What is the role of aspirin (acetylsalicylic acid) and clopidogrel in preventing future strokes in patients with a history of ischemic stroke?

Aspirin and Clopidogrel for Stroke Prevention

For patients with recent minor ischemic stroke (NIHSS ≤3) or high-risk TIA (ABCD2 score ≥4), dual antiplatelet therapy with aspirin plus clopidogrel should be initiated within 24 hours and continued for 21-90 days, followed by single antiplatelet therapy for long-term secondary prevention. 1, 2

Acute Phase Management (First 24 Hours to 90 Days)

When to Use Dual Antiplatelet Therapy

Dual therapy (aspirin + clopidogrel) is indicated for:

• Minor stroke with NIHSS score ≤3 initiated within 12-24 hours of symptom onset, ideally before emergency department discharge 1, 2
• High-risk TIA with ABCD2 score ≥4 started within 24 hours and continued for 21-90 days 1, 2
• Loading doses: Clopidogrel 300-600 mg plus aspirin 160 mg immediately after brain imaging excludes hemorrhage, followed by maintenance therapy of aspirin 81 mg plus clopidogrel 75 mg daily 2

The evidence is robust: The POINT trial demonstrated dual therapy reduces ischemic stroke risk from 6.3% to 4.6% (HR 0.72, p=0.01), preventing 15 ischemic strokes per 1,000 patients treated. 2

Critical Timing Window

• Dual therapy must be started within 24 hours of symptom onset to achieve maximum benefit; delaying beyond this window significantly diminishes efficacy 2
• Duration is strictly limited to 21-90 days maximum, after which patients must transition to single antiplatelet therapy 1, 2

Absolute Contraindications to Dual Therapy

Do not use dual antiplatelet therapy in:

• Active bleeding or intracranial hemorrhage 2
• Moderate-to-severe stroke (NIHSS >3) - use single agent instead 2
• Cardioembolic stroke (atrial fibrillation, mechanical valve, cardiac thrombus) - requires anticoagulation instead 2, 3
• Presentation >24 hours after symptom onset 2
• Post-thrombolysis until 24-hour scan excludes hemorrhage 2

Long-Term Secondary Prevention (After 90 Days)

Single Antiplatelet Therapy is Standard

For noncardioembolic ischemic stroke or TIA, choose one of the following options: 1

• Aspirin 50-325 mg daily (Class I, Level A evidence) 1, 3
• Clopidogrel 75 mg daily (Class I, Level A evidence) 1, 4
• Aspirin 25 mg + extended-release dipyridamole 200 mg twice daily (Class I, Level A evidence) 1

Clopidogrel or aspirin/dipyridamole combination are preferred over aspirin alone for long-term secondary prevention based on superior efficacy. 1 The CAPRIE trial showed clopidogrel reduced vascular events by 8.7% compared to aspirin (9.8% vs 10.6%, p=0.045), though benefit was heterogeneous across subgroups. 4

Why Long-Term Dual Therapy is Dangerous

Continuous dual antiplatelet therapy (aspirin + clopidogrel) beyond 90 days is contraindicated because it increases hemorrhage risk without additional stroke prevention benefit. 1, 5 The MATCH trial demonstrated combination therapy significantly increased major hemorrhage with a 1.3% absolute increase in life-threatening bleeding compared to monotherapy, without reducing ischemic events. 5 The CHARISMA trial similarly failed to show benefit (6.9% vs 7.4% event rate, p=0.22) while increasing bleeding. 4

Common Pitfalls to Avoid

Critical errors that compromise outcomes:

• Never continue dual therapy beyond 30-90 days unless there is a separate indication (e.g., recent acute coronary syndrome or vascular stenting) 1, 2, 5
• Never substitute dual antiplatelet therapy for anticoagulation in atrial fibrillation patients - the combination carries similar bleeding risk to warfarin without the stroke prevention benefit 2, 5
• Never delay dual therapy initiation beyond 24 hours in eligible patients, as this eliminates the therapeutic window 2
• Never use dual therapy for moderate-to-severe strokes (NIHSS >3) - these patients should receive single antiplatelet therapy only 2

Special Considerations

For Patients Already on Aspirin at Time of Stroke

The effectiveness of increasing aspirin dose or switching to another antiplatelet medication is not well established. 1 Consider adding clopidogrel for the acute 21-90 day period if patient meets criteria for dual therapy, then transition to single agent. 1

Gastrointestinal Protection

For patients at higher GI bleeding risk on dual therapy, proton pump inhibitors such as dexlansoprazole, lansoprazole, or pantoprazole can be used. Avoid omeprazole and esomeprazole as they significantly reduce clopidogrel's antiplatelet activity. 4

Alternative Administration Routes

For patients with dysphagia, consider enteral tube administration of aspirin 80 mg plus clopidogrel 75 mg daily, or rectal aspirin 325 mg suppository daily. 2

Algorithm Summary

Step 1: Determine stroke severity and timing

• NIHSS ≤3 and <24 hours → Proceed to Step 2
• NIHSS >3 or >24 hours → Single antiplatelet therapy only

Step 2: Exclude cardioembolic source

• No atrial fibrillation/cardiac thrombus → Proceed to Step 3
• Cardioembolic source present → Anticoagulation required

Step 3: Initiate dual therapy

• Load: Clopidogrel 300-600 mg + aspirin 160 mg
• Maintain: Clopidogrel 75 mg + aspirin 81 mg daily for 21-90 days

Step 4: Transition to long-term single agent

• Choose clopidogrel 75 mg daily OR aspirin/dipyridamole OR aspirin 50-325 mg daily
• Continue indefinitely for secondary prevention