In a patient with an acute ischemic stroke (no intracranial hemorrhage, no active bleeding or severe thrombocytopenia), when should antiplatelet therapy be started and what is the recommended first‑line regimen?

Antiplatelet Therapy in Acute Ischemic Stroke

For patients with acute ischemic stroke, aspirin 160–325 mg should be administered within 24–48 hours after ruling out intracranial hemorrhage on neuroimaging; if the patient received IV alteplase, delay aspirin until 24 hours post-thrombolysis. 1

Patient Stratification and Treatment Algorithm

Step 1: Rule Out Hemorrhage and Assess Stroke Severity

• Obtain urgent CT or MRI to exclude intracranial hemorrhage before any antiplatelet therapy. 1, 2
• Determine stroke severity using NIHSS:
  • Minor stroke: NIHSS ≤ 3
  • Moderate-to-severe stroke: NIHSS > 3 1, 2
• For high-risk TIA, calculate ABCD² score (≥4 qualifies as high-risk). 1, 2

Step 2: Select Antiplatelet Regimen Based on Timing and Severity

For Minor Stroke (NIHSS ≤3) or High-Risk TIA (ABCD² ≥4) Presenting Within 24 Hours:

Dual antiplatelet therapy is recommended:

• Loading doses (within 12–24 hours of onset):
  • Clopidogrel 300 mg (acceptable range 300–600 mg) 1, 2, 3
  • Aspirin 160–325 mg 1, 2, 3
• Maintenance phase (days 2–21):
  • Clopidogrel 75 mg daily + aspirin 75–100 mg daily 1, 2
• After exactly 21 days, transition to single antiplatelet therapy (aspirin 75–100 mg daily OR clopidogrel 75 mg daily) indefinitely. 1, 2

Evidence supporting this approach: The INSPIRES trial (2023) demonstrated that dual antiplatelet therapy initiated within 72 hours reduced new stroke from 9.2% to 7.3% (HR 0.79,95% CI 0.66–0.94), though moderate-to-severe bleeding increased from 0.4% to 0.9%. 3 The benefit is greatest when started within the first 24 hours. 1, 2

For Moderate-to-Severe Stroke (NIHSS >3) or Presentation >24 Hours:

Single antiplatelet therapy is recommended:

• Loading dose: Aspirin 160–325 mg within 24–48 hours of onset 1
• Maintenance: Aspirin 75–100 mg daily starting day 2, continued indefinitely 1

The evidence is robust: Two large trials (IST and CAST) involving over 40,000 patients demonstrated that aspirin 160–300 mg started within 48 hours reduces death or dependency (OR 0.95% CI 0.91–0.99), preventing 13 deaths or dependencies per 1000 patients treated. 1, 4, 5

Step 3: Critical Timing Considerations

If IV alteplase was administered:

• Delay all antiplatelet therapy until 24 hours after thrombolysis 1
• Obtain repeat neuroimaging before starting antiplatelets to confirm no hemorrhagic transformation 1

If mechanical thrombectomy was performed:

• The same 24-hour delay applies unless urgent stenting was required (see special circumstances below) 1

Special Circumstances

Patients Unable to Swallow:

• Administer aspirin 325 mg rectally OR aspirin 81 mg via nasogastric tube 1, 2
• Clopidogrel 75 mg can be crushed and given via enteral tube 2
• Avoid enteric-coated aspirin for loading doses due to delayed absorption 2

Patients with Severe Renal Impairment (CrCl <30 mL/min):

• Use aspirin monotherapy only (160–325 mg loading, then 75–100 mg daily) 2
• Clopidogrel is contraindicated due to accumulation of active metabolites and markedly increased bleeding risk 2

Patients Requiring Urgent Intracranial Stenting:

• Emerging evidence suggests that carefully selected patients may tolerate antiplatelets <24 hours post-tPA when stenting is necessary, though this remains off-guideline. 6 The standard 24-hour delay should be followed unless discussed with the neurointerventional team. 1

Absolute Contraindications to Antiplatelet Therapy

• Intracranial hemorrhage not yet ruled out on imaging 1, 2
• Active major bleeding 1
• Severe thrombocytopenia 1
• Known hypersensitivity to aspirin or clopidogrel 1

Common Pitfalls to Avoid

Never use aspirin as a substitute for thrombolysis or thrombectomy in eligible patients—this delays definitive reperfusion therapy and worsens outcomes. 1

Never continue dual antiplatelet therapy beyond 21–30 days in routine stroke prevention, as bleeding risk (HR 2.22–2.32) outweighs any benefit. 2

Never delay aspirin beyond 48 hours when eligibility criteria are met; the benefit is time-dependent with maximum efficacy in the first 24–48 hours. 1

Never use ticagrelor instead of clopidogrel for acute minor stroke—it is not recommended and may increase bleeding without proven benefit. 1

Never use glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) in acute ischemic stroke—they are potentially harmful. 1

Long-Term Secondary Prevention

After completing the acute phase (21 days of dual therapy for minor stroke, or immediate single therapy for moderate-to-severe stroke):

Continue single antiplatelet therapy indefinitely:

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

Exception: If a cardioembolic source (e.g., atrial fibrillation) is identified, switch to oral anticoagulation rather than continuing antiplatelet therapy. 1, 2