Efficacy and Safety of Ticagrelor in Relation to Aspirin Use Within the Week Before Randomization in the SOCRATES Trial

K.S. Lawrence Wong, MD; Pierre Amarenco, MD; Gregory W. Albers, MD; Hans Denison, MD, PhD; J. Donald Easton, MD; Scott R. Evans, PhD; Peter Held, MD, PhD; Anders Himmelmann, MD, PhD; Scott E. Kasner, MD; Mikael Knutsson, PhD; Per Ladenvall, MD, PhD; Kazuo Minematsu, MD, PhD; Carlos A. Molina, MD; Yongjun Wang, MD; S. Claiborne Johnston, MD, PhD

Disclosures

Stroke. 2018;49(7):1678-1685. 

In This Article

Methods

Data underlying the findings described in this article may be obtained in accordance with AstraZeneca's data sharing policy available at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

SOCRATES design and primary results have been presented previously.[3,10] The trial was approved by the relevant Institutional Review Board/Ethics Committee at each site. Patients provided written informed consent before any study-specific procedures were performed.

Patients (n=13 199) with a noncardioembolic, nonsevere ischemic stroke (National Institutes of Health Stroke Scale score of ≤5) or high-risk TIA (ABCD[2] score of ≥4 or symptomatic ipsilateral stenosis of an extra or intracranial artery) were randomized (interactive web-based randomization system) within 24 hours of symptom onset to double-blinded treatment with ticagrelor 180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 to 90 or aspirin 300 mg on day 1 followed by 100 mg daily for days 2 to 90.

Concomitant medication information, particularly aspirin use, was collected; including start and stop date for medications initiated or stopped during the month before randomization. The prior-aspirin subgroup were patients receiving any aspirin within 7 days before randomization. Atherosclerosis was assessed by atherosclerosis, small-vessel disease, cardiac pathology, other causes, dissection phenotyping (ASCOD) to assign stroke cause and grade; A0=no atherosclerotic disease; A1 (likely causal)=≥50% ipsilateral stenosis of extracranial or intracranial arteries or a mobile thrombus in the aortic arch; A2 (causal relationship possible but uncertain)=<50% stenosis of extracranial or intracranial artery or an aortic arch plaque of >4 mm in thickness without mobile thrombus; A3 (unlikely causal)=plaque without stenosis or a stenosis in an artery contralateral to the cerebral infarct or a concomitant coronary or peripheral arterial disease; A9=insufficient information to grade atherosclerosis (no assessment of either intracranial arteries or extracranial arteries).[11] The prior-aspirin group was also analyzed by aspirin dose (>150 mg versus ≤150 mg), to explore any dose-related impact on efficacy of prior-aspirin use, and by start day of aspirin treatment as either (1) starting the day before or the same day as randomization, representing patients receiving an acute treatment with aspirin after onset of symptoms but before randomization, for example, as part of prehospital emergency care or at the emergency ward, or (2) starting earlier than the day before randomization considered as a proxy for chronic treatment, that is, aspirin treatment was ongoing at the time of the index event, since the start date was out of the possible time window of 24 hours between the start of the index event and randomization.

The primary end point for SOCRATES was the time from randomization to first occurrence of any event from the composite of stroke (ischemic or hemorrhagic), myocardial infarction, or death at 90 days; each of these components was based on standard definitions.[10] An exploratory analysis of the primary end point at 7 days was performed; at this time point, because of platelet lifespan and renewal, any effect of aspirin intake before randomization is expected to have disappeared and a sufficient number of events was expected to have occurred to make it possible to detect an early treatment effect. The secondary efficacy end point was ischemic stroke. The primary safety end point was PLATO (Study of Platelet Inhibition and Patient Outcomes) major bleeding. An independent Clinical Event adjudication Committee, blinded to study treatment, adjudicated all components of the efficacy end point and classified all bleeding events, not considered as minimal by the investigator, according to the PLATO bleeding definition.[10,12]

Statistical Methods

The prior-aspirin subgroup analysis was prespecified and exploratory. Efficacy analyses were based on the intention-to-treat principle using adjudicated events and including all randomized patients. Safety analyses of bleeding events were performed for patients receiving at least one dose of randomized treatment. Time from randomization to the first occurrence of any event for a given end point was analyzed by the Cox proportional hazards model with treatment as the only factor. Interaction between treatment assignment and prior-aspirin indicator was evaluated by including terms for treatment, prior-aspirin indicator, and treatment-by-prior-aspirin indicator interaction in the Cox model. Interaction terms with a P value of <0.05 were considered to be statistically significant. This conservative approach of assessing interaction in subgroup analyses (rather than using P<0.10) was considered appropriate, given that the primary outcome of the SOCRATES trial was not statistically significant (P=0.07).[3]

Baseline characteristics were compared for patients in the prior-aspirin subgroup and those with no prior-aspirin usage. Categorical variables were presented as percentages and continuous variables as median with interquartile range or mean with SD. χ2 test and t test were performed for comparison of categorical variables and continuous variables, respectively. P values of <0.05 were considered significant.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....