, exploratory analysis reported in this study. The primary endpoint was the time to occurrence of stroke, myocardial infarction, or death within 90 days. Efficacy analysis was by intention to treat. The SOCRATES trial is registered with ClinicalTrials.gov, number NCT01994720.

Findings

Between Jan 7, 2014, and Oct 29, 2015, we randomly allocated 13 199 patients (6589 [50%] to ticagrelor and 6610 [50%] to aspirin). Potentially symptomatic ipsilateral atherosclerotic stenosis was reported in 3081 (23%) of 13 199 patients. We found a treatment-by-atherosclerotic stenosis interaction (p=0·017). 103 (6·7%) of 1542 patients with ipsilateral stenosis in the ticagrelor group and 147 (9·6%) of 1539 patients with ipsilateral stenosis in the aspirin group had an occurrence of stroke, myocardial infarction, or death within 90 days (hazard ratio 0·68 [95% CI 0·53–0·88]; p=0·003). In 10 118 patients with no ipsilateral stenosis, 339 (6·7%) of 5047 patients in the ticagrelor group had an occurrence of stroke, myocardial infarction, or death within 90 days compared with 350 (6·9%) of 5071 in the aspirin group (0·97 [0·84–1·13]; p=0·72). There were no significant differences in the proportion of life-threatening bleeding or major or minor bleeding events in patients with ipsilateral stenosis in the ticagrelor group compared with the aspirin group.

Interpretation

In this prespecified exploratory analysis, ticagrelor was superior to aspirin at preventing stroke, myocardial infarction, or death at 90 days in patients with acute ischaemic stroke or transient ischaemic attack when associated with ipsilateral atherosclerotic stenosis. An understanding of stroke mechanisms and causes is important to deliver safe and efficacious treatments for early stroke prevention.

Funding

AstraZeneca.

Introduction

Antiplatelet treatment is recommended after non-cardioembolic ischaemic strokes, and is intended to limit thrombosis superimposed on ulcerated atherosclerotic plaque and subsequent distal embolisation.1 However, in most trials of antiplatelet treatment for secondary stroke prevention, analyses were not done according to ischaemic stroke subtype—ie, atherosclerotic disease related, lacunar stroke, or stroke of unknown cause. The premise has been that patients with a non-cardioembolic ischaemic stroke should respond to antiplatelet agents because of the large overlap between underlying diseases, common risk factors (eg, hypertension, dyslipidaemia, diabetes, and cigarette smoking) in distinct causes of ischaemic stroke (eg, atherosclerotic disease, small-vessel disease, and cryptogenic strokes), and the fact that antiplatelet agents can limit thrombosis, even in the absence of ulcerated atherosclerotic plaques. Although evidence from meta-analysis and clinical trials2, 3, 4, 5 shows that early aspirin treatment is effective6 and that dual antiplatelet therapy is better than monotherapy, no previous antiplatelet trials have prespecified an analysis according to ischaemic stroke subtype.

Research in context

Evidence before this study

We searched PubMed with the search terms “ticagrelor”, “aspirin”, “TIA”, “minor stroke”, and “clinical trial” for reports published before Sept 1, 2016. The only published final results of a clinical trial comparing ticagrelor with aspirin in patients with transient ischaemic attack or minor ischaemic stroke were those from the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial. Overall, findings from the trial did not show that ticagrelor was better than aspirin for prevention of stroke, myocardial infarction, or death in patients with transient ischaemic attack and minor stroke.

Added value of this study

This prespecified exploratory analysis showed a significant treatment-by-symptomatic ipsilateral stenosis interaction, meaning that, in patients with symptomatic ipsilateral atherosclerosis stenosis, ticagrelor was better than aspirin for prevention of stroke, myocardial infarction, or death, whereas in patients without ipsilateral stenosis, ticagrelor had a neutral effect compared with aspirin. The safety profile in patients with ipsilateral stenosis, as in the overall population, was excellent. This analysis also showed that patients with symptomatic ipsilateral stenosis on aspirin have higher absolute proportions of stroke, myocardial infarction, or death than do those without ipsilateral stenosis, and that the absolute benefit of ticagrelor in individuals with ipsilateral stenosis was significantly greater.

Implications of all the available evidence

Ticagrelor has a beneficial effect in patients with atherosclerotic disease. However, patients with transient ischaemic attack or minor stroke and ipsilateral atherosclerotic stenosis are at high risk of recurrent stroke with an antiplatelet agent in monotherapy. To address this residual risk, further randomised trials with intense antiplatelet therapy (eg, dual antiplatelet therapy) should be done in patients with transient ischaemic attack or minor stroke.

Ticagrelor has been shown to be more effective than clopidogrel7 and placebo8 in patients with coronary atherosclerotic disease who were taking aspirin daily. In the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial, we compared ticagrelor 90 mg twice per day with aspirin 100 mg per day in patients with transient ischaemic attack and minor stroke of non-cardioembolic origin that occurred within the previous 24 h, and showed that ticagrelor had a non-significant 11% relative risk reduction in the composite endpoint of stroke, myocardial infarction, or death.9 Investigators systematically used the Atherosclerotis, Small-Vessel Disease, Cardiac Pathology, Other Causes, Dissection (ASCOD) phenotyping system to assign stroke cause.10, 11

In this prespecified exploratory analysis of the SOCRATES trial, we investigated whether patients with documented atherosclerotic disease, specifically those with potentially symptomatic stenosis ipsilateral to the index ischaemic stroke or transient ischaemic attack, would show greater benefit from ticagrelor compared with aspirin than those without ipsilateral stenosis, and we searched for a treatment-by-ipsilateral stenosis interaction.

Section snippets

Study design and patients

The SOCRATES trial was a randomised, double-blind, controlled trial. we recruited patients from 674 hospitals in 33 countries (appendix). patients aged 40 years or older were recruited within 24 h of symptom onset of a non-severe acute ischaemic stroke (National Institute of Health Stroke Score of ≤5) or a high-risk transient ischaemic attack (we defined high risk by an Age, Blood Pressure, Clinical Finding, Duration, Diabetes [ABCD2] score of ≥4, not limited to isolated numbness, isolated

Results

Between Jan 7, 2014, and Oct 29, 2015, we randomly allocated 13 199 patients (6589 [50%] to ticagrelor and 6610 [50%] to aspirin; figure 1). Table 1 shows the distribution of atherosclerotic and small-vessel disease. Of 4977 (37·7%) patients who had any form of atherosclerotic disease—ie, patients with documented atherosclerotic lesions, which were either potentially causal or present but probably not symptomatic and causal (A1, A2, or A3 in the ASCOD system; appendix), 168 (6·8%) of 2471

Discussion

In this exploratory analysis, we found that ticagrelor reduced the risk of stroke, myocardial infarction, and death at 90 days, compared with aspirin, in patients with minor ischaemic stroke or high-risk transient ischaemic attack with ipsilateral, potentially symptomatic atherosclerotic stenosis of intracranial or extracranial arteries, with a large relative risk reduction of more than 30%. In the patients without ipsilateral stenosis, we found no difference. We noted evidence of treatment

References (25)

  • SC Johnston et al.

    Ticagrelor versus aspirin in acute ischemic stroke or transient ischemic attack

    N Engl J Med

    (2016)
  • P Amarenco et al.

    The ASCOD phenotyping of ischemic stroke (updated ASCO phenotyping)

    Cerebrovasc Dis

    (2013)
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