Is it safe to take digoxin (Digitalis) and Eliquis (Apixaban) together?

Safety of Digoxin and Eliquis (Apixaban) Combination

Yes, digoxin and Eliquis (apixaban) can be safely used together without dose adjustments, as there is no clinically significant pharmacokinetic interaction between these medications. 1

Evidence for Safety

The most recent and highest-quality evidence directly addressing this combination comes from a 2025 population-based study that specifically examined DOAC-digoxin interactions:

• No increased bleeding risk was observed when DOACs (including apixaban) were used with digoxin, indicating the combination does not lead to a drug-drug interaction affecting anticoagulation safety 1
• The study found no increased risk of pharmacologically predictable DOAC safety outcomes when these medications were combined 1
• Apixaban is a substrate of both CYP3A4 enzymes and P-glycoprotein (P-gp) transporters, but digoxin does not significantly inhibit these pathways at therapeutic doses 2

Important Mortality Consideration

While the combination is safe from a bleeding and interaction standpoint, there is an important caveat:

• The 2025 study found a 35% higher risk of all-cause mortality (HR 1.35,99% CI 1.14-1.61) in patients taking DOAC plus digoxin compared to DOAC plus beta-blockers 1
• This mortality signal was consistent across different analytical approaches, with 24-63% higher odds depending on which drug was initiated first 1
• This mortality risk appears related to digoxin itself rather than a drug interaction with apixaban, as similar concerns about digoxin's long-term cardiovascular effects have been documented in heart failure guidelines 3

Clinical Management Recommendations

Monitoring Requirements

• Continue standard bleeding monitoring for apixaban (signs of unusual bleeding or bruising) without additional precautions specific to the combination 2
• Monitor digoxin levels targeting 0.5-1.0 ng/mL, as higher levels (>1.0 ng/mL) are associated with increased mortality without superior outcomes 3
• Assess renal function regularly, as it affects both apixaban dosing (25% renal elimination) and digoxin clearance 2, 4

Dosing Guidance

• No dose adjustments required for either medication when used together 2
• Use low-dose digoxin (0.125 mg daily or every other day) in patients >70 years old, with impaired renal function, or low lean body mass 3
• Standard apixaban dosing applies (typically 5 mg twice daily, or 2.5 mg twice daily if dose reduction criteria are met) 2

Critical Drug Interactions to Avoid

While digoxin and apixaban are safe together, be vigilant about other medications that can affect digoxin levels:

• Amiodarone requires a 50% reduction in digoxin dose due to significant P-gp inhibition 5, 4
• Macrolides (clarithromycin, erythromycin), verapamil, and quinidine can increase digoxin concentrations and toxicity risk 3, 4
• Diuretics (especially loop diuretics) increase digoxin intoxication risk 3-fold through electrolyte disturbances 6
• NSAIDs and ACE inhibitors can cause renal impairment, reducing digoxin clearance 4

Common Pitfalls to Avoid

• Do not assume therapeutic digoxin levels (up to 2 ng/mL) are safe - target lower levels (0.5-1.0 ng/mL) to minimize long-term cardiovascular risks 3
• Watch for hypokalemia and hypomagnesemia, which potentiate digoxin toxicity even at lower serum levels 3, 4
• Consider whether digoxin is still indicated - current guidelines downgraded digoxin to Class IIa recommendation due to narrow risk/benefit ratio, particularly in aging populations 3
• Beta-blockers are preferred over digoxin for rate control in atrial fibrillation when possible, given better mortality outcomes 3, 5, 1