What is the role of aspirin (acetylsalicylic acid) in the management of large ischemic strokes?

Aspirin in Large Ischemic Strokes

Aspirin should be administered at 160-325 mg within 24-48 hours of large ischemic stroke onset, but this recommendation comes with critical caveats: patients with large strokes face higher hemorrhagic transformation risk, and aspirin must be withheld if IV thrombolysis was given in the preceding 24 hours or if brain imaging has not excluded intracranial hemorrhage. 1

Evidence Base for Aspirin in Acute Ischemic Stroke

The recommendation for early aspirin stems from two landmark trials—the International Stroke Trial (IST) and Chinese Acute Stroke Trial (CAST)—which together enrolled 40,000 patients and demonstrated:

• Reduction in recurrent ischemic stroke by approximately 7 per 1000 patients during the acute treatment period 1
• Reduction in mortality during the 28-day treatment period, though long-term disability rates showed minimal improvement 1
• Small but significant increase in hemorrhagic transformation (0.1% absolute increase in intracranial hemorrhage) 1
• Net benefit of approximately 9 per 1000 reduction in further stroke or death despite hemorrhagic risks 2

Critical Contraindications and Timing Restrictions

Absolute Contraindications

• Do NOT administer aspirin within 24 hours of IV thrombolysis due to significantly increased risk of serious intracranial bleeding complications 1, 3
• Brain imaging must first exclude intracranial hemorrhage before any aspirin administration 1, 4

The Large Stroke Dilemma

Patients with moderate-to-severe (large) strokes present a particular challenge:

• Higher baseline risk of hemorrhagic transformation exists in severe strokes, making the small hemorrhagic risk from aspirin more clinically significant 1
• A 2023 study found that in patients at high risk for hemorrhagic transformation, higher aspirin doses (300 mg vs 200 mg) were associated with increased parenchymal hematoma risk 5
• Despite this, the combined IST/CAST analysis found no significant heterogeneity in aspirin's proportional benefit across stroke severity subgroups, suggesting the relative benefit remains consistent 2

Practical Dosing Algorithm for Large Strokes

Initial Assessment (Within First Hours)

• Obtain brain imaging (CT or MRI) to confirm ischemic stroke and exclude hemorrhage 1, 4
• Determine eligibility for IV thrombolysis—if given, aspirin is contraindicated for 24 hours 1
• Assess stroke severity using NIHSS and identify large vessel occlusion 1

Aspirin Initiation (24-48 Hours Post-Onset)

• Loading dose: 160-325 mg for most patients with confirmed ischemic stroke 1
• Consider lower end of dosing range (160-200 mg) in patients with large strokes who have additional hemorrhagic risk factors (advanced age, multiple microbleeds on MRI, lobar location) 3, 5
• Maintenance dose: 50-100 mg daily for long-term secondary prevention 3

Risk Stratification for Hemorrhagic Complications in Large Strokes

High-risk features that warrant particular caution include:

• Lobar infarct location (higher hemorrhagic transformation risk) 3
• Advanced age 3
• Presence and number of microbleeds on gradient echo MRI 3
• Apolipoprotein E ε2 or ε4 alleles 3
• Severe stroke (high NIHSS score) 1

Critical Pitfalls to Avoid

• Never use aspirin as a substitute for IV rtPA in eligible patients—aspirin is not an acute recanalization therapy 1
• Never combine aspirin with urgent anticoagulation in moderate-to-severe strokes due to unacceptably high intracranial hemorrhage risk 1
• Do not delay aspirin beyond 48 hours in patients without contraindications, as early administration (within 24-48 hours) is when benefit is demonstrated 1
• Avoid dual antiplatelet therapy (aspirin plus clopidogrel) in the acute setting of large strokes, as bleeding risk outweighs benefit—this differs from minor strokes where dual therapy may be considered 1

Management If Hemorrhagic Transformation Occurs

If hemorrhagic transformation develops after aspirin initiation:

• For non-lobar hemorrhages with strong antiplatelet indications (recent ACS, coronary stents, high thrombotic risk): restart aspirin at 3-7 days if clinically stable 3, 6
• For lobar hemorrhages or weaker indications: delay aspirin for minimum 4-6 weeks 3, 6

Evidence Quality and Guideline Strength

The American Heart Association/American Stroke Association provides Class I, Level of Evidence A recommendation for aspirin 325 mg within 24-48 hours after stroke onset in most patients 1. This represents the highest quality evidence from multiple large randomized controlled trials involving tens of thousands of patients 1, 2.

The key limitation is that while the IST and CAST trials included patients with large strokes, they did not specifically analyze this subgroup separately with sufficient power to detect differential effects 2. The proportional benefit appears consistent across severity levels, but the absolute hemorrhagic risk may be higher in severe strokes 1, 2.