Risk of Bleeding on NOACs With Other Medications in AF

Study Questions:

What effect do concurrent medications have on the bleeding risk in atrial fibrillation (AF) patients treated with non–vitamin K oral anticoagulants (NOACs)?


This was a retrospective cohort study of 91,330 patients with AF entered into a Taiwanese insurance database who were treated with dabigatran, rivaroxaban, or apixaban. Exposure to medications that can interfere with NOAC metabolism was analyzed. Major bleeding was defined as bleeding resulting in hospitalization with a primary diagnosis of a bleeding event.


There were 4,770 major bleeds in 2012-2016. The adjusted incidence of major bleeds (expressed as number of bleeds/1,000 person-years), was significantly higher with concomitant use of amiodarone (52 vs. 38), fluconazole (242 vs. 103), rifampin (103 vs. 66), and phenytoin (108 vs. 56). The risk of a major bleed was significantly lower with than without concomitant atorvastatin, digoxin, erythromycin, and clarithromycin. Verapamil, diltiazem, dronedarone, cyclosporine, ketoconazole, itraconazole, and variconazole had no effect on the risk of a major bleed.


In patients with AF who are anticoagulated with a NOAC, the concomitant use of amiodarone, fluconazole, rifampin, and phenytoin significantly increases the risk of a major bleeding complication.


The concomitant medications analyzed in this study are either P-glycoprotein competitors and/or CYP3A4 inhibitors that have the potential to increase the plasma concentration of the NOACs. This study provides helpful information for clinicians by identifying the medications that have a clinically significant effect and that should be avoided in combination with a NOAC, if possible. It is noteworthy that amiodarone, which often is used to treat persistent AF, had the least impact on bleeding risk, potentially having a favorable risk-benefit ratio if it is effective in suppressing AF.

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

Keywords: Amiodarone, Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Cyclosporine, Digoxin, Diltiazem, Erythromycin, Fluconazole, Hemorrhage, P-Glycoproteins, Phenytoin, Rifampin, Risk, Secondary Prevention, Verapamil, Vitamin K

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