THALES
The Acute Stroke or Transient Ischaemic Attack Treated with Ticagrelor and ASA [acetylsalicylic acid] for Prevention of Stroke and Death (THALES) trial
Clinical Question
In patients with mild-to-moderate acute noncardioembolic ischemic stroke or TIA, is 30-day treatment with ticagrelor and aspirin superior to aspirin alone in reducing the risk of subsequent stroke or death?
Study Overview
Objective
Ticagrelor plus aspirin versus aspirin alone in reducing stroke in patients with a minor acute ischemic stroke or high-risk TIA.
Study Summary
In patients with minor acute ischemic stroke or high-risk TIA treated within 24 hours of symptom onset, ticagrelor plus aspirin significantly reduced the risk of stroke or death at 30 days compared to aspirin alone, but with a higher risk of severe bleeding. This supports short-term dual antiplatelet therapy for selected patients.
Intervention
Multicenter, double-blind, placebo-controlled RCT. N=11,016 patients randomized within 24 hours of non-cardioembolic minor ischemic stroke (NIHSS ≤5) or high-risk TIA (ABCD² ≥6 or ≥50% stenosis in relevant artery) to: - Ticagrelor 180 mg loading dose, then 90 mg BID for 30 days + aspirin 300–325 mg loading then 75–100 mg daily - Matching placebo + aspirin (same regimen)
Bottom Line
Among patients with a mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5) or TIA not undergoing thrombolysis or thrombectomy, the risk of composite stroke or death within 30 days was lower with ticagrelor-aspirin than with aspirin alone. However, the incidence of disability did not differ significantly, and severe bleeding was more frequent with ticagrelor-aspirin.
Major Points
- Established ticagrelor + aspirin as an alternative DAPT option for acute minor stroke/TIA — the positive counterpart to the negative SOCRATES monotherapy trial. Proved that ticagrelor works for stroke prevention when combined with aspirin.
- 11,016 patients across 414 centers in 28 countries. Largest ticagrelor stroke trial. 90% had qualifying ischemic stroke (NIHSS ≤5), only 10% had TIA — more stroke-heavy than POINT (57% stroke).
- Primary outcome: stroke or death within 30 days: 5.5% ticagrelor-aspirin vs 6.6% aspirin alone (HR 0.83, 95% CI 0.71–0.96, p=0.02). NNT = 92 to prevent one event.
- Ischemic stroke specifically: 5.0% vs 6.3% (HR 0.79, 95% CI 0.68–0.93, p=0.004) — a 21% relative risk reduction, comparable to CHANCE and POINT.
- NO disability benefit: mRS >1 at 30 days was 23.8% vs 24.1% (OR 0.98, 95% CI 0.89–1.07, p=0.61) — despite preventing strokes, overall disability was not reduced, suggesting many prevented strokes were mild.
- Severe bleeding (GUSTO criteria) was significantly increased: 0.5% vs 0.1% (HR 3.99, 95% CI 1.74–9.14, p=0.001). NNH = 263. Intracranial hemorrhage: 0.4% vs 0.1% (HR 3.33, 95% CI 1.34–8.28, p=0.01). Fatal bleeding: 0.2% vs <0.1% — more concerning than clopidogrel-based DAPT.
- Key differences from POINT/CHANCE: (1) ticagrelor instead of clopidogrel, (2) 30-day DAPT (shorter than POINT's 90 days), (3) higher ABCD2 threshold for TIA (≥6 vs ≥4), (4) enrolled patients with NIHSS up to 5 (vs ≤3 in POINT).
- 43% Asian population — similar to CHANCE's Chinese population but more diverse geographically. Only 0.2% from North America — very limited US representation.
- The benefit-risk balance was less favorable than clopidogrel-based DAPT: ticagrelor-aspirin had higher bleeding (NNH 263) compared to POINT's clopidogrel-aspirin (NNH 200 over 90 days), with a higher NNT (92 vs 67).
- Established ticagrelor-aspirin as a 2020 AHA/ASA option for patients who cannot take clopidogrel (e.g., CYP2C19 poor metabolizers), though clopidogrel-based DAPT remains preferred in most guidelines due to better risk-benefit ratio.
Design
Study Type: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
Randomization: 1
Blinding: Double-blind
Enrollment Period: January 22, 2018, and October 7, 2019
Follow-up Duration: 30 days (treatment period) + 30 days (additional follow-up)
Centers: 414
Countries: 28 countries (e.g., Asia, Australia, Europe, North America, Central/South America)
Sample Size: 11016
Analysis: Intention-to-treat; time-to-first-event analysis using Cox proportional-hazards model for primary outcome and ischemic stroke; logistic regression for disability; adjusted P-value 0.04996 for primary outcome due to interim analysis. Safety outcomes exploratory if not in hierarchical testing.
Inclusion Criteria
- At least 40 years of age
- Mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score of 5 or less)
- High-risk TIA (ABCD² score of 6 or higher or symptomatic intracranial or extracranial arterial stenosis ≥50% narrowing)
- Randomization within 24 hours after symptom onset or last known normal
- Computed tomography or magnetic resonance imaging (MRI) of the brain before randomization to rule out intracranial bleeding or contraindications.
