Can Eliquis (apixaban) and aspirin (acetylsalicylic acid) be used together?

Can Eliquis and Aspirin Be Used Together?

Yes, Eliquis (apixaban) and aspirin can be used together in specific clinical situations, but this combination significantly increases bleeding risk and should only be employed when there is a clear indication for dual therapy—such as acute coronary syndrome (ACS), recent percutaneous coronary intervention (PCI), or stable coronary/peripheral artery disease—and only for the shortest duration necessary. 1

Key Evidence from FDA Labeling

The FDA label for apixaban explicitly warns that coadministration with antiplatelet agents increases bleeding risk 1:

• In the APPRAISE-2 trial (post-ACS patients), the combination was terminated early due to excessive bleeding: major bleeding occurred at 2.8% per year with apixaban versus 0.6% per year with placebo in patients on single antiplatelet therapy, and 5.9% per year versus 2.5% per year in those on dual antiplatelet therapy 1
• In the ARISTOTLE trial, concomitant aspirin increased bleeding risk on apixaban from 1.8% to 3.4% per year 1
• The label states: "Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding" 1

When Combination Therapy Is Appropriate

Acute Coronary Syndrome or Recent PCI (Most Common Indication)

For patients with atrial fibrillation requiring anticoagulation who experience ACS or undergo PCI, use apixaban with a P2Y12 inhibitor (clopidogrel preferred) WITHOUT aspirin for the majority of patients 2:

• "Triple therapy" (aspirin + P2Y12 inhibitor + anticoagulant) is no better than dual therapy (P2Y12 inhibitor + anticoagulant) at preventing thrombotic events but causes significantly more bleeding 3
• Triple therapy should be reserved only for patients at exceptionally high risk of stent thrombosis and should not exceed 30 days 3
• When triple therapy is necessary, aspirin dose should not exceed 100 mg 3
• Apixaban is preferred over warfarin in this setting due to lower bleeding risk 3

Stable Coronary or Peripheral Artery Disease

Combination therapy with aspirin plus low-dose rivaroxaban (not apixaban) may be considered for stable coronary and/or peripheral artery disease 3:

• The COMPASS trial demonstrated that aspirin plus rivaroxaban 2.5 mg twice daily was superior to aspirin alone for reducing cardiovascular events, with particular benefit in patients with diabetes 3
• However, this evidence applies specifically to rivaroxaban at the 2.5 mg dose, not to apixaban 3

Atrial Fibrillation Without Coronary Disease

Aspirin should NOT be used with apixaban for stroke prevention in atrial fibrillation alone 3:

• Antiplatelet drugs are not an alternative to oral anticoagulation and can lead to potential harm, especially in elderly patients 3
• The AVERROES trial showed apixaban alone was superior to aspirin for stroke prevention (HR 0.45,95% CI 0.32-0.62) with no significant difference in major bleeding 3, 4
• Adding aspirin to anticoagulation without an adequate indication provides no clear benefit for stroke or death prevention but increases bleeding 3

Duration of Combination Therapy

When combination therapy is indicated after ACS/PCI 3:

• 0-30 days: Triple therapy (aspirin + P2Y12 inhibitor + apixaban) only if exceptionally high thrombotic risk
• 1-6 months: Dual therapy with P2Y12 inhibitor (clopidogrel preferred) + apixaban
• 6-12 months: Either aspirin OR clopidogrel can be given with apixaban
• Beyond 12 months: Apixaban alone (discontinue antiplatelet therapy)

Critical Safety Considerations

Bleeding risk assessment is mandatory before initiating combination therapy 1:

• Patients with prior stroke/TIA have higher baseline bleeding risk (HR 2.88) but similar relative safety profile with apixaban versus warfarin 2
• Aspirin increases major or clinically relevant non-major bleeding particularly in patients WITHOUT prior stroke/TIA 2
• Proton pump inhibitor prophylaxis should be initiated in all patients on simultaneous antiplatelet and anticoagulant therapy 3
• Common bleeding risk factors include use of non-study aspirin and history of nosebleeds 5

Clinical Decision Algorithm

1. Does the patient have ACS or recent PCI (<12 months)?

   • Yes → Use apixaban + clopidogrel (without aspirin for most patients) 3, 2
   • No → Proceed to step 2

2. Does the patient have stable coronary/peripheral artery disease?

   • Yes → Consider aspirin + low-dose rivaroxaban (not apixaban) per COMPASS trial 3
   • No → Proceed to step 3

3. Is anticoagulation indicated for atrial fibrillation or VTE only?

   • Yes → Use apixaban alone; do NOT add aspirin 3, 4

The default position should be to avoid combining apixaban with aspirin unless there is a specific, time-limited indication for dual antithrombotic therapy, as the bleeding risk consistently outweighs benefits in most scenarios. 1, 2