Can a patient on Eliquis (apixaban) take Aleve (naproxen), a nonsteroidal anti-inflammatory drug (NSAID)?

Can a Patient on Eliquis Take Aleve?

Patients on Eliquis (apixaban) can take Aleve (naproxen), but this combination significantly increases bleeding risk and requires careful risk-benefit assessment, gastroprotection with a proton pump inhibitor, close monitoring, and use of the lowest effective NSAID dose for the shortest possible duration. 1, 2

Understanding the Bleeding Risk

The combination of apixaban and NSAIDs like naproxen creates a substantial bleeding hazard through multiple mechanisms:

• The FDA label for apixaban explicitly warns that long-term chronic use of NSAIDs increases bleeding risk, and patients should be advised about recognizing bleeding symptoms before taking any NSAID with apixaban 1

• In the ARISTOTLE trial, incident NSAID use during anticoagulation was associated with a 61% increased risk of major bleeding (HR 1.61,95% CI 1.11-2.33) and a 70% increased risk of clinically relevant nonmajor bleeding (HR 1.70,95% CI 1.16-2.48) 2

• A French case-crossover study found that NSAID exposure in anticoagulated patients increased gastrointestinal bleeding risk 3.59-fold (95% CI 1.58-8.17) and nongastrointestinal bleeding risk 2.72-fold (95% CI 1.23-6.04) 3

• NSAIDs cause bleeding through three distinct pathways: inhibiting platelet function (prolonging bleeding time), causing direct gastric mucosal injury, and potentially displacing warfarin from protein binding sites (though this mechanism is less relevant for apixaban) 4

When This Combination Might Be Acceptable

If naproxen is absolutely necessary, it represents the safest NSAID choice for cardiovascular patients, with the most favorable cardiovascular safety profile (relative risk 0.92 for vascular events) compared to other NSAIDs 5

The combination may be considered when:

• Pain is inadequately controlled by non-NSAID alternatives (acetaminophen, tramadol, topical agents) 5
• The anticipated duration of NSAID use is brief (days, not weeks) 6
• The patient has no history of gastrointestinal bleeding or peptic ulcer disease 6

Mandatory Risk Mitigation Strategies

If you proceed with this combination, the following measures are non-negotiable:

Gastroprotection

• Add a proton pump inhibitor (PPI) to reduce bleeding ulcer risk by 75-85% in high-risk patients taking anticoagulants 6, 7
• This is particularly critical for patients ≥65 years (who have 2-3.5-fold increased GI complication risk), those with prior GI bleeding, or those on concomitant aspirin or corticosteroids 6, 7

Dosing Strategy

• Use the lowest effective naproxen dose for the shortest duration possible 6, 5, 1
• Consider starting with 220 mg twice daily rather than higher doses, as bleeding risk increases linearly with NSAID dose 6

Monitoring Requirements

• Monitor blood pressure regularly, as NSAIDs increase BP by approximately 5 mm Hg through sodium retention 6, 5, 7
• Assess renal function at baseline and periodically, particularly in patients with pre-existing renal disease, heart failure, or those on ACE inhibitors/ARBs 5, 7
• Educate patients to recognize bleeding symptoms: unusual bruising, prolonged bleeding, red/pink/brown urine, black stools, severe headaches, or dizziness 1

Absolute Contraindications to This Combination

Never combine apixaban with naproxen in patients with:

• Severe renal disease (creatinine clearance ≤30 mL/min) 5, 7
• Active or recent gastrointestinal bleeding 6
• History of complicated peptic ulcer disease without PPI prophylaxis 6
• Decompensated heart failure or cirrhosis 5, 7
• Perioperative period for coronary artery bypass grafting 5

Safer Alternative Approaches

Before resorting to naproxen, attempt a stepped-care approach:

• Start with acetaminophen (up to 3-4 grams daily in patients without liver disease) 5
• Consider topical NSAIDs for localized musculoskeletal pain, especially in elderly patients ≥75 years 7
• Trial tramadol or other non-NSAID analgesics 5
• Implement non-pharmacological interventions (physical therapy, heat/cold therapy, weight loss if applicable) 5

If Celecoxib is an Option

Celecoxib may be preferable to naproxen when combined with apixaban, as it produces significantly less endoscopic gastroduodenal ulceration compared to traditional NSAIDs while maintaining similar cardiovascular safety 7

However, celecoxib still requires:

• PPI co-therapy in high-risk patients 7
• The same monitoring for blood pressure and renal function 7
• Avoidance in patients with severe renal or hepatic disease 7

Critical Pitfalls to Avoid

• Do not assume the combination is safe just because both drugs are commonly prescribed – the bleeding risk is real and clinically significant 2, 3
• Do not neglect gastroprotection – even a "short course" of NSAIDs can cause rapid gastric injury in anticoagulated patients 6
• Do not combine multiple NSAIDs (e.g., naproxen plus ibuprofen) as this dramatically increases toxicity without additional benefit 7
• Do not continue NSAIDs long-term without reassessment – re-evaluate if pain persists beyond 7-10 days 5
• Do not forget that over-the-counter NSAIDs count – many patients take ibuprofen or naproxen without mentioning it to their physician 6, 1