PDF: THALES
(2020)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)
Study Design
Arms: Array
Outcome
• Stroke or death at 30 days: 5.5% (ticagrelor) vs. 6.6% (placebo); HR 0.83 (95% CI 0.71–0.96); p=0.02
• Ischemic stroke: 5.0% vs. 6.3%; HR 0.79 (95% CI 0.68–0.93)
• Severe bleeding (BARC type 3–5): 0.5% vs. 0.1%; HR 3.99 (95% CI 1.74–9.14)
• Intracranial hemorrhage: 0.4% vs. 0.1%; HR 3.33 (95% CI 1.34–8.28)
• Ischemic stroke: 5.0% vs. 6.3%; HR 0.79 (95% CI 0.68–0.93)
• Severe bleeding (BARC type 3–5): 0.5% vs. 0.1%; HR 3.99 (95% CI 1.74–9.14)
• Intracranial hemorrhage: 0.4% vs. 0.1%; HR 3.33 (95% CI 1.34–8.28)
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, 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% (p=0.61) — despite preventing strokes, overall disability was not reduced, suggesting many prevented strokes were mild.
- Severe bleeding was significantly increased: 0.5% vs 0.1% (HR 3.99, p=0.001). NNH = 263. Intracranial hemorrhage: 0.4% vs 0.1% (HR 3.33, 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.
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 11016
- Follow-up
- 30 days (treatment period) + 30 days (additional follow-up)
- Centers
- 414
- Countries
- 28 countries (e.g., Asia, Australia, Europe, North America, Central/South America)
Primary Outcome
Definition: Composite of stroke (ischemic, hemorrhagic, or undetermined) or death within 30 days in a time-to-first-event analysis.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 362 (6.6%) patients, event rate 6.5% | 303 (5.5%) patients, event rate 5.4% | 0.83 (0.71 to 0.96) | 0.02 |
Limitations & 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.
Citation
N Engl J Med 2020;383:207-17.