Landmark Trials for Resumption of Antiplatelet and Anticoagulant Therapy After Stroke
The landmark trials that guide resumption of antithrombotic therapy after stroke are CHANCE and POINT for antiplatelet therapy in minor ischemic stroke/TIA, THALES for ticagrelor-based dual therapy, and RESTART for antiplatelet resumption after intracerebral hemorrhage. 1, 2, 3
Key Antiplatelet Trials for Ischemic Stroke
CHANCE and POINT Trials: Dual Antiplatelet Therapy
CHANCE and POINT established that aspirin plus clopidogrel started within 24–72 hours of minor stroke (NIHSS ≤3) or high-risk TIA reduces 90-day recurrent stroke from 9.2% to 7.3% (HR 0.79), with a modest increase in moderate-to-severe bleeding (0.9% vs 0.4%). 1, 2
These trials demonstrated maximum benefit when dual antiplatelet therapy (DAPT) is initiated within 12–24 hours, with efficacy persisting up to 72 hours from symptom onset. 2
The optimal DAPT duration is 21–90 days, after which patients must transition to single antiplatelet therapy (SAPT) because extending beyond 90 days provides no additional stroke protection and significantly increases hemorrhage risk. 1, 2, 4
THALES Trial: Ticagrelor-Based Dual Therapy
THALES (2020) compared aspirin plus ticagrelor versus aspirin alone in patients with minor-to-moderate stroke (NIHSS ≤5) within 24 hours, showing a modest reduction in recurrent stroke (5% vs 6.3%; NNT = 92) but increased severe bleeding (0.5% vs 0.1%; NNH = 263) and intracranial hemorrhage (0.4% vs 0.1%). 1, 2
Patients ≥70 years have markedly higher intracranial hemorrhage risk with ticagrelor-based DAPT, making aspirin-clopidogrel the preferred regimen in older adults. 2
The European Stroke Organisation issued a strong recommendation for 21 days of aspirin-clopidogrel (high-quality evidence) but only a weak recommendation for 30 days of aspirin-ticagrelor (moderate-quality evidence). 3
Long-Term Antiplatelet Trials
PRoFESS, ESPRIT, and ESPS-2 established that for long-term secondary prevention after the acute DAPT window, clopidogrel 75 mg daily, aspirin 50–325 mg daily, or aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily are equivalent first-line SAPT options. 1, 4
Meta-analyses demonstrate that switching to a different antiplatelet agent after recurrent stroke on prior therapy reduces relative stroke risk by 30% (HR 0.70), with registry data showing 90-day stroke rates of 6.9% (switch) versus 8.0% (continue aspirin). 2
Landmark Anticoagulation Trials
RESTART Trial: Antiplatelet Resumption After Intracerebral Hemorrhage
RESTART (2021) is the only randomized trial addressing antithrombotic resumption after intracerebral hemorrhage (ICH), enrolling 537 patients who had ICH while on antithrombotic therapy for occlusive vascular disease prevention. 5
After median follow-up of 3.0 years (extended to 7 years), restarting antiplatelet therapy showed no statistically significant increase in recurrent ICH (8.2% vs 9.3%; adjusted HR 0.87,95% CI 0.49–1.55) and a trend toward fewer major vascular events (26.8% vs 32.5%; HR 0.79,95% CI 0.58–1.08). 5
RESTART provides reassurance that antiplatelet therapy can be resumed after ICH when indicated for secondary prevention of major vascular events, though the decision must be individualized based on ICH location, burden of cerebral microbleeds, and competing vascular risk. 5
Ongoing Anticoagulation Timing Trials
Four major trials are currently in progress (OPTIMAS, ELAN, TIMING, and START) comparing different anticoagulation resumption protocols after stroke in patients with atrial fibrillation on direct oral anticoagulants (DOACs), addressing the critical gap in evidence for optimal timing. 6
Current practice for anticoagulation resumption after cardioembolic stroke balances the 0.03% daily baseline stroke recurrence risk (12.2% annual with CHADS₂ = 9) against the elevated hemorrhagic transformation risk in the first 2 weeks post-stroke due to reperfusion injury, impaired autoregulation, and blood-brain barrier disruption. 6
Reasonable timing strategies based on hemorrhagic transformation risk include: immediate initiation for TIA, 2–14 days for low hemorrhagic-transformation-risk strokes, and delaying beyond 14 days for high-risk strokes (large infarcts, hemorrhagic transformation on imaging, or post-thrombolysis). 2, 6
DOAC Failure Management
A 2025 meta-analysis of 14,307 patients who had ischemic stroke while on DOACs found that switching to warfarin was associated with higher recurrent ischemic stroke (RR 1.80,95% CI 1.42–2.29) and intracranial hemorrhage (RR 2.90,95% CI 2.01–4.18) compared to continuing the same DOAC or switching to another DOAC. 7
After breakthrough stroke on a DOAC, the evidence supports either continuing the same DOAC or switching to a different DOAC rather than switching to warfarin, as DOAC-based strategies have similar efficacy and safety profiles to each other but superior outcomes compared to warfarin. 7
Critical Implementation Principles
The 2026 AHA/ASA guideline for early acute ischemic stroke management incorporates updated evidence on thrombolytic eligibility and endovascular thrombectomy determination, which directly impacts the timing and safety of antithrombotic resumption. 8
Patients with prior myocardial infarction still require limiting DAPT to 21–90 days after stroke, then switching to SAPT, unless a separate cardiac indication (e.g., recent drug-eluting stent within 6–12 months) justifies extended DAPT. 2
Vigilant monitoring for bleeding complications during DAPT is mandatory, especially in patients ≥70 years, with structured transition from DAPT to SAPT within the 21–90 day window to avoid excess hemorrhage. 2, 9