What is the recommended antiplatelet therapy for patients at risk of ischemic stroke?

Antiplatelet Therapy for Ischemic Stroke Prevention

For patients with minor ischemic stroke (NIHSS ≤3-5) or high-risk TIA, initiate dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel within 12-24 hours of symptom onset, continue for 21-30 days, then transition to single antiplatelet therapy with either clopidogrel 75 mg daily or aspirin/extended-release dipyridamole for long-term secondary prevention. 1

Acute Phase Management (First 48 Hours)

For Minor Stroke or High-Risk TIA (NIHSS ≤3-5, ABCD2 ≥4)

Dual antiplatelet therapy is the standard of care for this population:

• Start aspirin plus clopidogrel within 12-24 hours after excluding intracranial hemorrhage on neuroimaging 1
• Loading doses: Aspirin 160-325 mg plus clopidogrel 300-600 mg on day 1 1
• Maintenance: Aspirin 81 mg daily plus clopidogrel 75 mg daily 1
• Duration: Continue DAPT for 21 days (aspirin/clopidogrel regimen) or 30 days (aspirin/ticagrelor regimen), then switch to single antiplatelet therapy 1

Alternative DAPT regimen:

• Aspirin 75-100 mg daily plus ticagrelor 90 mg twice daily can be used for mild-moderate stroke (NIHSS ≤5) 1
• Loading: Aspirin 300-325 mg plus ticagrelor 180 mg 1
• Continue for 30 days before transitioning to monotherapy 1

Recent evidence supports extended time windows: Patients initiating DAPT between 24-72 hours after symptom onset still derive benefit, with consistent stroke reduction and acceptable bleeding risk 2

For Moderate-to-Severe Stroke

• Aspirin monotherapy 160-325 mg within 48 hours of symptom onset is recommended 1, 3
• This reduces early recurrent stroke and improves long-term functional outcomes 4
• Do not use DAPT in this population—the combination of clopidogrel plus aspirin is not recommended for routine use beyond minor stroke/high-risk TIA 1

Long-Term Secondary Prevention (After Initial 21-30 Days)

Single antiplatelet therapy is the cornerstone of long-term prevention for noncardioembolic stroke:

First-Line Options (All Grade 1A)

The following agents are all acceptable for long-term use 1, 3:

• Clopidogrel 75 mg once daily (preferred) 1
• Aspirin 75-100 mg once daily plus extended-release dipyridamole 200 mg twice daily (preferred) 1
• Aspirin 75-100 mg once daily (acceptable but less preferred) 1
• Cilostazol 100 mg twice daily (acceptable but less preferred) 1

Hierarchy of preference: Clopidogrel or aspirin/extended-release dipyridamole are superior to aspirin monotherapy (Grade 2B) and to cilostazol (Grade 2C) 1, 3

What NOT to Use Long-Term

• Do not use long-term DAPT (aspirin plus clopidogrel) beyond the initial 21-30 day period—this increases bleeding risk without additional benefit (Grade 1B) 1
• Do not use oral anticoagulation for noncardioembolic stroke (Grade 1B) 1

Special Populations

Cardioembolic Stroke with Atrial Fibrillation

Oral anticoagulation, not antiplatelet therapy, is the treatment of choice:

• Warfarin (INR 2.0-3.0) or direct oral anticoagulants are recommended over aspirin or DAPT (Grade 1A-1B) 1, 3
• Dabigatran 150 mg twice daily is preferred over warfarin (Grade 2B) 1
• Bridge with aspirin until therapeutic anticoagulation is achieved 1
• Timing: Initiate anticoagulation within 1-2 weeks after stroke onset for most patients 1
• Delay anticoagulation in patients with extensive infarcts or hemorrhagic transformation 1

Embolic Stroke of Undetermined Source (ESUS)

• Use antiplatelet therapy, not anticoagulation 1, 3
• Follow the same long-term antiplatelet regimen as noncardioembolic stroke 1

Extracranial Artery Dissection

• Either antiplatelet therapy or anticoagulation for at least 3 months 1
• Both approaches are acceptable; choice depends on individual bleeding/thrombotic risk 1

Other Specific Etiologies

• Carotid web: Antiplatelet therapy recommended 1
• Fibromuscular dysplasia: Antiplatelet therapy plus lifestyle modification 1
• Positive antiphospholipid antibodies (without APS): Antiplatelet therapy 1

Critical Caveats and Pitfalls

CYP2C19 Poor Metabolizers

• Clopidogrel effectiveness depends on CYP2C19 metabolism 5
• Genetic testing is available to identify poor metabolizers 5
• Consider alternative P2Y12 inhibitor (ticagrelor) or aspirin/dipyridamole in confirmed poor metabolizers 5

Bleeding Risk Management

• DAPT increases bleeding risk but benefits outweigh risks in appropriate populations 1, 5
• Discontinue antiplatelet therapy 5 days before elective surgery with major bleeding risk 5
• Avoid concomitant use of NSAIDs, which further increase bleeding risk 5
• Do not combine with omeprazole or esomeprazole when using clopidogrel—these CYP2C19 inhibitors reduce clopidogrel effectiveness 5

Premature Discontinuation

• Stopping antiplatelet therapy prematurely increases cardiovascular event risk 5
• Ensure patients understand the importance of adherence 5

Drug Interactions

• Opioids decrease clopidogrel absorption—consider parenteral antiplatelet agents in patients requiring chronic opioids 5
• Warfarin, SSRIs, and SNRIs increase bleeding risk when combined with antiplatelets 5

Dosing Errors to Avoid

• Do not use aspirin doses >325 mg daily long-term—side effects increase without additional benefit 1, 6
• For long-term use, 75-100 mg aspirin daily is as effective as higher doses 1, 6
• Loading doses are essential for DAPT initiation to achieve rapid platelet inhibition 1

Timing Precision Matters

• The earlier DAPT is initiated (within 12-24 hours), the greater the benefit 1
• However, benefit persists even when initiated up to 72 hours after symptom onset 2
• Always exclude intracranial hemorrhage before starting any antiplatelet therapy 1