Do Aspirin (acetylsalicylic acid) and Clopidogrel increase the risk of hemorrhage in patients with large ischemic strokes?

From the Guidelines

Aspirin and clopidogrel combination therapy increases the risk of hemorrhage in patients with large ischemic infarcts, and therefore, single antiplatelet therapy with aspirin alone is generally preferred over dual therapy in these cases. This recommendation is based on the most recent and highest quality study available, which emphasizes the importance of balancing the benefits of antiplatelet therapy with the risks of bleeding in patients with ischemic stroke or transient ischemic attack (TIA) 1. The use of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is associated with an increased risk of hemorrhage, particularly in patients with large infarcts, due to the synergistic effect of these medications on platelet function 1.

Key Considerations

• The risk of hemorrhage is a significant concern in patients with large ischemic infarcts, and clinicians should carefully weigh the benefits and risks of antiplatelet therapy in these cases 1.
• Single antiplatelet therapy with aspirin alone (typically 81-325 mg daily) is generally preferred over dual therapy with aspirin and clopidogrel in patients with large infarcts 1.
• Patient-specific factors, such as age, blood pressure control, and renal function, should be considered when assessing bleeding risk in patients with ischemic stroke or TIA 1.
• Close monitoring for signs of intracranial bleeding is essential if dual therapy is absolutely necessary for other compelling indications, such as recent stent placement 1.

Recommendations

• For patients with noncardioembolic ischemic stroke or TIA, antiplatelet therapy is indicated in preference to oral anticoagulation to reduce the risk of recurrent ischemic stroke and other cardiovascular events while minimizing the risk of bleeding 1.
• For patients with recent minor (NIHSS score ≤3) noncardioembolic ischemic stroke or high-risk TIA (ABCD2 score ≥4), DAPT (aspirin plus clopidogrel) should be initiated early and continued for 21 to 90 days, followed by single antiplatelet therapy (SAPT) 1.

From the FDA Drug Label

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 The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0. 2%) were the same in both groups.

The use of aspirin and clopidogrel together may increase the risk of bleeding, including major bleeding and intracranial hemorrhage.

• Key points:
  • Concomitant use of other drugs that increase the risk of bleeding may further increase this risk.
  • The incidence of major bleeding and intracranial hemorrhage has been reported in clinical trials.
  • Patients with a history of bleeding problems or gastrointestinal ulcers may be at higher risk. The combination of aspirin and clopidogrel should be used with caution, especially in patients with large ischemic infarcts, due to the increased risk of hemorrhage 2.

From the Research

Risk of Hemorrhage with Aspirin and Clopidogrel

• The use of aspirin and clopidogrel in patients with large ischemic infarcts may increase the risk of hemorrhage, as suggested by several studies 3, 4, 5, 6.
• A study published in 2021 found that dual treatment with clopidogrel and aspirin increased major bleeding events, including intracranial bleeding and extracranial bleeding, compared to aspirin alone 3.
• Another study published in 2018 found that the combination of clopidogrel and aspirin was associated with a higher risk of major hemorrhage than aspirin alone at 90 days 4.
• A meta-analysis published in 2024 found that dual antiplatelet therapy with aspirin and clopidogrel was associated with a significantly increased risk of moderate or severe bleeding compared to aspirin alone 5.
• However, a study published in 2019 found that the addition of clopidogrel to aspirin for patients with transient ischemic attack or ischemic stroke appeared to significantly reduce the risk of ischemic stroke recurrence with a possible increase in the risk of bleeding compared to aspirin alone 6.

Comparison of Aspirin and Clopidogrel Monotherapy

• A systematic review and meta-analysis published in 2019 found that clopidogrel monotherapy was associated with a lower risk of bleeding compared to aspirin monotherapy in patients with recent ischemic stroke 7.
• The same study found that clopidogrel monotherapy was associated with a statistically significant risk reduction in the occurrence of major adverse cardiovascular and cerebrovascular events, any ischemic or hemorrhagic stroke, and recurrent ischemic stroke compared to aspirin monotherapy 7.

Key Findings

• The combination of aspirin and clopidogrel may increase the risk of hemorrhage in patients with large ischemic infarcts 3, 4, 5, 6.
• Clopidogrel monotherapy may be associated with a lower risk of bleeding and a reduced risk of major adverse cardiovascular and cerebrovascular events compared to aspirin monotherapy 7.