What are the safety and efficacy considerations for using alteplase (tissue plasminogen activator) in patients with acute ischemic stroke who have been on prior antiplatelet therapy?

Impact of Prior Antiplatelet Therapy on Alteplase Safety and Efficacy in Acute Ischemic Stroke

Prior antiplatelet therapy—whether monotherapy or dual therapy—is not a contraindication to alteplase administration in acute ischemic stroke, and treatment should proceed as the benefits outweigh the slightly increased bleeding risk. 1

Safety Profile with Prior Antiplatelet Use

Monotherapy

• IV alteplase is recommended for patients taking single antiplatelet agents (e.g., aspirin or clopidogrel alone) before stroke, as evidence demonstrates that clinical benefit outweighs a possible small increased risk of symptomatic intracranial hemorrhage (sICH). 1
• The 2018 AHA/ASA guidelines classify this as a Class I recommendation with Level of Evidence A, indicating the strongest level of evidence supporting treatment. 1

Dual Antiplatelet Therapy

• IV alteplase is recommended for patients on combination antiplatelet therapy (e.g., aspirin plus clopidogrel) despite a probable increased risk of sICH, as the benefit still outweighs the bleeding risk. 1
• This carries a Class I recommendation with Level of Evidence B-NR, reflecting slightly less robust but still compelling evidence. 1

Hemorrhagic Risk Considerations

Symptomatic Intracranial Hemorrhage Rates

• Patients on prior antiplatelet therapy demonstrate higher rates of symptomatic intracranial hemorrhage compared to those not on antiplatelet agents (OR 1.82; 95% CI 1.00-3.30; P=0.051 by SITS-MOST criteria). 2
• However, retrospective analysis of early antiplatelet administration (<24 hours post-alteplase) showed no increase in sICH (1.4% vs. 0%, p=0.1) in patients receiving alteplase alone without endovascular therapy. 3

Functional Outcomes

• Despite the increased bleeding risk, functional outcomes at 90 days remain comparable between patients with and without prior antiplatelet use after adjustment for baseline characteristics. 2
• No significant differences were observed in death or disability (mRS 2-6: adjusted OR 1.01; 95% CI 0.81-1.26; P=0.953) or severe disability/death (mRS 3-6: OR 0.95; 95% CI 0.75-1.20; P=0.662). 2

Dosing Considerations in Antiplatelet Users

Standard vs. Low-Dose Alteplase

• The ENCHANTED trial evaluated whether low-dose alteplase (0.6 mg/kg) might be safer than standard-dose (0.9 mg/kg) in patients on prior antiplatelet therapy. 2
• Low-dose alteplase showed a non-significant trend toward better outcomes in patients on prior antiplatelet therapy compared to those not on antiplatelet agents (mRS 2-6: OR 0.84; 95% CI 0.62-1.12 vs. OR 1.16; 95% CI 0.99-1.36; P-trend=0.053). 2
• However, current guidelines continue to recommend standard-dose alteplase (0.9 mg/kg, maximum 90 mg) regardless of prior antiplatelet use, as this remains the evidence-based standard of care. 1, 4

Critical Contraindications That DO Apply

Glycoprotein IIb/IIIa Inhibitors

• Antiplatelet agents that inhibit the glycoprotein IIb/IIIa receptor (e.g., abciximab, eptifibatide, tirofiban) should not be administered concurrently with IV alteplase outside a clinical trial (Class III: Harm; Level of Evidence B-R). 1

Coagulopathy Thresholds

• Platelet count <100,000/mm³ contraindicates alteplase administration, though treatment can be initiated before results are available and discontinued if platelets are found to be low. 1, 5
• Treatment can begin before platelet count availability in patients without thrombocytopenia history but must be stopped if platelets <100,000/mm³. 5

Post-Alteplase Antiplatelet Management

Timing of Antiplatelet Initiation

• All antiplatelet agents should be held for 24 hours post-alteplase administration. 4
• Antiplatelet therapy initiation should be delayed until after the 24-hour post-thrombolysis scan has excluded intracranial hemorrhage. 4
• Recent retrospective data suggest early antiplatelet administration (<24 hours) may be safe in select patients, but prospective validation is needed before changing practice. 3

Clinical Algorithm for Decision-Making

When evaluating a patient on antiplatelet therapy for alteplase:

1. Confirm the specific antiplatelet agent(s):

   • Aspirin, clopidogrel, ticagrelor, prasugrel → Proceed with alteplase 1
   • Glycoprotein IIb/IIIa inhibitors → Do NOT give alteplase 1

2. Check platelet count if available:

   • ≥100,000/mm³ → Proceed 1
   • <100,000/mm³ → Do NOT give alteplase 1
   • Unknown → May initiate but discontinue if <100,000/mm³ 5

3. Verify other standard eligibility criteria:

   • Time window (<3 hours or 3-4.5 hours with appropriate exclusions) 1
   • Blood pressure <185/110 mmHg or safely lowerable 1
   • No other absolute contraindications 5

4. Administer standard-dose alteplase (0.9 mg/kg, max 90 mg):

   • 10% as IV bolus over 1 minute 4
   • 90% as IV infusion over 60 minutes 4

5. Hold all antiplatelet agents for 24 hours post-treatment 4

Common Pitfalls to Avoid

• Do not withhold alteplase solely because a patient is on aspirin or clopidogrel—this is explicitly recommended in guidelines and represents a missed treatment opportunity. 1
• Do not confuse standard antiplatelet agents with glycoprotein IIb/IIIa inhibitors—only the latter are contraindicated. 1
• Do not restart antiplatelet therapy before 24 hours—wait for post-thrombolysis imaging to exclude hemorrhage. 4
• Do not use low-dose alteplase (0.6 mg/kg) in routine practice—while potentially beneficial in antiplatelet users, this requires further validation and is not current standard of care. 2