When to use single versus dual antiplatelet therapy (aspirin (acetylsalicylic acid) and/or clopidogrel) in patients with ischemic stroke?

Antiplatelet Therapy in Ischemic Stroke: Single vs. Dual Therapy

Use dual antiplatelet therapy (aspirin + clopidogrel) for 21 days in patients with minor ischemic stroke (NIHSS ≤3) or high-risk TIA (ABCD2 ≥4) presenting within 24 hours, then switch to single antiplatelet therapy; use single antiplatelet therapy from the start for moderate-to-severe strokes (NIHSS >3), low-risk TIA, or patients presenting beyond 24 hours. 1, 2

Dual Antiplatelet Therapy (DAPT) Indications

When to use DAPT:

• Minor ischemic stroke with NIHSS score ≤3 presenting within 24 hours of symptom onset 1, 2
• High-risk TIA defined as ABCD2 score ≥4 presenting within 24 hours 1, 2
• Must have noncardioembolic mechanism confirmed 1

DAPT dosing regimen:

• Loading dose: Aspirin 160-325 mg + clopidogrel 300-600 mg administered within 12-24 hours of symptom onset 1, 2
• Maintenance: Aspirin 81 mg daily + clopidogrel 75 mg daily for exactly 21 days 1, 2
• After 21 days: Switch to single antiplatelet therapy (aspirin 81 mg daily OR clopidogrel 75 mg daily) indefinitely 2

Critical timing consideration: The benefit of DAPT is maximal when initiated early, with most stroke prevention occurring in the first week, and the benefit-to-risk ratio favors DAPT only during the first 21 days 1, 3. Short-duration DAPT (≤1 month) started during the early acute phase reduces recurrent strokes by 25% compared to monotherapy while minimizing bleeding risk 3.

Single Antiplatelet Therapy Indications

When to use single antiplatelet therapy:

• Moderate-to-severe ischemic stroke with NIHSS >3 2
• Low-risk TIA with ABCD2 score <4 2
• Delayed presentation beyond 24 hours from symptom onset 2
• High bleeding risk including history of gastrointestinal hemorrhage, anticoagulant use, or coagulopathy 2
• Chronic microvascular/small vessel disease for secondary prevention 4

Single antiplatelet dosing:

• Acute phase: Aspirin 160-325 mg loading dose within 24-48 hours of stroke onset (delay to 24 hours post-thrombolysis if IV alteplase was given) 1
• Maintenance: Aspirin 75-100 mg daily OR clopidogrel 75 mg daily for long-term secondary prevention 1, 4

Evidence Supporting the 21-Day Duration

The 21-day duration for DAPT is based on high-quality evidence showing that 1, 5:

• DAPT reduces major ischemic events by 25% (hazard ratio 0.75) compared to aspirin alone 5
• For every 1000 patients treated with DAPT for 90 days, 15 ischemic strokes are prevented but 5 major hemorrhages occur 4
• Beyond 90 days, the risk of major hemorrhage increases dramatically (hazard ratio 2.22-2.32) without additional benefit 1, 2
• Pooled analysis demonstrates that prolonged DAPT beyond 21-30 days significantly increases bleeding risk while providing no incremental stroke prevention 1, 6

Critical Pitfalls to Avoid

• Do NOT continue DAPT beyond 21-30 days as bleeding risk (hazard ratio 2.32) outweighs any potential benefit 1, 5
• Do NOT use DAPT for moderate-to-severe strokes (NIHSS >3) as evidence supports this only for minor strokes 2
• Do NOT delay aspirin beyond 48 hours in patients requiring single antiplatelet therapy, as benefit is time-dependent 1
• Do NOT use enteric-coated aspirin for loading doses due to slower onset of action 1
• Do NOT substitute antiplatelet therapy for thrombolysis or mechanical thrombectomy in eligible patients 1

Special Consideration: Breakthrough Strokes on Aspirin

For patients who experience ischemic stroke while already on aspirin monotherapy, switching to or adding another antiplatelet agent (particularly clopidogrel) reduces major adverse cardiovascular events (hazard ratio 0.68) and recurrent stroke (hazard ratio 0.70), especially when initiated in the first days after the index event 7.

Bleeding Risk Mitigation

• Consider gastrointestinal protection with proton pump inhibitors in patients with risk factors for GI bleeding during DAPT 2
• Always rule out intracranial hemorrhage on neuroimaging before initiating any antiplatelet therapy 1
• The number needed to harm for intracranial bleeding with DAPT is 258, and for major bleeding is 113, indicating the absolute bleeding risk remains relatively low in appropriately selected patients 3