Which randomized trials have guided the choice between single‑antiplatelet therapy and dual‑antiplatelet therapy after acute ischemic stroke or high‑risk transient ischemic attack?

Key Randomized Trials Guiding SAPT vs DAPT in Stroke

The choice between single and dual antiplatelet therapy after acute ischemic stroke is determined by timing and stroke severity, with CHANCE (2013) and POINT (2018) establishing that short-duration DAPT (21-30 days) reduces recurrent stroke in minor stroke/high-risk TIA when started within 24 hours, while SPS-3 (2012) and MATCH (2004) demonstrated that long-duration DAPT increases bleeding without reducing stroke recurrence. 1

Short-Duration DAPT Trials (≤90 days)

CHANCE Trial (2013)

• Enrolled patients within 24 hours of minor stroke (NIHSS ≤3) or high-risk TIA 1
• Compared aspirin plus clopidogrel for 21 days versus aspirin alone 1
• Reduced recurrent ischemic stroke by 31% (RR 0.69,95% CI 0.58-0.82) 1
• Major bleeding risk was not significantly increased (RR 1.00,95% CI 0.25-4.00) 1
• This trial established the foundation for early DAPT in Asian populations 2

POINT Trial (2018)

• Enrolled patients within 12 hours of minor stroke (NIHSS ≤3) or high-risk TIA 1
• Compared aspirin plus clopidogrel for 90 days versus aspirin alone 1
• Reduced recurrent ischemic stroke by 27% (RR 0.73,95% CI 0.57-0.92) 1
• Increased major bleeding risk (RR 2.32,95% CI 1.10-4.86), with absolute rates of 0.9% vs 0.4% 1, 3
• Confirmed DAPT benefit in Western populations but highlighted bleeding concerns 2

THALES Trial (2020)

• Tested aspirin plus ticagrelor versus aspirin alone 2, 4
• Demonstrated stroke reduction but with higher bleeding risk than clopidogrel-based regimens 5
• Contributed to understanding that not all P2Y12 inhibitors have equivalent safety profiles 2, 6

Meta-Analysis of Short-Duration Trials

• Pooled analysis showed 32% reduction in recurrent ischemic stroke (RR 0.68,95% CI 0.55-0.83) 1, 3
• Major bleeding increased by 88% but confidence interval was wide (RR 1.88,95% CI 0.93-3.83), reflecting modest absolute risk 1
• Number needed to treat: 92 patients to prevent one stroke recurrence 7
• Number needed to harm: 263 patients for one major bleeding event 7

Long-Duration DAPT Trials (>90 days)

SPS-3 Trial (2012)

• Enrolled patients with lacunar stroke within 6 months (median 62 days after event) 1
• Compared aspirin plus clopidogrel versus aspirin alone for mean 3.4 years 1
• No reduction in recurrent ischemic stroke (RR 0.80,95% CI 0.62-1.03) 1
• Increased major bleeding by 86% (RR 1.86,95% CI 1.35-2.55) 1
• Increased intracranial hemorrhage by 60% (RR 1.60,95% CI 0.80-3.18) 1

MATCH Trial (2004)

• Enrolled patients within 3 months of stroke or TIA (mean 26.5 days) with additional vascular risk factors 1
• Compared aspirin plus clopidogrel versus clopidogrel alone for 18 months 1
• No reduction in recurrent ischemic stroke (RR 0.93,95% CI 0.80-1.08) 1
• Increased major bleeding by 234% (RR 3.34,95% CI 2.08-5.36) 1
• Increased intracranial hemorrhage by 89% (RR 1.89,95% CI 1.05-3.40) 1

Meta-Analysis of Long-Duration Trials

• No benefit for recurrent ischemic stroke (pooled RR 0.89,95% CI 0.79-1.02) 1
• Major bleeding increased by 142% (pooled RR 2.42,95% CI 1.37-4.30) 1, 3
• Intracranial hemorrhage increased by 76% (pooled RR 1.76,95% CI 1.13-2.76) 1
• High heterogeneity for bleeding outcomes (I²=75.5%) 1

Critical Distinctions Between Trial Designs

The divergent results are explained by timing of initiation and treatment duration 1:

• Short-duration trials initiated treatment within 12-24 hours when absolute stroke recurrence risk is highest 1, 3
• Long-duration trials initiated treatment at median 26-62 days when acute risk period had passed 1
• Bleeding risk accumulates over time, making prolonged DAPT increasingly hazardous 1
• The therapeutic window for DAPT benefit appears limited to the first 21-30 days 3, 6

Additional Supporting Trials

FASTER Trial

• Small trial (n=392) testing ultra-early DAPT within 24 hours 4
• Showed numerical benefit but was underpowered for definitive conclusions 4

CLAIR Trial

• Tested DAPT in symptomatic intracranial atherosclerotic disease 1
• Showed 54.4% reduction in microembolic signals on transcranial Doppler 1
• Supported DAPT use in large artery atherosclerosis subgroup 2

Common Pitfalls in Interpreting These Trials

• Do not extrapolate long-duration trial results to the acute setting – the risk-benefit ratio fundamentally differs 1
• Do not assume all P2Y12 inhibitors are equivalent – ticagrelor shows higher bleeding risk than clopidogrel 5
• Do not use DAPT beyond 30 days – this increases bleeding without additional stroke prevention 3, 7
• Do not delay DAPT initiation beyond 24 hours – efficacy diminishes with delayed treatment 3, 6
• Do not use DAPT in patients with moderate-to-severe stroke (NIHSS ≥4) – these patients were excluded from positive trials and show no benefit 8