Can a patient with atrial fibrillation be on a diltiazem (calcium channel blocker) drip and also take Eliquis (apixaban)?

Can a Patient Be on a Diltiazem Drip and Also Take Eliquis?

Yes, a patient with atrial fibrillation can be on a diltiazem drip and also take Eliquis (apixaban), but this combination requires caution due to a clinically significant drug-drug interaction that increases bleeding risk. 1, 2

Understanding the Drug-Drug Interaction

Diltiazem is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor, and apixaban is metabolized through both of these pathways. 1, 2 This pharmacokinetic interaction leads to:

• A 40% increase in apixaban plasma concentrations when combined with diltiazem 1
• Increased bleeding risk compared to using apixaban alone, with an adjusted hazard ratio of 1.56 for any bleeding-related hospitalization and 1.84 for major bleeding 2
• The bleeding risk is consistent across all levels of kidney function, affecting both patients with and without chronic kidney disease 2

Clinical Evidence on Safety

The evidence presents a nuanced picture:

• Recent large-scale studies show increased bleeding risk: A 2024 JAMA study of 204,155 Medicare beneficiaries found diltiazem was associated with 10.6 additional bleeding events per 1,000 person-years compared to metoprolol 3
• The risk is dose-dependent: Diltiazem doses exceeding 120 mg/day showed greater bleeding risk (HR 1.29) compared to lower doses (HR 1.13) 3
• However, one smaller 2019 study found no significant difference in bleeding rates between rivaroxaban users with and without diltiazem (23.1% vs 28.0%), though this was a smaller cohort of 286 patients 4

The weight of evidence, particularly the most recent and largest studies from 2022-2024, supports increased bleeding risk with this combination. 2, 3, 5

Guideline-Based Recommendations

The European Heart Rhythm Association guidelines classify the diltiazem-apixaban interaction as "yellow" (caution needed), indicating the interaction exists but is not contraindicated. 1 The guidelines note:

• The interaction is considered less severe than with verapamil (which causes up to 180% increase in dabigatran levels) 1
• No specific dose reduction of apixaban is recommended in the European label when combined with diltiazem 1
• However, caution is warranted especially with polypharmacy or in the presence of ≥2 bleeding risk factors 1

Practical Management Approach

When this combination is necessary for rate control in atrial fibrillation:

• Use the combination only when the benefit outweighs the risk, particularly when alternative rate-control agents are contraindicated or ineffective 2
• Consider using lower diltiazem doses (≤120 mg/day) when possible, as higher doses confer greater bleeding risk 3
• Monitor closely for signs of bleeding, including checking hemoglobin, assessing for bruising, hematuria, or gastrointestinal bleeding 2, 3
• Assess and modify bleeding risk factors before initiating the combination, including controlling hypertension, avoiding unnecessary antiplatelet agents, and addressing fall risk 1

Alternative Rate-Control Strategies

Consider these alternatives to minimize drug-drug interactions:

• Beta-blockers (metoprolol, esmolol) are preferred first-line agents for rate control in patients with preserved ejection fraction (LVEF >40%) and do not interact with apixaban 1, 6
• For patients with reduced ejection fraction (LVEF ≤40%), beta-blockers and/or digoxin are recommended, as diltiazem should be avoided due to negative inotropic effects 1
• Digoxin can be added to beta-blockers for combination therapy if monotherapy fails, providing better rate control at rest and during exercise 1, 6

Critical Pitfalls to Avoid

• Do not assume the interaction is negligible simply because it's not contraindicated—the bleeding risk is real and clinically significant 2, 3
• Do not use high-dose diltiazem (>120 mg/day) without strong justification, as this substantially increases bleeding risk 3
• Do not combine with antiplatelet agents unless there is a specific acute vascular indication, as this further compounds bleeding risk 1, 6
• Do not use diltiazem in patients with heart failure and reduced ejection fraction, as it has negative inotropic effects and beta-blockers are superior 1

Bottom Line

The combination of diltiazem drip and Eliquis is permissible but requires heightened vigilance for bleeding complications. 1, 2 When both medications are necessary, use the lowest effective diltiazem dose, closely monitor for bleeding, and strongly consider beta-blockers as a safer alternative for rate control when clinically appropriate. 3, 6