When should dual antiplatelet therapy be started in patients with a non‑cardioembolic ischemic stroke or transient ischemic attack, specifically regarding minor stroke (NIH Stroke Scale ≤3) or high‑risk TIA (ABCD2 score ≥4)?

When to Start Dual Antiplatelet Therapy in Stroke Patients

Dual antiplatelet therapy (aspirin plus clopidogrel) should be started within 24 hours—ideally within 12 hours—of symptom onset in patients with minor noncardioembolic ischemic stroke (NIHSS ≤3) or high-risk TIA (ABCD2 score ≥4), and continued for exactly 21 days before transitioning to single antiplatelet therapy. 1, 2, 3

Patient Selection Criteria

Before initiating dual antiplatelet therapy, confirm all of the following:

• Minor stroke severity: NIHSS score 0–3 (or ≤5 in some protocols) 1, 2, 3
• High-risk TIA: ABCD2 score ≥4 1, 2, 3
• Noncardioembolic mechanism: No atrial fibrillation or other cardioembolic source identified 1, 2, 3
• Presentation window: Within 24 hours of symptom onset (benefit extends to 72 hours but diminishes progressively) 1, 2, 4
• Imaging exclusion: CT or MRI has ruled out intracranial hemorrhage 1, 2, 3
• No recent thrombolysis: If alteplase was given, wait 24 hours and obtain post-thrombolysis imaging before starting antiplatelet therapy 1, 2

Loading Dose Protocol

Administer immediately after confirming eligibility:

• Clopidogrel: 300 mg loading dose (acceptable range 300–600 mg; the 300 mg dose from CHANCE trial may have modestly lower bleeding risk) 1, 2, 3
• Aspirin: 160–325 mg loading dose 1, 2, 3

The loading dose ensures rapid platelet inhibition, as standard 75 mg clopidogrel dosing takes approximately 5 days to achieve maximal effect. 2

Maintenance Phase (Days 2–21)

Continue dual therapy for exactly 21 days:

• Clopidogrel: 75 mg once daily 1, 2, 3
• Aspirin: 75–100 mg once daily 1, 2, 3

The Canadian Stroke Best Practice Guidelines specifically limit dual therapy to 21–30 days because the POINT trial demonstrated that treating 1,000 patients for 90 days prevents 15 ischemic strokes but causes 5 major hemorrhages. 1

Critical Timing Considerations

The therapeutic window is time-dependent:

• 0–24 hours: Maximum benefit (hazard ratio 0.74 for recurrent events; approximately 25–32% relative risk reduction) 5, 4
• 24–42 hours: Declining benefit (hazard ratio approaches 1.0 around 42 hours) 4
• 42–72 hours: Minimal to no benefit (hazard ratio 1.00) 4
• Beyond 72 hours: Potential harm (hazard ratio 1.25); use single antiplatelet therapy instead 4

A pooled analysis of CHANCE and POINT trials showed that the benefit of dual antiplatelet therapy is confined to the first 21 days, with most stroke prevention occurring in the first week. 5

Transition to Long-Term Therapy

After exactly 21 days, switch to single antiplatelet therapy indefinitely:

• First-line: Aspirin 75–100 mg daily 1, 2, 3
• Alternative: Clopidogrel 75 mg daily (for aspirin intolerance) 1, 2, 3
• Alternative: Aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily 2

Do not extend dual therapy beyond 21–30 days unless a separate cardiac indication exists (e.g., recent drug-eluting stent), as the risk of major hemorrhage increases significantly (hazard ratio 2.22–2.32) without additional stroke prevention benefit. 1, 6, 3

Absolute Contraindications

Do not use dual antiplatelet therapy if:

• NIHSS >3 (moderate-to-severe stroke)—use single antiplatelet therapy 2, 3
• Intracranial hemorrhage not ruled out on imaging 1, 2, 3
• Recent IV alteplase within 24 hours 1, 2, 3
• Active systemic bleeding or severe thrombocytopenia 2
• Presentation >72 hours after symptom onset 2, 4
• Cardioembolic mechanism requiring anticoagulation 2, 3

Special Populations & Practical Considerations

For patients with dysphagia or impaired swallowing:

• Administer clopidogrel 75 mg plus aspirin 81 mg via enteral feeding tube, or
• Use aspirin 325 mg rectal suppository daily as an alternative 1, 2

For patients with high gastrointestinal bleeding risk:

• Consider proton pump inhibitor prophylaxis during the 21-day dual therapy period 1, 2, 3
• In POINT (90-day study), extracranial bleeding was 0.9% with dual therapy versus 0.4% with monotherapy 1

For patients with planned urgent carotid intervention:

• Consult with the surgeon/interventionalist regarding antiplatelet selection, as aspirin monotherapy may be preferred to reduce perioperative bleeding risk 1

Common Pitfalls to Avoid

• Never use dual antiplatelet therapy as a substitute for thrombolysis or mechanical thrombectomy in eligible patients—this delays definitive treatment and worsens outcomes 2, 3
• Never continue dual therapy beyond 30 days in routine stroke prevention, as bleeding risk outweighs benefit 1, 6, 3
• Never use enteric-coated aspirin for the loading dose, as it has slower onset of action 2
• Never delay initiation beyond 24 hours when patients meet criteria, as efficacy is time-dependent with maximum benefit in the first 12–24 hours 1, 2, 4

Evidence Quality

The recommendation for 21-day dual antiplatelet therapy is supported by high-quality evidence (Class I, Level A) from two large randomized controlled trials—CHANCE (5,170 patients) and POINT (4,881 patients)—with a pooled analysis of 10,051 patients demonstrating consistent benefit. 1, 5, 7 The European Stroke Organisation issued a strong recommendation based on this high-quality evidence in 2021. 7

Real-world data from the READAPT study (1,920 patients) confirmed that dual antiplatelet therapy remains effective and safe even when applied more broadly than strict RCT criteria, with primary effectiveness outcomes occurring in 3.9% and major bleeding in only 0.6% of cases. 8