Risk for Bleeding-Related Hospitalizations With DOACs and Amiodarone

Quick Takes

  • Amiodarone has important drug-drug interactions with oral factor Xa inhibitors apixaban and rivaroxaban.
  • Concurrent use of amiodarone and apixaban/rivaroxaban was associated with higher rates of bleeding hospitalization than with flecainide or sotalol.
  • Rates of bleeding were higher among rivaroxaban users than apixaban users who also used amiodarone as compared to flecainide or sotalol.

Study Questions:

What is the risk of bleeding-related hospitalizations during treatment with amiodarone versus flecainide or sotalol for patients receiving apixaban or rivaroxaban?


The authors conducted a time-to-event analysis for bleeding-related hospitalizations (primary outcome) and ischemic stroke, systemic embolism, and death with or without recent (30-day) bleeding (secondary outcome). The analysis was conducted as a retrospective cohort study of US Medicare beneficiaries aged ≥65 years between 2012–2018 with continuous enrollment and no prior fills of oral anticoagulant prior to the study entry.


The study consisted of 91,590 patients (mean age 76.3 years, 52.5% female) who initiated anticoagulants and antiarrhythmic drugs, 54,997 using amiodarone and 36,613 with flecainide or sotalol. Risk for bleeding-related hospitalizations increased with amiodarone use as compared to flecainide or sotalol (rate difference [RD], 17.5 events [95% CI, 12.0-23.0] per 1,000 person-years; hazard ratio [HR], 1.44 [95% CI, 1.27-1.63]). Incidence of ischemic stroke or systemic embolism did not increase (RD, -2.1 events [95% CI, -4.7 to 0.4] per 1,000 person-years; HR, 0.80 [95% CI, 0.62-1.03]) between amiodarone versus flecainide or sotalol. The risk for death with a recent bleeding hospitalization was higher among amiodarone users as compared to flecainide or sotalol (RD, 9.1 events [95% CI, 5.8-12.3]; HR, 1.66 [95% CI, 1.35-2.03]). This was larger in patients with recent bleeding than the difference in the risk of death without recent bleeding between the amiodarone and other antiarrhythmic users (RD, 5.6 events [0.5-10.6] per 1,000 person-years; HR, 1.15 [95% CI, 1.00-1.31]; comparison, p = 0.003). The incidence of bleeding-related hospitalizations for rivaroxaban (RD, 28.0 per 1,000 person-years; 95% CI, 18.4-37.6) was greater than for apixaban (RD, 9.1 per 1,000 person-years; 95% CI, 2.8-15.3; comparison, p = 0.001).


The authors conclude that concurrent use of amiodarone along with apixaban or rivaroxaban is associated with a higher risk of bleeding-related hospitalization than use of flecainide or sotalol and apixaban or rivaroxaban.


Patients with atrial fibrillation are often initiated on both anticoagulants to reduce the risk of stroke as well as on antiarrhythmic medications, such as amiodarone, flecainide, or sotalol. However, amiodarone is known to inhibit cytochrome P450-3A4 (CYP3A4) hepatic metabolism pathway as the multidrug transporter P-glycoprotein (P-gp). These two processes are also involved in metabolism of commonly used oral factor Xa inhibitors, apixaban and rivaroxaban. As such, patients may experience higher drug levels of the anticoagulants with concurrent use of amiodarone. This contrasts with the concurrent use of these anticoagulants with flecainide or sotalol, neither of which inhibit CYP3A4 or P-gp. The study findings suggest that this drug-drug interaction between amiodarone and oral factor Xa inhibitors leads to increased risk of severe bleeding and bleeding-related death. Interestingly, the risk of bleeding is higher among patients using rivaroxaban than apixaban. Clinicians should be aware of this drug-drug interaction and consider if alternative antiarrhythmic medications might be appropriate so as to not increase bleeding risk or bleeding-associated deaths. Screening for these common drug-drug interactions is an important part of anticoagulation stewardship.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Geriatric Cardiology, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Amiodarone, Anti-Arrhythmia Agents, Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Drug Interactions, Embolism, Factor Xa Inhibitors, Flecainide, Geriatrics, Hemorrhage, Ischemic Stroke, Risk, Rivaroxaban, Secondary Prevention, Sotalol, Vascular Diseases

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