PDF: SOCRATES
(2016)Objective
To determine if ticagrelor is superior to aspirin for preventing vascular events after acute ischemic stroke or high-risk TIA.
Study Summary
• Ticagrelor was not significantly superior to aspirin for the prevention of stroke, MI, or death at 90 days in patients with minor ischemic stroke or high-risk TIA; • There was no significant difference in major bleeding between ticagrelor and aspirin.
Intervention
Ticagrelor 180 mg loading dose, then 90 mg twice daily vs. Aspirin 300 mg loading dose, then 100 mg daily.
Inclusion Criteria
Adults ≥40 years with non-cardioembolic minor stroke (NIHSS ≤5) or high-risk TIA (ABCD2 ≥4), randomized within 24 hours of symptom onset.
Study Design
Arms: Ticagrelor vs. Aspirin
Patients per Arm: Ticagrelor: 6589, Aspirin: 6610
Outcome
• Primary outcome (stroke/MI/death at 90 days): 6.7% ticagrelor vs. 7.5% aspirin (HR 0.89; 95% CI, 0.78–1.01; P=0.07). <br>• Ischemic stroke: 5.8% vs. 6.7% (HR 0.87; 95% CI, 0.76–1.00). <br>• No significant difference in major bleeding..
Bottom Line
In patients with acute ischemic stroke or TIA, treatment with ticagrelor for 90 days was not found to be superior to aspirin in reducing the rate of the primary composite endpoint of stroke, myocardial infarction, or death. Major bleeding rates were low and similar between the two groups.
Major Points
- Tested whether ticagrelor monotherapy was superior to aspirin for acute minor stroke/TIA — the largest head-to-head comparison of a P2Y12 inhibitor vs aspirin in acute cerebrovascular disease.
- 13,199 patients across 674 centers in 33 countries. Double-blind, double-dummy design — gold standard for antiplatelet comparison. Monotherapy design (not DAPT) — testing whether ticagrelor could REPLACE aspirin, not supplement it.
- Primary result was NEGATIVE: composite of stroke, MI, or death at 90 days was 6.7% ticagrelor vs 7.5% aspirin (HR 0.89, 95% CI 0.78–1.01, p=0.07). Narrowly missed significance by p=0.03.
- Ischemic stroke showed a nominally significant reduction: 5.8% vs 6.7% (HR 0.87, 95% CI 0.76–1.00, p=0.046). All stroke: HR 0.86, p=0.03. These p-values were not adjusted for multiple comparisons.
- Major bleeding was LOW and similar in both groups: 0.5% vs 0.6% (HR 0.83, p=0.45) — ticagrelor monotherapy was not associated with excess bleeding, unlike DAPT regimens.
- Dyspnea was significantly more common with ticagrelor (6.2% vs 1.4%) — a known class effect of ticagrelor (reversible P2Y12 inhibitor that also affects adenosine reuptake), and a major driver of drug discontinuation.
- Critical design insight: SOCRATES tested ticagrelor vs aspirin as MONOTHERAPY. The subsequent THALES trial tested ticagrelor + aspirin (DAPT) vs aspirin alone — and was positive. This suggests ticagrelor's benefit in stroke requires combination with aspirin.
- 73% of qualifying events were ischemic stroke (NIHSS ≤5), 27% were high-risk TIA. Both subgroups showed similar trends.
- Post hoc analysis (SOCRATES ABCD) showed that patients with ipsilateral large-artery atherosclerosis may have benefited more from ticagrelor — driving the hypothesis that ticagrelor may be superior for specific stroke mechanisms.
- Paved the way for THALES (2020), which successfully demonstrated ticagrelor + aspirin DAPT benefit for acute stroke/TIA — completing the ticagrelor story arc from SOCRATES (negative monotherapy) to THALES (positive DAPT).
Study Design
- Study Type
- International, multicenter, randomized, double-blind, double-dummy, parallel-group trial.
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy.
- Sample Size
- 13199
- Follow-up
- 90 days.
- Centers
- 674
- Countries
- 33 countries
Primary Outcome
Definition: A composite of stroke (ischemic or hemorrhagic), myocardial infarction, or death within 90 days.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 7.5% (497 patients) | 6.7% (442 patients) | 0.89 (0.78 to 1.01) | 0.07 |
Limitations & Criticisms
- The primary result was NEGATIVE (p=0.07) — any post hoc subgroup findings (like SOCRATES ABCD) must be interpreted as hypothesis-generating only.
- Monotherapy design (ticagrelor alone vs aspirin alone) — does not test the clinically relevant question of DAPT vs aspirin, which was later tested in THALES.
- Low enrollment of patients with large-artery atherosclerosis — the mechanism most likely to benefit from potent antiplatelet therapy was underrepresented.
- TIA event rates were lower than expected — some enrolled TIA patients may have had non-ischemic mimics, diluting the treatment effect.
- Excluded patients who received thrombolysis or thrombectomy — limits generalizability to the moderate-severe stroke population.
- Dyspnea rate of 6.2% (vs 1.4% aspirin) — a significant tolerability issue that drove higher discontinuation in the ticagrelor group.
- Industry-sponsored (AstraZeneca) — manufacturer of ticagrelor.
- 24-hour enrollment window was wider than POINT (12h) or CHANCE (24h), and the time-dependent benefit seen in POINT/CHANCE may have been diluted by later enrollment.
- No CYP2C19 genotyping — cannot assess whether ticagrelor's advantage (no hepatic activation needed) was greatest in clopidogrel poor metabolizers.
Citation
N Engl J Med 2016;375:35-43.