The following are key points to remember from this review article on select drug-drug interactions with direct oral anticoagulants (DOACs):

1. DOACs, including apixaban, betrixaban, dabigatran, edoxaban, and rivaroxaban, offer many therapeutic advantages over warfarin and other vitamin K antagonists. These include a more rapid and predictable anticoagulant response, limited need for routine laboratory monitoring, and fewer drug-food and drug-drug interactions.
2. Incorrect DOAC dosing can place patients at increased risk of thrombotic and/or bleeding complications. Unrecognized drug-drug interactions are an important reason for incorrect DOAC dosing.
3. The most common DOAC drug-drug interactions involved medications mediated by the cytochrome P450 enzyme (CYP450) and/or the transporter permeability glycoprotein (P-gp). Medications can either induce or inhibit one or more of these enzymes/transport proteins. With inhibition, serum concentrations of medication generally increase. With inducers, serum concentrations generally decline.
4. CYP3A4 is an important metabolizer for apixaban (20-25%) and rivaroxaban (50%) but not the other DOACs. P-gp is an important mediator for apixaban, betrixaban, dabigatran, and rivaroxaban.
5. Most patients taking DOAC medications are on >5 other medications, greatly increasing the chance of clinically important drug-drug interactions.
6. Amiodarone is mediated by CYP3A4 and CYP2C8. It is also an inhibitor of CYP3A4 and P-gp. Limited drug-drug interaction studies have shown amiodarone use was associated with elevated levels of dabigatran and rivaroxaban, especially in patients with reduced renal function. Therefore, concurrent use should be avoided in select populations. There may also be increased levels of edoxaban and betrixaban, with uncertain clinical impact for patients taking betrixaban.
7. Dronedarone is a moderate inhibitor of CYP3A4 and P-gp. It significantly elevates dabigatran levels, especially for patients with moderate-severe renal dysfunction. Therefore, dabigatran dosing should be reduced for patients with moderate renal dysfunction (creatinine clearance [CrCl] 30-50 ml/min). While concurrent use of dronedarone and factor Xa DOAC medications may lead to elevated DOAC levels, no increased risk of bleeding has been documented. Nonetheless, concurrent use of dronedarone and rivaroxaban should be avoided for patients with renal dysfunction (CrCl 15-80 ml/min), while a 50% dose reduction of edoxaban is recommended at any level of renal function.
8. Diltiazem and verapamil are both moderate-weak inhibitors of CYP3A4 and substrates for P-gp. Use of immediate-release verapamil just before dabigatran leads to markedly elevated dabigatran drug levels. Concurrent use of these drugs should be avoided in many patients with moderate-severe renal dysfunction (CrCl <30-50 ml/min). Elevations in rivaroxaban drug levels are also seen with concurrent use of diltiazem, leading to a recommendation to avoid concurrent use if CrCl <80 ml/min.
9. Food and Drug Administration package labels recommend avoiding concurrent use of apixaban and rivaroxaban with P-gp and CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, and phenobarbital). It may be reasonable to avoid concurrent use with other enzyme inducers (e.g., St. John’s wart, primidone) for all DOAC medications.
10. For all potential DOAC drug-drug interactions, warfarin may have a similar interaction. However, the use of international normalized ratio lab testing to ensure safe warfarin drug levels makes it a preferred option for many patients.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents

Keywords: Amiodarone, Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Creatinine, Cytochrome P-450 CYP3A, Diltiazem, Drug Interactions, Factor Xa, Glycoproteins, Hemorrhage, Kidney Diseases, Pharmaceutical Preparations, Secondary Prevention, Renal Insufficiency, Rifampin, Verapamil, Vitamin K, Warfarin

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