Do Aspirin (acetylsalicylic acid) or Clopidogrel (Plavix) increase the risk of hemorrhage when used alone in patients with large ischemic strokes?

From the Guidelines

Both aspirin and clopidogrel when used alone can increase the risk of hemorrhage in patients with large ischemic infarcts, though the risk is generally considered modest. For patients with large ischemic infarcts, the hemorrhagic risk must be carefully balanced against the benefit of preventing recurrent ischemic events. Aspirin (typically 81-325 mg daily) carries a slightly lower bleeding risk than clopidogrel (75 mg daily), but both medications inhibit platelet function and can potentially increase the risk of hemorrhagic transformation, particularly in the first few days after a large infarct when the blood-brain barrier is compromised.

Key Considerations

• The size of the infarct is a critical factor, with larger infarcts (especially those >1/3 of the middle cerebral artery territory) carrying higher hemorrhage risk.
• Clinicians should consider delaying antiplatelet therapy for 24-48 hours in patients with very large infarcts if hemorrhagic risk is deemed particularly high.
• Blood pressure control, avoidance of excessive anticoagulation, and close neurological monitoring are essential accompanying measures when using these medications in the setting of large ischemic strokes.
• The mechanism behind increased bleeding risk relates to the antiplatelet effects preventing clot stabilization in damaged vessels within the infarcted tissue, as noted in studies such as the CAPRIE trial 1.

Recommendations

• Aspirin and clopidogrel are both acceptable options for initial therapy in patients with noncardioembolic ischemic stroke or TIA, according to guidelines from the American Heart Association/American Stroke Association 1.
• The selection of an antiplatelet agent should be individualized on the basis of patient risk factor profiles, cost, tolerance, and other clinical characteristics, as recommended by guidelines 1.
• The addition of aspirin to clopidogrel increases the risk of hemorrhage and is not recommended for routine secondary prevention after ischemic stroke or TIA, as stated in guidelines 1.

From the FDA Drug Label

Use of drugs that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. Risk factors for bleeding include concomitant use of other drugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, and chronic use of NSAIDs) Bleeding CURE In CURE, clopidogrel use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin CAPRIE (Clopidogrel vs Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2% in those taking clopidogrel versus 2.7% in those taking aspirin;

Bleeding Risk:

• The use of clopidogrel alone may increase the risk of bleeding, as seen in the CAPRIE study where gastrointestinal hemorrhage occurred at a rate of 2% in those taking clopidogrel.
• Aspirin also increases the risk of bleeding, with a rate of 2.7% for gastrointestinal hemorrhage in the CAPRIE study.
• The risk of bleeding is a concern for both clopidogrel and aspirin, especially when used in patients with large ischemic infarcts. 2

From the Research

Risk of Hemorrhage with Aspirin or Clopidogrel

• The risk of hemorrhage when using aspirin or clopidogrel alone in patients with large ischemic infarcts is a significant concern 3, 4, 5, 6, 7.
• Studies have shown that dual antiplatelet therapy with clopidogrel and aspirin increases the risk of major bleeding events, including intracranial and extracranial bleeding, compared to aspirin alone 3, 5, 6, 7.
• However, clopidogrel monotherapy has been shown to have a lower risk of bleeding compared to aspirin monotherapy in some studies 4.
• The risk of hemorrhagic stroke is also a concern, with some studies suggesting that dual antiplatelet therapy may increase this risk, although the evidence is not consistent across all studies 3, 5, 6, 7.

Comparison of Aspirin and Clopidogrel

• Clopidogrel has been shown to be more effective than aspirin in reducing the risk of recurrent stroke, including ischemic and hemorrhagic stroke, in some studies 4, 5, 6.
• However, the risk of bleeding is a significant concern with dual antiplatelet therapy, and the benefits of clopidogrel over aspirin must be carefully weighed against this risk 3, 5, 6, 7.
• Aspirin monotherapy is still a commonly used treatment for patients with ischemic stroke, and the decision to use clopidogrel or dual antiplatelet therapy should be made on a case-by-case basis, taking into account the individual patient's risk factors and medical history 3, 4, 5, 6, 7.