Is it safe to take naproxen (nonsteroidal anti-inflammatory drug) with apixaban (anticoagulant)?

Combining Naproxen with Apixaban: Safety Considerations

The combination of naproxen with apixaban significantly increases bleeding risk and should be avoided whenever possible. If the combination is unavoidable, use the shortest duration necessary with close monitoring for bleeding complications.

Bleeding Risk Evidence

The FDA label for apixaban explicitly warns against combining it with NSAIDs like naproxen due to increased bleeding risk 1. This warning is based on both pharmacokinetic and pharmacodynamic interactions:

Pharmacokinetic Interaction

• Naproxen increases apixaban exposure by approximately 50-60% 1, 2
• Specifically, when co-administered, apixaban AUC increased by 54-55% and maximum concentration (Cmax) increased by 61% 2
• This occurs through increased apixaban bioavailability, likely via effects on P-glycoprotein transport 2
• Anti-factor Xa activity was approximately 60% higher with combination therapy compared to apixaban alone 2

Pharmacodynamic Interaction

• NSAIDs have independent antiplatelet effects that add to apixaban's anticoagulant effects 3, 1
• Bleeding time was significantly prolonged with combination therapy (9.1 minutes) compared to either agent alone (5.8 minutes for apixaban, 6.9 minutes for naproxen) 2
• The FDA specifically lists "long-term (chronic) use of nonsteroidal anti-inflammatory drugs (NSAIDs)" as increasing bleeding risk when combined with apixaban 1

Clinical Trial Data

Real-world evidence from the ARISTOTLE trial demonstrates the clinical significance of this interaction 4:

• Incident NSAID use during the trial was associated with a 61% increased risk of major bleeding (HR 1.61,95% CI 1.11-2.33) 4
• Clinically relevant non-major bleeding increased by 70% (HR 1.70,95% CI 1.16-2.48) 4
• Approximately 18% of patients in ARISTOTLE used NSAIDs at some point during the trial 4
• The increased bleeding risk occurred with both apixaban and warfarin, suggesting this is a class effect of NSAIDs rather than specific to apixaban 4

Clinical Management Algorithm

If NSAID therapy is being considered in a patient on apixaban:

1. First-line approach: Avoid the combination entirely 1

   • Consider alternative analgesics such as acetaminophen (which has minimal antiplatelet effects)
   • Evaluate if topical NSAIDs could provide adequate pain relief with lower systemic exposure

2. If combination is unavoidable 3, 1:

   • Use the lowest effective NSAID dose for the shortest duration possible
   • Consider gastrointestinal prophylaxis with a proton pump inhibitor 3
   • Counsel patients on bleeding warning signs (unusual bruising, prolonged bleeding, blood in urine/stool, severe headache) 1
   • Monitor closely for bleeding complications

3. Special considerations for aspirin 4:

   • Low-dose aspirin (for cardiovascular protection) was used by approximately 15% of patients in ARISTOTLE 4
   • While aspirin also increases bleeding risk, the cardiovascular benefits may outweigh risks in appropriate patients
   • This decision requires careful risk-benefit assessment based on individual cardiovascular risk

Common Pitfalls

Many patients are unaware of this interaction 5:

• A survey found that 66% of apixaban patients were uncertain or incorrect about the bleeding risk from combining NSAIDs with their anticoagulant 5
• Approximately 30% of apixaban patients regularly took NSAIDs (ibuprofen or naproxen) either daily or occasionally 5
• Healthcare providers must proactively educate patients about avoiding over-the-counter NSAIDs 5

The interaction applies to all NSAIDs, not just naproxen 3, 1:

• Ibuprofen, naproxen, indomethacin, and other traditional NSAIDs all carry this risk
• COX-2 selective inhibitors may have somewhat lower bleeding risk but still require caution 3