Introduction and rationale

Patients who experience an acute minor ischemic stroke or a transient ischemic attack (TIA) are at high risk of developing subsequent ischemic events, with particularly high risks of stroke in the first 90 days after the index cerebrovascular event 1-4. During this acute period, previously ischemic tissue remains at risk, ruptured plaques are highly thrombogenic, and platelet activation is high, factors that may contribute to greater acute instability and may justify known additional risks of hemorrhage from antiplatelet agents 5.

Current guidelines recommend antiplatelet therapy to prevent recurrent ischemic cardiovascular events in patients with acute ischemic stroke or TIA of noncardioembolic origin 6. Although a number of antiplatelet options are listed, monotherapy with aspirin 50–325 mg daily is the only option with an A rating for level of evidence and the only agent with evidence of benefit in the first few days after an event 6. However, the benefit of aspirin in the secondary prevention of ischemic stroke is modest, with only a 22% relative reduction in new ischemic events in the nonacute period 7, and recurrent stroke risks remain high in the acute period on aspirin. Furthermore, even moderate doses of aspirin are associated with a risk of hemorrhagic events, including gastrointestinal bleeding 8.

More intensive antiplatelet therapy may be more effective at reducing the risk of recurrent ischemia after TIA or acute ischemic stroke, but evidence is limited. The impact of adding clopidogrel to aspirin in patients with acute stroke/TIA was evaluated in a trial of 5170 Chinese patients [Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE)] 9. Compared with aspirin alone, the 90-day relative risk of stroke with clopidogrel plus aspirin decreased by 32%, and risk of hemorrhage was low. Results were similar in the Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence (FASTER) pilot trial of 392 patients primarily from Canada 10. To confirm these findings in other populations, an international trial [Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT)] is enrolling 5840 patients with acute ischemic stroke or TIA to test clopidogrel plus aspirin vs. aspirin alone 11, 12.

Ticagrelor is a potent antiplatelet agent that may be particularly effective and safe in patients with acute ischemic stroke or TIA. It is a reversibly binding and direct-acting oral antagonist of the P2Y12 receptor on platelets 13, 14. It does not require metabolic activation after ingestion and has more reliable antiplatelet activity than clopidogrel. In the study of Platelet Inhibition and Patient Outcomes (PLATO) of patients with acute coronary syndrome, ticagrelor significantly reduced the risk of recurrent ischemic events compared with clopidogrel 15. It has not been evaluated in patients with acute cerebral ischemia.

The Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial (NCT01994720) was designed to test ticagrelor in patients with acute cerebral ischemia. The objective of the SOCRATES study is to compare the effect of 90-day treatment with ticagrelor vs. aspirin for the prevention of major vascular events [composite of stroke (ischemic or hemorrhagic), myocardial infarction (MI), and death] when randomization can occur within 24 h after symptom onset of an acute ischemic stroke or TIA.

Methods Design

SOCRATES is a multicenter, randomized, double-blind, double-dummy, parallel-group superiority trial. Patients are randomized 1 : 1 to ticagrelor or aspirin within 24 h of the onset of symptoms of acute ischemic stroke or TIA and followed for 90 days on study drug with an additional 30-day follow-up on standard of care (Fig. 1). The study is being conducted in concordance with US Food and Drug Administration policies (CFR 21) and Good Clinical Practice guidelines. All outcome and major bleeding events will be adjudicated by an independent Clinical Event Adjudication Committee.

SOCRATES study design. BID, twice daily; QD, Daily; EoT, end of treatment; R, randomization; SCV, study closure visit; TIA, transient ischemic attack. aVisits 3 and 4 are telephone contacts. Visit 6 may be a telephone contact, if necessary. bAfter EoT Visit on Day 90, patients will be treated with standard of care therapy of investigator's choice.

Patient population

For this event-driven trial, an estimated 13 600 subjects will be enrolled from approximately 700 sites in 33 countries worldwide (Fig. 2; Table S1). Patients who can be randomized within 24 h of an acute ischemic stroke or TIA are included (Tables S2 and S3). Those with severe ischemic strokes or other major risk factors for hemorrhage are excluded. Those with low-risk TIA are also excluded. Other areas of exclusion include high risk of intolerance to study drug or inability to complete the trial period or procedures.

Countries participating in SOCRATES (shown in yellow).

Randomization

Randomization codes are computer generated in blocks to ensure approximate balance (1 : 1) between the two treatment arms. For patients who fulfill all eligibility requirements at Visit 1, the investigator accesses the interactive voice/web response system. This system allocates a randomization code and provides the investigator with unique treatment pack identification numbers for that patient for the Visit 1 supply of medication. Following randomization, the first dose of study medication is administered to the patient as soon as possible.

Treatment At Visit 1 (randomization), eligible patients are randomly assigned to one of two treatments: Treatment 1: Ticagrelor 180 mg (two 90-mg tablets) loading dose on Day 1 followed by 90 mg twice daily given orally together with aspirin placebo loading and daily doses. Treatment 2: Aspirin 300 mg (three 100-mg tablets) loading dose on Day 1, followed by 100 mg daily given orally together with ticagrelor placebo loading dose and twice daily dose.

The first dose of study medication is taken at Visit 1. Subsequent maintenance doses are taken morning and evening, at approximately 12-h intervals, for the remainder of the 90-day treatment period. At the end of 90 days of study treatment, patients are treated with standard-of-care therapy at the discretion of the investigator and followed for an additional 30 days.

Primary outcomes

The primary endpoint for the trial is time from randomization to first occurrence of any event from the composite of stroke (ischemic or hemorrhagic), MI, and death. Definitions are provided in the Supporting Information.

