What are the risks of using Eliquis (apixaban) and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) together?

Eliquis and NSAIDs: Bleeding Risk and Management

Avoid concurrent use of Eliquis (apixaban) and NSAIDs whenever possible, as this combination significantly increases bleeding risk, particularly gastrointestinal bleeding, which can be life-threatening. 1

Primary Risk: Increased Bleeding

The FDA label for apixaban explicitly warns that long-term (chronic) use of NSAIDs increases bleeding risk when combined with apixaban. 1 This risk manifests through multiple mechanisms:

• Gastrointestinal bleeding risk increases 2-3 fold when NSAIDs are combined with anticoagulants compared to anticoagulants alone. 2, 3
• The combination of anticoagulants with NSAIDs produces a 3-6 fold increased risk of GI bleeding compared to baseline. 4, 5
• Among patients on anticoagulant therapy who use NSAIDs, the adjusted odds ratio for hospitalization due to gastrointestinal bleeding is 3.59 (95% CI: 1.58-8.17). 3

Specific Bleeding Manifestations to Monitor

Patients taking this combination require vigilance for: 1

• Unusual bleeding from gums or frequent nosebleeds
• Heavier menstrual or vaginal bleeding
• Red, pink, or brown urine
• Red or black tarry stools
• Coughing up blood or blood clots
• Vomiting blood or coffee-ground appearing vomit
• Unexpected pain, swelling, or joint pain
• Headaches, dizziness, or weakness

Cardiovascular and Thrombotic Risks

Beyond bleeding, NSAIDs pose additional cardiovascular concerns: 6

• Cardiovascular event risk increases 40% (hazard ratio 1.40,95% CI: 1.30-1.49) when NSAIDs are used in patients on antithrombotic therapy after myocardial infarction. 6
• This increased cardiovascular risk occurs regardless of NSAID type or duration of use. 6

High-Risk Populations Requiring Extra Caution

Certain patient groups face amplified risks: 7

• Elderly patients (≥65 years) constitute the largest high-risk subset, with 87.1% of high-risk NSAID users being in this age group. 7
• Patients with history of GI ulcers or bleeding face substantially higher risk.
• Those with renal impairment experience compounded risks from both medications. 8, 4
• Patients with heart failure or hypertension should avoid NSAIDs entirely. 9

Spinal/Epidural Procedures: Critical Warning

The FDA label provides a black box warning regarding spinal or epidural hematoma risk: 1

• Patients on apixaban who take NSAIDs and undergo spinal/epidural anesthesia or spinal puncture face increased risk of spinal or epidural blood clots that can cause permanent paralysis.
• Watch for tingling, numbness, or muscle weakness, especially in legs and feet.
• This represents a medical emergency requiring immediate evaluation.

Management Algorithm When NSAIDs Cannot Be Avoided

If NSAIDs must be used despite anticoagulation: 4, 9

1. Use the lowest effective dose for the shortest possible duration. 9
2. Add gastroprotection with a proton pump inhibitor (PPI) in all patients, as this may reduce GI bleeding risk. 7, 4
3. Monitor closely for signs of bleeding, cardiac ischemia, heart failure exacerbation, and hypertension. 9
4. Check renal function as NSAIDs can cause volume-dependent renal failure. 4, 9
5. Consider topical NSAIDs instead of oral formulations, as they have less systemic absorption and fewer interactions. 8, 4

Preferred Alternatives to NSAIDs

Acetaminophen is the safer first-line analgesic alternative in patients taking apixaban. 8, 9 Additional options include:

• Non-pharmacological approaches: physical therapy, heat/cold therapy. 8
• Small doses of narcotics for short-term pain control (when appropriate). 9
• Non-acetylated salicylates with potentially lower cardiovascular risk. 9

Critical Pitfall to Avoid

Never assume that COX-2 selective inhibitors (coxibs) are safer than non-selective NSAIDs in this context. While guidelines from 2008 discuss differential GI risks between NSAID types, 7 more recent evidence demonstrates that all NSAIDs increase bleeding risk when combined with anticoagulants, regardless of selectivity. 2, 3, 6 The excess bleeding risk from combining COX-2 inhibitors with anticoagulants remains clinically significant (OR 2.18 for GI bleeding). 2

Patient Counseling Requirements

The FDA mandates that patients be informed: 1

• To tell all physicians and dentists they are taking apixaban before any procedure
• To report any unusual bleeding immediately
• That they may bruise more easily and bleeding may take longer to stop
• To avoid over-the-counter NSAIDs (ibuprofen, naproxen) without physician approval