SOCRATES Trial: Ticagrelor vs Aspirin
In patients with acute non-cardioembolic minor ischemic stroke or high-risk TIA, does ticagrelor monotherapy reduce the composite of stroke, MI, or death at 90 days compared with aspirin monotherapy?
Johnston et al. (NEJM 2016) · 13,199 patients
Population
Included
- Age 40 years or older
- Acute non-cardioembolic ischemic stroke with NIHSS score 5 or less, or high-risk TIA (ABCD2 score 4 or higher)
- Able to randomize within 24 hours of symptom onset
- No definite indication for anticoagulation
Core qualifying event
- At least 40 years of age
- An acute ischemic stroke with an NIHSS score of 5 or lower (range 0 to 42)
- Or a high-risk TIA (ABCD2 score of 4 or higher, or symptomatic intracranial or extracranial arterial stenosis)
Timing / imaging
- Randomization within 24 hours after symptom onset
- CT or MRI before randomization to rule out intracranial bleeding or other explanatory conditions
- Not considered to have had a cardioembolic stroke
- Had not received IV or intraarterial thrombolysis
Excluded
- Cardioembolic source requiring anticoagulation
- Prior stroke with modified Rankin Score greater than 2
- Planned carotid revascularization within 90 days
- Concomitant antiplatelet therapy other than the study drug
- High bleeding risk or active bleeding
Planned reperfusion / antithrombotic
- Other specific antiplatelet or anticoagulation therapy planned
- Carotid, cerebrovascular, or coronary revascularization planned that would require halting study treatment within 7 days
- IV or intraarterial thrombolysis or thrombectomy within 24 hours before randomization
- Need for strong CYP3A inhibitors or CYP3A substrates with narrow therapeutic indexes
- Need for NSAIDs for more than 7 consecutive days
Cardioembolic / contraindication
- Hypersensitivity to ticagrelor or aspirin
- A history of atrial fibrillation, ventricular aneurysm, or suspicion of a cardioembolic cause
Bleeding / comorbidity
- A known bleeding diathesis or coagulation disorder
- A history of symptomatic nontraumatic intracerebral hemorrhage at any time
- Gastrointestinal bleed within the past 6 months
- Major surgery within 30 days
- Severe liver disease
- Renal failure requiring dialysis
- Pregnant or lactating
- Unable to understand or comply with study procedures or follow-up
Source: Johnston et al., N Engl J Med 2016· Retrieved 2026-06-09
Primary Outcome
Negligible absolute difference
Event-free at 90 Days
Study Arms
- Agent
- Ticagrelor (monotherapy) plus aspirin placebo
- Dose
- Ticagrelor 180 mg loading (two 90-mg tablets) on day 1, then 90 mg twice daily on days 2 to 90, with loading and daily aspirin placebo
- Route
- Oral
- Frequency
- Twice daily (about 12-hour intervals)
- Duration
- 90-day treatment period
- Co-interventions
- Double-dummy (matching aspirin placebo); after 90 days, treatment at investigator discretion, followed an additional 30 days
Monotherapy comparison: ticagrelor alone vs aspirin alone
- Agent
- Aspirin (monotherapy) plus ticagrelor placebo
- Dose
- Aspirin 300 mg loading (three 100-mg tablets) on day 1, then 100 mg daily on days 2 to 90, with loading and twice-daily ticagrelor placebo
- Route
- Oral
- Frequency
- Once daily (with twice-daily ticagrelor placebo)
- Duration
- 90-day treatment period
- Co-interventions
- Double-dummy (matching ticagrelor placebo); after 90 days, treatment at investigator discretion, followed an additional 30 days
Aspirin monotherapy control
Safety
Major bleeding at 90 days
0.5%
0.6%
No significant difference in major bleeding between ticagrelor and aspirin (P=NS). /* claimId: socrates-safety-bleed | source: Johnston NEJM 2016 Table 2 */
Trial Design
Type
- Randomized double-blind trial
- 1:1 allocation (Ticagrelor vs. Aspirin)
Timeline
Enrolled 2014-2015
N
13,199
Enrollment
13,199 patients at 674 centers in 33 countries. Enrolled 2014 to 2015. Published NEJM 2016.
ClinicalTrials.gov
NCT01994720Bedside Pearl
SOCRATES showed ticagrelor monotherapy did not beat aspirin alone (P=0.07). The relevant question at the bedside is now DAPT composition: CHANCE/POINT established clopidogrel plus aspirin reduces early recurrence by roughly 30%; THALES showed ticagrelor plus aspirin works similarly but bleeds more. In patients with known or suspected CYP2C19 loss-of-function, ticagrelor-based DAPT may be considered, though direct head-to-head DAPT comparison data are limited.