Exclusion Criteria
- Intravenous or intraarterial thrombolysis or mechanical thrombectomy planned within 24 hours before randomization
- Planned use of anticoagulation or specific antiplatelet therapy other than aspirin
- Hypersensitivity to ticagrelor or aspirin
- History of atrial fibrillation or ventricular aneurysm or suspicion of a cardioembolic cause of TIA or stroke
- Planned carotid endarterectomy requiring discontinuation of trial medication within 3 days after randomization
- Known bleeding diathesis or coagulation disorder
- History of intracerebral hemorrhage
- Gastrointestinal bleeding within the past 6 months
- Major surgery within 30 days before randomization
Arms
| Field | Ticagrelor + Aspirin (DAPT) | Control |
|---|---|---|
| Intervention | Ticagrelor 180 mg loading dose (day 1) then 90 mg BID for 30 days, PLUS aspirin 300–325 mg loading (day 1) then 75–100 mg daily for 30 days. Reversible P2Y12 inhibitor + COX-1 inhibitor = dual pathway platelet inhibition. No hepatic activation required (unlike clopidogrel) — consistent antiplatelet effect regardless of CYP2C19 genotype. Ticagrelor matched placebo in the aspirin-alone arm ensured double-blinding. | Aspirin 300–325 mg loading dose (day 1) then 75–100 mg daily for 30 days, PLUS ticagrelor-matched placebo BID. Standard single antiplatelet therapy for acute minor stroke/TIA. |
| Duration | 30 days treatment + 30 days additional follow-up | 30 days treatment + 30 days additional follow-up |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of stroke (ischemic, hemorrhagic, or undetermined) or death within 30 days in a time-to-first-event analysis. | Primary | 362 (6.6%) patients, event rate 6.5% | 303 (5.5%) patients, event rate 5.4% | 0.83 | 0.02 |
| First subsequent ischemic stroke | Secondary | 345 (6.3%) patients, event rate 6.2% | 276 (5.0%) patients, event rate 5.0% | 0.79 | 0.004 |
| Overall disability (modified Rankin scale score >1) at end of treatment visit (30-34 days) | Secondary | 1284 (24.1%) | 1282 (23.8%) | 0.98 | 0.61 |
| Disabling stroke (modified Rankin scale score >2) | Secondary | 3.5% | 2.7% | ||
| Severe bleeding (primary safety outcome; GUSTO criteria) | Adverse | 7 (0.1%) patients, event rate 0.1% | 28 (0.5%) patients, event rate 0.5% | 3.99 | 0.001 |
| Intracranial hemorrhage or fatal bleeding (composite) | Adverse | 6 (0.1%) patients, event rate 0.1% | 22 (0.4%) patients, event rate 0.4% | 3.66 | 0.005 |
| Fatal bleeding | Adverse | 2 (<0.1%) patients | 11 (0.2%) patients | ||
| Intracranial hemorrhage | Adverse | 6 (0.1%) patients, event rate 0.1% | 20 (0.4%) patients, event rate 0.4% | 3.33 | 0.01 |
| Hemorrhagic stroke | Adverse | 2 (<0.1%) patients | 10 (0.2%) patients | ||
| Moderate or severe bleeding | Adverse | 11 (0.2%) patients, event rate 0.2% | 36 (0.7%) patients, event rate 0.6% | 3.27 | <0.001 |
| Premature permanent discontinuation of trial treatment owing to bleeding | Adverse | 32 (0.6%) patients, event rate 0.6% | 152 (2.8%) patients, event rate 2.9% | 4.8 | <0.001 |
Criticisms
- Excluded NIHSS >5 — cannot generalize to moderate-severe stroke, which is the majority of ischemic strokes presenting to acute stroke centers.
- NO disability benefit despite stroke reduction — mRS >1 was identical between groups, questioning the clinical meaningfulness of the prevented events.
- Severe bleeding was significantly increased (HR 3.99, NNH 263), including fatal bleeding and ICH — a worse safety profile than clopidogrel-based DAPT in CHANCE (no excess bleeding) or POINT (NNH 200).
- Very limited US enrollment (0.2%) — the trial was essentially conducted in Europe and Asia, limiting generalizability to US practice patterns.
- Excluded thrombolysis/thrombectomy patients — these patients have the highest recurrence risk and may benefit most from intensified antiplatelet therapy.
- Higher ABCD2 threshold for TIA (≥6 vs ≥4 in POINT) — more restrictive TIA inclusion makes cross-trial comparison difficult.
- Industry-sponsored (AstraZeneca) — manufacturer of ticagrelor.
- 30-day treatment period was shorter than POINT (90 days) or CHANCE (21 days DAPT + clopidogrel monotherapy) — different treatment durations limit head-to-head inference.
- Ticagrelor's twice-daily dosing and dyspnea side effect may reduce real-world adherence compared to once-daily clopidogrel.
- No direct comparison with clopidogrel-based DAPT — the clinical question of 'ticagrelor+ASA vs clopidogrel+ASA for acute stroke' remains unanswered by a head-to-head trial.
Subgroup Analysis
Consistent direction of benefit across prespecified primary-outcome subgroups (Figure 3): age (<65, 65–75, >75 yr), sex, race (White, Asian), weight, BMI, geographic region (Asia/Australia 43% vs Europe 51%), diagnosis of index event (stroke NIHSS ≤3, stroke NIHSS >3, TIA), time from index event to randomization (<12 h vs ≥12 h), diabetes, hypertension, previous ischemic stroke or TIA, previous ischemic heart disease, previous aspirin therapy, previous statin therapy, and smoking status. Directional signals of larger benefit in patients with previous ischemic stroke or TIA (HR 0.65, 95% CI 0.46–0.90) versus none (HR 0.89, 95% CI 0.75–1.05); subgroup CIs were not adjusted for multiple comparisons and no formal interaction tests were reported for the primary outcome.
Funding
AstraZeneca
Based on: THALES (The New England Journal of Medicine, 2020)
Authors: S. Claiborne Johnston, M.D., Ph.D., ..., and Yongjun Wang
Citation: N Engl J Med 2020;383:207-17.
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