Does giving aspirin (acetylsalicylic acid) 300 mg 1.5 hours before thrombolysis for stroke increase the risk of cerebral bleeding?

Aspirin 300 mg Given 1.5 Hours Before Thrombolysis Significantly Increases Cerebral Bleeding Risk and Should Be Avoided

Aspirin must not be administered within 24 hours before or after thrombolysis for acute ischemic stroke, as this combination significantly increases symptomatic intracranial hemorrhage and early mortality without improving outcomes. 1

Critical Guideline Recommendations

The American Stroke Association explicitly states that administering aspirin concurrently with or immediately after thrombolysis significantly increases symptomatic intracranial hemorrhage risk and must be avoided for at least 24 hours post-thrombolysis. 1 This recommendation extends to the pre-thrombolysis period as well, given the pharmacodynamic effects of aspirin persist well beyond administration. 1

Evidence of Harm from Combined Therapy

The strongest evidence comes from the Multicenter Acute Stroke Trial-Italy (MAST-I), which directly tested streptokinase plus aspirin versus streptokinase alone and found:

• Early case fatality (days 3-10) more than doubled with the combination (53 vs. 30 deaths; OR 2.1,95% CI 1.2-3.6). 2
• Cerebral deaths increased significantly (42 vs. 24; OR 2.0,95% CI 1.3-3.7), primarily due to hemorrhagic transformation (22 vs. 11; OR 2.2,95% CI 1.0-5.0). 2
• The death excess was solely attributable to the treatment combination and not explained by baseline prognostic factors. 2

Observational Data Confirms Increased Bleeding Risk

A large retrospective study of 235 consecutive patients treated with IV tPA found:

• Pre-treatment with antiplatelet agents (present in 30.6% of patients) was independently associated with parenchymal hematoma (adjusted OR 3.5,95% CI 1.5-7.8, P=0.002). 3
• The association with symptomatic intracerebral hemorrhage showed a trend toward increased risk (OR 1.9,95% CI 0.6-5.9). 3

A systematic review confirmed that aspirin monotherapy pretreatment increases bleeding risk of alteplase in both observational and randomized trials with no beneficial effect on clinical outcome. 4

Correct Treatment Algorithm

For Patients Eligible for Thrombolysis (Within 3-4.5 Hours)

1. If aspirin has already been given within the past 24 hours, this represents a relative contraindication to thrombolysis that must be carefully weighed against potential benefits. 1, 2

2. Administer IV alteplase 0.9 mg/kg (maximum 90 mg) if no contraindications exist, with 10% as bolus over 1 minute and 90% infused over 60 minutes. 5

3. Delay aspirin initiation until 24 hours after thrombolysis, following a repeat CT scan to exclude intracranial hemorrhage. 1, 5

4. After the 24-hour delay, initiate aspirin 160-325 mg for secondary stroke prevention. 1, 6

For Patients Outside the Thrombolysis Window

• Aspirin 160-325 mg should be administered within 24-48 hours of symptom onset after CT excludes hemorrhage. 7, 5
• This prevents approximately 5 deaths per 1,000 patients treated through reduction of early recurrent ischemic stroke. 8, 9

Historical Context and Mechanism of Harm

Earlier guidelines from 2003 reported an unacceptably high incidence of early mortality and intracranial hemorrhage when combining aspirin with thrombolytic agents. 1 The mechanism involves:

• Aspirin's irreversible inhibition of platelet cyclooxygenase persists for the platelet lifespan (7-10 days), creating a sustained antihemostatic effect. 7
• When combined with thrombolysis-induced fibrinolysis and potential disruption of the blood-brain barrier, this creates a compounded bleeding risk. 2
• The small increase in cerebral hemorrhage risk from aspirin alone (0.1% absolute increase) becomes clinically significant when added to thrombolysis-related bleeding risk. 1

Common Pitfalls to Avoid

Do not assume that aspirin given 1.5 hours before thrombolysis has "worn off"—aspirin's antiplatelet effects are irreversible and persist for days, not hours. 7, 4 The 1.5-hour timeframe provides no safety margin whatsoever.

Do not rationalize that aspirin might prevent early recurrent stroke during thrombolysis—the MAST-I trial showed no reduction in stroke recurrence with the combination (OR 1.4,95% CI 0.6-3.4), only increased mortality. 2