Secondary outcomes

The first secondary endpoint is ischemic stroke. Other secondary endpoints include (1) net clinical outcome, defined as the composite of stroke, MI, death, and life-threatening bleeding; (2) the composite of cardiovascular death, MI, and ischemic stroke; (3) all strokes, disabling strokes, and fatal strokes individually; and (4) all cause death, cardiovascular death, and MI individually. We will also assess severity of stroke and overall disability (based on the modified Rankin Scale), rate of worsening (progression) of the index stroke event by deterioration in clinical symptoms or an increase in the score on the National Institutes of Health Stroke Scale (NIHSS), expenditure of healthcare resources (hospitalizations, rehabilitation, and long-term care), and patient health-related quality of life assessed by EuroQoL-5 Dimensions questionnaire.

Safety endpoints will include time to first major bleeding event using the PLATO study definition 15, time to discontinuation of study medication due to any bleeding event, and incidence of serious and selected nonserious adverse events.

Data monitoring body

An independent DMC reports to the Executive Committee. The DMC is responsible for safeguarding the interests of study participants by assessing the safety of the intervention during the study, and for reviewing the overall conduct of the clinical study. The DMC has access to the individual treatment codes and is able to merge these with the collected study data while the study is ongoing. The DMC charter details precise roles, responsibilities, and procedures to ensure maintenance of the blinding and integrity of the study through the review of accumulating data and interactions with the Executive Committee. A single efficacy and futility interim analysis will occur when 50% of planned primary outcome events have been adjudicated.

Sample size

The study is event driven. Based on data from the FASTER trial 10, CHANCE trial 9, and Scandinavian Candesartan Acute Stroke Trial (SCAST) 16, a primary endpoint (stroke, MI, death) rate of 10% was originally assumed at three-months following randomization. With a hazards ratio of 0·8 in favor of ticagrelor, randomizing 9600 patients to aspirin and ticagrelor in a 1 : 1 ratio was expected to yield a planned 844 primary events, which provides 87·6% power at the final two-sided significance level of 4·98%. Based on lower than expected overall (blinded) event rate, and because the study period is fixed at three-months, the study protocol has been amended to allow randomization up to about 13 600 patients in order to generate 844 primary events.

Statistical analyses

All efficacy analyses will be based on the intention-to-treat principle using the full analysis set with events adjudicated by the Clinical Event Adjudication Committee. Analysis of the primary composite efficacy endpoint and the first secondary efficacy endpoint, ischemic stroke, will constitute the confirmatory analysis for ticagrelor vs. aspirin. The first secondary endpoint, time to first ischemic stroke, will be tested for confirmation only if the primary comparison is statistically significant. The time from randomization to the first occurrence of any event for a given endpoint will be compared using the Cox proportional hazards model with a factor for treatment group. The P value, hazard ratio, and 95% confidence interval will be reported. One interim analysis for both efficacy and futility will be performed when 50% of planned primary events (422 events) have been adjudicated. The boundary to consider early stopping for efficacy at the interim analysis is a two-sided P value < 0·001 for the primary endpoint. The futility stopping boundary is an observed hazards ratio greater than 0·954. The final analysis will be conducted at a significance level of 4·98% to account for the interim analysis with the family-wise error rate for the study controlled at 5·00%.

Study organization and funding

The Executive Committee is responsible for the overall design, interpretation, and supervision of the study, including the development of the protocol and any protocol amendments. The Executive Committee is also responsible for major study reporting, including presentations at international congresses and publications in peer-reviewed journals. The Executive Committee will make recommendations to the sponsor with regard to early stopping or modifications of the study based on the information received from the DMC. The Executive Committee membership is comprised of designated international academic leaders and nonvoting members of the sponsor, and operates under a separate charter.

Discussion

Prevention of new ischemia after acute ischemic stroke or TIA is clearly a health priority given the high rates of subsequent events and their resulting disability and mortality 5, 17. A similar scenario exists in the heart, with high risk of major MI and cardiac death in those presenting with cardiac ischemia 18. Although intensive approaches have been tested extensively for acute coronary syndromes, only a small number of definitive secondary prevention trials have been attempted in the acute setting after cerebral ischemia 9, 12, 16, 19, 20. Similarly, although a complex regimen including several antithrombotic agents is now standard of care for acute coronary syndrome ischemia 18, single antiplatelet agents remain the standard of care for TIA and minor stroke, with aspirin used most extensively worldwide 6.

With the positive results of the CHANCE trial comparing clopidogrel plus aspirin with aspirin alone 9, additional enthusiasm for intensive antiplatelet therapy in acute minor ischemic stroke has been generated. However, concerns about generalizability outside of China were raised, as well as concerns about the appropriate duration of treatment with clopidogrel plus aspirin 21. Aspirin alone remains a preferred treatment, but it is unclear whether new agents could improve upon its modest efficacy and known bleeding risks, and trials that only add agents to aspirin will not test for better replacement drugs.

SOCRATES addresses these areas of promise. It tests an antiplatelet agent of substantial potency, with more rapid onset and reliable antiplatelet activity than clopidogrel 13, 14, head-to-head against aspirin, the prevailing standard of care. Using the highest standards of trial design and carefully monitored sites across the world, it will produce reliable data evaluating a promising approach to a relatively neglected condition, acute nonsevere ischemic stroke, and TIA.

Summary and conclusions

The SOCRATES trial will provide important information about whether monotherapy with the P2Y12 inhibitor, ticagrelor, is superior to the current standard of care, aspirin monotherapy, for the prevention of major vascular events after an acute ischemic stroke or TIA.

Author contributions

All authors contributed to the design of the study and contribute to its oversight. Dr. Johnston wrote the first draft of the manuscript, which was edited by all other authors.